Pyrimidopyran compounds

Abstract

The present application relates to pyrimidopyran compounds, specifically, the compounds represented by formula (III) and pharma- ceutically acceptable salts thereof. TIFF2024504831000273.tif4649

Description

[Technical Field]

[0001] This application is CN202110139674.X, filed on February 1, 2021; CN202110258547.1, filed on March 9, 2021; CN202110706033.8, filed June 24, 2021; CN202210070174.X filed on January 20, 2022 Priority is claimed based on (Technical field) The present disclosure relates to pyrimidopyran compounds, specifically compounds represented by formula (III) and pharmaceutically acceptable salts thereof: [Background technology]

[0002] Mutations in the oncogene RAS gene are the most common activating mutations in human cancers, occurring in 30% of human tumors. The RAS gene family has three subtypes (KRAS, HRAS, and NRAS), and 85% of RAS-driven cancers are caused by mutations in the KRAS subtype. KRAS mutations are commonly found in solid tumors (e.g., lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer). In KRAS-mutated tumors, 80% of tumor-forming mutations occur at the 12th codon, with the most common mutations being p.G12D (41%), p.G12V (28%), and p.G12C (14%). KRAS is a murine sarcoma virus oncogene and an important member of the RAS protein family. KRAS acts like a molecular switch; when unmutated, it can suppress and regulate cell proliferation pathways. After mutation, the KRAS gene independently transmits growth and proliferation signals to downstream pathways, regardless of upstream growth factor receptor signals, leading to uncontrolled cell proliferation and tumor progression. The presence or absence of KRAS gene mutations also provides important indicators of tumor prognosis. Currently, KRAS G12CThe field is seeing a rise in small molecules that directly target KRAS mutations, with AMG510 (Amgen) and MRTX849 (Mirati Therapeutics) demonstrating KRAS mutations in clinical trials. G12C It has shown excellent therapeutic efficacy in patients with tumors that harbor KRAS mutations. G12D Small molecules targeting KRAS have not yet progressed to clinical trials. G12D Patients with tumors that carry mutations still lack access to personalized medicine. Summary of the Invention

[0003] The present disclosure provides a compound of formula (III) [ka] [In formula, substructure [ka] teeth, [ka] selected from the group consisting of: [ka] is selected from a single bond and a double bond; T1 is selected from CR7R8, NR9 and O; T2 is selected from CH and N; L1 is selected from -CH2- and a bond; R1, R 2、 R3, R4 and R5 are each independently H and C 1-3 alkyl, wherein C 1-3 Alkyl can have one, two or three R a may be optionally substituted with; R6 is C 6-10 aryl and 5-10 membered heteroaryl, wherein C 6-10 Aryl and 5- to 10-membered heteroaryl may have 1, 2, 3, 4, or 5 R bmay be optionally substituted with; R7 and R8 are each independently selected from H, CH3, and NH2; R9 is selected from H and CH3; R 10 is a 4- to 8-membered heterocycloalkyl and [ka] wherein 4 to 8 membered heterocycloalkyl and [ka] is 1, 2 or 3 R c may be optionally substituted with; R 11 and R 12 are independently H, C 1-3 Alkyl and C 3-5 cycloalkyl, wherein C 1-3 Alkyl and C 3-5 The cycloalkyl may be optionally substituted with 1, 2, or 3 halogens; substructure [ka] is a 5-6 membered heterocycloalkenyl; substructure [ka] is C 3-5 is cycloalkyl; substructure [ka] is a 4-5 membered heterocycloalkyl; m is selected from 0, 1 and 2; n is selected from 0, 1 and 2; p is selected from 1 and 2; q is selected from 1, 2 and 3; r is selected from 1 and 2; s is selected from 1, 2 and 3; R a are each independently selected from F, Cl, Br, and I; R b are F, Cl, Br, I, OH, NH2, CN, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl, -C(=O)C 1-3 Alkyl and C 3-5 cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl, -C(=O)C 1-3 Alkyl and C 3-5 The cycloalkyl may be optionally substituted with 1, 2, 3, 4, or 5 R; R c are H, F, Cl, Br, I, OH, CN, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-OC(=O)-C 1-3 independently selected from alkylamino; each R is independently selected from F, Cl, Br, and I. or a pharmaceutically acceptable salt thereof.

[0004] In some embodiments of the present disclosure, R, R, R, R, and R are each independently selected from H, CH, CHCH, and CH(CH), where CH, CHCH, and CH(CH) are selected from 1, 2, or 3 R a and optionally substituted with, and other variables as defined in this disclosure.

[0005] In some embodiments of the present disclosure, R1, R2, R3, R4, and R5 are each independently selected from H and CH3, and other variables are as defined in this disclosure.

[0006] In some embodiments of the present disclosure, the moiety [ka] teeth, [ka] and wherein the other variables are as defined in this disclosure.

[0007] In some embodiments of the present disclosure, the moiety [ka] teeth, [ka] and wherein the other variables are as defined in this disclosure.

[0008] In some embodiments of the present disclosure, R b are each independently selected from F, Cl, Br, I, OH, NH, CN, CH, CHCH, OCH, OCHCH, -CH=CH, -CH-CH=CH, -C≡CH, -C(=O)CH, and cyclopropyl, where CH, CHCH, OCH, OCHCH, -CH=CH, -CH-CH=CH, -C≡CH, -C(=O)CH, and cyclopropyl are optionally substituted with 1, 2, 3, 4, or 5 R, and all other variables are as defined in this disclosure.

[0009] In some embodiments of the present disclosure, R b are each independently selected from F, Cl, Br, I, OH, NH, CN, CH, CF, CHCH, CFCF, -CH=CH, -C≡CH, -C(=O)CH and cyclopropyl, and all other variables are as defined in this disclosure.

[0010] In some embodiments of the present disclosure, R6 is selected from phenyl, pyridyl, naphthyl, indolyl, and indazolyl, wherein phenyl, pyridyl, naphthyl, indolyl, and indazolyl are selected from 1, 2, 3, 4, or 5 R b and optionally substituted with, and other variables as defined in this disclosure.

[0011] In some embodiments of the present disclosure, R6 is [ka] and wherein the other variables are as defined in this disclosure.

[0012] In some embodiments of the present disclosure, R c are H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CF3, OCH3, OCF3, and [ka] and the other variables are as defined in this disclosure.

[0013] In some embodiments of the present disclosure, R 10 is selected from tetrahydropyrrolyl, hexahydro-1H-pyrrolidinyl, and 1,2,3,4-tetrahydroisoquinolinyl, wherein tetrahydropyrrolyl, hexahydro-1H-pyrrolidinyl, and 1,2,3,4-tetrahydroisoquinolinyl are selected from one, two, or three R c and optionally substituted with, and other variables as defined in this disclosure.

[0014] In some embodiments of the present disclosure, R 10 teeth, [ka] and wherein the other variables are as defined in this disclosure.

[0015] In some embodiments of the present disclosure, R 10 teeth [ka] and other variables are as defined in this disclosure.

[0016] In some embodiments of the present disclosure, R 11 and R 12 are each independently selected from H and CH3, and other variables are as defined in this disclosure.

[0017] The present disclosure provides a compound of formula (III) [ka] [In formula, substructure [ka] teeth, [ka] selected from the group consisting of: [ka] is selected from a single bond and a double bond; T1 is selected from CR7R8, NR9 and O; T2 is selected from CH and N; L1 is selected from -CH2- and a bond; R1, R2, R3, R4 and R5 are each independently H and C 1-3 alkyl, wherein C 1-3 Alkyl can have one, two or three R a may be optionally substituted with; R6 is C 6-10 aryl and 5-10 membered heteroaryl, wherein C 6-10 Aryl and 5- to 10-membered heteroaryl may have 1, 2, 3, 4, or 5 Rb may be optionally substituted with; R7 and R8 are each independently selected from H, CH3, and NH2; R9 is selected from H and CH3; R 10 is a 4- to 8-membered heterocycloalkyl and [ka] wherein 4 to 8 membered heterocycloalkyl and [ka] is 1, 2 or 3 R c may be optionally substituted with; R 11 and R 12 are independently H, C 1-3 Alkyl and C 3-5 cycloalkyl, wherein C 1-3 Alkyl and C 3-5 The cycloalkyl may be optionally substituted with 1, 2, or 3 halogens; substructure [ka] is a 5-6 membered heterocycloalkenyl; substructure [ka] is C 3-5 is cycloalkyl; substructure [ka] is a 4-5 membered heterocycloalkyl; m is selected from 0, 1 and 2; n is selected from 0, 1 and 2; p is selected from 1 and 2; q is selected from 1, 2 and 3; r is selected from 1 and 2; s is selected from 1, 2 and 3; R a are each independently selected from F, Cl, Br, and I; R b are F, Cl, Br, I, OH, NH2, CN, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl and C 3-5 cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl and C 3-5 The cycloalkyl may be optionally substituted with 1, 2, or 3 R; R c are H, F, Cl, Br, OH, CN, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O-CO-C 1-3 independently selected from alkylamino; each R is independently selected from F, Cl, and Br. or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments of the present disclosure, R, R, R, R, and R are each independently selected from H, CH, CHCH, and CH(CH), where CH, CHCH, and CH(CH) are selected from 1, 2, or 3 R a and optionally substituted with, and other variables as defined in this disclosure.

[0019] In some embodiments of the present disclosure, R1, R2, R3, R4, and R5 are each independently selected from H and CH3, and other variables are as defined in this disclosure.

[0020] In some embodiments of the present disclosure, the moiety [ka] teeth, [ka] and the other variables are as defined in this disclosure.

[0021] In some embodiments of the present disclosure, the moiety [ka] teeth, [ka] and the other variables are as defined in this disclosure.

[0022] In some embodiments of the present disclosure, R b are each independently selected from F, Cl, Br, I, OH, NH, CN, CH, CHCH, OCH, OCHCH, -CH=CH, -CH-CH=CH and -C≡CH, where CH, CHCH, OCH, OCHCH, -CH=CH, -CH-CH=CH and -C≡CH are optionally substituted with 1, 2 or 3 R, and all other variables are as defined in this disclosure.

[0023] In some embodiments of the present disclosure, R b are each independently selected from F, OH, NH2, CH3, CF3, CH2CH3, and -C≡CH, and all other variables are as defined in this disclosure.

[0024] In some embodiments of the present disclosure, R6 is selected from phenyl, naphthyl, indolyl, and indazolyl, wherein phenyl, naphthyl, indolyl, and indazolyl are selected from 1, 2, 3, 4, or 5 R b and optionally substituted with, and other variables as defined in this disclosure.

[0025] In some embodiments of the present disclosure, R6 is [ka] and the other variables are as defined in this disclosure.

[0026] In some embodiments of the present disclosure, R c are H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CF3, OCH3, OCF3 and [ka] and the other variables are as defined in this disclosure.

[0027] In some embodiments of the present disclosure, R 10 is selected from tetrahydropyrrolyl, hexahydro-1H-pyrrolidinyl, and 1,2,3,4-tetrahydroisoquinolinyl, wherein tetrahydropyrrolyl, hexahydro-1H-pyrrolidinyl, and 1,2,3,4-tetrahydroisoquinolinyl are selected from one, two, or three R c and optionally substituted with, and other variables as defined in this disclosure.

[0028] In some embodiments of the present disclosure, R 10 teeth, [ka] and the other variables are as defined in this disclosure.

[0029] In some embodiments of the present disclosure, R 11 and R 12 are each independently selected from H and CH3, and other variables are as defined in this disclosure.

[0030] The present disclosure provides a compound of formula (II) [ka] [In formula, substructure [ka] teeth, [ka] selected from the group consisting of: [ka] is selected from a single bond and a double bond; T1 is selected from CR7R8, NR9 and O; T2 is selected from CH and N; L1 is selected from -CH2- and a bond; R1, R2, R3, R4 and R5 are each independently H and C 1-3 alkyl, wherein C 1-3 Alkyl can have one, two or three R a may be optionally substituted with; R6 is C 6-10 aryl and 5-10 membered heteroaryl, wherein C 6-10 Aryl and 5- to 10-membered heteroaryl may have 1, 2, 3, 4, or 5 R b may be optionally substituted with; R7 and R8 are each independently selected from H, CH3, and NH2; R9 is selected from H and CH3; R 10 is a 4- to 8-membered heterocycloalkyl and [ka] wherein 4 to 8 membered heterocycloalkyl and [ka] is 1, 2 or 3 R c may be optionally substituted with; substructure [ka] is a 5-6 membered heterocycloalkenyl; substructure [ka] is C 3-5 is a cycloalkyl; substructure [ka] is a 4-5 membered heterocycloalkyl; m is selected from 0, 1 and 2; n is selected from 0, 1 and 2; p is selected from 1 and 2; q is selected from 1, 2 and 3; r is selected from 1 and 2; s is selected from 1, 2 and 3; R a are each independently selected from F, Cl, Br, and I; R b are F, Cl, Br, I, OH, NH2, CN, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl and C 3-5 cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl and C 3-5 The cycloalkyl may be optionally substituted with 1, 2, or 3 R; R c are H, F, Cl, Br, OH, CN, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O-CO-C 1-3 independently selected from alkylamino; each R is independently selected from F, Cl, and Br. or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments of the present disclosure, R, R, R, R, and R are each independently selected from H, CH, CHCH, and CH(CH), where CH, CHCH, and CH(CH) are selected from 1, 2, or 3 R a and optionally substituted with, and other variables as defined in this disclosure.

[0032] In some embodiments of the present disclosure, R1, R2, R3, R4, and R5 are each independently selected from H and CH3, and other variables are as defined in this disclosure.

[0033] In some embodiments of the present disclosure, the moiety [ka] teeth, [ka] and wherein the other variables are as defined in this disclosure.

[0034] In some embodiments of the present disclosure, the moiety [ka] teeth, [ka] and the other variables are as defined in this disclosure.

[0035] In some embodiments of the present disclosure, R bare each independently selected from F, Cl, Br, I, OH, NH, CN, CH, CHCH, OCH, OCHCH, -CH=CH, -CH-CH=CH and -C≡CH, where CH, CHCH, OCH, OCHCH, -CH=CH, -CH-CH=CH and -C≡CH are optionally substituted with 1, 2 or 3 R, and all other variables are as defined in this disclosure.

[0036] In some embodiments of the present disclosure, R b are each independently selected from F, OH, NH2, CH3, CF3, CH2CH3, and -C≡CH, and all other variables are as defined in this disclosure.

[0037] In some embodiments of the present disclosure, R6 is selected from phenyl, naphthyl, indolyl, and indazolyl, wherein phenyl, naphthyl, indolyl, and indazolyl are selected from 1, 2, 3, 4, or 5 R b and optionally substituted with, and other variables as defined in this disclosure.

[0038] In some embodiments of the present disclosure, R6 is [ka] and wherein the other variables are as defined in this disclosure.

[0039] In some embodiments of the present disclosure, R c are H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CF3, OCH3, OCF3 and [ka] and the other variables are as defined in this disclosure.

[0040] In some embodiments of the present disclosure, R 10is selected from tetrahydropyrrolyl, hexahydro-1H-pyrrolidinyl, and 1,2,3,4-tetrahydroisoquinolinyl, wherein tetrahydropyrrolyl, hexahydro-1H-pyrrolidinyl, and 1,2,3,4-tetrahydroisoquinolinyl are selected from one, two, or three R c and optionally substituted with, and other variables as defined in this disclosure.

[0041] In some embodiments of the present disclosure, R 10 teeth, [ka] and the other variables are as defined in this disclosure.

[0042] The present disclosure provides a compound of formula (I) [ka] [In the formula, [ka] is selected from a single bond and a double bond; T1 is selected from CR7R8 and NR9; where [ka] is a single bond, T2 is selected from CH and N; [ka] is a double bond, T2 is C; R1, R2, R3, R4 and R5 are each independently H and C 1-3 alkyl, wherein C 1-3 Alkyl can have one, two or three R a may be optionally substituted with; R6 is selected from phenyl and naphthyl, where phenyl and naphthyl are selected from 1, 2, 3, 4 or 5 R bmay be optionally substituted with; R7 and R8 are each independently selected from H, CH3, and NH2; R9 is selected from H and CH3; Alternatively, R1 and R2 are a substructure [ka] but [ka] form a ring with the atoms to which they are attached, so as to form a ring; Alternatively, R1 and R4 are a partial structure [ka] but [ka] form a ring with the atoms to which they are attached, so as to form a ring; Alternatively, R4 and R5 are a partial structure [ka] but [ka] form a ring with the atoms to which they are attached, so as to form a ring; or R2 and R7 together with the atoms to which they are attached form tetrahydropyrrolidinyl; Alternatively, R2 and R3 together with the atoms to which they are attached form C 3-5 forming a cycloalkyl; or R7 and R8 together with the atom to which they are attached form a 4- to 5-membered heterocycloalkyl; m is selected from 0, 1 and 2; n is selected from 0, 1 and 2; p is selected from 1 and 2; q is selected from 1, 2 and 3; r is selected from 1 and 2; s is selected from 1, 2 and 3; R a are each independently selected from F, Cl, Br, and I; R b are each independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3, and OCH3. or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments of the present disclosure, R, R, R, R, and R are each independently selected from H, CH, CHCH, and CH(CH), where CH, CHCH, and CH(CH) are selected from 1, 2, or 3 R a and optionally substituted with, and other variables as defined in this disclosure.

[0044] In some embodiments of the present disclosure, R1, R2, R3, R4, and R5 are each independently selected from H and CH3, and other variables are as defined in this disclosure.

[0045] In some embodiments of the present disclosure, the moiety [ka] teeth, [ka] and wherein the other variables are as defined in this disclosure.

[0046] In some embodiments of the present disclosure, the moiety [ka] teeth, [ka] and the other variables are as defined in this disclosure.

[0047] In some embodiments of the present disclosure, the moiety [ka] teeth, [ka] and other variables are as defined in this disclosure.

[0048] In some embodiments of the present disclosure, R2 and R7 together with the atoms to which they are attached [ka] and the other variables are as defined in this disclosure.

[0049] In some embodiments of the present disclosure, R2 and R3 together with the atoms to which they are attached [ka] and the other variables are as defined in this disclosure.

[0050] In some embodiments of the present disclosure, R7 and R8 together with the atoms to which they are attached [ka] and the other variables are as defined in this disclosure.

[0051] In some embodiments of the present disclosure, the moiety [ka] teeth, [ka] is selected from.

[0052] In some embodiments of the present disclosure, the moiety [ka] teeth, [ka] and the other variables are as defined in this disclosure.

[0053] In some embodiments of the present disclosure, R6 is [ka] and other variables are as defined in this disclosure.

[0054] In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt thereof is provided, the compound comprising: [ka] [In the formula, [ka] is selected from a single bond and a double bond; T2, R6, R 11 and R 12 are as defined in this disclosure] is selected from.

[0055] In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt thereof is provided, the compound comprising: [ka] [In the formula, [ka] is selected from a single bond and a double bond; T2, R6, R 11 and R 12 are as defined in this disclosure] is selected from.

[0056] In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt thereof is provided, the compound comprising: [ka] [In the formula, [ka] is selected from a single bond and a double bond; z is selected from 0, 1, 2, 3, 4 and 5; T2, R b , R 11 and R 12 are as defined in this disclosure] is selected from.

[0057] In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt thereof is provided, the compound comprising: [ka] [In the formula, [ka] is selected from a single bond and a double bond; R b1 , R b2 , R b3 , R b4 , R b5 , R b6 and R b7 are independently H, F, Cl, Br, I, OH, NH2, CN, and C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl, -C(=O)C 1-3 Alkyl and C 3-5 cycloalkyl, wherein C1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl, -C(=O)C 1-3 Alkyl and C 3-5 The cycloalkyl may be optionally substituted with 1, 2, 3, 4, or 5 R; Each R is independently selected from F, Cl, Br, and I; T2, R 11 and R 12 are as defined in this disclosure] is selected from.

[0058] In some embodiments of the present disclosure, R b1 , R b2 , R b3 , R b4 , R b5 , R b6 and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH, CN, CH, CHCH, OCH, OCHCH, -CH=CH, -CH-CH=CH, -C≡CH, -C(=O)CH, and cyclopropyl, where CH, CHCH, OCH, OCHCH, -CH=CH, -CH-CH=CH, -C≡CH, -C(=O)CH, and cyclopropyl are optionally substituted with 1, 2, 3, 4, or 5 R, and all other variables are as defined in this disclosure.

[0059] In some embodiments of the present disclosure, R b1 , R b2 , R b3 , R b4 , R b5 , R b6 and R b7are each independently selected from H, F, Cl, Br, I, OH, NH, CN, CH, CHF, CHF, CF, CHCH, CHCF, CFCF, OCH, OCF, -CH=CH, -C≡CH, -C(=O)CH, -C(=O)CF, and cyclopropyl, and all other variables are as defined in this disclosure.

[0060] In some embodiments of the present disclosure, R b1 , R b2 , R b3 , R b4 , R b5 , R b6 and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH, CN, CH, CF, CHCH, CFCF, -CH=CH, -C≡CH, -C(=O)CH and cyclopropyl, and all other variables are as defined in this disclosure.

[0061] In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt thereof is provided, the compound comprising: [ka] [In the formula, [ka] is selected from a single bond and a double bond; T2, R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R 11 and R 12 are as defined in this disclosure] is selected from.

[0062] The present disclosure also includes several embodiments resulting from combinations of any of the variables described above.

[0063] The present disclosure provides a compound of the formula [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Also provided is a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt thereof is provided, the compound comprising: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0065] In some embodiments of the present disclosure, a compound or a pharmaceutically acceptable salt thereof is provided, the compound comprising: [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0066] This disclosure also provides KRAS G12D There is also provided the use of the compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with a mutation.

[0067] The present disclosure also provides the use of the above compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a tumor-related disease.

[0068] (Technical Effects) The compounds of the present disclosure inhibit KRAS G12D The compounds of the present disclosure have excellent inhibitory effects against mutant kinases. They can effectively inhibit p-ERK and KRAS. G12D The compounds of the present disclosure have excellent cytostatic activity against mutant cells, can effectively inhibit tumor growth in vivo, and have excellent drug resistance.The compounds of the present disclosure have moderate to strong plasma binding rates and excellent pharmacokinetic properties.

[0069] (Related Definitions) Unless otherwise specified, the terms and phrases used herein have the following meanings: The absence of a specific definition for a particular term or phrase should not be construed as vague or indefinite, but should be understood in its conventional sense. Trade names used herein are intended to refer to the corresponding product or its active ingredient.

[0070] The term "pharmaceutically acceptable" as used herein in reference to a compound, substance, composition, and / or formulation means, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and affords a reasonable benefit / risk ratio.

[0071] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure prepared by reacting a compound having certain substituents of the present disclosure with a relatively low-toxicity acid or base. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by reacting the compound with a sufficient amount of base in a pure solvent or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by reacting the compound with a sufficient amount of acid in a pure solvent or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts (wherein inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphoric acid, and the like); and organic acid salts (wherein organic acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like); and salts of amino acids (such as, for example, arginine) and organic acids (such as, for example, glucuronic acid). Certain compounds of the present disclosure contain both basic and acidic functional groups and can be converted into any base or acid addition salt.

[0072] The pharmaceutically acceptable salts of the present disclosure can be prepared from the parent compound which contains an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of the compound with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture thereof.

[0073] The chemical compounds of the present disclosure may be present in particular geometric or stereoisomeric forms. The present invention contemplates and includes all such compounds, including cis and trans isomers, (-) and (+) enantiomers, (R) and (S) enantiomers, diastereoisomers, (D) isomers, (L) isomers, and racemic and other mixtures (e.g., enantiomer-enriched or diastereomeric-enriched mixtures), all of which are included within the scope of the present disclosure. Substituents (e.g., alkyl) can further contain asymmetric carbon atoms. All of these isomers and mixtures thereof are included within the scope of the present disclosure.

[0074] The chemical compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may contain radioactive isotopes (e.g., tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). As another example, hydrogen can be substituted with deuterium to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have the advantages of reduced adverse side effects, increased drug stability, enhanced efficacy, and an extended biological half-life. All variations in the isotopic composition of the chemical compounds of the present disclosure, regardless of isotope activity, are included within the scope of the present invention.

[0075] The term "optionally" means that the subsequent event or circumstance may, but need not, occur, and the term includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur.

[0076] The term "substituted" means that one or more specified hydrogen atoms are replaced with a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), two hydrogen atoms are replaced. Note that oxo groups are not substituted on aromatic ring groups. The term "optionally substituted" means that an atom may or may not be substituted with one substituent, and unless otherwise specified, the type and number of substituents may be arbitrary, provided that it is chemically possible.

[0077] When any variable (e.g., R) is present more than once in a compound's constitution or structure, each definition of that variable is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with up to two R, where each definition of R is independent. Furthermore, combinations of substituents and / or variants thereof are limited to those that result in stable compounds.

[0078] When the number of linker groups is 0 (for example, -(CRR)0-), this means that the linker group is a single bond.

[0079] When one of the variables is a single bond, it means that the two groups are directly linked by a single bond. For example, when L in ALZ represents a single bond, the structure of ALZ is essentially AZ.

[0080] If the listed linker groups do not specify an order of attachment, then the order is arbitrary. For example, [ka] when the linker group L is -MW-, -MW- connects ring A and ring B in the same order as reading from left to right; [ka] or by linking ring A and ring B in the reverse reading order, [ka] The combination of linker groups, substituents and / or variants thereof is limited to those that result in a stable compound.

[0081] Unless otherwise specified, if a group has one or more bondable moieties, any one or more moieties of the group can be bonded to other groups via a chemical bond. If the bonding site of a chemical bond is variable and H atoms are present at the bondable sites, when the bondable sites with H atoms are used for chemical bonding, the number of H atoms at that site decreases as the number of bonding chemical bonds increases, and the group becomes a group with the corresponding valence. The chemical bond between that moiety and other groups is represented by a straight solid bond ( [ka] ), straight dashed bond ( [ka] ), or a wavy line ( [ka] For example, the straight solid bond in -OCH3 indicates attachment to another group through the oxygen atom of the group. [ka] The straight broken bond indicates that the group is bonded to another group via two nitrogen atoms. [ka] The wavy lines indicate that the group is attached to another group through the carbon atoms in positions 1 and 2 of the phenyl group. [ka] indicates that any available bonding site on the piperidinyl group can be bonded to another group via one chemical bond, and there are at least four types [ka] Even if the H atom is written on the -N-, [ka] for, [ka] When a chemical bond is attached to this site, the hydrogen at that site is reduced by one, resulting in the corresponding monovalent piperidinyl group.

[0082] Unless otherwise noted, solid wedge bonds ( [ka] ) and wedge-shaped dashed bonds ( [ka] ) represents the absolute configuration of the stereocenter, and the straight solid bond ( [ka] ) and straight dashed bond ( [ka] ) indicates the relative configuration of the stereocenters, and the wavy line ( [ka] ) is a solid wedge-shaped connection ( [ka] ) or wedge-shaped dashed bond ( [ka] ) or a wavy line ( [ka] ) is a straight solid line connection ( [ka] ) or straight dashed bond ( [ka] ) For example, [ka] teeth, [ka] represents [ka] teeth, [ka] Represents.

[0083] Unless otherwise specified, the term "C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group of 1 to 3 carbon atoms. 1-3 C for alkyl 1-2 Alkyl, C 2-3 alkyl, etc., which may be monovalent (e.g., methyl), divalent (e.g., methylene) or polyvalent (e.g., methenyl). 1-3 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0084] Unless otherwise specified, the term "C 1-3 "Alkoxy" means an alkyl group containing 1 to 3 carbon atoms attached to the rest of the molecule via an oxygen atom. 1-3 Alkoxy groups include C 1-2 , C 2-3 C, C3, and C2 alkoxy groups. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0085] Unless otherwise specified, the term "C 1-3 "Alkylamino" means an alkyl group containing 1 to 3 carbon atoms that is attached to the rest of the molecule via an amino group. 1-3 The alkylamino group is C 1-2 , C3 and C2 alkylamino groups, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0086] Unless otherwise specified, "C 2-3 The term "alkenyl" is used to refer to a straight or branched chain hydrocarbon group of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position within the group. 2-3 Alkenyl includes C3 and C2 alkenyl. 2-3 Alkenyl may be monovalent, divalent or polyvalent. 2-3 Examples of alkenyl include, but are not limited to, vinyl, propenyl, and the like.

[0087] Unless otherwise specified, "C 2-3 The term "alkynyl" is used to refer to a straight or branched chain hydrocarbon group of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position within the group. 2-3 Alkynyl may be monovalent, divalent or polyvalent. 2-3 Alkynyl includes C3 and C2 alkynyl. 2-3 Examples of alkynyl include, but are not limited to, ethynyl, propynyl, and the like.

[0088] Unless otherwise specified, the term "4- to 5-membered heterocycloalkyl," alone or in combination with other terms, each refers to a saturated monocyclic group of 4 to 5 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. Additionally, nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p (wherein p is 1 or 2). In addition, in a "4- to 5-membered heterocycloalkyl," a heteroatom may be present at the position where the heterocycloalkyl group is attached to another molecule. 4- to 5-membered heterocycloalkyl includes 4- and 5-membered heterocycloalkyl. Examples of 4- to 5-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl), tetrahydrofuranyl (including tetrahydrofuran-2-yl), and the like.

[0089] Unless otherwise specified, "C 3-5 "Cycloalkyl" refers to a monocyclic saturated cyclic hydrocarbon group of 3 to 5 carbon atoms. 3-5 Cycloalkyl includes C 3-4 and C 4-5 cycloalkyl, etc., and may be monovalent, divalent or polyvalent. C 3-5 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0090] Unless otherwise specified, the term "C 6-10 Aromatic ring" and "C 6-10 The term "aryl" may be used interchangeably in this disclosure. 6-10 Aromatic ring" or "C 6-10 "Aryl" means a cyclic hydrocarbon group of 6 to 10 carbon atoms having a conjugated π-electron system, and each ring may be aromatic and may be a monocyclic, fused bicyclic, or fused tricyclic ring system. It may also be monovalent, divalent, or polyvalent. 6-10 Aryl includes C6-9 , C9, C 10 and C6 aryl. 6-10 Examples of aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0091] Unless otherwise specified, the terms "5- to 10-membered heteroaromatic ring" and "5- to 10-membered heteroaryl" may be used interchangeably. The term "5- to 10-membered heteroaryl" refers to a cyclic group having a conjugated π-electron system and consisting of 5 to 10 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the others are carbon atoms. Each ring may be an aromatic monocyclic, fused bicyclic, or fused tricyclic ring system, where the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p(wherein p is 1 or 2). A 5- to 10-membered heteroaryl can be bonded to other molecules via a heteroatom or a carbon atom. 5- to 10-membered heteroaryl groups include 10-, 9-, 9- to 10-, 5- to 8-, 5- to 7-, 5- to 6-, and 5- and 6-membered heteroaryl groups. Examples of 5- to 10-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (2-thiazolyl, 4-thiazolyl, etc.), and 5-thiazolyl), furyl (including 2-furyl and 3-furyl), thienyl (including 2-thienyl and 3-thienyl), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl), benzothiazolyl (including 5-benzothiazolyl), purinyl, benzimidazolyl (including 2-benzimidazolyl), benzoxazolyl, indolyl (including 5-indolyl), isoquinolyl (including 1-isoquinolyl, 5-isoquinolyl), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl), or quinolyl (including 3-quinolyl, 6-quinolyl, etc.).

[0092] Unless otherwise specified, the term "4- to 8-membered heterocycloalkyl," alone or in combination with other terms, each refers to a saturated cyclic group of 4 to 8 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. Additionally, nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p (wherein p is 1 or 2). The ring includes a monocyclic ring and a bicyclic ring, and the bicyclic ring includes a spiro ring, a fused ring, and a bridged ring. In addition, in a "4- to 8-membered heterocycloalkyl", a heteroatom may be present at the bonding position of the heterocycloalkyl group to another molecule. The 4- to 8-membered heterocycloalkyl includes 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl. Examples of 4-8 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-dithianyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or dioxepanyl, etc.

[0093] Unless otherwise indicated, the term "5- to 6-membered heterocycloalkenyl," alone or in combination with other terms, refers to a partially unsaturated cyclic group of 5 to 6 ring atoms, each containing at least one carbon-carbon double bond, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remaining atoms are carbon atoms. Additionally, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p(wherein p may be 1 or 2). A 5- or 6-membered heterocycloalkenyl is a monocyclic or bicyclic compound, and bicyclic rings include spiro rings, fused rings, and bridged rings, and any ring is non-aromatic. In addition, in a "5- or 6-membered heterocycloalkenyl", a heteroatom may be present at the bonding position of the heterocycloalkenyl group to another molecule. 5- or 6-membered heterocycloalkenyl groups include 5- and 6-membered heterocycloalkenyl groups. Examples of 5- or 6-membered heterocycloalkenyl groups include, but are not limited to, [ka] Examples include:

[0094] Unless otherwise noted, C n-n+m or C n -C n+m includes any specific case where the number of carbons is n to n+m. For example, C 1-12 Includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 and any range from n to n+m. For example, C 1-12 C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 and C 9-12 and the like. Similarly, n-membered to n+m-membered rings indicate that the number of ring atoms is n to n+m. For example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range of n to n+m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring.

[0095] The chemicals of the present disclosure can be produced by a variety of synthetic methods known to those skilled in the art, including the embodiments listed below, embodiments combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present disclosure.

[0096] The structure of the chemical compounds of the present disclosure can be confirmed by conventional methods known to those skilled in the art. Where the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art, such as single crystal X-ray diffraction (SXRD). In single crystal X-ray diffraction (SXRD), diffraction intensity data of the prepared single crystal was collected using a Bruker D8 venture diffractometer (scan mode: φ / ω scan, light source: CuKα radiation). After collecting the relevant data, the crystal structure was further analyzed by a direct method (Shelxs97) to determine the absolute configuration.

[0097] The solvents used in this disclosure are commercially available. The following abbreviations are used in this disclosure: hr = hour; LDA = lithium diisopropylamide; B2Pin2 = bis(pinacolato)diboron; Pd(dppf)Cl2·CH2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane adduct; DIPEA = N,N-diisopropylethylamine; NBS = N-bromosuccinimide; NIS = N-iodosuccinimide; PdCl2(PPh3)2 = dichlorobis(triphenylphosphine)palladium(II); CuI = copper iodide; Et3N = triethylamine; K4FeCN6 = potassium hexacyanoferrate(II); n-BuLi = n-butyllithium; PhNTf2 = N-phenyl-bis(trifluoromethanesulfonimide); Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium.

[0098] Compounds were named according to nomenclature common in the art or by ChemDraw® software; commercially available compounds used the supplier's catalogue name. DETAILED DESCRIPTION OF THE INVENTION

[0099] The present disclosure will be described in detail below using examples. However, these examples are not intended to be an adverse restriction on the present invention. The present invention is described in detail in the specification, and embodiments are also disclosed in the specification. It will be obvious to those skilled in the art that various changes and modifications can be made to the embodiments of the present disclosure without departing from the spirit and scope of the present invention.

[0100] Reference Example 1 [ka]

[0101] Step 1: Synthesis of Compound A1-2 In a dry three-neck flask (2 L), sodium hydride (39.12 g, 978.08 mmol, 60%) was added to N,N-dimethylformamide (510 mL). The heterogeneous gray reaction mixture was cooled to 0 °C. A solution of compound A1-1 (51 g, 407.53 mmol) in N,N-dimethylformamide (200 mL) was added dropwise under nitrogen. The mixture was allowed to react at 0 °C for an additional 0.5 h, and p-methoxybenzyl chloride (140.41 g, 896.57 mmol, 122.10 mL) was added. The mixture was slowly warmed to 20 °C and stirred for an additional 7.5 h under nitrogen. The resulting reaction solution was slowly added to saturated ammonium chloride (200 mL) and extracted with tert-butyl methyl ether (200 mL * 2). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 to 10:1) to obtain compound A1-2. 1H NMR (400MHz, CDCl3) δ: 7.23-7.18(m, 4H), 6.91-6.87(m, 1H), 6.82-6.76(m, 4H), 6.65-6.59(m, 2H), 4.20(s, 4H), 3.79(s, 6H), 2.19(s, 3H); MS m / z: 366.1 [M+H] +

[0102] Step 2: Synthesis of Compound A1-3 2,2,6,6-Tetramethylpiperidine (31.31 g, 221.65 mmol, 37.63 mL) was added to anhydrous tetrahydrofuran (300 mL). The mixture was cooled to -5 °C, and n-butyllithium (2.5 M, 94.57 mL) was added dropwise. The mixture was reacted at -5 to 0 °C for 15 min and then cooled to -60 °C. A solution of compound A1-2 (27 g, 73.88 mmol) in THF (60 mL) was added to the above reaction solution, and the reaction was continued at -60 °C for 0.5 h. N,N-dimethylformamide (108.00 g, 1.48 mol, 113.69 mL) was then added quickly. The reaction solution was stirred at -60 °C for an additional 10 min, and saturated ammonium chloride (400 mL) was added. The resulting mixture was extracted with tert-butyl methyl ether (200 mL * 2). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the resulting crude product was suspended in a mixed solvent (petroleum ether: tert-butyl methyl ether = 5:1, 70 mL) for 0.5 hours and filtered. The filter cake was dried. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 to 10:1). The filter cake and the purified product from column chromatography were combined to obtain compound A1-3. 1 H NMR (400MHz, CDCl3) δ: 10.43-10.35(m, 1H), 7.21-7.18(m, 5H), 6.92-6.81(m, 5H), 4.25(s, 4H), 3.80(s, 6H), 2.23(s, 3H); MS m / z: 394.2 [M+H] +

[0103] Step 3: Synthesis of Compound A1-4 Compound A1-3 (17.8 g, 45.24 mmol) was added to N,N-dimethylformamide (170 mL), and bromosuccinimide (8.05 g, 45.24 mmol) was added and stirred at 20 °C for 20 minutes. This reaction solution was added to water (300 mL) and extracted with tert-butyl methyl ether (150 mL * 2). The combined organic layer was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the resulting crude product was suspended in a mixed solvent (ethyl acetate: tert-butyl methyl ether = 1:1, 50 mL) for 0.5 hours and filtered. The filter cake was dried to obtain compound A1-4. 1 H NMR(400MHz, CDCl3) δ: 10.39(s, 1H), 7.17(d, J=8.8Hz, 4H), 6.89(d, J=8.8Hz, 1H), 6.85-6.82(m, 4H), 4.22(s, 4H), 3.79(s, 6H), 2.28(s, 3H); MS m / z: 472.1[M+H] + , 474.1[M+3H] +

[0104] Step 4: Synthesis of Compound A1-5 Compound A1-4 (19.3 g, 40.86 mmol) was added to N,N-dimethylformamide (190 mL), and copper iodide (15.56 g, 81.72 mmol) and methyl difluoro(fluorosulfonyl)acetate (39.25 g, 204.30 mmol, 25.99 mL) were added to the solution. The solution was heated to 100 °C and stirred for 1 h. The resulting mixture was then cooled. The reaction solution was filtered through Celite, and the filtrate was added to water (300 mL). This mixture was extracted with tert-butyl methyl ether (150 mL * 2). The combined organic layer was washed with saturated brine (200 mL * 2), dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 100:0 to 10:1) to give compound A1-5. 1H NMR(400MHz, CDCl3) δ: 10.37 (q, J=4.0Hz, 1H), 7.18-7.11(m, 4H), 6.89-6.82(m, 4H), 6.73(d, J=8.8Hz, 1H), 4.36(s, 4H), 3.81(s, 6H), 2.37-2.29(m, 3H); MS m / z: 484.0[M+Na] +

[0105] Step 5: Synthesis of Compound A1-6 Anhydrous tetrahydrofuran (50 mL) and sodium hydride (1.17 g, 29.26 mmol, 60%) were added to a dry three-neck flask, and the mixture was cooled to 0 °C. Ethyl acetoacetate (3.40 g, 29.26 mmol, 3.15 mL) was added dropwise under nitrogen, and the solution was stirred at 0 °C for 0.5 h. n-Butyllithium (2.5 M, 11.70 mL) was added dropwise. The reaction solution was stirred under the same conditions for an additional 0.5 h and cooled to -60 °C. A solution of compound A1-5 (4.5 g, 9.75 mmol) in tetrahydrofuran (20 mL) was added dropwise, and the mixture was stirred at -60 °C for an additional 0.5 h. Saturated ammonium chloride solution (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 to 3:1) to obtain compound A1-6. 1 H NMR (400MHz, CDCl3) δ: 7.18-7.15(m, 4H), 6.90-6.78(m, 4H), 6.61(d, J=8.8Hz, 1H), 5.72-5.57(m, 1H), 4.31(m, 4H), 3.81(s, 6H), 3.76(s, 3H), 3.56(s, 2H), 3.50-3.38(m, 1H), 2.98-2.93(m, 1H), 2.38-2.26(m, 3H); MS m / z: 578.1[M+H] +

[0106] Step 6: Synthesis of Compound A1-7 Compound A1-6 (3 g, 5.19 mmol) was added to anhydrous dichloromethane (30 mL) and N,N-dimethylformamide dimethyl acetal (742.74 mg, 6.23 mmol, 828.02 μL) was added. This solution was stirred at 20 °C for 16 h, and boron trifluoride diethyl etherate (884.66 mg, 6.23 mmol, 769.27 μL) was added. This mixture was stirred for an additional 1 h at 20 °C, and the resulting reaction solution was added to saturated sodium bicarbonate solution (20 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 100:0 to 3:1) to give compound A1-7. 1 H NMR(400MHz, CDCl3) δ: 8.43(d, J=0.8Hz, 1H), 7.21-7.10(m, 4H), 6.91-6.81(m, 4H), 6.70(d, J=8.8Hz, 1H), 5.93 (dd, J=3.2, 14.8Hz, MS m / z: 588.2[M+H] +

[0107] Step 7: Synthesis of Compound A1-8 Compound A1-7 (2.1 g, 3.57 mmol) was added to anhydrous tetrahydrofuran (21 mL), and the mixture was cooled to -60 °C. Lithium tri(sec-butyl)borohydride (1 M, 4.29 mL) was added under nitrogen and stirred at -60 °C for 0.5 h. The reaction solution was added to saturated ammonium chloride (30 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (30 mL * 2). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 100:0 to 3:1) to give compound A1-8. 1 H NMR(400MHz, CDCl3) δ: 7.167-7.14(m, 4H), 6.87-6.83(m, 4H), 6.63(d, J=8.8Hz, 1H), 5.05-5.00(m, 1H), 4.61-4.58(m, 1H), 4.42-4.24(m, 5H), 3.85-3.73(m, 10H), 3.13-3.05(m, 1H), 2.47-2.38(m, 1H), 2.35-2.31(m, 3H); MS m / z: 590.1[M+H] +

[0108] Step 8: Synthesis of Compound A1-9 Compound A1-8 (1.27 g, 2.15 mmol) was added to ethanol (15 mL) and water (3 mL), and sodium bicarbonate (3.62 g, 43.08 mmol, 1.68 mL) and methylisothiourea sulfate (4.05 g, 21.54 mmol) were added and stirred at 50 °C for 4 hours. Water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL * 2). The combined organic layer was washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 to 1:1) to obtain compound A1-9. 1H NMR(400MHz, CDCl3) δ: 7.22-7.14(m, 4H), 6.91-6.82(m, 4H), 6.65 (dd, J=8.4 Hz 1H), 5.12-5.08(m, 1H), 4.97-4.91(m, 1H), 4.67-4.57(m, 1H), 4.45-4.22(m, 4H), 3.88-3.74(m, 6H), 3.43-3.35(m, 1H), 2.77-2.72(m, 1H), 2.59(m, 3H), 2.40-2.31(m, 3H); MS m / z: 630.2[M+H] +

[0109] Step 9: Synthesis of compounds A1 and A2 Compound A1-9 (51 g, 81.00 mmol) was dissolved in dichloromethane (500 mL) and N,N-diisopropylethylamine (31.40 g, 242.99 mmol, 42.32 mL) was added. The mixture was cooled to 0-10 °C, and trifluoromethanesulfonic anhydride (34.28 g, 121.49 mmol, 20.05 mL) was slowly added and reacted at the same temperature for 15 min. The resulting reaction solution was poured into saturated aqueous ammonium chloride (400 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (50 mL * 2). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The organic solvent was removed under reduced pressure, and the resulting crude product was suspended in a mixed solvent (petroleum ether:tert-butyl methyl ether = 20:1, 100 mL) and filtered. The filter cake was dried to obtain A1-10. A1-10 (20 g) was purified by supercritical fluid chromatography (SFC) (column: DAICEL Chiralpak IG (250 mm x 50 mm, 10 μm); mobile phase A: CO₂, mobile phase B: EtOH containing 0.1% aqueous ammonia; gradient: EtOH%: 11% to 11%, 8 min). A1 (column: Chiralpak IG-3, 3 μm, 0.46 cm i.d. x 5 cm length; mobile phase A: CO₂, mobile phase B: EtOH containing 0.1% isopropylamine; gradient: B% = 5 to 50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi, Rt = 0.924 min, MS: m / z(ESI): 762.0 [M+H]). + , [ka] , concentration: 0.1682 g / 100 mL) and A2 (column: Chiralpak IG-3, 3 μm, 0.46 cm i.d. × 5 cm length; mobile phase A: CO2, mobile phase B: EtOH containing 0.1% isopropylamine; gradient: B% = 5 to 50%, 3 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 1800 psi, Rt = 1.073 min, chiral purity: 99.99%, MS: m / z(ESI): 762.0 [M+H] + [ka] , concentration: 0.3476g / 100mL). 1 H NMR (400MHz, CDCl3) δ: 7.03-7.14(m, 4H), 6.73-6.82(m, 4H), 6.57(d, J=8.4, 1H) 5.08(d, J=9.6, 1H), 4.92(d, J=15.6, 1H), 4.67(d, J=15.6, 1H), 4.24(q, J=10, 4H), 3.719(s, 6H) 3.42-3.59(m, 1H), 2.87-3.04(m, 1H), 2.47(s, 3H), 2.19-2.35(m, 3H)

[0110] Example 1 [ka]

[0111] Step 1: Preparation of Intermediate 1-1 Compound A2 (80 mg, 105.02 μmol) and compound 1-1A (26.75 mg, 126.03 μmol) was dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylamine (40.72 mg, 315.07 μmol, 54.88 μL) was added. The solution was heated to 100°C and stirred for 1 hour. The resulting mixture was cooled, and the organic solvent was removed under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 2:1) to obtain compound 1-1. MS m / z = 824.3 [M+H] +

[0112] Step 2: Preparation of Intermediate 1-2 Compound 1-1 (70 mg, 84.96 μmol) was dissolved in dichloromethane (2 mL) and m-chloroperbenzoic acid (34.50 mg, 169.92 μmol, 85% content) was added. The solution was stirred at 20°C for 3 hours, and the organic solvent was removed under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1) to obtain compound 1-2. MS m / z = 856.2 [M+H] +

[0113] Step 3: Preparation of Intermediate 1-3 Compound 1-2A (12.09 mg, 75.94 μmol) was dissolved in anhydrous toluene (1 mL) in an ice-water bath. Sodium tert-butoxide (7.30 mg, 75.94 μmol) was added, and the solution was stirred for an additional 30 minutes. A solution of compound 1-2 (50 mg, 58.42 μmol) in toluene (1 mL) was added, and the mixture was stirred for an additional 2 hours in an ice-water bath. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1) to obtain compound 1-3. MS m / z = 935.3 [M+H] +

[0114] Step 4: Preparation of Compound 1 Hydrochloride Compound 1-3 (40 mg, 42.78 μmol) was dissolved in anhydrous dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The solution was stirred at 20 °C for 2 hours, and the solvent was removed under reduced pressure. The resulting crude product was purified by high-performance liquid chromatography (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 15% to 45%, 9 min) to obtain the hydrochloride salt of compound 1. 1H NMR (400MHz, CD3OD) δ: 6.86-6.84(d, J=8.0Hz, 1H), 5.66-5.53(m, 1H), 5.27-5.25(m, 1H), 5.01-4.98(m, 1H), 4.84-4.77(m, 2H), 4.30-4.17(m, 2H), 4.12-3.82(m, 5H), 3.61-3.58(m, 1H), 3.51-3.38(m, 2H), 3.08-3.03(m, 1H), 2.80-2.47(m, 7H), 2.44-1.98(m, 10H); MS m / z=595.6 [M+H] +

[0115] Example 2 [ka]

[0116] Step 1: Preparation of Intermediate 2-1 Compound A2 (80 mg, 105.02 μmol) and compound 2-A1 (27.07 mg, 136.53 μmol) were dissolved in N,N-dimethylformamide (1.2 mL), and diisopropylethylamine (33.93 mg, 262.56 μmol, 45.73 μL) was added. The solution was heated to 100°C and stirred for 1 hour. The resulting mixture was cooled, and the organic solvent was removed under reduced pressure. The crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 3:1) to obtain compound 2-1. MS m / z = 810.1 [M+H] +

[0117] Step 2: Preparation of Intermediate 2-2 Compound 2-1 (73 mg, 90.13 μmol) was dissolved in dichloromethane (1 mL) and m-chloroperbenzoic acid (36.60 mg, 180.27 μmol, 85% content) was added. The solution was stirred at 20°C for 15 hours, and the organic solvent was removed under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:1) to obtain compound 2-2. MS m / z = 842.0 [M+H] +

[0118] Step 3: Preparation of Intermediate 2-3 Compound 1-2A (20.80 mg, 130.66 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL) at 15°C, and sodium tert-butoxide (12.56 mg, 130.66 μmol) was added and stirred for 30 minutes. Compound 2-2 (55 mg, 65.33 μmol) was added, and the reaction solution was stirred at the same temperature for an additional hour. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1) to obtain compound 2-3. MS m / z = 921.4 [M+H] +

[0119] Step 4: Preparation of Compound 2 Hydrochloride Compound 2-3 (42 mg, 45.60 μmol) was dissolved in anhydrous dichloromethane (0.5 mL), trifluoroacetic acid (0.25 mL) was added, and the mixture was stirred at 15°C for 2 hours. The solvent was removed under reduced pressure, and the resulting crude product was purified by high-performance liquid chromatography (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile) %: 12% to 42%, 9 min) to obtain the hydrochloride salt of compound 2. MS m / z = 581.6 [M+H] +

[0120] Example 3 [ka]

[0121] Step 1: Preparation of Intermediate 3-1 Compound A2 (80 mg, 105.02 μmol) and compound 3-1A (24.99 mg, 126.03 μmol) were dissolved in N,N-dimethylformamide (1.2 mL), and diisopropylethylamine (40.72 mg, 315.07 μmol, 54.88 μL) was added. The solution was heated to 100°C and stirred for 1 hour. The resulting mixture was cooled, and the organic solvent was removed under reduced pressure. The crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 2:1) to obtain compound 3-1. MS m / z = 810.2 [M+H] +

[0122] Step 2: Preparation of intermediate 3-2 Compound 3-1 (67 mg, 82.73 μmol) was dissolved in dichloromethane (1 mL) and m-chloroperbenzoic acid (33.59 mg, 165.45 μmol, 85% content) was added. The solution was stirred at 20°C for 5 hours, and the organic solvent was removed under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:1) to obtain compound 3-2. MS m / z = 842.4 [M+H] +

[0123] Step 3: Preparation of Intermediate 3-3 Compound 1-2A (15.13 mg, 95.02 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL) at 15°C, and sodium tert-butoxide (9.13 mg, 95.02 μmol) was added and stirred for 30 minutes. Compound 3-2 (40 mg, 47.51 μmol) was added, and the reaction solution was stirred at the same temperature for an additional hour. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1) to obtain compound 3-3. MS m / z = 921.4 [M+H] +

[0124] Step 4: Preparation of Compound 3 Hydrochloride Compound 3-3 (20 mg, 21.72 μmol) was dissolved in anhydrous dichloromethane (0.5 mL) and trifluoroacetic acid (0.25 mL) was added. The solution was stirred at 15°C for 2 hours, and the solvent was removed under reduced pressure. The resulting crude product was purified by high-performance liquid chromatography (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile) %: 12% to 42%, 9 min) to obtain the hydrochloride salt of compound 3. MS m / z = 581.6 [M+H] +

[0125] Example 5 [ka]

[0126] Step 1: Preparation of Intermediate 5-1 Compound A2 (80 mg, 105.02 μmol) and compound 5-1A (22.30 mg, 105.02 μmol) were dissolved in N,N-dimethylformamide (1 mL), and diisopropylethylamine (40.72 mg, 315.07 μmol, 54.88 μL) was added. The solution was heated to 100°C and stirred for 1 hour. The resulting mixture was cooled, and the organic solvent was removed under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 5:1) to obtain compound 5-1. MS m / z = 824.3 [M+H] +

[0127] Step 2: Preparation of Intermediate 5-2 Compound 5-1 (60 mg, 72.82 μmol) was dissolved in dichloromethane (2 mL) and m-chloroperbenzoic acid (29.57 mg, 145.64 μmol, 85% content) was added. The solution was stirred at 20°C for 16 hours, and the organic solvent was removed under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:1) to obtain compound 5-2. MS m / z = 856.3 [M+H] +

[0128] Step 3: Preparation of Intermediate 5-3 Compound 1-2A (12.09 mg, 75.94 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL) and sodium tert-butoxide (7.30 mg, 75.94 μmol) was added. This solution was stirred at 20°C for 30 minutes, and compound 5-2 (50 mg, 58.42 μmol) was added and stirred at the same temperature for an additional hour. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1) to obtain compound 5-3. MS m / z = 935.3 [M+H] +

[0129] Step 4: Preparation of compound 5 hydrochloride Compound 5-3 (22 mg, 23.53 μmol) was dissolved in anhydrous dichloromethane (1.4 mL) and trifluoroacetic acid (0.7 mL) was added. The solution was stirred at 20 °C for 1 hour, and the solvent was removed under reduced pressure. The resulting crude product was purified by high-performance liquid chromatography (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 20% to 50%, 9 min) to obtain the hydrochloride salt of compound 5. 1 H NMR (400MHz, CD3OD) δ: 6.86-6.84(d, J=8.4Hz, 1H), 5.69-5.51(m, 1H), 5.27-5.25(m, 1H), 5.09-5.04(m, 2H), 5.00-4.94(m, 4H), 4.81-4.78(m, 1H), 3.97-3.88(m, 3H), 3.72-3.68(m, 1H), 3.53-3.38(m, 5H), 3.05-3.01(m, 1H), 2.66-2.63(m, 2H), 2.52-2.45(m, 1H), 2.42-2.15(m, 10H); MS m / z: 595.1 [M+H] +

[0130] Example 6 [ka]

[0131] Step 1: Preparation of Intermediate 6-1 Compound A2 (80 mg, 105.02 μmol) and compound 6-1A (22.30 mg, 105.02 μmol) were dissolved in N,N-dimethylformamide (1 mL), and diisopropylethylamine (40.72 mg, 315.07 μmol, 54.88 μL) was added. The solution was heated to 100°C and stirred for 1 hour. The resulting mixture was cooled, and the organic solvent was removed under reduced pressure. The crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 5:1) to obtain compound 6-1. MS m / z = 824.5 [M+H] +

[0132] Step 2: Preparation of intermediate 6-2 Compound 6-1 (70 mg, 84.96 μmol) was dissolved in dichloromethane (1.5 mL) and m-chloroperbenzoic acid (34.50 mg, 169.92 μmol, 85% content) was added. The solution was stirred at 15°C for 6 hours, and the organic solvent was removed under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:1) to obtain compound 6-2. MS m / z = 856.4 [M+H] +

[0133] Step 3: Preparation of intermediate 6-3 Compound 1-2A (12.09 mg, 75.94 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL), sodium tert-butoxide (7.30 mg, 75.94 μmol) was added, and the mixture was stirred at 15 °C for 30 minutes. To this solution, a solution of compound 6-2 (50 mg, 58.42 μmol) in anhydrous tetrahydrofuran (0.2 mL) was added, and the mixture was stirred at the same temperature for 1.5 hours. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:1) to obtain compound 6-3. MS m / z = 935.6 [M+H] +

[0134] Step 4: Preparation of Compound 6 Hydrochloride Compound 6-3 (36 mg, 38.50 μmol) was dissolved in anhydrous dichloromethane (1.0 mL) and trifluoroacetic acid (0.5 mL) was added. The solution was stirred at 15°C for 2 hours, and the solvent was removed under reduced pressure. The resulting crude product was purified by high-performance liquid chromatography (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 15% to 45%, 9 min) to obtain the hydrochloride salt of compound 6. MS m / z: 595.6 [M+H] +

[0135] Example 7 [ka]

[0136] Step 1: Preparation of intermediate 7-2 Compound 7-1 (160 mg, 487.14 μmol) was dissolved in dichloromethane (2 mL) at 20 °C, trifluoroacetic acid (2 mL) was added, and the mixture was stirred at the same temperature for 18 h. The organic solvent was removed under reduced pressure to give crude product 7-2, which was used directly in the next step without further purification.

[0137] Step 2: Preparation of intermediate 7-3 Compound A2 (350.00 mg, 459.48 μmol) and compound 7-2 (50.62 mg, 459.48 μmol) were dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylamine (178.15 mg, 1.38 mmol, 240.10 μL) was added. The solution was heated to 100° C. and stirred for 1 hour. The resulting mixture was cooled to give a solution of compound 7-3, which was used directly in the next step without further purification. MS m / z: 722.1 [M+H] +

[0138] Step 3: Preparation of intermediate 7-4 The solution of intermediate 7-3 obtained in Step 2 was dissolved in dichloromethane (10 mL) at 20 °C, and diisopropylethylamine (177.26 mg, 1.37 mmol, 238.90 μL) and di-tert-butyl dicarbonate (149.67 mg, 685.78 μmol, 157.55 μL) were added. The solution was stirred at the same temperature for 18 h, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-15%) to give compound 7-4. 1 H NMR(400MHz, CD3OD) δ: 7.17-7.14(d, J=8.8Hz, 4H), 6.86-6.84(d, J=8.8Hz, 4H), 6.64-6.62(d, J=8.0Hz, 1H), 6.26-6.20(m, 2H), 5.20-5.16(m, 1H), 4.73-4.61(m, 4H), 4.35-4.29(m, 4H), 3.81(s, 6H), 3.35-2.81(m, 6H), 2.51(s, 3H), 2.35(s, 3H), 1.52(s, 9H); MS m / z: 822.3 [M+H] +

[0139] Step 4: Preparation of Intermediate 7-5 Compound 7-4 (50.06 mg, 60.91 μmol) was dissolved in methanol (5 mL) at 20 °C, and potassium peroxymonosulfate (37.44 mg, 60.91 μmol) was added. The solution was stirred at the same temperature for 1 hour, and the organic solvent was removed under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:1) to obtain compound 7-5. MS m / z: 838.3 [M+H] +

[0140] Step 5: Preparation of Intermediate 7-6 Compound 1-2A (7.42 mg, 46.60 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL) at 20 °C, and sodium tert-butoxide (4.48 mg, 46.60 μmol) was added. The mixture was stirred at the same temperature for 30 minutes. Compound 7-5 (30.04 mg, 35.85 μmol) was added to the solution, and the mixture was stirred at the same temperature for an additional hour. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1) to obtain compound 7-6. MS m / z = 933.5 [M+H] +

[0141] Step 6: Preparation of Compound 7 Hydrochloride Compound 7-6 (25 mg, 26.79 μmol) was dissolved in anhydrous dichloromethane (1.0 mL) at 20 °C, and trifluoroacetic acid (1 mL) was added. The solution was stirred at the same temperature for 1 hour, and the solvent was removed under reduced pressure. The resulting crude product was purified by high-performance liquid chromatography (column: Xtimate C18 150*40 mm*5 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile) %: 1% to 30%, 10 min) to obtain the hydrochloride salt of compound 7. MS m / z: 593.5 [M+H] +

[0142] Example 8 [ka]

[0143] Step 1: Preparation of Intermediate 8-2 Sodium hydride (2.33 g, 58.28 mmol, 60% content) was suspended in anhydrous tetrahydrofuran (120 mL) in an ice-water bath, and compound 8-1 (10 g, 44.83 mmol) was added. The mixture was stirred at the same temperature for 1 h and then cooled to -78 °C. n-Butyllithium (2.5 M, 30.48 mL) was added dropwise, and the reaction solution was stirred for an additional 1 h. Finally, N,N-dimethylformamide (16.38 g, 224.15 mmol, 17.25 mL) was added, and the mixture was stirred for 0.5 h. The reaction was quenched with 2 M hydrochloric acid (10 mL). The resulting mixture was then extracted with ethyl acetate (50 mL * 3), and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-30%) to give compound 8-2. 1 H NMR (400MHz, CDCl3) δ: 10.42(s, 1H), 9.10-9.06(m, 1H), 7.76-7.75(m, 1H), 7.67-7.66(m, 1H), 7.59-7.57(m, 2H), 7.46-7.45(m, 1H), 5.64(brs, 1H)

[0144] Step 2: Preparation of intermediate 8-3 Compound 8-2 (3.0 g, 17.42 mmol) was dissolved in anhydrous dichloromethane (50 mL) in an ice-water bath, and diisopropylethylamine (6.76 g, 52.27 mmol, 9.10 mL) and chloromethyl methyl ether (2.10 g, 26.14 mmol, 1.99 mL) were added. The solution was stirred for 2 h, and the organic solvent was removed under reduced pressure. The resulting residue was dissolved in ethyl acetate (100 mL) and washed with water (10 mL*3) and saturated brine (10 mL). The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-10%) to give compound 8-3. 1H NMR (400MHz, CDCl3) δ: 10.40(s, 1H), 9.14-9.11(m, 1H), 7.82-7.80(m, 1H), 7.78-7.77(m, 1H), 7.69-7.67(m, 1H), 7.57-7.55(m, 2H), 5.36(s, 2H), 3.55(s, 3H)

[0145] Step 3: Preparation of Intermediate 8-4 Sodium hydride (414.37 mg, 10.36 mmol, 60% content) was suspended in anhydrous tetrahydrofuran (8 mL) under nitrogen, and the mixture was cooled to 0 °C. Methyl acetoacetate (1.20 g, 10.36 mmol, 1.11 mL) was added, and the solution was stirred for 30 min. n-Butyllithium (2.5 M, 4.14 mL) was added dropwise, and the mixture was stirred for an additional 30 min. The reaction solution was cooled to -78 °C, and a solution of compound 8-3 (1.12 g, 5.18 mmol) in anhydrous tetrahydrofuran (2 mL) was added dropwise. The solution was stirred at the same temperature for an additional 1 h, and the reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (80 mL * 3), and the combined organic layers were dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether=0-75%) to give compound 8-4. 1 H NMR (400MHz, CDCl3) δ: 7.90-7.88(m, 1H), 7.79-7.77(m, 1H), 7.49-7.35(m, 4H), 5.98-5.95(m, 1H), 5.32(s, 2H), 3.78(s, 3H), 3.56(s, 2H), 3.53(s, 3H), 3.15-3.01(m, 3H); MS m / z: 350.2 [M+H2O] +

[0146] Step 4: Preparation of Intermediate 8-5 Compound 8-4 (2.43 g, 7.31 mmol) was dissolved in dichloromethane (15 mL) at 18 °C, and N,N-dimethylformamide dimethyl acetal (871.27 mg, 7.31 mmol, 971.31 μL) was added. The solution was stirred at the same temperature for 2 h, and then the reaction solution was cooled to 0 °C. Boron trifluoride diethyl etherate (1.04 g, 7.31 mmol, 902.37 μL) was added, and the solution was stirred for an additional 1 h. The organic solvent was removed under reduced pressure, and ethyl acetate (100 mL) was added to the resulting crude product. The mixture was washed with water (20 mL), saturated aqueous sodium bicarbonate solution (20 mL), and saturated brine (10 mL). The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-35%) to give compound 8-5. 1 H NMR (400MHz, CDCl3) δ: 8.54(s, 1H), 7.79-7.77(m, 2H), 7.49-7.35(m, 4H), 6.30-6.26(m, 1H), 5.32(s, 2H), 3.87(s, 3H), 3.56(s, 3H), 3.15-3.01(m, 2H); MS m / z: 343.2 [M+H] +

[0147] Step 5: Preparation of Intermediate 8-6 Compound 8-5 (1.42 g, 4.15 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) under nitrogen, and the solution was cooled to -78 °C. Lithium tri(sec-butyl)borohydride (1 M, 4.15 mL) was added dropwise and stirred at the same temperature for an additional 1 h. The reaction was quenched with water (1 mL), and the resulting mixture was diluted with ethyl acetate (80 mL). The organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-15%) to give compound 8-6. MS m / z: 367.1 [M+Na] +

[0148] Step 6: Preparation of Intermediate 8-7 Compound 8-6 (1.14 g, 3.31 mmol) and 2-methylthiourea (1.87 g, 9.93 mmol) were added to ethanol (20 mL) under nitrogen, and sodium carbonate (1.05 g, 9.93 mmol) was added. The solution was heated to 60 °C and stirred for 15 h. The organic solvent was removed under reduced pressure, and water (15 mL) and ethyl acetate (100 mL) were added to the residue. The mixture was adjusted to pH 5-6 with 6 M hydrochloric acid, and the layers were separated. The organic layer was washed with saturated brine (20 mL), and the organic solvent was removed under reduced pressure to give crude compound 8-7, which was used directly in the next step without further purification. MS m / z: 385.1 [M+H] +

[0149] Step 7: Preparation of Intermediate 8-8 Compound 8-7 (1.34 g, 3.49 mmol) was dissolved in N,N-dimethylformamide (20 mL) at 16 °C, and N,N-diisopropylethylamine (1.35 g, 10.47 mmol, 1.82 μL) and N-phenylbis(trifluoromethanesulfonimide) (1.87 g, 5.24 mmol) were added. The mixture was stirred at the same temperature for 3 h. It was diluted with ethyl acetate (100 mL). The mixture was washed with water (20 mL * 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-10%) to give compound 8-8. 1 H NMR(400MHz, CDCl3) δ: 7.92-7.90(m, 1H), 7.82-7.80(m, 1H), 7.49-7.46(m, 1H), 7.43-7.35(m, 3H), 5.50-5.47(m,1H), 5.32(s, MS m / z: 517.0 [M+H] +

[0150] Step 8: Preparation of Intermediate 8-9 Compound 8-8 (300 mg, 580.82 μmol) and compound 1-1A (160.29 mg, 755.07 μmol) were dissolved in N,N-dimethylformamide (3 mL), and diisopropylethylamine (225.20 mg, 1.74 mmol, 303.51 μL) was added. The solution was heated to 100 °C and stirred for 1 h. The resulting mixture was cooled, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-25%) to give compound 8-9. 1 H NMR (400MHz, CDCl3) δ: 7.98-7.96(m, 1H), 7.80-7.78(m, 1H), 7.49-7.36(m, 4H), 5.50-5.47(m, 1H), 5.31(s, 2H), 4.92-4.89(m, 1H), 4.78-4.75(m, 1H), 4.36-4.30(m, 2H), 3.97-3.78(m, 1H), 3.58-3.30(m, 6H), 3.19-3.12(m, 2H), 2.53(s, 3H), 1.78-1.46(m, 13H); MS m / z: 579.8 [M+H] +

[0151] Step 9: Preparation of Intermediates 8-10 Compound 8-9 (270 mg, 466.55 μmol) was dissolved in dichloromethane (2.5 mL) at 15 °C, and m-chloroperbenzoic acid (189.44 mg, 933.09 μmol, 85% content) was added. The solution was stirred at the same temperature for 18 hours, and the organic solvent was removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-60%) to give compound 8-10. MS m / z = 611.2 [M+H] +

[0152] Step 10: Preparation of Intermediates 8-11 Compound 1-2A (125.13 mg, 785.96 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL) at 15 °C, and sodium tert-butoxide (75.53 mg, 785.96 μmol) was added. The mixture was stirred at the same temperature for 1 hour. Compound 8-10 (240 mg, 392.98 μmol) was added to the reaction solution, and the mixture was stirred at the same temperature for an additional 0.5 hours. The organic solvent was then removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0-4%) to give compound 8-11. MS m / z = 690.3 [M+H] +

[0153] Step 11: Preparation of Compound 8 Hydrochloride Compound 8-11 (53 mg, 76.83 μmol) was dissolved in a solution of hydrogen chloride / dioxane (2 mL, 4 M) at 18 °C. The solution was stirred at the same temperature for 30 minutes, and the solvent was removed under reduced pressure. The resulting crude product was purified by high-performance liquid chromatography (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 9% to 39%, 9 min) to obtain the hydrochloride salt of compound 8. 1 H NMR (400MHz, D2O) δ: 7.95-7.93(m, 1H), 7.76-7.74(m, 1H), 7.48-7.36(m, 2H), 7.22-7.20(m, 2H), 5.95-5.47(m, 2H), 4.96-4.93(m, 1H), 4.66-4.53(m, 4H), 4.20-4.17(m, 2H), 3.87-3.68(m, 6H), 3.48-3.38(m, 2H), 3.17-3.15(m, 2H), 2.60-2.37(m, 2H), 2.28-2.23(m, 3H), 2.08-2.03(m, 4H), 1.88-1.85(m, 1H); MS m / z=546.3 [M+H] +

[0154] Example 9 [ka]

[0155] Step 1: Preparation of intermediate 9-6 Sodium hydride (346.70 mg, 8.67 mmol, 60% content) was suspended in anhydrous tetrahydrofuran (10 mL) under nitrogen, and the mixture was cooled to 0 °C. Methyl propionylacetate (1.13 g, 8.67 mmol, 1.07 mL) was added to this solution and stirred for 30 minutes. n-Butyllithium (2.5 M, 3.47 mL) was added dropwise, and the mixture was stirred for an additional 30 minutes to allow the reaction to proceed. The reaction solution was cooled to -78 °C, and a solution of compound A1-5 (2.0 g, 4.33 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise. This solution was stirred at the same temperature for an additional 1.5 hours, and the reaction was quenched with 0.5 M hydrochloric acid (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-35%) to give compound 9-6. MS m / z: 614.5 [M+Na] +

[0156] Step 2: Preparation of intermediate 9-7 Compound 9-6 (2.0 g, 3.38 mmol) was dissolved in dichloromethane (10 mL) at 20 °C, and N,N-dimethylformamide dimethyl acetal (1.21 g, 10.14 mmol, 1.35 mL) was added. The solution was stirred at the same temperature for 18 h, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-35%) to give compound 9-7. MS m / z: 602.2 [M+H] +

[0157] Step 3: Preparation of Intermediate 9-8 Compound 9-7 (750 mg, 1.25 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) under nitrogen. The solution was cooled to -78 °C, and lithium tri(sec-butyl)borohydride (1 M, 1.25 mL) was added dropwise. The mixture was stirred at the same temperature for 1 hour. The reaction was quenched with 0.5 M hydrochloric acid (5 mL), and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-20%) to give compound 9-8. MS m / z: 604.2 [M+H] +

[0158] Step 4: Preparation of Intermediate 9-9 Compound 9-8 (750 mg, 1.24 mmol) and 2-methylthiourea (701.63 mg, 3.73 mmol) were added to ethanol (10 mL) under nitrogen, and sodium carbonate (263.39 mg, 2.49 mmol) was added. The solution was heated to 60 °C and stirred for 15 h. The organic solvent was removed under reduced pressure, and water (10 mL) was added to the residue. The mixture was adjusted to pH 5-6 with 2 M hydrochloric acid and extracted with ethyl acetate (30 mL * 3). The combined organic layer was washed with saturated brine (10 mL), and the organic solvent was removed under reduced pressure to give crude compound 9-9, which was used directly in the next step without further purification. MS m / z: 666.4 [M+Na] +

[0159] Step 5: Preparation of Intermediates 9-10 Compound 9-9 (855 mg, 1.33 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 20 °C, and N,N-diisopropylethylamine (515.68 mg, 3.99 mmol, 694.99 μL) and N-phenylbis(trifluoromethanesulfonimide) (570.17 mg, 1.60 mmol) were added. The mixture was stirred at the same temperature for 3 h. The mixture was diluted with ethyl acetate (50 mL), washed with water (15 mL × 4), dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-15%) to give compound 9-10. MS m / z: 776.1 [M+H] +

[0160] Step 6: Preparation of Intermediates 9-11 Compounds 9-10 (240 mg, 309.38 μmol) and compound 1-1A (78.81 mg, 371.25 μmol) were dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylamine (119.95 mg, 928.13 μmol, 161.66 μL) was added. The solution was heated to 100°C and stirred for 1 hour. The resulting mixture was cooled, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-45%) to give compounds 9-11. MS m / z: 838.5 [M+H] +

[0161] Step 7: Preparation of Intermediates 9-12 Compounds 9-11 (260 mg, 310.28 μmol) were dissolved in dichloromethane (2 mL) at 20 °C, and m-chloroperbenzoic acid ( 125.98 The mixture was added with 1 mg of 10 ... +

[0162] Step 8: Preparation of Intermediates 9-13 Compound 1-2A (101.56 mg, 637.96 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL) at 20 °C, and sodium tert-butoxide (40.87 mg, 425.31 μmol) was added and stirred at the same temperature for 1 hour. Compound 9-12 (185 mg, 212.65 μmol) was added to this solution and stirred at the same temperature for an additional 1 hour. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-65%) to give compound 9-13. MS m / z = 949.3 [M+H] +

[0163] Step 9: Preparation of Compound 9 Compound 9-13 (151 mg, 159.11 μmol) was dissolved in trifluoroacetic acid (1.2 mL) at 20 °C and stirred at the same temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting crude product was purified by high-performance liquid chromatography (column: Phenomenex C18 80 * 40 mm * 3 μm; mobile phase: [0.5% aqueous ammonia / acetonitrile]; (acetonitrile) %: 47% ~ 77%, 8 min) to obtain compound 9. 1 H NMR (400MHz, CD3OD) δ: 6.74-6.72(d, J=8.8Hz, 1H), 5.38-5.24(m, 1H), 4.64-4.60(m, 2H), 4.20-4.10(m, 2H), 3.59-3.37(m,6H), 3.26-3.03(m, 5H), 2.40-2.37(m, 3H), 2.28-1.68(m, 11H), 1.21-1.17(m, 3H); MS m / z=609.3 [M+H] +

[0164] Example 10 [ka]

[0165] Step 1: Preparation of Intermediate 10-1 Compound A1-7 (518 mg, 881.62 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL) under nitrogen and cooled to -78 °C. Lithium dimethylcuprate (0.5 M, 5.29 mL) was added dropwise and stirred at the same temperature for 0.5 h. The reaction solution was added to water (10 mL) and ethyl acetate (50 mL), and the mixture was filtered. The layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL * 3). The organic layers were combined, and the organic solvent was removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-20%) to give compound 10-1. 1 H NMR(400MHz, CDCl3) δ: 7.17-7.14(m, 4H), 6.87-6.83(m, 4H), 6.63-6.61(d, J=7.2Hz, 1H), 5.42-5.39(m, 1H), 4.86-4.84(m, 1H), 4.38-4.24(m, 5H), 3.80-3.73(m, 9H), 3.13-3.05(m, 1H), 2.41-2.38(m, 4H), 1.48-1.37(m, 3H); MS m / z: 604.2 [M+H] +

[0166] Step 2: Preparation of Intermediate 10-2 Compound 10-1 (488 mg, 808.48 μmol) and 2-methylthiourea (456.53 mg, 2.43 mmol) were added to ethanol (5 mL) under nitrogen, and sodium carbonate (171.38 mg, 1.62 mmol) was added. The solution was heated to 60 °C and stirred for 32 h. The organic solvent was removed under reduced pressure, and water (20 mL) was added to the resulting residue. The mixture was adjusted to pH 5-6 with 2 M hydrochloric acid and extracted with ethyl acetate (100 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to give crude compound 10-2, which was used directly in the next step without further purification. MS m / z: 644.3 [M+H] +

[0167] Step 3: Preparation of Intermediate 10-3 Compound 10-2 (502 mg, 779.88 μmol) was dissolved in N,N-dimethylformamide (5 mL) at 20 °C, and N,N-diisopropylethylamine (302.38 mg, 2.34 mmol, 407.52 μL) and N-phenylbis(trifluoromethanesulfonimide) (417.92 mg, 1.17 mmol) were added. The mixture was stirred at the same temperature for 2 h. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-20%) to give compound 10-3. MS m / z: 776.1 [M+H] +

[0168] Step 4: Preparation of Intermediate 10-4 Compound 10-3 (185 mg, 238.48 μmol) and compound 1-1A (65.81 mg, 310.02 μmol) were dissolved in N,N-dimethylformamide (1.5 mL), and diisopropylethylamine (92.46 mg, 715.43 μmol, 124.62 μL) was added. The solution was heated to 100 °C and stirred for 1 h. The resulting mixture was cooled, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-30%) to give compound 10-4. MS m / z: 838.8 [M+H] +

[0169] Step 5: Preparation of Intermediate 10-5 Compound 10-4 (105.00 mg, 125.30 μmol) was dissolved in dichloromethane (2 mL) at 20 °C, and m-chloroperbenzoic acid (50.88 mg, 250.61 μmol, 85% content) was added. The mixture was stirred at the same temperature for 1.5 hours. The organic solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-35%) to obtain compound 10-5. MS m / z = 870.3 [M+H] +

[0170] Step 6: Preparation of Intermediate 10-6 Compound 1-2A (47.21 mg, 296.56 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL) at 20 °C, and sodium tert-butoxide (19.00 mg, 197.71 μmol) was added. The mixture was stirred at the same temperature for 1 hour. Compound 10-5 (86.00 mg, 98.85 μmol) was added to the solution, and the mixture was stirred at the same temperature for another 1 hour. The organic solvent was removed under reduced pressure, and saturated brine (1 mL) and ethyl acetate (5 mL) were added to the resulting crude product, and the layers were separated. The organic solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0-4%) to give compound 10-6. MS m / z = 949.5 [M+H] +

[0171] Step 7: Preparation of compound 10 formate salt Compound 10-6 (75.00 mg, 79.03 μmol) was dissolved in trifluoroacetic acid (1.5 mL) at 20 °C and stirred at the same temperature for 30 min. The solvent was removed under reduced pressure, and the resulting crude product was purified by high-performance liquid chromatography (column: Phenomenex C18, 150 × 40 mm × 5 μm; mobile phase: [0.025% aqueous formic acid / acetonitrile]; (acetonitrile) %: 5% to 35%, 10 min) to obtain the formate salt of compound 10. 1 H NMR (400MHz, CD3OD) δ: 8.51(s, 1H), 6.72-6.70(d, J=8.4Hz, 1H), 5.51-5.31(m, 3H), 4.36-4.19(m, 4H), 4.10-4.07(m, 2H), 3.71-3.40(m, 4H), 3.21-3.18(m, 2H), 2.82-2.70(m, 1H), 2.51-1.98(m, 15H), 1.51-1.47(m, 3H); MS m / z=609.6 [M+H] +

[0172] Example 11 [ka]

[0173] Step 1: Preparation of Intermediate 11-2 11-1 (10 g, 44.39 mmol, 1 equiv) was dissolved in THF (100 mL) and LDA (2 M, 24.41 mL, 1.1 equiv) was added dropwise at −78 °C. After the addition was complete, the mixture was stirred for 0.5 h. A solution of 11-2A (18.30 g, 46.61 mmol, 1.05 equiv) in THF (50 mL) was then added dropwise and stirred for 0.5 h, followed by stirring at room temperature for 0.5 h. The reaction was quenched by the addition of saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (500 mL * 2). After extraction, the combined organic layer was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness on a rotary evaporator, and the resulting residue was separated by column chromatography (eluent: 10% ethyl acetate / petroleum ether) to give 11-2.

[0174] Step 2: Preparation of intermediate 11-3 11-2 (15.2 g, 42.54 mmol, 1 equiv.), B2Pin2 (12.96 g, 51.04 mmol, 1.2 equiv.), Pd(dppf)Cl2·CHCl2 (3.47 g, 4.25 mmol, 0.1 equiv.), and KOAc (12.52 g, 127.61 mmol, 3 equiv.) were dissolved in 1,4-dioxane (130 mL) and reacted at 90 °C under nitrogen for 16 h. The mixture was cooled to room temperature, filtered through Celite, and separated by column chromatography (eluent: 10% ethyl acetate / petroleum ether) to give 11-3.

[0175] Step 3: Preparation of intermediate 11-4 To a solution of A2 (3.3 g, 4.33 mmol) and 11-3 (2.18 g, 6.50 mmol) in 1,4-dioxane (30 mL) and water (1 mL) was added sodium carbonate (1.38 g, 13.00 mmol) and 1,1-bis(diphenylphosphino)ferrocenedichloropalladium (530.68 mg, 649.84 μmol). The system was purged with nitrogen three times and heated and stirred at 90 °C for 12 h. The mixture was filtered, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was separated by column chromatography (eluent: 10-20% ethyl acetate / petroleum ether) to give 11-4. MS m / z: 821.4 [M+H] +

[0176] Step 4: Preparation of Intermediate 11-5 To a solution of 11-4 (530 mg, 645.61 μmol) in dichloromethane (50 mL), m-chloroperbenzoic acid (131.07 mg, 645.61 μmol) was added and stirred at 20 °C for 0.5 h. The reaction solution was washed successively with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness on a rotary evaporator, and the resulting residue was separated by column chromatography (eluent: 20-60% ethyl acetate / petroleum ether) to give 11-5. MS m / z: 859.3 [M+Na] +

[0177] Step 5: Preparation of Intermediate 11-6 To a solution of 1-2A (164.35 mg, 1.03 mmol) in tetrahydrofuran (15 mL), sodium tert-butoxide (99.21 mg, 1.03 mmol) was added at 20 °C and stirred at the same temperature for 0.5 h. 11-5 (720.00 mg, 860.29 μmol) was then added and stirred for an additional 0.5 h. The reaction solution was diluted with ethyl acetate (80 mL) and washed with saturated brine (30 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness on a rotary evaporator, and the resulting residue was separated by column chromatography (eluent: 0-5% methanol / dichloromethane) to give 11-6. MS m / z: 932.4 [M+H] +

[0178] Step 6: Preparation of Intermediate 11-7 Palladium hydroxide (467.12 mg, 3.33 mmol) was added to a solution of compound 11-6 (620 mg, 665.22 μmol) in ethanol (40 mL), and the mixture was reacted under a hydrogen atmosphere (50 psi) at 50° C. for 15 hours. The mixture was filtered, and the filtrate was evaporated to dryness using a rotary evaporator to give 11-7. MS m / z: 934.4 [M+H] +

[0179] Step 7: Preparation of Compound 11A Hydrochloride and Compound 11B Hydrochloride To a solution of 11-7 (500 mg, 535.31 μmol, 1 equiv.) in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added and stirred at 20°C for 1 hour. The solution was evaporated to dryness using a rotary evaporator, and the resulting residue was separated by preparative HPLC (column: Xtimate C18, 150*40 mm*5 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile) %: 10% to 30%, 10 min) to give compound 11A hydrochloride and compound 11B hydrochloride. MS m / z = 594.1 [M+H] + 11A Hydrochloride: 1H NMR (400MHz, CD3OD) δ=7.02(d, J =8.0Hz, 1H), 5.71-5.52(m, 1H), 5.26-5.16(m, 2H), 4.98-4.92(m, 1H), 4.78-4.67(m, 2H), 4.18(br s, 2H), 4.05-3.87(m, 3H), 3.58-3.44(m, 2H), 3.30-3.23(m, 1H), 3.02-2.93(m, 1H), 2.83-2.58(m, 2H), 2.54-2.38(m, 8H), 2.36-2.17(m, 5H), 2.04-1.86(m, 2H); 11B hydrochloride: 1 H NMR (400MHz, CD3OD) δ=6.95(d, J =8.4Hz, 1H), 5.73-5.50(m, 1H), 5.31-5.17(m, 2H), 5.05-4.95(m, 1H), 4.80-4.60(m, 2H), 4.23-3.85(m, 5H), 3.59-3.35(m, 3H), 3.05-2.69(m, 2H), 2.66-2.35(m, 10H), 2.33-1.91(m, 6H)

[0180] Example 12 [ka]

[0181] Step 1: Preparation of Intermediate 12-1 A 100 mL sealed bottle was charged with starting material A1-4 (5 g, 10.59 mmol) and copper powder (3.36 g, 52.93 mmol) under nitrogen, followed by DMSO (40 mL) and pentafluoroiodoethane (5.21 g, 21.17 mmol). After capping, the mixture was heated to 120 °C and stirred for 12 h. Saturated brine (50 mL) and tert-butyl methyl ether (200 mL) were added to the reaction solution, which was stirred for 10 min and filtered. The mixture was allowed to stand for phase separation, and the aqueous layer was removed. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by chromatography (eluent: 5% ethyl acetate / petroleum ether) to give compound 12-1. MS m / z = 512.1 [M+H]+

[0182] Step 2: Preparation of Intermediate 12-2 Sodium hydride (1.56 g, 39.10 mmol, 60% content) was added to tetrahydrofuran (50 mL) at 0 °C (ice-water bath) under nitrogen. After stirring for 15 minutes, ethyl acetoacetate (4.54 g, 39.10 mmol) was added dropwise. This mixture was stirred for an additional 15 minutes, and n-butyllithium (2.5 M, 15.64 mL) was added dropwise. This mixture was stirred for 30 minutes, and a solution of raw material 12-1 (4 g, 7.82 mmol) in tetrahydrofuran (10 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred at 25 °C for 1 hour. The reaction was quenched by the slow addition of saturated aqueous ammonium chloride (50 mL). tert-Butyl methyl ether (100 mL) was added to this mixture and stirred for 5 minutes. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography (eluent: 10-20% ethyl acetate / petroleum ether) to give compound 12-2. MS m / z=628.2 [M+H] +

[0183] Step 3: Preparation of Intermediate 12-3 To a solution of raw material 12-2 (1.6 g, 2.55 mmol) in dichloromethane (20 mL) was added dropwise DMF-DMA (486.09 mg, 4.08 mmol) under nitrogen at room temperature (25 °C) and stirred for 1 h. The reaction vessel was then cooled to 0 °C in an ice-water bath, and boron trifluoride diethyl etherate (542.77 mg, 3.82 mmol) was added and stirred for 1 h. Saturated aqueous sodium bicarbonate (20 mL) and dichloromethane (30 mL) were added to the reaction solution and stirred for 5 min. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography (eluent: 10-30% ethyl acetate / petroleum ether) to give compound 12-3. MS m / z = 638.1 [M+H] +

[0184] Step 4: Preparation of Intermediate 12-4 To a solution of the raw material 12-3 in tetrahydrofuran (15 mL) was added dropwise lithium tri(sec-butyl)borohydride (1 M, 1.73 mL) at -60 °C (dry ice / ethyl acetate bath) under nitrogen and stirred for 60 minutes. 0.5 M hydrochloric acid (2 mL), saturated brine (20 mL), and ethyl acetate (50 mL) were added to the reaction solution and stirred for 10 minutes. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography (eluent: 30% ethyl acetate / petroleum ether) to give compound 12-4. MS m / z = 640.2 [M+H] +

[0185] Step 5: Preparation of Intermediate 12-5 To a solution of the raw material 12-4 (1 g, 1.56 mmol) and S-methylisothiourea sulfate (1.31 g, 4.69 mmol) in ethanol (15 mL), sodium carbonate (331.43 mg, 3.13 mmol) was added and the mixture was heated to 45 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to remove most of the ethanol. 0.5 M hydrochloric acid (10 mL) and 2-methyltetrahydrofuran (30 mL) were added to the resulting residue and stirred for 10 min. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography (eluent: 10-30% ethyl acetate / petroleum ether) to give compound 12-5. MS m / z = 680.1 [M+H] +

[0186] Step 6: Preparation of Intermediate 12-6 To a solution of raw material 12-5 (0.6 g, 882.78 μmol) in dichloromethane (10 mL) was added DIPEA (228.19 mg, 1.77 mmol) under nitrogen at 0 °C (ice-water bath), followed by trifluoromethanesulfonic anhydride (373.60 mg, 1.32 mmol, 218.48 μL). The mixture was stirred for 1 hour, diluted with dichloromethane (20 mL), and then saturated aqueous ammonium chloride (20 mL) was added. The mixture was stirred for 10 minutes, the aqueous layer was removed, and the organic layer was concentrated under reduced pressure to give compound 12-6. MS m / z = 812.0 [M+H] +

[0187] Step 7: Preparation of Intermediate 12-7 To a solution of the raw material 12-6 (0.75 g, 923.95 μmol) in DMF (10 mL) was added DIPEA (358.24 mg, 2.77 mmol) and 1-1A (235.37 mg, 1.11 mmol) under nitrogen at room temperature (25 °C), and the mixture was heated to 50 °C and stirred for 30 min. Water (20 mL) and ethyl acetate (30 mL) were added to the reaction solution, and the mixture was stirred for 10 min. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography (eluent: 10-20% ethyl acetate / petroleum ether) to give compound 12-7. MS m / z = 874.2 [M+H] +

[0188] Step 8: Preparation of Intermediate 12-8 To a solution of raw material 12-7 (0.32 g, 366.16 μmol) in dichloromethane (5 mL) was added m-chloroperbenzoic acid (81.77 mg, 402.77 μmol, 85% content) under nitrogen at 0 °C (ice-water bath) and stirred for 2 h. The reaction solution was diluted with dichloromethane (20 mL), followed by the addition of saturated aqueous sodium bicarbonate (10 mL) and saturated Na2SO3 (10 mL). The mixture was stirred for 10 min (monitored by potassium iodide starch paper), the aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography (eluent: 10-30% ethyl acetate / petroleum ether) to give compound 12-8. MS m / z = 890.2 [M+H] +

[0189] Step 9: Preparation of Intermediate 12-9 To a solution of starting material 1-2A (85.87 mg, 539.36 μmol) in tetrahydrofuran (5 mL) was added sodium tert-butoxide (69.11 mg, 719.15 μmol) under nitrogen at 0°C (ice-water bath) and stirred for 30 minutes, followed by the addition of starting material 12-8 (0.32 g, 359.57 μmol). This mixture was stirred for 1 hour, and then saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (20 mL) were added to the reaction solution and stirred for 10 minutes. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The resulting residue was purified using a chromatography purification system (eluent: 10% methanol / dichloromethane) to obtain compound 12-9. MS m / z = 985.3 [M+H] +

[0190] Step 10: Preparation of Compound 12 Formate, Compound 12A, and Compound 12B To a solution of the raw material 12-9 (0.1 g, 101.52 μmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature (25 °C) and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: [0.025% formic acid aqueous solution / acetonitrile]; (acetonitrile) %: 1% to 35%, 8 min) to obtain the formate salt of 12. The formate salt of 12 was then subjected to chiral separation (column: DAICEL Chiralpak AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% aqueous ammonia containing MeOH]; (methanol) %: 40% to 40%, 10 min) to give compound 12A (Rt = 3.473 min) and compound 12B (Rt = 4.102 min). Compound 12A: 1H NMR (400MHz, CD3OD) δ=6.74(d, J=8.6Hz, 1H), 5.40-5.20(m, 1H), 5.16-5.06(m, 1H), 4.76-4.54(m, 3H), 4.20-4.05(m, 3H), 3.65(br s, 2H), 3.59-3.51(m, 1H), 3.49-3.39(m, 1H), 3.27-3.16(m, 3H), 3.12-2.97(m, 2H), 2.84(br dd, J=3.2, 17.7Hz, 1H), 2.36(br dd, J=2.7, 6.9Hz, 5H), 2.16-1.68(m, 8H); MS m / z=645.3[M+H] + Compound 12B: 1 H NMR (400MHz, CD3OD) δ=6.74(d, J=8.6Hz, 1H), 5.40-5.18(m, 1H), 5.10(br dd, J=3.9, 10.8Hz, 1H), 4.74-4.49(m, 3H), 4.21-4.08(m, 2H), 4.04(d, J=10.3Hz, 1H), 3.56-3.37(m, 4H), 3.29-3.13(m, 4H), 3.07-2.93(m, 2H), 2.83(br dd, J=3.1, 16.9Hz, 1H), 2.40-2.15(m, 5H), 2.14-1.63(m, 9H); MS m / z = 645.3 [M+H] +

[0191] Example 13

change

[0192] ステップ1: Manufacture of intermediate 13-1 Sodium hydride (10.17 g, 254.16 mmol, 60% content) was slowly added in portions to tetrahydrofuran (500 mL) at -5 °C. The system was purged with nitrogen three times, and then methyl acetoacetate (29.51 g, 254.16 mmol) was slowly added and reacted at the same temperature for 10 min. Next, n-butyllithium (2.5 M, 101.66 mL) was added dropwise. After the addition was complete, the mixture was stirred for 10 min and cooled to -10 °C. Next, a solution of A1-3 (50 g, 127.08 mmol) in tetrahydrofuran (100 mL) was added dropwise. After the addition was complete, the mixture was reacted for an additional 10 min. The reaction was quenched by the addition of saturated ammonium chloride solution (400 mL), and the mixture was extracted with ethyl acetate (500 mL * 2). After extraction, the combined organic layer was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness on a rotary evaporator, and the resulting residue was separated by column chromatography (eluent: 15-40% ethyl acetate / petroleum ether) to give 13-1.

[0193] Step 2: Preparation of intermediate 13-2 Dimethylformamide dimethyl acetal (21.89 g, 183.69 mmol) was added to a solution of 13-1 (58.5 g, 114.80 mmol) in dichloromethane (350 mL) and the mixture was allowed to react at 25 °C for 1 h. The mixture was cooled to 0 °C, and boron trifluoride diethyl ether complex (24.44 g, 172.21 mmol) was slowly added dropwise and allowed to react for an additional 15 min. Saturated sodium bicarbonate solution (350 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (300 mL * 2). After extraction, the combined organic layer was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness on a rotary evaporator, and the resulting residue was separated by column chromatography (eluent: 15-40% ethyl acetate / petroleum ether) to give 13-2. MS m / z: 520.3 [M+H] +

[0194] Step 3: Preparation of intermediate 13-3 To a solution of 13-2 (42.5 g, 81.80 mmol) in tetrahydrofuran (500 mL) was added dropwise lithium tri(sec-butyl)borohydride (1 M, 89.98 mL) at -60 °C and the mixture was allowed to react at the same temperature for 10 minutes. The reaction solution was poured into 1 N hydrochloric acid (1 L), and the mixture was extracted with ethyl acetate (1 L * 2). After extraction, the combined organic layer was washed with saturated brine (1.5 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness on a rotary evaporator, and the resulting residue was separated by column chromatography (eluent: 0-10% ethyl acetate / petroleum ether) to give 13-3. MS m / z: 522.3 [M+H] +

[0195] Step 4: Preparation of intermediate 13-4 To a solution of 13-3 (28.5 g, 54.64 mmol) and methylisothiourea sulfate (45.63 g, 163.93 mmol) in ethanol (400 mL), sodium carbonate (11.58 g, 109.28 mmol, 2 equivalents) was added and the mixture was heated and stirred at 50 °C for 18 hours. The reaction solution was concentrated under reduced pressure to remove most of the ethanol. Water (400 mL) and ethyl acetate (400 mL) were added, and the pH was adjusted to 4 with 1N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (400 mL). After extraction, the combined organic layer was washed with saturated brine (500 mL). A large amount of insoluble solid was present in the organic layer. This solid was filtered, and the filtrate was evaporated to dryness to give 13-4. 1 H NMR (400MHz, DMSO-d6) δ=7.20(d, J=8.4Hz, 4H), 6.88-6.80(m, 5H), 6.73(br d, J=6.4Hz, 1H), 4.90(dd, J=4.0, 10.0Hz, 1H), 4.68-4.41(m, MS m / z: 562.2 [M+H] +

[0196] Step 5: Preparation of Intermediate 13-5 To a solution of 13-4 (24.5 g, 43.62 mmol, 1 equiv.) in N,N-dimethylformamide (300 mL) was added diisopropylethylamine (16.91 g, 130.86 mmol), followed by N-phenyltrifluoromethanesulfonimide (18.70 g, 52.34 mmol). The mixture was stirred at 20 °C for 0.5 h, and the reaction solution was diluted with ethyl acetate (1.5 L). The mixture was then washed successively with water (800 mL * 2) and saturated brine (1 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness on a rotary evaporator, and the resulting residue was separated by column chromatography (eluent: 0-10% ethyl acetate / petroleum ether) to give 13-5. MS m / z: 694.1 [M+H] +

[0197] Step 6: Preparation of Intermediate 13-6 To a solution of 13-5 (21.5 g, 30.99 mmol) in N,N-dimethylformamide (150 mL) was added 1-1A (7.24 g, 34.09 mmol), and the mixture was heated at 90 °C for 1 h. The reaction solution was evaporated to dryness using a rotary evaporator, and the resulting residue was separated by column chromatography (eluent: 5-20% ethyl acetate / petroleum ether) to give 13-6. 1 H NMR(400MHz, CDCl3) δ 7.19(d, J=8.8Hz, 4H), 6.88-6.79(m, 5H), 6.63(d, J=8.0Hz, 1H), 5.12(dd, J=4.0, 10.8Hz, 1H), 4.88-4.70(m, 2H), 4.42-4.25(m, 2H), 4.20(s, 4H), 3.81(s, 6H), 3.48-3.42(m, 2H), 3.18-2.92(m, 4H), 2.53(s, 3H), 2.21(s, 3H), 2.03-1.89(m, 3H), 1.75-1.65(m, 1H), 1.52(s, 9H); MS m / z: 756.4 [M+H] +

[0198] Step 7: Preparation of Intermediate 13-7 13-6 (1 g, 1.32 mmol, 1 equiv.) was weighed, and DCM (30 mL) and m-CPBA (268.57 mg, 1.32 mmol, 85% content, 1 equiv.) were added and reacted at 25 °C for 1 h. Sodium bicarbonate was added to quench the reaction. The mixture was extracted with DCM, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give 13-7, which was used directly in the next step.

[0199] Step 8: Preparation of Intermediate 13-8 To a solution of 1-2A (404.09 mg, 2.54 mmol, 2 equiv.) in toluene (50 mL), sodium tert-butoxide (10 mg, 0.103 mmol) was added at 20 °C, followed by the addition of 13-7 (979.69 mg, 1.27 mmol, 1 equiv.). The mixture was reacted at 120 °C for 15 h, and the reaction solution was cooled to room temperature. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The resulting residue was separated by column chromatography (eluent: 0-5% methanol / dichloromethane) to give 13-8. MS m / z: 867.3 [M+H] +

[0200] Step 9: Preparation of Compound 13 Hydrochloride Trifluoroacetic acid (5 mL) was added to 13-8 (0.6 g, 692.02 μmol, 1 equivalent) and stirred at 55 °C for 5 hours. The reaction solution was evaporated to dryness using a rotary evaporator. The resulting residue was purified by preparative HPLC (column: Phenomenex C18 150*40 mm*5 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 1% to 30%, 10 min) to obtain the hydrochloride salt of compound 13. 1H NMR (400MHz, CD3OD) δ 7.57-7.50(m, 1H), 7.40-7.30(m, 1H), 5.74-5.55(m, 1H), 5.33-5.23(m, 1H), 5.21-5.11(m, 1H), 4.84-4.76(m, 2H), 4.34-4.22(m, 2H), 4.17-3.83(m, 5H), 3.71-3.61(m, 1H), 3.53-3.42(m, 1H), 3.36-3.22(m, 3H), 3.17-3.04(m, 1H), 2.85-2.47(m, 3H), 2.01-2.43(m, 10H); MS m / z: 527.2 [M+H] +

[0201] Example 14 [ka]

[0202] Step 1: Synthesis of intermediate 14-1 Compound 13-6 (200 mg, 264.57 μmol, 1 equiv.) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of N-chlorosuccinimide (45.93 mg, 343.94 μmol, 1.3 equiv.) and stirring at 25°C for 15 hours. This reaction solution was directly separated by high-performance liquid chromatography (column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [0.025% aqueous trifluoroacetic acid / acetonitrile]; acetonitrile %: 50%-80%, 8 min) to obtain the trifluoroacetate salt of compound 14-1. MS m / z = 790.4 [M+H] +

[0203] Step 2: Synthesis of intermediate 14-2 The trifluoroacetate salt of compound 14-1 (123 mg) was dissolved in anhydrous dichloromethane (2 mL), followed by the addition of m-chloroperbenzoic acid (31.59 mg) and stirring at 15°C for 15 hours. The reaction solution was evaporated to dryness using a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane = 0-3%) to obtain 14-2. MS m / z = 806.2 [M+H] +

[0204] Step 3: Synthesis of intermediate 14-3 Compound 1-2A (37.96 mg, 238.47 μmol, 3 equiv.), sodium tert-butoxide (15.28 mg, 158.98 μmol, 2 equiv.), and compound 14-2 (64.1 mg, 79.49 μmol, 1 equiv.) were added to toluene (2 mL) and stirred at 15 °C for 4 hours. The reaction solution was diluted with ethyl acetate (30 mL) and washed with water (5 mL) and saturated brine (5 mL). The organic layer was evaporated to dryness using a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 14-3. MS m / z = 901.3 [M+H] +

[0205] Step 4: Synthesis of compound 14 hydrochloride Compound 14-3 (67 mg, 74.32 μmol, 1 equivalent) was added to trifluoroacetic acid (2 mL) and stirred at 25°C for 4 hours. The reaction solution was evaporated to dryness using a rotary evaporator. Sodium carbonate (300 mg) and ethyl acetate (5 mL) were added to the resulting residue, stirred for 20 minutes, and filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Xtimate C18, 150*40 mm*5 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 1% to 30%, 10 min) to obtain compound 14 hydrochloride. MS m / z = 561.2 [M+H] +

[0206] Example 15 [ka]

[0207] Step 1: Preparation of Intermediate 15-1 13-6 (2.00 g, 2.64 mmol, 1 equiv.) was weighed, and DMF (50 mL) and NBS (940.54 mg, 5.28 mmol, 2 equiv.) were added. After the addition was complete, the mixture was reacted at 25 °C for 4 h. Sodium bicarbonate was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The resulting residue was separated by column chromatography (eluent: 5-20% ethyl acetate / petroleum ether) to give 15-1. MS m / z: 834.2 [M+H] +

[0208] Step 2: Preparation of intermediate 15-2 15-1 (1 g, 1.32 mmol, 1 equiv.) was weighed, DCM (30 mL) and m-CPBA (268.57 mg, 1.32 mmol, 85% content, 1 equiv.) were added, and the mixture was reacted at 25 °C for 1 h. Sodium bicarbonate was added to quench the reaction, and the mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give 15-2, which was used directly in the next step.

[0209] Step 3: Preparation of intermediate 15-3 To a solution of 1-2A (16 mg, 0.103 mmol) in tetrahydrofuran (15 mL), sodium tert-butoxide (10 mg, 0.103 mmol) was added at 20 °C and stirred at the same temperature for 0.5 h. 15-2 (73 mg, 86 μmol) was then added and stirred for an additional 0.5 h. The reaction solution was diluted with ethyl acetate (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness on a rotary evaporator, and the resulting residue was separated by column chromatography (eluent: 0-5% methanol / dichloromethane) to give 15-3. MS m / z: 946.8 [M+H] +

[0210] Step 4: Preparation of Compound 15 Hydrochloride Trifluoroacetic acid (1 mL) was added to 15-3 (40 mg, 1 equivalent) and stirred at 55°C for 2 hours. The reaction solution was evaporated to dryness using a rotary evaporator. The resulting residue was purified by preparative HPLC (column: Xtimate C18, 150*40 mm*5 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile) %: 1% to 30%, 10 min) to obtain the hydrochloride salt of compound 15. MS m / z: 605.0 [M+H] +

[0211] Example 16 [ka]

[0212] Step 1: Preparation of intermediate 16-1 13-6 (1 g, 1.32 mmol, 1 eq) was weighed, DMF (25 mL) and NIS (892.85 mg, 3.97 mmol, 3 eq) were added, and the mixture was allowed to react at 25 °C for 5 hours. The reaction was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with water and dried. The resulting residue was separated by column chromatography (eluent: 5-20% ethyl acetate / petroleum ether) to give 16-1. MS m / z: 882.2 [M+H] +

[0213] Step 2: Preparation of intermediate 16-2 16-1 (0.6 g, 680.40 μmol, 1 equiv.) was weighed, DCM (30 mL) and m-CPBA (138.14 mg, 680.40 μmol, 85% content, 1 equiv.) were added, and the mixture was allowed to react at 25 °C for 1 h. The reaction was quenched by adding sodium bicarbonate and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give 16-2, which was used directly in the next step.

[0214] Step 3: Preparation of intermediate 16-3 To a solution of 1-2A (132.99 mg, 835.34 μmol, 1.5 equiv.) in tetrahydrofuran (50 mL) was added sodium tert-butoxide (80.28 mg, 835.34 μmol, 1.5 equiv.) at 20 °C, followed by 16-2 (0.5 g, 556.90 μmol, 1 equiv.). After the addition was complete, the mixture was reacted at 25 °C for 15 h and then quenched by adding water. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator. The resulting residue was separated by column chromatography (eluent: 0-5% methanol / dichloromethane) to give 16-3. MS m / z: 993.2 [M+H] +

[0215] Step 4: Preparation of Compound 16 Hydrochloride Trifluoroacetic acid (5 mL) was added to 16-3 (0.3 g, 302.14 μmol, 1 equivalent) and stirred at 55°C for 5 hours. The reaction solution was evaporated to dryness using a rotary evaporator, and the resulting residue was purified by preparative HPLC (column: Xtimate C18, 150 x 40 mm x 5 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile) %: 1% to 30%, 10 min) to obtain the hydrochloride salt of compound 16. MS m / z: 653.3 [M+H] +

[0216] Example 17 [ka]

[0217] Step 1: Preparation of intermediate 17-1 16-1 (0.8 g, 907.20 μmol, 1 equiv.) was weighed, PdCl(PPh) (127.35 mg, 181.44 μmol, 0.2 equiv.), CuI (51.83 mg, 272.16 μmol, 0.3 equiv.), EtOH (20 mL), EtN (229.50 mg, 2.27 mmol, 315.68 μL, 2.5 equiv.), and trimethylsilylacetylene (330.91 mg, 1.81 mmol, 407.07 μL, 2 equiv.) were added, and the atmosphere was purged with nitrogen three times. The mixture was reacted at 80 °C for 5 h and then filtered through Celite. The filtrate was evaporated to dryness on a rotary evaporator, and the resulting residue was separated by column chromatography (eluent: 5-20% ethyl acetate / petroleum ether) to give 17-1. MS m / z: 936.4 [M+H] +

[0218] Step 2: Preparation of intermediate 17-2 17-1 (0.4 g, 427.21 μmol, 1 eq) was weighed, and DCM (10 mL) and m-CPBA (86.73 mg, 427.21 μmol, 85% content, 1 eq) were added. After the addition was complete, the mixture was reacted at 25 °C for 1 h, and sodium bicarbonate was added to quench the reaction. The mixture was extracted with DCM, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give 17-2, which was used directly in the next step. MS m / z: 952.4 [M+H] +

[0219] Step 3: Preparation of intermediate 17-3 To a solution of 1-2A (100.31 mg, 630.05 μmol, 1.5 equiv.) in tetrahydrofuran (5 mL), sodium tert-butoxide (60.55 mg, 630.05 μmol, 1.5 equiv.) was added at 20°C, followed by the addition of 17-2 (0.4 g, 420.04 μmol, 1 equiv.). After the addition was complete, the mixture was reacted at 25°C for 15 hours, and the reaction was quenched by adding water. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give 17-3. MS m / z: 1047.5 [M+H] +

[0220] Step 4: Preparation of intermediate 17-4 formate salt Trifluoroacetic acid (6 mL) was added to 17-3 (0.3 g, 302.14 μmol, 1 equiv.) and stirred at 25°C for 5 hours. The reaction solution was evaporated to dryness using a rotary evaporator, and the resulting residue was purified by preparative HPLC (column: Xtimate C18 150*40 mm*5 μm; mobile phase: [0.025% aqueous formic acid / acetonitrile]; (acetonitrile) %: 17%-57%, 8 min) to give the formate salt of compound 17-4. MS m / z: 707.4 [M+H] +

[0221] Step 5: Preparation of compound 17 The formate salt of 17-4 (30 mg) was weighed, THF (2 mL) and tetramethylammonium fluoride (11.86 mg, 127.30 μmol, 3 equivalents) were added, and the mixture was reacted at 60°C for 4 hours. The reaction solution was evaporated to dryness using a rotary evaporator. The resulting residue was purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (0.5% aqueous ammonia)-acetonitrile]; (acetonitrile)%: 43%-73%, 8 min) to give compound 17. MS m / z: 551.2 [M+H] +

[0222] Example 18 [ka] Step 1: Preparation of Intermediate 18-1 16-1 (0.4 g, 453.60 μmol, 1 equiv.) was weighed, and KFeCN (36.76 mg, 99.79 μmol, 0.22 equiv.), NaCO (48.08 mg, 453.60 μmol, 1 equiv.), Pd(OAc) (20.37 mg, 90.72 μmol, 0.2 equiv.), and DMAc (5 mL) were added. The system was purged with nitrogen three times. The mixture was reacted at 120 °C for 15 h and quenched by adding water. The mixture was extracted with ethyl acetate, and the organic layer was dried and evaporated to dryness on a rotary evaporator. The resulting residue was separated by column chromatography (eluent: 5-20% ethyl acetate / petroleum ether) to give 18-1. MS m / z: 781.2 [M+H] +

[0223] Step 2: Preparation of intermediate 18-2 18-1 (100 mg, 128.05 μmol, 1 equiv.) was weighed, and DCM (10 mL) and m-CPBA (26.00 mg, 128.05 μmol, 85% content, 1 equiv.) were added. After the addition was complete, the mixture was reacted at 25° C. for 1 h. Sodium bicarbonate was added to quench the reaction, and the mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give 18-2, which was used directly in the next step. MS m / z: 797.2 [M+H] +

[0224] Step 3: Preparation of intermediate 18-3 To a solution of 1-2A (27.97 mg, 175.67 μmol, 2 equiv.) in toluene (5 mL) was added sodium tert-butoxide (10.97 mg, 114.19 μmol, 1.3 equiv.) at 20°C, followed by 18-2 (70 mg, 87.84 μmol, 1 equiv.). After the addition was complete, the mixture was reacted at 120°C for 5 h and quenched by adding water. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give 18-3. MS m / z: 892.4 [M+H] +

[0225] Step 4: Preparation of compound 18 Trifluoroacetic acid (5 mL) was added to 18-3 (60 mg, 108.77 μmol, 1 equiv.) and stirred at 50°C for 2 hours. The reaction solution was evaporated to dryness using a rotary evaporator. The resulting residue was separated by acidic HPLC (column: Xtimate C18 150*40 mm*5 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 1% to 30%, 10 min) and basic HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [0.5% aqueous ammonia / acetonitrile]; (acetonitrile)%: 40% to 70%, 8 min), to give compound 18. MS m / z: 552.3 [M+H] +

[0226] Example 19 [ka]

[0227] Step 1: Preparation of intermediate 19-1 16-1 (0.1 g, 113.40 μmol, 1 equiv.) was weighed, and Pd(dppf)Cl2 (16.60 mg, 22.68 μmol, 0.2 equiv.), 1,4-dioxane (5 mL), HO (1 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (26.20 mg, 170.10 μmol, 28.85 μL, 1.5 equiv.), and K2CO3 (23.51 mg, 170.10 μmol, 1.5 equiv.) were added. The system was purged with nitrogen three times. The mixture was reacted at 95 °C for 15 h, and the reaction solution was evaporated to dryness on a rotary evaporator. The resulting residue was separated by column chromatography (eluent: 5-20% ethyl acetate / petroleum ether) to give 19-1. MS m / z: 782.3 [M+H] +

[0228] Step 2: Preparation of intermediate 19-2 19-1 (0.07 g, 89.52 μmol, 1 eq) was weighed, and DCM (10 mL) and m-CPBA (18.17 mg, 89.52 μmol, 85% content, 1 eq) were added. After the addition was complete, the mixture was reacted at 25 °C for 1 h, and sodium bicarbonate was added to quench the reaction. The mixture was extracted with DCM, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give 19-2, which was used directly in the next step. MS m / z: 798.3 [M+H] +

[0229] Step 3: Preparation of intermediate 19-3 To a solution of 1-2A (19.95 mg, 125.32 μmol, 2 equiv.) in toluene (5 mL), sodium tert-butoxide (9.03 mg, 93.99 μmol, 1.5 equiv.) was added at 20°C, followed by 19-2 (0.05 g, 62.66 μmol, 1 equiv.). After the addition was complete, the mixture was reacted at 120°C for 5 h, and water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness on a rotary evaporator to give 19-3. MS m / z: 893.3 [M+H] +

[0230] Step 4: Preparation of Compound 19 Hydrochloride Trifluoroacetic acid (3 mL) was added to 19-3 (50 mg, 55.99 μmol, 1 equivalent) and stirred at 55°C for 5 hours. The reaction solution was evaporated to dryness using a rotary evaporator, and the resulting residue was separated by acidic HPLC (chromatography column: Xtimate C18, 150*40 mm*5 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile) %: 1% to 30%, 10 min) to obtain the hydrochloride salt of compound 19. MS m / z: 553.3 [M+H] +

[0231] Example 20 [ka]

[0232] Step 1: Synthesis of intermediate 20-2 Compound 20-1 (85 g, 447.34 mmol, 1 equiv.), potassium carbonate (154.57 g, 1.12 mol, 2.5 equiv.), and potassium iodide (74.26 g, 447.34 mmol, 1 equiv.) were added to N-methylpyrrolidone (850 mL), and p-methoxybenzyl chloride (143.62 g, 917.04 mmol, 124.89 mL, 2.05 equiv.) was slowly added dropwise. The reaction slowly exothermed to 30 °C, and gas evolution was evident. The mixture was reacted for 1 h, poured into water (1 L), and then tert-butyl methyl ether (500 mL) was added. The mixture was stirred, the layers were separated, and the organic layer was collected. The aqueous layer was extracted with tert-butyl methyl ether (500 mL * 2). The combined organic layer was washed with saturated brine (1 L x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was added with petroleum ether (400 mL), slurried for 2 hours, and filtered. The filter cake was rinsed with petroleum ether (100 mL * 2), and the filtrate was evaporated to dryness on a rotary evaporator to give compound 20-2. MS m / z = 430.0 [M+H] +

[0233] Step 2: Synthesis of intermediate 20-3 2,2,6,6-Tetramethylpiperidine (39.39 g, 278.87 mmol, 47.34 mL, 3 equiv.) was added to anhydrous tetrahydrofuran (400 mL), the mixture was cooled to -10 °C, and the system was purged with nitrogen three times. n-Butyllithium (2.5 M, 111.55 mL, 3 equiv.) was added dropwise under nitrogen, and the mixture was reacted at -10 °C for 10 min and cooled to -60 °C. A solution of compound 20-2 (40 g, 92.96 mmol, 1 equiv.) in anhydrous tetrahydrofuran (100 mL) was added dropwise. The mixture was reacted for 0.5 h, and then N,N-dimethylformamide (67.94 g, 929.56 mmol, 71.52 mL, 10 equiv.) was added quickly. The mixture was reacted for 10 min, and saturated ammonium chloride (500 mL) was added. The mixture was extracted with ethyl acetate (200 mL*2), and the combined organic layers were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was slurried in a mixed solvent (100 mL, petroleum ether: tert-butyl methyl ether = 5:1) for 16 hours and filtered. The filter cake was washed with petroleum ether: tert-butyl methyl ether (5:1, 50 mL*2) and then rotary evaporated to dryness to give compound 20-3. 1 H NMR (400MHz, CDCl3) δ=10.35(s, 1H), 7.24-7.13(m, 5H), 6.90-6.77(m, 5H), 4.24(s, 4H), 3.79(s, 6H); MS m / z=458.0[M+H] +

[0234] Step 3: Synthesis of intermediate 20-4 Compound 20-3 (42 g, 91.64 mmol, 1 equiv.) was added to N,N-dimethylformamide (210 mL), and the system was purged with nitrogen three times. Copper iodide (3.49 g, 18.33 mmol, 0.2 equiv.) was added under nitrogen, and the mixture was heated to 80 °C. Methyl difluoro(fluorosulfonyl)acetate (52.82 g, 274.92 mmol, 34.98 mL, 3 equiv.) was added dropwise, heated to 100 °C, and reacted for 1 h. The reaction solution was filtered through Celite, and the filter cake was rinsed with tert-butyl methyl ether (300 mL * 4). The filtrate was washed successively with water (1 L) and saturated brine (1 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 20-4. 1 H NMR (400MHz, CDCl3) δ=10.44(s, 1H), 7.34(d, J=8.4Hz, 1H), 7.17(d, J=8.0Hz, 4H), 6.97 (t, J=8.4Hz, 1H), 6.86(d, J=8.4Hz, 4H), 4.39(s, 4H), 3.80(s, 6H); MS m / z=448.0[M+H] +

[0235] Step 4: Synthesis of intermediate 20-5 Sodium hydride (1.27 g, 31.85 mmol, 60% elution, 2.5 equiv.) was dissolved in tetrahydrofuran (60 mL), and the system was purged with nitrogen twice. The mixture was then cooled to 0 °C, and methyl acetoacetate (3.70 g, 31.85 mmol, 3.42 mL, 2.5 equiv.) was added and stirred for 10 min. n-Butyllithium (2.5 M, 12.74 mL, 2.5 equiv.) was then added, and the mixture was stirred for an additional 10 min and cooled to -15 °C. A solution of compound 20-4 (5.7 g, 12.74 mmol, 1 equiv.) in tetrahydrofuran (5 mL) was added, and the mixture was stirred for an additional 30 min. Saturated ammonium chloride (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give compound 20-5. MS m / z=586.2 [M+Na] +

[0236] Step 5: Synthesis of intermediate 20-6 Compound 20-5 (6 g, 10.39 mmol, 1 equiv.) was dissolved in dichloromethane (60 mL), and then N,N-dimethylformamide dimethyl acetal (2.48 g, 20.78 mmol, 2.76 mL, 2 equiv.) was added. The mixture was stirred at 25 °C for 12 h and then cooled to 0 °C. Boron trifluoride diethyl etherate (2.65 g, 18.70 mmol, 2.31 mL, 1.8 equiv.) was added, and the mixture was stirred at 25 °C for 1 h. The filtrate was slowly poured into saturated ammonium chloride solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL * 2). The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 20-6. MS m / z = 596.1 [M+Na] +

[0237] Step 6: Synthesis of intermediate 20-7 Compound 20-6 (4.2 g, 7.32 mmol, 1 equiv.) was dissolved in tetrahydrofuran (40 mL) and cooled to -65 °C. Lithium tri(sec-butyl)borohydride (1 M, 8.79 mL, 1.2 equiv.) was added. The mixture was stirred for 0.5 h, and water was added to quench the reaction. The reaction mixture was slowly poured into saturated ammonium chloride solution (10 mL), and the mixture was extracted with ethyl acetate (10 mL * 2). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 20-7. MS m / z = 576.2 [M+H] +

[0238] Step 7: Synthesis of intermediate 20-8 Compound 20-7 (2 g, 3.47 mmol, 1 equiv.) and S-methylisothiourea sulfate (4.84 g, 17.37 mmol, 5 equiv.) were dissolved in ethanol (40 mL) and water (5 mL). Sodium carbonate (1.29 g, 12.16 mmol, 3.5 equiv.) was then added and stirred at 50 °C for 16 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL * 2). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 20-8. MS m / z = 616.1 [M+H] +

[0239] Step 8: Synthesis of intermediate 20-9 Compound 20-8 (2.25 g, 3.65 mmol, 1 equiv.) and N,N-diisopropylethylamine (2.83 g, 21.93 mmol, 3.82 mL, 6 equiv.) were dissolved in dichloromethane (20 mL), and the mixture was cooled to 0 °C. Trifluoromethanesulfonic anhydride (4.64 g, 16.45 mmol, 2.71 mL, 4.5 equiv.) was then added and stirred at 0 °C for 0.5 h. The reaction solution was washed sequentially with saturated ammonium chloride (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified using a column (petroleum ether:ethyl acetate = 10:1) to give compound 20-9. MS m / z = 748.1 [M+H] +

[0240] Step 9: Synthesis of intermediate 20-10 Compound 20-9 (0.35 g, 468.10 μmol, 1 equiv.) and N,N-diisopropylethylamine (302.50 mg, 2.34 mmol, 407.68 μL, 5 equiv.) were dissolved in N,N-dimethylformamide (3 mL), and then 1-1A (248.43 mg, 1.17 mmol, 2.5 equiv.) was added and stirred at 50 °C for 0.5 h. Ethyl acetate (25 mL) was added to the reaction solution, and the mixture was washed sequentially with saturated ammonium chloride (25 mL) and saturated brine (25 mL * 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 20-10. 1 H NMR (400MHz, CDCl3) δ 7.24-7.27(m, 1H),7.14-7.17(m, 4H), 6.81-6.84(m, 5H), 5.13-5.16(m, 1H), 4.37-4.26(m, 6H), 3.89-3.79(m, MS m / z=810.3[M+H] +

[0241] Step 10: Synthesis of intermediate 20-11 Compound 20-10 (300 mg, 370.41 μmol, 1 equivalent) was dissolved in dichloromethane (3 mL), followed by the addition of m-chloroperbenzoic acid (97.76 mg, 481.54 μmol, 85% content, 1.3 equivalents) and stirring at 15 °C for 0.5 hours. The reaction solution was diluted with dichloromethane (20 mL), and the mixture was washed sequentially with 5% sodium thiosulfate (10 mL), saturated sodium bicarbonate (10 mL), and saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified using a column (petroleum ether: ethyl acetate = 5:1) to obtain compound 20-11. MS m / z = 826.3 [M+H] +

[0242] Step 11: Synthesis of intermediate 20-12 1-2A (77.10 mg, 484.31 μmol, 2.5 equiv.) was dissolved in tetrahydrofuran (3 mL), and the mixture was cooled to -15 °C. Sodium tert-butoxide (37.24 mg, 387.45 μmol, 2 equiv.) was then added, and the mixture was stirred at -15 °C for 0.5 h. Then, a solution of compound 20-11 (160 mg, 193.73 μmol, 1 equiv.) in tetrahydrofuran (1 mL) was added. The mixture was stirred for an additional 1 h, and the reaction solution was slowly poured into saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (15 mL * 2). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified using a column (dichloromethane:methanol = 50:1) to give compound 20-12. MS m / z = 921.4 [M+H] +

[0243] Step 12: Synthesis of Compound 20 Hydrochloride, Compound 20A, and Compound 20B Compound 20-12 (0.11 g, 119.43 μmol, 1 equiv.) was dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (1.36 g, 11.94 mmol, 884.31 μL, 100 equiv.) was added. The mixture was stirred at 15 °C for 5 h, and the reaction solution was slowly poured into water (10 mL). The layers were separated, and the aqueous layer was adjusted to pH 9 with saturated sodium bicarbonate and extracted with ethyl acetate (15 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was separated by preparative HPLC (column: Phenomenex Luna 80 * 30 mm * 3 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 5% to 25%, 8 min) to obtain the hydrochloride salt of compound 20. Next, the hydrochloride salt of compound 20 was subjected to chiral separation (column: DAICEL Chiralcel OD (250 mm * 30 mm, 10 μm); mobile phase: [ethanol containing 0.1% aqueous ammonia]; (ethanol) %: 40% to 40%, 12 min) to obtain compound 20A (Rt = 3.920) and compound 20B (Rt = 4.275). Compound 20A: 1H NMR(400MHz, CDCl3) δ 7.27-7.29(m, 2H), 6.75-6.79(m, 1H), 5.12-5.33(m, 2H), 4.75-4.79(m, 2H), 3.88-4.10(m, 5H), 2.96-3.58(m, 12H), 2.15-2.28(m, 3H), 1.87-1.96(m, 5H); MS m / z=581.2[M+H] + Compound 20B: 1 H NMR (400MHz, CDCl3) δ=7.30-7.27(m, 1H), 6.77 (t, J=8.4Hz, 1H), 5.34-5.17(m, 1H), 5.15-5.07(m, 1H), 4.80-4.71(m, 2H), 4.17-4.06(m, 3H), 3.97-3.86(m, 2H), 3.59(s, 2H), 3.49-3.08(m, 6H), 3.06-2.89(m, 3H), 2.31- 2.10(m, 3H), 2.06-1.65(m, 7H); MS m / z=581.2[M+H] +

[0244] Example 21

change

[0245] ステップ1: Synthesis of intermediate 21-2 Compound 21-1 (20 g, 137.40 mmol, 1 equiv.), N,N-dimethylformamide (200 mL), potassium iodide (22.81 g, 137.40 mmol, 1 equiv.), and anhydrous potassium carbonate (47.47 g, 343.50 mmol, 2.5 equiv.) were added to a pre-dried reaction flask, and p-methoxybenzyl chloride (44.11 g, 281.67 mmol, 38.36 mL, 2.05 equiv.) was added with stirring. The mixture was then heated to 65 °C and stirred for 4 hours. The reaction solution was cooled to room temperature and then filtered through Celite. The filter cake was rinsed with tert-butyl methyl ether (200 mL), and the filtrate was added to water (200 mL) for extraction. The aqueous layer was extracted with ethyl acetate (100 mL * 2), and the combined organic layers were washed with saturated brine (200 mL * 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was slurried with petroleum ether (50 mL) for 48 hours. The mixture was filtered, and the filter cake was collected and dried to give compound 21-2, which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ=7.18-7.17(m, 5H), 6.85-6.82(m, 6H), 4.24(s, 4H), 3.74-3.71(m, 6H); MS m / z=386.1[M+H] +

[0246] Step 2: Synthesis of intermediate 21-3 2,2,6,6-Tetramethylpiperidine (43.93 g, 311.00 mmol, 52.80 mL, 4 equiv) was dissolved in tetrahydrofuran (300 mL), and the mixture was then cooled to -5 °C. n-Butyllithium (2.5 M, 124.40 mL, 4 equiv) was added and stirred for 0.5 h. The mixture was then cooled to -60 °C, and a solution of compound 21-2 (30 g, 77.75 mmol, 1 equiv) in tetrahydrofuran (30 mL) was added and stirred for 0.5 h. N,N-Dimethylformamide (113.66 g, 1.55 mol, 119.64 mL, 20 equiv) was then added and stirred for an additional 0.5 h. Saturated ammonium chloride (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL). The layers were separated, and the organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give compound 21-3.

[0247] Step 3: Synthesis of intermediate 21-4 Sodium hydride (6.38 g, 159.47 mmol, 60% elution, 2.2 equiv.) was dissolved in tetrahydrofuran (300 mL), and the system was purged with nitrogen twice. The mixture was then cooled to 0 °C, and methyl acetoacetate (18.52 g, 159.47 mmol, 17.15 mL, 2.2 equiv.) was added and stirred for 10 min. n-Butyllithium (2.5 M, 63.79 mL, 2.2 equiv.) was then added, and the mixture was stirred for an additional 10 min and cooled to -15 °C. A solution of compound 21-3 (30 g, 72.49 mmol, 1 equiv.) in tetrahydrofuran (50 mL) was added, and the mixture was stirred for an additional 30 min. Saturated ammonium chloride (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give compound 21-4. MS m / z=530.2 [M+H] +

[0248] Step 4: Synthesis of intermediate 21-5 Compound 21-4 (20 g, 37.74 mmol, 1 equiv.) was dissolved in anhydrous dichloromethane (50 mL), and N,N-dimethylformamide dimethyl acetal (5.40 g, 45.28 mmol, 6.02 mL, 1.2 equiv.) was added under nitrogen and the mixture was reacted at 25 °C for 16 h. Boron trifluoride diethyl etherate (6.43 g, 45.28 mmol, 5.59 mL, 1.2 equiv.) was added, and the mixture was reacted at 20 °C for 1 h. The reaction solution was added to saturated sodium bicarbonate solution (50 mL), extracted with dichloromethane (20 mL * 2), and the layers were separated. The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to give compound 21-5. 1 H NMR (400MHz, CDCl3) δ=8.45(s, 1H), 7.14(m, 4H), 7.00-6.69(m, 6H), 5.80(m, 1H), 4.27-4.10(m, 5H), 3.79(m, 1H), 3.94-3.66(m, 8H), 2.98-2.73(m, 1H); MS m / z=540.2[M+H] +

[0249] Step 5: Synthesis of intermediate 21-6 Compound 21-5 (12 g, 22.22 mmol, 1 equiv.) was added to anhydrous tetrahydrofuran (30 mL), and lithium tri(sec-butyl)borohydride (11.83 g, 62.22 mmol, 13.60 mL, 2.8 equiv.) was added under nitrogen and reacted at -60 °C for 1 hour. Water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL * 2). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 3:1) to give compound 21-6. MS m / z = 542.2 [M+H] +

[0250] Step 6: Synthesis of intermediate 21-7 Compound 21-6 (5.5 g, 10.15 mmol, 1 equiv.) was added to ethanol (15 mL) and water (3 mL), and sodium bicarbonate (2.15 g, 20.30 mmol, 2 equiv.) and methylisothiourea sulfate (2.74 g, 30.44 mmol, 3 equiv.) were added. The mixture was reacted at 45-50 °C for 16 h. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL * 2). The combined organic layer was washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product, compound 21-7. The crude product was used directly in the next step. MS m / z = 582.2 [M+H] +

[0251] Step 7: Synthesis of intermediate 21-8 Compound 21-7 (6 g, 8.04 mmol, 1 equiv.) was added to anhydrous dichloromethane (20 mL), and N,N-diisopropylethylamine (3.12 g, 24.12 mmol, 4.20 mL, 3 equiv.) was added at 0 °C. The mixture was cooled to 0-10 °C, and trifluoromethanesulfonic anhydride (4.08 g, 14.47 mmol, 2.39 mL, 1.8 equiv.) was added dropwise slowly. The mixture was reacted at 0 °C for 0.5 h. The reaction solution was added to saturated ammonium chloride (20 mL), and the mixture was extracted with anhydrous dichloromethane (10 mL * 2). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to give compound 21-8. MS m / z=714.1[M+H] +

[0252] Step 8: Synthesis of intermediate 21-9 hydrochloride Compound 21-8 (0.8 g, 1.12 mmol, 1 equiv.), compound 1-1A (475.62 mg, 2.24 mmol, 2 equiv.), and DIPEA (434.33 mg, 3.36 mmol, 585.35 μL, 3 equiv.) were added to N,N-dimethylformamide (5 mL) and reacted at 50 °C for 1 hour. The reaction solution was added to saturated ammonium chloride (20 mL), and the mixture was extracted with ethyl acetate (20 mL * 2). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1), and then the product was separated by preparative HPLC (column: Phenomenex Luna C18, 250*50mm*10μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 65%~95%, 10 min) to obtain the hydrochloride salt of compound 21-9. MS m / z=776.3 [M+H] +

[0253] Step 9: Synthesis of intermediate 21-10 Compound 21-9 hydrochloride (1.2 g) was dissolved in N,N-dimethylformamide (5 mL), the mixture was cooled to 0 °C, and then N-bromosuccinimide (330.13 mg, 1.85 mmol, 1.2 equiv.) was added. The mixture was stirred at 20 °C for 1 hour, and water (30 mL) was added to it. The mixture was extracted with ethyl acetate (30 mL * 2). The combined organic layer was washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give compound 21-10. MS m / z = 856.1 [M+H] +

[0254] Step 10: Synthesis of intermediate 21-11 Dichloromethane (10 mL) was added to a dry reaction flask, followed by compound 21-10 (0.3 g, 350.8 μmol, 1 equiv) and stirring. Then, m-chloroperbenzoic acid (213.6 mg, 1052.3 μmol, 85% content, 3 equivalents) was added, and the reaction system was stirred at 25 °C for 1 hour. The reaction solution was diluted with dichloromethane (10 mL), and the mixture was washed twice with 5% sodium thiosulfate solution (5 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The obtained crude product was separated by preparative HPLC (column: Phenomenex Luna, 80*30 mm*3 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 50% to 80%, 8 min) to obtain compound 21-11. MS m / z=872.1 [M+H] +

[0255] Step 11: Synthesis of intermediate 21-12 hydrochloride Compound 1-2A (274.09 mg, 1.72 mmol, 5 equiv.) was added to anhydrous tetrahydrofuran (10 mL), and sodium tert-butoxide (148.91 mg, 1.55 mmol, 4.5 equiv.) was added and the mixture was allowed to react at -15 °C for 30 minutes. Compound 21-11 (0.3 g, 344.33 μmol, 1 equiv.) was added and the mixture was allowed to react at -15 °C for 1 hour. Saturated ammonium chloride solution (5 mL) was added to the reaction solution, and ethyl acetate (5 mL * 2) was added for extraction. The combined organic layer was washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18, 80*40mm*3μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 46%-66%, 7 min) to obtain compound 21-12 hydrochloride. MS m / z=967.3 [M+H] +

[0256] Step 12: Synthesis of Compound 21 Hydrochloride Compound 21-12 hydrochloride (90.00 mg) was added to a solution of trifluoroacetic acid (2.12 g, 18.63 mmol, 1.38 mL, 200 equivalents) in anhydrous dichloromethane (7 mL) and reacted at -10 to 0°C for 1 hour. The product was poured into water (10 mL), and the mixture was extracted with ethyl acetate (5 mL * 2). The combined organic layer was washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was separated by preparative HPLC (column: Phenomenex Luna, 80 * 30 mm * 3 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile) %: 15% to 35%, 8 min) to obtain the hydrochloride salt of compound 21. MS m / z = 627.1 [M+H] +

[0257] Example 22 [ka]

[0258] Step 1: Synthesis of intermediate 22-2 Compound 22-1 (50 g, 387.28 mmol, 1 equiv.), potassium iodide (64.29 g, 387.28 mmol, 1 equiv.), and anhydrous potassium carbonate (133.81 g, 968.19 mmol, 2.5 equiv.) were added to N,N-dimethylformamide (500 mL). p-Methoxybenzyl chloride (121.30 g, 774.55 mmol, 105.48 mL, 2 equiv.) was added dropwise with stirring and the mixture was reacted at 60 °C for 5 h. Water (300 mL) was added, and the mixture was extracted with ethyl acetate (200 mL * 2). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain compound 22-2. MS m / z=370.0[M+H] +

[0259] Step 2: Synthesis of intermediate 22-3 2,2,6,6-Tetramethylpiperidine (81.22 g, 574.98 mmol, 97.62 mL, 4 equiv.) was added to anhydrous tetrahydrofuran (500 mL) and cooled to -5 °C. n-Butyllithium (2.5 M, 229.99 mL, 4 equiv.) was added dropwise and reacted at -5 to 0 °C for 15 min. The mixture was then cooled to -60 °C. A solution of compound 22-2 (59 g, 143.75 mmol, 1 equiv.) in tetrahydrofuran (50 mL) was added, and the mixture was reacted at -60 °C for 0.5 h. N,N-Dimethylformamide (210.13 g, 2.87 mol, 221.19 mL, 20 equiv.) was quickly added, and the mixture was reacted at -60 °C for 10 min. The reaction solution was poured into saturated ammonium chloride (300 mL), and the mixture was extracted with tert-butyl methyl ether (100 mL * 2). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give compound 22-3. MS m / z=398.1 [M+H] +

[0260] Step 3: Synthesis of intermediate 22-4 NaH (5.31 g, 132.86 mmol, 60% content, 2.2 equiv.) and anhydrous tetrahydrofuran (150 mL) were reacted under nitrogen at 0 °C for 0.5 h. Methyl acetoacetate (15.43 g, 132.86 mmol, 14.28 mL, 2.2 equiv.) was added dropwise and the reaction was continued at 0 °C for 0.5 h. n-BuLi (2.5 M, 53.14 mL, 2.2 equiv.) was added dropwise and the reaction was continued at 0 °C for 0.5 h. The mixture was then cooled to -50 °C. A solution of compound 22-3 (24 g, 60.39 mmol, 1 equiv.) in anhydrous tetrahydrofuran (50 mL) was added dropwise and the mixture was reacted at -50 °C for 0.5 h. Saturated ammonium chloride solution (80 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL * 2). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 3:1) to give compound 22-4. 1H NMR (400MHz, CDCl3) δ=7.18-7.16(m, 4H), 6.84-6.82(m, 4H), 6.76(m, 1H), 6.48(m 1H), 5.52-5.44(m, 1H), 4.21(s, 4H), 3.88-3.67(m, 9H), 3.53(s, 2H), 3.30(d, J=4Hz, 1H), 3.01-2.88(m, 2H); MS m / z=514.2[M+H] +

[0261] Step 4: Synthesis of intermediate 22-5 Compound 22-4 (12 g, 23.37 mmol, 1 equiv.) was dissolved in anhydrous dichloromethane (50 mL). N,N-dimethylformamide dimethyl acetal (4.18 g, 35.05 mmol, 4.66 mL, 1.5 equiv.) was added under nitrogen and the mixture was reacted at 25 °C for 16 h. Boron trifluoride diethyl etherate (6.63 g, 46.74 mmol, 5.77 mL, 2 equiv.) was added and the mixture was reacted at 20 °C for 1 h. The reaction solution was added to saturated sodium bicarbonate solution (20 mL) and the layers were separated. The aqueous layer was further extracted with dichloromethane (20 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0-3:1) to give compound 22-5. MS m / z = 524.2 [M+H] +

[0262] Step 5: Synthesis of intermediate 22-6 Compound 22-5 (10.5 g, 20.06 mmol, 1 equiv.) was added to anhydrous tetrahydrofuran (30 mL), and lithium tri(sec-butyl)borohydride (1 M, 22.06 mL, 1.1 equiv.) was added under nitrogen and reacted at -60 °C for 1 h. Dilute hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL * 2). The layers were separated, and the combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 3:1) to give compound 22-6. MS m / z = 526.2 [M+H]+

[0263] Step 6: Synthesis of intermediate 22-7 Compound 22-6 (4 g, 7.61 mmol, 1 equiv.) was added to ethanol (16 mL) and water (4 mL), and sodium bicarbonate (1.61 g, 15.22 mmol, 2 equiv.) and methylisothiourea sulfate (2.06 g, 22.83 mmol, 3 equiv.) were added. The mixture was reacted at 45-50 °C for 16 h. The reaction mixture was added to water (10 mL) and extracted with ethyl acetate (10 mL * 2). The combined organic layer was washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product, compound 22-7. The crude product was used directly in the next step. MS m / z = 566.2 [M+H] +

[0264] Step 7: Synthesis of intermediate 22-8 Compound 22-7 (4.8 g, 4.67 mmol, 1 equiv.) was added to anhydrous dichloromethane (20 mL), and trifluoromethanesulfonic anhydride (1.98 g, 7.00 mmol, 1.16 mL, 1.5 equiv.) was added. The mixture was cooled to 0-10 °C. N,N-Diisopropylethylamine (1.81 g, 14.00 mmol, 2.44 mL, 3 equiv.) was slowly added dropwise and reacted at 0 °C for 0.5 h. The reaction solution was added to saturated ammonium chloride (20 mL), and the layers were separated. The organic layer was washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to give compound 22-8. 1 H NMR (400MHz, CDCl3) δ=7.17-7.15(m, 4H), 6.86-6.83(m, 4H), 6.75-6.72(m, 1H), 6.54-6.50(m, 1H), 5.09-5.00(m, 2H), 4.83-4.79(m, 1H), 4.23-4.20(m, 5H), 3.82-3.80(m, 7H), 2.56(s, 3H); MS m / z=698.1[M+H] +

[0265] Step 8: Synthesis of intermediate 22-9 Compound 22-8 (3.7 g, 5.30 mmol, 1 equiv.), compound 1-1A (2.25 g, 10.61 mmol, 2 equiv.), and N,N-diisopropylethylamine (2.06 g, 15.91 mmol, 2.77 mL, 3 equiv.) were added to N,N-dimethylformamide (20 mL) and reacted at 50 °C for 1 hour. The reaction solution was added to saturated ammonium chloride (20 mL), and the mixture was extracted with ethyl acetate (20 mL * 2). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 22-9. 1 H NMR (400MHz, CDCl3) δ=7.17-7.15(m, 4H), 6.85-6.83(m, 4H), 6.72-6.70(m, 1H), 6.50-6.46(m, 1H), 5.11-5.07(m, 1H), 4.83-4.71(m, 2H), 4.32-4.23(m, 6H), 3.80(s, 6H), 3.43-2.84(m, 5H), 2.51(s, 3H), 2.01-1.93(m, 3H), 1.69-1.66(m, 2H), 1.50(s, 9H); MS m / z=760.3[M+H] +

[0266] Step 9: Synthesis of intermediate 22-10 Compound 22-9 (0.6 g, 789.58 μmol, 1 equiv.) was dissolved in N,N-dimethylformamide (10 mL), N-bromosuccinimide (98.37 mg, 552.70 μmol, 0.7 equiv.) was added, and the mixture was reacted at 0-10°C for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 2). The combined organic layer was washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated by preparative thin layer chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 22-10. MS m / z = 838.2 [M+H] +

[0267] Step 10: Synthesis of intermediate 22-11 Compound 22-10 (0.3 g, 357.65 μmol, 1 equiv.), methyl difluoro(fluorosulfonyl)acetate (343.55 mg, 1.79 mmol, 227.52 μL, 5 equiv.), and copper iodide (136.23 mg, 715.31 μmol, 2 equiv.) were dissolved in N,N-dimethylformamide (10 mL). The system was purged with nitrogen three times and reacted at 100°C under nitrogen for 2 hours. The reaction solution was poured into water (10 mL), and the mixture was extracted with tert-butyl methyl ether (10 mL * 2). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250*70mm, 15μm); mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 50%-98%, 20 min), and the separated solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 22-11. MS m / z=828.3 [M+H] +

[0268] Step 11: Synthesis of intermediate 22-12 Dichloromethane (10 mL) was added to a dried reaction flask, followed by compound 22-11 (130 mg, 157.02 μmol, 1 equiv.) and stirring. m-Chloroperbenzoic acid (22.32 mg, 109.92 μmol, 85% content, 0.7 equiv.) was then added, and the reaction mixture was stirred at 25 °C for 1 h. The reaction solution was diluted with dichloromethane (10 mL), and the mixture was washed twice with 5% sodium thiosulfate solution (5 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The resulting crude product was separated by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound 22-12. 1H NMR (400MHz, CDCl3) δ=7.17-7.10(m, 4H), 6.87-6.83(m, 4H), 6.58-6.53(m, 1H), 5.21-5.10(m, 1H), 4.87-4.75(m, 2H), MS m / z=844.3[M+H] +

[0269] Step 12: Synthesis of intermediate 22-13 Compound 1-2A (226.38 mg, 1.42 mmol, 20 equiv.) was added to anhydrous tetrahydrofuran (10 mL), and sodium tert-butoxide (109.32 mg, 1.14 mmol, 16 equiv.) was added. The mixture was allowed to react at -15 °C for 15 minutes. Compound 22-12 (60 mg, 71.10 μmol, 1 equiv.) was added, and the mixture was allowed to react at -15 °C for 1 hour. Saturated ammonium chloride (5 mL) was added to the reaction solution, and the reaction solution was combined. The mixture was extracted with ethyl acetate (10 mL * 3). The combined organic layer was washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give compound 22-13. MS m / z = 939.5 [M+H] +

[0270] Step 13: Synthesis of Compound 22 Hydrochloride Compound 22-13 (60.00 mg, 63.90 μmol, 1 equiv.) was added to a solution of trifluoroacetic acid (1.46 g, 12.78 mmol, 946.19 μL, 200 equiv.) in anhydrous dichloromethane (5 mL) and reacted at -10 to 0°C for 1 hour. The product was poured into water (10 mL), and the aqueous layer was extracted with ethyl acetate (5 mL * 2). The combined organic layer was washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18, 80 * 40 mm * 3 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 1% to 30%, 7 min) to obtain the hydrochloride salt of compound 22. 1 H NMR (400MHz, CD3OD) δ=6.65-6.60(m, 1H), 6.74-6.53(m, 1H), 5.66-5.53(m, 1H), 5.22-5.19(m, 1H), 4.99-4.96(m, 3H), 4.25-4.18(m, 2H), 4.04-3.87(m, 5H), 3.55-3.38(m, 3H), 3.08-2.73(m, 1H), 2.67-1.87(m, 11H); MS m / z=599.2[M+H] +

[0271] Example 23 [ka]

[0272] Step 1: Synthesis of intermediate 23-2 Compound 23-1 (1.2 g, 4.78 mmol, 1 equivalent) and bis-(4-methoxybenzyl)amine (2.46 g, 9.56 mmol, 2 equivalents) were added to N-methylpyrrolidone (30 mL) and reacted at 200 °C for 1 hour using a microwave. The reaction solution was diluted with ethyl acetate (250 mL), and the mixture was then washed with water (20 mL × 3) and saturated brine (20 mL). The organic layer was dried and filtered to remove the drying agent. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was purified using a column (ethyl acetate / petroleum ether = 0-35%) to obtain compound 23-2. MS m / z = 428.6 [M+H] +

[0273] Step 2: Synthesis of intermediate 23-3 Compound 23-2 (4 g, 9.36 mmol, 1 equiv.) was dissolved in anhydrous tetrahydrofuran (20 mL) and cooled to -78 °C under nitrogen. Then, n-butyllithium (2.5 M, 6.74 mL, 1.1 equiv.) was added dropwise, and the reaction was stirred for 1 h after the addition was complete. N,N-dimethylformamide (2.05 g, 28.08 mmol, 3 equiv.) was then added dropwise, and the reaction was stirred for 0.5 h after the addition was complete. The reaction was quenched with saturated ammonium chloride (10 mL) and water (20 mL), and the mixture was then extracted with ethyl acetate (50 mL × 2). The combined organic layers were evaporated to dryness on a rotary evaporator to obtain the crude product. This crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-15%) to obtain compound 23-3. 1 H-NMR (400MHz, CDCl3) δ: 9.93(s, 1H), 7.23(s, 1H), 7.15(d, J=8.8Hz, 4H), 6.86(d, J=8.8Hz, 4H), 6.49(s, 1H), 4.77(s, 4H), 3.81(s, 6H), 2.26(s, 3H)

[0274] Step 3: Synthesis of intermediate 23-4 Compound 23-3 (2.09 g, 2.66 mmol, 1 equiv.) was dissolved in DMF (20 mL), followed by the addition of NBS (988.15 mg, 5.55 mmol, 1 equiv.) and stirring under nitrogen at room temperature (20 °C) for 2 h. The reaction solution was diluted with ethyl acetate (60 mL), and the mixture was then washed with water (20 mL × 3) and saturated brine (20 mL). The organic layer was evaporated to dryness on a rotary evaporator to obtain the crude product. This crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-25%) to obtain compound 23-4.

[0275] Step 4: Synthesis of intermediate 23-5 Compound 23-4 (1.98 g, 4.34 mmol, 1 equiv.) and methyl difluoro(fluorosulfonyl)acetate (4.17 g, 2.17 mmol, 5 equiv.) were added to DMF (20 mL), followed by CuI (205 mg, 1.08 mol, 1 equiv.). The solution was purged with nitrogen and stirred in an oil bath (100 °C) for 8 h. The reaction solution was evaporated to dryness on a rotary evaporator to obtain the crude product. This crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-25%) to obtain compound 23-5. MS m / z = 445.1 [M+H]. +

[0276] Step 5: Synthesis of intermediate 23-6 Sodium hydride (899.91 mg, 22.50 mmol, 60% content, 2 equiv.) was suspended in anhydrous tetrahydrofuran (50 mL) and cooled to 0 °C under nitrogen. Methyl acetoacetate (2.61 g, 22.50 mmol, 2.42 mL, 2.0 equiv.) was then slowly added dropwise, and the mixture was stirred for 30 min after the addition was complete. n-Butyllithium (2.5 M, 9.0 mL, 2 equiv.) was then added dropwise, and the mixture was stirred for 30 min after the addition was complete. The ice bath was removed, and the mixture was cooled to -78 °C. Finally, a solution of compound 23-5 (5 g, 11.25 mmol, 1 equiv.) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred for 1 h after the addition was complete. Water (20 mL) was added to the reaction solution to quench the reaction, and the mixture was then extracted with ethyl acetate (50 mL × 3). The combined organic layer was evaporated to dryness on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-45%) to obtain compound 23-6. MS m / z = 561.2 [M+H] +

[0277] Step 6: Synthesis of intermediate 23-7 Compound 23-6 (2.9 g, 5.17 mmol, 1 equiv.) and N,N-dimethylformamide dimethyl acetal (1.85 g, 15.52 mmol, 2.06 mL, 3 equiv.) were added to anhydrous dichloromethane (20 mL), and the mixture was stirred at room temperature (20 °C) for 24 h. After cooling to 0 °C, boron trifluoride diethyl etherate (734.25 mg, 5.17 mmol, 636.26 μL, 1 equiv.) was added to the mixture. After the addition was complete, the mixture was stirred at 20 °C for 1 h. The reaction solution was evaporated to dryness on a rotary evaporator to obtain the crude product. This crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain compound 23-7. MS m / z = 593.1 [M+Na] +

[0278] Step 7: Synthesis of intermediate 23-8 Compound 23-7 (635 mg, 1.11 mmol, 1 equiv.) was dissolved in anhydrous tetrahydrofuran (5 mL) and cooled to -78 °C under nitrogen. Then, lithium tri(sec-butyl)borohydride (1 M, 1.11 mL, 1 equiv.) was added dropwise. After the addition was complete, the reaction was stirred for 1 hour. The reaction was quenched with 1 M hydrochloric acid (1 mL), followed by the addition of saturated brine (20 mL) and ethyl acetate (50 mL) and stirring for 5 minutes. The organic layer was separated and evaporated to dryness on a rotary evaporator to obtain the crude product. The crude product was purified using a column (ethyl acetate / petroleum ether = 0-25%) to obtain compound 23-8. MS m / z = 573.2 [M+H] +

[0279] Step 8: Synthesis of intermediate 23-9 Compound 23-8 (630 mg, 1.1 mmol, 1 equiv.) and 2-methylthiourea monosulfate (621.31 mg, 3.30 mmol, 3 equiv.) were added to absolute ethanol (10 mL), followed by the addition of sodium carbonate (233.24 mg, 2.2 mmol, 2 equiv.). The solution was placed in an oil bath (60 °C) and stirred for 18 h. The reaction solution was evaporated to dryness using a rotary evaporator, and water (5 mL) and ethyl acetate (50 mL) were added to the resulting residue. The mixture was adjusted to pH 6-7 with 2 M hydrochloric acid, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The solvent was removed from the filtrate under reduced pressure to give compound 23-9. MS m / z = 613.2 [M+H] +

[0280] Step 9: Synthesis of intermediate 23-10 Compound 23-9 (541 mg, 883.63 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (4 mL), followed by the addition of PhNTf2 (473.19 mg, 1.32 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (342.38 mg, 2.65 mmol, 461.43 μL, 3 equiv.) and stirring at room temperature (20 °C) for 1.5 h. The reaction solution was diluted with ethyl acetate (100 mL), and the mixture was washed with water (10 mL × 3) and saturated brine (10 mL). The organic layer was evaporated to dryness on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain compound 23-10. MS m / z = 745.3 [M+H] +

[0281] Step 10: Synthesis of intermediate 23-11 Compound 23-10 (240 mg, 322.27 μmol, 1 equiv.) and compound 1-1A (82.1 mg, 386.72 μmol, 1.3 equiv.) were added to N,N-dimethylformamide (3 mL), followed by N,N-diisopropylethylamine (124.95 mg, 966.80 μmol, 168.40 μL, 3 equiv.). The solution was placed in an oil bath (100 °C) and stirred for 1 hour. The reaction solution was evaporated to dryness on a rotary evaporator to obtain the crude product. This crude product was purified using a column (ethyl acetate / petroleum ether = 0-35%) to obtain compound 23-11. MS m / z = 807.4 [M+H] +

[0282] Step 11: Synthesis of intermediate 23-12 Compound 23-11 (210 mg, 260.27 μmol, 1 equivalent) was dissolved in anhydrous dichloromethane (2 mL), and m-chloroperbenzoic acid (105.67 mg, 520.49 μmol, 85% content, 2 equivalents) was added and stirred at 20°C for 2 hours. The reaction solution was evaporated to dryness using a rotary evaporator to obtain the crude product. This crude product was purified using a column (ethyl acetate / petroleum ether = 0-45%) to obtain compound 23-12. MS m / z = 839.3 [M+H] +

[0283] Step 12: Synthesis of intermediate 23-13 Compound 1-2A (121.83 mg, 765.26 μmol, 3 equiv.) and sodium tert-butoxide (49.03 mg, 510.17 μmol, 2 equiv.) were added to tetrahydrofuran (2 mL) and stirred for 1 hour. A solution of compound 23-12 (214 mg, 255.09 μmol, 1 equiv.) in tetrahydrofuran (1 mL) was then added and stirred at 20°C for 1 hour. The reaction solution was evaporated to dryness using a rotary evaporator, and ethyl acetate (30 mL) and saturated brine (5 mL) were added to the resulting residue. The mixture was stirred until clear. The organic layer was separated and evaporated to dryness using a rotary evaporator to obtain the crude product. This crude product was purified using a column (methanol / dichloromethane = 0-10%) to obtain compound 23-13. MS m / z = 918.2 [M+H] +

[0284] Step 13: Synthesis of Compound 23 Formate Compound 23-13 (194 mg, 221.32 μmol, 1 equivalent) was added to trifluoroacetic acid (2 mL) and stirred at 55°C for 15 hours. The reaction solution was evaporated to dryness using a rotary evaporator, and sodium carbonate (300 mg) and ethyl acetate (5 mL) were added to the resulting residue. The mixture was stirred for 20 minutes and filtered. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. This crude product was separated by preparative high-performance liquid chromatography (separation conditions: column: Phenomenex C18, 150*40 mm*5 μm; mobile phase: [0.025% aqueous formic acid / acetonitrile]; (acetonitrile) %: 1% to 30%, 10 min) to obtain the formate salt of compound 23. MS m / z = 578.4 [M+H] +

[0285] Example 24 [ka]

[0286] Step 1: Synthesis of intermediate 24-1 Sodium hydride (866.75 mg, 21.67 mmol, 60% content, 2 equiv.) was suspended in anhydrous tetrahydrofuran (50 mL) and cooled to 0 °C under nitrogen. Compound 24-1A (3.38 g, 21.67 mmol, 2 equiv.) was then slowly added dropwise, and the mixture was stirred for 30 minutes after the addition was complete. n-Butyllithium (2.5 M, 8.67 mL, 2 equiv.) was then added dropwise, and the mixture was stirred for 30 minutes after the addition was complete. The ice bath was removed, and the mixture was cooled to -78 °C. Finally, a solution of compound A1-5 (5 g, 10.84 mmol, 1 equiv.) in anhydrous tetrahydrofuran (10 mL) was added dropwise to the mixture, and the mixture was stirred for 1 hour after the addition was complete. Water (30 mL) was added to the reaction solution to quench the reaction, and the mixture was then extracted with ethyl acetate (50 mL × 3). The combined organic layer was evaporated to dryness on a rotary evaporator to obtain the crude product. This crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-45%) to obtain compound 24-1. MS m / z = 640.1 [M+Na] +

[0287] Step 2: Synthesis of intermediate 24-2 Compound 24-1 (6.50 g, 10.52 mmol, 1 equiv.) and N,N-dimethylformamide dimethyl acetal (3.76 g, 31.57 mmol, 4.19 mL, 3 equiv.) were added to anhydrous dichloromethane (20 mL) and stirred at room temperature (20 °C) for 24 h. The mixture was then cooled to 0 °C. Finally, boron trifluoride diethyl etherate (1.49 g, 10.52 mmol, 1.30 mL, 1 equiv.) was added to the mixture. After the addition was complete, the mixture was stirred at 20 °C for 4 h. The reaction was quenched by adding saturated sodium bicarbonate solution (20 mL), and the mixture was then extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-45%) to give compound 24-2. MS m / z=628.2 [M+H] +

[0288] Step 3: Synthesis of intermediate 24-3 Compound 24-2 (5.0 g, 7.97 mmol, 1 equiv.) was dissolved in anhydrous tetrahydrofuran (30 mL) and cooled to -78 °C under nitrogen. Then, lithium tri(sec-butyl)borohydride (1 M, 7.97 mL, 1 equiv.) was added dropwise. After the addition was complete, the reaction was stirred for 1 hour. The reaction was quenched with 1 M hydrochloric acid (10 mL), and the mixture was then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were concentrated to give the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-25%) to give compound 24-3. MS m / z = 630.2 [M+H] +

[0289] Step 4: Synthesis of intermediate 24-4 Compound 24-3 (2.93 g, 4.65 mmol, 1 equiv.) and 2-methylthiourea monosulfate (2.63 g, 13.96 mmol, 3 equiv.) were added to absolute ethanol (10 mL), followed by the addition of sodium carbonate (986.43 mg, 9.31 mmol, 2 equiv.). The solution was placed in an oil bath (60 °C) and stirred for 18 h. The reaction solution was evaporated to dryness using a rotary evaporator, and water (15 mL) and ethyl acetate (80 mL) were added to the resulting residue. The mixture was adjusted to pH 6–7 with 2 M hydrochloric acid, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered to remove the drying agent. The filtrate was concentrated to give the crude product, compound 24-4. MS m / z = 670.2 [M+H] +

[0290] Step 5: Synthesis of intermediate 24-5 Compound 24-4 (3.15 g, 4.70 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (30 mL), and then compound PhNTf2 (2.52 g, 7.06 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (1.82 g, 14.11 mmol, 2.46 mL, 3 equiv.) were added. The solution was stirred at room temperature (20 °C) for 2 h. The reaction solution was evaporated to dryness on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-15%) to obtain compound 24-5. MS m / z = 802.2 [M+H] +

[0291] Step 6: Synthesis of intermediate 24-6 Compound 24-5 (3.15 g, 4.70 mmol, 1 equiv.) was dissolved in N,N-dimethylformamide (30 mL), and then compound 1-1A (2.52 g, 7.06 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (1.82 g, 14.11 mmol, 2.46 mL, 3 equiv.) were added. The solution was stirred at room temperature (20 °C) for 2 h. The reaction solution was evaporated to dryness on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-15%) to obtain compound 24-6. MS m / z = 864.3 [M+H] +

[0292] Step 7: Synthesis of intermediate 24-7 Compound 24-6 (160 mg, 185.19 μmol, 1 equivalent) was dissolved in anhydrous dichloromethane (2 mL), and m-chloroperbenzoic acid (75.19 mg, 370.37 μmol, 85% content, 2 equivalents) was added and stirred at 20 °C for 15 hours. The reaction solution was evaporated to dryness using a rotary evaporator to obtain the crude product. This crude product was purified using a column (ethyl acetate / petroleum ether = 0-25%) to obtain compound 24-7. MS m / z = 896.3 [M+H] +

[0293] Step 8: Synthesis of intermediate 24-8 Compound 1-2A (35.89 mg, 225.45 μmol, 2 equivalents) and sodium tert-butoxide (21.67 mg, 225.45 μmol, 2 equivalents) were added to tetrahydrofuran (1 mL) and stirred for 1 hour. A solution of compound 24-7 (101 mg, 112.72 μmol, 1 equivalent) in tetrahydrofuran (1 mL) was then added and stirred at 25°C for 1 hour. The reaction solution was concentrated to obtain the crude product. This crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-65%) to obtain compound 24-8. MS m / z = 975.4 [M+H] +

[0294] Step 9: Synthesis of Compound 24A Hydrochloride and Compound 24B Compound 24-8 (94 mg, 96.40 μmol, 1 equivalent) was added to trifluoroacetic acid (2 mL) and stirred at 25 °C for 1 hour. The mixture was concentrated to give the crude product. The crude product was separated by preparative high-performance liquid chromatography (separation conditions: Phenomenex C18, 150 mm x 40 mm x 5 μm; mobile phase [0.025% aqueous formic acid / acetonitrile]; (acetonitrile)%: 5% to 35%, 10 min), followed by chiral separation (column: DAICEL Chiralpak IG (250 mm x 30 mm, 10 μm); mobile phase: [0.1% aqueous ammonia in ethanol]; (ethanol)%: 45% to 45%, retention time Rt = 2.034 min) to give compound 24B. MS m / z = 635.9 [M+H] + Another isomer (retention time Rt = 2.469 min) was further separated by preparative high-performance liquid chromatography (column: Welch Xtimate C18, 100 x 40 mm x 3 μm; mobile phase: [0.025% aqueous formic acid / acetonitrile]; (acetonitrile) %: 10% to 40%, 8 min). HCl / 1,4-dioxane (0.5 mL) was added to give the hydrochloride salt of compound 24A. MS m / z = 635.8 [M+H] +

[0295] Example 25 [ka]

[0296] Step 1: Synthesis of intermediate 25-1 Compound 16-1 (00 mg, 113.40 μmol, 1 equiv.), compound 25-1A (42.71 mg, 170.10 μmol, 47.56 μL, 50% THF solution, 1.5 equiv.), and potassium carbonate (31.35 mg, 226.80 μmol, 2 equiv.) were added to a dioxane (2 mL) / water (0.4 mL) mixture, followed by the addition of Pd(dppf)Cl2 (16.60 mg, 22.68 μmol, 0.2 equiv.). The solution was purged with nitrogen, heated to 95 °C, and stirred for 15 h. The reaction solution was concentrated to give the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-30%) to give compound 25-1.

[0297] Step 2: Synthesis of intermediate 25-2 Compound 25-1 (72 mg, 93.51 μmol, 1 equivalent) was dissolved in anhydrous dichloromethane (1 mL), and m-chloroperbenzoic acid (18.98 mg, 93.51 μmol, 85% content, 1 equivalent) was added. The mixture was stirred at 15°C for 1 hour. The reaction solution was concentrated to give compound 25-2. MS m / z = 786.3 [M+H] +

[0298] Step 3: Synthesis of intermediate 25-3 Compound 1-2A (45.57 mg, 286.27 μmol, 3 equiv.), sodium tert-butoxide (18.34 mg, 190.85 μmol, 2 equiv.), and compound 25-2 (75 mg, 95.42 μmol, 1 equiv.) were added to toluene (2 mL) and stirred at 15°C for 2 hours. The reaction solution was diluted with ethyl acetate (30 mL), and then the mixture was washed with water (5 mL) and saturated brine (5 mL). The organic layer was concentrated to obtain the crude product. This crude product was purified by column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 25-3. MS m / z = 881.9 [M+H] +

[0299] Step 4: Synthesis of intermediate 25 hydrochloride Compound 25-3 (71 mg, 80.58 μmol, 1 equivalent) was added to trifluoroacetic acid (2 mL) and stirred at 50°C for 5 hours. The reaction solution was concentrated to obtain a crude product. This crude product was separated by preparative high-performance liquid chromatography (column: Xtimate C18, 150*40 mm*5 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile) %: 1% to 30%, 10 min) to obtain the hydrochloride salt of compound 25. MS m / z = 541.3 [M+H] +

[0300] Example 26 [ka]

[0301] Step 1: Preparation of intermediate 26-1 To a solution of 17-3 (420 mg, 0.40 mmol) in tetrahydrofuran (10 mL), tetramethylammonium fluoride (150 mg, 1.61 mmol) was added and heated at 60° C. for 16 hours. The mixture was then diluted with ethyl acetate (50 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 26-1. MS m / z: 891.6 [M+1] +

[0302] Step 2: Preparation of intermediate 26-2 Palladium on carbon (20 mg, 10% content) was added to a solution of 26-1 (250 mg, 280.57 μmol, 1 equivalent) in methanol (10 mL), and the mixture was stirred under a hydrogen atmosphere (15 psi) at 20° C. for 1 hour. The mixture was filtered, and the filtrate was concentrated to give 26-2. MS m / z: 895.6 [M+1] +

[0303] Step 3: Preparation of compound 26 hydrochloride To a solution of 26-2 (220 mg, 245.79 μmol, 1 equivalent) in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added and stirred at 45° C. for 20 hours. The reaction solution was evaporated to dryness using a rotary evaporator, and the resulting residue was purified by preparative HPLC (column: Phenomenex C18 150*40 mm*5 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile)%: 1% to 30%, 10 min) to obtain the hydrochloride salt of compound 26. 1 H NMR (400MHz, CD3OD) δ=6.71(d, J=9.0Hz, 1H), 5.48-5.19(m, 2H), 4.74-4.59(m, 3H), 4.31-4.14(m, 3H), 3.97-3.52(m, 4H), 3.48-3.37(m, 2H), 3.30-3.06(m, 3H), 2.92-2.63(m, 3H), 2.45-2.27(m, 2H), 2.24(s, 3H), 2.22-1.84(m, 8H), 1.12 (t, J=7.4Hz, 3H); MS m / z: 555.2 [M+1] +

[0304] Example 27 [ka]

[0305] Step 1: Preparation of intermediate 27-1 15-3 (200 mg, 0.212 mmol) and cyclopropylboronic acid (92 mg, 1.059 mmol) were added to a mixture of 1,4-dioxane (10 mL) and water (1 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (20 mg) and sodium carbonate (45 mg, 0.425 mmol). The system was purged with nitrogen three times, and the reaction was carried out at 90 °C for 15 hours. The mixture was then filtered. The filtrate was evaporated to dryness using a rotary evaporator, and the resulting residue was separated by preparative thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to give 27-1. MS m / z: 907.6 [M+H] +

[0306] Step 2: Preparation of compound 27 hydrochloride To a solution of 27-1 (60 mg, 0.066 mmol) in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, stirred at 20 °C for 1 hour, and concentrated. The resulting residue was purified by preparative HPLC (column: Phenomenex C18, 150 x 40 mm x 5 μm; mobile phase: [0.05% hydrochloric acid / acetonitrile]; (acetonitrile) %: 1% to 30%, 10 min) to obtain the hydrochloride salt of compound 27. MS m / z: 565.5 [M+H] +

[0307] Example 28 [ka]

[0308] Step 1: Preparation of Compound 28 Trifluoroacetate To a solution of 26-1 (50 mg, 56.11 μmol) in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added and stirred for 2 hours at 20° C. The reaction solution was concentrated, and the resulting residue was purified by preparative HPLC (column: Welch Xtimate C18, 100*40 mm*3 μm; mobile phase: [0.025% aqueous trifluoroacetic acid / acetonitrile]; (acetonitrile)%: 0% to 30%, 8 min) to obtain the trichloroacetate salt of compound 28. 1 H NMR (400MHz, CD3OD) δ=6.69(d, J=8.4Hz, 1H), 5.69-5.15(m, 2H), 4.75- 4.71(m, 2H), 4.60-4.36(m, 4H), 4.22-3.96(m, 3H), 3.95-3.65(m, 5H), 3.53-3.42(m, 1H), 3.21-3.11(m, 1H), 3.07-2.97(m, 1H), 2.75-2.55(m, 2H), 2.45(s, 3H), 2.43-2.25(m, 4H), 2.20-1.96(m, 7H)

[0309] Example 29 [ka]

[0310] Step 1: Synthesis of intermediate 29-2 Compound 29-1 (50 g, 139.46 mmol, 1 equiv.) was added to anhydrous dichloromethane (500 mL), and N,N-diisopropylethylenediamine (54.07 g, 418.39 mmol, 72.87 mL, 3 equiv.) was added. The mixture was cooled to 0 °C, and chloromethyl methyl ether (15.59 g, 193.64 mmol, 14.71 mL, 1.39 equiv.) was slowly added dropwise. The mixture was slowly warmed to 18 °C and reacted for 1 h. The reaction solution was then added to ice water (500 mL). This was extracted with DCM (100 mL * 2). The combined organic layers were then washed with saturated sodium carbonate (500 mL), saturated ammonium chloride (500 mL), and half-saturated brine (500 mL), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0 to 50%) to obtain compound 29-2. MS m / z = 403.2 [M+H] +

[0311] Step 2: Synthesis of intermediate 29-3 Compound 29-2 (36 g, 89.42 mmol, 1 equiv.) and N,N-diisopropylethylenediamine (34.67 g, 268.27 mmol, 46.73 mL, 3 equiv.) were added to anhydrous dichloromethane (360 mL) and cooled to -40 °C. Trifluoromethanesulfonic anhydride (37.85 g, 134.14 mmol, 22.13 mL, 1.5 equiv.) was added dropwise and the reaction was allowed to proceed for 1 h. The reaction solution was added to ice water (300 mL), the layers were separated, and the mixture was extracted. The organic layer was washed successively with saturated sodium bicarbonate solution (200 mL), saturated ammonium chloride (200 mL), and brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-30%) to give compound 29-3. 1H NMR (400MHz, CDCl3) δ=7.71(dd, J=5.2, 9.2Hz, 1H), 7.43(d, J=2.4Hz, 1H), 7.36(d, J=2.0Hz, 1H), 7.33 (t, J=8.8Hz, 1H), 5.28(s, 2H), 3.53(s, 3H), 1.28-1.18(m, 21H)

[0312] Step 3: Synthesis of intermediate 29-4 Compound 29-3 (34 g, 63.59 mmol, 1 equiv.) was added to N,N-dimethylformamide (340 mL), and vinyltributyltin (42.03 g, 132.55 mmol, 38.56 mL, 2.08 equiv.) and lithium chloride (10.78 g, 254.38 mmol, 5.21 mL, 4 equiv.) were added. The system was purged with nitrogen three times, and bis(triphenylphosphine)palladium dichloride (4.46 g, 6.36 mmol, 0.1 equiv.) was added under nitrogen and the reaction mixture was allowed to react at 30 °C for 20 h. 20% aqueous KF solution (300 mL) and tert-butyl methyl ether (300 mL) were added to the reaction mixture, which was stirred for 20 min and then filtered through Celite. The filter cake was rinsed with tert-butyl methyl ether (50 mL * 4), and the aqueous layer was removed. The organic layer was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (ethyl acetate / petroleum ether = 20%) to give compound 29-4. MS m / z = 413.3 [M+H] +

[0313] Step 4: Synthesis of intermediate 29-5 Compound 29-4 (20 g, 48.47 mmol, 1 equiv.) was added to anhydrous tetrahydrofuran (200 mL) and water (50 mL) and cooled to 0 °C. Sodium periodate (31.10 g, 145.42 mmol, 8.06 mL, 3 equiv.) and osmium tetroxide (1.5 g, 5.90 mmol, 306.12 μL, 1.22 e -1(equivalent) was added. The mixture was slowly warmed to 18°C ​​and reacted for 1 hour. The reaction solution was added to 10% sodium thiosulfate solution (300mL), and the mixture was extracted with ethyl acetate (100mL*2). The organic layer was washed with saturated brine (500mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the obtained crude product was purified by column (ethyl acetate / petroleum ether = 20%) to obtain compound 29-5. MS m / z = 415.3 [M+H] +

[0314] Step 5: Synthesis of intermediate 29-7 To a solution of compound 29-6 (1 g, 4.05 mmol) and 1-1A (1.03 g, 4.86 mmol) in dichloromethane, N,N-diisopropylethylamine (1.05 g, 8.11 mmol) was added and stirred at room temperature (25 °C). Water (20 mL) and dichloromethane (50 mL) were added to the reaction solution and stirred for 5 minutes. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The resulting residue was purified using a chromatography purification system (ethyl acetate / petroleum ether = 20%) to obtain compound 29-7. MS m / z = 423.1 [M+H] +

[0315] Step 6: Synthesis of intermediate 29-8 To a solution of compound 29-7 (0.6 g, 1.42 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (0.1 g, 2.84 mmol) in portions at 0 °C (ice-water bath) under nitrogen. The mixture was allowed to warm to 25 °C and stirred for 2 hours. Water (0.1 g), 15% aqueous sodium hydroxide solution (0.1 g), and water (0.3 g) were added dropwise in that order, stirred for 30 minutes, and filtered. The filter cake was washed with tetrahydrofuran (10 mL), and the filtrate was concentrated under reduced pressure to give compound 29-8. MS m / z = 381.1 [M+H] +

[0316] Step 7: Synthesis of intermediate 29-9 To a solution of compound 29-8 (0.5 g, 1.33 mmol) in tetrahydrofuran (10 mL) was added dropwise lithium diisopropylamide (1.51 mL, 3.02 mmol, 2 M) under nitrogen at -65 °C (dry ice / ethyl acetate bath). After stirring the mixture for 30 minutes, a solution of compound 29-5 (0.5 g, 1.51 mmol) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was returned to 25 °C. To this solution were added 0.1 M dilute hydrochloric acid (15 mL) and ethyl acetate (20 mL) and stirred for 10 minutes. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography (ethyl acetate / petroleum ether = 20%) to give compound 29-9. MS m / z = 795.4 [M+H] +

[0317] Step 8: Synthesis of intermediate 29-10 To a solution of compound 29-9 (0.51 g, 641.44 μmol) in tetrahydrofuran (10 mL) was added dropwise n-butyllithium (2.5 M, 564.47 μL) under nitrogen at -65 °C (dry ice / ethyl acetate bath). After stirring the mixture for 30 minutes, a solution of p-toluenesulfonyl chloride (183.43 mg, 962.16 μmol) in tetrahydrofuran (3 mL) was added dropwise. The mixture was returned to 25 °C and stirred for 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride (50 mL), followed by the addition of ethyl acetate (50 mL) for extraction. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by chromatography (ethyl acetate / petroleum ether = 30%) to give compound 29-10. MS m / z = 777.4 [M+H] +

[0318] Step 9: Synthesis of intermediate 29-11 To a solution of compound 29-10 (45 mg, 57.91 μmol) in dichloromethane (2 mL), m-chloroperbenzoic acid (14.11 mg, 69.49 μmol, 85% content) was added and stirred at room temperature (25 °C) for 2 hours. To this reaction solution, saturated aqueous sodium bicarbonate solution (2 mL), saturated aqueous sodium sulfite solution (2 mL), and dichloromethane (5 mL) were added and stirred for 5 minutes. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate = 20%) to obtain compound 29-11. MS m / z = 793.4 [M+H] +

[0319] Step 10: Synthesis of intermediate 29-12 To a solution of compound 1-2A (32.12 mg, 201.76 μmol) in tetrahydrofuran (2 mL) was added sodium tert-butoxide (19.39 mg, 201.76 μmol) under nitrogen at 0°C (ice-water bath). The mixture was stirred for 30 minutes, and then compound 29-11 (40 mg, 50.44 μmol) was added. The mixture was returned to 25°C and stirred for 2 hours. 0.5 M hydrochloric acid was added to the reaction solution to adjust the pH to approximately 6. Ethyl acetate (5 mL) and saturated brine (2 mL) were added and stirred for 5 minutes. The aqueous layer was removed, and the organic layer was concentrated under reduced pressure to give compound 29-12. MS m / z = 888.5 [M+H] +

[0320] Step 11: Synthesis of intermediate 29-13 To a solution of compound 29-12 (45 mg, 50.67 μmol) in dichloromethane (1 mL), hydrochloric acid / ethyl acetate (4 M, 126.67 μL) was added and stirred at room temperature (25 °C) for 2 hours. The reaction solution was concentrated under reduced pressure to give the trifluoroacetate salt of compound 29-13. MS m / z = 744.4 [M+H] +

[0321] Step 12: Synthesis of Compound 29A and Compound 29B To a solution of compound 29-13 (40 mg, trifluoroacetic acid) in DMF (1 mL), cesium fluoride (40.83 mg, 268.82 μmol) and potassium carbonate (22.29 mg, 161.29 μmol) were added and stirred at room temperature (25 °C) for 2 hours. The reaction solution was filtered and washed with methanol (5 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (Phenomenex Luna C18, 75 x 30 mm x 3 μm column; mobile phase: [0.025% formic acid in water / acetonitrile]; acetonitrile %: 10% to 40%, 8 min), followed by chiral separation (DAICEL Chiralcel OD column, 250 mm x 30 mm, 10 μm column; mobile phase: [0.1% aqueous ammonia in methanol]; methanol %: 40% to 40%, 12 min) to give compound 29A (Rt = 1.386 min) and compound 29B (Rt = 2.079 min). MS m / z = 588.3 [M+H] +

[0322] Biological Assay Data: Assay Example 1: KRAS G12D Inhibitory activity assay 1. Purpose Compounds that can effectively inhibit the binding of KRAS to GTP were screened using the TR-FRET method. 2. Materials and equipment used [Table 1] 3. Reagent Preparation a. Stock Reagents: 1) KRAS Nucleotide Exchange Buffer 1000 mM HEPES (20 mL), 500 mM EDTA (20 mL), 5 M sodium chloride (10 mL), 100% Tween 20 (0.1 mL), and water (949.9 mL) were weighed to prepare a 1 L solution, which was sterilized by filtration and stored at 4°C. 2) KRAS assay buffer 1000 mM HEPES (20 mL), 1000 mM magnesium chloride (10 mL), 5 M sodium chloride (30 mL), 100% Tween 20 (0.05 mL), and water (939.95 mL) were weighed to prepare 1 L of solution, which was sterilized by filtration and stored at 4°C. 3)KRAS / Bodipy GDP / Tb-SA mixture 95 μM KRAS G12D Protein (9.5 μL) and KRAS nucleotide exchange buffer (440.5 μL) were weighed and mixed. The mixture was incubated at room temperature for 1 hour, and then the solution was adjusted to 1 L with 17.9 μM Tb-SA (8.4 μL), 5 mM Bodipy GDP (1.8 μL), and KRAS assay buffer (9539.8 μL). After mixing, the solution was left at room temperature for 6 hours and then stored at -80°C. b. Assay Reagents: 1) KRAS kinase solution The KRAS / Bodipy GDP / Tb-SA mixture (73.3 μL) and KRAS assay buffer (2126.7 μL) were weighed to prepare a 2200 μL solution. 2)SOS / GTP mixture 166 μM SOS protein (1.59 μL), 100 mM GTP (198 μL), and KRAS assay buffer (2000.41 μL) were weighed to prepare 2200 μL of solution.

[0323] 4. Assay Method 1) The concentration of the stock solution of the control compound was 1 mM, and the concentration of the stock solution of the compound to be assayed was 10 mM. The control compound (9 μL) and the compound to be assayed were transferred to a 384-LDV plate. 2) The compounds on the LDV plate were serially diluted 3-fold with Bravo to give 10 concentrations. 3) The compound (9 nL) from the LDV plate was transferred to the assay plate using ECHO. 4) Using a Dragonfly automatic sampler, a mixture of 3 nM Kras / 0.5 nM TB-SA / 30 nM Bodipy GDP (3 μL) and Ras buffer (3 μL) were added sequentially to each well of the assay plate, and the assay plate was centrifuged at 1000 rpm / min for 1 minute. 5) The assay plate was incubated at room temperature for 1 hour. 6) Using a Dragonfly automatic sampler, a mixture (3 μL) of 120 nM SOS / 9 mM GTP was added to each well of the assay plate, and the assay plate was centrifuged at 1000 rpm / min for 1 minute. 7) The assay plate was incubated at room temperature for 1 hour. 8) The plate was read on Envision and the data was collected. 9) Data were analyzed using Excel and Xlfit to obtain the IC values ​​for the compounds assayed. 50 was calculated.

[0324] 5. Assay Results The results are shown in Table 2. [Table 2] Assay conclusion: Compounds of the present disclosure inhibit KRAS G12D It has an excellent inhibitory effect on enzymes.

[0325] Assay Example 2: p-ERK Inhibition Assay in AGS Cells 1. Purpose Compounds that can effectively inhibit p-ERK in AGS cells were screened by HTRF. 2. Assay Method 1) AGS cells were seeded into a clear 96-well cell culture plate. Each well contained 80 μL of cell suspension and 10,000 cells. The cell plate was incubated overnight at 37°C in a carbon dioxide incubator. 2) After incubation, the cell supernatant was removed. 80 μL of medium containing 0.02% serum was added to each well. The cell plate was incubated overnight at 37°C in a carbon dioxide incubator. 3) Compound (2 μL) was weighed and added to cell culture medium (78 μL). After the mixture was thoroughly mixed, compound solution (20 μL) was weighed and added to the corresponding well of the cell plate. The cell plate was returned to the carbon dioxide incubator and incubated for an additional 3 hours. 4) After the incubation was completed, the cell supernatant was removed. 1x cell lysate (50 μL) was added to each well, and the mixture was incubated at room temperature with shaking for 30 minutes. 5) The phospho-ERK1 / 2 Eu cryptate antibody and the phospho-ERK1 / 2 d2 antibody were diluted 20-fold with the detection buffer. 6) 16 μL of the cell lysate supernatant was added to each well of a new 384-well white microplate, followed by 2 μL of diluted phospho-ERK1 / 2 Eu cryptate antibody and 2 μL of diluted phospho-ERK1 / 2 d2 antibody. The mixture was incubated at room temperature for at least 4 hours. 7) After the incubation was completed, the HTRF was read using a multi-label analyzer (excitation wavelength: 320 nm, emission wavelength: 615 nm, 665 nm). 8) IC of the compound assayed 50 was calculated.

[0326] 3. Assay Results The results are shown in Table 3. [Table 3] Assay conclusion: The compounds of the present disclosure have excellent inhibitory effects on p-ERK in AGS cells.

[0327] Assay Example 3: p-ERK Inhibition Assay in GP2D Cells 1. Purpose Compounds that can effectively inhibit p-ERK in GP2D cells were screened by HTRF. 2. Assay Method 1) GP2D cells were seeded into a transparent 96-well cell culture plate. Each well contained 80 μL of cell suspension and 8,000 cells. The cell plate was incubated overnight at 37°C in a carbon dioxide incubator. 2) Compound (2 μL) was weighed and added to cell culture medium (78 μL). After the mixture was thoroughly mixed, compound solution (20 μL) was weighed and added to the corresponding well of the cell plate. The cell plate was returned to the carbon dioxide incubator and incubated for an additional hour. 3) After the incubation was completed, the cell supernatant was removed. 1x cell lysate (50 μL) was added to each well, and the mixture was incubated at room temperature with shaking for 30 minutes. 4) The phospho-ERK1 / 2 Eu cryptate antibody and the phospho-ERK1 / 2 d2 antibody were diluted 20-fold with the detection buffer. 5) 16 μL of the cell lysate supernatant was added to each well of a new 384-well white microplate, followed by 2 μL of diluted phospho-ERK1 / 2 Eu cryptate antibody and 2 μL of diluted phospho-ERK1 / 2 d2 antibody. The mixture was incubated at room temperature for at least 4 hours. 6) After the incubation was completed, the HTRF was read using a multi-label analyzer (excitation wavelength: 320 nm, emission wavelength: 615 nm, 665 nm). 7) IC of the compound assayed 50 was calculated.

[0328] 3. Assay Results The results are shown in Table 4. [Table 4] Assay conclusion: The compounds of the present disclosure have excellent inhibitory effects on p-ERK in GP2D cells.

[0329] Assay Example 4: p-ERK inhibition assay in PANC0403 cells 1. Materials used in the assay: PANC0403 cells (Nanjing Kebai), RPMI-1640 medium (Biological Industries), fetal bovine serum (Biosera), and Advanced phospho-ERK1 / 2 (THR202 / TYR204) kit (Cisbio). The composition of the Advanced phospho-ERK1 / 2 (THR202 / TYR204) kit is shown in Table 5. TIFF0007762985000202.tif591602.Assay method 1) PANC0403 cells were seeded into a transparent 96-well cell culture plate. Each well contained 80 μL of cell suspension and 10,000 PANC0403 cells. The cell plate was incubated overnight at 37°C in a carbon dioxide incubator. 2) The compounds to be assayed were diluted with 100% DMSO to an initial concentration of 2 mM, then serially diluted five-fold with a pipette to obtain eight concentrations (2 mM to 25.6 nM). Compounds (2 μL) were weighed and added to starvation medium (78 μL). After thorough mixing, compound solutions (20 μL) were weighed and added to the corresponding wells of the cell plate. The cell plate was returned to the carbon dioxide incubator and incubated for an additional 3 hours. At this time, compound concentrations ranged from 10 μM to 0.128 nM, and the DMSO concentration was 0.5%. 3) After the incubation was completed, the cell supernatant was removed. Cell lysate (50 μL) was added to each well, and the mixture was incubated at room temperature with shaking for 30 minutes. 4) The phospho-ERK1 / 2 Eu cryptate antibody and the phospho-ERK1 / 2 d2 antibody were diluted 20-fold with the detection buffer. 5) 16 μL of the cell lysate supernatant was added to each well of a new 384-well white microplate, followed by 2 μL of diluted phospho-ERK1 / 2 Eu cryptate antibody and 2 μL of diluted phospho-ERK1 / 2 d2 antibody. The mixture was incubated overnight at room temperature. 6) After the incubation was completed, the HTRF was read using a multi-label analyzer (excitation wavelength: 320 nm, emission wavelength: 615 nm, 665 nm).

[0330] 3. Data Analysis Raw data were converted to percent inhibition using the formula: (sample-min) / (max-min)*100%, and IC was calculated by four-parameter curve fitting ("log(inhibitor) vs response--slope change" mode in GraphPad Prism). 50 got the value. Maximum well: Positive control well reading is 1x lysate value. Minimum wells: Negative control well readings are cell lysate in 0.5% DMSO cell wells.

[0331] 4. Assay Results The results are shown in Table 6. [Table 5] Assay conclusion: The compounds of the present disclosure have excellent inhibitory effects on p-ERK in PANC0403 cells.

[0332] Assay Example 5: Anti-cell proliferation effects of compounds in tumor cell lines AsPC-1 and GP2D Test objectives In this assay, the cell growth inhibitory effect of the compounds was tested by detecting the effect of the compounds on the cellular activity in vitro in tumor cell lines AsPC-1 and GP2D. What to use in the assay [Table 6] Ultra Low Cluster 96-well Plate (Corning-7007) CELLSTAR 96-well plate (Greiner-#655090) CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega-G9683) 2104-10 EnVision plate reader (PerkinElmer) RPMI 1640, DMEM, PBS (phosphate buffered saline), FBS (fetal bovine serum), antifungal antibiotics, L-glutamine, DMSO (dimethyl sulfoxide)

[0333] Assay Methods and Steps Cell culture medium Tumor cell lines were cultured in a 5% CO2 incubator at 37°C according to the culture conditions indicated in the culture method. Cells were passaged periodically, and cells in the logarithmic growth phase were used for plating.

[0334] Cell plating Cells were stained with trypan blue and viable cells were counted. The cell concentration was adjusted to an appropriate concentration. [Table 7] The cell suspension (135 μL) was added to each well of the ULA culture plate, and the same volume of culture medium without cells was added to blank control wells. After plating, the ULA culture plate was immediately centrifuged (1000 rpm) at room temperature for 10 minutes. (Note: Subsequent operations after centrifugation must be carried out carefully to avoid unnecessary shock.) The culture plates were incubated overnight in an incubator (37°C, 5% CO2, 100% relative humidity).

[0335] Preparation of 10x compound working solutions and cell treatment with compounds (Day 1) A 10x compound working solution (10x working solution / DMSO) was prepared, and then 15 μL of this working solution was added to the ULA culture plate, and 15 μL of a mixed solution of DMSO and cell culture medium was added to the vehicle control and blank control, respectively. The 96-well cell plate was returned to the incubator and incubated for 120 hours. The cells were monitored daily for three-dimensional colony formation until the end of the assay.

[0336] CellTiter-Glo Luminescent Cell Viability Assay (Day 5) The following steps were performed according to the instructions of the CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega #G9683). 150 μL (the same volume as the cell culture medium in each well) of CellTiter-Glo 3D reagent was added to each well, and the cell plate was wrapped in aluminum foil to protect from light. The culture plate was shaken on a shaker for 5 minutes. Before proceeding to the next step, the mixture in the well was carefully pipetted up and down 10 times to thoroughly mix, to ensure that the spherical colonies of cells were well separated. The solution in the ULA plate was then transferred to a black clear bottom culture plate (#655090) and left at room temperature for 25 minutes to allow the luminescent signal to stabilize. Luminescent signals were detected with a 2104 EnVision plate reader.

[0337] Data analysis The inhibition rate (IR) of the assay compounds was calculated using the following formula: IR(%)=(1-(RLU of compound-RLU of blank control) / (RLU of vehicle control-RLU of blank control))*100%. The inhibition rates of different concentrations of compounds were calculated in Excel, and then the inhibition curves were drawn using GraphPad Prism software to calculate the minimum inhibition rate, maximum inhibition rate, and IC 50 The relevant parameters were calculated, including

[0338] Assay Results The results are shown in Table 9. [Table 8] Assay Conclusion: Compounds of the present disclosure inhibit KRAS G12D It has an inhibitory effect on cell mutation.

[0339] Assay Example 6: Plasma Protein Binding (PPB) Assay the purpose The protein binding rates of the compounds in plasma of CD-1 mice, Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and humans were determined by equilibrium dialysis.

[0340] Assay Method Plasma samples from the five species listed above were prepared with the compound (concentration: 2 μM). The plasma samples were added to a 96-well rapid equilibrium dialysis device and dialyzed for 4 hours at 37 ± 1°C using phosphate-buffered saline as the dialysate. Warfarin was used as a control compound in this assay. The concentrations of the analyte in the plasma and dialysis buffer were determined by LC-MS / MS.

[0341] Assay Results The unbound fraction (%) of the hydrochloride salt of Compound 1 at the assay concentration (2 μM) is shown in Table 10 below. [Table 9] The recovery rate (%) of Compound 1 in the dialysis device was 82.4 to 109.5%, which satisfied the recovery rate and stability required for this assay.

[0342] Assay Results Compounds of the present disclosure exhibit excellent free concentrations at the assay concentration (2 μM) in the plasma of the five species mentioned above.

[0343] Assay Example 7: Pharmacokinetic study of assay compounds administered orally and intravenously in CD-1 mice the purpose This is done to evaluate the pharmacokinetics of orally and intravenously administered compounds in CD-1 mice.

[0344] Assay steps The test compounds were mixed in 5% DMSO + 95% (10% HP-β-CD) aqueous solution. This mixture was vortexed and sonicated to prepare clear solutions at 0.5 mg / mL (for intravenous administration) or 3 mg / mL (for oral administration). These solutions were filtered through a microporous membrane before use. Male SD mice aged 7–10 weeks were selected and administered intravenously with a solution of the candidate compound at a dose of approximately 2 mg / kg or orally with a solution of the candidate compound at a dose of approximately 30 mg / kg. Whole blood samples were collected at specified intervals and prepared to obtain plasma. Drug concentrations were analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA).

[0345] Assay Results The results are shown in Tables 11 and 12. [Table 10] Assay conclusion: The compounds of the present disclosure have excellent oral bioavailability.

[0346] Assay Example 8: In vivo pharmacological assay Assay Method A subcutaneous xenograft tumor model of human colon cancer GP2D cells was established in Balb / c nude mice. Matrigel was added to the tumor cells at a volume ratio of 1:1, and 0.2 mL (2 × 10 6 ) GP2D cells were implanted subcutaneously into the right dorsal region of each mouse. The average tumor volume was 149 mm 3 When the serotonin concentration reached 100 mg / kg, six mice in each group were administered the corresponding drug. On the day of the assay, each group was administered the corresponding drug. Group 1 (G1) served as the negative control group and was administered 5% DMSO + 95% (10% HP-β-CD) alone by oral gavage. Groups 2 (G2) to 4 (G4) were administered the hydrochloride salt of Compound 1. The dosage and administration method are shown in Table 13. [Table 11]

[0347] Note: PO means oral administration, QD means once daily, BID means once daily 2 It means times.

[0348] During the assay, animal weights and tumor sizes were measured twice a week. Animal clinical symptoms were also observed and recorded daily. The most recent body weight of the animals was used as a reference for each administration. The length (a) and width (b) of the tumor were measured with a digital caliper. The tumor volume (TV) was calculated using the formula TV = a × b. 2 / 2.

[0349] Assay Results The hydrochloride salt of compound 1 showed excellent inhibitory effects against human colon cancer GP2D xenograft tumors in mice. After 20 days of administration, the tumor growth inhibition rate (TGI (%)) of Group 2 (G2, 3 mg / kg, PO, BID) on day 20 was 19.4%, while the tumor growth inhibition rates (TGI (%)) of Group 3 (G3, 10 mg / kg, PO, BID) and Group 4 (G4, 30 mg / kg, PO, BID) on day 20 were 53.9% and 83.7%, respectively. Detailed results are shown in Table 14. [Table 12] Note: N / A means not applicable.

[0350] Assay conclusion: In terms of in vivo efficacy, the compounds of the present disclosure exhibit excellent tumor suppressive effects in GP2D cell lines, with a clear dose-dependence.

Claims

1. Formula (III) 【Chemistry 1】 [In the formula, the substructure 【Chemistry 2】 teeth, 【Transformation 3】 selected from the group consisting of: 【Chemistry 4】 is a single bond; T 1 is CR 7 R 8 , N.R. 9 and O; T 2 is selected from CH and N; L 1 is -CH 2 - and; R 1 , R 2 , R 3 , R 4 and R 5 are independently H and C 1-3 alkyl, wherein C 1-3 Alkyl can have one, two or three R a may be optionally substituted with; R 6 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein C 6-10 Aryl and 5- to 10-membered heteroaryl may have 1, 2, 3, 4, or 5 R b may be optionally substituted with; R 7 and R 8 are independently H, CH 3 and N.H. 2 Selected from; R 9 H and CH 3 Selected from; R 10 teeth, 【Transformation 5】 where 【Transformation 6】 is 1, 2 or 3 R c may be optionally substituted with; R 11 and R 12 are independently H, C 1-3 Alkyl and C 3-5 cycloalkyl, wherein C 1-3 Alkyl and C 3-5 The cycloalkyl may be optionally substituted with 1, 2, or 3 halogens; m is selected from 0, 1 and 2; n is selected from 0, 1 and 2; p is selected from 0, 1 and 2; q is selected from 1, 2 and 3; r is selected from 1 and 2; s is selected from 1, 2 and 3; R a are each independently selected from F, Cl, Br, and I; R b are F, Cl, Br, I, OH, and NH, respectively. 2 , C.N., C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl, -C(=O)C 1-3 Alkyl and C 3-5 cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl, -C(=O)C 1-3 Alkyl and C 3-5 The cycloalkyl may be optionally substituted with 1, 2, 3, 4, or 5 R; R c are H, F, Cl, Br, I, OH, CN, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-OC(=O)-C 1-3 independently selected from alkylamino; Each R is independently selected from F, Cl, Br, and I. or a pharmaceutically acceptable salt thereof.

2. In the formula, R 1 , R 2 , R 3 , R 4 and R 5 However, each independently H, CH 3 , C.H. 2 CH 3 and CH(CH 3 ) 2 where CH 3 , C.H. 2 CH 3 and CH(CH 3 ) 2 is one, two or three R a 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with:

3. In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are independently H and CH 3 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

4. In the formula, the substructure 【Transformation 7】 but, 【Transformation 8】 10. The compound of claim 1, selected from the group consisting of:

5. In the formula, R b are F, Cl, Br, I, OH, and NH 2 , C.N., C.H. 3 , C.H. 2 CH 3 , OCH 3 , OCH 2 CH 3 , -CH=CH 2 , -CH 2 -CH=CH 2 , -C≡CH, -C(=O)CH 3 and cyclopropyl, wherein CH 3 , C.H. 2 CH 3 , OCH 3 , OCH 2 CH 3 , -CH=CH 2 , -CH 2 -CH=CH 2 , -C≡CH, -C(=O)CH 3 and cyclopropyl is optionally substituted with 1, 2, 3, 4, or 5 R, or a pharmaceutically acceptable salt thereof.

6. In the formula, R b are F, Cl, Br, I, OH, and NH 2 , C.N., C.H. 3 , C.F. 3 , C.H. 2 CH 3 , C.F. 2 CF 3 , -CH=CH 2 , -C≡CH, -C(=O)CH 3 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein the compound is independently selected from:

7. In the formula, R 6 is selected from phenyl, pyridyl, naphthyl, indolyl, and indazolyl, wherein phenyl, pyridyl, naphthyl, indolyl, and indazolyl are selected from 1, 2, 3, 4, or 5 R b 7. The compound of any one of claims 1, 5 and 6, or a pharmaceutically acceptable salt thereof, optionally substituted with:

8. In the formula, R 6 but, 【Chemistry 9】 8. The compound of claim 7, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

9. In the formula, R c are H, F, Cl, Br, OH, CN, and CH 3 , C.H. 2 CH 3 , OCH 3 , and 【Chemistry 10】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, independently selected from:

10. In the formula, R 10 but, 【Chemistry 11】 10. The compound of any one of claims 1 and 9, selected from: or a pharmaceutically acceptable salt thereof.

11. In the formula, R 11 and R 12 are independently H and CH 3 2. The compound of claim 1, selected from:

12. Formula (III) 【Chemistry 12】 [In the formula, R c are H, F, Cl, Br, OH, CN, and CH 3 , C.H. 2 CH 3 , C.H. 2 CF 3 , OCH 3 , OCF 3 , and 【Chemistry 13】 and the other variables are as defined in any one of claims 1 to 8 and 10 to 11. or a pharmaceutically acceptable salt thereof.

13. The following formula 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 or a pharmaceutically acceptable salt thereof.

14. The compound is 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 14. The compound of claim 13, selected from: or a pharmaceutically acceptable salt thereof.

15. Formula (I) 【Transformation 58】 [In the formula, 【Chemistry 59】 is a single bond; T 1 is CR 7 R 8 and N.R. 9 Selected from; T 2 is selected from CH and N; R 1 and R 2 is a substructure 【Transformation 60】 but 【Chemistry 61】 or R 1 and R 4 is a substructure 【Transformation 62】 but 【Transformation 63】 or R 4 and R 5 is a substructure 【Chemistry 64】 but 【Transformation 65】 form a ring with the atoms to which they are attached, so as to form a ring; R 1 , R 2 , R 3 , R 4 and R 5 are independently H and C 1-3 alkyl, wherein C 1-3 Alkyl can have one, two or three R a may be optionally substituted with; R 6 is selected from phenyl and naphthyl, where phenyl and naphthyl are selected from 1, 2, 3, 4 or 5 R b may be optionally substituted with; R 7 and R 8 are independently H, CH 3 and N.H. 2 Selected from; R 9 H and CH 3 Selected from; m is selected from 0, 1 and 2; n is selected from 0, 1 and 2; p is selected from 1 and 2; q is selected from 1, 2 and 3; r is selected from 1 and 2; s is selected from 1, 2 and 3; R a are each independently selected from F, Cl, Br, and I; R b are F, Cl, Br, I, OH, and NH, respectively. 2 , C.N., C.H. 3 , CF 3 and OCH 3 are selected independently from or a pharmaceutically acceptable salt thereof.

16. In the formula, R 1 , R 2 , R 3 , R 4 and R 5 However, each independently H, CH 3 , C.H. 2 CH 3 and CH(CH 3 ) 2 where CH 3 , C.H. 2 CH 3 and CH(CH 3 ) 2 is one, two or three R a 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, optionally substituted with:

17. In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are independently H and CH 3 17. The compound of claim 15 or 16, or a pharmaceutically acceptable salt thereof, selected from:

18. In the formula, the substructure 【Chemical Formula 66】 but, 【Transformation 67】 16. The compound of claim 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

19. In the formula, the substructure 【Transformation 68】 but, 【Transformation 69】 16. The compound of claim 15, selected from: or a pharmaceutically acceptable salt thereof.

20. In the formula, the substructure 【Transformation 70】 but, 【Chemistry 71】 16. The compound of claim 15, wherein:

21. In the formula, the substructure 【Chemistry 72】 but, 【Transformation 73】 16. The compound of claim 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

22. In the formula, R 6 but 【Chemistry 74】 16. The compound of claim 15, wherein:

23. Formula (II) 【Chemistry 75】 [In the formula, the substructure 【Transformation 76】 teeth, 【Chemical 77】 selected from the group consisting of: 【Transformation 78】 is a single bond; T 1 is CR 7 R 8 , N.R. 9 and O; T 2 is selected from CH and N; L 1 is -CH 2 - and; R 1 , R 2 , R 3 , R 4 and R 5 are each independently H and C 1-3 alkyl, wherein C 1-3 Alkyl can have one, two or three R a may be optionally substituted with; R 6 is C 6-10 aryl and 5- to 10-membered heteroaryl, wherein C 6-10 Aryl and 5- to 10-membered heteroaryl may have 1, 2, 3, 4, or 5 R b may be optionally substituted with; R 7 and R 8 are each independently H, CH 3 and N.H. 2 Selected from; R 9 H and CH 3 Selected from; R 10 is hexahydro-1H-pyrrolidinyl, where hexahydro-1H-pyrrolidinyl is a group selected from the group consisting of one, two, or three R c may be optionally substituted with; m is selected from 0, 1 and 2; n is selected from 0, 1 and 2; p is selected from 1 and 2; q is selected from 1, 2 and 3; r is selected from 1 and 2; s is selected from 1, 2 and 3; R a are each independently selected from F, Cl, Br, and I; R b are F, Cl, Br, I, OH, and NH, respectively. 2 , C.N., C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl and C 3-5 cycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkynyl, C 2-3 Alkenyl and C 3-5 The cycloalkyl may be optionally substituted with 1, 2, or 3 R; R c are H, F, Cl, Br, OH, CN, and C, respectively. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O-CO-C 1-3 independently selected from alkylamino; Each R is independently selected from F, Cl, and Br. or a pharmaceutically acceptable salt thereof.

24. In the formula, R 1 , R 2 , R 3 , R 4 and R 5 However, each independently H, CH 3 , C.H. 2 CH 3 and CH(CH 3 ) 2 where CH 3 , C.H. 2 CH 3 and CH(CH 3 ) 2 is 1, 2 or 3 R a 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, optionally substituted with:

25. In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are independently H and CH 3 25. The compound of claim 23 or 24, or a pharmaceutically acceptable salt thereof, selected from:

26. In the formula, the substructure 【Chemistry 79】 but, 【Chemistry 80】 24. The compound of claim 23, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

27. In the formula, R b are F, Cl, Br, I, OH, and NH 2 , C.N., C.H. 3 , C.H. 2 CH 3 , OCH 3 , OCH 2 CH 3 , -CH=CH 2 , -CH 2 -CH=CH 2 and -C≡CH, where CH 3 , C.H. 2 CH 3 , OCH 3 , OCH 2 CH 3 , -CH=CH 2 , -CH 2 -CH=CH 2 and -C≡CH are optionally substituted with 1, 2 or 3 R, or a pharmaceutically acceptable salt thereof.

28. In the formula, R b are F, OH, and NH 2 , C.H. 3 , C.F. 3 , C.H. 2 CH 3 and -C≡CH, or a pharmaceutically acceptable salt thereof.

29. In the formula, R 6 is selected from phenyl, naphthyl, indolyl, and indazolyl, where phenyl, naphthyl, indolyl, and indazolyl are selected from 1, 2, 3, 4, or 5 R b 29. The compound of any one of claims 23, 27, or 28, or a pharmaceutically acceptable salt thereof, optionally substituted with:

30. In the formula, R 6 but, 【Chemistry 81】 30. The compound of claim 29, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

31. In the formula, R c are H, F, Cl, Br, OH, CN, and CH 3 , C.H. 2 CH 3 , OCH 3 , and 【Chemistry 82】 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, independently selected from:

32. In the formula, R 10 but, 【Chemistry 83】 32. The compound of any one of claims 23, 30, or 31, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

33. KRAS G12D A pharmaceutical composition comprising a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for treating a disease associated with a mutation.

Images