Pyrimidine-pyran compounds

Abstract

This relates to a class of pyrimidine-pyran compounds, specifically disclosing compounds of formula (III) and their pharmaceutically acceptable salts.

Description

[0001] This invention claims the following priority:

[0002] CN202110139674.X, application date: February 1, 2021;

[0003] CN202110258547.1, application date: March 9, 2021;

[0004] CN202110706033.8, application date: June 24, 2021;

[0005] CN202210070174.X, application date: January 20, 2022. Technical Field

[0006] This invention relates to a class of pyrimidine-pyran compounds, specifically to compounds of formula (III) and their pharmaceutically acceptable salts. Background Technology

[0007] RAS oncogene mutations are the most common activating mutations in human cancers, occurring in 30% of human tumors. The RAS gene family includes three subtypes (KRAS, HRAS, and NRAS), with 85% of RAS-driven cancers caused by mutations in the KRAS subtype. KRAS mutations are common in solid tumors such as lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal cancer. In KRAS-mutant tumors, 80% of oncogenic mutations occur at codon 12, with the most common mutations including p.G12D (41%), p.G12V (28%), and p.G12C (14%).

[0008] KRAS is an oncogene of murine sarcoma virus and an important member of the RAS protein. KRAS acts like a molecular switch, normally controlling and regulating cell growth pathways. Mutations in the KRAS gene can lead to uncontrolled cell growth and proliferation, independent of upstream growth factor receptor signals, transmitting growth and proliferation signals downstream, resulting in uncontrolled cell growth and tumor progression. Furthermore, the presence or absence of KRAS gene mutations is an important indicator of tumor prognosis.

[0009] Currently, small molecules that directly target KRAS mutations are mainly concentrated in KRAS. G12C In this field, Amgen's AMG510 and Mirati Therapeutics' MRTX849 are being studied in clinical trials for their effects on KRAS. G12C Patients with mutated tumors have shown good treatment outcomes. However, there is still no KRAS... G12D Small molecules enter clinical research stage, KRAS G12D Patients with mutated tumors have not yet benefited from precision medicine. Summary of the Invention

[0010] This invention provides compounds of formula (III) or pharmaceutically acceptable salts thereof.

[0011]

[0012] Structural unit Selected from Selected from single or double bonds;

[0013] T1 is selected from CR7R8, NR9, and O;

[0014] T2 is selected from CH and N;

[0015] L1 is selected from -CH2- and bonds;

[0016] R1, R2, R3, R4, and R5 are independently selected from H and C, respectively. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. a replace;

[0017] R6 is selected from C 6-10 Aryl and 5-10 heteroaryl, the C 6-10 Aryl and 5-10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. b Substitution; R7 and R8 are independently selected from H, CH3, and NH2, respectively;

[0018] R9 is selected from H and CH3;

[0019] R 10 Selected from 4-8 membered heterocyclic alkyl groups and The 4-8 membered heterocyclic alkyl groups and Choose 1, 2, or 3 Rs c replace;

[0020] R 11 and R 12 Selected independently from H and C respectively 1-3 Alkyl and C 3-5 cycloalkyl, the C 1-3 Alkyl and C 3-5 The cycloalkyl group may be optionally substituted with one, two or three halogens;

[0021] Structural unit Selected from 5-6 membered heterocyclic alkenyl groups;

[0022] Structural unit Selected from C 3-5 cycloalkyl;

[0023] Structural unit Selected from 4-5 membered heterocyclic alkyl groups;

[0024] m is selected from 0, 1, or 2;

[0025] n is selected from 0, 1, or 2;

[0026] p is selected from 1 or 2;

[0027] q is selected from 1, 2, or 3;

[0028] r is selected from 1 or 2;

[0029] s is selected from 1, 2, or 3;

[0030] Each R a They were each independently selected from F, Cl, Br, and I;

[0031] Each R b Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl, -C(=O)C 1-3 Alkyl and C 3-5 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl, -C(=O)C 1-3 Alkyl and C 3-5 The cycloalkyl group may be optionally substituted with 1, 2, 3, 4 or 5 Rs;

[0032] Each R c Each of the following is independently selected from H, F, Cl, Br, I, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-OC(=O)-C 1-3 Alkylamino;

[0033] Each R is independently selected from F, Cl, Br and I.

[0034] In some embodiments of the present invention, R1, R2, R3, R4, and R5 are each independently selected from H, CH3, CH2CH3, and CH(CH3)2, wherein CH3, CH2CH3, and CH(CH3)2 are optionally selected by one, two, or three Rs. a Replacement, other variables as defined in this invention.

[0035] In some embodiments of the present invention, R1, R2, R3, R4 and R5 are independently selected from H and CH3, respectively, and other variables are as defined in the present invention.

[0036] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in this invention.

[0037] In some embodiments of the present invention, the structural unit Selected from

[0038] Other variables are as defined in this invention.

[0039] In some embodiments of the present invention, the respective R b The radicals are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -C≡CH, -C(=O)CH3 and cyclopropyl, wherein CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -C≡CH, -C(=O)CH3 and cyclopropyl are optionally substituted by 1, 2, 3, 4 or 5 Rs, and other variables are as defined in this invention.

[0040] In some embodiments of the present invention, the respective R b The radicals are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3, CH2CH3, CF2CF3, -CH=CH2, -C≡CH, -C(=O)CH3 and cyclopropyl, and other variables are as defined in this invention.

[0041] In some embodiments of the invention, R6 is selected from phenyl, pyridyl, naphthyl, indole, and indazole, wherein the phenyl, pyridyl, naphthyl, indole, and indazole are optionally surrounded by 1, 2, 3, 4, or 5 R6 groups. b Replacement, other variables as defined in this invention.

[0042] In some embodiments of the present invention, R6 is selected from... Other variables are as defined in this invention.

[0043] In some embodiments of the present invention, the respective R c The elements are independently selected from H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CF3, OCH3, OCF3, and Other variables are as defined in this invention.

[0044] In some embodiments of the present invention, the R 10 The group is selected from tetrahydropyrrole, hexahydro-1H-pyrrolizinyl, and 1,2,3,4-tetrahydroisoquinolinyl, wherein the tetrahydropyrrole, hexahydro-1H-pyrrolizinyl, and 1,2,3,4-tetrahydroisoquinolinyl are optionally surrounded by 1, 2, or 3 R groups. c Replacement, other variables as defined in this invention.

[0045] In some embodiments of the present invention, the R 10 Selected from Other variables are as defined in this invention.

[0046] In some embodiments of the present invention, the R 10 Selected from Other variables are as defined in this invention.

[0047] In some embodiments of the present invention, the R 11 and R 12 The variables are independently selected from H and CH3, respectively, and other variables are as defined in this invention.

[0048] This invention provides compounds of formula (III) or pharmaceutically acceptable salts thereof.

[0049]

[0050] Structural unit Selected from

[0051] Selected from single or double bonds;

[0052] T1 is selected from CR7R8, NR9, and O;

[0053] T2 is selected from CH and N;

[0054] L1 is selected from -CH2- and bonds;

[0055] R1, R2, R3, R4, and R5 are independently selected from H and C, respectively. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. a replace;

[0056] R6 is selected from C 6-10 Aryl and 5-10 heteroaryl, the C 6-10 Aryl and 5-10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. b replace;

[0057] R7 and R8 are independently selected from H, CH3 and NH2, respectively;

[0058] R9 is selected from H and CH3;

[0059] R 10 Selected from 4-8 membered heterocyclic alkyl groups and The 4-8 membered heterocyclic alkyl groups and Choose 1, 2, or 3 Rs c replace;

[0060] R 11 and R 12 Selected independently from H and C respectively 1-3 Alkyl and C 3-5 cycloalkyl, the C 1-3 Alkyl and C 3-5 The cycloalkyl group may be optionally substituted with one, two or three halogens;

[0061] Structural unit Selected from 5-6 membered heterocyclic alkenyl groups;

[0062] Structural unit Selected from C 3-5 cycloalkyl;

[0063] Structural unit Selected from 4-5 membered heterocyclic alkyl groups;

[0064] m is selected from 0, 1, or 2;

[0065] n is selected from 0, 1, or 2;

[0066] p is selected from 1 or 2;

[0067] q is selected from 1, 2, or 3;

[0068] r is selected from 1 or 2;

[0069] s is selected from 1, 2, or 3;

[0070] Each R a They were each independently selected from F, Cl, Br, and I;

[0071] Each R b Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl and C 3-5 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl and C3-5 The cycloalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0072] Each R c Each of the following is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O-CO-C 1-3 Alkylamino; each R is independently selected from F, Cl, and Br;

[0073] In some embodiments of the present invention, R1, R2, R3, R4, and R5 are each independently selected from H, CH3, CH2CH3, and CH(CH3)2, wherein CH3, CH2CH3, and CH(CH3)2 are optionally selected by one, two, or three Rs. a Replacement, other variables as defined in this invention.

[0074] In some embodiments of the present invention, R1, R2, R3, R4 and R5 are independently selected from H and CH3, respectively, and other variables are as defined in the present invention.

[0075] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in this invention.

[0076] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in this invention.

[0077] In some embodiments of the present invention, the respective R b The variables are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, and -C≡CH, respectively. The CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, and -C≡CH are optionally replaced by 1, 2, or 3 Rs. Other variables are as defined in this invention.

[0078] In some embodiments of the present invention, the respective R b The variables are independently selected from F, OH, NH2, CH3, CF3, CH2CH3 and -C≡CH, respectively, and other variables are as defined in this invention.

[0079] In some embodiments of the invention, R6 is selected from phenyl, naphthyl, indole, and indazole, wherein the phenyl, naphthyl, indole, and indazole are optionally surrounded by 1, 2, 3, 4, or 5 R6 groups. b Replacement, other variables as defined in this invention.

[0080] In some embodiments of the present invention, R6 is selected from... Other variables are as defined in this invention.

[0081] In some embodiments of the present invention, the respective R c The elements are independently selected from H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CF3, OCH3, OCF3, and Other variables are as defined in this invention.

[0082] In some embodiments of the present invention, the R 10 The group is selected from tetrahydropyrrole, hexahydro-1H-pyrrolizinyl, and 1,2,3,4-tetrahydroisoquinolinyl, wherein the tetrahydropyrrole, hexahydro-1H-pyrrolizinyl, and 1,2,3,4-tetrahydroisoquinolinyl are optionally surrounded by 1, 2, or 3 R groups. c Replacement, other variables as defined in this invention.

[0083] In some embodiments of the present invention, the R 10 Selected from Other variables are as defined in this invention.

[0084] In some embodiments of the present invention, the R 11 and R 12 The variables are independently selected from H and CH3, respectively, and other variables are as defined in this invention.

[0085] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0086]

[0087] Structural unit Selected from Selected from single or double bonds;

[0088] T1 is selected from CR7R8, NR9, and O;

[0089] T2 is selected from CH and N;

[0090] L1 is selected from -CH2- and bonds;

[0091] R1, R2, R3, R4, and R5 are independently selected from H and C, respectively. 1-3 Alkyl, the C1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. a replace;

[0092] R6 is selected from C 6-10 Aryl and 5-10 heteroaryl, the C 6-10 Aryl and 5-10 heteroaryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. b replace;

[0093] R7 and R8 are independently selected from H, CH3 and NH2, respectively;

[0094] R9 is selected from H and CH3;

[0095] R 10 Selected from 4-8 membered heterocyclic alkyl groups and The 4-8 membered heterocyclic alkyl groups and Choose 1, 2, or 3 Rs c Replacement; structural unit Selected from 5-6 membered heterocyclic alkenyl groups;

[0096] Structural unit Selected from C 3-5 Cycloalkyl groups;

[0097] Structural unit Selected from 4-5 membered heterocyclic alkyl groups;

[0098] m is selected from 0, 1, or 2;

[0099] n is selected from 0, 1, or 2;

[0100] p is selected from 1 or 2;

[0101] q is selected from 1, 2, or 3;

[0102] r is selected from 1 or 2;

[0103] s is selected from 1, 2, or 3;

[0104] Each R a They were each independently selected from F, Cl, Br, and I;

[0105] Each R b Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl and C 3-5 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl and C 3-5The cycloalkyl group may be optionally substituted with 1, 2 or 3 Rs;

[0106] Each R c Each of the following is independently selected from H, F, Cl, Br, OH, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy and -C 1-3 Alkyl-O-CO-C 1-3 Alkylamino; each R is independently selected from F, Cl, and Br;

[0107] In some embodiments of the present invention, R1, R2, R3, R4, and R5 are each independently selected from H, CH3, CH2CH3, and CH(CH3)2, wherein CH3, CH2CH3, and CH(CH3)2 are optionally selected by one, two, or three Rs. a Replacement, other variables as defined in this invention.

[0108] In some embodiments of the present invention, R1, R2, R3, R4 and R5 are independently selected from H and CH3, respectively, and other variables are as defined in the present invention.

[0109] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in this invention.

[0110] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in this invention.

[0111] In some embodiments of the present invention, the respective R b The variables are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, and -C≡CH, respectively. The CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, and -C≡CH are optionally replaced by 1, 2, or 3 Rs. Other variables are as defined in this invention.

[0112] In some embodiments of the present invention, the respective R b The variables are independently selected from F, OH, NH2, CH3, CF3, CH2CH3 and -C≡CH, respectively, and other variables are as defined in this invention.

[0113] In some embodiments of the invention, R6 is selected from phenyl, naphthyl, indole, and indazole, wherein the phenyl, naphthyl, indole, and indazole are optionally surrounded by 1, 2, 3, 4, or 5 R6 groups. b Replacement, other variables as defined in this invention.

[0114] In some embodiments of the present invention, R6 is selected from... Other variables are as defined in this invention.

[0115] In some embodiments of the present invention, the respective R c The elements are independently selected from H, F, Cl, Br, OH, CN, CH3, CH2CH3, CH2CF3, OCH3, OCF3, and Other variables are as defined in this invention.

[0116] In some embodiments of the present invention, the R 10 The group is selected from tetrahydropyrrole, hexahydro-1H-pyrrolizinyl, and 1,2,3,4-tetrahydroisoquinolinyl, wherein the tetrahydropyrrole, hexahydro-1H-pyrrolizinyl, and 1,2,3,4-tetrahydroisoquinolinyl are optionally surrounded by 1, 2, or 3 R groups. c Replacement, other variables as defined in this invention.

[0117] In some embodiments of the present invention, the R 10 Selected from Other variables are as defined in this invention.

[0118] This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0119] Selected from single or double bonds;

[0120] T1 is selected from CR7R8 and NR9;

[0121] when Selected from single bonds, T2 is selected from CH and N;

[0122] when T2 is selected from a double bond;

[0123] R1, R2, R3, R4, and R5 are independently selected from H and C, respectively. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. a replace;

[0124] R6 is selected from phenyl and naphthyl groups, wherein the phenyl and naphthyl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. b replace;

[0125] R7 and R8 are independently selected from H, CH3 and NH2, respectively;

[0126] R9 is selected from H and CH3;

[0127] Alternatively, R1 and R2 can form rings with the adjacent atoms to create structural units. form Alternatively, R1 and R4 can form rings with the adjacent atoms to create structural units. form Alternatively, R4 and R5 can form rings with the adjacent atoms to create structural units. form Alternatively, R2 and R7 can form a tetrahydropyrrolidinyl group with the attached atoms;

[0128] Alternatively, R2 and R3 form C with the adjacent atoms. 3-5 Cycloalkyl groups;

[0129] Alternatively, R7 and R8 can form 4-5 membered heterocyclic alkyl groups with the atoms attached to them;

[0130] m is selected from 0, 1, or 2;

[0131] n is selected from 0, 1, or 2;

[0132] p is selected from 1 or 2;

[0133] q is selected from 1, 2, or 3;

[0134] r is selected from 1 or 2;

[0135] s is selected from 1, 2, or 3;

[0136] Each R a They were each independently selected from F, Cl, Br, and I;

[0137] Each R b The components are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3 and OCH3, respectively.

[0138] In some embodiments of the present invention, R1, R2, R3, R4, and R5 are each independently selected from H, CH3, CH2CH3, and CH(CH3)2, wherein CH3, CH2CH3, and CH(CH3)2 are optionally selected by one, two, or three Rs. a Replacement, other variables as defined in this invention.

[0139] In some embodiments of the present invention, R1, R2, R3, R4 and R5 are independently selected from H and CH3, respectively, and other variables are as defined in the present invention.

[0140] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in this invention.

[0141] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in this invention.

[0142] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in this invention.

[0143] In some embodiments of the invention, R2 and R7 form with adjacent atoms Other variables are as defined in this invention.

[0144] In some embodiments of the invention, R2 and R3 form with adjacent atoms Other variables are as defined in this invention.

[0145] In some embodiments of the invention, R7 and R8 form with adjacent atoms Other variables are as defined in this invention.

[0146] In some embodiments of the present invention, the structural unit Selected from

[0147] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in this invention.

[0148] In some embodiments of the present invention, R6 is selected from... Other variables are as defined in this invention.

[0149] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0150]

[0151] in,

[0152] Selected from single and double bonds;

[0153] T2, R6, R 11 and R 12 As defined in this invention.

[0154] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0155]

[0156] in,

[0157] Selected from single and double bonds;

[0158] T2, R6, R 11 and R 12 As defined in this invention.

[0159] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0160]

[0161] in,

[0162] Selected from single and double bonds;

[0163] z is selected from 0, 1, 2, 3, 4, and 5;

[0164] T2, R b R 11 and R 12 As defined in this invention.

[0165] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0166]

[0167] in,

[0168] Selected from single and double bonds;

[0169] R b1 R b2 R b3 R b4 R b5 R b6 and R b7 Each of the following is independently selected from H, F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl, -C(=O)C 1-3 Alkyl and C 3-5 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl, -C(=O)C 1-3Alkyl and C 3-5 The cycloalkyl group may be optionally substituted with 1, 2, 3, 4 or 5 Rs;

[0170] Each R is independently selected from F, Cl, Br, and I;

[0171] T2, R 11 and R 12 As defined in this invention.

[0172] In some embodiments of the present invention, the R b1 R b2 R b3 R b4 R b5 R b6 and R b7 The radicals are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -C≡CH, -C(=O)CH3 and cyclopropyl, wherein CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -C≡CH, -C(=O)CH3 and cyclopropyl are optionally substituted by 1, 2, 3, 4 or 5 Rs, and other variables are as defined in this invention.

[0173] In some embodiments of the present invention, the R b1 R b2 R b3 R b4 R b5 R b6 and R b7 The radicals are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CHF2, CH2F, CF3, CH2CH3, CH2CF3, CF2CF3, OCH3, OCF3, -CH=CH2, -C≡CH, -C(=O)CH3, -C(=O)CF3, and cyclopropyl, with other variables as defined in this invention.

[0174] In some embodiments of the present invention, the R b1 R b2 R b3 R b4 R b5 R b6 and R b7 The radicals are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CF3, CH2CH3, CF2CF3, -CH=CH2, -C≡CH, -C(=O)CH3 and cyclopropyl, and other variables are as defined in this invention.

[0175] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0176]

[0177] in,

[0178] Selected from single and double bonds;

[0179] T2, R b1 R b2 R b3 R b4 R b5 R b6 R b7 R 11 and R 12 As defined in this invention.

[0180] Some solutions in this invention are derived from arbitrary combinations of the above variables.

[0181] The present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof.

[0182]

[0183]

[0184]

[0185] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0186]

[0187]

[0188]

[0189] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from...

[0190]

[0191]

[0192]

[0193]

[0194]

[0195] This invention also provides the above-mentioned compounds or pharmaceutically acceptable salts thereof for the preparation of treatments for KRAS. G12D Application in drugs for mutation-related diseases.

[0196] The present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating tumor-related diseases.

[0197] Technical effect

[0198] The compound of this invention affects KRAS G12D The mutant enzyme exhibits strong inhibitory activity, effectively inhibiting p-ERK and KRAS. G12D The mutated cells exhibit good cell proliferation inhibitory activity, effectively suppressing tumor growth in vivo, and demonstrate excellent drug resistance. The compounds of this invention exhibit moderate to high plasma binding rates and good pharmacokinetic properties.

[0199] Related definitions

[0200] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0201] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0202] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0203] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0204] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0205] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0206] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0207] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0208] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0209] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0210] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0211] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0212] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0213] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key like express represent

[0214] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0215] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0216] Unless otherwise specified, the term "C" 1-3 "Alkylamino" refers to alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via an amino group. The C 1-3 Alkylamino groups include C 1-2 C3 and C2 alkylamino groups, etc. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, etc.

[0217] Unless otherwise specified, "C 2-3 "Alkenyl" is used to denote a hydrocarbon group consisting of 2 to 3 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located at any position within the group. The C... 2-3 Alkenyl groups include C3 and C2 alkenyl groups; the C 2-3 Alkenes can be monovalent, divalent, or polyvalent. C 2-3 Examples of alkenyl groups include, but are not limited to, vinyl and propenyl groups.

[0218] Unless otherwise specified, "C 2-3 "Alkyne" is used to denote a hydrocarbon group consisting of 2 to 3 carbon atoms, either straight-chain or branched, containing at least one carbon-carbon triple bond. The carbon-carbon triple bond can be located at any position within the group. It can be monovalent, divalent, or polyvalent. The C... 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, acetylenyl and propynyl.

[0219] Unless otherwise specified, the term "4-5 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated monocyclic group consisting of 4 to 5 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). Furthermore, with respect to the "4-5 membered heterocyclic alkyl", the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 4-5 membered heterocyclic alkyl group includes both 4-membered and 5-membered heterocyclic alkyl groups. Examples of 4-5 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxobutyl, thiobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.) or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.).

[0220] Unless otherwise specified, "C 3-5 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic system. 3-5 Cycloalkyl groups include C 3-4 and C 4-5 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-5 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.

[0221] Unless otherwise specified, the term "C" in this invention refers to... 6-10 "Aromatic ring" and "C" 6-10 "Aryl" can be used interchangeably; the term "C" is used interchangeably. 6-10 "Aromatic ring" or "C" 6-10 "Aryl" indicates a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated π-electron system. It can be a monocyclic, fused bicyclic, or fused tricyclic system, where each ring is aromatic. It can be monovalent, divalent, or polyvalent. 6-10 Aryl groups include C 6-9 C9, C 10 And C6 aryl, etc. C 6-10 Examples of aryl groups include, but are not limited to, phenyl and naphthyl groups (including 1-naphthyl and 2-naphthyl groups).

[0222] Unless otherwise specified, the terms "5-10-membered heteroaryl" and "5-10-membered heteroaryl" are used interchangeably in this invention. The term "5-10-membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. It can be a monocyclic, fused bicyclic, or fused tricyclic system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)).p (where p is 1 or 2). 5-10-membered heteroaryl groups can be attached to the rest of the molecule via heteroatoms or carbon atoms. These 5-10-membered heteroaryl groups include 10-membered, 9-membered, 9-10-membered, 5-8-membered, 5-7-membered, 5-6-membered, 5-membered, and 6-membered heteroaryl groups, etc. Examples of the 5-10 membered heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl, and 5-isooxazolyl), and thiazolyl (including 2-thiazolyl, 4-...). Thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indole (including 5-indole, etc.), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), or quinolinyl (including 3-quinolinyl and 6-quinolinyl, etc.).

[0223] Unless otherwise specified, the term "4-8 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 4 to 8 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding the "4-8 membered heterocyclic alkyl," the heteroatom can occupy the connection position between the heterocyclic alkyl and the rest of the molecule. The 4-8 membered heterocyclic alkyl includes 4-6, 5-6, 4, 5, and 6 membered heterocyclic alkyls, etc. Examples of 4-8 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, or dioxacycloheptyl, etc.

[0224] Unless otherwise specified, the term "5-6 membered heterocyclic alkenyl" on its own or in combination with other terms respectively refers to a partially unsaturated cyclic group consisting of 5 to 6 ring atoms comprising at least one carbon-carbon double bond, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings, and any ring in this system is non-aromatic. Furthermore, regarding the "5-6 membered heterocyclic alkenyl," the heteroatom can occupy the connection position between the heterocyclic alkenyl and the rest of the molecule. The 5-6 membered heterocyclic alkenyl includes 5-membered and 6-membered heterocyclic alkenyl groups, etc. Examples of 5-6 membered heterocyclic alkenyl groups include, but are not limited to, those mentioned above.

[0225] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0226] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by 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 invention.

[0227] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0228] The solvents used in this invention are commercially available. The following abbreviations are used in this invention: hr represents hour; LDA represents lithium diisopropylamino; B2Pin2 represents pinacol diborate; Pd(dppf)Cl2·CH2Cl2 represents [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex; DIPEA represents N,N-diisopropylethylamine; NBS represents N-bromosuccinimide; NIS represents N-iodosuccinimide; PdCl2(PPh3)2 represents bis(triphenylphosphine)palladium dichloride; CuI represents cuprous iodide; Et3N represents triethylamine; K4FeCN6 represents potassium ferrocyanide; n-BuLi represents n-butyllithium; PhNTf2 represents N-phenylbis(trifluoromethanesulfonyl)imide; Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride.

[0229] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Detailed Implementation

[0230] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0231] Reference Example 1

[0232]

[0233] Step 1: Synthesis of compound A1-2

[0234] In a dry 2L three-necked flask, sodium hydride (39.12 g, 978.08 mmol, 60%) was added to N,N-dimethylformamide (510 mL). The reaction system was a heterogeneous gray color. The mixture was cooled to 0 °C, and a solution of compound A1-1 (51 g, 407.53 mmol) in N,N-dimethylformamide (200 mL) was added dropwise under nitrogen protection. The reaction was continued at 0 °C for 0.5 hours. Then, p-methoxybenzyl chloride (140.41 g, 896.57 mmol, 122.10 mL) was added, and the mixture was slowly heated to 20 °C and stirred under nitrogen protection for 7.5 hours. The reaction solution was slowly added to 200 mL of saturated ammonium chloride and extracted with methyl tert-butyl ether (200 mL * 2). The combined organic phases were washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 ~ 10:1) to obtain compound A1-2. 1 H 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] + .

[0235] Step 2: Synthesis of compound A1-3

[0236] 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 minutes, then cooled to -60 °C, and a tetrahydrofuran (60 mL) solution of compound A1-2 (27 g, 73.88 mmol) was added. The mixture was reacted at -60 °C for 0.5 hours, and N,N-dimethylformamide (108.00 g, 1.48 mol, 113.69 mL) was quickly added. The reaction mixture was stirred at -60 °C for another 10 minutes. Add 400 mL of saturated ammonium chloride to the reaction solution, extract with methyl tert-butyl ether (200 mL * 2), wash the combined organic phases with 200 mL of saturated brine, dry with anhydrous sodium sulfate, filter, remove organic solvent under reduced pressure, and the crude product is slurried with a mixed solvent (petroleum ether: methyl tert-butyl ether = 5:1, 70 mL) for 0.5 hours, filtered, dried, concentrated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 ~ 10:1), and combine the filter cake and column chromatography to obtain compound A1-3. 1 HNMR(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] + .

[0237] Step 3: Synthesis of compound A1-4

[0238] Compound A1-3 (17.8 g, 45.24 mmol) was added to N,N-dimethylformamide (170 mL), followed by bromosuccinimide (8.05 g, 45.24 mmol). The reaction mixture was stirred at 20 °C for 20 minutes. The reaction mixture was then added to 300 mL of water and extracted with methyl tert-butyl ether (150 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was then slurried in a mixed solvent (ethyl acetate: methyl tert-butyl ether = 1:1, 50 mL) for 0.5 hours, filtered, and 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] + Step 4: Synthesis of compound A1-5

[0239] Compound A1-4 (19.3 g, 40.86 mmol) was added to N,N-dimethylformamide (190 mL). Under nitrogen atmosphere, cuprous iodide (15.56 g, 81.72 mmol) and methyl fluorosulfonyl difluoroacetate (39.25 g, 204.30 mmol, 25.99 mL) were added to the reaction mixture. The mixture was heated to 100 °C and stirred for 1 hour. After cooling, the reaction mixture was filtered through diatomaceous earth. The filtrate was added to 300 mL of water and extracted with methyl tert-butyl ether (150 mL * 2). The combined organic phases were washed with saturated brine (200 mL * 2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:0-10:1) to obtain compound A1-5. 1 H 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] + .

[0240] Step 5: Synthesis of compound A1-6

[0241] Anhydrous tetrahydrofuran (50 mL) and sodium hydride (1.17 g, 29.26 mmol, 60%) were added to a dry three-necked flask. The mixture was cooled to 0 °C, and methyl acetoacetate (3.40 g, 29.26 mmol, 3.15 mL) was added dropwise under nitrogen protection. The reaction mixture was stirred at 0 °C for 0.5 hours. Then, n-butyllithium (2.5 M, 11.70 mL) was added dropwise, and the reaction mixture was stirred at the same conditions for 0.5 hours. The mixture was then cooled to -60 °C, and a tetrahydrofuran solution of compound A1-5 (4.5 g, 9.75 mmol) (20 mL) was added dropwise. The reaction mixture was stirred at -60 °C for 0.5 hours. 100 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with 30 mL of ethyl acetate. The organic phase was washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:0-3:1) to obtain compound A1-6. 1H 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),4.3 1(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] + .

[0242] Step 6: Synthesis of compound A1-7

[0243] Compound A1-6 (3 g, 5.19 mmol) was added to anhydrous dichloromethane (30 mL), followed by N,N-dimethylformamide dimethyl acetal (742.74 mg, 6.23 mmol, 828.02 μL). The reaction mixture was stirred at 20 °C for 16 hours. Boron trifluoride diethyl ether (884.66 mg, 6.23 mmol, 769.27 μL) was added, and the mixture was stirred at 20 °C for another hour. The reaction mixture was then added to 20 mL of saturated sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted with 20 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:0-3:1) to obtain 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,1H),4.35(s,4H),3.8(s,3H),3.81(s,6H),3.38-3.29(m,1H),2.68(dd,J=3.6,16.8Hz,1H),2.39-2.24(m,3H). MS m / z:588.2[M+H] + .

[0244] Step 7: Synthesis of compound A1-8

[0245] Compound A1-7 (2.1 g, 3.57 mmol) was added to anhydrous tetrahydrofuran (21 mL), cooled to -60 °C, and under nitrogen protection, tri-sec-butylborohydride (1 M, 4.29 mL) was added. The reaction mixture was stirred at -60 °C for 0.5 hours. The reaction mixture was then added to 30 mL of saturated ammonium chloride, separated, and extracted with ethyl acetate (30 mL * 2). The combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:0 = 3:1) to obtain 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] + .

[0246] Step 8: Synthesis of Compound A1-9

[0247] Compound A1-8 (1.27 g, 2.15 mmol) was added to ethanol (15 mL) and water (3 mL), followed by sodium bicarbonate (3.62 g, 43.08 mmol, 1.68 mL) and methyl isothiourea sulfate (4.05 g, 21.54 mmol). The reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was then added to 40 mL of water and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:0-1:1) to obtain compound A1-9. 1 H NMR(400MHz, CDCl3)δ:7.22-7.14(m,4H),6.91-6.82(m,4H),6.65(dd,J=8.4Hz 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),3.8 8-3.74(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]+ .

[0248] Step 9: Synthesis of compounds A1 and A2

[0249] 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 to the reaction solution. The reaction was carried out at this temperature for 15 minutes. The reaction solution was poured into a saturated ammonium chloride aqueous solution (400 mL), and the mixture was separated. The aqueous phase was extracted with dichloromethane (50 mL * 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was slurried in a mixed solvent (petroleum ether: methyl tert-butyl ether = 20:1, 100 mL), filtered, and the filter cake was dried to obtain A1-10. 20 g of A1-10 was purified by supercritical liquid chromatography (SFC) (column: DAICELCHIRALPAK IG (250 mm * 50 mm, 10 μm); mobile phase: A (CO2) and B (0.1% NH3H2O ​​EtOH); gradient: EtOH%: 11%-11%, 8 min). A1 was obtained (column: Chiralpak IG-3, 3 μm, 0.46 cm id × 5 cm / L; mobile phase: A (CO2) and B (EtOH, containing 0.1% isopropylamine); gradient: B% = 5-50%, 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)). + Optical rotation: Concentration: 0.1682 g / 100 mL. A2 (Column: Chiralpak IG-3, 3 μm, 0.46 cm⁻¹ × 5 cm L; Mobile phase: A (CO₂) and B (EtOH, containing 0.1% isopropylamine); Gradient: B% = 5–50%, 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] + Optical rotation: Concentration: 0.3476 g / 100 mL. 1H 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).

[0250] Example 1

[0251]

[0252] Step 1: Preparation of intermediate 1-1

[0253] Compound A2 (80 mg, 105.02 μmol) and compound 1-1A (26.75 mg, 126.03 μmol) were dissolved in N,N-dimethylformamide (2 mL), and diisopropylethylamine (40.72 mg, 315.07 μmol, 54.88 μL) was added. The reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling, the organic solvent was removed under reduced pressure. The crude product was purified by thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 2:1) to obtain compound 1-1. MS m / z = 824.3 [M+H] + .

[0254] Step 2: Preparation of intermediates 1-2

[0255] Compound 1-1 (70 mg, 84.96 μmol) was dissolved in dichloromethane (2 mL), and m-chloroperoxybenzoic acid (34.50 mg, 169.92 μmol, 85% purity) was added. The reaction mixture was stirred at 20 °C for 3 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: dichloromethane: methanol = 10:1) to obtain compound 1-2. MS m / z = 856.2 [M+H] + .

[0256] Step 3: Preparation of intermediates 1-3

[0257] Compound 1-2A (12.09 mg, 75.94 μmol) was dissolved in anhydrous toluene (1 mL) under ice-water bath conditions. Sodium tert-butoxide (7.30 mg, 75.94 μmol) was added, and the reaction mixture was stirred for 30 minutes. Then, a toluene solution of compound 1-2 (50 mg, 58.42 μmol) was added, and the reaction mixture was stirred for 2 hours under ice-water bath conditions. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: dichloromethane: methanol = 10:1) to obtain compound 1-3. MS m / z = 935.3 [M+H] + .

[0258] Step 4: Preparation of the hydrochloride salt of compound 1

[0259] Compounds 1-3 (40 mg, 42.78 μmol) were dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 20 °C for 2 hours. The solvent was removed under reduced pressure, and the crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18150*30 mm*4 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 15%-45%, 9 min) to obtain the hydrochloride salt of compound 1. 1 H 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] + .

[0260] Example 2

[0261]

[0262] Step 1: Preparation of intermediate 2-1

[0263] 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 reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling, the organic solvent was removed under reduced pressure. The crude product was purified by thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 3:1) to obtain compound 2-1. MS m / z = 810.1 [M+H] + .

[0264] Step 2: Preparation of intermediate 2-2

[0265] Compound 2-1 (73 mg, 90.13 μmol) was dissolved in dichloromethane (1 mL), and m-chloroperoxybenzoic acid (36.60 mg, 180.27 μmol, 85% purity) was added. The reaction mixture was stirred at 20 °C for 15 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 1:1) to obtain compound 2-2. MS m / z = 842.0 [M+H] + .

[0266] Step 3: Preparation of intermediate 2-3

[0267] Compound 1-2A (20.80 mg, 130.66 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL) at 15 °C. Sodium tert-butoxide (12.56 mg, 130.66 μmol) was added, and the reaction mixture was stirred for 30 minutes. Compound 2-2 (55 mg, 65.33 μmol) was then added, and the reaction mixture was stirred for 1 hour at the same temperature. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: dichloromethane: methanol = 10:1) to obtain compound 2-3. MS m / z = 921.4 [M+H] + .

[0268] Step 4: Preparation of the hydrochloride salt of compound 2

[0269] Compounds 2-3 (42 mg, 45.60 μmol) were dissolved in anhydrous dichloromethane (0.5 mL), and trifluoroacetic acid (0.25 mL) was added. The reaction mixture was stirred at 15 °C for 2 hours. The solvent was removed under reduced pressure, and the crude product was purified by high-performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 12%-42%, 9 min) to obtain the hydrochloride salt of compound 2. MS m / z = 581.6 [M+H] + .

[0270] Example 3

[0271]

[0272] Step 1: Preparation of intermediate 3-1

[0273] 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 reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling, the organic solvent was removed under reduced pressure. The crude product was purified by thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 2:1) to obtain compound 3-1. MS m / z = 810.2 [M+H] + .

[0274] Step 2: Preparation of intermediate 3-2

[0275] Compound 3-1 (67 mg, 82.73 μmol) was dissolved in dichloromethane (1 mL), and m-chloroperoxybenzoic acid (33.59 mg, 165.45 μmol, 85% purity) was added. The reaction mixture was stirred at 20 °C for 5 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 1:1) to obtain compound 3-2. MS m / z = 842.4 [M+H] + .

[0276] Step 3: Preparation of intermediate 3-3

[0277] Compound 1-2A (15.13 mg, 95.02 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL) at 15 °C. Sodium tert-butoxide (9.13 mg, 95.02 μmol) was added, and the reaction mixture was stirred for 30 minutes. Compound 3-2 (40 mg, 47.51 μmol) was then added, and the reaction mixture was stirred for 1 hour at the same temperature. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: dichloromethane: methanol = 10:1) to obtain compound 3-3. MS m / z = 921.4 [M+H] + .

[0278] Step 4: Preparation of the hydrochloride salt of compound 3

[0279] 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 reaction mixture was stirred at 15 °C for 2 hours. The solvent was removed under reduced pressure, and the crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 12%-42%, 9 min) to obtain the hydrochloride salt of compound 3. MS m / z = 581.6 [M+H] + .

[0280] Example 5

[0281]

[0282] Step 1: Preparation of Intermediate 5-1

[0283] 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 reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling, the organic solvent was removed under reduced pressure. The crude product was purified by thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 5:1) to obtain compound 5-1. MS m / z = 824.3 [M+H] + .

[0284] Step 2: Preparation of intermediate 5-2

[0285] Compound 5-1 (60 mg, 72.82 μmol) was dissolved in dichloromethane (2 mL), and m-chloroperoxybenzoic acid (29.57 mg, 145.64 μmol, 85% purity) was added. The reaction mixture was stirred at 20 °C for 16 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 1:1) to obtain compound 5-2. MS m / z = 856.3 [M+H] + .

[0286] Step 3: Preparation of intermediate 5-3

[0287] 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. The reaction mixture was stirred at 20 °C for 30 minutes. Compound 5-2 (50 mg, 58.42 μmol) was then added, and the reaction mixture was stirred at the same temperature for 1 hour. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: dichloromethane: methanol = 10:1) to obtain compound 5-3. MS m / z = 935.3 [M+H] + .

[0288] Step 4: Preparation of the hydrochloride salt of compound 5

[0289] 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 reaction mixture was stirred at 20 °C for 1 hour. The solvent was removed under reduced pressure, and the crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 20%-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] + .

[0290] Example 6

[0291]

[0292] Step 1: Preparation of intermediate 6-1

[0293] 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 reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling, the organic solvent was removed under reduced pressure. The crude product was purified by thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 5:1) to obtain compound 6-1. MS m / z = 824.5 [M+H] + .

[0294] Step 2: Preparation of intermediate 6-2

[0295] Compound 6-1 (70 mg, 84.96 μmol) was dissolved in dichloromethane (1.5 mL), and m-chloroperoxybenzoic acid (34.50 mg, 169.92 μmol, 85% purity) was added. The reaction mixture was stirred at 15 °C for 6 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 1:1) to obtain compound 6-2. MS m / z = 856.4 [M+H] + .

[0296] Step 3: Preparation of intermediate 6-3

[0297] 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. The reaction mixture was stirred at 15 °C for 30 minutes. Then, a solution of compound 6-2 (50 mg, 58.42 μmol) in anhydrous tetrahydrofuran (0.2 mL) was added, and the reaction mixture was stirred at the same temperature for 1.5 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 1:1) to obtain compound 6-3. MS m / z = 935.6 [M+H] + .

[0298] Step 4: Preparation of the hydrochloride salt of compound 6

[0299] 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 reaction mixture was stirred at 15 °C for 2 hours. The solvent was removed under reduced pressure, and the crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 15%-45%, 9 min) to obtain the hydrochloride salt of compound 6. MS m / z: 595.6 [M+H] + .

[0300] Example 7

[0301]

[0302] Step 1: Preparation of intermediate 7-2

[0303] Compound 7-1 (160 mg, 487.14 μmol) was dissolved in dichloromethane (2 mL) at 20 °C, and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at this temperature for 18 hours. The organic solvent was removed under reduced pressure to give crude product 7-2, which was used directly in the next reaction without further purification.

[0304] Step 2: Preparation of intermediate 7-3

[0305] 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 reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling, a solution of compound 7-3 was obtained, which was used directly in the next reaction without further purification. MS m / z: 722.1 [M+H] + .

[0306] Step 3: Preparation of intermediate 7-4

[0307] At 20°C, the intermediate 7-3 solution obtained in step 2 was dissolved in dichloromethane (10 mL), 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 reaction mixture was stirred at this temperature for 18 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–15%) to obtain compound 7-4. 1H 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] + .

[0308] Step 4: Preparation of intermediate 7-5

[0309] Compound 7-4 (50.06 mg, 60.91 μmol) was dissolved in methanol (5 mL) at 20 °C, and potassium monoperoxysulfate (37.44 mg, 60.91 μmol) was added. The reaction mixture was stirred at this temperature for 1 hour. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: petroleum ether: ethyl acetate = 1:1) to obtain compound 7-5. MS m / z: 838.3 [M+H] + .

[0310] Step 5: Preparation of intermediate 7-6

[0311] Compound 1-2A (7.42 mg, 46.60 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL) at 20 °C. Sodium tert-butoxide (4.48 mg, 46.60 μmol) was added, and the reaction mixture was stirred at this temperature for 30 minutes. Compound 7-5 (30.04 mg, 35.85 μmol) was then added, and the reaction mixture was stirred at this temperature for 1 hour. The organic solvent was removed under reduced pressure, and the crude product was purified by thin-layer chromatography (developing solvent: dichloromethane: methanol = 10:1) to obtain compound 7-6. MS m / z = 933.5 [M+H] + .

[0312] Step 6: Preparation of the hydrochloride salt of compound 7

[0313] 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 reaction mixture was stirred at this temperature for 1 hour. The solvent was removed under reduced pressure, and the crude product was purified by high-performance liquid chromatography (HPLC) (column: Ultimate C18150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10 min) to obtain the hydrochloride salt of compound 7. MS m / z: 593.5 [M+H] + .

[0314] Example 8

[0315]

[0316] Step 1: Preparation of intermediate 8-2

[0317] Under ice-water bath conditions, sodium hydride (2.33 g, 58.28 mmol, 60% purity) was suspended in anhydrous tetrahydrofuran (120 mL), and compound 8-1 (10 g, 44.83 mmol) was added. The reaction mixture was stirred at this temperature for 1 hour, then cooled to -78 °C, and n-butyllithium (2.5 M, 30.48 mL) was added dropwise. The reaction mixture was stirred for 1 hour, and finally N,N-dimethylformamide (16.38 g, 224.15 mmol, 17.25 mL) was added. The resulting reaction mixture was stirred for 0.5 hours. The reaction was quenched with 2 M hydrochloric acid aqueous solution (10 mL), and then extracted with ethyl acetate (50 mL * 3). The organic phases were combined, 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 obtain 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).

[0318] Step 2: Preparation of intermediate 8-3

[0319] Compound 8-2 (3.0 g, 17.42 mmol) was dissolved in anhydrous dichloromethane (50 mL) under ice-water bath conditions. Diisopropylethylamine (6.76 g, 52.27 mmol, 9.10 mL) and chloromethyl ether (2.10 g, 26.14 mmol, 1.99 mL) were added, and the reaction mixture was stirred for 2 hours. The organic solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The residue was washed with water (10 mL x 3) and saturated brine (10 mL), and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–10%) to obtain compound 8-3. 1 H NMR(400MHz, CDCl3)δ:10.40(s,1H),9.14-9.11(m,1H),7.82-7.80(m,1H),7.7 8-7.77(m,1H),7.69-7.67(m,1H),7.57-7.55(m,2H),5.36(s,2H),3.55(s,3H).

[0320] Step 3: Preparation of intermediate 8-4

[0321] Under nitrogen protection, sodium hydride (414.37 mg, 10.36 mmol, 60% purity) was suspended in anhydrous tetrahydrofuran (8 mL). The mixture was cooled to 0 °C, and methyl acetoacetate (1.20 g, 10.36 mmol, 1.11 mL) was added dropwise. The reaction mixture was stirred for 30 minutes, and n-butyllithium (2.5 M, 4.14 mL) was added dropwise. The reaction mixture was stirred for another 30 minutes. The reaction mixture was cooled to -78 °C, and an anhydrous tetrahydrofuran solution of compound 8-3 (1.12 g, 5.18 mmol) (2 mL) was added dropwise. The reaction mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (80 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–75%) to obtain 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] + .

[0322] Step 4: Preparation of intermediate 8-5

[0323] 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 reaction mixture was stirred at this temperature for 2 hours. The reaction mixture was then cooled to 0 °C, and boron trifluoride diethyl ether (1.04 g, 7.31 mmol, 902.37 μL) was added. The reaction mixture was stirred for 1 hour. The organic solvent was removed under reduced pressure. The crude product was then washed with ethyl acetate (100 mL), water (20 mL), saturated sodium bicarbonate aqueous solution (20 mL), and saturated brine (10 mL). 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 obtain 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] + .

[0324] Step 5: Preparation of intermediate 8-6

[0325] Under nitrogen protection, compound 8-5 (1.42 g, 4.15 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL). The reaction solution was cooled to -78 °C, and tri-sec-butylborohydride (1 M, 4.15 mL) was added dropwise. The reaction solution was stirred at this temperature for 1 hour. The reaction solution was quenched with water (1 mL), diluted with ethyl acetate (80 mL), and the organic phase was washed with water (20 mL) and saturated brine (20 mL). The solution was 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] + .

[0326] Step 6: Preparation of intermediate 8-7

[0327] Under nitrogen protection, compound 8-6 (1.14 g, 3.31 mmol) and 2-methylthiourea (1.87 g, 9.93 mmol) were added to ethanol (20 mL), followed by sodium carbonate (1.05 g, 9.93 mmol). The reaction mixture was heated to 60 °C and stirred for 15 hours. The organic solvent was removed under reduced pressure. Water (15 mL) and ethyl acetate (100 mL) were added to the residue, and the pH was adjusted to 5-6 with 6 M hydrochloric acid solution. The mixture was separated, and the organic phase was washed with saturated brine (20 mL). The organic solvent was removed under reduced pressure to obtain crude compound 8-7, which was used directly in the next reaction without further purification. MS m / z: 385.1 [M+H] + .

[0328] Step 7: Preparation of intermediate 8-8

[0329] 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(trifluoromethanesulfonate)imide (1.87 g, 5.24 mmol) were added. The reaction mixture was stirred at this temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (20 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–10%) to obtain 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),5.50-5.4 7(m,1H),5.32(s,2H),5.06-5.02(m,1H),4.94-4.90(m,1H),3.54(s,3H),3.40-3.22(m,2H),2.55(s,3H).MS m / z:517.0[M+H] + .

[0330] Step 8: Preparation of intermediates 8-9

[0331] 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 reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling, 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 obtain 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] + .

[0332] Step 9: Preparation of intermediates 8-10

[0333] Compounds 8-9 (270 mg, 466.55 μmol) were dissolved in dichloromethane (2.5 mL) at 15 °C, and m-chloroperoxybenzoic acid (189.44 mg, 933.09 μmol, 85% purity) was added. The reaction mixture was stirred at this temperature for 18 hours. The organic solvent was removed under reduced pressure, and the 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] + Step 10: Preparation of intermediate 8-11

[0334] Compound 1-2A (125.13 mg, 785.96 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL) at 15 °C. Sodium tert-butoxide (75.53 mg, 785.96 μmol) was added, and the reaction mixture was stirred at this temperature for 1 hour. Compound 8-10 (240 mg, 392.98 μmol) was then added, and the reaction mixture was stirred at this temperature for 0.5 hours. 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 8-11. MS m / z = 690.3 [M+H] + .

[0335] Step 11: Preparation of the hydrochloride salt of compound 8

[0336] Compound 8-11 (53 mg, 76.83 μmol) was dissolved in a dioxane solution of hydrogen chloride (2 mL, 4 M) at 18 °C, and the reaction mixture was stirred at this temperature for 30 minutes. The solvent was removed under reduced pressure, and the crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*30 mm*4 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 9%-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] + .

[0337] Example 9

[0338]

[0339] Step 1: Preparation of intermediate 9-6

[0340] Under nitrogen protection, sodium hydride (346.70 mg, 8.67 mmol, 60% purity) was suspended in anhydrous tetrahydrofuran (10 mL). The mixture was cooled to 0 °C, and methyl propionyl acetate (1.13 g, 8.67 mmol, 1.07 mL) was added dropwise. The reaction mixture was stirred for 30 minutes, and n-butyllithium (2.5 M, 3.47 mL) was added dropwise. The reaction mixture was stirred for another 30 minutes. The reaction mixture was cooled to -78 °C, and an anhydrous tetrahydrofuran (10 mL) solution of compound A1-5 (2.0 g, 4.33 mmol) was added dropwise. The reaction mixture was stirred at this temperature for 1.5 hours. The reaction solution was quenched with 0.5M hydrochloric acid aqueous solution (20 mL), separated, and the aqueous phase was extracted with ethyl acetate (50 mL * 2). The combined organic phases were washed with 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 = 0–35%) to give compound 9-6. MS m / z: 614.5 [M + Na] + .

[0341] Step 2: Preparation of intermediate 9-7

[0342] 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 reaction mixture was stirred at this temperature for 18 hours. The organic solvent was removed under reduced pressure, and 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] + .

[0343] Step 3: Preparation of intermediate 9-8

[0344] Under nitrogen protection, compound 9-7 (750 mg, 1.25 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The reaction solution was cooled to -78 °C, and tri-sec-butylborohydride (1 M, 1.25 mL) was added dropwise. The reaction solution was stirred at this temperature for 1 hour. The reaction solution was quenched with 0.5 M hydrochloric acid aqueous solution (5 mL), extracted with ethyl acetate (100 mL), washed with 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 = 0–20%) to give compound 9-8. MS m / z: 604.2 [M+H] + .

[0345] Step 4: Preparation of intermediate 9-9

[0346] Under nitrogen protection, compounds 9-8 (750 mg, 1.24 mmol) and 2-methylthiourea (701.63 mg, 3.73 mmol) were added to ethanol (10 mL), followed by sodium carbonate (263.39 mg, 2.49 mmol). The reaction mixture was heated to 60 °C and stirred for 15 hours. The organic solvent was removed under reduced pressure. Water (10 mL) was added to the residue, and the pH was adjusted to 5-6 with 2 M hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (10 mL) and the organic solvent was removed under reduced pressure to obtain crude compound 9-9. This compound was used directly in the next reaction without further purification. MS m / z: 666.4 [M + Na] + .

[0347] Step 5: Preparation of intermediate 9-10

[0348] Compound 9-9 (855 mg, 1.33 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 20 °C, followed by the addition of N,N-diisopropylethylamine (515.68 mg, 3.99 mmol, 694.99 μL) and N-phenylbis(trifluoromethanesulfonate)imide (570.17 mg, 1.60 mmol). The reaction mixture was stirred at this temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (15 mL x 4), dried over anhydrous sodium sulfate, filtered, 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 9-10. MS m / z: 776.1 [M+H] + .

[0349] Step 6: Preparation of intermediate 9-11

[0350] Compounds 9-10 (240 mg, 309.38 μmol) and 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 reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling, 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 compound 9-11. MS m / z: 838.5 [M+H] + .

[0351] Step 7: Preparation of intermediates 9-12

[0352] Compound 9-11 (260 mg, 310.28 μmol) was dissolved in dichloromethane (2 mL) at 20 °C, and m-chloroperoxybenzoic acid (125.98 mg, 620.55 μmol, 85% purity) was added. The reaction mixture was stirred at this temperature for 15 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–25%) to obtain compound 9-12. MS m / z = 870.3 [M+H] + .

[0353] Step 8: Preparation of intermediates 9-13

[0354] Compound 1-2A (101.56 mg, 637.96 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL) at 20 °C. Sodium tert-butoxide (40.87 mg, 425.31 μmol) was added, and the reaction mixture was stirred at this temperature for 1 hour. Compound 9-12 (185 mg, 212.65 μmol) was then added, and the reaction mixture was stirred at this temperature for another hour. The organic solvent was removed under reduced pressure, and the 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] + .

[0355] Step 9: Preparation of Compound 9

[0356] Compound 9-13 (151 mg, 159.11 μmol) was dissolved in trifluoroacetic acid (1.2 mL) at 20 °C, and the reaction mixture was stirred at this temperature for 1 hour. The solvent was removed under reduced pressure, and the crude product was purified by high performance liquid chromatography (HPLC) (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (0.5% 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] + .

[0357] Example 10

[0358]

[0359] Step 1: Preparation of intermediate 10-1

[0360] Under nitrogen protection, compound A1-7 (518 mg, 881.62 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL). The reaction solution was cooled to -78 °C, and lithium dimethyl copper (0.5 M, 5.29 mL) was added dropwise. The reaction solution was stirred at this temperature for 0.5 hours. The reaction solution was then added to water (10 mL) and ethyl acetate (50 mL), filtered, and separated. The aqueous phase was extracted with ethyl acetate (20 mL * 3). The organic phases were combined, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–20%) 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] + .

[0361] Step 2: Preparation of intermediate 10-2

[0362] Under nitrogen protection, compound 10⁻¹ (488 mg, 808.48 μmol) and 2-methylthiourea (456.53 mg, 2.43 mmol) were added to ethanol (5 mL), followed by sodium carbonate (171.38 mg, 1.62 mmol). The reaction mixture was heated to 60 °C and stirred for 32 hours. The organic solvent was removed under reduced pressure. Water (20 mL) was added to the residue, and the pH was adjusted to 5-6 with 2 M hydrochloric acid solution. The mixture was extracted with ethyl acetate (100 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to obtain crude compound 10⁻². This compound was used directly in the next reaction without further purification. MS m / z: 644.3 [M + H] + .

[0363] Step 3: Preparation of intermediate 10-3

[0364] Compound 10⁻² (502 mg, 779.88 μmol) was dissolved in N,N-dimethylformamide (5 mL) at 20 °C. N,N-diisopropylethylamine (302.38 mg, 2.34 mmol, 407.52 μL) and N-phenylbis(trifluoromethanesulfonate)imide (417.92 mg, 1.17 mmol) were added, and the reaction mixture was stirred at this temperature for 2 hours. The organic solvent was removed under reduced pressure, and the 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] + .

[0365] Step 4: Preparation of intermediate 10-4

[0366] 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 reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling, 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] + .

[0367] Step 5: Preparation of intermediate 10-5

[0368] Compound 10⁻⁴ (105.00 mg, 125.30 μmol) was dissolved in dichloromethane (2 mL) at 20 °C, and m-chloroperoxybenzoic acid (50.88 mg, 250.61 μmol, 85% purity) was added. The reaction mixture was stirred at this temperature for 1.5 hours. The organic solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–35%) to give compound 10⁻⁵. MS m / z = 870.3 [M + H] + Step 6: Preparation of intermediate 10-6

[0369] Compound 1-2A (47.21 mg, 296.56 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL) at 20 °C. Sodium tert-butoxide (19.00 mg, 197.71 μmol) was added, and the reaction mixture was stirred at this temperature for 1 hour. Compound 10-5 (86.00 mg, 98.85 μmol) was then added, and the reaction mixture was stirred at this temperature for another hour. The organic solvent was removed under reduced pressure. The crude product was then added to saturated brine (1 mL) and ethyl acetate (5 mL), separated, and the organic solvent was removed under reduced pressure. 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] + .

[0370] Step 7: Preparation of formate of compound 10

[0371] Compound 10-6 (75.00 mg, 79.03 μmol) was dissolved in 1.5 mL of trifluoroacetic acid at 20 °C, and the reaction mixture was stirred at this temperature for 30 minutes. The solvent was removed under reduced pressure, and the crude product was purified by high performance liquid chromatography (column: Phenomenex C18 150*40 mm*5 μm; mobile phase: [water (0.025% formic acid)-acetonitrile]; (acetonitrile)%: 5%-35%, 10 minutes) 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] + .

[0372] Example 11

[0373]

[0374] Step 1: Preparation of intermediate 11-2

[0375] Dissolve 11-1 (10 g, 44.39 mmol, 1 eq) in THF (100 mL), and add LDA (2 M, 24.41 mL, 1.1 eq) dropwise at -78 °C. After the addition is complete, continue stirring for 0.5 hr. Then add 11-2A (18.30 g, 46.61 mmol, 1.05 eq) in THF (50 mL), and stir for 0.5 hr. Stir at room temperature for 0.5 hr. Quench the reaction with saturated ammonium chloride solution, extract with ethyl acetate (500 mL * 2), combine the extracted organic phases, wash with 1 L saturated brine, dry with anhydrous sodium sulfate, filter, and evaporate to dryness. Separate 11-2 by column chromatography (eluent: 10% ethyl acetate / petroleum ether).

[0376] Step 2: Preparation of intermediate 11-3

[0377] 11-2 (15.2 g, 42.54 mmol, 1 eq), B2Pin2 (12.96 g, 51.04 mmol, 1.2 eq), Pd(dppf)Cl2·CH2Cl2 (3.47 g, 4.25 mmol, 0.1 eq), and KOAc (12.52 g, 127.61 mmol, 3 eq) were dissolved in 1,4-dioxane (130 mL) and reacted at 90 °C for 16 h under nitrogen protection. After cooling to room temperature, the mixture was passed through diatomaceous earth and separated by column chromatography (eluent: 10% ethyl acetate / petroleum ether) to obtain 11-3.

[0378] Step 3: Preparation of intermediate 11-4

[0379] To a mixed solution of A2 (3.3 g, 4.33 mmol) and 11-3 (2.18 g, 6.50 mmol) in 30 mL of 1,4-dioxane and 1 mL of water, sodium carbonate (1.38 g, 13.00 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (530.68 mg, 649.84 μmol) were added. The mixture was purged three times with nitrogen, and the system was stirred and heated at 90 °C for 12 hours. The mixture was filtered, the filtrate was evaporated to dryness, and 11-4 was obtained by column chromatography (eluent: 10–20% ethyl acetate / petroleum ether). MS m / z: 821.4 [M+H] + .

[0380] Step 4: Preparation of intermediate 11-5

[0381] To a solution of 11-4 (530 mg, 645.61 μmol) in 50 mL of dichloromethane, m-chloroperoxybenzoic acid (131.07 mg, 645.61 μmol) was added, and the mixture was stirred at 20 °C for 0.5 h. The reaction solution was washed successively with 30 mL of saturated sodium bicarbonate solution and 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. 11-5 was obtained by column chromatography (eluent: 20–60% ethyl acetate / petroleum ether). MS m / z: 859.3 [M+Na] + .

[0382] Step 5: Preparation of intermediate 11-6

[0383] At 20 °C, sodium tert-butoxide (99.21 mg, 1.03 mmol) was added to a solution of 1-2A (164.35 mg, 1.03 mmol) in 15 mL of tetrahydrofuran. The mixture was stirred at this temperature for 0.5 h. Then, 11-5 (720.00 mg, 860.29 μmol) was added, and stirring continued for another 0.5 h. The reaction mixture was diluted with 80 mL of ethyl acetate, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was then separated by column chromatography (eluent: 0–5% methanol / dichloromethane) to obtain 11-6. MS m / z: 932.4 [M+H] + .

[0384] Step 6: Preparation of intermediate 11-7

[0385] Palladium hydroxide (467.12 mg, 3.33 mmol) was added to a 40 mL ethanol solution of compound 11-6 (620 mg, 665.22 μmol). The mixture was reacted at 50 °C under a hydrogen pressure of 50 psi for 15 hours. The mixture was filtered, and the filtrate was evaporated to dryness to obtain 11-7. MS m / z: 934.4 [M+H] + .

[0386] Step 7: Preparation of hydrochloride salts of compound 11A and compound 11B

[0387] To a solution of 11-7 (500 mg, 535.31 μmol, 1 eq) in dichloromethane (5 mL), 5 mL of trifluoroacetic acid was added. The mixture was stirred at 20 °C for 1 hour. The reaction solution was then evaporated to dryness. The hydrochloride salts of compound 11A and compound 11B were separated by preparative HPLC (column: Ultimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 10%-30%, 10 min). MS m / z = 594.1 [M+H] + The hydrochloride of 11A: 1¹H 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).

[0388] Example 12

[0389]

[0390]

[0391] Step 1: Preparation of Intermediate 12-1

[0392] Under nitrogen protection, starting material A1-4 (5 g, 10.59 mmol) and copper powder (3.36 g, 52.93 mmol) were added to a 100 mL sealed container, followed by DMSO (40 mL) and pentafluoroiodoethane (5.21 g, 21.17 mmol). After sealing, the mixture was heated to 120 °C and stirred for 12 hours. 50 mL of saturated brine and 200 mL of methyl tert-butyl ether were added to the reaction mixture, and the mixture was stirred for 10 minutes. The mixture was filtered, and the aqueous phase was removed by separation under reduced pressure. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 5% ethyl acetate / petroleum ether) to obtain compound 12-1. MS m / z = 512.1 [M+H] + .

[0393] Step 2: Preparation of intermediate 12-2

[0394] Under nitrogen protection in an ice-water bath at 0°C, sodium hydride (1.56 g, 39.10 mmol, 60% purity) was added to tetrahydrofuran (50 mL). After stirring for 15 minutes, ethyl acetoacetate (4.54 g, 39.10 mmol) was added dropwise. Stirring continued for another 15 minutes, followed by the addition of n-butyllithium (2.5 M, 15.64 mL). Stirring continued for 30 minutes, and then a tetrahydrofuran (10 mL) solution of starting material 12-1 (4 g, 7.82 mmol) was added dropwise. The resulting mixture was allowed to rise naturally to room temperature (25°C) and stirred for 1 hour. The reaction mixture was quenched by slowly adding 50 mL of saturated ammonium chloride aqueous solution. 100 mL of methyl tert-butyl ether was added and stirred for 5 minutes. The aqueous phase was removed, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 10-20% ethyl acetate / petroleum ether) to give compound 12-2. MS m / z = 628.2 [M+H] + .

[0395] Step 3: Preparation of intermediate 12-3

[0396] Under nitrogen protection at 25°C, DMF-DMA (486.09 mg, 4.08 mmol) was added dropwise to a solution of 1.6 g (2.55 mmol) of starting material 12-2 in 20 mL of dichloromethane. The mixture was stirred for 1 hour, then cooled to 0°C in an ice-water bath. Boron trifluoride diethyl ether (542.77 mg, 3.82 mmol) was added, and the mixture was stirred for 1 hour. 20 mL of saturated sodium bicarbonate aqueous solution and 30 mL of dichloromethane were added to the reaction mixture, and the mixture was stirred for 5 minutes. The aqueous phase was removed, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 10-30% ethyl acetate / petroleum ether) to give compound 12-3. MS m / z = 638.1 [M+H] + .

[0397] Step 4: Preparation of intermediate 12-4

[0398] Under nitrogen protection in a dry ice-ethyl acetate bath at 60°C, trisec-butylborohydride (1M, 1.73 mL) was added dropwise to a tetrahydrofuran (15 mL) solution of starting material 12-3. The resulting mixture was stirred for 60 minutes. 2 mL of 0.5 M HCl aqueous solution, 20 mL of saturated brine, and 50 mL of ethyl acetate were added to the reaction mixture, and the mixture was stirred for 10 minutes. The aqueous phase was removed, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 30% ethyl acetate / petroleum ether) to give compound 12-4. MS m / z = 640.2 [M+H] + .

[0399] Step 5: Preparation of intermediate 12-5

[0400] Sodium carbonate (331.43 mg, 3.13 mmol) was added to a 15 mL ethanol solution of starting material 12-4 (1 g, 1.56 mmol) and S-methylisothiourea sulfate (1.31 g, 4.69 mmol). The resulting mixture was heated to 45 °C and stirred for 12 hours. The reaction solution was concentrated under reduced pressure to remove most of the ethanol. 10 mL of 0.5 M dilute hydrochloric acid and 30 mL of 2-methyltetrahydrofuran were added to the residue, and the mixture was stirred for 10 minutes to remove the aqueous phase. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: 10-30% ethyl acetate / petroleum ether) to give compound 12-5. MS m / z = 680.1 [M+H] + .

[0401] Step 6: Preparation of intermediate 12-6

[0402] Under nitrogen protection in an ice-water bath at 0°C, DIPEA (228.19 mg, 1.77 mmol) was added to a solution of reactant 12-5 (0.6 g, 882.78 μmol) in 10 mL of dichloromethane, followed by the dropwise addition of trifluoromethanesulfonic anhydride (373.60 mg, 1.32 mmol, 218.48 μL), and the mixture was stirred for 1 hour. The reaction solution was diluted with 20 mL of dichloromethane, followed by the addition of 20 mL of saturated ammonium chloride aqueous solution, and stirred for 10 minutes. The aqueous phase was removed, and the organic phase was concentrated under reduced pressure to give compound 12-6. MS m / z = 812.0 [M+H] + .

[0403] Step 7: Preparation of intermediate 12-7

[0404] Under nitrogen protection at room temperature (25°C), DIPEA (358.24 mg, 2.77 mmol) and 1-1A (235.37 mg, 1.11 mmol) were added to a 10 mL DMF solution of starting material 12-6 (0.75 g, 923.95 μmol), and the mixture was heated to 50°C and stirred for 30 minutes. 20 mL of water and 30 mL of ethyl acetate were added to the reaction mixture, and the mixture was stirred for 10 minutes. The aqueous phase was removed, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 10-20% ethyl acetate / petroleum ether) to give compound 12-7. MS m / z = 874.2 [M+H] + .

[0405] Step 8: Preparation of intermediate 12-8

[0406] Under nitrogen protection in an ice-water bath at 0°C, a solution of 0.32 g (366.16 μmol) of reactant 12-7 in 5 mL of dichloromethane was added, followed by the addition of m-chloroperoxybenzoic acid (81.77 mg, 402.77 μmol, 85% purity) and stirring for 2 hours. The solution was then diluted with 20 mL of dichloromethane, followed by the addition of 10 mL of saturated sodium bicarbonate aqueous solution and 10 mL of saturated Na₂SO₃ solution, and stirred for 10 minutes (detected by starch-potassium iodide test paper). The aqueous phase was removed, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 10-30% ethyl acetate / petroleum ether) to give compound 12-8. MS m / z = 890.2 [M+H] + .

[0407] Step 9: Preparation of intermediate 12-9

[0408] Under nitrogen protection in an ice-water bath at 0°C, sodium tert-butoxide (69.11 mg, 719.15 μmol) was added to a tetrahydrofuran (5 mL) solution of starting material 1-2A (85.87 mg, 539.36 μmol). After stirring for 30 minutes, starting material 12-8 (0.32 g, 359.57 μmol) was added, and the mixture was stirred for 1 hour. 10 mL of saturated ammonium chloride aqueous solution and 20 mL of ethyl acetate were added to the reaction mixture, and the mixture was stirred for 10 minutes. The aqueous phase was removed, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 10% methanol / dichloromethane) to give compound 12-9. MS m / z = 985.3 [M+H] + .

[0409] Step 10: Preparation of the formate of compound 12, compound 12A, and compound 12B

[0410] At room temperature (25°C), trifluoroacetic acid (0.5 mL) was added to a solution of 0.1 g (101.52 μmol) of raw material 12-9 in dichloromethane (1.5 mL), and the mixture was stirred for 4 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (0.025% formic acid)-acetonitrile]; (acetonitrile)%: 1%-35%, 8 min) to obtain the formate of 12. Chiral separation was then performed (column: DAICL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​MeOH]; (methanol)%: 40%-40%, 10 min) to obtain compound 12A (Rt = 3.473 min) and compound 12B (Rt = 4.102 min).

[0411] 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] + .

[0412] 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] + .

[0413] Example 13

[0414]

[0415] Step 1: Preparation of Intermediate 13-1

[0416] At -5°C, sodium hydrogen phosphate (10.17 g, 254.16 mmol, 60% purity) was slowly added in portions to tetrahydrofuran (500 mL), purged three times with nitrogen. After the addition was complete, methyl acetoacetate (29.51 g, 254.16 mmol) was slowly added, and the system was reacted at this temperature for 10 min. Then, n-butyllithium (2.5 M, 101.66 mL) was added dropwise, and the mixture was stirred for another 10 min after the addition was complete. The mixture was cooled to -10°C, and a tetrahydrofuran solution of Al-3 (50 g, 127.08 mmol) (100 mL) was added dropwise, and the mixture was reacted for another 10 min after the addition was complete. The reaction was quenched with 400 mL of saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (500 mL * 2). The extracted organic phases were combined, washed with 1 L of saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. 13-1 was obtained by column chromatography (eluent: 15-40% ethyl acetate / petroleum ether).

[0417] Step 2: Preparation of intermediate 13-2

[0418] To a solution of 13-1 (58.5 g, 114.80 mmol) in 350 mL of dichloromethane, dimethylformamide dimethyl acetal (21.89 g, 183.69 mmol) was added. The reaction was carried out at 25 °C for 1 hour, then cooled to 0 °C. Boron trifluoride diethyl ether (24.44 g, 172.21 mmol) was slowly added dropwise, and the reaction was continued for 15 min. 350 mL of saturated sodium bicarbonate solution was added to the system, and the mixture was extracted with dichloromethane (300 mL x 2). The extracted organic phases were combined, washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. 13-2 was obtained by column chromatography (eluent: 15–40% ethyl acetate / petroleum ether). MS m / z: 520.3 [M+H] + .

[0419] Step 3: Preparation of intermediate 13-3

[0420] At -60°C, tri-sec-butylborohydride (1M, 89.98mL) was added dropwise to a tetrahydrofuran (500mL) solution of 13-2 (42.5g, 81.80mmol), and the system was reacted at this temperature for 10min. The reaction solution was poured into 1L of 1N hydrochloric acid solution and extracted with ethyl acetate (1L*2). The extracted organic phases were combined, washed with saturated brine (1.5L), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The resulting product was separated by column chromatography (eluent: 0–10% ethyl acetate / petroleum ether) to obtain 13-3. MS m / z: 522.3 [M+H] + .

[0421] Step 4: Preparation of intermediate 13-4

[0422] Sodium carbonate (11.58 g, 109.28 mmol, 2 eq) was added to an ethanol (400 mL) solution of 13-3 (28.5 g, 54.64 mmol) and methyl isothiourea sulfate (45.63 g, 163.93 mmol). The system was stirred and heated at 50 °C for 18 hours. Most of the ethanol was removed by vacuum concentration. 400 mL of water and 400 mL of ethyl acetate were added to the system, and the pH was adjusted to 4 with 1 N hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (400 mL). The extracted organic phases were combined. The mixture was washed with 500 mL of saturated brine. Many insoluble solids were present in the organic phase. The solids were filtered off and dried to obtain 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,2H),4.15(s,4H),3.71(s,6H),2.80-2.64(m,2H),2.47(s,3H),2.14(s,3H). MS m / z:562.2[M+H] + .

[0423] Step 5: Preparation of intermediate 13-5

[0424] To a solution of 13-4 (24.5 g, 43.62 mmol, 1 eq) in 300 mL of N,N-dimethylformamide, diisopropylethylamine (16.91 g, 130.86 mmol) was added, followed by N-phenyltrifluoromethylsulfonamide (18.70 g, 52.34 mmol). The mixture was stirred at 20 °C for 0.5 h. The reaction solution was diluted with 1.5 L of ethyl acetate, washed successively with water (800 mL x 2) and saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. 13-5 was obtained by column chromatography (eluent: 0–10% ethyl acetate / petroleum ether). MS m / z: 694.1 [M+H] + .

[0425] Step 6: Preparation of intermediate 13-6

[0426] Add 1-1A (7.24 g, 34.09 mmol) to a solution of 13-5 (21.5 g, 30.99 mmol) in N'N-dimethylformamide (150 mL), heat the system at 90 °C for 1 hour, evaporate the reaction solution to dryness, and separate 13-6 by column chromatography (eluent: 5-20% ethyl acetate / petroleum ether). 1H NMR(400MHz, CDCl3) δ7.19(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] + .

[0427] Step 7: Preparation of intermediate 13-7

[0428] Weigh 13-6 (1 g, 1.32 mmol, 1 eq), add DCM (30 mL) and m-CPBA (268.57 mg, 1.32 mmol, 85% purity, 1 eq), and react at 25 °C for 1 hour. Quench with sodium bicarbonate, extract with DCM, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain 13-7, which is directly added to the next step. Step 8: Preparation of intermediate 13-8

[0429] Sodium tert-butoxide (10 mg, 0.103 mmol) was added to a 50 mL solution of 1-2A (404.09 mg, 2.54 mmol, 2 eq) in toluene at 20 °C, followed by 13-7 (979.69 mg, 1.27 mmol, 1 eq). The reaction was carried out at 120 °C for 15 h. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. 13-8 was obtained by column chromatography (eluent: 0–5% methanol / dichloromethane). MS m / z: 867.3 [M+H] + Step 9: Preparation of the hydrochloride salt of compound 13

[0430] Trifluoroacetic acid (5 mL) was added to 13-8 (0.6 g, 692.02 μmol, 1 eq). The system was stirred at 55 °C for 5 hours. The reaction solution was evaporated to dryness and separated by preparative HPLC (column: Phenomenex C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10 min) to obtain the hydrochloride salt of compound 13. 1H NMR (400MHz, CD3OD) δ7.57-7.50(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] + .

[0431] Example 14

[0432]

[0433] Step 1: Synthesis of Intermediate 14-1

[0434] Compound 13-6 (200 mg, 264.57 μmol, 1 eq) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of N-chlorosuccinimide (45.93 mg, 343.94 μmol, 1.3 eq). The reaction mixture was stirred at 25 °C for 15 hours. The reaction mixture was then directly separated by high-performance liquid chromatography (HPLC) under the following conditions: (column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [water (0.025% trifluoroacetic acid)-acetonitrile]; acetonitrile %: 50%-80%, 8 min), yielding the trifluoroacetate of compound 14-1. MS m / z = 790.4 [M+H] + .

[0435] Step 2: Synthesis of intermediate 14-2

[0436] The trifluoroacetate of compound 14-1 (123 mg) was dissolved in anhydrous dichloromethane (2 mL), and then m-chloroperoxybenzoic acid (31.59 mg) was added. The reaction mixture was stirred at 15 °C for 15 hours. The reaction mixture was evaporated to dryness to obtain the crude product, which was purified by column chromatography (methanol / dichloromethane = 0–3%) to give 14-2. MS m / z = 806.2 [M+H] + .

[0437] Step 3: Synthesis of intermediate 14-3

[0438] Compound 1-2A (37.96 mg, 238.47 μmol, 3 eq), sodium tert-butoxide (15.28 mg, 158.98 μmol, 2 eq), and compound 14-2 (64.1 mg, 79.49 μmol, 1 eq) were added to toluene (2 mL), and the mixture was stirred at 15 °C for 4 hours. The reaction solution was diluted with 30 mL of ethyl acetate, then washed with 5 mL of water and 5 mL of saturated brine. The organic phase was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (methanol / dichloromethane = 0–5%) to give compound 14-3. MS m / z = 901.3 [M+H] + .

[0439] Step 4: Synthesis of the hydrochloride salt of compound 14

[0440] Compound 14-3 (67 mg, 74.32 μmol, 1 eq) was added to trifluoroacetic acid (2 mL) and stirred at 25 °C for 4 hours. The reaction solution was evaporated to dryness, and 300 mg of sodium carbonate and 5 mL of ethyl acetate were added to the residue and stirred for 20 minutes. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was preparatively separated by high performance liquid chromatography (HPLC) (separation conditions: column: Ultimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10 min) to obtain the hydrochloride salt of compound 14, MS m / z = 561.2 [M+H). + .

[0441] Example 15

[0442]

[0443] Step 1: Preparation of Intermediate 15-1

[0444] Weigh 13-6 (2.00 g, 2.64 mmol, 1 eq), add DMF (50 mL) and NBS (940.54 mg, 5.28 mmol, 2 eq), and react at 25 °C for 4 hours. Quench with sodium bicarbonate, extract with ethyl acetate, dry to dryness with anhydrous sodium sulfate, and evaporate to dryness. Separate to 15-1 by column chromatography (eluent: 5–20% ethyl acetate / petroleum ether). MS m / z: 834.2 [M+H] + .

[0445] Step 2: Preparation of Intermediate 15-2

[0446] Weigh 15-1 (1 g, 1.32 mmol, 1 eq), add DCM (30 mL) and m-CPBA (268.57 mg, 1.32 mmol, 85% purity, 1 eq), and react at 25 °C for 1 hour. Quench with sodium bicarbonate, extract with DCM, dry to anhydrous sodium sulfate, and evaporate to dryness to obtain 15-2, which is directly added to the next step.

[0447] Step 3: Preparation of Intermediate 15-3

[0448] At 20°C, sodium tert-butoxide (10 mg, 0.103 mmol) was added to a solution of 1-2A (16 mg, 0.103 mmol) in 15 mL of tetrahydrofuran. The mixture was stirred at this temperature for 0.5 h, followed by the addition of 15-2 (73 mg, 86 μmol), and stirring continued for another 0.5 h. The reaction mixture was diluted with 10 mL of ethyl acetate, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was then separated by column chromatography (eluent: 0–5% methanol / dichloromethane) to obtain 15-3. MS m / z: 946.8 [M+H] + .

[0449] Step 4: Preparation of the hydrochloride salt of compound 15

[0450] Trifluoroacetic acid (1 mL) was added to 15-3 (40 mg, 1 eq), and the mixture was stirred at 55 °C for 2 hours. The reaction solution was evaporated to dryness, and the hydrochloride salt of compound 15 was obtained by preparative HPLC (column: Ultimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10 min). MS m / z: 605.0 [M+H] + .

[0451] Example 16

[0452]

[0453] Step 1: Preparation of Intermediate 16-1

[0454] Weigh 13-6 (1 g, 1.32 mmol, 1 eq), add DMF (25 mL), and NIS (892.85 mg, 3.97 mmol, 3 eq). React at 25 °C for 5 hours. Quench with water, extract with ethyl acetate, wash with water, and dry. Separate to 16-1 by column chromatography (eluent: 5–20% ethyl acetate / petroleum ether). MS m / z: 882.2 [M+H] + .

[0455] Step 2: Preparation of Intermediate 16-2

[0456] Weigh 16-1 (0.6 g, 680.40 μmol, 1 eq), add DCM (30 mL) and m-CPBA (138.14 mg, 680.40 μmol, 85% purity, 1 eq), and react at 25 °C for 1 hour. Quench with sodium bicarbonate, extract with DCM, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain 16-2, which is directly added to the next step.

[0457] Step 3: Preparation of intermediate 16-3

[0458] At 20°C, sodium tert-butoxide (80.28 mg, 835.34 μmol, 1.5 eq) was added to a 50 mL solution of 1-2A (132.99 mg, 835.34 μmol, 1.5 eq), followed by 16-2 (0.5 g, 556.90 μmol, 1 eq). The reaction was carried out at 25°C for 15 hours. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. 16-3 was obtained by column chromatography (eluent: 0–5% methanol / dichloromethane). MS m / z: 993.2 [M+H] + .

[0459] Step 4: Preparation of the hydrochloride salt of compound 16

[0460] Trifluoroacetic acid (5 mL) was added to 16-3 (0.3 g, 302.14 μmol, 1 eq). The mixture was stirred at 55 °C for 5 hours. The reaction solution was evaporated to dryness and separated by preparative HPLC (column: Ultimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile) %: 1%-30%, 10 min) to obtain the hydrochloride salt of compound 16. MS m / z: 653.3 [M+H] + .

[0461] Example 17

[0462]

[0463] Step 1: Preparation of Intermediate 17-1

[0464] Weigh 16-1 (0.8 g, 907.20 μmol, 1 eq), add PdCl2(PPh3)2 (127.35 mg, 181.44 μmol, 0.2 eq), CuI (51.83 mg, 272.16 μmol, 0.3 eq), EtOH (20 mL), Et3N (229.50 mg, 2.27 mmol, 315.68 μL, 2.5 eq), and trimethylsilylacetylene (330.91 mg, 1.81 mmol, 407.07 μL, 2 eq). Replace with nitrogen three times and react at 80 °C for 5 hours. Pass through diatomaceous earth, evaporate to dryness, and separate by column chromatography (eluent: 5–20% ethyl acetate / petroleum ether) to obtain 17-1. MS m / z: 936.4 [M+H] + .

[0465] Step 2: Preparation of Intermediate 17-2

[0466] Weigh 0.4 g (427.21 μmol, 1 eq) of 17-1, add 10 mL of DCM and m-CPBA (86.73 mg, 427.21 μmol, 85% purity, 1 eq), and react at 25 °C for 1 hour. Quench with sodium bicarbonate, extract with DCM, dry to anhydrous sodium sulfate, and evaporate to dryness to obtain 17-2, which can be directly added to the next step. MS m / z: 952.4 [M+H] + .

[0467] Step 3: Preparation of intermediate 17-3

[0468] At 20 °C, sodium tert-butoxide (60.55 mg, 630.05 μmol, 1.5 eq) was added to a 5 mL solution of 1-2A (100.31 mg, 630.05 μmol, 1.5 eq), followed by 17-2 (0.4 g, 420.04 μmol, 1 eq). The reaction was carried out at 25 °C for 15 h. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. This yielded 17-3. MS m / z: 1047.5 [M+H] + .

[0469] Step 4: Preparation of formate of intermediate 17-4

[0470] Trifluoroacetic acid (6 mL) was added to 17-3 (0.3 g, 302.14 μmol, 1 eq). The mixture was stirred at 25 °C for 5 hours. The reaction solution was evaporated to dryness and separated by preparative HPLC column (Xtimate C18 150*40 mm*5 μm; mobile phase: [water (0.025% formic acid)-acetonitrile]; (acetonitrile) %: 17%-57%, 8 min) to obtain the formate salt of compound 17-4. MS m / z: 707.4 [M+H]+ .

[0471] Step 5: Preparation of Compound 17

[0472] Weigh 30 mg of formate of 17-4, add 2 mL of THF and 11.86 mg of tetramethylammonium fluoride (127.30 μmol, 3 eq), and react at 60 °C for 4 h. Directly evaporate to dryness, and separate by HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (0.5% ammonia)-acetonitrile]; (acetonitrile) %: 43%-73%, 8 min) to obtain compound 17. MS m / z: 551.2 [M+H] + .

[0473] Example 18

[0474]

[0475] Step 1: Preparation of Intermediate 18-1

[0476] Weigh 16-1 (0.4 g, 453.60 μmol, 1 eq), add K4FeCN6 (36.76 mg, 99.79 μmol, 0.22 eq), Na2CO3 (48.08 mg, 453.60 μmol, 1 eq), Pd(OAc)2 (20.37 mg, 90.72 μmol, 0.2 eq), and DMAc (5 mL). Replace with nitrogen three times, and react at 120 °C for 15 h. Quench with water, extract with ethyl acetate, dry, and evaporate to dryness. Separate 18-1 by column chromatography (eluent: 5–20% ethyl acetate / petroleum ether). MS m / z: 781.2 [M+H] + .

[0477] Step 2: Preparation of intermediate 18-2

[0478] Weigh 18-1 (100 mg, 128.05 μmol, 1 eq), add DCM (10 mL) and m-CPBA (26.00 mg, 128.05 μmol, 85% purity, 1 eq), and react at 25 °C for 1 hour. Quench with sodium bicarbonate, extract with DCM, dry to anhydrous sodium sulfate, and evaporate to dryness to obtain 18-2, which can be directly added to the next step. MS m / z: 797.2 [M+H] + .

[0479] Step 3: Preparation of intermediate 18-3

[0480] At 20 °C, sodium tert-butoxide (10.97 mg, 114.19 μmol, 1.3 eq) was added to a 5 mL solution of 1-2A (27.97 mg, 175.67 μmol, 2 eq) in toluene, followed by 18-2 (70 mg, 87.84 μmol, 1 eq). The reaction mixture was then incubated at 120 °C for 5 hours. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to give 18-3. MS m / z: 892.4 [M+H] + .

[0481] Step 4: Preparation of Compound 18

[0482] Trifluoroacetic acid (5 mL) was added to 18-3 (60 mg, 108.77 μmol, 1 eq). The system was stirred at 50 °C for 2 hours. The reaction solution was evaporated to dryness. The mixture was first separated by acidic HPLC (column: Ultimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile) %: 1%-30%, 10 min), followed by alkaline separation (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (0.5% ammonia)-acetonitrile]; (acetonitrile) %: 40%-70%, 8 min) to obtain compound 18. MS m / z: 552.3 [M+H] + .

[0483] Example 19

[0484]

[0485] Step 1: Preparation of Intermediate 19-1

[0486] Weigh 16-1 (0.1 g, 113.40 μmol, 1 eq), add Pd(dppf)Cl2 (16.60 mg, 22.68 μmol, 0.2 eq), 1,4-dioxane (5 mL), H2O (1 mL), pinacol vinylborate (26.20 mg, 170.10 μmol, 28.85 μL, 1.5 eq), and K2CO3 (23.51 mg, 170.10 μmol, 1.5 eq). Replace with nitrogen three times and react at 95 °C for 15 h. Directly evaporate to dryness. Separate 19-1 by column chromatography (eluent: 5–20% ethyl acetate / petroleum ether). MS m / z: 782.3 [M+H] + .

[0487] Step 2: Preparation of Intermediate 19-2

[0488] Weigh 19-1 (0.07 g, 89.52 μmol, 1 eq), add DCM (10 mL), add m-CPBA (18.17 mg, 89.52 μmol, 85% purity, 1 eq), and react at 25 °C for 1 hour. Quench with sodium bicarbonate, extract with DCM, dry to anhydrous sodium sulfate, and evaporate to dryness to obtain 19-2, which can be directly added to the next step. MS m / z: 798.3 [M+H] + .

[0489] Step 3: Preparation of intermediate 19-3

[0490] At 20 °C, sodium tert-butoxide (9.03 mg, 93.99 μmol, 1.5 eq) was added to a 5 mL solution of 1-2A (19.95 mg, 125.32 μmol, 2 eq) in toluene, followed by 19-2 (0.05 g, 62.66 μmol, 1 eq). The reaction was carried out at 120 °C for 5 h. The reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to give 19-3. MS m / z: 893.3 [M+H] + .

[0491] Step 4: Preparation of the hydrochloride salt of compound 19

[0492] Trifluoroacetic acid (3 mL) was added to 19-3 (50 mg, 55.99 μmol, 1 eq). The system was stirred at 55 °C for 5 hours. The reaction solution was evaporated to dryness and separated by acidic HPLC (column: Ultimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10 min) to obtain the hydrochloride salt of compound 19. MS m / z: 553.3 [M+H] + .

[0493] Example 20

[0494]

[0495] Step 1: Synthesis of intermediate 20-2

[0496] Compound 20-1 (85 g, 447.34 mmol, 1 eq), potassium carbonate (154.57 g, 1.12 mol, 2.5 eq), and potassium iodide (74.26 g, 447.34 mmol, 1 eq) were added to N-methylpyrrolidone (850 mL). p-Methoxybenzyl chloride (143.62 g, 917.04 mmol, 124.89 mL, 2.05 eq) was slowly added dropwise. The system slowly exothermicly heated to 30 °C, producing significant gas, and reacted for 1 hour. The reaction solution was poured into 1 L of water, and then 500 mL of methyl tert-butyl ether was added with stirring. After separation, the organic phase was collected, and the aqueous phase was extracted with methyl tert-butyl ether (500 mL x 2). The combined organic phases were washed with saturated brine (1 L x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add 400 mL of petroleum ether to the crude product, slurry for 2 hours, filter, wash the filter cake with petroleum ether (100 mL * 2), and evaporate to dryness to obtain compound 20-2. MS m / z = 430.0 [M + H] + .

[0497] Step 2: Synthesis of intermediate 20-3

[0498] 2,2,6,6-Tetramethylpiperidine (39.39 g, 278.87 mmol, 47.34 mL, 3 eq) was added to anhydrous tetrahydrofuran (400 mL), cooled to -10 °C, purged three times with nitrogen, and n-butyllithium (2.5 M, 111.55 mL, 3 eq) was added dropwise under nitrogen protection. After reacting at -10 °C for 10 minutes, the temperature was lowered to -60 °C, and an anhydrous tetrahydrofuran solution of compound 20-2 (40 g, 92.96 mmol, 1 eq) (100 mL) was added dropwise. After reacting for 0.5 hours, N,N-dimethylformamide (67.94 g, 929.56 mmol, 71.52 mL, 10 eq) was quickly added, and the reaction was allowed to proceed for 10 minutes. The reaction solution was added to 500 mL of saturated ammonium chloride and extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then slurried in 100 mL of a mixed solvent (petroleum ether: methyl tert-butyl ether = 5:1) for 16 hours, filtered, and the filter cake was washed with petroleum ether: methyl tert-butyl ether = 5:1, 50 mL x 2, and then 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] + .

[0499] Step 3: Synthesis of intermediate 20-4

[0500] Compound 20-3 (42 g, 91.64 mmol, 1 eq) was added to N,N-dimethylformamide (210 mL), purged three times with nitrogen, and cuprous iodide (3.49 g, 18.33 mmol, 0.2 eq) was added under nitrogen protection. The mixture was heated to 80 °C, and methyl fluorosulfonyl difluoroacetate (52.82 g, 274.92 mmol, 34.98 mL, 3 eq) was added dropwise. The mixture was then heated to 100 °C and reacted for 1 hour. The reaction mixture was filtered through diatomaceous earth. The filter cake was washed with methyl tert-butyl ether (300 mL * 4), then washed with 1 L of water, then washed with 1 L of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 20-4. 1 HNMR (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] + .

[0501] Step 4: Synthesis of intermediate 20-5

[0502] Sodium hydroxide (1.27 g, 31.85 mmol, 60% purity, 2.5 eq) was dissolved in tetrahydrofuran (60 mL), purged twice with nitrogen, and then cooled to 0 °C. Methyl acetoacetate (3.70 g, 31.85 mmol, 3.42 mL, 2.5 eq) was added, and the mixture was stirred for 10 min. Then, n-butyllithium (2.5 M, 12.74 mL, 2.5 eq) was added, and the mixture was stirred for another 10 min. The mixture was cooled to -15 °C, and compound 20-4 (5.7 g, 12.74 mmol, 1 eq) in tetrahydrofuran (5 mL) was added, and the mixture was stirred for another 30 min. 100 mL of saturated ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 20-5. MS m / z = 586.2 [M + Na + .

[0503] Step 5: Synthesis of intermediate 20-6

[0504] Compound 20-5 (6 g, 10.39 mmol, 1 eq) was dissolved in dichloromethane (60 mL), followed by the addition of N,N-dimethylformamide dimethyl acetal (2.48 g, 20.78 mmol, 2.76 mL, 2 eq). The mixture was stirred at 25 °C for 12 hr, then cooled to 0 °C, and the boron trifluoride diethyl ether complex (2.65 g, 18.70 mmol, 2.31 mL, 1.8 eq) was added. The mixture was stirred at 25 °C for 1 hr. The filtrate was slowly poured into 50 mL of saturated ammonium chloride solution and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column purification (petroleum ether:ethyl acetate = 10:1) yielded compound 20-6. MS m / z = 596.1 [M + Na] + .

[0505] Step 6: Synthesis of intermediate 20-7

[0506] Compound 20-6 (4.2 g, 7.32 mmol, 1 eq) was dissolved in tetrahydrofuran (40 mL), cooled to -65 °C, and then tri-sec-butylborohydride (1 M, 8.79 mL, 1.2 eq) was added. Stirring was continued for 0.5 hr. The reaction mixture was quenched with water, and the reaction mixture was slowly poured into 10 mL of saturated ammonium chloride solution. Extraction was performed with ethyl acetate (10 mL * 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 20-7. MS m / z = 576.2 [M + H] + .

[0507] Step 7: Synthesis of intermediate 20-8

[0508] Compound 20-7 (2 g, 3.47 mmol, 1 eq) and S-methylisothiourea sulfate (4.84 g, 17.37 mmol, 5 eq) were dissolved in ethanol (40 mL) and water (5 mL), followed by the addition of sodium carbonate (1.29 g, 12.16 mmol, 3.5 eq). The mixture was stirred at 50 °C for 16 h. 50 mL of water was added to the reaction mixture, and the solution was extracted with ethyl acetate (40 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 20-8. MS m / z = 616.1 [M+H] + .

[0509] Step 8: Synthesis of intermediate 20-9

[0510] Compound 20-8 (2.25 g, 3.65 mmol, 1 eq) and N,N-diisopropylethylamine (2.83 g, 21.93 mmol, 3.82 mL, 6 eq) were dissolved in dichloromethane (20 mL), cooled to 0 °C, and then trifluoromethanesulfonic anhydride (4.64 g, 16.45 mmol, 2.71 mL, 4.5 eq) was added. The mixture was stirred at 0 °C for 0.5 hr. The reaction solution was washed with saturated ammonium chloride (20 mL), then with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The solution was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) for compound 20-9. MS m / z = 748.1 [M+H] + .

[0511] Step 9: Synthesis of intermediate 20-10

[0512] Compound 20-9 (0.35 g, 468.10 μmol, 1 eq) and N,N-diisopropylethylamine (302.50 mg, 2.34 mmol, 407.68 μL, 5 eq) were dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 1-1A (248.43 mg, 1.17 mmol, 2.5 eq). The mixture was stirred at 50 °C for 0.5 hr. 25 mL of ethyl acetate was added to the reaction mixture, followed by washing with saturated ammonium chloride (25 mL), then saturated brine (25 mL x 2), and the solution was dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated. Column purification (petroleum ether:ethyl acetate = 10:1) yielded compound 20-10. 1 H NMR (400MHz, CDCl3) δ7.24-7.27(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,8H),3.46-3.39(m,3H),2.97-3.07(m,2H),2.52(s,3H),1.93-1.99(m,3H),1.64-1.68(m,2H),1.50(s,9H). MS m / z=810.3[M+H] + .

[0513] Step 10: Synthesis of intermediate 20-11

[0514] Compound 20-10 (300 mg, 370.41 μmol, 1 eq) was dissolved in dichloromethane (3 mL), followed by the addition of m-chloroperoxybenzoic acid (97.76 mg, 481.54 μmol, 85% purity, 1.3 eq). The mixture was stirred at 15 °C for 0.5 hr. The reaction solution was diluted with 20 mL of dichloromethane, washed with 5% sodium thiosulfate (10 mL), saturated sodium bicarbonate (10 mL), and saturated brine (10 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The solution was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 20-11. MS m / z = 826.3 [M+H] + .

[0515] Step 11: Synthesis of intermediate 20-12

[0516] Dissolve 1-2A (77.10 mg, 484.31 μmol, 2.5 eq) in tetrahydrofuran (3 mL), cool to -15 °C, then add sodium tert-butoxide (37.24 mg, 387.45 μmol, 2 eq), and continue stirring at -15 °C for 0.5 hr. Then add a tetrahydrofuran solution of compound 20-11 (160 mg, 193.73 μmol, 1 eq) and continue stirring for 1 hr. Slowly pour the filtrate into 20 mL of saturated ammonium chloride solution, extract with ethyl acetate (15 mL * 2), wash the organic phase with saturated brine (20 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify by column chromatography (dichloromethane:methanol = 50:1) to give compound 20-12. MS m / z = 921.4 [M + H] + .

[0517] Step 12: Synthesis of the hydrochloride salt of compound 20, compound 20A, and compound 20B

[0518] Compound 20-12 (0.11 g, 119.43 μmol, 1 eq) was dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (1.36 g, 11.94 mmol, 884.31 μL, 100 eq) was added. The mixture was stirred at 15 °C for 5 hours. The filtrate was slowly poured into 10 mL of water, and the mixture was separated. The aqueous phase was adjusted to pH 9 with saturated sodium bicarbonate and extracted with ethyl acetate (15 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Pre-HPLC separation was performed (column: Phenomenex Luna 80 * 30 mm * 3 μm; mobile phase: [water (0.05% hydrochloric acid) - acetonitrile]; (acetonitrile) %: 5% - 25%, 8 min) to obtain the hydrochloride salt of compound 20. Chiral separation was then performed (chromatographic column: DAICEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: [0.1% ammonia and ethanol]; (ethanol)%: 40%-40%, 12min), yielding compound 20A (Rt=3.920) and compound 20B (Rt=4.275).

[0519] Compound 20A: 1 H NMR (400MHz, CDCl3) δ7.27-7.29(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] + .

[0520] 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), 4.1 MS m / z=581.2[M+H] + .

[0521] Example 21

[0522]

[0523] Step 1: Synthesis of intermediate 21-2

[0524] Compound 21-1 (20 g, 137.40 mmol, 1 eq), N,N-dimethylformamide (200 mL), potassium iodide (22.81 g, 137.40 mmol, 1 eq), and anhydrous potassium carbonate (47.47 g, 343.50 mmol, 2.5 eq) were added to a pre-dried reaction flask. While stirring, p-methoxybenzyl chloride (44.11 g, 281.67 mmol, 38.36 mL, 2.05 eq) was added, and the mixture was then heated to 65°C. The mixture was stirred at ℃ for 4 hours, then cooled to room temperature. It was then filtered through a diatomaceous earth filter, and the filter cake was washed with 200 mL of methyl tert-butyl ether. The filtrate was then extracted with 200 mL of water. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was slurried with 50 mL of petroleum ether for 48 hours, filtered, and the filter cake was collected and dried to obtain the product, 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] + .

[0525] Step 2: Synthesis of intermediate 21-3

[0526] 2,2,6,6-Tetramethylpiperidine (43.93 g, 311.00 mmol, 52.80 mL, 4 eq) was dissolved in tetrahydrofuran (300 mL), then cooled to -5 °C, and n-butyllithium (2.5 M, 124.40 mL, 4 eq) was added. The mixture was stirred for 0.5 hr, then cooled to -60 °C, and compound 21-2 (30 g, 77.75 mmol, 1 eq) in tetrahydrofuran (30 mL) was added. The mixture was stirred for 0.5 hr, then N,N-dimethylformamide (113.66 g, 1.55 mol, 119.64 mL, 20 eq) was added, and the mixture was stirred for another 0.5 hr. 200 mL of saturated ammonium chloride was added to the reaction mixture. The mixture was extracted with ethyl acetate (200 mL), separated, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The compound 21-3 was purified by column chromatography (petroleum ether: ethyl acetate = 10:1).

[0527] Step 3: Synthesis of intermediate 21-4

[0528] Sodium hydroxide (6.38 g, 159.47 mmol, 60% purity, 2.2 eq) was dissolved in tetrahydrofuran (300 mL), substituted twice with N2, and then cooled to 0 °C. Methyl acetoacetate (18.52 g, 159.47 mmol, 17.15 mL, 2.2 eq) was added, and the mixture was stirred for 10 min. Then, n-butyllithium (2.5 M, 63.79 mL, 2.2 eq) was added, and the mixture was stirred for another 10 min. The mixture was cooled to -15 °C, and compound 21-3 (30 g, 72.49 mmol, 1 eq) in tetrahydrofuran (50 mL) was added, and the mixture was stirred for another 30 min. 100 mL of saturated ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 21-4. MS m / z = 530.2 [M + H] + .

[0529] Step 4: Synthesis of intermediate 21-5

[0530] Compound 21-4 (20 g, 37.74 mmol, 1 eq) was dissolved in anhydrous dichloroethylene (50 mL). Under nitrogen protection, N,N-dimethylformamide dimethyl acetal (5.40 g, 45.28 mmol, 6.02 mL, 1.2 eq) was added, and the reaction was carried out at 25 °C for 16 h. Boron trifluoride diethyl ether (6.43 g, 45.28 mmol, 5.59 mL, 1.2 eq) was added, and the reaction was carried out at 20 °C for 1 h. The reaction solution was added to 50 mL of saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1-1:1) to give compound 21-5. 1 HNMR (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] + .

[0531] Step 5: Synthesis of intermediate 21-6

[0532] Compound 21-5 (12 g, 22.22 mmol, 1 eq) was added to anhydrous tetrahydrofuran (30 mL), and tri-sec-butylborohydride (11.83 g, 62.22 mmol, 13.60 mL, 2.8 eq) was added under nitrogen protection. The reaction mixture was reacted at -60 °C for 1 hour. The reaction solution was added to 40 mL of water and extracted with ethyl acetate (20 mL * 2). The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 = 3:1) to give compound 21-6. MS m / z = 542.2 [M + H] + .

[0533] Step 6: Synthesis of intermediates 21-7

[0534] Compound 21-6 (5.5 g, 10.15 mmol, 1 eq) was added to ethanol (15 mL) and water (3 mL), followed by sodium bicarbonate (2.15 g, 20.30 mmol, 2 eq) and methyl isothiourea sulfate (2.74 g, 30.44 mmol, 3 eq). The reaction mixture was reacted at 45–50 °C for 16 h. The reaction solution was extracted with water (20 mL) and ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The crude product was directly used in the next step to give compound 21-7. MS m / z = 582.2 [M + H] + .

[0535] Step 7: Synthesis of intermediates 21-8

[0536] Compound 21-7 (6 g, 8.04 mmol, 1 eq) was added to 20 mL of anhydrous dichloromethane. N,N-diisopropylethylamine (3.12 g, 24.12 mmol, 4.20 mL, 3 eq) 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 eq) was slowly added dropwise. The reaction was allowed to proceed at 0 °C for 0.5 hr. The reaction mixture was then added to 20 mL of saturated ammonium chloride and extracted with two 10 mL solutions of anhydrous dichloromethane. The combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to give compound 21-8. MS m / z = 714.1 [M+H] + .

[0537] Step 8: Synthesis of hydrochloride of intermediate 21-9

[0538] Compound 21-8 (0.8 g, 1.12 mmol, 1 eq), compound 1-1A (475.62 mg, 2.24 mmol, 2 eq), and DIPEA (434.33 mg, 3.36 mmol, 585.35 μL, 3 eq) 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), extracted with ethyl acetate (20 mL * 2), and the organic phases were combined. The mixture was then washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1), followed by preparative HPLC (column: Phenomenex Luna C18 250 * 50 mm * 10 μm; mobile phase: [water (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] + .

[0539] Step 9: Synthesis of intermediates 21-10

[0540] The hydrochloride salt (1.2 g) of compound 21-9 was dissolved in N,N-dimethylformamide (5 mL), cooled to 0 °C, and then N-bromosuccinimide (330.13 mg, 1.85 mmol, 1.2 eq) was added. The mixture was stirred at 20 °C for 1 hr. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by column chromatography (petroleum ether:ethyl acetate = 3:1–1:1) to give compound 21-10. MS m / z = 856.1 [M+H] + .

[0541] Step 10: Synthesis of intermediates 21-11

[0542] 10 mL of dichloromethane was added to a dry reaction flask, followed by compound 21-10 (0.3 g, 350.8 μmol, 1 eq). Stirring was initiated, and then m-chloroperoxybenzoic acid (213.6 mg, 1052.3 μmol, 85% content, 3 eq) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction solution was diluted with 10 mL of dichloromethane, washed twice with 5 mL of 5% sodium thiosulfate solution and 10 mL of saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 50%-80%, 8 min) to obtain compound 21-11. MS m / z = 872.1 [M+H]+ .

[0543] Step 11: Synthesis of hydrochloride of intermediate 21-12

[0544] Compound 1-2A (274.09 mg, 1.72 mmol, 5 eq) was added to anhydrous tetrahydrofuran (10 mL), followed by sodium tert-butoxide (148.91 mg, 1.55 mmol, 4.5 eq). The reaction was carried out at -15 °C for 30 min. Compound 21-11 (0.3 g, 344.33 μmol, 1 eq) was then added, and the reaction was carried out at -15 °C for 1 hr. 5 mL of saturated ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL * 2). The organic phases were combined, washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, and concentrated. Preparative HPLC separation was performed (column: Phenomenex Luna C18 80 * 40 mm * 3 μm; mobile phase: [water (0.05% hydrochloric acid) - acetonitrile]; (acetonitrile) %: 46%-66%, 7 min) to obtain the hydrochloride salt of compound 21-12. MS m / z = 967.3 [M+H] + .

[0545] Step 12: Synthesis of the hydrochloride salt of compound 21

[0546] The hydrochloride salt of compound 21-12 (90.00 mg) was added to anhydrous dichlorotrifluoroacetic acid (2.12 g, 18.63 mmol, 1.38 mL, 200 eq) in 7 mL of trifluoroacetic acid and reacted at -10 to 0 °C for 1 hour. The product was poured into 10 mL of water and extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and concentrated. Preparative HPLC separation was performed (column: Phenomenex Luna 80 x 30 mm x 3 μm; mobile phase: [water (0.05% hydrochloric acid) - acetonitrile]; (acetonitrile) %: 15%-35%, 8 min) to obtain the hydrochloride salt of compound 21. MS m / z = 627.1 [M + H] + .

[0547] Example 22

[0548]

[0549] Step 1: Synthesis of intermediate 22-2

[0550] Compound 22-1 (50 g, 387.28 mmol, 1 eq), potassium iodide (64.29 g, 387.28 mmol, 1 eq), and anhydrous potassium carbonate (133.81 g, 968.19 mmol, 2.5 eq) were added to N,N-dimethylformamide (500 mL). p-Methoxybenzyl chloride (121.30 g, 774.55 mmol, 105.48 mL, 2 eq) was added dropwise with stirring, and the reaction was carried out at 60 °C for 5 hours. The reaction solution was added to 300 mL of water, and ethyl acetate (200 mL x 2) was added for extraction. The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0-0:1) to give compound 22-2. MS m / z = 370.0 [M+H] + .

[0551] Step 2: Synthesis of intermediate 22-3

[0552] 2,2,6,6-Tetramethylpiperidine (81.22 g, 574.98 mmol, 97.62 mL, 4 eq) was added to anhydrous tetrahydrofuran (500 mL), cooled to -5 °C, and n-butyllithium (2.5 M, 229.99 mL, 4 eq) was added dropwise. The mixture was reacted at -5 to 0 °C for 15 minutes, cooled to -60 °C, and a tetrahydrofuran (50 mL) solution of compound 22-2 (59 g, 143.75 mmol, 1 eq) was added. The mixture was then reacted at -60 °C. After 0.5 hours, N,N-dimethylformamide (210.13 g, 2.87 mol, 221.19 mL, 20 eq) was rapidly added, and the reaction was carried out at -60 °C for 10 min. The reaction solution was poured into 300 mL of saturated ammonium chloride and extracted with methyl tert-butyl ether (100 mL * 2). The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The 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] + .

[0553] Step 3: Synthesis of intermediate 22-4

[0554] NaH (5.31 g, 132.86 mmol, 60% purity, 2.2 eq) and anhydrous tetrahydrofuran (150 mL) were reacted at 0 °C for 0.5 hr under nitrogen protection. Methyl acetoacetate (15.43 g, 132.86 mmol, 14.28 mL, 2.2 eq) was added dropwise, and the reaction was carried out at 0 °C for 0.5 hr. n-BuLi (2.5 M, 53.14 mL, 2.2 eq) was added dropwise, and the reaction was carried out at 0 °C for 0.5 hr. The mixture was then cooled to -50 °C, and an anhydrous tetrahydrofuran solution (50 mL) of compound 22-3 (24 g, 60.39 mmol, 1 eq) was added dropwise, and the reaction was carried out at -50 °C for 0.5 hr. Add 80 mL of saturated ammonium chloride solution to the reaction solution, extract with ethyl acetate (50 mL * 2), combine the organic phases, wash with 100 mL of saturated brine, dry with anhydrous sodium sulfate and concentrate, and purify the crude product by column chromatography (petroleum ether: ethyl acetate = 1:0-3:1) to obtain compound 22-4. 1 H NMR(400MHz, CDCl3)δ=7.18–7.16(m,4H),6.84-6.82(m,4H),6.76(m,1H),6.48(m1H),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] + .

[0555] Step 4: Synthesis of intermediate 22-5

[0556] Compound 22-4 (12 g, 23.37 mmol, 1 eq) was dissolved in anhydrous dichloromethane (50 mL). Under nitrogen protection, N,N-dimethylformamide dimethyl acetal (4.18 g, 35.05 mmol, 4.66 mL, 1.5 eq) was added, and the reaction was carried out at 25 °C for 16 h. Boron trifluoride diethyl ether (6.63 g, 46.74 mmol, 5.77 mL, 2 eq) was added, and the reaction was carried out at 20 °C for 1 h. The reaction mixture was added to 20 mL of saturated sodium bicarbonate solution, and the mixture was separated. The aqueous phase was further extracted with 20 mL of dichloromethane. The combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The 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] + .

[0557] Step 5: Synthesis of intermediate 22-6

[0558] Compound 22-5 (10.5 g, 20.06 mmol, 1 eq) was added to anhydrous tetrahydrofuran (30 mL), and tri-sec-butylborohydride (1 M, 22.06 mL, 1.1 eq) was added under nitrogen protection. The reaction mixture was reacted at -60 °C for 1 hour. The reactants were added to 30 mL of dilute hydrochloric acid and extracted separately with ethyl acetate (10 mL * 2). The combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-3:1) to give compound 22-6. MS m / z = 526.2 [M + H] + .

[0559] Step 6: Synthesis of intermediate 22-7

[0560] Compound 22-6 (4 g, 7.61 mmol, 1 eq) was added to ethanol (16 mL) and water (4 mL), followed by sodium bicarbonate (1.61 g, 15.22 mmol, 2 eq) and methyl isothiourea sulfate (2.06 g, 22.83 mmol, 3 eq). The reaction mixture was reacted at 45–50 °C for 16 h. The reactants were then added to 10 mL of water and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The crude product was directly added to the next step to give compound 22-7. MS m / z = 566.2 [M + H] + .

[0561] Step 7: Synthesis of intermediate 22-8

[0562] Compound 22-7 (4.8 g, 4.67 mmol, 1 eq) was added to anhydrous dichloromethane (20 mL), followed by trifluoromethanesulfonic anhydride (1.98 g, 7.00 mmol, 1.16 mL, 1.5 eq). The mixture was cooled to 0-10 °C, and N,N-diisopropylethylamine (1.81 g, 14.00 mmol, 2.44 mL, 3 eq) was slowly added dropwise. The reaction was carried out at 0 °C for 0.5 hr. The mixture was then added to 20 mL of saturated ammonium chloride. The mixture was separated from the stock solution, and the organic phase was washed with saturated brine (5 mL x 2). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-5:1) to give compound 22-8. 1H 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] + .

[0563] Step 8: Synthesis of intermediate 22-9

[0564] Compound 22-8 (3.7 g, 5.30 mmol, 1 eq), compound 1-1A (2.25 g, 10.61 mmol, 2 eq), and N,N-diisopropylethylamine (2.06 g, 15.91 mmol, 2.77 mL, 3 eq) were added to N,N-dimethylformamide (20 mL), and reacted at 50 °C for 1 hour. The reaction solution was added to 20 mL of saturated ammonium chloride, extracted with ethyl acetate (20 mL * 2), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and the 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] + .

[0565] Step 9: Synthesis of intermediate 22-10

[0566] Compound 22-9 (0.6 g, 789.58 μmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (98.37 mg, 552.70 μmol, 0.7 eq) was added. The mixture was reacted at 0-10 °C for 1 hour. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated. The product compound 22-10 was obtained by separation using preparative petroleum ether:ethyl acetate (1:1). MS m / z = 838.2 [M+H] + .

[0567] Step 10: Synthesis of intermediate 22-11

[0568] Compound 22-10 (0.3 g, 357.65 μmol, 1 eq), methyl fluorosulfonyl difluoroacetate (343.55 mg, 1.79 mmol, 227.52 μL, 5 eq), and cuprous iodide (136.23 mg, 715.31 μmol, 2 eq) were dissolved in N,N-dimethylformamide (10 mL). The mixture was purged three times with nitrogen and reacted at 100 °C for 2 hours under nitrogen protection. The reaction solution was poured into 10 mL of water and extracted with methyl tert-butyl ether (10 mL * 2). The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. Preparative HPLC was performed (column: Phenomenex Luna C18 (250*70mm, 15μm); mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile) %: 50%-98%, 20 min) for separation. The separated solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution, then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 22-11. MS m / z = 828.3 [M+H] + Step 11: Synthesis of intermediates 22-12

[0569] 10 mL of dichloromethane was added to a dry reaction flask, followed by compound 22-11 (130 mg, 157.02 μmol, 1 eq). Stirring was initiated, and then m-chloroperoxybenzoic acid (22.32 mg, 109.92 μmol, 85% purity, 0.7 eq) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction solution was diluted with 10 mL of dichloromethane, washed twice with 5 mL of 5% sodium thiosulfate solution and 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 22-12 was then separated using a preparative plate (dichloromethane:methanol = 10:1). 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), 4.44-4.22(m,6H),3.80(s,6H),3.58-3.44(m,3H),3.20-3.14(m,2H),2.97(m,4H),2.05-1.92(m,4H),1.49(s,9H), MS m / z=844.3[M+H] + .

[0570] Step 12: Synthesis of intermediates 22-13

[0571] Compound 1-2A (226.38 mg, 1.42 mmol, 20 eq) was added to anhydrous tetrahydrofuran (10 mL), followed by sodium tert-butoxide (109.32 mg, 1.14 mmol, 16 eq). The reaction was carried out at -15 °C for 15 min. Compound 22-12 (60 mg, 71.10 μmol, 1 eq) was then added, and the reaction was carried out at -15 °C for 1 hr. 5 mL of saturated ammonium chloride was added to the reaction mixture. The mixtures were combined and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and separated using a preparative plate (dichloromethane:methanol = 10:1) to obtain compound 22-13. MS m / z = 939.5 [M+H] + .

[0572] Step 13: Synthesis of the hydrochloride salt of compound 22

[0573] Compound 22-13 (60.00 mg, 63.90 μmol, 1 eq) was added to trifluoroacetic acid (1.46 g, 12.78 mmol, 946.19 μL, 200 eq) and anhydrous dichloroethylene (5 mL), and reacted at -10 to 0 °C for 1 hour. The product was poured into 10 mL of water, and the aqueous phase was extracted with ethyl acetate (5 mL * 2). The organic phases were combined, washed with saturated brine (5 mL * 2), dried over anhydrous sodium sulfate, and concentrated. Preparative HPLC separation (column: Phenomenex luna C18 80 * 40 mm * 3 μm; mobile phase: [water (0.05% hydrochloric acid) - acetonitrile]; (acetonitrile) %: 1%-30%, 7 min) yielded the hydrochloride salt of compound 22. 1HNMR (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] + .

[0574] Example 23

[0575]

[0576] Step 1: Synthesis of intermediate 23-2

[0577] Compound 23-1 (1.2 g, 4.78 mmol, 1 eq) and bis-(4-methoxybenzyl)-amine (2.46 g, 9.56 mmol, 2 eq) were added to N-methylpyrrolidone (30 mL), and the mixture was reacted in a microwave oven at 200 °C for 1 hour. The reaction solution was diluted with 250 mL of ethyl acetate, then washed with water (20 mL × 3) and 20 mL of saturated brine. The organic phase was dried, and the drying agent was removed by filtration. The solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0–35%) to give compound 23-2. MS m / z = 428.6 [M + H] + .

[0578] Step 2: Synthesis of intermediate 23-3

[0579] Compound 23-2 (4 g, 9.36 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (20 mL) and cooled to -78 °C under nitrogen protection. Then, n-butyllithium (2.5 M, 6.74 mL, 1.1 eq) was added dropwise. After the addition was complete, the mixture was stirred for 1 hour. Next, N,N-dimethylformamide (2.05 g, 28.08 mmol, 3 eq) was added dropwise, and the mixture was stirred for 0.5 hours. The reaction was quenched with 10 mL of saturated ammonium chloride and 20 mL of water, followed by extraction with ethyl acetate (50 mL × 2). The organic phases were combined and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0–15%) to give compound 23-3. 1H-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).

[0580] Step 3: Synthesis of intermediate 23-4

[0581] Compound 23-3 (2.09 g, 2.66 mmol, 1 eq) was dissolved in DMF (20 mL), and then NBS (988.15 mg, 5.55 mmol, 1 eq) was added. The reaction mixture was stirred at room temperature (20 °C) for 2 hours under nitrogen protection. The reaction mixture was diluted with 60 mL of ethyl acetate, and then washed with water (20 mL × 3) and 20 mL of saturated brine. The organic phase was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0–25%) to obtain compound 23-4.

[0582] Step 4: Synthesis of intermediate 23-5

[0583] Compound 23-4 (1.98 g, 4.34 mmol, 1 eq) and methyl fluorosulfonyl difluoroacetate (4.17 g, 2.17 mmol, 5 eq) were added to DMF (20 mL), followed by CuI (205 mg, 1.08 mol, 1 eq). The resulting reaction solution was purged with nitrogen and then stirred in an oil bath at 100 °C for 8 hours. The reaction solution was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0–25%) to give compound 23-5. MS m / z = 445.1 [M+H] + .

[0584] Step 5: Synthesis of intermediate 23-6

[0585] Sodium hydrogen sulfide (899.91 mg, 22.50 mmol, 60% purity, 2 eq) was suspended in anhydrous tetrahydrofuran (50 mL), cooled to 0 °C under nitrogen protection, and then methyl acetoacetate (2.61 g, 22.50 mmol, 2.42 mL, 2.0 eq) was slowly added dropwise, stirring for 30 minutes after the addition was complete. Then, n-butyllithium (2.5 M, 9.0 mL, 2 eq) was added dropwise, stirring 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 23-5 (5 g, 11.25 mmol, 1 eq) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the reaction was stirred for 1 hour after the addition was complete. The reaction was quenched with 20 mL of water, and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined and evaporated to dryness 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] + .

[0586] Step 6: Synthesis of intermediate 23-7

[0587] Compound 23-6 (2.9 g, 5.17 mmol, 1 eq) and N,N-dimethylformamide dimethyl acetal (1.85 g, 15.52 mmol, 2.06 mL, 3 eq) were added to anhydrous dichloromethane (20 mL). The mixture was stirred at 20 °C for 24 hours, then cooled to 0 °C. Finally, boron trifluoride diethyl ether (734.25 mg, 5.17 mmol, 636.26 μL, 1 eq) was added, and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0–40%) to give compound 23-7. MS m / z = 593.1 [M + Na] + .

[0588] Step 7: Synthesis of intermediate 23-8

[0589] Compound 23-7 (635 mg, 1.11 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (5 mL), cooled to -78 °C under nitrogen protection, and then tri-sec-butylborohydride (1 M, 1.11 mL, 1 eq) was added dropwise. The mixture was stirred for 1 hour, and the reaction was quenched with 1 mL of 1 M hydrochloric acid. Then, 20 mL of saturated brine and 50 mL of ethyl acetate were added and stirred for 5 minutes. The organic phase was separated, and the solution was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0–25%) to give compound 23-8. MS m / z = 573.2 [M+H] + .

[0590] Step 8: Synthesis of intermediates 23-9

[0591] Compound 23-8 (630 mg, 1.1 mmol, 1 eq) and 2-methylthiourea monosulfate (621.31 mg, 3.30 mmol, 3 eq) were added to anhydrous ethanol (10 mL), followed by sodium carbonate (233.24 mg, 2.2 mmol, 2 eq). The resulting reaction solution was stirred in an oil bath at 60 °C for 18 hours. The reaction solution was evaporated to dryness, and 5 mL of water and 50 mL of ethyl acetate were added to the residue. The pH was adjusted to 6-7 with 2 M hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The solvent was removed from the filtrate under reduced pressure to obtain compound 23-9. MS m / z = 613.2 [M+H] + .

[0592] Step 9: Synthesis of intermediate 23-10

[0593] Compound 23-9 (541 mg, 883.63 mmol, 1 eq) was dissolved in N,N-dimethylformamide (4 mL), followed by the addition of PhNTf2 (473.19 mg, 1.32 mmol, 1.5 eq) and N,N-diisopropylethylamine (342.38 mg, 2.65 mmol, 461.43 μL, 3 eq). The resulting reaction solution was stirred at room temperature (20 °C) for 1.5 h. The reaction solution was diluted with 100 mL of ethyl acetate, then washed with water (10 mL × 3) and 10 mL of saturated brine. The organic phase was evaporated to dryness to give the crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0–10%) to give compound 23-10. MS m / z = 745.3 [M + H] + .

[0594] Step 10: Synthesis of intermediate 23-11

[0595] Compound 23-10 (240 mg, 322.27 μmol, 1 eq) and compound 1-1A (82.1 mg, 386.72 μmol, 1.3 eq) were added to N,N-dimethylformamide (3 mL), followed by N,N-diisopropylethylamine (124.95 mg, 966.80 μmol, 168.40 μL, 3 eq). The resulting reaction solution was stirred in an oil bath at 100 °C for 1 hour. The reaction solution was evaporated to dryness to obtain the crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0–35%) to give compound 23-11. MS m / z = 807.4 [M+H] + .

[0596] Step 11: Synthesis of intermediate 23-12

[0597] Compound 23-11 (210 mg, 260.27 μmol, 1 eq) was dissolved in anhydrous dichloromethane (2 mL), and then m-chloroperoxybenzoic acid (105.67 mg, 520.49 μmol, 85% purity, 2 eq) was added. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was evaporated to dryness to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0–45%) to give compound 23-12. MS m / z = 839.3 [M+H] + .

[0598] Step 12: Synthesis of intermediates 23-13

[0599] Compound 1-2A (121.83 mg, 765.26 μmol, 3 eq) and sodium tert-butoxide (49.03 mg, 510.17 μmol, 2 eq) were added to tetrahydrofuran (2 mL) and stirred for 1 hour. Then, a tetrahydrofuran solution of compound 23-12 (214 mg, 255.09 μmol, 1 eq) (1 mL) was added, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was evaporated to dryness, and 30 mL of ethyl acetate and 5 mL of saturated brine were added to the residue and stirred until clear. The organic phase was separated, evaporated to dryness to obtain the crude product, and purified by column chromatography (methanol / dichloromethane = 0–10%) to obtain compound 23-13. MS m / z = 918.2 [M+H] + .

[0600] Step 13: Synthesis of the formate of compound 23

[0601] Compound 23-13 (194 mg, 221.32 μmol, 1 eq) was added to trifluoroacetic acid (2 mL) and stirred at 55 °C for 15 hours. The reaction solution was evaporated to dryness, and 300 mg of sodium carbonate and 5 mL of ethyl acetate were added to the residue and stirred for 20 minutes. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was preparatively separated by high performance liquid chromatography (HPLC): (Separation conditions: column: Phenomenex C18 150*40 mm*5 μm; mobile phase: [water (0.025% formic acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10 min), yielding the formate salt of compound 23. MS m / z = 578.4 [M+H] + .

[0602] Example 24

[0603]

[0604] Step 1: Synthesis of intermediate 24-1

[0605] Sodium hydroxide (866.75 mg, 21.67 mmol, 60% purity, 2 eq) was suspended in anhydrous tetrahydrofuran (50 mL), cooled to 0 °C under nitrogen protection, and then compound 24-1A (3.38 g, 21.67 mmol, 2 eq) was slowly added dropwise, stirring for 30 minutes after the addition was complete. Then, n-butyllithium (2.5 M, 8.67 mL, 2 eq) was added dropwise, stirring for 30 minutes after the addition was complete. The ice bath was removed, and the mixture was cooled to -78 °C. Finally, an anhydrous tetrahydrofuran solution of compound A1-5 (5 g, 10.84 mmol, 1 eq) was added dropwise, and the reaction was stirred for 1 hour after the addition was complete. The reaction was quenched with 30 mL of water, and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0–45%) to obtain compound 24-1. MSm / z = 640.1 [M + Na] + .

[0606] Step 2: Synthesis of intermediate 24-2

[0607] Compound 24-1 (6.50 g, 10.52 mmol, 1 eq) and N,N-dimethylformamide dimethyl acetal (3.76 g, 31.57 mmol, 4.19 mL, 3 eq) were added to anhydrous dichloromethane (20 mL). The mixture was stirred at 20 °C for 24 hours, then cooled to 0 °C. Finally, boron trifluoride diethyl ether (1.49 g, 10.52 mmol, 1.30 mL, 1 eq) was added, and the mixture was stirred at 20 °C for 4 hours. The reaction was quenched by adding 20 mL of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0–45%) to obtain compound 24-2. MS m / z = 628.2 [M+H] + Step 3: Synthesis of intermediate 24-3

[0608] Compound 24-2 (5.0 g, 7.97 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to -78 °C under nitrogen protection, and then tri-sec-butylborohydride (1 M, 7.97 mL, 1 eq) was added dropwise. After the addition was complete, the mixture was stirred for 1 hour, and the reaction was quenched with 10 mL of 1 M hydrochloric acid. The mixture was then extracted with ethyl acetate (3 × 50 mL), the organic phases were combined, and the mixture was concentrated to give a 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] + .

[0609] Step 4: Synthesis of intermediate 24-4

[0610] Compound 24-3 (2.93 g, 4.65 mmol, 1 eq) and 2-methylthiourea monosulfate (2.63 g, 13.96 mmol, 3 eq) were added to anhydrous ethanol (10 mL), followed by sodium carbonate (986.43 mg, 9.31 mmol, 2 eq). The resulting reaction solution was stirred in an oil bath at 60 °C for 18 hours. The reaction solution was evaporated to dryness, and 15 mL of water and 80 mL of ethyl acetate were added to the residue. The pH was adjusted to 6-7 with 2 M hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate was concentrated to obtain crude compound 24-4. MS m / z = 670.2 [M + H] + .

[0611] Step 5: Synthesis of intermediate 24-5

[0612] Compound 24-4 (3.15 g, 4.70 mmol, 1 eq) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of compound PhNTf2 (2.52 g, 7.06 mmol, 1.5 eq) and N,N-diisopropylethylamine (1.82 g, 14.11 mmol, 2.46 mL, 3 eq). The resulting reaction solution was stirred at room temperature (20 °C) for 2 hours. The reaction solution was evaporated to dryness to obtain the crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0–15%) to give compound 24-5. MS m / z = 802.2 [M+H] + .

[0613] Step 6: Synthesis of intermediate 24-6

[0614] Compound 24-5 (3.15 g, 4.70 mmol, 1 eq) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of compound 1-1A (2.52 g, 7.06 mmol, 1.5 eq) and N,N-diisopropylethylamine (1.82 g, 14.11 mmol, 2.46 mL, 3 eq). The resulting reaction solution was stirred at room temperature (20 °C) for 2 hours. The reaction solution was evaporated to dryness to obtain the crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0–15%) to give compound 24-6. MS m / z = 864.3 [M+H] + .

[0615] Step 7: Synthesis of intermediate 24-7

[0616] Compound 24-6 (160 mg, 185.19 μmol, 1 eq) was dissolved in anhydrous dichloromethane (2 mL), followed by the addition of m-chloroperoxybenzoic acid (75.19 mg, 370.37 μmol, 85% purity, 2 eq). The reaction mixture was stirred at 20 °C for 15 hours. The reaction mixture was evaporated to dryness to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0–25%) to give compound 24-7. MS m / z = 896.3 [M+H] + .

[0617] Step 8: Synthesis of intermediate 24-8

[0618] Compound 1-2A (35.89 mg, 225.45 μmol, 2 eq) and sodium tert-butoxide (21.67 mg, 225.45 μmol, 2 eq) were added to tetrahydrofuran (1 mL) and stirred for 1 hour. Then, a tetrahydrofuran solution of compound 24-7 (101 mg, 112.72 μmol, 1 eq) was added, and the final reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0–65%) to give compound 24-8. MS m / z = 975.4 [M+H] + .

[0619] Step 9: Synthesis of the hydrochloride salt of compound 24A and compound 24B

[0620] Compound 24-8 (94 mg, 96.40 μmol, 1 eq) was added to trifluoroacetic acid (2 mL) and stirred at 25 °C for 1 hour. The mixture was concentrated to obtain a crude product, which was then subjected to preparative separation by high-performance liquid chromatography (HPLC) under the following conditions: Phenomenex C18 150*40 mm*5 μm; mobile phase [water (0.025% formic acid)-acetonitrile]; (acetonitrile) %: 5%-35%, 10 min). Chiral separation was then performed under the following conditions: column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase: [0.1% ammonia-ethanol]; (ethanol) %: 45%-45%. The retention time was Rt = 2.034 min, yielding compound 24B. MS m / z = 635.9 [M+H] + The isomer (retention time Rt = 2.469 min) was further separated by high-performance liquid chromatography (HPLC) under the following conditions (column: Welch Ultimate C18 100*40mm*3μm; mobile phase: [water (0.025% formic acid)-acetonitrile]; (acetonitrile)%: 10%-40%, 8 min). 0.5 mL of HCl / 1,4-dioxane was added to give the hydrochloride salt of compound 24A. MS m / z = 635.8 [M+H]+ .

[0621] Example 25

[0622]

[0623] Step 1: Synthesis of Intermediate 25-1

[0624] Compound 16-1 (00 mg, 113.40 μmol, 1 eq), compound 25-1A (42.71 mg, 170.10 μmol, 47.56 μL, 50% THF solution, 1.5 eq), and potassium carbonate (31.35 mg, 226.80 μmol, 2 eq) were added to a mixed solvent of dioxane (2 mL) / water (0.4 mL), followed by the addition of Pd(dppf)Cl2 (16.60 mg, 22.68 μmol, 0.2 eq). The resulting reaction solution was purged with nitrogen and heated to 95 °C with stirring for 15 hours. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (ethyl acetate / petroleum ether = 0–30%) to obtain compound 25-1.

[0625] Step 2: Synthesis of intermediate 25-2

[0626] Compound 25-1 (72 mg, 93.51 μmol, 1 eq) was dissolved in anhydrous dichloromethane (1 mL), followed by the addition of m-chloroperoxybenzoic acid (18.98 mg, 93.51 μmol, 85% purity, 1 eq). The reaction mixture was stirred at 15 °C for 1 hour. The reaction mixture was then concentrated to obtain compound 25-2. MS m / z = 786.3 [M+H] + .

[0627] Step 3: Synthesis of intermediate 25-3

[0628] Compound 1-2A (45.57 mg, 286.27 μmol, 3 eq), sodium tert-butoxide (18.34 mg, 190.85 μmol, 2 eq), and compound 25-2 (75 mg, 95.42 μmol, 1 eq) were added to toluene (2 mL) and stirred at 15 °C for 2 hours. The reaction mixture was diluted with 30 mL of ethyl acetate, then washed with 5 mL of water and 5 mL of saturated brine. The organic phase was concentrated to obtain the crude product, which was purified by column chromatography (methanol / dichloromethane = 0–5%) to give compound 25-3. MS m / z = 881.9 [M+H] + .

[0629] Step 4: Synthesis of hydrochloride of intermediate 25

[0630] Compound 25-3 (71 mg, 80.58 μmol, 1 eq) was added to trifluoroacetic acid (2 mL), and the mixture was stirred at 50 °C for 5 hours. The reaction solution was concentrated to obtain the crude product, which was then preparatively separated by high-performance liquid chromatography (HPLC) (separation conditions: column: Ultimate C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10 min), yielding the hydrochloride salt of compound 25, MS m / z = 541.3 [M+H). + .

[0631] Example 26

[0632]

[0633] Step 1: Preparation of Intermediate 26-1

[0634] To a 10 mL solution of tetrahydrofuran (420 mg, 0.40 mmol), tetramethylammonium fluoride (150 mg, 1.61 mmol) was added, and the mixture was heated at 60 °C for 16 hours. The solution was then diluted with 50 mL of ethyl acetate, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 26-1. MS m / z: 891.6 [M+1] + .

[0635] Step 2: Preparation of intermediate 26-2

[0636] Palladium / carbon (20 mg, 10% purity) was added to a methanol (10 mL) solution of 26-1 (250 mg, 280.57 μmol, 1 eq). The mixture was stirred at 20 °C and 15 psi for 1 hour. The solution was filtered, and the filtrate was concentrated to obtain 26-2. MS m / z: 895.6 [M+1] + .

[0637] Step 3: Preparation of the hydrochloride salt of compound 26

[0638] Trifluoroacetic acid (3 mL) was added to a solution of 26-2 (220 mg, 245.79 μmol, 1 eq) in dichloromethane (3 mL), and the mixture was stirred at 45 °C for 20 hours. The reaction solution was then evaporated to dryness. The hydrochloride salt of compound 26 was obtained by preparative HPLC (column: Phenomenex C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10 min). 1H 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] + .

[0639] Example 27

[0640]

[0641] Step 1: Preparation of Intermediate 27-1

[0642] 15-3 (200 mg, 0.212 mmol) and cyclopropylboronic acid (92 mg, 1.059 mmol) were added to a mixed solution of 1,4-dioxane (10 mL) and water (1 mL), followed by the addition of diphenylphosphine ferrocene palladium dichloride (20 mg) and sodium carbonate (45 mg, 0.425 mmol). The mixture was purged three times with nitrogen and reacted at 90 °C for 15 hours. After filtration, the filtrate was evaporated to dryness and separated by preparative thin-layer chromatography (developing solvent: dichloromethane / methanol = 10:1) to obtain 27-1. MS m / z: 907.6 [M+H] + .

[0643] Step 2: Preparation of the hydrochloride salt of compound 27

[0644] To a solution of 27-1 (60 mg, 0.066 mmol) in dichloromethane (2 mL), 2 mL of trifluoroacetic acid was added. The mixture was stirred at 20 °C for 1 hour, concentrated, and then separated by preparative HPLC (column: Phenomenex C18 150*40 mm*5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; (acetonitrile)%: 1%-30%, 10 min). MS m / z: 565.5 [M+H] + .

[0645] Example 28

[0646]

[0647] Step 1: Preparation of trifluoroacetate of compound 28

[0648] Trifluoroacetic acid (0.5 mL) was added to a solution of 26-1 (50 mg, 56.11 μmol) in dichloromethane (0.5 mL). The system was stirred at 20 °C for 2 hours. The reaction solution was concentrated and the trifluoroacetate of compound 28 was obtained by preparative HPLC (column: Welch Xtimate C18 100*40 mm*3 μm; mobile phase: [water (0.025% trifluoroacetic acid)-acetonitrile]; (acetonitrile)%: 0%-30%, 8 min). 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).

[0649] Example 29

[0650]

[0651] Step 1: Synthesis of intermediate 29-2

[0652] Compound 29-1 (50 g, 139.46 mmol, 1 eq) was added to anhydrous dichloromethane (500 mL), followed by N,N-diisopropylethylenediamine (54.07 g, 418.39 mmol, 72.87 mL, 3 eq). The mixture was cooled to 0 °C, and chloromethyl methyl ether (15.59 g, 193.64 mmol, 14.71 mL, 1.39 eq) was slowly added dropwise. The mixture was then slowly heated to 18 °C and reacted for 1 hour. The reaction solution was added to 500 mL of ice water and extracted with DCM (100 mL * 2). The organic phases were combined and washed with 500 mL of saturated sodium carbonate, 500 mL of saturated ammonium chloride, and 500 mL of semi-saturated brine, respectively. After drying with anhydrous sodium sulfate, the solution was filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0–50%) to obtain compound 29-2. MS m / z = 403.2 [M + H] + .

[0653] Step 2: Synthesis of intermediate 29-3

[0654] Compound 29-2 (36 g, 89.42 mmol, 1 eq) and N,N-diisopropylethylenediamine (34.67 g, 268.27 mmol, 46.73 mL, 3 eq) were added to anhydrous dichloromethane (360 mL), cooled to -40 °C, and trifluoromethanesulfonic anhydride (37.85 g, 134.14 mmol, 22.13 mL, 1.5 eq) was added dropwise. The reaction mixture was allowed to react for 1 hour. The reaction solution was added to 300 mL of ice water, and the mixture was extracted separately. The organic phase was washed with 200 mL of saturated sodium bicarbonate solution, then with 200 mL of saturated ammonium chloride solution, and then with 200 mL of brine. After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0–30%) to give compound 29-3. 1 H 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).

[0655] Step 3: Synthesis of intermediate 29-4

[0656] Compound 29-3 (34 g, 63.59 mmol, 1 eq) was added to N,N-dimethylformamide (340 mL), followed by vinyltributyltin (42.03 g, 132.55 mmol, 38.56 mL, 2.08 eq) and lithium chloride (10.78 g, 254.38 mmol, 5.21 mL, 4 eq). The mixture was purged three times with nitrogen. Under nitrogen protection, triphenylphosphine palladium dichloride (4.46 g, 6.36 mmol, 0.1 eq) was added, and the reaction was carried out at 30 °C for 20 hours. 300 mL of 20% KF aqueous solution and 300 mL of methyl tert-butyl ether were added to the reaction mixture, and the mixture was stirred for 20 minutes. The mixture was filtered through a diatomaceous earth filter, and the filter cake was washed with methyl tert-butyl ether (50 mL x 4) to remove the aqueous phase. The organic phase was washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 20%) to give compound 29-4. MS m / z = 413.3 [M+H] + .

[0657] Step 4: Synthesis of intermediate 29-5

[0658] Compound 29-4 (20 g, 48.47 mmol, 1 eq) was added to anhydrous tetrahydrofuran (200 mL) and water (50 mL), cooled to 0 °C, and then sodium periodate (31.10 g, 145.42 mmol, 8.06 mL, 3 eq) and osmium tetroxide (1.5 g, 5.90 mmol, 306.12 μL, 1.22 e⁻¹ eq) were added. The mixture was slowly heated to 18 °C and reacted for 1 hour. The reaction solution was added to 300 mL of 10% sodium thiosulfate solution, extracted with ethyl acetate (100 mL * 2), washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 20%) to give compound 29-5. MS m / z = 415.3 [M + H] + .

[0659] Step 5: Synthesis of intermediate 29-7

[0660] N,N-diisopropylethylamine (1.05 g, 8.11 mmol) was added to a dichloromethane solution of compound 29-6 (1 g, 4.05 mmol) and 1-1A (1.03 g, 4.86 mmol), and the resulting mixture was stirred at room temperature (25 °C) for 2 hours. Water (20 mL) and dichloromethane (50 mL) were added to the reaction mixture, and the mixture was stirred for 5 minutes. The aqueous phase was removed, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 20%) to obtain compound 29-7. MS m / z = 423.1 [M+H] + .

[0661] Step 6: Synthesis of intermediate 29-8

[0662] Under nitrogen protection at 0°C in an ice-water bath, lithium aluminum hydride (0.1 g, 2.84 mmol) was added in portions to a tetrahydrofuran (5 mL) solution of compound 29-7 (0.6 g, 1.42 mmol). The resulting mixture was allowed to rise naturally to 25°C and stirred for 2 hours. Water (0.1 g), 15% sodium hydroxide aqueous solution (0.1 g), and water (0.3 g) were then added dropwise to the reaction mixture, and the mixture was stirred for 30 minutes. The mixture was filtered, and 10 mL of tetrahydrofuran was added. The filtrate was concentrated under reduced pressure to give compound 29-8. MS m / z = 381.1 [M+H] + .

[0663] Step 7: Synthesis of intermediate 29-9

[0664] Under nitrogen protection in a dry ice-ethyl acetate bath at 65°C, diisopropylaminolithium (1.51 mL, 3.02 mmol, 2 M) was added dropwise to a tetrahydrofuran (10 mL) solution of compound 29-8 (0.5 g, 1.33 mmol). After stirring for 30 minutes, a tetrahydrofuran (5 mL) solution of compound 29-5 (0.5 g, 1.51 mmol) was added dropwise. The mixture was allowed to rise naturally to 25°C. 0.1 M dilute hydrochloric acid aqueous solution (15 mL) and ethyl acetate (20 mL) were added to the reaction solution, and the mixture was stirred for 10 minutes. The aqueous phase was removed, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 20%) to give compound 29-9. MS m / z = 795.4 [M+H] + .

[0665] Step 8: Synthesis of intermediate 29-10

[0666] Under nitrogen protection in a dry ice-ethyl acetate bath at 65°C, n-butyllithium (2.5 M, 564.47 μL) was added dropwise to a tetrahydrofuran (10 mL) solution of compound 29-9 (0.51 g, 641.44 μmol). After stirring for 30 minutes, a tetrahydrofuran (3 mL) solution of p-toluenesulfonyl chloride (183.43 mg, 962.16 μmol) was added dropwise. The resulting mixture was allowed to rise naturally to 25°C and stirred for 2 hours. The reaction was quenched by adding 50 mL of saturated ammonium chloride aqueous solution, followed by extraction with 50 mL of ethyl acetate to remove the aqueous phase. The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 30%) to give compound 29-10. MS m / z = 777.4 [M+H] + .

[0667] Step 9: Synthesis of intermediates 29-11

[0668] To a solution of compound 29-10 (45 mg, 57.91 μmol) in dichloromethane (2 mL), m-chloroperoxybenzoic acid (14.11 mg, 69.49 μmol, 85% purity) was added, and the resulting mixture was stirred at room temperature (25 °C) for 2 hours. Then, 2 mL of saturated sodium bicarbonate aqueous solution, 2 mL of saturated sodium sulfite aqueous solution, and 5 mL of dichloromethane were added to the reaction mixture, and the mixture was stirred for 5 minutes. The aqueous phase was removed, and the organic phase was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 20%) to give compound 29-11. MS m / z = 793.4 [M+H] + .

[0669] Step 10: Synthesis of intermediates 29-12

[0670] Under nitrogen protection in an ice-water bath at 0°C, sodium tert-butoxide (19.39 mg, 201.76 μmol) was added to a 2 mL solution of tetrahydrofuran containing compound 1-2A (32.12 mg, 201.76 μmol). After stirring for 30 minutes, compound 29-11 (40 mg, 50.44 μmol) was added. The resulting mixture was allowed to rise naturally to 25°C and stirred for 2 hours. The pH was adjusted to approximately 6 by adding 0.5 M dilute hydrochloric acid to the reaction solution. 5 mL of ethyl acetate and 2 mL of saturated brine were added and stirred for 5 minutes. The aqueous phase was removed, and the organic phase was concentrated under reduced pressure to obtain compound 29-12. MS m / z = 888.5 [M+H] + .

[0671] Step 11: Synthesis of intermediates 29-13

[0672] A solution of compound 29-12 (45 mg, 50.67 μmol) in dichloromethane (1 mL) was added to ethyl hydrochloride (4 M, 126.67 μL). The resulting mixture was stirred at room temperature (25 °C) for 2 hours. The reaction solution was then concentrated under reduced pressure to obtain the trifluoroacetate of compound 29-13. MS m / z = 744.4 [M+H] + Step 12: Synthesis of Compounds 29A and 29B

[0673] Cesium fluoride (40.83 mg, 268.82 μmol) and potassium carbonate (22.29 mg, 161.29 μmol) were added to a DMF (1 mL) solution of compound 29-13 (40 mg, trifluoroacetate). The resulting mixture was stirred at room temperature (25 °C) for 2 hours. The reaction solution was filtered, washed with 5 mL of methanol, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (0.025% formic acid)-acetonitrile]; acetonitrile %: 10%-40%, 8 min), followed by chiral separation (column: DAICEL CHIRALCEL). OD (250mm*30mm, 10μm); mobile phase: [0.1% ammonia / methanol]; methanol %: 40%-40%, 12min), yielding compound 29A (Rt = 1.386min) and compound 29B (Rt = 2.079min). MS m / z = 588.3 [M+H] + .

[0674] Biological test data:

[0675] Experimental Example 1. KRAS G12D Inhibition activity test

[0676] 1. Purpose

[0677] Compounds that can effectively inhibit the binding of KRAS and GTP were screened using the TR-FRET method.

[0678] 2. Consumables and Instruments

[0679] Table 1. Consumables and Instruments

[0680]

[0681]

[0682] 3. Reagent preparation

[0683] a. Storage of reagents:

[0684] 1) KRAS nucleotide exchange buffer

[0685] Take 20 mL of 1000 mM HEPES, 20 mL of 500 mM EDTA, 10 mL of 5 M sodium chloride, 100% 0.1 mL of Tween 20, and 949.9 mL of water to prepare a 1 L solution. Sterilize by filtration and store at 4 °C.

[0686] 2) KRAS experimental buffer

[0687] Take 20 mL of 1000 mM HEPES, 10 mL of 1000 mM magnesium chloride, 30 mL of 5 M sodium chloride, 100% 0.05 mL of Tween 20, and 939.95 mL of water to prepare a 1 L solution. Sterilize by filtration and store at 4 °C.

[0688] 3) KRAS / Bodipy GDP / Tb-SA mixture

[0689] Take 9.5 μL of 95 μM KRAS G12D The protein was mixed with 440.5 μL of KRAS nucleotide exchange buffer and incubated at room temperature for 1 hour. Then, it was mixed with 8.4 μL of 17.9 μM Tb-SA, 1.8 μL of 5 mM Bodipy GDP, and 9539.8 μL of KRAS experimental buffer to prepare a 1 L solution. After mixing, the solution was allowed to stand at room temperature for 6 hours and then stored at -80°C.

[0690] b. Experimental reagents:

[0691] 1) KRAS enzyme solution

[0692] Take 73.3 μL of KRAS / Bodipy GDP / Tb-SA mixture and 2126.7 μL of KRAS experimental buffer to prepare a 2200 μL solution.

[0693] 2) SOS / GTP mixture

[0694] Prepare a 2200 μL solution by taking 1.59 μL of 166 μM SOS protein, 198 μL of 100 mM GTP, and 2000.41 μL of KRAS experimental buffer.

[0695] 4. Experimental Procedure

[0696] 1) The concentration of the control compound stock solution was 1 mM, and the concentration of the test compound stock solution was 10 mM. Transfer 9 μL of the control compound and the test compound to a 384-LDV plate;

[0697] 2) Use Bravo to perform a 10-point 3-fold dilution of the compound on the LDV plate;

[0698] 3) Use ECHO to transfer 9 nL of the compound from the LDV plate to the experimental plate;

[0699] 4) Using the Dragonfly autosampler, add 3 μL of 3 nM Kras / 0.5 nM TB-SA / 30 nM BodipyGDP mixture and 3 μL of Ras buffer to each well of the experimental plate, and centrifuge the experimental plate at 1000 rpm / min for 1 minute.

[0700] 5) The experimental plate was incubated at room temperature for 1 hour;

[0701] 6) Using the Dragonfly autopilot, add 3 μL of 120 nM SOS / 9 mM GTP mixture to each well of the experimental plate, and centrifuge the experimental plate at 1000 rpm / min for 1 minute.

[0702] 7) The experimental plate was incubated at room temperature for 1 hour;

[0703] 8) Use Envision to read the board and record the data;

[0704] 9) Use Excel and XLfit for data analysis to calculate the IC of the test compound. 50 .

[0705] 5. Experimental Results

[0706] The results are shown in Table 2.

[0707] Table 2. Effects of compounds on KRAS G12D Enzyme-inhibited IC 50 value

[0708] Compound numbering <![CDATA[KRAS G12D IC 50 (nM)]]> Hydrochloride salt of compound 1 2.5 Hydrochloride salt of compound 2 23 Hydrochloride salt of compound 3 425 Hydrochloride salt of compound 5 12.7 Hydrochloride salt of compound 6 30 Hydrochloride salt of compound 7 0.1 Hydrochloride salt of compound 8 78.3 Compound 9 1.1 Formate of compound 10 3.3

[0709] Experimental conclusion: The compounds of this invention exhibit significant KRAS. G12D Enzyme inhibition.

[0710] Experimental Example 2. AGS Cell p-ERK Inhibition Test

[0711] 1. Purpose

[0712] Compounds that can effectively inhibit p-ERK in AGS cells were screened using the HTRF method.

[0713] 2. Experimental Procedure

[0714] 1) AGS cells were seeded in clear 96-well cell culture plates with 80 μL of cell suspension per well, containing 10,000 cells per well. The cell culture plates were placed in a CO2 incubator and incubated overnight at 37°C.

[0715] 2) After incubation, discard the cell supernatant, add 80 μL of culture medium per well containing 0.02% serum, and place the cell plate in a CO2 incubator overnight at 37°C.

[0716] 3) Add 2 μL of the compound to 78 μL of cell culture medium, mix well, then add 20 μL of the compound solution to the corresponding wells of the cell plate, and put the cell plate back into the CO2 incubator for 3 hours.

[0717] 4) After incubation, discard the cell supernatant and add 50 μL of 1X cell lysis buffer to each well, then incubate at room temperature with shaking for 30 minutes.

[0718] 5) Dilute Phospho-ERK1 / 2Eu Cryptate antibody and Phospho-ERK1 / 2d2 antibody 20-fold using detection buffer;

[0719] 6) Transfer 16 μL of cell lysate supernatant to each well of a new 384 white microplate, then add 2 μL of Phospho-ERK1 / 2Eu Cryptate antibody dilution buffer and 2 μL of Phospho-ERK1 / 2d2 antibody dilution buffer, and incubate at room temperature for at least 4 hours;

[0720] 7) After incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm;

[0721] 8) Calculate the IC of the compound to be tested. 50 .

[0722] 3 Experimental Results

[0723] The results are shown in Table 3.

[0724] Table 3 shows the IC50 values ​​of the compounds on the inhibition of p-ERK in AGS cells. 50value

[0725] Compound numbering <![CDATA[AGS p-ERK IC 50 (nM)]]> Hydrochloride salt of compound 1 45

[0726] Experimental conclusion: The compound of this invention has a significant inhibitory effect on p-ERK in AGS cells.

[0727] Experimental Example 3. GP2D Cell p-ERK Inhibition Test

[0728] 1. Purpose

[0729] Compounds that can effectively inhibit p-ERK in GP2D cells were screened using the HTRF method.

[0730] 2. Experimental Procedure

[0731] 1) GP2D cells were seeded in clear 96-well cell culture plates, with 80 μL of cell suspension per well, containing 8000 cells per well. The cell culture plates were placed in a CO2 incubator and incubated overnight at 37°C.

[0732] 2) Add 2 μL of the compound to 78 μL of cell culture medium, mix well, then add 20 μL of the compound solution to the corresponding wells of the cell plate, and put the cell plate back into the CO2 incubator to continue incubation for 1 hour;

[0733] 3) After incubation, discard the cell supernatant and add 50 μL of 1X cell lysis buffer to each well, then incubate at room temperature with shaking for 30 minutes;

[0734] 4) Dilute Phospho-ERK1 / 2Eu Cryptate antibody and Phospho-ERK1 / 2d2 antibody 20-fold using detection buffer;

[0735] 5) Transfer 16 μL of cell lysate supernatant to each well of a new 384 white microplate, then add 2 μL of Phospho-ERK1 / 2Eu Cryptate antibody dilution buffer and 2 μL of Phospho-ERK1 / 2d2 antibody dilution buffer, and incubate at room temperature for at least 4 hours.

[0736] 6) After incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm;

[0737] 7) Calculate the IC of the compound to be tested. 50 .

[0738] 3 Experimental Results

[0739] The results are shown in Table 4.

[0740] Table 4. IC50 of the compounds on the inhibition of p-ERK in GP2D cells 50 value

[0741]

[0742]

[0743] Experimental conclusion: The compound of this invention has a significant inhibitory effect on p-ERK in GP2D cells.

[0744] Experimental Example 4. PANC0403 Cell p-ERK Inhibition Test

[0745] 1. Experimental materials:

[0746] PANC0403 cells were purchased from Nanjing Kebai; RPMI-1640 medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; and Advanced Phospho-ERK1 / 2 (THR202 / TYR204) KIT was purchased from Cisbio.

[0747] The ingredients of Advanced Phospho-ERK1 / 2(THR202 / TYR204)KIT are shown in Table 5.

[0748] Table 5

[0749] Ingredient name Storage temperature Advanced PhosphoERK1 / 2Eu Cryptate antibody ≤-16℃ Advanced PhosphoERK1 / 2d2 antibody ≤-16℃ Blocking reagent(stock solution100X) ≤-16℃ Lysis buffer#1(stock solution 4X) ≤-16℃ Detection buffer(ready-to-use) ≤-16℃

[0750] 2. Experimental Methods:

[0751] 1) PANC0403 cells were seeded in clear 96-well cell culture plates with 80 μL of cell suspension per well, containing 10,000 PANC0403 cells per well. The cell culture plates were placed in a CO2 incubator and incubated overnight at 37°C.

[0752] 2) Dilute the test compound to 2 mM with 100% DMSO as the first concentration, and then dilute it 5-fold to the 8th concentration using a pipette, i.e., from 2 mM to 25.6 nM. Take 2 μL of the compound and add it to 78 μL of cell starvation medium. After mixing, take 20 μL of the compound solution and add it to the corresponding well of the cell plate. Place the cell plate back in the CO2 incubator and continue incubation for 3 hours. At this time, the compound concentration is 10 μM to 0.128 nM, and the DMSO concentration is 0.5%.

[0753] 3) After incubation, discard the cell supernatant and add 50 μL of cell lysis buffer to each well, then incubate at room temperature with shaking for 30 minutes.

[0754] 4) Dilute Phospho-ERK1 / 2Eu Cryptate antibody and Phospho-ERK1 / 2d2 antibody 20-fold using detection buffer;

[0755] 5) Take 16 μL of cell lysate supernatant into each well of a new 384 white microplate, then add 2 μL of Phospho-ERK1 / 2Eu Cryptate antibody dilution and 2 μL of Phospho-ERK1 / 2d2 antibody dilution, and incubate overnight at room temperature;

[0756] 6) After incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm.

[0757] 3. Data Analysis:

[0758] The original data is converted into inhibition rate using the equation (Sample-Min) / (Max-Min)*100%. The IC50 value can then be obtained by curve fitting using four parameters (obtained in GraphPad Prism using log(inhibitor) vs. response--Variable slope mode).

[0759] Max well: Positive control well reading is 1X lysis buffer.

[0760] Min wells: Negative control wells read 0.5% DMSO cell lysate.

[0761] 4. Experimental Results

[0762] The results are shown in Table 6.

[0763] Table 6. IC50 of the compounds on p-ERK inhibition in PANC0403 cells 50 value

[0764] Compound numbering <![CDATA[PANC0403 p-ERK IC 50 (nM)]]> Compound 29B 574.2

[0765] Experimental conclusion: The compound of this invention has a significant inhibitory effect on p-ERK in PANC0403 cells.

[0766] Experimental Example 5. Antiproliferative effects of the compound in tumor cell lines AsPC-1 and GP2D

[0767] Research Objective

[0768] This experiment investigated the inhibitory effect of the compound on cell proliferation by examining its influence on in vitro cell viability in tumor cell lines AsPC-1 and GP2D.

[0769] Experimental materials

[0770] Table 7. Experimental Materials

[0771] cell lines Tumor types Growth characteristics Cultivation methods AsPC-1 pancreatic cancer Adhesive growth RPMI 1640 + 10% FBS GP2D colon cancer Adhesive growth DMEM + 10% FBS + 2mM L-glutamine

[0772] Ultra Low Cluster-96 well plate (Corning-7007)

[0773] Greiner CELLSTAR 96-well plate (#655090)

[0774] Promega CellTiter-Glo 3D Chemiluminescence Assay for Cell Viability (Promega-G9683)

[0775] 2104-10 EnVision board reader, PerkinElmer

[0776] RPMI 1640, DMEM, PBS (phosphate buffered saline), FBS (fetal bovine serum), Antibiotic-antimycotic, L-glutamine, DMSO (dimethyl sulfoxide)

[0777] Experimental methods and procedures

[0778] Cell culture

[0779] The tumor cell lines were cultured under the conditions indicated in the culture protocol at 37°C in a 5% CO2 incubator. Cells were passaged periodically, and cells in the logarithmic growth phase were used for plating.

[0780] Cell plating

[0781] Cells were stained with trypan blue and viable cells were counted.

[0782] Adjust the cell concentration to a suitable level.

[0783] Table 8. Cell Density

[0784] cell lines Density (per pore) AsPC-1 7000 cells GP2D 8000 cells

[0785] Add 135 μL of cell suspension to each well of the ULA culture plate, and add the same volume of cell-free culture medium to the blank control well.

[0786] After plating, immediately centrifuge the ULA culture plate at 1000 rpm for 10 minutes at room temperature. Note: After centrifugation, be sure to handle subsequent operations with care to avoid unnecessary shaking.

[0787] The culture plates were incubated overnight in an incubator at 37°C, 5% CO2, and 100% relative humidity.

[0788] Preparation of 10X compound working solution and cell treatment with the compound (Day 1)

[0789] After preparing the 10X compound working solution (DMSO 10X working solution), add 15 μL of the 10X compound working solution to each ULA culture plate, and add 15 μL of DMSO-cell culture medium mixture to the solvent control and blank control.

[0790] Return the 96-well cell plate to the incubator and incubate for 120 hours.

[0791] Observe the cell spheroidization process daily until the end of the experiment.

[0792] CellTiter-Glo luminescence assay for cell viability (day 5)

[0793] The following steps were performed in accordance with the instructions for the Promega CellTiter-Glo 3D luminescence assay kit (Promega#G9683).

[0794] Add 150 μL (equal to the volume of cell culture medium in each well) of CellTiter-Glo 3D reagent to each well. Wrap the cell plate with aluminum foil to protect it from light.

[0795] Shake the culture plate on a track shaker for 5 minutes.

[0796] Carefully pipette up and down 10 times to mix the mixture in the airway. Ensure the cell spheroids are fully separated before proceeding to the next step.

[0797] The solution in the ULA culture plate was then transferred to a black-bottomed culture plate (#655090) and left at room temperature for 25 minutes to stabilize the luminescence signal.

[0798] The light emission signal was detected on the 2104EnVision reader.

[0799] Data Analysis

[0800] The inhibition rate (IR) of the detected compound is calculated using the following formula: IR (%) = (1 – (RLU compound – RLU blank control) / (RLU solvent control – RLU blank control)) * 100%. The inhibition rates of different compound concentrations are calculated in Excel, and then inhibition curves are plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC50, are calculated using GraphPad Prism software. 50 .

[0801] Experimental results

[0802] The results are shown in Table 9.

[0803] Table 9. Compounds and their effects on KRAS G12D Cellular inhibition of IC 50 value

[0804] Compound numbering <![CDATA[KRAS G12D AsPC-1IC 50 (nM)]]> <![CDATA[KRAS G12D GP2D IC 50 (nM)]]> Hydrochloride salt of compound 1 315 37 Hydrochloride salt of compound 2 1865 332

[0805] Experimental conclusion: The compound of this invention possesses KRAS. G12D Inhibitory effect on cell mutation.

[0806] Experimental Example 6. Plasma Protein Binding Assay (PPB)

[0807] Experimental Objective

[0808] The protein binding rates of the compounds in CD-1 mice, Sprague-Dawley rats, beagles, cynomolgus monkeys, and human plasma were determined using the equilibrium dialysis method.

[0809] Experimental methods

[0810] Plasma samples of the five species were prepared at a compound concentration of 2 μM and placed in a 96-well rapid equilibration dialysis apparatus. Dialysis was performed with phosphate buffer at 37 ± 1 °C for 4 h. Warfarin was used as a control compound in this experiment. The concentrations of the analytes in the plasma and dialysis buffer were determined by LC-MS / MS.

[0811] Experimental results

[0812] The unbound percentage (%) of the hydrochloride salt of compound 1 at a test concentration of 2 μM is shown in Table 10 below.

[0813] Table 10 PPB Test Results

[0814] Compound numbering Unbound PPB H / C / D / R / M Hydrochloride salt of compound 1 7.0 / 6.3 / 5.2 / 3.0 / 2.7

[0815] The recovery rate (%) of compound 1 in the dialysis apparatus was 82.4–109.5, which met the requirements of this experiment for recovery rate and stability.

[0816] Experimental conclusions

[0817] At a test concentration of 2 μM, the compounds of the present invention exhibited good free concentrations in the plasma of the above five species.

[0818] Experimental Example 7. Pharmacokinetic Study of Test Compounds by Oral and Intravenous Injection in CD-1 Mice

[0819] Experimental Objective

[0820] The pharmacokinetics of the compound were tested in CD-1 mice after oral and intravenous administration.

[0821] Experimental steps

[0822] The test compound was mixed with 5% DMSO + 95% (10% HP-β-CD) aqueous solution, vortexed and sonicated to prepare a 0.5 mg / mL clear solution (intravenous) or a 3 mg / mL clear solution (oral). The solution was then filtered through a microporous membrane for later use. Male SD mice aged 7 to 10 weeks were selected and administered the candidate compound solution intravenously at a dose of approximately 2 mg / kg. The candidate compound solution was also administered orally at a dose of approximately 30 mg / kg. Whole blood was collected over a certain period to prepare plasma. Drug concentration was analyzed by LC-MS / MS using Phoenix WinNonlin software (USA).

[0823] Pharsight (the company) calculates pharmacokinetic parameters.

[0824] Experimental results

[0825] The results are shown in Tables 11 and 12.

[0826] Table 11. Intravenous (IV) PK Data

[0827] Test sample Hydrochloride salt of compound 1 Hydrochloride salt of compound 11A Compound 20B Dosage (mg / kg) 1.82 2.14 2.04 <![CDATA[C0(nM)]]> 1400 1593 449 <![CDATA[T 1 / 2 (h)]]> 23.1 15.6 11.2 <![CDATA[V d (L / kg)]]> 148 56.2 97.2 Cl (mL / Kg / min) 106 62.8 138 <![CDATA[AUC 0-last (nM.h)]]> 353 690 371

[0828] Table 12 Oral (PO) PK Data

[0829] Test sample Hydrochloride salt of compound 1 Hydrochloride salt of compound 11A Compound 20B Dosage (mg / kg) 29.3 30.3 30.3 <![CDATA[C max (nM)]]> 228 617 2095 <![CDATA[T max ]]> 4.5 2 1.5 <![CDATA[T 1 / 2 (h)]]> ND 8 14.4 <![CDATA[AUC 0-inf (nM.h)]]> 1350 2403 4710 F 25.5％ 23.2％ 85％

[0830] Experimental conclusions

[0831] The compounds of this invention have good oral bioavailability.

[0832] Experimental Example 8. In vivo pharmacodynamic study

[0833] Experimental methods:

[0834] A mouse model of subcutaneous xenograft of human colon cancer GP2D cells into Balb / c nude tumors was established. 0.2 mL (2 × 10⁻⁶ cells) of the cell line was used. 6 GP2D cells (with matrix gel, volume ratio 1:1) were subcutaneously inoculated into the right posterior dorsal region of each mouse. Tumors were inoculated when the average volume reached 149 mm². 3 The animals were divided into groups of 6 for administration. On the day of the experiment, the animals were given the corresponding drugs according to their groups. Group 1 (G1) served as a negative control group and was given 5% DMSO + 95% (10% HP-β-CD) by gavage alone. Groups 2 through 4 (G4) were given the hydrochloride salt of compound 1. The dosage and administration regimen are shown in Table 13.

[0835] Table 13. Pharmacodynamic studies of the test substances against human diffuse large B-lymphoma TMD8 mouse xenografts.

[0836] Note: PO means oral administration, QD means once daily, and BID means twice daily.

[0837] During the experiment, the animals' weight and tumor size were measured twice a week, and their clinical symptoms were observed and recorded daily. Each administration was based on the animal's most recent weight.

[0838] The length (a) and width (b) of the tumor are measured using digital vernier calipers. The formula for calculating tumor volume (TV) is: TV = a × b 2 / 2.

[0839] Experimental results:

[0840] Compound 1 hydrochloride had a significant inhibitory effect on human colon cancer xenografts in GP2D mice. After 20 days of administration, the tumor volume inhibition rate (TGI) of group G2 (3 mg / kg, PO, BID) was 19.4% on day 20; the tumor volume inhibition rate (TGI) of group G3 (10 mg / kg, PO, BID) and group G4 (30 mg / kg, PO, BID) were 53.9% and 83.7% on day 20, respectively. Detailed results are shown in Table 14.

[0841] Table 14. Effects of test substances on tumor size in a human colon cancer GP2D mouse xenograft model.

[0842]

[0843] Note: N / A indicates not detected.

[0844] Experimental conclusion: In terms of in vivo efficacy, the compounds of this invention showed good tumor-inhibiting effects in the GP2D cell line, with obvious dose-related effects.

Claims

1. A compound of Formula (III) or a pharmaceutically acceptable salt thereof, structural unit selected from is a single bond; T1 is NR9; T2 is selected from CH and N; L1 is -CH2-; R1, R2, R3, R4and R5are each independently selected from the group consisting of H and C 1-3 alkyl; R6is selected from phenyl, pyridyl and naphthyl, which phenyl, pyridyl and naphthyl are optionally substituted with 1, 2, 3, 4 or 5 R b substituents; R9 is selected from H and CH3; R 10 is hexahydro-1H-pyrrolizinyl, which is optionally substituted by 1, 2 or 3 R c substituents; R 11 and R 12 are each independently selected from H, C 1-3 alkyl and C 3-5 cycloalkyl, said C 1-3 alkyl and C 3-5 cycloalkyl being optionally substituted with 1, 2 or 3 halogens; m is 1; n is 1; p is 1; q is selected from 1, 2, or 3; r is selected from 1 or 2; s is selected from 1, 2, or 3; Each R b Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl, -C(=O)C 1-3 Alkyl and C 3-5 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl, -C(=O)C 1-3 Alkyl and C 3-5 The cycloalkyl group may be optionally substituted with 1, 2, 3, 4 or 5 Rs; each R is independently selected from H, F, Cl, Br, I and C1-C4alkyl; c each R is independently selected from H, F, Cl, Br, I and C1-C4alkyl; 1-3 alkyl; each R is independently selected from F, Cl, Br, and I.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1, R2, R3, R4, and R5 are each independently selected from H, CH3, CH2CH3, and CH(CH3)2.

3. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein, R1, R2, R3, R4, and R5 are each independently selected from H and CH3.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, each R b is independently selected from F, CI, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -CºCH, -C(=O)CH3, and cyclopropyl, said CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, -CºCH, -C(=O)CH3, and cyclopropyl being optionally substituted with 1, 2, 3, 4 or 5 R.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein, Each R b The groups are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3, CH2CH3, CF2CF3, -CH=CH2, -C≡CH, -C(=O)CH3 and cyclopropyl, respectively.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R6is selected from 8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Each R c They are independently selected from H, F, Cl, Br, CH3 and CH2CH3, respectively.

9. A compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein, R 10 is hexahydro-1H-pyrrolizinyl, which is optionally substituted by 1, 2 or 3 R c substituents; Each R c They are independently selected from H, F, Cl, Br, CH3, CH2CH3 and CH2CF3, respectively; the other variables are as defined in any one of claims 1-7.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1, 8, or 9, wherein, R 10 For 11. The compound of claim 1 or 9, or a pharmaceutically acceptable salt thereof, wherein, R 11 and R 12 are each independently selected from H and CH3.

12. A compound of the following formula or a pharmaceutically acceptable salt thereof, 13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, selected from, 14. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, is a single bond; T1 is NR9; T2 is selected from CH and N; R1, R2, R3, R4and R5are each independently selected from the group consisting of H and C 1-3 alkyl; R6is selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by 1, 2, 3, 4 or 5 R b substituents; R9 is selected from H and CH3; Alternatively, R1and R2form a ring with the atoms to which they are attached to the structure unit form Alternatively, R1and R4form a ring with the atoms to which they are attached to the structural unit form Alternatively, R4and R5form a ring with the atoms to which they are attached to the structural unit form m is 1; n is 1; p is 1; q is selected from 1, 2, or 3; r is selected from 1 or 2; s is selected from 1, 2, or 3; Each R b The components are independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CF3 and OCH3, respectively.

15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein, the R1, R2, R3, R4, and R5 are each independently selected from H, CH3, CH2CH3, and CH(CH3)2.

16. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein, the R1, R2, R3, R4, and R5 are each independently selected from H and CH3.

17. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein, The structural unit selected from 18. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein, The structural unit selected from 19. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein, The structural unit selected from 20. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein, The structural unit selected from 21. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein, The structural unit selected from .

22. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein, said R6is selected from 23. A compound of Formula (II) or a pharmaceutically acceptable salt thereof, Structural unit selected from is a single bond; T1 is NR9; T2 is selected from CH and N; L1 is -CH2-; R1, R2, R3, R4and R5are each independently selected from the group consisting of H and C 1-3 alkyl; R6is selected from C 6-10 aryl and 5-10 membered heteroaryl, said C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 R b substituents; R9 is selected from H and CH3; R 10 is hexahydro-1H-pyrrolizinyl, which is optionally substituted by 1, 2 or 3 R c substituents; m is 1; n is; p is 1; q is selected from 1, 2, or 3; r is selected from 1 or 2; s is selected from 1, 2, or 3; Each R b Each of the following is independently selected from F, Cl, Br, I, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl and C 3-5 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 alkynyl group, C 2-3 alkenyl and C 3-5 The cycloalkyl group may be optionally substituted with 1, 2 or 3 Rs; each R is independently selected from H, F, Cl, Br, and C1-C4alkyl; c each R is independently selected from H, F, Cl, Br, and C1-C4alkyl; 1-3 alkyl; each R is independently selected from F, Cl, and Br.

24. The compound or pharmaceutically acceptable salt thereof of claim 23, wherein, the R1, R2, R3, R4, and R5 are each independently selected from H, CH3, CH2CH3, and CH(CH3)2.

25. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein, the R1, R2, R3, R4, and R5 are each independently selected from H and CH3.

26. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein, The structural unit selected from 27. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein, The structural unit selected from 28. The compound or pharmaceutically acceptable salt thereof of claim 23, wherein, each R b is independently selected from F, CI, Br, I, OH, NH2, CN, CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, and -CºCH, said CH3, CH2CH3, OCH3, OCH2CH3, -CH=CH2, -CH2-CH=CH2, and -CºCH being optionally substituted with 1, 2, or 3 R.

29. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein, Each R b They are independently selected from F, OH, NH2, CH3, CF3, CH2CH3 and -C≡CH, respectively.

30. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein, said R6is selected from phenyl, naphthyl, indolyl and indazolyl, said phenyl, naphthyl, indolyl and indazolyl being optionally substituted with 1, 2, 3, 4 or 5 R b substituents.

31. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein, said R6is selected from 32. The compound or pharmaceutically acceptable salt thereof of claim 23, wherein, Each R c They are independently selected from H, F, Cl, Br, CH3 and CH2CH3, respectively.

33. The compound or pharmaceutically acceptable salt thereof of claim 23, wherein, The R 10 is 34. Use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 33 in the manufacture of a medicament for the treatment of a disease associated with a KRAS G12D mutation.

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