TWI880239B - A oxazine compound, its pharmaceutical composition and application - Google Patents

Abstract

The present invention provides a oxazine compound, a pharmaceutical composition and an application thereof. Specifically, the compound has a structure shown in Formula I, which can interfere with the interaction between SOS1 protein and RAS protein, and is expected to be used in the preparation of drugs for treating diseases such as tumors caused by RAS mutations.

Description

A oxazine compound, its pharmaceutical composition and application

The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a oxazine compound, a pharmaceutical composition thereof and an application thereof.

Rat sarcoma protein (RAS protein) is an important signal transduction regulator in the human body, regulating important physiological processes including cell proliferation, differentiation, migration and survival. RAS belongs to guanosine triphosphate hydrolase (GTPase), and regulates multiple important signal pathways such as downstream RAF/MEK/ERK and PI3K/AKT through the cycle of RAS binding to guanosine triphosphate (GTP) in an active state and RAS binding to guanosine diphosphate (GDP) in an inactive state. This cycle includes two processes, in which negative regulation catalyzes the hydrolysis of RAS-GTP to RAS-GDP through GTPase activating protein (GAP), and positive regulation guanylate exchange factor (GEF) catalyzes the dissociation of RAS and GDP, and then RAS will bind to the high concentration of GTP in the cell. SOS1 (Son of Sevenless 1) is one of the most widely expressed and functionally important GEFs in the human body.

The RAS protein family includes KRAS (Kirsten rat sarcoma viral oncogene), NRAS (neuroblastoma RAS viral oncogene) and HRAS (Harvey murine sarcoma viral oncogene), among which KRAS mutations are the most common. KRAS mutations cause the protein to remain in the RAS-GTP state, continuously activating downstream signaling pathways. SOS1 plays an important role in this physiological process of carcinogenesis. Deleting SOS1 can effectively reduce the growth rate of KRAS mutant tumors without affecting the growth of KRAS wild-type cell lines.

Small molecule inhibitors bind to the catalytic pocket of SOS1, affecting the binding of SOS1 to RAS proteins, and can effectively inhibit the phosphorylation level of downstream RAS signaling pathways such as ERK (extracellular regulated protein kinases), thereby inhibiting tumor growth. Currently, 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. However, this field still urgently needs to develop effective drugs that can inhibit the interaction between SOS1 and RAS mutant proteins.

The purpose of the present invention is to provide a new oxazine compound and a pharmaceutical composition containing the same, which can effectively inhibit the interaction between SOS1 and RAS mutant protein.

In a first aspect, the present invention provides a compound of formula I, a pharmaceutically acceptable salt, a chiral isomer, a non-chiral isomer, a tautomer, a cis-trans isomer, a solvate, a polymorph, a deuterated compound or a combination thereof. wherein ^R1 is selected from: H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 carbocyclic group, optionally substituted 4-8 membered heterocyclic group, cyano, or ； wherein R ^1a and R ^1b are each independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclic group or optionally substituted 4-8 membered heterocyclic group; 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 carbocyclic group, optionally substituted 4-16 membered heterocyclic group; wherein the substitution refers to substitution by one or more R; R ³ and R ⁴ are each independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C3-C6 carbocyclic group, optionally substituted 4-8 membered heterocyclic group; wherein the substitution refers to substitution by one or more R; The A ring is selected from: 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, amine, 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 alkylsulfonyl, optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, 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 connected form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbocyclic group; wherein the substitution in R refers to substitution by one or more groups selected from the group consisting of: H, halogen, cyano, amine, hydroxyl, oxo ( ), R' substituted or unsubstituted C1-C6 alkyl, R' substituted or unsubstituted C1-C6 alkoxy, R' substituted or unsubstituted C1-C6 alkylsulfonyl, R' substituted or unsubstituted C3-C16 carbocyclic group, R' substituted or unsubstituted 4-16 membered heterocyclic group, R' substituted or unsubstituted C6-C16 aryl, R' substituted or unsubstituted 5-16 membered heteroaryl, N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , CH ₂ -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), hydroxyl, cyano, -CD ₃ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 carbocyclic group and 4-8 membered heterocyclic group, wherein each of the alkyl, alkenyl, alkynyl, carbocyclic group and heterocyclic group is optionally further substituted by one or more substituents selected from the following: 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 carbocyclic group, 4-8 membered heterocyclic group, C1-C4 halogenated alkyl-, -C1-C4 alkylOH, -C1-C4 alkylO-C1-C4 alkyl, OC1-C4 halogenated alkyl, cyano, nitro, -C(O)-OH, C(O)OC1-C6 alkyl, CON(C1-C6 alkyl) ₂ , CONH(C1-C6 alkyl), CONH ₂ , NHC(O)(C1-C6 alkyl), NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl), -SO ₂ (C1-C6 halogenated alkyl), -SO ₂ NH ₂ , SO ₂ NH(C1-C6 alkyl), SO ₂ NH(phenyl), -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl), NHSO ₂ (C1-C6 halogenated alkyl) and C1-C6 alkylNH ₂ , wherein R'' is one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, oxo ( ), C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group.

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

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 Preferably, the A ring 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; R is as defined above.

In another preferred embodiment, the A ring is selected from: , , , , , , , , , or wherein R ^d1 , R ^d2 , and R ^d3 are independently selected from the group consisting of H, halogen, amine, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl, or optionally substituted 5-16 membered heteroaryl; and R ^d4 are independently selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, and ; R ^d5 is selected from: hydrogen, optionally substituted C6-C10 aromatic group or optionally substituted 5-16 heteroaromatic ring group; Z is selected from: O or NR ^N ; ^RN is selected from: H or optionally substituted C1-C6 alkyl; q is independently 0, 1, 2 or 3; wherein the substitution refers to substitution by one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, oxo ( ), R' substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfonyl, C3-C16 carbocyclic group, 4-16 membered heterocyclic group, N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , CH ₂ -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , and CH ₂ -(4-8 membered heterocyclic group), wherein R' is selected from one or more groups of the following groups: H, halogen, cyano, amine, hydroxyl, oxo ( ), C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group.

In another preferred embodiment, ring A is , , , , , , , , , , , , , , , , , , or ; wherein 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 is 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 following group: H, halogen, cyano, amine, hydroxyl, oxo ( ), C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group.

In another preferred embodiment, ^R2 is ; R ^2' is selected from: 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 above; Indicates the attachment position of the group.

In another preferred embodiment, the B ring 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 following groups: OH, halogen, cyano, amine, hydroxyl, oxo ( ), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, C3-C6 carbocyclic group, 4-6 membered heterocyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group, COR'''; wherein R''' is selected from the following substituted or unsubstituted groups: 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 following group: OH, halogen, cyano, amine, oxo ( ), C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclic group, 4-6 membered heterocyclic group, C6-C10 aryl group or 5-10 membered heteroaryl group.

In another preferred embodiment, ^R2 is .

In another preferred embodiment, the compound has a structure shown in formula I' wherein m is 0, 1 or 2; Y is selected from: O, S, SO, SO ₂ , CR _y R' _y , NR''_y; wherein R _y and R' _y are each independently selected from: H, OH, halogen, cyano, amine, oxo ( ), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, C3-C6 carbocyclic group, 4-6 membered heterocyclic group, C6-C10 aryl group, or 5-10 membered heteroaryl group; _R''y is selected from: H, C1-C6 alkyl, C1-C6 halogenated alkyl, C3-C6 carbocyclic group, 4-6 membered heterocyclic group, C6-C10 aryl group, 5-10 membered heteroaryl group, COR'''_y; wherein, R''' _y is selected from the group consisting of substituted or unsubstituted 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, amine, oxo ( ), C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclic group, 4-6 membered heterocyclic group; R ¹ , R ⁴ , R ^2' , and A are as defined above.

In another preferred embodiment, Y is _NR'y ; wherein _R'y is selected from: H, C1-C6 alkyl, C1-C6 halogenated alkyl, C3-C6 carbocyclic group, 4-6 membered heterocyclic group, preferably, _R'y is selected from: H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

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 following groups: OH, halogen, cyano, amine, oxo ( ), C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclic group, 4-6 membered heterocyclic group; preferably, _R''y is selected from: , , , , , .

In another preferred embodiment, ^R2 is selected from: , , , , , , , , , , , , , , , .

In another preferred example, R ³ is 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 above.

In another preferred embodiment, R ¹ , R ² , R ³ , R ⁴ , Ring A, Ring B, Y, m and R ^2′ are groups corresponding to the specific compounds in the embodiments.

In another preferred embodiment, the compound is selected from the following group: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

The second aspect of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises: (1) a therapeutically effective amount of one or more selected from the compound described in the first aspect, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer, solvate, polymorph and deuterated product as an active ingredient; and (2) optionally, a pharmaceutically acceptable carrier.

The third aspect of the present invention provides a use of the compound described in the first aspect, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated form thereof, or the drug composition described in the second aspect in the preparation of a drug for preventing or treating RAS mutation-mediated cancer.

In another preferred example, the cancer is selected from: lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyosarcoma, 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.

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. Due to space limitations, they will not be described one by one here.

The inventors have developed a new oxazine compound through extensive and in-depth research, which can effectively inhibit the interaction between SOS1 and RAS mutant protein. On this basis, the present invention was completed.

Terminology

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.

As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of" or "consisting of.

The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

Group Definition

Definitions of standard chemical terms can be found in the reference literature, 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 employed. Unless specific definitions are set forth, the terms employed herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques may be used in chemical syntheses, chemical analyses, drug preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or as described herein. The above techniques and methods can generally be carried out according to conventional methods well known in the art, based on the descriptions in the various general and more specific literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable structural moieties and compounds.

When substituents are described by a conventional chemical formula written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

The section headings used herein are for the purpose of organizing the article only and should not be construed as limiting 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 theses, are incorporated herein by reference in their entirety.

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, C1-C6 alkyl 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.

In addition to the foregoing, when used in the specification and scope of the patent application of this application, unless otherwise specifically indicated, the following terms have the meanings as shown below.

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

"Hydroxy" refers to an -OH group.

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

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

"Nitro" refers to _-NO2 .

"Cyano" refers to -CN.

"Carboxyl" refers to -COOH.

In the present application, as a group or as part of other groups (e.g., in groups such as halogen-substituted alkyl), the term "alkyl" refers to a fully saturated straight or branched hydrocarbon chain 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, etc. For the purposes of the present invention, the term "alkyl" preferably refers to an alkyl group containing 1 to 6 carbon atoms.

In the present application, the term "alkenyl", as a group or part of other groups, means a straight or branched hydrocarbon chain group consisting only of carbon atoms 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 through 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.

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 only of carbon atoms 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, etc.

In the present application, as a group or part of other groups, the term "carbocyclic (base)" 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 can be connected to the rest of the molecule through one or more single bonds via any suitable carbon atom. Unless otherwise specifically indicated in this specification, the carbon atoms in the carbocyclic group can be optionally oxidized. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-dihydroindenyl, 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-pentadienyl, etc. In the present invention, the carbocyclic group is preferably a cycloalkyl group, such as a C3-C10 cycloalkyl group, a C3-C8 cycloalkyl group or a C3-C6 cycloalkyl group.

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), and typical cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc.

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

In the present application, as a group or part of other groups, the term "heterocyclic (base)" 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 specifically indicated in the 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 atom in the heterocyclic group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic group can be partially or completely saturated. The heterocyclic radical may be attached to the rest of the molecule via a carbon atom or a heteroatom and via one or more single bonds. In heterocyclic radicals comprising fused rings, one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic radical is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic radical containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic radical 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]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2 In some embodiments, the present invention comprises a cyclopentyl group, azocyclobutyl group, a pyranyl group, a tetrahydropyranyl group, a thiopyranyl group, a tetrahydrofuranyl group, an oxazinyl group, a dioxolanyl group, a tetrahydroisoquinolyl group, a decahydroisoquinolyl group, an imidazolinyl group, an imidazolidinyl group, a quinolizinyl group, a thiazolidinyl group, an isothiazolidinyl group, an isoxazolidinyl group, a dihydroindolyl group, an octahydroindolyl group, an octahydroisoindolyl group, a pyrrolidinyl group, a pyrazolidinyl group, a phthalimide group, and the like.

In the present application, the term "aryl" as a radical or part of another radical 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 may be a monocyclic, bicyclic, tricyclic or polycyclic ring system, and may 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.

In this application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In the present application, as a group or part of other groups, the term "heteroaryl" means a 5- to 16-membered concentric ring system group 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 specifically indicated in the specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a carbocyclic group or a heterocyclic group defined above, provided that the heteroaryl group is connected to the rest of the molecule through one or more single bonds via atoms on the heteroaromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. For the purpose 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, oxazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, oxolinyl, 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]oxazine, [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]oxazine, imidazo[1,2-a]pyrazine, etc.

In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

In this application, the term "absent" means that the two sides of the groups defined above are directly connected by a chemical bond. For example, "A-B-C where B is absent" means "A-C".

In this application, “ " ” indicates the attachment position of group R.

In this application, unless otherwise specified in the scope of the application, "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that the hydrogen on the aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl. 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, for example, 1, 2, 3 or 4 substituents, and the substituents are independently selected from: deuterium (D), halogen, OH, oxo (=O), hydroxyl, cyano, -CD ₃ , -C1-C6 alkyl (preferably -C1-3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, carbocyclic group (preferably C3-C8 carbocyclic group), aryl, heterocyclic group (preferably 3-8 membered heterocyclic group), heteroaryl, aryl C1-C6 alkyl, heteroaryl C1-C6 alkyl, C1-C6 halogenated alkyl-, OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 alkenyl, O cycloalkyl, O heterocyclic group, O aryl, O heteroaryl, OC1-C6 alkylphenyl, -C1-C6 alkyl OH (preferably -C1-C4 alkyl OH), -C1-C6 alkyl SH, -C1-C6 alkyl O-C1-C6 alkyl, OC1-C6 halogenated alkyl, NH ₂ , C1-C6 alkyl NH ₂ (preferably C1-C3 alkyl NH ₂ ), 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 (wherein R ⁱ and R ⁱⁱ is 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 halogenated alkyl, OC(O)C1-C6 alkyl (preferably OC(O)C1-C3 alkyl), -S(O) ₂ -C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O) ₂ -phenyl, -S(O) ₂ -C1-C6 halogenated alkyl, _-S (O) _2NH2 , S(O) ₂ NH(C1-C6 alkyl), S(O) ₂ NH(phenyl), -NHS(O) ₂ (C1-C6 alkyl), -NHS(O) ₂ (phenyl) and NHS(O) ₂ (C1-C6 halogenated alkyl), wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclic and heteroaryl groups is optionally further substituted with one or more substituents selected from the group consisting of halogen, -OH, oxo (=O), -NH ₂ , carbocyclic group, 3-8 membered heterocyclic group, C1-C4 alkyl, C1-C4 halogenated alkyl-, -OC1-C4 alkyl, -C1-C4 alkylOH, -C1-C4 alkylO-C1-C4 alkyl, OC1-C4 halogenated alkyl, cyano group, nitro group, -C(O)-OH, C(O)OC1-C6 alkyl, CON(C1-C6 alkyl) ₂ , CONH(C1-C6 alkyl), CONH ₂ , NHC(O)(C1-C6 alkyl), NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl), -SO ₂ (C1-C6 halogenated alkyl), -SO ₂ NH ₂ , SO ₂ NH(C1-C6 alkyl), SO ₂ NH(phenyl), -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl) and NHSO ₂ (C1-C6 halogenated alkyl). When an atom or group is substituted with multiple substituents, the substituents may be the same or different. The terms "part", "structural part", "chemical part", "group", "chemical group" as used herein refer to a specific fragment or functional group 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 can be used interchangeably.

In the present invention, unless otherwise specified, an amine group refers to a group having a -NRR' structure, wherein RR' is independently H, an alkyl group (such as a C1-C6 alkyl group), an alkylcarbonyl group (such as a C1-C6 alkylCO), an arylalkyl group (such as a phenyl C1-C6 alkyl group), a heteroarylalkyl group (such as a 5-6-membered heteroaryl C1-C6 alkyl group), etc. In the present invention, an amine group may be _NH2 or a substituted amine group, wherein "substituted amine group" refers to an amine group substituted by one or two alkyl groups, alkylcarbonyl groups, arylalkyl groups, heteroarylalkyl groups as defined above, for example, a monoalkylamine group, a dialkylamine group, an alkylamide group, an arylalkylamine group, a heteroarylalkylamine group. Preferably, in the present invention, an amine group includes: _NH2 , _NHCH3 , , , , , , , -NHCOCH ₃ , -NHCH ₂ Ph, etc.

In the present invention, "plurality" means 2, 3 or 4.

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

In the present invention, N(C1-C6 alkyl) ₂ , or (C1-C6 alkyl) ₂ amine, means that the two hydrogen atoms on NH ₂ are replaced by two C1-C6 alkyl atoms, for example , , , or wait.

Active ingredients

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, chiral isomers, non-chiral isomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated compounds or combinations thereof.

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

When the compounds of the present invention contain olefinic double bonds, unless otherwise specified, the compounds of the present invention are intended to include both E- and Z-geometric isomers.

"Tautomers" refer to isomers formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are also intended to be included within the scope of the present invention.

The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms and may therefore produce chiral isomers, non-chiral isomers 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 preparation of the compounds of the present invention may select racemates, non-chiral isomers or chiral isomers as raw materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for preparing/isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) 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 ; AM 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.

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

"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic acid or organic acid that can retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include but are not limited to hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, etc.; organic acid salts include but are not limited to formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, caproates, octanoates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates. , maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, appletate, glutamine, pyroglutamine, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include but are not limited to sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, diamines, and tertiary amines, substituted amines, including naturally 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, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

It will also be appreciated by those skilled in the art 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, amine, alkyl and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amine, amidino and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable alkyl 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.

Protective 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, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. Protective groups can also be polymeric resins.

Pharmaceutical compositions and methods of administration

In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the drug into the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

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 administration method and dosage of the original drug 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 at 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 them taken alone.

Drugs or active ingredients that can be used in combination with the compound 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, larvatinib, oclatinib), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, cabozantinib, sunitinib, etc.), PI3 K inhibitors (such as Dactolisib, Taselisib, etc.), BTK inhibitors (such as Ibrutinib, Tilabutinib, Acalabrutinib, Zebutinib, Vicabrutinib, 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.

The term "pharmaceutically acceptable" as used herein 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, i.e., the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, 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.

The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

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, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) buffers, 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 glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffering agent.

Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be adopted are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsule form with one or more of the above-mentioned excipients.

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 inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and flavoring agents.

In addition to the active compounds, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar or mixtures of these substances.

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

The "tumor" described in the present invention 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 rhabdomyosarcoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, brain glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer. The terms "preventive", "prevention" and "prevention" used herein include reducing the possibility of the occurrence or deterioration of a disease or condition in a patient.

As used herein, the term "treat" and other similar synonyms include the following meanings: (i) preventing a disease or condition from occurring in a mammal, particularly when such mammal is susceptible to the disease or condition but has not yet been diagnosed with the disease or condition; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing the disease or condition to regress; or (iv) alleviating the symptoms caused by the disease or condition.

As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be the elimination and/or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide a significant symptom-relieving effect clinically. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.

As used herein, the terms "administering," "administering," "dosing," and the like refer to methods that enable a compound or composition to be delivered to the desired site for biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), 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.

As used herein, the terms "drug combination", "drug combination", "combination therapy", "administration of other treatments", "administration of other therapeutic agents" and the like refer to drug treatments obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, combined administration or sequential administration with variable intervals of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

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

Preparation method of compound

The following schemes describe methods for preparing compounds of Formula I. In some cases, the order of 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 in this specification or known in the art, and such combinations may be easily performed by those skilled in the art to which the present invention pertains.

It will also be appreciated by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amine, alkyl and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, allyl, etc. Suitable protecting groups for amine, amidino and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyl, allyloxycarbonyl, p-toluenesulfonyl, t-pentanoyl, trifluoroacetyl, etc. Suitable alkyl 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.

Protective 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, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. Protective groups can also be polymeric resins.

Usually, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C-150°C, preferably 10°C-100°C). The reaction time is usually 0.1 hour to 60 hours, preferably 0.5-48 hours.

Preferably, the compound of formula I can be prepared by the following method: (1) Compounds a and b are reacted in the presence of a strong base to generate compound c, wherein the strong base is selected from the group consisting of n-butyl lithium, diisopropyl lithium amide, tert-butyl lithium, sec-butyl lithium, hexamethyldisilazide lithium, or a combination thereof; (2) Compound c undergoes an aromatic nucleophilic substitution reaction with compound d in the presence of a base to generate compound I, wherein the strong base is selected from the group consisting of sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilamide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, 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; Alternatively, (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 hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, n-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilamide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, 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; (2) Compound e and compound b are reacted in the presence of a strong base to generate compound I, wherein the strong base is selected from the group consisting of n-butyl lithium, diisopropyl lithium amide, tert-butyl lithium, sec-butyl lithium, lithium hexamethyldisilazide, or a combination thereof; wherein X ¹ , X ² , R ¹ , R ² , and Ring A are as defined above.

The main advantages of the present invention are: 1. The compound of the present application has a novel structure; 2. The compound of the present application can effectively inhibit the binding of SOS1 to RAS protein; 3. The compound of the present application has good pharmacokinetics and efficacy.

The technical solution of the present invention is further described below through specific implementations. Those skilled in the art should understand that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

The experimental methods without specifying specific conditions in the following examples are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts.

Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources.

In each example, ¹ H 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 a Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, LCMS-2020 mass spectrometer; and preparative HPLC separation was performed using a Gilson -281 liquid chromatograph.

Embodiment

Preparation of intermediates

1. Preparation of intermediate A

(1) Add cuprous cyanide (8.73 g, 97.5 mmol) to a solution of compound A-1 (10.0 g, 48.8 mmol) in N,N -dimethylformamide (100.0 mL). Stir the reaction mixture at 100°C for 16 hours under nitrogen. Add water (100.0 mL) to the reaction mixture, extract with ethyl acetate (200.0 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The crude product is separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 5:1) to obtain compound A-2 .

¹ H NMR (400 MHz, DMSO- d 6) δ 8.15 (d, J = 5.2 Hz, 1H), 7.69 (d, J = 5.2 Hz, 1H), 2.65 (s, 3H).

(2) Add hydrazine hydrochloride (2.92 g, 27.78 mmol) to a solution of compound A-2 (3.50 g, 23.2 mmol) in ethanol (20.0 mL). Stir the reaction solution at 80°C for 12 hours under nitrogen protection. Concentrate the reaction solution under reduced pressure, add water (50.0 mL), extract with ethyl acetate (50.0 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain crude compound A-3 .

MS-ESI [M+H] ⁺ , calcd. 166, found 166.

(3) Add tert-butyl nitrite (2.50 g, 24.2 mmol) and cuprous chloride (2.40 g, 24.2 mmol) to a solution of compound A-3 (2.00 g, 12.1 mmol) in acetonitrile (30.0 mL). Stir the reaction solution at 60°C for 12 hours under nitrogen protection. Concentrate the reaction solution under reduced pressure, add water (30.0 mL), extract with ethyl acetate (50.0 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether/ethyl acetate = 10:1 to 1:1) to obtain compound A.

MS-ESI [M+H] ⁺ , calcd. 185, found 185.

Example 1 Synthesis of Compound 1

(1) Add intermediate A (203 mg, 894 μmol) and lithium diisopropylamide (2.00 mol/L, 609 μL) to a solution of compound 1-1 (150 mg, 812 μmol) in tetrahydrofuran (6.0 mL). Stir the reaction mixture at -78°C for 1 hour under nitrogen protection. Add saturated aqueous ammonium chloride solution (100.0 mL), add water (100.0 mL), extract with ethyl acetate (100.0 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 3:1) to obtain compound 1-2 . MS-ESI [M +H] ⁺ , calcd. 412, found 412.

(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 solution was stirred at 25°C for 10 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain compound 1-3 . MS-ESI [M+H] ⁺ , calculated value 410, found value 410. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 3.62-3.78 (m, 2H), 3.17-3.33 (m, 2H), 2.93 (s, 3H), 2.33 (br d, J = 14.0 Hz, 2H), 1.74 (br d, J = 4.0 Hz, 2H), 1.58 (d, J = 6.0 Hz, 3H), 1.46 (s, 9H).

(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 protection. Water (100.0 mL) was added to the reaction solution, 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 10: 1) to obtain compound 1-5 . MS-ESI [M+H] ⁺ , calculated value 608, found value 608.

(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, found value 508.

(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, found value 524.

(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, 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, concentrated under reduced pressure, and 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 minutes) to obtain the formate salt of compound 1 . MS-ESI [M+H] ⁺ , calcd. 494, found 494. ¹ H NMR (400 MHz, MeOD) δ 7.79 (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).

Example 2 Synthesis of Compound 2

(1) Compound 2-1 (29.7 mg, 146 μmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1,1' -biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) methanesulfonate (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 protection. Water (30.0 mL) was added to the reaction solution, 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 0: 1) to obtain compound 2-2 . MS-ESI [M+H] ⁺ , calculated value 577, found value 577.

(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 solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 2-3 . MS-ESI [M+H] ⁺ , calculated value 477, found value 477.

(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 solution was stirred at 25°C for 5 hours, water (10.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 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 minutes) to obtain the formate salt of compound 2. MS-ESI [M+H] ⁺ , calculated value 493, found value 493. ¹ H NMR (400 MHz, MeOD) δ 7.78 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 5.69 (q, J = 6.8 Hz, 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 = 7.2 Hz, 6H), 1.95-2.22 (m, 2H), 1.70-1.83 (m, 1H), 1.60 (d, J = 6.8 Hz, 4H), 1.13 (s, 3H).

Embodiment 3- Embodiment 6 Synthetic compounds 3- Compound 6

The synthesis method in Example 2 was adopted to synthesize compounds 3 to 6 using corresponding raw materials . Compound MS-ESI [M+H] ^{+ 1H} NMR (400 MHz, MeOD) Calculated value 507, measured value 507 7.78 (s, 1H), 7.66-7.69 (m, 1H), 7.47 - 7.53 (m, 1H), 7.22 - 7.28 (m, 1H), 5.68 (q, J = 6.4 Hz, 1H), 4.88 (s, 1H), 3.45 - 3.49 (m, 2H), 3.12 - 3.18 (m, 4H), 2.54 - 2.64 (m, 6H), 1.98 - 2.25 (m, 2H), 1.76 - 1.82 (m, 1H), 1.62 - 1.70 (m, 1H), 1.56 - 1.63 (m, 3H), 1.32 (s, 3H), 1.14 (s, 3H) Calculated value 521, measured value 521 7.77 (s, 1H), 7.65 - 7.70 (m, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.25 (s, 1H), 5.63 - 5.71 (m, 1H), 4.85 - 4.86 (m, 1H), 3.37 - 3.50 (m, 3H), 3.16 (s, 2H), 2.55 - 2.63 (m, 6H), 2.15 (d, J = 11.2 Hz, 2H), 1.74 - 1.86 (m, 1H), 1.68 (s, 1H), 1.58-1.62 (m, 3H), 1.31-1.38 (m, 6H), 1.12-1.21 (m, 3H) Calculated value 535, measured value 535 7.74 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 5.65-5.73 (m, 1H), 4.83-4.85 (m, 1H), 2.96-3.02 (m, 2H), 2.61 (s, 3H), 2.58 (s, 3H), 2.39-2.48 (m, 2H), 1.84-2.03 (m, 3H), 1.69 (d, J = 13.2 Hz, 1H), 1.55-1.63 (m, 3H), 1.41-1.47 (m, 1H), 1.35-1.39 (m, 1H), 1.01-1.10 (m, 3H), 0.93-1.00 (m, 6H), 0.87-0.92 (m, 1H) Calculated value 519, measured value 519 7.76 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.19 - 7.30 (m, 1H), 5.69 (d, J = 6.8 Hz, 1H), 4.85 (s, 1H), 3.70 (s, 2H), 3.18 (s, 2H), 2.89 (s, 2H), 2.75 (d, J = 5.2 Hz, 1H), 2.57 - 2.64 (m, 6H), 1.84 - 2.13 (m, 2H), 1.65 - 1.77 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1.39 - 1.57 (m, 1H), 1.11 (s, 3H), 0.56 - 0.77 (m, 2H)

Example 7 Synthesis of Compound 7

(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 protection. The reaction solution 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, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1: 0 to 1: 2) to obtain compound 7-2 .

(2) Add trifluoroacetic acid (1.39 g, 12.1 mmol) to a solution of compound 7-2 (110 mg, 206 μmol) in dichloromethane (4.0 mL). Stir the reaction mixture 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, found value 434.

(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 solution was stirred at 25°C for 5 hours, water (10.0 mL) was added to the reaction solution, 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 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, found value 450. ¹ H NMR (400 MHz, MeOD) δ 7.70-7.72 (m, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 5.60 (qd, J = 6.8, 3.6 Hz, 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 = 7.2 Hz, 3H), 1.46 (br d, J = 13.6 Hz, 1H), 1.06 (s, 3H).

Test example

Determination of the inhibitory effect of compounds on the binding of SOS1 to KRAS (G12C) mutant protein [ Homogeneous time-resolved fluorescence (HTRF) method ] :

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

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.

3. Experimental method: Preparation of 1x concentration buffer (prepared and used immediately): 4-hydroxyethylpiperazineethanesulfonic acid (Hepes): 5 mmol/L; Sodium chloride: 150 mmol/L; Ethylenediaminetetraacetic acid: 10 mmol/L; Ethylphenylpolyethylene glycol (Igepal): 0.0025%; Potassium fluoride: 100 mmol/L; Dithiothreitol (DTT): 1 mmol/L; Bovine serum albumin (BSA): 0.05%.

The compound stock solution concentration was 1000 μmol/L, and 5-fold dilution was performed to set 8 gradient concentrations. The compound to be tested was diluted into a 2% DMSO working solution with a 1-fold concentration buffer, and 5 μL/well was added to the corresponding wells. Each concentration was set for duplicate detection. A mixed working solution of KRAS (G12C) mutant protein (200 nM) and Mab Anti GST-Eu cryptate (1 μg/uL) was prepared with a 1-fold concentration buffer. The mixed working solution was placed at 25°C for 5 minutes and 2.5 μL/well was added to the corresponding wells. Prepare a mixed working solution of SOS1 protein (80 nM) and Mab Anti 6HIS-XL665 (8 μg/uL) with 1x buffer concentration, and add 2.5 μL/well to the corresponding wells. Add 2.5 μL of Mab Anti 6HIS-XL665 (8 μg/μL) dilution to the blank wells. Incubate the reaction system at 25℃ for 60 minutes. After the reaction, read HTRF using a multi-label analyzer.

4. Data processing:

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

Table 1 Test compound IC ₅₀ (nM) Formate of Example 1 60.87 Formate of Example 2 28.44 Embodiment 3 17.79 Embodiment 4 25.75 Embodiment 5 32.99 Embodiment 6 24.15 Embodiment 7 74.48

From the test data in Table 1, it can be seen that the compound of 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 tumor drugs for treating RAS mutations.

The applicant declares that the present invention uses the above-mentioned embodiments to illustrate the oxazine compounds, the pharmaceutical compositions containing the same and their applications, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. The technical personnel in the relevant technical field should understand that any improvement of the present invention, the equivalent replacement of the raw materials of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

without.

Claims (17)

A compound represented by formula I, a pharmaceutically acceptable salt thereof, a chiral isomer, a non-chiral isomer, a tautomeric isomer, a cis-trans isomer or a combination thereof, Wherein, ^R1 is selected from: H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C6 carbocyclic group, cyano or ; wherein R ^1a is selected from: H, optionally substituted C1-C6 alkyl; wherein the substitution refers to substitution by one or more R; R ² is ; R ^2' is selected from: 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-C6 carbocyclic group or an optionally substituted 4-8 membered heterocyclic group; wherein the substitution refers to substitution by one or more groups selected from the following group: OH, halogen, cyano, amine, hydroxyl, oxo ( ), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, C3-C6 carbocyclic group, 4-6 membered heterocyclic group, COR'''; wherein R''' is selected from the following substituted or unsubstituted groups: C1-C6 alkyl, C1-C6 alkoxy; wherein the substitution refers to substitution by one or more groups selected from the following group: OH, halogen, cyano, amine, oxo ( ), C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclic group, 4-6 membered heterocyclic group; ^R3 and ^R4 are each independently selected from: H, optionally substituted C1-C6 alkyl; wherein the substitution refers to substitution by one or more R; Ring A is selected from: optionally substituted phenyl, 5-6 membered heteroaryl, optionally substituted C3-C8 carbocyclic 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; wherein the substitution refers to substitution by one or more R; R are each independently selected from: H, halogen, cyano, amine, 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 alkylsulfonyl, optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, 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 connected form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbocyclic group; wherein the substitution in R refers to substitution by one or more groups selected from the group consisting of: H, halogen, cyano, amine, hydroxyl, oxo ( ), R' substituted or unsubstituted C1-C6 alkyl, R' substituted or unsubstituted C1-C6 alkoxy, R' substituted or unsubstituted C1-C6 alkylsulfonyl, R' substituted or unsubstituted C3-C16 carbocyclic group, R' substituted or unsubstituted 4-16 membered heterocyclic group, R' substituted or unsubstituted C6-C16 aryl, R' substituted or unsubstituted 5-16 membered heteroaryl, N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , CH ₂ -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), hydroxyl, cyano, -CD ₃ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 carbocyclic group and 4-8 membered heterocyclic group, wherein each of the alkyl, alkenyl, alkynyl, carbocyclic group and heterocyclic group is optionally further substituted by one or more substituents selected from the following: 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 carbocyclic group, 4-8 membered heterocyclic group, C1-C4 halogenated alkyl-, -C1-C4 alkylOH, -C1-C4 alkylO-C1-C4 alkyl, OC1-C4 halogenated alkyl, cyano, nitro, -C(O)-OH, C(O)OC1-C6 alkyl, CON(C1-C6 alkyl) ₂ , CONH(C1-C6 alkyl), CONH ₂ , NHC(O)(C1-C6 alkyl), NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO ₂ (C1-C6 alkyl), -SO ₂ (phenyl), -SO ₂ (C1-C6 halogenated alkyl), -SO ₂ NH ₂ , SO ₂ NH(C1-C6 alkyl), SO ₂ NH(phenyl), -NHSO ₂ (C1-C6 alkyl), -NHSO ₂ (phenyl), NHSO ₂ (C1-C6 halogenated alkyl) and C1-C6 alkylNH ₂ , wherein R'' is one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, oxo ( ), C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group. A compound as described in claim 1, a pharmaceutically acceptable salt, a chiral isomer, a non-chiral isomer, a tautomer, a cis-trans isomer or a combination thereof, wherein R ¹ is selected from: H, a halogen or an optionally substituted C1-C3 alkyl; wherein the substitution refers to substitution by one or more R, and R is defined as described in claim 1. The compound as described in claim 2, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer or a combination thereof, wherein R ¹ is selected from: H, halogen or methyl. A compound as described in claim 1, a pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer or a combination thereof, wherein 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, and R is defined as described in claim 1. The compound as claimed in claim 1, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer or a combination thereof, wherein the A ring is selected from: , , , , , , , , or ; wherein R ^d1 , R ^d2 , and R ^d3 are independently selected from: H, halogen, amine, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or optionally substituted C1-C6 alkylsulfonyl; R ^d4 are independently selected from: halogen, optionally substituted C1-C6 alkyl, and ; R ^d5 is selected from: hydrogen, optionally substituted C6 aromatic group or optionally substituted 5-6 heteroaromatic ring group; Z is selected from: O or NR ^N ; ^RN is selected from: H or optionally substituted C1-C6 alkyl; q is independently 0, 1, 2 or 3; wherein the substitution refers to substitution by one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, oxo ( ), R' substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfonyl, C3-C16 carbocyclic group, 4-16 membered heterocyclic group, N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , CH ₂ -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , and CH ₂ -(4-8 membered heterocyclic group), wherein R' is selected from one or more groups of the following groups: H, halogen, cyano, amine, hydroxyl, oxo ( ), C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group. The compound of claim 1, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer or a combination thereof, wherein Ring A is , , , , , , , , , , , , , , , , or ; Indicates the attachment position of the group. The compound as claimed in claim 1, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer or combination thereof, wherein the compound has a structure shown in formula I' wherein m is 0, 1 or 2; Y is selected from: O, S, CR _y R' _y , NR''_y; wherein R _y and R' _y are each independently selected from: H, OH, halogen, cyano, amine, oxo ( ), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl, C1-C6 halogenated alkoxy, C3-C6 carbocyclic group or 4-6 membered heterocyclic group; _R''y is selected from: H, C1-C6 alkyl, C1-C6 halogenated alkyl, C3-C6 carbocyclic group, 4-6 membered heterocyclic group, _COR''y ; wherein, _R''y is selected from the following group which is substituted or unsubstituted: C1-C6 alkyl, C1-C6 alkoxy; wherein, the substitution refers to substitution by one or more groups selected from the following group: OH, halogen, cyano, amine, oxo ( ), C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclic group, 4-6 membered heterocyclic group; R ^2' is selected from: H, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl; R ¹ , R ⁴ , A are defined as in claim 1. The compound as claimed in claim 7, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer or a combination thereof, wherein _R''y is a COC1-C6 alkyl group; wherein the alkyl group is optionally substituted with one or more groups selected from the group consisting of OH, halogen, cyano, amine, oxo ( ), C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclic group, 4-6 membered heterocyclic group. The compound as claimed in claim 8, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer or a combination thereof, wherein _R''y is selected from: , , , , , . The compound as claimed in claim 1, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer or a combination thereof, wherein R ² is selected from: , , , , , , , , , , , , , , . A compound as described in claim 1, a pharmaceutically acceptable salt, a chiral isomer, a non-chiral isomer, a tautomer, a cis-trans isomer or a combination thereof, wherein R ³ is selected from: H and an optionally substituted C1-C3 alkyl; wherein the substitution refers to substitution by one or more R; R ⁴ is H; and R is defined as described in claim 1. The compound as described in claim 11, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer or a combination thereof, wherein R ³ is H. The compound as claimed in claim 1, its pharmaceutically acceptable salt, chiral isomer, non-chiral isomer, tautomer, cis-trans isomer or a combination thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . A pharmaceutical composition comprising: (1) a therapeutically effective amount of one or more of a compound selected from any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, a chiral isomer, a non-chiral isomer, a tautomer and a cis-trans isomer as an active ingredient; and (2) optionally, a pharmaceutically acceptable carrier. Use of a compound as described in any one of claims 1 to 13, a pharmaceutically acceptable salt, a chiral isomer, a non-chiral isomer, a tautomer or a cis-trans isomer thereof, or a pharmaceutical composition as described in claim 14 in the preparation of a drug for treating RAS mutation-mediated cancer. The use as described in claim 15, wherein the cancer is selected from: lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal carcinoma, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer. The use as described in claim 16, wherein the cancer is selected from non-small cell lung cancer, pancreatic cancer and colorectal cancer.