Benzylamino-substituted tricyclic heterocyclic compound, composition thereof, preparation thereof and use thereof

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and relates to a benzylamino-substituted tricyclic heterocyclic compound as represented by formula I, a composition thereof, a preparation thereof and the use thereof. Specifically, the general formula of the tricyclic heterocyclic ring has a structure as represented by formula I. The compound of the present invention has excellent in-vitro inhibitory activity against SOS1, and has good in-vivo inhibitory activity against an NCI-H358 subcutaneous xenograft tumor. In addition, the compound of the present invention has characteristics such as relatively low plasma clearance, relatively long drug half-life, relatively good exposure and relatively high bioavailability, has good pharmacokinetic properties, does not show strong inhibition against various CYP enzyme subtypes, is high in terms of levels of safety, has in-vivo anti-tumor activity, and is relatively low in terms of levels of toxicity.

Description

Benzylamino-substituted tricyclic heterocyclic compounds and their compositions, preparations and uses Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry and relates to a series of novel benzylamino-substituted tricyclic heterocyclic compounds, pharmaceutical compositions and pharmaceutical preparations containing the same, and medical uses thereof. Background Art

[0002] KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, bile duct cancer, and thyroid cancer. RAS is a GTP-binding protein. RAS exists in two main forms in the body: an inactive state bound to GDP and an activated state bound to GTP. Its activity is regulated by two proteins: guanylate exchange factors (GEFs), such as SOS1, which release GDP from RAS proteins, allowing GTP binding and activation of RAS; and GTPase-activating proteins, which activate the GTPase activity of RAS proteins, hydrolyzing GTP bound to RAS proteins into GDP, inactivating RAS. When in the GTP-bound state, RAS family proteins are active and engage effector proteins (including RAF and PI3K) to promote pathways such as RAF / MEK / ERK and PI3K / AKT / mTOR. These pathways influence various cellular processes, such as proliferation, survival, and metabolism.

[0003] SOS1 has two binding sites for RAS family proteins: one is a catalytic site that binds to GDP-bound RAS family proteins to promote guanine nucleotide exchange, and the other is an allele site that binds to GTP-bound RAS family proteins, thereby further increasing SOS1's catalytic GEF function (Biochem. Pharmacol., 2011, 82(9): 1049-1056). SOS1 plays an important role in the activation of mutant KRAS and oncogenic signaling in cancer (Nat. Commun., 2012, 3: 1168). In tumor cells carrying KRAS mutations, reducing SOS1 content can reduce the proliferation rate of tumor cells, while no effect is observed in KRAS wild-type cell lines.

[0004] RAS, the first oncogene to be identified, is the most frequently mutated oncogene, accounting for 25% of human cancers. In recent decades, the interaction between RAS family proteins and SOS1 has gained increasing recognition. Currently, only Boehringer Ingelheim's SOS1 inhibitor, BI1701963, has entered Phase I clinical trials, and no SOS1 inhibitors have been developed or marketed. Therefore, the development of new SOS1 inhibitors holds immense clinical value and broad market potential.

[0005] Summary of the Invention

[0006] Problems to be solved by the invention

[0007] In order to develop new SOS1 inhibitors, the present invention aims to provide a novel benzylamino-substituted tricyclic heterocyclic compound and its composition, preparation and use. The derivative has excellent SOS1 inhibitory activity in vitro, as well as good in vivo pharmacodynamics and pharmacokinetic properties, and is highly safe.

[0008] Solutions for solving problems

[0009] In a first aspect, the present invention provides a compound having a structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof:

[0010] in:

[0011] Every one independently represents a single bond or a double bond;

[0012] X is selected from CR6, C(R6)2 and C(=O);

[0013] Y is selected from CR7 and C(R7)2;

[0014] z is selected from N and NR 8 , or, Z is absent; when Z is absent, Y is directly connected to the phthalazine ring via a single bond;

[0015] Ring A is selected from phenyl and thienyl;

[0016] Every R 1 independently selected from methyl, ethyl, phenyl, halogen and cyano, wherein the methyl, ethyl or phenyl group is optionally substituted with one or more substituents selected from methylaminomethyl, dimethylaminomethyl, hydroxyl and halogen;

[0017] R 2 and R 3 are independently hydrogen;

[0018] R 4 is methyl;

[0019] R 5 Selected from C 1-8 Alkyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-8 The alkyl group is optionally substituted with one or more deuterium; the 3-8 membered heterocyclic group contains a heteroatom selected from O, N and S, and the 3-8 membered heterocyclic group is optionally substituted with one or more C 1-8 Alkyl substitution;

[0020] If present, each R 6 are independently hydrogen;

[0021] Every R 7 are independently selected from hydrogen and methyl; or, two R 7 Together with the carbon atom to which it is attached, it forms a cyclopropyl group;

[0022] If present, R 8 is selected from methyl and cyclopropyl, wherein the methyl group is optionally substituted with one or more deuterium groups;

[0023] n is 1 or 2;

[0024] Furthermore, when Z is absent, Y is C(R7)2, and X is C(=O), the two R 7 not connected and distinct from one another;

[0025] Also, does not contain the following compounds:

[0026] In a second aspect, the present invention provides the following non-limiting examples of the compounds having the structure of Formula I:

[0027] (1) 2-methyl-3-((1R)-1-((1,2,4,9-tetramethyl-3-oxo-1,2,3,4-tetrahydropyridazino[4,5-g]quinoxalin-6-yl)amino)ethyl)benzonitrile;

[0028] (2) 9-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-1,3,4,6-tetramethyl-3,4-dihydropyridazino[4,5-g]quinoxalin-2(1H)-one;

[0029] (3) 9-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3,6-dimethyl-1,4-bis(methyl-d3)-3,4-dihydropyridazino[4,5-g]quinoxalin-2(1H)-one;

[0030] (4) (R)-2-methyl-3-(1-((1,2,2,4,9-pentamethyl-3-oxo-1,2,3,4-tetrahydropyridazino[4,5-g]quinoxalin-6-yl)amino)ethyl)benzonitrile;

[0031] (5) (R)-9-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-1,3,3,4,6-pentamethyl-3,4-dihydropyridazino[4,5-g]quinoxalin-2(1H)-one;

[0032] (6) (R)-1,3,3,4,6-pentamethyl-9-((1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-3,4-dihydropyridazino[4,5-g]quinoxalin-2(1H)-one;

[0033] (7) (R)-9-((1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-1,3,3,4,6-pentamethyl-3,4-dihydropyridazino[4,5-g]quinoxalin-2(1H)-one;

[0034] (8) 3-((1R)-1-((4-cyclopropyl-1,2,9-trimethyl-3-oxo-1,2,3,4-tetrahydropyridazino[4,5-g]quinoxalin-6-yl)amino)ethyl)-2-methylbenzonitrile;

[0035] (9) 3-((1R)-1-((1-cyclopropyl-2,4,9-trimethyl-3-oxo-1,2,3,4-tetrahydropyridazino[4,5-g]quinoxalin-6-yl)amino)ethyl)-2-methylbenzonitrile;

[0036] (10) (R)-2-methyl-3-(1-((1′,4′,9′-trimethyl-3′-oxo-3′,4′-dihydro-1′H-spiro[cyclopropane-1,2′-pyridazino[4,5-g]quinoxalin]-6′-yl)amino)ethyl)benzonitrile;

[0037] (11) (R)-2-methyl-3-(1-((2,4,9-trimethyl-3-oxo-3,4-dihydropyridazino[4,5-g]quinoxalin-6-yl)amino)ethyl)benzonitrile;

[0038] (12) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-methyl-1-(tetrahydrofuran-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-g]phthalazin-8-amine;

[0039] (13) 2-methyl-3-((1R)-1-((5-methyl-1-(tetrahydrofuran-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-g]phthalazin-8-yl)amino)ethyl)benzonitrile;

[0040] (14) 2-methyl-3-((1R)-1-((5-methyl-1-(tetrahydrofuran-3-yl)-1H-pyrrolo[2,3-g]phthalazin-8-yl)amino)ethyl)benzonitrile;

[0041] (15) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-methyl-1-(tetrahydrofuran-3-yl)-1H-pyrrolo[2,3-g]phthalazin-8-amine;

[0042] (16) 2-methyl-3-((1R)-1-((3,3,5-trimethyl-1-(tetrahydrofuran-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-g]phthalazin-8-yl)amino)ethyl)benzonitrile;

[0043] (17) (R)-3-(1-((1-isopropyl-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-g]phthalazin-8-yl)amino)ethyl)-2-methylbenzonitrile;

[0044] (18) (R)-3-(1-((1-cyclobutyl-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-g]phthalazin-8-yl)amino)ethyl)-2-methylbenzonitrile;

[0045] (19) (R)-3-(1-((1-cyclopentyl-5-methyl-2,3-dihydro-1H-pyrrolo[2,3-g]phthalazin-8-yl)amino)ethyl)-2-methylbenzonitrile;

[0046] (20) 2-methyl-3-((1R)-1-((5-methyl-1-(tetrahydro-2H-pyran-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-g]phthalazin-8-yl)amino)ethyl)benzonitrile;

[0047] (21) (R)-2-methyl-3-(1-((5-methyl-1-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-g]phthalazin-8-yl)amino)ethyl)benzonitrile;

[0048] (22) 2-methyl-3-((1R)-1-((5-methyl-1-(1-methylpyrrolidin-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-g]phthalazin-8-yl)amino)ethyl)benzonitrile; and

[0049] (23) 5-Methyl-N-((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-1-(tetrahydrofuran-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-g]phthalazin-8-amine.

[0050] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0051] Preferably, in the above-mentioned pharmaceutical composition, the pharmaceutically acceptable carrier includes (but is not limited to) a diluent (or filler), a binder, a disintegrant, a lubricant, a wetting agent, a thickener, a glidant, a flavoring agent, an olfactory agent, a preservative, an antioxidant, a pH regulator, a solvent, a cosolvent, a surfactant, a light-shielding agent (opacifying agent), etc.

[0052] In a fourth aspect, the present invention provides a pharmaceutical preparation, which is made from the above-mentioned compound having the structure of Formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or is made from the above-mentioned pharmaceutical composition.

[0053] In a fifth aspect, the present invention provides the use of the above-mentioned compound having the structure of Formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation in the preparation of a medicament for preventing and / or treating a disease mediated at least in part by the SOS1 protein.

[0054] Preferably, in the above use, the disease mediated at least in part by the SOS1 protein is cancer, in particular a cancer selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[0055] In a sixth aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound having the structure of Formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, and at least one additional cancer therapeutic agent.

[0056] In one or more embodiments, the cancer therapeutic agent is selected from trametinib and cediranib.

[0057] In a seventh aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned compound having the structure of Formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, and at least one additional cancer therapeutic agent.

[0058] In an eighth aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, which is used as a drug.

[0059] In a ninth aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, or the aforementioned pharmaceutical composition, or the aforementioned pharmaceutical preparation, for preventing and / or treating a disease mediated at least in part by the SOS1 protein.

[0060] In a tenth aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, which is used to prevent and / or treat cancer.

[0061] In an eleventh aspect, the present invention provides a method for preventing and / or treating a disease mediated at least in part by the SOS1 protein, comprising administering a preventive and / or therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, or the pharmaceutical composition or pharmaceutical preparation thereof to an individual in need thereof.

[0062] In a twelfth aspect, the present invention provides a method for preventing and / or treating cancer, which comprises administering a preventively and / or therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, or the aforementioned pharmaceutical composition, or the aforementioned pharmaceutical preparation to an individual in need thereof.

[0063] In one or more embodiments, the disease mediated at least in part by the SOS1 protein is cancer, in particular a cancer selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[0064] Effects of the Invention

[0065] The compounds of the present invention exhibit excellent in vitro inhibitory activity against SOS1 and good in vivo inhibitory activity against NCI-H358 subcutaneous xenograft tumors. Furthermore, the compounds of the present invention exhibit low plasma clearance, long half-life, good exposure, and high bioavailability, along with favorable pharmacokinetic properties and lack of strong inhibition against any CYP enzyme subtype, demonstrating a high safety profile. Furthermore, the compounds of the present invention and their combinations with other anticancer agents exhibit good in vivo tumor inhibitory activity. Furthermore, the compounds of the present invention exhibit low toxicity to various organs. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] FIG1 is a graph showing the tumor growth inhibition rates (TGI) of compound 1, compound 13, compound 14, and the positive control compound 1.

[0067] FIG2 is a graph showing the inhibition of tumor volume changes by compound 1, compound 13, compound 14, and the positive control compound 1. DETAILED DESCRIPTION

[0068] Before the present invention is further described, it is to be understood that the present invention is not limited to the particular embodiments described herein; it is to be understood that the terminology used herein is for the purpose of describing only and not limiting of the particular embodiments.

[0069] [Definition of terms]

[0070] Unless otherwise specified, the following terms have the following meanings.

[0071] The term "pharmaceutically acceptable salt" refers to a salt of a compound having the structure of Formula I that is substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by reacting the compounds of the present invention with pharmaceutically acceptable inorganic or organic acids, which are also known as acid addition salts. Common inorganic acids include (but are not limited to) hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid (which can form sulfates or acid sulfates), phosphoric acid (which can form phosphates or acid phosphates), etc. Common organic acids include (but are not limited to) trifluoroacetic acid, citric acid (which can form citric acid monosalt, disalt or trisalt), maleic acid (which can form maleic acid monosalt or disalt), fumaric acid (which can form fumaric acid monosalt or disalt), succinic acid (which can form succinic acid monosalt or disalt), tartaric acid (which can form tartaric acid monosalt or disalt), oxalic acid (which can form oxalic acid monosalt or disalt), malonic acid (which can form malonic acid monosalt or disalt), malic acid (which can form malic acid monosalt or disalt), oxalic acid (which can form oxalic acid monosalt or disalt), lactic acid, pyruvic acid, salicylic acid, formic acid, acetic acid, propionic acid, benzoic acid, glycolic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0072] The term "hydrate" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and water through non-covalent intermolecular forces. Common hydrates include (but are not limited to) hemihydrates, monohydrates, dihydrates, trihydrates, and the like.

[0073] The term "solvate" refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, formed by binding at least one solvent molecule through non-covalent intermolecular forces. The term "solvate" includes "hydrates." Common solvates include (but are not limited to) hydrates, ethanolates, and acetonides. It should be understood that the present invention encompasses all solvate forms that possess SOS1 inhibitory activity.

[0074] The term "isomers" refers to compounds that have the same number and types of atoms, and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0075] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a perpendicular asymmetric plane due to at least one chiral factor (including a chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane-polarized light. Because the compounds of the present invention contain asymmetric centers and other chemical structures that may lead to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Because the compounds of the present invention and their salts contain asymmetric carbon atoms, they can exist as single stereoisomers, racemates, enantiomers, and mixtures of diastereomers. Generally, these compounds can be prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in a single stereoisomer (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, or ≥80%). As described below, a single stereoisomer of a compound is synthesized from an optically active starting material containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, for example, by conversion to a mixture of diastereoisomers followed by separation or recrystallization, chromatography, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds with a specific stereochemistry are either commercially available or prepared as described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are nonsuperimposable mirror images of each other. The term "diastereomer" or "diastereomers" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the invention.

[0076] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted via a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or prototropic tautomers) include, but are not limited to, interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0077] The term "cis-trans isomers" refers to stereoisomers formed by the different positions of the atoms (or groups) on either side of a double bond or ring system relative to a reference plane; in cis isomers, the atoms (or groups) are on the same side of the double bond or ring system, and in trans isomers, the atoms (or groups) are on opposite sides of the double bond or ring system. Unless otherwise indicated, all cis- and trans-isomeric forms of the compounds of the present invention are within the scope of the present invention.

[0078] The term "isotopically labeled" refers to a compound in which a specific atom in the structure is replaced by an isotope thereof. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as 2 H(D), 3 H(T), 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 S and 37 Cl.

[0079] The term "prodrug" refers to a derivative compound that, upon application to a patient, is capable of providing, directly or indirectly, a compound of the invention. Particularly preferred derivative compounds or prodrugs are compounds that, when administered to a patient, can increase the bioavailability of the compound of the invention (e.g., facilitate absorption into the bloodstream) or compounds that facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the invention are within the scope of the invention, and various prodrug forms are well known in the art.

[0080] The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof.

[0081] The term "cycloalkyl" refers to a cyclic, saturated aliphatic hydrocarbon group of 3 to 6 (e.g., 3, 4, 5, 6) carbon atoms, which may be monocyclic or bicyclic. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0082] The term "heterocyclyl" refers to a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) cyclic saturated and / or unsaturated aliphatic hydrocarbon group, which may be monocyclic or bicyclic, which may contain one or more (e.g., 1, 2, 3 or 4) heteroatoms selected from N, O or S, and may be monocyclic, fused, bridged or spirocyclic.

[0083] The term "methyl" refers to a -CH3 or -Me group.

[0084] The term "ethyl" refers to a -CH2CH3, -C2H5 or -Et group.

[0085] The term "isopropyl" refers to a -CH(CH3)2 or -i-Pr group.

[0086] The term "cyclopropyl" refers to or a -cyc-Pr group.

[0087] The term "cyclobutyl" refers to or a -cyc-Bu group.

[0088] The term "cyclopentyl" refers to or a -cyc-amyl group.

[0089] The term "tetrahydropyrrolyl" or "pyrrolidine" refers to Group; Accordingly, the term "tetrahydropyrrol-3-yl" or "pyrrolidin-3-yl" refers to group.

[0090] The term "tetrahydrofuranyl" refers to Group; accordingly, the term "tetrahydrofuran-3-yl" refers to group.

[0091] The term "tetrahydropyranyl" refers to Group; accordingly, the term "tetrahydropyran-3-yl" refers to group, while the term "tetrahydropyran-4-yl" refers to group.

[0092] The term "phenyl" refers to -C6H5 or -Ph group.

[0093] The term "thienyl" refers to or -C4H3S group; accordingly, the term "thiophen-2-yl" refers to group.

[0094] The term "phthalazine" refers to Accordingly, the term "phthalazine ring" refers to a ring system derived from phthalazine.

[0095] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and chlorine (Cl) in Group VII of the Periodic Table of Elements. r ) and iodine (I).

[0096] The term "hydroxy" refers to an -OH group.

[0097] The term "cyano" refers to a -CN group.

[0098] The term "methylaminomethyl" refers to a -CH2NHCH3 group; correspondingly, the term "dimethylaminomethyl" refers to a -CH2N(CH3)2 group.

[0099] The term "single bond" refers to sp 3 A covalent chemical bond between heteroatoms used to connect or interact with each other; accordingly, the term "double bond" refers to a sp 2 Covalent chemical bonds between hybrid atoms.

[0100] The term "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both occurrence of the event or circumstance and non-occurrence of the event or circumstance. 4d "Optionally" substituted with halogen means R 4d It may be unsubstituted or may be singly, poly- or fully substituted with halogen atoms. It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and / or cannot be synthesized will be introduced.

[0101] [Benzylamino-substituted tricyclic heterocyclic compounds]

[0102] The present invention provides a series of novel benzylamino-substituted tricyclic heterocyclic compounds or pharmaceutically acceptable forms thereof, such as salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotope-labeled substances or prodrugs of such compounds.

[0103] In one embodiment of the present invention, the structure of the compound is shown in Formula I:

[0104] in:

[0105] Every one independently represents a single bond or a double bond;

[0106] X is selected from CR6, C(R6)2 and C(=O);

[0107] Y is selected from CR7 and C(R7)2;

[0108] Z is selected from N and NR 8, or, Z is absent; when Z is absent, Y is directly connected to the phthalazine ring via a single bond;

[0109] Ring A is selected from phenyl and thienyl (especially thien-2-yl);

[0110] Every R 1 independently selected from methyl, ethyl, phenyl, halogen and cyano, wherein the methyl, ethyl or phenyl group is optionally substituted with one or more substituents selected from methylaminomethyl, dimethylaminomethyl, hydroxyl and halogen;

[0111] R 2 and R 3 are independently hydrogen;

[0112] R 4 is methyl;

[0113] R 5 Selected from C 1-8 Alkyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-8 The alkyl group is optionally substituted with one or more deuterium; the 3-8 membered heterocyclic group contains a heteroatom selected from O, N and S, and the 3-8 membered heterocyclic group is optionally substituted with one or more C 1-8 Alkyl substitution;

[0114] If present, each R 6 are independently hydrogen;

[0115] Every R 7 are independently selected from hydrogen and methyl; or, two R 7 Together with the carbon atom to which it is attached, it forms a cyclopropyl group;

[0116] If present, R 8 is selected from methyl and cyclopropyl, wherein the methyl group is optionally substituted with one or more deuterium groups;

[0117] n is 1 or 2;

[0118] Furthermore, when Z is absent, Y is C(R7)2, and X is C(=O), the two R 7 not connected and distinct from one another;

[0119] Also, does not contain the following compounds:

[0120] "If there is, every R 6 "Independently hydrogen" means that when X is selected from CR6 or C(R6)2, each R 6 are independently hydrogen.

[0121] In a preferred embodiment of the present invention, ring A in formula I is selected from phenyl and thien-2-yl.

[0122] In a preferred embodiment of the present invention, each R 1 independently selected from -CH3, -CH2F, -CHF2, -CF3, -CH2OH, -CH2CH3, -CHFCH3, -CF2CH3, -CH2CH2OH, -CHFCH2OH, -CF2CH2OH, -F, -Cl, -Br,

[0123] In a more preferred embodiment of the present invention, each R in Formula I 1 Independently selected from -CH3, -CHF2, -CF2CH2OH, -F,

[0124] In a preferred embodiment of the present invention, ring A in formula I is thien-2-yl, n is 1, R 1 Substitution is performed at any substitutable position of A, preferably as shown in Formula IA or Formula IA':

[0125] in:

[0126] Every one independently represents a single bond or a double bond;

[0127] R 1 Selected from

[0128] X, Y, Z, and R 5 As defined in Formula I.

[0129] In another preferred embodiment of the present invention, ring A in formula I is phenyl, n is 2, and 2 R 1 Independently substitute at any substitutable position of A, preferably as shown in Formula IB or Formula IB':

[0130] in:

[0131] Every one independently represents a single bond or a double bond;

[0132] Every R 1 independently selected from -CH3, -CHF2, -CF2CH2OH, -F and -CN;

[0133] X, Y, Z, and R 5 As defined in Formula I.

[0134] In a more preferred embodiment of the present invention, Selected from Preferred

[0135] In a preferred embodiment of the present invention, in Formula I, Formula IA, Formula IA', Formula IB or Formula IB' Selected from

[0136] In a more preferred embodiment of the present invention, in Formula I, Formula IA, Formula IA', Formula IB or Formula IB' Selected from

[0137] In a preferred embodiment of the present invention, R 5 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-4 The alkyl group is optionally substituted with one or more deuterium; the 3-6 membered heterocyclic group contains heteroatoms selected from O and N, and the 3-6 membered heterocyclic group is optionally substituted with one or more C 1-4 Alkyl substitution.

[0138] In a preferred embodiment of the present invention, R 5 Selected from -CH3, -CH2D, -CHD2, -CD3, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl and tetrahydrofuran-3-yl.

[0139] In a more preferred embodiment of the present invention, R 5 Selected from -CH3, -CD3, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylpyrrolidin-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl and tetrahydrofuran-3-yl.

[0140] In a preferred embodiment of the present invention, R 8 Selected from -CH3, -CH2D, -CHD2, -CD3 and cyclopropyl.

[0141] In a more preferred embodiment of the present invention, R 8 Selected from -CH3, -CD3 and cyclopropyl.

[0142] In a preferred embodiment of the present invention, for The compound at this time is shown in Formula IA-1 or Formula IA'-1:

[0143] Where: R 1 As defined in Formula IA or Formula IA'.

[0144] In a preferred embodiment of the present invention, for The compound at this time is shown in Formula IA-2 or Formula IA'-2:

[0145] Where: R 1 As defined in Formula IA or Formula IA'.

[0146] In a preferred embodiment of the present invention, Selected from In this case, the compound is represented by any one of Formulas IB-1 to IB-16 or any one of Formulas IB'-1 to IB'-16:

[0147] Where: R 1 As defined in Formula IB or Formula IB'.

[0148] In a more preferred embodiment of the present invention, Selected from In this case, the compound is represented by any one of Formula IB-1, Formula IB-2 and Formula IB-5 or any one of Formula IB'-1, Formula IB'-2 and Formula IB'-5, wherein: R 1 As defined in Formula IB or Formula IB'.

[0149] Specifically, the benzylamino-substituted tricyclic heterocyclic compounds of the present invention include (but are not limited to) the following compounds:

[0150] [Pharmaceutical composition]

[0151] The term "pharmaceutical composition" refers to a composition that can be used as a medicament, which comprises a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers.

[0152] The term "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient that is compatible with the active ingredient of the drug and is harmless to the subject, including (but not limited to) one or more of a diluent (or filler), a binder, a disintegrant, a lubricant, a wetting agent, a thickener, a glidant, a flavoring agent, an olfactory agent, a preservative, an antioxidant, a pH adjuster, a solvent, a cosolvent, a surfactant, an opacifying agent (opacifying agent), etc.

[0153] The present invention provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof.

[0154] In one embodiment of the present invention, the above-mentioned pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0155] The term "pharmaceutical composition" may also include a compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopically labeled or prodrug thereof, or a pharmaceutical composition of the present invention or a pharmaceutical formulation of the present invention, and at least one additional cancer therapeutic agent.

[0156] The term "cancer therapeutic agent" refers to a pharmaceutical composition or pharmaceutical formulation that is effective in controlling and / or combating cancer.

[0157] In one embodiment of the present invention, the compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopically labeled or prodrug, or the pharmaceutical composition or pharmaceutical formulation of the present invention can be administered alone or in combination with other cancer therapeutic agents (or anti-tumor drugs). The combined therapy can be achieved by simultaneous, sequential or separate administration of different cancer therapeutic agents.

[0158] In one embodiment of the present invention, the cancer is pancreatic cancer, non-small cell lung cancer, or colorectal cancer.

[0159] [Drug preparations]

[0160] The term "pharmaceutical preparation" refers to a finished drug prepared in a certain form for use by patients.

[0161] The present invention provides a pharmaceutical preparation, which is prepared from the pharmaceutical composition of the present invention.

[0162] In one embodiment of the present invention, the pharmaceutical preparation is a solid preparation for oral administration, including (but not limited to) pharmaceutically acceptable capsules, tablets, pills, powders, granules, etc. The solid preparation can be coated or microencapsulated with a coating or shell material (such as an enteric coating or other materials known in the art). The solid preparation can contain an opacifying agent, and the active ingredient therein can 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 waxes. In addition, the active ingredient can also be formed into a microcapsule form with one or more of the above-mentioned carriers.

[0163] In another embodiment of the present invention, the pharmaceutical preparation is a liquid dosage form for oral administration, including (but not limited to) pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like.

[0164] In another embodiment of the present invention, the above-mentioned pharmaceutical preparation is a dosage form for parenteral injection, including but not limited to physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions.

[0165] In another embodiment of the present invention, the pharmaceutical preparation is in the form of a topical administration, including but not limited to ointments, powders, suppositories, drops, sprays, inhalants and the like.

[0166] [Medical use]

[0167] Whether it is the compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled or prodrug, or the pharmaceutical composition of the present invention, or the pharmaceutical preparation of the present invention, it can exhibit inhibitory activity against SOS1. Therefore, the present invention provides the use of the compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled or prodrug, or the pharmaceutical composition of the present invention, or the pharmaceutical preparation of the present invention in the preparation of a medicament for preventing and / or treating a disease mediated at least in part by the SOS1 protein.

[0168] The present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, or a pharmaceutical composition or pharmaceutical preparation of the present invention in the preparation of a medicament for preventing and / or treating cancer.

[0169] The term "cancer" refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, decreased cell differentiation, inappropriate ability to invade surrounding tissues, and / or the ability to establish new growths at ectopic locations. Non-limiting examples of cancer include, but are not limited to, pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma.

[0170] The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled or prodrug thereof, or a pharmaceutical composition of the present invention or a pharmaceutical preparation of the present invention, for use in preventing and / or treating a disease (particularly cancer) mediated at least in part by the SOS1 protein.

[0171] The present invention also provides a method for preventing and / or treating a disease (particularly cancer) mediated at least in part by the SOS1 protein, comprising administering a preventively and / or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention to an individual in need thereof.

[0172] In one embodiment of the present invention, the cancer is pancreatic cancer, non-small cell lung cancer, or colorectal cancer.

[0173] The technical solutions of the present invention will be further described below with reference to specific examples. Unless otherwise specified, the reagents, materials, instruments, etc. used in the following examples can be obtained through conventional commercial means, and the experimental methods used are all conventional methods in the art.

[0174] In the following examples, the following abbreviations are used:

[0175] THF Tetrahydrofuran

[0176] PE petroleum ether

[0177] EA Ethyl acetate

[0178] Diox 1,4-dioxane

[0179] MeOH methanol

[0180] EtOH

[0181] AcOH acetic acid

[0182] DMF N,N-dimethylformamide

[0183] DIPEA N,N-Diisopropylethylamine

[0184] TEA triethylamine

[0185] DCM dichloromethane

[0186] DCE 1,2-dichloroethane

[0187] DMAP 4-dimethylaminopyridine

[0188] Boc tert-butyloxycarbonyl

[0189] Pyr Pyridine

[0190] Tol Toluene

[0191] MeCN Acetonitrile

[0192] TFA trifluoroacetic acid

[0193] NBS N-bromosuccinimide

[0194] Comparative Example 1: Preparation of positive control compound 1

[0195] (1) Synthesis route of compound 1-1

[0196] Synthesis of compound 1-1b:

[0197] Under nitrogen, compound 1-1a (20.00 g, 106.36 mmol, 1.0 eq), THF (150 mL), (R)-tert-butylsulfenamide (19.31 g, 159.54 mmol, 1.5 eq), and tetraethyl titanate (74.65 g, 327.26 mmol, 2.0 eq) were added to the reaction flask in sequence. The temperature was raised to 80°C and the reaction was stirred for 4 h. After the reaction system was cooled to room temperature, water (150 mL) was added and extracted with EA (150 mL*2). The organic phase was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (eluent: PE / EA = 5 / 1, v / v) to obtain compound 1-1b (28.0 g); MS: m / z 292.1 [M+1]. + ;

[0198] Synthesis of compound 1-1c:

[0199] Compound 1-1b (28.00 g, 96.19 mmol, 1.0 eq), THF (400 mL), and water (6 mL) were added to the reaction flask in sequence. After cooling to -60 to -50°C, sodium borohydride (6.58 g, 173.14 mmol, 1.8 eq) was slowly added. After the addition, the temperature was raised to -5 to 0°C and stirring was continued for 30 min. Water (300 mL) was added to the system to quench the reaction, and EA (300 mL x 2) was added for extraction. The organic phase was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (eluent: PE / EA = 5 / 1, v / v) to obtain compound 1-1c (22.2 g); MS: m / z 294.1 [M+1]. + ;

[0200] Synthesis of compound 1-1:

[0201] Compound 1-1c (22.20 g, 75.76 mmol, 1.0 eq), Diox (50 mL), and 4 M HCl (40 mL) were added sequentially to the reaction flask and stirred at room temperature for 2 h. The pH of the system was adjusted to 8-9 using 1 M NaOH aqueous solution, and the mixture was extracted with EA (100 mL x 2). The organic phase was dried over anhydrous Na2SO4 and concentrated. The resulting solid was slurried with PE to obtain compound 1-1 (10.0 g); MS: m / z 190.1 [M+1] + .

[0202] (2) Synthesis route of compound 1-2

[0203] Synthesis of compound 1-2b:

[0204] At 0°C, concentrated H2SO4 (160 mL) and compound 1-2a (20.0 g, 91.76 mmol, 1.0 eq) were added sequentially to the reaction flask. KNO3 (9.27 g, 91.76 mmol, 1.0 eq) was then slowly added in portions. The reaction system was allowed to react at room temperature for 1 h. After completion of the reaction, the system was slowly poured into ice water (500 mL) and stirred. After returning to room temperature, the mixture was filtered, the filter cake was rinsed twice with water, and dried to obtain compound 1-2b (25.00 g) in a yield of 100%; MS: m / z 261.8 [M-1]. + ;

[0205] Synthesis of compound 1-2c:

[0206] Compound 1-2b (25.00 g, 95.08 mmol, 1.0 eq), MeOH (400 mL), and concentrated H2SO4 (4.26 g, 120.41 mmol, 1.2 eq) were added sequentially to a reaction flask. The reaction system was heated to 70°C and allowed to react for 16 h. The system was then cooled to room temperature, concentrated to remove most of the solvent, and filtered. The resulting solid was rinsed twice with water and dried to afford compound 1-2c (18.00 g) in a yield of 71.2%; MS: m / z 277.8 [M+1]. + ;

[0207] Synthesis of compound 1-2d:

[0208] Compound 1-2c (10.00 g, 36.11 mmol, 1.0 eq), DMF (100 mL), DL-alanine methyl ester hydrochloride (7.56 g, 54.16 mmol, 1.5 eq) and TEA (9.14 g, 90.28 mmol, 2.5 eq) were added to the reaction flask in sequence. The reaction system was heated to 80°C and reacted for 2 h. The system was then cooled to room temperature, stirred with water (300 mL), and filtered. The filter cake was rinsed twice with water and dried to obtain compound 1-2d (12.50 g) in a yield of 96.9%; MS: m / z 360.8 [M+1]. + ;

[0209] Synthesis of compound 1-2e:

[0210] Compound 1-2d (12.50 g, 34.72 mmol, 1.0 eq), anhydrous EtOH (150 mL), and SnCl2 (32.90 g, 173.6 mmol, 5.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 95°C and reacted for 3 h. The system was then cooled to room temperature and a saturated aqueous NaHCO3 solution was added to adjust the pH to neutral. EA (150 mL) was added, stirred, and filtered. The filter cake was rinsed with EA (200 mL*3). The filtrate was separated, and the organic phase was washed with water and saturated brine in sequence, then dried over anhydrous Na2SO4, filtered, and concentrated to give compound 1-2e (6.10 g). Yield: 59.2%; MS: m / z 299.0 [M+1]. + ;

[0211] Synthesis of compound 1-2f:

[0212] Compound 1-2e (6.10 g, 20.47 mmol, 1.0 eq) and DMF (110 mL) were added to the reaction flask in sequence at 0°C, and NaH (4.09 g, 102.35 mmol, 5.0 eq) was slowly added in batches. After stirring for 20 min, CH3I (311.6 g, 81.88 mmol, 4.0 eq) was added. After reacting for 30 min, water (150 mL) was added to the system to quench the reaction. EA (150 mL*3) was added for extraction. The organic layers were combined, washed with water and saturated brine in sequence, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (eluent: PE / EA = 3:1, v / v) to give compound 1-2f (2.50 g). Yield: 37.5%; MS: m / z 327.0 [M+1]. + ;

[0213] Synthesis of compound 1-2h:

[0214] Under nitrogen protection, compound 1-2f (2.50 g, 7.67 mmol, 1.0 eq), Diox (30 mL), tributyl (1-ethoxyethylene) tin (4.15 g, 11.5 mmol, 1.5 eq), Pd (dppf) 2 Cl 2 (0.84 g, 1.15 mmol, 0.15 eq) and TEA (2.32 g, 23.01 mmol, 3.0 eq) were added to the reaction flask in sequence, and the reaction system was heated to 90 ° C and reacted for 7 h. The system was cooled to room temperature and the pH was adjusted to weakly acidic by adding dilute HCl. The reaction product was converted from compound 1-2g to compound 1-2h as monitored by TLC and HR-MS. EA (50 mL*3) was added for extraction. The organic layers were combined and washed once with water and saturated brine, respectively. The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (eluent: PE / EA = 1:1, v / v) to give compound 1-2h (1.79 g) in a yield of 80.6%; MS: m / z 291.2 [M+1]. + ;

[0215] Synthesis of compound 1-2i:

[0216] Compound 1-2h (1.79 g, 6.17 mmol, 1.0 eq), anhydrous EtOH (20 mL), and hydrazine hydrate (1.54 g, 24.68 mmol, 4.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 95°C and allowed to react for 2 h. The system was then cooled to room temperature, concentrated to remove most of the solvent, and filtered. The resulting solid was dried to afford compound 1-2i (1.50 g) in a yield of 89.8%; MS: m / z 273.0 [M+1]. + .

[0217] Synthesis of compound 1-2:

[0218] Compound 1-2i (1.50 g, 5.51 mmol, 1.0 eq), POCl3 (20 mL) and N,N-diethylaniline (1.23 g, 8.26 mmol, 1.5 eq) were added to the reaction flask in sequence. The reaction system was heated to 108°C and reacted for 2 h. The system was then concentrated under low pressure to remove the solvent, ice water (20 mL) was added, and the pH was adjusted to 7-8 with saturated aqueous NaHCO3 solution. EA was added for extraction (30 mL*3). The organic layers were combined, washed once with water and saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (eluent: PE / EA = 1:2, v / v) to give compound 1-2 (1.21 g) in a yield of 75.6%; MS: m / z 291.0 [M+1]. + .

[0219] (3) Synthesis route of positive control compound 1

[0220] Under nitrogen protection, compound 1-2 (300.0 mg, 1.03 mmol, 1.0 eq), Tol (6 mL), compound 1-1 (255.9 mg, 2.07 mmol, 2.0 eq), Pd(dba)3 (372.1 mg, 0.62 mmol, 0.6 eq), Xantphos (470.2 mg, 1.24 mmol, 1-2 eq) and K3PO4 (862.5 mg, 6.20 mmol, 6.0 eq) were added to a microwave tube in sequence, and the reaction was carried out at 110°C for 2 h. The mixture was filtered, concentrated to remove the solvent, and purified by column chromatography (EA / MeOH = 20 / 1, v / v) to give the positive control compound 1 (83.21 mg) in a yield of 18.3%; MS: m / z 444.2 [M+1] + .

[0221] Example 1: Preparation of Compound 1

[0222] Compound 1 (29.5 mg) was synthesized in a 54% yield by following the same procedures as the positive control compound 1, except that compound 1-1 was replaced by compound 1-5. MS: m / z 415.4 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ8.57 (s, 1H), 8.23 ​​(d, J=10.2Hz, 1H), 7.88 (t, J=8. 7Hz, 1H), 7.66-7.63 (m, 1H), 7.35 (q, J=8.0Hz, 1H), 7.04 (d, J=4.3Hz, 1H), 5 .49 (p, J=6.9Hz, 1H), 4.39-4.29 (m, 1H), 3.57 (d, J=5.1Hz, 3H), 3.07 (d, J=1 .6Hz, 3H), 2.72 (s, 3H), 2.69 (s, 3H), 1.69-1.56 (m, 3H), 1.18-1.15 (m, 3H).

[0223] Example 2: Preparation of Compound 2

[0224] Compound 2 (18.8 mg) was synthesized in a yield of 21% by following the same procedures as the positive control compound 1, except that compound 1-1 was replaced by compound 2-1. MS: m / z 474.4 [M+1] + .

[0225] Example 3: Preparation of Compound 3

[0226] Compound 3-1 (0.88 g) was synthesized in a 69% yield by following the same procedures as compound 1-2 except that iodomethane was replaced with perdeuterated iodomethane. MS: m / z 297.1 [M+1] + Except for replacing compound 1-2 with compound 3-1, the rest of the operation was basically similar to that of the positive control compound 1 to synthesize compound 3 (8.8 mg) with a yield of 23%; MS: m / z 450.4 [M+1] + .

[0227] Example 4: Preparation of Compound 4

[0228] Compound 4-1 (0.58 g) was synthesized in a yield of 71% by following the same procedures as compound 1-2 except that DL-alanine methyl ester hydrochloride was replaced with 2-aminoisobutyric acid methyl ester. MS: m / z 305.1 [M+1] + Compound 4 (18.3 mg) was synthesized in a 53% yield by following the same procedures as the positive control compound 1, except that compound 1-2 was replaced by compound 4-1; MS: m / z 429.4 [M+1] + .

[0229] Example 5: Preparation of Compound 5

[0230] Compound 5 (23.8 mg) was synthesized in a yield of 22% by following the same procedures as the positive control compound 1, except that compound 1-2 was replaced by compound 4-1 and compound 1-1 was replaced by compound 2-1. MS: m / z 488.4 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ7.82 (t, J=7.0Hz, 1H), 7.63 (t, J=7.5Hz, 1H), 7.38 (t, J=7.8Hz, 1H), 7.23 (s, 1H), 7.07 (s, 1H) , 5.22-5.11 (m, 2H), 4.38 (q, J=6.6Hz, 1H), 3.37 (s, 3H), 3.01 (s, 3H), 2.74 (s, 3H), 1.37 (s, 6H), 1.27 (d, J=6.7Hz, 3H).

[0231] Example 6: Preparation of Compound 6

[0232] Under nitrogen protection, compound 4-1 (100.0 mg, 0.34 mmol, 1.0 eq), Tol (6 mL), compound 1-3 (227.7 mg, 0.66 mmol, 2.0 eq), Pd (dba) 3 (180.7 mg, 0.21 mmol, 0.6 eq), Xantphos (228.4 mg, 41.3 mmol, 1.2 eq) and K 3 PO 4 (418.9 mg, 2.07 mmol, 6.0 eq) were added to a microwave tube in sequence, and the reaction was carried out at 110 ° C for 2 h. The mixture was filtered, concentrated to remove the solvent, and purified by column chromatography (EA / MeOH=20 / 1, v / v) to give compound 6a (35.11 mg, 0.06 mmol). DCM (5 mL) was added as solvent, TFA (0.2 mL) was added, and the mixture was stirred at room temperature for 10 min. The pH value was adjusted to 8 with aqueous NaHCO3 solution, and the mixture was extracted with DCM (10 mL*3). The organic phases were combined, concentrated in vacuo, and purified by column chromatography (EA / MeOH=4 / 1, v / v) to give compound 6 (2.35 mg). Yield: 7.99%; MS: m / z 515.3[M+1] + .

[0233] Example 7: Preparation of Compound 7

[0234] Under nitrogen protection, compound 4-1 (100.0 mg, 0.34 mmol, 1.0 eq), Tol (6 mL), compound 1-4 (171.1 mg, 0.66 mmol, 2.0 eq), Pd(dba)3 (180.7 mg, 0.21 mmol, 0.6 eq), Xantphos (228.4 mg, 41.3 mmol, 1.2 eq) and K3PO4 (418.9 mg, 2.07 mmol, 6.0 eq) were added to a microwave tube in sequence, and the reaction was carried out at 110 ° C. for 2 h. The mixture was filtered, concentrated to remove the solvent, and purified by column chromatography (EA / MeOH = 4 / 1, v / v) to give compound 7 (5.11 mg) in a yield of 2.94%; MS: m / z 529.4 [M+1] + .

[0235] Example 8: Preparation of Compound 8

[0236] (1) Synthesis route of compound 8-1

[0237] Synthesis of compound 8-1a:

[0238] Compound 1-2e (4.00 g, 13.42 mmol, 1.0 eq), (Boc)2O (3.80 g, 17.45 mmol, 1.3 eq), DMAP (655.9 mg, 5.37 mmol, 0.4 eq) and DCM (40 mL) were added to the reaction flask in sequence and reacted at room temperature overnight. The reaction system was poured into water (100 mL) and extracted with DCM (120 mL*3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography (PE / EA=5 / 14, v / v) to give compound 8-1a (3.44 g) in a yield of 64.4%; MS: m / z 343.2 [M- t Bu+1] + ;

[0239] Synthesis of compound 8-1b:

[0240] Compound 8-1a (1.87 g, 4.70 mmol, 1.0 eq), cyclopropylboronic acid (1.21 g , 14.10mmol, 3.0eq), Cu(OAc)2(0.85g, 4.70mmol, 1.0eq), Pyr(2.23g, 28.20mmol, 6.0eq) and MeCN(20mL), react at 60℃ for 40h, pour the reaction system into cold water(20mL), extract with EA(50mL*3), combine the organic phases, dry over anhydrous Na2SO4, filter, concentrate in vacuo, and purify by column chromatography(PE / EA=3 / 1, v / v) to give compound 8-1b(1.70g), yield: 82.9%; MS: m / z 383.2[M- t Bu+1] + ;

[0241] Synthesis of compound 8-1c:

[0242] Compound 8-1b (1.70 g, 3.88 mmol, 1.0 eq), DCM (35 mL) and TFA (5 mL) were added to the reaction flask in sequence and stirred at room temperature for 2 h. The reaction system was spin-dried and redissolved with DCM (15 mL). The pH value was adjusted to 8 with saturated aqueous NaHCO3 solution and extracted with DCM (20 mL*3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and spin-dried to give compound 8-1c (1.29 g) in a yield of 98.5%; MS: m / z 339.1 [M+1]. + ;

[0243] The synthesis procedures of compound 8-1d to compound 8-1 are basically the same as the synthesis procedures of compound 1-2e to compound 1-2 in Comparative Example 1.

[0244] Compound 8-1d (yield 90.5%), MS: m / z 353.0 [M+1] + Compound 8-1e (yield 81.2%), MS: m / z 345.2 [M+1] + Compound 8-1f (yield 85.1%), MS: m / z 317.1 [M+1] + Compound 8-1g (yield 91.2%), MS: m / z 353.0 [M+1] + Compound 8-1 (yield 73.5%), MS: m / z 317.1 [M+1] + ;

[0245] (2) Synthesis route of compound 8

[0246] Under nitrogen protection, compound 8-1 (90.0 mg, 0.28 mmol, 1.0 eq), Tol (6 mL), compound 1-5 (91.0 mg, 0.56 mmol, 2.0 eq), Pd(dba)3 (155.7 mg, 0.17 mmol, 0.6 eq), Xantphos (198.0 mg, 0.34 mmol, 1.2 eq) and K3PO4 (362.7 mg, 1.68 mmol, 6.0 eq) were added to a microwave tube in sequence, and the reaction was carried out at 110 ° C. for 2 h. The mixture was filtered, concentrated to remove the solvent, and purified by column chromatography (EA / MeOH = 20 / 1, v / v) to give compound 8 (20.21 mg). Yield: 16.2%; MS: m / z 441.4 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ8.73 (d, J=15.2Hz, 1H), 8.44-8.39 (m, 1H), 8.05-7.94 (m, 1H) ), 7.87-7.67(m, 1H), 7.48(s, 1H), 6-27-6.17(m, 1H), 4.63-4.52(m, 1H), 3.35-3.28( m, 1H), 3.22 (d, J = 3.8Hz, 3H), 3.12 (d, J = 2.5Hz, 3H), 2.56 (d, J = 7.0Hz, 2H), 2.09-2.0 3(m, 3H), 1.81-1.70(m, 3H), 1.67-1.60(m, 4H), 1.45-1.34(m, 1H), 0.91-0.84(m, 1H).

[0247] Example 9: Preparation of Compound 9

[0248] (1) Synthesis route of compound 9-1

[0249] Synthesis of compound 9-1a:

[0250] Compound 1-2c (10.00 g, 36.11 mmol, 1.0 eq), DCE (50 mL), and cyclopropylamine (4.12 g, 72.22 mmol, 2.0 eq) were added to the reaction flask in sequence. The reaction system was heated to 80°C and reacted for 2 h. The system was then cooled to room temperature, stirred with water (100 mL), extracted with DCM (150 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated to afford compound 9-1a (10.2 g). Yield: 89.5%; MS: m / z 315.1 [M+1] + ;

[0251] Synthesis of compound 9-1b:

[0252] Compound 9-1a (10.0 g, 31.85 mmol, 1.0 eq), anhydrous EtOH (100 mL), and anhydrous SnCl2 (18.11 g, 95.54 mmol, 3 eq) were added to the reaction flask in sequence and reacted at 90°C for 2 h. After cooling to room temperature, the reaction system was poured into water / EA (1000 mL / 1000 mL) and stirred. The mixture was filtered and the filter cake was rinsed with EA three times. The retained liquid phase was extracted with EA (150 mL*5). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford compound 9-1b (5.20 g). Yield: 57.5%; MS: m / z 285.1 [M+1] + ;

[0253] Synthesis of compound 9-1c:

[0254] Under nitrogen protection, compound 9-1b (5.2 g, 18.31 mmol, 1.0 eq) and DIPEA (8.5 mL, 36.62 mmol, 2 eq) were added to the reaction flask in sequence, and anhydrous DCM (60 mL) was used as solvent. Then, 2-bromopropionyl bromide (3.74 g, 27.46 mmol, 1.5 eq) was added under ice bath stirring. After the addition, the mixture was moved to room temperature and reacted for 2 h. The reaction system was poured into cold water (100 mL), extracted with DCM (100*3), and the mixture was combined. The organic phase was dried over anhydrous Na2SO4, filtered, and spun down to dryness. MeCN (20 mL) was then added, followed by DIPEA (9 mL) and the temperature was raised to 80°C for overnight reaction. After completion of the reaction, the reaction system was poured into water (30 mL) and extracted with DCM (50 mL*3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE / EA = 1 / 1, v / v) to give compound 9-1c (2.9 g) in a yield of 46.8%; MS: m / z 339.1 [M+1]. + ;

[0255] The synthesis operation of compound 9-1d to compound 9-1 is basically the same as the synthesis operation of compound 1-2e to compound 1-2 in Comparative Example 1.

[0256] Compound 9-1d (yield 88.2%), MS: m / z 353.0 [M+1] + Compound 9-1e (yield 82.8%), MS: m / z 316.1 [M+1] + Compound 9-1f (yield 86.4%), MS: m / z 299.1 [M+1] + Compound 9-1 (yield 75.6%), MS: m / z 317.1 [M+1] + ;

[0257] (2) Synthesis route of compound 9

[0258] Under nitrogen protection, compound 9-1 (100.0 mg, 0.32 mmol, 1.0 eq), Tol (6 mL), compound 1-5 (101.0 mg, 0.64 mmol, 2.0 eq), Pd(dba)3 (172.8 mg, 0.20 mmol, 0.6 eq), Xantphos (219.8 mg, 0.38 mmol, 1.2 eq) and K3PO4 (398.9 mg, 1.92 mmol, 6.0 eq) were added to a microwave tube in sequence, and the reaction was carried out at 110 ° C. for 2 h. The mixture was filtered, concentrated to remove the solvent, and purified by column chromatography (EA / MeOH = 20 / 1, v / v) to give compound 9 (22.11 mg). Yield: 15.9%; MS: m / z 441.4 [M+1] + .

[0259] Example 10: Preparation of Compound 10

[0260] (1) Synthesis route of compound 10-1

[0261] Synthesis of compound 10-1a:

[0262] The synthesis operation of compound 1-2d in Comparative Example 1 was basically the same to obtain compound 10-1a (5.84 g) with a yield of 95%; MS: m / z 373.1 [M+1] + ;

[0263] Synthesis of compound 10-1b:

[0264] Compound 10-1a (3.20 g, 8.60 mmol, 1.0 eq) was added to a reaction flask, followed by iron powder (1.45 g, 3 eq). AcOH (30 mL) was used as solvent and the reaction was carried out at 90°C for 1 h. The reaction system was poured into cold water (100 mL), and the pH value was adjusted to 8 with potassium carbonate. The mixture was extracted with EA (100 mL*3). The organic phases were combined, washed three times with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 10-1b (2.80 g). Yield: 100%; MS: m / z 311.2 [M+1] + ;

[0265] The synthesis procedures of compound 10-1c to compound 10-1 are basically the same as the synthesis procedures of compound 1-2e to compound 1-2 in Comparative Example 1.

[0266] 10-1c (yield 82.4%), MS: m / z 339.0 [M+1] + ; 10-1d (yield 86.5%), MS: m / z 303.1 [M+1] +; 10-1e (yield 83.5%), MS: m / z 285.1 [M+1] + ; 10-1 (yield 77.8%), MS: m / z 303.1 [M+1] + ;

[0267] (2) Synthesis route of compound 10

[0268] Under nitrogen protection, compound 10-1 (100.0 mg, 0.33 mmol, 1.0 eq), Tol (6 mL), compound 1-5 (106.0 mg, 0.66 mmol, 2.0 eq), Pd(dba)3 (181.9 mg, 0.20 mmol, 0.6 eq), Xantphos (229.8 mg, 0.40 mmol, 1.2 eq) and K3PO4 (412.6 mg, 1.98 mmol, 6.0 eq) were added to a microwave tube in sequence, and the reaction was carried out at 110 ° C. for 2 h. The mixture was filtered, concentrated to remove the solvent, and purified by column chromatography (EA / MeOH = 20 / 1, v / v) to give compound 10 (55.01 mg). Yield: 39.1%; MS: m / z 427.4 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ7.91 (s, 1H), 7.78 (d, J=7.9Hz, 1H), 7.62 (d, J=7.6Hz, 2H), 7.33 (t, J=7.8Hz, 1H), 7.00 (s, 1H), 5.59 (t, J=7.0Hz, 1H), 3.52 (s, 3H), 2.82 (s, 3H), 2.69 (s, 3H), 2.60 (s, 3H), 1.58 (d, J=7.0Hz, 3H), 1.45-1.31 (m, 2H), 1.29-1.08 (m, 2H).

[0269] Example 11: Preparation of Compound 11

[0270] (1) Synthesis route of compound 11-1

[0271] The synthesis operations of compound 11-1a to compound 11-1 are basically the same as the synthesis operations of compound 1-2f to compound 1-2 in Comparative Example 1.

[0272] Compound 11-1a (yield 89.7%), MS: m / z 413.0 [M+1] + Compound 11-1b (yield 85.5%), MS: m / z 405.2 [M+1] +Compound 11-1c (yield 84.7%), MS: m / z 377.1 [M+1] + Compound 11-1d (yield 65.7%), MS: m / z 359.2 [M+1] + Compound 11-1 (yield 77.4%), MS: m / z 277.1 [M+1] + ;

[0273] (2) Synthesis route of compound 11

[0274] Synthesis of compound 11-1e:

[0275] Under nitrogen protection, compound 11-1 (100.0 mg, 0.36 mmol, 1.0 eq), Tol (6 mL), compound 1-5 (116.0 mg, 0.72 mmol, 2.0 eq), Pd(dba)3 (199.0 mg, 0.22 mmol, 0.6 eq), Xantphos (251.6 mg, 0.43 mmol, 1.2 eq) and K3PO4 (4461.3 mg, 2.16 mmol, 6.0 eq) were added to a microwave tube in sequence, and the reaction was carried out at 110°C for 2 h. The mixture was filtered, concentrated to remove the solvent, and purified by column chromatography (EA / MeOH = 10 / 1, v / v) to give compound 11-1e (23.11 mg) in a yield of 15.9%; MS: m / z 401.4 [M+1] + ;

[0276] Synthesis of compound 11:

[0277] Compound 11-1e (23.0 mg, 0.06 mmol, 1 eq), MnO2 (50.0 mg, 0.6 mmol, 10 eq) and DCM (5 mL) were added to the reaction flask and stirred at room temperature for 1 h. The mixture was filtered through a pad of celite, rinsed with DCM (30 mL), and the filtrate was dried and purified by column chromatography (EA / MeOH = 10 / 1, v / v) to give compound 11 (7.35 mg) in a yield of 32.1%; MS: m / z 399.4 [M+1] + ; 1H NMR (400MHz, DMSO-d6): δ8.36 (s, 1H), 8.31 (s, 1H), 7.87 (d, J = 6.6Hz, 1H), 7.80 (d, J = 7.9Hz, 1H), 7.63 (d, J = 7.7Hz, 1H) , 7.34 (t, J=7.7Hz, 1H), 5.67-5.63 (m, 1H), 3.80 (s, 3H), 2.71 (s, 3H), 2.69 (s, 3H), 2.54 (s, 3H), 1.62 (d, J=7.0Hz, 3H).

[0278] Comparative Example 2: Preparation of positive control compound 2

[0279] The positive control compound 2 (39.5 mg) was synthesized in a yield of 24% by following the same procedures as for compound 11 except that compound 1-5 was replaced by compound 1-1; MS: m / z 428.2 [M+1] + .

[0280] Example 12: Preparation of Compound 12

[0281] (1) Synthesis route of compound 12-1

[0282] Synthesis of compound 12-1b:

[0283] Compound 12-1a (20.0 g, 114.2 mmol, 1.0 eq) and AcOH (150 mL) were added to a reaction flask at 10°C, followed by the slow addition of sodium cyanoborohydride (32.6 g, 342.7 mmol, 3 eq). After the addition, the mixture was allowed to react at room temperature for 2 h. The reaction system was poured into ice water (500 mL), and the pH was adjusted to 8 with solid sodium carbonate. The mixture was extracted with EA (300 mL*3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography (PE / EA=3 / 1, v / v) to give compound 12-1b (11.3 g) in a yield of 55.9%; MS: m / z 178.2 [M+1]. + ;

[0284] Synthesis of compound 12-1c:

[0285] Compound 12-1b (7.00 g, 39.5 mmol, 1.0 eq), tetrahydrofuran-3(2H)-one (6.81 g, 779.1 mmol, 2 eq), MeOH (80 mL) and AcOH (2 mL) were added to the reaction flask in sequence. Sodium triacetoxyborohydride (22.43 g, 118.6 mmol, 3 eq) was added slowly in batches at 0°C-10°C. The temperature was naturally warmed to room temperature after the addition. The reaction was allowed to react overnight. The reaction system was spin-dried, diluted with water (100 mL), and extracted with EA (150 mL*3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography (PE / EA=5 / 1, v / v) to give compound 12-1c (4.16 g) in a yield of 42.6%; MS: m / z 248.2[M+1]. + ;

[0286] Synthesis of compound 12-1d:

[0287] Compound 12-1c (4.1 g, 16.6 mmol, 1.0 eq) and DMF (40 mL) were added to the reaction flask, and NBS (3.25 g, 18.3 mmol, 1.1 eq) was slowly added under ice bath. After the addition, the mixture was moved to room temperature and reacted for 2 h. The reaction system was poured into cold water (50 mL) and extracted with EA (50 mL*3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (60 mL*3), dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography (PE / EA=2 / 1, v / v) to give compound 12-1d (3.9 g) in a yield of 72.4%; MS: m / z 326.0 [M+1]. + ;

[0288] The synthesis operation of compound 12-1e to compound 12-1 is basically the same as the synthesis operation of compound 1-2g to compound 1-2 in Comparative Example 1.

[0289] Compound 12-1e (yield 74.4%), MS: m / z 318.2 [M+1] + Compound 12-1f (yield 85.3%), MS: m / z 290.1 ​​[M+1] + Compound 12-1g (yield 84.5%), MS: m / z 272.1 [M+1] + Compound 12-1 (yield 77.4%), MS: m / z 290.1 ​​[M+1] + ;

[0290] (2) Synthesis route of compound 12

[0291] Under nitrogen protection, compound 12-1 (30.0 mg, 0.11 mmol, 1.0 eq), Tol (6 mL), compound 1-1 (39.2 mg, 0.22 mmol, 2.0 eq), Pd(dba)3 (57.03 mg, 0.07 mmol, 0.6 eq), Xantphos (72.1 mg, 0.13 mmol, 1.2 eq) and K3PO4 (132.2 mg, 0.65 mmol, 6.0 eq) were added to a microwave tube in sequence, and the reaction was carried out at 110 ° C. for 2 h. The mixture was filtered, concentrated to remove the solvent, and purified by column chromatography (EA / MeOH = 10 / 1, v / v) to give compound 12 (2.00 mg). Yield: 4.4%; MS: m / z 443.4 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ7.75 (s, 1H), 7.70-7.66 (m, 2H), 7.58 (s, 1H), 7.48 (t, J=7 .1Hz, 1H), 7.26 (t, J=8.2Hz, 1H), 7.25 (t, J=54.1Hz, 1H), 5.66-5.59 (m, 1H), 4.80-4 .74 (m, 1H), 4.01-3.93 (m, 1H), 3.92-3.83 (m, 2H), 3.81-3.65 (m, 3H), 3.18 (t, J=8. 3Hz, 2H), 2.57 (s, 3H), 2.40-2.29 (m, 1H), 2.10-1.99 (m, 1H), 1.66 (d, J=7.0Hz, 3H).

[0292] Example 13: Preparation of Compound 13

[0293] Compound 13 (19.9 mg) was synthesized in a 51% yield by following the same procedures as for compound 12, except that compound 1-1 was replaced by compound 1-5. MS: m / z 414.4 [M+1] + ; 1H NMR (400MHz, DMSO-d6): δ7.94 (s, 1H), 7.80 (d, J=7.9Hz, 1H), 7.74 (s, 1H), 7.64 (d, J=7 .6Hz, 1H), 7.55 (s, 1H), 7.35 (t, J=7.8Hz, 1H), 5.44-5.38 (m, 1H), 4.82-4.77 (m, 1H), 3 .99(q, J=7.7Hz, 1H), 3.94-3.84(m, 2H), 3.78(q, J=8.5Hz, 3H), 3.21(t, J=8.3Hz, 2H), 2.69 (s, 3H), 2.61 (s, 3H), 2.40-2.30 (m, 1H), 2.09-2.04 (m, 1H), 1.61 (d, J=6.9Hz, 3H).

[0294] Example 14: Preparation of Compound 14

[0295] Compound 13 (25.0 mg, 0.06 mmol, 1 eq), MnO2 (50.0 mg, 0.6 mmol, 10 eq) and DCM (5 mL) were added to the reaction flask and stirred at room temperature for 1 h. The mixture was filtered through a pad of celite, rinsed with DCM (30 mL), and the filtrate was dried and purified by column chromatography (EA / MeOH = 10 / 1, v / v) to give compound 14 (10.66 mg) in a yield of 42.8%; MS: m / z 412.4 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ8.95 (s, 1H), 8.37 (s, 1H), 7.98-7.94 (m, 2H), 7.86 (d, J= 8.0, 1H), 7.61 (d, J=7.6Hz, 1H), 7.32 (t, J=7.8Hz, 1H), 6.90 (d, J=3.3Hz, 1H), 5.6 1(t, J=6.5Hz, 1H), 5.575.49(m, 1H), 4.22-4.10(m, 2H), 4.03-3.91(m, 2H), 2.75( s, 3H), 2.70 (s, 3H), 2.69-2.61 (m, 1H), 2.30-2.19 (m, 1H), 1.64 (d, J=6.9Hz, 3H).

[0296] Example 15: Preparation of Compound 15

[0297] Compound 15 (9.9 mg) was synthesized in a 43% yield by following the same procedures as for compound 14, except that compound 13 was replaced by compound 12. MS: m / z 441.4 [M+1]+ ; 1 H NMR (400MHz, DMSO-d6): δ9.17 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 7.97 (dd, J=3.4, 1.2 Hz, 1H), 7.76 (t, J=7.7Hz, 1H), 7.49 (t, J=7.1Hz, 1H), 7.27 (s, 1H), 7.25 (t, J=54.2Hz, 1H), 6.92 (d, J=3.3Hz, 1H), 5.78-5.71 (m, 1H), 5.64-5.58 (m, 1H), 4.20-4.11 (m, 2H), 4 .04-3.88 (m, 2H), 2.77 (s, 3H), 2.74-2.61 (m, 1H), 2.26 (s, 1H), 1.73 (d, J=7.0Hz, 3H).

[0298] Example 16: Preparation of Compound 16

[0299] (1) Synthesis route of compound 16-1

[0300] Synthesis of compound 16-1b:

[0301] Compound 16-1a (5.0 g, 26.2 mmol, 1.0 eq), CH3I (7.43 g, 52.4 mmol, 2.0 eq), and DMF (100 mL) were added to a reaction flask. The reaction system was cooled to 0°C, and 60% NaH (2.10 g, 25.4 mmol, 2.0 eq) was slowly added in portions. The reaction was maintained at 0°C for 1 h. The reaction solution was added to ice water (200 mL) and extracted with EA (200 mL*3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (300 mL*3), dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography (PE / EA = 2 / 1, v / v) to obtain compound 16-1b (5.1 g) in a yield of 89.1%; MS: m / z 220.0 [M+1]. + ;

[0302] Synthesis of compound 16-1c:

[0303] Under nitrogen, compound 16-1b (5.0 g, 22.8 mmol, 1.0 eq) and anhydrous THF (100 mL) were added to the reaction flask. The temperature of the system was lowered to -15°C, and sodium borohydride (2.6 g, 68.7 mmol, 3 eq) was slowly added portionwise. Boron trifluoride etherate (11.3 g, 79.6 mmol, 3.5 eq) was then slowly added dropwise to the system. After the addition, the mixture was warmed to room temperature and reacted for 4 h. The reaction system was cooled to 0°C, the pH was adjusted to 4 with 1 M HCl, and the mixture was stirred at room temperature for 2 h. The mixture was extracted with EA (150 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography (PE / EA = 2 / 1, v / v) to afford compound 16-1c (3.88 g) in an 82.9% yield. MS: m / z 206.1 [M+1]. + ;

[0304] Synthesis of compound 16-1d:

[0305] Compound 16-1c (3.8 g, 18.5 mmol, 1.0 eq) and MeCN (50 mL) were added to the reaction flask, and NBS (3.3 g, 18.5 mmol, 1.0 eq) was slowly added at -30°C. After reacting for 0.5 h, the reaction system was poured into cold water (50 mL) and extracted with EA (50 mL*3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography (PE / EA=5 / 1, v / v) to give compound 16-1d (3.0 g) in a yield of 72.4%; MS: m / z 283.8 [M+1]. + ;

[0306] Synthesis of compound 16-1e:

[0307] Compound 16-1d (3.0 g, 10.5 mmol, 1.0 eq), tetrahydrofuran-3(2H)-one (1.82 g, 21.1 mmol, 2 eq), MeOH (40 mL) and AcOH (0.5 mL) were added sequentially to the reaction flask. Sodium cyanoborohydride (2.6 g, 41.99 mmol, 4 eq) was added slowly in portions at 0°C-10°C. After the addition, the temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. The reaction system was spin-dried, diluted with water (100 mL), and extracted with EA (150 mL*3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography (PE / EA=10 / 1, v / v) to give compound 16-1e (4.1 g) in a yield of 80.1%; MS: m / z 353.9 [M+1]. + ;

[0308] The synthesis procedures of compound 16-1f to compound 16-1 are basically the same as the synthesis procedures of compound 1-2f to compound 1-2 in Comparative Example 1.

[0309] Compound 16-1f (yield 73.3%), MS: m / z 346.2 [M+1] + Compound 16-1g (yield 82.8%), MS: m / z 317.2 [M+1] + Compound 16-1h (yield 78.4%), MS: m / z 300.1 [M+1] + Compound 16-1 (yield 74.6%), MS: m / z 318.1 [M+1] + ;

[0310] (2) Synthesis route of compound 16

[0311] Under nitrogen protection, compound 16-1 (100.0 mg, 0.315 mmol, 1.0 eq), Tol (6 mL), compound 1-5 (101.0 mg, 0.63 mmol, 2.0 eq), Pd2(dba)3 (173.3 mg, 0.19 mmol, 0.6 eq), Xantphos (218.9 mg, 0.38 mmol, 1.2 eq) and K3PO4 (401.6 mg, 1.89 mmol, 6.0 eq) were added to a microwave tube in sequence, and the reaction was carried out at 110°C for 2 h. The mixture was filtered, concentrated to remove the solvent, and purified by column chromatography (EA / MeOH=20 / 1, v / v) to give compound 16 (32.51 mg). Yield: 23.4%; MS: m / z 442.4 [M+1] + .

[0312] Example 17: Preparation of Compound 17

[0313] The reaction conditions were similar to those in Example 12 except that tetrahydrofuran-3(2H)-one was replaced by acetone and compound 1-1 was replaced by compound 1-5. Compound 17 (18.7 mg) was obtained in a yield of 24.7%. MS: m / z 386.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6): δ7.85-7.81 (m, 1H), 7.77 (d, J=8.1Hz, 1H), 7.71 (s , 1H), 7.64 (d, J=7.9Hz, 1H), 7.40 (s, 1H), 7.35 (t, J=7.9Hz, 1H), 5.44-5.38 (m, 1H), 4.30-4.23 (m, 1H), 3.71 (t, J = 8.4Hz, 2H), 3.20 (t, J = 8.5Hz, 2H), 2. 68 (s, 3H), 2.58 (d, J=7.8Hz, 3H), 1.59 (d, J=7.0Hz, 3H), 1.30-1.26 (m, 6H).

[0314] Compound 17-1a (yield 76.5%), MS: m / z 220.1 [M+1] + Compound 17-1b (yield 77.1%), MS: m / z 298.0 [M+1] + Compound 17-1c (yield 80.3%), MS: m / z 290.2 [M+1] + Compound 17-1d (yield 84.8%), MS: m / z 262.1 [M+1] + Compound 17-1e (yield 72.5%), MS: m / z 244.1 [M+1] + Compound 17-1f (yield 73.9%), MS: m / z 262.1 [M+1] + .

[0315] Example 18: Preparation of Compound 18

[0316] The reaction conditions were similar to those in Example 12 except that tetrahydrofuran-3(2H)-one was replaced by cyclobutanone and compound 1-1 was replaced by compound 1-5. Compound 18 (15.3 mg) was obtained in a yield of 20.8%. MS: m / z 398.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6): δ8.05 (d, J=6.6Hz, 1H), 7.83 (d, J=7.9Hz, 1H), 7.71 ( s, 1H), 7.63 (d, J=7.7, 1H), 7.47 (s, 1H), 7.35 (t, J=7.8Hz, 1H), 5.44-5.34 (m , 1H), 4.59-4.53 (m, 1H), 3.87-3.82 (m, 2H), 3.21 (t, J=8.3Hz, 2H), 2.68 (s, 3 H), 2.61 (s, 3H), 2.39-2.23 (m, 4H), 1.79-1.70 (m, 2H), 1.61 (d, J=6.9Hz, 3H).

[0317] Compound 18-1a (yield 72.5%), MS: m / z 232.1 [M+1] + Compound 18-1b (yield 77.4%), MS: m / z 310.0 [M+1] + Compound 18-1c (yield 81.4%), MS: m / z 302.2 [M+1] + Compound 18-1d (yield 85.3%), MS: m / z 274.1 [M+1] + Compound 18-1e (yield 70.5%), MS: m / z 256.1 [M+1] + Compound 18-1f (yield 71.4%), MS: m / z 274.1 [M+1] + .

[0318] Example 19: Preparation of Compound 19

[0319] Except that tetrahydrofuran-3(2H)-one was replaced by cyclopentanone and compound 1-1 was replaced by compound 1-5, other conditions were basically the same as those in Example 12 to prepare compound 19 (25.3 mg) with a yield of 18.3%; MS: m / z 412.2 [M+1] + .

[0320] Compound 19-1a (yield 68.8%), MS: m / z 246.1 [M+1] + Compound 19-1b (yield 71.5%), MS: m / z 324.0 [M+1] + Compound 19-1c (yield 78.3%), MS: m / z 316.2 [M+1] + Compound 19-1d (yield 88.5%), MS: m / z 288.1 [M+1] +Compound 19-1e (yield 72.7%), MS: m / z 270.1 [M+1] + Compound 19-1f (yield 73.6%), MS: m / z 288.1 [M+1] + .

[0321] Example 20: Preparation of Compound 20

[0322] Except that tetrahydrofuran-3(2H)-one was replaced by tetrahydro-2H-pyran-3-one and compound 1-1 was replaced by compound 1-5, other conditions were basically the same as those in Example 12 to prepare compound 20 (15.3 mg) with a yield of 11.8%; MS: m / z 428.2 [M+1] + .

[0323] Compound 20-1a (yield 77.4%), MS: m / z 262.1 [M+1] + Compound 20-1b (yield 76.6%), MS: m / z 340.0 [M+1] + Compound 20-1c (yield 78.3%), MS: m / z 332.2 [M+1] + Compound 20-1d (yield 88.2%), MS: m / z 304.1 [M+1] + Compound 20-1e (yield 72.5%), MS: m / z 286.1 [M+1] + Compound 20-1f (yield 75.3%), MS: m / z 304.1 [M+1] + .

[0324] Example 21: Preparation of Compound 21

[0325] The reaction conditions were similar to those in Example 12 except that tetrahydrofuran-3(2H)-one was replaced by tetrahydro-2H-pyran-4-one and compound 1-1 was replaced by compound 1-5. Compound 21 (9.3 mg) was obtained in a yield of 8.6%. MS: m / z 428.2 [M+1] + .

[0326] Compound 21-1a (yield 78.8%), MS: m / z 262.1 [M+1] + Compound 21-1b (yield 75.8%), MS: m / z 340.0 [M+1] + Compound 21-1c (yield 79.3%), MS: m / z 332.2 [M+1] +Compound 21-1d (yield 87.4%), MS: m / z 304.1 [M+1] + Compound 21-1e (yield 75.3%), MS: m / z 286.1 [M+1] + Compound 21-1f (yield 73.9%), MS: m / z 304.1 [M+1] + .

[0327] Example 22: Preparation of Compound 22

[0328] Except that tetrahydrofuran-3(2H)-one was replaced with N-Cbz-pyrrolidin-3-one, other conditions were basically the same as those in Example 12 to obtain compound 22a (45 mg). MS: m / z 547.3 [M+1] + ;

[0329] Compound 22a (45 mg), palladium carbon (20 mg) and methanol (5 mL) were added to a reaction flask, and the hydrogen atmosphere was replaced three times. The reaction was carried out at 55°C for 48 h. The reaction was completed under mass spectrometry monitoring and purified (dichloromethane / methanol: 5 / 1, v / v) to obtain compound 22 (5.3 mg). MS: m / z 427.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ7.94 (s, 1H), 7.80 (d, J=7.9Hz, 1H), 7.74 (s, 1H), 7.64 (d, J=7.6H z, 1H), 7.55 (s, 1H), 7.35 (t, J=7.8Hz, 1H), 5.44-5.38 (m, 1H), 4.82-4.77 (m, 1H), 3.99 (q, J=7.7Hz, 1H), 3.94-3.84 (m, 2H), 3.78 (q, J=8.5Hz, 3H), 3.57 (s, 3H), 3.21 (t, J=8.3Hz, 2H ), 2.69 (s, 3H), 2.61 (s, 3H), 2.40-2.30 (m, 1H), 2.09-2.04 (m, 1H), 1.61 (d, J=6.9Hz, 3H).

[0330] Compound 22-1a (yield 69.7%), MS: m / z 381.2 [M+1] + Compound 22-1b (yield 67.4%), MS: m / z 459.1 [M+1] + Compound 22-1c (yield 71.5%), MS: m / z 451.2 [M+1] + Compound 22-1d (yield 84.4%), MS: m / z 423.2 [M+1]+ Compound 22-1e (yield 79.5%), MS: m / z 405.2 [M+1] + Compound 22-1f (yield 70.7%), MS: m / z 423.1 [M+1] + .

[0331] Example 23: Preparation of Compound 23

[0332] Except that 1-1 was replaced by 1-3, other conditions were basically the same as those in Example 12 to obtain compound 23a (18.0 mg) with a yield of 26.5%; MS: m / z 600.3 [M+1] + ;

[0333] Compound 23a (18 mg) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was reacted at room temperature for 2 h. After completion of the reaction, saturated sodium bicarbonate solution was added to adjust the pH to 7-8. The mixture was extracted with dichloromethane (10 mL*3), concentrated, and purified by thin-layer chromatography (dichloromethane / methanol = 5 / 1, v / v) to afford compound 23 (13 mg) in a yield of 87%. MS: m / z 500.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ7.94 (s, 1H), 7.82-7.80 (m, 2H), 7.74 (s, 1H), 7.66-7.63 (m, 2H) , 7.55(s, 1H), 7.32(s, 1H), 7.25(s, 1H), 5.44-5.38(m, 1H), 4.82-4.77(m, 1H), 4.25(s, 1 H), 3.99 (q, J=7.7Hz, 1H), 3.94-3.84 (m, 4H), 3.78 (q, J=8.5Hz, 3H), 3.46 (s, 3H), 3.21 (t , J=8.3Hz, 2H), 2.69 (s, 3H), 2.40-2.30 (m, 1H), 2.09-2.04 (m, 1H), 1.61 (d, J=6.9Hz, 3H).

[0334] Experimental Example 1: KRAS-G12C / SOS1 IC 50 Activity test

[0335] The inhibition rate of KRAS-G12C / SOS1 was detected using the Binding Assay method to evaluate the inhibitory effect of the compounds of the present invention on KRAS-G12C / SOS1.

[0336] 1.1 Experimental Materials

[0337] 1.1.1 Reagents and consumables

[0338] 1.1.2 Instruments

[0339] Centrifuge (manufacturer: Eppendorf, model: 5430)

[0340] Microplate reader (Manufacturer: Perkin Elmer, Model: Envision )

[0341] Echo 550 (Manufacturer: Labcyte, Model: Echo 550)

[0342] 1.2 Kinase reaction process

[0343] (1) Compound Preparation: Test compound concentration gradients were set at 500 nM, 125 nM, 31.25 nM, 7.81 nM, 1.95 nM, 0.488 nM, 0.122 nM, and 0.03 nM. The test compounds were diluted to 200-fold the final concentration in 100% DMSO in a 384-well plate. Using an Echo550 dispenser, 50 nL of the compound at 200-fold the final concentration was transferred to the target 384-well plate. 50 nL of 100% DMSO was added to each of the negative and positive control wells.

[0344] (2) Prepare a Tag1-SOS1 solution with a final concentration of 4 times using dilution buffer.

[0345] (3) Add 2.5 μl of Tag1-SOS1 solution at 4 times the final concentration to a 384-well plate.

[0346] (4) Prepare a Tag2-KRAS-G12C solution with a final concentration of 4 times using dilution buffer.

[0347] (5) Add 2.5 μl of Tag2-KRAS-G12C solution at 4 times the final concentration to the compound wells; add 2.5 μl of dilution buffer to the negative control wells.

[0348] (6) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 15 minutes.

[0349] (7) Prepare 1x final concentration of Anti-Tag1-TB3+ solution and 1x final concentration of Anti-Tag2-XL665 solution using detection buffer. Mix the two solutions and add 5 μl of Mix solution to each well.

[0350] (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 120 minutes.

[0351] (9) Read the results using an Envision microplate reader and record the ratio of Em665 to Em620.

[0352] 1.3 Data Analysis

[0353] 1.3.1 Inhibition rate calculation formula

[0354] Wherein: Min signal represents the average absorbance of pure DMSO wells; Max signal represents the average absorbance of enzyme, substrate, detection reagent, and DMSO mixture wells; Compound signal represents the average absorbance of sample wells.

[0355] 1.3.2 Fitting the dose-effect curve

[0356] The log value of compound concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis. The log (inhibitor) vs. response-Variable slope of the analysis software GraphHPad Prism 5 was used to fit the dose-effect curve to obtain the IC value of each compound on the enzyme activity. 50 value.

[0357] The fitting formula is: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)×HillSlope))

[0358] Among them: Top represents the top platform, and the Top standard of the curve is generally between 80% and 120%; Bottom represents the bottom platform, and the Bottom of the curve is generally between -20% and 20%.

[0359] In vitro inhibitory activity test results (IC 50 (represented) as shown in Table 1.

[0360] Table 1. Effects of the compounds of the present invention on KRAS-G12C / SOS1

[0361] As shown in Table 1, the compounds of the present invention have strong inhibitory activity against KRAS-G12C / SOS1 and are significantly better than positive control compound 2 and positive control compound 3 (positive control compound 3 is derived from compound 107 of patent CN115536660A).

[0362] Experimental Example 2: Effects of Compounds on Phosphorylation of ERK, a Downstream Protein of SOS1 in NCI-H358 and MKN1 Cells

[0363] 1. Experimental materials, consumables and instruments

[0364] 1.1 Materials

[0365] 1.2 Consumables

[0366] 1.3 Instruments

[0367] 2. Experimental Methods

[0368] The final concentrations of the test compounds were 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.123 μM, 0.041 μM, 0.0137 μM, 0.0045 μM, 0.0015 μM, and 0.00051 μM. After incubation of the serially diluted compounds with the cells overnight for 3 hours, the cells were fixed, permeabilized, blocked, and incubated overnight in the primary antibody. Fluorescence signals were then detected using an infrared fluorescent dye-labeled secondary antibody using the Odyssey Dual-Color Infrared Fluorescence Imaging System.

[0369] The specific steps are as follows:

[0370] Day 1: NCI-H358 / MKN1 cells were seeded into 384-well cell culture plates and cultured overnight in a 37°C, 5% carbon dioxide cell culture incubator.

[0371] The next day, the compound was added to the plate using Echo550 and incubated for another 3 hours in a 37°C, 5% CO2 incubator. Finally, the cell culture plate was fixed with paraformaldehyde, permeabilized with methanol, and blocked with blocking buffer. A mixture of primary antibodies (rabbit anti-pERK, mouse anti-GAPDH) was added and incubated overnight at 4°C.

[0372] Day 3: Discard the primary antibody and add a secondary antibody mixture (goat anti-rabbit 800CW, goat anti-mouse 680RD). Incubate at room temperature in the dark. Finally, wash with PBST, centrifuge the cell culture plate upside down for 1 minute, and read the fluorescence signal value using Odyssey CLx.

[0373] 3. Data Analysis

[0374] ERK phosphorylation was calculated according to the following formula:

[0375] Relative inhibition rate (%) = (fluorescence signal ratio of compound - average value of positive control) / (average value of negative control - average value of positive control) * 100%;

[0376] Among them: the negative control is DMSO, and the positive control is the positive control compound 1 mentioned above.

[0377] XLFit 5.0 calculates IC by fitting parameter formula 50 value:

[0378] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope));

[0379] Wherein: X is the log value of compound concentration, Y is the average relative inhibition rate of p-ERK between duplicate wells, Bottom is the minimum inhibition rate of the compound, and Top is the maximum inhibition rate of the compound.

[0380] 4. Experimental Results

[0381] IC of the compounds of the present invention 50 The results are shown in Table 2.

[0382] Table 2. Effects of the compounds of the present invention on the phosphorylation of ERK, a downstream protein of SOS1, in NCI-H358 and MKN1 cells

[0383] As shown in Table 2, the compounds of the present invention can significantly inhibit the phosphorylation of pERK downstream of NCI-H358 and MKN1, and have excellent anti-cell proliferation activity.

[0384] Experimental Example 3: Effects of Compounds on Cytochrome P450 Enzymes CYP3A4, CYP2B6, and CYP1A2

[0385] 1. Experimental Materials

[0386] Human liver microsomes, catalog number 452117, were purchased from Corning;

[0387] NADPH, product number BD11658, was purchased from Bidler.

[0388] 2. Experimental Methods

[0389] (1) Add 1 μL of 2 mM test compound or quality control inhibitor (ketoconazole for CYP3A4 and CYP2B6 inhibitors, furafylline for CYP1A2 inhibitor) to a final concentration of 10 μM; DMSO was used as a negative control. All experiments were performed in duplicate.

[0390] (2) Prepare a mixed solution system containing phosphate, ultrapure water, MgCl2, and human liver microsomes according to the table below;

[0391] (3) Take 1 μL of the substrate stock solution prepared as shown in the table below and add it to the above mixture;

[0392] (4) Preheat the reaction system in a 37°C water bath for 5 min, then add 20 μL of 10 mM NADPH solution to start the reaction. The final NADPH concentration is 1 mM and incubate at 37°C for the time shown in the table above.

[0393] (5) After the incubation, at the designated time point, 400 μL of cold methanol (internal standard, 500 nM Labetalol, 100 nM Alprazolam, and 2 μM Ketoprofen) was added to terminate the reaction. The sample was centrifuged at 3220 g for 60 min to precipitate the protein. 100 μL of the supernatant was taken and diluted with 100 μL of ultrapure water (based on the peak shape and signal intensity of LC-MS / MS) for LC-MS / MS analysis.

[0394] 3. Experimental Results

[0395] IC of the compounds of the present invention 50 The results are shown in Table 3.

[0396] Table 3. Inhibition rate of CYP enzymes by the compounds of the present invention

[0397] As shown in Table 3, under the condition of 10 μM, the compounds of the present invention did not show strong inhibition on each CYP enzyme subtype, and the DDI risk was low.

[0398] Experimental Example 4: Plasma kinetic study of the compound in CD-1 mice

[0399] 1. Experimental Animals

[0400] CD-1 mice, SPF grade, male, were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd.

[0401] 2. Experimental Methods

[0402] The pharmacokinetic characteristics of the compounds in rodents were tested following oral and intravenous administration using standard protocols.

[0403] In the experiment, the candidate compounds were formulated into clear solutions and administered orally and intravenously to mice in a pH 4.5 acetate buffer. Six mice were administered each compound orally and intravenously, with an oral dose of 10 mg / kg (drug solution concentration of 1 mg / mL, administration volume of 10 μL / g) and an intravenous dose of 3 mg / kg (drug solution concentration of 0.3 mg / mL, administration volume of 10 μL / g).

[0404] Sampling was performed at 0.0833 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. Whole blood samples were immediately placed on ice after collection and centrifuged at 4 ° C and 2000 g for 5 min within 0.5 h after collection to separate the plasma. The upper layer sample was collected into a sample tube, frozen in a -10 to -30 ° C refrigerator within 0.5 h, and transferred to a -60 to -90 ° C refrigerator within 24 h.

[0405] 3. Data Analysis

[0406] The concentration of each prototype drug in plasma samples at each time point was detected by LC-MS / MS, and the plasma clearance (CL) and peak time (T) were calculated using WinNonlin software. max ), half-life (t 1 / 2 ), peak concentration (C max ), area under the drug-time curve (AUC 0-t ), tissue distribution volume (vd), mean residence time (MRT 0-t ) and bioavailability (F) and other PK parameters.

[0407] 4. Experimental Results

[0408] The pharmacokinetic test results of the compounds of the present invention are shown in Table 4. Table 4. Pharmacokinetic test results of the compounds of the present invention

[0409] As shown in Table 4, the compounds of the present invention have the characteristics of low plasma clearance, long drug half-life, good exposure and high bioavailability, and have good pharmacokinetic properties. The results of compounds 1, 13 and 14 are better than those of the positive control compound 1.

[0410] Experimental Example 5: In vivo pharmacodynamic study of the compound in the human lung cancer NCI-H358 subcutaneous xenograft tumor model

[0411] 1. Experimental Animals

[0412] NCG mice, SPF grade, female, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0413] 2. Experimental Methods

[0414] NCI-H358 tumor cells (5×10 7 6-8 week-old female NCG nude mice (weighing approximately 20 g) were inoculated subcutaneously with 100 μL of dapoxetine per mouse ( / mL, 100 μL / mouse). Mice were maintained in an SPF-grade laboratory environment and had free access to a commercially certified standard diet.

[0415] When the average tumor volume of mice grew to 150 mm 3 At about 3 d, the rats were divided into groups, each group had 6 rats, and the test compound was orally administered daily (twice a day, 50 mpk each time, the solvent was 5% DMSO, 5% Tween 80, 40% PEG400, 50% water); blank group (5% DMSO, 5% Tween 80, 40% PEG400, 50% water).

[0416] Tumor volume was measured every two days using a two-dimensional caliper and animals were weighed every day. After 21 consecutive days of administration, the inhibition rate (TGI / 100%) was calculated based on the final tumor volume.

[0417] The tumor volume was calculated as follows:

[0418] V=1 / 2*a*b 2 ;

[0419] Where: a represents the long diameter of the tumor, and b represents the short diameter of the tumor.

[0420] Table 5. In vivo pharmacodynamics test results of the compounds of the present invention

[0421] As shown in Figures 1 and 2 and Table 5, the compounds of the present invention have good in vivo efficacy and are superior to the positive control compound 1.

[0422] Although the present invention has been described with reference to the specific examples above, it should not be construed as being limited thereto, but rather as encompassing the general aspects disclosed above and susceptible of various modifications and embodiments without departing from the spirit and scope of the invention.

[0423] Experimental Example 6: In vivo pharmacodynamic study of the compound of the present invention in a human pancreatic cancer NCI-H358 subcutaneous xenograft tumor model

[0424] 1. Experimental Animals

[0425] NCG mice, SPF grade, female, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0426] 2. Experimental Methods

[0427] NCI-H358 tumor cells (5×10 7 6-8 week-old female NCG nude mice (weighing approximately 20 g) were inoculated subcutaneously with 100 μL of dapoxetine per mouse ( / mL, 100 μL / mouse). Mice were maintained in an SPF-grade laboratory environment and had free access to a commercially certified standard diet.

[0428] When the average tumor volume of mice grew to 130 mm 3At about 14:00, the mice were divided into groups, with 6 mice in each group, and the test compound was orally administered daily (the drug solvent was 5% DMSO, 5% Tween 80, 40% PEG400, 50% water).

[0429] Tumor volume was measured every two days using a two-dimensional caliper and animals were weighed every day. After 21 consecutive days of administration, the inhibition rate (TGI / 100%) was calculated based on the final tumor volume.

[0430] The tumor volume was calculated as follows:

[0431] V=1 / 2×a×b 2 ;

[0432] Where: a represents the long diameter of the tumor, and b represents the short diameter of the tumor.

[0433] Table 6. In vivo pharmacodynamics test results of the compounds of the present invention

[0434] As shown in Table 6, the compound 14 of the present invention has better in vivo efficacy after combined administration with trametinib or cediranib, and the tumor inhibition rate reaches more than 90%.

[0435] Experimental Example 7: In vivo pharmacodynamic study of the compound of the present invention in a human pancreatic cancer Miapaca2 subcutaneous xenograft tumor model

[0436] 1. Experimental Animals

[0437] NCG mice, SPF grade, female, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0438] 2. Experimental Methods

[0439] Miapaca2 tumor cells (5×10 7 6-8 week-old female NCG nude mice (weighing approximately 20 g) were inoculated subcutaneously with 100 μL of dapoxetine per mouse ( / mL, 100 μL / mouse). Mice were maintained in an SPF-grade laboratory environment and had free access to a commercially certified standard diet.

[0440] When the average tumor volume of mice grew to 130 mm 3 At about 3 d, the rats were divided into groups, with 6 rats in each group, and the test compounds were orally administered daily (twice a day, compound 14, 50 mpk each time, the solvent was 5% DMSO, 5% Tween 80, 40% PEG400, 50% water; trametinib, 0.125 mpk each time, the solvent was 5% DMSO, 5% Tween 80, 40% PEG400, 50% water); a blank group (5% DMSO, 5% Tween 80, 40% PEG400, 50% water).

[0441] Tumor volume was measured every two days using a two-dimensional caliper and animals were weighed every day. After 26 consecutive days of administration, the inhibition rate (TGI / 100%) was calculated based on the final tumor volume.

[0442] The tumor volume was calculated as follows:

[0443] V=1 / 2×a×b 2 ;

[0444] Where: a represents the long diameter of the tumor, and b represents the short diameter of the tumor.

[0445] Table 7. In vivo pharmacodynamics test results of the compounds of the present invention

[0446] As shown in Table 6, the combined administration of compound 14 of the present invention and trametinib has better in vivo efficacy, with a tumor inhibition rate of 90.1%.

[0447] Experimental Example 8: Toxicity test of SD rats after repeated administration of the compound of the present invention via oral gavage for 2 weeks

[0448] Twenty-one SD rats were randomly divided according to body weight into three dose groups: a vehicle control group, low-dose and high-dose Compound 14 groups (dosages of 0, 200, and 300 mg / kg / day, respectively), and a toxicity test group and a toxicity satellite group. The toxicity test group consisted of two rats per group (of both sexes); the toxicity satellite group consisted of three males per group. Each dose group of Compound 14 was orally gavaged with the corresponding concentration of Compound 14 at a dose volume of 10 mL / kg. The vehicle control group was administered with 5% DMSO, 5% Tween 80, 40% PEG 400, and 50% acetate buffer, pH 4.5, at the same dose volume. Dosing was performed twice daily for 14 consecutive days (28 doses total), with the day of the first dose designated as Day 1 (D1).

[0449] During the experiment, the general condition of the animals in each group was observed every day, and their body weight was measured twice a week. The food intake of the animals in the toxicity test group was measured once a week. At the end of administration (D15), the hematology, coagulation, and blood biochemistry of the animals in the toxicity test group were tested, and 2 animals / group / sex were dissected and euthanized for gross anatomical observation, organ weighing, and histopathological examination.

[0450] Blood samples were collected from animals in the toxic satellite group compound 14 group before the first and last administration and 0.5h, 1h, 2h, 4h, 4.5h, 5h, 8h, and 24h after administration, and from animals in the toxic satellite group vehicle control group before the first and last administration and 1h after administration to detect the plasma concentration of compound 14, and Phoenix WinNonlin was used to calculate C max 、T max , AUC last Toxicokinetic parameters.

[0451] Under the experimental conditions, SD rats were administered Compound 14 by oral gavage twice daily for 2 consecutive weeks (28 doses total) at doses of 200 mg / kg / day and 300 mg / kg / day. No animals in the groups experienced moribundity, death, or other severe toxic reactions. No significant abnormal changes in the animals' general condition, body weight, food intake, hematology, coagulation, blood biochemistry, or organ weights or coefficients, which could be toxicologically significant and related to Compound 14, were observed at any time during the study.

[0452] Toxicokinetic results showed that the AUC of compound 14 in SD rats after the first and last administration was last and C max Both increased with the increase of administration dose (at the first and last doses of 200 mg / kg / day, the AUCs of male rats were 62996 h·ng / mL and 85232 h·ng / mL, respectively; at the first and last doses of 300 mg / kg / day, the AUCs of male rats were 112966 h·ng / mL and 121246 h·ng / mL, respectively); the AUClast (last / first) ratios were 1.35 and 1.07, respectively. After 14 days of continuous administration, there was no obvious accumulation trend of the compound.

[0453] The tissue distribution results showed that at the end of the dosing period, the concentrations of compound 14 in the liver, kidney, pancreas, lung, heart, spleen and stomach of SD rats increased with increasing dose, and the distribution order was: stomach > liver > kidney > lung > spleen ≈ pancreas > heart.

[0454] Gross autopsy showed that there were no obvious test substance-related histopathological changes in the heart, liver, spleen, lung, kidney, stomach, and pancreas of the animals in the high-dose group of the toxicity test group.

[0455] In summary, SD rats were orally gavaged with 200 mg / kg / day and 300 mg / kg / day of compound 14 twice a day for 2 consecutive weeks (28 times in total), and the maximum tolerated dose (MTD) was > 300 mg / kg / day.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, in: Every independently represents a single bond or a double bond; X is selected from CR6, C(R6)2 and C(=O); Y is selected from CR7 and C(R7)2; Z is selected from N and NR 8 , or, Z is absent; when Z is absent, Y is directly connected to the phthalazine ring via a single bond; Ring A is selected from phenyl and thienyl (especially thien-2-yl); Every R 1 independently selected from methyl, ethyl, phenyl, halogen and cyano, wherein the methyl, ethyl or phenyl is optionally substituted with one or more substituents selected from methylaminomethyl, dimethylaminomethyl, hydroxyl and halogen; R 2 and R 3 are independently hydrogen; R 4 is methyl; R 5 Selected from C 1-8 Alkyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-8 The alkyl group is optionally substituted with one or more deuterium; the 3-8 membered heterocyclic group contains heteroatoms selected from O, N and S, and the 3-8 membered heterocyclic group is optionally substituted with one or more C 1-8 Alkyl substitution; If present, each R 6 are independently hydrogen; Every R 7 are independently selected from hydrogen and methyl; or, two R 7 Together with the carbon atom to which it is attached, it forms a cyclopropyl group; If present, R 8 is selected from methyl and cyclopropyl, wherein the methyl is optionally substituted with one or more deuterium; n is 1 or 2; Furthermore, when Z is absent, Y is C(R7)2, and X is C(=O), the two R 7 Not connected and distinct from each other; Also, does not contain the following compounds:

2. The compound according to claim 1 or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, characterized in that: Ring A is selected from phenyl and thiophen-2-yl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, characterized in that: Every R 1 independently selected from -CH3, -CH2F, -CHF2, -CF3, -CH2OH, -CH2CH3, -CHFCH3, -CF2CH3, -CH2CH2OH, -CHFCH2OH, -CF2CH2OH, -F, -Cl, -Br, -CN, Preferably, each R 1 Independently selected from -CH3, -CHF2, -CF2CH2OH, -F, -CN, 4. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, characterized in that: The compound is shown in Formula IA or Formula IA': in: Every independently represent a single bond or a double bond; R 1 Selected from X, Y, Z, and R 5 As defined in claim 1.

5. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, characterized in that: The compound is shown in Formula IB or Formula IB': in: Every independently represent a single bond or a double bond; Every R 1 Independently selected from -CH3, -CHF2, -CF2CH2OH, -F and -CN; X, Y, Z, and R 5 As defined in claim 1.

6. The compound according to claim 5 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, characterized in that: Selected from Best 7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, characterized in that: Selected from Preferably, Selected from 8. The compound according to claim 1 or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, characterized in that: R 5 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-4 The alkyl group is optionally substituted with one or more deuterium; the 3-6 membered heterocyclic group contains heteroatoms selected from O and N, and the 3-6 membered heterocyclic group is optionally substituted with one or more C 1-4 Alkyl substitution; Preferably, R 5 is selected from -CH3, -CH2D, -CHD2, -CD3, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl and tetrahydrofuran-3-yl; More preferably, R 5 Selected from -CH3, -CD3, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylpyrrolidin-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl and tetrahydrofuran-3-yl.

9. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, characterized in that: R 8 is selected from -CH3, -CH2D, -CHD2, -CD3 and cyclopropyl; Preferably, R 8 Selected from -CH3, -CD3 and cyclopropyl.

10. The compound according to claim 4 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, characterized in that: The compound is shown in Formula IA-1 or Formula IA'-1: Where: R 1 As defined in claim 4.

11. The compound according to claim 4 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, characterized in that: The compound is shown in Formula IA-2 or Formula IA'-2: Where: R 1 As defined in claim 4.

12. The compound according to claim 5 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, characterized in that: The compound is as shown in any one of formulas IB-1 to IB-16 or any one of formulas IB'-1 to IB'-16, preferably any one of formulas IB-1, IB-2 and IB-5 or any one of formulas IB'-1, IB'-2 and IB'-5: Where: R 1 As defined in claim 5.

13. A compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, characterized in that: The compound is selected from the following compounds:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof; Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

15. A pharmaceutical preparation, which is prepared from the pharmaceutical composition according to claim 14; Preferably, the pharmaceutical preparation is a solid preparation for oral administration, a liquid dosage form for oral administration, a dosage form for parenteral injection or a dosage form for topical administration.

16. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, a pharmaceutical composition according to claim 14, or a pharmaceutical preparation according to claim 15 in the preparation of a medicament for preventing and / or treating a disease mediated at least in part by SOS1 protein; Preferably, the disease at least partly mediated by SOS1 protein is cancer, such as pancreatic cancer, non-small cell lung cancer and colorectal cancer.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopically labeled or prodrug thereof, a pharmaceutical composition according to claim 14, or a pharmaceutical formulation according to claim 15, and at least one additional cancer therapeutic agent; Preferably, the cancer therapeutic agent is selected from trametinib and cediranib.

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