Purple KRAS inhibitors and uses thereof

Abstract

The invention discloses a general KRAS inhibitor, the structure of which is shown as a formula I. In the formula, the definition of each substituent group is shown in the description and claims. The general KRAS inhibitor has the advantages of easily available raw materials, simple synthesis, wide action range and strong effect, and can reduce or avoid the possibility of drug resistance generation. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a pan-KRAS inhibitor and uses thereof. Background Art

[0002] Malignant tumors are one of the major diseases that seriously threaten human life and health. RAS gene has a very high mutation frequency in human tumors. The product it encodes, RAS protein, is a guanine nucleotide binding protein and a key molecular switch in the cell signal transduction pathway. It plays a vital regulatory role in life processes such as cell proliferation, differentiation and apoptosis. Mutation of RAS gene leads to uncontrolled cell signaling pathways and is closely related to the occurrence, development and poor prognosis of 30% of human malignant tumors.

[0003] KRAS protein is the most common mutant subtype in the RAS family, accounting for about 85% of the total number of RAS family mutations. KRAS was once considered an undruggable target, mainly based on two reasons: (1) KRAS has an extremely strong affinity for endogenous ligand GDP / GTP, reaching the picomolar level, making it impossible to develop competitive inhibitors; (2) KRAS protein has a smooth surface and no deep pockets, making it impossible to develop allosteric inhibitors. Therefore, people have always hoped to develop anti-tumor drugs targeting KRAS protein, but the process has been slow. However, after nearly three decades of efforts, research on KRAS mutant inhibitors has made great progress. For example, AMG510 developed by Amgen, as a KRAS G12C inhibitor, was approved by the US FDA in 2021 for the treatment of non-small cell lung cancer and colorectal cancer. Therefore, the development of small molecule inhibitors targeting KRAS is of great significance.

[0004] Currently available KRAS-related drugs such as AMG510, MRTX849, and IBI351 launched in China are all drugs targeting single KRAS mutations. They have a narrow range of use and are prone to drug resistance. Summary of the invention

[0005] The purpose of the present invention is to provide a pan-KRAS inhibitor to solve the shortcomings of single mutation inhibitors, such as narrow application range and easy generation of drug resistance.

[0006] In a first aspect of the present invention, there is provided a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0007]

[0008] Wherein, A1 is CR4 or N; A2 is CR5 or N; A3 is CR6 or N; A4 is CR7 or N;

[0009] L is selected from chemical bonds, C 1-20 Alkylene, C 1-20 Alkyleneoxy, C 2-20 Alkenylene, C 2-20 Alkynylidene, -(SO)2-, -C 1-20 Alkylene CO-, carbonyl or sulfoxide;

[0010] R1 is selected from: C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 1-20 Alkoxy, -NR a R b , C 6-20 Aryl, C 3-20 Cycloalkyl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl; wherein R a , R b Each independently selected from: hydrogen, C 1-20 Alkyl, C 3-20 Cycloalkyl, -C 1-10 Alkylene C 3-20 Cycloalkyl, 3-20 membered heterocyclic group;

[0011] R1 is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, -NR c R d , C 6-20 Aryl, C 3-20 Cycloalkyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, -COOC 1-20 Alkyl, -COC 1-20 Alkyl, -COC 2-20 Alkenyl, -COOC 2-20 alkenyl; wherein R c , R d are independently hydrogen, C 1-20 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic group or -COOC 1-20 alkyl;

[0012] R2 is selected from: H, C 1-20 Alkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, Hydroxyl, -NR e R f , C 6-20 Aryl, C 3-20Cycloalkyl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, wherein R e , R f Each independently is H, C 1-20 Alkyl, C 3-20 Cycloalkyl or 4-10 membered heterocyclic group;

[0013] R2 is optionally substituted by one or more groups selected from the group consisting of halogen, C 1-20 Alkyl (C 1-6 Alkyl), -COOC 1-20 Alkyl (-COOC 1-6 Alkyl), hydroxyl, C 1-20 Alkoxy, C 1-20 Haloalkyl;

[0014] R3 is selected from: halogen, C 1-20 Alkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 6-20 Aryl, C 3-20 Cycloalkyl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl;

[0015] R3 is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 1-20 Alkoxy, -O-(C 1-20 Alkylene)-OC 1-20 Alkyl, -C 2-20 AlkynylideneSi(C 1-20 alkyl)3, 5-20 membered heteroaryl, C 6-20 Aryl, -(C 1-20 Alkylene)C 6-20 Aryl;

[0016] R4, R5, R6, and R7 are each independently selected from the group consisting of: H, halogen, hydroxy, amino, cyano, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 6-20 Aryl, C 3-20 Cycloalkyl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl.

[0017] In another preferred embodiment, the compound has a structure shown in Formula II:

[0018]

[0019] Wherein, R1, R2, R3, and L are as defined above.

[0020] In another preferred embodiment, the compound has a structure shown in Formula III:

[0021]

[0022] In the formula, R1, R2, R3 and L are as defined above.

[0023] In another preferred embodiment, L is selected from a chemical bond, C 1-10 Alkylene, C 1-10 Alkyleneoxy, C 2-10 Alkenylene, C 2-10 Alkynylidene, -(SO)2-, -C 1-10 Alkylene CO-, carbonyl, sulfoxide.

[0024] In another preferred embodiment, L is selected from a chemical bond, C 1-6 Alkylene, C 1-6 Alkyleneoxy, C 2-6 Alkenylene, C 2-6 Alkynylidene, -(SO)2-, -C 1-6 Alkylene CO-, carbonyl, sulfoxide.

[0025] In another preferred embodiment, L is a chemical bond, C 1-4 Alkylene or -C 1-4 AlkyleneCO-.

[0026] When L is a chemical bond, R2 is connected to N. 1-4 Alkylene or -C 1-4 When alkylene is CO-, C 1-4 The alkylene group is attached to the nitrogen.

[0027] In another preferred embodiment, R2 is selected from: H, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, Hydroxyl, -NR e R f , C 6-10 Aryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein R e , R f Each independently is H, C 1-10 Alkyl, C 3-10 Cycloalkyl or 4-8 membered heterocyclic group;

[0028] R2 is optionally substituted by one or more groups selected from the group consisting of halogen, C 1-10 Alkyl, -COOC 1-10 Alkyl, hydroxyl, C1-10 Alkoxy, C 1-10 Halogenated alkyl.

[0029] In another preferred embodiment, R2 is selected from: H, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, -NR e R f , phenyl, C 3-6 Cycloalkyl, 4-9 membered heterocyclyl or 5-8 membered heteroaryl, wherein R e , R f Each independently is H, C 1-4 Alkyl, C 3-6 Cycloalkyl 5-8 membered heterocyclic group;

[0030] R2 is optionally substituted by one or more groups selected from the group consisting of halogen, C 1-6 Alkyl, -COOC 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl.

[0031] In another preferred embodiment, R2 is selected from: H, hydroxyl, -NR e R f , phenyl, 5-8 membered heterocyclic group;

[0032] R e , R f Each independently is H, C 1-4 Alkyl or 5-6 membered heterocyclic group;

[0033] R2 is optionally substituted by one or more groups selected from the group consisting of halogen, C 1-4 Alkyl, -COOC 1-4 alkyl.

[0034] In another preferred embodiment, R2 is selected from the following group: H, -N(CH3)2, -COOH, phenyl,

[0035] In another preferred embodiment, -L-R2 is selected from the following group: H, -(CH2)2N(CH3)2, -CH2CON(CH3)2, -CH2phenyl, -CH2COOH,

[0036] In another preferred embodiment, the compound has a structure shown in Formula IV:

[0037]

[0038] In another preferred embodiment, R1 and R3 are defined as above.

[0039] In another preferred embodiment, R1 is selected from: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR a R b , C 6-10 Aryl, C 3-10 Cycloalkyl, 3-15 membered heterocyclyl or 5-10 membered heteroaryl; wherein R a , R b Each independently selected from: hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, -C 1-6 Alkylene C 3-10 Cycloalkyl, 3-10 membered heterocyclic group;

[0040] R1 is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, -NR c R d , C 6-10 Aryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -COOC 1-10 Alkyl, -COC 1-10 Alkyl, -COC 2-10 Alkenyl, -COOC 2-10 alkenyl; wherein R c , R d are independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group or -COOC 1-10 alkyl.

[0041] In another preferred embodiment, R1 is selected from: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -NR a R b , C 6-10 Aryl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group or 5-8 membered heteroaryl; wherein R a , Rb Each independently selected from: hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C 1-4 Alkylene C 3-6 Cycloalkyl, 3-8 membered heterocyclic group;

[0042] R1 is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR c R d , C 6-10 Aryl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, 5-8 membered heteroaryl, -COOC 1-6 Alkyl, -COC 1-6 Alkyl, -COC 2-6 Alkenyl, -COOC 2-6 alkenyl; wherein R c , R d are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or -COOC 1-6 alkyl.

[0043] In another preferred embodiment, R1 is selected from: -NR a R b , 5-8 membered heterocyclic group;

[0044] Among them, R a , R b Each independently selected from: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-4 Alkylene C 3-6 Cycloalkyl, 4-6 membered heterocyclic group;

[0045] R1 is optionally substituted by one or more groups selected from the group consisting of: 1-4 Alkyl, -NR c R d ,-COOC 1-4 Alkyl, -COC 2-4 alkenyl;

[0046] Among them, R c , R d are independently hydrogen, C 1-4 Alkyl or -COOC 1-4 alkyl.

[0047] In another preferred embodiment, R1 is selected from: -NR a R b , is optionally substituted, and the substituents are as defined above.

[0048] In another preferred embodiment, R1 is selected from:

[0049] In another preferred embodiment, the compound has a structure selected from the following group:

[0050]

[0051]

[0052] In another preferred embodiment, Optionally replaced by

[0053] In another preferred embodiment, Optionally replaced by

[0054] In another preferred embodiment, Optionally replaced by

[0055] In another preferred embodiment, R3 is selected from: halogen, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 6-14 Aryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-15 membered heteroaryl;

[0056] R3 is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -O-(C 1-10 Alkylene)-OC 1-10 Alkyl, -C 2-10 AlkynylideneSi(C 1-10 alkyl)3, 5-10 membered heteroaryl, C 6-10 Aryl, -(C 1-10 Alkylene)C 6-10 Aryl.

[0057] In another preferred embodiment, R3 is selected from: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6Alkynyl, C 6-14 Aryl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl or 5-12 membered heteroaryl;

[0058] R3 is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -O-(C 1-6 Alkylene)-OC 1-6 Alkyl, -C 2-6 AlkynylideneSi(C 1-6 alkyl)3, 5-8 membered heteroaryl, C 6-10 Aryl, -(C 1-6 Alkylene)C 6-10 Aryl.

[0059] In another preferred embodiment, R3 is selected from: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 6-14 Aryl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl;

[0060] R3 is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -O-(C 1-4 Alkylene)-OC 1-4 Alkyl, -C 2-4 AlkynylideneSi(C 1-4 alkyl)3, 5-6 membered heteroaryl, C 6-10 Aryl, -(C 1-4 Alkylene)C 6-20 Aryl.

[0061] In another preferred embodiment, R3 is selected from the following group: Cl,

[0062] In another preferred embodiment, R1 is selected from:

[0063] -L-R2 is selected from the group consisting of:

[0064] R3 is selected from:

[0065] In another preferred embodiment, R1 is selected from: -L-R2 is R3 is

[0066] In another preferred embodiment, the compound is selected from the following group: I-1 to I-111.

[0067] The second aspect of the present invention provides a pharmaceutical composition comprising:

[0068] The compound represented by the general formula (I) as described in the first aspect, its stereoisomer or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0069] The third aspect of the present invention provides the use of the compound represented by the general formula (I) described in the first aspect, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the second aspect for preparing a pan-KRAS inhibitor; or for preparing a drug for preventing and / or treating KRAS mutated tumors.

[0070] In another preferred embodiment, the KRAS mutated tumor is selected from the following diseases with KRAS mutation: gastric cancer (such as gastric adenocarcinoma), lung cancer, colon cancer, lymphoma, leukemia, multiple myeloma, mesothelioma, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, neuroblastoma, neurothexoma, glioma, glioblastoma and astrocytoma, cervical cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, and thyroid cancer.

[0071] In another preferred embodiment, the KRAS mutation is KRAS G12C mutation, KRAS G12D mutation or KRAS G12S mutation.

[0072] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equal or similar purpose. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0073] The inventors of the present application have developed a pan-KRAS inhibitor through extensive and in-depth research, which has excellent anti-proliferative activity against AGS, H358, and A549, and has low toxicity to normal lung epithelial cells Beas-2B, and can be used as a pan-KRAS mutation inhibitor for the preparation of drugs for treating malignant tumors with multiple KRAS mutations. On this basis, the present invention was completed.

[0074] the term

[0075] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0076] In the present invention, the halogen is F, Cl, Br or I.

[0077] In the present invention, the term "C1-C6" refers to having 1, 2, 3, 4, 5 or 6 carbon atoms, "C1-C8" refers to having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. "3-8 membered" refers to having 3, 4, 5, 6, 7 or 8 ring atoms, and so on.

[0078] In the present invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon group, for example, the term "C 1-20 "Alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms, preferably C 1-10 Alkyl. "C 1-10 The term “alkyl” is understood as meaning preferably a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, the radical has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms (“C 1-6 alkyl), for example methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly, the radical having 1, 2 or 3 carbon atoms (“C 1-3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0079] "Alkylene" refers to a straight or branched chain saturated aliphatic group having a specified number of carbon atoms and connecting at least two other groups, i.e., a divalent hydrocarbon group. The two groups connected to the alkylene group can be connected to the same or different atoms on the alkylene group. For example, a straight chain alkylene group can be -(CH2) n -divalent radical, wherein n is 1, 2, 3, 4, 5, 6, 7 or 8. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene. The alkylene group may be substituted or unsubstituted.

[0080] "Alkoxy" refers to the group -O-alkyl, and the alkyl has the above definition. For example, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and butoxy, etc.

[0081] In the present invention, the term "alkenyl" refers to a straight or branched hydrocarbon group containing at least one double bond, for example, "C 2-20 "Alkenyl" is understood to mean a straight-chain or branched hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 ... or 20 carbon atoms, in particular 2 or 3 carbon atoms ("C 2-3 "alkenyl"), it being understood that, in the case where the alkenyl contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, -enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-hexenyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent ...1-enyl, (Z)-pent-1-enyl, isopropenyl, 2-hexenyl, (E)-pent-2- -methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl 1-ethylprop-1-enyl, 1-propylvinyl, and 1-isopropylvinyl.

[0082] "Alkenylene" refers to a straight or branched aliphatic group having the specified number of carbon atoms and containing at least one double bond that links at least two other groups.

[0083] In the present invention, the term "alkynyl" refers to a straight or branched chain alkynyl group containing a triple bond, such as "C2-20 “Alkynyl” is understood as meaning a straight-chain or branched hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 . . . or 20 carbon atoms, in particular 2 or 3 carbon atoms (“C2-C3-ynyl”). Such alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0084] "Alkyne" refers to a straight or branched aliphatic group having the specified number of carbon atoms and containing at least one triple bond linking at least two other groups.

[0085] In the present invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group, such as "C 3-20 "Cycloalkyl" is understood to be a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C 3-10 The term "Cycloalkyl" 3-10 "Cycloalkyl" is understood to be a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring.

[0086] In the present invention, the term "aryl" refers to a hydrocarbon group containing one or more aromatic rings. 6-20 "Aryl" is understood to mean an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-14 The term "C 6-14The term "aryl" is understood to mean preferably an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms ("C6 aryl"), for example phenyl or biphenyl, or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 "aryl"), for example anthracenyl.

[0087] The term "heteroaryl" means an aromatic cyclic group containing at least one (e.g. 1, 2, 3, 4 or 5) ring heteroatom (e.g. N, O or S), for example, the term "5-20 membered heteroaryl" is understood to include monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, may additionally be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or azinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0088] In the present invention, the term "heterocyclyl" means a saturated or unsaturated, non-aromatic cyclic group containing at least one (such as 1, 2, 3, 4 or 5) ring heteroatom (such as N, O or S), and "3-20 membered heterocyclyl" means a saturated or unsaturated monocyclic or bicyclic hydrocarbon ring containing 3 to 20 atoms, which contains 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclyl group can be connected to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to, a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,2,3,6-tetrahydropyridine or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta [c] pyrrole-2 (1H) -yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e. it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.

[0089] Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, pyridyl or pyridylene includes pyridine-2-yl, pyridine-2-yl, pyridine-3-yl, pyridine-3-yl, pyridine-4-yl and pyridine-4-yl; thienyl or thienylene includes thien-2-yl, thien-2-yl, thien-3-yl and thien-3-yl.

[0090] Unless otherwise specified, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, heteroaryl, heterocyclyl and aryl groups described herein are substituted and unsubstituted groups. Possible substituents include, but are not limited to, hydroxy, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, C6-C10 aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkylamino, C6-C10 arylamino, dialkylamino, C6-C10 arylamino, C1-C10 alkylsulfamoyl, C6-C10 arylsulfamoyl, C1-C10 alkylimino, C1-C10 alkylsulfoimino, C6-C10 arylsulfoimino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, C6-C10 arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, ureido, cyano, acyl, thioacyl, acyloxy, carboxyl and carboxylate groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl groups may also be condensed with each other.

[0091] In the present invention, the substitution is mono- or poly-substitution, and the poly-substitution is di-, tri-, tetra- or penta-substitution. The di-substitution means having two substituents, and so on.

[0092] Pharmaceutically acceptable salts of the present invention can be salts formed by negatively charged groups on anions and compounds of formula I. Suitable negatively charged groups are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronide, lactate, glutarate or maleate. Similarly, salts can be formed by negatively charged groups on cations and compounds of formula I. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions and ammonium ions, such as tetramethylammonium ions.

[0093] In another preferred embodiment, "pharmaceutically acceptable salt" refers to the salts formed by the compound of formula I with an acid selected from the following group: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid; or the sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt formed by the compound of formula I with an inorganic base; or the methylamine salt, ethylamine salt or ethanolamine salt formed by the compound of general formula I with an organic base.

[0094] Pharmaceutical composition

[0095] The present invention also provides a pharmaceutical composition, which comprises an active ingredient within a safe and effective amount range and a pharmaceutically acceptable carrier.

[0096] The "active ingredient" described in the present invention refers to the compound of formula I described in the present invention.

[0097] The "active ingredient" and pharmaceutical composition of the present invention are used to prepare drugs for treating multiple KRAS mutant malignant tumors. The "active ingredient" and pharmaceutical composition of the present invention can be used as a pan-KRAS inhibitor to inhibit KRAS mutants. The KRAS mutated malignant tumor is selected from the following diseases with KRAS mutation: colon cancer, diffuse large B-cell lymphoma, follicular lymphoma, other lymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer; brain tumors, including neuroblastoma, schwannoma, glioma, glioblastoma and astrocytoma; cervical cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer, parathyroid tumors, uterine tumors and soft tissue sarcoma, cardiovascular disease, neurodegenerative diseases, malaria, AIDS, gout, diabetes, renal failure, chronic lung disease.

[0098] "Safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably, 10-200 mg of active ingredient per dose. Preferably, the "one dose" is one tablet.

[0099] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0100] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0101] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0102] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices.

[0103] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.

[0104] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0105] The compounds of the present invention can be administered alone or in combination with other therapeutic drugs (such as anti-tumor drugs).

[0106] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0107] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods for which specific conditions are not indicated in the following examples are usually performed under conventional conditions (such as the conditions described in Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0108] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0109] Example 1 Synthesis of Compound I-1

[0110]

[0111] 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 2.65 mmol) and 8-BOC-3,8-diazabicyclo[3.2.1]octane (842 mg, 3.97 mol) were dissolved in anhydrous ethanol (15 ml), triethylamine (321 mg, 3.18 mol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the ethanol was concentrated to one-third of the volume, pure water (30 ml) was added, and the mixture was extracted three times with ethyl acetate (20 ml), the organic phases were combined, washed three times with saturated brine (30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel chromatography to obtain 850 mg of yellow solid I-1 with a yield of 88%.

[0112] Example 2 Synthesis of Compound I-2

[0113]

[0114] Compound I-1 (200 mg, 548 μmol) was dissolved in anhydrous DMF (10 ml), N, N-dimethylaminoethyl bromide hydrobromide (191 mg, 822 μmol) was added, sodium hydride (purity 60%, 43 mg, 1.09 mmol) was added at 0°C under nitrogen protection, and the mixture was heated to room temperature and stirred for 2 hours. After the reaction was completed, pure water (50 ml) was added, and the mixture was extracted three times with ethyl acetate (20 ml*3), the organic phases were combined, washed three times with saturated brine (30 ml*3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel chromatography to obtain 126 mg of light yellow oil I-2 with a yield of 52%. 1 H NMR (400MHz, CDCl3) δ7.84(s,1H),5.14(s,1H),4.76–4.50(m,1H),4.43(t,J=6.5Hz,2H),3.94(d,J=61.5Hz,2H ), 3.21 (d, J = 13.0Hz, 1H), 3.09 (d, J = 13.1Hz, 1H), 2.82 (t, J = 6.6Hz, 2H), 2.28 (s, 6H), 2.06 (s, 4H), 1.45 (s, 9H).

[0115] Example 3 Synthesis of Compound I-3

[0116]

[0117] Compound I-2 (120 mg, 275 μmol) was dissolved in dioxane (10 ml), 1-naphthaleneboric acid (94 mg, 550 μmol) was added, anhydrous potassium carbonate (114 mg, 825 μmol) was dissolved in pure water (3 ml), and the potassium carbonate solution was mixed with the above 1,4-dioxane solution. Tetrakis(triphenylphosphine)palladium (37 mg, 27 μmol) was added. Stir for 5 h at 75 ° C under nitrogen protection. After the reaction was completed, pure water (30 ml) was added, and the mixture was extracted three times with ethyl acetate (15 ml*3), the organic phases were combined, washed three times with saturated brine (30 ml*3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, separated and purified by silica gel chromatography, and 87 mg of light yellow oil I-3 was obtained, with a yield of 60%. It was used directly in the next step. Reaction.

[0118] Example 4 Synthesis of Compound I-4

[0119]

[0120] Compound I-3 (87 mg, 163 μmol) was dissolved in dioxane (1 ml), and a 4N HCl solution in dioxane (2 ml) was added. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to adjust the system to alkaline. The mixture was extracted three times with dichloromethane (10 ml*3). The organic phases were combined, washed three times with saturated brine (15 ml*3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel chromatography to obtain 65 mg of foamy solid I-4 with a yield of 92%. 1 H NMR (400MHz, cdcl3) δ8.84–8.80(m,1H),8.10(d,J=7.2Hz,1H),7.98(s,1H),7.95–7.87(m,2H),7.56(t,J=7.7Hz,1H),7.52–7. 45(m,2H),4.58(t,J=6.6Hz,4H),3.75(s,2H),3.67–3.41(m,2H),2.92(t,J=6.7Hz,2H),2.35(s,6H),2.30(s,2H),1.85(s,3H).

[0121] Example 5 Synthesis of Compound I-5

[0122]

[0123] Referring to Example 3, the compound 1-naphthaleneboric acid was replaced with ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane to obtain a yellow oil I-5 with a yield of 58%, which was directly used in the next step.

[0124] Example 6 Synthesis of Compound I-6

[0125]

[0126] Compound I-5 (105 mg, 133 μmol) was dissolved in tetrahydrofuran (5 ml), and 1N tetrabutylammonium fluoride solution in tetrahydrofuran (1 ml) was added. The mixture was stirred at room temperature for 1 h. After the reaction, pure water (20 ml) was added. The mixture was extracted three times with ethyl acetate (15 ml*3). The organic phases were combined, washed three times with saturated brine (20 ml*3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 82 mg of crude yellow oil I-6 with a yield of 97%. The product was used directly in the next step.

[0127] Example 7 Synthesis of Compound I-7

[0128]

[0129] Referring to Example 4, compound I-3 was replaced by I-6 to obtain 56 mg of yellow solid compound I-7 with a yield of 88%. 1H NMR (400MHz, cd3od) δ8.25 (s, 1H), 7.81 (dd, J = 9.7, 5.6 Hz, 1H), 7.30-7.23 (m, 3H), 4.64-4.34 (m, 4H), 3.66 (d, J = 18.2 Hz, 3H), 3.48 (s, 1H), 3.34 (s, 1H), 2.94-2.81 (m, 2H), 2.29 (d, J = 2.1 Hz, 6H), 1.85 (s, 4H).

[0130] Example 8 Synthesis of Compound I-8

[0131]

[0132] Referring to Example 2, the compound N,N-dimethylaminoethyl bromide hydrobromide was replaced with 2-bromo-N,N-dimethylacetamide to obtain a yellow oil I-8 with a yield of 53%. 1 H NMR (400MHz, CDCl3) δ7.96 (s, 1H), 5.20 (s, 2H), 4.43 (s, 2H), 3.85 (d, J = 82.5Hz, 2H), 3 .27(s,1H),3.10(s,3H),2.97(s,3H),2.01(s,2H),1.74(d,J=9.6Hz,2H),1.50(s,9H).

[0133] Example 9 Synthesis of Compound I-9

[0134]

[0135] Referring to Example 3, compound I-2 was replaced by compound I-8 to obtain yellow oil I-9 with a yield of 62%, which was directly used in the next step.

[0136] Example 10 Synthesis of Compound I-10

[0137]

[0138] Referring to Example 4, compound I-3 was replaced by I-9 to obtain yellow solid I-10 with a yield of 93%. 1H NMR(400MHz,cdcl3)δ8.68(d,J=7.5Hz,1H),8.09–8.01(m,2H),7.89(dd,J=14.5,7.5Hz,2H),7.54(t,J=7.7Hz,1H),7.49–7.44(m,2H ),5.31(s,2H),4.47(s,2H),3.74(s,2H),3.48(s,2H),3.10(d,J=2.1Hz,3H),2.99(d,J=2.3Hz,3H),2.06–1.96(m,2H),1.86(s,3H).

[0139] Example 11 Synthesis of Compound I-11

[0140]

[0141] Referring to Example 9, the compound 1-naphthaleneboric acid was replaced with ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane to obtain a yellow oil I-11 with a yield of 52%. The product was directly used in the next step.

[0142] Example 12 Synthesis of Compound I-12

[0143]

[0144] Referring to Example 6, compound I-5 was replaced by I-11 to obtain yellow oil I-12 with a yield of 95%. The product was directly used in the next step.

[0145] Example 13 Synthesis of Compound I-13

[0146]

[0147] Referring to Example 7, compound I-6 was replaced by I-12 to obtain yellow solid I-13 with a yield of 85%. 1 H NMR(400MHz,dmso)δ10.01(s,1H),8.29(s,1H),7.90(t,J=7.6Hz,1H),7.40(t,J=9.0Hz,1H),7.29(s,1H),7.14 (s,1H),5.21(s,2H),4.23(s,2H),3.77(s,1H),3.52(d,J=16.1Hz,2H),3.02(s,3H),2.81(s,3H),1.65(s,4H).

[0148] Example 14 Synthesis of Compound I-14

[0149]

[0150] Referring to Example 9, 1-naphthaleneboric acid was replaced with 2-fluoro-6-hydroxyphenylboric acid to obtain yellow oily compound I-14 with a yield of 40%, which was directly used in the next step.

[0151] Example 15 Synthesis of Compound I-15

[0152]

[0153] Referring to Example 4, compound I-3 was replaced by I-14 to obtain yellow solid I-15 with a yield of 86%. 1 H NMR (400MHz, cdcl3) δ13.74(s,1H),8.01(s,1H),7.22(dd,J=8.2,6.4Hz,1H),6.77(d,J=8.3Hz,1H),6.63(d d,J=11.8,8.2Hz,1H),5.25(s,2H),3.80(s,2H),3.63(s,2H),3.15(s,3H),2.99(s,3H),1.92–1.81(m,4H).

[0154] Example 16 Synthesis of Compound I-16

[0155]

[0156] Compound I-1 (200 mg, 548 μmol), 1-methyl-2-chloromethylpyrrolidine hydrochloride (140 mg, 822 μmol), and potassium iodide (9 mg, 55 μmol) were dissolved in DMF (10 ml), and potassium carbonate (227 mg, 1.64 mmol) was added. Stir at 95 ° C for 3 h. After the reaction, pure water (60 ml) was added, and ethyl acetate (20 ml * 3) was used for extraction three times. The organic phases were combined, washed three times with saturated brine (30 ml * 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel chromatography to obtain 115 mg of light yellow oil I-16, with a yield of 45%. 1H NMR(400MHz,cdcl3)δ7.87(s,1H),4.73(s,1H),4.55–4.24(m,4H),3.83(d,J=89.2Hz,2H),3.20(s,1H),3.05(d,J=7.8Hz,1H),3.02 –2.79(m,1H),2.74(s,1H),2.32(d,J=17.7Hz,3H),2.23(q,J=8.5Hz,1H),2.00(s,2H),1.92(s,2H),1.74–1.63(m,3H),1.46(s,9H).

[0157] Example 17 Synthesis of Compound I-17

[0158]

[0159] Referring to Example 3, compound I-2 was replaced by compound I-16 to obtain yellow oil I-17 with a yield of 65%, which was directly used in the next step.

[0160] Example 18 Synthesis of Compound I-18

[0161]

[0162] Referring to Example 4, compound I-3 was replaced by I-17 to obtain yellow solid I-18 with a yield of 87%. 1 H NMR (400MHz, DMSO) δ8.81–8.77(m,1H),8.39(s,1H),8.10–8.00(m,3H),7.63(t,J=7 .7Hz,1H),7.55(td,J=5.4,2.7Hz,2H),4.54(dd,J=13.8,4.4Hz,3H),4.41–4.34(m, 1H),4.15(d,J=4.8Hz,2H),3.05(q,J=7.3Hz,4H),2.92(s,1H),2.39(s,3H),2.00(d ,J=8.9Hz,2H),1.86(d,J=7.5Hz,2H),1.79(q,J=6.3Hz,2H),1.69(q,J=6.9Hz,2H).

[0163] Example 19 Synthesis of Compound I-19

[0164]

[0165] Referring to Example 17, 1-naphthaleneboronic acid was replaced with ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane to obtain yellow oil I-19 with a yield of 42%. It was used directly in the next step.

[0166] Example 20 Synthesis of Compound I-20

[0167]

[0168] Referring to Example 6, compound I-5 was replaced by compound I-19 to obtain yellow oil I-20 with a yield of 95%. The product was directly used in the next step.

[0169] Example 21 Synthesis of Compound I-21

[0170]

[0171] Referring to Example 7, compound I-6 was replaced by compound I-20 to obtain yellow solid I-21 with a yield of 90%. 1 HNMR (400MHz, DMSO) δ10.03 (s, 1H), 8.26 (d, J = 4.4Hz, 1H), 7.90 (dd, J = 9.2, 5.9Hz, 1H),7.41(t,J=9.0Hz,1H),7.29(d,J=2.6Hz,1H),7.17(dd,J=8.6,2.6Hz,1H),4.4 2–4.10(m,4H),3.81(s,1H),3.51(d,J=20.3Hz,3H),3.38(s,2H),2.92–2.87(m,1H ),2.69–2.63(m,1H),2.22(d,J=3.4Hz,3H),2.15–2.07(m,1H),1.73–1.54(m,8H).

[0172] Example 22 Synthesis of Compound I-22

[0173]

[0174] Referring to Example 16, the compound 1-methyl-2-chloromethylpyrrolidine hydrochloride was replaced with N-(2-chloroethyl)pyrrolidine hydrochloride to obtain a yellow oily compound I-22 with a yield of 43%. 1H NMR(400MHz,cdcl3)δ7.88(d,J=2.0Hz,1H),4.74(s,1H),4.48(t,J=6.9Hz,4H),4.02–3.14(m,3H ), 2.97 (t, J = 7.0Hz, 2H), 2.57 (q, J = 4.5Hz, 4H), 2.01 (s, 2H), 1.75 (t, J = 3.4Hz, 6H), 1.49 (s, 9H).

[0175] Example 23 Synthesis of Compound I-23

[0176]

[0177] Referring to Example 3, compound I-2 was replaced by compound I-22 to obtain yellow oil I-23 with a yield of 55%, which was directly used in the next step.

[0178] Example 24 Synthesis of Compound I-24

[0179]

[0180] Referring to Example 4, compound I-3 was replaced by compound I-23 to obtain foamy solid I-24 with a yield of 95%. 1 H NMR (400MHz, DMSO) δ8.77–8.70(m,1H),8.29(s,1H),8.01(dd,J=11.6,7.8Hz,3H),7.61(t,J=7.7Hz,1H),7.52(pd,J= 6.8,1.6Hz,2H),4.46(t,J=6.5Hz,4H),3.60(s,4H),2.92(t,J=6.5Hz,2H),2.51(d,J=1.8Hz,4H),1.78–1.60(m,8H).

[0181] Example 25 Synthesis of Compound I-25

[0182]

[0183] Referring to Example 23, 1-naphthaleneboronic acid was replaced with ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane to obtain a yellow oil with a yield of 44%. It was used directly in the next step.

[0184] Example 26 Synthesis of Compound I-26

[0185]

[0186] Referring to Example 6, Compound I-5 was replaced by Compound I-25 to obtain yellow solid I-26 with a yield of 93%, which was directly used in the next step.

[0187] Example 27 Synthesis of Compound I-27

[0188]

[0189] Referring to Example 7, compound I-6 was replaced by compound I-26 to obtain yellow solid I-27 with a yield of 94%. 1 HNMR(400MHz,D2O)δ10.02(s,1H),8.26(s,1H),7.91(dd,J=9.2,5.9Hz,1H),7.41(t,J=9.0Hz,1H),7.29(d,J=2.6Hz,1H),7.16(d,J= 2.6Hz,1H),4.51–4.17(m,4H),3.80(s,1H),3.52(d,J=19.6Hz,4H),2.84(t,J=6.6Hz,2H),2.43(q,J=6.7Hz,4H),1.69–1.55(m,8H).

[0190] Example 28 Synthesis of Compound I-28

[0191]

[0192] Referring to Example 1, the compound 8-BOC-3,8-diazabicyclo[3.2.1]octane was replaced with (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine to obtain a white solid compound I-28 with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ11.02(s,1H),7.96(s,1H),4.65(s,2H),4.22(s,1H),4.00(s ,1H),3.49(s,1H),3.28(d,J=13.7Hz,1H),3.11(s,1H),1.50(s,9H),1.38(s,3H).

[0193] Example 29 Synthesis of Compound I-29

[0194]

[0195] Referring to Example 2, the compound N,N-dimethylaminoethyl bromide hydrobromide was replaced with 2,6-dimethylbenzyl bromide to obtain yellow oily compound I-29 with a yield of 60%. 1H NMR(400MHz,cdcl3)δ7.80(s,1H),7.15(dd,J=8.4,6.7Hz,1H),7.06(d,J=7.5Hz,2H),5.50(s,2H),3 .96(d,J=14.0Hz,3H),3.56–2.98(m,4H),2.39(s,6H),1.49(d,J=1.3Hz,9H),1.33(d,J=6.7Hz,3H).

[0196] Example 30 Synthesis of Compound I-30

[0197]

[0198] Referring to Example 14, compound I-8 was replaced by I-29 to obtain yellow oily compound I-30 with a yield of 35%, which was directly used in the next step.

[0199] Example 31 Synthesis of Compound I-31

[0200]

[0201] Referring to Example 4, compound I-3 was replaced by I-30 to obtain colorless oily compound I-31 with a yield of 95%, which was directly used in the next step.

[0202] Example 32 Synthesis of Compound I-32

[0203]

[0204] Compound I-31 (50 mg, 112 μmol) was dissolved in anhydrous DCM (3 ml), potassium carbonate (23 mg, 168 μmol) was added, and nitrogen was protected. Acrylamide (12 mg, 134 μmol) was dissolved in anhydrous DCM (1 ml) and slowly dripped into the former DCM solution. The mixture was heated to room temperature and stirred for 2 h. After the reaction was completed, the mixture was washed three times with pure water (5 ml*3), three times with saturated brine (5 ml*3), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The mixture was separated and purified by silica gel chromatography to obtain 46 mg of white foam solid I-32 with a yield of 82.5%. 1H NMR(400MHz,dmso)δ12.56(s,1H),8.27(s,1H),7.33(td,J=8.3,6.2Hz,1H),7.12(dd,J =8.4,6.6Hz,1H),7.04(d,J=7.5Hz,2H),6.86–6.73(m,3H),6.19(d,J=16.6Hz,1H),5.7 5(dd,J=10.4,2.3Hz,1H),5.51(s,2H),4.83(s,1H),4.29(t,J=15.8Hz,1H),4.17–3.97 (m,1H),3.70–3.43(m,2H),3.15(d,J=21.1Hz,2H),2.37(s,6H),1.24(d,J=2.7Hz,3H).

[0205] Example 33 Synthesis of Compound I-33

[0206]

[0207] Referring to Example 30, 2-fluoro-6-hydroxyphenylboronic acid was replaced with 1-naphthaleneboronic acid to obtain yellow oily compound I-33 with a yield of 45%, which was directly used in the next step.

[0208] Example 34 Synthesis of Compound I-34

[0209]

[0210] Referring to Example 4, compound I-3 was replaced by I-33 to obtain colorless oily compound I-34 with a yield of 92%, which was directly used in the next step.

[0211] Example 35 Synthesis of Compound I-35

[0212]

[0213] Referring to Example 32, compound I-31 was replaced by I-34 to obtain white foamy solid I-34 with a yield of 85%. 1H NMR(400MHz,dmso)δ8.73(d,J=8.1Hz,1H),8.27(s,1H),8.08–8.01(m,3H),7.64(dd,J=8.2,7.1Hz ,1H),7.58–7.52(m,2H),7.13(dd,J=8.4,6.5Hz,1H),7.05(d,J=7.5Hz,2H),6.83(dd,J=17.4,9.2H z,1H),6.18(d,J=16.7Hz,1H),5.74(dd,J=10.4,2.3Hz,1H),5.57(s,2H),4.82(s,1H),4.36(s,1H ), 4.00 (d, J = 14.0Hz, 1H), 3.53 (d, J = 56.9Hz, 2H), 3.13 (s, 2H), 2.42 (s, 6H), 1.25 (d, J = 4.1Hz, 3H).

[0214] Example 36 Synthesis of Compound I-36

[0215]

[0216] Referring to Example 29, 2,6-dimethylbenzyl bromide was replaced with benzyl bromide to obtain yellow oily compound I-36 with a yield of 63%. 1 H NMR (400MHz, cdcl3) δ7.88(s,1H),7.35–7.26(m,5H),5.52(s,2H),4.72–3.92(m,4H),3.50–3.02(m,3H),1.49(s,9H),1.35(q,J=4.3Hz,3H).

[0217] Example 37 Synthesis of Compound I-37

[0218]

[0219] Referring to Example 14, compound I-8 was replaced by I-36 to obtain yellow oily compound I-37 with a yield of 35%, which was directly used in the next step.

[0220] Example 38 Synthesis of Compound I-38

[0221]

[0222] Referring to Example 4, compound I-3 was replaced by I-37 to obtain colorless oily compound I-37 with a yield of 94%, which was directly used in the next step.

[0223] Example 39 Synthesis of Compound I-39

[0224]

[0225] Referring to Example 32, compound I-31 was replaced by I-39 to obtain white foamy solid I-39 with a yield of 83%. 1 H NMR(400MHz, CDCl3)δ7.96(s,1H),7.41–7.36(m,2H),7.35–7.27(m,3H),7.2 6–7.23(m,1H),6.81(dd,J=8.4,1.2Hz,1H),6.69–6.53(m,2H),6.40(dd,J=1 6.7,1.8Hz,1H),5.80(dd,J=10.4,1.9Hz,1H),5.58(s,2H),4.97–4.30(m,3H ),4.09–3.90(m,1H),3.69–3.51(m,2H),3.31(d,J=96.3Hz,1H),1.42(s,3H).

[0226] Example 40 Synthesis of Compound I-40

[0227]

[0228] Referring to Example 23, 1-naphthaleneboronic acid was used instead of quinoline-3-boronic acid to obtain yellow oily compound I-40 with a yield of 43%, which was used directly in the next step.

[0229] Example 41 Synthesis of Compound I-41

[0230]

[0231] Referring to Example 4, compound I-3 was replaced by I-40 to obtain yellow solid compound I-41 with a yield of 92%. 1 HNMR(400MHz,cdcl3)δ10.01(d,J=2.1Hz,1H),9.21(d,J=2.1Hz,1H),8.15(d,J=8.4H z,1H),8.01–7.97(m,1H),7.90(s,1H),7.75(ddd,J=8.4,6.8,1.5Hz,1H),7.61–7.56 (m,1H),5.33(s,1H),4.70(t,J=7.1Hz,2H),3.22(d,J=12.2Hz,2H),3.13(t,J=7.1Hz ,2H),2.89(d,J=12.2Hz,2H),2.71(d,J=6.0Hz,4H),2.16(s,6H),1.84–1.78(m,4H).

[0232] Example 42 Synthesis of Compound I-42

[0233]

[0234] Referring to Example 23, 1-naphthaleneboronic acid was used instead of quinoline-5-boronic acid to obtain yellow oily compound I-42 with a yield of 42%, which was used directly in the next step.

[0235] Example 43 Synthesis of Compound I-43

[0236]

[0237] Referring to Example 4, compound I-3 was replaced by I-42 to obtain yellow solid compound I-43 with a yield of 91%. 1 HNMR(400MHz,cdcl3)δ9.31(d,J=8.7Hz,1H),8.93–8.89(m,1H),8.24(d,J= 7.2Hz,1H),8.18(d,J=8.4Hz,1H),7.97(d,J=1.6Hz,1H),7.82–7.75(m,1H) ,7.40(dd,J=9.0,4.0Hz,1H),4.64(t,J=7.0Hz,4H),3.77(s,2H),3.50(s,2 H),3.11(t,J=6.9Hz,2H),2.68(s,4H),2.32(s,1H),1.86(d,J=7.9Hz,4H).

[0238] Example 44 Synthesis of Compound I-44

[0239]

[0240] Referring to Example 3, the compound 1-naphthaleneboronic acid was replaced with 3-biphenylboronic acid to obtain yellow oil I-44 with a yield of 46%, which was directly used in the next step.

[0241] Example 45 Synthesis of Compound I-45

[0242]

[0243] Referring to Example 4, compound I-3 was replaced by I-44 to obtain white solid compound I-44 with a yield of 88%. 1HNMR(400MHz,cd3od)δ8.72(t,J=1.9Hz,1H),8.47(d,J=7.8Hz,1H),8.22(d,J=2. 8Hz,1H),7.75–7.71(m,1H),7.70–7.66(m,2H),7.58–7.53(m,1H),7.48(t,J=7.7 Hz,2H),7.38(t,J=7.4Hz,1H),4.78–4.66(m,4H),4.05(s,2H),3.68–3.57(m,3H) ,3.11(t,J=6.4Hz,2H),2.47(d,J=2.9Hz,6H),2.06(s,2H),1.95(d,J=8.1Hz,2H).

[0244] Example 46 Synthesis of Compound I-46

[0245]

[0246] Referring to Example 23, 1-naphthaleneboric acid was used to replace 3-biphenylboric acid to obtain yellow oily compound I-46 with a yield of 47%, which was directly used in the next step.

[0247] Example 47 Synthesis of Compound I-47

[0248]

[0249] Referring to Example 4, compound I-3 was replaced by I-46 to obtain white solid compound I-47 with a yield of 89%. 1 HNMR(400MHz,cdcl3)δ8.71(s,1H),8.48(d,J=7.8Hz,1H),7.93(s,1H),7.69(t,J=7.4Hz,3H),7.52(dt,J=16.1,7.6Hz,3H),7.3 9(t,J=7.4Hz,1H),4.71(t,J=7.0Hz,4H),3.85(s,2H),3.60(d,J=38.6Hz,2H),3.17(s,2H),2.76(s,4H),1.90(d,J=16.6Hz,8H).

[0250] Example 48 Synthesis of Compound I-48

[0251]

[0252] Referring to Example 17, 1-naphthaleneboronic acid was used instead of 3-biphenylboronic acid to obtain yellow oily compound I-48 with a yield of 42%, which was used directly in the next step.

[0253] Example 49 Synthesis of Compound I-49

[0254]

[0255] Referring to Example 4, compound I-3 was replaced by I-48 to obtain white solid compound I-49 with a yield of 95%. 1 HNMR(400MHz,cdcl3)δ8.71(t,J=1.8Hz,1H),8.46(dt,J=7.8,1.4Hz,1H),7.92(s,1H),7.69(dt,J=6.5 ,1.3Hz,3H),7.51(dt,J=18.6,7.8Hz,3H),7.41–7.36(m,1H),4.65(dd,J=13.8,4.4Hz,2H),4.52(dd,J =13.8,7.8Hz,2H),4.03(d,J=3.6Hz,2H),3.19(dd,J=9.5,6.5Hz,1H),3.11(q,J=7.3Hz,1H),2.97–2.9 0(m,1H),2.53(s,3H),2.38–2.30(m,1H),2.14–2.05(m,2H),1.93–1.83(m,4H),1.39(t,J=7.4Hz,2H).

[0256] Example 50 Synthesis of Compound I-50

[0257]

[0258] Referring to Example 23, 1-naphthaleneboric acid was used to replace 1-benzyl-1H-pyrazole-4-boric acid to obtain yellow oily compound I-50 with a yield of 45%, which was directly used in the next step.

[0259] Example 51 Synthesis of Compound I-51

[0260]

[0261] Referring to Example 4, compound I-3 was replaced by I-50 to obtain yellow solid compound I-51 with a yield of 92%. 1 HNMR(400MHz,cdcl3)δ8.18(s,1H),8.08(s,1H),7.83(s,1H),7.32(p,J=6.7Hz,3H),5.34(s,2H),4.56 (t,J=7.1Hz,4H),3.75(s,2H),3.41(s,2H),3.04(t,J=7.1Hz,2H),2.65(s,4H),1.80(d,J=26.9Hz,9H).

[0262] Example 52 Synthesis of Compound I-52

[0263]

[0264] Referring to Example 23, 1-naphthaleneboronic acid was used to replace 5-benzothiazolepinacol borate to obtain yellow oily compound I-52 with a yield of 33%, which was directly used in the next step.

[0265] Example 53 Synthesis of Compound I-53

[0266]

[0267] Referring to Example 4, compound I-3 was replaced by I-53 to obtain yellow solid compound I-53 with a yield of 94%. 1 HNMR(400MHz,dmso)δ9.46(s,1H),9.07(d,J=1.5Hz,1H),8.57(dd,J=8.5,1.6Hz,1H),8.27–8.25(m,2H),5.22(s,1H),4.75(s,1 H),4.52(t,J=6.4Hz,2H),2.93(t,J=6.5Hz,4H),2.75(d,J=12.5Hz,2H),2.54(t,J=2.8Hz,5H),2.04(s,4H),1.63–1.59(m,4H).

[0268] Example 54 Synthesis of Compound I-54

[0269]

[0270] Referring to Example 1, the compound 8-BOC-3,8-diazabicyclo[3.2.1]octane was replaced with 3-(dimethylamino)pyrrolidine dihydrochloride to obtain a white solid compound I-54 with a yield of 86%. 1 H NMR(400MHz, CDCl3)δ8.11(s,1H),4.11–4.02(m,2H),3.85(td,J=10.2,7.1Hz,1H),3.65–3.56(m,1H),2. 95(ddd,J=15.3,9.0,6.6Hz,1H),2.39(d,J=9.4Hz,6H),2.07(dq,J=12.4,9.5Hz,1H),1.97–1.86(m,1H).

[0271] Example 55 Synthesis of Compound I-55

[0272]

[0273] Referring to Example 22, compound I-1 was replaced by I-54 to obtain yellow oily compound I-55 with a yield of 43%. 1 HNMR (400MHz, CDCl3) δ7.85 (s, 1H), 4.47 (t, J = 6.9Hz, 2H), 4.15–4.04 (m, 1H) ,3.96(td,J=9.7,6.1Hz,1H),3.78(td,J=10.0,7.2Hz,1H),3.65–3.55(m,1H) ,2.99(t,J=6.9Hz,2H),2.78(tt,J=9.0,6.5Hz,1H),2.60–2.56(m,4H),2.32( d,J=4.9Hz,6H),2.25–2.15(m,1H),1.95–1.85(m,1H),1.74(h,J=3.2Hz,4H).

[0274] Example 56 Synthesis of Compound I-56

[0275]

[0276] Referring to Example 3, the compound I-2 was replaced by I-55, and the compound 1-naphthaleneboronic acid was replaced by triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)silane to obtain compound I-56 with a yield of 43%. It was directly used in the next step.

[0277] Example 57 Synthesis of Compound I-57

[0278]

[0279] Referring to Example 6, compound I-2 was replaced by I-56 to obtain yellow oily compound I-57 with a yield of 89%, which was directly used in the next step.

[0280] Example 58 Synthesis of Compound I-58

[0281]

[0282] Referring to Example 4, compound I-3 was replaced by I-57 to obtain white foam compound I-58 with a yield of 93%. 1HNMR(400MHz,dmso)δ9.99(d,J=4.1Hz,1H),8.22(d,J=41.2Hz,1H),7.81(d,J=8.1Hz,1H), 7.47–7.42(m,1H),7.38(d,J=7.0Hz,1H),7.32(d,J=2.6Hz,1H),7.26(t,J=3.0Hz,1H),4.7 7(d,J=20.1Hz,2H),4.40(s,2H),3.93(d,J=77.4Hz,2H),3.56(s,1H),2.82(d,J=58.0Hz,3 H), 2.45 (s, 4H), 2.26 (s, 3H), 2.17 (s, 3H), 1.95 (s, 1H), 1.73 (s, 1H), 1.59 (d, J = 5.8Hz, 4H).

[0283] Example 59 Synthesis of Compound I-59

[0284]

[0285] Referring to Example 23, 1-naphthaleneboronic acid was used instead of benzofuran-3-boronic acid to obtain yellow oily compound I-59 with a yield of 45%, which was directly used in the next step.

[0286] Example 60 Synthesis of Compound I-60

[0287]

[0288] Referring to Example 4, compound I-3 was replaced by I-59 to obtain white solid compound I-60 with a yield of 93%. 1 HNMR(400MHz,dmso)δ8.74(s,1H),8.56–8.52(m,1H),8.24(s,1H),7.69–7.65(m,1H),7.41–7.38(m,2H),5.17(s,1H),4.74( s,1H),4.52(t,J=6.6Hz,2H),2.95(t,J=6.6Hz,4H),2.75(s,2H),2.54(t,J=2.8Hz,5H),2.04(s,4H),1.62(p,J=3.1Hz,4H).

[0289] Example 61 Synthesis of Compound I-61

[0290]

[0291] Dissolve compound I-1 (200 mg, 548 μmol) in anhydrous DMF (10 ml), add ethyl bromoacetate (137 mg, 822 μmol), add sodium hydride (purity 60%, 43 mg, 1.09 mmol) at 0°C under nitrogen protection, warm to room temperature and stir for 2 hours, after the reaction is completed. Add pure water (20 ml), continue stirring for 2 hours, after the reaction is completed, adjust to acidity with dilute hydrochloric acid. Then extract three times with ethyl acetate (20 ml*3), combine the organic phases, wash three times with saturated brine (30 ml*3), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 153 mg of yellow solid I-61 with a yield of 66%. Use it directly in the next step.

[0292] Example 62 Synthesis of Compound I-62

[0293]

[0294] Compound I-61 (153 mg, 361 μmol), HATU (206 mg, 543 μmol) and DIPEA (94 mg, 724 μmol) were dissolved in anhydrous DCM (10 ml), stirred at room temperature for 0.5 h, and then 1-Boc-3-methylaminopyrrolidine (109 mg, 543 μmol) was added, and stirred at room temperature for 3 h. After the reaction was completed, the mixture was washed three times with saturated brine (30 ml*3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 142 mg of a yellow oil with a yield of 65%. 1 H NMR (400MHz, CDCl3) δ7.94(s,1H),5.19(s,4H),4.63(s,1H),4.03(s,2H),3.54(t,J=9.8Hz,2H ), 3.22 (dd, J = 41.5, 28.5Hz, 4H), 2.94 (d, J = 51.0Hz, 3H), 2.04 (s, 6H), 1.46 (d, J = 4.5Hz, 18H).

[0295] Example 63 Synthesis of Compound I-63

[0296]

[0297] Referring to Example 40, compound I-22 was replaced by I-62 to obtain yellow oil I-63 with a yield of 42%, which was directly used in the next step.

[0298] Example 64 Synthesis of Compound I-64

[0299]

[0300] Referring to Example 4, compound I-3 was replaced by I-63 to obtain white solid compound I-64 with a yield of 87%. 1 HNMR(400MHz,cd3od)δ9.83(s,1H),9.30(s,1H),8.24(s,1H),8.08(s,2H),7.83(s,1H),7.67(s,1H),5.44(s ,2H),4.63(s,1H),3.64(s,2H),3.40(s,2H),3.26(s,3H),3.09(s,4H),2.89(d,J=13.5Hz,3H),2.19(s,6H).

[0301] Example 65 Synthesis of Compound I-65

[0302]

[0303] Referring to Example 63, quinoline-3-boric acid was replaced with 1-naphthaleneboric acid to obtain yellow oil I-65 with a yield of 47%, which was used directly in the next step.

[0304] Example 66 Synthesis of Compound I-66

[0305]

[0306] Referring to Example 4, compound I-3 was replaced by I-65 to obtain white solid compound I-66 with a yield of 94%. 1 HNMR(400MHz,cdcl3)δ8.66(d,J=8.1Hz,1H),8.02(d,J=8.9Hz,2H),7.89(dd,J=14.0 ,7.9Hz,2H),7.55(t,J=7.7Hz,1H),7.50–7.42(m,2H),5.33(d,J=42.4Hz,3H),4.67(d ,J=132.7Hz,2H),3.70(s,2H),3.24(d,J=12.0Hz,2H),3.15(d,J=9.8Hz,1H),3.07(s ,2H),2.91(d,J=18.6Hz,4H),2.33(s,3H),2.09(s,4H),1.82(dd,J=13.8,7.0Hz,1H).

[0307] Example 67 Synthesis of Compound I-67

[0308]

[0309] Referring to Example 1, the compound 8-BOC-3,8-diazabicyclo[3.2.1]octane was replaced with 1-Boc-3-methylaminopyrrolidine to obtain white solid I-67 in a yield of 85%. 1 H NMR (400MHz, CDCl3) δ11.99(s,1H),8.01(s,1H),5.76(s,1H),3.75–3.59(m,2 H),3.44(s,2H),3.33(s,3H),2.23(s,1H),2.10(d,J=9.8Hz,1H),1.48(s,9H).

[0310] Example 68 Synthesis of Compound I-68

[0311]

[0312] Referring to Example 22, compound I-1 was replaced by I-67 to obtain yellow oily compound I-68 with a yield of 43%. 1 HNMR (400MHz, CDCl3) δ7.92(s,1H),5.69(s,1H),4.55(t,J=6.8Hz,2H),3.67(td,J=11.7,5.1Hz,2H),3.41(d,J=9.9Hz,2H),3.28( s,3H),3.11(t,J=6.8Hz,2H),2.71(d,J=6.1Hz,4H),2.23–2.16(m,1H),2.06(d,J=21.7Hz,1H),1.82(h,J=3.1Hz,4H),1.47(s,9H).

[0313] Example 69 Synthesis of Compound I-69

[0314]

[0315] Referring to Example 40, compound I-22 was replaced by I-68 to obtain yellow oil I-69 with a yield of 46%, which was directly used in the next step.

[0316] Example 70 Synthesis of Compound I-70

[0317]

[0318] Referring to Example 4, compound I-3 was replaced by I-69 to obtain white foam compound I-70 with a yield of 92%. 1HNMR(400MHz,cdcl3)δ10.00(d,J=2.1Hz,1H),9.20(d,J=2.0Hz,1H),8.14(d,J=8.4Hz, 1H),8.02–7.96(m,2H),7.74(ddd,J=8.4,6.8,1.4Hz,1H),7.58(t,J=7.5Hz,1H),4.68(t ,J=7.0Hz,2H),3.41(s,4H),3.29(s,1H),3.17(t,J=8.5Hz,1H),3.09(t,J=7.1Hz,3H), 2.68(d,J=6.3Hz,4H),2.29(s,2H),1.99(dd,J=13.7,7.2Hz,1H),1.79(p,J=3.0Hz,4H).

[0319] Example 71 Synthesis of Compound I-71

[0320]

[0321] Referring to Example 1, the compound 8-BOC-3,8-diazabicyclo[3.2.1]octane was replaced with (1S,2S)-(+)-N,N-dimethylcyclohexanediamine to obtain white solid I-71 with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ7.85(s,1H),7.34(s,1H),4.37–4.24(m,1H),2.73(s,1H),2.50(s,6H),2.37(d, J=12.1Hz,1H),2.02–1.96(m,1H),1.89(d,J=12.5Hz,1H),1.77(d,J=12.4Hz,1H),1.48–1.29(m,4H).

[0322] Example 72 Synthesis of Compound I-72

[0323]

[0324] Referring to Example 22, compound I-1 was replaced by I-71 to obtain yellow oily compound I-72 with a yield of 39%. 1HNMR(400MHz,cdcl3)δ7.87(s,1H),6.62(s,1H),4.46(dd,J=7.5,6.4Hz,2H),3.81(s,1H),2.98(t,J=7.0Hz,2H),2.7 0(s,1H),2.58(td,J=4.8,2.0Hz,4H),2.26(s,6H),1.92(t,J=11.8Hz,3H),1.75(p,J=3.1Hz,5H),1.31–1.24(m,4H).

[0325] Example 73 Synthesis of Compound I-73

[0326]

[0327] Referring to Example 40, compound I-22 was replaced by I-72 to obtain white solid I-73 with a yield of 42%. 1 H NMR (400MHz, cdcl3) δ10.02(d,J=2.1Hz,1H),9.23(d,J=2.1Hz,1H),8.15(d,J=8.4Hz,1H ),7.98(d,J=7.8Hz,2H),7.75(ddd,J=8.4,6.9,1.5Hz,1H),7.59(t,J=7.5Hz,1H),6.57( s,1H),4.66(dd,J=7.9,6.3Hz,2H),3.98(s,1H),3.08(t,J=7.1Hz,2H),2.92(s,1H),2.6 6(d,J=5.9Hz,4H),2.31(s,6H),2.18–1.91(m,5H),1.87–1.75(m,5H),1.36–1.29(m,2H).

[0328] Example 74 Synthesis of Compound I-74

[0329]

[0330] Referring to Example 23, 1-naphthaleneboric acid was replaced with 9-anthraceneboric acid to obtain yellow oily compound I-74 with a yield of 43.5%, which was directly used in the next step.

[0331] Example 75 Synthesis of Compound I-75

[0332]

[0333] Referring to Example 4, compound I-3 was replaced by I-74 to obtain white solid compound I-75 with a yield of 93%. 1HNMR(400MHz,cdcl3)δ8.51(s,1H),8.03(d,J=8.4Hz,3H),7.85(d,J=8.8Hz,2H),7.40(dt,J=29.9,7.2Hz,4H),4.86(d,J=99 .4Hz,2H),4.59(s,2H),3.67(d,J=25.3Hz,1H),3.23(s,2H),3.09(s,2H),2.90(s,1H),2.60(s,5H),2.22(d,J=105.8Hz,8H).

[0334] Example 76 Synthesis of Compound I-76

[0335]

[0336] Referring to Example 23, 1-naphthaleneboric acid was replaced with 9-phenanthreneboric acid to obtain yellow oily compound I-76 with a yield of 42%, which was directly used in the next step.

[0337] Example 77 Synthesis of Compound I-77

[0338]

[0339] Referring to Example 4, compound I-3 was replaced by I-76 to obtain white solid compound I-77 with a yield of 91%. 1 HNMR(400MHz,cdcl3)δ8.80–8.69(m,3H),8.31(s,1H),8.02–7.96(m,2H),7.72–7.55(m,4H),4.65(t,J =6.9Hz,4H),3.75(s,4H),3.11(t,J=6.9Hz,2H),2.67(p,J=3.6Hz,4H),2.18(s,1H),1.89–1.77(m,8H).

[0340] Example 78 Synthesis of Compound I-78

[0341]

[0342] Referring to Example 56, the compound triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane was replaced with quinoline-3-boric acid to obtain white solid compound I-78 with a yield of 38%. 1H NMR(400MHz,cdcl3)δ10.03(s,1H),9.22(d,J=2.1Hz,1H),8.15(d,J=8.4Hz,1H),7.98(t,J=6.4Hz,1H), 7.93(s,1H),7.74(ddd,J=8.4,6.8,1.4Hz,1H),7.58(t,J=7.5Hz,1H),4.69(t,J=7.1Hz,2H),4.38–4.25( m,1H),4.05(s,1H),3.91–3.77(m,0H),3.70–3.61(m,1H),3.11(t,J=7.0Hz,2H),3.03(s,1H),2.87(d,J= 8.9Hz,1H),2.68(d,J=6.1Hz,5H),2.39(s,8H),2.16–2.08(m,0H),2.02–1.94(m,1H),1.85–1.73(m,4H).

[0343] Example 79 Synthesis of Compound I-79

[0344]

[0345] Referring to Example 1, 8-BOC-3,8-diazabicyclo[3.2.1]octane was replaced with 1-(dimethylamino)cyclobutanemethylamine to obtain white solid I-79 with a yield of 80%. 1 H NMR (400MHz, MeOD) δ8.12(s,1H),3.93(s,2H),2.31(s,6H),2.12(td,J=9.4,2.5Hz,2H),2.02(ddt,J=12.6,10.6,3.4Hz,2H),1.87–1.78(m,2H).

[0346] Example 80 Synthesis of Compound I-80

[0347]

[0348] Referring to Example 22, compound I-1 was replaced by I-79 to obtain yellow oily compound I-80 with a yield of 39%. 1HNMR (400MHz, CDCl3) δ7.94(d,J=25.4Hz,1H),6.53(d,J=81.7Hz,1H),4.47(t,J=6.9Hz,2H),3.80–3.63(m,2H),2.99(t,J=6.9Hz,2H ),2.58(d,J=5.8Hz,4H),2.38–2.30(m,2H),2.25(d,J=18.9Hz,6H),1.75(dt,J=10.4,4.9Hz,5H),1.66(ddd,J=12.3,8.7,2.6Hz,2H).

[0349] Example 81 Synthesis of Compound I-81

[0350]

[0351] Referring to Example 40, compound I-22 was replaced by I-80 to obtain white solid I-81 with a yield of 36%. 1 H NMR(400MHz,cdcl3)δ10.05(s,1H),9.25(s,1H),8.16(d,J=8.4Hz,1H),8.05–7.98(m,2H),7.75(ddd,J=8.4,6.9,1.5Hz,1H),7.59(td,J=7.4,1.2H z,1H),6.51(s,1H),4.69(t,J=7.0Hz,2H),4.07(s,2H),3.12(t,J=7.0Hz ,2H),2.69(d,J=6.0Hz,4H),2.40(s,6H),1.94(s,1H),1.89–1.74(m,8H).

[0352] Example 82 Synthesis of Compound I-82

[0353]

[0354] Referring to Example 22, the compound N-(2-chloroethyl)pyrrolidine hydrochloride was replaced with N-(3-chloropropyl)tetrahydropyrrolidine hydrochloride to obtain yellow oily compound I-82 with a yield of 47%. 1 H NMR(400MHz,cdcl3)δ7.84(s,1H),5.16(s,1H),4.62(s,1H),4.40(t,J=7.0Hz,2H),4.03(s,2H),3.17( dd,J=46.2,13.1Hz,2H),2.51(t,J=7.4Hz,6H),2.18–1.94(m,6H),1.77(p,J=3.1Hz,4H),1.46(s,9H).

[0355] Example 83 Synthesis of Compound I-83

[0356]

[0357] Referring to Example 40, compound I-22 was replaced by I-82 to obtain yellow oily compound I-83 with a yield of 51%, which was directly used in the next step.

[0358] Example 84 Synthesis of Compound I-84

[0359]

[0360] Referring to Example 4, compound I-3 was replaced by I-82 to obtain yellow oily compound I-84 with a yield of 96%. 1 HNMR(400MHz,cdcl3)δ9.99(d,J=2.1Hz,1H),9.20(d,J=2.1Hz,1H),8.16(d,J=8.4Hz,1H), 7.99(dd,J=8.2,1.4Hz,1H),7.89(s,1H),7.75(ddd,J=8.4,6.8,1.5Hz,1H),7.59(ddd,J=8. 2,6.9,1.2Hz,1H),5.34(s,1H),4.59(t,J=6.9Hz,3H),3.70(s,1H),3.23(d,J=12.3Hz,2H), 2.88(d,J=12.2Hz,2H), 2.64(d,J=9.5Hz,6H), 2.28(t,J=7.4Hz,2H), 1.83(p,J=3.0Hz,4H).

[0361] Example 85 Synthesis of Compound I-85

[0362]

[0363] Referring to Example 77, quinoline-3-boric acid was replaced with benzofuran-3-boric acid to obtain white solid compound I-85 with a yield of 42%. 1H NMR(400MHz,dmso)δ8.75(d,J=26.4Hz,1H),8.59(s,1H),8.20(d,J=46.3Hz,1H),7.67(s,1H),7.40(t,J=4.6Hz,2H),4.54(s,2H),4.19–3.98(m, 2H),3.76(d,J=59.5Hz,1H),3.54(d,J=32.8Hz,1H),3.00(s,2H),2.87( s,1H),2.58(s,4H),2.29(s,6H),2.00(s,1H),1.86(s,1H),1.62(s,4H).

[0364] Example 86 Synthesis of Compound I-86

[0365]

[0366] Referring to Example 77, quinoline-3-boric acid was replaced with 5-indoleboric acid pinacol ester to obtain yellow solid compound I-86 with a yield of 47%. 1 H NMR(400MHz,dmso)δ11.25(s,1H),8.73(s,1H),8.30(d,J=8.7Hz,1H),8.17(d,J=46.4Hz,1H),7 .45(d,J=8.6Hz,1H),7.38(t,J=2.7Hz,1H),6.56(s,1H),4.54(d,J=6.9Hz,2H),4.17(dt,J=27.6 ,10.2Hz,1H),4.04(dd,J=18.4,9.6Hz,1H),3.76(dd,J=49.4,9.2Hz,1H),3.58(d,J=10.3Hz,1H) ,3.00(d,J=53.0Hz,3H),2.67(s,4H),2.32(s,6H),2.03(s,1H),1.94–1.81(m,1H),1.66(s,4H).

[0367] Example 87 Synthesis of Compound I-87

[0368]

[0369] Referring to Example 77, quinoline-3-boric acid was replaced with benzothiophene-3-boric acid to obtain yellow solid compound I-87 with a yield of 38%. 1H NMR(400MHz,dmso)δ9.28–9.22(m,1H),8.75(d,J=24.3Hz,1H),8.21(d,J=48.8Hz,1H),8.06( d,J=8.0Hz,1H),7.50(t,J=7.6Hz,1H),7.42(t,J=7.5Hz,1H),4.56(t,J=6.5Hz,2H),4.20–3.9 9(m,2H),3.76(dd,J=47.7,9.0Hz,1H),3.61–3.50(m,1H),3.06(s,2H),2.89(s,1H),2.63(s, 4H), 2.30 (d, J = 3.6Hz, 6H), 2.21 (s, 1H), 1.94 (dt, J = 54.9, 10.4Hz, 1H), 1.66 (d, J = 6.2Hz, 4H).

[0370] Example 88 Synthesis of Compound I-88

[0371]

[0372] Referring to Example 77, quinoline-3-boric acid was replaced with 4-fluoronaphthalene-1-boric acid to obtain white solid compound I-88 with a yield of 46%. 1 H NMR(400MHz,dmso)δ8.91(d,J=11.6Hz,1H),8.32(d,J=51.3Hz,1H),8.17–8.07( m,2H),7.65(t,J=7.2Hz,2H),7.45(t,J=9.3Hz,1H),4.56(s,2H),4.06(s,2H),3 .87(d,J=9.1Hz,1H),3.65(s,1H),3.50(s,1H),3.17(s,2H),2.98(s,1H),2.74( s,4H),2.32(d,J=25.7Hz,6H),2.13(d,J=52.3Hz,2H),1.88(s,1H),1.70(s,4H).

[0373] Example 89 Synthesis of Compound I-89

[0374]

[0375] Referring to Example 23, 1-naphthaleneboric acid was replaced with benzothiophene-3-boric acid to obtain yellow oily compound I-89 with a yield of 46%, which was directly used in the next step.

[0376] Example 90 Synthesis of Compound I-90

[0377]

[0378] Referring to Example 4, compound I-3 was replaced by I-89 to obtain yellow solid compound I-90 with a yield of 91%. 1 HNMR(400MHz,dmso)δ9.17(d,J=8.2Hz,1H),8.70(s,1H),8.25(s,1H),8.06(d,J=8.0Hz,1H),7.52–7.47(m,1H),7.42(t,J=7.5Hz,1H),5.1 6(s,1H),4.75(s,1H),4.53(t,J=6.7Hz,2H),2.96(t,J=6.7Hz,4H),2.75(s,2H),2.53(d,J=6.0Hz,5H),2.04(s,4H),1.62(q,J=3.4Hz,4H).

[0379] Example 91 Synthesis of Compound I-91

[0380]

[0381] Referring to Example 23, 1-naphthaleneboric acid was replaced with 5-indoleboric acid pinacol ester to obtain yellow oily compound I-91 with a yield of 46%, which was directly used in the next step.

[0382] Example 92 Synthesis of Compound I-92

[0383]

[0384] Referring to Example 4, compound I-3 was replaced by I-91 to obtain yellow solid compound I-92 with a yield of 95%. 1 HNMR(400MHz,dmso)δ11.23(s,1H),8.69(d,J=1.5Hz,1H),8.26(dd,J=8.6,1.6Hz ,1H),8.18(s,1H),7.44(d,J=8.6Hz,1H),7.38(t,J=2.7Hz,1H),6.56(dt,J=2.8, 1.5Hz,1H),5.20(s,1H),4.74(s,1H),4.50(t,J=6.5Hz,2H),2.94(t,J=6.6Hz,4H ),2.75(d,J=12.3Hz,2H),2.54(p,J=3.6Hz,5H),2.03(s,4H),1.65–1.61(m,4H).

[0385] Example 93 Synthesis of Compound I-93

[0386]

[0387] Referring to Example 1, 8-BOC-3,8-diazabicyclo[3.2.1]octane was replaced with 3-N-Boc-N-methylaminopyrrolidine to obtain white solid compound I-93 with a yield of 95%. 1 H NMR (400MHz, CDCl3) δ12.22(s,1H),7.96(d,J=6.8Hz,1H),4.96(d,J=45.1Hz,1H),4.14–3.96(m,2H),3.86(q, J=8.8Hz,1H),3.65(dd,J=11.5,8.0Hz,1H),2.85(d,J=15.2Hz,3H),2.39–2.11(m,2H),1.49(d,J=5.3Hz,9H).

[0388] Example 94 Synthesis of Compound I-94

[0389]

[0390] Referring to Example 22, compound I-1 was replaced by I-93 to obtain yellow oily compound I-94 with a yield of 47%. 1 HNMR (400MHz, CDCl3) δ7.88(d,J=1.7Hz,1H),4.93(d,J=42.4Hz,1H),4.54(t,J=6.8Hz,2H),4.11–3.95(m,2H),3.82(q,J=8.7Hz,1H) ,3.62(dd,J=12.3,4.9Hz,1H),3.08(t,J=6.8Hz,2H),2.83(d,J=13.7Hz,3H),2.67(d,J=6.0Hz,4H),2.36–1.99(m,6H),1.48(s,9H).

[0391] Example 95 Synthesis of Compound I-95

[0392]

[0393] Referring to Example 59, compound I-22 was replaced by I-94 to obtain yellow oily compound I-95 with a yield of 42%, which was used directly in the next step.

[0394] Example 96 Synthesis of Compound I-96

[0395]

[0396] Referring to Example 4, compound I-3 was replaced by I-95 to obtain white solid compound I-96 with a yield of 96%. 1H NMR(400MHz,cdcl3)δ8.65–8.60(m,1H),8.49(s,1H),7.90(s,1H),7.53(dt,J =6.8,2.8Hz,1H),7.35(td,J=6.8,3.9Hz,2H),4.64(t,J=7.2Hz,2H),4.13–3.7 8(m,4H),3.58(d,J=32.3Hz,1H),3.45(s,1H),3.10(t,J=7.2Hz,2H),2.67(dt, J=6.4,3.6Hz,4H),2.53(s,3H),2.27(d,J=23.9Hz,1H),1.78(p,J=3.0Hz,5H).

[0397] Example 97 Synthesis of Compound I-97

[0398]

[0399] Referring to Example 22, the compound N-(2-chloroethyl)pyrrolidine hydrochloride was replaced with 1-(2-chloroethyl)piperidine hydrochloride to obtain yellow oily compound I-97 with a yield of 51%. 1 H NMR (400MHz, CDCl3) δ7.83(s,1H),5.16(s,1H),4.62(s,1H),4.46(t,J=7.1Hz,2H),3.95(d,J=64.6Hz,2H),3.16(dd,J=45.8,12.8Hz ,2H),2.82(t,J=7.1Hz,2H),2.47(t,J=5.3Hz,4H),2.07(d,J=26.0Hz,4H),1.53(t,J=5.8Hz,4H),1.46(s,9H),1.40(q,J=6.0Hz,2H).

[0400] Example 98 Synthesis of Compound I-98

[0401]

[0402] Referring to Example 59, compound I-22 was replaced by I-97 to obtain yellow oily compound I-98 with a yield of 47%, which was directly used in the next step.

[0403] Example 99 Synthesis of Compound I-99

[0404]

[0405] Referring to Example 4, compound I-3 was replaced by I-98 to obtain white solid compound I-99 with a yield of 96%. 1H NMR(400MHz,dmso)δ8.73(s,1H),8.55(dd,J=6.0,3.2Hz,1H),8.24(s,1H),7.66(dt,J=7.1,3.6Hz,1H),7.39(dd,J=6.0,3.2Hz,2H),5.17(s,1H) ,4.76(s,1H),4.52(d,J=7.0Hz,2H),2.93(s,2H),2.78(q,J=8.2Hz,4H) ,2.46(s,5H),2.05(s,4H),1.39(q,J=5.4Hz,4H),1.31(d,J=5.9Hz,2H).

[0406] Example 100 Synthesis of Compound I-100

[0407]

[0408] Referring to Example 1, 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine was replaced with 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine to obtain white solid compound I-100 with a yield of 85%. 1 H NMR (400MHz, CDCl3) δ11.37(s,1H),7.12(dd,J=3.6,2.3Hz,1H),6.43(dd,J=3.7,2.0Hz,1H),4.95(s,2H),3.98(d,J=12.9Hz,1H ),3.83(d,J=12.9Hz,1H),3.26(d,J=12.8Hz,1H),3.15(d,J=12.9Hz,1H),2.07(q,J=9.6Hz,2H),1.97–1.84(m,2H),1.46(s,9H).

[0409] Example 101 Synthesis of Compound I-101

[0410]

[0411] Referring to Example 22, compound I-1 was replaced by I-100 to obtain yellow oily compound I-101 with a yield of 48%. 1HNMR(400MHz, CDCl3)δ7.10(d,J=3.6Hz,1H),6.37(d,J=3.7Hz,1H),4.91(s,2H),4 .40(t,J=6.5Hz,2H),3.94(d,J=12.8Hz,1H),3.80(d,J=12.9Hz,1H),3.23(d,J=12. 9Hz,1H),3.12(d,J=12.9Hz,1H),3.04(t,J=6.5Hz,2H),2.69(d,J=6.3Hz,4H),2.04 (dd,J=12.7,2.6Hz,2H),1.91(t,J=4.4Hz,1H),1.84(p,J=3.3Hz,5H),1.45(s,9H).

[0412] Example 102 Synthesis of Compound I-102

[0413]

[0414] Referring to Example 59, compound I-22 was replaced by I-101 to obtain yellow oily compound I-102 with a yield of 43%, which was directly used in the next step.

[0415] Example 103 Synthesis of Compound I-103

[0416]

[0417] Referring to Example 4, compound I-3 was replaced by I-102 to obtain white solid compound I-103 with a yield of 96%. 1 H NMR(400MHz,dmso)δ8.61(s,1H),8.58–8.55(m,1H),7.66–7.63(m,1H),7.37(dd,J=6 .0,3.2Hz,2H),7.30(d,J=3.5Hz,1H),6.58(d,J=3.6Hz,1H),4.91(s,2H),4.37(t,J= 6.7Hz,2H),2.95(d,J=12.2Hz,2H),2.88(t,J=6.7Hz,2H),2.67(dd,J=12.3,2.1Hz,2 H), 2.54 (td, J=4.8, 1.9Hz, 5H), 2.01 (dd, J=12.4, 8.6Hz, 4H), 1.66 (p, J=3.0Hz, 4H).

[0418] Example 104 Synthesis of Compound I-104

[0419]

[0420] Referring to Example 93, the compound benzofuran-3-boric acid was replaced with quinoline-3-boric acid to obtain yellow oily compound I-104 with a yield of 47%, which was directly used in the next step.

[0421] Example 105 Synthesis of Compound I-105

[0422]

[0423] Referring to Example 4, compound I-3 was replaced by I-105 to obtain white solid compound I-105 with a yield of 93%. 1 HNMR(400MHz,dmso)δ9.90(t,J=2.0Hz,1H),9.24(d,J=2.1Hz,1H),8.18(dd,J=9.0,5.7Hz, 2H),8.08(d,J=8.4Hz,1H),7.82(ddd,J=8.4,6.8,1.4Hz,1H),7.67(t,J=7.5Hz,1H),4.54(t ,J=6.5Hz,2H),4.02–3.79(m,4H),3.64(dd,J=10.4,4.0Hz,1H),3.52–3.41(m,1H),2.94(t, J=6.5Hz,2H),2.54(q,J=3.0Hz,4H),2.38(s,3H),2.23–1.90(m,2H),1.60(p,J=3.0Hz,4H).

[0424] Example 106 Synthesis of Compound I-106

[0425]

[0426] Referring to Example 68, N-(2-chloroethyl)pyrrolidine hydrochloride was replaced with 1H-pyrrolidine-7a-(2-chloroethyl)hexahydrochloride to obtain yellow oily compound I-106 with a yield of 32%. 1H NMR (400MHz, cdcl3) δ7.93 (s, 1H), 4.45 (t, J = 7.2 Hz, 2H), 3.73 (dd, J = 13.4, 7.4 Hz, 3H), 3.42 (s, 2H), 3.29 (s, 3H), 2.86 (dd, J = 11.9, 6.1 Hz, 2H), 2.58 (t, J = 7.3 Hz, 2H), 2.21 (s, 2H), 2.11-1.98 (m, 8H), 1.84 (d, J = 4.0 Hz, 2H), 1.47 (s, 9H).

[0427] Example 107 Synthesis of Compound I-107

[0428]

[0429] Referring to Example 40, compound I-22 was replaced by I-106 to obtain yellow oily compound I-107 with a yield of 46%, which was directly used in the next step.

[0430] Example 108 Synthesis of Compound I-108

[0431]

[0432] Referring to Example 4, compound I-3 was replaced by I-107 to obtain white solid compound I-108 with a yield of 97%. 1 HNMR(400MHz,cdcl3)δ10.02(d,J=2.1Hz,1H),9.19(d,J=2.1Hz,1H),8.15(d ,J=8.4Hz,1H),8.01–7.97(m,2H),7.77–7.73(m,1H),7.59(ddd,J=8.1,6.8, 1.2Hz,1H),5.82(s,1H),4.61–4.57(m,2H),3.41(s,5H),3.25–2.99(m,6H), 2.69–2.63(m,2H),2.35–2.22(m,2H),2.21–2.10(m,7H),1.68–1.63(m,2H).

[0433] Example 109 Synthesis of Compound I-109

[0434]

[0435] Referring to Example 68, N-(2-chloroethyl)pyrrolidine hydrochloride was replaced with (2R,7AS)-7A-(chloromethyl)-2-fluorohexahydro-1H-pyrrolidine to obtain yellow oily compound I-109 with a yield of 35%. 1 H NMR (400MHz, CDCl3) δ7.91 (s, 1H), 5.71 (d, J = 3.3Hz, 1H), 5.19–5.03 (m, 1H), 4.25(qd,J=13.8,3.3Hz,2H),3.70(t,J=9.8Hz,3H),3.43(d,J=9.7Hz,2H),3. 28(d,J=12.0Hz,4H),3.16(d,J=17.1Hz,1H),3.10–3.00(m,1H),2.95–2.88( m,1H),2.33–2.17(m,3H),2.11–1.98(m,2H),1.91–1.78(m,2H),1.48(s,9H).

[0436] Example 110 Synthesis of Compound I-110

[0437]

[0438] Referring to Example 40, compound I-22 was replaced by I-109 to obtain yellow oily compound I-110 with a yield of 49%, which was directly used in the next step.

[0439] Example 111 Synthesis of Compound I-111

[0440]

[0441] Referring to Example 4, compound I-3 was replaced by I-110 to obtain white solid compound I-111 with a yield of 96%. 1 HNMR(400MHz,dmso)δ9.89(d,J=2.1Hz,1H),9.26–9.22(m,1H),8.27(s,1H),8.18(d,J=8.1Hz,1H),8.08(dd,J=8.4,1.1H z,1H),7.83(ddd,J=8.4,6.9,1.4Hz,1H),7.67(ddd,J=8.2,6.9,1.2Hz,1H),5.91(s,1H),5.34(s,1H),5.21(s,1H),4.38( d,J=13.9Hz,1H),4.22(d,J=13.8Hz,1H),3.49(s,3H),3.23–3.11(m,3H),3.02(dd,J=12.4,9.4Hz,2H),2.97–2.85(m,2H) ,2.81(q,J=8.3Hz,1H),2.43(dd,J=14.8,4.8Hz,1H),2.23(tt,J=16.1,7.0Hz,2H),1.95–1.80(m,4H),1.68–1.58(m,1H).

[0442] Example 112 Antiproliferative Activity Test of AGS, A549, H358, and Beas-2B Cells

[0443] Experimental principle: AGS cells are gastric adenocarcinoma cells with KRAS G12D mutation, A549 cells are lung cancer cells with KRAS G12S mutation, H358 cells are lung cancer cells with KRAS G12C mutation, and Beas-2B are normal lung epithelial cells. The activity of the compound prepared in the above example was detected by luminescence method to detect the effect on the proliferation ability of AGS, H358, and A549 cells after administration, and the toxicity of the compound to non-KRAS mutant Beas-2B cells was investigated. MRTX1133 was selected as the positive drug.

[0444] The anti-proliferation activity test contents of AGS, A549, H358 and Beas-2B cells are as follows:

[0445] 1. Collect cells in the logarithmic phase, adjust the concentration of the cell suspension, add 100 μl to each well (96-well flat-bottom plate), plate the cells at a density of 2000-3000 cells / well in the cell culture plate, and allow them to attach for 12-14 hours. Each cell line is also attached to 6 wells on the control plate at the same density.

[0446] 2. After the cells adhered, add 30μl of Cell Titer-Lite reagent to the control plate, incubate for 30 minutes, and read the RLU value on the microplate reader, which is recorded as Day 0. The test compound was diluted 6 times in a 2-fold ratio and added to a 96-well plate (6 replicates), each well containing 200μl of culture medium, the highest concentration was 1μM (positive drug was 200nM), and the DMSO content was 0.05%.

[0447] 3. After incubation for 72 hours, replace the culture medium so that each well contains 100 μl of culture medium and add 30 μl of Cell Titer-Lite reagent. After incubation for 30 minutes, read the RLU value on the microplate reader and record it as Day 3.

[0448] The above method can detect the anti-proliferative activity of the compound on AGS, A549, H358, and Beas-2B cells, and calculate the cell survival rate.

[0449] Survival rate = (RLU experimental group Day3-RLUday0) / (RLU blank control Day3-RLUday0)*100%.

[0450] The data were transferred to GraphPad Prism and the half-inhibitory concentration values ​​were obtained by fitting the parameters of the dose-response curves.

[0451] The half-maximal inhibitory concentration of each compound on AGS, H358, A549, and Beas-2B is shown in Table 1.

[0452] Table 1

[0453]

[0454]

[0455] As shown in Table 1, some of the compounds of the present invention have excellent antiproliferative activity against AGS, H358, and A549, and have low toxicity to normal lung epithelial cells Beas-2B. It can be seen that some of the compounds of the present invention can be used as pan-KRAS mutation inhibitors. Therefore, the compounds of the present invention can be used to prepare drugs for treating malignant tumors with multiple KRAS mutations.

[0456] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

Claims

1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, in, A1 is CR4 or N; A2 is CR5 or N; A3 is CR6 or N; A4 is CR7 or N; L is selected from chemical bonds, C 1-20 Alkylene, C 1-20 Alkyleneoxy, C 2-20 Alkenylene, C 2-20 Alkynylidene, -(SO)2-, -C 1-20 Alkylene CO-, carbonyl or sulfoxide; R1 is selected from: C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 1-20 Alkoxy, -NR a R b , C 6-20 Aryl, C 3-20 Cycloalkyl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl; wherein R a , R b Each independently selected from: hydrogen, C 1-20 Alkyl, C 3-20 Cycloalkyl, -C 1-10 Alkylene C 3-20 Cycloalkyl, 3-20 membered heterocyclic group; R1 is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-20 Alkyl, C 1-20 Haloalkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, -NR c R d , C 6-20 Aryl, C 3-20 Cycloalkyl, 3-20 membered heterocyclyl, 5-20 membered heteroaryl, -COOC 1-20 Alkyl, -COC 1-20 Alkyl, -COC 2-20 Alkenyl, -COOC 2-20 alkenyl; wherein R c , R d are independently hydrogen, C 1-20 Alkyl, C 3-20 Cycloalkyl, 3-20 membered heterocyclic group or -COOC 1-20 alkyl; R2 is selected from: H, C 1-20 Alkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, Hydroxyl, -NR e R f , C 6-20 Aryl, C 3-20 Cycloalkyl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, wherein R e , R f Each independently is H, C 1-20 Alkyl, C 3-20 Cycloalkyl or 4-10 membered heterocyclic group; R2 is optionally substituted by one or more groups selected from the group consisting of halogen, C 1-20 Alkyl (C 1-6 Alkyl), -COOC 1-20 Alkyl (-COOC 1-6 Alkyl), hydroxyl, C 1-20 Alkoxy, C 1-20 Haloalkyl; R3 is selected from: halogen, C 1-20 Alkyl, C 1-20 Alkoxy, C 2-20 Alkenyl, C 2-20 Alkynyl, C 6-20 Aryl, C 3-20 Cycloalkyl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl; R3 is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 1-20 Alkoxy, -O-(C 1-20 Alkylene)-OC 1-20 Alkyl, -C 2-20 AlkynylideneSi(C 1-20 alkyl)3, 5-20 membered heteroaryl, C 6-20 Aryl, -(C 1-20 Alkylene)C 6-20 Aryl; R4, R5, R6, and R7 are each independently selected from the group consisting of: H, halogen, hydroxy, amino, cyano, C 1-20 Alkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, C 6-20 Aryl, C 3-20 Cycloalkyl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl.

2. The compound according to claim 1, characterized in that The compound has a structure shown in Formula II: In the formula, R1, R2, R3 and L are as defined in claim 1.

3. The compound according to claim 1, characterized in that The compound has a structure shown in Formula III: In the formula, R1, R2, R3 and L are as defined in claim 1.

4. The compound according to claim 1, characterized in that R1 is selected from: C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -NR a R b , C 6-10 Aryl, C 3-10 Cycloalkyl, 3-15 membered heterocyclyl or 5-10 membered heteroaryl; wherein R a , R b Each independently selected from: hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, -C 1-6 Alkylene C 3-10 Cycloalkyl, 3-10 membered heterocyclic group; R1 is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, -NR c R d , C 6-10 Aryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -COOC 1-10 Alkyl, -COC 1-10 Alkyl, -COC 2-10 Alkenyl, -COOC 2-10 alkenyl; wherein R c , R d are independently hydrogen, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group or -COOC 1-10 alkyl.

5. The compound according to claim 1, characterized in that R2 is selected from: H, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, Hydroxyl, -NR e R f , C 6-10 Aryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein R e , R f Each independently is H, C 1-10 Alkyl, C 3-10 Cycloalkyl or 4-8 membered heterocyclic group; R2 is optionally substituted by one or more groups selected from the group consisting of halogen, C 1-10 Alkyl, -COOC 1-10 Alkyl, hydroxyl, C 1-10 Alkoxy, C 1-10 Halogenated alkyl.

6. The compound according to claim 1, characterized in that R3 is selected from: halogen, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 6-14 Aryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl or 5-15 membered heteroaryl; R3 is optionally substituted by one or more groups selected from the group consisting of halogen, hydroxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Alkoxy, -O-(C 1-10 Alkylene)-OC 1-10 Alkyl, -C 2-10 AlkynylideneSi(C 1-10 alkyl)3, 5-10 membered heteroaryl, C 6-10 Aryl, -(C 1-10 Alkylene)C 6-10 Aryl.

7. The compound according to claim 1, characterized in that The compound is selected from the group consisting of:

8. A pharmaceutical composition, characterized in that Include: The compound represented by the general formula (I) as claimed in claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof; and A pharmaceutically acceptable carrier.

9. The use of the compound represented by the general formula (I) according to claim 1 or the pharmaceutical composition according to claim 8, characterized in that: Used for preparing pan-KRAS inhibitors; or used for preparing drugs for preventing and / or treating KRAS mutated tumors.

10. The use according to claim 9, characterized in that The tumor with KRAS mutation is selected from the following diseases with KRAS mutation: gastric cancer, lung cancer, colon cancer, lymphoma, leukemia, multiple myeloma, mesothelioma, malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer, breast cancer, bile duct and gallbladder cancer, bladder cancer, neuroblastoma, neurothexoma, glioma, glioblastoma and astrocytoma, cervical cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancer.

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