Pyridazine compound as well as pharmaceutical composition and application thereof

Abstract

The invention provides a pyridazine compound as well as a pharmaceutical composition and application thereof. Specifically, the compound has a structure as shown in formula (I), can interfere with the interaction between SOS1 protein and RAS protein, and is expected to be used for preparing medicines for treating diseases such as RAS mutation tumors and the like. # imgabs0 #

Description

A pyridazine compound, its pharmaceutical composition and application Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a pyridazine compound, a pharmaceutical composition and an application thereof. Background Art

[0002] Rat sarcoma protein (RAS protein) is a crucial signal transduction regulator in the human body, regulating important physiological processes including cell proliferation, differentiation, migration, and survival. RAS is a guanosine triphosphate hydrolase (GTPase), and it regulates multiple important downstream signaling pathways, including RAF / MEK / ERK and PI3K / AKT, through a cycle of active states, in which RAS binds to guanosine triphosphate (GTP), and inactive states, in which RAS binds to guanosine diphosphate (GDP). This cycle involves two steps: negative regulation, through GTPase-activating proteins (GAPs), catalyzing the hydrolysis of RAS-GTP to RAS-GDP; and positive regulation, through guanine nucleotide exchange factors (GEFs), catalyzing the dissociation of RAS from GDP. RAS then binds to high intracellular concentrations of GTP. SOS1 (Son of Sevenless 1) is one of the most widely expressed and functionally important GEFs in the human body.

[0003] The RAS protein family includes KRAS (Kirsten rat sarcoma viral oncogene), NRAS (neuroblastoma RAS viral oncogene), and HRAS (Harvey murine sarcoma viral oncogene). KRAS mutations are the most common cause of tumors. KRAS mutations cause the protein to remain in a RAS-GTP state, continuously activating downstream signaling pathways. SOS1 plays a crucial role in this oncogenic process. Knocking out SOS1 effectively reduces the growth rate of KRAS-mutant tumors while maintaining the growth of KRAS wild-type cell lines.

[0004] Small molecule inhibitors bind to the catalytic pocket of SOS1, affecting the binding of SOS1 to RAS protein, and can effectively inhibit the phosphorylation level of downstream RAS signaling pathways such as ERK (extracellular regulated protein kinases), thereby inhibiting tumor growth. At present, the small molecule SOS1 inhibitor BI-1701963 (WO2018115380, WO2019122129) developed by Boehringer Ingelheim is in Phase I clinical research and is collaborating with Mirati's KRAS G12C inhibitor MRTX-849 to develop a combination drug regimen. In addition, Bayer (WO2018172250, WO2019201848) and Revolution (WO2020180770, WO2020180768) have also published multiple patents in this field, but this field still urgently needs to develop effective drugs that can inhibit the interaction between SOS1 and RAS mutant proteins.

[0005] Summary of the Invention

[0006] The present invention aims to provide a new pyridazine compound and a pharmaceutical composition containing the same, which can effectively inhibit the interaction between SOS1 and RAS mutant proteins.

[0007] In a first aspect, the present invention provides a compound of formula I, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form, or a combination thereof.

[0008] in,

[0009] R 1 Selected from: H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 4-8 membered heterocyclyl, cyano, Among them, R 1a and R 1b Each is independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl or optionally substituted 4-8 membered heterocyclyl; wherein the substitution refers to substitution by one or more R;

[0010] R 2 is selected from: optionally substituted C1-C6 alkyl, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclyl; wherein the substitution refers to substitution by one or more R;

[0011] R 3 and R 4Each is independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 4-8 membered heterocyclyl; wherein the substitution refers to substitution by one or more R;

[0012] Ring A is selected from the group consisting of optionally substituted C6-C16 aryl, optionally substituted 5-16-membered heteroaryl, optionally substituted C3-C16 carbocyclic and C6-C10 aryl, optionally substituted 4-16-membered heterocyclic and C6-C10 aryl, optionally substituted C3-C16 carbocyclic and 5-16-membered heteroaryl, or optionally substituted 4-16-membered heterocyclic and 5-16-membered heteroaryl; wherein the substitution refers to substitution by one or more R;

[0013] R is independently selected from: H, halogen, cyano, amino, hydroxyl, oxo Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylsulfone, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclyl, optionally substituted C6-C16 aryl, optionally substituted 5-16 membered heteroaryl or COR'; or any two adjacent R's and the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl or an optionally substituted C3-C8 membered carbocyclyl; wherein the substitution in R refers to substitution by one or more groups selected from the group consisting of H, halogen, cyano, amino, hydroxyl, oxo R' substituted or unsubstituted C1-C6 alkyl, R' substituted or unsubstituted C1-C6 alkoxy, R' substituted or unsubstituted C1-C6 alkylsulfone, R' substituted or unsubstituted C3-C16 carbocyclyl, R' substituted or unsubstituted 4-16 membered heterocyclyl, R' substituted or unsubstituted C6-C16 aryl, R' substituted or unsubstituted 5-16 membered heteroaryl, -N(R' substituted or unsubstituted C1-C6 alkyl)2, -CH2-N(R' substituted or unsubstituted C1-C6 alkyl)2, wherein R' is independently selected from one or more groups of the following groups: H, halogen , deuterium (D), -OH, oxo (=O), mercapto, cyano, -CD3, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 carbocyclyl and 4-8 membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl and heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), -NH2, -N(R" substituted or unsubstituted C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N(C -C1-C6 alkyl) (C1-C6 alkylphenyl), -NH (C1-C6 alkylphenyl), -N (C1-C6 alkyl) (aryl), -NH (aryl), C3-C8 carbocyclyl, 4-8 membered heterocyclyl, C1-C4 haloalkyl-, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C (O) -OH, -C (O) OC1-C6 alkyl, -CON (C1-C6 alkyl) 2, -CONH (C1-C6 alkyl), -CONH2, -NHC (O) (C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl), -NHSO2(C1-C6 haloalkyl) and -C1-C6 alkyl-NH2, wherein R" is selected from one or more groups of the following groups: H, halogen, cyano, amino, hydroxy, oxo C1-C6 alkyl and C1-C6 alkoxy;

[0014] Indicates the attachment position of the group.

[0015] In another preferred embodiment, the R 1 is selected from: H, halogen, optionally substituted C1-C3 alkyl or optionally substituted C3-C8 carbocyclyl, preferably, R 1is selected from: H, halogen or methyl; wherein the substitution refers to substitution by one or more R, and R is as defined above.

[0016] In another preferred embodiment, the A ring is selected from: optionally substituted C6-C10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C8 carbocyclic and C6-C10 aryl, optionally substituted 4-8 membered heterocyclic and C6-C10 aryl, optionally substituted C3-C8 carbocyclic and 5-10 membered heteroaryl or optionally substituted 4-8 membered heterocyclic and 5-10 membered heteroaryl; preferably, the A ring is optionally substituted phenyl, 5-6 membered heteroaryl, optionally substituted C3-C8 carbocyclic and phenyl, optionally substituted The A ring is selected from the group consisting of an optionally substituted 4-8 membered heterocyclic phenyl group, an optionally substituted C3-C8 carbocyclic 5-6 membered heteroaryl group, or an optionally substituted 4-8 membered heterocyclic 5-6 membered heteroaryl group; more preferably, the A ring is selected from the group consisting of an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrazinyl group, an optionally substituted thienyl group, an optionally substituted furanyl group, an optionally substituted pyrrolyl group, an optionally substituted thiazolyl group, an optionally substituted imidazolyl group, and an optionally substituted pyrazolyl group; wherein the substitution refers to substitution by one or more R; and R is defined as above.

[0017] In another preferred embodiment, the A ring is selected from:

[0018] Among them, R d1 、R d2 、R d3 Each of the following is independently selected from: H, halogen, amino, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylsulfone, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclyl, optionally substituted C6-C16 aryl or optionally substituted 5-16 membered heteroaryl;

[0019] R d4 are independently selected from: halogen, optionally substituted C1-C6 alkyl and

[0020] R d5 is selected from: hydrogen, an optionally substituted C6-C10 membered aromatic group, or an optionally substituted 5-16 membered heteroaromatic ring group;

[0021] Z is selected from: O or NR N ; R N Selected from: H or optionally substituted C1-C6 alkyl;

[0022] q is each independently 0, 1, 2 or 3;

[0023] Wherein, the substitution refers to substitution by one or more groups selected from the group consisting of: H, halogen, cyano, amino, hydroxyl, oxo R' substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfone, C3-C16 carbocyclyl, 4-16 membered heterocyclyl, -N(R' substituted or unsubstituted C1-C6 alkyl)2, -CH2-N(R' substituted or unsubstituted C1-C6 alkyl)2, and -CH2-(4-8 membered heterocyclyl), wherein R' is selected from one or more groups of the following groups: H, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl and C1-C6 alkoxy;

[0024] Indicates the attachment position of the group.

[0025] In another preferred embodiment, ring A is where R d5a and R d5b are independently selected from: H or substituted or unsubstituted C1-C3 alkyl, or R d5a 、R d5b and the connected N atom form a 4-8 membered heterocyclic group; R d5c Selected from: H, halogen or substituted or unsubstituted C1-C3 alkyl;

[0026] Wherein, the substitution refers to substitution by one or more groups selected from the group consisting of: H, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl and C1-C6 alkoxy;

[0027] Indicates the attachment position of the group.

[0028] In another preferred embodiment, R 2 for

[0029] R 2’ is selected from the group consisting of: H, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl;

[0030] Ring B is selected from: an optionally substituted C3-C16 carbocyclyl or an optionally substituted 4-16 membered heterocyclyl; wherein the substitution refers to substitution by one or more R; R is defined as above;

[0031] Indicates the attachment position of the group.

[0032] In another preferred embodiment, ring B is selected from: an optionally substituted C3-C6 carbocyclic group or an optionally substituted 4-7 membered heterocyclic group; wherein the substitution refers to substitution by one or more groups selected from the group consisting of OH, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, COR"'; wherein R"' is selected from the following groups: substituted or unsubstituted: C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl; wherein the substitution refers to substitution by one or more groups selected from the following groups: OH, halogen, cyano, amino, oxo C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl.

[0033] In another preferred embodiment, R 2 for

[0034] In another preferred embodiment, the compound has the structure shown in formula I'

[0035] Wherein, m is 0, 1 or 2;

[0036] Y is selected from: O, S, SO, SO2, CR y R' y 、NR” y ;

[0037] Among them, R y and R' y Each independently selected from: H, OH, halogen, cyano, amino, oxo C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl;

[0038] R” y Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, COR"' y ; Among them, R"' y substituted or unsubstituted groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclic group, 4-6 membered heterocyclic group; wherein the substitution refers to substitution by one or more groups selected from the group consisting of OH, halogen, cyano, amino, oxo C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl;

[0039] R 1 、R 4 、R 2’ , A is defined as above.

[0040] In another preferred embodiment, Y is NR" y ; Among them, R” y Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, preferably, R" y Selected from: H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0041] In another preferred embodiment, R" y is a COC1-C6 alkyl group; wherein the alkyl group is optionally substituted by one or more groups selected from the group consisting of OH, halogen, cyano, amino, oxo C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl; preferably, R" y Selected from:

[0042] In another preferred embodiment, R 2 Selected from:

[0043] In another preferred embodiment, R 3 Selected from: H and optionally substituted C1-C3 alkyl; wherein, the substitution refers to substitution by one or more R; preferably, R 3 is H;

[0044] R 4 is H;

[0045] The definition of R is as described above.

[0046] In another preferred embodiment, R 1 、R 2 、R 3 、R 4 , A ring, B ring, Y, m and R 2’ is the group corresponding to the specific compound in the examples.

[0047] In another preferred embodiment, the compound is selected from the following group:

[0048] The second aspect of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises:

[0049] (1) a therapeutically effective amount of one or more selected from the group consisting of the compound of the first aspect, its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs and deuterated forms thereof as an active ingredient; and

[0050] (2) Optionally, a pharmaceutically acceptable carrier.

[0051] In a third aspect, the present invention provides a use of the compound described in the first aspect, its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs or deuterated forms, or the pharmaceutical composition described in the third aspect in the preparation of a medicament for preventing or treating RAS mutation-mediated cancers.

[0052] In another preferred embodiment, the cancer is selected from the group consisting of lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyomas, synovial sarcomas, endometriomas, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer, in particular, selected from non-small cell lung cancer, pancreatic cancer and colorectal cancer.

[0053] 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 described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0054] After extensive and in-depth research, the present inventors developed a new pyridazine compound that can effectively inhibit the interaction between SOS1 and RAS mutant proteins. Based on this, the present invention was completed.

[0055] Terminology

[0056] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0057] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0058] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0059] Group Definition

[0060] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0061] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0062] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0063] Certain chemical groups defined herein are preceded by a simplified notation to indicate the total number of carbon atoms present in the group. For example, a C1-C6 alkyl group refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in substituents of the group.

[0064] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0065] In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0066] "Hydroxy" refers to an -OH group.

[0067] "Hydroxyalkyl" refers to an alkyl group, as defined below, substituted with a hydroxy (-OH) group.

[0068] "Carbonyl" refers to a -C(=O)- group.

[0069] "Nitro" refers to -NO2.

[0070] "Cyano" refers to -CN.

[0071] "Carboxyl" refers to -COOH.

[0072] In the present application, as a group or part of other groups (for example, as used in groups such as halogen-substituted alkyl), the term "alkyl" refers to a fully saturated straight or branched hydrocarbon chain radical consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and connected to the rest of the molecule by one or more single bonds, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl. For the purposes of the present invention, the term "alkyl" preferably refers to an alkyl group containing 1 to 6 carbon atoms.

[0073] In this application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by one or more single bonds, such as but not limited to ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0074] As used herein, the term "alkynyl" as a group or as part of another group refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by one or more single bonds, such as, but not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0075] In the present application, the term "carbocycle" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include a fused ring system, a bridged ring system or a spirocyclic system, having 3 to 16 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and which is a saturated or unsaturated ring (i.e., cycloalkyl, cycloalkenyl, etc.) and may be connected to the rest of the molecule through one or more single bonds via any suitable carbon atom. Unless otherwise specified in this specification, the carbon atoms in the carbocycle group may be optionally oxidized. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-dihydroindanyl, octahydro-4,7-methylene-1H-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, , bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl and octahydro-2,5-methylene-pentalenyl, etc. In the present invention, the carbocyclic group is preferably a cycloalkyl group, such as C3-C10 cycloalkyl, C3-C8 cycloalkyl or C3-C6 cycloalkyl.

[0076] In the present application, the term "cycloalkyl" as a group or part of other groups refers to the above-mentioned fully saturated carbon ring (group), typical cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc.

[0077] In the present application, the term "cycloalkenyl" as a group or a part of other groups refers to a partially unsaturated carbon ring (group). Typical cycloalkenyl groups include but are not limited to cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

[0078] In the present application, the term "heterocyclic ring (base)" as a group or part of another group means a stable 3- to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless otherwise specified in this specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic or more ring system, which can include a fused ring system, a bridged ring system or a spirocyclic system; the nitrogen, carbon or sulfur atoms in the heterocyclic group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic group can be partially or fully saturated. The heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom and by one or more single bonds. In a heterocyclic group containing a fused ring, one or more rings can be an aryl or heteroaryl group as defined below, provided that the point of connection to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2-azabicyclo[2.2.2]octanyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolane, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0079] In this application, the term "aryl" as a group or part of another group means a conjugated hydrocarbon ring system radical having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic or higher ring system, and can also be fused to a carbocyclic or heterocyclic group as defined above, provided that the aryl group is connected to the rest of the molecule through one or more single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like.

[0080] In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted by an aryl group as defined above.

[0081] In this application, the term "heteroaryl" as a group or part of another group means a 5- to 16-membered conjugated ring system having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specified in this specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a carbocyclic or heterocyclic group as defined above, provided that the heteroaryl group is connected to the rest of the molecule through one or more single bonds via atoms in the heteroaromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophenyl, oxatriol, oxazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.

[0082] As used herein, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

[0083] In this application, the term "absent" means that the two sides of the group defined above are directly connected by a chemical bond. For example, "ABC in which B is absent" means "AC".

[0084] In this application, in Indicates the attachment position of the group R.

[0085] In this application, unless otherwise specified in the claims, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted aryl" means that the hydrogen atoms on the aryl group may or may not be substituted, and the description includes both substituted and unsubstituted aryl groups. For example, in the absence of explicit listing of substituents, the terms "optionally substituted", "substituted" or "substituted by" as used herein mean that one or more hydrogen atoms on a given atom or group are independently replaced by one or more, e.g., 1, 2, 3 or 4, substituents independently selected from the group consisting of: deuterium (D), halogen, -OH, oxo (=O), mercapto, cyano, -CD3, -C1-C6 alkyl (preferably -C1-3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl (preferably C3-C8 carbocyclyl), aryl, heterocyclyl (preferably 3-8 membered heterocyclyl), heteroaryl, aryl-C1-C6 alkyl-, heteroaryl-C1-C6 alkyl-, C1-C6 haloalkyl-, -OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 alkenyl, -O cycloalkyl, -O heterocyclyl, -O aromatic -C1-C6 alkylphenyl, -C1-C6 alkyl-OH (preferably -C1-C4 alkyl-OH), -C1-C6 alkyl-SH, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 haloalkyl, -NH2, -C1-C6 alkyl-NH2 (preferably -C1-C3 alkyl-NH2), -N(C1-C6 alkyl)2 (preferably -N(C1-C3 alkyl)2), -NH(C1-C6 alkyl) (preferably -NH(C1-C3 alkyl)), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(aryl), -NH(aryl), nitro, -C(O)-OH, -C(O)OC1-C6 alkyl (preferably -C(O)OC1-C3 alkyl), -CONR i R ii (where R i and R iiis H, D and C1-6 alkyl, preferably C1-3 alkyl), -NHC(O)(C1-C6 alkyl), -NHC(O)(phenyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(phenyl), -C(O)C1-C6 alkyl, -C(O)heteroaryl (preferably -C(O)-5-7 membered heteroaryl), -C(O)C1-C6 alkylphenyl, -C(O)C1-C6 haloalkyl, -OC(O)C1-C6 alkyl (preferably -O C(O)C1-C3 alkyl), -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-C1-C6 haloalkyl, -S(O)2NH2, -S(O)2NH(C1-C6 alkyl), -S(O)2NH(phenyl), -NHS(O)2(C1-C6 alkyl), -NHS(O)2(phenyl) and -NHS(O)2(C1-C6 haloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aromatic Each of the heterocyclic group, heteroaryl and heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of halogen, -OH, oxo (=O), -NH2, carbocyclyl, 3-8 membered heterocyclyl, C1-C4 alkyl, C1-C4 haloalkyl-, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), -CONH2, -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C6 haloalkyl). When an atom or group is substituted with multiple substituents, the substituents may be the same or different. As used herein, the terms "part," "moiety," "chemical moiety," "group," and "chemical group" refer to specific fragments or functional groups in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule. In the present invention, "optionally substituted" and "substituted or unsubstituted" have the same meaning and are used interchangeably.

[0086] In the present invention, unless otherwise specified, amino refers to a group having a -NRR' structure, wherein RR' is independently H, alkyl (such as C1-C6 alkyl), alkylcarbonyl (such as C1-C6 alkyl CO), arylalkyl (such as phenyl C1-C6 alkyl), heteroarylalkyl (such as 5-6 membered heteroaryl C1-C6 alkyl), etc. In the present invention, amino can be NH2 or substituted amino, wherein "substituted amino" refers to an amino substituted by one or two alkyl, alkylcarbonyl, arylalkyl, heteroarylalkyl groups as defined above, for example, monoalkylamino, dialkylamino, alkylamido, arylalkylamino, heteroarylalkylamino. Preferably, in the present invention, amino includes: NH2, NHCH3, -NHCOCH3, -NHCH2Ph, etc.

[0087] In the present invention, "plurality" refers to 2, 3 or 4.

[0088] In the present invention, C(O)OC1-C6 alkyl, i.e. represents a C1-C6 alkyl substituted ester group, for example,

[0089] In the present invention, N (C1-C6 alkyl) 2, or (C1-C6 alkyl) 2 amino, represents that the two hydrogen atoms on NH2 are replaced by two C1-C6 alkyl atoms, for example, wait.

[0090] Active ingredient

[0091] As used herein, "compound of the present invention" or "active ingredient" refers to the compound represented by Formula I, and also includes pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated forms, or combinations thereof.

[0092] "Stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention is intended to encompass various stereoisomers and mixtures thereof.

[0093] When the compounds of the present invention contain olefinic double bonds, and unless specified otherwise, it is intended that the compounds of the present invention include both E- and Z- geometric isomers.

[0094] "Tautomers" refer to isomers formed when a proton is shifted from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are intended to be encompassed within the scope of the present invention.

[0095] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, diastereomers, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0096] Conventional techniques for preparing / isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography, see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0097] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0098] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0099] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0100] Those skilled in the art will also appreciate that in the methods described below, the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, sulfhydryl, and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino, and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable sulfhydryl protecting groups include -C(O)-R" (wherein R" is alkyl, aryl, or aralkyl), p-methoxybenzyl, trityl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or aralkyl esters.

[0101] Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, TW and PGM Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. Protecting groups can also be polymeric resins.

[0102] Pharmaceutical compositions and methods of administration

[0103] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0104] The compounds of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. Drug combination also includes taking the compound of formula I and one or more other known drugs during overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of each drug taken alone.

[0105] The drugs or active ingredients that can be used in combination with the compounds of general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, etc.), CD20 antibodies (such as rituximab, ibrutinib, etc.), KRAS inhibitors (such as AMG510, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, cabozantinib, sunitinib, etc.), PI3K inhibitors (such as levofloxacin, ... K inhibitors (such as Dactolisib, Taselisib, etc.), BTK inhibitors (such as Ibrutinib, Tilabrutinib, Acalabrutinib, Zanubrutinib, Vecabuzinib, etc.), HDAC inhibitors (such as Vorinostat, Fimepinostat, Givinostat, Tucidinostat, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib, etc.), ERK inhibitors (such as BVD523, HH2710, etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068) or their combinations.

[0106] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0107] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0108] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0109] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0110] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0111] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent 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-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0112] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0113] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0114] Compositions for parenteral injection may comprise 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.

[0115] The term "tumor" as used herein includes, but is not limited to, lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdoid tumor, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, and bladder cancer. As used herein, the terms "preventive," "prevention," and "prevention" include reducing the likelihood of a patient developing or worsening a disease or condition.

[0116] As used herein, the term "treat" and other similar synonyms include the following meanings:

[0117] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0118] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0119] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0120] (iv) Alleviate the symptoms of the disease or condition.

[0121] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to provide some relief to some degree from one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant alleviation of symptoms. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0122] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods by which a compound or composition can be delivered to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injections or infusions), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0123] As used herein, the terms "pharmaceutical combination," "drug combination," "combination therapy," "administration of another therapy," "administration of another therapeutic agent," and the like refer to a pharmaceutical therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously as a single entity or single dosage form. The term "non-fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously, in combination, or sequentially at variable intervals as separate entities. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0124] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0125] Preparation method of compound

[0126] The following schemes describe methods for preparing compounds of Formula I. In some cases, the order of the steps in the reaction schemes may be altered to facilitate the reaction or to avoid unwanted side reaction products. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described herein or known in the art, and such combinations may be readily performed by those skilled in the art.

[0127] Those skilled in the art will also appreciate that in the methods described below, the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, sulfhydryl, and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, allyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyl, allyloxycarbonyl, p-toluenesulfonyl, pivaloyl, trifluoroacetyl, and the like. Suitable sulfhydryl protecting groups include -C(O)-R" (wherein R" is alkyl, aryl, or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl, or aralkyl esters.

[0128] Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, TW and PGM Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. Protecting groups can also be polymeric resins.

[0129] Typically, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C-150°C, preferably 10°C-100°C), and the reaction time is typically 0.1 hour to 60 hours, preferably 0.5 to 48 hours.

[0130] Preferably, the compound of formula I can be prepared by the following method:

[0131] (1) Compounds a and b are reacted in the presence of a strong base to form compound c, wherein the strong base is selected from the group consisting of n-butyl lithium, lithium diisopropylamide, tert-butyl lithium, sec-butyl lithium, lithium hexamethyldisilazide, or a combination thereof;

[0132] (2) In the presence of a base, compound c undergoes an aromatic nucleophilic substitution reaction with compound d to generate compound I, wherein the strong base is selected from the group consisting of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, potassium carbonate, cesium carbonate, sodium carbonate, sodium phosphate, potassium phosphate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or a combination thereof; or compound c undergoes a Buchwald-Hartwig reaction with compound d to generate compound I;

[0133] or

[0134] (1) In the presence of a base, compound a undergoes an aromatic nucleophilic substitution reaction with compound d to generate compound e, wherein the strong base is selected from the group consisting of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, potassium carbonate, cesium carbonate, sodium carbonate, sodium phosphate, potassium phosphate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or a combination thereof; or compound a undergoes a Buchwald-Hartwig reaction with compound d to generate compound e;

[0135] (2) Compounds e and b are reacted in the presence of a strong base to form compound I, wherein the strong base is selected from the group consisting of n-butyl lithium, lithium diisopropylamide, tert-butyl lithium, sec-butyl lithium, lithium hexamethyldisilazide, or a combination thereof;

[0136] Among them, X 1 、X 2 、R 1 、R 2 , The definition of A ring is as described above.

[0137] The main advantages of the present invention are:

[0138] 1. The compound of this application has a novel structure;

[0139] 2. The compounds of the present application can effectively inhibit the binding of SOS1 to RAS protein;

[0140] 3. The compounds of the present application have good pharmacokinetics and efficacy.

[0141] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0142] In the following examples, the experimental methods without specific conditions are generally carried out under conventional conditions or the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are by weight.

[0143] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0144] In each embodiment, 1H NMR was recorded by a BRUKER AVANCE NEO 400 MHz nuclear magnetic resonance instrument, and the chemical shift was expressed in δ (ppm). Liquid chromatography-mass spectrometry (LCMS) was recorded by Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, and LCMS-2020 mass spectrometers. Preparative HPLC separations were performed using a Gilson-281 liquid chromatograph.

[0145] Example

[0146] Preparation of intermediates

[0147] 1. Preparation of Intermediate A

[0148] (1) To a solution of compound A-1 (10.0 g, 48.8 mmol) in N,N-dimethylformamide (100.0 mL) was added cuprous cyanide (8.73 g, 97.5 mmol). The reaction mixture was stirred at 100°C under nitrogen for 16 hours. Water (100.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 5:1) to obtain compound A-2.

[0149] 1 H NMR (400MHz, DMSO-d6) δ8.15 (d, J = 5.2 Hz, 1H), 7.69 (d, J = 5.2 Hz, 1H), 2.65 (s, 3H).

[0150] (2) To a solution of compound A-2 (3.50 g, 23.2 mmol) in ethanol (20.0 mL) was added hydrazine hydrochloride (2.92 g, 27.78 mmol). The reaction mixture was stirred at 80°C under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure, water (50.0 mL) was added, and the mixture was extracted with ethyl acetate (50.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound A-3.

[0151] MS-ESI[M+H] + , calculated value 166, measured value 166.

[0152] (3) To a solution of compound A-3 (2.00 g, 12.1 mmol) in acetonitrile (30.0 mL) were added tert-butyl nitrite (2.50 g, 24.2 mmol) and cuprous chloride (2.40 g, 24.2 mmol). The reaction mixture was stirred at 60°C under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure, water (30.0 mL) was added, and the mixture was extracted with ethyl acetate (50.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 1:1) to obtain compound A.

[0153] MS-ESI[M+H] + , calculated value 185, measured value 185.

[0154] Example 1 Synthesis of Compound 1

[0155] (1) To a solution of compound 1-1 (150 mg, 812 μmol) in tetrahydrofuran (6.0 mL) were added intermediate A (203 mg, 894 μmol) and lithium diisopropylamide (2.00 mol / L, 609 μL). The reaction mixture was stirred at -78°C under nitrogen for 1 hour. Saturated aqueous ammonium chloride solution (100.0 mL) and water (100.0 mL) were added, and the mixture was extracted with ethyl acetate (100.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 1-2. MS-ESI [M+H] + , calculated value 412, measured value 412.

[0156] (2) Manganese dioxide (633 mg, 7.28 mmol) was added to a solution of compound 1-2 (300 mg, 728 μmol) in dichloromethane (3.0 mL). The reaction mixture was stirred at 25°C for 10 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain compound 1-3. MS-ESI [M+H] + , calculated value 410, measured value 410. 1 H NMR (400MHz, CDCl3) δ8.07(s,1H),3.62-3.78(m,2H),3.17-3.33(m,2H),2.93(s,3H),2.33(br d,J=14.0Hz,2H),1.74(br d, J=4.0Hz, 2H), 1.58 (d, J=6.0Hz, 3H), 1.46 (s, 9H).

[0157] (3) Compound 1-4 (31.4 mg, 134 μmol), palladium acetate (2.74 mg, 12.2 μmol), cesium carbonate (79.5 mg, 244 μmol) and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (15.19 mg, 24.4 μmol) were added to a solution of compound 1-3 (50.0 mg, 122 μmol) in dioxane (2.0 mL). The reaction mixture was stirred at 80°C for 2 hours under nitrogen. Water (100.0 mL) was added to the reaction mixture and extracted with ethyl acetate (100.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound 1-5. MS-ESI [M+H] + , calculated value 608, measured value 608.

[0158] (4) Trifluoroacetic acid (93.8 mg, 823 μmol) was added to a solution of compound 1-5 (50.0 mg, 82.3 μmol) in dichloromethane (5.0 mL). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 1-6. MS-ESI [M+H] + , calculated value 508, measured value 508.

[0159] (5) To a solution of compound 1-6 (40.0 mg, 64.4 μmol) in ethanol (5.0 mL) were added paraformaldehyde (9.66 mg, 322 μmol), triethylamine (6.51 mg, 64.4 μmol), acetic acid (387 μg, 6.44 μmol), and sodium cyanoborohydride (7.39 mg, 118 μmol). The reaction mixture was stirred at 25°C for 10 hours. Water (100.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-7. MS-ESI [M+H] + , calculated value 524, measured value 524.

[0160] (6) Iron (20.8 mg, 372 μmol) and ammonium chloride (1.99 mg, 37.2 μmol) were added to a solution of compound 1-7 (20.0 mg, 37.2 μmol) in ethanol (2.0 mL). The reaction mixture was stirred at 60°C for 1 hour, and water (100.0 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (100.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (C18-1, 150 mm × 30 mm 5 μm, A: water (0.225% formic acid); B: acetonitrile, 25%-65%: 25 min) to obtain the formate salt of compound 1. MS-ESI [M+H]+ , calculated value 494, measured value 494. 1 H NMR(400MHz,MeOD)δ7.79(s,1H),6.96(br s,2H),6.77(s,1H),5.32-5.39(m,2H),3.07-3.26(m,2H),2.86(br s,4H),2.62(s,3H),2.02-2.26(m,2H),1.57-1.85(m,6H),1.13(br s,3H).

[0161] Example 2 Synthesis of Compound 2

[0162] (1) Compound 2-1 (29.7 mg, 146 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (10.2 mg, 12.2 μmol), cesium carbonate (119 mg, 365 μmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (11.3 mg, 24.1 μmol) were added to a solution of compound 1-3 (50.0 mg, 122 μmol) in dioxane (2.0 mL). The reaction mixture was stirred at 100°C for 5 hours under nitrogen. The reaction mixture was added with water (30.0 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 2-2. MS-ESI [M+H] + , calculated value 577, measured value 577.

[0163] (2) Trifluoroacetic acid (462.00 mg, 4.05 mmol) was added to a solution of compound 2-2 (30.0 mg, 52.0 μmol) in dichloromethane (1.5 mL). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 2-3. MS-ESI [M+H] + , calculated value 477, measured value 477.

[0164] (3) To a solution of compound 2-3 (20.0 mg, 41.9 μmol) in ethanol (3.0 mL) were added paraformaldehyde (7.88 mg), acetic acid (2.52 mg, 41.9 μmol), and sodium cyanoborohydride (3.96 mg, 62.9 μmol). The reaction mixture was stirred at 25°C for 5 hours, and water (10.0 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 100 mm × 30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 15%-45%: 10 min) to obtain the formate salt of compound 2. MS-ESI [M+H] + , calculated value 493, measured value 493. 1 H NMR(400MHz,MeOD)δ7.78(s,1H),7.68 (d,J=7.6Hz,1H),7.50(d,J=7.6Hz,1H),7.24(t,J=7.6Hz,1H),5.69(q,J=6.8Hz,1H),4.89-4.94(m,1H),3.32-3.42(m,3H) ,3.15(s,2H),2.84(s,2H),2.60(d,J=7.2Hz,6H),1.95-2.22(m,2H),1.70-1.83(m,1H),1.60(d,J=6.8Hz,4H),1.13(s,3H).

[0165] Example 3-Example 6 Synthesis of Compound 3-Compound 6

[0166] The synthesis method in Example 2 was adopted to synthesize Compound 3-Compound 6 using the corresponding raw materials.

[0167] Example 7 Synthesis of Compound 7

[0168] (1) Compound 7-1 (150 mg, 365 μmol), palladium(II) acetate (8.22 mg, 36.5 μmol), cesium carbonate (298 mg, 914 μmol), and 2,2-bis(diphenylphosphino)-1,1-binaphthyl (45.5 mg, 73.1 μmol) were added to a solution of compound 1-3 (70.5 mg, 439 μmol) in dioxane (5.0 mL). The reaction mixture was stirred at 90°C for 2 hours under nitrogen. The reaction mixture was filtered, water (30.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:2) to obtain compound 7-2.

[0169] (2) Trifluoroacetic acid (1.39 g, 12.1 mmol) was added to a solution of compound 7-2 (110 mg, 206 μmol) in dichloromethane (4.0 mL). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 7-3. MS-ESI [M+H] + , calculated value 434, measured value 434.

[0170] (3) To a solution of compound 7-3 (90.0 mg, 207 μmol) in ethanol (30.0 mL) were added paraformaldehyde (31.1 mg), acetic acid (12.4 mg, 207 μmol), and sodium cyanoborohydride (19.5 mg, 311 μmol). The reaction mixture was stirred at 25°C for 5 hours, and water (10.0 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 150 mm × 30 mm 5 μm, A: water (ammonium bicarbonate); B: acetonitrile, 32%-72%: 36 minutes) to obtain compound 7. MS-ESI [M+H] + , calculated value 450, measured value 450. 1 H NMR (400MHz, MeOD) δ7.70-7.72(m,2H),7.50(d,J=7.6Hz,1H),7.25(t,J=7.6Hz,1H),5.60(qd,J=6.8,3.6Hz,1H),4.83(br s,1H),2.96-3.04(m,2H),2.73(s,3H),2.60-2.69(m,2H),2.58(s,3H),2.53 (s,3H),1.89-2.01(m,2H),1.67-1.74(m,1H),1.59(d,J=7.2Hz,3H),1.46(br d,J=13.6Hz,1H),1.06(s,3H).

[0171] Test example

[0172] Determination of the inhibitory effect of compounds on the binding of SOS1 to KRAS (G12C) mutant protein (HTRF method):

[0173] 1. Experimental principle: HTRF method is used to detect the inhibitory effect of compounds on the binding of SOS1 and KRAS (G12C) mutant protein.

[0174] 2. Experimental Materials: KRAS (G12C) mutant protein was purchased from Pujian Biotechnology Co., Ltd.; SOS1 protein was purchased from Cytoskeleton Co., Ltd.; labeled antibodies Mab Anti 6HIS-XL665 and Mab Anti GST-Eu cryptate were purchased from Cisbio.

[0175] 3. Experimental method: 1x buffer solution (prepared immediately for use): 4-hydroxyethylpiperazineethanesulfonic acid (Hepes): 5 mmol / L; sodium chloride: 150 mmol / L; ethylenediaminetetraacetic acid: 10 mmol / L; ethylphenyl polyethylene glycol (Igepal): 0.0025%; potassium fluoride: 100 mmol / L; dithiothreitol (DTT): 1 mmol / L; bovine serum albumin (BSA): 0.05%;

[0176] Starting with a 1000 μmol / L stock solution, the compound was diluted 5-fold across eight concentrations. Each compound was diluted to a 2% DMSO working solution in 1x buffer, with 5 μL / well added to the corresponding wells. Each concentration was assayed in duplicate. A mixed working solution of KRAS (G12C) mutant protein (200 nM) and Mab Antibody GST-Eu cryptate (1 μg / μL) was prepared in 1x buffer. This mixed working solution was incubated at 25°C for 5 minutes, and 2.5 μL / well was added to the corresponding wells. A mixed working solution of SOS1 protein (80 nM) and Mab Antibody 6HIS-XL665 (8 μg / μL) was prepared in 1x buffer, and 2.5 μL / well was added to the corresponding wells. 2.5 μL of the 8 μg / μL Mab Antibody 6HIS-XL665 dilution was added to a blank well. The reaction system was incubated at 25°C for 60 minutes. After the reaction, HTRF was read using a multi-label analyzer.

[0177] 4. Data processing:

[0178] The IC of the compounds was calculated using Graphpad software. 50 The results are shown in Table 1.

[0179] Table 1

[0180] As can be seen from the test data in Table 1, the compound represented by Formula I of the present invention has a good inhibitory effect on the binding of SOS1 to KRAS (G12C) mutant protein, and has the potential to be used in the preparation of drugs for treating RAS mutant tumors.

[0181] The applicant states that while the present invention illustrates the pyridazine compounds, pharmaceutical compositions containing the same, and their uses through the aforementioned embodiments, the present invention is not limited to these embodiments, and does not necessarily rely on these embodiments for implementation. Those skilled in the art will appreciate that any improvements to the present invention, equivalent substitutions for raw materials in the products of the present invention, addition of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form, or combination thereof, in, R 1 Selected from: H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 4-8 membered heterocyclyl, cyano, Among them, R 1a and R 1b Each is independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl or optionally substituted 4-8 membered heterocyclyl; wherein the substitution refers to substitution by one or more R; R 2 is selected from: optionally substituted C1-C6 alkyl, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclyl; wherein the substitution refers to substitution by one or more R; R 3 and R 4 Each is independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 4-8 membered heterocyclyl; wherein the substitution refers to substitution by one or more R; Ring A is selected from the group consisting of optionally substituted C6-C16 aryl, optionally substituted 5-16-membered heteroaryl, optionally substituted C3-C16 carbocyclic and C6-C10 aryl, optionally substituted 4-16-membered heterocyclic and C6-C10 aryl, optionally substituted C3-C16 carbocyclic and 5-16-membered heteroaryl, or optionally substituted 4-16-membered heterocyclic and 5-16-membered heteroaryl; wherein the substitution refers to substitution by one or more R; R is independently selected from: H, halogen, cyano, amino, hydroxyl, oxo Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylsulfone, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclyl, optionally substituted C6-C16 aryl, optionally substituted 5-16 membered heteroaryl or COR'; or any two adjacent R's and the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl or an optionally substituted C3-C8 membered carbocyclyl; wherein the substitution in R refers to substitution by one or more groups selected from the group consisting of H, halogen, cyano, amino, hydroxyl, oxo R' substituted or unsubstituted C1-C6 alkyl, R' substituted or unsubstituted C1-C6 alkoxy, R' substituted or unsubstituted C1-C6 alkylsulfone, R' substituted or unsubstituted C3-C16 carbocyclyl, R' substituted or unsubstituted 4-16 membered heterocyclyl, R' substituted or unsubstituted C6-C16 aryl, R' substituted or unsubstituted 5-16 membered heteroaryl, -N(R' substituted or unsubstituted C1-C6 alkyl)2, -CH2-N(R' substituted or unsubstituted C1-C6 alkyl)2, wherein R' is independently selected from one or more groups of the following groups: H, halogen, deuterium (D), -OH, oxo (=O), mercapto, cyano, -CD3, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 carbocyclyl and 4-8 membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl and heterocyclyl Optionally further substituted by one or more substituents selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), -NH2, -N(R" substituted or unsubstituted C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(aryl), -NH(aryl), C3-C8 carbocyclyl, 4- 8-membered heterocyclic group, C1-C4 haloalkyl-, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), -CONH2, -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl) , -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl), -NHSO2(C1-C6 haloalkyl) and -C1-C6 alkyl-NH2, wherein R" is selected from one or more groups of the following groups: H, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group.

2. The compound of claim 1, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: The R 1 is selected from: H, halogen, optionally substituted C1-C3 alkyl or optionally substituted C3-C8 carbocyclyl, preferably, R 1 is selected from: H, halogen or methyl; wherein the substitution refers to substitution by one or more R, and the definition of R is as described in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form, or combination thereof, wherein: The A ring is selected from: optionally substituted C6-C10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C8 carbocyclic and C6-C10 aryl, optionally substituted 4-8 membered heterocyclic and C6-C10 aryl, optionally substituted C3-C8 carbocyclic and 5-10 membered heteroaryl or optionally substituted 4-8 membered heterocyclic and 5-10 membered heteroaryl; preferably, the A ring is optionally substituted phenyl, 5-6 membered heteroaryl, optionally substituted C3-C8 carbocyclic and phenyl, optionally substituted 4-8 membered heterocyclic phenyl, optionally substituted C3-C8 carbocyclic 5-6 membered heteroaryl or optionally substituted 4-8 membered heterocyclic 5-6 membered heteroaryl; more preferably, ring A is selected from: optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted thienyl, optionally substituted furanyl, optionally substituted pyrrolyl, optionally substituted thiazolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl; wherein, the substitution refers to substitution by one or more R; the definition of R is as described in claim 1.

4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: The A ring is selected from: Among them, R d1 、R d2 、R d3 Each of the following is independently selected from: H, halogen, amino, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylsulfone, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclyl, optionally substituted C6-C16 aryl or optionally substituted 5-16 membered heteroaryl; R d4 are independently selected from: halogen, optionally substituted C1-C6 alkyl and R d5 is selected from: hydrogen, an optionally substituted C6-C10 membered aromatic group, or an optionally substituted 5-16 membered heteroaromatic ring group; Z is selected from: O or NR N ; R N Selected from: H or optionally substituted C1-C6 alkyl; q is each independently 0, 1, 2 or 3; Wherein, the substitution refers to substitution by one or more groups selected from the group consisting of: H, halogen, cyano, amino, hydroxyl, oxo R' substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfone, C3-C16 carbocyclyl, 4-16 membered heterocyclyl, -N(R' substituted or unsubstituted C1-C6 alkyl)2, -CH2-N(R' substituted or unsubstituted C1-C6 alkyl)2, and -CH2-(4-8 membered heterocyclyl), wherein R' is selected from one or more groups of the following groups: H, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group.

5. The compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: Ring A is where R d5a and R d5b are independently selected from: H or substituted or unsubstituted C1-C3 alkyl, or R d5a 、R d5b and the connected N atom form a 4-8 membered heterocyclic group; R d5c Selected from: H, halogen or substituted or unsubstituted C1-C3 alkyl; Wherein, the substitution refers to substitution by one or more groups selected from the group consisting of: H, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group.

6. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: R 2 for R 2’ is selected from the group consisting of: H, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl; Ring B is selected from: an optionally substituted C3-C16 carbocyclic group or an optionally substituted 4-16 membered heterocyclic group; wherein the substitution refers to substitution by one or more R; R is defined as described in claim 1; Indicates the attachment position of the group.

7. The compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: The compound has the structure shown in formula I' Wherein, m is 0, 1 or 2; Y is selected from: O, S, SO, SO2, CR y R' y 、NR” y ; Among them, R y and R' y Each independently selected from: H, OH, halogen, cyano, amino, oxo C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl; R” y Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 carbocyclyl, 4-6 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, COR"' y ; Among them, R"' y substituted or unsubstituted groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclic group, 4-6 membered heterocyclic group; wherein the substitution refers to substitution by one or more groups selected from the group consisting of OH, halogen, cyano, amino, oxo C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl; R 2’ is selected from the group consisting of: H, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl; R 1 、R 4 , A is defined as in claim 1.

8. The compound of claim 7, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: R” y is a COC1-C6 alkyl group; wherein the alkyl group is optionally substituted by one or more groups selected from the group consisting of OH, halogen, cyano, amino, oxo C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 4-6 membered heterocyclyl; preferably, R" y Selected from:

9. The compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: R 2 Selected from:

10. The compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: R 3 Selected from: H and optionally substituted C1-C3 alkyl; wherein, the substitution refers to substitution by one or more R; preferably, R 3 is H; R 4 is H; R is defined as in claim 1.

11. The compound according to any one of claims 1 to 10, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or combination thereof, characterized in that: The compound is selected from the group consisting of:

12. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (1) a therapeutically effective amount of one or more of the compound selected from any one of claims 1 to 11, and pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs, and deuterated forms thereof as an active ingredient; and (2) Optionally, a pharmaceutically acceptable carrier.

13. Use of the compound according to any one of claims 1 to 11, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated form, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for preventing or treating RAS mutation-mediated cancer.

14. The use according to claim 13, characterized in that The cancer is selected from the group consisting of lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdoid tumor, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer, in particular selected from non-small cell lung cancer, pancreatic cancer and colorectal cancer.

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