TW202333713A - Pyridazine compound, and pharmaceutical composition and use thereof - Google Patents

Abstract

Provided are a pyridazine compound, and a pharmaceutical composition and the use thereof. Specifically, the compound has a structure as shown in formula (I), can interfere with the interaction between an SOS1 protein and an RAS protein, and is expected to be used in the preparation of a drug for treating diseases such as tumors with RAS mutations.

Description

A kind of pyridazine compound, its pharmaceutical composition and application

The invention belongs to the field of medicinal chemistry, and specifically relates to a pyridazine compound, its pharmaceutical composition and application.

Rat sarcoma protein (RAS protein) is an important signaling regulator in the human body, regulating important physiological processes including cell proliferation, differentiation, migration and survival. RAS belongs to guanosine triphosphate hydrolase (GTPase), which regulates downstream RAF/MEK/ through the recycling of the active state of RAS bound to guanosine triphosphate (GTP) and the inactive state of RAS bound to guanosine diphosphate (GDP). There are many important message pathways such as ERK and PI3K/AKT. This cycle includes two processes, in which the negative regulation catalyzes the hydrolysis of RAS-GTP to RAS-GDP through GTPase activating protein (GAP), and the positive regulation guanylate exchange factor (GEF) catalyzes the dissociation of RAS and GDP, and then RAS Binds to high intracellular concentrations of GTP. SOS1 (Son of Sevenless 1) is one of the most widely expressed and most functional 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 tumors caused by 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 carcinogenic physiological process. Knocking out SOS1 can effectively reduce the growth rate of KRAS mutant tumors and does not affect the growth of KRAS wild-type cell lines.

Small molecule inhibitors bind to the catalytic pocket of SOS1 and affect the binding of SOS1 to RAS protein. They 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 the phase I clinical research stage, and is cooperating 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, there is still an urgent need in this field 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 pyridazine compound and a pharmaceutical composition containing the same, which can effectively inhibit the interaction between SOS1 and RAS mutant protein.

The first aspect of the present invention provides a compound represented by formula I, its pharmaceutically acceptable salts, apral isomers, non-alpral isomers, tautomers, cis-trans isomers, and solvates , polymorphs, deuterated forms or combinations thereof, Wherein, X ^{1 is} selected from: CH, oxygen atom, sulfur atom, nitrogen atom or -NH; Preferably, X ¹ is CH; X ² is selected from: sulfur atom, oxygen atom, nitrogen atom, -NR ^x ,; ^wherein , R ^x is selected from: H ^, optionally substituted C1-C3 alkyl; preferably, : H, halogen, optionally substituted C1-C3 alkyl group, optionally substituted C3-C8 carbocyclic group, optionally substituted 4-8 membered heterocyclic group, cyano group, or ; Wherein, R ^1a and R ^1b are each independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl or optionally substituted 4-8 membered heterocyclyl; wherein , the substitution means 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 heterocycle base; wherein, the substitution means substitution by one or more R; Ring A is selected from: optionally substituted C6-C16 aryl, optionally substituted 5-16 membered heteroaryl, optionally substituted C3- C16 carbocyclic C6-C10 aryl, optionally substituted 4-16 membered heterocyclic C6-C10 aryl, optionally substituted C3-C16 carbocyclic 5-16 membered heteroaryl or optionally substituted 4 -16-membered heterocyclyl and 5-16-membered heteroaryl; wherein the substitution means substitution by one or more R; each R is independently selected from: H, halogen, cyano, amine, hydroxyl, oxo base( ), optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, N (optionally substituted C ₁ -C ₆ alkyl) ₂ , NH (optionally substituted C ₁ -C ₆ alkyl), -N (optionally substituted C ₁ -C ₆ alkyl) (optionally substituted C ₁ -C ₆ alkyl phenyl), -NH (optionally substituted C ₁ -C ₆ alkylphenyl), optionally substituted C1-C6 alkyl -S-, -S(O) ₂ -optionally substituted C1-C6 Alkyl, -S(O)-optionally substituted C1-C6 alkyl, -S(O) ₂ -optionally substituted phenyl, -S(O) ₂ NH ₂ , S(O) ₂ NH (any optionally substituted C1-C6 alkyl), S(O) ₂ NH (optionally substituted phenyl), -NHS(O) ₂ (optionally substituted C1-C6 alkyl), -NHS(O) ₂ ( optionally substituted phenyl), optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclyl, optionally substituted C6-C16 aryl or optionally substituted 5-16 membered heterocyclic group Aryl; or any two adjacent R and the atoms connected thereto 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 Substituted with 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 alkyl group, 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 , CH ₂ -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , where R' is selected from one or more of the following groups Groups: H, halogen, deuterium (D), halogen, OH, oxo (=O), mercapto, cyano, -CD ₃ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkene base, C2-C6 alkynyl, C3-C8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is optionally One or more substituents selected from the following are further substituted: H, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), -NH ₂ , 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 cycloalkyl, 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), 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 haloalkyl), -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 haloalkyl) and C1-C6 alkyl NH ₂ , where R'' is selected from one of the following groups or Multiple groups: 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 means substitution by one or more R, and R is as defined above.

In another preferred example, the A ring is selected from: optionally substituted C6-C10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C8 carbocyclyl and C6-C10 aryl. base, optionally substituted 4-8 membered heterocycla C6-C10 aryl, optionally substituted C3-C8 carbocycla 5-10 membered heteroaryl or optionally substituted 4-8 membered heterocycla 5- 10-membered heteroaryl; preferably A ring is optionally substituted phenyl, 5-6-membered heteroaryl, optionally substituted C3-C8 carbocyclophenyl, optionally substituted 4-8-membered heterocyclyl Phenyl, optionally substituted C3-C8 carbocyclic 5-6 membered heteroaryl or optionally substituted 4-8 membered heterocyclic 5-6 membered heteroaryl; more preferably, A ring is selected from: any optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrrolyl, optionally substituted thiazolyl, optionally substituted optionally substituted imidazolyl, optionally substituted pyrazolyl; wherein, the substitution means substitution by one or more R; R is as defined above.

In another preferred embodiment, the A ring is , , , , , , , , , , , , or ;wherein, q is 0, 1, 2, 3 or 4, each R ^d is independently selected from: H, halogen, amino group, hydroxyl, cyano group, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy group, optionally substituted C1-C6 alkyl group, optionally substituted C3-C16 carbocyclyl group, optionally substituted 4-16 membered heterocyclyl group, optionally substituted C6-C16 Aryl or optionally substituted 5-16 membered heteroaryl, or any two adjacent R ^d and the carbon atoms connected to them form an optionally substituted 4-8 membered heterocyclyl or optionally substituted C3-C8 1-membered carbocyclic group; wherein, the substitution refers to substitution with one or more groups selected from the following group: 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 alkyl group, R' substituted or unsubstituted C3-C16 carbocyclyl, R' substituted or unsubstituted 4-16 membered heterocyclyl, N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , CH ₂ -N(R' substituted or unsubstituted Substituted C1-C6 alkyl) ₂ , and CH ₂ -(4-8 membered heterocyclyl), wherein R' is selected from one or more groups of 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 A ring is selected from: , , , , , , , , , or ; Wherein, R ^d1 , R ^d2 , and R ^d3 are each independently selected from: H, halogen, amino group, hydroxyl, cyano group, optionally substituted C1-C6 alkyl group, optionally substituted C1-C6 alkoxy group, Optionally substituted C1-C6 alkyl group, 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 ; q is 0, 1, 2 or 3; R ^d5 is selected from: hydrogen, optionally substituted C6-C10-membered aromatic group or optionally substituted 5-16-membered heteroaromatic ring group; Z is selected from: O or NR ^N ; R ^N is selected from: H or optionally substituted C1-C6 alkyl; wherein, the substitution means substitution with one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl , oxo group ( ), R'-substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylpropyl, C3-C16 carbocyclyl, 4-16 membered heterocyclyl, 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 heterocyclyl), where R' is selected from One or more groups 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 A ring 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 From: H, halogen or substituted or unsubstituted C1-C3 alkyl; wherein the substitution means substitution with one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl, Oxo group ( ), C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group.

In another preferred example, the R ² is , wherein, X ³ is selected from: CR ^2' or N; Preferably, R ² is ; R ^2' is selected from: methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio , difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl; Ring B is selected from: optionally substituted C3-C16 carbocyclyl or optionally substituted 4- 16-membered heterocyclyl; wherein the substitution means substitution by one or more R; R is as defined above; Indicates the attachment position of the group.

In another preferred example, B ring is selected from: optionally substituted C3-C11 carbocyclyl or optionally substituted 4-11 membered heterocyclyl. More preferably, B ring is selected from: optionally substituted C5- C11 carbocyclyl or optionally substituted 5-11 membered heterocyclyl, more preferably, B ring is selected from: optionally substituted C5-C8 carbocyclyl or optionally substituted 5-8 membered heterocyclyl, more preferably Preferably, Ring B is an optionally substituted 6-membered heterocyclyl group, such as an optionally substituted tetrahydropyranyl group ( ), optionally substituted piperidinyl ( ); wherein the substitution means substitution by one or more R; R is as defined above.

In another preferred embodiment, Ring B is selected from: optionally substituted 4-6-membered monocyclic heterocyclyl or optionally substituted 7-11-membered spiroheterocyclyl or optionally substituted 7-11-membered bridged heterocyclyl group, wherein the substitution means substitution with one or more groups selected from the following group: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 ring Alkyl group, 4-6 membered heterocyclic group, C2-C6 alkenyl group, C2-C6 alkynyl group, (CH ₂ ) _1-2 C3-C6 cycloalkyl group, (CH ₂ ) _1-2 4-6 membered heterocyclic group base, C(O)C1-C6 alkyl, C(O)C1-C6 alkoxy, C(O)C3-C6 cycloalkyl, C(O)4-6 membered heterocyclyl, CONH(C1- C6 alkyl), CON(C1-C6 alkyl) ₂ , 5-8 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4- 6-membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, 5-8-membered heteroaryl can be optionally substituted by 1-3 groups selected from the following group: halogen, hydroxyl, amine group, Cyano, NH (C1-C6 alkyl), N (C1-C6 alkyl) ₂ , C1-C6 alkyl, C1-C6 alkoxy.

In another preferred example, R ² is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In another preferred embodiment, X ¹ , X ² , R ¹ , R ² , A ring, B ring 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: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In a second aspect, the present invention provides a compound represented by Formula II, or a salt, solvate, polymorph or deuterated product thereof, .

In a third aspect, the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition includes: (1) A therapeutically effective amount selected from the compound described in the first aspect, its pharmaceutically acceptable salts, apral isomers, non-apral isomers, tautomers, cis-trans isomers, and solvents one or more of compounds, polymorphs and deuterated compounds as active ingredients; and (2) Optionally, a pharmaceutically acceptable carrier.

The fourth aspect of the present invention provides a compound described in the first aspect, its pharmaceutically acceptable salts, apral isomers, non-arp isomers, tautomers, cis-trans isomers, and solvates , polymorphs or deuterated products or the use of the pharmaceutical composition described in the third aspect in the preparation of drugs for preventing or treating cancer mediated by RAS mutations.

In another preferred embodiment, 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 rhabdomyomas, synovium Sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer, especially 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.

Detailed implementation

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

Terminology

Unless otherwise defined, 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 "contains" or "includes" can be open, semi-closed and closed. In other words, the term also includes "consisting essentially of," or "consisting of."

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

Group definition

Definitions of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise stated, conventional methods within the skill in the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods, were used. Unless specific definitions are given, the terminology employed herein in connection with the description of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for using the kit can be used, or the reaction and purification can be carried out in accordance with methods known in the art or the instructions of the present invention. The above techniques and methods can generally be implemented in accordance with conventional methods well known in the art, as described in the various general and more specific documents cited and discussed in this specification. In this specification, groups and their substituents may be selected by those skilled in the art to provide stable moieties and compounds.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes substituents that are chemically equivalent when the structural formula is written from right to left. For example, -CH ₂ O- is equivalent to -OCH ₂ -.

The section headings used in this article are for the purpose of organizing the article 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, operating manuals, and theses, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by a simplified notation to represent 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 question.

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

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

"Hydroxy" refers to the -OH group.

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

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

"Nitro" refers to -NO ₂ .

"Cyano" refers to -CN.

"Amine" refers to _-NH2 .

"Substituted amine" refers to an amine substituted by one or two alkyl, alkylcarbonyl, arylalkyl, heteroarylalkyl groups as defined below, for example, monoalkylamino, dialkyl ylamine group, alkylamide group, arylalkylamino group, heteroarylalkylamine group.

"Carboxy" refers to -COOH.

In this application, the term "alkyl", as a group or part of another group (for example, in a group such as a halogen-substituted alkyl group), refers to a fully saturated straight or branched hydrocarbon chain radical, Consists only of carbon atoms and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is connected to the rest of the molecule by 1 or more single bonds, Examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third 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 from 1 to 6 carbon atoms.

In this application, the term "alkenyl", as a group or part of another group, means 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 vinyl, propenyl, alkenyl, etc. Propyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

As used herein, the term "alkynyl" as a group or part of another group means 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 a linear or branched hydrocarbon chain group connected to the rest of the molecule through one or more single bonds, such as but not limited to ethynyl, 1-propyne base, 1-butynyl, heptynyl, octynyl, etc.

In this application, as a group or part of another group, the term "carbocyclic (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 spiro ring system having from 3 to 16 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, more preferably from 3 to 6 carbon atoms, and It is a saturated or unsaturated ring (ie, cycloalkyl, cycloalkenyl, etc.) and can be connected to the rest of the molecule via 1 or more single bonds via any suitable carbon atom. Unless otherwise specifically stated in the specification, the carbon atoms in the carbocyclyl group may be optionally oxidized. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, indanyl, octahydro-4, 7-methylene-1H-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexenyl Hexadienyl, 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 Base-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-cyclopentadienyl, etc.

In this application, as a group or part of other groups, the term "cycloalkyl" refers to the above-mentioned fully saturated carbocyclic ring (group), preferably C3-C6 cycloalkyl. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc.

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

In this application, the term "heterocycle", as a group or part of another group, means from 2 to 14 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. It consists of stable 3- to 20-membered non-aromatic cyclic groups. Unless otherwise specified in this specification, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, a bridged ring system or a spirocyclic ring system; in its heterocyclic group The nitrogen, carbon, or sulfur atoms may be optionally oxidized; the nitrogen atoms may be optionally quaternized; and the heterocyclyl may be partially or fully saturated. A heterocyclyl group may be connected to the remainder of the molecule via a carbon atom or a heteroatom and through one or more single bonds. In heterocyclyl groups containing fused rings, one or more of the rings may be an aryl or heteroaryl group as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl 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. group, 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 heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2-azabicyclo[2.2.2]octyl , 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, dioxopentyl, tetrahydroisoquinyl Phinyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolyl, octahydroindolyl, octahydroindolyl Hydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimide, etc.

In this application, the term "aryl" as a group or part of another group means a conjugated hydrocarbon ring system group having from 6 to 18 carbon atoms, preferably from 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system and may also be fused to a carbocyclyl or heterocyclyl group as defined above, provided that the aryl group is via The atoms in the aromatic ring are connected to the rest of the molecule through 1 or more single bonds. 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-Benzoxazine-3(4H)-one-7-yl, etc.

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

In this application, the term "heteroaryl" as a group or part of another group means a ring having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 nitrogen atoms in the ring. , 5- to 16-membered conjugated ring system groups of heteroatoms of oxygen and sulfur. Unless otherwise specified in this specification, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and can also be condensed with a carbocyclic or heterocyclic group as defined above, provided that the heteroaryl group The aryl group is connected to the rest of the molecule via 1 or more single bonds via an atom on the heteroaromatic ring. A nitrogen, carbon, or sulfur atom in a heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. For the purposes of the present invention, a heteroaryl group 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 12-membered aromatic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. A stable 5- to 10-membered aromatic group composed of heteroatoms of 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, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolinyl, isoindolyl, indazolyl, isoindazolyl , purinyl, quinolyl, isoquinolinyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, terazolyl, terolinyl, phenanthridinyl, phenanthrolinyl, acridine base, phenazine base, isothiazolyl base, benzothiazolyl base, benzothienyl base, oxtriazolyl base, cinnolinyl base, quinazolinyl base, phenylthio base, indanyl base, o-phenanthroline base, Isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [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 wait.

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

In this application, the term "absent" means that both sides of the group defined above are directly connected by chemical bonds. For example, "B does not exist in A-B-C" means "A-C".

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

In this application, unless otherwise specified in the scope of the patent application, "optionally" and "optionally" mean that the subsequently described event or situation may or may not occur, and the description includes both the occurrence and the non-occurrence of the event or situation. What happened. For example, "optionally substituted aryl" means that the hydrogen on the aryl group is substituted or unsubstituted, and this description includes both substituted and unsubstituted aryl groups. For example, where a substituent is not explicitly listed, the terms "optionally substituted,""substituted," or "substituted by" as used herein mean that one or more of a given atom or group hydrogen atoms are independently substituted by one or more, such as 1, 2, 3 or 4 substituents, the substituents are independently selected from: deuterium (D), halogen, OH, oxo (=O), mercapto , cyano group, -CD ₃ , -C1-C6 alkyl (preferably -C1-3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl (preferably C3-C8 carbocyclyl), aromatic Base, 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 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 haloalkyl, 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 (where R ⁱ and R ⁱⁱ are 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 yuan hetero Aryl), C(O)C1-C6 alkylphenyl, C(O)C1-C6 haloalkyl, 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 haloalkyl, -S(O ) ₂ NH ₂ , 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 haloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl Each is optionally further substituted with one or more substituents selected from: halogen, -OH, oxo (=O), -NH ₂ , carbocyclyl, 3-8 membered heterocyclyl, C1-C4 alkyl Base, C1-C4 haloalkyl-, -OC1-C4 alkyl, -C1-C4 alkyl OH, -C1-C4 alkyl O-C1-C4 alkyl, OC1-C4 haloalkyl, cyano group, 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 haloalkyl ), -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 haloalkyl). When an atom or group is substituted by multiple substituents, the substituents may be the same or different. As used herein, the terms "moiety,""moiety,""chemicalmoiety,""group," and "chemical group" refer to a specific fragment or functional group in a molecule. Chemical moieties are generally thought of as chemical entities 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, (C1-C4 alkyl) ₂ amino groups represent amines substituted by 2 C1-C4 alkyl groups, for example, they can be , , , or wait.

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

In the present invention, C(O)OC1-C6 alkyl, that is , represents a C1-C6 alkyl substituted ester group, for example, it can be , , , , , .

In the present invention, N(C1-C6 alkyl) ₂ , or (C1-C6 alkyl) ₂ amine group, represents that the two hydrogens on NH ₂ are replaced by 2 C1-C6 alkyl groups, for example, it can be , , , or wait.

Intermediates

Intermediates refer to semi-finished products, which are products formed during the production of the required products. Typically, inventors can proceed to the production of products from intermediates as starting materials. Therefore, screening suitable intermediates can optimize the process route, thereby increasing the yield and saving time and cost.

In the present invention, the intermediate refers to the following compounds Among them, R ₁ , X ¹ and X ² are defined as above.

Preferably, the intermediate is .

Preparation method of intermediate

In the present invention, the preparation method of the intermediate includes the steps: (i) In a solvent (such as N,N -dimethylformamide (DMF)), compound a-1 reacts with a cyanating reagent (such as cuprous cyanide) to obtain compound a-2; (ii) In In a solvent (such as ethanol), compound a-2 reacts with hydrazine or its salt (such as hydrazine hydrochloride) to obtain compound a-3; (iii) In a solvent (such as acetonitrile), compound a-3 is reacted with nitrite (such as nitrite). Reaction in the presence of tert-butyl nitrate) and cuprous chloride gives compound a.

In each of the above steps, the reaction time and reaction temperature can be selected according to the specific reactants.

active ingredients

As used herein, "compound of the present invention" or "active ingredient" refers to the compound represented by Formula I, and also includes its pharmaceutically acceptable salts, parapolymers, non-parapolymers, and tautomers. , cis-trans isomers, solvates, polymorphs, deuterated compounds or combinations thereof.

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

When a compound of the present invention contains an olefinic double bond, the compounds of the present invention are intended to contain E- and Z-geometric isomers unless otherwise stated.

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

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to parachiral, non-parachiral, and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof. In the preparation of the compound of the present invention, racemates, non-parapalloisomers or parapalloisomers can be selected as raw materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.

Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from suitable optically pure precursors, or the 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 this application, the term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but are not limited to formate, acetate, 2,2-dichloroacetate, trichloroacetate, etc. Fluoroacetate, propionate, caproate, caprylate, caprate, undecenoate, glycolate, gluconate, lactate, sebacate, adipate, glutarate acid salt, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, Laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, 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 salts" refer to salts formed with inorganic or organic bases 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, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: first, second and third 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-diethylamine Ethylene glycol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine , piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

Those skilled in the art will also understand 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, thiol and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl base), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amine, amidino and guanidino groups include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include -C(O)-R'' (where R'' is an alkyl, aryl or aralkyl group), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.

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 detailed in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymer resin.

Pharmaceutical compositions and methods of administration

As used herein, "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. The medium includes a pharmaceutically acceptable carrier. The purpose of pharmaceutical compositions is to promote the administration of drugs to organisms and facilitate the absorption of active ingredients to 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 original administration mode and dosage of the drug can remain unchanged, while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or several other drugs, a pharmaceutical composition containing one or several known drugs and the compound of formula I can be preferably used. Drug combinations also include administration of a compound of formula I with one or more other known drugs for overlapping periods of time. When a 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 that of the compound alone.

Drugs or active ingredients that can be combined with the compound described in 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, ibrutinumab, etc.), KRAS inhibitors ( Such as AMG510, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, occalatinib), EGFR inhibitors (such as afatinib, gefitinib , erlotinib, lapatinib, dacomitinib, icotinib, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, carbo tinib, sunitinib, etc.), PI3K inhibitors (such as Dactolisib, Taselisib, etc.), BTK inhibitors (such as ibrutinib, tirabrutinib, akabrutinib, zanubrutinib, Vicat Brutinib, 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 Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068), or combinations thereof.

As used herein, the term "pharmaceutically acceptable" refers to substances (such as carriers or diluents) that do not affect the biological activity or properties of the compounds of the invention and are relatively non-toxic, i.e., the substances can be administered to an individual without causing adverse biological reactions. or interact in an undesirable manner with any component contained in the composition.

In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory authorities as acceptable for human or livestock use , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.

The administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical 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 compatibilizers, for example, starch , lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, for example, Glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarding solvents, such as paraffin; (f) absorption acceleration agents, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, stearic acid Calcium, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents 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 used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated 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, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

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

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

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

The "tumors" mentioned in the present invention include, but are not limited to, lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyomas, synovial sarcoma, Endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, brain glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer and other diseases. As used herein, the terms "prophylactic," "prevention," and "preventing" include reducing the likelihood of the occurrence or progression of a disease or condition in a patient.

As used herein, the term "treatment" and other similar synonyms include the following meanings: (i) prevent the occurrence of a disease or condition in mammals, particularly where such mammals are susceptible to but have not been diagnosed as suffering from the disease or condition; (ii) To inhibit a disease or condition, that is, to arrest its progression; (iii) Alleviation of a disease or condition, i.e., resolution of the disease or condition; or (iv) Reduce the symptoms of the disease or condition.

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 that, when administered, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. quantity. The result may be a reduction 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 clinically significant relief of a condition. The effective amount appropriate in any individual case can be determined using techniques such as dose escalation trials.

As used herein, the terms "administering," "administering," "administering," and the like refer to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral route, transduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), local administration and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

As used herein, the terms "drug combination," "drug combination," "combination," "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, which Includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or a single dosage form. The term "variable combination" means that at least one compound described herein and at least one synergistic formulation are administered to a patient simultaneously, jointly, or sequentially at variable intervals as 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 contains a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount. The “safe and effective dose” refers to the amount of compound that 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/dose, more preferably, it contains 10-1000 mg of the compound of the present invention/dose. Preferably, the "dose" is a capsule or tablet.

Preparation methods of compounds

Methods for preparing compounds of formula I are described in the following schemes. In some cases, the order of steps in performing a reaction scheme can be changed to facilitate the reaction or avoid undesired side reaction products. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such combinations can be easily performed by those skilled in the art to which the present invention belongs.

Those skilled in the art will also understand 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, thiol and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl base), tetrahydropyranyl, benzyl, allyl, etc. Suitable protecting groups for amine, amidino and guanidine groups include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyl, allyl Oxycarbonyl, p-toluenesulfonyl, pivalyl, trifluoroacetyl, etc. Suitable thiol protecting groups include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.

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 detailed in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymer resin.

Generally, 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 to 48 hours.

Preferably, the compound of formula I can be prepared by the following method: (1) Compounds a and b-1 undergo Friedel-Crafts acylation in the presence of a Lewis acid to generate compound c. The Lewis acid is selected from: aluminum trichloride, tin dichloride, zinc chloride, trifluoride Boron, titanium tetrachloride, tetraisopropyl titanium oxide, etc.; or compound a reacts with compound b-2 in the presence of a strong base to form compound c, the strong base being selected from the following group: n-butyl lithium, diisopropyl lithium, etc. Lithium propylamide, third butyllithium, second butyllithium, lithium hexamethyldisilazide, or combinations thereof; (2) In the presence of a base, aromatic nucleophilic substitution of compound c and compound d The reaction generates compound I, and the reducing agent is selected from the following group: sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, n-butyllithium, lithium diisopropylamide, Lithium hexamethyldisilamide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, potassium carbonate, cesium carbonate, sodium carbonate, sodium phosphate, potassium phosphate, triethylamine, diamine Isopropylethylamine, 1.8-diazabicyclo[5.4.0]undecane-7-ene, or a combination thereof; or the Buchwald-Hartwig reaction of compound c and compound d to produce compound I; wherein, X ¹ , X ² , R ¹ , R ² , and A ring are as defined above.

The main advantages of the present invention: 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 and RAS protein; 3. The compound of the present application has good pharmacokinetics and efficacy.

The technical solution of the present invention will be 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.

Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

The experimental materials and reagents used in the following examples can be obtained from commercially available channels unless otherwise specified.

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 performed by Shimadzu LC-20AD, SIL-20A, CTO-20AC ,SPD-M20A, CBM-20A, LCMS-2020 mass spectrometer records; Gilson-281 model liquid chromatograph was used for preparative HPLC separation.

Example

Preparation of intermediates

1. Preparation of intermediate A

(1) To a solution of compound A-1 (10.0 g, 48.8 mmol) in N,N -dimethylformamide (100 mL), add copper cyanide (8.73 g, 97.5 mmol). The reaction solution was stirred at 100°C for 16 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (200 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 .

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) To a solution of compound A-2 (3.50 g, 23.2 mmol) in ethanol (20.0 mL), add hydrazine hydrochloride (2.92 g, 27.78 mmol). The reaction solution was stirred at 80°C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, water (50.0 mL) was added, and 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 .

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

(3) To a solution of compound A-3 (2.00 g, 12.1 mmol) in acetonitrile (30.0 mL), add tert-butyl nitrite (2.50 g, 24.2 mmol) and cuprous chloride (2.40 g, 24.2 mmol) . The reaction solution was stirred at 60°C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, water (30.0 mL) was added, 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 subjected to silica gel column chromatography (petroleum ether). /ethyl acetate = 10:1 to 1:1) to isolate compound A-4 .

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

(4) To a solution of compound A-4 (1.00 g, 5.42 mmol) in toluene (10.0 mL), add compound A-5 (1.52 g, 6.50 mmol), palladium acetate (122 mg, 542 μmol), cesium carbonate ( 3.53 g, 10.8 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (675 mg, 1.08 mmol). The reaction solution was stirred at 105°C for 2 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate). =1:0 to 10:1) to obtain compound A.

MS-ESI [M+H] ⁺ , calculated value 383, measured value 383.

2. Preparation of intermediate B

(1) To a solution of compound B-1 (2.00 g, 20.0 mmol) in bromoform (10.0 mL), a solution of potassium hydroxide (3.36 g, 59.9 mmol) in methanol (2.43 mL) was added dropwise at 0°C. The reaction solution was stirred at 25°C for 12 hours under nitrogen protection. Dichloromethane (30.0 mL) was added to the reaction solution, extracted with water (15.0 mL × 3), 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 B-2 .

¹ H NMR (400 MHz, DMSO- d 6) δ 3.69 (s, 3H), 3.57 (dd, J = 7.2, 3.2 Hz, 4H), 3.16 (s, 3H), 1.84-1.92 (m, 2H), 1.71-1.76 (m, 2H).

(2) To a solution of compound B-2 (5.00 g, 28.7 mmol) in tetrahydrofuran (30. mL), add lithium hydroxide monohydrate (3.61 g, 86.1 mmol) and water (10.0 mL). The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, water (10.0 mL) was added, the pH was adjusted to 5 with dilute hydrochloric acid, extracted with ethyl acetate (15.0 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound B. -3 .

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.74-3.78 (m, 4H), 3.33 (s, 3H), 2.11-2.14 (m, 1H), 2.05-2.11 (m, 1H), 1.86-1.89 (m , 1H), 1.82-1.86 (m, 1H).

(3) To a solution of compound B-3 (3.30 g, 20.6 mmol) in dichloromethane (30.0 mL), add diisopropylethylamine (7.99 g, 61.8 mmol), the hydrochloride of compound B-4 (2.01 g, 20.6 mmol) and propylphosphonic anhydride (26.2 g, 41.2 mmol, 50%). The reaction solution was stirred at 25°C for 1 hour under nitrogen protection. Dichloromethane (20.0 mL) was added to the reaction solution, washed with water (10.0 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 1 : 0 to 2 : 1) Compound B is isolated.

MS-ESI [M+H] ⁺ , calculated value 204, measured value 204.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.73-3.79 (m, 4H), 3.72 (s, 3H), 3.32 (s, 3H), 3.23 (s, 3H), 2.05-2.15 (m, 2H), 1.92-2.00 (m, 2H).

Example 1 Synthesis of Compound 1

(1) Add lithium diisopropylamide (2.0 mol/L, 523 μL) to a solution of intermediate A (100 mg, 262 μmol) in tetrahydrofuran (6.0 mL). The reaction solution was stirred at -78°C under nitrogen protection for 1 hour. A solution of dimethyl carbonate (70.7 mg, 785 μmol) in tetrahydrofuran (6.0 mL) was added. The reaction solution was stirred at 0°C under nitrogen protection for 2 hours, and then saturated dimethyl carbonate was added. Ammonium chloride aqueous solution (100 mL), add water (100 mL), extract with ethyl acetate (100 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to silica gel column chromatography. (Dichloromethane/methanol = 1:0 to 10:1) Compound 1-1 was isolated.

(2) To a solution of compound 1-1 (40.0 mg, 90.8 μmol) in tetrahydrofuran (30. mL), add lithium hydroxide monohydrate (6.53 mg, 273 μmol) and water (1.0 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, water (50.0 mL) was added, washed with ethyl acetate (50.0 mL × 2), the aqueous phase was adjusted to pH 5 with dilute hydrochloric acid, extracted with ethyl acetate (50.0 mL × 2), and the organic phases were combined. , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 1-2 .

MS-ESI [M+H] ⁺ , calculated value 427, measured value 427.

(3) To a solution of compound 1-2 (20.0 mg, 46.9 μmol) in dichloromethane (4.0 mL), add compound 1-3 (9.68 mg, 56.3 μmol), propyl phosphoric anhydride (74.6 mg, 117 μmol, 50 %) and diisopropylethylamine (30.3 mg, 235 μmol). The reaction solution was stirred at 25°C for 2 hours, then saturated aqueous sodium bicarbonate solution (30.0 mL) was added, 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 Compounds 1-4 .

MS-ESI [M+H] ⁺ , calculated value 508, measured value 508.

(4) Add palladium on carbon (0.05 g, 10%) to a solution of compound 1-4 (20.0 mg, 39.4 μmol) in tetrahydrofuran (3.0 mL). The reaction solution was stirred at 25°C for 10 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered and concentrated under reduced pressure. The crude product was analyzed by preparative high-performance liquid chromatography (Welch Xtimate C18, 150 mm × 30 mm 5 μm, A: water ( Ammonium bicarbonate); B: acetonitrile, 25%-60%: 12 minutes) to isolate compound 1 .

MS-ESI [M+H] ⁺ , calculated value 478, measured value 478.

¹ H NMR (400 MHz, MeOD) δ 8.38 (s, 1H), 6.97 (s, 2H), 6.77 (s, 1H), 5.31-5.45 (m, 2H), 4.08-4.34 (m, 4H), 3.81 (d, J = 13.6 Hz, 1H), 2.65 (s, 3H), 2.19 (t, J = 7.6 Hz, 1H), 1.96 (d, J = 9.2 Hz, 1H), 1.62 (d, J = 7.2 Hz , 3H).

Example 2 Synthesis of Compound 2

(1) Add lithium diisopropylamide (2.0 mol/L, 1.31 mL) to a solution of intermediate A (250 mg, 654 μmol) in tetrahydrofuran (3.0 mL). The reaction solution was stirred at -78°C for 1 hour under nitrogen protection. A solution of compound B (399 mg, 1.96 mmol) in tetrahydrofuran (3.0 mL) was added. The reaction solution was stirred at 0°C for 2 hours under nitrogen protection, and then saturated chlorine was added. Ammonium aqueous solution (100 mL), add water (100 mL), extract with ethyl acetate (100 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is analyzed by preparative high-performance liquid chromatography ( Welch Xtimate C18, 150 mm × 30 mm 5 μm, A: water (ammonium bicarbonate); B: acetonitrile, 40%-80%: 12 minutes) to isolate compound 2-1 .

MS-ESI [M+H] ⁺ , calculated value 525, measured value 525.

(2) Add palladium on carbon (0.10 g, 10%) to a solution of compound 2-1 (100 mg, 191 μmol) in tetrahydrofuran (3.0 mL). The reaction solution was stirred at 25°C for 10 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered and concentrated under reduced pressure. The crude product was analyzed by preparative high-performance liquid chromatography (Welch Xtimate C18, 150 mm × 30 mm 5 μm, A: water ( Ammonium bicarbonate); B: acetonitrile, 37%-74%: 12 minutes) to isolate compound 2 .

MS-ESI [M+H] ⁺ , calculated value 495, measured value 495.

¹ H NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 6.98 (d, J = 5.6 Hz, 2H), 6.78 (s, 1H), 5.41 (q, J = 6.8 Hz, 1H), 3.76- 3.92 (m, 4H), 3.32-3.34 (m, 3H),, 2.66 (s, 3H), 2.04-2.14 (m, 4H), 1.63 (d, J = 7.2 Hz, 3H).

Example 3 Synthesis of Compound 3

(1) To a solution of compound 3-1 (1.00 g, 6.21 mmol) in toluene (10.0 mL), add compound 3-2 (2.31 g, 12.4 mmol), tris[dibenzylideneacetone]dipalladium (569 mg , 621 μmol), sodium tert-butoxide (1.19 g, 12.4 mmol) and 2-dicyclohexylphosphonyl-2'-(N,N-dimethylamine)-biphenyl (244 mg, 621 μmol). The reaction solution was stirred at 100°C for 10 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol= 1:0 to 10:1) to obtain compound 3-3 . MS-ESI [M+H] ⁺ , calculated value 267, measured value 267.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20 (s, 1H), 6.97 (s, 1H), 3.83 (s, 3H), 3.51-3.60 (m, 4H), 2.83-2.92 (m, 4H), 1.474 (s, 9H).

(2) Trifluoroacetic acid (214 mg, 1.88 mmol) was added to a solution of compound 3-3 (100 mg, 375 μmol) in dichloromethane (2.0 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 3-4 . MS-ESI [M+H] ⁺ , calculated value 167, measured value 167.

(3) To a solution of compound 1-2 (100 mg, 234 μmol) in dichloromethane (4.0 mL), add compound 3-4 (46.8 mg, 281 μmol), propylphosphonic anhydride (373 mg, 586 μmol, 50 %) and diisopropylethylamine (151 mg, 1.17 μmol). The reaction solution was stirred at 25°C for 2 hours, then saturated aqueous sodium bicarbonate solution (30.0 mL) was added, 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 Compound 3-5 . MS-ESI [M+H] ⁺ , calculated value 575, measured value 575.

(4) Add palladium on carbon (0.1 g, 10%) to a solution of compound 3-5 (80.0 mg, 139 μmol) in tetrahydrofuran (2.0 mL). The reaction solution was stirred at 25°C for 10 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered and concentrated under reduced pressure. The crude product was analyzed by preparative high-performance liquid chromatography (Welch Xtimate C18, 150 mm × 30 mm 5 μm, A: water ( 0.225% formic acid); B: acetonitrile, 15%-45%: 10 minutes) to isolate the formate salt of compound 3 . MS-ESI [M+H] ⁺ , calculated value 545, measured value 545.

¹ H NMR (400 MHz, MeOD) δ 8.17 (s, 1H), 7.29 (d, J = 14.0 Hz, 3H), 6.75-7.00 (m, 2H), 3.87-3.97 (m, 5H), 3.81 (s , 3H), 3.03-3.08 (m, 4H), 2.65 (s, 3H), 1.54-1.72 (m, 3H).

Example 4 Synthesis of Compound 4

(1) Add lithium diisopropylamide (2.00 mol/L, 1.22 mL) to a solution of compound A-4 (150 mg, 812 mmol) in tetrahydrofuran (6.0 mL). The reaction solution was stirred at -78°C for 1 hour under nitrogen protection. Compound 4-1 (330 mg, 1.62 mmol) was added. The reaction solution was stirred at -78°C for 1 hour under nitrogen protection. Slowly warm to room temperature and continue stirring for 2 seconds. hours. Add saturated aqueous ammonium chloride solution (5.0 mL), add water (5.0 mL), extract with dichloromethane (5.0 mL × 2), combine the organic phases, wash with saturated brine (5.0 mL × 2), and dry 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 1:1) to obtain compound 4-1 .

MS-ESI [M +H] ⁺ , calculated value 327, measured value 327.

(2) The synthesis of compound 4-2 refers to patent WO2021127429. To a solution of compound 4-2 (160 mg, 35.0 μmol) in toluene (1.0 mL), add compound 4-2 (100 mg, 306 μmol), palladium acetate (7.91 mg, 35.2 μmol), diisopropylethyl amines (45.2 mg, 350), cesium carbonate (228 mg, 699 μmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (43.9 mg, 70.4 μmol). The reaction solution was stirred at 100°C for 4 hours under nitrogen protection. Water (30.0 mL) was added to the reaction solution, extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, washed with saturated brine (5.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was Compound 4-3 was isolated by silica gel column chromatography (dichloromethane/methanol = 1:0 to 20:1).

MS-ESI [M+H] ⁺ , calculated value 748, measured value 748.

(3) Add tetrabutylammonium fluoride (1.00 mol/L, 88.2 μL) to a solution of compound 4-3 (44.0 mg, 58.8 μmol) in tetrahydrofuran (1.0 mL) at 0°C. The reaction solution was stirred at 25°C for 1 hour. Water (5.0 mL) was added to the reaction solution, extracted with ethyl acetate (5.0 mL × 2), the organic phases were combined, washed with saturated brine (5.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was Compound 4 was isolated by preparative high-performance liquid chromatography (Phenomenex C18, 75 mm × 30 mm 3 μm, A: water (ammonium bicarbonate); B: acetonitrile, 31%-61%: 10 minutes). MS-ESI [M+H] ⁺ , calculated value 510, measured value 510.

¹ H NMR (400 MHz, MeOD) δ 9.00 (s, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 5.72 (q, J = 6.8 Hz, 1H), 4.03 (t, J = 14.0 Hz, 2H), 3.77-3.93 (m, 4H), 3.32 (br s, 3H), 2.64 (s, 3H) , 2.03-2.14 (m, 4H), 1.67 (d, J = 6.8 Hz, 3H).

Example 5 Synthesis of Compound 5

(1) To a solution of compound 5-1 (1.70 g, 6.56 mmol) in dichloromethane (5.0 mL), add diisopropylethylamine (4.24 g, 32.8 mmol), the hydrochloride of compound B-4 (959 mg, 9.83 mmol) and propylphosphonic anhydride (10.4 g, 16.4 mmol, 50%). The reaction solution was stirred at 25°C for 1 hour under nitrogen protection. The reaction solution was diluted with dichloromethane (30.0 mL), and washed with saturated sodium bicarbonate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 5-2 . MS-ESI [M-Boc+H] ⁺ , calculated value 203, measured value 203.

(2) Add lithium diisopropylamide (2.00 mol/L, 5.42 mL) to a solution of compound 5-2 (500 mg, 2.71 mmol) in tetrahydrofuran (6.0 mL). The reaction solution was stirred at -78°C for 1 hour under nitrogen protection. Intermediate A-4 (983 mg, 3.25 mmol) was added. The reaction solution was stirred at 0°C for 2 hours under nitrogen protection. A 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, and concentrate under reduced pressure. The crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate). = 1 : 0 to 10 : 1) Compound 5-3 is isolated. MS-ESI [M +H] ⁺ , calculated value 426, measured value 426.

(3) To the solution of compound 5-3 (150 mg, 352 μmol) in dioxane (2.0 mL), add compound A-5 (90.7 mg, 388 μmol) and palladium acetate (7.91 mg, 35.2 μmol). Cesium carbonate (229 mg, 704 μmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (43.9 mg, 70.4 μmol). The reaction solution was stirred at 80°C for 2 hours under nitrogen protection. Water (100.0 mL) was added to the reaction solution, 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 subjected to silica gel column chromatography (petroleum ether/ethyl acetate). =1: 0 to 10: 1) Compound 5-4 is isolated. MS-ESI [M+H] ⁺ , calculated value 624, measured value 624.

(4) Trifluoroacetic acid (128 mg, 1.12 mmol) was added to a solution of compound 5-4 (70.0 mg, 112 μmol) in dichloromethane (5.0 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 5-5 . MS-ESI [M+H] ⁺ , calculated value 524, measured value 524.

(5) To the solution of compound 5-5 (50.0 mg, 78.4 μmol) in ethanol (5.0 mL), paraformaldehyde (11.8 mg, 392 μmol), triethylamine (7.94mg, 78.4 μmol), and acetic acid (471 μg , 7.84 μmol) and sodium cyanoborohydride (7.39 mg, 118 μmol). The reaction solution was stirred at 25°C for 10 hours. Water (100.0 mL) was added to the reaction solution, 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 to obtain compound 5- 6 . MS-ESI [M+H] ⁺ , calculated value 538, measured value 538.

(6) Add iron (20.8 mg, 372 μmol) and ammonium chloride (1.99 mg, 37.2 μmol) to the solution of compound 5-6 (20.0 mg, 37.2 μmol) in ethanol (2.0mL). The reaction solution was stirred at 60°C for 1 hour. Water (100.0 mL) was added to the reaction solution, 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 prepared with high efficiency Compound 5 was isolated by liquid chromatography (C18-1, 150 mm × 30 mm 5 μm, A: water (ammonium bicarbonate); B: acetonitrile, 25%-65%: 25 minutes). MS-ESI [M+H] ⁺ , calculated value 508, measured value 508.

¹ H NMR (400 MHz, MeOD) δ 8.94 (s, 1H), 6.97 (br d, J = 6.4 Hz, 2H), 6.77 (s, 1H), 5.40 (q, J = 7.2 Hz, 1H), 3.28 (s, 3H), 2.76 (br d, J = 10.8 Hz, 2H), 2.65 (s, 3H), 2.46-2.56 (m, 2H), 2.34 (s, 3H), 2.15-2.24 (m, 2H) , 2.01-2.12 (m, 2H), 1.62 (d, J = 7.2 Hz, 3H).

Example 6 Synthesis of Compound 6

(1) The synthesis of compound 6-1 refers to patent WO2021127429. To a solution of compound 6-1 (100 mg, 227 μmol) in dioxane (2.0 mL), compound 5-3 (107 mg, 250 μmol), palladium acetate (5.11 mg, 22.6 μmol), cesium carbonate ( 148 mg, 455 μmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (28.3 mg, 45.5 μmol). The reaction solution was stirred at 80°C for 1 hour under nitrogen protection. Water (10.0 mL) was added to the reaction solution, extracted with ethyl acetate (5.0 mL × 2), the organic phases were combined, washed with saturated brine (5.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was Compound 6-2 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 10:1).

MS-ESI [M+H] ⁺ , calculated value 829, measured value 829.

(2) Trifluoroacetic acid (138 mg, 1.21 mmol) was added to a solution of compound 6-2 (100 mg, 121 μmol) in dichloromethane (3.0 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 6-3 .

MS-ESI [M+H] ⁺ , calculated value 729, measured value 729.

(3) To the solution of trifluoroacetate (60.0 mg, 82.3 μmol) of compound 6-3 in ethanol (2.0 mL), paraformaldehyde (2.4 mg, 412 μmol) and triethylamine (8.33 mg, 82.3 μmol) were added , acetic acid (4.94 mg, 82.3 μmol) and sodium cyanoborohydride (5.17 mg, 82.3 μmol). The reaction solution was stirred at 25°C for 1 hour. Water (100.0 mL) was added to the reaction solution, 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 compound 6- 4 .

MS-ESI [M+H] ⁺ , calculated value 743, measured value 743.

(4) Add tetrabutylammonium fluoride (1.00 mol/L, 101 μL) to a solution of compound 6-4 (50.0 mg, 67.3 μmol) in tetrahydrofuran (1.0 mL) at 0°C. The reaction solution was stirred at 25°C for 1 hour. Water (5.0 mL) was added to the reaction solution, extracted with ethyl acetate (5.0 mL × 2), the organic phases were combined, washed with saturated brine (5.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was Compound 6 was isolated by preparative high-performance liquid chromatography (Welch Xtimate C18, 150 mm × 25 mm 5 μm, A: water (0.225% formic acid); B: acetonitrile, 5%-35%: 25 minutes).

MS-ESI [M+H] ⁺ , calculated value 505, measured value 505.

¹ H NMR (400 MHz, MeOD) δ 8.98 (s, 1H), 7.64 (s, 1H), 7.57 (br d, J = 6.8 Hz, 1H), 7.33-7.44 (m, 2H), 5.53 (q, J = 7.2 Hz, 1H), 3.86 (t, J = 13.6 Hz, 2H), 3.17-3.23 (m, 2H), 2.99-3.09 (m, 2H), 2.72 (s, 3H), 2.66 (s, 3H ), 2.37 (br d, J = 14.0 Hz, 2H), 2.15-2.25 (m, 2H), 1.67 (d, J = 7.2 Hz, 3H).

Example 7 Synthesis of Compound 7

(1) The synthesis of compound 7-1 refers to patent WO2021127429. To a solution of compound 7-1 (35.0 mg, 141 μmol) in dioxane (2.0 mL), compound 5-3 (50.2 mg, 118 μmol), palladium acetate (2.65 mg, 11.8 μmol), cesium carbonate ( 76.9 mg, 236 μmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (14.7 mg, 23.6 μmol). The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, extracted with ethyl acetate (5.0 mL × 2), the organic phases were combined, washed with saturated brine (5.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was Compound 7-2 was isolated by silica gel column chromatography (dichloromethane/methanol = 1:0 to 20:1).

MS-ESI [M+H] ⁺ , calculated value 637, measured value 637.

(2) Trifluoroacetic acid (154 mg, 1.35 mmol) was added to a solution of compound 7-2 (20.0 mg, 31.4 μmol) in dichloromethane (1.0 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 7-3 .

MS-ESI [M+H] ⁺ , calculated value 537, measured value 537.

(3) To the solution of trifluoroacetate (30.0 mg, 55.9 μmol) of compound 7-3 in ethanol (0.5 mL), paraformaldehyde (5.04 mg, 168 μmol) and triethylamine (8.33 mg, 82.3 μmol) were added , acetic acid (4.94 mg, 82.3 μmol) and sodium cyanoborohydride (3.51 mg, 55.9 μmol). The reaction solution was concentrated under reduced pressure, and the crude product was separated by preparative high-performance liquid chromatography (Welch Xtimate C18, 100 mm × 30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 15%-35%: 10 minutes) Compound 7 was obtained. MS-ESI [M+H] ⁺ , calculated value 551, measured value 551.

¹ H NMR (400 MHz, MeOD) δ 9.02 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 6.8 Hz, 1H), 7.35 (t, J = 6.8 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 5.73 (q, J = 6.8 Hz, 1H), 3.35 (d, J = 11.2 Hz, 6H), 3.00-3.19 (m, 2H), 2.69-2.83 (m, 2H), 2.59-2.67 (m, 3H), 2.32-2.50 (m, 2H), 2.13-2.28 (m, 2H), 1.62-1.71 (m, 3H), 1.29 (br s, 6H).

Example 8 Synthesis of Compound 8

(1) To a solution of compound 8-1 (1 g, 6.94 mmol) in dichloromethane (30.0 mL), add diisopropylethylamine (4.48 g, 34.7 mmol), the hydrochloride of compound 8-2 (1.01 g, 10.4 mmol) and propylphosphonic anhydride (6.62 g, 10.4 mmol, 50%). The reaction solution was stirred at 25°C for 2 hours under nitrogen protection. Dichloromethane (20.0 mL) was added to the reaction solution, washed with water (10.0 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (dichloromethane/methanol = 1: 0 to 50: 1) Compound 8-3 is isolated. MS-ESI [M+H] ⁺ , calculated value 188, measured value 188.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.73-3.81 (m, 2H), 3.66 (s, 3H), 3.58-3.66 (m, 2H), 3.21 (s, 3H), 2.14-2.23 (m, 2H ), 1.52-1.61 (m, 2H), 1.29 (s, 3H).

(2) Add lithium diisopropylamide (2.0 mol/L, 0.26 mL) to the solution of intermediate A (50 mg, 130 μmol) in tetrahydrofuran (1.0 mL). The reaction solution was stirred at -78°C for 1 hour under nitrogen protection. A solution of compound 8-3 (73.4 mg, 392 mmol) in tetrahydrofuran (1.0 mL) was added. The reaction solution was stirred at -78°C to 0°C for 2 hours under nitrogen protection. , then add saturated aqueous ammonium chloride solution (10.0 mL), add water (10.0 mL), extract with ethyl acetate (10.0 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is prepared High performance liquid chromatography (Welch Xtimate C18, 100 mm × 30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 30%-60%: 30 minutes) separated the formate salt of compound 8-4 . MS-ESI [M+H] ⁺ , calculated value 509, measured value 509.

(2) Add iron powder (5.49 mg, 98.3 μmol) and hydrochloric acid (1 mol/L, 100 μL) to a solution of compound 8-4 formate (5 mg, 9.83 μmol) in ethanol (2.0 mL). The reaction solution was stirred at 65°C for 1 hour. The reaction solution was filtered and concentrated under reduced pressure. The crude product was subjected to preparative high-performance liquid chromatography (Welch Xtimate C18, 100 mm × 30 mm 10 μm, A: water (0.225% formic acid); B: Acetonitrile, 20%-50%: 25 minutes), the formate salt of compound 8 was isolated. MS-ESI [M+H] ⁺ , calculated value 479, measured value 479.

¹ H NMR (400 MHz, MeOD) δ 8.76 (s, 1H), 6.97 (s, 2H), 6.78 (s, 1H), 5.39 (q, J = 6.8 Hz, 1H), 3.77-3.87 (m, 2H ), 3.61 (ddd, J = 11.6, 8.8, 3.2 Hz, 2H), 2.65 (s, 3H), 2.31-2.41 (m, 2H), 1.78-1.88 (m, 2H), 1.63 (d, J = 7.2 Hz, 3H), 1.61 (s, 3H).

Example 9 Synthesis of Compound 9

(1) Add lithium diisopropylamide (2.00 mol/L, 0.61 mL) to a solution of compound A-4 (150 mg, 812 μmol) in tetrahydrofuran (6.0 mL). The reaction solution was stirred at -78°C for 1 hour under nitrogen protection. Compound 8-1 (203 mg, 894 μmol) was added. The reaction solution was stirred at 0°C for 2 hours under nitrogen protection. A saturated aqueous ammonium chloride solution (100 mL) was added. Add water (100 mL), extract with ethyl acetate (100 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 1 : 0 to 3 : 1) Compound 9-2 is isolated. MS-ESI [M +H] ⁺ , calculated value 412, measured value 412.

(2) To a solution of compound 9-2 (300 mg, 728 μmol) in dichloroethane (3.0 mL), manganese dioxide (633 mg, 7.28 mmol) was added. The reaction solution was stirred at 25°C for 10 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 9-3 . MS-ESI [M+H] ⁺ , calculated value 410, measured value 410.

(3) To the solution of compound 9-3 (50.0 mg, 122 μmol) in dioxane (2.00 mL), add compound A-5 (31.4 mg, 134 μmol) and palladium acetate (2.74 mg, 12.2 μmol). Cesium carbonate (79.5 mg, 244 μmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (15.19 mg, 24.4 μmol). The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, 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 subjected to silica gel column chromatography (petroleum ether/ethyl acetate). Esters = 1 : 0 to 10 : 1) Compound 9-4 was isolated. MS-ESI [M+H] ⁺ , calculated value 608, measured value 608.

(4) Trifluoroacetic acid (93.8 mg, 823 mmol) was added to a solution of compound 9-4 (50.0 mg, 82.3 μmol) in dichloromethane (5.0 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 9-5 . MS-ESI [M+H] ⁺ , calculated value 508, measured value 508.

(5) To the solution of compound 9-5 (40.0 mg, 64.4 μmol) in ethanol (5.0 mL), paraformaldehyde (9.66 mg, 322 μmol), triethylamine (6.51 mg, 64.4 μmol), and acetic acid (387 μg , 6.44 μmol) and sodium cyanoborohydride (6.07 mg, 96.5 μmol). The reaction solution was stirred at 25°C for 10 hours. Water (100.0 mL) was added to the reaction solution, 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 to obtain compound 9- 6 . MS-ESI [M+H] ⁺ , calculated value 524, measured value 524.

(6) Add iron (20.8 mg, 372 μmol) and ammonium chloride (1.99 mg, 37.2 μmol) to the solution of compound 9-6 (19.4 mg, 37.2 μmol) in ethanol (2.0 mL). The reaction solution was stirred at 60°C for 1 hour. Water (100.0 mL) was added to the reaction solution, 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 prepared with high efficiency Liquid chromatography (C18-6, 100 mm × 30 mm 5 μm, A: water (0.225% formic acid); B: acetonitrile, 8%-38%: 15 minutes) separated the formate salt of compound 9 . MS-ESI [M+H] ⁺ , calculated value 492, measured value 492.

¹ H NMR (400 MHz, MeOD) δ 8.80 (s, 1H), 6.98 (s, 2H), 6.79 (s, 1H), 5.41 (q, J = 7.2 Hz, 1H), 3.20-3.28 (m, 2H ), 2.90-3.04 (m, 2H), 2.72 (s, 3H), 2.54-2.69 (m, 5H), 1.96-2.09 (m, 2H), 1.62-1.69 (m, 6H).

Example 10 Synthesis of Compound 10

(1) To a solution of compound 9-3 (51.8 mg, 126 μmol) in dioxane (2.00 mL), add compound 10-1 (28.7 mg, 155 μmol), methanesulfonic acid (2-dicyclohexylphosphine Palladium(II)(2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) (21.1 mg, 25.3 μmol) and cesium carbonate (103 mg, 316 μmol). The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, extracted with ethyl acetate (10.0 mL × 2), the organic phases were combined, washed with saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was Compound 10-2 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 2:3). MS-ESI [M+H] ⁺ , calculated value 563, measured value 563.

(2) To a solution of compound 10-2 (22.0 mg, 39.1 μmol) in dichloromethane (1.0 mL), trifluoroacetic acid (0.1 mL) was added. The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 10-3 . MS-ESI [M+H] ⁺ , calculated value 463, measured value 463.

(3) To the solution of trifluoroacetate (30.0 mg, 52.0 μmol) of compound 10-3 in ethanol (1.0 mL), paraformaldehyde (15.6 mg, 520 μmol) and triethylamine (6.51 mg, 64.4 μmol) were added. , acetic acid (387 μg, 6.44 μmol) and sodium cyanoborohydride (8.17 mg, 130 μmol). The reaction solution was stirred at 25°C for 10 hours. Water (30.0 mL) was added to the reaction solution, extracted with ethyl acetate (30.0 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was prepared with high efficiency Compound 10 was isolated by liquid chromatography (Welch Xtimate C18, 150 mm × 30 mm 5 μm, A: water (ammonium bicarbonate); B: acetonitrile, 50%-85%: 14 minutes). MS-ESI [M+H] ⁺ , calculated value 477, measured value 477. ¹ H NMR (400 MHz, MeOD) δ 8.79 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.42-7.51 (m, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.83-7.15 (m, 1H), 5.71 (q, J = 7.2 Hz, 1H), 2.67 (d, J = 6.4 Hz, 2H), 2.61-2.64 (m, 3H), 2.42-2.51 (m, 2H) , 2.31-2.41 (m, 2H), 2.28 (s, 3H), 1.82-1.91 (m, 2H), 1.69 (d, J = 7.2 Hz, 3H), 1.57 (s, 3H).

Example 11 , 13 , 18 synthetic compounds 11 , 13 and 18

Compounds 11 , 13 and 18 were synthesized using the synthesis method in Example 10 and using corresponding raw materials. compound MS-ESI [M+H] ^{+ 1} H NMR (400 MHz, MeOD) Calculated value 535, measured value 535 8.75-8.91 (m, 1H), 8.41-8.48 (m, 1H), 7.50-7.58 (m, 1H), 7.32-7.39 (m, 1H), 7.14 (t, J =8.0 Hz, 1H), 5.68- 5.77 (m, 1H), 2.88-3.01 (m, 2H), 2.71 (br d, J = 6.8 Hz, 2H), 2.64 (s, 3H), 1.96-2.07 (m, 2H), 1.68-1.70 (m , 5H), 1.27-1.34 (m, 9H) Calculated value 491, measured value 491 8.83 (s, 1H), 7.72 ( J = 8.0 Hz, 1H), 7.52 ( J = 7.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 5.74 (q, J = 6.8 Hz, 1H) , 3.27-3.29 (m, 2H), 3.02 (s, 2H), 2.77 (s, 3H), 2.63 (s, 3H), 2.55-2.63 (m, 5H), 2.04 (s, 2H), 1.66 (s , 3H), 1.59-1.65 (m, 3H) Calculated value 448, measured value 448 8.76 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 5.62 (q, J = 6.8 Hz, 1H), 2.74 (s, 3H), 2.67 (br d, J = 6.0 Hz, 2H), 2.62 (s, 3H), 2.42-2.48 (m, 2H), 2.32-2.40 (m, 2H), 2.29 (s, 3H), 1.86 (br t, J = 10.0 Hz, 2H), 1.62 (d, J = 7.2 Hz, 3H), 1.57 (s, 3H)

Example 12 Synthesis of Compound 12

(1) Add lithium diisopropylamide (2.00 mol/L, 1.84 mL) to a solution of compound A-4 (400 mg, 2.17 mmol) in tetrahydrofuran (8.0 mL). The reaction solution was stirred at -78°C for 1 hour under nitrogen protection. Compound 12-1 (305 mg, 2.38 mmol) was added. The reaction solution was stirred at -65°C for 2 hours under nitrogen protection. A saturated aqueous ammonium chloride solution (30.0 mL ), add water (30.0 mL), extract with ethyl acetate (30.0 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate). = 1 : 0 to 1 : 1) Compound 12-2 was isolated. MS-ESI [M +H] ⁺ , calculated value 313, measured value 313.

(2) To a solution of compound 12-2 (170 mg, 543 μmol) in dichloroethane (2.0 mL), manganese dioxide (1.89 g, 21.7 mmol) was added. The reaction solution was stirred at 70°C for 48 hours. The reaction solution was filtered and concentrated under reduced pressure. The crude product was separated by preparative thin layer chromatography (petroleum ether/ethyl acetate = 2:1) to obtain compound 12-3 . MS-ESI [M+H] ⁺ , calculated value 311, measured value 311.

(3) To a solution of compound 12-3 (13.5 mg, 16.1 μmol) in dioxane (2.00 mL), add compound 12-4 (18.3 mg, 96.5 μmol), methanesulfonic acid (2-dicyclohexylphosphine Palladium(II)(2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) (13.5 mg, 16.1 μmol), cesium carbonate (52.4 mg, 161 μmol). The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. Water (10.0 mL) was added to the reaction solution, 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 analyzed by preparative high-performance liquid chromatography (Xtimate C18, 100 mm × 30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 38%-58%: 10 minutes) Compound 12 was isolated. MS-ESI [M+H] ⁺ , calculated value 464, measured value 464. ¹ H NMR (400 MHz, MeOD) δ 8.80 (s, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 6.8 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.83-7.14 (m, 1H), 5.68 (q, J = 6.8 Hz, 1H), 3.82 (ddd, J = 11.6, 6.0, 3.6 Hz, 2H), 3.61 (ddd, J = 11.2, 8.4, 2.8 Hz, 2H), 2.63 (s, 3H), 2.37 (dd, J = 13.9, 1.3 Hz, 2H), 1.79-1.88 (m, 2H), 1.69 (d, J = 6.8 Hz, 3H), 1.62 ( s, 3H).

Example 14 , 15 , 17 synthetic compounds 14 , 15 and 17

Compounds 14 , 15 and 17 were synthesized using the synthesis method in Example 12 and using corresponding raw materials. compound MS-ESI [M+H] ^{+ 1} H NMR (400 MHz, MeOD) Calculated value 478, measured value 478 8.89 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 5.63 (q, J = 6.8 Hz, 1H), 3.79-3.90 (m, 2H), 3.62 (ddd, J = 11.6, 8.8, 2.8 Hz, 2H), 2.71 (s, 3H), 2.61 (s, 3H), 2.31-2.43 (m, 2H), 1.79-1.90 (m, 2H), 1.67 (d, J = 6.8 Hz, 3H), 1.63 (s, 3H) Calculated value 522, measured value 522 8.78 (s, 1H), 7.53 (t, J = 6.4 Hz, 1H), 7.31-7.39 (m, 1H), 7.13 (t, J = 7.6 Hz, 1H), 5.71 (q, J = 6.8 Hz, 1H ), 3.79-3.87 (m, 2H), 3.62 (ddd, J = 11.6, 8.4, 2.8 Hz, 2H), 2.63 (s, 3H), 2.37 (dd, J = 13.6, 1.2 Hz, 2H), 1.79- 1.88 (m, 2H), 1.67 (d, J = 7.2 Hz, 3H), 1.62 (s, 3H), 1.29 (d, J = 3.6 Hz, 6H) Calculated value 435, measured value 435 8.75 (s, 1H), 7.68-7.77 (m, 1H), 7.50-7.56 (m, 1H), 7.27 (t, J = 8.0 Hz, 1H), 5.31-5.38 (m, 1H), 3.78-3.88 ( m, 2H), 3.56-3.67 (m, 2H), 2.74 (s, 3H), 2.62 (s, 3H), 1.99-2.08 (m, 2H), 1.79-1.87 (m, 2H), 1.62 (t, J = 3.6 Hz, 6H)

Example 16 synthetic compounds 16

Compound 16 was synthesized using the synthesis method in Example 8 and using corresponding raw materials. compound MS-ESI [M+H] ^{+ 1} H NMR (400 MHz, MeOD) Calculated value 493, measured value 493 8.77 (s, 1H), 6.97 (s, 2H), 6.78 (s, 1H), 5.37 (q, J = 7.2 Hz, 1H), 3.83 (dt, J = 12.0, 4.0 Hz, 2H), 3.46-3.57 (m, 3H), 2.65 (s, 3H), 2.43 (br dd, J = 14.0, 2.0 Hz, 2H), 2.14 (q, J = 7.6 Hz, 2H), 1.75-1.85 (m, 2H), 1.63 (d, J = 7.2 Hz, 3H), 0.81 (t, J = 7.6 Hz, 3H)

Example 19 Synthesis of Compound 19

(1) To a solution of compound 9-3 (600 mg, 1.46 mmol) in dimethylstyrene (10.0 mL), add compound 13-1 (356 mg, 1.76 mmol), diisopropylethylamine (945 mg, 7.32 mmol) and potassium fluoride (850 mg, 14.64 mmol). The reaction solution was stirred at 100°C for 12 hours under nitrogen protection. Water (30.0 mL) was added to the reaction solution, extracted with ethyl acetate (30.0 mL × 2), the organic phases were combined, washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was Compound 19-1 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 1:1). MS-ESI [M+H] ⁺ , calculated value 577, measured value 577.

(2) To a solution of compound 19-1 (700 mg, 1.21 mmol) in dichloromethane (10.0 mL), trifluoroacetic acid (2.0 mL) was added. The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, and sodium bicarbonate aqueous solution was added to adjust the pH value to 8-9. Water (30.0 mL) was added and extracted with dichloromethane (30.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and reduced. Concentrate under pressure to obtain compound 19-2 . MS-ESI [M+H] ⁺ , calculated value 477, measured value 477.

(3) To a solution of compound 19-2 (18.2 mg, 202 μmol) in dichloromethane (3.0 mL), add diisopropylethylamine (65.1 mg, 503 μmol), compound 19-3 (18.2 mg, 202 μmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorourea phosphate (95.7 mg, 252 μmol). The reaction solution was stirred at 25°C for 1 hour under nitrogen protection. The reaction solution was diluted with dichloromethane (30.0 mL), and washed with water (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was analyzed by preparative high performance liquid chromatography (Xtimate C18, 150 mm × 30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 14%- 54%: 25 minutes) The formate salt of compound 19 was isolated. MS-ESI [M+H] ⁺ , calculated value 549, measured value 549. ¹ H NMR (400 MHz, MeOD) δ 8.80 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 4.8 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 5.73 (q, J = 3.2 Hz, J = 10.0 Hz, 1H), 4.10-4.22 (m, 2H), 3.92-4.02 (m, 1H), 3.62-3.72 (m, 1H), 3.39 (s , 3H), 3.32-3.38 (m, 1H), 3.21-3.28 (m, 1H), 2.59-2.65 (m, 6H), 2.37-2.47 (m, 2H), 1.74-1.85 (m, 2H), 1.58 -1.68 (m, 6H).

Example 20-29 synthetic compounds 20-29

Compounds 20-29 were synthesized using the synthesis method in Example 19 and corresponding raw materials. compound MS-ESI [M+H] ^{+ 1} H NMR (400 MHz, MeOD) Calculated value 562, measured value 562 8.79 (s, 1H), 7.71 (d, J = 8.4 Hz 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 5.70-5.76 (m, 1H) , 3.94-4.03 (m, 1H), 3.68-3.76 (m, 1H), 3.48-3.61 (m, 2H), 3.35-3.46 (m, 2H), 2.60-2.64 (m, 6H), 2.50 (s, 6H), 2.32-2.44 (m, 2H), 1.76-1.87 (m, 2H), 1.61-1.66 (m, 6H) Calculated value 549, measured value 549 8.82 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 5.64-5.78 (m, 1H ), 4.52-4.69 (m, 2H), 3.88-4.08 (m, 1H), 3.39-3.82 (m, 2H), 2.60-2.67 (m, 6H), 2.37-2.50 (m, 2H), 1.74-1.88 (m, 2H),1.59-167 (m, 6H) 1.25-1.38 (m, 3H) Calculated value 519, measured value 519 8.80 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 5.62-5.79. (m, 1H), 3.88-4.00 (m, 1H), 3.64-3.79 (m, 1H), 3.36-3.47 (m, 1H), 3.13-3.27 (m, 1H), 2.54-2.66(m, 6H), 2.32- 2.45 (m, 2H), 2.10 (s, 3H), 1.72-1.84 (m, 2H), 1.56-1.68 (m, 6H) Calculated value 545, measured value 545 8.82 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 5.71 (q, J = 4.8 Hz, J = 6.2 Hz, 1H), 3.94 - 4.00 (m, 2H), 3.56 - 3.68 (m, 1H), 3.22 - 3.29 (m, 1H), 2.64 (s, 3H), 2.61 (s, 3H) , 2.37 - 2.50 (m, 2H), 1.93 - 2.00 (m, 1H), 1.75 - 1.83 (m, 2H), 1.61 - 1.67 (m, 6H), 0.84 - 0.90 (m, 2H), 0.77 - 0.84 ( m, 2H) Calculated value 561, measured value 561 8.82 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 5.71 (q, J = 4.8 Hz, J = 6.2 Hz, 1H), 4.82 - 4.84 (m, 2H), 4.77 - 4.82 (m, 2H), 4.13 - 4.26 (m, 1H), 3.96 - 4.06 (m, 1H), 3.35 - 3.42 ( m, 1H), 3.19 - 3.24 (m, 2H), 2.64 (s, 3H), 2.61 (s, 3H), 2.33-2.46 (m, 2H), 1.78 - 1.88 (m, 1H), 1.68 - 1.75 ( m, 1H), 1.64 (d, J = 6.8 Hz, 3H), 1.62 (s, 3H) Calculated value 575, measured value 575 8.81 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 5.70 - 5.74 (m, 1H ), 3.92 - 4.03 (m, 2H), 3.77 - 3.91 (m, 4H), 3.42 - 3.54 (m, 2H), 3.19 - 3.27 (m, 1H), 2.59 - 2.65 (m, 6H), 2.40 - 2.45 (m, 2H), 2.04 - 2.18 (m, 2H), 1.74 - 1.87 (m, 2H), 1.61 - 1.65 (m, 6H) Calculated value 589, measured value 589 8.82 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 5.68 - 5.73 (m, 1H ), 3.93 - 3.98 (m, 3H), 3.81 - 3.84 (m, 1H), 3.45 - 3.54 (m, 3H), 3.19 - 3.26 (m, 1H), 2.92 - 2.96 (m, 1H), 2.60 - 2.66 (m, 6H), 2.40 - 2.43 (m, 2H), 1.72 - 1.87 (m, 4H), 1.62 - 1.66 (m, 6H), 1.56 - 1.59 (m, 2H) Calculated value 574, measured value 574 9.04 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.33 - 7.40 (m, 1H), 5.51 (q, J = 4.8 Hz, J = 6.8 Hz, 1H), 4.78 - 4.85 (m, 2H), 4.52 (d, J = 8.8 Hz, 2H), 4.12 - 4.23 (m, 2H), 3.96 - 4.09 (m, 2H), 3.51 - 3.56 ( m, 1H), 2.91 - 2.96 (m, 3H), 2.79 (s, 3H), 2.60 (s, 3H), 2.39 - 2.45 (m, 2H), 1.77 - 1.94 (m, 2H), 1.72 (d, J = 6.4 Hz, 3H), 1.65 (s, 3H) Calculated value 561, measured value 561 8.87 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 6.8, 1H), 5.64 - 5.69(m, 1H) , 7.47 (t, J = 7.2, 1H), 4.52 - 4.55(m, 1H), 4.49 - 4.52(m, 1H), 3.88 - 4.15(m, 1H), 3.48 - 3.56(m,1H), 3.34 - 3.43(m, 1H), 3.24 - 3.29(m, 1H), 2.84 - 3.01(m, 2H), 2.67(s, 3H), 2.61(s, 3H), 2.36 - 2.39(m, 2H), 1.62 - 1.67 (m, 2H), 1.60 - 1.63(m, 6H) Calculated value 570, measured value 570 8.86 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 7.2 Hz, 1H), 5.66 - 5.70 (m, 1H ), 3.94 - 4.08 (m, 2H), 2.60 - 2.66 (m, 6H), 2.44 - 2.52 (m, 2H), 1.85 - 1.91 (m, 2H), 1.61 - 1.68 (m, 6H), 1.57 (s , 4H), 1.29 (t, J = 6.8 Hz, 2H)

Example 30 Synthesis of Compound 30

Compound 19-2 was separated by preparative high performance liquid chromatography (Xtimate C18, 150 mm × 30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 16%-54%: 25 minutes) to obtain compound 30 . Formate. MS-ESI [M+H] ⁺ , calculated value 477, measured value 477. ¹ H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 5.54 (q, J = 7.2 Hz, 1H), 3.35 - 3.40 (m, 2H), 3.09 - 3.15 (m, 2H), 2.76 (s, 3H), 2.60 (s, 3H), 1.72 (s , 6H), 1.22 - 1.33 (m, 4H).

Example 31 Synthesis of Compound 31

To a solution of compound 19-2 (70.0 mg, 146 μmol) in dichloromethane (5.0 mL), triethylamine (14.8 mg, 146 μmol) and compound 31-1 (23.6 mg, 220 μmol) were added at 0°C. . The reaction solution was stirred at 0°C for 1 hour under nitrogen protection. The reaction solution was diluted with water (30.0 mL), and extracted with dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was analyzed by preparative high performance liquid chromatography (Xtimate C18, 150 mm × 30 mm 5 μm, A: water (0.225% formic acid); B: acetonitrile, 18%- 58%: 25 minutes) The formate salt of compound 31 was isolated. MS-ESI [M+H] ⁺ , calculated value 548, measured value 548. ¹ H NMR (400 MHz, MeOD) δ 8.79 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 5.71 (q, J = 4.8 Hz, J = 6.8 Hz, 1H), 3.41 - 3.47 (m, 2H), 3.12 (t, J = 10.8 Hz, 2H), 2.84 (s, 6H), 2.57 - 2.64 (m, 6H), 2.34 - 2.41 (m, 2H), 1.81 (t, J = 10.4 Hz, 2H), 1.56 - 1.66 (m, 6H).

Example 32 synthetic compounds 32

Compound 32 was synthesized using the synthesis method in Example 31 and using corresponding raw materials . compound MS-ESI [M+H] ^{+ 1} H NMR (400 MHz, MeOD) Calculated value 590, measured value 590 8.79 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 5.72 (q, J = 6.8 Hz, 1H), 3.63 - 3.69 (m, 4H), 3.47 - 3.55 (m, 2H), 3.23 - 3.28 (m, 4H), 3.12 - 3.18 (m, 2H), 2.60 - 2.64 (m, 6H), 2.34 - 2.42 (m, 2H), 1.77 - 1.86 (m, 2H), 1.59 - 1.65 (m, 6H)

Example 33 Synthesis of Compound 33

To a solution of compound 19-2 (80.0 mg, 168 μmol) in N,N-dimethylformamide (1.0 mL) at 0°C, triethylamine (21.7 mg, 168 μmol) was added, compound 33-1 ( 77.9 mg, 336 μmol). The reaction solution was stirred at 25°C for 2 hours under nitrogen protection. The reaction solution was diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was analyzed by preparative high performance liquid chromatography (Xtimate C18, 150 mm × 30 mm 5 μm, A: water (0.225% formic acid); B: acetonitrile, 34%- 74%: 25 min) The formate salt of compound 33 was isolated. MS-ESI [M+H] ⁺ , calculated value 559, measured value 559. ¹ H NMR (400 MHz, MeOD) δ 8.82 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 5.61-5.74 (m, 1H), 3.05 (q, J = 5.2 Hz, J = 15.2 Hz, 2H), 2.81-2.88 (m, 2H), 2.66 (s, 3H), 2.61 (s, 3H ), 2.54-2.60 (m, 2H), 2.36-2.47 (m, 2H), 1.83-1.93 (m, 2H), 1.65 (d, J = 6.8 Hz, 3H), 1.57 (s, 3H).

Example 34 Synthesis of Compound 34

To a solution of compound 19-2 (70.0 mg, 146 μmol) in methanol (5.0 mL) was added compound 34-1 (15.8 mg, 220 μmol), acetic acid (1.76 mg, 29.3 μmol) and sodium cyanoborohydride (13.8 mg , 220 μmol). The reaction solution was stirred at 25°C for 1 hour. Water (15.0 mL) was added to the reaction solution, extracted with ethyl acetate (15.0 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was prepared with high efficiency. Compound 34 was isolated by liquid chromatography (Phenomenex C18, 75 mm × 30 mm 3 μm, A: water (ammonium bicarbonate); B: acetonitrile, 34%-74%: 25 minutes). MS-ESI [M+H] ⁺ , calculated value 533, measured value 533. ¹ H NMR (400 MHz, MeOD) δ 8.77 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 5.72 (q, J = 4.8 Hz, J = 6.8 Hz, 1H), 4.68 (t, J = 6.4 Hz, 2H), 4.56 - 4.60 (m, 2H), 3.42 - 3.46 (m, 1H), 3.42 - 3.52 (m, 1H), 2.62 (s, 6H), 2.52-2.56 (m, 2H), 2.43-2.48 (m, 2H), 2.16 - 2.24 (m, 2H), 1.87 (t, J=10.0 Hz, 2H), 1.62 (d, J=6.8 Hz, 3H), 1.57 (s, 3H).

Example 35 synthetic compounds 35

Compound 35 was synthesized using the synthesis method in Example 33 and using corresponding raw materials . compound MS-ESI [M+H] ^{+ 1} H NMR (400 MHz, MeOD) Calculated value 547, measured value 547 9.16 - 9.45 (m, 1H), 7.77 - 7.81 (m, 1H), 7.60 - 7.63 (m, 1H), 7.32 - 7.41 (m, 1H), 5.48 - 5.58 (m, 1H), 3.63 - 3.85 (m , 5H), 3.34 - 3.51 (m, 2H), 3.22 - 3.28 (m, 1H), 2.98 - 3.11 (m, 1H), 2.83 - 2.87 (m, 1H), 2.80 (s, 3H), 2.58 - 2.69 (m, 3H), 2.49 - 2.54 (m, 2H), 2.26 - 2.35 (m, 1H), 2.01 - 2.09 (m, 2H), 1.67 - 1.78 (m, 6H)

Example 36-38 synthetic compounds 36-38

Compounds 36-38 were synthesized using the synthesis method in Example 34 and corresponding raw materials. compound MS-ESI [M+H] ^{+ 1} H NMR (400 MHz, MeOD) Calculated value 505, measured value 505 8.82 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.22 - 7.31 (m, 1H), 5.68 - 5.74 (m, 1H), 3.22 - 3.28 (m, 2H), 2.83 - 3.06 (m, 4H), 2.56 - 2.67 (m, 8H), 1.97 - 2.09 (m, 2H), 1.57 - 1.67 (m, 6H), 1.28 (t, J = 7.2 Hz, 3H) Calculated value 533, measured value 533 8.84 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 5.70-5.77 (m, 1H ), 2.67-2.80 (m, 2H), 2.61-2.64 (m, 6H), 2.48-2.60 (m, 2H), 2.27-2.29 (m, 1H), 2.04-2.07 (m, 3H), 1.60-1.68 (m, 6H), 1.35-1.38 (m, 1H), 1.27-1.31 (m, 1H), 1.00-1.03 (m, 6H), 0.83-0.87 (m, 1H) Calculated value 519, measured value 519 8.78 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 5.70-5.76 (m, 1H ), 2.92 (s, 3H), 2.61-2.62 (m, 8H), 2.50-2.53 (m, 2H), 1.89-1.94 (m, 2H), 1.63 (d, J = 6.8 Hz, 3H), 1.59 ( s, 3H), 1.15 (d, J = 6.4 Hz, 6H)

Test example

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

1. Experimental principle: Use homogeneous time resolved fluorescence (HTRF) method 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 Company.

3. Experimental method: Preparation of 1-fold concentration buffer (prepared for immediate 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%.

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

4. Data processing:

Use Graphpad software to calculate the IC ₅₀ of the compound. The results are shown in Table 1.

Table 1 test compound IC ₅₀ (nM) Example 1 389.4 Example 2 62.78 Example 3 340.90 Example 4 125.70 Example 5 123.30 Example 6 340.40 Example 7 25.85 Example 8 50.89 Example 9 18.96 Example 10 81.84 Example 11 73.93 Example 12 152.9 Example 13 38.62 Example 14 572.60 Example 15 75.60 Example 16 105.80 Example 18 113.20 Example 19 102.60 Example 20 44.04 Example 21 36.21 Example 22 45.17 Example 23 224.1 Example 24 69.57 Example 25 89.75 Example 26 242.2 Example 27 92.95 Example 28 111.7 Example 29 239.8 Example 30 99.27 Example 31 387.8 Example 32 193.7 Example 33 221.5 Example 35 130.7 Example 36 44.88 Example 37 195.0 Example 38 31.59

It can be seen from the test data in Table 1 that the compound represented by Formula I of the present invention has a better inhibitory effect on the binding of SOS1 and KRAS (G12C) mutant protein, and has the potential to be used to prepare tumor drugs for the treatment of RAS mutations.

The applicant declares that the present invention illustrates the pyridazine compounds, pharmaceutical compositions containing them and their applications through the above examples, but the present invention is not limited to the above examples, which does not mean that the present invention must rely on the above implementations. Example can be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent replacement of raw materials of the product of the present invention, addition of auxiliary ingredients, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

without.

Claims (13)

A compound represented by formula I, its pharmaceutically acceptable salts, apral isomers, non-alpral isomers, tautomers, cis-trans isomers, solvates, polymorphs, and deuterated products or combination thereof, Wherein, X ^{1 is} selected from: CH, oxygen atom, sulfur atom, nitrogen atom or -NH; Preferably, X ¹ is CH; X ² is selected from: sulfur atom, oxygen atom, nitrogen atom, -NR ^x ; ^wherein , R ^x is selected from: H ^, optionally substituted C1-C3 alkyl; preferably, H, halogen, optionally substituted C1-C3 alkyl group, optionally substituted C3-C8 carbocyclic group, optionally substituted 4-8 membered heterocyclic group, cyano group, or ; Wherein, R ^1a and R ^1b are each independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl or optionally substituted 4-8 membered heterocyclyl; wherein , the substitution means 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 heterocycle base; wherein, the substitution means substitution by one or more R; Ring A is selected from: optionally substituted C6-C16 aryl, optionally substituted 5-16 membered heteroaryl, optionally substituted C3- C16 carbocyclic C6-C10 aryl, optionally substituted 4-16 membered heterocyclic C6-C10 aryl, optionally substituted C3-C16 carbocyclic 5-16 membered heteroaryl or optionally substituted 4 -16-membered heterocyclyl and 5-16-membered heteroaryl; wherein the substitution means substitution by one or more R; each R is independently selected from: H, halogen, cyano, amine, hydroxyl, oxo base( ), optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, N (optionally substituted C ₁ -C ₆ alkyl) ₂ , NH (optionally substituted C ₁ -C ₆ alkyl), -N (optionally substituted C ₁ -C ₆ alkyl) (optionally substituted C ₁ -C ₆ alkyl phenyl), -NH (optionally substituted C ₁ -C ₆ alkylphenyl), optionally substituted C1-C6 alkyl -S-, -S(O) ₂ -optionally substituted C1-C6 Alkyl, -S(O)-optionally substituted C1-C6 alkyl, -S(O) ₂ -optionally substituted phenyl, -S(O) ₂ NH ₂ , S(O) ₂ NH (any optionally substituted C1-C6 alkyl), S(O) ₂ NH (optionally substituted phenyl), -NHS(O) ₂ (optionally substituted C1-C6 alkyl), -NHS(O) ₂ ( optionally substituted phenyl), optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclyl, optionally substituted C6-C16 aryl or optionally substituted 5-16 membered heterocyclic group Aryl; or any two adjacent R and the atoms connected thereto form an optionally substituted 4-8-membered heterocyclic group or an optionally substituted C3-C8-membered carbocyclic group; wherein the substitution in R means Substituted with 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 alkyl group, 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 , CH ₂ -N(R' substituted or unsubstituted C1-C6 alkyl) ₂ , where R' is selected from one or more of the following groups Groups: H, halogen, deuterium (D), halogen, OH, oxo (=O), mercapto, cyano, -CD ₃ , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkene base, C2-C6 alkynyl, C3-C8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is optionally One or more substituents selected from the following are further substituted: H, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), -NH ₂ , 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 cycloalkyl, 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), 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 haloalkyl), -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 haloalkyl) and C1-C6 alkyl NH ₂ , where R'' is selected from one of the following groups Or multiple groups: H, halogen, cyano, amine, hydroxyl, oxo ( ), C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group. Compounds as described in claim 1, their pharmaceutically acceptable salts, parapolymers, non-parapoisomers, tautomers, cis-trans isomers, solvates, polymorphs, Deuterated substances or combinations thereof, wherein, 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 means substitution by one or more R, and R is as defined in claim 1. Compounds as described in claims 1 and 2, their pharmaceutically acceptable salts, parapolymers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated products or combinations thereof, in, The A ring is selected from: optionally substituted C6-C10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C8 carbocyclic C6-C10 aryl, optionally substituted 4 -8-membered heterocycla C6-C10 aryl, optionally substituted C3-C8 carbocycla 5-10 membered heteroaryl or optionally substituted 4-8 membered heterocycla 5-10 membered heteroaryl; preferred Ring A is an optionally substituted phenyl group, a 5-6 membered heteroaryl group, an optionally substituted C3-C8 carbocyclic acene group, an optionally substituted 4-8 membered heterocyclic acene group, an optionally substituted C3-C8 carbocyclic 5-6 membered heteroaryl or optionally substituted 4-8 membered heterocyclic 5-6 membered heteroaryl; more preferably, A ring is selected from: optionally substituted phenyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrrolyl, optionally substituted thiazolyl, optionally substituted imidazolyl, optionally substituted Selected substituted pyrazolyl; wherein said substitution means substitution by one or more R; R is as defined in claim 1. The compound as described in any one of claims 1 to 3, its pharmaceutically acceptable salts, parapal isomers, non-parapal isomers, tautomers, cis-trans isomers, and solvates, Polymorphs, deuterated forms or combinations thereof, wherein the A ring is selected from: , , , , , , , , , or ; Wherein, R ^d1 , R ^d2 , and R ^d3 are each independently selected from: H, halogen, amino group, hydroxyl, cyano group, optionally substituted C1-C6 alkyl group, optionally substituted C1-C6 alkoxy group, Optionally substituted C1-C6 alkyl group, 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 ; q is 0, 1, 2 or 3; R ^d5 is selected from: hydrogen, optionally substituted C6-C10-membered aromatic group or optionally substituted 5-16-membered heteroaromatic ring group; Z is selected from: O or NR ^N ; R ^N is selected from: H or optionally substituted C1-C6 alkyl; wherein, the substitution means substitution with one or more groups selected from the following group: H, halogen, cyano, amine, hydroxyl , oxo group ( ), R'-substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylpropyl, C3-C16 carbocyclyl, 4-16 membered heterocyclyl, 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 heterocyclyl), where R' is selected from One or more groups from the following group: H, halogen, cyano, amine, hydroxyl, oxo ( ), C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group. The compound as described in any one of claims 1 to 4, its pharmaceutically acceptable salts, parapal isomers, non-parapal isomers, tautomers, cis-trans isomers, and solvates, Polymorphs, deuterated compounds or combinations thereof, wherein A ring 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 means substitution with one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxygen Daiji( ), C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group. The compound as described in any one of claims 1 to 5, its pharmaceutically acceptable salts, parapal isomers, non-parapal isomers, tautomers, cis-trans isomers, and solvates, Polymorphs, deuterated forms or combinations thereof, wherein R ² is , wherein, X ³ is selected from: CR ^2' or N; Preferably, R ² is ; R ^2' is selected from: methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio , difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl; Ring B is selected from: optionally substituted C3-C16 carbocyclyl or optionally substituted 4- 16-membered heterocyclyl; wherein the substitution means substitution by one or more R; R is as defined in claim 1; Indicates the attachment position of the group. The compound as described in claim 6, its pharmaceutically acceptable salts, parapolymers, non-parapoisomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterium Substitutes or combinations thereof, wherein, B ring is selected from: optionally substituted C3-C11 carbocyclyl or optionally substituted 4-11 membered heterocyclyl, more preferably, B ring is selected from: optionally substituted C5- C11 carbocyclyl or optionally substituted 5-11 membered heterocyclyl, more preferably, B ring is selected from: optionally substituted C5-C8 carbocyclyl or optionally substituted 5-8 membered heterocyclyl, more preferably Preferably, Ring B is an optionally substituted 6-membered heterocyclyl group, such as an optionally substituted tetrahydropyranyl group ( ), optionally substituted piperidinyl ( ); wherein, the substitution refers to being replaced by one or more R; the definition of R is as stated in claim 1. The compound as described in claim 1, its pharmaceutically acceptable salts, parapolymers, non-parapoisomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterium substitutes or combinations thereof, wherein R ² is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . The compound as described in any one of claims 1 to 8, its pharmaceutically acceptable salts, parapal isomers, non-parapal isomers, tautomers, cis-trans isomers, and solvates, Polymorphs, deuterated forms or combinations thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . A compound represented by formula II, or a salt, solvate, polymorph or deuterated product thereof, . A pharmaceutical composition, wherein the pharmaceutical composition includes: (1) A therapeutically effective amount selected from the compound described in any one of claims 1 to 9, its pharmaceutically acceptable salts, parapolymers, non-parapolymers, tautomers, and cis One or more of anti-isomers, solvates, polymorphs and deuterated forms as the active ingredient; and (2) Optionally, a pharmaceutically acceptable carrier. A compound as described in any one of claims 1 to 9, its pharmaceutically acceptable salts, apral isomers, non-alpral isomers, tautomers, cis-trans isomers, and solvates , polymorphs or deuterated products or the use of the pharmaceutical composition according to claim 11 in the preparation of drugs for preventing or treating cancer mediated by RAS mutations. The use according to claim 12, 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 striated muscle tumors, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, brain glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer , especially selected from non-small cell lung cancer, pancreatic cancer and colorectal cancer.