Spirocyclic compounds as KRAS-G12C inhibitors

Abstract

The present invention relates to spirocyclic compounds as shown in formula I as KRAS-G12C inhibitors, which can be used for preparing drugs for treating tumors mediated by KRAS G12C. JPEG2024509330000090.jpg6352

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical science, and more specifically, the present invention relates to a spirocyclic compound that can be used as a KRAS-G12C inhibitor for preparing a drug for treating tumors mediated by KRAS G12C.

Background Art

[0002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog ("KRAS") is a guanosine triphosphate (GTP) enzyme and a member of the RAS oncogene family. KRAS functions as a molecular switch that cycles between an inactive state (guanosine diphosphate (GDP)-bound) and an active (GTP-bound) state, and transmits upstream cell signals received from various tyrosine kinases to downstream effectors to regulate various processes, including cell proliferation (Current Opin Pharmcol. 2013(13):394-401). KRAS is one of the most common mutations in cancer. Approximately 22% of cancer patients, especially pancreatic cancer (68%), cholangiocarcinoma (27%) and lung cancer (17%) have KRAS mutations. Here, the incidence rates of KRAS G12C in non-small cell lung cancer, colorectal cancer, and pancreatic cancer are 48%, 10%, and 1%, respectively. The KRAS protein lacks an ideal small molecule binding pocket, and because it has a very high affinity for GTP that is abundant in cells, it is difficult to design specific small molecule drugs. Among various known mutations, the KRAS G12C mutation is considered the most promising drug discovery target. Several covalent inhibitors targeting KRAS G12C, such as Amgen's AMG 510 and Mirati Therapeutics' MRTX849, are currently in clinical trials. These compounds all covalently bind to KRAS G12C at cysteine residue 12, keep KRAS G12C in an inactive GDP-bound state, and inhibit KRAS-dependent signal transduction.

[0003] After more than 30 years of research efforts, KRAS inhibitors have made some progress, but there is still no KRAS inhibitor that shows sufficient safety and efficacy to obtain regulatory approval. Therefore, pharmaceutical companies need to continue to develop new KRAS inhibitors and use them in the treatment of various diseases such as cancer.

[0004] WO2020 / 236940 discloses compound 819, and the binding force between compound 819 and KRAS G12C was predicted by software based on two methods, MMGBSA and CovDock, but the synthesis method, characterization data, and any biological test results of the compound are not provided.

[0005]

Chemical formula

Summary of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to provide a spirocyclic compound or a pharmaceutically acceptable salt thereof.

[0007] Another object of the present invention is to provide a pharmaceutical composition containing the spirocyclic compound or a pharmaceutically acceptable salt thereof.

[0008] Another object of the present invention is to provide the application of the spirocyclic compound or a pharmaceutically acceptable salt thereof, or a composition containing the spirocyclic compound or a pharmaceutically acceptable salt thereof, in the preparation of an antitumor drug.

Means for Solving the Problems

[0009] The first aspect of the present invention provides a compound represented by formula I, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuteride or a combination thereof,

[0010]

Chemical formula

[0011]

Chemical formula

[0012] In a preferred example, R 2 is hydrogen, an optionally substituted C1-C4 alkyl group, an optionally substituted saturated or unsaturated 3-8 membered carbocyclic group, an optionally substituted saturated or unsaturated 4-12 membered heterocyclic group, an optionally substituted saturated or unsaturated 3-8 membered heterocyclic fused 6-10 membered aromatic ring group, an optionally substituted saturated or unsaturated 3-8 membered heterocyclic fused 5-10 membered heteroaromatic ring group, an optionally substituted 6-10 membered aromatic ring group or an optionally substituted 5-10 membered heteroaromatic ring group, where the optionally substituted substituent described for R 2 is deuterium, halogen, hydroxy group, cyano group, oxo, C1-C3 alkoxy group, -NR c R d -CO 2 R 7 -CONR e R f -SO 2 NR g R h is selected from an optionally substituted 3-8 membered saturated or unsaturated carbocyclic group and an optionally substituted 4-8 membered saturated or unsaturated heterocyclic group, R c and R d are each independently selected from hydrogen, an optionally substituted C1-C6 alkyl group, an optionally substituted 3-8 membered carbocyclic group and an optionally substituted 4-8 membered heterocyclic group, or R c and R d together with the N to which they are attached form an optionally substituted 4-8 membered heterocyclic ring, R e and R f are each independently selected from hydrogen, an optionally substituted C1-C6 alkyl group, an optionally substituted 3-8 membered carbocyclic group and an optionally substituted 4-8 membered heterocyclic group, or R e and R f together with the N to which they are attached form an optionally substituted 4-8 membered heterocyclic ring, R g and R h are each independently selected from hydrogen, an optionally substituted C1-C6 alkyl group, an optionally substituted 3-8 membered carbocyclic group, and an optionally substituted 4-8 membered heterocyclic group, or R g and R h together with the N to which they are attached form an optionally substituted 4-8 membered heterocyclic ring, R 7 is hydrogen or an optionally substituted C1-C4 alkyl group, Preferably, said L 2 is absent, -O-, -S-, or -NR 6 -, where R 6 is hydrogen or a C1-C4 alkyl group, Preferably, said R a is hydrogen, fluorine, an optionally substituted C1-C3 alkyl group, an optionally substituted 4-6 membered saturated heterocyclic group, or an acetyl group, wherein the optionally substituted substituent described for R a is selected from the group consisting of a methyl group, an ethyl group, -N(R 5 ) 2 , a halogen, a C1-C3 alkoxy group, and a 4-6 membered saturated heterocyclic group, Each R 5 is independently hydrogen or a C1-C3 alkyl group, Preferably, said R a ’, R b are each independently hydrogen, fluorine, or a C1-C3 alkyl group, Preferably, said W is -(CR 8 R 9 )- or -NR 10 -, where R 8 , R 9 and R 10 are independently hydrogen or a C1-C3 alkyl group, Preferably, said X is -(CR 11 R 12 ) m- wherein each R 11is, independently of each other, hydrogen or a C1-C3 alkyl group, each R 12 is, independently of each other, hydrogen or a C1-C3 alkyl group, m is 1, 2 or 3, and more preferably, m is 1 or 2.

[0013] In another preferred example,

[0014]

Chemical formula

[0015]

Chemical formula

[0016]

Chemical formula

[0017]

Chemical formula

[0018] In another preferred example, R 1 is

[0019] [Chemical formula] and preferably, R 1 is

[0020] [Chemical formula] is as follows.

[0021] In another preferred example, R 2 is hydrogen, an optionally substituted C1-C4 alkyl group, an optionally substituted 6-10 membered aromatic ring group or an optionally substituted 5-10 membered heteroaromatic ring group, where the optionally substituted substituent described in R 2 is halogen, a hydroxy group, a cyano group, oxo, a C1-C3 alkoxy group, -NR c R d , -CO 2 R 7 , -CONR e R f , a C1-C4 alkyl sulfoxide group, a C1-C4 alkyl sulfone group, -SO 2 NR g R h , an optionally substituted 3-8 membered saturated or unsaturated carbocyclic group, and an optionally substituted 4-8 membered saturated or unsaturated heterocyclic group, selected from R c and R d are each independently selected from hydrogen, an optionally substituted C1-C6 alkyl group, an optionally substituted 3-8 membered carbocyclic group and an optionally substituted 4-8 membered heterocyclic group, or R c and R d together with the N to which they are attached form an optionally substituted 4-8 membered heterocyclic ring, R e and R fis independently selected from hydrogen, an optionally substituted C1-C6 alkyl group, an optionally substituted 3-8 membered carbocyclic group and an optionally substituted 4-8 membered heterocyclic group, or R e and R f together with the N to which they are attached form an optionally substituted 4-8 membered heterocyclic ring, R g and R h are independently selected from hydrogen, an optionally substituted C1-C6 alkyl group, an optionally substituted 3-8 membered carbocyclic group and an optionally substituted 4-8 membered heterocyclic group, or R g and R h together with the N to which they are attached form an optionally substituted 4-8 membered heterocyclic ring, R 7 is hydrogen or an optionally substituted C1-C4 alkyl group.

[0022] Preferably, R 2 is

[0023]

Chemical formula

[0024] In another preferred example,

[0025]

Chemical formula

[0026]

Chemical formula

[0027] In another preferred example, the compound is selected from the group consisting of the following.

[0028] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0029] The compounds of the present invention can be prepared according to the synthesis method of the examples or a method similar thereto.

[0030] The second aspect of the present invention provides a pharmaceutical composition, and the pharmaceutical composition (1) one or more selected from a therapeutically effective amount of the above compound of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuteride as an active ingredient, and (2) optionally, a pharmaceutically acceptable carrier.

[0031] Furthermore, the pharmaceutical composition may further contain other pharmaceutically acceptable therapeutic agents, particularly other anti-tumor drugs, or can be used in combination with other pharmaceutically acceptable therapeutic agents. The therapeutic agents include, but are not limited to, anti-tumor drugs that act on the DNA chemical structure such as cisplatin; anti-tumor drugs that affect de novo synthesis such as methotrexate (MTX), 5-fluorouracil (5FU); anti-tumor drugs that affect transcription elongation such as doxorubicin, epirubicin, aclarubicin, mitomycin; anti-tumor drugs that act on tubulin synthesis such as paclitaxel, vinorelbine; aromatase inhibitors such as aminoglutethimide, lanreotide, letrozole, anastrozole; cell signaling pathway inhibitors such as epidermal growth factor receptor inhibitors gefitinib, erlotinib, lapatinib, mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors trametinib, cobimetinib, cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors such as palbociclib, Src homology 2 domain-containing phosphatase (SHP2) inhibitors, SOS1 inhibitors; programmed death receptor-1 / programmed death ligand-1 (PD-1 / PD-L1) inhibitors such as nivolumab, pembrolizumab.

[0032] A third aspect of the present invention provides the use of the above-mentioned compound of the present invention, its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated compounds or its pharmaceutical composition for preparing a drug for preventing or treating KRAS G12C mutation-mediated cancer. In a preferred example, the cancer associated with KRAS G12C is selected from the group consisting of lung cancer (including non-small cell lung cancer), pancreatic cancer, colorectal cancer, leukemia, Ewing sarcoma, breast cancer, prostate cancer, T cell lymphoma, B cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrial tumor, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer.

[0033] In another preferred example, the cancer associated with the KRAS G12C is selected from non-small cell lung cancer, pancreatic cancer, or colorectal cancer.

Advantages of the Invention

[0034] It should be understood that within the scope of the present invention, by combining each of the above technical features of the present invention with the technical features specifically described below (for example, in the examples), new or preferred technical solutions can be formed. Due to space limitations, it will not be repeated here.

Brief Description of the Drawings

[0035]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0036] Explanation of Terms

[0037] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which the present invention belongs.

[0038] As used in this specification, the terms "comprising" or "including" can be open-ended, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of".

[0039] Definition of Groups

[0040] Standard scientific term definitions can be found in the references (including Carey and Sundberg, "ADVANCED ORGANIC CHEMISTRY 4TH ED.", Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise specified, conventional methods within the scope of those skilled in the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy, and pharmacological methods, are used. Unless specifically defined, the terms used herein in the context of analytical chemistry, organic synthetic chemistry, and related descriptions of drugs and medicinal chemistry are terms known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for the kit, or according to methods known in the art or the description of the present invention. Generally, the above-mentioned techniques and methods can be carried out according to conventional methods well-known in the art, as described in a plurality of general and specific documents cited and discussed herein. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0041] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.

[0042] The section headings used herein are for the sole purpose of organizing the article and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are hereby incorporated by reference in their entirety.

[0043] Before a particular chemical group defined in this specification, an abbreviation indicating the total number of carbon atoms present in the group is attached. For example, a C1-C6 alkyl group refers to an alkyl group defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the abbreviation does not include the carbon that can be present in the substituents of the group.

[0044] In addition to the above, when used in the specification and claims of this application, unless otherwise specified, it has the meanings as shown below.

[0045] In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0046] The "hydroxy group" refers to the -OH group.

[0047] The "hydroxyalkyl group" refers to an alkyl group as defined below substituted by a hydroxy group (-OH).

[0048] The "carbonyl group" refers to -C(=O)-yl.

[0049] The "nitro group" refers to -NO 2 and points.

[0050] The "cyano group" refers to -CN.

[0051] The "amino group" refers to -NH 2 and points.

[0052] The "substituted amino group" refers to an amino group substituted by one or two alkyl groups, alkylcarbonyl groups, arylcycloalkyl groups, heteroarylcycloalkyl groups as defined below, for example, monoalkylamino group, dialkylamino group, alkylamide group, arylcycloalkylamino group, heteroarylcycloalkylamino group.

[0053] The "carboxy group" refers to -COOH.

[0054] In the present application, as a group or part of another group (for example, a group such as a halogen-substituted alkyl group), the term "alkyl group" consists of only carbon atoms and hydrogen atoms, has 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is a completely saturated straight-chain or branched-chain hydrocarbon chain group bonded to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, 2-methylbutyl group, 2,2-dimethylpropyl group, n-hexyl group, heptyl group, 2-methylhexyl group, 3-methylhexyl group, octyl group, nonyl group, and decyl group. In the case of the present invention, the term "alkyl group" preferably refers to an alkyl group containing 1 to 6 carbon atoms.

[0055] In the present application, as a group or part of another group, the term "alkenyl group" consists of only carbon atoms and hydrogen atoms, contains at least one double bond, has, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and is a straight-chain or branched-chain hydrocarbon chain group bonded to the rest of the molecule by a single bond. Examples include, but are not limited to, vinyl group, propenyl group, allyl group, but-1-enyl group, but-2-enyl group, pent-1-enyl group, pent-1,4-dienyl group, etc.

[0056] In the present specification, as a group or part of another group, the term "alkynyl group" consists of only carbon atoms and hydrogen atoms, contains at least one carbon-carbon triple bond, has, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and is a straight-chain or branched-chain hydrocarbon chain group bonded to the rest of the molecule by a single bond. Examples include, but are not limited to, ethynyl group, 1-propynyl group, 1-butynyl group, heptynyl group, octynyl group, etc.

[0057] As used herein, the term "carbocyclic group", as a radical or part of another radical, refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which can include a fused ring system, a bridged ring system or a spiro ring system having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, which can be saturated or unsaturated and can be bonded to the remainder of the molecule by a single bond through any suitable carbon atom. Unless otherwise specified herein, the carbon atoms in the carbocyclic group can optionally be oxidized. Examples of carbocyclic groups include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, adamantyl group, 2,3-indanyl group, octahydro-4,7-methylene-1H-indenyl group, 1,2,3,4-tetrahydro-naphthyl group, 5,6,7,8-tetrahydro-naphthyl group, cyclopentenyl group, cyclohexenyl group, cyclohexadienyl group, 1H-indenyl group, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl group, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl group, fluorenyl group, bicyclo[2.2.1]heptyl group, 7,7-dimethyl-bicyclo[2.2.1]heptyl group, bicyclo[2.2.1]heptenyl group, bicyclo[2.2.2]octyl group, bicyclo[3.1.1]heptyl group, bicyclo[3.2.1]octyl group, bicyclo[2.2.2]octenyl group, bicyclo[3.2.1]octenyl group and octahydro-2,5-methylene-pentalenyl group, etc.

[0058] In the present application, as a group or part of another group, the term "heterocyclic group" refers to a stable 3- to 20-membered non-aromatic cyclic group composed of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specified herein, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or polycyclic ring system, which can include a fused ring system, a bridged ring system, or a spiro ring system. The nitrogen, carbon, or sulfur atoms in the heterocyclic group can optionally be oxidized, the nitrogen atoms can optionally be quaternized, and the heterocyclic group can be partially or fully saturated. The heterocyclic group can be bonded to the rest of the molecule by a single bond via a carbon atom or a heteroatom. In a heterocyclic group containing a fused ring, one or more rings can be an aromatic ring group or a heteroaromatic ring group defined below, provided that the bonding point with the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged ring, or spiro ring group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged ring, or spiro ring group containing a heteroatom selected from nitrogen, oxygen, and sulfur. Examples of the heterocyclic group include, but are not limited to, pyrrolidinyl group, morpholinyl group, piperazinyl group, homopiperazinyl group, piperidinyl group, thiomorpholinyl group, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl group, pyranyl group, tetrahydropyranyl group, thianyl group, tetrahydrofuryl group, oxazinyl group, dioxolanyl group, tetrahydroisoquinolinyl group, decahydroisoquinolinyl group, imidazolinyl group, imidazolidinyl group, quinazinyl group, thiazolidinyl group, isothiazolidinyl group, isoxazolidinyl group, indolinyl group, octahydroindolyl group, octahydroisoindolyl group, pyrrolidinyl group, pyrazolidinyl group, phthalimidyl group, etc.

[0059] In the present application, as a radical or as part of another radical, the term "aromatic ring (group)" refers to a conjugated hydrocarbon ring system radical having 6 to 18 carbon atoms (preferably 6 to 10 carbon atoms). For the purposes of the present invention, the aromatic ring (group) can be a monocyclic, bicyclic, tricyclic or polycyclic ring system and can also be fused to the carbocyclic or heterocyclic radical defined above, provided that the aromatic ring (group) is attached to the remainder of the molecule by a single bond via an atom on the aromatic ring. Examples of the aromatic ring (group) include, but are not limited to, phenyl group, naphthyl group, anthracenyl group, phenanthrenyl group, fluorenyl group, 2,3-dihydro-1H-isoindolyl group, 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.

[0060] In the present application, the term "arylcycloalkyl group" refers to an alkyl group defined above substituted by an aromatic ring group defined above.

[0061] In the present application, as a group or part of another group, the term "heteroaromatic ring (group)" refers to a 5- to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specified in the present specification, the heteroaromatic ring (group) can be a monocyclic, bicyclic, tricyclic or polycyclic ring system, and can also be condensed to the carbocyclic group or heterocyclic group defined above, provided that the heteroaromatic ring (group) is bonded to the rest of the molecule by a single bond through an atom on the heteroaromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaromatic ring (group) can be optionally oxidized, and the nitrogen atom can be optionally quaternized. For the purposes of the present invention, the heteroaromatic ring (group) is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.Examples of the heteroaromatic ring (group) include, but are not limited to, thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, oxazolyl group, oxadiazolyl group, isoxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, benzimidazolyl group, benzopyrazolyl group, indolyl group, furyl group, pyrrolyl group, triazolyl group, tetrazolyl group, triazinyl group, indradinyl group, isoindolyl group, indazolyl group, isoindazolyl group, purinyl group, quinolinyl group, isoquinolinyl group, diazinnaphthyl group, naphthyridinyl group, quinoxalinyl group, pteridinyl group, carbazolyl group, carbolinyl group, phenanthridinyl group, phenanthrolinyl group, acridinyl group, phenazinyl group, isothiazolyl group, benzothiazolyl group, benzothienyl group, oxatriazolyl group, cinnolinyl group, quinazolinyl group, phenylthio group, indolizinyl group, o-phenanthrolin group, isoxazolyl group, phenoxazinyl group, phenothiazinyl group, 4,5,6,7-tetrahydrobenzo[b]thienyl group, naphthopyridyl group, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.

[0062] In the present application, the term "heteroaryl cycloalkyl group" refers to the alkyl group defined above substituted by the heteroaromatic ring group defined above.

[0063] In the present application, the term "absent" means that both sides of the group defined above are directly connected by a chemical bond. For example, "B is absent in A-B-C" means "A-C".

[0064] In the present application,

[0065]

Chemical formula

[0066]

Chemical formula

[0067] In this application, unless otherwise specified in the claims, "optionally" and "optionally substituted" mean that the events or circumstances described later may or may not occur, and the description refers to both the occurrence and non-occurrence of the events or circumstances. For example, "optionally substituted aromatic ring group" means that the hydrogen on the aromatic ring group may or may not be substituted, and the description includes both substituted and unsubstituted aromatic ring groups. For example, when the substituents are not explicitly listed, the terms "optionally substituted", "substituted" or "substituted by" as used herein mean that one or more hydrogen atoms on a given atom or group may be independently substituted by one or more, for example, 1, 2, 3 or 4 substituents, and the substituents are independently deuterium (D), halogen, -OH, mercapto group, cyano group, -CD 3 , -C 1 -C 6 alkyl group (preferably -C 1-3 alkyl group), C 2 -C 6 alkenyl group, C 2 -C 6 alkynyl group, cycloalkyl group (preferably 3-8 membered cycloalkyl group), aromatic ring group, heterocyclic group (preferably 3-8 membered heterocyclic group), heteroaromatic ring group, aromatic ring group-C 1 -C 6 alkyl group-, heteroaromatic ring group-C 1 -C 6 alkyl group-, C 1 -C 6 halogenated alkyl-, -OC 1 -C 6 alkyl group (preferably -OC 1 -C 3 alkyl group), -OC 2 -C 6 alkenyl group, -OC1 -C 6 Alkylphenyl group, -C 1 -C 6 Alkyl-OH (preferably -C 1 -C 4 Alkyl-OH), -C 1 -C 6 Alkyl-SH, -C 1 -C 6 Alkyl-O-C 1 -C 6 Alkyl group, -OC 1 -C 6 Haloalkyl group, NH 2 、-C 1 -C 6 AlkylNH 2 (preferably -C 1 -C 3 AlkylNH 2 )、-N(C 1 -C 6 Alkyl group) 2 (preferably -N(C 1 -C 3 Alkyl) 2 )、-NH(C 1 -C 6 Alkyl group)(preferably -NH(C 1 -C 3 Alkyl))、-N(C 1 -C 6 Alkyl group)(C 1 -C 6 Alkylphenyl group)、-NH(C 1 -C 6 Alkylphenyl group)、Nitro group、-C(O)-OH、-C(O)OC 1 -C 6 Alkyl group(preferably -C(O)OC 1 -C 3 Alkyl group)、-CONR i R ii (wherein, R i and R ii are H, D and C 1-6 Alkyl group, preferably C 1-3 Alkyl group)、-NHC(O)(C 1 -C 6 Alkyl group)、-NHC(O)(phenyl)、-N(C1 -C 6 (alkyl group)C(O)(C 1 -C 6 (alkyl group), -N(C 1 -C 6 (alkyl group)C(O)(phenyl), -C(O)C 1 -C 6 (alkyl group), -C(O)heteroaromatic group (preferably -C(O)-5-7 membered heteroaromatic group), -C(O)C 1 -C 6 (alkylphenyl group), -C(O)C 1 -C 6 (halogenated alkyl group), -OC(O)C 1 -C 6 (alkyl group (preferably -OC(O)C 1 -C 3 (alkyl group)), -S(O) 2 -C 1 -C 6 (alkyl group), -S(O)-C 1 -C 6 (alkyl group), -S(O) 2 -phenyl group, -S(O) 2 -C 1 -C 6 (halogenated alkyl group), -S(O) 2 NH 2 , -S(O) 2 NH(C 1 -C 6 (alkyl group), -S(O) 2 NH(phenyl), -NHS(O) 2 (C 1 -C 6 (alkyl group), -NHS(O) 2 (phenyl) and -NHS(O) 2 (C 1 -C 6 (halogenated alkyl group)) selected from, wherein each of said alkyl group, cycloalkyl group, phenyl group, aromatic ring group, heterocyclic group and heteroaromatic group is halogen, -OH, -NH 2 , cycloalkyl group, 3-8 membered heterocyclic group, C 1 -C 4 (alkyl group), C 1 -C 4 (halogenated alkyl)-, -OC1 -C 4 alkyl group, -C 1 -C 4 alkyl group-OH, -C 1 -C 4 alkyl group-O-C 1 -C 4 alkyl group, -OC 1 -C 4 halogenated alkyl group, cyano group, nitro group, -C(O)-OH, -C(O)OC 1 -C 6 alkyl group, -CON(C 1 -C 6 alkyl group) 2 , -CONH(C 1 -C 6 alkyl group), -CONH 2 , -NHC(O)(C 1 -C 6 alkyl group), -NH(C 1 -C 6 alkyl group)C(O)(C 1 -C 6 alkyl group), -SO 2 (C 1 -C 6 alkyl group), -SO 2 (phenyl), -SO 2 (C 1 -C 6 halogenated alkyl group), -SO 2 NH 2 , -SO 2 NH(C 1 -C 6 alkyl group), -SO 2 NH(phenyl), -NHSO 2 (C 1 -C 6 alkyl group), -NHSO 2 (phenyl) and -NHSO 2 (C 1 -C 6It is further optionally substituted by one or more substituents selected from (haloalkyl group). When one atom or group is substituted by a plurality of substituents, the substituents may be the same or different. As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" refer to a specific segment or functional group within a molecule. A chemical moiety is generally considered to be a chemical entity that is embedded in or attached to a molecule.

[0068] "Stereoisomers" refer to compounds that are composed of the same atoms, bonded by the same bonds, but have different three-dimensional structures. The present invention encompasses various stereoisomers and mixtures thereof.

[0069] When the compounds of the present invention contain an olefinic double bond, unless otherwise specified, it is intended that the compounds of the present invention include both E-geometric isomers and Z-geometric isomers.

[0070] "Tautomers" refer to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are also within the scope of the present invention.

[0071] The compounds of the present invention or pharmaceutically acceptable salts thereof can contain one or more chiral carbon atoms, and thus can generate enantiomers, diastereomers and other stereoisomers. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof. In the preparation of the compounds of the present invention, racemates, diastereomers or enantiomers can be selected as raw materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.

[0072] Conventional techniques for preparing / separating individual isomers involve chiral synthesis from a suitable optically pure precursor, or resolution of a racemate (or racemate of a salt or derivative) using methods such as chiral high performance liquid chromatography, for example, Gerald Gubitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral Separations, Annu.R e v. Anal.Chem. 3:341 - 63, 2010; Fumiss et al. (eds.), VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809 - 816; Heller, Acc.Chem.R e s. 1990, 23, 128 can be referred to.

[0073] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0074] The term "pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc. Organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, caprylate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, etc. These salts can be prepared by methods known in the art.

[0075] "Pharmaceutically acceptable basic addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. Salts derived from organic bases include primary amines, secondary amines and tertiary amines such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc., for example natural substituted amines, cyclic amines and substituted amines including basic ion exchange resins, but are not limited thereto. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0076] In the present application, "pharmaceutical composition" refers to a formulation of a biologically active compound and a medium generally accepted in the art for delivering the compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert biological activity.

[0077] As used herein, the term "pharmaceutically acceptable" refers to substances (e.g., carriers or diluents) that do not affect the biological activity or properties of the compounds of the present invention and are relatively non-toxic, i.e., the substances can be administered to an individual without causing harmful biological reactions or harmful interactions with any of the components contained in the composition.

[0078] In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent that has been approved by the relevant government regulatory agency as acceptable for human or veterinary use.

[0079] The "tumors" described in the present invention include, but are not limited to, diseases such as lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrial tumor, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer, etc.

[0080] As used herein, the terms "preventive", "prevention" and "prevention" include reducing the possibility of a disease or condition occurring or worsening in a patient.

[0081] As used herein, the term "treatment" and other similar synonyms include the following meanings. (i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such a mammal is susceptible to the disease or disorder but has not been diagnosed as having the disease or disorder, (ii) Inhibiting a disease or disorder, i.e., preventing its onset, (iii) Alleviating a disease or disorder, i.e., regressing the state of the disease or disorder, or (iv) Reducing the symptoms caused by the disease or disorder.

[0082] As used herein, the terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refer to an amount of at least one agent or compound that, after administration, is sufficient to alleviate to some extent one or more symptoms of the disease or disorder being treated. The result can be a reduction and / or alleviation of signs, symptoms or causes, or any other desirable change in the biological system. For example, an "effective amount" for use in therapy is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant alleviation of symptoms. Techniques such as dose escalation studies can be used to measure the effective amount suitable for the case here.

[0083] As used herein, terms such as "oral administration", "administration", "dosing", etc. refer to methods by which a compound or composition can be delivered to the desired site of biological action. These methods include, but are not limited to, oral administration routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), domiciliary administration and rectal administration. Those skilled in the art are familiar with the administration techniques useful for the compounds and methods described herein, as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and e Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0084] As used herein, the terms "drug combination", "drug co - administration", "combined administration", "administration of other therapies", "administration of other therapeutic agents", etc. refer to a drug therapy obtained by mixing or combining two or more active ingredients, which includes both fixed combinations and non - fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic formulation in the form of a single entity or a single dosage form. The term "non - fixed combination" refers to the simultaneous, concomitant or sequential administration to a patient, at variable intervals, of at least one compound described herein and at least one synergistic formulation as separate entities. This also applies to cocktail therapies, for example, the administration of three or more active ingredients.

[0085] Those skilled in the art should further understand that in the methods described below, it is necessary to protect the functional groups of the intermediate compounds with appropriate protecting groups. Such functional groups include hydroxy groups, amino groups, mercapto groups and carboxylic acids. Suitable hydroxy - protecting groups include trialkylsilyl groups or diarylcycloalkylsilyl groups (e.g., t - butyldimethylsilyl group, t - butyldiphenylsilyl group or trimethylsilyl group), tetrahydropyranyl group, benzyl group, etc. Suitable protecting groups for amino groups, amidino groups and guanidino groups include t - butoxycarbonyl group, benzyloxycarbonyl group, etc. Suitable mercapto - protecting groups include - C(O)-R” (where R” is an alkyl group, an aromatic ring group or an arylcycloalkyl group), p - methoxybenzyl group, trityl group, etc. Suitable carboxy - protecting groups include alkyl groups, aromatic ring groups or arylcycloalkyl ester systems.

[0086] Protecting groups are those known to those skilled in the art and can be introduced and removed according to the standard techniques described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organic Synthesis, (1999), 4th Ed., Wiley. The protecting group may be a polymer resin.

[0087] Beneficial effects

[0088] 1. Provide a compound of formula I or a pharmaceutically acceptable salt thereof.

[0089] 2. Provide a pharmaceutical composition having a novel structure for preventing and treating diseases associated with the KRAS G12C mutation.

[0090] Specific embodiments

Examples

[0091] Hereinafter, the technical solutions of the present invention will be further described through specific embodiments. It is obvious to those skilled in the art that the above embodiments are only for helping to understand the present invention and should not be regarded as specific limitations to the present invention.

[0092] In the following experimental methods where no conditions are specifically indicated, usually, follow the conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, the percentages and parts are by weight percentage and parts by weight.

[0093] The experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

[0094] In each example, 11H NMR was recorded on a BRUKER AVANCE NEO 400 MHz nuclear magnetic resonance spectrometer, and the chemical shifts are expressed in δ (ppm). Liquid chromatography mass spectrometry (LCMS) was recorded on a Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, LCMS-2020 mass spectrometer. A Gilson-281 model liquid chromatograph was used for preparative HPLC separation.

[0095] Preparation of Intermediates

[0096] 1. Preparation of Intermediate A

[0097]

Chemical Structure

[0098]

Chemical Structure

[0099] MS-ESI [M+H] + , calculated value 236, measured value 236.

[0100] (2) Compound A-3 (50.8 g, 216 mmol) and ethyl acetate (95.1 g, 1.08 mol) were dissolved in tetrahydrofuran (500 mL). Under nitrogen gas protection at -78 °C, lithium diisopropylamide (2 mol / L, 216 mL, tetrahydrofuran solution) was added dropwise, and the reaction solution was stirred at -78 °C for 3 hours. The temperature was raised to 0 °C, and saturated ammonium chloride aqueous solution (500 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (1000 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain Compound A-4.

[0101] MS-ESI[M+H] + , calculated value 324, measured value 324.

[0102] 1 H NMR(400MHz,CDCl 3 )δ 7.18-7.26(m,4H),5.21(s,1H),4.17(qd,J=7.2,3.2Hz,2H),3.17(ddd,J=16.4,8.4,5.6Hz,1H),2.88-2.93(m,1H),2.73-2.87(m,2H),2.64-2.72(m,1H),2.32(ddd,J=13.6,8.4,5.6Hz,1H),1.24-1.27(m,3H),1.19(s,9H).

[0103] (3) To a solution of Compound A-4 (15.6 g, 48.2 mmol) in ethanol (100 mL) was added a dioxane solution of hydrochloric acid (4 mol / L, 30 mL). Under nitrogen gas protection, the reaction solution was stirred at 25 °C for 5 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude Compound A-5.

[0104] MS-ESI[M-NH 2 +H] + , calculated value 203, measured value 203.

[0105] (4) To a solution of hydrochloride of compound A-5 (12.0 g, 46.9 mmol) in ethanol (50.0 mL), add compound A-6 (46.9 g, 469 mmol), copper oxide (373 mg, 4.69 mmol), and triethylamine (4.75 g, 46.9 mmol). Under the protection of nitrogen gas, react the reaction solution at 85 °C for 4 hours with sealing. Add water (500 mL) to the reaction solution, extract with ethyl acetate (500 mL × 2), combine the organic phases, wash with saturated brine (500 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound A-7.

[0106] MS-ESI[M+H] + , calculated value 320, measured value 320.

[0107] 1 H NMR(400MHz,CDCl 3 )δ 7.13-7.26(m,4H),4.09-4.15(m,4H),2.87-2.99(m,2H),2.76(q,J=6.8Hz,2H),2.63(br d,J=14.8Hz,1H),2.54(dd,J=11.2,6.4Hz,1H),2.42-2.45(m,2H),2.28-2.36(m,1H),2.17(ddd,J=13.2,8.4,4.8Hz,1H),1.18-1.26(m,6H).

[0108] (5) To a solution of compound A-7 (13.7 g, 42.9 mmol) in ethanol (100 mL), add paraformaldehyde (6.44 g) and sodium cyanoborohydride (8.09 g, 129 mmol). Under the protection of nitrogen gas, react the reaction solution at 25 °C for 1 hour. Add water (150 mL) to the reaction solution, extract with ethyl acetate (200 mL × 2), combine the organic phases, wash with saturated brine (150 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain compound A-8.

[0109] MS-ESI [M+H] + , calculated value 334, measured value 334.

[0110] 1 H NMR (400 MHz, CDCl 3 ) δ 7.11 - 7.26 (m, 4H), 4.07 - 4.12 (m, 2H), 3.81 - 3.97 (m, 2H), 2.79 - 3.00 (m, 3H), 2.74 - 2.78 (m, 1H), 2.57 - 2.73 (m, 2H), 2.24 - 2.48 (m, 4H), 2.17 (s, 3H), 1.22 - 1.26 (m, 3H), 1.01 (t, J = 7.2 Hz, 3H).

[0111] (6) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 121 mL, in tetrahydrofuran solution) was added to a solution of compound A-8 (13.4 g, 40.2 mmol) in tetrahydrofuran (500 mL), and the reaction solution was reacted at -78 °C for 1 hour under nitrogen gas protection. Water (500 mL) was added to the reaction solution, and it was extracted with ethyl acetate (500 mL × 2). The organic phases were combined, washed with saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound A.

[0112] MS-ESI [M+H] + , calculated value 288, measured value 288.

[0113] 1 H NMR (400 MHz, CDCl 3 ) δ 7.19 - 7.27 (m, 4H), 4.20 - 4.31 (m, 2H), 3.44 - 3.61 (m, 1H), 3.18 - 3.31 (m, 1H), 2.90 - 2.99 (m, 2H), 2.69 (br t, J = 13.2 Hz, 1H), 2.30 - 2.44 (m, 1H), 2.16 - 2.29 (m, 1H), 2.06 - 2.15 (m, 3H), 1.61 - 1.96 (m, 2H), 1.30 - 1.34 (m, 3H).

[0114] Example 1. Synthesis of Compound 1

[0115]

Chemical Structure

[0116] MS-ESI[M+H] + , calculated value 300, measured value 300.

[0117] 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (br s, 1H), 12.28 (br s, 1H), 7.23 - 7.27 (m, 3H), 7.21 (br s, 1H), 3.49 (br d, J = 16.8 Hz, 1H), 3.05 (br d, J = 16.4 Hz, 1H), 2.84 - 2.95 (m, 2H), 2.57 - 2.69 (m, 1H), 2.40 - 2.48 (m, 1H), 2.15 (dt, J = 13.2, 8.4 Hz, 1H), 1.98 (s, 3H), 1.59 - 1.69 (m, 1H).

[0118] (2) To a solution of compound 1-2 (1.66 g, 5.54 mmol) in water (15.0 mL), sodium hydroxide (443 mg, 11.1 mmol) and dimethyl sulfate (1.93 mg, 15.3 mmol) were added. The reaction mixture was stirred at 0 °C for 2 h under nitrogen gas protection. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 1:2) to obtain compound 1-3.

[0119] MS-ESI[M+H] + , calculated value 314, measured value 314.

[0120] 1 1H NMR (400 MHz, DMSO-d6) δ 12.66 (br s, 1H), 7.21 - 7.26 (m, 3H), 7.15 - 7.20 (m, 1H), 3.55 (br d, J = 17.2 Hz, 1H), 3.12 - 3.20 (m, 1H), 2.90 (br t, J = 7.2 Hz, 2H), 2.77 (br d, J = 17.6 Hz, 1H), 2.54 (br d, J = 18.4 Hz, 1H), 2.44 (s, 3H), 2.18 (dt, J = 13.2, 8.4 Hz, 1H), 2.00 (s, 3H), 1.61 (dt, J = 13.2, 6.4 Hz, 1H).

[0121] (3) Phosphorus oxychloride (6.60 g, 43.0 mmol) was added to a solution of compound 1 - 3 (840 mg, 2.68 mmol) in trichloromethane (4.0 mL), and the reaction solution was stirred at 80 °C for 1 hour under nitrogen gas protection. The reaction solution was concentrated under reduced pressure, ice water (50.0 mL) was added, and the mixture was extracted with dichloromethane (50.0 mL × 1). The organic phase was washed with saturated aqueous sodium bicarbonate solution (50.0 mL × 2) and saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1 - 4.

[0122] MS-ESI [M + H] + , calculated value 332, measured value 332.

[0123] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.27 (br s, 1H), 7.18 - 7.26 (m, 3H), 3.95 (br d, J = 16.8 Hz, 1H), 3.48 - 3.60 (m, 1H), 3.04 - 3.22 (m, 1H), 2.97 - 3.04 (m, 1H), 2.89 - 2.97 (m, 2H), 2.54 (s, 3H), 2.23 - 2.31 (m, 1H), 2.20 (s, 3H), 1.65 - 1.71 (m, 1H).

[0124] (4) To a solution of Compound 1-4 (200 mg, 603 μmol) in dichloromethane (5.0 mL) was added m-chloroperbenzoic acid (123 mg, 606 μmol), and the reaction mixture was stirred at 0 °C for 5 h under nitrogen gas protection. Saturated aqueous sodium sulfite solution (30.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20.0 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (20.0 mL × 2) and saturated brine (20.0 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 1-5.

[0125] MS-ESI[M+H] + , calculated value 348, measured value 348.

[0126] (5) To a solution of Compound 1-5 (206 mg, 592 μmol) in N,N-dimethylformamide (10.0 mL) was added Compound 1-6 (552 mg, 2.96 mmol), and the reaction mixture was stirred at 25 °C for 16 h under nitrogen gas protection. Ethyl acetate (30.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (20.0 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative thin-layer chromatography (dichloromethane / methanol = 10:1) to obtain Compound 1-7.

[0127] MS-ESI[M+H] + , calculated value 498, measured value 498.

[0128] (6) To a solution of Compound 1-7 (32.0 mg, 64.3 μmol) in tetrahydrofuran (3.0 mL) were added Compound 1-8 (22.2 mg, 193 μmol) and sodium t-butoxide (18.6 mg, 194 μmol), and the reaction mixture was stirred at 25 °C for 1 h under nitrogen gas protection. Ethyl acetate (20.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 1-9.

[0129] MS-ESI[M+H] + , calculated value 549, measured value 549.

[0130] (7) To a solution of compound 1-9 (35.0 mg, 63.8 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction mixture was stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 1-10.

[0131] MS-ESI[M+H] + , calculated value 449, measured value 449.

[0132] (8) To a solution of the trifluoroacetate salt of compound 1-10 (35.0 mg, 62.2 μmol) in dichloromethane (2.0 mL) were added triethylamine (31.5 mg, 331 μmol) and compound 1-11 (16.9 mg, 187 μmol), and the reaction mixture was stirred at -78 °C for 1 hour under nitrogen gas protection. Dichloromethane (20.0 mL) was added to the reaction mixture, and it was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high performance liquid chromatography (3_Phenomenex Luna C18, 70 mm × 30 mm 3 μm, A: water (10 mmol / L ammonium bicarbonate); B: acetonitrile, 20%-70%: 40 minutes) to obtain compound 1.

[0133] MS-ESI[M+H] + , calculated value 503, measured value 503.

[0134] 11H NMR (400 MHz, MeOD) δ 7.20 - 7.31 (m, 4H), 6.81 (dd, J = 16.8, 10.4 Hz, 1H), 6.26 (dd, J = 16.8, 1.6 Hz, 1H), 5.80 (dd, J = 10.4, 1.6 Hz, 1H), 4.34 - 4.41 (m, 1H), 4.27 - 4.33 (m, 1H), 3.85 (br d, J = 3.2 Hz, 2H), 3.74 - 3.81 (m, 2H), 3.63 - 3.72 (m, 4H), 3.54 (br s, 2H), 3.08 (dt, J = 9.6, 4.8 Hz, 1H), 2.95 - 3.04 (m, 2H), 2.82 - 2.94 (m, 2H), 2.70 - 2.78 (m, 1H), 2.49 (s, 3H), 2.39 - 2.46 (m, 1H), 2.35 (q, J = 8.8 Hz, 1H), 2.20 (s, 3H), 2.05 - 2.13 (m, 1H), 1.85 - 1.91 (m, 1H), 1.76 - 1.84 (m, 2H), 1.65 - 1.74 (m, 1H).

[0135] Example 2. Synthesis of Compound 2

[0136]

Chemical Structure

[0137] MS-ESI [M+H] +, calculated value 521, measured value 521.

[0138] 1 H NMR (400 MHz, MeOD) δ 7.25 - 7.30 (m, 4H), 5.28 - 5.35 (m, 1H), 5.24 (dd, J = 19.2, 4.0 Hz, 1H), 4.70 (dt, J = 12.4, 3.6 Hz, 1H), 4.47 - 4.55 (m, 1H), 3.81 - 3.90 (m, 3H), 3.73 - 3.78 (m, 4H), 3.61 - 3.71 (m, 3H), 3.52 - 3.61 (m, 2H), 3.21 (dt, J = 11.2, 8.0 Hz, 1H), 3.04 - 3.12 (m, 1H), 3.02 (s, 3H), 2.95 - 3.01 (m, 2H), 2.88 - 2.94 (m, 1H), 2.47 (dt, J = 13.2, 8.4 Hz, 1H), 2.32 - 2.40 (m, 1H), 2.24 (s, 3H), 2.14 - 2.20 (m, 1H), 2.09 (br dd, J = 14.4, 7.2 Hz, 1H), 1.97 - 2.04 (m, 1H), 1.89 (ddd, J = 13.2, 8.4, 4.4 Hz, 1H).

[0139] Example 3. Synthesis of Compound 3

[0140]

Chemical Structure

[0141] MS-ESI [M+H] + , calculated value 284, measured value 284.

[0142] 11H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.76 (s, 1H), 7.22 - 7.27 (m, 3H), 7.18 - 7.22 (m, 1H), 3.41 - 3.45 (m, 1H), 3.02 (br d, J = 16.0 Hz, 1H), 2.81 - 2.93 (m, 2H), 2.56 (br d, J = 17.2 Hz, 1H), 2.32 (d, J = 17.2 Hz, 1H), 2.16 (dt, J = 13.2, 8.4 Hz, 1H), 1.97 (s, 3H), 1.62 (ddd, J = 13.2, 8.4, 4.4 Hz, 1H).

[0143] (2) Compound 3-1 (328 mg, 1.16 mmol) was dissolved in phosphorus oxychloride (4.95 g, 32.3 mmol), and the reaction solution was stirred at 80 °C for 16 hours under nitrogen gas protection. The reaction solution was concentrated under reduced pressure, ice water (50.0 mL) was added, and the mixture was extracted with dichloromethane (50.0 mL × 1). The organic phase was washed with saturated aqueous sodium bicarbonate solution (50.0 mL × 2) and saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 3-2.

[0144] MS-ESI [M+H] + , calculated value 320, measured value 320.

[0145] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.27 (br d, J = 5.2 Hz, 3H), 7.19 (br d, J = 4.4 Hz, 1H), 3.98 (d, J = 17.6 Hz, 1H), 3.55 (br d, J = 17.6 Hz, 1H), 3.11 - 3.22 (m, 1H), 2.91 - 3.05 (m, 3H), 2.23 - 2.31 (m, 1H), 2.20 (s, 3H), 1.62 (td, J = 8.8, 4.4 Hz, 1H).

[0146] (3) To a solution of compound 3-2 (140 mg, 437 μmol) in N,N-dimethylformamide (5.0 mL) were added potassium carbonate (151 mg, 1.09 mmol) and compound 3-3 (82.1 mg, 364 μmol), and the reaction mixture was stirred at 50 °C for 6 hours under a nitrogen gas atmosphere. Ethyl acetate (30.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 3-4.

[0147] MS-ESI[M+H] + , calculated value 509, measured value 509.

[0148] (4) To a solution of compound 3-4 (120 mg, 236 μmol) in dioxane (5.0 mL) were added compound 3-5 (81.5 mg, 708 μmol), cesium carbonate (231 mg, 709 μmol), and methanesulfonic acid (2-dicyclohexylphosphino-2´,6´-diisopropoxy-1,1´-biphenyl)(2-amino-1,1´-biphenyl-2-yl)palladium (39.4 mg, 47.1 μmol), and the reaction mixture was stirred at 110 °C for 4 hours under a nitrogen gas atmosphere. Ethyl acetate (20.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1:2) to obtain compound 3-6.

[0149] MS-ESI[M+H] + , calculated value 588, measured value 588.

[0150] 11H NMR (400 MHz, MeOD) δ 7.19 - 7.29 (m, 4H), 4.59 - 4.65 (m, 1H), 4.30 - 4.41 (m, 2H), 3.92 - 4.16 (m, 3H), 3.68 - 3.76 (m, 2H), 3.41 (br dd, J = 14.0, 3.6 Hz, 1H), 3.14 - 3.25 (m, 2H), 2.96 - 3.11 (m, 4H), 2.73 - 2.95 (m, 4H), 2.54 (br d, J = 3.6 Hz, 3H), 2.43 (td, J = 13.2, 8.4 Hz, 2H), 2.21 (d, J = 2.8 Hz, 3H), 2.07 - 2.17 (m, 1H), 1.81 - 1.92 (m, 3H), 1.67 - 1.77 (m, 1H), 1.51 (s, 9H).

[0151] (5) To a solution of Compound 3 - 6 (30.0 mg, 51.0 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction solution was stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude Compound 3 - 7.

[0152] MS - ESI [M + H] + , calculated value 488, measured value 488.

[0153] (6) To a solution of the trifluoroacetate salt of Compound 3 - 7 (30.0 mg, 49.9 μmol) in dichloromethane (2.0 mL) were added triethylamine (25.2 mg, 249 μmol) and Compound 3 - 8 (13.6 mg, 150 μmol), and the reaction solution was stirred at -78 °C for 1 hour under nitrogen gas protection. Dichloromethane (20.0 mL) was added to the reaction solution, and it was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high - performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0% - 30%: 8 minutes) to obtain the formate salt of Compound 3.

[0154] MS - ESI [M + H] + , calculated value 542, measured value 542.

[0155] 1 1H NMR (400 MHz, MeOD) δ 7.25 - 7.31 (m, 4H), 6.82 (br d, J = 11.6 Hz, 1H), 6.30 (br d, J = 16.4 Hz, 1H), 5.84 (br d, J = 10.4 Hz, 1H), 5.04 (br s, 1H), 4.72 (dt, J = 12.4, 3.2 Hz, 1H), 4.54 (dd, J = 12.4, 7.2 Hz, 1H), 4.18 - 4.40 (m, 1H), 3.96 - 4.18 (m, 2H), 3.79 - 3.88 (m, 3H), 3.65 - 3.71 (m, 1H), 3.45 - 3.62 (m, 1H), 3.31 - 3.44 (m, 1H), 3.13 - 3.26 (m, 2H), 3.04 - 3.13 (m, 2H), 3.03 (d, J = 5.2 Hz, 3H), 2.89 - 3.01 (m, 4H), 2.43 - 2.52 (m, 1H), 2.32 - 2.40 (m, 1H), 2.26 (d, J = 2.4 Hz, 3H), 2.14 - 2.20 (m, 1H), 2.09 (br dd, J = 14.0, 7.6 Hz, 1H), 1.99 - 2.05 (m, 1H), 1.87 - 1.96 (m, 1H).

[0156] Example 4. Synthesis of Compound 4

[0157] [Chemical formula] (1) To a solution of Compound 3 - 2 (200 mg, 625 μmol) in N - methylpyrrolidone (5.0 mL) were added potassium carbonate (259 mg, 1.87 mmol) and Compound 4 - 1 (250 mg, 1.25 mmol), and the reaction mixture was stirred at 50 °C for 16 h under nitrogen gas protection. Ethyl acetate (30.0 mL) was added to the reaction mixture, and it was washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative thin - layer chromatography (petroleum ether / ethyl acetate = 1:0 - 4:1) to obtain Compound 4 - 2.

[0158] MS - ESI [M + H] + , calculated value 484, measured value 484.

[0159] (2) To a solution of compound 4-2 (160 mg, 331 μmol) in dioxane (5.0 mL) were added compound 4-3 (115 mg, 999 μmol), cesium carbonate (323 mg, 991 μmol), and (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium (55.3 mg, 66.1 μmol). The reaction mixture was stirred at 110 °C for 4 hours under nitrogen gas protection. Ethyl acetate (20.0 mL) was added to the reaction mixture, and it was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative thin-layer chromatography (dichloromethane / methanol = 10:1) to obtain compound 4-4.

[0160] MS-ESI[M+H] + , calculated value 563, measured value 563.

[0161] 1 H NMR (400 MHz, MeOD) δ 7.18 - 7.30 (m, 4H), 4.32 - 4.40 (m, 2H), 4.21 (br s, 1H), 4.02 (br s, 1H), 3.76 - 3.98 (m, 2H), 3.50 - 3.75 (m, 3H), 3.38 - 3.50 (m, 1H), 3.32 - 3.38 (m, 1H), 3.07 - 3.20 (m, 2H), 2.97 - 3.05 (m, 2H), 2.87 - 2.96 (m, 2H), 2.84 (br d, J = 2.8 Hz, 1H), 2.54 (s, 2H), 2.38 - 2.48 (m, 2H), 2.19 (s, 3H), 2.05 - 2.14 (m, 1H), 1.80 - 1.93 (m, 3H), 1.68 - 1.77 (m, 1H), 1.49 (d, J = 0.8 Hz, 9H), 1.17 - 1.37 (m, 3H).

[0162] (3) Trifluoroacetic acid (1.0 mL) was added to a solution of compound 4-4 (80.0 mg, 142 μmol) in dichloromethane (3.0 mL), and the reaction mixture was stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 4-5.

[0163] MS-ESI [M+H] + , calculated value 463, measured value 463.

[0164] (4) To a solution of the trifluoroacetate of compound 4-5 (70.0 mg, 121 μmol) in dichloromethane (2.0 mL) were added triethylamine (61.4 mg, 607 μmol) and compound 4-6 (33.0 mg, 365 μmol), and the reaction mixture was stirred at -78 °C for 1 hour under nitrogen gas protection. Dichloromethane (20.0 mL) was added to the reaction mixture, and it was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0% - 30%: 8 minutes) to obtain the formate salt of compound 4.

[0165] MS-ESI [M+H] + , calculated value 517, measured value 517.

[0166] 1 H NMR (400 MHz, MeOD) δ 7.23 - 7.33 (m, 4H), 6.73 - 6.90 (m, 1H), 6.29 (br dd, J = 16.4, 2.4 Hz, 1H), 5.81 (dd, J = 10.4, 1.6 Hz, 1H), 4.71 (dd, J = 12.4, 3.2 Hz, 1H), 4.40 - 4.54 (m, 2H), 4.11 - 4.33 (m, 1H), 3.90 - 4.02 (m, 1H), 3.64 - 3.87 (m, 5H), 3.50 - 3.62 (m, 1H), 3.37 - 3.49 (m, 1H), 3.09 - 3.29 (m, 2H), 3.04 - 3.09 (m, 1H), 3.03 (s, 3H), 2.87 - 3.02 (m, 3H), 2.43 - 2.53 (m, 1H), 2.31 - 2.42 (m, 1H), 2.25 (s, 3H), 2.14 - 2.22 (m, 1H), 2.06 - 2.13 (m, 1H), 1.98 - 2.05 (m, 1H), 1.88 - 1.97 (m, 1H), 1.17 - 1.38 (m, 3H).

[0167] Example 5. Synthesis of Compound 5

[0168]

Chem.

[0169] MS-ESI [M+H] + , calculated value 270, measured value 270.

[0170] 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.0, 2.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 3.43 - 3.53 (m, 1H), 3.10 - 3.13 (m, 2H), 3.04 - 3.10 (m, 1H), 1.32 (s, 9H).

[0171] (2) Ethyl acetate (22.9 g, 260 mmol) was dissolved in tetrahydrofuran (300 mL), and lithium diisopropylamide (2 mol / L, 52.0 mL, tetrahydrofuran solution) was added dropwise at -78 °C under nitrogen gas protection. The reaction solution was stirred at -78 °C for 1 hour. A solution of compound 5-3 (14.0 g, 51.9 mmol) in tetrahydrofuran (50.0 mL) was added dropwise to the reaction solution, and stirring was continued at -78 °C for 3 hours. The temperature was raised to 0 °C, and a saturated aqueous ammonium chloride solution (200 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (200 mL×1), the organic phases were combined, washed with a saturated aqueous ammonium chloride solution (200 mL×1) and saturated brine (200 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound 5-4.

[0172] MS-ESI[M+H] + , calculated value 358, measured value 358.

[0173] 1 H NMR(400MHz,CDCl 3 )δ 7.21-7.24(m,1H),7.15-7.20(m,2H),5.24(s,1H),4.15-4.21(m,2H),3.13(ddd,J=16.4,8.8,5.2Hz,1H),2.83-2.90(m,1H),2.73-2.83(m,2H),2.67-2.73(m,1H),2.33(ddd,J=13.2,8.4,5.2Hz,1H),1.25-1.28(m,3H),1.20(s,9H).

[0174] (3) To a solution of compound 5-4 (5.10 g, 14.3 mmol) in ethanol (40.0 mL) was added a dioxane solution of hydrochloric acid (4 mol / L, 15.0 mL), and the reaction solution was stirred at 25 °C for 2 hours under nitrogen gas protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 5-5.

[0175] MS-ESI[M-NH 2 +H] +, Calculated value: 237, Measured value: 237.

[0176] (4) To a solution of hydrochloride salt of compound 5-5 (4.0 g, 13.8 mmol) in ethanol (20.0 mL), add compound 5-6 (15.7 g, 157 mmol), copper oxide (219 mg, 2.75 mmol), and triethylamine (4.18 g, 41.4 mmol). Under the protection of nitrogen gas, react the reaction solution at 85 °C for 8 hours with sealing. Add water (200 mL) to the reaction solution, extract with ethyl acetate (200 mL × 2), combine the organic phases, wash with saturated brine (200 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 6:1) to obtain compound 5-7.

[0177] MS-ESI[M+H] + , Calculated value: 354, Measured value: 354.

[0178] 1 H NMR(400MHz,CDCl 3 )δ 7.02 - 7.25(m,3H),4.07 - 4.16(m,4H),2.86 - 2.91(m,1H),2.77 - 2.85(m,1H),2.69 - 2.77(m,2H),2.58 - 2.65(m,1H),2.37 - 2.58(m,4H),2.32(dt,J = 13.2,8.4Hz,1H),2.16(ddd,J = 13.2,8.4,4.4Hz,1H),1.25(t,J = 7.2Hz,3H),1.20(t,J = 7.2Hz,3H).

[0179] (5) To a solution of compound 5-7 (1.0 g, 2.83 mmol) in ethanol (15.0 mL), paraformaldehyde (500 mg) and sodium cyanoborohydride (533 mg, 8.48 mmol) were added. The reaction mixture was stirred at 25 °C for 16 h under nitrogen protection. Water (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL×1). The combined organic phases were washed with saturated brine (50.0 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0~4:1) to obtain compound 5-8.

[0180] MS-ESI[M+H] + , calculated value 368, measured value 368.

[0181] 1 H NMR(400MHz,CDCl 3 )δ 7.13-7.21(m,2H),7.06-7.10(m,1H),4.08-4.16(m,2H),3.87-3.94(m,2H),2.83-2.89(m,3H),2.73-2.77(m,1H),2.59-2.70(m,2H),2.41(dt,J=7.6,6.4Hz,2H),2.31-2.37(m,1H),2.20-2.28(m,1H),2.17(s,3H),1.25(t,J=7.2Hz,3H),1.04(t,J=7.2Hz,3H).

[0182] (6) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 4.89 mL, in tetrahydrofuran) was added to a solution of compound 5-8 (600 mg, 1.63 mmol) in tetrahydrofuran (10.0 mL). The reaction mixture was stirred at -78 °C for 2 h under nitrogen protection. Saturated aqueous ammonium chloride solution (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50.0 mL×1). The combined organic phases were washed with saturated brine (50.0 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0~6:1) to obtain compound 5-9.

[0183] MS-ESI [M+H] + Calculated value: 322, measured value: 322.

[0184] 1 H NMR (400 MHz, CDCl 3 ) δ 7.17 - 7.23 (m, 2H), 7.11 - 7.15 (m, 1H), 4.22 - 4.32 (m, 2H), 3.50 (d, J = 15.2 Hz, 1H), 3.22 - 3.33 (m, 1H), 3.08 - 3.16 (m, 1H), 2.86 - 2.93 (m, 2H), 2.54 - 2.64 (m, 1H), 2.20 - 2.37 (m, 2H), 2.09 (s, 3H), 1.78 (ddd, J = 13.2, 8.4, 4.4 Hz, 1H), 1.30 - 1.34 (m, 3H).

[0185] (7) To a solution of compound 5-9 (440 mg, 1.37 mmol) in ethanol (10.0 mL) were added compound 5-10 (208 mg, 2.37 mmol) and sodium ethoxide (279 mg, 4.10 mmol), and the reaction mixture was stirred at 80 °C for 12 h under nitrogen gas protection. The reaction solution was concentrated under reduced pressure, ethanol (15.0 mL) and water (5.0 mL) were added, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 5-11.

[0186] MS-ESI [M+H] + Calculated value: 334, measured value: 334.

[0187] 1 H NMR (400 MHz, DMSO-d6) δ 12.20 - 12.60 (m, 2H), 7.19 - 7.36 (m, 3H), 3.36 - 3.56 (m, 1H), 3.06 (br s, 1H), 2.84 - 2.94 (m, 2H), 2.65 - 2.77 (m, 1H), 2.37 - 2.49 (m, 3H), 2.20 (br s, 1H), 1.99 (br s, 1H), 1.68 (br s, 1H).

[0188] (8) To a solution of intermediate 5-11 (360 mg, 1.08 mmol) in water (10.0 mL) was added chloroacetic acid (590 mg, 6.24 mmol), and the reaction mixture was stirred at 100 °C for 16 h under nitrogen gas protection. The reaction mixture was filtered, and saturated aqueous sodium bicarbonate solution was added to the filtrate to adjust the pH value to 8, and a solid was precipitated. It was filtered, and the filter cake was dried to obtain compound 5-12.

[0189] MS-ESI[M+H] + , calculated value 318, measured value 318.

[0190] 1 H NMR(400MHz,DMSO-d6)δ 11.03(s,1H),10.78(s,1H),7.27-7.32(m,2H),7.21(d,J=1.6Hz,1H),3.43(br d,J=16.0Hz,1H),3.01(br d,J=16.0Hz,1H),2.83-2.93(m,2H),2.62(br d,J=17.6Hz,1H),2.32(d,J=17.2Hz,1H),2.19(dt,J=13.2,8.4Hz,1H),1.97(s,3H),1.65(ddd,J=13.2,8.4,4.4Hz,1H).

[0191] (9) Compound 5-12 (210 mg, 661 μmol) was dissolved in phosphorus oxychloride (8.25 g, 53.8 mmol), and the reaction mixture was stirred at 80 °C for 2 h under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, ice water (50.0 mL) was added, and it was extracted with dichloromethane (50.0 mL×1). The organic phase was washed with saturated aqueous sodium bicarbonate solution (50.0 mL×2) and saturated brine (500 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 5-13.

[0192] MS-ESI[M+H] + , calculated value 356, measured value 356.

[0193] 1 H NMR(400MHz,CDCl 3)δ 7.28 - 7.37 (m, 2H), 7.22 (s, 1H), 3.87 - 4.04 (m, 1H), 3.51 (br d, J = 18.0 Hz, 1H), 3.14 (br d, J = 17.6 Hz, 1H), 2.88 - 2.96 (m, 3H), 2.23 (dt, J = 13.2, 8.4 Hz, 1H), 2.10 (s, 3H), 1.58 - 1.69 (m, 1H).

[0194] (10) To a solution of compound 5 - 13 (150 mg, 423 μmol) in N - methylpyrrolidone (5.0 mL) are added potassium carbonate (292 mg, 2.11 mmol) and the hydrochloride salt of compound 5 - 14 (126 mg, 636 μmol), and the reaction solution is stirred at 50 °C for 12 hours under nitrogen gas protection. Ethyl acetate (30.0 mL) is added to the reaction solution, and it is washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 5 - 15.

[0195] MS - ESI [M + H] + , calculated value 443, measured value 443.

[0196] (11) To a solution of compound 5 - 15 (187 mg, 422 μmol) in dichloromethane (10.0 mL) are added triethylamine (214 mg, 2.11 mmol) and di - t - butyl carbonate (920 mg, 4.22 mmol), and the reaction solution is stirred at 25 °C for 12 hours. Dichloromethane (20.0 mL) is added to the reaction solution, and it is washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to obtain compound 5 - 16.

[0197] MS - ESI [M + H] + , calculated value 543, measured value 543.

[0198] (12) To a solution of compound 5-16 (80.0 mg, 147 μmol) in dioxane (5.0 mL) were added compound 5-17 (50.9 mg, 442 μmol), potassium carbonate (61.0 mg, 441 μmol), tris(dibenzylideneacetone)dipalladium (27.0 mg, 29.5 μmol), and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (28.1 mg, 58.9 μmol). The reaction mixture was stirred at 110 °C for 6 hours under a nitrogen gas atmosphere. Ethyl acetate (40.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (40.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative thin-layer chromatography (dichloromethane / methanol = 1:0 to 15:1) to obtain compound 5-18.

[0199] MS-ESI[M+H] + , calculated value 622, measured value 622.

[0200] 1 H NMR (400 MHz, MeOD) δ 7.18 - 7.31 (m, 3H), 4.62 - 4.67 (m, 1H), 4.49 (br s, 1H), 4.39 - 4.45 (m, 1H), 3.89 - 4.23 (m, 4H), 3.67 - 3.77 (m, 2H), 3.43 (br d, J = 14.0 Hz, 2H), 3.24 (br dd, J = 14.0, 3.6 Hz, 2H), 2.88 - 3.03 (m, 5H), 2.73 (br s, 3H), 2.41 - 2.50 (m, 1H), 2.24 - 2.41 (m, 1H), 2.20 - 2.24 (m, 3H), 2.09 - 2.20 (m, 1H), 1.93 - 2.05 (m, 2H), 1.76 - 1.92 (m, 3H), 1.51 (d, J = 1.6 Hz, 9H).

[0201] (13) Trifluoroacetic acid (1.0 mL) was added to a solution of compound 5-18 (70.0 mg, 113 μmol) in dichloromethane (3.0 mL), and the reaction mixture was stirred at 25 °C for 1 hour under a nitrogen gas atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 5-19.

[0202] MS-ESI[M+H]+ Calculated value: 522, measured value: 522.

[0203] (14) To a solution of trifluoroacetate of compound 5-19 (60.0 mg, 94.3 μmol) in dichloromethane (2.0 mL), triethylamine (28.6 mg, 283 μmol) and compound 5-20 (17.1 mg, 189 μmol) are added, and the reaction solution is stirred at -78 °C for 30 minutes under nitrogen gas protection. Dichloromethane (20.0 mL) is added to the reaction solution, and it is washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by preparative high performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0% - 30%: 8 minutes) to obtain the formate salt of compound 5.

[0204] MS-ESI [M+H] + Calculated value: 576, measured value: 576.

[0205] 1 H NMR (400 MHz, MeOD) δ 7.25 - 7.30 (m, 2H), 7.22 (d, J = 17.6 Hz, 1H), 6.80 (br s, 1H), 6.30 (br d, J = 16.4 Hz, 1H), 5.84 (br d, J = 10.8 Hz, 1H), 5.03 (br s, 1H), 4.69 (br dd, J = 12.4, 3.6 Hz, 1H), 4.50 (ddd, J = 12.4, 7.2, 1.6 Hz, 1H), 4.17 - 4.36 (m, 1H), 3.94 - 4.16 (m, 2H), 3.72 - 3.84 (m, 3H), 3.59 - 3.65 (m, 1H), 3.41 - 3.58 (m, 1H), 3.28 (br d, J = 1.6 Hz, 1H), 3.08 - 3.18 (m, 2H), 2.97 - 3.06 (m, 5H), 2.84 - 2.96 (m, 4H), 2.42 - 2.51 (m, 1H), 2.30 - 2.40 (m, 1H), 2.24 (d, J = 1.6 Hz, 3H), 2.11 - 2.19 (m, 1H), 2.07 (br dd, J = 14.4, 7.6 Hz, 1H), 1.96 - 2.03 (m, 1H), 1.87 - 1.95 (m, 1H).

[0206] Example 6. Synthesis of Compounds 6 and 7

[0207]

Chemical Structure

[0208] MS-ESI[M+H] + , calculated value 254, measured value 254.

[0209] 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 - 7.48 (m, 1H), 7.16 - 7.20 (m, 1H), 6.93 - 7.00 (m, 1H), 3.46 - 3.56 (m, 1H), 3.05 - 3.21 (m, 3H), 1.30 - 1.36 (s, 9H).

[0210] (2) Ethyl acetate (22.4 g, 254 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium diisopropylamide (2 mol / L, 50.9 mL, tetrahydrofuran solution) was added dropwise at -78 °C under nitrogen gas protection. The reaction solution was stirred at -78 °C for 1 hour. A solution of compound 6-3 (12.9 g, 50.9 mmol) in tetrahydrofuran (50.0 mL) was added dropwise to the reaction solution, and stirring was continued at -78 °C for 3 hours. The temperature was raised to 0 °C, and a saturated aqueous ammonium chloride solution (200 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (200 mL×1), the organic phases were combined, washed with a saturated aqueous ammonium chloride solution (200 mL×1) and saturated brine (200 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound 6-4.

[0211] MS-ESI[M+H] + , calculated value 342, measured value 342.

[0212] 1 H NMR(400MHz,CDCl 3 )δ 7.27-7.30(m,1H),7.01-7.07(m,1H),6.82-6.90(m,1H),5.05-5.11(s,1H),4.15-4.24(m,2H),3.29-3.39(m,2H),2.88-2.98(m,1H),2.64-2.73(m,1H),2.28-2.39(m,1H),1.25-1.30(t,3H),1.16-1.20(s,9H).

[0213] (3) A dioxane solution of hydrochloric acid (4 mol / L, 40.0 mL) was added to a solution of compound 6-4 (12.4 g, 36.3 mmol) in ethanol (120 mL), and the reaction solution was stirred at 25 °C for 2 hours under nitrogen gas protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride of crude compound 6-5.

[0214] MS-ESI[M-NH 2 +H] + , calculated value 221, measured value 221.

[0215] (4) To a solution of hydrochloride salt (9.94 g, 36.3 mmol) of Compound 6-5 in ethanol (80.0 mL), add Compound 6-6 (37.6 g, 376 mmol), copper oxide (577 mg, 7.26 mmol), and triethylamine (3.67 g, 36.3 mmol). Under the protection of nitrogen gas, react the reaction solution at 85 °C for 8 hours with sealing. Add water (200 mL) to the reaction solution, extract with ethyl acetate (200 mL × 2), combine the organic phases, wash with saturated brine (200 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 6:1) to obtain Compound 6-7.

[0216] MS-ESI[M+H] + , calculated value 338, measured value 338.

[0217] 1 H NMR(400MHz,CDCl 3 )δ 7.16 - 7.22(m,1H),6.96 - 7.01(m,1H),6.80 - 6.87(m,1H),4.06 - 4.17(m,4H),2.95 - 3.07(m,2H),2.86 - 2.94(m,1H),2.65 - 2.81(m,3H),2.26 - 2.51(m,5H),1.22 - 1.26(t,3H),1.14 - 1.20(t,3H).

[0218] (5) To a solution of Compound 6-7 (3.0 g, 8.89 mmol) in ethanol (15.0 mL), add paraformaldehyde (1.33 g) and sodium cyanoborohydride (1.68 g, 26.6 mmol). Under the protection of nitrogen gas, react the reaction solution at 25 °C for 16 hours. Add water (50.0 mL) to the reaction solution, extract with ethyl acetate (50 mL × 1), combine the organic phases, wash with saturated brine (50.0 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain Compound 6-8.

[0219] MS-ESI [M+H] + Calculated value: 352, measured value: 352.

[0220] 1 H NMR (400 MHz, CDCl 3 ) δ 7.16 - 7.22 (m, 1H), 6.93 - 6.99 (m, 1H), 6.79 - 6.86 (m, 1H), 4.07 - 4.14 (m, 2H), 3.88 - 3.99 (m, 2H), 2.95 - 3.08 (m, 3H), 2.83 - 2.92 (m, 1H), 2.72 - 2.80 (m, 1H), 2.60 - 2.68 (m, 1H), 2.29 - 2.46 (m, 4H), 2.19 - 2.23 (s, 3H), 1.22 - 1.27 (t, 3H), 1.00 - 1.06 (t, 3H).

[0221] (6) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 25.6 mL, in THF solution) was added to a solution of compound 6 - 8 (3.00 g, 8.54 mmol) in tetrahydrofuran (30.0 mL). The reaction mixture was stirred at -78 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50.0 mL × 1). The combined organic phases were washed with saturated brine (50.0 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 6:1) to obtain compound 6 - 9.

[0222] MS-ESI [M+H] + Calculated value: 306, measured value: 306.

[0223] 1 H NMR (400 MHz, CDCl 3 ) δ 7.21 - 7.26 (m, 1H), 6.99 - 7.02 (m, 1H), 6.87 - 6.93 (m, 1H), 4.19 - 4.36 (m, 2H), 3.58 - 3.64 (m, 1H), 2.85 - 3.30 (m, 5H), 2.25 - 2.35 (m, 2H), 2.18 - 2.22 (m, 3H), 1.72 - 1.81 (m, 1H), 1.30 - 1.35 (m, 3H).

[0224] (7) To a solution of compound 6-9 (2.00 g, 6.55 mmol) in ethanol (20.0 mL) was added compound 6-10 (997 mg, 13.1 mmol) and sodium ethoxide (1.34 g, 19.6 mmol), and the reaction mixture was stirred at 80 °C for 12 h under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, ethanol (50.0 mL) was added, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 6-11.

[0225] MS-ESI[M+H] + , calculated value 318, measured value 318.

[0226] 1 H NMR (400 MHz, DMSO-d6) δ 11.61 - 12.93 (s, 2H), 7.28 - 7.36 (m, 1H), 7.06 - 7.14 (m, 1H), 6.97 - 7.04 (m, 1H), 3.44 - 3.53 (m, 2H), 2.79 - 3.04 (m, 4H), 2.16 - 2.28 (m, 1H), 1.98 - 2.11 (s, 3H), 1.61 - 1.70 (m, 1H).

[0227] (8) To a solution of intermediate 6-11 (1.90 g, 5.99 mmol) in water (10.0 mL) was added chloroacetic acid (2.26 g, 23.9 mmol), and the reaction mixture was stirred at 100 °C for 16 h under nitrogen gas protection. The reaction mixture was filtered, saturated aqueous sodium bicarbonate solution was added to the filtrate to adjust the pH value to 8, and a solid was precipitated. It was filtered, and the filter cake was dried to obtain compound 6-12.

[0228] MS-ESI[M+H] + , calculated value 302, measured value 302.

[0229] 11H NMR (400 MHz, DMSO-d6) δ 10.98 - 11.04 (s, 1H), 10.73 - 10.80 (s, 1H), 7.29 - 7.36 (m, 1H), 7.07 - 7.12 (m, 1H), 6.96 - 7.04 (m, 1H), 3.39 - 3.47 (m, 1H), 2.76 - 3.02 (m, 4H), 2.29 - 2.37 (m, 1H), 2.18 - 2.27 (m, 1H), 2.02 - 2.08 (s, 3H), 1.60 - 1.68 (m, 1H).

[0230] (9) Compound 6 - 12 (800 mg, 2.66 mmol) was dissolved in phosphorus oxychloride (13.2 g, 86.0 mmol), and the reaction solution was stirred at 80 °C for 2 hours under nitrogen gas protection. The reaction solution was concentrated under reduced pressure, ice water (10.0 mL) and saturated sodium bicarbonate aqueous solution (50.0 mL) were added, extracted with dichloromethane (50.0 mL × 1), the organic phase was washed with saturated sodium bicarbonate aqueous solution (50.0 mL × 2) and saturated brine (50.0 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 6 - 13.

[0231] MS - ESI [M + H] + , calculated value 338, measured value 338.

[0232] (10) To a solution of Compound 6 - 13 (500 mg, 1.48 mmol) in N-methylpyrrolidone (5.0 mL) were added potassium carbonate (1.02 g, 7.39 mmol) and hydrochloride of Compound 6 - 14 (439 mg, 2.22 mmol), and the reaction solution was stirred at 50 °C for 12 hours under nitrogen gas protection. Ethyl acetate (30.0 mL) was added to the reaction solution, washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 6 - 15.

[0233] MS - ESI [M + H] + , calculated value 427, measured value 427.

[0234] 11H NMR (400 MHz, DMSO-d6) δ 7.26 - 7.37 (m, 1H), 7.07 - 7.16 (m, 1H), 6.95 - 7.05 (m, 1H), 3.36 - 3.96 (m, 6H), 3.22 - 3.31 (m, 1H), 2.65 - 3.11 (m, 8H), 2.23 - 2.39 (m, 1H), 2.09 - 2.19 (m, 3H), 1.55 - 1.83 (m, 1H), 1.19 - 1.39 (m, 1H).

[0235] (11) To a solution of compound 6 - 15 (1.40 g, 3.28 mmol) in dichloromethane (20.0 mL) were added triethylamine (2.14 g, 21.1 mmol) and di-t-butyl carbonate (3.58 mg, 16.4 mmol). The reaction mixture was stirred at 25 °C for 12 h. Dichloromethane (20.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 6:1) to obtain compound 6 - 16.

[0236] MS-ESI [M+H] + , calculated value 527, measured value 527.

[0237] (12) To a solution of compound 6 - 16 (900 mg, 1.71 mmol) in dioxane (10.0 mL) were added compound 6 - 17 (590 mg, 5.12 mmol), cesium carbonate (1.67 g, 5.12 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2´,6´-diisopropoxy-1,1´-biphenyl)(2-amino-1,1´-biphenyl-2-yl)palladium (285.6 mg, 341 μmol). The reaction mixture was stirred at 110 °C for 6 h under nitrogen gas protection. Ethyl acetate (40.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (40.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 - 15:1) to obtain compound 6 - 18.

[0238] MS-ESI [M+H] +, Calculated value 606, measured value 606.

[0239] 1 H NMR (400 MHz, CDCl 3 ) δ 7.22 - 7.26 (m, 1H), 7.01 - 7.06 (m, 1H), 6.87 - 6.94 (m, 1H), 4.54 - 4.64 (m, 1H), 4.24 - 4.40 (m, 1H), 3.78 - 4.08 (m, 3H), 3.51 - 3.77 (m, 3H), 3.19 - 3.39 (m, 3H), 2.80 - 3.16 (m, 7H), 2.64 - 2.73 (m, 3H), 2.29 - 2.35 (s, 3H), 1.79 - 1.99 (m, 4H), 1.55 - 1.75 (m, 4H), 1.49 - 1.55 (s, 9H).

[0240] (13) Trifluoroacetic acid (1.0 mL) is added to a dichloromethane (3.0 mL) solution of compound 6 - 18 (342 mg, 564 μmol), and the reaction solution is stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution is concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 6 - 19.

[0241] MS - ESI [M + H] + , Calculated value 506, measured value 506.

[0242] (14) Triethylamine (22.0 mg, 217 μmol) and compound 6 - 20 (29.5 mg, 326 μmol) are added to a dichloromethane (2.0 mL) solution of the trifluoroacetate salt of compound 6 - 19 (110 mg, 217 μmol), and the reaction solution is stirred at -78 °C for 30 minutes under nitrogen gas protection. Dichloromethane (20.0 mL) is added to the reaction solution, and it is washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by reverse column chromatography (acetonitrile / water = 0:1 to 1:19) to obtain compound 6 - 21.

[0243] MS - ESI [M + H] + , Calculated value 560, measured value 560.

[0244] Compound 6-21 was resolved by chiral supercritical fluid chromatography to obtain Compounds 6 and 7.

[0245] Separation conditions: Chromatography column model: AD-H; Chromatography column specifications: 0.46 cm I.D. × 15 cm L, injection volume: 2 μL, mobile phase: carbon dioxide: ethanol (0.1% triethylamine) = 70:30, detection wavelength: 254 nm, column temperature: 25 °C.

[0246] The retention time of Compound 6 was 4.071 minutes, and the ee value was 99.42%.

[0247] MS-ESI [M+H] + , calculated value 560, measured value 560.

[0248] 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (td, J = 7.6, 5.2 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 7.03 - 6.97 (m, 1H), 6.95 - 6.78 (m, 1H), 6.19 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 8.8 Hz, 1H), 5.00 - 4.72 (m, 1H), 4.24 (d, J = 6.8 Hz, 1H), 4.00 (dd, J = 10.8, 6.4 Hz, 2H), 3.93 - 3.80 (m, 2H), 3.74 - 3.58 (m, 2H), 3.53 - 3.45 (m, 1H), 3.29 - 3.12 (m, 2H), 3.07 - 2.96 (m, 4H), 2.96 - 2.89 (m, 2H), 2.84 - 2.74 (m, 2H), 2.40 - 2.28 (m, 4H), 2.20 - 2.08 (m, 4H), 1.91 (dq, J = 12.4, 8.4 Hz, 1H), 1.77 - 1.68 (m, 1H), 1.68 - 1.62 (m, 2H), 1.60 - 1.51 (m, 1H).

[0249] The retention time of Compound 7 was 4.436 minutes, and the ee value was 98.76%.

[0250] MS-ESI [M+H] + , calculated value 560, measured value 560.

[0251] 1 1H NMR (400 MHz, DMSO-d6) δ 7.31 (dt, J = 12.8, 6.4 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 7.04 - 6.95 (m, 1H), 6.91 - 6.79 (m, 1H), 6.18 (d, J = 17.2 Hz, 1H), 5.78 (d, J = 8.8 Hz, 1H), 5.00 - 4.55 (m, 1H), 4.27 - 4.17 (m, 1H), 4.13 - 3.91 (m, 2H), 3.91 - 3.72 (m, 2H), 3.67 - 3.47 (m, 3H), 3.14 - 2.90 (m, 9H), 2.81 (d, J = 17.6 Hz, 1H), 2.39 - 2.24 (m, 4H), 2.16 (s, 3H), 2.09 - 1.99 (m, 1H), 1.96 - 1.85 (m, 1H), 1.83 - 1.70 (m, 1H), 1.69 - 1.60 (m, 2H), 1.60 - 1.49 (m, 1H).

[0252] Example 7. Synthesis of Compounds 8 and 9

[0253] [Chemical formula] (1) To a solution of compound 6 - 19 (160 mg, 316 μmol) in dichloromethane (2.0 mL) were added triethylamine (32.0 mg, 316 μmol), tricyclic propylphosphonic anhydride (503 mg, 791 μmol, 470 μL, 50% ethyl acetate solution), and hydrochloride salt of compound 7 - 1 (600 mg, 4.75 mmol), and the reaction mixture was stirred at 25 °C for 30 minutes. Dichloromethane (20.0 mL) was added to the reaction mixture, and it was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 7 - 2.

[0254] MS - ESI [M + H] + , calculated value 578, measured value 578.

[0255] (2) Compound 7 - 2 was separated by chiral supercritical fluid chromatography to obtain compounds 8 and 9.

[0256] Separation conditions: Chromatography column model: AD-H; Chromatography column specifications: 0.46 cm I.D.×15 cm L, injection volume: 2 μL, mobile phase: carbon dioxide: ethanol (0.1% triethylamine) = 70:30, detection wavelength: 254 nm, column temperature: 25 °C.

[0257] The retention time of Compound 8 is 3.689 minutes, and the ee value is 98.44%.

[0258] MS-ESI[M+H] + , calculated value 578, measured value 578.

[0259] 1 H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.27 (m, 1H), 7.10 (d, J = 7.6 Hz, 1H), 7.02 - 6.95 (m, 1H), 5.43 - 5.35 (m, 1H), 5.35 - 5.20 (m, 1H), 4.30 - 4.22 (m, 1H), 4.06 (s, 1H), 3.97 - 3.88 (m, 1H), 3.86 - 3.83 (m, 1H), 3.71 (d, J = 14.4 Hz, 2H), 3.20 (dd, J = 13.6, 3.6 Hz, 1H), 3.05 - 2.89 (m, 6H), 2.84 - 2.75 (m, 1H), 2.44 - 2.32 (m, 4H), 2.26 (s, 1H), 2.13 (s, 3H), 1.98 - 1.89 (m, 1H), 1.77 - 1.65 (m, 3H), 1.65---1.52 (m, 1H), 1.52 - 1.41 (m, 2H), 1.20 (s, 1H), 0.91 (t, J = 6.8 Hz, 2H).

[0260] The retention time of Compound 9 is 4.059 minutes, and the ee value is 97.90%.

[0261] MS-ESI[M+H] + , calculated value 578, measured value 578.

[0262] 11H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J = 5.2 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.05 - 6.92 (m, 1H), 5.39 (d, J = 13.6 Hz, 1H), 5.35 - 5.17 (m, 1H), 4.22 (d, J = 10.4 Hz, 1H), 4.09 - 3.98 (m, 1H), 3.90 (d, J = 13.6 Hz, 1H), 3.85 - 3.74 (m, 1H), 3.53 (d, J = 7.3 Hz, 2H), 3.14 - 3.06 (m, 2H), 3.06 - 2.92 (m, 5H), 2.85 - 2.78 (m, 1H), 2.39 - 2.28 (m, 4H), 2.22 - 2.09 (m, 4H), 1.91 (s, 2H), 1.82 - 1.71 (m, 1H), 1.70 - 1.62 (m, 2H), 1.58 - 1.51 (m, 1H), 1.22 - 1.11 (m, 1H), 1.08 - 0.77 (m, 2H).

[0263] Example 8. Synthesis of Compound 10

[0264]

Chemical Structure

[0265] MS-ESI [M+H] + , calculated value 292, measured value 292.

[0266] 1 1H NMR (400 MHz, CDCl 3)δ 7.18 - 7.25 (m, 1H), 7.00 - 7.05 (m, 1H), 6.89 (t, J = 9.2 Hz, 1H), 4.22 - 4.29 (m, 2H), 3.35 - 3.57 (m, 1H), 3.14 - 3.27 (m, 1H), 3.01 - 3.14 (m, 1H), 2.85 - 2.99 (m, 2H), 2.42 - 2.69 (m, 2H), 2.34 (br d, J = 6.0 Hz, 1H), 2.08 - 2.20 (m, 2H), 1.30 - 1.34 (m, 3H).

[0267] (2) To a solution of compound 8 - 1 (970 mg, 3.33 mmol) in ethanol (10.0 mL) were added compound 8 - 2 (507 mg, 6.66 mmol) and sodium ethoxide (679 mg, 9.98 mmol), and the reaction mixture was stirred at 80 °C for 16 h under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 8 - 3.

[0268] MS - ESI [M + H] + , calculated value 304, measured value 304.

[0269] 1 H NMR (400 MHz, DMSO - d6) δ 12.39 (br s, 1H), 12.25 (br s, 1H), 7.29 (td, J = 7.6, 5.2 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.93 - 7.01 (m, 1H), 3.50 (br s, 1H), 3.39 - 3.40 (m, 1H), 3.00 - 3.08 (m, 1H), 2.81 - 2.90 (m, 1H), 2.66 - 2.74 (m, 1H), 2.56 (s, 1H), 1.97 - 2.16 (m, 2H).

[0270] (3) To a solution of intermediate 8 - 3 (470 mg, 1.55 mmol) in water (10.0 mL) was added chloroacetic acid (560 mg, 5.93 mmol), and the reaction mixture was stirred at 100 °C for 16 h under nitrogen gas protection. The reaction mixture was filtered, and saturated aqueous sodium bicarbonate solution was added to the filtrate to adjust the pH value to 8, and a solid was precipitated. It was filtered, and the filter cake was dried to obtain compound 8 - 4.

[0271] MS-ESI [M+H] + , calculated value 288, measured value 288.

[0272] 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.78 (s, 1H), 7.27 - 7.32 (m, 2H), 7.21 (d, J = 1.6 Hz, 1H), 3.43 (br d, J = 16.0 Hz, 1H), 3.01 (br d, J = 16.0 Hz, 1H), 2.83 - 2.93 (m, 2H), 2.62 (br d, J = 17.6 Hz, 1H), 2.32 (d, J = 17.2 Hz, 1H), 2.19 (dt, J = 13.2, 8.4 Hz, 1H), 1.97 (s, 3H), 1.65 (ddd, J = 13.2, 8.4, 4.4 Hz, 1H).

[0273] (4) Compound 8 - 4 (200 mg, 696 μmol) was dissolved in phosphorus oxychloride (8.25 g, 53.8 mmol), triethylamine (141 mg, 1.39 mmol) was added, and the reaction solution was stirred at 85 °C for 16 hours under nitrogen gas protection. Ice water (10.0 mL) and saturated aqueous sodium bicarbonate solution (50.0 mL) were added to the reaction solution, and it was extracted with dichloromethane (50.0 mL × 1). The organic phase was washed with saturated aqueous sodium bicarbonate solution (50.0 mL × 2) and saturated brine (50.0 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 8 - 5.

[0274] MS-ESI [M+H] + , calculated value 324, measured value 324.

[0275] 1 H NMR (400 MHz, DMSO-d6) δ 7.29 (td, J = 7.6, 5.2 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.89 - 7.01 (m, 1H), 3.83 - 3.96 (m, 1H), 3.66 - 3.77 (m, 1H), 3.18 (s, 1H), 3.04 - 3.15 (m, 3H), 2.84 - 2.96 (m, 1H), 2.03 - 2.15 (m, 2H).

[0276] (5) To a solution of compound 8-5 (200 mg, 617 μmol) in N-methylpyrrolidone (5.0 mL) are added potassium carbonate (426 mg, 3.08 mmol) and the hydrochloride salt of compound 8-6 (183 mg, 924 μmol), and the reaction mixture is stirred at 50 °C for 12 hours under nitrogen gas protection. Ethyl acetate (30.0 mL) is added to the reaction mixture, and it is washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 8-7.

[0277] MS-ESI[M+H] + , calculated value 413, measured value 413.

[0278] (6) To a solution of compound 8-7 (250 mg, 605 μmol) in dichloromethane (10.0 mL) are added triethylamine (307 mg, 3.03 mmol) and di-t-butyl carbonate (264 mg, 1.21 mmol), and the reaction mixture is stirred at 25 °C for 12 hours. Dichloromethane (20.0 mL) is added to the reaction mixture, and it is washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:1) to obtain compound 8-8.

[0279] MS-ESI[M+H] + , calculated value 513, measured value 513.

[0280] 1 H NMR(400MHz,CDCl 3 )δ 7.28-7.43(m,1H),7.03-7.17(m,1H),6.87-6.94(m,1H),4.31-4.95(m,2H),4.18-4.26(m,1H),3.93-4.00(m,1H),3.64-3.91(m,2H),3.32-3.45(m,3H),3.07-3.30(m,3H),2.89-3.07(m,2H),2.66-2.85(m,3H),2.21-2.38(m,1H),1.50-1.52(m,9H).

[0281] (7) To a solution of compound 8-8 (205 mg, 400 μmol) in dioxane (5.0 mL) were added compound 8-9 (138 mg, 1.20 mmol), cesium carbonate (391 mg, 1.20 mmol), and (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium (66.9 mg, 80.0 μmol). The reaction mixture was stirred at 110 °C for 6 hours under nitrogen gas protection. Ethyl acetate (40.0 mL) was added to the reaction mixture, and it was washed with saturated brine (40.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative thin-layer chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 8-10.

[0282] MS-ESI[M+H] + , calculated value 592, measured value 592.

[0283] 1 H NMR(400MHz,MeOD)δ 7.25-7.32(m,1H),7.08-7.17(m,1H),6.88-6.98(m,1H),4.62-4.67(m,1H),4.41(br s,2H),3.93-4.08(m,3H),3.77-3.91(m,2H),3.59-3.75(m,1H),3.09-3.17(m,2H),2.97-3.08(m,4H),2.94(s,1H),2.75-2.90(m,2H),2.64(br s,3H),2.13-2.31(m,4H),1.90(br s,2H),1.80(br s,1H),1.58(br s,1H),1.51(s,9H).

[0284] (8) Trifluoroacetic acid (1.0 mL) was added to a solution of compound 8-10 (100 mg, 169 μmol) in dichloromethane (3.0 mL), and the reaction mixture was stirred at 25 °C for 30 minutes under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 8-11.

[0285] MS-ESI[M+H] + , calculated value 492, measured value 492.

[0286] (9) To a solution of the trifluoroacetate salt of compounds 8-11 (40.0 mg, 66.1 μmol) in dichloromethane (2.0 mL) were added triethylamine (20.1 mg, 199 μmol) and compound 8-12 (6.6 mg, 72.9 μmol), and the reaction mixture was stirred at -78 °C for 30 minutes under nitrogen gas protection. Dichloromethane (20.0 mL) was added to the reaction mixture, and it was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high-performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0% - 30%: 8 minutes) to obtain the formate salt of compound 10.

[0287] MS-ESI[M+H] + , calculated value 546, measured value 546.

[0288] 1 H NMR(400MHz,MeOD)δ 7.32(tdd,J=8.0,5.2,3.2Hz,1H),7.15(dd,J=7.2,3.2Hz,1H),6.89-6.98(m,1H),6.72-6.89(m,1H),6.29(br d,J=16.4Hz,1H),5.83(br d,J=10.4Hz,1H),5.04(br s,1H),4.64-4.84(m,2H),4.51-4.57(m,1H),4.07-4.27(m,2H),3.90-4.05(m,2H),3.77-3.90(m,2H),3.52-3.74(m,2H),3.10-3.27(m,5H),3.04(d,J=4.4Hz,3H),2.92-3.03(m,3H),2.27-2.43(m,3H),2.18(br dd,J=12.8,6.8Hz,1H),2.10(br dd,J=14.4,7.2Hz,1H),2.01-2.07(m,1H).

[0289] Example 9. Synthesis of Compound 11

[0290]

Chemical Structure

[0291] MS-ESI[M+H] + , calculated value 254, measured value 254.

[0292] 1 H NMR(400MHz,CDCl 3 )δ 7.41(dd,J=8.0,2.4Hz,1H),7.35(dd,J=8.4,4.8Hz,1H),7.20(td,J=8.4,2.4Hz,1H),3.45-3.55(m,1H),3.11-3.17(m,1H),3.07-3.11(m,2H),1.32(s,9H).

[0293] (2) Ethyl acetate (32.9 g, 260 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium diisopropylamide (2 mol / L, 56.0 mL, tetrahydrofuran solution) was added dropwise at -78 °C under nitrogen gas protection. The reaction solution was stirred at -78 °C for 1 hour. A solution of compound 11-3 (18.9 g, 74.6 mmol) in tetrahydrofuran (100 mL) was added dropwise to the reaction solution, and stirring was continued at -65 °C for 3 hours. The temperature was raised to 0 °C, and saturated aqueous ammonium chloride solution (500 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (500 mL × 2), the organic phases were combined, washed with saturated aqueous ammonium chloride solution (500 mL × 1) and saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:1) to obtain compound 11-4.

[0294] MS-ESI[M+H] + , calculated value 342, measured value 342.

[0295] 1 H NMR(400MHz,CDCl 3 )δ 7.18(dd,J=8.4,5.2Hz,1H),6.92-7.00(m,1H),6.88(dd,J=8.8,2.4Hz,1H),5.24(s,1H),4.14-4.22(m,2H),3.06-3.17(m,1H),2.82-2.89(m,1H),2.75-2.81(m,2H),2.68-2.74(m,1H),2.34(ddd,J=13.2,8.4,5.2Hz,1H),1.26(t,J=7.2Hz,3H),1.20(s,9H).

[0296] (3) To a solution of compound 11-4 (6.90 g, 19.6 mmol) in ethanol (60.0 mL) was added a dioxane solution of hydrochloric acid (4 mol / L, 20.0 mL), and the reaction solution was stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 11-5.

[0297] MS-ESI[M-NH 2+H] + , calculated value 221, measured value 221.

[0298] (4) To a solution of hydrochloride salt of compound 11-5 (5.37 g, 19.6 mmol) in ethanol (30.0 mL), compound 11-6 (19.9 g, 198 mmol), copper oxide (312 mg, 3.92 mmol), and triethylamine (5.96 g, 58.9 mmol) were added. The reaction solution was sealed and reacted at 85 °C for 8 hours under nitrogen gas protection. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound 11-7.

[0299] MS-ESI[M+H] + , calculated value 338, measured value 338.

[0300] 1 H NMR(400MHz,CDCl 3 )δ 7.12(dd,J=8.0,5.2Hz,1H),6.85 - 6.96(m,2H),4.06 - 4.15(m,4H),2.81 - 2.94(m,2H),2.70 - 2.80(m,2H),2.58 - 2.70(m,2H),2.49 - 2.55(m,1H),2.41 - 2.45(m,2H),2.34(dt,J=13.6,8.4Hz,1H),2.17(ddd,J=13.2,8.4,4.4Hz,1H),1.25(t,J=7.2Hz,3H),1.20(t,J=7.2Hz,3H).

[0301] (5) To a solution of compound 11-7 (5.93 g, 17.6 mmol) in ethanol (80.0 mL), paraformaldehyde (5.28 g) and sodium cyanoborohydride (3.31 g, 52.7 mmol) are added. The reaction solution is reacted at 25 °C for 16 hours under nitrogen gas protection. Water (100 mL) is added to the reaction solution, and the mixture is extracted with ethyl acetate (100 mL × 1). The organic phases are combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 9:1) to obtain compound 11-8.

[0302] MS-ESI[M+H] + , calculated value 352, measured value 352.

[0303] 1 H NMR(400MHz,CDCl 3 )δ 7.09(dd,J=8.0,5.2Hz,1H),6.87-6.95(m,2H),4.11(qd,J=7.2,2.0Hz,2H),3.91(qd,J=7.2,1.2Hz,2H),2.82-2.88(m,3H),2.72-2.76(m,1H),2.62(td,J=7.2,3.2Hz,2H),2.38-2.46(m,2H),2.32-2.37(m,1H),2.21-2.28(m,1H),2.18(s,3H),1.25(t,J=7.2Hz,3H),1.03(t,J=7.2Hz,3H).

[0304] (6) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 17.1 mL, in tetrahydrofuran solution) was added to a solution of compound 11-8 (2.00 g, 5.69 mmol) in tetrahydrofuran (20.0 mL). The reaction mixture was stirred at -65 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (100 mL×1). The combined organic phases were washed with saturated brine (100 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound 11-9.

[0305] MS-ESI[M+H] + , calculated value 306, measured value 306.

[0306] 1 H NMR(400MHz,CDCl 3 ) δ 7.10-7.18(m,1H),6.87-7.03(m,2H),4.21-4.32(m,2H),3.49(d,J=13.2Hz,1H),2.92-3.37(m,2H),2.76-2.92(m,2H),2.49-2.67(m,1H),2.33-2.44(m,1H),2.19-2.31(m,1H),2.06-2.13(m,3H),1.76-1.86(m,1H),1.32(t,J=7.2Hz,3H).

[0307] (7) Compound 11-10 (663 mg, 8.71 mmol) and sodium ethoxide (889 mg, 13.1 mmol) were added to a solution of compound 11-9 (1.33 g, 4.36 mmol) in ethanol (15.0 mL). The reaction mixture was stirred at 80 °C for 12 hours under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 11-11.

[0308] MS-ESI[M+H] + , calculated value 318, measured value 318.

[0309] 1 1H NMR (400 MHz, DMSO-d6) δ 7.27 (dd, J = 8.4, 5.2 Hz, 1H), 7.07 (td, J = 8.8, 2.4 Hz, 1H), 6.98 (d, J = 9.2 Hz, 1H), 3.47 (d, J = 16.4 Hz, 1H), 3.03 (d, J = 16.4 Hz, 1H), 2.81 - 2.92 (m, 2H), 2.62 (d, J = 17.6 Hz, 1H), 2.41 (d, J = 17.6 Hz, 1H), 2.19 (dt, J = 13.6, 8.4 Hz, 1H), 1.98 (s, 3H), 1.66 (ddd, J = 13.2, 8.4, 4.4 Hz, 1H).

[0310] (8) To a solution of compound 11-11 (1.36 g, 1.08 mmol) in water (15.0 mL) is added chloroacetic acid (1.77 g, 18.7 mmol), and the reaction solution is stirred at 100 °C for 16 hours under nitrogen gas protection. The reaction solution is filtered, saturated aqueous sodium bicarbonate solution is added to the filtrate to adjust the pH value to 8, and a solid precipitates. It is filtered, and the filter cake is dried to obtain compound 11-12.

[0311] MS-ESI [M+H] + , calculated value 302, measured value 302.

[0312] 1 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.76 (s, 1H), 7.27 (dd, J = 8.4, 5.2 Hz, 1H), 7.08 (td, J = 8.8, 2.4 Hz, 1H), 6.99 (dd, J = 9.2, 2.4 Hz, 1H), 3.44 (d, J = 16.0 Hz, 1H), 3.01 (d, J = 16.0 Hz, 1H), 2.80 - 2.91 (m, 2H), 2.61 (d, J = 17.6 Hz, 1H), 2.33 (d, J = 17.2 Hz, 1H), 2.21 (dt, J = 13.2, 8.4 Hz, 1H), 1.98 (s, 3H), 1.67 (ddd, J = 13.2, 8.4, 4.4 Hz, 1H).

[0313] (9) Compound 11-12 (1.00 g, 3.32 mmol) was dissolved in phosphorus oxychloride (16.5 g, 108 mmol), and the reaction solution was stirred at 80 °C for 2 hours under nitrogen gas protection. The reaction solution was concentrated under reduced pressure, ice water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL × 1). The organic phase was washed with saturated aqueous sodium bicarbonate solution (100 mL × 2) and saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain Compound 11-13.

[0314] MS-ESI[M+H] + , calculated value 338, measured value 338.

[0315] 1 H NMR (400 MHz, DMSO-d6) δ 7.29 (dd, J = 8.4, 5.2 Hz, 1H), 7.09 (td, J = 8.8, 2.4 Hz, 1H), 6.98 (dd, J = 9.2, 2.4 Hz, 1H), 3.93 (d, J = 17.6 Hz, 1H), 3.51 (d, J = 17.6 Hz, 1H), 3.12 (d, J = 18.0 Hz, 1H), 2.87 - 2.97 (m, 3H), 2.25 (dt, J = 13.2, 8.4 Hz, 1H), 2.11 (s, 3H), 1.66 (dt, J = 13.2, 6.4 Hz, 1H).

[0316] (10) Potassium carbonate (245 mg, 1.77 mmol) and Compound 11-14 (200 mg, 888 μmol) were added to a solution of Compound 11-13 (200 mg, 591 μmol) in N-methylpyrrolidone (5.0 mL), and the reaction solution was stirred at 50 °C for 10 hours under nitrogen gas protection. Ethyl acetate (30.0 mL) was added to the reaction solution, and the mixture was washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain Compound 11-15.

[0317] MS-ESI[M+H] +, Calculated value 527, measured value 527.

[0318] 1 H NMR (400 MHz, MeOD) δ 7.21 - 7.30 (m, 1H), 7.01 (td, J = 8.8, 2.4 Hz, 1H), 6.89 - 6.98 (m, 1H), 4.63 (s, 1H), 4.09 - 4.28 (m, 1H), 3.92 - 4.05 (m, 2H), 3.68 - 3.85 (m, 2H), 3.45 (dd, J = 14.0, 3.6 Hz, 1H), 3.25 (dd, J = 13.6, 3.6 Hz, 1H), 3.06 - 3.20 (m, 1H), 2.80 - 3.03 (m, 6H), 2.39 - 2.50 (m, 1H), 2.23 (d, J = 1.6 Hz, 3H), 1.89 (ddt, J = 13.2, 7.6, 4.0 Hz, 1H), 1.51 (d, J = 1.2 Hz, 9H).

[0319] (11) To a solution of compound 11 - 15 (220 mg, 417 μmol) in dioxane (8.0 mL) were added compound 11 - 16 (144 mg, 1.25 mmol), cesium carbonate (409 mg, 1.26 mmol), and methanesulfonic acid (2 - dicyclohexylphosphino - 2´,6´ - diisopropoxy - 1,1´ - biphenyl)(2 - amino - 1,1´ - biphenyl - 2 - yl)palladium (70.0 mg, 83.7 μmol), and the reaction mixture was stirred at 110 °C for 4 hours under nitrogen gas protection. Ethyl acetate (50.0 mL) was added to the reaction mixture, and it was washed with saturated brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 - 9:1) to obtain compound 11 - 17.

[0320] MS - ESI [M + H] + , Calculated value 606, measured value 606.

[0321] 11H NMR (400 MHz, MeOD) δ 7.26 (t, J = 5.6 Hz, 1H), 6.98 - 7.08 (m, 1H), 6.86 - 6.98 (m, 1H), 4.63 (d, J = 7.6 Hz, 1H), 4.26 - 4.46 (m, 2H), 3.92 - 4.17 (m, 3H), 3.65 - 3.82 (m, 2H), 3.42 (dd, J = 13.6, 3.6 Hz, 1H), 3.14 - 3.29 (m, 2H), 3.07 - 3.13 (m, 1H), 2.95 - 3.06 (m, 3H), 2.88 - 2.94 (m, 2H), 2.77 - 2.88 (m, 2H), 2.53 (d, J = 4.0 Hz, 3H), 2.34 - 2.49 (m, 2H), 2.23 (d, J = 2.0 Hz, 3H), 2.04 - 2.16 (m, 1H), 1.78 - 1.94 (m, 3H), 1.67 - 1.78 (m, 1H), 1.51 (d, J = 1.6 Hz, 9H).

[0322] (12) To a solution of compound 11 - 17 (170.0 mg, 281 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction mixture was stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 11 - 18.

[0323] MS - ESI [M + H] + , calculated value 506, measured value 506.

[0324] (13) To a solution of the trifluoroacetate salt of compound 11 - 18 (160.0 mg, 258 μmol) in dichloromethane (5.0 mL) were added triethylamine (78.1 mg, 775 μmol) and compound 11 - 19 (46.7 mg, 516 μmol), and the reaction mixture was stirred at - 65 °C for 30 minutes under nitrogen gas protection. Dichloromethane (30.0 mL) was added to the reaction mixture, which was washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high - performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0% - 30%: 8 minutes) to obtain the formate salt of compound 11.

[0325] MS-ESI [M+H] + Calculated value: 560, measured value: 560.

[0326] 1 H NMR (400 MHz, MeOD) δ 7.28 (t, J = 6.0 Hz, 1H), 6.93 - 7.11 (m, 2H), 6.81 (s, 1H), 6.29 (d, J = 16.4 Hz, 1H), 5.84 (d, J = 10.4 Hz, 1H), 4.90 - 5.14 (m, 1H), 4.68 - 4.75 (m, 1H), 4.55 (dd, J = 12.4, 7.2 Hz, 1H), 4.17 - 4.38 (m, 1H), 3.89 - 4.16 (m, 2H), 3.80 (d, J = 15.6 Hz, 3H), 3.65 - 3.72 (m, 1H), 3.54 (s, 1H), 3.04 - 3.30 (m, 4H), 3.02 (d, J = 5.2 Hz, 3H), 2.89 - 3.01 (m, 5H), 2.44 - 2.54 (m, 1H), 2.32 - 2.41 (m, 1H), 2.26 (s, 3H), 2.13 - 2.20 (m, 1H), 2.09 (dd, J = 14.4, 7.6 Hz, 1H), 1.97 - 2.05 (m, 1H), 1.88 - 1.96 (m, 1H).

[0327] Example 10. Synthesis of Compound 12

[0328]

Chemical Structure

[0329] MS-ESI[M+H] + , calculated value 578, measured value 578.

[0330] 1 H NMR(400MHz,MeOD)δ 7.23 - 7.31(m,1H),7.02(td,J = 8.8,2.0Hz,1H),6.95(ddd,J = 11.2,9.2,2.4Hz,1H),5.21 - 5.43(m,2H),4.58(dt,J = 12.0,4.4Hz,1H),4.43 - 4.50(m,1H),3.97 - 4.35(m,3H),3.71 - 3.82(m,2H),3.39 - 3.60(m,3H),3.32(s,1H),3.26 - 3.30(m,1H),3.03 - 3.23(m,2H),2.88 - 3.03(m,6H),2.85(d,J = 7.6Hz,3H),2.43 - 2.53(m,1H),2.25 - 2.33(m,1H),2.24(d,J = 2.0Hz,3H),1.96 - 2.10(m,2H),1.85 - 1.95(m,2H).

[0331] Example 11. Synthesis of Compound 13

[0332]

Chemical Structure

[0333] MS-ESI[M+H] + , calculated value 604, measured value 604.

[0334] 1 H NMR (400 MHz, MeOD) δ 7.28 - 7.35 (m, 1H), 7.06 - 7.13 (m, 1H), 6.89 - 6.98 (t, 1H), 6.10 - 6.20 (m, 1H), 4.88 - 5.04 (m, 1H), 4.48 - 4.54 (m, 1H), 4.29 - 4.40 (m, 2H), 3.89 - 4.23 (m, 3H), 3.63 - 3.71 (m, 5H), 3.40 - 3.58 (m, 1H), 3.14 - 3.27 (m, 4H), 2.83 - 3.13 (m, 7H), 2.71 - 2.79 (m, 1H), 2.45 - 2.54 (m, 4H), 2.32 - 2.39 (m, 1H), 2.25 - 2.30 (s, 3H), 2.04 - 2.14 (m, 1H), 1.78 - 1.93 (m, 3H), 1.66 - 1.75 (m, 1H).

[0335] Example 12. Synthesis of compound 14

[0336]

Chemical Structure

[0337] 1 H NMR (400 MHz, CDCl 3 ) δ 6.90 - 7.04 (m, 1H), 6.07 - 6.16 (m, 1H), 5.09 - 5.14 (m, 1H), 4.98 - 5.03 (m, 1H), 4.19 - 4.26 (m, 2H), 1.29 - 1.33 (m, 3H).

[0338] (2) To a solution of compound 14-2 (400 mg, 3.03 mmol) in tetrahydrofuran (3.0 mL) were added lithium hydroxide (381 mg, 9.08 mmol) and water (3.0 mL), and the reaction mixture was stirred at 25 °C for 12 hours under nitrogen gas protection. An aqueous hydrochloric acid solution (20 mL, 1 mol / L) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50.0 mL × 2). The combined organic phases were washed with saturated brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 14-3.

[0339] 1 H NMR (400 MHz, DMSO-d6) δ 12.36 - 12.68 (s, 1H), 6.80 - 6.96 (m, 1H), 5.88 - 6.04 (m, 1H), 5.03 - 5.22 (m, 2H).

[0340] (3) To a solution of compound 14-3 (45.3 mg, 435 μmol) in dichloromethane (2.0 mL) were added triethylamine (14.7 mg, 145 μmol), the trifluoroacetate salt of compound 6-19 (90.0 mg, 145 μmol), and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 290 μmol), and the reaction mixture was stirred at 25 °C for 30 minutes. Dichloromethane (20.0 mL) was added to the reaction mixture, and it was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high-performance liquid chromatography (Phenomenex Gemini-NX C18, 70 mm × 30 mm 3 μm, A: water (10 mmol / L NH 4 HCO 3 ); B: acetonitrile, 35%-75%: 11 minutes) to obtain compound 14.

[0341] MS-ESI[M+H] + , calculated value 592, measured value 592.

[0342] 1 H NMR (400 MHz, MeOD) δ 7.28-7.35 (m, 1H), 7.06-7.13 (m, 1H), 6.89-6.98 (t, 1H), 6.56-6.84 (m, 1H), 5.02-5.19 (m, 1H), 4.28-4.41 (m, 2H), 3.86-4.19 (m, 3H), 3.65-3.74 (m, 2H), 3.34-3.61 (m, 3H), 2.83-3.28 (m, 10H), 2.70-2.80 (m, 1H), 2.43-2.53 (m, 4H), 2.32-2.40 (m, 1H), 2.25-2.31 (s, 3H), 2.04-2.13 (m, 1H), 1.78-1.94 (m, 3H), 1.65-1.75 (m, 1H).

[0343] Example 13. Synthesis of Compound 15

[0344]

Chemical Structure

[0345] MS-ESI[M+H] + , calculated value 617, measured value 617.

[0346] 1 H NMR(400MHz,MeOD)δ 7.29-7.37(m,1H),7.07-7.15(m,1H),6.73-7.03(m,3H),4.90-5.20(m,1H),4.65-4.73(m,1H),4.51-4.57(m,1H),3.85-4.47(m,3H),3.61-3.82(m,6H),3.42-3.59(m,1H),3.04-3.29(m,6H),2.87-3.03(m,6H),2.67-2.80(m,6H),2.34-2.56(m,2H),2.26-2.33(m,3H),1.88-2.20(m,4H).

[0347] Example 14. Synthesis of Compound 16

[0348]

Chemical Structure

[0349] MS-ESI[M+H] + , calculated value 574, measured value 574.

[0350] 1 H NMR (400 MHz, MeOD) δ 7.29 - 7.36 (m, 1H), 7.08 - 7.14 (m, 1H), 6.90 - 6.99 (m, 1H), 5.31 - 5.39 (m, 1H), 5.14 - 5.24 (m, 1H), 4.89 - 5.07 (m, 1H), 4.67 - 4.73 (m, 1H), 4.48 - 4.56 (m, 1H), 3.89 - 4.32 (m, 3H), 3.76 - 3.85 (m, 1H), 3.63 - 3.74 (m, 3H), 3.34 - 3.49 (m, 1H), 3.15 - 3.27 (m, 3H), 2.85 - 3.14 (m, 9H), 2.45 - 2.56 (m, 1H), 2.33 - 2.41 (m, 1H), 2.27 - 2.32 (m, 3H), 2.02 - 2.22 (m, 3H), 1.97 - 2.01 (m, 3H), 1.87 - 1.95 (m, 1H).

[0351] Example 15. Synthesis of Compound 17

[0352]

Chemical Structure

[0353] MS-ESI[M+H] + , calculated value 572, measured value 572.

[0354] 1 H NMR (400 MHz, MeOD) δ 7.29 - 7.36 (m, 1H), 7.06 - 7.15 (m, 1H), 6.90 - 6.99 (m, 1H), 4.66 - 4.75 (m, 1H), 4.35 - 4.58 (m, 2H), 4.01 - 4.32 (m, 2H), 3.66 - 3.86 (m, 4H), 3.39 - 3.60 (m, 1H), 2.85 - 3.27 (m, 12H), 2.34 - 2.57 (m, 2H), 2.27 - 2.33 (m, 3H), 2.06 - 2.21 (m, 5H), 1.87 - 2.04 (m, 2H), 1.61 - 1.75 (m, 1H).

[0355] Example 16. Synthesis of Compound 18

[0356]

Chemical Structure

[0357] MS-ESI[M+H] + , calculated value 270, measured value 270.

[0358] 1 H NMR(400MHz,CDCl 3 )δ 7.35-7.40(m,1H),7.27-7.32(m,2H),3.45-3.60(m,1H),3.06-3.15(m,3H),1.36(s,9H).

[0359] (2) Dissolve ethyl acetate (3.27 g, 37.1 mmol) in tetrahydrofuran (20.0 mL). Dropwise add lithium diisopropylamide (2 mol / L, 7.4 mL, tetrahydrofuran solution) at -65 °C under nitrogen gas protection. Stir the reaction mixture at -78 °C for 1 hour. Dropwise add a tetrahydrofuran (20.0 mL) solution of compound 18-3 (2.00 g, 7.41 mmol) to the reaction mixture and continue stirring at -65 °C for 2 hours. Warm the reaction mixture to 0 °C, add saturated ammonium chloride aqueous solution (50.0 mL) to quench the reaction, extract with ethyl acetate (50.0 mL × 2), combine the organic phases, wash with saturated ammonium chloride aqueous solution (50.0 mL × 1) and saturated brine (50.0 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 18-4.

[0360] MS-ESI [M+H] + , Calculated value: 358, Measured value: 358.

[0361] 1 H NMR (400 MHz, CDCl 3 3) δ 7.21 - 7.25 (m, 1H), 7.14 - 7.19 (m, 2H), 5.14 (s, 1H), 4.11 - 4.20 (m, 2H), 3.68 (d, J = 15.6 Hz, 1H), 3.33 (dt, J = 16.4, 8.4 Hz, 1H), 2.90 (ddd, J = 16.4, 9.2, 3.6 Hz, 1H), 2.78 (d, J = 15.6 Hz, 1H), 2.68 (ddd, J = 13.2, 9.2, 3.6 Hz, 1H), 2.29 - 2.38 (m, 1H), 1.23 - 1.27 (m, 3H), 1.20 (s, 9H).

[0362] (3) To a solution of compound 18 - 4 (1.40 g, 3.91 mmol) in ethanol (15.0 mL) is added a dioxane solution of hydrochloric acid (4 mol / L, 5.0 mL), and the reaction solution is stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution is concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 18 - 5.

[0363] MS-ESI [M+H] + , Calculated value: 254, Measured value: 254.

[0364] (4) To a solution of the hydrochloride salt of compound 18 - 5 (1.14 g, 3.93 mmol) in ethanol (12.0 mL) are added compound 18 - 6 (8.17 g, 81.6 mmol), copper oxide (62.5 mg, 786 μmol), and triethylamine (1.19 g, 11.8 mmol), and the reaction solution is sealed and reacted at 85 °C for 8 hours under nitrogen gas protection. Water (100 mL) is added to the reaction solution, and it is extracted with ethyl acetate (100 mL × 2). The organic phases are combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound 18 - 7.

[0365] MS-ESI [M+H]+ Calculated value: 354, Measured value: 354.

[0366] 1 H NMR (400 MHz, CDCl 3 ) δ 7.02 - 7.18 (m, 3H), 4.09 - 4.14 (m, 2H), 4.02 (q, J = 7.2 Hz, 2H), 2.86 - 3.03 (m, 3H), 2.72 - 2.86 (m, 2H), 2.63 - 2.72 (m, 1H), 2.41 - 2.50 (m, 4H), 2.29 (m, 1H), 1.22 - 1.26 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H).

[0367] (5) Paraformaldehyde (900 mg) and sodium cyanoborohydride (480 mg, 7.64 mmol) were added to a solution of compound 18 - 7 (900 mg, 2.54 mmol) in ethanol (15.0 mL), and the reaction mixture was stirred at 25 °C for 10 h under nitrogen protection. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30.0 mL × 1). The combined organic phases were washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 15:1) to obtain compound 18 - 8.

[0368] MS - ESI [M + H] + Calculated value: 368, Measured value: 368.

[0369] 1 H NMR (400 MHz, CDCl 3)δ 7.08 - 7.16 (m, 2H), 7.01 - 7.06 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.80 (dtt, J = 10.4, 7.2, 3.6 Hz, 2H), 3.32 (d, J = 13.6 Hz, 1H), 2.94 (d, J = 13.6 Hz, 1H), 2.87 - 2.92 (m, 2H), 2.74 (dt, J = 12.8, 7.2 Hz, 1H), 2.50 - 2.56 (m, 1H), 2.43 - 2.49 (m, 2H), 2.35 (dt, J = 14.0, 8.0 Hz, 1H), 2.20 - 2.28 (m, 1H), 2.14 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[0370] (6) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 6.4 mL, in tetrahydrofuran solution) was added to a solution of compound 18 - 8 (780 mg, 2.12 mmol) in tetrahydrofuran (10.0 mL). The reaction mixture was stirred at -65 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50.0 mL × 1). The combined organic phases were washed with saturated brine (50.0 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 19:1) to obtain compound 18 - 9.

[0371] MS-ESI[M+H] + , calculated value 322, measured value 322.

[0372] 1 H NMR(400MHz,CDCl 3 )δ 7.15 - 7.20 (m, 2H), 7.10 - 7.14 (m, 1H), 4.26 - 4.34 (m, 1H), 4.17 - 4.25 (m, 1H), 3.61 (d, J = 15.2 Hz, 1H), 3.04 - 3.17 (m, 2H), 2.71 - 3.04 (m, 3H), 2.24 - 2.30 (m, 1H), 2.15 - 2.22 (m, 1H), 2.14 (s, 3H), 1.76 (ddd, J = 13.2, 8.4, 2.4 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H).

[0373] (7) To a solution of compound 18-9 (475 mg, 1.48 mmol) in ethanol (10.0 mL) were added compound 18-10 (225 mg, 2.96 mmol) and sodium ethoxide (301 mg, 4.42 mmol), and the reaction mixture was stirred at 80 °C for 12 h under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 18-11.

[0374] MS-ESI[M+H] + , calculated value 334, measured value 334.

[0375] 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 12.27 (s, 1H), 7.23 - 7.31 (m, 3H), 3.52 (d, J = 16.4 Hz, 1H), 2.88 - 3.04 (m, 4H), 2.30 - 2.37 (m, 1H), 2.16 - 2.25 (m, 1H), 2.03 (s, 3H), 1.66 (t, J = 10.0 Hz, 1H).

[0376] (8) To a solution of compound 18-11 (320 mg, 959 μmol) in water (10.0 mL) was added chloroacetic acid (410 g, 4.34 mmol), and the reaction mixture was stirred at 100 °C for 16 h under nitrogen gas protection. The reaction mixture was filtered, and saturated aqueous sodium bicarbonate solution was added to the filtrate to adjust the pH value to 8, and a solid was precipitated. It was filtered, and the filter cake was dried to obtain compound 18-12.

[0377] MS-ESI[M+H] + , calculated value 318, measured value 318.

[0378] 11H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.76 (s, 1H), 7.22 - 7.33 (m, 3H), 3.47 (d, J = 15.2 Hz, 1H), 2.85 - 2.99 (m, 4H), 2.13 - 2.25 (m, 2H), 2.02 (s, 3H), 1.59 - 1.69 (m, 1H).

[0379] (9) Compound 18 - 12 (260 mg, 818 μmol) was dissolved in phosphorus oxychloride (8.25 g, 53.8 mmol), and the reaction solution was stirred at 80 °C for 6 hours under nitrogen gas protection. The reaction solution was diluted with dichloromethane (30.0 mL), saturated aqueous sodium bicarbonate solution (30.0 mL) was added, the pH value was adjusted to 8 with saturated aqueous sodium carbonate solution, the organic phase was separated, washed with saturated aqueous sodium bicarbonate solution (30.0 mL × 2) and saturated brine (30.0 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 18 - 13.

[0380] MS-ESI [M+H] + , calculated value 356, measured value 356.

[0381] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.15 - 7.26 (m, 3H), 3.72 - 4.23 (m, 2H), 3.43 - 3.69 (m, 2H), 3.00 - 3.08 (m, 1H), 2.81 - 2.96 (m, 2H), 2.31 (s, 3H), 0.77 - 1.27 (m, 1H).

[0382] (10) To a solution of Compound 18 - 13 (180 mg, 508 μmol) in N-methylpyrrolidone (5.0 mL) were added potassium carbonate (211 mg, 1.53 mmol) and Compound 18 - 14 (137 mg, 608 μmol), and the reaction solution was stirred at 50 °C for 10 hours under nitrogen gas protection. Ethyl acetate (30.0 mL) was added to the reaction solution, washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 ~ 6:1) to obtain Compound 18 - 15.

[0383] MS-ESI[M+H] + Calculated value: 543, measured value: 543.

[0384] 1 H NMR (400 MHz, MeOD) δ 7.14 - 7.34 (m, 3H), 4.64 (s, 1H), 4.10 - 4.25 (m, 1H), 3.88 - 4.10 (m, 3H), 3.71 (d, J = 9.6 Hz, 2H), 3.33 - 3.49 (m, 2H), 3.15 - 3.30 (m, 2H), 3.01 (dt, J = 17.6, 8.8 Hz, 3H), 2.75 (dd, J = 18.0, 3.6 Hz, 1H), 2.38 - 2.52 (m, 1H), 2.24 (d, J = 0.8 Hz, 3H), 1.78 - 1.87 (m, 1H), 1.51 (d, J = 1.6 Hz, 9H).

[0385] (11) To a solution of compound 18 - 15 (150 mg, 276 μmol) in dioxane (5.0 mL) were added compound 18 - 16 (95.4 mg, 828 μmol), potassium carbonate (115 mg, 832 μmol), 2 - dicyclohexylphosphino - 2´,4´,6´ - triisopropylbiphenyl (52.6 mg, 110 μmol), and bis(dibenzylideneacetone)palladium (50.6 mg, 55.3 μmol). The reaction mixture was stirred at 110 °C for 4 hours under nitrogen gas protection. Ethyl acetate (20.0 mL) was added to the reaction mixture, and it was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 18 - 17.

[0386] MS-ESI[M+H] + Calculated value: 622, measured value: 622.

[0387] 11H NMR (400 MHz, MeOD) δ 7.16 - 7.31 (m, 3H), 4.62 (s, 1H), 4.38 - 4.54 (m, 2H), 4.13 - 4.25 (m, 1H), 3.91 - 4.12 (m, 3H), 3.62 - 3.72 (m, 2H), 3.36 - 3.51 (m, 2H), 3.12 - 3.20 (m, 2H), 2.91 - 3.08 (m, 4H), 2.65 - 2.76 (m, 4H), 2.48 (d, J = 8.4 Hz, 1H), 2.24 (s, 3H), 2.07 - 2.22 (m, 2H), 1.93 (d, J = 8.4 Hz, 2H), 1.77 - 1.88 (m, 3H), 1.51 (d, J = 2.4 Hz, 9H).

[0388] (12) To a solution of compound 18 - 17 (120.0 mg, 193 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL), and the reaction mixture was stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 18 - 18.

[0389] MS - ESI [M + H] + , calculated value 522, measured value 522.

[0390] (13) To a solution of the trifluoroacetate salt of compound 18 - 18 (50.0 mg, 78.6 μmol) in dichloromethane (2.0 mL) were added triethylamine (23.9 mg, 236 μmol) and compound 18 - 19 (14.3 mg, 158 μmol), and the reaction mixture was stirred at -65 °C for 30 minutes under nitrogen gas protection. Dichloromethane (20.0 mL) was added to the reaction mixture, and it was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high-performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0% - 30%: 8 minutes) to obtain the formate salt of compound 18.

[0391] MS - ESI [M + H] + , calculated value 576, measured value 576.

[0392] 1 1H NMR (400 MHz, MeOD) δ 7.21 - 7.29 (m, 3H), 6.80 (s, 1H), 6.30 (d, J = 16.8 Hz, 1H), 5.84 (d, J = 10.0 Hz, 1H), 4.67 (d, J = 12.4 Hz, 1H), 4.46 - 4.53 (m, 1H), 4.18 - 4.38 (m, 1H), 4.00 - 4.18 (m, 2H), 3.62 - 3.84 (m, 4H), 3.45 - 3.62 (m, 2H), 3.33 - 3.38 (m, 1H), 3.15 - 3.28 (m, 2H), 2.98 - 3.14 (m, 4H), 2.96 (d, J = 9.2 Hz, 3H), 2.91 (d, J = 4.0 Hz, 1H), 2.73 (dd, J = 17.6, 3.2 Hz, 1H), 2.44 - 2.51 (m, 1H), 2.33 (dt, J = 8.4, 6.4 Hz, 1H), 2.25 (s, 3H), 2.10 - 2.17 (m, 1H), 2.02 - 2.09 (m, 1H), 1.93 - 2.02 (m, 1H), 1.79 - 1.88 (m, 1H).

[0393] Example 17. Synthesis of Compound 19

[0394] [Chemical formula] To a solution of Compound 19-1 (21.3 mg, 237 μmol) in dichloromethane (2.0 mL) were added triethylamine (23.9 mg, 236 μmol), the trifluoroacetate salt of Compound 18-18 (90.0 mg, 145 μmol), and a solution of tricyclic propylphosphonic anhydride (150 mg, 236 μmol, 50% ethyl acetate solution). The reaction mixture was stirred at 25 °C for 30 minutes. Dichloromethane (20.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high-performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0% - 20%: 8 minutes) to obtain the formate salt of Compound 19.

[0395] MS-ESI [M+H] + , calculated value 594, measured value 595.

[0396] 1 H NMR (400 MHz, MeOD) δ 7.21 - 7.29 (m, 3H), 5.37 (d, J = 17.6 Hz, 1H), 5.29 (d, J = 7.6 Hz, 1H), 4.64 (d, J = 10.0 Hz, 1H), 4.48 (dt, J = 12.0, 5.6 Hz, 2H), 4.34 (d, J = 13.2 Hz, 1H), 4.08 - 4.26 (m, 2H), 4.03 (d, J = 10.4 Hz, 1H), 3.66 - 3.73 (m, 2H), 3.48 - 3.63 (m, 3H), 3.37 (s, 1H), 3.18 - 3.25 (m, 1H), 2.95 - 3.07 (m, 4H), 2.92 (d, J = 10.0 Hz, 3H), 2.73 (dd, J = 18.0, 3.6 Hz, 1H), 2.49 (q, J = 10.4 Hz, 1H), 2.28 - 2.36 (m, 1H), 2.25 (s, 3H), 2.00 - 2.12 (m, 2H), 1.92 - 1.99 (m, 1H), 1.79 - 1.86 (m, 1H), 1.67 (s, 1H).

[0397] Example 18. Synthesis of Compound 20

[0398]

Chemical Structure

[0399] MS-ESI [M+H] + , calculated value 250, measured value 250.

[0400] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.17 (d, J = 8.0 Hz, 1H), 7.35 - 7.42 (m, 1H), 7.22 - 7.26 (m, 1H), 7.19 (d, J = 7.6 Hz, 1H), 3.23 - 3.34 (m, 1H), 3.06 (m, 1H), 2.85 - 2.90 (m, 2H), 1.95 - 2.07 (m, 2H), 1.33 (s, 9H).

[0401] (2) Ethyl acetate (60.1 g, 682 mmol) was dissolved in tetrahydrofuran (400 mL), and lithium diisopropylamide (2 mol / L, 137 mL, tetrahydrofuran solution) was added dropwise at -65 °C under nitrogen gas protection. The reaction solution was stirred at -65 °C for 1 hour. A solution of compound 20-3 (34.0 g, 136 mmol) in tetrahydrofuran (200 mL) was added dropwise to the reaction solution, and stirring was continued at -65 °C for 2 hours. The temperature was raised to 0 °C, and a saturated aqueous ammonium chloride solution (500 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with a saturated aqueous ammonium chloride solution (500 mL × 1) and saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 2:1) to obtain compound 20-4.

[0402] MS-ESI [M+H] + , calculated value 338, measured value 338.

[0403] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.32 - 7.40 (m, 1H), 7.13 - 7.21 (m, 2H), 7.08 - 7.13 (m, 1H), 5.19 (s, 1H), 4.11 - 4.20 (m, 2H), 2.86 - 2.98 (m, 1H), 2.80 - 2.86 (m, 2H), 2.70 - 2.78 (m, 1H), 2.42 - 2.51 (m, 1H), 2.04 - 2.17 (m, 2H), 1.76 - 1.86 (m, 1H), 1.24 - 1.28 (m, 3H), 1.23 (s, 9H).

[0404] (3) To a solution of compound 20-4 (6.0 g, 17.8 mmol) in ethanol (60.0 mL) is added a dioxane solution of hydrochloric acid (4 mol / L, 20.0 mL), and the reaction solution is stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution is concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 20-5.

[0405] MS-ESI[M-NH 2 +H] + , calculated value 217, measured value 217.

[0406] (4) To a solution of the hydrochloride salt of compound 20-5 (4.80 g, 17.8 mmol) in ethanol (60.0 mL) are added compound 5-6 (18.2 g, 182 mmol), copper oxide (283 mg, 3.56 mmol), and triethylamine (5.40 g, 53.4 mmol), and the reaction solution is sealed and reacted at 85 °C for 8 hours under nitrogen gas protection. Water (200 mL) is added to the reaction solution, and the mixture is extracted with ethyl acetate (200 mL × 2). The organic phases are combined, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound 20-7.

[0407] MS-ESI[M+H] + , calculated value 334, measured value 334.

[0408] 1 H NMR(400MHz,CDCl 3 )δ 7.53(d,J=6.4Hz,1H),7.09-7.18(m,2H),7.03-7.08(m,1H),4.09-4.15(m,4H),2.73-2.80(m,4H),2.62(d,J=14.0Hz,2H),2.40-2.46(m,3H),2.08(d,J=10.0Hz,1H),1.85-1.99(m,3H),1.25(t,J=7.2Hz,3H),1.21(t,J=7.2Hz,3H).

[0409] (5) To a solution of compound 20-7 (4.32 g, 13.0 mmol) in ethanol (60.0 mL) were added paraformaldehyde (3.89 g) and sodium cyanoborohydride (2.45 g, 38.9 mmol), and the reaction solution was reacted at 25 °C for 16 hours under nitrogen gas protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 1). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound 20-8.

[0410] MS-ESI[M+H] + , calculated value 348, measured value 348.

[0411] 1 H NMR (400 MHz, MeOD) δ 7.43 - 7.52 (m, 1H), 7.05 - 7.13 (m, 2H), 6.95 - 7.04 (m, 1H), 4.04 - 4.12 (m, 2H), 3.73 - 3.83 (m, 2H), 2.79 (s, 2H), 2.76 (d, J = 7.2 Hz, 1H), 2.71 (t, J = 6.4 Hz, 2H), 2.56 - 2.63 (m, 1H), 2.39 - 2.48 (m, 1H), 2.30 - 2.38 (m, 1H), 2.21 (s, 3H), 2.10 - 2.15 (m, 2H), 1.81 - 1.90 (m, 1H), 1.70 - 1.80 (m, 1H), 1.22 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H).

[0412] (6) At -65 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 17.8 mL, in tetrahydrofuran solution) was added to a solution of compound 20-8 (3.10 g, 8.92 mmol) in tetrahydrofuran (60.0 mL). The reaction mixture was stirred at -65 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 1). The organic phase was washed successively with saturated aqueous ammonium chloride solution (100 mL × 1) and saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound 20-9.

[0413] MS-ESI[M+H] + , calculated value 302, measured value 302.

[0414] 1 H NMR(400MHz,CDCl 3 )δ 7.49-7.75(m,1H),7.21(t,J=6.4Hz,1H),7.10-7.17(m,1H),7.05(d,J=7.6Hz,1H),4.20-4.33(m,2H),3.45-3.63(m,1H),3.14-3.28(m,1H),2.64-2.76(m,3H),2.51-2.63(m,1H),2.01-2.14(m,3H),1.80-2.00(m,2H),1.63-1.80(m,3H),1.30-1.34(m,3H).

[0415] (7) Compound 20-10 (1.91 g, 25.1 mmol) and sodium ethoxide (2.56 g, 37.6 mmol) were added to a solution of compound 20-9 (3.78 g, 12.5 mmol) in ethanol (70.0 mL). The reaction mixture was stirred at 80 °C for 8 hours under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 20-11.

[0416] MS-ESI[M+H] +, Calculated value: 314, Measured value: 314.

[0417] (8) To a solution of intermediate 20-11 (3.36 g, 10.7 mmol) in water (80.0 mL), chloroacetic acid (4.05 g, 42.9 mmol) is added, and the reaction solution is stirred at 100 °C for 16 hours under nitrogen gas protection. The reaction solution is filtered, saturated aqueous sodium bicarbonate solution is added to the filtrate to adjust the pH value to 8, and a solid precipitates. It is filtered, and the filter cake is dried to obtain compound 20-12.

[0418] MS-ESI[M+H] + , Calculated value: 298, Measured value: 298.

[0419] 1 H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),10.69(s,1H),7.45-7.51(m,1H),7.17-7.24(m,1H),7.11-7.17(m,1H),7.04-7.10(m,1H),3.46-3.52(m,1H),2.99-3.07(m,1H),2.65-2.72(m,2H),2.52-2.55(m,2H),1.95(s,3H),1.84-1.91(m,1H),1.71-1.80(m,1H),1.51-1.64(m,2H).

[0420] (9) Compound 20-12 (1.00 g, 3.36 mmol) is dissolved in phosphorus oxychloride (10 mL), and the reaction solution is stirred at 100 °C for 12 hours in a sealed container under nitrogen gas protection. The reaction solution is concentrated under reduced pressure, ice water (100 mL) is added, extracted with dichloromethane (100 mL×1), the organic phase is washed with saturated aqueous sodium bicarbonate solution (100 mL×2) and saturated brine (100 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 20-13.

[0421] MS-ESI[M+H] + , Calculated value: 334, Measured value: 334.

[0422] (10) To a solution of compound 20-13 (782 mg, 2.34 mmol) in N-methylpyrrolidone (10.0 mL) were added potassium carbonate (970 mg, 7.02 mmol) and compound 20-14 (633 mg, 2.81 mmol), and the reaction mixture was stirred at 50 °C for 12 h under a nitrogen gas atmosphere. The reaction mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The combined organic phases were washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 20-15.

[0423] MS-ESI[M+H] + , calculated value 523, measured value 523.

[0424] (11) To a solution of compound 20-15 (500 mg, 956 μmol) in dioxane (10.0 mL) were added compound 20-16 (330 mg, 2.87 mmol), cesium carbonate (934 mg, 2.88 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2´,6´-diisopropoxy-1,1´-biphenyl)(2-amino-1,1´-biphenyl-2-yl)palladium (160 mg, 191 μmol), and the reaction mixture was stirred at 110 °C for 12 h under a nitrogen gas atmosphere. Ethyl acetate (50.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 9:1) to obtain compound 20-17.

[0425] MS-ESI[M+H] + , calculated value 602, measured value 602.

[0426] (12) To a solution of compound 20-17 (368 mg, 611 μmol) in dichloromethane (6.0 mL) was added trifluoroacetic acid (3.08 g, 27.0 mmol), and the reaction solution was stirred at 25 °C for 30 minutes under nitrogen gas protection. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 20-18.

[0427] MS-ESI[M+H] + , calculated value 502, measured value 502.

[0428] (13) To a solution of the trifluoroacetate salt of compound 20-18 (175 mg, 284 μmol) in dichloromethane (3.0 mL) was added triethylamine (28.8 mg, 284 μmol), and the mixture was cooled to -78 °C. Compound 20-19 (38.6 mg, 426 μmol) was added, and the reaction mixture was stirred at -78 °C for 5 minutes under nitrogen gas protection. Dichloromethane (30.0 mL) was added to the reaction solution, and the mixture was washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high performance liquid chromatography (Xtimate C18, 100 mm × 30 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 0% - 30%: 10 minutes) to obtain the formate salt of compound 20.

[0429] MS-ESI[M+H] + , calculated value 556, measured value 556.

[0430] 11H NMR (400 MHz, MeOD) δ 7.47 - 7.58 (m, 1H), 7.07 - 7.28 (m, 3H), 6.70 - 6.95 (m, 1H), 5.84 - 5.84 (m, 1H), 5.77 - 5.90 (m, 1H), 4.66 - 4.67 (m, 1H), 4.46 - 4.53 (m, 1H), 4.29 - 4.41 (m, 1H), 3.96 - 4.25 (m, 3H), 3.72 - 3.87 (m, 3H), 3.56 - 3.70 (m, 2H), 3.20 - 3.28 (m, 1H), 3.09 - 3.18 (m, 2H), 3.01 - 3.08 (m, 2H), 2.94 - 3.00 (m, 3H), 2.85 - 2.93 (m, 1H), 2.63 - 2.84 (m, 3H), 2.29 - 2.40 (m, 1H), 2.11 - 2.22 (m, 4H), 1.93 - 2.10 (m, 4H), 1.75 - 1.87 (m, 2H).

[0431] Example 19. Synthesis of Compound 21

[0432]

Chemical Structure

[0433] MS-ESI [M+H] + , calculated value 574, measured value 574.

[0434] 11H NMR (400 MHz, MeOD) δ 7.52 - 7.53 (m, 1H), 7.19 - 7.26 (m, 1H), 7.14 - 7.18 (m, 1H), 7.09 - 7.13 (m, 1H), 5.22 - 5.47 (m, 2H), 4.66 - 4.70 (m, 1H), 4.46 - 4.53 (m, 1H), 4.16 - 4.17 (m, 2H), 3.66 - 3.86 (m, 4H), 3.46 - 3.65 (m, 2H), 3.33 - 3.40 (m, 1H), 3.22 - 3.29 (m, 1H), 3.05 - 3.19 (m, 4H), 3.01 - 3.04 (m, 1H), 2.90 - 3.00 (m, 4H), 2.72 - 2.82 (m, 2H), 2.28 - 2.40 (m, 1H), 2.09 - 2.15 (m, 4H), 1.92 - 2.06 (m, 4H), 1.75 - 1.86 (m, 2H).

[0435] Example 20. Synthesis of Compound 22

[0436] [Chemical Structure] (1) To a toluene (500 mL) solution of Compound 22 - 1 (25.0 g, 168 mmol), add Compound 22 - 2 (26.5 g, 219 mmol) and tetraethyl titanate (77.0 g, 337 mmol). Stir the reaction solution at 120 °C for 12 hours under nitrogen gas protection. Add water (400 mL) to the reaction solution, filter, wash the filter cake with ethyl acetate (400 mL × 2), combine the organic phases, wash with saturated brine (500 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain Compound 22 - 3.

[0437] MS - ESI [M + H] + , calculated value 252, measured value 252.

[0438] 1 1H NMR (400 MHz, CDCl 3)δ 7.98 - 8.03 (m, 1H), 7.35 - 7.42 (m, 1H), 6.89 - 7.02 (m, 2H), 4.27 - 4.42 (m, 2H), 3.46 - 3.56 (m, 1H), 3.22 - 3.34 (m, 1H), 1.32 - 1.34 (s, 9H).

[0439] (2) Ethyl acetate (54.6 g, 620 mmol) was dissolved in tetrahydrofuran (1000 mL), and lithium diisopropylamide (2 mol / L, 155 mL, tetrahydrofuran solution) was added dropwise at -78 °C under nitrogen gas protection. The reaction solution was stirred at -78 °C for 1 hour. A solution of compound 22-3 (39.0 g, 155 mmol) in tetrahydrofuran (500 mL) was added dropwise to the reaction solution, and stirring was continued at -78 °C for 3 hours. Saturated aqueous ammonium chloride solution (2000 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (2000 mL). The organic phases were combined, washed with saturated aqueous ammonium chloride solution (2000 mL) and saturated brine (2000 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound 22-4.

[0440] MS-ESI[M+H] + , calculated value 340, measured value 340.

[0441] (3) Hydrochloric acid dioxane solution (4 mol / L, 15.0 mL) was added to a solution of compound 22-4 (5.00 g, 14.7 mmol) in ethanol (50.0 mL), and the reaction solution was stirred at 25 °C for 2 hours under nitrogen gas protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 22-5.

[0442] MS-ESI[M-NH 2 +H] + , calculated value 219, measured value 219.

[0443] (4) To a solution of hydrochloride salt of compound 22-5 (4.00 g, 14.7 mmol) in ethanol (40.0 mL), add compound 22-6 (14.7 g, 147 mmol), copper oxide (234 mg, 2.94 mmol), and triethylamine (1.49 g, 14.7 mmol). Under the protection of nitrogen gas, react the reaction solution at 85 °C for 8 hours with sealing. Add water (100 mL) to the reaction solution, extract with ethyl acetate (200 mL × 2), combine the organic phases, wash with saturated brine (100 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 6:1) to obtain compound 22-7.

[0444] MS-ESI[M+H] + , calculated value 336, measured value 336.

[0445] 1 H NMR(400MHz,CDCl 3 )δ 7.34-7.42(m,1H),7.08-7.16(m,1H),6.85-6.95(m,1H),6.77-6.83(m,1H),4.30-4.37(m,1H),4.18-4.26(m,1H),4.11-4.15(m,5H),2.75-2.79(m,2H),2.48-2.59(m,2H),2.42-2.45(m,2H),2.28-2.37(m,1H),2.05-2.12(m,1H),1.25-1.27(m,3H),1.20-1.24(m,3H) (5) To a solution of compound 22-7 (3.00 g, 8.94 mmol) in ethanol (30.0 mL), add paraformaldehyde (1.34 g) and sodium cyanoborohydride (1.69 g, 26.8 mmol). Under the protection of nitrogen gas, react the reaction solution at 25 °C for 16 hours. Add water (100 mL) to the reaction solution, extract with ethyl acetate (100 mL), wash the organic phase with saturated brine (50 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound 22-8.

[0446] MS-ESI [M+H] + , Calculated value 350, measured value 350.

[0447] 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 - 7.37 (m, 1H), 7.09 - 7.15 (m, 1H), 6.82 - 6.88 (m, 1H), 6.74 - 6.81 (m, 1H), 4.26 - 4.34 (m, 1H), 4.15 - 4.23 (m, 1H), 4.06 - 4.14 (m, 2H), 3.88 - 3.99 (m, 2H), 2.89 - 2.98 (m, 1H), 2.70 - 2.81 (m, 3H), 2.32 - 2.46 (m, 3H), 2.24 - 2.30 (m, 1H), 2.22 - 2.24 (m, 3H), 1.20 - 1.27 (m, 3H), 1.02 - 1.08 (t, 3H).

[0448] (6) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 15 mL, in THF solution) was added to a solution of compound 22-8 (1.75 g, 5.01 mmol) in tetrahydrofuran (30.0 mL). The reaction mixture was reacted at -78 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (70 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (500 mL × 1). The organic phases were combined, washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 6:1) to obtain compound 22-9.

[0449] MS-ESI [M+H] + , Calculated value 304, measured value 304.

[0450] (7) To a solution of compound 22-9 (1.03 g, 3.40 mmol) in ethanol (30.0 mL) were added compound 22-10 (516 mg, 6.79 mmol) and sodium ethoxide (693 mg, 10.1 mmol), and the reaction mixture was stirred at 80 °C for 12 h under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 22-11.

[0451] MS-ESI[M+H] + , calculated value 316, measured value 316.

[0452] 1 H NMR (400 MHz, DMSO-d6) δ 11.54 - 12.84 (m, 2H), 7.37 - 7.42 (m, 1H), 7.12 - 7.18 (m, 1H), 6.92 - 6.99 (m, 1H), 6.75 - 6.81 (m, 1H), 4.22 - 4.31 (m, 1H), 3.92 - 4.01 (t, 1H), 3.51 - 3.60 (d, 1H), 3.02 - 3.11 (d, 1H), 2.70 - 2.77 (s, 2H), 2.03 - 2.13 (m, 1H), 1.88 - 1.96 (m, 3H), 1.54 - 1.63 (d, 1H).

[0453] (8) To a solution of intermediate 22-11 (1.05 g, 3.33 mmol) in water (100.0 mL) was added chloroacetic acid (1.26 g, 13.3 mmol), and the reaction mixture was stirred at 100 °C for 16 h under nitrogen gas protection. The reaction mixture was filtered, and saturated aqueous sodium bicarbonate solution was added to the filtrate to adjust the pH value to 8, and a solid was precipitated. It was filtered, and the filter cake was dried to obtain compound 22-12.

[0454] MS-ESI[M+H] + , calculated value 300, measured value 300.

[0455] (9) Compound 22-12 (1.70 g, 5.68 mmol) was dissolved in phosphorus oxychloride (16.5 g, 107 mmol), and the reaction solution was stirred at 100 °C for 12 hours under nitrogen gas protection. The reaction solution was concentrated under reduced pressure, extracted with dichloromethane (40 mL), and the organic phase was washed with saturated aqueous sodium bicarbonate solution (20 mL × 2) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 22-13.

[0456] MS-ESI[M+H] + , calculated value 336, measured value 336.

[0457] (10) Potassium carbonate (1.23 g, 8.92 mmol) and Compound 22-14 (846 mg, 3.57 mmol) were added to a solution of Compound 22-13 (1.00 g, 2.97 mmol) in N-methylpyrrolidone (10.0 mL), and the reaction solution was stirred at 50 °C for 12 hours under nitrogen gas protection. Ethyl acetate (30.0 mL) was added to the reaction solution, and it was washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 22-15.

[0458] MS-ESI[M+H] + , calculated value 525, measured value 525.

[0459] (11) Compound 22-16 (460 mg, 4.00 mmol), cesium carbonate (1.30 g, 4.00 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2´,6´-diisopropoxy-1,1´-biphenyl)(2-amino-1,1´-biphenyl-2-yl)palladium (223 mg, 266 μmol) were added to a solution of Compound 22-15 (700 mg, 1.33 mmol) in dioxane (10.0 mL), and the reaction solution was stirred at 110 °C for 6 hours under nitrogen gas protection. Ethyl acetate (40.0 mL) was added to the reaction solution, and it was washed with saturated brine (40.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 15:1) to obtain Compound 22-17.

[0460] MS-ESI[M+H] + Calculated value 604, measured value 604.

[0461] (12) Trifluoroacetic acid (1.54 g) was added to a solution of compound 22-17 (150.0 mg, 248 μmol) in dichloromethane (3.0 mL), and the reaction solution was stirred at 25 °C for 1 hour under nitrogen gas protection. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phase was washed with saturated aqueous sodium bicarbonate solution (50 mL × 1) and saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 22-18.

[0462] MS-ESI[M+H] + Calculated value 504, measured value 504.

[0463] (13) Triethylamine (14.7 mg, 145 μmol) and compound 22-19 (26.3 mg, 291 μmol) were added to a solution of the trifluoroacetate salt of compound 22-18 (120.0 mg, 194 μmol) in dichloromethane (2.0 mL), and the reaction solution was stirred at -78 °C for 30 minutes under nitrogen gas protection. Dichloromethane (20.0 mL) was added to the reaction solution, and the mixture was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative high-performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0% - 30%: 8 minutes) to obtain the formate salt of compound 22.

[0464] MS-ESI[M+H] + Calculated value 558, measured value 558.

[0465] 11H NMR (400 MHz, MeOD) δ 7.40 - 7.46 (m, 1H), 7.13 - 7.19 (m, 1H), 6.94 - 7.00 (m, 1H), 6.73 - 6.90 (m, 2H), 6.22 - 6.35 (m, 1H), 5.77 - 5.88 (m, 1H), 4.95 - 5.12 (m, 1H), 4.67 - 4.73 (m, 1H), 4.48 - 4.55 (m, 1H), 3.99 - 4.39 (m, 5H), 3.56 - 3.84 (m, 5H), 3.36 - 3.53 (m, 1H), 3.09 - 3.28 (m, 5H), 2.97 - 3.02 (m, 3H), 2.84 - 2.93 (m, 1H), 2.31 - 2.44 (m, 2H), 1.97 - 2.19 (m, 6H), 1.68 - 1.79 (m, 1H).

[0466] Example 21. Synthesis of Compound 23

[0467]

Chemical Structure

[0468] MS - ESI [M + H] + , calculated value 576, measured value 576.

[0469] 11H NMR (400 MHz, MeOD) δ 7.83 - 7.96 (m, 1H), 7.38 - 7.44 (m, 1H), 7.11 - 7.19 (m, 1H), 6.97 - 7.04 (m, 1H), 5.19 - 5.51 (m, 2H), 4.95 - 5.16 (m, 2H), 4.37 - 4.72 (m, 4H), 3.98 - 4.30 (m, 4H), 3.59 - 3.82 (m, 5H), 3.19 - 3.27 (m, 1H), 3.03 - 3.13 (m, 4H), 2.67 - 2.76 (m, 4H), 2.37 - 2.54 (m, 2H), 1.77 - 2.30 (m, 6H).

[0470] Example 22. Synthesis of Compound 24

[0471]

Chemical Structure

[0472] MS-ESI [M+H] + , calculated value 266, measured value 266.

[0473] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.38 - 7.43 (m, 1H), 7.28 - 7.34 (m, 1H), 6.93 - 6.98 (m, 1H), 3.87 - 3.90 (m, 3H), 3.40 - 3.51 (m, 1H), 3.01 - 3.08 (m, 3H), 1.31 - 1.34 (s, 9H).

[0474] (2) Dissolve ethyl acetate (15.8 g, 179 mmol) in tetrahydrofuran (500 mL), and dropwise add lithium diisopropylamide (2 mol / L, 44.8 mL, tetrahydrofuran solution) under nitrogen gas protection at -78 °C. Stir the reaction solution at -78 °C for 1 hour. Dropwise add a solution of compound 24-3 (11.9 g, 44.8 mmol) in tetrahydrofuran (500 mL) to the reaction solution, and continue stirring at -78 °C for 3 hours. Add saturated ammonium chloride aqueous solution (1000 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (1000 mL), combine the organic phases, wash with saturated ammonium chloride aqueous solution (1000 mL×1) and saturated brine (1000 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0~4:1) to obtain compound 24-4.

[0475] MS-ESI[M+H] + , calculated value 354, measured value 354.

[0476] (3) Add a dioxane solution of hydrochloric acid (4 mol / L, 15.0 mL) to a solution of compound 24-4 (8.00 g, 22.6 mmol) in ethanol (50.0 mL), and stir the reaction solution at 25 °C for 2 hours under nitrogen gas protection. Concentrate the reaction solution under reduced pressure to obtain the hydrochloride salt of crude compound 24-5.

[0477] MS-ESI[M-NH 2 +H] + , calculated value 233, measured value 233.

[0478] (4) To a solution of hydrochloride salt of compound 24-5 (6.40 g, 22.4 mmol) in ethanol (40.0 mL), compound 24-6 (22.4 g, 223 mmol), copper oxide (356 mg, 4.48 mmol), and triethylamine (2.27 g, 22.4 mmol) were added. The reaction mixture was sealed and reacted at 85 °C for 8 hours under nitrogen gas protection. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 6:1) to obtain compound 24-7.

[0479] MS-ESI[M+H] + , calculated value 350, measured value 350.

[0480] (5) Paraformaldehyde (1.60 g) and sodium cyanoborohydride (2.05 g, 32.6 mmol) were added to a solution of compound 24-7 (3.80 g, 10.8 mmol) in ethanol (30.0 mL). The reaction mixture was reacted at 25 °C for 16 hours under nitrogen gas protection. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound 24-8.

[0481] MS-ESI[M+H] + , calculated value 364, measured value 364.

[0482] 1 H NMR(400MHz,CDCl 3)δ 7.12 - 7.21 (m, 1H), 6.82 - 6.89 (m, 1H), 6.67 - 6.75 (m, 1H), 4.08 - 4.16 (m, 3H), 3.91 - 3.94 (m, 1H), 3.80 - 3.83 (m, 3H), 2.75 - 2.94 (m, 4H), 2.60 - 2.68 (m, 2H), 2.27 - 2.48 (m, 4H), 2.13 - 2.21 (m, 3H), 1.24 - 1.27 (m, 3H), 1.01 - 1.07 (t, 3H).

[0483] (6) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 38 mL, in tetrahydrofuran solution) was added to a solution of compound 24-8 (4.60 g, 12.6 mmol) in tetrahydrofuran (100.0 mL), and the reaction solution was reacted at -78 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (70 mL) was added to the reaction solution, and it was extracted with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 6:1) to obtain compound 24-9.

[0484] MS-ESI[M+H] + , calculated value 318, measured value 318.

[0485] (7) Compound 24-10 (959 mg, 12.6 mmol) and sodium ethoxide (1.29 g, 18.9 mmol) were added to a solution of compound 24-9 (2.00 g, 6.30 mmol) in ethanol (30.0 mL), and the reaction solution was stirred at 80 °C for 12 hours under nitrogen gas protection. The reaction solution was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 24-11.

[0486] MS-ESI[M+H] + , calculated value 330, measured value 330.

[0487] 11H NMR (400 MHz, DMSO-d6) δ 12.19 - 12.46 (m, 2H), 7.21 - 7.27 (m, 1H), 6.83 - 6.88 (m, 1H), 6.75 - 6.82 (m, 1H), 3.77 - 3.81 (m, 3H), 3.43 - 3.53 (m, 1H), 2.98 - 3.10 (m, 1H), 2.58 - 2.83 (m, 3H), 2.38 - 2.45 (m, 1H), 2.09 - 2.19 (m, 1H), 1.91 - 2.02 (s, 3H), 1.58 - 1.69 (m, 1H).

[0488] (8) To a solution of Intermediate 24-11 (1.72 g, 5.22 mmol) in water (10.0 mL) was added chloroacetic acid (1.97 g, 20.8 mmol), and the reaction mixture was stirred at 100 °C for 16 h under nitrogen gas protection. The reaction mixture was filtered, and saturated aqueous sodium bicarbonate solution was added to the filtrate to adjust the pH value to 8, and a solid was precipitated. The solid was filtered and the filter cake was dried to obtain Compound 24-12.

[0489] MS-ESI [M+H] + , calculated value 314, measured value 314.

[0490] 1 1H NMR (400 MHz, DMSO-d6) δ 10.95 - 11.02 (s, 1H), 10.70 - 10.76 (s, 1H), 7.20 - 7.26 (t, 1H), 6.77 - 6.87 (dd, 2H), 3.78 - 3.81 (m, 3H), 3.37 - 3.46 (m, 1H), 2.96 - 3.04 (m, 1H), 2.55 - 2.87 (m, 3H), 2.27 - 2.35 (m, 1H), 2.09 - 2.20 (m, 1H), 1.94 - 1.99 (s, 3H), 1.57 - 1.68 (m, 1H).

[0491] (9) Compound 24-12 (1.34 g, 4.28 mmol) is dissolved in phosphorus oxychloride (16.5 g, 107 mmol), and the reaction solution is stirred at 100 °C for 12 hours under nitrogen gas protection. The reaction solution is concentrated under reduced pressure, extracted with dichloromethane (40 mL), and the organic phase is washed with saturated aqueous sodium bicarbonate solution (20 mL × 2) and saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 24-13.

[0492] MS-ESI[M+H] + , calculated value 350, measured value 350.

[0493] (10) Potassium carbonate (1.33 g, 9.59 mmol) and Compound 24-14 (864 mg, 3.84 mmol) are added to a solution of Compound 24-13 (1.12 g, 3.20 mmol) in N-methylpyrrolidone (10.0 mL), and the reaction solution is stirred at 50 °C for 12 hours under nitrogen gas protection. Ethyl acetate (30.0 mL) is added to the reaction solution, washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 24-15.

[0494] MS-ESI[M+H] + , calculated value 539, measured value 539.

[0495] (11) Compound 24-16 (448 mg, 3.90 mmol), cesium carbonate (1.27 g, 3.90 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2´,6´-diisopropoxy-1,1´-biphenyl)(2-amino-1,1´-biphenyl-2-yl)palladium (217 mg, 259 μmol) are added to a solution of Compound 24-15 (700 mg, 1.30 mmol) in dioxane (10.0 mL), and the reaction solution is stirred at 110 °C for 6 hours under nitrogen gas protection. Ethyl acetate (40.0 mL) is added to the reaction solution, washed with saturated brine (40.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 15:1) to obtain Compound 24-17.

[0496] MS-ESI[M+H] + Calculated value: 618, Measured value: 618.

[0497] (12) To a solution of compound 24-17 (430.0 mg, 696 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.54 g), and the reaction solution was stirred at 25 °C for 1 hour under nitrogen gas protection. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phase was washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 24-18.

[0498] MS-ESI[M+H] + Calculated value: 518, Measured value: 518.

[0499] (13) To a solution of the trifluoroacetate salt of compound 24-18 (100.0 mg, 158 μmol) in dichloromethane (2.0 mL) were added triethylamine (16.0 mg, 158 μmol) and compound 24-19 (21.4 mg, 237 μmol), and the reaction solution was stirred at -78 °C for 30 minutes under nitrogen gas protection. Dichloromethane (20.0 mL) was added to the reaction solution, and the mixture was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative high-performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm × 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0% - 30%: 8 minutes) to obtain the formate salt of compound 24.

[0500] MS-ESI[M+H] + Calculated value: 558, Measured value: 572.

[0501] 11H NMR (400 MHz, MeOD) δ 7.24 - 7.31 (m, 1H), 6.78 - 6.94 (m, 3H), 6.23 - 6.36 (m, 1H), 5.79 - 5.88 (m, 1H), 4.61 - 4.86 (m, 2H), 4.52 - 4.60 (m, 1H), 3.91 - 4.36 (m, 4H), 3.76 - 3.90 (m, 6H), 3.58 - 3.74 (m, 2H), 3.06 - 3.28 (m, 4H), 3.01 - 3.04 (m, 3H), 2.86 - 3.00 (m, 4H), 2.35 - 2.52 (m, 2H), 2.28 - 2.32 (m, 3H), 1.92 - 2.21 (m, 4H).

[0502] Example 23. Synthesis of Compound 25

[0503] [Chemical formula] At 0 °C, triethylamine (14.7 mg, 145 μmol), compound 25 - 1 (71.2 mg, 791 μmol), and tricyclic propylphosphonic anhydride solution (302 mg, 474 μmol, 50% ethyl acetate solution) were added to a dichloromethane (2.0 mL) solution of compound 24 - 18 (100 mg, 158 μmol). The reaction solution was stirred at 25 °C for 30 minutes. Dichloromethane (20.0 mL) was added to the reaction solution, and it was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high - performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm × 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0% - 30%: 8 minutes) to obtain the formate salt of compound 25.

[0504] MS - ESI [M + H] + , calculated value 590, measured value 590.

[0505] 11H NMR (400 MHz, MeOD) δ 7.21 - 7.32 (m, 1H), 6.83 - 6.90 (m, 2H), 5.23 - 5.43 (m, 2H), 4.69 - 4.74 (m, 1H), 4.50 - 4.57 (m, 1H), 4.00 - 4.36 (m, 3H), 3.63 - 3.88 (m, 8H), 3.40 - 3.58 (m, 1H), 2.81 - 3.29 (m, 12H), 2.34 - 2.50 (m, 2H), 2.23 - 2.28 (m, 3H), 1.89 - 2.21 (m, 4H).

[0506] Example 24. Synthesis of Compounds 26 and 27

[0507] [Chemical Structure Diagram] (1) To a solution of Compound 8-8 (3.00 g, 5.69 mmol) in dioxane (80.0 mL) were added Compound 26-1 (1.81 mg, 11.4 mmol), cesium carbonate (5.56 g, 17.1 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2´,6´-diisopropoxy-1,1´-biphenyl)(2-amino-1,1´-biphenyl-2-yl)palladium(II) (300 mg, 359 μmol). The reaction mixture was stirred at 110 °C for 4 hours under nitrogen gas protection. Ethyl acetate (200 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 8:1) to obtain Compound 26-2.

[0508] MS-ESI [M+H] + , calculated value 650, measured value 650.

[0509] (2) To a solution of Compound 26-2 (3.24 g, 4.99 mmol) in dichloromethane (50.0 mL) was added a dioxane solution of hydrochloric acid (1.25 mL, 4 mol / L). The reaction mixture was stirred at 25 °C for 30 minutes under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of crude Compound 26-3.

[0510] MS-ESI [M+H] + , calculated value 550, measured value 550.

[0511] (3) To a solution of hydrochloride salt of compound 26-3 (2.60 g, 4.44 mmol) in dichloromethane (30.0 mL) were added triethylamine (1.35 g, 13.3 mmol) and compound 26-4 (803 mg, 8.87 μmol), and the reaction solution was stirred at -78 °C for 30 minutes under nitrogen gas protection. Dichloromethane (60.0 mL) was added to the reaction solution, and it was washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 25:1) to obtain compound 26-5.

[0512] (4) Compound 26-5 was resolved by chiral supercritical fluid chromatography to obtain compounds 26 and 27.

[0513] Separation conditions: Chromatography column model: Chiralpak OX-3, Chromatography column specification: 100 × 4.6 mm I.D., 3 μm, Injection volume: 10 μL, Mobile phase: Carbon dioxide: Isopropanol (0.05% diethylamine) = 60:40, Detection wavelength: 254 nm, Column temperature: 35 °C.

[0514] The retention time of compound 6 is 2.047 minutes, and the ee value is 99.28%.

[0515] MS-ESI [M+H] + , calculated value 604, measured value 604.

[0516] 11H NMR (400 MHz, MeOD) δ 7.31 (td, J = 7.6, 5.2 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.91 - 6.97 (m, 1H), 6.71 - 6.90 (m, 1H), 6.28 (d, J = 16.4 Hz, 1H), 5.83 (d, J = 10.4 Hz, 1H), 5.19 - 5.37 (m, 1H), 5.03 (s, 1H), 4.54 (s, 1H), 4.16 - 4.22 (m, 1H), 4.10 (d, J = 10.4 Hz, 3H), 3.52 - 3.79 (m, 3H), 3.39 - 3.51 (m, 1H), 3.21 - 3.28 (m, 2H), 3.19 (d, J = 9.6 Hz, 2H), 3.11 (d, J = 3.2 Hz, 1H), 3.04 - 3.09 (m, 1H), 2.99 - 3.04 (m, 2H), 2.89 - 2.98 (m, 2H), 2.85 (s, 1H), 2.49 (dt, J = 13.2, 8.8 Hz, 1H), 2.27 - 2.32 (m, 3H), 2.19 - 2.27 (m, 1H), 2.12 - 2.19 (m, 1H), 2.05 - 2.12 (m, 1H), 1.93 - 2.02 (m, 2H), 1.84 - 1.93 (m, 2H).

[0517] The retention time of Compound 7 is 3.558 minutes, and the ee value is 98.36%.

[0518] MS-ESI [M+H] + , calculated value 604, measured value 604.

[0519] 11H NMR (400 MHz, MeOD) δ 7.32 (td, J = 7.6, 5.2 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.91 - 6.97 (m, 1H), 6.72 - 6.91 (m, 1H), 6.29 (d, J = 16.4 Hz, 1H), 5.83 (d, J = 10.4 Hz, 1H), 5.22 - 5.39 (m, 1H), 5.07 (s, 1H), 4.50 - 4.78 (m, 1H), 4.18 - 4.27 (m, 2H), 4.14 (d, J = 10.4 Hz, 1H), 3.91 - 4.13 (m, 2H), 3.62 - 3.74 (m, 2H), 3.37 - 3.61 (m, 1H), 3.25 - 3.29 (m, 2H), 3.20 - 3.24 (m, 2H), 3.08 - 3.20 (m, 3H), 3.06 (d, J = 5.2 Hz, 1H), 2.98 - 3.05 (m, 2H), 2.90 (d, J = 18.0 Hz, 1H), 2.48 (dt, J = 13.2, 8.4 Hz, 1H), 2.28 - 2.37 (m, 1H), 2.24 - 2.28 (m, 3H), 2.18 - 2.24 (m, 1H), 2.10 - 2.16 (m, 1H), 1.94 - 2.03 (m, 2H), 1.90 (ddd, J = 13.2, 8.4, 4.4 Hz, 2H).

[0520] Example 25. Synthesis of Compounds 28 and 29

[0521]

Chemical Structure

[0522] (4) Compound 28-2 is resolved by chiral supercritical fluid chromatography to obtain Compounds 28 and 29.

[0523] Separation conditions: Chromatography column model: Chiralpak OX-3, Chromatography column specifications: 50×4.6 mm I.D., 3 μm, Injection volume: 10 μL, Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 2.5 minutes, 40% isocratic elution for 0.5 minutes, 5% isocratic elution for 1 minute, Detection wavelength: 254 nm, Column temperature: 35 °C.

[0524] The retention time of Compound 28 is 1.457 minutes and the ee value is 100%.

[0525] MS-ESI[M+H] + , Calculated value 622, Measured value 622.

[0526] 11H NMR (400 MHz, MeOD) δ 7.32 (td, J = 7.6, 5.2 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.90 - 6.97 (m, 1H), 5.34 - 5.41 (m, 1H), 5.28 - 5.34 (m, 1H), 5.19 - 5.28 (m, 1H), 4.92 (s, 1H), 4.79 - 4.88 (m, 1H), 4.15 - 4.23 (m, 1H), 4.13 (s, 1H), 4.06 - 4.11 (m, 2H), 3.90 - 4.06 (m, 1H), 3.69 (s, 2H), 3.45 (d, J = 13.2 Hz, 1H), 3.23 - 3.29 (m, 1H), 3.17 - 3.23 (m, 2H), 3.16 (d, J = 5.2 Hz, 1H), 3.10 - 3.15 (m, 1H), 3.06 - 3.10 (m, 1H), 3.04 (d, J = 8.8 Hz, 2H), 2.98 - 3.01 (m, 1H), 2.93 - 2.98 (m, 1H), 2.87 (d, J = 18.0 Hz, 1H), 2.49 (dt, J = 13.2, 8.8 Hz, 1H), 2.27 - 2.32 (m, 3H), 2.19 - 2.27 (m, 1H), 2.13 - 2.18 (m, 1H), 2.06 - 2.12 (m, 1H), 1.96 - 2.02 (m, 1H), 1.92 - 1.96 (m, 1H), 1.88 - 1.92 (m, 1H), 1.79 - 1.88 (m, 1H).

[0527] The retention time of Compound 29 is 1.588 minutes, and the ee value is 95.44%.

[0528] MS-ESI [M+H] + , calculated value 622, measured value 622.

[0529] 11H NMR (400 MHz, MeOD) δ 7.32 (td, J = 7.6, 5.2 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.91 - 6.97 (m, 1H), 5.38 (s, 1H), 5.29 - 5.35 (m, 1H), 5.25 (d, J = 13.6 Hz, 1H), 4.91 (s, 1H), 4.86 - 4.87 (m, 1H), 4.24 (d, J = 14.0 Hz, 1H), 4.14 - 4.22 (m, 2H), 3.96 - 4.12 (m, 2H), 3.63 - 3.71 (m, 2H), 3.27 (d, J = 3.6 Hz, 2H), 3.24 (d, J = 3.2 Hz, 2H), 3.20 (s, 1H), 3.13 - 3.18 (m, 2H), 3.06 - 3.13 (m, 2H), 2.99 - 3.06 (m, 2H), 2.89 (d, J = 18.0 Hz, 1H), 2.44 - 2.51 (m, 1H), 2.28 (s, 3H), 2.22 - 2.26 (m, 1H), 2.19 (s, 1H), 2.12 (d, J = 9.2 Hz, 1H), 1.96 - 2.04 (m, 2H), 1.90 (td, J = 8.8, 4.4 Hz, 2H).

[0530] Example 26. Synthesis of Compound 30

[0531] [Chemical Structure] (1) To a toluene (500 mL) solution of Compound 30-1 (20.0 g, 150 mmol) were added Compound 30-2 (21.9 g, 181 mmol) and tetraethyl titanate (68.5 g, 300 mmol), and the reaction mixture was stirred at 110 °C for 12 hours under nitrogen gas protection. Water (200 mL) and ethyl acetate (500 mL) were added to the reaction mixture, and the mixture was filtered. The filter cake was washed with ethyl acetate (500 mL × 4). The organic phases were combined, washed with saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:2) to obtain Compound 30-3.

[0532] MS-ESI [M+H] + , calculated value 237, measured value 237.

[0533] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 8.05 (dd, J = 7.6, 1.6 Hz, 1H), 7.28 (dd, J = 8.0, 4.8 Hz, 1H), 3.49 - 3.59 (m, 1H), 3.25 - 3.31 (m, 2H), 3.11 - 3.20 (m, 1H), 1.33 (s, 9H).

[0534] (2) Ethyl acetate (24.3 g, 276 mmol) was dissolved in tetrahydrofuran (150 mL), and lithium diisopropylamide (2 mol / L, 55 mL, tetrahydrofuran solution) was added dropwise at -65 °C under nitrogen gas protection. The reaction solution was stirred at -65 °C for 1 hour. A solution of compound 30 - 3 (13.0 g, 55.0 mmol) in tetrahydrofuran (150 mL) was added dropwise to the reaction solution, and stirring was continued at -65 °C for 2 hours. The temperature was raised to 0 °C, and saturated aqueous ammonium chloride solution (200 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated aqueous ammonium chloride solution (200 mL × 1) and saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 32:1) to obtain compound 30 - 4.

[0535] MS - ESI [M + H] + , calculated value 325, measured value 325.

[0536] 1 1H NMR (400 MHz, MeOD) δ 8.42 (d, J = 5.2 Hz, 1H), 7.77 - 7.83 (m, 1H), 7.25 - 7.33 (m, 1H), 4.08 - 4.19 (m, 2H), 3.17 - 3.25 (m, 1H), 2.97 - 3.15 (m, 2H), 2.85 - 2.97 (m, 1H), 2.60 - 2.69 (m, 1H), 2.41 - 2.54 (m, 1H), 1.17 - 1.22 (m, 12H).

[0537] (3) A solution of compound 30-4 (7.40 g, 22.8 mmol) in ethanol (60.0 mL) is added with a dioxane solution of hydrochloric acid (4 mol / L, 20.0 mL), and the reaction solution is stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution is concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 30-5.

[0538] MS-ESI[M+H] + , calculated value 221, measured value 221.

[0539] (4) To a solution of the hydrochloride salt of compound 30-5 (5.86 g, 22.8 mmol) in ethanol (50.0 mL) are added compound 5-6 (23.1 g, 231 mmol), copper oxide (363 mg, 4.56 mmol), and triethylamine (6.94 g, 68.6 mmol), and the reaction solution is sealed and reacted at 85 °C for 8 hours under nitrogen gas protection. Water (200 mL) is added to the reaction solution, and it is extracted with ethyl acetate (200 mL × 2). The organic phases are combined, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 2:1) to obtain compound 30-7.

[0540] MS-ESI[M+H] + , calculated value 321, measured value 321.

[0541] 1 H NMR(400MHz,MeOD)δ 8.37(d,J=4.4Hz,1H),7.75(dd,J=7.6,1.2Hz,1H),7.26(dd,J=7.6,5.2Hz,1H),4.13(q,J=7.2Hz,2H),4.06(q,J=7.2Hz,2H),2.97-3.10(m,2H),2.82-2.87(m,1H),2.75-2.80(m,1H),2.71(dt,J=10.8,6.0Hz,1H),2.48-2.59(m,1H),2.43-2.48(m,2H),2.28-2.39(m,2H),1.24(t,J=7.2Hz,3H),1.15(t,J=7.2Hz,3H).

[0542] (5) To a solution of compound 30-7 (1.00 g, 3.12 mmol) in ethanol (15.0 mL), paraformaldehyde (937 mg) and sodium cyanoborohydride (589 mg, 9.37 mmol) were added, and the reaction solution was reacted at 25 °C for 14 hours under nitrogen gas protection. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL × 1). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 30-8.

[0543] MS-ESI[M+H] + , calculated value 335, measured value 335.

[0544] 1 H NMR (400 MHz, MeOD) δ 8.36 (dd, J = 5.2, 1.6 Hz, 1H), 7.72 (dd, J = 7.6, 1.6 Hz, 1H), 7.25 (dd, J = 7.6, 5.2 Hz, 1H), 4.07 - 4.13 (m, 2H), 3.90 (qd, J = 7.2, 1.2 Hz, 2H), 2.98 - 3.04 (m, 2H), 2.94 - 2.97 (m, 1H), 2.84 - 2.89 (m, 1H), 2.64 - 2.71 (m, 1H), 2.57 - 2.63 (m, 1H), 2.40 - 2.46 (m, 3H), 2.25 - 2.32 (m, 1H), 2.20 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H).

[0545] (6) At -65 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 8.0 mL, in tetrahydrofuran solution) was added to a solution of compound 30-8 (900 mg, 2.69 mmol) in tetrahydrofuran (20.0 mL). The reaction mixture was stirred at -65 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 1). The organic phase was washed successively with saturated aqueous ammonium chloride solution (100 mL × 1) and saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 30-9.

[0546] MS-ESI[M+H] + , calculated value 289, measured value 289.

[0547] 1 H NMR (400 MHz, MeOD) δ 8.42 (dd, J = 5.2, 1.6 Hz, 1H), 7.71 (dd, J = 7.6, 1.6 Hz, 1H), 7.32 (dd, J = 7.6, 5.2 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.45 (d, J = 15.2 Hz, 1H), 3.32 - 3.39 (m, 1H), 3.22 - 3.28 (m, 1H), 3.04 - 3.11 (m, 2H), 2.58 - 2.69 (m, 1H), 2.44 - 2.49 (m, 1H), 2.34 - 2.40 (m, 1H), 2.07 (s, 3H), 1.85 - 1.93 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H).

[0548] (7) Compound 30-10 (269 mg, 3.53 mmol) and sodium ethoxide (361 mg, 5.30 mmol) were added to a solution of compound 30-9 (510 mg, 1.77 mmol) in ethanol (8.0 mL). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 30-11.

[0549] MS-ESI [M+H] + , calculated value 301, measured value 301.

[0550] 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 12.64 (s, 1H), 8.66 - 8.73 (m, 1H), 8.59 (s, 1H), 7.56 (s, 1H), 4.10 (s, 1H), 3.96 (d, J = 14.4 Hz, 1H), 3.43 (d, J = 18.8 Hz, 4H), 3.18 (s, 2H), 2.89 (d, J = 16.0 Hz, 1H), 2.67 (s, 1H), 2.20 (s, 1H).

[0551] (8) To a solution of intermediate 30 - 11 (531 mg, 1.77 mmol) in water (10.0 mL) is added chloroacetic acid (670 mg, 7.09 mmol), and the reaction solution is stirred at 100 °C for 16 hours under nitrogen gas protection. The reaction solution is filtered, saturated aqueous sodium bicarbonate solution is added to the filtrate to adjust the pH value to 8, and a solid precipitates. It is filtered, and the filter cake is dried to obtain compound 30 - 12.

[0552] MS-ESI [M+H] + , calculated value 285, measured value 285.

[0553] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 2H), 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 7.58 (dd, J = 7.6, 1.6 Hz, 1H), 7.24 (dd, J = 7.6, 4.8 Hz, 1H), 3.39 (s, 1H), 3.07 (d, J = 16.0 Hz, 1H), 2.90 - 2.99 (m, 2H), 2.61 (d, J = 17.2 Hz, 1H), 2.39 (d, J = 17.6 Hz, 1H), 2.21 (dt, J = 13.6, 8.4 Hz, 1H), 1.96 (s, 3H), 1.70 (ddd, J = 13.6, 8.0, 5.6 Hz, 1H).

[0554] (9) Compound 30-12 (300 mg, 1.06 mmol) is dissolved in phosphorus oxychloride (9.90 g, 64.6 mmol), and the reaction solution is stirred at 100 °C for 12 hours in a sealed container under nitrogen gas protection. The reaction solution is concentrated under reduced pressure, slowly added to ice water (50 mL), extracted with dichloromethane (50 mL × 1), the organic phase is washed with saturated aqueous sodium carbonate solution (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 30-13.

[0555] MS-ESI[M+H] + , calculated value 321, measured value 321.

[0556] (10) Potassium carbonate (436 mg, 3.15 mmol) and Compound 30-14 (284 mg, 1.26 mmol) are added to a solution of Compound 30-13 (338 mg, 1.05 mmol) in N-methylpyrrolidone (5.0 mL), and the reaction solution is stirred at 50 °C for 3 hours under nitrogen gas protection. The reaction solution is poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The combined organic phases are washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain Compound 30-15.

[0557] MS-ESI[M+H] + , calculated value 510, measured value 510.

[0558] 1 H NMR (400 MHz, MeOD) δ 8.44 (d, J = 4.4 Hz, 1H), 7.65 - 7.74 (m, 1H), 7.28 - 7.37 (m, 1H), 4.43 (s, 2H), 3.98 - 4.08 (m, 2H), 3.87 (d, J = 14.4 Hz, 2H), 3.68 - 3.80 (m, 2H), 2.97 (d, J = 5.2 Hz, 2H), 2.93 (s, 2H), 2.83 - 2.87 (m, 2H), 2.82 (d, J = 4.0 Hz, 2H), 2.45 - 2.54 (m, 1H), 2.21 (s, 3H), 1.48 (s, 9H).

[0559] (11) To a solution of Compound 30-15 (300 mg, 588 μmol) in dioxane (10.0 mL) were added Compound 30-16 (203 mg, 1.76 mmol), cesium carbonate (575 mg, 1.76 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2´,6´-diisopropoxy-1,1´-biphenyl)(2-amino-1,1´-biphenyl-2-yl)palladium (98.4 mg, 118 μmol). The reaction mixture was stirred at 110 °C for 4 hours under a nitrogen gas atmosphere. Ethyl acetate (20.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 5:1) to obtain Compound 30-17.

[0560] MS-ESI[M+H] + , calculated value 589, measured value 589.

[0561] (12) Trifluoroacetic acid (1.54 g, 13.5 mmol) was added to a solution of Compound 30-17 (110 mg, 187 μmol) in dichloromethane (3.0 mL). The reaction mixture was stirred at 25 °C for 1 hour under a nitrogen gas atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude Compound 30-18.

[0562] MS-ESI[M+H] + , calculated value 489, measured value 489.

[0563] (13) To a solution of trifluoroacetate of compound 30-18 (90.0 mg, 149 μmol) in dichloromethane (5.0 mL) was added triethylamine (45.0 mg, 445 μmol), and the mixture was cooled to -65 °C. Compound 30-19 (27.0 mg, 298 μmol) was added, and the mixture was stirred at -65 °C for 30 minutes under nitrogen gas protection. Dichloromethane (30.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative high-performance liquid chromatography (Gemini-NX C18 75×30 mm×3 um, A: water (10 mM ammonium bicarbonate); B: acetonitrile, 10%-40%: 10 minutes) to obtain compound 30.

[0564] MS-ESI[M+H] + , calculated value 543, measured value 543.

[0565] 1 H NMR(400MHz,MeOD)δ 8.44(d,J=4.8Hz,1H),7.62-7.75(m,1H),7.27-7.37(m,1H),6.83(d,J=13.2Hz,1H),6.29(d,J=16.4Hz,1H),5.84(d,J=10.4Hz,1H),4.43-4.68(m,1H),4.29-4.41(m,2H),4.19(d,J=14.0Hz,1H),4.10(s,1H),4.00(d,J=10.0Hz,1H),3.71-3.82(m,2H),3.44-3.64(m,1H),3.27(s,1H),3.15-3.23(m,1H),3.04-3.15(m,4H),2.88-2.99(m,3H),2.74(dt,J=14.0,6.8Hz,1H),2.50-2.56(m,1H),2.49(d,J=2.4Hz,3H),2.35(qd,J=8.8,2.0Hz,1H),2.21(s,3H),2.09(dq,J=12.4,8.4Hz,1H),1.91-2.01(m,1H),1.77-1.86(m,2H),1.63-1.75(m,1H).

[0566] Example 27. Synthesis of Compound 31

[0567] [Chemical formula] To a solution of compound 31-1 (58.3 mg, 648 μmol) in ethyl acetate (5.0 mL), 4A molecular sieves (130 mg), triethylamine (65.6 mg, 648 μmol), the trifluoroacetate of compound 30-18 (130 mg, 216 μmol), and a solution of tricyclic propylphosphonic anhydride (549 mg, 863 μmol, 50% ethyl acetate solution) were added, and the reaction solution was stirred at 25 °C for 30 minutes. The reaction solution was filtered, the filter cake was washed with ethyl acetate (10.0 mL × 3), the filtrate was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high performance liquid chromatography (Phenomenex Gemini-NX C18, 75 mm × 30 mm 3 μm, A: water (10 mmol / L ammonium bicarbonate); B: acetonitrile, 25%-50%: 8 minutes) to obtain compound 31.

[0568] MS-ESI [M+H] + , calculated value 561, measured value 561.

[0569] 11H NMR (400 MHz, MeOD) δ 8.44 (d, J = 4.8 Hz, 1H), 7.69 (ddd, J = 13.2, 7.6, 1.6 Hz, 1H), 7.33 (dt, J = 7.6, 5.2 Hz, 1H), 5.32 - 5.44 (m, 1H), 5.20 - 5.32 (m, 1H), 4.28 - 4.39 (m, 2H), 4.14 - 4.26 (m, 1H), 4.10 (d, J = 5.2 Hz, 1H), 3.93 - 4.07 (m, 1H), 3.63 - 3.80 (m, 2H), 3.37 - 3.57 (m, 1H), 3.32 - 3.34 (m, 1H), 3.20 - 3.30 (m, 1H), 3.04 - 3.20 (m, 5H), 2.95 - 3.04 (m, 1H), 2.94 (d, J = 6.4 Hz, 2H), 2.76 (dt, J = 13.6, 6.8 Hz, 1H), 2.50 (d, J = 2.4 Hz, 3H), 2.47 (d, J = 3.6 Hz, 1H), 2.33 - 2.42 (m, 1H), 2.21 (d, J = 1.2 Hz, 3H), 2.09 (dq, J = 12.4, 8.4 Hz, 1H), 1.91 - 2.01 (m, 1H), 1.77 - 1.87 (m, 2H), 1.65 - 1.76 (m, 1H).

[0570] Example 28. Synthesis of Compounds 32 and 33

[0571] [Chemical formula] (1) To a solution of compound 20 - 15 (800 mg, 1.53 mmol) in dioxane (15.0 mL) were added compound 32 - 1 (487 mg, 3.06 mmol), cesium carbonate (382 mg, 2.76 mmol), and (2 - dicyclohexylphosphino - 2´,6´ - diisopropoxybiphenyl)(2 - amino - 1,1´ - biphenyl - 2 - yl)palladium(II) methanesulfonate (80.0 mg, 95.7 μmol). The reaction mixture was stirred at 110 °C for 3 hours under nitrogen gas protection. Ethyl acetate (80.0 mL) was added to the reaction mixture, and it was washed with water (50.0 mL × 1) and saturated brine (50.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 16:1) to obtain compound 32 - 2.

[0572] MS-ESI[M+H] + , Calculated value 646, measured value 646.

[0573] 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 (t, J = 7.2 Hz, 1H), 7.19 - 7.24 (m, 1H), 7.14 (t, J = 6.8 Hz, 1H), 7.06 - 7.09 (m, 1H), 4.59 (s, 1H), 4.09 (s, 2H), 3.96 (s, 1H), 3.63 - 3.83 (m, 3H), 3.34 (dd, J = 14.0, 3.2 Hz, 1H), 3.23 (s, 2H), 3.16 (d, J = 8.0 Hz, 1H), 3.05 - 3.14 (m, 3H), 2.79 - 3.05 (m, 4H), 2.74 (d, J = 5.6 Hz, 2H), 2.69 (d, J = 2.8 Hz, 1H), 2.27 (s, 1H), 2.21 (s, 1H), 2.10 - 2.16 (m, 3H), 1.89 - 1.99 (m, 4H), 1.84 (d, J = 10.0 Hz, 2H), 1.77 (s, 1H), 1.67 - 1.76 (m, 2H), 1.51 (s, 9H).

[0574] (2) To a solution of compound 32 - 2 (810 mg, 1.25 mmol) in dichloromethane (10.0 mL) was added a dioxane solution of hydrochloric acid (3.12 mL, 4 mol / L), and the reaction solution was stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 32 - 3.

[0575] MS-ESI[M+H] + , Calculated value 546, measured value 546.

[0576] (3) To a solution of hydrochloride salt of compound 32-3 (830 mg, 1.43 mmol) in dichloromethane (3.0 mL), triethylamine (433 mg, 4.28 mmol) and compound 32-4 (258 mg, 2.85 mmol) are added, and the reaction solution is stirred at -78 °C for 1 hour under nitrogen gas protection. Dichloromethane (60.0 mL) is added to the reaction solution, washed with saturated brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (dichloromethane / methanol = 1:0 - 16:1) to obtain compound 32-5.

[0577] (4) Compound 32-5 is resolved by chiral supercritical fluid chromatography to obtain compounds 32 and 33.

[0578] Separation conditions: Chromatography column model: Chiralpak OX-3, Chromatography column specification: 50 × 4.6 mm I.D., 3 μm, Injection volume: 10 μL, Mobile phase: A: Carbon dioxide, B: Ethanol (0.05% diethylamine), B%: 5% - 40% gradient elution for 2.5 minutes, 40% fixed concentration elution for 0.5 minutes, 5% fixed concentration elution for 1 minute, Detection wavelength: 254 nm, Column temperature: 35 °C.

[0579] The retention time of compound 32 is 1.759 minutes, and the ee value is 100%.

[0580] MS-ESI[M+H] + , Calculated value 600, Measured value 600.

[0581] 11H NMR (400 MHz, MeOD) δ 7.51 (d, J = 8.0 Hz, 1H), 7.19 - 7.25 (m, 1H), 7.13 - 7.18 (m, 1H), 7.07 - 7.12 (m, 1H), 6.80 (s, 1H), 6.29 (d, J = 16.4 Hz, 1H), 5.83 (d, J = 10.4 Hz, 1H), 5.21 - 5.42 (m, 1H), 5.02 (s, 1H), 4.23 - 4.53 (m, 1H), 4.22 (s, 1H), 4.13 (d, J = 8.4 Hz, 2H), 4.09 (s, 1H), 3.75 - 3.87 (m, 2H), 3.57 - 3.75 (m, 1H), 3.35 - 3.57 (m, 2H), 3.15 (d, J = 15.2 Hz, 1H), 3.04 - 3.12 (m, 2H), 2.93 - 3.04 (m, 2H), 2.88 (s, 2H), 2.76 (d, J = 5.6 Hz, 2H), 2.26 - 2.39 (m, 1H), 2.13 - 2.26 (m, 2H), 2.12 (s, 3H), 2.03 - 2.10 (m, 1H), 2.01 (d, J = 8.4 Hz, 2H), 1.92 - 1.99 (m, 2H), 1.90 (d, J = 6.8 Hz, 1H), 1.66 - 1.84 (m, 2H).

[0582] The retention time of Compound 33 is 1.966 minutes, and the ee value is 99.36%.

[0583] MS-ESI [M+H] + , calculated value 600, measured value 600.

[0584] 11H NMR (400 MHz, MeOD) δ 7.51 (d, J = 7.6 Hz, 1H), 7.19 - 7.25 (m, 1H), 7.13 - 7.18 (m, 1H), 7.07 - 7.12 (m, 1H), 6.82 (d, J = 10.0 Hz, 1H), 6.29 (d, J = 16.4 Hz, 1H), 5.84 (d, J = 10.4 Hz, 1H), 5.25 - 5.43 (m, 1H), 5.07 (s, 1H), 4.32 (d, J = 14.0 Hz, 1H), 4.18 - 4.29 (m, 2H), 4.11 (d, J = 10.0 Hz, 1H), 4.00 (d, J = 11.2 Hz, 1H), 3.70 - 3.85 (m, 2H), 3.46 - 3.69 (m, 1H), 3.36 - 3.45 (m, 2H), 3.20 (dd, J = 14.0, 3.6 Hz, 2H), 3.14 (d, J = 8.4 Hz, 1H), 3.07 - 3.10 (m, 1H), 3.03 (s, 1H), 2.99 (s, 1H), 2.94 (s, 1H), 2.74 - 2.81 (m, 2H), 2.29 - 2.43 (m, 1H), 2.23 - 2.29 (m, 1H), 2.16 - 2.23 (m, 1H), 2.12 (s, 3H), 2.08 (d, J = 10.0 Hz, 1H), 2.04 (d, J = 5.2 Hz, 2H), 1.95 - 2.00 (m, 2H), 1.92 (d, J = 6.8 Hz, 1H), 1.71 - 1.83 (m, 2H).

[0585] Example 29. Synthesis of Compound 34

[0586]

Chemical Structure

[0587] MS-ESI[M+H] + , calculated value 666, measured value 666.

[0588] (2) Trifluoroacetic acid (2.0 mL) was added to a dichloromethane (6.0 mL) solution of Compound 34-2 (485 mg, 728 μmol). The reaction mixture was stirred at 25 °C for 1 hour under a nitrogen gas atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude Compound 34-3.

[0589] MS-ESI[M+H] + , calculated value 566, measured value 566.

[0590] (3) To a solution of trifluoroacetate of compound 34-3 (150 mg, 221 μmol) in dichloromethane (3.0 mL) were added triethylamine (67.0 mg, 662 μmol) and compound 34-4 (39.9 mg, 441 μmol). The reaction mixture was stirred at -65 °C for 30 minutes under nitrogen gas protection. Dichloromethane (20.0 mL) was added to the reaction mixture, and it was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 7% - 27%: 7 minutes) to obtain the formate salt of compound 34.

[0591] MS-ESI[M+H] + , calculated value 620, measured value 620.

[0592] 1 H NMR(400MHz,MeOD)δ 7.20-7.30(m,3H),6.82(d,J=11.6Hz,1H),6.29(d,J=16.8Hz,1H),5.84(d,J=10.4Hz,1H),5.41-5.64(m,1H),5.03(s,1H),4.38-4.64(m,3H),4.02-4.23(m,2H),3.83-3.95(m,1H),3.76-3.83(m,2H),3.71-3.76(m,2H),3.50-3.70(m,1H),3.32-3.44(m,3H),3.08-3.28(m,2H),2.97-3.08(m,2H),2.76-2.96(m,2H),2.73(d,J=18.0Hz,1H),2.55-2.68(m,1H),2.43-2.55(m,2H),2.28-2.41(m,2H),2.25(d,J=2.4Hz,3H),2.10-2.20(m,1H),1.77-1.91(m,1H).

[0593] Example 30. Synthesis of Compound 35

[0594]

Chemical Structure

[0595] MS-ESI[M+H] + , calculated value 638, measured value 638.

[0596] 1 H NMR(400MHz,MeOD)δ 7.23 - 7.30(m,3H),5.28 - 5.45(m,2H),5.13 - 5.25(m,1H),3.90 - 3.98(m,2H),3.83 - 3.90(m,2H),3.77 - 3.83(m,1H),3.60 - 3.77(m,1H),3.50(dd,J = 14.8,8.8Hz,1H),3.18 - 3.23(m,1H),3.13(dd,J = 18.4,5.6Hz,2H),3.05(s,3H),2.93 - 3.01(m,4H),2.77 - 2.84(m,1H),2.53 - 2.71(m,2H),2.35 - 2.43(m,1H),2.28 - 2.34(m,1H),2.12(d,J = 4.4Hz,3H),2.06 - 2.09(m,1H),1.99(s,1H),1.94(s,1H),1.77 - 1.83(m,1H),1.66 - 1.76(m,3H).

[0597] Example 31. Synthesis of Compounds 36 and 37

[0598] [Chemical formula] (1) To a solution of compound 35-1 (1.02 g, 11.3 mmol) in ethyl acetate (20.0 mL), 4A molecular sieves (2.0 g), triethylamine (1.15 g, 11.3 mmol), the hydrochloride salt of compound 32-3 (2.2 g, 3.78 mmol), and a solution of tricyclic propylphosphonic anhydride (9.62 g, 15.1 mmol, 50% ethyl acetate solution) were added, and the reaction solution was stirred at 25 °C for 30 minutes. The reaction solution was filtered, the filter cake was washed with ethyl acetate (10.0 mL × 3), the filtrate was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 16:1) to obtain compound 36-2.

[0599] (2) Compound 36-2 was resolved by chiral supercritical fluid chromatography to obtain compounds 36 and 37.

[0600] Separation conditions: Chromatography column model: Chiralpak OD-3, Chromatography column specification: 50 × 4.6 mm I.D., 3 μm, Injection volume: 4.0 μL, Mobile phase: A: Carbon dioxide, B: Ethanol (0.05% diethylamine), B%: 5% - 40% gradient elution for 2.5 minutes, 40% isocratic elution for 0.5 minutes, 5% isocratic elution for 1 minute, Detection wavelength: 254 nm, Column temperature: 35 °C.

[0601] The retention time of compound 36 is 1.567 minutes, and the ee value is 98.46%.

[0602] MS-ESI[M+H] + , Calculated value 618, Measured value 618.

[0603] 11H NMR (400 MHz, MeOD) δ 7.51 (d, J = 7.6 Hz, 1H), 7.19 - 7.25 (m, 1H), 7.15 (t, J = 7.2 Hz, 1H), 7.07 - 7.12 (m, 1H), 5.37 - 5.46 (m, 1H), 5.30 - 5.36 (m, 1H), 5.25 - 5.30 (m, 1H), 4.86 (s, 1H), 4.61 (s, 1H), 4.25 - 4.32 (m, 1H), 4.22 (d, J = 11.2 Hz, 1H), 4.11 - 4.19 (m, 2H), 4.10 (s, 1H), 3.77 (d, J = 3.2 Hz, 2H), 3.51 (d, J = 15.2 Hz, 1H), 3.39 - 3.49 (m, 2H), 3.33 - 3.38 (m, 1H), 3.13 (d, J = 1.6 Hz, 1H), 3.05 - 3.12 (m, 2H), 3.00 (s, 2H), 2.90 - 2.95 (m, 1H), 2.73 - 2.80 (m, 2H), 2.31 - 2.45 (m, 1H), 2.30 (d, J = 7.6 Hz, 1H), 2.18 (d, J = 8.4 Hz, 1H), 2.12 (s, 3H), 2.07 (s, 1H), 2.04 (s, 1H), 2.00 (s, 1H), 1.97 (d, J = 3.2 Hz, 2H), 1.75 - 1.85 (m, 2H).

[0604] The retention time of Compound 37 was 1.778 minutes and the ee value was 99.36%.

[0605] MS-ESI [M+H] + , calculated value 618, measured value 618.

[0606] 11H NMR (400 MHz, MeOD) δ 7.51 (d, J = 7.2 Hz, 1H), 7.17 - 7.23 (m, 1H), 7.14 (td, J = 7.2, 1.2 Hz, 1H), 7.04 - 7.10 (m, 1H), 5.34 - 5.41 (m, 1H), 5.29 - 5.34 (m, 1H), 5.18 - 5.28 (m, 1H), 4.27 (d, J = 13.6 Hz, 1H), 4.10 - 4.25 (m, 2H), 4.01 - 4.10 (m, 1H), 3.80 - 4.01 (m, 1H), 3.74 (q, J = 14.8 Hz, 2H), 3.32 - 3.62 (m, 1H), 3.25 - 3.29 (m, 1H), 3.24 (d, J = 8.4 Hz, 1H), 3.19 - 3.22 (m, 2H), 3.17 (d, J = 6.8 Hz, 2H), 3.08 (s, 1H), 3.01 - 3.06 (m, 1H), 2.98 (s, 1H), 2.87 - 2.98 (m, 1H), 2.69 - 2.79 (m, 2H), 2.20 - 2.47 (m, 1H), 2.14 - 2.20 (m, 1H), 2.11 (s, 3H), 2.09 (s, 1H), 1.99 - 2.07 (m, 1H), 1.98 (s, 1H), 1.95 (d, J = 4.0 Hz, 2H), 1.87 - 1.93 (m, 1H), 1.80 - 1.87 (m, 1H), 1.57 - 1.80 (m, 2H).

[0607] Example 32. Synthesis of Compound 38

[0608] [Chemical Structure Diagram] (1) To a solution of compound 38 - 1 (25.0 g, 168 mmol) in acetonitrile (250 mL), add benzyl bromide (43.3 g, 253 mmol) and cesium carbonate (110 g, 338 mmol). Stir the reaction mixture at 20 °C for 12 hours under nitrogen gas protection. Concentrate the reaction mixture under reduced pressure, add water (50.0 mL), extract with ethyl acetate (40.0 mL × 2), combine the organic phases, wash with saturated brine (50.0 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 38 - 2.

[0609] MS-ESI [M+H] + , calculated value 239, measured value 239.

[0610] 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 - 7.40 (m, 4H), 7.30 - 7.31 (m, 2H), 7.20 - 7.26 (m, 1H), 7.02 - 7.04 (d, J = 8 Hz, 1H), 5.12 (s, 2H), 3.03 - 3.06 (m, 2H), 2.62 - 2.65 (m, 2H).

[0611] (2) To a toluene (200 mL) solution of compound 38 - 2 (20.0 g, 83.9 mmol), add compound 38 - 3 (13.2 g, 109 mmol) and tetraethyl titanate (38.3 g, 168 mmol). Stir the reaction mixture at 120 °C for 12 hours under nitrogen gas protection. Add water (400 mL) to the reaction mixture, filter, wash the filter cake with ethyl acetate (400 mL × 2), combine the organic phases, wash with saturated brine (500 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 38 - 4.

[0612] MS-ESI [M+H] + , calculated value 342, measured value 342.

[0613] 1 H NMR (400 MHz, CDCl 3 ) δ 7.26 - 7.44 (m, 7H), 6.99 - 7.01 (d, J = 8 Hz, 1H), 5.15 (s, 2H), 3.42 - 3.50 (m, 1H), 3.07 - 3.14 (m, 3H), 1.32 (s, 9H).

[0614] (3) Dissolve ethyl acetate (13.7 g, 156 mmol) in tetrahydrofuran (50.0 mL), and dropwise add lithium diisopropylamide (2 mol / L, 39.0 mL, tetrahydrofuran solution) under nitrogen gas protection at -78 °C. Stir the reaction solution at -78 °C for 1 hour. Dropwise add a solution of compound 38-4 (13.3 g, 39.0 mmol) in tetrahydrofuran (500 mL) to the reaction solution, and continue stirring at -78 °C for 3 hours. Add saturated aqueous ammonium chloride solution (1000 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (1000 mL), combine the organic phases, wash with saturated aqueous ammonium chloride solution (1000 mL×1) and saturated brine (1000 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:1) to obtain compound 38-5.

[0615] MS-ESI[M+H] + , calculated value 430, measured value 430.

[0616] (4) Add a dioxane solution of hydrochloric acid (4 mol / L, 18.0 mL) to a solution of compound 38-5 (6.80 g, 15.8 mmol) in ethanol (54.0 mL), and stir the reaction solution at 25 °C for 30 minutes under nitrogen gas protection. Concentrate the reaction solution under reduced pressure to obtain the hydrochloride salt of crude compound 38-6.

[0617] MS-ESI[M-NH 2 +H] + , calculated value 309, measured value 309.

[0618] (5) To a solution of hydrochloride of Compound 38-6 (5.70 g, 15.8 mmol) in ethanol (40.0 mL), add Compound 38-7 (15.8 g, 158 mmol), copper oxide (250 mg, 3.15 mmol), and triethylamine (1.60 g, 15.7 mmol). Under the protection of nitrogen gas, react the reaction solution at 78 °C for 12 hours with sealing. Add water (200 mL) to the reaction solution, extract with ethyl acetate (100 mL × 2), combine the organic phases, wash with saturated brine (100 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:1) to obtain Compound 38-8.

[0619] MS-ESI[M+H] + , calculated value 426, measured value 426.

[0620] (6) To a solution of Compound 38-8 (6.20 g, 14.6 mmol) in ethanol (60.0 mL), add paraformaldehyde (2.20 g) and sodium cyanoborohydride (2.75 g, 43.7 mmol). Under the protection of nitrogen gas, react the reaction solution at 30 °C for 12 hours. Add water (100 mL) to the reaction solution, extract with ethyl acetate (200 mL × 2), combine the organic phases, wash with saturated brine (200 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain Compound 38-9.

[0621] MS-ESI[M+H] + , calculated value 440, measured value 440.

[0622] 1 H NMR(400MHz,CDCl 3)δ 7.40 - 7.45 (m, 2H), 7.34 - 7.40 (m, 2H), 7.28 - 7.33 (m, 1H), 7.11 - 7.16 (t, 1H), 6.86 - 6.88 (d, J = 7.2 Hz, 1H), 6.75 - 6.77 (d, J = 8.0 Hz, 1H), 5.02 - 5.11 (m, 2H), 4.07 - 4.13 (m, 2H), 3.83 - 3.97 (m, 2H), 2.83 - 2.97 (m, 3H), 2.71 - 2.81 (m, 2H), 2.61 - 2.69 (m, 2H), 2.36 - 2.47 (m, 3H), 2.22 - 2.35 (m, 2H), 1.79 - 1.88 (m, 1H), 1.24 (m, 3H), 1.00 - 1.04 (t, 3H).

[0623] (7) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 39.6 mL, in tetrahydrofuran solution) was added to a solution of compound 38-9 (5.80 g, 13.2 mmol) in tetrahydrofuran (60.0 mL), and the reaction solution was reacted at -78 °C for 1 hour under nitrogen gas protection. Saturated aqueous ammonium chloride solution (300 mL) was added to the reaction solution, and it was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 38-10.

[0624] MS-ESI[M+H] + , calculated value 394, measured value 394.

[0625] (8) Compound 38-11 (1.51 g, 11.8 mmol) and sodium ethoxide (2.02 g, 29.7 mmol) were added to a solution of compound 38-10 (3.90 g, 9.91 mmol) in ethanol (40.0 mL), and the reaction solution was stirred at 80 °C for 12 hours under nitrogen gas protection. The reaction solution was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 38-12.

[0626] MS-ESI[M+H] +, calculated value 406, measured value 406.

[0627] (9) To a solution of intermediate 38-12 (3.50 g, 8.64 mmol) in water (40.0 mL) is added chloroacetic acid (7.34 g, 77.6 mmol), and the reaction solution is stirred at 100 °C for 12 hours under nitrogen gas protection. The reaction solution is filtered, saturated aqueous sodium bicarbonate solution is added to the filtrate to adjust the pH value to 8, and a solid precipitates. It is filtered, and the filter cake is dried to obtain compound 38-13.

[0628] MS-ESI[M+H] + , calculated value 390, measured value 390.

[0629] 1 H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 11.17 (s, 1H), 7.45 - 7.58 (m, 3H), 7.32 - 7.43 (m, 4H), 7.11 (br s, 1H), 5.17 (s, 2H), 4.05 - 4.17 (m, 1H), 3.80 - 3.96 (m, 1H), 3.24 - 3.29 (m, 1H), 2.88 - 3.03 (m, 2H), 2.61 - 2.74 (m, 1H), 2.54 - 2.60 (m, 1H), 2.43 - 2.48 (m, 3H), 1.96 - 2.17 (m, 1H).

[0630] (10) Compound 38-13 (1.00 g, 2.57 mmol) is dissolved in phosphorus oxychloride (16.5 g, 107 mmol), and the reaction solution is stirred at 80 °C for 12 hours under nitrogen gas protection. The reaction solution is concentrated under reduced pressure, extracted with dichloromethane (100 mL × 2), the organic phase is washed with saturated aqueous sodium bicarbonate solution (100 mL × 2) and saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 38-14.

[0631] MS-ESI[M+H] + , calculated value 426, measured value 426.

[0632] (11) To a solution of compound 38-14 (1.10 g, 2.58 mmol) in N-methylpyrrolidone (10.0 mL) were added potassium carbonate (1.07 g, 7.74 mmol) and compound 38-15 (697 mg, 3.10 mmol). The reaction mixture was stirred at 50 °C for 12 h under nitrogen gas protection. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20.0 mL × 2). The combined organic phases were washed with saturated brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:1) to obtain compound 38-16.

[0633] MS-ESI[M+H] + , calculated value 615, measured value 615.

[0634] (12) To a solution of compound 38-16 (790 mg, 1.28 mmol) in dioxane (10.0 mL) were added compound 38-17 (445 mg, 3.85 mmol), cesium carbonate (1.26 g, 3.85 mmol) and (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium (215 mg, 257 μmol). The reaction mixture was stirred at 110 °C for 6 h under nitrogen gas protection. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40.0 mL × 2). The combined organic phases were washed with saturated brine (40.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 38-18.

[0635] MS-ESI[M+H] + , calculated value 694, measured value 694.

[0636] (13) Compound 38-18 (200 mg, 288 μmol) is added to trifluoroacetic acid (10.0 mL), and the reaction solution is stirred at 50 °C for 3 hours under nitrogen gas protection. The reaction solution is concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 38-19.

[0637] MS-ESI[M+H] + , calculated value 504, measured value 504.

[0638] (14) Triethylamine (42.2 mg, 417 μmol) and compound 38-20 (15.1 mg, 167 μmol) are added to a dichloromethane (1.0 mL) solution of the trifluoroacetate salt of compound 38-19 (70.0 mg, 139 μmol), and the reaction solution is stirred at -78 °C for 30 minutes under nitrogen gas protection. Dichloromethane (20.0 mL) is added to the reaction solution, and it is washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by preparative high performance liquid chromatography (Phenomenex Luna C18, 100 mm × 30 mm × 3 μm + YMC AQ, 100 mm × 30 mm × 10 μm, A: water (0.05% hydrochloric acid); B: methanol, 0% - 40%: 20 minutes) to obtain the hydrochloride salt of compound 38.

[0639] MS-ESI[M+H] + , calculated value 558, measured value 558.

[0640] 11H NMR (400 MHz, MeOD) δ 7.24 - 7.31 (m, 2H), 6.84 (br s, 2H), 6.25 - 6.37 (m, 1H), 5.82 - 5.92 (m, 1H), 5.01 - 5.19 (m, 2H), 4.77 (br s, 3H), 4.13 (br s, 2H), 3.99 - 4.06 (m, 1H), 3.85 (br d, J = 6.8 Hz, 3H), 3.45 - 3.68 (m, 2H), 3.33 - 3.44 (m, 1H), 3.23 - 3.29 (m, 1H), 3.11 - 3.22 (m, 2H), 3.10 (d, J = 1.4 Hz, 3H), 2.98 - 3.08 (m, 2H), 2.73 - 2.85 (m, 5H), 2.39 - 2.52 (m, 2H), 2.14 - 2.29 (m, 2H), 2.04 - 2.12 (m, 1H).

[0641] Example 33. Synthesis of Compound 39

[0642]

Chemical Structure

[0643] MS - ESI [M + H] + , calculated value 576, measured value 576.

[0644] 11H NMR (400 MHz, MeOD) δ 6.95 - 7.39 (m, 2H), 6.76 - 6.91 (m, 1H), 5.22 - 5.47 (m, 2H), 4.54 - 4.67 (m, 5H), 4.32 - 4.50 (m, 2H), 3.99 - 4.26 (m, 3H), 3.68 - 3.92 (m, 3H), 3.42 - 3.62 (m, 3H), 3.18 - 3.27 (m, 2H), 3.10 - 3.17 (m, 2H), 2.93 - 3.07 (m, 4H), 2.52 - 2.86 (m, 3H), 2.37 (br s, 1H), 2.10 - 2.27 (m, 3H), 1.94 - 2.08 (m, 1H).

[0645] Example 34. Synthesis of Compounds 40 and 41

[0646]

Chemical Structure

[0647] MS-ESI [M+H] + , calculated value 190, measured value 190.

[0648] (2) Magnesium sulfate (89.1 g, 740 mmol), water (300 mL) and potassium permanganate (253 g, 1.60 mol) were added to a solution of compound 40-2 (101 g, 534 mmol) in acetone (1.0 L), and the reaction solution was stirred at 25 °C for 3 hours under nitrogen gas protection. It was filtered, water (600 mL) was added, extracted with dichloromethane (500 mL × 1), the organic phase was washed with saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound 40-3.

[0649] 1 1H NMR (400 MHz, CDCl 3)δ 8.60 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 7.6, 0.8 Hz, 1H), 2.98 (t, J = 6.0 Hz, 2H), 2.66 - 2.75 (m, 2H), 2.24 (s, 3H), 2.03 - 2.15 (m, 2H).

[0650] (3) To a solution of compound 40-3 (140 g, 689 mmol) in water (1.0 L) is added concentrated hydrochloric acid (12 mol / L, 459 mL), and the reaction solution is stirred at 110 °C for 3 hours under nitrogen gas protection. It is concentrated under reduced pressure, an aqueous sodium hydroxide solution (2 mol / L) is added to adjust the pH value to 8, filtered, and the filter cake is washed with water (100 mL×1) to obtain compound 40-4.

[0651] MS-ESI[M+H] + , calculated value 162, measured value 162.

[0652] (4) To a solution of compound 40-4 (90.0 g, 558 mmol) in dichloromethane (1.0 L) is added boron trifluoride diethyl etherate (119 g, 838 mmol), and the mixture is stirred at 0 °C for 20 minutes. Isoamyl nitrite (74.9 g, 726 mmol) is added, and the reaction solution is stirred at 0 °C for 40 minutes under nitrogen gas protection. Methyl t-butyl ether (200 mL) is added, filtered, and the filter cake is washed with methyl t-butyl ether (200 mL), dissolved in xylene (100 mL), and stirred at 120 °C for 30 minutes. An aqueous sodium hydroxide solution (2 mol / L) is added to adjust the pH value to 8, extracted with ethyl acetate (200 mL×3), the organic phases are combined, washed with saturated brine (500 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0~10:1) to obtain compound 40-5.

[0653] MS-ESI[M+H] + , calculated value 165, measured value 165.

[0654] 1 H NMR(400MHz,CDCl3 ) δ 7.42 (d, J = 8.0, 5.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 11.2, 8.4 Hz, 1H), 2.98 (t, J = 6.0 Hz, 2H), 2.64 - 2.69 (m, 2H), 2.09 - 2.17 (m, 2H).

[0655] (5) To a toluene (400 mL) solution of compound 40-5 (40.0 g, 244 mmol), add t-butylsulfinamide (35.4 g, 292 mmol) and tetraethyl titanate (111 g, 487 mmol). Stir the reaction solution at 100 °C for 3 hours under nitrogen gas protection. Add water (200 mL) to the reaction solution, filter, wash the filter cake with ethyl acetate (200 mL × 3), combine the organic phases, wash with saturated brine (300 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 5:1) to obtain compound 40-6.

[0656] MS-ESI [M+H] + , calculated value 268, measured value 268.

[0657] 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 (td, J = 8.0, 5.2 Hz, 1H), 6.93 - 7.01 (m, 2H), 3.35 (d, J = 17.6, 8.0, 6.0 Hz, 1H), 3.08 (d, J = 5.6 Hz, 1H), 2.83 - 2.90 (m, 2H), 1.91 - 2.01 (m, 2H), 1.34 (s, 9H).

[0658] (6) Ethyl acetate (49.4 g, 561 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium diisopropylamide (2 mol / L, 112 mL, tetrahydrofuran solution) was added dropwise at -78 °C under nitrogen gas protection. The reaction solution was stirred at -78 °C for 1 hour. A solution of compound 40-6 (30.0 g, 112 mmol) in tetrahydrofuran (100 mL) was added dropwise to the reaction solution, and stirring was continued at -78 °C for 2 hours. A saturated aqueous ammonium chloride solution (200 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with a saturated aqueous ammonium chloride solution (200 mL × 1) and saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 40-7.

[0659] MS-ESI[M+H] + , calculated value 356, measured value 356.

[0660] 1 H NMR(400MHz,CDCl 3 )δ 7.25(d,J=8.0,5.6Hz,1H),7.00(d,J=7.6Hz,1H),6.88(d,J=12.4,8.4Hz,1H),4.01-4.13(m,2H),3.03-3.21(m,2H),2.88(d,J=16.8,4.8Hz,1H),2.70-2.80(m,1H),2.19-2.34(m,2H),2.10(m,J=13.6,Hz,1H),1.71-1.82(m,1H),1.20(s,9H),1.14(t,J=7.2Hz,3H).

[0661] (7) To a solution of compound 40-7 (20.0 g, 56.3 mmol) in ethanol (100 mL) was added a dioxane solution of hydrochloric acid (4 mol / L, 141 mL), and the reaction solution was stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 40-8.

[0662] (8) To a solution of hydrochloride of compound 40-8 (18.0 g, 62.6 mmol) in ethanol (200 mL), ethyl acrylate (93.9 g, 188 mmol), copper oxide (995 mg, 12.5 mmol), and triethylamine (19.0 g, 188 mmol) were added. Under the protection of nitrogen gas, the reaction solution was sealed and reacted at 85 °C for 10 hours. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 2:1) to obtain compound 40-9.

[0663] MS-ESI[M+H] + , calculated value 352, measured value 352.

[0664] (9) To a solution of compound 40-9 (15.0 g, 42.7 mmol) in ethanol (200 mL), paraformaldehyde (5.50 g), acetic acid (2.56 g, 42.7 mmol), and sodium cyanoborohydride (8.05 g, 128 mmol) were added. Under the protection of nitrogen gas, the reaction solution was reacted at 30 °C for 12 hours. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 40-10.

[0665] 1 H NMR(400MHz,CDCl 3 )δ 7.11(d,J=7.6,5.2Hz,1H),6.76-6.89(m,2H),4.05-4.13(m,2H),3.79-3.93(m,2H),2.68-2.87(m,6H),2.38(m,J=14.8,7.6Hz,2H),2.23(s,3H),2.08-2.18(m,2H),1.69-1.87(m,2H),1.18-1.29(m,3H),0.97(t,J=7.2Hz,3H).

[0666] (10) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 82.1 mL, in tetrahydrofuran solution) was added to a solution of compound 40-10 (10.0 g, 27.4 mmol) in tetrahydrofuran (100 mL). The reaction mixture was reacted at 0 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (300 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (300 mL). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 5:1) to obtain compound 40-11.

[0667] MS-ESI[M+H] + , calculated value 320, measured value 320.

[0668] (11) Thiourea (3.81 g, 50.1 mmol) and sodium ethoxide (5.11 g, 75.2 mmol) were added to a solution of compound 40-11 (8.00 g, 25.0 mmol) in ethanol (20.0 mL). The reaction mixture was stirred at 80 °C for 12 hours under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 40-12.

[0669] MS-ESI[M+H] + , calculated value 332, measured value 332.

[0670] (12) Chloroacetic acid (18.0 g, 190 mmol) was added to a solution of intermediate 40-12 (9.00 g, 27.2 mmol) in water (60.0 mL). The reaction mixture was stirred at 100 °C for 12 hours under nitrogen gas protection. The reaction mixture was filtered, and saturated aqueous sodium bicarbonate solution was added to the filtrate to adjust the pH value to 8, and a solid was precipitated. It was filtered, and the filter cake was dried to obtain compound 40-13.

[0671] MS-ESI[M+H] + , calculated value 316, measured value 316.

[0672] 1 1H NMR (400 MHz, MeOD) δ 7.24 (m, J = 7.6, 5.2 Hz, 1H), 6.89 - 7.01 (m, 2H), 3.58 - 3.66 (m, 1H), 3.08 - 3.26 (m, 2H), 2.60 - 2.84 (m, 3H), 2.11 (s, 3H), 1.89 - 2.02 (m, 2H), 1.61 - 1.81 (m, 2H).

[0673] (13) Compound 40 - 13 (8.00 g, 25.4 mmol) was dissolved in phosphorus oxychloride (15.6 g), and the reaction solution was stirred at 100 °C for 3 hours under nitrogen gas protection. The reaction solution was concentrated under reduced pressure, extracted with dichloromethane (200 mL), and the organic phase was washed with saturated aqueous sodium bicarbonate solution (200 mL × 2) and saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 40 - 14.

[0674] MS-ESI [M+H] + , calculated value 352, measured value 352.

[0675] (14) Potassium carbonate (7.06 g, 51.1 mmol) and Compound 40 - 15 (4.99 g, 22.1 mmol) were added to a solution of Compound 40 - 14 (600 mg, 17.0 mmol) in N-methylpyrrolidone (50.0 mL), and the reaction solution was stirred at 50 °C for 3 hours under nitrogen gas protection. Ethyl acetate (200 mL) was added to the reaction solution, washed with saturated brine (200 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 10:1) to obtain Compound 40 - 16.

[0676] MS-ESI [M+H] + , calculated value 541, measured value 541.

[0677] (15) To a solution of compound 40-16 (1.00 g, 1.85 mmol) in dioxane (20.0 mL) were added compound 40-17 (442 mg, 2.78 mmol), cesium carbonate (1.81 g, 5.54 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (100 mg, 120 μmol), and the reaction mixture was stirred at 110 °C for 3 hours under nitrogen gas protection. Ethyl acetate (50.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (50.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 30:1) to obtain compound 40-18.

[0678] MS-ESI[M+H] + , calculated value 664, measured value 664.

[0679] 1 H NMR (400 MHz, MeOD) δ 7.22 (td, J = 7.6, 5.2 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.91 (dd, J = 12.4, 8.0 Hz, 1H), 5.13 - 5.43 (m, 1H), 4.60 (d, J = 12.4 Hz, 2H), 4.04 - 4.23 (m, 3H), 3.84 - 4.04 (m, 2H), 3.56 - 3.77 (m, 2H), 3.40 (dd, J = 13.6, 3.6 Hz, 1H), 3.22 - 3.29 (m, 2H), 3.10 - 3.22 (m, 3H), 2.94 - 3.05 (m, 3H), 2.71 - 2.86 (m, 3H), 2.22 - 2.36 (m, 1H), 2.13 - 2.18 (m, 3H), 2.04 - 2.13 (m, 2H), 1.94 - 2.02 (m, 3H), 1.83 - 1.93 (m, 2H), 1.56 - 1.82 (m, 2H), 1.51 (d, J = 2.4 Hz, 9H).

[0680] (16) A dioxane solution of hydrochloric acid (4 mol / L, 5.0 mmol) was added to a dichloromethane (10.0 mL) solution of compound 40-18 (910 mg, 1.37 mmol), and the reaction solution was stirred at 25 °C for 2 hours under nitrogen gas protection. The pH value was adjusted to 8 with a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phase was washed with a saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 40-19.

[0681] MS-ESI[M+H] + , calculated value 564, measured value 564.

[0682] (17) Triethylamine (362 mg, 3.58 mmol) and acryloyl chloride (216 mg, 2.39 mmol) were added to a dichloromethane (10.0 mL) solution of compound 40-19 (672 mg, 1.19 mmol), and the reaction solution was stirred at -65 °C for 30 minutes under nitrogen gas protection. Dichloromethane (20.0 mL) was added to the reaction solution, and the mixture was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 30:1) to obtain compound 40-20.

[0683] (18) Compound 40-20 was resolved by chiral supercritical fluid chromatography to obtain compounds 40 and 41.

[0684] Separation conditions: Chromatography column model: (S,S)-Whelk-0-1.8, Chromatography column specification: 50 × 4.6 mm I.D., 1.8 μm, Injection volume: 10.0 μL, Mobile phase: A: Carbon dioxide, B: Ethanol (0.05% diethylamine), B%: 40% Elution for 7 minutes, Detection wavelength: 254 nm, Column temperature: 35 °C.

[0685] The retention time of compound 40 was 2.328 minutes, and the ee value was 100%.

[0686] MS-ESI[M+H] + Calculated value: 618, Measured value: 618.

[0687] 1 H NMR(400MHz,MeOD)δ 7.22(m,J=7.6,5.2Hz,1H),6.98(d,J=7.6Hz,1H),6.91(dd,J=12.4,8.0Hz,1H),6.28(d,J=16.8Hz,1H),5.83(d,J=10.4Hz,1H),5.18 - 5.37(m,1H),5.03(s,1H),4.70 - 4.85(m,2H),4.10 - 4.32(m,3H),3.90 - 4.10(m,2H),3.65 - 3.80(m,2H),3.38 - 3.51(m,1H),3.18 - 3.28(m,3H),3.08 - 3.18(m,2H),2.95 - 3.02(m,2H),2.89(s,2H),2.67 - 2.84(m,2H),2.16 - 2.41(m,2H),2.16(s,3H),2.03 - 2.13(m,2H),1.94 - 2.03(m,3H),1.85 - 1.93(m,2H),1.68 - 1.79(m,1H). The retention time of Compound 41 is 1.677 minutes, and the ee value is 100%.

[0688] MS-ESI[M+H] + Calculated value: 618, Measured value: 618.

[0689] 11H NMR (400 MHz, MeOD) δ 7.22 (td, J = 7.6, 5.2 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.92 (dd, J = 12.4, 8.0 Hz, 1H), 6.29 (d, J = 16.8 Hz, 1H), 5.83 (d, J = 10.4 Hz, 1H), 5.14 - 5.41 (m, 1H), 5.08 (s, 1H), 4.70 - 4.84 (m, 2H), 4.11 - 4.40 (m, 3H), 3.92 - 4.11 (m, 2H), 3.60 - 3.78 (m, 2H), 3.37 - 3.60 (m, 1H), 3.21 - 3.29 (m, 3H), 3.17 - 3.21 (m, 2H), 3.12 - 3.17 (m, 2H), 2.94 - 3.01 (m, 2H), 2.72 - 2.86 (m, 2H), 2.17 - 2.34 (m, 2H), 2.16 (s, 3H), 2.03 - 2.13 (m, 2H), 1.94 - 2.02 (m, 3H), 1.82 - 1.92 (m, 2H), 1.68 - 1.80 (m, 1H).

[0690] Example 35. Synthesis of Compounds 42 and 43

[0691]

Chemical Structure

[0692] (2) Compound 42-2 was resolved by chiral supercritical fluid chromatography to obtain Compounds 42 and 43.

[0693] Separation conditions: Chromatography column model: Chiralpak OX-3, Chromatography column specifications: 100×4.6 mm I.D., 3 μm, Injection volume: 10.0 μL, Mobile phase: A: Carbon dioxide, B: Ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 4 minutes, Detection wavelength: 254 nm, Column temperature: 35 °C.

[0694] The retention time of Compound 42 is 1.385 minutes and the ee value is 100%.

[0695] MS-ESI[M+H] + , Calculated value 636, Measured value 636.

[0696] 1 H NMR(400 MHz, MeOD) δ 7.22(td, J = 7.6, 5.2 Hz, 1H), 6.98(d, J = 7.6 Hz, 1H), 6.92(dd, J = 12.8, 8.0 Hz, 1H), 5.29 - 5.44(m, 2H), 5.18 - 5.28(m, 1H), 4.11 - 4.19(m, 2H), 4.05 - 4.11(m, 2H), 3.71 - 3.78(m, 1H), 3.63 - 3.68(m, 1H), 3.46(d, J = 13.2 Hz, 1H), 3.32 - 3.33(m, 1H), 3.22 - 3.30(m, 3H), 3.13 - 3.22(m, 2H), 2.99 - 3.12(m, 3H), 2.89 - 2.99(m, 2H), 2.75 - 2.88(m, 2H), 2.22 - 2.33(m, 1H), 2.18(s, 1H), 2.16(s, 3H), 2.04 - 2.14(m, 2H), 1.95 - 2.04(m, 3H), 1.88 - 1.88(m, 3H), 1.76 - 1.94(m, 1H).

[0697] The retention time of Compound 43 is 2.071 minutes and the ee value is 100%.

[0698] MS-ESI[M+H] + , Calculated value 636, Measured value 636.

[0699] 11H NMR (400 MHz, MeOD) δ 7.22 (td, J = 7.6, 5.2 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.91 (dd, J = 12.8, 8.0 Hz, 1H), 5.29 - 5.43 (m, 2H), 5.26 (s, 1H), 4.27 (d, J = 13.6 Hz, 1H), 4.18 (q, J = 10.4 Hz, 2H), 3.99 (d, J = 11.2 Hz, 1H), 3.71 - 3.79 (m, 1H), 3.59 - 3.68 (m, 1H), 3.38 - 3.56 (m, 1H), 3.36 (d, J = 2.4 Hz, 1H), 3.27 (d, J = 3.6 Hz, 3H), 3.21 - 3.27 (m, 2H), 3.05 - 3.20 (m, 3H), 2.85 - 3.05 (m, 2H), 2.65 - 2.84 (m, 2H), 2.26 - 2.40 (m, 1H), 2.19 - 2.26 (m, 1H), 2.16 (s, 3H), 2.04 - 2.15 (m, 2H), 1.96 - 2.04 (m, 3H), 1.77 - 1.96 (m, 3H), 1.65 - 1.77 (m, 1H).

[0700] Example 36. Synthesis of Compounds 44 and 45

[0701] [Chemical Structure] (1) To a toluene (50.0 mL) solution of Compound 44-1 (5.00 g, 30.0 mmol) was added Compound 44-2 (4.36 g, 36.0 mmol) and tetraethyl titanate (13.7 g, 60.0 mmol), and the reaction solution was stirred at 110 °C for 12 hours under nitrogen gas protection. Water (150 mL) was added to the reaction solution, and the mixture was filtered. The filter cake was washed with ethyl acetate (150 mL × 2). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain Compound 44-3.

[0702] MS-ESI [M+H] + , calculated value 270, measured value 270.

[0703] 11H NMR (400 MHz, CDCl 3 ) δ 7.70 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 3.46 - 3.56 (m, 1H), 3.06 - 3.19 (m, 3H), 1.33 (s, 9H).

[0704] (2) Ethyl acetate (8.16 g, 92.6 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium diisopropylamide (2 mol / L, 18.5 mL, tetrahydrofuran solution) was added dropwise under nitrogen gas protection at -78 °C. The reaction solution was stirred at -65 °C for 1 hour. A solution of compound 44 - 3 (5.0 g, 18.5 mmol) in tetrahydrofuran (500 mL) was added dropwise to the reaction solution, and stirring was continued at -65 °C for 2 hours. A saturated aqueous ammonium chloride solution (50.0 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL). The organic phases were combined, washed with a saturated aqueous ammonium chloride solution (100 mL × 1) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 6:1) to obtain compound 44 - 4.

[0705] MS-ESI [M+H] + , calculated value 358, measured value 358.

[0706] (3) A dioxane solution of hydrochloric acid (4 mol / L, 10.0 mL) was added to a solution of compound 44 - 4 (2.30 g, 6.43 mmol) in ethanol (15.0 mL), and the reaction solution was stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 44 - 5.

[0707] (4) A solution of hydrochloride salt of compound 44-5 (2.30 g, 9.06 mmol) in ethanol (20.0 mL) was added with compound 44-6 (9.08 g, 90.6 mmol), copper oxide (144 mg, 1.81 mmol), and triethylamine (2.75 g, 27.2 mmol). The reaction solution was sealed and reacted at 85 °C for 12 hours under nitrogen gas protection. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 6:1) to obtain compound 44-7.

[0708] MS-ESI[M+H] + , calculated value 354, measured value 354.

[0709] 1 H NMR(400MHz,CDCl 3 )δ 7.19 - 7.23(m,1H),7.12 - 7.19(m,2H),4.06 - 4.16(m,4H),2.95 - 3.06(m,1H),2.81 - 2.93(m,1H),2.67 - 2.79(m,2H),2.59 - 2.67(m,1H),2.48 - 2.55(m,1H),2.42 - 2.48(m,2H),2.34(dt,J=13.6,8.0Hz,1H),2.19(ddd,J=13.6,8.8,4.4Hz,1H),1.25(t,J=7.2Hz,3H),1.20(t,J=7.2Hz,3H).

[0710] (5) To a solution of compound 44-7 (2.00 g, 5.65 mmol) in ethanol (20.0 mL), paraformaldehyde (2.00 g) and sodium cyanoborohydride (1.07 g, 17.0 mmol) were added, and the reaction solution was reacted at 25 °C for 10 hours under nitrogen gas protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 6:1) to obtain compound 44-8.

[0711] MS-ESI[M+H] + , calculated value 368, measured value 368.

[0712] 1 H NMR(400MHz,CDCl 3 )δ 7.18-7.24(m,1H),7.12-7.17(m,2H),4.11(q,J=7.2Hz,2H),3.82-3.98(m,2H),2.83-3.02(m,3H),2.71-2.81(m,1H),2.56-2.68(m,2H),2.23-2.48(m,4H),2.17(s,3H),1.25(t,J=7.2Hz,3H),1.02(t,J=7.2Hz,3H).

[0713] (6) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 8.16 mL, tetrahydrofuran solution) was added to a solution of compound 44-8 (1.50 g, 4.08 mmol) in tetrahydrofuran (15.0 mL), and the reaction solution was reacted at -65 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (50.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50.0 mL). The combined organic phases were washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 6:1) to obtain compound 44-9.

[0714] MS-ESI[M+H]+ 、Calculated value: 322, Measured value: 322.

[0715] (7) To a solution of compound 44-9 (1.08 g, 3.36 mmol) in ethanol (10.0 mL) were added compound 44-10 (510 mg, 6.71 mmol) and sodium ethoxide (685 mg, 10.1 mmol), and the reaction mixture was stirred at 80 °C for 12 hours under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 44-11.

[0716] MS-ESI[M+H] + 、Calculated value: 334, Measured value: 334.

[0717] 1 H NMR (400 MHz, DMSO-d6) δ 12.42 - 12.50 (m, 1H), 12.31 (br d, J = 2.0 Hz, 1H), 7.13 - 7.51 (m, 3H), 3.36 - 3.42 (m, 2H), 2.85 - 2.99 (m, 2H), 2.63 - 2.70 (m, 1H), 2.53 (br d, J = 2.0 Hz, 1H), 2.29 - 2.37 (m, 1H), 2.16 - 2.28 (m, 1H), 1.88 - 2.15 (m, 3H).

[0718] (8) To a solution of intermediate 44-11 (848 mg, 2.54 mmol) in water (10.0 mL) was added chloroacetic acid (1.20 g, 12.7 mmol), and the reaction mixture was stirred at 100 °C for 16 hours under nitrogen gas protection. The reaction mixture was filtered, saturated aqueous sodium bicarbonate solution was added to the filtrate to adjust the pH value to 8, and a solid was precipitated. It was filtered, and the filter cake was dried to obtain compound 44-12.

[0719] MS-ESI[M+H] + 、Calculated value: 318, Measured value: 318.

[0720] 11H NMR (400 MHz, DMSO-d6) δ 11.03 (br s, 1H), 10.78 (br s, 1H), 7.28 (s, 2H), 7.15 - 7.20 (m, 1H), 2.75 - 3.25 (m, 4H), 2.31 - 2.40 (m, 2H), 2.20 (dt, J = 13.6, 8.0 Hz, 1H), 1.96 (s, 3H), 1.69 (ddd, J = 13.6, 8.8, 4.8 Hz, 1H).

[0721] (9) Compound 44 - 12 (236 mg, 743 μmol) was dissolved in phosphorus oxychloride (13.3 g, 86.7 mmol), and the reaction solution was stirred at 80 °C for 6 hours under nitrogen gas protection. The reaction solution was concentrated under reduced pressure, extracted with dichloromethane (10.0 mL), and the organic phase was washed with saturated aqueous sodium bicarbonate solution (10.0 mL × 2) and saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 44 - 13.

[0722] MS-ESI [M+H] + , calculated value 354, measured value 354.

[0723] (10) To a solution of Compound 44 - 13 (600 mg, 1.69 mmol) in N-methylpyrrolidone (10.0 mL) were added potassium carbonate (701 mg, 5.08 mmol) and Compound 44 - 14 (419 mg, 1.86 mmol), and the reaction solution was stirred at 50 °C for 10 hours under nitrogen gas protection. Ethyl acetate (30.0 mL) was added to the reaction solution, and it was washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain Compound 44 - 15.

[0724] MS-ESI [M+H] + , calculated value 543, measured value 543.

[0725] (11) To a solution of compound 44-15 (200 mg, 367 μmol) in dioxane (5.00 mL) were added compound 44-16 (175 mg, 1.10 mmol), potassium carbonate (127 mg, 1.10 mmol), tris(dibenzylideneacetone)dipalladium (67.4 mg, 73.6 μmol), and 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (68.6 mg, 147 μmol). The reaction mixture was stirred at 110 °C for 4 hours under a nitrogen gas atmosphere. Ethyl acetate (20.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 3:1) to obtain compound 44-17.

[0726] MS-ESI[M+H] + , calculated value 666, measured value 666.

[0727] (12) Trifluoroacetic acid (2.85 g, 24.9 mmol) was added to a solution of compound 44-17 (74.0 mg, 111 μmol) in dichloromethane (3.0 mL). The reaction mixture was stirred at 25 °C for 1 hour under a nitrogen gas atmosphere. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phase was washed with saturated aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 44-18.

[0728] MS-ESI[M+H] + , calculated value 566, measured value 566.

[0729] (13) At 0 °C, to a solution of compound 44-18 (65.0 mg, 114 μmol) in ethyl acetate (3.0 mL) were added triethylamine (34.8 mg, 344 μmol), compound 44-19 (31.0 mg, 344 μmol), 4A molecular sieve (40.0 mg), and a solution of tricyclic propylphosphonic anhydride (219 mg, 344 μmol, 50% ethyl acetate solution). The reaction mixture was stirred at 25 °C for 1 hour. Dichloromethane (10.0 mL) was added to the reaction mixture, and it was washed with saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high-performance liquid chromatography (Phenomenex Luna C18, 75 mm × 30 mm × 3 μm, A: water (10 mmol / L ammonium bicarbonate); B: acetonitrile, 41% - 61%: 11 minutes) to obtain compound 44-20.

[0730] (14) Compound 44-20 was resolved by chiral supercritical fluid chromatography to obtain compounds 44 and 45.

[0731] Separation conditions: Chromatography column model: Chiralpak IC-3, Chromatography column specifications: 50 × 4.6 mm I.D., 3 μm, Injection volume: 8.0 μL, Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% isocratic elution for 4 minutes, Detection wavelength: 254 nm, Column temperature: 35 °C.

[0732] The retention time of compound 44 was 1.342 minutes, and the ee value was 98.64%.

[0733] MS-ESI[M+H] + , calculated value 638, measured value 638.

[0734] 11H NMR (400 MHz, MeOD) δ 7.24 - 7.32 (m, 2H), 7.16 (dd, J = 7.2, 1.2 Hz, 1H), 5.32 - 5.40 (m, 1H), 5.23 - 5.31 (m, 1H), 4.09 - 4.31 (m, 4H), 4.00 (br d, J = 12.4 Hz, 1H), 3.71 (s, 2H), 3.27 (br s, 2H), 3.20 - 3.23 (m, 1H), 2.90 - 3.16 (m, 8H), 2.39 - 2.50 (m, 1H), 2.16 - 2.25 (m, 5H), 2.08 - 2.15 (m, 1H), 1.96 - 2.04 (m, 2H), 1.91 (ddd, J = 13.6, 8.8, 4.4 Hz, 2H), 1.25 - 1.36 (m, 4H).

[0735] The retention time of Compound 45 was 1.807 minutes, and the ee value was 97.24%.

[0736] MS-ESI [M+H] + , calculated value 638, measured value 638.

[0737] 1 1H NMR (400 MHz, MeOD) δ 7.24 - 7.32 (m, 2H), 7.16 (dd, J = 7.2, 1.2 Hz, 1H), 5.32 - 5.40 (m, 1H), 5.23 - 5.31 (m, 1H), 4.09 - 4.31 (m, 4H), 4.00 (br d, J = 12.4 Hz, 1H), 3.71 (s, 2H), 3.27 (br s, 2H), 3.20 - 3.23 (m, 1H), 2.90 - 3.16 (m, 8H), 2.39 - 2.50 (m, 1H), 2.16 - 2.25 (m, 5H), 2.08 - 2.15 (m, 1H), 1.96 - 2.04 (m, 2H), 1.91 (ddd, J = 13.6, 8.8, 4.4 Hz, 2H), 1.25 - 1.36 (m, 4H).

[0738] Example 37. Synthesis of Compounds 46 and 47

[0739]

Chemical Structure

[0740] MS-ESI[M+H] + , calculated value 254, measured value 254.

[0741] 1 H NMR(400MHz,CDCl 3 )δ 7.59(d,J=8.0Hz,1H),7.28-7.34(m,1H),7.13-7.20(m,1H),3.44-3.55(m,1H),3.10-3.20(m,3H),1.32(s,9H).

[0742] (2) Dissolve ethyl acetate (27.0 g, 306 mmol) in tetrahydrofuran (200 mL), dropwise add lithium diisopropylamide (2 mol / L, 61.2 mL, tetrahydrofuran solution) at -78 °C under nitrogen gas protection, and stir the reaction solution at -78 °C for 1 hour. Dropwise add a tetrahydrofuran (200 mL) solution of Compound 46-3 (15.5 g, 61.2 mmol) to the reaction solution, and continue to stir at -78 °C for 2 hours. Add saturated ammonium chloride aqueous solution (200 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated ammonium chloride aqueous solution (200 mL × 1) and saturated brine (100 mL × 3), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 2:1) to obtain Compound 46-4.

[0743] MS-ESI [M+H] + , calculated value 342, measured value 342.

[0744] 1 H NMR (400 MHz, CDCl 3 ) δ 7.16 - 7.24 (m, 1H), 6.91 - 7.02 (m, 2H), 4.12 - 4.22 (m, 2H), 3.13 - 3.24 (m, 1H), 2.83 - 2.97 (m, 2H), 2.67 - 2.80 (m, 2H), 2.30 - 2.41 (m, 1H), 1.25 (t, J = 8.0 Hz, 3H), 1.19 (s, 9H).

[0745] (3) To a solution of compound 46 - 4 (4.50 g, 13.2 mmol) in ethanol (30.0 mL) was added a dioxane solution of hydrochloric acid (4 mol / L, 10.0 mL), and the reaction solution was stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 46 - 5.

[0746] (4) To a solution of the hydrochloride salt of compound 46 - 5 (6.32 g, 13.2 mmol) in ethanol (40.0 mL) were added compound 46 - 6 (13.8 g, 138 mmol), copper oxide (209 mg, 2.63 mmol), and triethylamine (2.66 g, 26.3 mmol). The reaction solution was sealed and reacted at 80 °C for 12 hours under nitrogen gas protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL × 2). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 2:1) to obtain compound 46 - 7.

[0747] MS-ESI [M+H] + , calculated value 338, measured value 338.

[0748] 1 H NMR (400 MHz, CDCl 3)δ 7.14 - 7.21 (m, 1H), 6.98 - 7.07 (m, 1H), 6.90 (t, J = 8.0 Hz, 1H), 4.07 - 4.15 (m, 4H), 2.94 - 3.06 (m, 1H), 2.84 - 2.92 (m, 1H), 2.61 - 2.79 (m, 3H), 2.49 - 2.56 (m, 1H), 2.40 - 2.47 (m, 2H), 2.30 - 2.39 (m, 1H), 2.16 - 2.25 (m, 1H), 1.22 - 1.26 (m, 3H), 1.20 (t, J = 8.0 Hz, 3H).

[0749] (5) To a solution of compound 46 - 7 (4.10 g, 12.2 mmol) in ethanol (50.0 mL) were added paraformaldehyde (3.65 g), sodium cyanoborohydride (2.29 g, 36.5 mmol) and acetic acid (1.46 g, 24.3 mmol), and the reaction mixture was stirred at 35 °C for 15 h under nitrogen gas protection. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 2:1) to obtain compound 46 - 8.

[0750] MS - ESI [M + H] + , calculated value 352, measured value 352.

[0751] 1 H NMR (400 MHz, CDCl 3 )δ 7.12 - 7.19 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.89 (t, J = 8.0 Hz, 1H), 4.05 - 4.15 (m, 2H), 3.84 - 3.96 (m, 2H), 2.84 - 2.98 (m, 3H), 2.72 - 2.81 (m, 1H), 2.56 - 2.68 (m, 2H), 2.28 - 2.47 (m, 4H), 2.16 (s, 3H), 1.20 - 1.27 (m, 3H), 0.99 - 1.05 (m, 3H).

[0752] At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 29.0 mL, in tetrahydrofuran solution) was added to a solution of compound 46-8 (3.40 g, 9.68 mmol) in tetrahydrofuran (50.0 mL). The reaction mixture was stirred at -78 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (50.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50.0 mL). The combined organic phases were washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 2:1) to obtain compound 46-9.

[0753] MS-ESI[M+H] + , calculated value 306, measured value 306.

[0754] 1 H NMR(400MHz,CDCl 3 )δ 7.19-7.26(m,1H),7.02-7.14(m,1H),6.88-7.01(m,1H),4.21-4.32(m,2H),3.47-3.57(m,1H),3.13-3.33(m,2H),2.88-3.06(m,2H),2.61-2.73(m,1H),2.34-2.44(m,1H),2.22-2.33(m,1H),2.06-2.13(m,3H),1.77-1.89(m,1H),1.30-1.34(m,3H).

[0755] (7) Compound 46-10 (1.25 g, 16.4 mmol) and sodium ethoxide (1.67 g, 24.6 mmol) were added to a solution of compound 46-9 (2.50 g, 8.19 mmol) in ethanol (50.0 mL). The reaction mixture was stirred at 80 °C for 15 hours under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 46-11.

[0756] MS-ESI[M+H] + , calculated value 318, measured value 318.

[0757] 1 1H NMR (400 MHz, DMSO-d6) δ 7.28 - 7.35 (m, 1H), 7.03 - 7.12 (m, 2H), 3.41 - 3.51 (m, 1H), 3.06 (d, J = 16.0 Hz, 1H), 2.82 - 2.99 (m, 2H), 2.59 - 2.69 (m, 1H), 2.51 - 2.53 (m, 1H), 2.16 - 2.27 (m, 1H), 1.98 (s, 3H), 1.68 - 1.76 (m, 1H).

[0758] (8) To a solution of Intermediate 46-11 (2.20 g, 6.93 mmol) in water (50.0 mL) was added chloroacetic acid (3.30 g, 34.9 mmol), and the reaction mixture was stirred at 100 °C for 15 h under nitrogen gas protection. The reaction mixture was filtered, and saturated aqueous sodium bicarbonate solution was added to the filtrate to adjust the pH value to 8, and a solid was precipitated. The solid was filtered and the filter cake was dried to obtain Compound 46-12.

[0759] MS-ESI [M+H] + , calculated value 302, measured value 302.

[0760] 1 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.78 (s, 1H), 7.27 - 7.35 (m, 1H), 7.02 - 7.12 (m, 2H), 3.43 (s, 1H), 2.99 - 3.06 (m, 1H), 2.82 - 2.96 (m, 2H), 2.54 - 2.63 (m, 1H), 2.33 - 2.43 (m, 1H), 2.17 - 2.27 (m, 1H), 1.97 (s, 3H), 1.65 - 1.77 (m, 1H).

[0761] (9) Compound 46-12 (400 mg, 1.33 mmol) was dissolved in phosphorus oxychloride (10.0 mL), and the reaction mixture was stirred at 80 °C for 12 h under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, extracted with dichloromethane (20.0 mL), and the organic phase was washed with saturated aqueous sodium bicarbonate solution (20.0 mL × 2) and saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 46-13.

[0762] MS-ESI[M+H] + Calculated value: 338, measured value: 338.

[0763] (10) To a solution of compound 46-13 (600 mg, 1.31 mmol) in N-methylpyrrolidone (20.0 mL) are added potassium carbonate (701 mg, 3.94 mmol) and compound 46-14 (444 mg, 1.97 mmol), and the reaction mixture is stirred at 50 °C for 5 hours under nitrogen gas protection. Ethyl acetate (50.0 mL) is added to the reaction mixture, and it is washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 46-15.

[0764] MS-ESI[M+H] + Calculated value: 527, measured value: 527.

[0765] 1 H NMR (400 MHz, CDCl 3 ) δ 7.20 - 7.26 (m, 1H), 6.93 - 7.07 (m, 2H), 3.96 - 4.07 (d, J = 12.0 Hz, 2H), 3.59 - 3.85 (m, 2H), 3.38 - 3.52 (m, 1H), 3.21 - 3.31 (m, 1H), 2.94 - 3.12 (m, 6H), 2.61 - 2.74 (m, 2H), 2.30 - 2.43 (m, 1H), 2.18 - 2.28 (m, 3H), 1.82 - 1.94 (m, 2H), 1.50 (s, 9H).

[0766] (11) To a solution of compound 46-15 (500 mg, 949 μmol) in dioxane (15.0 mL) were added compound 46-16 (227 mg, 1.42 mmol), cesium carbonate (927 mg, 2.85 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (159 mg, 190 μmol). The reaction mixture was stirred at 110 °C for 4 hours under a nitrogen gas atmosphere. Ethyl acetate (50.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 46-17.

[0767] MS-ESI[M+H] + , calculated value 650, measured value 650.

[0768] 1 H NMR(400MHz,CDCl 3 )δ 7.18-7.25(m,1H),6.90-7.03(m,2H),4.13-4.18(m,1H),3.91-4.08(m,2H),3.73-3.89(m,1H),3.62-3.72(m,1H),3.55(br d,J=12.0Hz,1H),3.13-3.48(m,4H),2.86-3.11(m,6H),2.57-2.78(m,2H),2.28-2.43(m,2H),2.12-2.27(m,5H),1.59-2.02(m,8H),1.42-1.57(m,9H).

[0769] (12) Trifluoroacetic acid (1.54 g, 13.5 mmol) was added to a solution of compound 46-17 (300 mg, 462 μmol) in dichloromethane (5.0 mL). The reaction mixture was stirred at 25 °C for 2 hours under a nitrogen gas atmosphere. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phase was washed with an aqueous saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 46-18.

[0770] MS-ESI [M+H] + , calculated value 550, measured value 550.

[0771] (13) At 0 °C, to a solution of compound 46-18 (150 mg, 273 μmol) in ethyl acetate (3.0 mL) were added triethylamine (82.8 mg, 819 μmol), compound 46-19 (73.7 mg, 819 μmol), 4A molecular sieve (150 mg) and a solution of tricyclic propylphosphonic anhydride (521 mg, 819 μmol, 50% ethyl acetate solution). The reaction mixture was stirred at 25 °C for 1 hour. Dichloromethane (10.0 mL) was added to the reaction mixture, and it was washed with saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 46-20.

[0772] (14) Compound 46-20 was resolved by chiral supercritical fluid chromatography to obtain compounds 46 and 47.

[0773] Separation conditions: Chromatography column model: Chiralpak OX-3, Chromatography column specification: 10 × 4.6 mm I.D., 3 μm, Injection volume: 8.0 μL, Mobile phase: A: Carbon dioxide, B: Ethanol (0.05% diethylamine), B%: 5% - 40% gradient elution for 4 minutes, 40% constant concentration elution for 1 minute, 10% constant concentration elution for 1 minute, Detection wavelength: 254 nm, Column temperature: 35 °C.

[0774] The retention time of compound 46 was 3.680 minutes, and the ee value was 100%.

[0775] MS-ESI [M+H] + , calculated value 622, measured value 622.

[0776] 11H NMR (400 MHz, MeOD) δ 7.27 - 7.34 (m, 1H), 6.98 - 7.09 (m, 1H), 6.98 - 7.03 (m, 1H), 5.25 - 5.45 (m, 3H), 4.89 - 5.01 (m, 1H), 4.26 - 4.40 (m, 2H), 4.04 - 4.23 (m, 3H), 3.69 - 3.82 (m, 2H), 3.44 - 3.62 (m, 4H), 3.08 - 3.29 (m, 3H), 3.03 - 3.08 (m, 1H), 2.90 - 3.02 (m, 5H), 2.33 - 2.53 (m, 3H), 2.23 (s, 4H), 2.10 - 2.17 (m, 2H), 1.98 - 2.06 (m, 1H), 1.86 - 2.06 (m, 1H).

[0777] The retention time of Compound 47 was 4.052 minutes and the ee value was 98.44%.

[0778] MS-ESI [M+H] + , calculated value 622, measured value 622.

[0779] 1 1H NMR (400 MHz, MeOD) δ 7.24 - 7.33 (m, 1H), 6.95 - 7.08 (m, 2H), 5.19 - 5.43 (m, 3H), 4.25 (d, J = 12.0 Hz, 1H), 4.03 - 4.22 (m, 3H), 3.96 - 4.03 (m, 1H), 3.71 (s, 2H), 3.18 - 3.28 (m, 4H), 3.09 - 3.17 (m, 2H), 2.96 - 3.08 (m, 3H), 2.93 (d, J = 4.0 Hz, 2H), 2.42 - 2.52 (m, 1H), 2.27 - 2.39 (m, 1H), 2.16 - 2.27 (m, 4H), 2.05 - 2.15 (m, 1H), 1.84 - 2.03 (m, 4H), 1.29 (s, 3H).

[0780] Example 38. Synthesis of Compounds 48 and 49

[0781]

Chemical Structure

[0782] MS-ESI[M+H] + , calculated value 268, measured value 268.

[0783] 1 H NMR(400MHz,CDCl 3 )δ 7.95(d,J=7.64Hz,1H),7.18-7.24(m,1H),7.11-7.17(m,1H),3.22-3.32(m,1H),3.03-3.11(m,1H),2.77-2.95(m,2H),1.91-2.10(m,2H)1.32(s,9H).

[0784] (2) Ethyl acetate (8.57 g, 97.2 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium diisopropylamide (2 mol / L, 19.4 mL, tetrahydrofuran solution) was added dropwise at -78 °C under nitrogen gas protection. The reaction mixture was stirred at -78 °C for 1 hour. A tetrahydrofuran (200 mL) solution of compound 48-3 (15.5 g, 61.2 mmol) was added dropwise to the reaction mixture, and stirring was continued at -78 °C for 2 hours. Saturated aqueous ammonium chloride solution (200 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated aqueous ammonium chloride solution (200 mL × 1) and saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 48-4.

[0785] MS-ESI[M+H] + Calculated value: 356, measured value: 356.

[0786] 1 H NMR (400 MHz, CDCl 3 ) δ 7.08 - 7.20 (m, 2H), 6.92 (d, J = 9.2, 1.6 Hz, 1H), 5.17 (s, 1H), 4.13 - 4.21 (m, 2H), 2.81 - 2.88 (m, 2H), 2.68 - 2.80 (m, 2H), 2.39 - 2.49 (m, 1H), 2.11 - 2.18 (m, 1H), 2.04 - 2.10 (m, 1H), 1.74 - 1.86 (m, 1H), 1.25 - 1.28 (m, 3H), 1.22 - 1.24 (m, 9H).

[0787] (3) To a solution of compound 48 - 4 (3.70 g, 10.4 mmol) in ethanol (30.0 mL) is added a dioxane solution of hydrochloric acid (4 mol / L, 10.0 mL), and the reaction solution is stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution is concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 48 - 5.

[0788] (4) To a solution of the hydrochloride salt of compound 48 - 5 (2.60 g, 10.3 mmol) in ethanol (40.0 mL) are added compound 48 - 6 (10.3 g, 103 mmol), copper oxide (164 mg, 2.07 mmol), and triethylamine (3.14 g, 31.0 mmol), and the reaction solution is sealed and reacted at 85 °C for 12 hours under nitrogen gas protection. Water (50.0 mL) is added to the reaction solution, and the mixture is extracted with ethyl acetate (50.0 mL × 2). The organic phases are combined, washed with saturated brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 48 - 7.

[0789] MS-ESI[M+H] + Calculated value: 352, measured value: 352.

[0790] 11H NMR (400 MHz, CDCl 3 ) δ 7.36 (s, 1H), 7.14 (q, 1H), 6.81 - 6.94 (m, 1H), 4.06 - 4.19 (m, 4H), 2.72 - 2.86 (m, 3H), 2.57 - 2.69 (m, 2H), 2.43 (s, 3H), 2.02 - 2.11 (m, 1H), 1.94 (d, J = 4.8 Hz, 2H), 1.84 (d, J = 10.8, 5.6 Hz, 1H) 1.25 (m, 3H), 1.21 (t, J = 7.2 Hz, 3H).

[0791] (5) To a solution of compound 48 - 7 (1.90 g, 5.41 mmol) in ethanol (30.0 mL), paraformaldehyde (1.62 g) and sodium cyanoborohydride (1.02 g, 16.2 mmol) were added. The reaction mixture was stirred at 30 °C for 16 h under nitrogen protection. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 - 0:1) to obtain compound 48 - 8.

[0792] MS - ESI [M + H] + , calculated value 366, measured value 366.

[0793] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.31 (d, J = 8.0 Hz, 1H), 7.05 - 7.12 (m, 1H), 6.81 - 6.88 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.81 - 3.92 (m, 2H), 2.69 - 2.81 (m, 4H), 2.54 - 2.68 (m, 2H), 2.31 - 2.48 (m, 2H), 2.21 (s, 3H), 2.04 - 2.13 (m, 2H), 1.81 (q, J = 6.4 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H).

[0794] (6) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 9.30 mL, in tetrahydrofuran solution) was added to a solution of compound 48-8 (1.70 g, 4.65 mmol) in tetrahydrofuran (30.0 mL), and the reaction mixture was reacted at -78 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (50.0 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (50.0 mL). The organic phases were combined, washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 48-9.

[0795] MS-ESI[M+H] + , calculated value 320, measured value 320.

[0796] 1 H NMR(400MHz,CDCl 3 )δ 7.26 - 7.56(m,1H),7.13 - 7.24(m,1H),6.81 - 7.01(m,1H),4.08 - 4.36(m,2H),3.42 - 3.61(m,1H),3.09 - 3.21(m,1H),2.86 - 2.96(m,1H),2.49 - 2.77(m,2H),2.26 - 2.48(m,1H),2.01(s,3H),1.61 - 1.81(m,3H),1.59(s,2H),1.28 - 1.35(m,3H).

[0797] (7) Compound 48-10 (572 mg, 7.51 mmol) and sodium ethoxide (767 mg, 11.2 mmol) were added to a solution of compound 48-9 (1.20 g, 3.76 mmol) in ethanol (20.0 mL), and the reaction mixture was stirred at 80 °C for 15 hours under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 6 with hydrochloric acid (1 mol / L). A solid was precipitated, filtered, and the filter cake was dried to obtain compound 48-11.

[0798] MS-ESI[M+H] + , calculated value 332, measured value 332.

[0799] (8) To a solution of intermediate 48-11 (1.10 g, 3.25 mmol) in water (30.0 mL) is added chloroacetic acid (1.25 g, 13.2 mmol), and the reaction solution is stirred at 100 °C for 12 hours under nitrogen gas protection. The reaction solution is filtered, saturated aqueous sodium bicarbonate solution is added to the filtrate to adjust the pH value to 8, and a solid precipitates. It is filtered, and the filter cake is dried to obtain compound 48-12.

[0800] MS-ESI[M+H] + , calculated value 316, measured value 316.

[0801] 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.75 (s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.20 - 7.32 (m, 1H), 7.04 (t, J = 8.4 Hz, 1H), 3.52 (d, J = 14.8 Hz, 1H), 3.05 (d, J = 14.0 Hz, 1H), 2.81 (d, J = 16.4 Hz, 1H), 2.52 - 2.59 (m, 2H), 2.40 - 2.48 (m, 1H), 1.94 (s, 4H), 1.70 - 1.80 (m, 1H), 1.47 - 1.61 (m, 2H).

[0802] (9) Compound 48-12 (200 mg, 634 μmol) is dissolved in phosphorus oxychloride (2.0 mL), and the reaction solution is stirred at 80 °C for 12 hours under nitrogen gas protection. The reaction solution is concentrated under reduced pressure, extracted with dichloromethane (20.0 mL), and the organic phase is washed with saturated aqueous sodium bicarbonate solution (20.0 mL × 2) and saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 48-13.

[0803] MS-ESI[M+H] + , calculated value 352, measured value 352.

[0804] (10) To a solution of compound 48-13 (150 mg, 425 μmol) in N-methylpyrrolidone (5.0 mL) were added potassium carbonate (176 mg, 1.28 mmol) and compound 48-14 (115 mg, 551 μmol), and the reaction mixture was stirred at 50 °C for 5 h under a nitrogen gas atmosphere. Ethyl acetate (50.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 48-15.

[0805] MS-ESI[M+H] + , calculated value 541, measured value 541.

[0806] 1 H NMR(400MHz,CDCl 3 )δ 7.35(s,1H),7.20(s,1H),6.83-7.01(m,1H),4.57(s,1H),4.00(s,2H),3.82(d,J=11.2Hz,1H),3.72(dd,J=6.0,3.2Hz,1H),3.30-3.66(m,2H),3.08-3.29(m,3H),2.80-3.07(m,3H),2.65(d,J=6.8Hz,2H),2.42-2.52(m,1H),2.12(s,2H),2.02(s,1H),1.19-1.94(m,1H),1.64-1.78(m,2H),1.50(d,J=2.0Hz,9H).

[0807] (11) To a solution of compound 48-15 (440 mg, 813 μmol) in dioxane (10.0 mL), add compound 48-16 (388 mg, 2.44 mmol), cesium carbonate (794 mg, 2.44 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (136 mg, 162 μmol). Stir the reaction solution at 110 °C for 4 hours under nitrogen gas protection. Add ethyl acetate (50.0 mL) to the reaction solution, wash it with saturated brine (50.0 mL × 2), dry it over anhydrous sodium sulfate, filter it, concentrate it under reduced pressure, and separate the crude product by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 48-17.

[0808] MS-ESI[M+H] + , calculated value 664, measured value 664.

[0809] (12) To a solution of compound 48-17 (270 mg, 406 μmol) in dichloromethane (5.0 mL), add a dioxane solution of hydrochloric acid (4 mol / L, 36.7 μmol). Stir the reaction solution at 25 °C for 2 hours under nitrogen gas protection. Adjust the pH value to 8 with saturated aqueous sodium bicarbonate solution, extract it with dichloromethane (20 mL × 2), wash the organic phase with saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (50 mL), dry it over anhydrous sodium sulfate, filter it, concentrate it under reduced pressure, and separate the crude product by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 48-18.

[0810] MS-ESI[M+H] + , calculated value 564, measured value 564.

[0811] (13) At 0 °C, to a solution of Compound 48-18 (200 mg, 354 μmol) in ethyl acetate (1.0 mL) were added triethylamine (17.9 mg, 177 μmol), Compound 48-19 (35.9 mg, 354 μmol), 4A molecular sieve (100 mg), and a solution of tricyclic propylphosphonic anhydride (677 mg, 1.06 mmol, 50% ethyl acetate solution). The reaction mixture was stirred at 25 °C for 1 hour. Dichloromethane (10.0 mL) was added to the reaction mixture, and it was washed with saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain Compound 48-20.

[0812] (14) Compound 48-20 was resolved by chiral supercritical fluid chromatography to obtain Compounds 48 and 49.

[0813] Separation conditions: Chromatography column model: Chiralpak OD-3, Chromatography column specification: 50 × 4.6 mm I.D., 3 μm, Injection volume: 8.0 μL, Mobile phase: A: Carbon dioxide, B: Ethanol (0.05% diethylamine), B%: 5% - 40% gradient elution for 2.5 minutes, 40% constant concentration elution for 0.5 minutes, 5% constant concentration elution for 1 minute, Detection wavelength: 254 nm, Column temperature: 35 °C.

[0814] The retention time of Compound 48 was 1.743 minutes, and the ee value was 98.58%.

[0815] MS-ESI[M+H] + , Calculated value 636, Measured value 636.

[0816] 1¹H NMR (400 MHz, MeOD) δ 7.37 (d, J = 8.0 Hz, 1H), 7.20 - 7.27 (m, 1H), 6.94 (t, J = 8.8 Hz, 1H), 5.24 - 5.42 (m, 3H), 4.38 - 4.63 (m, 1H), 4.20 - 4.25 (m, 1H), 4.08 - 4.19 (m, 3H), 3.77 (s, 2H), 3.46 - 3.60 (m, 1H), 3.35 (d, J = 2.8 Hz, 1H), 3.28 (s, 1H), 3.04 - 3.14 (m, 3H), 2.89 - 3.02 (m, 4H), 2.43 - 2.55 (m, 1H), 2.27 - 2.39 (m, 1H), 2.15 - 2.26 (m, 2H), 2.12 (s, 3H), 1.97 - 2.08 (m, 4H), 1.85 - 1.97 (m, 2H), 1.70 - 1.84 (m, 2H), 1.28 - 1.53 (m, 2H) The retention time of Compound 49 was 1.937 minutes, and the ee value was 98.18%.

[0817] MS - ESI [M + H] + , calculated value 636, measured value 636.

[0818] 1 ¹H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.0 Hz, 1H), 7.39 - 7.46 (m, 1H), 7.16 (t, J = 8.4 Hz, 1H), 5.63 (t, J = 3.6 Hz, 0.5H), 5.50 (d, J = 3.2 Hz, 0.5H), 5.30 - 5.43 (m, 2H), 4.62 (s, 1H), 4.53 - 4.59 (m, 3H), 3.94 - 4.03 (m, 2H), 3.83 - 3.93 (m, 3H), 3.41 - 3.49 (m, 4H), 3.38 (s, 1H), 3.10 - 3.28 (m, 2H), 2.87 - 3.10 (m, 3H), 2.57 - 2.64 (m, 4H), 2.51 - 2.57 (m, 1H), 2.40 (d, J = 8.4 Hz, 1H), 2.25 - 2.37 (m, 3H), 2.13 - 2.24 (m, 4H), 1.81 - 1.91 (m, 1H), 1.28 - 1.51 (m, 1H).

[0819] Example 39. Synthesis of Compounds 50 and 51

[0820] [Chemical formula] (1) To a toluene (240 mL) solution of Compound 50-1 (20.0 g, 111 mmol), add Compound 50-2 (16.1 g, 133 mmol) and tetraethyl titanate (50.5 g, 221 mmol). Stir the reaction solution at 110 °C for 13 hours under nitrogen gas protection. Add water (200 mL) to the reaction solution, filter, wash the filter cake with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 5:1) to obtain Compound 50-3.

[0821] MS-ESI [M+H] + , calculated value 284, measured value 284.

[0822] 1 H NMR (400 MHz, CDCl 3 ) δ 8.07 - 8.14 (m, 1H), 7.49 (dd, J = 7.6, 1.2 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 3.03 - 3.33 (m, 2H), 2.86 - 3.02 (m, 2H), 2.05 - 2.13 (m, 1H), 1.96 - 2.04 (m, 1H), 1.33 (s, 9H).

[0823] (2) Ethyl acetate (26.9 g, 305 mmol) was dissolved in tetrahydrofuran (320 mL), and lithium diisopropylamide (2 mol / L, 60.9 mL, tetrahydrofuran solution) was added dropwise at -78 °C under nitrogen gas protection. The reaction solution was stirred at -78 °C for 1 hour. A solution of compound 50-3 (15.5 g, 61.2 mmol) in tetrahydrofuran (200 mL) was added dropwise to the reaction solution, and stirring was continued at -78 °C for 3 hours. Saturated aqueous ammonium chloride solution (200 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated aqueous ammonium chloride solution (200 mL × 1) and saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 50-4.

[0824] MS-ESI[M+H] + , calculated value 372, measured value 372.

[0825] 1 H NMR(400MHz,CDCl 3 )δ 7.31(dd,J=17.2,8.0Hz,2H),7.09-7.16(m,1H),4.11-4.19(m,2H),2.75-2.90(m,4H),2.41-2.49(m,1H),2.06-2.18(m,2H),1.78-1.89(m,1H),1.25-1.28(m,3H),1.24(s,9H).

[0826] (3) To a solution of compound 50-4 (17.1 g, 46.0 mmol) in ethanol (80.0 mL) was added a dioxane solution of hydrochloric acid (4 mol / L, 38.9 mL), and the reaction solution was stirred at 25 °C for 1 hour under nitrogen gas protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 50-5.

[0827] (4) To a solution of hydrochloride salt of compound 50-5 (4.60 g, 15.1 mmol) in ethanol (30.0 mL), add compound 50-6 (15.1 g, 151 mmol), copper(II) oxide (241 mg, 3.02 mmol), and triethylamine (1.53 g, 15.1 mmol). Under the protection of nitrogen gas, react the reaction solution at 85 °C for 12 hours with sealing. Add water (90.0 mL) to the reaction solution, extract with ethyl acetate (40.0 mL × 3), combine the organic phases, wash with saturated brine (30.0 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 50-7.

[0828] MS-ESI[M+H] + , calculated value 368, measured value 368.

[0829] (5) To a solution of compound 50-7 (2.30 g, 6.25 mmol) in ethanol (20.0 mL), add paraformaldehyde (1.88 g) and sodium cyanoborohydride (1.18 g, 18.8 mmol). Under the protection of nitrogen gas, react the reaction solution at 25 °C for 25 hours. Add water (30.0 mL) to the reaction solution, extract with ethyl acetate (15.0 mL × 3), combine the organic phases, wash with saturated brine (15.0 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 50-8.

[0830] MS-ESI[M+H] + , calculated value 382, measured value 382.

[0831] 1 H NMR(400MHz,CDCl 3)δ 7.48 (d, J = 8.0 Hz, 1H), 7.20 - 7.24 (m, 1H), 7.05 - 7.11 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.79 - 3.96 (m, 2H), 2.70 - 2.86 (m, 5H), 2.54 - 2.65 (m, 1H), 2.31 - 2.50 (m, 2H), 2.22 (s, 3H), 1.99 - 2.16 (m, 2H), 1.84 (quin, J = 6.4 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H).

[0832] (6) At -78 °C, potassium bis(trimethylsilyl)amide (1 mol / L, 13.4 mL, in tetrahydrofuran solution) was added to a solution of compound 50-8 (1.70 g, 4.45 mmol) in tetrahydrofuran (35.0 mL), and the reaction mixture was reacted at -78 °C for 2 hours under nitrogen gas protection. Saturated aqueous ammonium chloride solution (15.0 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (50.0 mL). The organic phases were combined, washed with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 50-9.

[0833] MS-ESI [M+H] + , calculated value 336, measured value 336.

[0834] 1 H NMR (400 MHz, CDCl 3 )δ 7.47 - 7.59 (m, 1H), 7.23 - 7.26 (m, 1H), 7.11 - 7.22 (m, 1H), 4.20 - 4.34 (m, 2H), 3.46 - 3.64 (m, 1H), 2.93 - 3.32 (m, 3H), 2.44 - 2.73 (m, 3H), 2.01 (d, J = 14.4 Hz, 4H), 1.66 - 1.84 (m, 3H), 1.33 (t, J = 7.2 Hz, 3H).

[0835] (7) To a solution of compound 50-9 (1.29 g, 3.84 mmol) in ethanol (25.0 mL) are added compound 50-10 (585 mg, 7.68 mmol) and sodium ethoxide (784 mg, 11.5 mmol), and the reaction mixture is stirred at 80 °C for 15 h under nitrogen gas protection. The reaction mixture is concentrated under reduced pressure, and the pH value is adjusted to 6 with hydrochloric acid (1 mol / L). A solid precipitates, is filtered, and the filter cake is dried to obtain compound 50-11.

[0836] MS-ESI[M+H] + , calculated value 348, measured value 348.

[0837] 1 H NMR(400MHz,CDCl 3 )δ 7.54(dd,J=7.6,1.2Hz,1H),7.28-7.33(m,1H),7.20-7.27(m,1H),7.04-7.19(m,1H),3.53(d,J=16.4Hz,2H),3.02(d,J=16.4Hz,1H),2.88(d,J=17.6Hz,1H),2.52-2.64(m,2H),1.91-1.96(m,1H),1.89(s,3H),1.47-1.73(m,3H).

[0838] (8) To a solution of intermediate 50-11 (1.18 g, 3.39 mmol) in water (75.0 mL) is added chloroacetic acid (3.21 g, 33.9 mmol), and the reaction mixture is stirred at 110 °C for 12 h under nitrogen gas protection. The reaction mixture is filtered, saturated aqueous sodium bicarbonate solution is added to the filtrate to adjust the pH value to 8, and a solid precipitates. It is filtered, and the filter cake is dried to obtain compound 50-12.

[0839] MS-ESI[M+H] + , calculated value 332, measured value 332.

[0840] (9) Compound 50-12 (1.20 g, 3.62 mmol) is dissolved in phosphorus oxychloride (10.0 mL), and the reaction solution is stirred at 80 °C for 12 hours under nitrogen gas protection. The reaction solution is concentrated under reduced pressure, extracted with dichloromethane (20.0 mL), and the organic phase is washed with saturated aqueous sodium bicarbonate solution (20.0 mL × 2) and saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 50-13.

[0841] MS-ESI[M+H] + , calculated value 368, measured value 368.

[0842] (10) Potassium carbonate (585 mg, 4.23 mmol) and Compound 50-14 (381 mg, 1.69 mmol) are added to a solution of Compound 50-13 (520 mg, 1.41 mmol) in N-methylpyrrolidone (5.0 mL), and the reaction solution is stirred at 50 °C for 4 hours under nitrogen gas protection. Ethyl acetate (50.0 mL) is added to the reaction solution, washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain Compound 50-15.

[0843] MS-ESI[M+H] + , calculated value 557, measured value 557.

[0844] 1 H NMR (400 MHz, CDCl 3 ) δ 7.42-7.56 (m, 1H), 7.29-7.42 (m, 1H), 7.11-7.24 (m, 1H), 4.50-4.68 (m, 1H), 3.92-4.09 (m, 2H), 3.56 (s, 3H), 3.28-3.54 (m, 1H), 2.96-3.26 (m, 5H), 2.44-2.79 (m, 3H), 2.06-2.19 (m, 3H), 1.62-1.99 (m, 4H), 1.51 (d, J = 2.4 Hz, 9H).

[0845] (11) To a solution of compound 50-15 (230 mg, 412 μmol) in dioxane (5.00 mL), add compound 50-16 (197 mg, 1.24 mmol), potassium carbonate (171 mg, 1.24 mmol), tris(dibenzylideneacetone)dipalladium (75.6 mg, 82.5 μmol), and 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (77.0 mg, 165 μmol). Stir the reaction mixture at 90 °C for 5 hours under nitrogen gas protection. Add ethyl acetate (20.0 mL) to the reaction mixture, wash it with saturated brine (20.0 mL × 2), dry it over anhydrous sodium sulfate, filter it, concentrate it under reduced pressure, and separate the crude product by preparative high-performance liquid chromatography (Xtimate C18, 150 mm × 40 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 20%-50%: 10 minutes) to obtain the formate salt of compound 50-17.

[0846] MS-ESI[M+H] + , calculated value 680, measured value 680.

[0847] (12) To a solution of the formate salt of compound 50-17 (80 mg, 118 μmol) in dichloromethane (1.0 mL), add trifluoroacetic acid (1.0 mL). Stir the reaction mixture at 25 °C for 1 hour under nitrogen gas protection. Concentrate it under reduced pressure to remove trifluoroacetic acid, adjust the pH value to 8 with saturated aqueous sodium bicarbonate solution, extract it with dichloromethane (20 mL × 2), wash the organic phase with saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (50 mL), dry it over anhydrous sodium sulfate, filter it, and concentrate it under reduced pressure to obtain compound 50-18.

[0848] MS-ESI[M+H] + , calculated value 580, measured value 580.

[0849] (13) At 0 °C, to a solution of Compound 50-18 (55.0 mg, 94.8 μmol) in ethyl acetate (1.0 mL) were added triethylamine (57.6 mg, 79.2 μmol), Compound 50-19 (25.6 mg, 284 μmol), 4A molecular sieve (100 mg), and a solution of tricyclic propylphosphonic anhydride (181 mg, 284 mmol, 50% ethyl acetate solution). The reaction mixture was stirred at 25 °C for 1 hour. Ethyl acetate (10.0 mL) was added to the reaction mixture, and it was washed with saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative high-performance liquid chromatography (Phenomenex C18, 75 mm × 30 mm 3 μm, A: water (10 mmol / L ammonium bicarbonate); B: acetonitrile, 38% - 78%: 28 minutes) to obtain Compound 50-20.

[0850] (14) Compound 50-20 was resolved by chiral supercritical fluid chromatography to obtain Compounds 50 and 51.

[0851] Separation conditions: Chromatography column model: Chiralpak OD-3, Chromatography column specification: 50 × 4.6 mm I.D., 3 μm, Injection volume: 8.0 μL, Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5% - 40% gradient elution for 2.5 minutes, 40% isocratic elution for 0.5 minutes, 5% isocratic elution for 1 minute, Detection wavelength: 254 nm, Column temperature: 35 °C.

[0852] The retention time of Compound 50 was 1.657 minutes, and the ee value was 99.30%.

[0853] MS-ESI[M+H] + , calculated value 652, measured value 652.

[0854] 11H NMR (400 MHz, MeOD) δ 7.53 (d, J = 7.6 Hz, 1H), 7.26 - 7.32 (m, 1H), 7.17 - 7.25 (m, 1H), 5.11 - 5.48 (m, 3H), 4.30 (d, J = 13.6 Hz, 1H), 4.10 - 4.22 (m, 2H), 4.00 (d, J = 11.2 Hz, 1H), 3.70 - 3.82 (m, 2H), 3.61 (q, J = 7.2 Hz, 1H), 2.90 - 3.31 (m, 11H), 2.55 (ddd, J = 17.2, 12.0, 5.2 Hz, 1H), 2.06 - 2.39 (m, 6H), 1.84 - 2.06 (m, 5H), 1.77 (d, J = 11.2 Hz, 2H), 1.15 - 1.33 (m, 2H) The retention time of Compound 51 was 1.810 minutes, and the ee value was 100%.

[0855] MS-ESI [M+H] + , calculated value 652, measured value 652.

[0856] 1 1H NMR (400 MHz, MeOD) δ 7.53 (d, J = 7.6 Hz, 1H), 7.26 - 7.32 (m, 1H), 7.17 - 7.25 (m, 1H), 5.11 - 5.48 (m, 3H), 4.30 (d, J = 13.6 Hz, 1H), 4.10 - 4.22 (m, 2H), 4.00 (d, J = 11.2 Hz, 1H), 3.70 - 3.82 (m, 2H), 3.61 (q, J = 7.2 Hz, 1H), 2.90 - 3.31 (m, 11H), 2.55 (ddd, J = 17.2, 12.0, 5.2 Hz, 1H), 2.06 - 2.39 (m, 6H), 1.84 - 2.06 (m, 5H), 1.77 (d, J = 11.2 Hz, 2H), 1.15 - 1.33 (m, 2H).

[0857] Test Example 1

[0858] Inhibitory effect of the compound on the growth of NCI-H358 cells

[0859] 1. Test principle: NCI-H358 cells are a human non-small cell lung cancer cell line that expresses KRAS G12C. The compounds referred to in the present invention inhibit NCI-H358 cell proliferation by covalently binding to KRAS G12C.

[0860] 2. Test materials: NCI-H358 cells were purchased from ATCC, CellTiter-GloR was purchased from Promega (product number G7571), RPMI-1640 was purchased from ATCC (product number 30-2001), fetal bovine serum (FBS) was purchased from EXCELL (product number FND500), penicillin-streptomycin was purchased from Gibco (product number 15140-122), 0.25% trypsin-ethylenediaminetetraacetic acid digestive solution (Trypsin-EDTA) was purchased from Gibco (product number 25200-072), dimethyl sulfoxide (DMSO) was purchased from Sigma (product number D2650), 96-well plates were purchased from Corning (product number 3610), incubators were purchased from Thermo (model 3111), inverted microscopes were purchased from Nikon (product number TS-100), automatic cell counting devices were purchased from Life technologies (model Countess II), microplate readers were purchased from PerkinElmer (model Envision), and data processing software is GraphPad Prism 5.0.

[0861] 3. Test method: Cells in the logarithmic growth phase were resuspended in growth medium (RPMI-1640 + 10% FBS) and diluted to the target density (2000 / mL). The above cell suspension was inoculated into a 96-well plate at 100 μL per well and incubated overnight in an incubator at 37°C with 5% CO 2 The medium is used as a background control group.

[0862] Dissolve the compound to be tested in DMSO to prepare a stock solution with a concentration of 10 mmol / L. First, dilute the stock solution to 2 mmol / L with DMSO, and then perform serial dilutions three-fold to create a total of 10 concentrations. Take 3 μL of the solution at each concentration and dilute it with 197 μL of growth medium respectively. Next, add 50 μL / well to a 96-well plate seeded with cells. Incubate the cells added with the compound to be tested in an incubator at 37 °C and 5% CO 2 Place it in an incubator and incubate for 72 hours. Equilibrate the 96-well plate at room temperature, add 40 μL of CellTiter-Glo reagent to each well, mix for 2 minutes with a vortex, incubate at room temperature for 60 minutes, read the luminescence value with an EnVision microplate reader, and calculate the IC 50 of the compound using GraphP...

Claims

1. A compound represented by formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, or deuteride thereof, wherein 【Chemical 1】 the partial structure in formula I represented by the following formula 【Chemical Formula 2】 is a group of the following formula: [Chemical Formula 3] selected from the group consisting of In the formula, each R ３ is independently oxo, a C1-C3 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a cyano group, -C(O)OR ４ , -CON(R ４ ), ２ or -N(R ４ ), ２ and here, the C1-C3 alkyl group may be optionally substituted by a cyano group, a halogen, -OR ４ or -N(R ４ ), ２ each R ４ is independently hydrogen or a C1-C3 alkyl group, R in the formula I above １ is a group of the following formula 【Chemical Formula 4】 and In the formula, R ａ is hydrogen, halogen, an optionally substituted C1-C3 alkyl group, -N(R ５ ) ２ , an optionally substituted 4-6 membered saturated heterocyclic group, a C1-C3 alkoxy group, a C1-C3 alkylthio group, or an acetyl group, where R ａ The optionally substituted substituents described in are methyl, ethyl, -N(R ５ ) ２ , halogen, a C1-C3 alkoxy group, and a 4-6 membered saturated heterocyclic group; ５ are each independently hydrogen or a C1-C3 alkyl group; R ａ ', R ｂ are each independently hydrogen, halogen, or a C1-C3 alkyl group; L in the formula I above ２ is -O-, -S-, -NR ６ -, where R ６ is hydrogen or a C1-C4 alkyl group, R in the formula I ２ is an optionally substituted C1-C4 alkyl group, where the optionally substituted substituent described for R ２ is selected from an optionally substituted 3- to 8-membered saturated carbon ring group and an optionally substituted 4- to 8-membered saturated heterocyclic ring group, the spiro ring structure in formula I represented by the following formula [Chemical Formula 5] is a group of the following formula: 【Chemical Formula 6】 selected from the group consisting of In the formula, R １０ is independently hydrogen or a C1-C3 alkyl group, and о represents the number of R １３ and is 0, 1, 2 or 3. Each R １３ is independently selected from the group consisting of a halogen, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C3-C6 carbocyclic group, a C1-C3 alkoxy group, and a halogenated C1-C3 alkoxy group. Y in the formula I is -NR １４ -, where R １４ is hydrogen, a C1-C6 alkyl group, or a C1-C6 halogenated alkyl group, Z in the formula I is -(CR １５ R １６ )-, where R １５ and R １６ are independently hydrogen or a C1-C3 alkyl group, characterized in that the compound represented by formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate or deuteride thereof.

2. Said R ａ is hydrogen, fluorine, or an optionally substituted C1-C3 alkyl group, where the optionally substituted substituent described in R ａ is selected from the group consisting of a methyl group, an ethyl group, -N(R ５ ), a halogen, and a C1-C3 alkoxy group, and each R ２ is independently hydrogen or a C1-C3 alkyl group, ５ ​ Said R ａ ’ and R ｂ are each independently hydrogen, fluorine or a C1-C3 alkyl group, characterized in that The compound according to formula I of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate or deuteride thereof.

3. The partial structure in formula I represented by the following formula 【Chemical Formula 7】 is a group of the following formula: [Chemical Formula 8] selected from the group consisting of, characterized in that the compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate or deuteride thereof.

4. R in the formula I above １ is a group of the following formula: 【Chemical Formula 9】 characterized in that the compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate or deuteride thereof.

5. R in the formula I above ２ is a group of the following formula: 【Chemical Formula 10】 and In the formula, n represents the number of substituents R ２ ´ selected from 0, 1, 2, and 3, and each R ２ ’ is independently a halogen, a C1-C3 alkyl group, a halogenated C1-C3 alkyl group, a hydroxy group, a cyano group, oxo, a C1-C3 alkoxy group, -NR ｃ R ｄ , -CO ２ R ７ , -CONR ｅ R ｆ , or a C1-C4 alkyl sulfoxide group, R ｃ and R ｄ are each independently selected from hydrogen and an optionally substituted C1-C6 alkyl group, or R ｃ and R ｄ together with the N to which they are attached form an optionally substituted 4- to 8-membered heterocyclic ring, R ｅ and R ｆ are each independently selected from hydrogen and an optionally substituted C1-C6 alkyl group, or R ｅ and R ｆ together with the N to which they are attached form an optionally substituted 4- to 8-membered heterocyclic ring, R ７ is hydrogen or an optionally substituted C1-C4 alkyl group, characterized in that the compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate or deuteride thereof.

6. The spiro ring structure in formula I represented by the following formula 【Chemical Formula 11】 is a group of the following formula: 【Chemical Formula 12】 selected from the group consisting of wherein, R １０ is independently hydrogen or a C1-C3 alkyl group, o represents the number of substituents R which is 0, 1, 2 or 3 １３ and R １３ is each independently a halogen, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C3-C6 carbocyclic group, a C1-C3 alkoxy group or a halogenated C1-C3 alkoxy group, characterized in that the compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate or deuteride thereof.

7. characterized in that the compound is selected from the group consisting of the compounds listed in the following table the compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate or deuteride thereof. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】

8. A pharmaceutical composition, wherein (1) A therapeutically effective amount of one or more active ingredients selected from the group consisting of the compound according to any one of claims 1 to 7, and a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate and deuteride thereof, and (2) Optionally, a pharmaceutically acceptable carrier, characterized in that the pharmaceutical composition. (Claim 9) The pharmaceutical composition according to claim 8 for preventing or treating KRAS G12C mutation-mediated cancer. (Claim 10) The cancer is selected from the group consisting of lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T cell lymphoma, B cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrial tumor, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer. The pharmaceutical composition according to claim 9. (Claim 11) The cancer is selected from the group consisting of non-small cell lung cancer, pancreatic cancer and colorectal cancer. The pharmaceutical composition according to claim 9.

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