Spirocyclic compounds as KRAS-G12C inhibitors

Abstract

This invention relates to spirocyclic compounds of formula (I) as KRAS-GI2C inhibitors, which can be used to prepare drugs for treating KRAS G12C-mediated tumors.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically, to a class of spirocyclic compounds that can be used as KRAS-G12C inhibitors to prepare drugs for treating KRAS G12C-mediated tumors. Background Technology

[0002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRAS”) is a guanosine triphosphate (GTP) enzyme and a member of the RAS oncogene family. KRAS acts as a molecular switch that cycles between an inactive (guanosine diphosphate (GDP)-bound) and an active (GTP-bound) state to regulate a variety of processes, including cell proliferation, by transducing upstream cellular signals received from various tyrosine kinases to downstream effectors (Current Opin Pharmcol. 2013(13):394-401).

[0003] KRAS is one of the most common mutations in cancer. Approximately 22% of cancer patients have KRAS mutations, particularly in pancreatic cancer (68%), cholangiocarcinoma (27%), and lung cancer (17%). KRAS G12C occurs in 48% of non-small cell lung cancer, 10% of colorectal cancer, and 1% of pancreatic cancer. The lack of an ideal small molecule binding pocket for KRAS proteins and their high affinity for the abundant intracellular GTP make the design of specific small molecule drugs challenging. Among the various known mutations, KRAS G12C mutations are considered the most promising drug targets. Currently, several covalent inhibitors targeting KRAS G12C are in clinical trials, such as Amgen's AMG 510 and Mirati Therapeutics' MRTX849. These compounds covalently bind KRAS G12C at cysteine ​​residue 12, maintaining KRAS G12C in an inactive GDP-binding state and inhibiting KRAS-dependent signaling.

[0004] After more than 30 years of research, KRAS inhibitors have made some progress, but none have yet received regulatory approval demonstrating sufficient safety and efficacy. Therefore, pharmaceutical companies need to continue their efforts to develop new KRAS inhibitors and utilize them to treat various diseases, such as cancer.

[0005] WO2020 / 236940 discloses compound 819, and the binding affinity of compound 819 to KRAS G12C was predicted using software based on both MMGBSA and CovDock methods. However, it does not provide the synthetic method, characterization data, or any biological test results for this compound.

[0006] Summary of the Invention

[0007] The purpose of this invention is to provide a spirocyclic compound or a pharmaceutically acceptable salt thereof.

[0008] Another object of the present invention is to provide a pharmaceutical composition comprising the aforementioned spirocyclic compound or a pharmaceutically acceptable salt thereof.

[0009] Another object of the present invention is to provide the use 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 medicament.

[0010] In a first aspect, the present invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a tautomer, a cis-trans isomer, a solvate, a polymorph, a deuterated compound, or a combination thereof.

[0011]

[0012] in,

[0013] A is a 4-12 element saturated or partially saturated single ring, parallel ring, bridged ring, or helical ring, wherein the saturated or partially saturated single ring, parallel ring, bridged ring, or helical ring is optionally composed of one or more R 3 replace;

[0014] Each R 3 Each can be independently oxo, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, or -C(O)OR. 4 -CON(R) 4 )2 or -N(R 4 )2, wherein the C1-C3 alkyl group is optionally replaced by a cyano group, a halogen, or an OR group. 4 or -N(R) 4 )2 replaces;

[0015] Each R 4 Each is independently hydrogen or C1-C3 alkyl;

[0016] U is either N or CH;

[0017] L 1 Not present or NR NAnd when U is N, L 1 If it does not exist, then when U is CH, L 1 For NR N ;

[0018] R N It is hydrogen or C1-C3 alkyl;

[0019] R 1 yes

[0020]

[0021] in,

[0022] R a It is hydrogen, halogen, optionally substituted C1-C3 alkyl, -N(R) 5 2. Optionally substituted 4-6 membered saturated heterocyclic groups, C1-C3 alkoxy groups, C1-C3 alkylthio groups, or acetyl groups, wherein R a The optional substituents described herein are selected from the group consisting of: methyl, ethyl, -N(R) 5 2. Halogens, C1-C3 alkoxy groups, 4-6 membered saturated heterocyclic groups;

[0023] Each R 5 Each is independently hydrogen or C1-C3 alkyl;

[0024] R a’ R b Each is independently hydrogen, halogen, or C1-C3 alkyl;

[0025] L 2 It does not exist, -O-, -S-, -NR 6 -, -SO-, -SO2- or -CO-, where R 6 It is hydrogen or C1-C4 alkyl;

[0026] R 2 It is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted saturated or unsaturated 3-8-membered carbon cycloyl group, optionally substituted saturated or unsaturated 4-12-membered heterocyclic group, optionally substituted saturated or unsaturated 3-8-membered carbon cycloyl group with 6-10-membered aromatic cycloyl group, optionally substituted saturated or unsaturated 3-8-membered carbon cycloyl group with 5-10-membered heteroaromatic cycloyl group, optionally substituted saturated or unsaturated 3-8-membered heterocyclic group with 6-10-membered aromatic cycloyl group, optionally substituted saturated or unsaturated 3-8-membered heterocyclic group with 5-10-membered heteroaromatic cycloyl group, optionally substituted 6-10-membered aromatic cycloyl group, or optionally substituted 5-10-membered heteroaromatic cycloyl group; wherein R 2 The optional substituents described herein are selected from: deuterium, halogen, hydroxyl, cyano, oxo, C1-C3 alkoxy, -NR. c R d -CO2R7 -CONR e R f C1-C4 alkyl sulfoxide, C1-C4 alkyl sulfone, -SO2NR g R h Optionally substituted 3-8 member saturated or unsaturated carbocyclic groups and optionally substituted 4-8 member saturated or unsaturated heterocyclic groups;

[0027] R c and R d Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R c With R d Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0028] R e and R f Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R e With R f Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0029] R g and R h Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R g With R h Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0030] R 7 It is hydrogen or an optional substituted C1-C4 alkyl group;

[0031] W is -(CR) 8 R 9 )-、-NR 10 -, O or S, where R 8 R 9 and R 10 It is independently hydrogen or C1-C3 alkyl;

[0032] X is -(CR) 11 R 12 ) m -or-(C=O)-, where each R 11 Each is independently hydrogen or C1-C3 alkyl, each R 12 Each is independently hydrogen or C1-C3 alkyl;

[0033] m = 1, 2, or 3;

[0034] B is a 6-10 membered aromatic ring or a 5-8 membered heteroaromatic ring, wherein the 6-10 membered aromatic ring or the 5-8 membered heteroaromatic ring is not substituted or optionally is replaced by one or more R. 13 replace;

[0035] Each R 13 Each of these can be independently a halogen, hydroxyl, amino, C1-C3 alkylamino, (C1-C3 alkyl)2amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 carbocycloyl, C1-C3 alkoxy, or haloC1-C3 alkoxy.

[0036] Y is -NR 14 -, where R 14 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 carbocyclic group;

[0037] Z is -(CR) 15 R 16 )-, where R 15 and R 16 It is either hydrogen or C1-C3 alkyl.

[0038] In a preferred embodiment, R 2 It is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted saturated or unsaturated 3-8-membered carbon cycloyl group, optionally substituted saturated or unsaturated 4-12-membered heterocyclic group, optionally substituted saturated or unsaturated 3-8-membered heterocyclic group with 6-10-membered aromatic ring, optionally substituted saturated or unsaturated 3-8-membered heterocyclic group with 5-10-membered heteroaromatic ring, optionally substituted 6-10-membered aromatic ring, or optionally substituted 5-10-membered heteroaromatic ring, wherein R 2 The optional substituents described herein are selected from: deuterium, halogen, hydroxyl, cyano, oxo, C1-C3 alkoxy, -NR. c R d -CO2R 7 -CONR e R f C1-C4 alkyl sulfoxide, C1-C4 alkyl sulfone, -SO2NR g R h Optionally substituted 3-8 member saturated or unsaturated carbocyclic groups and optionally substituted 4-8 member saturated or unsaturated heterocyclic groups;

[0039] R c and R d Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R c With R d Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0040] R e and R f Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R e With R f Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0041] R g and R h Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R g With R h Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0042] R 7 It is hydrogen or an optional substituted C1-C4 alkyl group;

[0043] Preferably, the L 2 Is it non-existent, -O-, -S-, or -NR? 6 -, where R 6 It is hydrogen or C1-C4 alkyl;

[0044] Preferably, the R a It is hydrogen, fluorine, optionally substituted C1-C3 alkyl, optionally substituted 4-6 membered saturated heterocyclic group or acetyl group;

[0045] Where R a The optional substituents described herein are selected from the group consisting of: methyl, ethyl, -N(R) 5 2. Halogens, C1-C3 alkoxy groups, 4-6 membered saturated heterocyclic groups;

[0046] Each R 5 Each is independently hydrogen or C1-C3 alkyl;

[0047] Preferably, the R a’ R b Each can be independently hydrogen, fluorine, or C1-C3 alkyl;

[0048] Preferably, W is -(CR) 8 R 9 - or -NR 10 -, where R 8 R 9 and R 10 It is independently hydrogen or C1-C3 alkyl;

[0049] Preferably, X is -(CR) 11 R 12 )m -; where each R 11 Each is independently hydrogen or C1-C3 alkyl, each R 12 Each is independently hydrogen or C1-C3 alkyl; m is 1, 2 or 3; more preferably, m is 1 or 2.

[0050] In another preferred embodiment, The portion represented is selected from the following group:

[0051]

[0052] n represents the substituent R 3 The number of elements, where n is 0, 1, 2, or 3;

[0053] Each R 3 Each can be independently oxo, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, or -C(O)OR. 4 -CON(R) 4 )2 or -N(R 4 )2, wherein the C1-C3 alkyl group may optionally be replaced by a cyano group, a halogen, or an OR group. 4 or -N(R) 4 )2 replaces;

[0054] Each R 4 Each is independently hydrogen or C1-C3 alkyl;

[0055] Preferably, The portion represented is selected from the following group:

[0056]

[0057] In another preferred embodiment, R 1 yes

[0058]

[0059] Preferably, R 1 yes

[0060] In another preferred embodiment, R 2 It is hydrogen, an optionally substituted C1-C4 alkyl group, an optionally substituted 6-10 membered aromatic cyclic group, or an optionally substituted 5-10 membered heteroaromatic cyclic group; wherein R 2 The optional substituents described herein are selected from: halogen, hydroxyl, cyano, oxo, C1-C3 alkoxy, -NR c R d -CO2R 7 -CONRe R f C1-C4 alkyl sulfoxide, C1-C4 alkyl sulfone, -SO2NR g R h Optionally substituted 3-8 member saturated or unsaturated carbocyclic groups and optionally substituted 4-8 member saturated or unsaturated heterocyclic groups;

[0061] R c and R d Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R c With R d Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0062] R e and R f Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R e With R f Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0063] R g and R h Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R g With R h Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0064] R 7 It is hydrogen or optionally substituted C1-C4 alkyl.

[0065] Preferably, R 2 yes Where n represents the substituent R 2 The number of ' is selected from: 0, 1, 2, and 3; each R 2’ Each of the following can be independently a halogen, C1-C3 alkyl, halo-C1-C3 alkyl, hydroxyl, cyano, oxo, C1-C3 alkoxy, or -NR. c R d -CO2R 7 -CONR e R f C1-C4 alkyl sulfoxide, C1-C4 alkyl sulfone, -SO2NR g R h Optional substituted 3-8 member saturated or unsaturated carbocyclic groups or optional substituted 4-8 member saturated or unsaturated heterocyclic groups;

[0066] R c and R d Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R c With R d Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0067] R e and R f Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R e With R f Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0068] R g and R h Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl groups, optionally substituted 3-8 membered carbocyclic groups, and optionally substituted 4-8 membered heterocyclic groups, or R g With R h Together with the attached N, it forms an optionally substituted 4-8 membered heterocycle;

[0069] R 7 It is hydrogen or optionally substituted C1-C4 alkyl.

[0070] In another preferred embodiment, The representative spiral rings are selected from the following group:

[0071]

[0072] R 10 It is independently hydrogen or C1-C3 alkyl;

[0073] o indicates the substituent R 13 The number is 0, 1, 2 or 3;

[0074] R 13 Each is independently a halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C6 carbocyclic group, a C1-C3 alkoxy group, or a haloC1-C3 alkoxy group.

[0075] In another preferred embodiment, the compound is selected from the group consisting of:

[0076]

[0077]

[0078]

[0079]

[0080] The compounds of the present invention can be prepared according to the synthesis methods described in the examples or similar methods.

[0081] A second aspect of the present invention provides a pharmaceutical composition comprising:

[0082] (1) A therapeutically effective amount of one or more selected from the compounds of the present invention, pharmaceutically acceptable salts thereof, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs, and deuterated derivatives as the active ingredient; and

[0083] (2)Optionally, a pharmaceutically acceptable carrier.

[0084] Furthermore, the pharmaceutical composition may further include other pharmaceutically acceptable therapeutic agents or be used in combination with other pharmaceutically acceptable therapeutic agents, particularly other antitumor drugs. These therapeutic agents include, but are not limited to: antitumor drugs that act on the chemical structure of DNA, such as cisplatin; antitumor drugs that affect nucleic acid synthesis, such as methotrexate (MTX), 5-fluorouracil (5FU), etc.; antitumor drugs that affect nucleic acid transcription, such as doxorubicin, epirubicin, aclarubicin, sclerosomycin, etc.; antitumor drugs that act on microtubule synthesis, such as paclitaxel, vinorelbine, etc.; aromatase inhibitors, such as ammoniaglutide, lantron, letrozole, renin, etc.; and cell signaling pathway inhibitors, such as epidermal growth factor receptor inhibitors gefitinib, erlotinib, lapatinib, etc. Inhibitors of mitogen-activated extracellular signal-regulated kinases (MEKs) such as trametinib and cobimetinib; inhibitors of cyclin-dependent kinase 4 / 6 (CDK4 / 6) such as palbociclib; inhibitors of Src homotyrosine phosphatase (SHP2); inhibitors of SOS1; and inhibitors of programmed death receptor-1 / programmed death ligand-1 (PD-1 / PD-L1) such as nivolumab and pembrolizumab.

[0085] In a third aspect, the present invention provides the use of the compounds of the present invention as described above, pharmaceutically acceptable salts thereof, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated compounds, or pharmaceutical compositions thereof for the preparation of a medicament for the prevention or treatment of KRAS G12C mutation-mediated cancers. In a preferred embodiment, the KRAS G12C-related cancers are selected from the group consisting of: lung cancer (including non-small cell 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 carcinoma, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, and bladder cancer. In another preferred embodiment, the KRAS G12C-related cancers are selected from non-small cell lung cancer, pancreatic cancer, or colorectal cancer.

[0086] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0087] Figure 1 The in vivo efficacy results of the test substance in a female BALB / c nude mouse model with subcutaneous NCI-H358 tumor transplantation are shown.

[0088] Figure 2 The in vivo efficacy results of the test substance in the BALB / c nude mouse NCI-H1373-luc intracranial inoculation model are shown.

[0089] Terminology Explanation

[0090] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0091] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0092] Group definition

[0093] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg, "Advanced Organic Chemistry 4th Edition," Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, UV / VIS spectroscopy, and pharmacological methods, are used. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art, based on the descriptions in the various summary and more specific references cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0094] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0095] The chapter headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter. All references or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0096] Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to alkyl groups having a total of 1 to 6 carbon atoms as defined below. The total number of carbon atoms in the simplified symbols does not include carbons that may be present in substituents of the group.

[0097] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0098] In this application, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0099] "Hydroxy group" refers to the -OH group.

[0100] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group (-OH) as defined below.

[0101] "Carbonyl" refers to the -C(=O)- group.

[0102] "Nitro" refers to -NO2.

[0103] "Cyano" refers to -CN.

[0104] "Amino" refers to -NH2.

[0105] "Substituted amino" refers to an amino group that is substituted by one or two alkyl, alkylcarbonyl, aromatic cycloalkyl, or heteroaromatic cycloalkyl groups as defined below, such as monoalkylamino, dialkylamino, alkylamide, aromatic cycloalkylamino, or heteroaromatic cycloalkylamino.

[0106] The "carboxyl group" refers to -COOH.

[0107] In this application, as a group or part of other groups (e.g., in halogen-substituted alkyl groups), the term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon chain group composed only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, and decyl. For the purposes of this invention, the term "alkyl" preferably refers to an alkyl group containing 1 to 6 carbon atoms.

[0108] In this application, as part of a group or other group, the term "alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by single bonds, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0109] As used herein, or as part of other groups, the term "alkynyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by single bonds, such as, but not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octyynyl, etc.

[0110] In this application, as part of a group or other group, the term "carbocyclic group" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms. It may include fused ring systems, bridged ring systems, or spirocyclic systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and may be saturated or unsaturated and may be connected to the rest of the molecule via single bonds through any suitable carbon atom. Unless otherwise specifically indicated in this specification, the carbon atoms in the carbocyclic group may optionally be oxidized. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-dihydroindenyl, octahydro-4,7-methylene-1H-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, and 6,7,8,9-tetrahydro-5H-benzocyclo Heptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl and octahydro-2,5-methylene-benzocyclopentadienyl, etc.

[0111] In this application, as part of a group or other group, the term "heterocyclic group" means a stable 3- to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specifically indicated in this specification, a heterocyclic group can be a monocyclic, bicyclic, tricyclic, or more ring system, which may include fused ring systems, bridged ring systems, or spirocyclic systems; the nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be connected to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclic groups containing fused rings, one or more rings may be aromatic or heteroaromatic groups as defined below, provided that the connection point with the remainder of the molecule is a non-aromatic ring atom. For the purposes of this invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged, or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, aziridine, pyranyl, tetrahydropyranyl, thiaranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, quinazinyl, thiazoalkyl, isothiazyl, isoxazylalkyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolyl, phthalimide, etc.

[0112] In this application, as a group or part of other groups, the term "aromatic ring (group)" means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably 6 to 10 carbon atoms). For the purposes of this invention, the aromatic ring (group) can be a monocyclic, bicyclic, tricyclic, or more ring system, and can also be fused with carbocyclic or heterocyclic groups as defined above, provided that the aromatic ring (group) is connected to the rest of the molecule via single bonds through atoms on the aromatic ring. Examples of aromatic rings (groups) include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc.

[0113] In this application, the term "aromatic cycloalkyl" refers to an alkyl group as defined above that is replaced by an aromatic cycloalkyl group as defined above.

[0114] In this application, as part of a group or other group, the term "heteroaromatic ring (group)" means a 5- to 16-membered conjugated cyclic group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically indicated in this specification, the heteroaromatic ring (group) may be a monocyclic, bicyclic, tricyclic, or more ring system, and may be fused with a carbocyclic or heterocyclic group as defined above, provided that the heteroaromatic ring (group) is connected to the rest of the molecule via single bonds through atoms on the heteroaromatic ring. The nitrogen, carbon, or sulfur atoms in the heteroaromatic ring (group) may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of this 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 heteroaromatic rings (groups) include, but are not limited to, thiophene, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolithyl, triazolyl, tetrazolyl, triazinyl, inazinyl, isoindolyl, indazolyl, isoindazolyl, purine, quinolinyl, isoquinolinyl, diazonyl, naphthidyl, quinoxolinyl, pteridyl, carbazolyl, carbazolyl, phenanthridine, phenanthroxolinyl, acridineyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophene. Oxatriazolyl, cyclolinyl, quinazolinyl, phenylthioyl, indene, o-diazaphenyl, isoxazolyl, phenoxazinyl, phenthiazinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, naphthopyridyl, [1,2,4]triazolo[4,3-b]pyrazine, [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]pyrazine, imidazo[1,2-a]pyrazine, etc.

[0115] In this application, the term "heteroaromatic cycloalkyl" refers to an alkyl group as defined above that has been replaced by a heteroaromatic cycloalkyl group as defined above.

[0116] In this application, the term "non-existent" means that the two sides of the group defined above are directly connected by chemical bonds. For example, "B is non-existent in ABC" means "AC".

[0117] In this application, In This indicates the connection position of group R.

[0118] In this application, unless specifically stated in the claims, "optionally" or "optionally substituted" means that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aromatic ring group" means that the hydrogen on the aromatic ring group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aromatic ring groups. For example, where no substituent is explicitly listed, the terms "optionally substituted," "substituted," or "substituted with" as used herein mean that one or more hydrogen atoms on a given atom or group are independently substituted by one or more, for example, 1, 2, 3, or 4 substituents, which are independently selected from: deuterium (D), halogen, -OH, mercapto, cyano, -CD3, -C1-C6 alkyl (preferably -C 1-3 Alkyl), C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl (preferably 3-8 membered cycloalkyl), aromatic cycloyl, heterocyclic (preferably 3-8 membered heterocyclic), heteroaromatic cycloyl, aromatic cycloyl-C1-C6 alkyl-, heteroaromatic cycloyl-C1-C6 alkyl-, C1-C6 haloalkyl-, -OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 alkenyl, -OC1-C6 alkylphenyl, -C1-C6 alkyl-OH (preferably -C1-C4 alkyl-OH), -C1-C6 alkyl-SH, -C1-C6 alkyl-O-C 1-C6 alkyl, -OC1-C6 haloalkyl, -NH2, -C1-C6 alkyl-NH2 (preferably -C1-C3 alkyl-NH2), -N(C1-C6 alkyl)2 (preferably -N(C1-C3 alkyl)2), -NH(C1-C6 alkyl) (preferably -NH(C1-C3 alkyl)), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), nitro, -C(O)-OH, -C(O)OC1-C6 alkyl (preferably -C(O)OC1-C3 alkyl), -CONR i R ii (where R) i and R ii It is H, D and C 1-6 Alkyl, preferably C 1-3Alkyl), -NHC(O) (C1-C6 alkyl), -NHC(O) (phenyl), -N(C1-C6 alkyl)C(O) (C1-C6 alkyl), -N(C1-C6 alkyl)C(O) (phenyl), -C(O)C1-C6 alkyl, -C(O) heteroaromatic cycloyl (preferably -C(O)-5-7 membered heteroaromatic cycloyl), -C(O)C1-C6 alkylphenyl, -C(O)C1-C6 haloalkyl, -OC(O)C1-C6 alkyl (preferably -OC(O)C1-C 3 alkyl), -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-C1-C6 haloalkyl, -S(O)2NH2, -S(O)2NH (C1-C6 alkyl), -S(O)2NH (phenyl), -NHS(O)2 (C1-C6 alkyl), -NHS(O)2 (phenyl) and -NHS(O)2 (C1-C6 haloalkyl), wherein the alkyl, cycloalkyl, phenyl, aromatic cycloyl, heterocyclic and heterocyclic groups are... Each of the aromatic cyclic groups may optionally be further substituted by one or more substituents selected from the following: halogen, -OH, -NH2, cycloalkyl, 3-8 membered heterocyclic, C1-C4 alkyl, C1-C4 haloalkyl-, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl)2, -CONH( C1-C6 alkyl), -CONH2, -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C6 haloalkyl). When an atom or group is substituted by multiple substituents, the substituents may be the same or different. The terms "part," "structural part," "chemical part," "group," and "chemical group" as used herein refer to a specific segment or functional group in a molecule. A chemical part is generally considered to be a chemical entity embedded or attached to a molecule.

[0119] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds, but with different three-dimensional structures. This invention will cover various stereoisomers and mixtures thereof.

[0120] When the compounds of the present invention contain alkene double bonds, unless otherwise stated, the compounds of the present invention are intended to contain E- and Z-geometric isomers.

[0121] "Tautomer" refers to an isomer formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. All tautomer forms of the compounds of this invention are also included within the scope of this invention.

[0122] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may produce enantiomers, diastereomers, and other stereoisomers. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention aims to include all possible isomers, as well as their racemic and optically pure forms. The preparation of the compounds of the present invention may select racemic, diastereomer, or enantiomer as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0123] Conventional techniques for preparing / separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography, as seen in Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AMStalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3: 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0124] In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0125] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0126] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0127] In this application, "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0128] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0129] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or animal use.

[0130] The term "tumor" as used in this invention includes, but is not limited to, lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal carcinoma, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, and bladder cancer.

[0131] The terms “preventive,” “prevention,” and “avoidance” used in this article include reducing the likelihood of a patient developing or worsening a disease or condition.

[0132] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0133] (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0134] (ii) To suppress a disease or symptom, that is, to curb its development;

[0135] (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0136] (iv) To alleviate the symptoms caused by the disease or condition.

[0137] As used herein, the terms "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" refer to an amount of at least one drug or compound that, when taken, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition containing the compounds disclosed herein that is clinically necessary to provide significant symptom relief. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation testing.

[0138] As used herein, the terms “administration,” “application,” “dosage,” etc., refer to methods that deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein, such as those discussed in Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current ed.; Pergamon; and Remington's, *Pharmaceutical Sciences* (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0139] As used herein, the terms “drug combination,” “drug co-administration,” “combination therapy,” “administration of other treatments,” and “administration of other therapeutic agents” refer to drug therapy obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term “fixed combination” refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or single dosage form. The term “non-fixed combination” refers to the simultaneous, combined, or sequential administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity at variable intervals. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0140] Those skilled in the art will also understand that, in the methods described below, the functional groups of the intermediate compounds may require protection by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acids. Suitable hydroxyl protecting groups include trialkylsilyl or diaromatic cycloalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidine, and guanidine protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R" (where R is an alkyl, aromatic cycloyl, or aromatic cycloalkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl, aromatic cycloyl, or aromatic cycloalkyl esters.

[0141] Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is detailed in Greene, TW & PGMUTS, Protective Groups in OrganiSynthesis, (1999), 4th Ed., Wiley. Protecting groups can also be polymer resins.

[0142] Beneficial effects

[0143] 1. A compound as shown in Formula I or a pharmaceutically acceptable salt thereof is provided.

[0144] 2. A novel pharmaceutical composition is provided for the preparation of drugs for the prevention and treatment of diseases associated with KRAS G12C mutations. Detailed Implementation

[0145] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0146] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. Percentages and parts are weight percentages and parts by weight.

[0147] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0148] In each embodiment, 1 ¹H NMR was recorded using a BRUKER AVANCE NEO 400MHz NMR spectrometer, and chemical shifts are expressed as δ (ppm). Liquid chromatography-mass spectrometry (LC-MS) was performed using a Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, or LCMS-2020 mass spectrometer. Preparative HPLC separations were performed using a Gilson-281 liquid chromatograph.

[0149] Preparation of intermediates

[0150] 1. Preparation of intermediate A

[0151]

[0152] The synthetic route for intermediate A is shown below:

[0153]

[0154] (1) Compound A-2 (50.0 g, 413 mmol) and tetraethyl titanate (188 g, 825 mmol) were added to a toluene (500 mL) solution of compound A-1 (59.9 g, 454 mmol). The reaction solution was stirred at 130 °C for 12 hours under nitrogen protection. Water (400 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (400 mL × 2). The combined organic phases were 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 0:1) to obtain compound A-3.

[0155] MS-ESI[M+H] + Calculated value 236, measured value 236.

[0156] (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 protection at -78 °C, diisopropylaminolithium (2 mol / L, 216 mL, tetrahydrofuran solution) was added dropwise. The reaction mixture 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 quench the reaction mixture. 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.

[0157] MS-ESI[M+H] + Calculated value 324, measured value 324.

[0158] 1 H NMR (400MHz, CDCl3) δ7.18-7.26(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),2.8 8-2.93(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).

[0159] (3) A solution of dioxane hydrochloric acid (4 mol / L, 30 mL) was added to an ethanol (100 mL) solution of compound A-4 (15.6 g, 48.2 mmol). The reaction solution was stirred at 25 °C for 5 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound A-5.

[0160] MS-ESI[M-NH2+H] + Calculated value 203, measured value 203.

[0161] (4) Compound A-6 (46.9 g, 469 mmol), copper oxide (373 mg, 4.69 mmol), and triethylamine (4.75 g, 46.9 mmol) were added to an ethanol (50.0 mL) solution of the hydrochloride salt of compound A-5 (12.0 g, 46.9 mmol). The reaction solution was sealed and reacted at 85 °C for 4 hours under nitrogen protection. Water (500 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (500 mL × 2). The combined organic phases were 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 0:1) to obtain compound A-7.

[0162] MS-ESI[M+H] + Calculated value 320, measured value 320.

[0163] 1 H NMR (400MHz, CDCl3) δ7.13-7.26(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).

[0164] (5) Paraformaldehyde (6.44 g) and sodium cyanoborohydride (8.09 g, 129 mmol) were added to an ethanol (100 mL) solution of compound A-7 (13.7 g, 42.9 mmol). The reaction solution was reacted at 25 °C for 1 hour under nitrogen protection. Water (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (150 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 = 3:1) to obtain compound A-8.

[0165] MS-ESI[M+H] + Calculated value 334, measured value 334.

[0166] 1H NMR(400MHz, CDCl3)δ7.11-7.26(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=7.2Hz,3H).

[0167] (6) Add potassium bis(trimethylsilyl)amino (1 mol / L, 121 mL, tetrahydrofuran solution) to a tetrahydrofuran (500 mL) solution of compound A-8 (13.4 g, 40.2 mmol) at -78 °C. The reaction solution was reacted at -78 °C for 1 hour under nitrogen protection. Water (500 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound A.

[0168] MS-ESI[M+H] + Calculated value 288, measured value 288.

[0169] 1 H NMR (400MHz, CDCl3) δ7.19-7.27(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=13.2Hz,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).

[0170] Example 1: Synthesis of Compound 1

[0171]

[0172] (1) Compound 1-1 (1.06 g, 13.9 mmol) and sodium ethoxide (1.42 g, 20.9 mmol) were added to an ethanol (30.0 mL) solution of intermediate A (2.0 g, 6.96 mmol). The reaction solution was stirred at 80 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and ethanol (15.0 mL) and water (5.0 mL) were added. The pH was adjusted to 6 with hydrochloric acid (1 mol / L). The solid precipitated, filtered, and the filter cake was dried to obtain compound 1-2.

[0173] MS-ESI[M+H] + Calculated value 300, measured value 300.

[0174] 1 H NMR (400MHz, DMSO-d6) δ12.43(br s,1H),12.28(br s,1H),7.23-7.27(m,3H),7.21(br s,1H),3.49(br d,J=16.8Hz,1H),3.05(br d,J=16.4Hz,1H),2.84-2.95(m,2H),2.57-2.69(m,1H),2.40-2.48(m,1H),2.15(dt,J=13.2,8.4Hz,1H),1.98(s,3H),1.59-1.69(m,1H).

[0175] (2) Sodium hydroxide (443 mg, 11.1 mmol) and dimethyl sulfate (1.93 mg, 15.3 mmol) were added to a water (15.0 mL) solution of compounds 1-2 (1.66 g, 5.54 mmol). The reaction solution was stirred at 0 °C for 2 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). 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 1:2) to obtain compounds 1-3.

[0176] MS-ESI[M+H] + Calculated value 314, measured value 314.

[0177] 1 H NMR (400MHz, DMSO-d6) δ12.66(br s,1H),7.21-7.26(m,3H),7.15-7.20(m,1H),3.55(br d,J=17.2Hz,1H),3.12-3.20(m,1H),2.90(br t,J=7.2Hz,2H),2.77(br d,J=17.6Hz,1H),2.54(br d,J=18.4Hz,1H),2.44(s,3H),2.18(dt,J=13.2,8.4Hz,1H),2.00(s,3H),1.61(dt,J=13.2,6.4Hz,1H).

[0178] (3) Phosphorus oxychloride (6.60 g, 43.0 mmol) was added to a chloroform (4.0 mL) solution of compounds 1-3 (840 mg, 2.68 mmol). The reaction solution was stirred at 80 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure, and ice water (50.0 mL) was added. The solution was 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 (500 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compounds 1-4.

[0179] MS-ESI[M+H] + Calculated value 332, measured value 332.

[0180] 1 H NMR(400MHz, CDCl3)δ7.27(br s,1H),7.18-7.26(m,3H),3.95(br d,J=16.8Hz,1H),3.48-3.60(m,1H),3.04-3.22(m,1H),2.97-3.04(m,1H),2.8 9-2.97(m,2H),2.54(s,3H),2.23-2.31(m,1H),2.20(s,3H),1.65-1.71(m,1H).

[0181] (4) To a solution of compounds 1-4 (200 mg, 603 μmol) in dichloromethane (5.0 mL), add m-chloroperoxybenzoic acid (123 mg, 606 μmol). The reaction mixture is stirred at 0 °C for 5 hours under nitrogen protection. Add saturated sodium sulfite aqueous solution (30.0 mL) to the reaction mixture, extract with dichloromethane (20.0 mL), wash the organic phase with saturated sodium bicarbonate aqueous solution (20.0 mL × 2) and saturated brine (20.0 mL × 1), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compounds 1-5.

[0182] MS-ESI[M+H] + Calculated value 348, measured value 348.

[0183] (5) Compound 1-6 (552 mg, 2.96 mmol) was added to a solution of compound 1-5 (206 mg, 592 μmol) in N,N-dimethylformamide (10.0 mL). The reaction solution was stirred at 25 °C for 16 hours under nitrogen protection. Ethyl acetate (30.0 mL) was added to the reaction solution, and the mixture was washed with saturated brine (20.0 mL × 5). The solution was 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 1-7.

[0184] MS-ESI[M+H] + Calculated value 498, measured value 498.

[0185] (6) Compound 1-8 (22.2 mg, 193 μmol) and sodium tert-butoxide (18.6 mg, 194 μmol) were added to a tetrahydrofuran (3.0 mL) solution of compounds 1-7 (32.0 mg, 64.3 μmol). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. Ethyl acetate (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 to obtain compounds 1-9.

[0186] MS-ESI[M+H] + Calculated value 549, measured value 549.

[0187] (7) Add 1.0 mL of trifluoroacetic acid to a solution of compounds 1-9 (35.0 mg, 63.8 μmol) in dichloromethane (3.0 mL), and stir the reaction solution at 25 °C for 1 hour under nitrogen protection. Concentrate the reaction solution under reduced pressure to obtain the crude trifluoroacetate of compounds 1-10.

[0188] MS-ESI[M+H] + Calculated value 449, measured value 449.

[0189] (8) Triethylamine (31.5 mg, 331 μmol) and compound 1-11 (16.9 mg, 187 μmol) were added to a solution of trifluoroacetate (35.0 mg, 62.2 μmol) in dichloromethane (2.0 mL). The reaction solution was stirred at -78 °C for 1 hour under nitrogen 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, 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 min) to obtain compound 1.

[0190] MS-ESI[M+H] + Calculated value 503, measured value 503.

[0191] 1H NMR(400MHz,MeOD)δ7.20-7.31(m,4H),6.81(dd,J=16.8,10.4Hz,1H),6.26(dd,J=16.8, 1.6Hz,1H),5.80(dd,J=10.4,1.6Hz,1H),4.34-4.41(m,1H),4.27-4.33(m,1H),3.85(br d,J=3.2Hz,2H),3.74-3.81(m,2H),3.63-3.72(m,4H),3.54(br s,2H),3.08(dt,J=9.6,4.8Hz,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=8.8Hz,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).

[0192] Example 2: Synthesis of Compound 2

[0193]

[0194] Triethylamine (108 mg, 1.07 μmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (81.2 mg, 214 μmol) were added to a dichloromethane (2.0 mL) solution of compound 2-1 (19.2 mg, 213 μmol), and the reaction solution was stirred at 25 °C for 0.5 h. Trifluoroacetate of compound 1-10 (60.0 mg, 107 μmol) was then added to the reaction solution, and stirring was continued for another 0.5 h. The reaction solution was added to dichloromethane (20.0 mL), washed with saturated saline (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated into the formate salt of compound 2 by preparative high performance liquid chromatography (Phenomenex Luna C18, 70 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0%-30%: 35 min).

[0195] MS-ESI[M+H] + Calculated value 521, measured value 521.

[0196] 1H NMR (400MHz, MeOD) δ7.25-7.30(m,4H),5.28-5.35(m,1H),5.24(dd,J=19.2,4.0Hz,1H),4.70(dt,J= 12.4,3.6Hz,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=11.2,8.0Hz,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=13.2,8.4Hz,1H),2.32-2.40(m,1H),2.24(s,3H),2.14-2.20(m,1H),2.09(br dd,J=14.4,7.2Hz,1H),1.97-2.04(m,1H),1.89(ddd,J=13.2,8.4,4.4Hz,1H).

[0197] Example 3: Synthesis of Compound 3

[0198]

[0199] (1) To a 10.0 mL solution of intermediate 1-2 (500 mg, 1.67 mmol) in water, chloroacetic acid (1.27 g, 13.9 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution, causing a solid to precipitate. The solid was then filtered, and the filter cake was dried to obtain compound 3-1.

[0200] MS-ESI[M+H] + Calculated value: 284, Measured value: 284.

[0201] 1 H NMR (400MHz, DMSO-d6) δ11.01(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=16.0Hz,1H),2.81-2.93(m,2H),2.56(br d,J=17.2Hz,1H),2.32(d,J=17.2Hz,1H),2.16(dt,J=13.2,8.4Hz,1H),1.97(s,3H),1.62(ddd,J=13.2,8.4,4.4Hz,1H).

[0202] (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 protection. The reaction solution was concentrated under reduced pressure, and ice water (50.0 mL) was added. The solution was extracted with dichloromethane (50.0 mL × 1), and the organic phase was washed with saturated sodium bicarbonate aqueous solution (50.0 mL × 2) and saturated brine (500 mL × 1). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 3-2.

[0203] MS-ESI[M+H] + Calculated value 320, measured value 320.

[0204] 1 H NMR (400MHz, CDCl3) δ7.27(br d,J=5.2Hz,3H),7.19(br d,J=4.4Hz,1H),3.98(d,J=17.6Hz,1H),3.55(br d,J=17.6Hz,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=8.8,4.4Hz,1H).

[0205] (3) Potassium carbonate (151 mg, 1.09 mmol) and compound 3-3 (82.1 mg, 364 μmol) were added to a solution of compound 3-2 (140 mg, 437 μmol) in N,N-dimethylformamide (5.0 mL). The reaction solution was stirred at 50 °C for 6 hours under nitrogen 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 preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 3-4.

[0206] MS-ESI[M+H] + Calculated value 509, measured value 509.

[0207] (4) 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) were added to a solution of compound 3-4 (120 mg, 236 μmol) in dioxane (5.0 mL). The reaction solution was stirred at 110 °C for 4 hours under nitrogen protection. Ethyl acetate (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, 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.

[0208] MS-ESI[M+H] + Calculated value 588, measured value 588.

[0209] 1 H NMR(400MHz,MeOD)δ7.19-7.29(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=14.0,3.6Hz,1H),3.14-3.25(m,2H),2.96-3.11(m,4H),2.73-2.95(m,4H),2.54(br d,J=3.6Hz,3H),2.43(td,J=13.2,8.4Hz,2H),2.21(d,J=2.8Hz,3H),2.07-2.17(m,1H),1.81-1.92(m,3H),1.67-1.77(m,1H),1.51(s,9H).

[0210] (5) Add 1.0 mL of trifluoroacetic acid to a solution of compound 3-6 (30.0 mg, 51.0 μmol) in dichloromethane (3.0 mL), and stir the reaction solution at 25 °C for 1 hour under nitrogen protection. Concentrate the reaction solution under reduced pressure to obtain the crude trifluoroacetate of compound 3-7.

[0211] MS-ESI[M+H] + Calculated value 488, measured value 488.

[0212] (6) Triethylamine (25.2 mg, 249 μmol) and compound 3-8 (13.6 mg, 150 μmol) were added to a dichloromethane (2.0 mL) solution of trifluoroacetate (30.0 mg, 49.9 μmol) of compounds 3-7. The reaction solution was stirred at -78 °C for 1 hour under nitrogen 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, 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 min) to obtain the formate of compound 3.

[0213] MS-ESI[M+H] + Calculated value 542, measured value 542.

[0214] 1 H NMR (400MHz, MeOD) δ7.25-7.31(m,4H),6.82(br d,J=11.6Hz,1H),6.30(brd,J=16.4Hz,1H),5.84(br d,J=10.4Hz,1H),5.04(br s,1H),4.72(dt,J=12.4,3.2Hz,1H),4.54(dd,J=12.4,7.2Hz,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=5.2Hz,3H),2.89-3.01(m,4H), 2.43-2.52(m,1H),2.32-2.40(m,1H),2.26(d,J=2.4Hz,3H),2.14-2.20(m,1H),2.09(br dd,J=14.0,7.6Hz,1H),1.99-2.05(m,1H),1.87-1.96(m,1H).

[0215] Example 4: Synthesis of Compound 4

[0216]

[0217] (1) Potassium carbonate (259 mg, 1.87 mmol) and compound 4-1 (250 mg, 1.25 mmol) were added to a solution of N-methylpyrrolidone (5.0 mL) containing 200 mg, 625 μmol of compound 3-2. The reaction solution was stirred at 50 °C for 16 hours under nitrogen 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 preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound 4-2.

[0218] MS-ESI[M+H] + Calculated value 484, measured value 484.

[0219] (2) Compound 4-3 (115 mg, 999 μmol), cesium carbonate (323 mg, 991 μmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (55.3 mg, 66.1 μmol) were added to a solution of compound 4-2 (160 mg, 331 μmol) in dioxane (5.0 mL). The reaction solution was stirred at 110 °C for 4 hours under nitrogen protection. Ethyl acetate (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, concentrated under reduced pressure, and the crude product was separated by preparative thin-layer chromatography (dichloromethane / methanol = 10:1) to obtain compound 4-4.

[0220] MS-ESI[M+H] + Calculated value 563, measured value 563.

[0221] 1 H NMR(400MHz,MeOD)δ7.18-7.30(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),3.32-3.3 8(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=2.8Hz,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=0.8Hz,9H),1.17-1.37(m,3H).

[0222] (3) Add 1.0 mL of trifluoroacetic acid to a solution of compound 4-4 (80.0 mg, 142 μmol) in dichloromethane (3.0 mL), and stir the reaction solution at 25 °C for 1 hour under nitrogen protection. Concentrate the reaction solution under reduced pressure to obtain the crude trifluoroacetate of compound 4-5.

[0223] MS-ESI[M+H] + Calculated value 463, measured value 463.

[0224] (4) Triethylamine (61.4 mg, 607 μmol) and compound 4-6 (33.0 mg, 365 μmol) were added to a dichloromethane (2.0 mL) solution of trifluoroacetate (70.0 mg, 121 μmol) of compound 4-5. The reaction solution was stirred at -78 °C for 1 hour under nitrogen 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, 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 min) to obtain the formate of compound 4.

[0225] MS-ESI[M+H] + Calculated value 517, measured value 517.

[0226] 1 H NMR(400MHz,MeOD)δ7.23-7.33(m,4H),6.73-6.90(m,1H),6.29(br dd,J=16.4,2.4Hz,1H),5.81(dd,J=10.4,1.6Hz,1H),4.71(dd,J=12.4,3.2Hz,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),3.09-3.2 9(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).

[0227] Example 5: Synthesis of Compound 5

[0228]

[0229] (1) Compound 5-2 (16.6 g, 137 mmol) and tetraethyl titanate (62.3 g, 273 mmol) were added to a toluene (400 mL) solution of compound 5-1 (25.0 g, 150 mmol). The reaction solution was stirred at 120 °C for 16 hours under nitrogen protection. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (400 mL × 2). The combined organic phases were 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 2:1) to obtain compound 5-3.

[0230] MS-ESI[M+H] + Calculated value 270, measured value 270.

[0231] 1 H NMR (400MHz, CDCl3) δ7.73(d,J=2.0Hz,1H),7.44(dd,J=8.0,2.0Hz,1H),7.33(d,J =8.0Hz,1H),3.43-3.53(m,1H),3.10-3.13(m,2H),3.04-3.10(m,1H),1.32(s,9H).

[0232] (2) Ethyl acetate (22.9 g, 260 mmol) was dissolved in tetrahydrofuran (300 mL), and diisopropylaminolithium (2 mol / L, 52.0 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. Compound 5-3 (14.0 g, 51.9 mmol) in tetrahydrofuran (50.0 mL) solution was added dropwise to the reaction mixture, and stirring was continued at -78 °C for 3 hours. The temperature was raised to 0 °C, and saturated ammonium chloride aqueous solution (200 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (200 mL × 1), and the combined organic phases were washed with saturated ammonium chloride aqueous solution (200 mL × 1) and saturated brine (200 mL × 1). The mixture was 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.

[0233] MS-ESI[M+H] + Calculated value 358, measured value 358.

[0234] 1H NMR (400MHz, CDCl3) δ7.21-7.24(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).

[0235] (3) A solution of dioxane hydrochloric acid (4 mol / L, 15.0 mL) was added to an ethanol (40.0 mL) solution of compound 5-4 (5.10 g, 14.3 mmol). The reaction solution was stirred at 25 °C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 5-5.

[0236] MS-ESI[M-NH2+H] + Calculated value 237, measured value 237.

[0237] (4) Compound 5-6 (15.7 g, 157 mmol), copper oxide (219 mg, 2.75 mmol), and triethylamine (4.18 g, 41.4 mmol) were added to an ethanol (20.0 mL) solution of the hydrochloride salt of compound 5-5 (4.0 g, 13.8 mmol). The reaction solution was sealed and reacted at 85 °C for 8 hours under nitrogen protection. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were 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 6:1) to obtain compound 5-7.

[0238] MS-ESI[M+H] + Calculated value 354, measured value 354.

[0239] 1H NMR (400MHz, CDCl3) δ7.02-7.25(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,1 H), 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).

[0240] (5) Paraformaldehyde (500 mg) and sodium cyanoborohydride (533 mg, 8.48 mmol) were added to an ethanol (15.0 mL) solution of compound 5-7 (1.0 g, 2.83 mmol). The reaction solution was reacted at 25 °C for 16 hours under nitrogen protection. Water (50.0 mL) was added to the reaction solution, 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 to 4:1) to obtain compound 5-8.

[0241] MS-ESI[M+H] + Calculated value 368, measured value 368.

[0242] 1 H NMR (400MHz, CDCl3) δ7.13-7.21(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),2.5 9-2.70(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).

[0243] (6) At -78℃, potassium bis(trimethylsilyl)amino (1 mol / L, 4.89 mL, tetrahydrofuran solution) was added to a tetrahydrofuran (10.0 mL) solution of compound 5-8 (600 mg, 1.63 mmol). The reaction solution was reacted at -78℃ for 2 hours under nitrogen protection. A saturated ammonium chloride aqueous solution (50.0 mL) was added to the reaction solution, 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 to 6:1) to obtain compound 5-9.

[0244] MS-ESI[M+H] + Calculated value 322, measured value 322.

[0245] 1 H NMR (400MHz, CDCl3) δ7.17-7.23(m,2H),7.11-7.15(m,1H),4.22-4.32(m,2H),3.50(d,J=15.2Hz,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=13.2,8.4,4.4Hz,1H),1.30-1.34(m,3H).

[0246] (7) Compound 5-10 (208 mg, 2.37 mmol) and sodium ethoxide (279 mg, 4.10 mmol) were added to a 10.0 mL ethanol solution of compound 5-9 (440 mg, 1.37 mmol). The reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and ethanol (15.0 mL) and water (5.0 mL) were added. The pH was adjusted to 6 with hydrochloric acid (1 mol / L). The solid precipitated, filtered, and the filter cake was dried to obtain compound 5-11.

[0247] MS-ESI[M+H] + Calculated value 334, measured value 334.

[0248] 1H NMR (400MHz, DMSO-d6) δ12.20-12.60(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).

[0249] (8) Chloroacetic acid (590 mg, 6.24 mmol) was added to a 10.0 mL aqueous solution of intermediate 5-11 (360 mg, 1.08 mmol). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution, causing a solid to precipitate. The solid was filtered again, and the filter cake was dried to obtain compound 5-12.

[0250] MS-ESI[M+H] + Calculated value 318, measured value 318.

[0251] 1 H NMR (400MHz, DMSO-d6) δ11.03(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).

[0252] (9) Compound 5-12 (210 mg, 661 μmol) was dissolved in phosphorus oxychloride (8.25 g, 53.8 mmol), and the reaction solution was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and ice water (50.0 mL) was added. The solution was extracted with dichloromethane (50.0 mL × 1), and the organic phase was washed with saturated sodium bicarbonate aqueous solution (50.0 mL × 2) and saturated brine (500 mL × 1). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 5-13.

[0253] MS-ESI[M+H] + Calculated value 356, measured value 356.

[0254] 1H NMR (400MHz, CDCl3) δ7.28-7.37(m,2H),7.22(s,1H),3.87-4.04(m,1H),3.51(br d,J=18.0Hz,1H),3.14(br d,J=17.6Hz,1H),2.88-2.96(m,3H),2.23(dt,J=13.2,8.4Hz,1H),2.10(s,3H),1.58-1.69(m,1H).

[0255] (10) Potassium carbonate (292 mg, 2.11 mmol) and the hydrochloride salt of compound 5-14 (126 mg, 636 μmol) were added to a solution of N-methylpyrrolidone (5.0 mL) containing 150 mg, 423 μmol of compound 5-13. The reaction solution was stirred at 50 °C for 12 hours under nitrogen 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, and concentrated under reduced pressure to obtain compound 5-15.

[0256] MS-ESI[M+H] + Calculated value 443, measured value 443.

[0257] (11) To a solution of compound 5-15 (187 mg, 422 μmol) in dichloromethane (10.0 mL), triethylamine (214 mg, 2.11 mmol) and di-tert-butyl carbonate (920 mg, 4.22 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 hours. Dichloromethane (20.0 mL) was added to the reaction mixture, and the solution 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 = 6:1) to obtain compound 5-16.

[0258] MS-ESI[M+H] + Calculated value 543, measured value 543.

[0259] (12) Compound 5-17 (50.9 mg, 442 μmol), potassium carbonate (61.0 mg, 441 μmol), tris(dibenzylacetone)dipalladium (27.0 mg, 29.5 μmol), and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (28.1 mg, 58.9 μmol) were added to a solution of compound 5-16 (80.0 mg, 147 μmol) in dioxane (5.0 mL). The reaction solution was stirred at 110 °C for 6 hours under nitrogen protection. Ethyl acetate (40.0 mL) was added to the reaction solution, 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.

[0260] MS-ESI[M+H] + Calculated value 622, measured value 622.

[0261] 1 H NMR (400MHz, MeOD) δ7.18-7.31(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=14.0Hz,2H),3.24(br dd,J=14.0,3.6Hz,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=1.6Hz,9H).

[0262] (13) Add 1.0 mL of trifluoroacetic acid to a solution of compound 5-18 (70.0 mg, 113 μmol) in dichloromethane (3.0 mL), and stir the reaction solution at 25 °C for 1 hour under nitrogen protection. Concentrate the reaction solution under reduced pressure to obtain the crude trifluoroacetate of compound 5-19.

[0263] MS-ESI[M+H] + Calculated value 522, measured value 522.

[0264] (14) Triethylamine (28.6 mg, 283 μmol) and compound 5-20 (17.1 mg, 189 μmol) were added to a dichloromethane (2.0 mL) solution of trifluoroacetate (60.0 mg, 94.3 μmol) of compound 5-19. The reaction solution was stirred at -78 °C for 0.5 h under nitrogen 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, 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 min) to obtain the formate salt of compound 5.

[0265] MS-ESI[M+H] + Calculated value 576, measured value 576.

[0266] 1 H NMR (400MHz, MeOD) δ7.25-7.30(m,2H),7.22(d,J=17.6Hz,1H),6.80(br s,1H),6.30(br d,J=16.4Hz,1H),5.84(br d,J=10.8Hz,1H),5.03(br s,1H),4.69(br dd,J=12.4,3.6Hz,1H),4.50(ddd,J=12.4,7.2,1.6Hz,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=1.6Hz,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=1.6Hz,3H),2.11-2.19(m,1H),2.07(br dd,J=14.4,7.6Hz,1H),1.96-2.03(m,1H),1.87-1.95(m,1H).

[0267] Example 6: Synthesis of Compounds 6 and 7

[0268]

[0269] (1) Compound 6-2 (18.3 g, 151 mmol) and tetraethyl titanate (69.0 g, 302 mmol) were added to a toluene (400 mL) solution of compound 6-1 (25.0 g, 166 mmol). The reaction solution was stirred at 120 °C for 16 hours under nitrogen protection. Water (400 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (400 mL × 2). The combined organic phases were 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 0:1) to obtain compound 6-3.

[0270] MS-ESI[M+H] + Calculated value 254, measured value 254.

[0271] 1 H NMR (400MHz, CDCl3) δ7.42-7.48(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).

[0272] (2) Ethyl acetate (22.4 g, 254 mmol) was dissolved in tetrahydrofuran (200 mL), and diisopropylaminolithium (2 mol / L, 50.9 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. Compound 6-3 (12.9 g, 50.9 mmol) in tetrahydrofuran (50.0 mL) solution was added dropwise to the reaction mixture, and stirring was continued at -78 °C for 3 hours. The temperature was raised to 0 °C, and saturated ammonium chloride aqueous solution (200 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL × 1), and the combined organic phases were washed with saturated ammonium chloride aqueous solution (200 mL × 1) and saturated brine (200 mL × 1). The mixture was 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.

[0273] MS-ESI[M+H] + Calculated value 342, measured value 342.

[0274] 1H NMR (400MHz, CDCl3) δ7.27-7.30(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).

[0275] (3) A solution of dioxane in hydrochloric acid (4 mol / L, 40.0 mL) was added to an ethanol (120 mL) solution of compound 6-4 (12.4 g, 36.3 mmol). The reaction solution was stirred at 25 °C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 6-5.

[0276] MS-ESI[M-NH2+H] + Calculated value 221, measured value 221.

[0277] (4) Compound 6-6 (37.6 g, 376 mmol), copper oxide (577 mg, 7.26 mmol), and triethylamine (3.67 g, 36.3 mmol) were added to an ethanol (80.0 mL) solution of the hydrochloride salt of compound 6-5 (9.94 g, 36.3 mmol). The reaction solution was sealed and reacted at 85 °C for 8 hours under nitrogen protection. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were 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 6:1) to obtain compound 6-7.

[0278] MS-ESI[M+H] + Calculated value 338, measured value 338.

[0279] 1 H NMR (400MHz, CDCl3) δ7.16-7.22(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).

[0280] (5) Paraformaldehyde (1.33 g) and sodium cyanoborohydride (1.68 g, 26.6 mmol) were added to an ethanol (15.0 mL) solution of compound 6-7 (3.0 g, 8.89 mmol). The reaction solution was reacted at 25 °C for 16 hours under nitrogen protection. Water (50.0 mL) was added to the reaction solution, 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 to 4:1) to obtain compound 6-8.

[0281] MS-ESI[M+H] + Calculated value 352, measured value 352.

[0282] 1 H NMR (400MHz, CDCl3) δ7.16-7.22(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).

[0283] (6) At -78℃, potassium bis(trimethylsilyl)amino (1 mol / L, 25.6 mL, tetrahydrofuran solution) was added to a tetrahydrofuran (30.0 mL) solution of compound 6-8 (3.00 g, 8.54 mmol). The reaction solution was reacted at -78℃ for 2 hours under nitrogen protection. A saturated ammonium chloride aqueous solution (50.0 mL) was added to the reaction solution, 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 to 6:1) to obtain compound 6-9.

[0284] MS-ESI[M+H] + Calculated value 306, measured value 306.

[0285] 1H NMR (400MHz, CDCl3) δ7.21-7.26(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).

[0286] (7) Compound 6-10 (997 mg, 13.1 mmol) and sodium ethoxide (1.34 g, 19.6 mmol) were added to a 20.0 mL ethanol solution of compound 6-9 (2.00 g, 6.55 mmol). The reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and ethanol (50.0 mL) was added. The pH was adjusted to 6 with hydrochloric acid (1 mol / L). The solid precipitated was filtered, and the filter cake was dried to obtain compound 6-11.

[0287] MS-ESI[M+H] + Calculated value 318, measured value 318.

[0288] 1 H NMR (400MHz, DMSO-d6) δ11.61-12.93(s,2H),7.28-7.36(m,1H),7.06-7.14(m,1H),6.97-7.04(m,1 H),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).

[0289] (8) To a 10.0 mL aqueous solution of intermediate 6-11 (1.90 g, 5.99 mmol), chloroacetic acid (2.26 g, 23.9 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution, causing a solid to precipitate. The solid was then filtered, and the filter cake was dried to obtain compound 6-12.

[0290] MS-ESI[M+H] + Calculated value 302, measured value 302.

[0291] 1H NMR (400MHz, DMSO-d6) δ10.98-11.04(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).

[0292] (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 protection. The reaction solution was concentrated under reduced pressure, and ice water (10.0 mL) and saturated sodium bicarbonate aqueous solution (50.0 mL) were added. The solution was extracted with dichloromethane (50.0 mL × 1), and the organic phase was washed with saturated sodium bicarbonate aqueous solution (50.0 mL × 2) and saturated brine (50.0 mL × 1). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 6-13.

[0293] MS-ESI[M+H] + Calculated value 338, measured value 338.

[0294] (10) Potassium carbonate (1.02 g, 7.39 mmol) and the hydrochloride salt of compound 6-14 (439 mg, 2.22 mmol) were added to a solution of N,-methylpyrrolidone (5.0 mL) containing 500 mg, 1.48 mmol of compound 6-13. The reaction solution was stirred at 50 °C for 12 hours under nitrogen 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, and concentrated under reduced pressure to obtain compound 6-15.

[0295] MS-ESI[M+H] + Calculated value 427, measured value 427.

[0296] 1 H NMR(400MHz,DMSO-d6)δ7.26-7.37(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).

[0297] (11) To a solution of compound 6-15 (1.40 g, 3.28 mmol) in dichloromethane (20.0 mL), triethylamine (2.14 g, 21.1 mmol) and di-tert-butyl carbonate (3.58 mg, 16.4 mmol) were added. The reaction mixture was stirred at 25 °C for 12 hours. Dichloromethane (20.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (20.0 mL × 2). The mixture was 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 to 6:1) to obtain compound 6-16.

[0298] MS-ESI[M+H] + Calculated value 527, measured value 527.

[0299] (12) 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) were added to a solution of compound 6-16 (900 mg, 1.71 mmol) in dioxane (10.0 mL). The reaction solution was stirred at 110 °C for 6 hours under nitrogen protection. Ethyl acetate (40.0 mL) was added to the reaction solution, 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 to 15:1) to obtain compound 6-18.

[0300] MS-ESI[M+H] + Calculated value 606, measured value 606.

[0301] 1 H NMR (400MHz, CDCl3) δ7.22-7.26(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),2.2 9-2.35(s,3H),1.79-1.99(m,4H),1.55-1.75(m,4H),1.49-1.55(s,9H).

[0302] (13) Trifluoroacetic acid (1.0 mL) was added to a solution of compound 6-18 (342 mg, 564 μmol) in dichloromethane (3.0 mL). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetate of compound 6-19.

[0303] MS-ESI[M+H] + Calculated value 506, measured value 506.

[0304] (14) Triethylamine (22.0 mg, 217 μmol) and compound 6-20 (29.5 mg, 326 μmol) were added to a solution of trifluoroacetate (110 mg, 217 μmol) in dichloromethane (2.0 mL). The reaction solution was stirred at -78 °C for 0.5 hours under nitrogen 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, concentrated under reduced pressure, and the crude product was separated by reverse column chromatography (acetonitrile / water = 0:1 to 1:19) to obtain compound 6-21.

[0305] MS-ESI[M+H] + Calculated value 560, measured value 560.

[0306] (15) Compounds 6 and 7 were separated by chiral supercritical fluid chromatography.

[0307] Separation conditions: Column type: AD-H; Column size: 0.46cm ID×15cm L; Injection volume: 2μL; Mobile phase: carbon dioxide: ethanol (0.1% triethylamine) = 70:30; Detection wavelength: 254nm; Column temperature: 25℃.

[0308] Compound 6 had a retention time of 4.071 minutes and an ee value of 99.42%.

[0309] MS-ESI[M+H] + Calculated value 560, measured value 560.

[0310] 1H NMR (400MHz, DMSO-d6) δ7.31(td,J=7.6,5.2Hz,1H),7.10(d,J=7.6Hz,1H),7.03-6.97(m,1H),6.95-6.78(m,1H),6.19(d, J=16.8Hz,1H),5.77(d,J=8.8Hz,1H),5.00-4.72(m,1H),4.24(d,J=6.8Hz,1H),4.00(dd,J=10.8,6.4Hz,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=12.4,8.4Hz,1H),1.77-1.68(m,1H),1.68-1.62(m,2H),1.60-1.51(m,1H).

[0311] Compound 7 had a retention time of 4.436 minutes and an ee value of 98.76%.

[0312] MS-ESI[M+H] + Calculated value 560, measured value 560.

[0313] 1 H NMR(400MHz, DMSO-d6)δ7.31(dt,J=12.8,6.4Hz,1H),7.11(d,J=7.2Hz,1H),7.04-6.95(m,1H),6.91-6.79 (m,1H),6.18(d,J=17.2Hz,1H),5.78(d,J=8.8Hz,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=17.6Hz,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).

[0314] Example 7 Synthesis of compounds 8 and 9

[0315]

[0316] (1) Triethylamine (32.0 mg, 316 μmol), tricyclic propylphosphonic anhydride (503 mg, 791 μmol, 470 μL, 50% ethyl acetate solution), and hydrochloride of compound 7-1 (600 mg, 4.75 mmol) were added to a dichloromethane (2.0 mL) solution of compound 6-19 (160 mg, 316 μmol). The reaction solution was stirred at 25 °C for 0.5 hours. 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 to obtain crude compound 7-2.

[0317] MS-ESI[M+H] + Calculated value 578, measured value 578.

[0318] (2) Compound 7-2 was separated into compounds 8 and 9 by chiral supercritical fluid chromatography.

[0319] Separation conditions: Column type: AD-H; Column size: 0.46cm ID×15cm L; Injection volume: 2μL; Mobile phase: carbon dioxide: ethanol (0.1% triethylamine) = 70:30; Detection wavelength: 254nm; Column temperature: 25℃.

[0320] Compound 8 had a retention time of 3.689 minutes and an ee value of 98.44%.

[0321] MS-ESI[M+H] + Calculated value 578, measured value 578.

[0322] 1H NMR (400MHz, DMSO-d6) δ7.35-7.27(m,1H),7.10(d,J=7.6Hz,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=14.4Hz,2H),3.20 (dd,J=13.6,3.6Hz,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=6.8Hz,2H).

[0323] Compound 9 had a retention time of 4.059 minutes and an ee value of 97.90%.

[0324] MS-ESI[M+H] + Calculated value 578, measured value 578.

[0325] 1 H NMR (400MHz, DMSO-d6) δ7.31(d,J=5.2Hz,1H),7.11(d,J=8.0Hz,1H),7.05-6.92(m,1H),5.39(d,J=13.6Hz,1H) ,5.35-5.17(m,1H),4.22(d,J=10.4Hz,1H),4.09-3.98(m,1H),3.90(d,J=13.6Hz,1H),3.85-3.74(m,1H),3.53 (d,J=7.3Hz,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).

[0326] Example 8 Synthesis of Compound 10

[0327]

[0328] (1) At -78 °C, potassium bis(trimethylsilyl)amino (1 mol / L, 9.0 mL, tetrahydrofuran solution) was added to a tetrahydrofuran (10.0 mL) solution of compound 6-7 (1.00 g, 2.96 mmol). The reaction solution was reacted at -78 °C for 2 hours under nitrogen protection. A saturated ammonium chloride aqueous solution (50.0 mL) was added to the reaction solution, 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 to 6:1) to obtain compound 8-1.

[0329] MS-ESI[M+H] + Calculated value 292, measured value 292.

[0330] 1 H NMR (400MHz, CDCl3) δ7.18-7.25(m,1H),7.00-7.05(m,1H),6.89(t,J=9.2Hz,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=6.0Hz,1H),2.08-2.20(m,2H),1.30-1.34(m,3H).

[0331] (2) Compound 8-2 (507 mg, 6.66 mmol) and sodium ethoxide (679 mg, 9.98 mmol) were added to a 10.0 mL ethanol solution of compound 8-1 (970 mg, 3.33 mmol). The reaction solution was stirred at 80 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The precipitated solid was filtered, and the filter cake was dried to obtain compound 8-3.

[0332] MS-ESI[M+H] + Calculated value 304, measured value 304.

[0333] 1H NMR (400MHz, DMSO-d6) δ12.39(br s,1H),12.25(br s,1H),7.29(td,J=7.6,5.2Hz,1H),7.10(d,J=7.6Hz,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).

[0334] (3) Chloroacetic acid (560 mg, 5.93 mmol) was added to a 10.0 mL aqueous solution of intermediate 8-3 (470 mg, 1.55 mmol). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution, causing a solid to precipitate. The solid was then filtered and dried to obtain compound 8-4.

[0335] MS-ESI[M+H] + Calculated value 288, measured value 288.

[0336] 1 H NMR (400MHz, DMSO-d6) δ11.03(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).

[0337] (4) Compound 8-4 (200 mg, 696 μmol) was dissolved in phosphorus oxychloride (8.25 g, 53.8 mmol), and triethylamine (141 mg, 1.39 mmol) was added. The reaction solution was stirred at 85 °C for 16 hours under nitrogen protection. Ice water (10.0 mL) and saturated sodium bicarbonate aqueous solution (50.0 mL) were added to the reaction solution, and the mixture was 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 8-5.

[0338] MS-ESI[M+H]+ Calculated value 324, measured value 324.

[0339] 1 H NMR(400MHz, DMSO-d6)δ7.29(td,J=7.6,5.2Hz,1H),7.13(d,J=7.6Hz,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).

[0340] (5) Potassium carbonate (426 mg, 3.08 mmol) and the hydrochloride salt of compound 8-6 (183 mg, 924 μmol) were added to a solution of N-methylpyrrolidone (5.0 mL) containing 200 mg, 617 μmol of compound 8-5. The reaction solution was stirred at 50 °C for 12 hours under nitrogen 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, and concentrated under reduced pressure to obtain compound 8-7.

[0341] MS-ESI[M+H] + Calculated value 413, measured value 413.

[0342] (6) To a solution of compound 8-7 (250 mg, 605 μmol) in dichloromethane (10.0 mL), triethylamine (307 mg, 3.03 mmol) and di-tert-butyl carbonate (264 mg, 1.21 mmol) were added. The reaction mixture was stirred at 25 °C for 12 hours. Dichloromethane (20.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (20.0 mL × 2). The mixture was 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 to 1:1) to obtain compound 8-8.

[0343] MS-ESI[M+H] + Calculated value 513, measured value 513.

[0344] 1H NMR (400MHz, CDCl3) δ7.28-7.43(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).

[0345] (7) Compound 8-9 (138 mg, 1.20 mmol), cesium carbonate (391 mg, 1.20 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (66.9 mg, 80.0 μmol) were added to a solution of compound 8-8 (205 mg, 400 μmol) in dioxane (5.0 mL). The reaction solution was stirred at 110 °C for 6 hours under nitrogen protection. Ethyl acetate (40.0 mL) was added to the reaction solution, 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 10:1) to obtain compound 8-10.

[0346] MS-ESI[M+H] + Calculated value 592, measured value 592.

[0347] 1 H NMR(400MHz,MeOD)δ7.25-7.32(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).

[0348] (8) Add 1.0 mL of trifluoroacetic acid to a solution of compound 8-10 (100 mg, 169 μmol) in dichloromethane (3.0 mL), and stir the reaction solution at 25 °C for 0.5 hours under nitrogen protection. Concentrate the reaction solution under reduced pressure to obtain the crude trifluoroacetate of compound 8-11.

[0349] MS-ESI[M+H] + Calculated value 492, measured value 492.

[0350] (9) Triethylamine (20.1 mg, 199 μmol) and compound 8-12 (6.6 mg, 72.9 μmol) were added to a dichloromethane (2.0 mL) solution of trifluoroacetate (40.0 mg, 66.1 μmol) of compound 8-11. The reaction solution was stirred at -78 °C for 0.5 hours under nitrogen 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, 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 min) to obtain the formate salt of compound 10.

[0351] MS-ESI[M+H] + Calculated value 546, measured value 546.

[0352] 1 H NMR (400MHz, MeOD) δ7.32(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).

[0353] Example 9 Synthesis of Compound 11

[0354]

[0355]

[0356] (1) Compound 11-2 (29.1 g, 240 mmol) and tetraethyl titanate (91.4 g, 401 mmol) were added to a toluene (400 mL) solution of compound 11-1 (30.0 g, 200 mmol). The reaction solution was stirred at 120 °C for 16 hours under nitrogen protection. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 5). The combined organic phases were 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 10:1) to obtain compound 11-3.

[0357] MS-ESI[M+H] + Calculated value 254, measured value 254.

[0358] 1 H NMR (400MHz, CDCl3) δ7.41 (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).

[0359] (2) Ethyl acetate (32.9 g, 260 mmol) was dissolved in tetrahydrofuran (200 mL), and diisopropylaminolithium (2 mol / L, 56.0 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. Compound 11-3 (18.9 g, 74.6 mmol) in tetrahydrofuran (100 mL) solution was added dropwise to the reaction mixture, and stirring was continued at -65 °C for 3 hours. The temperature was raised to 0 °C, and saturated ammonium chloride aqueous solution (500 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (500 mL × 2), and the combined organic phases were washed with saturated ammonium chloride aqueous solution (500 mL × 1) and saturated brine (500 mL × 1). The mixture was 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.

[0360] MS-ESI[M+H] + Calculated value 342, measured value 342.

[0361] 1H NMR (400MHz, CDCl3) δ7.18 (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).

[0362] (3) A solution of dioxane hydrochloric acid (4 mol / L, 20.0 mL) was added to an ethanol (60.0 mL) solution of compound 11-4 (6.90 g, 19.6 mmol). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 11-5.

[0363] MS-ESI[M-NH2+H] + Calculated value 221, measured value 221.

[0364] (4) 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 to an ethanol (30.0 mL) solution of the hydrochloride salt of compound 11-5 (5.37 g, 19.6 mmol). The reaction solution was sealed and reacted at 85 °C for 8 hours under nitrogen protection. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were 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.

[0365] MS-ESI[M+H] + Calculated value 338, measured value 338.

[0366] 1H NMR(400MHz, CDCl3)δ7.12(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(d dd,J=13.2,8.4,4.4Hz,1H), 1.25(t,J=7.2Hz,3H), 1.20(t,J=7.2Hz,3H).

[0367] (5) Paraformaldehyde (5.28 g) and sodium cyanoborohydride (3.31 g, 52.7 mmol) were added to an ethanol (80.0 mL) solution of compound 11-7 (5.93 g, 17.6 mmol). The reaction solution was reacted at 25 °C for 16 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 1). 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 9:1) to obtain compound 11-8.

[0368] MS-ESI[M+H] + Calculated value 352, measured value 352.

[0369] 1 H NMR (400MHz, CDCl3) δ7.09 (dd, J=8.0, 5.2Hz, 1H), 6.87-6.95 (m, 2H), 4.11 (q d, 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).

[0370] (6) Add bis(trimethylsilyl)aminopotassium (1 mol / L, 17.1 mL, tetrahydrofuran solution) to a tetrahydrofuran (20.0 mL) solution of compound 11-8 (2.00 g, 5.69 mmol) at -78 °C. The reaction solution was reacted at -65 °C for 2 hours under nitrogen protection. Add saturated ammonium chloride aqueous solution (100 mL) to the reaction solution, extract with ethyl acetate (100 mL × 1), combine the organic phases, wash with saturated brine (100 mL × 1), dry with 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 10:1) to obtain compound 11-9.

[0371] MS-ESI[M+H] + Calculated value 306, measured value 306.

[0372] 1 H NMR (400MHz, CDCl3) δ7.10-7.18(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).

[0373] (7) Compound 11-10 (663 mg, 8.71 mmol) and sodium ethoxide (889 mg, 13.1 mmol) were added to an ethanol (15.0 mL) solution of compound 11-9 (1.33 g, 4.36 mmol). The reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The precipitated solid was filtered, and the filter cake was dried to obtain compound 11-11.

[0374] MS-ESI[M+H] + Calculated value 318, measured value 318.

[0375] 1H NMR (400MHz, DMSO-d6) δ7.27 (dd, J=8.4, 5.2Hz, 1H), 7.07 (td, J=8.8, 2.4Hz, 1H ),6.98(d,J=9.2Hz,1H),3.47(d,J=16.4Hz,1H),3.03(d,J=16.4Hz,1H),2.81- 2.92(m,2H),2.62(d,J=17.6Hz,1H),2.41(d,J=17.6Hz,1H),2.19(dt,J=13.6,8.4Hz,1H),1.98(s,3H),1.66(ddd,J=13.2,8.4,4.4Hz,1H).

[0376] (8) To a 15.0 mL aqueous solution of compound 11-11 (1.36 g, 1.08 mmol), chloroacetic acid (1.77 g, 18.7 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution, causing a solid to precipitate. The solid was then filtered, and the filter cake was dried to obtain compound 11-12.

[0377] MS-ESI[M+H] + Calculated value 302, measured value 302.

[0378] 1 H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 10.76 (s, 1H), 7.27 (dd, J = 8.4, 5.2Hz, 1H), 7 .08(td,J=8.8,2.4Hz,1H),6.99(dd,J=9.2,2.4Hz,1H),3.44(d,J=16.0Hz,1H),3.0 1(d,J=16.0Hz,1H),2.80-2.91(m,2H),2.61(d,J=17.6Hz,1H),2.33(d,J=17.2Hz, 1H), 2.21 (dt, J=13.2, 8.4Hz, 1H), 1.98 (s, 3H), 1.67 (ddd, J=13.2, 8.4, 4.4Hz, 1H).

[0379] (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 protection. The reaction solution was concentrated under reduced pressure, and ice water (100 mL) was added. The solution was extracted with dichloromethane (100 mL × 1), and the organic phase was washed with saturated sodium bicarbonate aqueous solution (100 mL × 2) and saturated brine (100 mL × 1). The solution was 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.

[0380] MS-ESI[M+H] + Calculated value 338, measured value 338.

[0381] 1 H NMR (400MHz, DMSO-d6) δ7.29(dd,J=8.4,5.2Hz,1H),7.09(td,J=8.8,2.4Hz,1H),6.98(dd,J=9.2,2.4Hz,1H),3.93(d,J=17.6Hz,1H),3. 51(d,J=17.6Hz,1H),3.12(d,J=18.0Hz,1H),2.87-2.97(m,3H),2.25(dt,J=13.2,8.4Hz,1H),2.11(s,3H),1.66(dt,J=13.2,6.4Hz,1H).

[0382] (10) Potassium carbonate (245 mg, 1.77 mmol) and compound 11-14 (200 mg, 888 μmol) were added to a solution of N-methylpyrrolidone (5.0 mL) containing 200 mg, 591 μmol of compound 11-13. The reaction solution was stirred at 50 °C for 10 hours under nitrogen protection. Ethyl acetate (30.0 mL) was added to the reaction solution, and the mixture was washed with saturated brine (30.0 mL × 5). The solution was 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.

[0383] MS-ESI[M+H] + Calculated value 527, measured value 527.

[0384] 1H NMR(400MHz,MeOD)δ7.21-7.30(m,1H),7.01(td,J=8.8,2.4Hz,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. 6Hz,1H),3.25(dd,J=13.6,3.6Hz,1H),3.06-3.20(m,1H),2.80-3.03(m,6H),2.39-2.50 (m,1H),2.23(d,J=1.6Hz,3H),1.89(ddt,J=13.2,7.6,4.0Hz,1H),1.51(d,J=1.2Hz,9H).

[0385] (11) 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) were added to a solution of compound 11-15 (220 mg, 417 μmol) in dioxane (8.0 mL). The reaction solution was stirred at 110 °C for 4 hours under nitrogen protection. Ethyl acetate (50.0 mL) was added to the reaction solution, and the solution 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 11-17.

[0386] MS-ESI[M+H] + Calculated value 606, measured value 606.

[0387] 1H NMR(400MHz,MeOD)δ7.26(t,J=5.6Hz,1H),6.98-7.08(m,1H),6.86-6.98(m,1H),4.63(d,J=7.6Hz,1H),4.2 6-4.46(m,2H),3.92-4.17(m,3H),3.65-3.82(m,2H),3.42(dd,J=13.6,3.6Hz,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=4.0Hz,3H),2.34-2.49(m ,2H),2.23(d,J=2.0Hz,3H),2.04-2.16(m,1H),1.78-1.94(m,3H),1.67-1.78(m,1H),1.51(d,J=1.6Hz,9H).

[0388] (12) Add 1.0 mL of trifluoroacetic acid to a solution of compound 11-17 (170.0 mg, 281 μmol) in dichloromethane (3.0 mL), and stir the reaction solution at 25 °C for 1 hour under nitrogen protection. Concentrate the reaction solution under reduced pressure to obtain the crude trifluoroacetate of compound 11-18.

[0389] MS-ESI[M+H] + Calculated value 506, measured value 506.

[0390] (13) Triethylamine (78.1 mg, 775 μmol) and compound 11-19 (46.7 mg, 516 μmol) were added to a solution of trifluoroacetate (160.0 mg, 258 μmol) in dichloromethane (5.0 mL). The reaction solution was stirred at -65 °C for 0.5 hours under nitrogen 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 (Phenomenex Luna C18, 100 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0%-30%: 8 min) to obtain the formate of compound 11.

[0391] MS-ESI[M+H] + Calculated value 560, measured value 560.

[0392] 1H NMR (400MHz, MeOD) δ7.28(t,J=6.0Hz,1H),6.93-7.11(m,2H),6.81(s,1H),6.29(d,J=16.4Hz,1H),5.84(d,J=10.4Hz,1H ),4.90-5.14(m,1H),4.68-4.75(m,1H),4.55(dd,J=12.4,7.2Hz,1H),4.17-4.38(m,1H),3.89-4.16(m,2H),3.80(d,J=15 .6Hz,3H),3.65-3.72(m,1H),3.54(s,1H),3.04-3.30(m,4H),3.02(d,J=5.2Hz,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=14.4,7.6Hz,1H),1.97-2.05(m,1H),1.88-1.96(m,1H).

[0393] Example 10 Synthesis of Compound 12

[0394]

[0395] Triethylamine (73.5 mg, 726 μmol), trifluoroacetate of compound 11-18 (150 mg, 242 μmol), and tricyclic propylphosphophosphate anhydride (462 mg, 726 μmol, 50% ethyl acetate solution) were added to a dichloromethane (5.0 mL) solution of compound 12-1 (65.4 mg, 726 μmol). The reaction mixture was stirred at 25 °C for 1 hour. 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, 70 mm × 30 mm 3 μm, A: water (0.225% formic acid); B: acetonitrile, 0%–30%: 8 min) to obtain the formate salt of compound 12.

[0396] MS-ESI[M+H] + Calculated value 578, measured value 578.

[0397] 1H NMR(400MHz,MeOD)δ7.23-7.31(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=7.6H z,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).

[0398] Example 11 Synthesis of Compound 13

[0399]

[0400] Triethylamine (14.7 mg, 145 μmol), trifluoroacetate of compound 6-19 (90.0 mg, 145 μmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg, 290 μmol) were added to a dichloromethane (2.0 mL) solution of compound 13-1 (45.3 mg, 435 μmol). The reaction mixture was stirred at 25 °C for 0.5 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, 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 NH4HCO3); B: acetonitrile, 35%–75%: 11 min) to obtain compound 13.

[0401] MS-ESI[M+H] + Calculated value: 604, Measured value: 604.

[0402] 1H NMR(400MHz,MeOD)δ7.28-7.35(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).

[0403] Example 12 Synthesis of Compound 14

[0404]

[0405] (1) Silver fluoride (1.97 g, 15.5 mmol) was added to a solution of compound 14-1 (1.0 g, 5.18 mmol) in acetonitrile (10.0 mL). The reaction solution was stirred at 25 °C for 24 hours under nitrogen protection. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 14-2.

[0406] 1 H NMR (400MHz, CDCl3) δ6.90-7.04(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).

[0407] (2) Lithium hydroxide (381 mg, 9.08 mmol) and water (3.0 mL) were added to a tetrahydrofuran (3.0 mL) solution of compound 14-2 (400 mg, 3.03 mmol). The reaction solution was stirred at 25 °C for 12 hours under nitrogen protection. Hydrogen chloride aqueous solution (20 mL, 1 mol / L) was added to the reaction solution, 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.

[0408] 1H NMR (400MHz, DMSO-d6) δ12.36-12.68(s,1H),6.80-6.96(m,1H),5.88-6.04(m,1H),5.03-5.22(m,2H).

[0409] (3) Triethylamine (14.7 mg, 145 μmol), trifluoroacetate of compound 6-19 (90.0 mg, 145 μmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg, 290 μmol) were added to a dichloromethane (2.0 mL) solution of compound 14-3 (45.3 mg, 435 μmol). The reaction solution was stirred at 25 °C for 0.5 hours. The reaction solution was added to dichloromethane (20.0 mL), washed with saturated saline (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 NH4HCO3); B: acetonitrile, 35%–75%: 11 min) to obtain compound 14.

[0410] MS-ESI[M+H] + Calculated value 592, measured value 592.

[0411] 1 H NMR(400MHz,MeOD)δ7.28-7.35(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).

[0412] Example 13 Synthesis of Compound 15

[0413]

[0414] Triethylamine (14.7 mg, 145 μmol), trifluoroacetate of compound 6-19 (90.0 mg, 145 μmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg, 290 μmol) were added to a dichloromethane (2.0 mL) solution of compound 15-1 (45.3 mg, 435 μmol). The reaction mixture was stirred at 25 °C for 0.5 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, 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 min) to obtain the formate salt of compound 15.

[0415] MS-ESI[M+H] + Calculated value: 617, Measured value: 617.

[0416] 1 H NMR(400MHz,MeOD)δ7.29-7.37(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).

[0417] Example 14 Synthesis of Compound 16

[0418]

[0419] Triethylamine (14.7 mg, 145 μmol), trifluoroacetate of compound 6-19 (90.0 mg, 145 μmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg, 290 μmol) were added to a dichloromethane (2.0 mL) solution of compound 16-1 (45.3 mg, 435 μmol). The reaction mixture was stirred at 25 °C for 0.5 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, 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 min) to obtain the formate salt of compound 16.

[0420] MS-ESI[M+H] + Calculated value: 574, Measured value: 574.

[0421] 1 H NMR(400MHz,MeOD)δ7.29-7.36(m,1H),7.08-7.14(m,1H),6.90-6.99(m,1H),5.31-5.39(m,1H),5.1 4-5.24(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).

[0422] Example 15 Synthesis of Compound 17

[0423]

[0424] Triethylamine (14.7 mg, 145 μmol), trifluoroacetate of compound 6-19 (90.0 mg, 145 μmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg, 290 μmol) were added to a dichloromethane (2.0 mL) solution of compound 17-1 (45.3 mg, 435 μmol). The reaction mixture was stirred at 25 °C for 0.5 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, 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 min) to obtain the formate salt of compound 17.

[0425] MS-ESI[M+H] + Calculated value 572, measured value 572.

[0426] 1 H NMR(400MHz,MeOD)δ7.29-7.36(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),3.66-3.8 6(m,4H),3.39-3.60(m,1H),2.85-3.27(m,12H),2.34-2.57(m,2H),2.2 7-2.33(m,3H),2.06-2.21(m,5H),1.87-2.04(m,2H),1.61-1.75(m,1H).

[0427] Example 16 Synthesis of Compound 18

[0428]

[0429]

[0430] (1) Compound 18-2 (21.0 g, 173 mmol) and tetraethyl titanate (65.9 g, 289 mmol) were added to a toluene (300 mL) solution of compound 18-1 (24.0 g, 144 mmol). The reaction solution was stirred at 120 °C for 12 hours under nitrogen protection. Water (100 mL) and ethyl acetate (400 mL) were added to the reaction solution. The mixture was filtered, and the filter cake was washed with ethyl acetate (400 mL × 4). The combined organic phases were washed with saturated brine (400 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 5:1) to obtain compound 18-3.

[0431] MS-ESI[M+H] + Calculated value 270, measured value 270.

[0432] 1 H NMR (400MHz, CDCl3) δ7.35-7.40(m,1H),7.27-7.32(m,2H),3.45-3.60(m,1H),3.06-3.15(m,3H),1.36(s,9H).

[0433] (2) Ethyl acetate (3.27 g, 37.1 mmol) was dissolved in tetrahydrofuran (20.0 mL), and diisopropylaminolithium (2 mol / L, 7.4 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -65 °C. The reaction mixture was stirred at -78 °C for 1 hour. A tetrahydrofuran solution of compound 18-3 (2.00 g, 7.41 mmol) was added dropwise to the reaction mixture, and stirring was continued at -65 °C for 2 hours. The temperature was raised to 0 °C, and a saturated ammonium chloride aqueous solution (50.0 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50.0 mL × 2), and the combined organic phases were washed with a saturated ammonium chloride aqueous solution (50.0 mL × 1) and a saturated brine solution (50.0 mL × 1). The mixture was 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 18-4.

[0434] MS-ESI[M+H] + Calculated value 358, measured value 358.

[0435] 1H NMR (400MHz, CDCl3) δ7.21-7.25(m,1H),7.14-7.19(m,2H),5.14(s,1H),4.11-4.20(m,2H),3.68(d,J=15.6Hz,1H),3.33(dt,J=16.4,8.4Hz,1H), 2.90(ddd,J=16.4,9.2,3.6Hz,1H),2.78(d,J=15.6Hz,1H),2.68(ddd,J= 13.2,9.2,3.6Hz,1H),2.29-2.38(m,1H),1.23-1.27(m,3H),1.20(s,9H).

[0436] (3) A solution of dioxane hydrochloric acid (4 mol / L, 5.0 mL) was added to an ethanol (15.0 mL) solution of compound 18-4 (1.40 g, 3.91 mmol). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 18-5.

[0437] MS-ESI[M+H] + Calculated value 254, measured value 254.

[0438] (4) Compound 18-6 (8.17 g, 81.6 mmol), copper oxide (62.5 mg, 786 μmol), and triethylamine (1.19 g, 11.8 mmol) were added to an ethanol (12.0 mL) solution of the hydrochloride salt of compound 18-5 (1.14 g, 3.93 mmol). The reaction solution was sealed and reacted at 85 °C for 8 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 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 10:1) to obtain compound 18-7.

[0439] MS-ESI[M+H] + Calculated value 354, measured value 354.

[0440] 1H NMR (400MHz, CDCl3) δ7.02-7.18(m,3H),4.09-4.14(m,2H),4.02(q,J=7.2Hz,2H),2.86-3.03(m,3H),2.72-2.8 6(m,2H),2.63-2.72(m,1H),2.41-2.50(m,4H),2.29(m,1H),1.22-1.26(t,J=7.2Hz,3H),1.12(t,J=7.2Hz,3H).

[0441] (5) Paraformaldehyde (900 mg) and sodium cyanoborohydride (480 mg, 7.64 mmol) were added to an ethanol (15.0 mL) solution of compound 18-7 (900 mg, 2.54 mmol). The reaction solution was reacted at 25 °C for 10 hours under nitrogen protection. Water (30.0 mL) was added to the reaction solution, 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 to 15:1) to obtain compound 18-8.

[0442] MS-ESI[M+H] + Calculated value 368, measured value 368.

[0443] 1 H NMR (400MHz, CDCl3) δ7.08-7.16(m,2H),7.01-7.06(m,1H),4.10(q,J=7.2Hz,2H),3.80(d tt,J=10.4,7.2,3.6Hz,2H),3.32(d,J=13.6Hz,1H),2.94(d,J=13.6Hz,1H),2.87-2.92(m, 2H),2.74(dt,J=12.8,7.2Hz,1H),2.50-2.56(m,1H),2.43-2.49(m,2H),2.35(dt,J=14.0 ,8.0Hz,1H),2.20-2.28(m,1H),2.14(s,3H),1.24(t,J=7.2Hz,3H),0.91(t,J=7.2Hz,3H).

[0444] (6) At -78℃, potassium bis(trimethylsilyl)amino (1 mol / L, 6.4 mL, tetrahydrofuran solution) was added to a tetrahydrofuran (10.0 mL) solution of compound 18-8 (780 mg, 2.12 mmol). The reaction solution was reacted at -65℃ for 2 hours under nitrogen protection. A saturated ammonium chloride aqueous solution (50.0 mL) was added to the reaction solution, 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 to 19:1) to obtain compound 18-9.

[0445] MS-ESI[M+H] + Calculated value 322, measured value 322.

[0446] 1 H NMR (400MHz, CDCl3) δ7.15-7.20(m,2H),7.10-7.14(m,1H),4.26-4.34(m,1H),4.17-4.25(m,1H),3.61(d,J=15.2Hz,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=13.2,8.4,2.4Hz,1H),1.31(t,J=7.2Hz,3H).

[0447] (7) Compound 18-10 (225 mg, 2.96 mmol) and sodium ethoxide (301 mg, 4.42 mmol) were added to a 10.0 mL ethanol solution of compound 18-9 (475 mg, 1.48 mmol). The reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The precipitated solid was filtered, and the filter cake was dried to obtain compound 18-11.

[0448] MS-ESI[M+H] + Calculated value 334, measured value 334.

[0449] 1H NMR (400MHz, DMSO-d6) δ12.41(s,1H),12.27(s,1H),7.23-7.31(m,3H),3.52(d,J=16.4Hz,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=10.0Hz,1H).

[0450] (8) To a 10.0 mL aqueous solution of compound 18-11 (320 mg, 959 μmol), chloroacetic acid (410 g, 4.34 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution, causing a solid to precipitate. The solid was then filtered, and the filter cake was dried to obtain compound 18-12.

[0451] MS-ESI[M+H] + Calculated value 318, measured value 318.

[0452] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.76(s,1H),7.22-7.33(m,3H),3.47(d,J= 15.2Hz,1H),2.85-2.99(m,4H),2.13-2.25(m,2H),2.02(s,3H),1.59-1.69(m,1H).

[0453] (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 protection. The reaction solution was diluted with dichloromethane (30.0 mL), and saturated sodium bicarbonate aqueous solution (30.0 mL) was added. The pH was adjusted to 8 with saturated sodium carbonate aqueous solution. The organic phase was separated and washed with saturated sodium bicarbonate aqueous solution (30.0 mL × 2) and saturated brine (30.0 mL × 1). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 18-13.

[0454] MS-ESI[M+H] + Calculated value 356, measured value 356.

[0455] 1H NMR (400MHz, CDCl3) δ7.15-7.26(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).

[0456] (10) Potassium carbonate (211 mg, 1.53 mmol) and compound 18-14 (137 mg, 608 μmol) were added to a solution of N-methylpyrrolidone (5.0 mL) containing 18-13 (180 mg, 508 μmol). The reaction mixture was stirred at 50 °C for 10 hours under nitrogen protection. Ethyl acetate (30.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (30.0 mL × 5). The mixture was 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 18-15.

[0457] MS-ESI[M+H] + Calculated value 543, measured value 543.

[0458] 1 H NMR(400MHz,MeOD)δ7.14-7.34(m,3H),4.64(s,1H),4.10-4.25(m,1H),3 .88-4.10(m,3H),3.71(d,J=9.6Hz,2H),3.33-3.49(m,2H),3.15-3.30(m, 2H),3.01(dt,J=17.6,8.8Hz,3H),2.75(dd,J=18.0,3.6Hz,1H),2.38-2.5 2(m,1H),2.24(d,J=0.8Hz,3H),1.78-1.87(m,1H),1.51(d,J=1.6Hz,9H).

[0459] (11) Compound 18-16 (95.4 mg, 828 μmol), potassium carbonate (115 mg, 832 μmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (52.6 mg, 110 μmol), and bis(di-benzylacetone)palladium (50.6 mg, 55.3 μmol) were added to a solution of compound 18-15 (150 mg, 276 μmol) in dioxane (5.0 mL). The reaction solution was stirred at 110 °C for 4 hours under nitrogen protection. Ethyl acetate (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, 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.

[0460] MS-ESI[M+H] + Calculated value 622, measured value 622.

[0461] 1 H NMR(400MHz,MeOD)δ7.16-7.31(m,3H),4.62(s,1H),4.38-4.54(m,2H),4.13-4.2 5(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=8.4Hz,1H),2.24(s,3H),2. 07-2.22(m,2H),1.93(d,J=8.4Hz,2H),1.77-1.88(m,3H),1.51(d,J=2.4Hz,9H).

[0462] (12) Add 1.0 mL of trifluoroacetic acid to a solution of compound 18-17 (120.0 mg, 193 μmol) in dichloromethane (3.0 mL), and stir the reaction solution at 25 °C for 1 hour under nitrogen protection. Concentrate the reaction solution under reduced pressure to obtain the crude trifluoroacetate of compound 18-18.

[0463] MS-ESI[M+H] + Calculated value 522, measured value 522.

[0464] (13) Triethylamine (23.9 mg, 236 μmol) and compound 18-19 (14.3 mg, 158 μmol) were added to a dichloromethane (2.0 mL) solution of trifluoroacetate (50.0 mg, 78.6 μmol) of compound 18-18. The reaction solution was stirred at -65 °C for 0.5 h under nitrogen 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, 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 min) to obtain the formate of compound 18.

[0465] MS-ESI[M+H] + Calculated value 576, measured value 576.

[0466] 1 H NMR (400MHz, MeOD) δ7.21-7.29(m,3H),6.80(s,1H),6.30(d,J=16.8Hz,1H),5.84(d,J=10.0Hz,1H),4.67(d,J=12.4Hz,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=9.2Hz,3H),2.91(d,J=4.0Hz,1H),2.73(dd,J=17.6,3.2Hz,1H),2.44-2.51(m, 1H), 2.33 (dt, J = 8.4, 6.4Hz, 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).

[0467] Example 17 Synthesis of Compound 19

[0468]

[0469] Triethylamine (23.9 mg, 236 μmol), trifluoroacetate of compound 18-18 (90.0 mg, 145 μmol), and tricyclic propyl phosphate anhydride solution (150 mg, 236 μmol, 50% ethyl acetate solution) were added to a dichloromethane (2.0 mL) solution of compound 19-1 (21.3 mg, 237 μmol). The reaction mixture was stirred at 25 °C for 0.5 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, 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 min) to obtain the formate salt of compound 19.

[0470] MS-ESI[M+H] + Calculated value: 594, Actual value: 595.

[0471] 1 H NMR (400MHz, MeOD) δ7.21-7.29(m,3H),5.37(d,J=17.6Hz,1H),5.29(d,J=7.6Hz,1H),4.64(d,J=10.0Hz,1H),4.48(dt ,J=12.0,5.6Hz,2H),4.34(d,J=13.2Hz,1H),4.08-4.26(m,2H),4.03(d,J=10.4Hz,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=10.0Hz,3H),2.73(dd,J=18.0,3.6Hz,1H),2.49(q ,J=10.4Hz,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).

[0472] Example 18 Synthesis of Compound 20

[0473]

[0474] (1) Compound 20-2 (29.9 g, 247 mmol) and tetraethyl titanate (93.6 g, 410 mmol) were added to a toluene (500 mL) solution of compound 20-1 (30.0 g, 205 mmol). The reaction solution was stirred at 110 °C for 16 hours under nitrogen protection. Water (200 mL) and ethyl acetate (300 mL) were added to the reaction solution. The mixture was filtered, and the filter cake was washed with ethyl acetate (300 mL × 4). The organic phases were combined, washed with saturated brine (300 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 11:1) to obtain compound 20-3.

[0475] MS-ESI[M+H] + Calculated value 250, measured value 250.

[0476] 1 H NMR (400MHz, CDCl3) δ8.17(d,J=8.0Hz,1H),7.35-7.42(m,1H),7.22-7.26(m,1H),7.19(d,J=7 .6Hz,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).

[0477] (2) Ethyl acetate (60.1 g, 682 mmol) was dissolved in tetrahydrofuran (400 mL), and diisopropylaminolithium (2 mol / L, 137 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -65 °C. The reaction mixture was stirred at -65 °C for 1 hour. Compound 20-3 (34.0 g, 136 mmol) in tetrahydrofuran (200 mL) solution was added dropwise to the reaction mixture, and stirring was continued at -65 °C for 2 hours. The temperature was raised to 0 °C, and saturated ammonium chloride aqueous solution (500 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (500 mL × 2), the organic phases were combined, washed with saturated ammonium chloride aqueous 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 2:1) to obtain compound 20-4.

[0478] MS-ESI[M+H] + Calculated value 338, measured value 338.

[0479] 1H NMR (400MHz, CDCl3) δ7.32-7.40(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).

[0480] (3) A solution of dioxane hydrochloric acid (4 mol / L, 20.0 mL) was added to an ethanol (60.0 mL) solution of compound 20-4 (6.0 g, 17.8 mmol). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 20-5.

[0481] MS-ESI[M-NH2+H] + Calculated value 217, measured value 217.

[0482] (4) Compound 5-6 (18.2 g, 182 mmol), copper oxide (283 mg, 3.56 mmol), and triethylamine (5.40 g, 53.4 mmol) were added to an ethanol (60.0 mL) solution of the hydrochloride salt of compound 20-5 (4.80 g, 17.8 mmol). The reaction solution was sealed and reacted at 85 °C for 8 hours under nitrogen 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 10:1) to obtain compound 20-7.

[0483] MS-ESI[M+H] + Calculated value 334, measured value 334.

[0484] 1H NMR (400MHz, CDCl3) δ7.53 (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).

[0485] (5) Paraformaldehyde (3.89 g) and sodium cyanoborohydride (2.45 g, 38.9 mmol) were added to an ethanol (60.0 mL) solution of compound 20-7 (4.32 g, 13.0 mmol). The reaction solution was reacted at 25 °C for 16 hours under nitrogen 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.

[0486] MS-ESI[M+H] + Calculated value 348, measured value 348.

[0487] 1 H NMR(400MHz,MeOD)δ7.43-7.52(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=7.2Hz,1H),2.71(t,J=6.4Hz,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=7.2Hz,3H),0.94(t,J=7.2Hz,3H).

[0488] (6) Add bis(trimethylsilyl)amino potassium (1 mol / L, 17.8 mL, tetrahydrofuran solution) to a tetrahydrofuran solution of compound 20-8 (3.10 g, 8.92 mmol) at -65 °C. The reaction solution was reacted at -65 °C for 2 hours under nitrogen protection. Add saturated ammonium chloride aqueous solution (100 mL) to the reaction solution, extract with ethyl acetate (100 mL × 1), wash the organic phase successively with saturated ammonium chloride aqueous solution (100 mL × 1) and saturated brine (100 mL × 1), dry with 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 10:1) to obtain compound 20-9.

[0489] MS-ESI[M+H] + Calculated value 302, measured value 302.

[0490] 1 H NMR (400MHz, CDCl3) δ7.49-7.75(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).

[0491] (7) Compound 20-10 (1.91 g, 25.1 mmol) and sodium ethoxide (2.56 g, 37.6 mmol) were added to an ethanol (70.0 mL) solution of compound 20-9 (3.78 g, 12.5 mmol). The reaction solution was stirred at 80 °C for 8 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The precipitated solid was filtered, and the filter cake was dried to obtain compound 20-11.

[0492] MS-ESI[M+H] + Calculated value 314, measured value 314.

[0493] (8) To an aqueous solution (80.0 mL) of intermediate 20-11 (3.36 g, 10.7 mmol), chloroacetic acid (4.05 g, 42.9 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution, causing a solid to precipitate. The solid was then filtered, and the filter cake was dried to obtain compound 20-12.

[0494] MS-ESI[M+H] + Calculated value 298, measured value 298.

[0495] 1 H NMR (400MHz, DMSO-d6) δ10.98(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).

[0496] (9) Compound 20-12 (1.00 g, 3.36 mmol) was dissolved in phosphorus oxychloride (10 mL). The reaction solution was stirred at 100 °C for 12 hours under nitrogen protection in a sealed tube. The reaction solution was concentrated under reduced pressure, and ice water (100 mL) was added. The solution was extracted with dichloromethane (100 mL × 1). The organic phase was washed with saturated sodium bicarbonate aqueous solution (100 mL × 2) and saturated brine (100 mL × 1). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 20-13.

[0497] MS-ESI[M+H] + Calculated value 334, measured value 334.

[0498] (10) Potassium carbonate (970 mg, 7.02 mmol) and compound 20-14 (633 mg, 2.81 mmol) were added to a solution of N-methylpyrrolidone (10.0 mL) containing compound 20-13 (782 mg, 2.34 mmol). The reaction mixture was stirred at 50 °C for 12 hours under nitrogen protection. The reaction mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The organic phases were combined, washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, 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.

[0499] MS-ESI[M+H] + Calculated value 523, measured value 523.

[0500] (11) 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) were added to a solution of compound 20-15 (500 mg, 956 μmol) in dioxane (10.0 mL). The reaction solution was stirred at 110 °C for 12 hours under nitrogen protection. Ethyl acetate (50.0 mL) was added to the reaction solution, 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.

[0501] MS-ESI[M+H] + Calculated value 602, measured value 602.

[0502] (12) Trifluoroacetic acid (3.08 g, 27.0 mmol) was added to a solution of compound 20-17 (368 mg, 611 μmol) in dichloromethane (6.0 mL). The reaction solution was stirred at 25 °C for 0.5 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of crude compound 20-18.

[0503] MS-ESI[M+H] + Calculated value 502, measured value 502.

[0504] (13) Triethylamine (28.8 mg, 284 μmol) was added to a solution of trifluoroacetate (175 mg, 284 μmol) of compound 20-18 in dichloromethane (3.0 mL), the mixture was cooled to -78 °C, and compound 20-19 (38.6 mg, 426 μmol) was added. The mixture was stirred at -78 °C for 5 minutes under nitrogen 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, 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 min) to obtain the formate salt of compound 20.

[0505] MS-ESI[M+H] + Calculated value 556, measured value 556.

[0506] 1H NMR(400MHz,MeOD)δ7.47-7.58(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).

[0507] Example 19 Synthesis of Compound 21

[0508]

[0509] Triethylamine was added to adjust the pH to 7 in a dichloromethane solution of compound 20-18. The solution was cooled to 0°C, and compound 21-1 (92.2 mg, 1.02 mmol) and tricyclic propylphosphophosphate anhydride (279 mg, 438 μmol) were added. The mixture was heated to 25°C and reacted for 0.5 hours. The reaction mixture was poured into water (30.0 mL) and extracted with dichloromethane (30.0 mL × 2). The organic phases were combined, washed with saturated brine (30.0 mL × 1), 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 min) to obtain the formate salt of compound 21.

[0510] MS-ESI[M+H] + Calculated value: 574, Measured value: 574.

[0511] 1H NMR(400MHz,MeOD)δ7.52-7.53(m,1H),7.19-7.26(m,1H),7.14-7.18(m,1H),7.09-7.13(m,1H),5.2 2-5.47(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).

[0512] Example 20 Synthesis of Compound 22

[0513]

[0514] (1) Compound 22-2 (26.5 g, 219 mmol) and tetraethyl titanate (77.0 g, 337 mmol) were added to a toluene (500 mL) solution of compound 22-1 (25.0 g, 168 mmol). The reaction mixture was stirred at 120 °C for 12 hours under nitrogen protection. Water (400 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was washed with ethyl acetate (400 mL × 2). The combined organic phases were washed with saturated brine (500 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 22-3.

[0515] MS-ESI[M+H] + Calculated value 252, measured value 252.

[0516] 1 H NMR (400MHz, CDCl3) δ7.98-8.03(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).

[0517] (2) Ethyl acetate (54.6 g, 620 mmol) was dissolved in tetrahydrofuran (1000 mL), and diisopropylaminolithium (2 mol / L, 155 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. Compound 22-3 (39.0 g, 155 mmol) in tetrahydrofuran (500 mL) solution was added dropwise to the reaction mixture, and stirring was continued at -78 °C for 3 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (2000 mL), extracted with ethyl acetate (2000 mL), and the combined organic phases were washed with saturated ammonium chloride aqueous 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.

[0518] MS-ESI[M+H] + Calculated value 340, measured value 340.

[0519] (3) A solution of dioxane hydrochloric acid (4 mol / L, 15.0 mL) was added to an ethanol (50.0 mL) solution of compound 22-4 (5.00 g, 14.7 mmol). The reaction solution was stirred at 25 °C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 22-5.

[0520] MS-ESI[M-NH2+H] + Calculated value 219, measured value 219.

[0521] (4) Compound 22-6 (14.7 g, 147 mmol), copper oxide (234 mg, 2.94 mmol), and triethylamine (1.49 g, 14.7 mmol) were added to an ethanol (40.0 mL) solution of the hydrochloride salt of compound 22-5, and the reaction mixture was sealed in a tube at 85 °C for 8 hours under nitrogen 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 22-7.

[0522] MS-ESI[M+H] + Calculated value 336, measured value 336.

[0523] 1H NMR (400MHz, CDCl3) δ7.34-7.42(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)

[0524] (5) Paraformaldehyde (1.34 g) and sodium cyanoborohydride (1.69 g, 26.8 mmol) were added to an ethanol (30.0 mL) solution of compound 22-7 (3.00 g, 8.94 mmol). The reaction solution was reacted at 25 °C for 16 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The combined organic phases were 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 22-8.

[0525] MS-ESI[M+H] + Calculated value 350, measured value 350.

[0526] 1 H NMR (400MHz, CDCl3) δ7.33-7.37(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).

[0527] (6) Add bis(trimethylsilyl)aminopotassium (1 mol / L, 15 mL, tetrahydrofuran solution) to a tetrahydrofuran (30.0 mL) solution of compound 22-8 (1.75 g, 5.01 mmol) at -78 °C. The reaction solution was reacted at -78 °C for 2 hours under nitrogen protection. Add saturated ammonium chloride aqueous solution (70 mL) to the reaction solution, extract with ethyl acetate (500 mL × 1), combine the organic phases, wash with saturated brine (50 mL × 1), dry with 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 22-9.

[0528] MS-ESI[M+H] + Calculated value 304, measured value 304.

[0529] (7) Compound 22-10 (516 mg, 6.79 mmol) and sodium ethoxide (693 mg, 10.1 mmol) were added to an ethanol (30.0 mL) solution of compound 22-9 (1.03 g, 3.40 mmol). The reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The solid precipitated was filtered, and the filter cake was dried to obtain compound 22-11.

[0530] MS-ESI[M+H] + Calculated value 316, measured value 316.

[0531] 1 H NMR (400MHz, DMSO-d6) δ11.54-12.84(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,1 H),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).

[0532] (8) To an aqueous solution (100.0 mL) of intermediate 22-11 (1.05 g, 3.33 mmol), chloroacetic acid (1.26 g, 13.3 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution, causing a solid to precipitate. The solid was then filtered, and the filter cake was dried to obtain compound 22-12.

[0533] MS-ESI[M+H]+ Calculated value 300, measured value 300.

[0534] (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 protection. The reaction solution was concentrated under reduced pressure, extracted with dichloromethane (40 mL), and the organic phase was washed with saturated sodium bicarbonate aqueous solution (20 mL × 2) and saturated brine (200 mL). After drying with anhydrous sodium sulfate, the solution was filtered and concentrated under reduced pressure to obtain compound 22-13.

[0535] MS-ESI[M+H] + Calculated value 336, measured value 336.

[0536] (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). The reaction solution was stirred at 50 °C for 12 hours under nitrogen 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, and concentrated under reduced pressure to obtain compound 22-15.

[0537] MS-ESI[M+H] + Calculated value 525, measured value 525.

[0538] (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). The reaction solution was stirred at 110 °C for 6 hours under nitrogen protection. Ethyl acetate (40.0 mL) was added to the reaction solution, 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 to 15:1) to obtain compound 22-17.

[0539] MS-ESI[M+H] + Calculated value: 604, Measured value: 604.

[0540] (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). The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phase was washed with saturated sodium bicarbonate aqueous solution (50 mL × 1) and saturated brine (50 mL × 1). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude trifluoroacetate of compound 22-18.

[0541] MS-ESI[M+H] + Calculated value 504, measured value 504.

[0542] (13) Triethylamine (14.7 mg, 145 μmol) and compound 22-19 (26.3 mg, 291 μmol) were added to a dichloromethane (2.0 mL) solution of trifluoroacetate (120.0 mg, 194 μmol) of compound 22-18. The reaction solution was stirred at -78 °C for 0.5 h under nitrogen 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, 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 min) to obtain the formate of compound 22.

[0543] MS-ESI[M+H] + Calculated value 558, measured value 558.

[0544] 1 H NMR(400MHz,MeOD)δ7.40-7.46(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),2.9 7-3.02(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).

[0545] Example 21 Synthesis of Compound 23

[0546]

[0547] Triethylamine (14.7 mg, 145 μmol), compound 23-1 (160.0 mg, 1.78 mmol), and propylphosphonic tricyclic anhydride solution (679.98 mg, 1.07 mol, 50% ethyl acetate) were added to a dichloromethane (2.0 mL) solution of compound 22-18 (220 mg, 356 μmol) at 0 °C. The reaction mixture was stirred at 25 °C for 0.5 h. Dichloromethane (20.0 mL) was added to the reaction mixture, which 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 Genimi NX C18, 150 mm × 40 mm 5 μm, A: water (0.05% hydrochloric acid); B: acetonitrile, 58%–35%: 10 min) to obtain the hydrochloride salt of compound 23.

[0548] MS-ESI[M+H] + Calculated value 576, measured value 576.

[0549] 1 H NMR (400MHz, MeOD) δ7.83-7.96(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),3.0 3-3.13(m,4H),2.67-2.76(m,4H),2.37-2.54(m,2H),1.77-2.30(m,6H).

[0550] Example 22 Synthesis of Compound 24

[0551]

[0552] (1) Compound 24-2 (19.4 g, 160 mmol) and tetraethyl titanate (56.2 g, 246 mmol) were added to a toluene (500 mL) solution of compound 24-1 (20.0 g, 123 mmol). The reaction mixture was stirred at 120 °C for 12 hours under nitrogen protection. Water (400 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was washed with ethyl acetate (400 mL × 2). The combined organic phases were washed with saturated brine (500 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 24-3.

[0553] MS-ESI[M+H] + Calculated value 266, measured value 266.

[0554] 1 H NMR (400MHz, CDCl3) δ7.38-7.43(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).

[0555] (2) Ethyl acetate (15.8 g, 179 mmol) was dissolved in tetrahydrofuran (500 mL), and diisopropylaminolithium (2 mol / L, 44.8 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. Compound 24-3 (11.9 g, 44.8 mmol) in tetrahydrofuran (500 mL) solution was added dropwise to the reaction mixture, and stirring was continued at -78 °C for 3 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (1000 mL), extracted with ethyl acetate (1000 mL), and the combined organic phases were washed with saturated ammonium chloride aqueous solution (1000 mL × 1) and saturated brine (1000 mL). The mixture was 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 24-4.

[0556] MS-ESI[M+H] + Calculated value 354, measured value 354.

[0557] (3) A solution of dioxane hydrochloric acid (4 mol / L, 15.0 mL) was added to an ethanol (50.0 mL) solution of compound 24-4 (8.00 g, 22.6 mmol). The reaction solution was stirred at 25 °C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 24-5.

[0558] MS-ESI[M-NH2+H] + Calculated value 233, measured value 233.

[0559] (4) 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 to an ethanol (40.0 mL) solution of the hydrochloride salt of compound 24-5 (6.40 g, 22.4 mmol). The reaction solution was sealed and reacted at 85 °C for 8 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, 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.

[0560] MS-ESI[M+H] + Calculated value 350, measured value 350.

[0561] (5) Paraformaldehyde (1.60 g) and sodium cyanoborohydride (2.05 g, 32.6 mmol) were added to an ethanol (30.0 mL) solution of compound 24-7 (3.80 g, 10.8 mmol). The reaction solution was reacted at 25 °C for 16 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The combined organic phases were 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.

[0562] MS-ESI[M+H] + Calculated value 364, measured value 364.

[0563] 1 H NMR (400MHz, CDCl3) δ7.12-7.21(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).

[0564] (6) Add bis(trimethylsilyl)aminopotassium (1 mol / L, 38 mL, tetrahydrofuran solution) to a tetrahydrofuran solution of compound 24-8 (4.60 g, 12.6 mmol) at -78 °C. The reaction solution was reacted at -78 °C for 2 hours under nitrogen protection. Add saturated ammonium chloride aqueous solution (70 mL) to the reaction solution, extract with ethyl acetate (200 mL), combine the organic phases, wash with saturated brine (50 mL), dry with 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 24-9.

[0565] MS-ESI[M+H] + Calculated value 318, measured value 318.

[0566] (7) Compound 24-10 (959 mg, 12.6 mmol) and sodium ethoxide (1.29 g, 18.9 mmol) were added to an ethanol (30.0 mL) solution of compound 24-9 (2.00 g, 6.30 mmol). The reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The precipitated solid was filtered, and the filter cake was dried to obtain compound 24-11.

[0567] MS-ESI[M+H] + Calculated value 330, measured value 330.

[0568] 1 H NMR (400MHz, DMSO-d6) δ12.19-12.46(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).

[0569] (8) To a 10.0 mL aqueous solution of intermediate 24-11 (1.72 g, 5.22 mmol), chloroacetic acid (1.97 g, 20.8 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution, causing a solid to precipitate. The solid was then filtered, and the filter cake was dried to obtain compound 24-12.

[0570] MS-ESI[M+H] +Calculated value 314, measured value 314.

[0571] 1 H NMR(400MHz,DMSO-d6)δ10.95-11.02(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),3.3 7-3.46(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).

[0572] (9) Compound 24-12 (1.34 g, 4.28 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 protection. The reaction solution was concentrated under reduced pressure, extracted with dichloromethane (40 mL), and the organic phase was washed with saturated sodium bicarbonate aqueous 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.

[0573] MS-ESI[M+H] + Calculated value 350, measured value 350.

[0574] (10) Potassium carbonate (1.33 g, 9.59 mmol) and compound 24-14 (864 mg, 3.84 mmol) were added to a solution of compound 24-13 (1.12 g, 3.20 mmol) in N-methylpyrrolidone (10.0 mL). The reaction solution was stirred at 50 °C for 12 hours under nitrogen 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, and concentrated under reduced pressure to obtain compound 24-15.

[0575] MS-ESI[M+H] + Calculated value 539, measured value 539.

[0576] (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) were added to a solution of compound 24-15 (700 mg, 1.30 mmol) in dioxane (10.0 mL). The reaction solution was stirred at 110 °C for 6 hours under nitrogen protection. Ethyl acetate (40.0 mL) was added to the reaction solution, 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 to 15:1) to obtain compound 24-17.

[0577] MS-ESI[M+H] + Calculated value: 618, Measured value: 618.

[0578] (12) Trifluoroacetic acid (1.54 g) was added to a solution of compound 24-17 (430.0 mg, 696 μmol) in dichloromethane (3.0 mL). The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude trifluoroacetate of compound 24-18.

[0579] MS-ESI[M+H] + Calculated value 518, measured value 518.

[0580] (13) Triethylamine (16.0 mg, 158 μmol) and compound 24-19 (21.4 mg, 237 μmol) were added to a dichloromethane (2.0 mL) solution of trifluoroacetate (100.0 mg, 158 μmol) of compound 24-18. The reaction solution was stirred at -78 °C for 0.5 h under nitrogen 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, 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 min) to obtain the formate of compound 24.

[0581] MS-ESI[M+H] + Calculated value: 558, measured value: 572.

[0582] 1H NMR(400MHz,MeOD)δ7.24-7.31(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).

[0583] Example 23 Synthesis of Compound 25

[0584]

[0585] Triethylamine (14.7 mg, 145 μmol), compound 25-1 (71.2 mg, 791 μmol), and a solution of tricyclic propyl phosphate anhydride (302 mg, 474 μmol, 50% ethyl acetate) were added to a dichloromethane (2.0 mL) solution of compound 24-18 (100 mg, 158 μmol) at 0 °C. The reaction mixture was stirred at 25 °C for 0.5 h. Dichloromethane (20.0 mL) was added to the reaction mixture, which 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 min) to obtain the formate salt of compound 25.

[0586] MS-ESI[M+H] + Calculated value 590, measured value 590.

[0587] 1 H NMR(400MHz,MeOD)δ7.21-7.32(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),4.00-4.3 6(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).

[0588] Example 24 Synthesis of compounds 26 and 27

[0589]

[0590] (1) Compound 26-1 (1.81 mg, 11.4 mmol), cesium carbonate (5.56 g, 17.1 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (300 mg, 359 μmol) were added to a solution of compound 8-8 (3.00 g, 5.69 mmol) in dioxane (80.0 mL). The reaction solution was stirred at 110 °C for 4 hours under nitrogen protection. Ethyl acetate (200 mL) was added to the reaction solution, and the mixture was 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 8:1) to obtain compound 26-2.

[0591] MS-ESI[M+H] + Calculated value 650, measured value 650.

[0592] (2) A solution of dioxane (50.0 mL) containing 3.24 g (4.99 mmol) of compound 26-2 was added to a solution of dichloromethane (1.25 mL, 4 mol / L) containing hydrochloric acid. The reaction mixture was stirred at 25 °C for 0.5 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 26-3.

[0593] MS-ESI[M+H] + Calculated value 550, measured value 550.

[0594] (3) Triethylamine (1.35 g, 13.3 mmol) and compound 26-4 (803 mg, 8.87 μmol) were added to a solution of compound 26-3 hydrochloride (2.60 g, 4.44 mmol) in dichloromethane (30.0 mL). The reaction solution was stirred at -78 °C for 0.5 hours under nitrogen protection. Dichloromethane (60.0 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 silica gel column chromatography (dichloromethane / methanol = 1:0 to 25:1) to obtain compound 26-5.

[0595] (4) Compounds 26 and 27 were separated by chiral supercritical fluid chromatography.

[0596] Separation conditions: Column type: Chiralpak OX-3; Column size: 100×4.6mm ID, 3μm; Injection volume: 10μL; Mobile phase: Carbon dioxide:isopropanol (0.05% diethylamine) = 60:40; Detection wavelength: 254nm; Column temperature: 35℃.

[0597] Compound 6 had a retention time of 2.047 minutes and an ee value of 99.28%.

[0598] MS-ESI[M+H] + Calculated value: 604, Measured value: 604.

[0599] 1 H NMR (400MHz, MeOD) δ7.31(td,J=7.6,5.2Hz,1H),7.10(d,J=7.6Hz,1H),6.91-6.97(m,1H),6.71-6.90(m,1H),6.28(d,J=16.4Hz,1H),5.83(d ,J=10.4Hz,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=10.4Hz,3H),3.52-3.79(m,3H),3.39-3.51(m,1H ),3.21-3.28(m,2H),3.19(d,J=9.6Hz,2H),3.11(d,J=3.2Hz,1H),3.04-3.09(m,1H),2.99-3.04(m,2H),2.89-2.98(m,2H),2.85(s,1H),2.4 9(dt,J=13.2,8.8Hz,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).

[0600] Compound 7 had a retention time of 3.558 minutes and an ee value of 98.36%.

[0601] MS-ESI[M+H] + Calculated value: 604, Measured value: 604.

[0602] 1H NMR (400MHz, MeOD) δ7.32(td,J=7.6,5.2Hz,1H),7.10(d,J=7.6Hz,1H),6.91-6.97(m,1H),6.72-6.91(m,1H),6.29(d,J=16.4Hz,1H),5.83(d,J=10. 4Hz,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=10.4Hz,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),3.0 6(d,J=5.2Hz,1H),2.98-3.05(m,2H),2.90(d,J=18.0Hz,1H),2.48(dt,J= 13.2,8.4Hz,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=13.2,8.4,4.4Hz,2H).

[0603] Example 25 Synthesis of compounds 28 and 29

[0604]

[0605] To a solution of compound 28-1 (848 mg, 9.42 mmol) in ethyl acetate (20.0 mL), 1.80 g of 4A molecular sieve, 1.59 g of triethylamine (1.57 mmol), 1.84 g of hydrochloride of compound 26-3 (3.14 mmol), and a solution of tricyclic propyl phosphate anhydride (5.99 g, 9.42 mmol, 50% ethyl acetate solution) were added. The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture 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 24:1) to obtain compound 28-2.

[0606] (4) Compound 28-2 was separated into compounds 28 and 29 by chiral supercritical fluid chromatography.

[0607] Separation conditions: Column type: Chiralpak OX-3; Column size: 50×4.6mm ID, 3μm; Injection volume: 10μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 2.5 min, 40% fixed concentration elution for 0.5 min, 5% fixed concentration elution for 1 min; Detection wavelength: 254nm; Column temperature: 35℃.

[0608] Compound 28 had a retention time of 1.457 minutes and an ee value of 100%.

[0609] MS-ESI[M+H] + Calculated value 622, measured value 622.

[0610] 1 H NMR(400MHz,MeOD)δ7.32(td,J=7.6,5.2Hz,1H),7.10(d,J=7.6Hz,1H),6.90-6.9 7(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=13.2Hz,1H),3.23-3.29(m,1H),3.17-3.23(m,2H),3 .16(d,J=5.2Hz,1H),3.10-3.15(m,1H),3.06-3.10(m,1H),3.04(d,J=8.8Hz,2H) ,2.98-3.01(m,1H),2.93-2.98(m,1H),2.87(d,J=18.0Hz,1H),2.49(dt,J=13.2,8 .8Hz,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).

[0611] Compound 29 had a retention time of 1.588 minutes and an ee value of 95.44%.

[0612] MS-ESI[M+H] + Calculated value 622, measured value 622.

[0613] 1 H NMR (400MHz, MeOD) δ7.32(td,J=7.6,5.2Hz,1H),7.11(d,J=7.6Hz,1H),6.91-6.97(m,1H),5.38(s,1H),5.29-5.35(m,1H),5.25(d,J= 13.6Hz,1H),4.91(s,1H),4.86-4.87(m,1H),4.24(d,J=14.0Hz,1H),4.14-4.22(m,2H),3.96-4.12(m,2H),3.63-3.71(m,2H),3.27(d ,J=3.6Hz,2H),3.24(d,J=3.2Hz,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=18.0Hz,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=9.2Hz,1H),1.96-2.04(m,2H),1.90(td,J=8.8,4.4Hz,2H).

[0614] Example 26 Synthesis of Compound 30

[0615]

[0616] (1) Compound 30-2 (21.9 g, 181 mmol) and tetraethyl titanate (68.5 g, 300 mmol) were added to a toluene (500 mL) solution of compound 30-1 (20.0 g, 150 mmol). The reaction solution was stirred at 110 °C for 12 hours under nitrogen protection. Water (200 mL) and ethyl acetate (500 mL) were added to the reaction solution. The mixture was filtered, and 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.

[0617] MS-ESI[M+H] + Calculated value 237, measured value 237.

[0618] 1H NMR (400MHz, CDCl3) δ8.71 (dd, J=4.8, 1.6Hz, 1H), 8.05 (dd, J=7.6, 1.6Hz, 1H), 7.28 (dd, J=8.0,4.8Hz,1H),3.49-3.59(m,1H),3.25-3.31(m,2H),3.11-3.20(m,1H),1.33(s,9H).

[0619] (2) Ethyl acetate (24.3 g, 276 mmol) was dissolved in tetrahydrofuran (150 mL), and diisopropylaminolithium (2 mol / L, 55 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -65 °C. The reaction mixture was stirred at -65 °C for 1 hour. Compound 30-3 (13.0 g, 55.0 mmol) in tetrahydrofuran (150 mL) solution was added dropwise to the reaction mixture, and stirring was continued at -65 °C for 2 hours. The temperature was raised to 0 °C, and saturated ammonium chloride aqueous solution (200 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (200 mL × 2), the organic phases were combined, washed with saturated ammonium chloride aqueous 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.

[0620] MS-ESI[M+H] + Calculated value 325, measured value 325.

[0621] 1 H NMR(400MHz,MeOD)δ8.42(d,J=5.2Hz,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).

[0622] (3) A solution of dioxane hydrochloric acid (4 mol / L, 20.0 mL) was added to an ethanol (60.0 mL) solution of compound 30-4 (7.40 g, 22.8 mmol). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 30-5.

[0623] MS-ESI[M+H] + Calculated value 221, measured value 221.

[0624] (4) Compound 5-6 (23.1 g, 231 mmol), copper oxide (363 mg, 4.56 mmol), and triethylamine (6.94 g, 68.6 mmol) were added to an ethanol (50.0 mL) solution of the hydrochloride salt of compound 30-5 (5.86 g, 22.8 mmol). The reaction solution was sealed and reacted at 85 °C for 8 hours under nitrogen 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 2:1) to obtain compound 30-7.

[0625] MS-ESI[M+H] + Calculated value 321, measured value 321.

[0626] 1 H NMR (400MHz, MeOD) δ8.37 (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).

[0627] (5) Paraformaldehyde (937 mg) and sodium cyanoborohydride (589 mg, 9.37 mmol) were added to an ethanol (15.0 mL) solution of compound 30-7 (1.00 g, 3.12 mmol). The reaction solution was reacted at 25 °C for 14 hours under nitrogen 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 3:1) to obtain compound 30-8.

[0628] MS-ESI[M+H] + Calculated value 335, measured value 335.

[0629] 1H NMR (400MHz, MeOD) δ8.36 (dd, J=5.2, 1.6Hz, 1H), 7.72 (dd, J=7.6, 1.6Hz, 1H), 7.25 (dd ,J=7.6,5.2Hz,1H),4.07-4.13(m,2H),3.90(qd,J=7.2,1.2Hz,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),2.40-2.4 6(m,3H),2.25-2.32(m,1H),2.20(s,3H),1.24(t,J=7.2Hz,3H),1.02(t,J=7.2Hz,3H).

[0630] (6) At -65℃, potassium bis(trimethylsilyl)amino (1 mol / L, 8.0 mL, tetrahydrofuran solution) was added to a tetrahydrofuran (20.0 mL) solution of compound 30-8 (900 mg, 2.69 mmol). The reaction solution was reacted at -65℃ for 2 hours under nitrogen protection. A saturated ammonium chloride aqueous solution (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 1). The organic phase was washed successively with a saturated ammonium chloride aqueous solution (100 mL × 1) and a saturated brine solution (100 mL × 1). The mixture was 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.

[0631] MS-ESI[M+H] + Calculated value 289, measured value 289.

[0632] 1 H NMR (400MHz, MeOD) δ8.42 (dd, J=5.2, 1.6Hz, 1H), 7.71 (dd, J=7.6, 1.6Hz, 1H), 7. 32(dd,J=7.6,5.2Hz,1H),4.28(q,J=7.2Hz,2H),3.45(d,J=15.2Hz,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=7.2Hz,3H).

[0633] (7) Compound 30-10 (269 mg, 3.53 mmol) and sodium ethoxide (361 mg, 5.30 mmol) were added to an ethanol (8.0 mL) solution of compound 30-9 (510 mg, 1.77 mmol). The reaction solution was stirred at 80 °C for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The precipitated solid was filtered, and the filter cake was dried to obtain compound 30-11.

[0634] MS-ESI[M+H] + Calculated value 301, measured value 301.

[0635] 1 H NMR(400MHz,DMSO-d6)δ12.77(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 = 14.4Hz, 1H), 3.43 (d, J = 18.8Hz, 4H), 3.18 (s, 2H), 2.89 (d, J = 16.0Hz, 1H), 2.67 (s, 1H), 2.20 (s, 1H).

[0636] (8) Chloroacetic acid (670 mg, 7.09 mmol) was added to a 10.0 mL aqueous solution of intermediate 30-11 (531 mg, 1.77 mmol). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution, causing a solid to precipitate. The solid was then filtered and dried to obtain compound 30-12.

[0637] MS-ESI[M+H] + Calculated value 285, measured value 285.

[0638] 1 H NMR (400MHz, DMSO-d6) δ10.92 (s, 2H), 8.44 (dd, J = 4.8, 1.6Hz, 1H), 7.58 (dd, J=7.6,1.6Hz,1H),7.24(dd,J=7.6,4.8Hz,1H),3.39(s,1H),3.07(d,J=16.0 Hz,1H),2.90-2.99(m,2H),2.61(d,J=17.2Hz,1H),2.39(d,J=17.6Hz,1H),2 .21(dt,J=13.6,8.4Hz,1H),1.96(s,3H),1.70(ddd,J=13.6,8.0,5.6Hz,1H).

[0639] (9) Compound 30-12 (300 mg, 1.06 mmol) was dissolved in phosphorus oxychloride (9.90 g, 64.6 mmol). The reaction solution was stirred at 100 °C for 12 hours under nitrogen protection in a sealed tube. The reaction solution was concentrated under reduced pressure and slowly added to ice water (50 mL). It was extracted with dichloromethane (50 mL × 1). The organic phase was washed with saturated sodium carbonate aqueous 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.

[0640] MS-ESI[M+H] + Calculated value 321, measured value 321.

[0641] (10) Potassium carbonate (436 mg, 3.15 mmol) and compound 30-14 (284 mg, 1.26 mmol) were added to a solution of N-methylpyrrolidone (5.0 mL) containing compound 30-13 (338 mg, 1.05 mmol). The reaction mixture was stirred at 50 °C for 3 hours under nitrogen protection. The reaction mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The organic phases were combined, washed with saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, 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 30-15.

[0642] MS-ESI[M+H] + Calculated value 510, measured value 510.

[0643] 1 H NMR (400MHz, MeOD) δ8.44(d,J=4.4Hz,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=14.4Hz,2H),3. 68-3.80(m,2H),2.97(d,J=5.2Hz,2H),2.93(s,2H),2.83-2.87(m,2H),2.82(d,J=4.0Hz,2H),2.45-2.54(m,1H),2.21(s,3H),1.48(s,9H).

[0644] (11) 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) were added to a solution of compound 30-15 (300 mg, 588 μmol) in dioxane (10.0 mL). The reaction solution was stirred at 110 °C for 4 hours under nitrogen protection. Ethyl acetate (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, 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.

[0645] MS-ESI[M+H] + Calculated value 589, measured value 589.

[0646] (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 solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate of crude compound 30-18.

[0647] MS-ESI[M+H] + Calculated value 489, measured value 489.

[0648] (13) Triethylamine (45.0 mg, 445 μmol) was added to a solution of trifluoroacetate (90.0 mg, 149 μmol) in dichloromethane (5.0 mL), the mixture was cooled to -65 °C, and compound 30-19 (27.0 mg, 298 μmol) was added. The mixture was stirred at -65 °C for 0.5 hours under nitrogen 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, concentrated under reduced pressure, and the crude product was separated by preparative high performance liquid chromatography (Gemini-NX C18 75 × 30 mm × 3 μm, A: water (10 mM ammonium bicarbonate); B: acetonitrile, 10%-40%: 10 min) to obtain compound 30.

[0649] MS-ESI[M+H] + Calculated value 543, measured value 543.

[0650] 1H NMR (400MHz, MeOD) δ8.44(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),3.44-3.6 4(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).

[0651] Example 27 Synthesis of Compound 31

[0652]

[0653] To a solution of compound 31-1 (58.3 mg, 648 μmol) in ethyl acetate (5.0 mL), 130 mg of 4A molecular sieve, 65.6 mg of triethylamine (648 μmol), 130 mg of trifluoroacetate of compound 30-18 (216 μmol), and a solution of tricyclic propyl phosphate anhydride (549 mg, 863 μmol, 50% ethyl acetate) were added. The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture 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 min) to obtain compound 31.

[0654] MS-ESI[M+H] + Calculated value 561, measured value 561.

[0655] 1H NMR (400MHz, MeOD) δ8.44(d,J=4.8Hz,1H),7.69(ddd,J=13.2,7.6,1.6Hz,1H),7.33(dt,J=7.6,5.2Hz,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=5.2Hz,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. 4Hz,2H),2.76(dt,J=13.6,6.8Hz,1H),2.50(d,J=2.4Hz,3H),2.47(d,J =3.6Hz,1H),2.33-2.42(m,1H),2.21(d,J=1.2Hz,3H),2.09(dq,J=12. 4,8.4Hz,1H),1.91-2.01(m,1H),1.77-1.87(m,2H),1.65-1.76(m,1H).

[0656] Example 28 Synthesis of compounds 32 and 33

[0657]

[0658] (1) Compound 32-1 (487 mg, 3.06 mmol), cesium carbonate (382 mg, 2.76 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (80.0 mg, 95.7 μmol) were added to a solution of compound 20-15 (800 mg, 1.53 mmol) in dioxane (15.0 mL). The reaction solution was stirred at 110 °C for 3 hours under nitrogen protection. Ethyl acetate (80.0 mL) was added to the reaction solution, and the mixture was washed with water (50.0 mL × 1) and saturated brine (50.0 mL × 3). The mixture was 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.

[0659] MS-ESI[M+H] + Calculated value: 646, Measured value: 646.

[0660] 1H NMR (400MHz, CDCl3) δ7.53(t,J=7.2Hz,1H),7.19-7.24(m,1H),7.14(t,J=6.8Hz,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=14.0,3.2Hz,1H),3.23(s,2H),3.16(d,J=8.0Hz ,1H),3.05-3.14(m,3H),2.79-3.05(m,4H),2.74(d,J=5.6Hz,2H),2.69(d,J=2.8Hz,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 = 10.0Hz, 2H), 1.77 (s, 1H), 1.67-1.76 (m, 2H), 1.51 (s, 9H).

[0661] (2) A solution of dioxane (3.12 mL, 4 mol / L) in hydrochloric acid was added to a solution of compound 32-2 (810 mg, 1.25 mmol) in dichloromethane (10.0 mL). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 32-3.

[0662] MS-ESI[M+H] + Calculated value 546, measured value 546.

[0663] (3) Triethylamine (433 mg, 4.28 mmol) and compound 32-4 (258 mg, 2.85 mmol) were added to a solution of compound 32-3 hydrochloride (830 mg, 1.43 mmol) in dichloromethane (3.0 mL). The reaction solution was stirred at -78 °C for 1 hour under nitrogen protection. Dichloromethane (60.0 mL) was added to the reaction solution, and the mixture was washed with saturated brine (30.0 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 32-5.

[0664] (4) Compounds 32 and 33 were separated by chiral supercritical fluid chromatography.

[0665] Separation conditions: Column type: Chiralpak OX-3; Column size: 50×4.6mm ID, 3μm; Injection volume: 10μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 2.5 min, 40% fixed concentration elution for 0.5 min, 5% fixed concentration elution for 1 min; Detection wavelength: 254nm; Column temperature: 35℃.

[0666] Compound 32 had a retention time of 1.759 minutes and an ee value of 100%.

[0667] MS-ESI[M+H] + Calculated value 600, measured value 600.

[0668] 1 H NMR(400MHz,MeOD)δ7.51(d,J=8.0Hz,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=16.4Hz,1H),5.83 (d,J=10.4Hz,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=8.4Hz,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=15.2Hz,1H),3.04-3.12(m ,2H),2.93-3.04(m,2H),2.88(s,2H),2.76(d,J=5.6Hz,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 .4Hz,2H),1.92-1.99(m,2H),1.90(d,J=6.8Hz,1H),1.66-1.84(m,2H).

[0669] Compound 33 had a retention time of 1.966 minutes and an ee value of 99.36%.

[0670] MS-ESI[M+H] + Calculated value 600, measured value 600.

[0671] 1H NMR(400MHz,MeOD)δ7.51(d,J=7.6Hz,1H),7.19-7.25(m,1H),7.13-7.18(m,1H),7 .07-7.12(m,1H),6.82(d,J=10.0Hz,1H),6.29(d,J=16.4Hz,1H),5.84(d,J=10.4H z,1H),5.25-5.43(m,1H),5.07(s,1H),4.32(d,J=14.0Hz,1H),4.18-4.29(m,2H), 4.11(d,J=10.0Hz,1H),4.00(d,J=11.2Hz,1H),3.70-3.85(m,2H),3.46-3.69(m,1 H),3.36-3.45(m,2H),3.20(dd,J=14.0,3.6Hz,2H),3.14(d,J=8.4Hz,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=10.0Hz,1H), 2.04(d,J=5.2Hz,2H),1.95-2.00(m,2H),1.92(d,J=6.8Hz,1H),1.71-1.83(m,2H).

[0672] Example 29 Synthesis of Compound 34

[0673]

[0674] (1) Compound 34-1 (220 mg, 1.38 mmol), potassium carbonate (382 mg, 2.76 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (176 mg, 369 μmol), and bis(di-benzylacetone)palladium (169 mg, 185 μmol) were added to a solution of compound 18-15 (500 mg, 920 μmol) in dioxane (10.0 mL). The reaction mixture was stirred at 110 °C for 4 hours under nitrogen 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, 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 34-2.

[0675] MS-ESI[M+H] + Calculated value: 666, Measured value: 666.

[0676] (2) Trifluoroacetic acid (2.0 mL) was added to a solution of compound 34-2 (485 mg, 728 μmol) in dichloromethane (6.0 mL). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 34-3.

[0677] MS-ESI[M+H] + Calculated value 566, measured value 566.

[0678] (3) Triethylamine (67.0 mg, 662 μmol) and compound 34-4 (39.9 mg, 441 μmol) were added to a solution of trifluoroacetate (150 mg, 221 μmol) in dichloromethane (3.0 mL). The reaction solution was stirred at -65 °C for 0.5 hours under nitrogen 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, 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 min) to obtain the formate of compound 34.

[0679] MS-ESI[M+H] + Calculated value 620, measured value 620.

[0680] 1 H NMR (400MHz, MeOD) δ7.20-7.30(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).

[0681] Example 30 Synthesis of Compound 35

[0682]

[0683] To a solution of compound 35-1 (108 mg, 1.20 mmol) in ethyl acetate (10.0 mL), 4A molecular sieve (270 mg), triethylamine (121 mg, 1.20 mmol), trifluoroacetate of compound 34-3 (270 mg, 397 μmol), and tricyclic propyl phosphate anhydride solution (1.02 g, 1.60 mmol, 50% ethyl acetate solution) were added. The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture 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, 40%–70%: 10 min) to obtain compound 35.

[0684] MS-ESI[M+H] + Calculated value: 638, Actual value: 638.

[0685] 1 H NMR(400MHz,MeOD)δ7.23-7.30(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).

[0686] Example 31 Synthesis of compounds 36 and 37

[0687]

[0688] (1) To a solution of compound 35-1 (1.02 g, 11.3 mmol) in ethyl acetate (20.0 mL), 4A molecular sieve (2.0 g), triethylamine (1.15 g, 11.3 mmol), hydrochloride of compound 32-3 (2.2 g, 3.78 mmol), and propylphosphotricyclic anhydride solution (9.62 g, 15.1 mmol, 50% ethyl acetate solution) were added. The reaction mixture was stirred at 25 °C for 0.5 hours. The reaction mixture 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.

[0689] (2) Compound 36-2 was separated into compounds 36 and 37 by chiral supercritical fluid chromatography.

[0690] Separation conditions: Column type: Chiralpak OD-3; Column size: 50×4.6mm ID, 3μm; Injection volume: 4.0μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 2.5 min, 40% fixed concentration elution for 0.5 min, 5% fixed concentration elution for 1 min; Detection wavelength: 254nm; Column temperature: 35℃.

[0691] Compound 36 had a retention time of 1.567 minutes and an ee value of 98.46%.

[0692] MS-ESI[M+H] + Calculated value: 618, Measured value: 618.

[0693] 1H NMR(400MHz,MeOD)δ7.51(d,J=7.6Hz,1H),7.19-7.25(m,1H),7.15(t,J=7 .2Hz,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=11.2Hz ,1H),4.11-4.19(m,2H),4.10(s,1H),3.77(d,J=3.2Hz,2H),3.51(d,J=15. 2Hz,1H),3.39-3.49(m,2H),3.33-3.38(m,1H),3.13(d,J=1.6Hz,1H),3.0 5-3.12(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=7.6Hz,1H),2.18(d,J=8.4Hz,1H),2.12(s,3H),2.07( s,1H),2.04(s,1H),2.00(s,1H),1.97(d,J=3.2Hz,2H),1.75-1.85(m,2H).

[0694] Compound 37 had a retention time of 1.778 minutes and an ee value of 99.36%.

[0695] MS-ESI[M+H] + Calculated value: 618, Measured value: 618.

[0696] 1H NMR(400MHz,MeOD)δ7.51(d,J=7.2Hz,1H),7.17-7.23(m,1H),7.14(td,J=7.2, 1.2Hz,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=13.6Hz,1H),4.10-4.25(m,2H),4.01-4.10(m,1H),3.80-4. 01(m,1H),3.74(q,J=14.8Hz,2H),3.32-3.62(m,1H),3.25-3.29(m,1H),3.24(d ,J=8.4Hz,1H),3.19-3.22(m,2H),3.17(d,J=6.8Hz,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=4.0Hz,2H),1.87-1.93(m,1H),1.80-1.87(m,1H),1.57-1.80(m,2H).

[0697] Example 32 Synthesis of Compound 38

[0698]

[0699] (1) Benzyl bromide (43.3 g, 253 mmol) and cesium carbonate (110 g, 338 mmol) were added to a solution of compound 38-1 (25.0 g, 168 mmol) in acetonitrile (250 mL). The reaction solution was stirred at 20 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, water (50.0 mL) was added, and the mixture was extracted with ethyl acetate (40.0 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 3:1) to obtain compound 38-2.

[0700] MS-ESI[M+H] + Calculated value 239, measured value 239.

[0701] 1H NMR (400MHz, CDCl3) δ7.32-7.40(m,4H),7.30-7.31(m,2H),7.20-7.26(m,1H) ,7.02-7.04(d,J=8Hz,1H),5.12(s,2H),3.03-3.06(m,2H),2.62-2.65(m,2H).

[0702] (2) Compound 38-3 (13.2 g, 109 mmol) and tetraethyl titanate (38.3 g, 168 mmol) were added to a toluene (200 mL) solution of compound 38-2 (20.0 g, 83.9 mmol). The reaction mixture was stirred at 120 °C for 12 hours under nitrogen protection. Water (400 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was washed with ethyl acetate (400 mL × 2). The combined organic phases were washed with saturated brine (500 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 3:1) to obtain compound 38-4.

[0703] MS-ESI[M+H] + Calculated value 342, measured value 342.

[0704] 1 H NMR (400MHz, CDCl3) δ7.26-7.44(m,7H),6.99-7.01(d,J=8Hz,1H),5.15(s,2H),3.42-3.50(m,1H),3.07-3.14(m,3H),1.32(s,9H).

[0705] (3) Ethyl acetate (13.7 g, 156 mmol) was dissolved in tetrahydrofuran (50.0 mL), and diisopropylaminolithium (2 mol / L, 39.0 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -78 °C. The reaction solution was stirred at -78 °C for 1 hour. A tetrahydrofuran solution of compound 38-4 (13.3 g, 39.0 mmol) in 500 mL was added dropwise to the reaction solution, and the mixture was stirred at -78 °C for 3 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (1000 mL), extracted with ethyl acetate (1000 mL), and the combined organic phases were washed with saturated ammonium chloride aqueous solution (1000 mL × 1) and saturated brine (1000 mL). The mixture was 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 38-5.

[0706] MS-ESI[M+H] + Calculated value 430, measured value 430.

[0707] (4) A solution of dioxane hydrochloric acid (4 mol / L, 18.0 mL) was added to an ethanol (54.0 mL) solution of compound 38-5 (6.80 g, 15.8 mmol). The reaction solution was stirred at 25 °C for 0.5 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 38-6.

[0708] MS-ESI[M-NH2+H] + Calculated value 309, measured value 309.

[0709] (5) Compound 38-7 (15.8 g, 158 mmol), copper oxide (250 mg, 3.15 mmol), and triethylamine (1.60 g, 15.7 mmol) were added to an ethanol (40.0 mL) solution of the hydrochloride salt of compound 38-6 (5.70 g, 15.8 mmol). The reaction solution was sealed and reacted at 78 °C for 12 hours under nitrogen protection. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 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 1:1) to obtain compound 38-8.

[0710] MS-ESI[M+H] + Calculated value 426, measured value 426.

[0711] (6) Paraformaldehyde (2.20 g) and sodium cyanoborohydride (2.75 g, 43.7 mmol) were added to an ethanol (60.0 mL) solution of compound 38-8 (6.20 g, 14.6 mmol). The reaction solution was reacted at 30 °C for 12 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were 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 38-9.

[0712] MS-ESI[M+H] + Calculated value 440, measured value 440.

[0713] 1H NMR (400MHz, CDCl3) δ7.40-7.45(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=7.2Hz,1H),6.75-6.77(d,J=8.0Hz,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).

[0714] (7) Add bis(trimethylsilyl)aminopotassium (1 mol / L, 39.6 mL, tetrahydrofuran solution) to a tetrahydrofuran (60.0 mL) solution of compound 38-9 (5.80 g, 13.2 mmol) at -78 °C. The reaction solution was reacted at -78 °C for 1 hour under nitrogen protection. Add saturated ammonium chloride aqueous solution (300 mL) to the reaction solution, extract with ethyl acetate (200 mL × 2), combine the organic phases, wash with saturated brine (200 mL × 2), dry with 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 38-10.

[0715] MS-ESI[M+H] + Calculated value 394, measured value 394.

[0716] (8) Compound 38-11 (1.51 g, 11.8 mmol) and sodium ethoxide (2.02 g, 29.7 mmol) were added to an ethanol (40.0 mL) solution of compound 38-10 (3.90 g, 9.91 mmol). The reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The solid precipitated was filtered, and the filter cake was dried to obtain compound 38-12.

[0717] MS-ESI[M+H] + Calculated value 406, measured value 406.

[0718] (9) To an aqueous solution (40.0 mL) containing intermediate 38-12 (3.50 g, 8.64 mmol), chloroacetic acid (7.34 g, 77.6 mmol) was added. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution, causing a solid to precipitate. The solid was then filtered, and the filter cake was dried to obtain compound 38-13.

[0719] MS-ESI[M+H] + Calculated value 390, measured value 390.

[0720] 1 H NMR(400MHz,DMSO-d6)δ11.37(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).

[0721] (10) Compound 38-13 (1.00 g, 2.57 mmol) was dissolved in phosphorus oxychloride (16.5 g, 107 mmol), and the reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, extracted with dichloromethane (100 mL × 2), and the organic phase was washed with saturated sodium bicarbonate aqueous 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.

[0722] MS-ESI[M+H] + Calculated value 426, measured value 426.

[0723] (11) Potassium carbonate (1.07 g, 7.74 mmol) and compound 38-15 (697 mg, 3.10 mmol) were added to a solution of N-methylpyrrolidone (10.0 mL) containing compound 38-14 (1.10 g, 2.58 mmol). The reaction mixture was stirred at 50 °C for 12 hours under nitrogen 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.

[0724] MS-ESI[M+H] + Calculated value: 615, Actual value: 615.

[0725] (12) Compound 38-17 (445 mg, 3.85 mmol), cesium carbonate (1.26 g, 3.85 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (215 mg, 257 μmol) were added to a solution of compound 38-16 (790 mg, 1.28 mmol) in dioxane (10.0 mL). The reaction solution was stirred at 110 °C for 6 hours under nitrogen protection. Water (30.0 mL) was added to the reaction solution, 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.

[0726] MS-ESI[M+H] + Calculated value: 694, Measured value: 694.

[0727] (13) Compound 38-18 (200 mg, 288 μmol) was added to trifluoroacetic acid (10.0 mL), and the reaction solution was stirred at 50 °C for 3 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude compound 38-19.

[0728] MS-ESI[M+H] + Calculated value 504, measured value 504.

[0729] (14) Triethylamine (42.2 mg, 417 μmol) and compound 38-20 (15.1 mg, 167 μmol) were added to a dichloromethane (1.0 mL) solution of trifluoroacetate (70.0 mg, 139 μmol) of compound 38-19. The reaction solution was stirred at -78 °C for 0.5 hours under nitrogen protection. Dichloromethane (20.0 mL) was added to the reaction solution, and the solution 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 + YMC AQ, 100 mm × 30 mm × 10 μm, A: water (0.05% hydrochloric acid); B: methanol, 0%-40%: 20 min) to obtain the hydrochloride salt of compound 38.

[0730] MS-ESI[M+H] + Calculated value 558, measured value 558.

[0731] 1 H NMR (400MHz, MeOD) δ7.24-7.31(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=6.8Hz,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 .4Hz,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).

[0732] Example 33 Synthesis of Compound 39

[0733]

[0734] Triethylamine (18.1 mg, 180 μmol), compound 39-1 (113 mg, 1.25 mmol), and tricyclic propyl phosphate tricyclic anhydride solution (341 mg, 536 μmol, 50% ethyl acetate solution) were added to a dichloromethane (2.0 mL) solution of trifluoroacetate of compound 38-19 at 0 °C. The reaction solution was stirred at 0 °C for 0.5 h. 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, 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 min) to obtain the formate salt of compound 39.

[0735] MS-ESI[M+H] + Calculated value 576, measured value 576.

[0736] 1H NMR(400MHz,MeOD)δ6.95-7.39(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,4 H),2.52-2.86(m,3H),2.37(brs,1H),2.10-2.27(m,3H),1.94-2.08(m,1H).

[0737] Example 34 Synthesis of compounds 40 and 41

[0738]

[0739] (1) Acetic anhydride (139 g, 1.36 mol) was added to a 1.0 L ethanol solution of compound 40-1 (100 g, 679 mmol). The reaction solution was stirred at 30 °C for 1 hour under nitrogen protection. The ethanol was removed by concentration under reduced pressure to obtain crude compound 40-2.

[0740] MS-ESI[M+H] + Calculated value 190, measured value 190.

[0741] (2) Magnesium sulfate (89.1 g, 740 mmol), water (300 mL), and potassium permanganate (253 g, 1.60 mol) were added to a 1.0 L acetone solution of compound 40-2 (101 g, 534 mmol). The reaction mixture was stirred at 25 °C for 3 hours under nitrogen protection. After filtration, water (600 mL) was added, and the mixture was 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.

[0742] 1 H NMR (400MHz, CDCl3) δ8.60(d,J=8.4Hz,1H),7.45(t,J=8.0Hz,1H),6.94(d,J=7.6,0 .8Hz,1H),2.98(t,J=6.0Hz,2H),2.66-2.75(m,2H),2.24(s,3H),2.03-2.15(m,2H).

[0743] (3) Concentrated hydrochloric acid (12 mol / L, 459 mL) was added to a 1.0 L aqueous solution of compound 40-3 (140 g, 689 mmol). The reaction solution was stirred at 110 °C for 3 hours under nitrogen protection. The solution was concentrated under reduced pressure, and sodium hydroxide aqueous solution (2 mol / L) was added to adjust the pH to 8. The solution was filtered, and the filter cake was washed with water (100 mL × 1) to obtain compound 40-4.

[0744] MS-ESI[M+H] + Calculated value 162, measured value 162.

[0745] (4) To a solution of compound 40-4 (90.0 g, 558 mmol) in dichloromethane (1.0 L), add boron trifluoride diethyl ether (119 g, 838 mmol) and stir at 0 °C for 20 minutes. Add isoamyl nitrite (74.9 g, 726 mmol), and stir the reaction mixture at 0 °C for 40 minutes under nitrogen protection. Add methyl tert-butyl ether (200 mL), filter, wash the filter cake with methyl tert-butyl ether (200 mL), dissolve in xylene (100 mL), and stir at 120 °C for 30 minutes. Add sodium hydroxide aqueous solution (2 mol / L), adjust the pH to 8, extract with ethyl acetate (200 mL × 3), combine the organic phases, wash with saturated brine (500 mL × 1), dry with 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 10:1) to obtain compound 40-5.

[0746] MS-ESI[M+H] + Calculated value 165, measured value 165.

[0747] 1 H NMR (400MHz, CDCl3) δ7.42 (d, J=8.0, 5.2Hz, 1H), 7.06 (d, J=7.6Hz, 1H), 6.98 (d, J=11.2,8.4Hz,1H),2.98(t,J=6.0Hz,2H),2.64-2.69(m,2H),2.09-2.17(m,2H).

[0748] (5) To a toluene (400 mL) solution of compound 40-5 (40.0 g, 244 mmol), tert-butylsulfinamide (35.4 g, 292 mmol) and tetraethyl titanate (111 g, 487 mmol) were added. The reaction mixture was stirred at 100 °C for 3 hours under nitrogen protection. Water (200 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was washed with ethyl acetate (200 mL × 3), and the combined organic phases were washed with saturated brine (300 mL). The mixture was 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 40-6.

[0749] MS-ESI[M+H] + Calculated value 268, measured value 268.

[0750] 1 H NMR (400MHz, CDCl3) δ7.32 (td, J=8.0, 5.2Hz, 1H), 6.93-7.01 (m, 2H), 3.35 (d, J=17.6, 8. 0, 6.0Hz, 1H), 3.08 (d, J = 5.6Hz, 1H), 2.83-2.90 (m, 2H), 1.91-2.01 (m, 2H), 1.34 (s, 9H).

[0751] (6) Ethyl acetate (49.4 g, 561 mmol) was dissolved in tetrahydrofuran (200 mL), and diisopropylaminolithium (2 mol / L, 112 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. Compound 40-6 (30.0 g, 112 mmol) in tetrahydrofuran (100 mL) solution was added dropwise to the reaction mixture, and stirring was continued at -78 °C for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with saturated ammonium chloride aqueous 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.

[0752] MS-ESI[M+H] + Calculated value 356, measured value 356.

[0753] 1H NMR (400MHz, CDCl3) δ7.25(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),2.8 8(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).

[0754] (7) A solution of dioxane hydrochloric acid (4 mol / L, 141 mL) was added to an ethanol (100 mL) solution of compound 40-7 (20.0 g, 56.3 mmol). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 40-8.

[0755] (8) To a 200 mL ethanol solution of the hydrochloride salt of compound 40-8 (18.0 g, 62.6 mmol), ethyl acrylate (93.9 g, 188 mmol), copper oxide (995 mg, 12.5 mmol), and triethylamine (19.0 g, 188 mmol) were added. The reaction solution was sealed and reacted at 85 °C for 10 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 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 2:1) to obtain compound 40-9.

[0756] MS-ESI[M+H] + Calculated value 352, measured value 352.

[0757] (9) Paraformaldehyde (5.50 g), acetic acid (2.56 g, 42.7 mmol), and sodium cyanoborohydride (8.05 g, 128 mmol) were added to an ethanol (200 mL) solution of compound 40-9 (15.0 g, 42.7 mmol). The reaction solution was reacted at 30 °C for 12 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The combined organic phases were 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.

[0758] 1H NMR(400MHz, CDCl3)δ7.11(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).

[0759] (10) At -78℃, potassium bis(trimethylsilyl)amino (1 mol / L, 82.1 mL, tetrahydrofuran solution) was added to a tetrahydrofuran (100 mL) solution of compound 40-10 (10.0 g, 27.4 mmol). The reaction solution was reacted at 0℃ for 2 hours under nitrogen protection. A saturated ammonium chloride aqueous solution (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 mL). The combined organic phases were 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.

[0760] MS-ESI[M+H] + Calculated value 320, measured value 320.

[0761] (11) Thiourea (3.81 g, 50.1 mmol) and sodium ethoxide (5.11 g, 75.2 mmol) were added to an ethanol (20.0 mL) solution of compound 40-11 (8.00 g, 25.0 mmol). The reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The precipitated solid was filtered, and the filter cake was dried to obtain compound 40-12.

[0762] MS-ESI[M+H] + Calculated value 332, measured value 332.

[0763] (12) To a solution of intermediate 40-12 (9.00 g, 27.2 mmol) in 60.0 mL of water, chloroacetic acid (18.0 g, 190 mmol) was added. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution, causing a solid to precipitate. The solid was then filtered, and the filter cake was dried to obtain compound 40-13.

[0764] MS-ESI[M+H] + Calculated value 316, measured value 316.

[0765] 1 H NMR(400MHz,MeOD)δ7.24(m,J=7.6,5.2Hz,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).

[0766] (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 protection. The reaction solution was concentrated under reduced pressure, extracted with dichloromethane (200 mL), and the organic phase was washed with saturated sodium bicarbonate aqueous 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.

[0767] MS-ESI[M+H] + Calculated value 352, measured value 352.

[0768] (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). The reaction solution was stirred at 50 °C for 3 hours under nitrogen protection. Ethyl acetate (200 mL) was added to the reaction solution, and the mixture was washed with saturated brine (200 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 10:1) to obtain compound 40-16.

[0769] MS-ESI[M+H] + Calculated value 541, measured value 541.

[0770] (15) Compound 40-17 (442 mg, 2.78 mmol), cesium carbonate (1.81 g, 5.54 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (100 mg, 120 μmol) were added to a solution of compound 40-16 (1.00 g, 1.85 mmol) in dioxane (20.0 mL). The reaction solution was stirred at 110 °C for 3 hours under nitrogen protection. Ethyl acetate (50.0 mL) was added to the reaction solution, 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.

[0771] MS-ESI[M+H] + Calculated value: 664, Measured value: 664.

[0772] 1 H NMR(400MHz,MeOD)δ7.22(td,J=7.6,5.2Hz,1H),6.98(d,J=7.6Hz,1H),6.91(dd,J=12.4,8.0Hz,1H),5.13-5.4 3(m,1H),4.60(d,J=12.4Hz,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. 6Hz,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=2.4Hz,9H).

[0773] (16) A solution of dioxane (4 mol / L, 5.0 mmol) in hydrochloric acid was added to a solution of compound 40-18 (910 mg, 1.37 mmol) in dichloromethane (10.0 mL). The reaction mixture was stirred at 25 °C for 2 hours under nitrogen protection. The pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phase was washed with saturated sodium bicarbonate aqueous solution (20 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 40-19.

[0774] MS-ESI[M+H]+ Calculated value: 564, Measured value: 564.

[0775] (17) Triethylamine (362 mg, 3.58 mmol) and acryloyl chloride (216 mg, 2.39 mmol) were added to a solution of compound 40-19 (672 mg, 1.19 mmol) in dichloromethane (10.0 mL). The reaction solution was stirred at -65 °C for 0.5 hours under nitrogen 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, 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 40-20.

[0776] (18) Compounds 40 and 41 were separated by chiral supercritical fluid chromatography.

[0777] Separation conditions: Column type: (S,S)-Whelk-0-1.8; Column size: 50×4.6mm ID, 1.8μm; Injection volume: 10.0μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% elution for 7 min; Detection wavelength: 254nm; Column temperature: 35℃.

[0778] Compound 40 has a retention time of 2.328 minutes and an ee value of 100%.

[0779] MS-ESI[M+H] + Calculated value: 618, Measured value: 618.

[0780] 1H NMR (400MHz, MeOD) δ7.22(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).

[0781] Compound 41 has a retention time of 1.677 minutes and an ee value of 100%.

[0782] MS-ESI[M+H] + Calculated value: 618, Measured value: 618.

[0783] 1 H NMR (400MHz, MeOD) δ7.22(td,J=7.6,5.2Hz,1H),6.98(d,J=7.6Hz,1H),6.92(dd,J=12.4,8.0Hz,1H),6.29(d,J=16.8Hz ,1H),5.83(d,J=10.4Hz,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).

[0784] Example 35 Synthesis of compounds 42 and 43

[0785]

[0786] (1) Triethylamine (809 mg, 7.99 mmol), compound 42-1 (719 mg, 7.98 mmol), 4A molecular sieve (1.50 g), and propylphosphotricyclic anhydride solution (6.78 g, 10.6 mmol, 50% ethyl acetate solution) were added to a solution of compound 40-19 (1.50 g, 2.66 mmol) in ethyl acetate (15.0 mL) at 0 °C. The reaction solution was stirred at 25 °C for 0.5 hours. Ethyl acetate (50.0 mL) was added to the reaction solution, 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 30:1) to obtain compound 42-2.

[0787] (2) Compound 42-2 was separated into compounds 42 and 43 by chiral supercritical fluid chromatography.

[0788] Separation conditions: Column type: Chiralpak OX-3; Column size: 100×4.6mm ID, 3μm; Injection volume: 10.0μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 4 minutes; Detection wavelength: 254nm; Column temperature: 35℃.

[0789] Compound 42 has a retention time of 1.385 minutes and an ee value of 100%.

[0790] MS-ESI[M+H] + Calculated value: 636, Measured value: 636.

[0791] 1H NMR (400MHz, MeOD) δ7.22(td,J=7.6,5.2Hz,1H),6.98(d,J=7.6Hz,1H),6.92(dd,J=12.8,8.0Hz,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=13.2Hz,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).

[0792] Compound 43 has a retention time of 2.071 minutes and an ee value of 100%.

[0793] MS-ESI[M+H] + Calculated value: 636, Measured value: 636.

[0794] 1 H NMR (400MHz, MeOD) δ7.22(td,J=7.6,5.2Hz,1H),6.98(d,J=7.6Hz,1H),6.91(dd,J=12.8,8.0Hz,1H),5.29-5.43(m,2H),5.26(s ,1H),4.27(d,J=13.6Hz,1H),4.18(q,J=10.4Hz,2H),3.99(d,J=11.2Hz,1H),3.71-3.79(m,1H),3.59-3.68(m,1H),3.38-3.56( m,1H),3.36(d,J=2.4Hz,1H),3.27(d,J=3.6Hz,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).

[0795] Example 36 Synthesis of compounds 44 and 45

[0796]

[0797] (1) Compound 44-2 (4.36 g, 36.0 mmol) and tetraethyl titanate (13.7 g, 60.0 mmol) were added to a toluene (50.0 mL) solution of compound 44-1 (5.00 g, 30.0 mmol). The reaction solution was stirred at 110 °C for 12 hours under nitrogen 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 combined organic phases were 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.

[0798] MS-ESI[M+H] + Calculated value 270, measured value 270.

[0799] 1 H NMR (400MHz, CDCl3) δ7.70 (d, J=7.6Hz, 1H), 7.50 (d, J=8.0Hz, 1H), 7.30 (t, J=7.6Hz, 1H), 3.46-3.56 (m, 1H), 3.06-3.19 (m, 3H), 1.33 (s, 9H).

[0800] (2) Ethyl acetate (8.16 g, 92.6 mmol) was dissolved in tetrahydrofuran (200 mL), and diisopropylaminolithium (2 mol / L, 18.5 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -78 °C. The reaction mixture was stirred at -65 °C for 1 hour. Compound 44-3 (5.0 g, 18.5 mmol) in tetrahydrofuran (500 mL) solution was added dropwise to the reaction mixture, and stirring was continued at -65 °C for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (50.0 mL), extracted with ethyl acetate (100 mL), and the combined organic phases were washed with saturated ammonium chloride aqueous solution (100 mL × 1) and saturated brine (100 mL). The mixture was 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 44-4.

[0801] MS-ESI[M+H] + Calculated value 358, measured value 358.

[0802] (3) A solution of dioxane hydrochloric acid (4 mol / L, 10.0 mL) was added to an ethanol (15.0 mL) solution of compound 44-4 (2.30 g, 6.43 mmol). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 44-5.

[0803] (4) Compound 44-6 (9.08 g, 90.6 mmol), copper oxide (144 mg, 1.81 mmol), and triethylamine (2.75 g, 27.2 mmol) were added to an ethanol (20.0 mL) solution of the hydrochloride salt of compound 44-5 (2.30 g, 9.06 mmol). The reaction solution was sealed and reacted at 85 °C for 12 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, 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 44-7.

[0804] MS-ESI[M+H] + Calculated value 354, measured value 354.

[0805] 1 H NMR (400MHz, CDCl3) δ7.19-7.23(m,1H),7.12-7.19(m,2H),4.06-4.16(m,4 H),2.95-3.06(m,1H),2.81-2.93(m,1H),2.67-2.79(m,2H),2.59-2.67(m,1 H),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).

[0806] (5) Paraformaldehyde (2.00 g) and sodium cyanoborohydride (1.07 g, 17.0 mmol) were added to an ethanol (20.0 mL) solution of compound 44-7 (2.00 g, 5.65 mmol). The reaction solution was reacted at 25 °C for 10 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The combined organic phases were 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.

[0807] MS-ESI[M+H] + Calculated value 368, measured value 368.

[0808] 1 H NMR (400MHz, CDCl3) δ7.18-7.24(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).

[0809] (6) At -78℃, potassium bis(trimethylsilyl)amino (1 mol / L, 8.16 mL, tetrahydrofuran solution) was added to a tetrahydrofuran (15.0 mL) solution of compound 44-8 (1.50 g, 4.08 mmol). The reaction solution was reacted at -65℃ for 2 hours under nitrogen protection. A saturated ammonium chloride aqueous 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.

[0810] MS-ESI[M+H] + Calculated value 322, measured value 322.

[0811] (7) Compound 44-10 (510 mg, 6.71 mmol) and sodium ethoxide (685 mg, 10.1 mmol) were added to an ethanol (10.0 mL) solution of compound 44-9 (1.08 g, 3.36 mmol). The reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The precipitated solid was filtered, and the filter cake was dried to obtain compound 44-11.

[0812] MS-ESI[M+H] + Calculated value 334, measured value 334.

[0813] 1H NMR(400MHz,DMSO-d6)δ12.42-12.50(m,1H),12.31(br d,J=2.0Hz,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=2.0Hz,1H),2.29-2.37(m,1H),2.16-2.28(m,1H),1.88-2.15(m,3H).

[0814] (8) To a 10.0 mL aqueous solution of intermediate 44-11 (848 mg, 2.54 mmol), chloroacetic acid (1.20 g, 12.7 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution, causing a solid to precipitate. The solid was then filtered, and the filter cake was dried to obtain compound 44-12.

[0815] MS-ESI[M+H] + Calculated value 318, measured value 318.

[0816] 1 H NMR(400MHz,DMSO-d6)δ11.03(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=13.6,8.0Hz,1H),1.96(s,3H),1.69(ddd,J=13.6,8.8,4.8Hz,1H).

[0817] (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 protection. The reaction solution was concentrated under reduced pressure, extracted with dichloromethane (10.0 mL), and the organic phase was washed with saturated sodium bicarbonate aqueous 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.

[0818] MS-ESI[M+H] + Calculated value 354, measured value 354.

[0819] (10) Potassium carbonate (701 mg, 5.08 mmol) and compound 44-14 (419 mg, 1.86 mmol) were added to a solution of N-methylpyrrolidone (10.0 mL) containing 600 mg, 1.69 mmol of compound 44-13. The reaction solution was stirred at 50 °C for 10 hours under nitrogen 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 44-15.

[0820] MS-ESI[M+H] + Calculated value 543, measured value 543.

[0821] (11) Compound 44-16 (175 mg, 1.10 mmol), potassium carbonate (127 mg, 1.10 mmol), tris(diphenylacetone)palladium (67.4 mg, 73.6 μmol), and 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (68.6 mg, 147 μmol) were added to a solution of compound 44-15 (200 mg, 367 μmol) in dioxane (5.00 mL). The reaction solution was stirred at 110 °C for 4 hours under nitrogen protection. Ethyl acetate (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, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 3:1) to obtain compound 44-17.

[0822] MS-ESI[M+H] + Calculated value: 666, Measured value: 666.

[0823] (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 nitrogen protection. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 44-18.

[0824] MS-ESI[M+H] + Calculated value 566, measured value 566.

[0825] (13) Triethylamine (34.8 mg, 344 μmol), compound 44-19 (31.0 mg, 344 μmol), 4A molecular sieve (40.0 mg), and propyl phosphate tricyclic anhydride solution (219 mg, 344 μmol, 50% ethyl acetate solution) were added to a solution of compound 44-18 (65.0 mg, 114 μmol) in ethyl acetate (3.0 mL) at 0 °C. The reaction solution was stirred at 25 °C for 1 hour. Dichloromethane (10.0 mL) was added to the reaction solution, and the mixture 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 min) to obtain compound 44-20.

[0826] (14) Compounds 44 and 45 were separated by chiral supercritical fluid chromatography.

[0827] Separation conditions: Column type: Chiralpak IC-3; Column size: 50×4.6mm ID, 3μm; Injection volume: 8.0μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 4 minutes; Detection wavelength: 254nm; Column temperature: 35℃.

[0828] Compound 44 had a retention time of 1.342 minutes and an ee value of 98.64%.

[0829] MS-ESI[M+H] + Calculated value: 638, Actual value: 638.

[0830] 1 H NMR (400MHz, MeOD) δ7.24-7.32(m,2H),7.16(dd,J=7.2,1.2Hz,1H),5.32-5.40(m,1H),5.23-5.31(m,1H),4.09-4.31(m,4H),4.00(br d,J=12.4Hz,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=13.6,8.8,4.4Hz,2H),1.25-1.36(m,4H).

[0831] Compound 45 had a retention time of 1.807 minutes and an ee value of 97.24%.

[0832] MS-ESI[M+H] + Calculated value: 638, Actual value: 638.

[0833] 1 H NMR (400MHz, MeOD) δ7.24-7.32(m,2H),7.16(dd,J=7.2,1.2Hz,1H),5.32-5.40(m,1H),5.23-5.31(m,1H),4.09-4.31(m,4H),4.00(br d,J=12.4Hz,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=13.6,8.8,4.4Hz,2H),1.25-1.36(m,4H).

[0834] Example 37 Synthesis of compounds 46 and 47

[0835]

[0836] (1) Compound 46-2 (20.3 g, 168 mmol) and tetraethyl titanate (63.8 g, 280 mmol) were added to a toluene (300 mL) solution of compound 46-1 (21.0 g, 140 mmol). The reaction mixture was stirred at 110 °C for 2 hours under nitrogen protection. Water (200 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was washed with ethyl acetate (500 mL × 3). The combined organic phases were 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 2:1) to obtain compound 46-3.

[0837] MS-ESI[M+H] + Calculated value 254, measured value 254.

[0838] 1 H NMR (400MHz, CDCl3) δ7.59 (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).

[0839] (2) Ethyl acetate (27.0 g, 306 mmol) was dissolved in tetrahydrofuran (200 mL), and the solution was heated at -78 °C under nitrogen.

[0840] Under atmospheric protection, lithium diisopropylamino (2 mol / L, 61.2 mL, tetrahydrofuran solution) was added dropwise, and the reaction mixture was stirred at -78°C for 1 hour. A tetrahydrofuran solution (200 mL) containing 15.5 g (61.2 mmol) of compound 46-3 was added dropwise, and stirring was continued at -78°C for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated ammonium chloride aqueous solution (200 mL × 1) and saturated brine (100 mL × 3). The mixture was 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 46-4.

[0841] MS-ESI[M+H] + Calculated value 342, measured value 342.

[0842] 1 H NMR (400MHz, CDCl3) δ7.16-7.24(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=8.0Hz,3H),1.19(s,9H).

[0843] (3) A solution of dioxane hydrochloric acid (4 mol / L, 10.0 mL) was added to an ethanol (30.0 mL) solution of compound 46-4 (4.50 g, 13.2 mmol). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 46-5.

[0844] (4) Compound 46-6 (13.8 g, 138 mmol), copper oxide (209 mg, 2.63 mmol), and triethylamine (2.66 g, 26.3 mmol) were added to an ethanol (40.0 mL) solution of the hydrochloride salt of compound 46-5 (6.32 g, 13.2 mmol). The reaction solution was sealed and reacted at 80 °C for 12 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 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 2:1) to obtain compound 46-7.

[0845] MS-ESI[M+H] + Calculated value 338, measured value 338.

[0846] 1 H NMR (400MHz, CDCl3) δ7.14-7.21(m,1H),6.98-7.07(m,1H),6.90(t,J=8.0Hz,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=8.0Hz,3H).

[0847] (5) Paraformaldehyde (3.65 g), sodium cyanoborohydride (2.29 g, 36.5 mmol), and acetic acid (1.46 g, 24.3 mmol) were added to an ethanol (50.0 mL) solution of compound 46-7 (4.10 g, 12.2 mmol). The reaction solution was reacted at 35 °C for 15 hours under nitrogen protection. Water (30.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The combined organic phases were 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 2:1) to obtain compound 46-8.

[0848] MS-ESI[M+H] + Calculated value 352, measured value 352.

[0849] 1 H NMR (400MHz, CDCl3) δ7.12-7.19(m,1H),7.02(d,J=8.0Hz,1H),6.89(t,J=8.0Hz,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).

[0850] (6) At -78 °C, potassium bis(trimethylsilyl)amino (1 mol / L, 29.0 mL, tetrahydrofuran solution) was added to a tetrahydrofuran (50.0 mL) solution of compound 46-8 (3.40 g, 9.68 mmol). The reaction solution was reacted at -78 °C for 2 hours under nitrogen protection. A saturated ammonium chloride aqueous solution (50.0 mL) was added to the reaction solution, 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.

[0851] MS-ESI[M+H] + Calculated value 306, measured value 306.

[0852] 1 H NMR (400MHz, CDCl3) δ7.19-7.26(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).

[0853] (7) Compound 46-10 (1.25 g, 16.4 mmol) and sodium ethoxide (1.67 g, 24.6 mmol) were added to an ethanol (50.0 mL) solution of compound 46-9 (2.50 g, 8.19 mmol). The reaction solution was stirred at 80 °C for 15 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The precipitated solid was filtered, and the filter cake was dried to obtain compound 46-11.

[0854] MS-ESI[M+H] + Calculated value 318, measured value 318.

[0855] 1H NMR (400MHz, DMSO-d6) δ7.28-7.35(m,1H),7.03-7.12(m,2H),3.41-3.51(m,1H),3.06(d,J=16.0Hz,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).

[0856] (8) To a 50.0 mL aqueous solution of intermediate 46-11 (2.20 g, 6.93 mmol), chloroacetic acid (3.30 g, 34.9 mmol) was added. The reaction mixture was stirred at 100 °C for 15 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate solution, causing a solid to precipitate. The solid was then filtered, and the filter cake was dried to obtain compound 46-12.

[0857] MS-ESI[M+H] + Calculated value 302, measured value 302.

[0858] 1 H NMR (400MHz, DMSO-d6) δ11.02(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).

[0859] (9) Compound 46-12 (400 mg, 1.33 mmol) was dissolved in phosphorus oxychloride (10.0 mL), and the reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, extracted with dichloromethane (20.0 mL), and the organic phase was washed with saturated sodium bicarbonate aqueous 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.

[0860] MS-ESI[M+H] + Calculated value 338, measured value 338.

[0861] (10) Potassium carbonate (701 mg, 3.94 mmol) and compound 46-14 (444 mg, 1.97 mmol) were added to a solution of compound 46-13 (600 mg, 1.31 mmol) in N-methylpyrrolidone (20.0 mL). The reaction solution was stirred at 50 °C for 5 hours under nitrogen protection. Ethyl acetate (50.0 mL) was added to the reaction solution, and the mixture was washed with saturated brine (30.0 mL × 5). The solution was 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 46-15.

[0862] MS-ESI[M+H] + Calculated value 527, measured value 527.

[0863] 1 H NMR (400MHz, CDCl3) δ7.20-7.26(m,1H),6.93-7.07(m,2H),3.96-4.07(d,J=12.0Hz,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).

[0864] (11) Compound 46-16 (227 mg, 1.42 mmol), cesium carbonate (927 mg, 2.85 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (159 mg, 190 μmol) were added to a solution of compound 46-15 (500 mg, 949 μmol) in dioxane (15.0 mL). The reaction solution was stirred at 110 °C for 4 hours under nitrogen protection. Ethyl acetate (50.0 mL) was added to the reaction solution, 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 10:1) to obtain compound 46-17.

[0865] MS-ESI[M+H] + Calculated value 650, measured value 650.

[0866] 1H NMR (400MHz, CDCl3) δ7.18-7.25(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).

[0867] (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 nitrogen protection. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated sodium bicarbonate aqueous 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.

[0868] MS-ESI[M+H] + Calculated value 550, measured value 550.

[0869] (13) Triethylamine (82.8 mg, 819 μmol), compound 46-19 (73.7 mg, 819 μmol), 4A molecular sieve (150 mg), and propylphosphonic tricyclic anhydride solution (521 mg, 819 μmol, 50% ethyl acetate solution) were added to a solution of compound 46-18 (150 mg, 273 μmol) in ethyl acetate (3.0 mL) at 0 °C. The reaction solution was stirred at 25 °C for 1 hour. Dichloromethane (10.0 mL) was added to the reaction solution, and the mixture 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.

[0870] (14) Compounds 46 and 47 were separated by chiral supercritical fluid chromatography.

[0871] Separation conditions: Column type: Chiralpak OX-3; Column size: 10×4.6mm ID, 3μm; Injection volume: 8.0μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 4 min, 40% fixed concentration elution for 1 min, 10% fixed concentration elution for 1 min; Detection wavelength: 254nm; Column temperature: 35℃.

[0872] Compound 46 has a retention time of 3.680 minutes and an ee value of 100%.

[0873] MS-ESI[M+H] + Calculated value 622, measured value 622.

[0874] 1 H NMR(400MHz,MeOD)δ7.27-7.34(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,2 H),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).

[0875] Compound 47 had a retention time of 4.052 minutes and an ee value of 98.44%.

[0876] MS-ESI[M+H] + Calculated value 622, measured value 622.

[0877] 1H NMR(400MHz,MeOD)δ7.24-7.33(m,1H),6.95-7.08(m,2H),5.19-5.43(m,3H),4.25(d ,J=12.0Hz,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=4.0Hz,2H),2.42-2.52(m,1H),2.2 7-2.39(m,1H),2.16-2.27(m,4H),2.05-2.15(m,1H),1.84-2.03(m,4H),1.29(s,3H).

[0878] Example 38 Synthesis of compounds 48 and 49

[0879]

[0880] (1) Compound 48-2 (3.69 g, 30.4 mmol) and tetraethyl titanate (13.8 g, 60.9 mmol) were added to a toluene (150 mL) solution of compound 48-1 (5.00 g, 30.4 mmol). The reaction solution was stirred at 120 °C for 10 hours under nitrogen protection. Water (300 mL) was added to the reaction solution, and the mixture was filtered. The filter cake was washed with ethyl acetate (300 mL × 3). The combined organic phases were 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 0:1) to obtain compound 48-3.

[0881] MS-ESI[M+H] + Calculated value 268, measured value 268.

[0882] 1 H NMR (400MHz, CDCl3) δ7.95 (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).

[0883] (2) Ethyl acetate (8.57 g, 97.2 mmol) was dissolved in tetrahydrofuran (50 mL), and diisopropylaminolithium (2 mol / L, 19.4 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. A tetrahydrofuran 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. The reaction was quenched by adding saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated ammonium chloride aqueous solution (200 mL × 1) and saturated brine (100 mL × 3). The mixture was 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.

[0884] MS-ESI[M+H] + Calculated value 356, measured value 356.

[0885] 1 H NMR (400MHz, CDCl3) δ7.08-7.20(m,2H),6.92(d,J=9.2,1.6Hz,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).

[0886] (3) A solution of dioxane hydrochloric acid (4 mol / L, 10.0 mL) was added to an ethanol (30.0 mL) solution of compound 48-4 (3.70 g, 10.4 mmol). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 48-5.

[0887] (4) Compound 48-6 (10.3 g, 103 mmol), copper oxide (164 mg, 2.07 mmol), and triethylamine (3.14 g, 31.0 mmol) were added to an ethanol (40.0 mL) solution of the hydrochloride salt of compound 48-5 (2.60 g, 10.3 mmol). The reaction solution was sealed and reacted at 85 °C for 12 hours under nitrogen protection. Water (50.0 mL) was added to the reaction solution, 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, 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 48-7.

[0888] MS-ESI[M+H] + Calculated value 352, measured value 352.

[0889] 1 H NMR(400MHz, CDCl3)δ7.36(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,2 H), 2.43 (s, 3H), 2.02-2.11 (m, 1H), 1.94 (d, J = 4.8Hz, 2H), 1.84 (d, J = 10.8, 5.6Hz, 1H) 1.25 (m, 3H), 1.21 (t, J = 7.2Hz, 3H).

[0890] (5) Paraformaldehyde (1.62 g) and sodium cyanoborohydride (1.02 g, 16.2 mmol) were added to an ethanol (30.0 mL) solution of compound 48-7 (1.90 g, 5.41 mmol). The reaction solution was reacted at 30 °C for 16 hours under nitrogen protection. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The combined organic phases were 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 0:1) to obtain compound 48-8.

[0891] MS-ESI[M+H] + Calculated value 366, measured value 366.

[0892] 1H NMR (400MHz, CDCl3) δ7.31(d,J=8.0Hz,1H),7.05-7.12(m,1H),6.81-6.88(m,1H),4.09(q,J=7.2Hz,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=6.4Hz,2H),1.23(t,J=7.2Hz,3H),1.01(t,J=7.2Hz,3H).

[0893] (6) At -78 °C, potassium bis(trimethylsilyl)amino (1 mol / L, 9.30 mL, tetrahydrofuran solution) was added to a tetrahydrofuran (30.0 mL) solution of compound 48-8 (1.70 g, 4.65 mmol). The reaction solution was reacted at -78 °C for 2 hours under nitrogen protection. A saturated ammonium chloride aqueous 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 0:1) to obtain compound 48-9.

[0894] MS-ESI[M+H] + Calculated value 320, measured value 320.

[0895] 1 H NMR (400MHz, CDCl3) δ7.26-7.56(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).

[0896] (7) Compound 48-10 (572 mg, 7.51 mmol) and sodium ethoxide (767 mg, 11.2 mmol) were added to an ethanol (20.0 mL) solution of compound 48-9 (1.20 g, 3.76 mmol). The reaction solution was stirred at 80 °C for 15 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The precipitated solid was filtered, and the filter cake was dried to obtain compound 48-11.

[0897] MS-ESI[M+H] + Calculated value 332, measured value 332.

[0898] (8) To a 30.0 mL aqueous solution of intermediate 48-11 (1.10 g, 3.25 mmol), chloroacetic acid (1.25 g, 13.2 mmol) was added. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution, causing a solid to precipitate. The solid was then filtered and dried to obtain compound 48-12.

[0899] MS-ESI[M+H] + Calculated value 316, measured value 316.

[0900] 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),10.75(s,1H),7.38(d,J=7.6Hz,1H),7.20-7.32(m,1H),7.04(t,J=8.4Hz,1H),3.52(d,J=14.8Hz,1H ), 3.05 (d, J = 14.0Hz, 1H), 2.81 (d, J = 16.4Hz, 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).

[0901] (9) Compound 48-12 (200 mg, 634 μmol) was dissolved in phosphorus oxychloride (2.0 mL), and the reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, extracted with dichloromethane (20.0 mL), and the organic phase was washed with saturated sodium bicarbonate aqueous 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.

[0902] MS-ESI[M+H] + Calculated value 352, measured value 352.

[0903] (10) Potassium carbonate (176 mg, 1.28 mmol) and compound 48-14 (115 mg, 551 μmol) were added to a solution of N-methylpyrrolidone (5.0 mL) containing 150 mg, 425 μmol of compound 48-13. The reaction solution was stirred at 50 °C for 5 hours under nitrogen protection. Ethyl acetate (50.0 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 0:1) to obtain compound 48-15.

[0904] MS-ESI[M+H] + Calculated value 541, measured value 541.

[0905] 1 H NMR(400MHz, CDCl3)δ7.35(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),2.1 2(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).

[0906] (11) Compound 48-16 (388 mg, 2.44 mmol), cesium carbonate (794 mg, 2.44 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (136 mg, 162 μmol) were added to a solution of compound 48-15 (440 mg, 813 μmol) in dioxane (10.0 mL). The reaction solution was stirred at 110 °C for 4 hours under nitrogen protection. Ethyl acetate (50.0 mL) was added to the reaction solution, 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 10:1) to obtain compound 48-17.

[0907] MS-ESI[M+H] + Calculated value: 664, Measured value: 664.

[0908] (12) A solution of dioxane (5.0 mL) containing 270 mg, 406 μmol of compound 48-17 was added to a solution of dichloromethane (4 mol / L, 36.7 μmol) containing dioxane. The reaction mixture was stirred at 25 °C for 2 hours under nitrogen protection. The pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phase was washed with saturated sodium bicarbonate aqueous solution (20 mL) and 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 (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 48-18.

[0909] MS-ESI[M+H] + Calculated value: 564, Measured value: 564.

[0910] (13) Triethylamine (17.9 mg, 177 μmol), compound 48-19 (35.9 mg, 354 μmol), 4A molecular sieve (100 mg), and propylphosphonic tricyclic anhydride solution (677 mg, 1.06 mmol, 50% ethyl acetate solution) were added to a solution of compound 48-18 (200 mg, 354 μmol) in ethyl acetate (1.0 mL) at 0 °C. The reaction solution was stirred at 25 °C for 1 hour. Dichloromethane (10.0 mL) was added to the reaction solution, and the mixture 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.

[0911] (14) Compounds 48 and 49 were separated by chiral supercritical fluid chromatography.

[0912] Separation conditions: Column type: Chiralpak OD-3; Column size: 50×4.6mm ID, 3μm; Injection volume: 8.0μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 2.5 min, 40% fixed concentration elution for 0.5 min, 5% fixed concentration elution for 1 min; Detection wavelength: 254nm; Column temperature: 35℃.

[0913] Compound 48 had a retention time of 1.743 minutes and an ee value of 98.58%.

[0914] MS-ESI[M+H] + Calculated value: 636, Measured value: 636.

[0915] 1H NMR(400MHz,MeOD)δ7.37(d,J=8.0Hz,1H),7.20-7.27(m,1H),6.94(t,J=8.8Hz,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. 8Hz,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),2.1 5-2.26(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)

[0916] Compound 49 had a retention time of 1.937 minutes and an ee value of 98.18%.

[0917] MS-ESI[M+H] + Calculated value: 636, Measured value: 636.

[0918] 1 H NMR(400MHz,MeOD)δ7.61(d,J=8.0Hz,1H),7.39-7.46(m,1H),7.16(t,J=8.4Hz,1H),5.63(t,J=3.6Hz,0.5H ),5.50(d,J=3.2Hz,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),2.51-2.5 7(m,1H),2.40(d,J=8.4Hz,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).

[0919] Example 39 Synthesis of compounds 50 and 51

[0920]

[0921] (1) Compound 50-2 (16.1 g, 133 mmol) and tetraethyl titanate (50.5 g, 221 mmol) were added to a toluene (240 mL) solution of compound 50-1 (20.0 g, 111 mmol). The reaction mixture was stirred at 110 °C for 13 hours under nitrogen protection. Water (200 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was washed with ethyl acetate (100 mL × 3). The combined organic phases were washed with 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 to 5:1) to obtain compound 50-3.

[0922] MS-ESI[M+H] + Calculated value: 284, Measured value: 284.

[0923] 1 H NMR (400MHz, CDCl3) δ8.07-8.14(m,1H),7.49(dd,J=7.6,1.2Hz,1H),7.21(t,J=8.0Hz,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).

[0924] (2) Ethyl acetate (26.9 g, 305 mmol) was dissolved in tetrahydrofuran (320 mL), and diisopropylaminolithium (2 mol / L, 60.9 mL, tetrahydrofuran solution) was added dropwise under nitrogen protection at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. Compound 50-3 (15.5 g, 61.2 mmol) in tetrahydrofuran (200 mL) solution was added dropwise to the reaction mixture, and stirring was continued at -78 °C for 3 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated ammonium chloride aqueous solution (200 mL × 1) and saturated brine (100 mL × 3). The mixture was 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.

[0925] MS-ESI[M+H] + Calculated value 372, measured value 372.

[0926] 1H NMR (400MHz, CDCl3) δ7.31 (dd, J=17.2, 8.0Hz, 2H), 7.09-7.16 (m, 1H), 4.11-4.19 (m, 2H), 2.75-2.9 0(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).

[0927] (3) A solution of dioxane hydrochloric acid (4 mol / L, 38.9 mL) was added to an ethanol (80.0 mL) solution of compound 50-4 (17.1 g, 46.0 mmol). The reaction solution was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 50-5.

[0928] (4) Compound 50-6 (15.1 g, 151 mmol), copper oxide (241 mg, 3.02 mmol), and triethylamine (1.53 g, 15.1 mmol) were added to an ethanol (30.0 mL) solution of the hydrochloride salt of compound 50-5 (4.60 g, 15.1 mmol). The reaction solution was sealed and reacted at 85 °C for 12 hours under nitrogen protection. Water (90.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40.0 mL × 3). The combined organic phases were washed with saturated brine (30.0 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 to 3:1) to obtain compound 50-7.

[0929] MS-ESI[M+H] + Calculated value 368, measured value 368.

[0930] (5) Paraformaldehyde (1.88 g) and sodium cyanoborohydride (1.18 g, 18.8 mmol) were added to an ethanol (20.0 mL) solution of compound 50-7 (2.30 g, 6.25 mmol). The reaction solution was reacted at 25 °C for 25 hours under nitrogen protection. Water (30.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15.0 mL × 3). The combined organic phases were washed with saturated brine (15.0 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 3:1) to obtain compound 50-8.

[0931] MS-ESI[M+H] + Calculated value 382, ​​measured value 382.

[0932] 1H NMR (400MHz, CDCl3) δ7.48(d,J=8.0Hz,1H),7.20-7.24(m,1H),7.05-7.11(m,1H),4.10(q,J=7.2Hz,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=6.4Hz,2H),1.24(t,J=7.2Hz,3H),1.01(t,J=7.2Hz,3H).

[0933] (6) At -78℃, potassium bis(trimethylsilyl)amino (1 mol / L, 13.4 mL, tetrahydrofuran solution) was added to a tetrahydrofuran (35.0 mL) solution of compound 50-8 (1.70 g, 4.45 mmol). The reaction solution was reacted at -78℃ for 2 hours under nitrogen protection. A saturated ammonium chloride aqueous solution (15.0 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 0:1) to obtain compound 50-9.

[0934] MS-ESI[M+H] + Calculated value 336, measured value 336.

[0935] 1 H NMR (400MHz, CDCl3) δ7.47-7.59(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=14.4Hz,4H),1.66-1.84(m,3H),1.33(t,J=7.2Hz,3H).

[0936] (7) Compound 50-10 (585 mg, 7.68 mmol) and sodium ethoxide (784 mg, 11.5 mmol) were added to an ethanol (25.0 mL) solution of compound 50-9 (1.29 g, 3.84 mmol). The reaction solution was stirred at 80 °C for 15 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 6 with hydrochloric acid (1 mol / L). The precipitated solid was filtered, and the filter cake was dried to obtain compound 50-11.

[0937] MS-ESI[M+H]+ Calculated value 348, measured value 348.

[0938] 1 H NMR (400MHz, CDCl3) δ7.54(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=16.4H z,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).

[0939] (8) To a water (75.0 mL) solution of intermediate 50-11 (1.18 g, 3.39 mmol), chloroacetic acid (3.21 g, 33.9 mmol) was added. The reaction mixture was stirred at 110 °C for 12 hours under nitrogen protection. The reaction mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution, causing a solid to precipitate. The solid was filtered again, and the filter cake was dried to obtain compound 50-12.

[0940] MS-ESI[M+H] + Calculated value 332, measured value 332.

[0941] (9) Compound 50-12 (1.20 g, 3.62 mmol) was dissolved in phosphorus oxychloride (10.0 mL), and the reaction solution was stirred at 80 °C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, extracted with dichloromethane (20.0 mL), and the organic phase was washed with saturated sodium bicarbonate aqueous 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.

[0942] MS-ESI[M+H] + Calculated value 368, measured value 368.

[0943] (10) Potassium carbonate (585 mg, 4.23 mmol) and compound 50-14 (381 mg, 1.69 mmol) were added to a solution of N-methylpyrrolidone (5.0 mL) containing compound 50-13 (520 mg, 1.41 mmol). The reaction mixture was stirred at 50 °C for 4 hours under nitrogen protection. Ethyl acetate (50.0 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (30.0 mL × 5). The mixture was 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 50-15.

[0944] MS-ESI[M+H] + Calculated value 557, measured value 557.

[0945] 1 H NMR (400MHz, CDCl3) δ7.42-7.56(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=2.4Hz,9H).

[0946] (11) Compound 50-16 (197 mg, 1.24 mmol), potassium carbonate (171 mg, 1.24 mmol), tris(diphenylacetone)palladium (75.6 mg, 82.5 μmol), and 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (77.0 mg, 165 μmol) were added to a solution of compound 50-15 (230 mg, 412 μmol) in dioxane (5.00 mL). The reaction solution was stirred at 90 °C for 5 hours under nitrogen protection. The reaction solution was added to ethyl acetate (20.0 mL), 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 (Xtimate C18, 150 mm × 40 mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 20%-50%: 10 min) to obtain the formate salt of compound 50-17.

[0947] MS-ESI[M+H] + Calculated value: 680, Actual value: 680.

[0948] (12) Trifluoroacetic acid (1.0 mL) was added to a solution of the formate (80 mg, 118 μmol) of compound 50-17 in dichloromethane (1.0 mL). The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. The trifluoroacetic acid was removed by concentration under reduced pressure. The pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (20 mL × 2). The organic phase was washed with saturated sodium bicarbonate aqueous solution (20 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 50-18.

[0949] MS-ESI[M+H] + Calculated value 580, measured value 580.

[0950] (13) Triethylamine (57.6 mg, 79.2 μmol), compound 50-19 (25.6 mg, 284 μmol), 4A molecular sieve (100 mg), and propylphosphonic tricyclic anhydride solution (181 mg, 284 mmol, 50% ethyl acetate solution) were added to a 1.0 mL ethyl acetate solution of compound 50-18 (55.0 mg, 94.8 μmol) at 0 °C. The reaction solution was stirred at 25 °C for 1 hour. Ethyl acetate (10.0 mL) was added to the reaction solution, 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 min) to obtain compound 50-20.

[0951] (14) Compounds 50 and 51 were separated by chiral supercritical fluid chromatography.

[0952] Separation conditions: Column type: Chiralpak OD-3; Column size: 50×4.6mm ID, 3μm; Injection volume: 8.0μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 2.5 min, 40% fixed concentration elution for 0.5 min, 5% fixed concentration elution for 1 min; Detection wavelength: 254nm; Column temperature: 35℃.

[0953] Compound 50 had a retention time of 1.657 minutes and an ee value of 99.30%.

[0954] MS-ESI[M+H] + Calculated value: 652, Actual value: 652.

[0955] 1H NMR(400MHz,MeOD)δ7.53(d,J=7.6Hz,1H),7.26-7.32(m,1H),7.17-7.25(m,1H),5.11 -5.48(m,3H),4.30(d,J=13.6Hz,1H),4.10-4.22(m,2H),4.00(d,J=11.2Hz,1H),3.70- 3.82(m,2H),3.61(q,J=7.2Hz,1H),2.90-3.31(m,11H),2.55(ddd,J=17.2,12.0,5.2H z,1H),2.06-2.39(m,6H),1.84-2.06(m,5H),1.77(d,J=11.2Hz,2H),1.15-1.33(m,2H)

[0956] Compound 51 has a retention time of 1.810 minutes and an ee value of 100%.

[0957] MS-ESI[M+H] + Calculated value: 652, Actual value: 652.

[0958] 1 H NMR(400MHz,MeOD)δ7.53(d,J=7.6Hz,1H),7.26-7.32(m,1H),7.17-7.25(m,1H),5.11 -5.48(m,3H),4.30(d,J=13.6Hz,1H),4.10-4.22(m,2H),4.00(d,J=11.2Hz,1H),3.70- 3.82(m,2H),3.61(q,J=7.2Hz,1H),2.90-3.31(m,11H),2.55(ddd,J=17.2,12.0,5.2Hz ,1H),2.06-2.39(m,6H),1.84-2.06(m,5H),1.77(d,J=11.2Hz,2H),1.15-1.33(m,2H).

[0959] Experimental Example 1

[0960] Inhibitory effect of compound on the proliferation of NCI-H358 cells

[0961] 1. Experimental Principle: NCI-H358 cells are a human non-small cell lung cancer cell line expressing KRAS G12C. The compounds involved in this invention inhibit the proliferation of NCI-H358 cells by covalently binding to KRAS G12C.

[0962] 2. Experimental Materials: NCI-H358 cells were purchased from ATCC; CellTiter-GloR was purchased from Promega (catalog number G7571); RPMI-1640 was purchased from ATCC (catalog number 30-2001); fetal bovine serum (FBS) was purchased from EXCELL (catalog number FND500); penicillin-streptomycin was purchased from Gibco (catalog number 15140-122); 0.25% trypsin-EDTA digestion solution was purchased from Gibco (catalog number 25200-072); dimethyl sulfoxide (DMSO) was purchased from Sigma (catalog number D2650); 96-well plates were purchased from Corning (catalog number 3610); incubators were purchased from Thermo (model 3111); inverted microscopes were purchased from Nikon (catalog number TS-100); automated cell counters were purchased from Life. Technologies (model CountessII); microplate reader purchased from PerkinElmer (model Envision); data processing software: GraphPad Prism 5.0.

[0963] 3. Experimental 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 cell suspension was seeded at 100 μL per well in a 96-well plate and incubated overnight at 37°C in a 5% CO2 incubator. The culture medium served as a background control.

[0964] The test compound was dissolved in DMSO to prepare a stock solution with a concentration of 10 mmol / L. The stock solution was first diluted to 2 mmol / L with DMSO, then serially diluted 3-fold to obtain 10 concentrations. 3 μL of each concentration was diluted with 197 μL of growth medium. Then, 50 μL of each solution was added to a 96-well plate seeded with cells. The cells were incubated at 37°C in a 5% CO2 incubator for 72 hours. The 96-well plate was equilibrated at room temperature, and 40 μL of CellTiter-Glo reagent was added to each well. The mixture was vortexed for 2 minutes and incubated at room temperature for 60 minutes. The luminescence value was read using an EnVision microplate reader, and the IC50 of the compound was calculated using GraphPad Prism 5.0 software. 50 .

[0965] The specific test results are shown in Table 1 (each compound number is the compound number specified in the examples), where A represents IC. 50 <100nM, B represents 100nM <IC 50 <1μM, where C represents 1μM <IC 50 <10μM.

[0966] Table 1

[0967] 1 C 3% formate A 4% formate C 5 B 6 A 7 B 8 B 10 formate B 11% formate C 12% formate C 14 C 15% formate B 17% formate B 18% formate A 19% formate B 20% formate A 21% formate B 22% formate B 23% hydrochloride C 24% formate B 25% formate C 26 A 28 A 32 A 33 A 34% formate A 35 A 36 A 37 B 40 A 41 B 42 A 43 B 44 A 45 B 46 A

[0968] 48 A 49 C 50 A 51 C

[0969] As can be seen from the test data in Table 1, the compound shown in Formula I of the present invention has a better inhibitory effect on the growth of H358 cells and has the potential to be used in the preparation of drugs for treating and preventing cancer.

[0970] Test Example 2

[0971] Determination of the pharmacokinetic properties of the compound in rats

[0972] 1. Test purpose: This study aims to determine the pharmacokinetic characteristics of the compounds of some embodiments of the present invention in SD rats after single intravenous injection (IV) and oral administration (PO) by LC-MS / MS method.

[0973] 2. Test materials: The test drugs were self-prepared compounds of the embodiments of the present invention; the positive compounds AMG-510 and MRTX-849 were purchased from Chengdu Zhihuizhongxin Biomedical Co., Ltd.; SD male rats were from the Experimental Animal Business Department of Shanghai Institute of Planned Parenthood Research. Animal production license number (SCXK (Shanghai) 2018-0006).

[0974] 3. Test method: <>

[0975] Preparation of 0.5% methylcellulose: Weigh 5 g of methylcellulose and dissolve it in 1000 mL of pure water.

[0976] Preparation of oral formulation: Weigh the required amount of the test compound and dissolve it in 0.5% methylcellulose solution to obtain a suspension or solution of 0.5 mg / mL.

[0977] Preparation of intravenous injection formulation: Weigh the required amount of the test compound and dissolve it in 0.5 mL of dimethyl sulfoxide to prepare a solution of 4 mg / mL. Take 0.25 mL of the above solution, add 0.5 mL of polyethylene glycol 15 hydroxystearate (solutol) and 4.25 mL of normal saline to obtain a solution of 0.2 mg / mL.

[0978] Administration: After fasting overnight, SD male rats were orally administered (PO), and the single intravenous injection (IV) group did not need to fast. The administration dose and volume are shown in the following table. Feed was given 4 hours after administration.

[0979]

[0980] Sample Collection: Blood was collected via the jugular vein or other suitable vein, 0.2 mL at each time point. Samples were placed in test tubes containing dipotassium ethylenediaminetetraacetate (EDTA) and kept on ice before centrifugation. Within 1 hour of collection, blood samples were centrifuged at 2–8°C and 6800 g for 6 minutes and stored at -80°C. Blood collection time points for intravenous administration were 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration; blood collection time points for oral administration were 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. Specific test results are shown in Table 2.

[0981] Table 2

[0982]

[0983]

[0984] The data in Table 2 show that some of the compounds in the embodiments of this invention have excellent pharmacokinetic properties in rats, even better than those of the positive compounds.

[0985] Experimental Example 3

[0986] Whole blood stability assay of the compound

[0987] 1. Experimental objective: To determine the whole blood stability of compounds by monitoring the clearance rate of parent compounds after incubation with whole blood of dogs and rats for compounds from certain embodiments of the present invention.

[0988] 2. Test materials: The test drugs were self-made compounds from the embodiments of this invention; the positive compounds AMG-510 and MRTX-849 were purchased from Chengdu Zhihui Zhongxin Biomedical Co., Ltd.

[0989] 3. Test methods:

[0990] Solution preparation: Weigh the required amount of the analyte and dissolve it in dimethyl sulfoxide to prepare a 10 mmol / L stock solution. Then, dilute the stock solution of the analyte to 1 mmol / L and 0.2 mmol / L respectively with 70% acetonitrile aqueous solution to prepare working solutions.

[0991] Add the working solution to whole blood to achieve a concentration of 5 μmol / L for the analyte. Take 90 μL of the solution and add 90 μL of water, mixing thoroughly. Then add 600 μL of acetonitrile stop solution containing propranolol as an internal standard. Incubate at 37°C with gentle shaking. At 30, 60, 120, and 240 minutes, take 90 μL of the mixture and place it in a clean 96-well plate pre-filled with 90 μL of water, mix thoroughly, and then add 600 μL of acetonitrile stop solution containing propranolol as an internal standard. Centrifuge at 5000g for 15 minutes. Take 80 μL of the supernatant and place it in a 96-well plate pre-filled with 160 μL of ultrapure water, then analyze by LC-MS / MS.

[0992] The specific test results are shown in Table 3.

[0993] Table 3

[0994] AMG510 111.3 87.5 MRTX849 783.9 369.0 28 258.9 380.4

[0995] The data above show that some of the compounds in the embodiments of this invention have excellent whole blood stability.

[0996] Test Example 4

[0997] H358 pERK inhibitory activity

[0998] 1. Objective: To detect the inhibitory effect of the test compound on ERK phosphorylation in NCI-H358 cells.

[0999] 2. Experimental Materials: The test reagents were prepared in-house using the compounds described in the embodiments of this invention; the positive compound AMG-510 was purchased from Chengdu Zhihui Zhongxin Biomedical Co., Ltd.; NCI-H358 cells were purchased from Wuhan Pronosai Life Science Technology Co., Ltd.; 96-well cell culture plates were purchased from Corning; incubators were purchased from Thermo Fisher Scientific; PRMI1640 culture medium was purchased from Biological Industries; dimethyl sulfoxide was purchased from Sinopharm Chemical Reagent Co., Ltd.; pipettes were purchased from Thermo Fisher Scientific; 384-well microplates were purchased from Greiner; the phospho-ERK (Thr202 / Tyr204) kit was purchased from Cisbio; and the multi-label analyzer was purchased from PerkinElmer.

[1000] 3. Experimental Method: 80 μL of NCI-H358 cell suspension was seeded into each well of a clear 96-well cell culture plate, containing 10,000 cells per well. The cell culture plates were incubated overnight at 37°C with 5% CO2. After incubation, the cell supernatant was discarded, and 80 μL of PRMI 1640 medium containing 0.02% serum was added to each well. The cell culture plates were then incubated overnight at 37°C with 5% CO2. The test compound was diluted to 4 mmol / L with 100% DMSO as the first concentration, and then further diluted 5-fold to the 8th concentration using a pipette. 2 μL of the compound or DMSO (as a negative control) was added to 158 μL of cell culture medium, mixed well, and then 20 μL of the compound solution was added to the corresponding well of the cell culture plate. No compound or DMSO was added to the wells of the blank control group. The cell culture plates were returned to the incubator and incubated for another hour at 37°C with 5% CO2. After incubation, discard the cell supernatant and add 50 μL of 1X cell lysis buffer to each well. Incubate at room temperature with shaking for 30 minutes. Dilute the phosphorylated ERK1 / 2 Eu cavitation compound antibody and the phosphorylated ERK1 / 2 d2 antibody 20-fold using detection buffer. Transfer 16 μL of cell lysis supernatant to each well into a new 384 white microplate, add 2 μL of phosphorylated ERK1 / 2 Eu cavitation compound antibody dilution buffer and 2 μL of phosphorylated ERK1 / 2 d2 antibody dilution buffer, and incubate at room temperature for 4 hours. After incubation, read the signals at 615 nm and 665 nm using a multilabel analyzer. Calculate the inhibition percentage using the following formulas: Ratio = (Signal at 665 nm / Signal at 615 nm) × 10000; Inhibition percentage = (Analysis compound ratio - Negative control ratio) / (Blank ratio - Negative control ratio) × 100%.

[1001] The specific test results are shown in Table 4.

[1002] Table 4

[1003] AMG510 88.33 MRTX849 67.61 26 2.98 28 42.73

[1004] The data above show that the compounds in some embodiments of the present invention have good inhibitory activity against H358ERK phosphorylation.

[1005] Experimental Example 5

[1006] Cell selectivity assay

[1007] 1. Objective: To detect the inhibitory effect of the test compound on the proliferation of NCI-H23, NCI-H2122, HCC827, Mia paca2, A549 and SW837 cell lines.

[1008] 2. Experimental Materials: The test reagents were prepared in-house using the compounds described in the embodiments of this invention; positive control compounds AMG-510 and MRTX849 were purchased from Chengdu Zhihui Zhongxin Biomedical Co., Ltd.; NCI-H23, NCI-H2122, HCC827, Mia paca2, A549, and SW837 cell lines were purchased from ATCC; CellTiter-Glo was purchased from Promega (catalog number G7571); DMEM medium was purchased from ATCC (catalog number 30-2002); RPMI-1640 medium was purchased from ATCC (catalog number 30-2001); F-12K medium was purchased from ATCC (catalog number 30-2004); Leibovitz's... L-15 culture medium was purchased from ATCC (catalog number 30-2008); fetal bovine serum (FBS) was purchased from EXCELL (catalog number FND500); penicillin-streptomycin was purchased from Gibco (catalog number 15140-122); 0.25% trypsin-EDTA digestion solution was purchased from Gibco (catalog number 25200-072); dimethyl sulfoxide (DMSO) was purchased from Sigma (catalog number D2650); 96-well cell culture plates were purchased from Corning (catalog number 3610); incubators were purchased from NuAire (model NU-5700E); biosafety cabinets were purchased from AuAire (model NU-543-600S); inverted microscopes were purchased from Nikon (catalog number TS-100); and automated cell counters were purchased from Life Technologies (model Countess). II); the microplate reader was purchased from PerkinElmer (model Envision); the data processing software was GraphPad Prism 5.0.

[1009] 3. Experimental methods:

[1010] Cells in the logarithmic growth phase were resuspended in growth medium (RPMI-1640 + 10% FBS for NCI-H23, NCI-H2122, and HCC827; DMEM + 10% FBS + 2.5% horse serum for Mia paca2; F-12K + 10% FBS for A549; and Leibovitz's L-15 + 10% FBS for SW837) and diluted to the target density (800 / well, 1500 / well, 3000 / well, 2000 / well, 1000 / well, and 2000 / well for NCI-H23, NCI-H2122, HCC827, Mia paca2, A549, and SW837, respectively). The cell suspension was seeded at a rate of 100 μL per well into 96-well plates and incubated overnight at 37°C in a 5% CO2 incubator. The culture medium served as a background control; DMSO served as a negative control.

[1011] The test compound was dissolved in DMSO to prepare a stock solution with a concentration of 10 mmol / L. The stock solution was first diluted to 2 mmol / L with DMSO, then serially diluted 5-fold to obtain 8 concentrations. 3 μL of each concentration was diluted with 197 μL of growth medium. Then, 50 μL of each solution was added to a 96-well plate seeded with cells. The cells were incubated at 37°C in a 5% CO2 incubator for 72 hours. The 96-well plate was equilibrated at room temperature, and 40 μL of CellTiter-Glo reagent was added to each well. The mixture was vortexed for 2 minutes and incubated at room temperature for 60 minutes. The luminescence value was read using an EnVision microplate reader, and the IC50 of the compound was calculated using GraphPad Prism 5.0 software. 50 .

[1012] The specific test results are shown in Table 5.

[1013] Table 5

[1014]

[1015] The data above show that the compounds in some embodiments of the present invention have good selectivity for KRAS G12C mutant cell lines.

[1016] Experimental Example 6

[1017] Mouse pharmacokinetics study

[1018] 1. Experimental Objective: This study aims to determine the pharmacokinetic characteristics of some of the compounds of the present invention in male ICR mice after single intravenous (IV) and oral (PO) administration by LC-MS / MS.

[1019] 2. Experimental materials: The test drugs were prepared by the compounds in the embodiments of this invention; the positive compound AMG-510 was purchased from Chengdu Zhihui Zhongxin Biomedical Co., Ltd.; the male ICR mice were obtained from Sino-British SIPPR Lab Animal Ltd, Shanghai.

[1020] 3. Test methods:

[1021] Preparation of 0.5% methylcellulose: Weigh 5g of methylcellulose and dissolve it in 1000mL of purified water.

[1022] Preparation of oral prescription: Weigh the required amount of the test compound, dissolve it in 0.5% methylcellulose solution to obtain a suspension or solution of 0.5 mg / mL.

[1023] Preparation of the intravenous injection prescription: Weigh the required amount of the test compound, dissolve it in 0.5 mL of dimethyl sulfoxide, and prepare a solution with a concentration of 4 mg / mL. Take 0.06 mL of the above solution, add 0.12 mL of polyethylene glycol 15-hydroxystearate (solutol) and 1.02 mL of physiological saline to obtain a solution with a concentration of 0.2 mg / mL.

[1024] Administration: Male ICR mice were fasted overnight before oral administration (PO), while the single intravenous injection (IV) group did not require fasting. Dosage and administration volume are shown in the table below. Patients were fed 4 hours after administration.

[1025]

[1026]

[1027] Sample Collection: Blood was collected via the jugular vein or other suitable vein, 0.03 mL at each time point. Samples were placed in tubes containing dipotassium EDTA and kept on ice before centrifugation. Within 1 hour of collection, blood samples were centrifuged at 2–8°C and 6800 g for 6 minutes and stored at -80°C. Blood collection time points for intravenous and oral administration were 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration.

[1028] The specific test results are shown in Table 6.

[1029] Table 6

[1030]

[1031] The data in Table 6 show that some of the compounds in the embodiments of this invention have excellent pharmacokinetic properties in mice, even better than those of the positive compounds.

[1032] Experimental Example 7

[1033] Canine pharmacokinetics study

[1034] 1. Experimental Objective: This study aims to determine the pharmacokinetic characteristics of some of the compounds of the present invention in beagle dogs after single intravenous (IV) and oral (PO) administration by LC-MS / MS.

[1035] 2. Test materials: The test drug was a compound prepared in accordance with the embodiments of the present invention; Beagle dogs were derived from Medicilon Colony: 999M-004.

[1036] 3. Test methods:

[1037] Preparation of 0.5% methylcellulose: Weigh 5g of methylcellulose and dissolve it in 1000mL of purified water.

[1038] Preparation of oral prescription: Weigh the required amount of the test compound, dissolve it in 0.5% methylcellulose solution to obtain a suspension or solution of 1 mg / mL.

[1039] Preparation of the intravenous injection prescription: Weigh an appropriate amount of the test compound and dissolve it in dimethyl sulfoxide to prepare a 10 mg / mL solution. Take 3 mL of the above solution, add 6 mL of polyethylene glycol 15-hydroxystearate (solutol) and 51 mL of physiological saline to obtain a 0.5 mg / mL solution.

[1040] Administration: Beagles were fasted overnight before oral administration (PO). Fasting was not required for the single intravenous (IV) administration group. Dosage and volume are shown in the table below. Feeding was administered 4 hours after administration.

[1041]

[1042] Sample Collection: Blood was collected via the jugular vein or other suitable vein, 1 mL at each time point. Samples were placed in test tubes containing dipotassium ethylenediaminetetraacetate (EDTA) and kept on ice before centrifugation. Within one hour of blood collection, the blood samples were centrifuged at 2-8°C and 2200g for 10 minutes and s...

Claims

1. A compound of Formula I, a pharmaceutically acceptable salt thereof, or a combination thereof. in, The portion represented is selected from the following group: ； n represents the substituent R 3 The number of elements, where n is 0, 1, 2, or 3; Each R 3 Each is independently a C1-C3 alkyl group, wherein the C1-C3 alkyl group may optionally be substituted with a cyano group; R 1 yes ,or ; in, R a It is hydrogen, halogen, optionally substituted C1-C3 alkyl, C1-C3 alkoxy, wherein R a The optional substituents described herein are selected from the group consisting of: methyl, ethyl, -N(R) 5 2. Halogens, C1-C3 alkoxy groups; Each R 5 Each is independently hydrogen or a C1-C3 alkyl group; R a’ R b Each is independently hydrogen, halogen, or C1-C3 alkyl; L 2 It is -O-; R 2 Selected from the following group: , , , Where n represents the substituent R 2' The number, selected from: 0, 1, 2, and 3; each R 2’ They are halogens and C1-C3 alkyl groups, respectively, and are independent of each other. The representative spiral rings are selected from the following group: 、 、 、 ； o indicates the substituent R 13 The number can be 0, 1, 2, or 3; R 13 Each is independently a halogen, hydroxyl group, or halogenated C1-C3 alkoxy group; Y is -NR 14 -, where R 14 It is hydrogen, C1-C6 alkyl; Z is -(CR) 15 R 16 )-, where R 15 and R 16 It is either hydrogen or C1-C3 alkyl.

2. The compound of formula I as claimed in claim 1, wherein its pharmaceutically acceptable salt or combination thereof is characterized in that, R 2 yes , Where n represents the substituent R 2' The number, selected from: 0, 1, or 2; each R 2’ They are halogens and C1-C3 alkyl groups, respectively.

3. The compound of formula I as claimed in claim 1, wherein its pharmaceutically acceptable salt or combination thereof is characterized in that, The R a It is a C1-C3 alkyl group with hydrogen, fluorine, or optional substitution; Where R a The optional substituents described herein are selected from the group consisting of methyl, ethyl, and halogen. Each R 5 Each is independently hydrogen or C1-C3 alkyl.

4. The compound of formula I as claimed in claim 1, wherein its pharmaceutically acceptable salt or combination thereof is characterized in that, The R a’ R b Each can be independently hydrogen, fluorine, or C1-C3 alkyl.

5. The compound according to any one of claims 1-4, wherein a pharmaceutically acceptable salt or combination thereof is characterized in that, The portion represented is selected from the following group: 、 、 、 。 6. The compound of claim 1, wherein its pharmaceutically acceptable salt or combination thereof, is characterized in that, R 1 yes , , , , , , , ,or .

7. The compound of formula I as claimed in claim 1, wherein its pharmaceutically acceptable salt or combination thereof is characterized in that, R 1 yes , , , , , , ,or .

8. The compound of claim 1, wherein a pharmaceutically acceptable salt thereof or a combination thereof, is characterized in that, R 2 yes , Where n represents the substituent R 2' The number, selected from: 0, 1, 2, and 3; each R 2’ They are halogens and C1-C3 alkyl groups, respectively.

9. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, or a combination thereof:

10. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (1) A therapeutically effective amount of one or more compounds selected from any one of claims 1 to 9, or pharmaceutically acceptable salts thereof, as the active ingredient; and (2) Optionally, a pharmaceutically acceptable carrier.

11. Use of the compound of any one of claims 1 to 9, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 10 for the preparation of a medicament for the prevention or treatment of KRAS G12C mutation-mediated cancer.

12. The use as described in claim 11, characterized in that, The cancers mentioned are selected from lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyosarcoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, cervical cancer, head and neck cancer, and bladder cancer.

13. The use as described in claim 11, characterized in that, The cancers mentioned are selected from non-small cell lung cancer, pancreatic cancer, and colorectal cancer.

14. The use as described in claim 11, characterized in that, The cancers mentioned are selected from nasopharyngeal carcinoma, esophageal cancer, and thyroid cancer.

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