Heterocyclic substituted pyrimidinopyran compound and application thereof

Abstract

The invention discloses a heterocyclic substituted pyrimidinopyran compound and application thereof, and particularly discloses a compound shown as a formula (VII) and pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Heterocyclic substituted pyrimidopyran compounds and their applications

[0001] The present invention claims the following priority:

[0002] CN202210731477.1, application date: June 24, 2022;

[0003] CN202210743845.4, application date: June 27, 2022;

[0004] CN202210969097.1, application date: August 12, 2022;

[0005] CN202211494347.7, application date: November 25, 2022;

[0006] CN202310010084.6, application date: January 4, 2023;

[0007] CN202310082801.6, application date: February 3, 2023;

[0008] CN202310206933.5, application date: March 6, 2023. Technical Field

[0009] The present invention relates to a class of heterocyclic substituted pyrimidopyran compounds and applications thereof, and particularly to a compound represented by formula (VII) and pharmaceutically acceptable salts thereof. Background Art

[0010] 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), of which 85% of RAS-driven cancers are caused by mutations in the KRAS subtype. KRAS is a murine sarcoma viral oncogene and an important member of the RAS protein. KRAS is like a molecular switch that, when normal, controls the pathways that regulate cell growth. When the KRAS gene mutates, it can independently transmit growth and proliferation signals to downstream pathways without relying on upstream growth factor receptor signals, resulting in uncontrolled cell growth and tumor progression. At the same time, whether the KRAS gene is mutated is also an important indicator of tumor prognosis.

[0011] 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%). Each year in the United States, approximately 166,000 new patients with KRAS single mutations are diagnosed (G12D and G12V mutations account for the highest proportion), approximately 9,000 new patients with KRAS amplification, and approximately 4,000 new patients with KRAS multiple mutations. The vast majority of patients currently lack effective targeted therapy drugs.

[0012] Currently, small molecules that directly target KRAS mutations are mainly focused on KRAS G12C Among them, Amgen's AMG510 and Mirati Therapeutics' MRTX849 have been approved for marketing in the United States and have a therapeutic effect on KRAS. G12C Patients with tumors harboring KRAS mutations have shown good therapeutic effects. However, no small molecules targeting pan-KRAS mutations have entered clinical research to date, and patients with pan-KRAS mutations and KRAS amplified tumors have yet to benefit from precision medicine.

[0013] Summary of the Invention

[0014] The present invention provides a compound represented by formula (VII) or a pharmaceutically acceptable salt thereof,

[0015] in,

[0016] Ring B is selected from 5-12 membered heterocycloalkenyl and 7-12 membered tricyclic heterocycloalkyl, said 5-12 membered heterocycloalkenyl and 7-12 membered tricyclic heterocycloalkyl are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R e substituted, ring A is selected from

[0017] Alternatively, Ring B is selected from Ring A is selected from

[0018] Ring C is selected from 5-6 membered nitrogen-containing heteroaryl groups;

[0019] Each R1 is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-3 Alkyl-OC 1-3Alkyl, -SH, -C(=O)-NR a R b 、-C(=O)-R c 、 C 3-6 Cycloalkyl and 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-3 Alkyl-OC 1-3 Alkyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0020] Alternatively, R1 on two adjacent atoms and the atom to which they are attached form a 5-6 membered heterocycloalkenyl, and the 5-6 membered heterocycloalkenyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R;

[0021] R2 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein the phenyl, naphthyl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2, 3, 4 or 5 R d replace;

[0022] R6 and R7 are independently selected from H, C 1-3 Alkyl, F, Cl, Br and I;

[0023] T1 is selected from CH2 and O;

[0024] T2 is selected from O and S;

[0025] R a Selected from H and C 1-3 Alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 R0;

[0026] R b Selected from H and C 1-3 Alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 R0;

[0027] R c Selected from H, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0028] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl and C2-4 Alkynyl, the C 1-3 Alkyl and C 2-4 Alkynyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R0;

[0029] Each R e Each independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0030] Each R is independently selected from F, Cl, Br, I and C 1-3 alkyl;

[0031] Each R0 is independently selected from D, F, Cl, Br and I;

[0032] m is selected from 0, 1, 2, 3, 4 and 5;

[0033] n is selected from 0, 1 and 2.

[0034] The present invention also provides a compound represented by formula (VII) or a pharmaceutically acceptable salt thereof,

[0035] in,

[0036] Ring A is selected from

[0037] Ring B is selected from 5-12 membered heterocycloalkenyl and 7-12 membered tricyclic heterocycloalkyl, said 5-12 membered heterocycloalkenyl and 7-12 membered tricyclic heterocycloalkyl are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R e replace;

[0038] Alternatively, Ring A is selected from Ring B is selected from

[0039] Ring C is selected from 5-6 membered nitrogen-containing heteroaryl groups;

[0040] Each R1 is independently selected from halogen, OH, NH2, CN, C 1-3 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-3 Alkyl-OC 1- 3 alkyl, -SH, -C(=O)-NR a R b 、-C(=O)-R c 、 C 3-6 Cycloalkyl and 5-6 membered heteroaryl, the C1-3 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-3 Alkyl-OC 1-3 Alkyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0041] Alternatively, R1 on two adjacent atoms and the atom to which they are attached form a 5-6 membered heterocycloalkenyl, and the 5-6 membered heterocycloalkenyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R;

[0042] R2 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein the phenyl, naphthyl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2, 3, 4 or 5 R d replace;

[0043] R3 is selected from H;

[0044] R4 is selected from F;

[0045] R5 is selected from H;

[0046] R6 and R7 are independently selected from H, C 1-3 Alkyl and halogen;

[0047] T1 is selected from CH and O;

[0048] T2 is selected from O and S;

[0049] R a Selected from H and C 1-3 Alkyl, the C 1-3 The alkyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0050] R b Selected from H and C 1-3 Alkyl, the C 1-3 The alkyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0051] R c Selected from H, C 3-6 Cycloalkyl and 5-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl and 5-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0052] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl and C 2-4 Alkynyl, the C 1-3Alkyl and C 2-4 Alkynyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0053] Each R e Each independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0054] Each R is independently selected from F, Cl, Br, I and C 1-3 alkyl;

[0055] m is selected from 0, 1, 2, 3, 4 and 5;

[0056] n is selected from 0, 1 and 2.

[0057] The present invention also provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,

[0058] in,

[0059] Ring A is selected from

[0060] Ring B is selected from described Each independently optionally replaced by 1, 2, 3, 4, 5 or 6 R e replace;

[0061] Alternatively, Ring B is selected from 5-12 membered heterocycloalkenyl and 7-12 membered tricyclic heterocycloalkyl, wherein the 5-12 membered heterocycloalkenyl and 7-12 membered tricyclic heterocycloalkyl are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R e replace;

[0062] Ring C is selected from 5-6 membered nitrogen-containing heteroaryl groups;

[0063] Each R1 is independently selected from halogen, OH, NH2, CN, C 1-3 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-3 Alkyl-OC 1- 3 alkyl, -SH, -C(=O)-NR a R b 、-C(=O)-R c 、 C 3-6 Cycloalkyl and 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-3 Alkyl-OC1-3 Alkyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0064] Alternatively, R1 on two adjacent atoms and the atom to which they are attached form a 5-6 membered heterocycloalkenyl, and the 5-6 membered heterocycloalkenyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R;

[0065] R2 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein the phenyl, naphthyl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2, 3, 4 or 5 R d replace;

[0066] R6 and R7 are independently selected from H, C 1-3 Alkyl and halogen;

[0067] T1 is selected from CH and O;

[0068] R a Selected from H and C 1-3 Alkyl, the C 1-3 The alkyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0069] R b Selected from H and C 1-3 Alkyl, the C 1-3 The alkyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0070] R c Selected from H, C 3-6 Cycloalkyl and 5-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl and 5-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0071] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl and C 2-4 Alkynyl, the C 1-3 Alkyl and C 2-4 Alkynyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0072] Each R e Each independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0073] Each R is independently selected from F, Cl, Br, I and C 1-3 alkyl;

[0074] m is selected from 0, 1, 2, 3, 4 and 5;

[0075] n is selected from 0, 1 and 2.

[0076] The present invention also provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,

[0077] in,

[0078] R1 is selected from halogen, OH, C 1-3 Alkyl, -C(=O)-NR a R b 、-C(=O)-R c and 5-6 membered heteroaryl, the C 1-3 Alkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0079] R2 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein the phenyl, naphthyl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2, 3, 4 or 5 R d replace;

[0080] Ring A is selected from

[0081] Ring B is selected from

[0082] T1 is selected from CH and O;

[0083] R a Selected from H and C 1-3 alkyl;

[0084] R b Selected from H and C 1-3 alkyl;

[0085] R c Selected from H, C 3-6 Cycloalkyl and 5-6 membered heterocycloalkyl;

[0086] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl and C 2-4 Alkynyl, the C 1-3 Alkyl and C 2-4 Alkynyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0087] Each R e Each independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0088] Each R is independently selected from F, Cl, Br, I and C 1-3alkyl;

[0089] m is selected from 0, 1, 2 and 3;

[0090] n is selected from 0, 1 and 2.

[0091] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the formula (V-1),

[0092] in,

[0093] R1, R2, R6, R7, Ring B, Ring C and m are as defined herein.

[0094] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the formula (V-1),

[0095] in,

[0096] R1, R2, Ring B, Ring C and m are as defined herein.

[0097] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the formula (IV-3),

[0098] in,

[0099] R1 is selected from halogen, OH, C 1-3 Alkyl and 5-6 membered heteroaryl, the C 1-3 Alkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R;

[0100] R, R1, R2, Ring A, Ring B and m are as defined herein.

[0101] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the formula (IV-1),

[0102] in,

[0103] R1, R2, Ring B and m are as defined herein.

[0104] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the formula (P-1),

[0105] in,

[0106] Ring B is selected from and 5-12 membered heterocycloalkenyl and described and 5-12 membered heterocycloalkenyl are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R e replace;

[0107] R1, R2, R6, R7, each R e , Ring C and m are as defined in the present invention;

[0108] The carbon atom marked with "*" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer.

[0109] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the formula (P-2),

[0110] in,

[0111] Ring B is selected from described Each independently optionally replaced by 1, 2, 3, 4, 5 or 6 R e replace;

[0112] p is selected from 1, 2, 3, 4 or 5;

[0113] R1, each R e , each R d and m is as defined in the present invention;

[0114] The carbon atom marked with "*" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer.

[0115] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of formula (P-2-1), (P-2-2) and (P-2-3),

[0116] in,

[0117] p is selected from 1, 2, 3, 4 or 5;

[0118] R1, R e , each R d and m is as defined in the present invention;

[0119] The carbon atom marked with "*" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer.

[0120] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the formula (IV-2),

[0121] in,

[0122] Ring A is selected from

[0123] Alternatively, Ring A is selected from

[0124] R1 is selected from halogen, OH, C 1-3 Alkyl, -C(=O)-NR a R b and -C(=O)-R c ;

[0125] R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are each independently optionally substituted by 1, 2, 3, 4 or 5 R d replace;

[0126] R 3a and R 4a connected to make the structural units Selected from R 5a Selected from H;

[0127] Or, R 4a and R 5a Connected to form described Optional 1 or 2 R e Replacement, R 3a Selected from H;

[0128] R a Selected from H and C 1-3 alkyl;

[0129] R b Selected from H and C 1-3 alkyl;

[0130] R c Selected from 5-6 membered heterocycloalkyl;

[0131] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl and C 2-4 Alkynyl, the C 1-3 Alkyl and C 2-4 Alkynyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0132] Each R e Each independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0133] m is selected from 0, 1, 2 and 3.

[0134] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the formula (I-1),

[0135] in,

[0136] Ring A is selected from

[0137] R1, R2, R3, R4, R5, R6, R7, Ring C and m are as defined herein.

[0138] In some embodiments of the present invention, each R mentioned above is independently selected from F, Cl, Br, I, CH3, CH2CH3 and CH2CH2CH3, and other variables are as defined in the present invention.

[0139] In some embodiments of the present invention, the above R is selected from F and CH3, and other variables are as defined in the present invention.

[0140] In some embodiments of the present invention, the above R0 is selected from D, and other variables are as defined in the present invention.

[0141] In some embodiments of the present invention, the above R a is selected from H, CH3, CD3 and CH(CH3)2, and other variables are as defined herein.

[0142] In some embodiments of the present invention, the above R a is selected from H, CH3 and CH(CH3)2, and the other variables are as defined herein.

[0143] In some embodiments of the present invention, the above R b is selected from H, CH3, CD3 and CH(CH3)2, and other variables are as defined herein.

[0144] In some embodiments of the present invention, the above R b is selected from H, CH3 and CH(CH3)2, and the other variables are as defined herein.

[0145] In some embodiments of the present invention, the above R c is selected from H, cyclopropyl, tetrahydropyrrolyl and morpholinyl, and other variables are as defined herein.

[0146] In some embodiments of the present invention, the above R c is selected from tetrahydropyrrolyl and morpholinyl, and other variables are as defined herein.

[0147] In some embodiments of the present invention, the above R dare independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CF2H, CF3, CH2CH3, CF2CF3, -C≡CH, -C≡CF, -C≡CBr, -C≡CCH3 and -C≡CCF3, and other variables are as defined in the present invention.

[0148] In some embodiments of the present invention, the above R d are independently selected from F, Cl, NH2, OH, CH3, CF3, CH2CH3, -C≡CH and -C≡CCH3, and other variables are as defined in the present invention.

[0149] In some embodiments of the present invention, the above R e are independently selected from H and F, and other variables are as defined in the present invention.

[0150] In some embodiments of the present invention, the above T1 is selected from CH, and other variables are as defined in the present invention.

[0151] In some embodiments of the present invention, the above-mentioned T1 is selected from O, and other variables are as defined in the present invention.

[0152] In some embodiments of the present invention, the above T2 is selected from O, and other variables are as defined in the present invention.

[0153] In some embodiments of the present invention, each of the above R1 is independently selected from F, Cl, Br, I, OH, NH2, CN, CH3, CH2CH3, CH2CH2CH3, -CH=CH2, -CH2-CH=CH2, OCH3, OCH2CH3, OCH2CH2CH3, -CH3OCH3, -CH3OCH2CH3, -CH2CH3OCH3, -CH2CH2CH3OCH3, -SH, Cyclopropyl, cyclobutyl, pyridine, pyrimidine, thiophene, 1,2,4-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, the CH3, CH2CH3, CH2CH2CH3, -CH=CH2, -CH2-CH=CH2, Cyclopropyl, cyclobutyl, pyridine, pyrimidine, thiophene, 1,2,4-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole are each independently optionally substituted with 1, 2, 3 or 4 R groups, and the other variables are as defined herein.

[0154] In some embodiments of the present invention, the above R1 is selected from F, Cl, Br, I, OH, CH3, CH2CH3, CH2CH2CH3, pyridine, pyrimidine, thiophene, 1,2,4-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, wherein CH3, CH2CH3, CH2CH2CH3, pyridine, pyrimidine, thiophene, 1,2,4-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole are each independently optionally substituted with 1, 2, 3 or 4 R, and other variables are as defined herein.

[0155] In some embodiments of the present invention, each of the above R1 is independently selected from F, Cl, Br, OH, NH2, CN, CH3, CH(CH3)2, Cyclopropyl, CF3, Other variables are as defined in the present invention.

[0156] In some embodiments of the present invention, each of the above R1 is independently selected from F, Cl, OH, NH2, CN, CH3, CH(CH3)2, Cyclopropyl, Other variables are as defined in the present invention.

[0157] In some embodiments of the present invention, the above R1 is selected from F, Cl, OH, CH3, CF3, Other variables are as defined in the present invention.

[0158] In some embodiments of the present invention, the above R1 is selected from F, Cl, OH, CH3, Other variables are as defined in the present invention.

[0159] In some embodiments of the present invention, the above R2 is selected from phenyl, naphthyl, indolyl, pyridyl, pyrrolyl, benzopyrimidinyl and quinolyl, and the phenyl, naphthyl, indolyl, pyridyl, pyrrolyl, benzopyrimidinyl and quinolyl are independently optionally substituted by 1, 2, 3, 4 or 5 R d Substitution, other variables are as defined in the present invention.

[0160] In some embodiments of the present invention, the above R2 is selected from phenyl, naphthyl and pyridyl, and the phenyl, naphthyl and pyridyl are independently optionally substituted by 1, 2, 3, 4 or 5 R d Substitution, other variables are as defined in the present invention.

[0161] In some embodiments of the present invention, the above R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are independently optionally substituted by 1, 2, 3, 4 or 5 R d Substitution, other variables are as defined in the present invention.

[0162] In some embodiments of the present invention, the above R2 is selected from Other variables are as defined in the present invention.

[0163] In some embodiments of the present invention, the above R2 is selected from Other variables are as defined in the present invention.

[0164] In some embodiments of the present invention, the above R2 is selected from Other variables are as defined in the present invention.

[0165] In some embodiments of the present invention, the ring C is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl and pyrimidinyl, and other variables are as defined in the present invention.

[0166] In some embodiments of the present invention, the ring C is selected from pyrazolyl and imidazolyl, and other variables are as defined in the present invention.

[0167] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0168] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0169] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0170] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0171] In some embodiments of the present invention, the ring B is selected from 8-9 membered heterocycloalkenyl, and other variables are as defined in the present invention.

[0172] In some embodiments of the present invention, the ring B is selected from 5-12 membered heterocycloalkenyl, 7-12 membered tricyclic heterocycloalkyl and described 5-12 membered heterocycloalkenyl and 7-12 membered tricyclic heterocycloalkyl are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R e Substitution, other variables are as defined in the present invention.

[0173] In some embodiments of the present invention, the ring B is selected from 5-12 membered heterocycloalkenyl, said 5-12 membered heterocycloalkenyl groups are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R e Substituted; or; Ring B is selected from Other variables are as defined in the present invention.

[0174] In some embodiments of the present invention, the ring B is selected from Other variables are as defined in the present invention.

[0175] In some embodiments of the present invention, the ring B is selected from Other variables are as defined in the present invention.

[0176] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0177] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0178] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0179] In some embodiments of the present invention, the ring A is selected from Ring B is selected from Other variables are as defined in the present invention.

[0180] In some embodiments of the present invention, the ring A is selected from Ring B is selected from Other variables are as defined in the present invention.

[0181] In some embodiments of the present invention, the R1 on the two adjacent atoms and the atoms to which they are connected form a 5-6 membered heterocycloalkenyl group, and the 5-6 membered heterocycloalkenyl group is optionally substituted by 1, 2, 3, 4 or 5 R, so that the structural unit Selected from Other variables are as defined in the present invention.

[0182] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0183] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0184] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0185] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0186] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0187] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0188] In some embodiments of the present invention, the ring B is selected from Structural unit Selected from Other variables are as defined in the present invention.

[0189] In some embodiments of the present invention, the ring B is selected from Structural unit Selected from Other variables are as defined in the present invention.

[0190] In some embodiments of the present invention, the above structural unit Selected from Ring B is selected from Other variables are as defined in the present invention.

[0191] In some embodiments of the present invention, the above structural unit Selected from Ring B is selected from Other variables are as defined in the present invention.

[0192] In some embodiments of the present invention, the above R6 is selected from H, and other variables are as defined in the present invention.

[0193] In some embodiments of the present invention, the above R7 is selected from H, and other variables are as defined in the present invention.

[0194] The present invention also provides a compound represented by formula (I) and a pharmaceutically acceptable salt thereof,

[0195] in,

[0196] Ring A is selected from

[0197] Alternatively, Ring A is selected from

[0198] R1 is selected from halogen, OH, C 1-3 Alkyl, -C(=O)-NR a R b and -C(=O)-R c ;

[0199] R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are each independently optionally substituted by 1, 2, 3, 4 or 5 R d replace;

[0200] R3 is selected from H, R4 is selected from F, and R5 is selected from H;

[0201] Alternatively, R3 and R4 are connected to make the structural unit Selected from R5 is selected from H;

[0202] Alternatively, R4 and R5 are connected to form described Optional 1 or 2 R e substituted, R3 is selected from H;

[0203] R a Selected from H and C 1-3 alkyl;

[0204] Rb Selected from H and C 1-3 alkyl;

[0205] R c Selected from 5-6 membered heterocycloalkyl;

[0206] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl and C 2-4 Alkynyl, the C 1-3 Alkyl and C 2-4 Alkynyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0207] Each R e Each independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3;

[0208] m is selected from 0, 1, 2 and 3.

[0209] The present invention also provides a compound represented by formula (I) and a pharmaceutically acceptable salt thereof

[0210] in,

[0211] Ring A is selected from

[0212] R1 is selected from halogen, OH, C 1-3 Alkyl, -C(=O)-NR a R b and -C(=O)-R c ;

[0213] R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are each independently optionally substituted by 1, 2, 3, 4 or 5 R d replace;

[0214] R3 is selected from H, R4 is selected from F, and R5 is selected from H;

[0215] Alternatively, R3 and R4 are connected to make the structural unit Selected from R5 is selected from H;

[0216] Alternatively, R4 and R5 are connected to make the structural unit Selected from R3 is selected from H;

[0217] R a Selected from H and C 1-3 alkyl;

[0218] R b Selected from H and C 1-3alkyl;

[0219] R c Selected from 5-6 membered heterocycloalkyl;

[0220] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl and C 2-4 Alkynyl, the C 1-3 Alkyl and C 2-4 Alkynyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0221] m is selected from 0, 1, 2 or 3.

[0222] The present invention also provides a compound represented by formula (I) and a pharmaceutically acceptable salt thereof

[0223] in,

[0224] Ring A is selected from

[0225] Alternatively, Ring A is selected from

[0226] R1 is selected from halogen, OH, C 1-3 Alkyl, -C(=O)-NR a R b and -C(=O)-R c ;

[0227] R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are each independently optionally substituted by 1, 2, 3, 4 or 5 R d replace;

[0228] R3 is selected from H, R4 is selected from F, and R5 is selected from H;

[0229] R a Selected from H and C 1-3 alkyl;

[0230] R b Selected from H and C 1-3 alkyl;

[0231] R c Selected from 5-6 membered heterocycloalkyl;

[0232] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl and C 2-4 Alkynyl, the C 1-3 Alkyl and C 2-4Alkynyl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 halogens;

[0233] m is selected from 0, 1, 2 and 3.

[0234] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R a is selected from H, CH3 and CH(CH3)2, and the other variables are as defined herein.

[0235] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R b is selected from H, CH3 and CH(CH3)2, and the other variables are as defined herein.

[0236] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R c is selected from tetrahydropyrrolyl and morpholinyl, and other variables are as defined herein.

[0237] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R d are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CF2H, CF3, CH2CH3, CF2CF3, -C≡CH, -C≡CF, -C≡CBr, -C≡CCH3 and -C≡CCF3, and other variables are as defined in the present invention.

[0238] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R d are independently selected from F, Cl, NH2, OH, CH3, CF3, CH2CH3, -C≡CH and -C≡CCH3, and other variables are as defined in the present invention.

[0239] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from F, Cl, OH, CH3, Other variables are as defined in the present invention.

[0240] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is selected from phenyl and naphthyl, and the phenyl and naphthyl are independently optionally substituted by 1, 2, 3, 4 or 5 R d Substitution, other variables are as defined in the present invention.

[0241] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is selected from Other variables are as defined in the present invention.

[0242] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is selected from Other variables are as defined in the present invention.

[0243] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from Other variables are as defined in the present invention.

[0244] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.

[0245] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.

[0246] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.

[0247] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.

[0248] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.

[0249] In some embodiments of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.

[0250] Some other solutions of the present invention are obtained by any combination of the above variables.

[0251] The present invention provides the following compounds or pharmaceutically acceptable salts thereof:

[0252] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0253] The present invention also provides the following synthesis method:

[0254] Synthesis method 1:

[0255] Synthesis method 2:

[0256] The present invention also provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating pan-KRAS-related diseases.

[0257] The present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumor-related diseases.

[0258] Test method 1: H358 cell experiment

[0259] 1 Experimental Purpose

[0260] IC of test compounds for inhibition of H358 cell proliferation 50 .

[0261] 2 Reagents

[0262] The main reagents used in this study included RPMI-1640 culture medium, penicillin / streptomycin antibiotics purchased from Vicente, and fetal bovine serum purchased from Biosera.

[0263] CellTiter-Glo (cell viability chemiluminescence detection reagent) was purchased from Promega. NCI-H358 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences.

[0264] 3 Instruments

[0265] The main instrument used in this study was the Nivo multi-label analyzer (PerkinElmer).

[0266] 4 Experimental methods:

[0267] 1) Seed NCI-H358 cells in a white 96-well plate, with 80 μL of cell suspension per well, containing 4,000 NCI-H358 cells. Incubate the plate in a CO2 incubator overnight.

[0268] 2) Use a dispenser to dilute the compound to be tested 5-fold to the 9th concentration, that is, from 2mM to 5.12nM, and set up a double-well experiment. Add 78μL of culture medium to the middle plate, and then transfer 2μL of the gradient diluted compound per well to the middle plate according to the corresponding position. After mixing, transfer 20μL per well to the cell plate. The concentration range of the compound transferred to the cell plate is 10μM to 0.0256nM. The cell plate is placed in a carbon dioxide incubator and cultured for 5 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis. Add 25μL of cell viability chemiluminescence detection reagent to each well of this cell plate and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Use a multi-label analyzer to read the readings.

[0269] 3) Add 25 μL of cell viability chemiluminescent detection reagent to each well of the cell plate and incubate at room temperature for 10 minutes to allow the luminescent signal to stabilize. Read the results using a multi-label analyzer.

[0270] Data Analysis:

[0271] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)×100%. 50 The value can be obtained by four-parameter curve fitting (obtained using the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism).

[0272] Test method 2. Anti-cell proliferation effect of the compound in the tumor cell line AsPC-1

[0273] Study Objectives

[0274] This study investigated the inhibitory effect of compounds on cell proliferation by detecting their effects on in vitro cell activity in the tumor cell line AsPC-1.

[0275] Experimental Materials

[0276] Ultra Low Cluster-96-well Plate (Corning-7007)

[0277] Greiner CELLSTAR 96-well plates (#655090)

[0278] Promega CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega-G9683)

[0279] 2104-10 EnVision plate reader, PerkinElmer

[0280] RPMI 1640, DMEM, PBS (phosphate buffered saline), FBS (fetal bovine serum), Antibiotic-antimycotic (antibiotic-antifungal), L-glutamine (L-glutamine), DMSO (dimethyl sulfoxide)

[0281] Experimental methods and steps

[0282] Cell culture

[0283] Tumor cell lines were cultured in an incubator at 37°C and 5% CO2 according to the culture conditions indicated in the culture method. Cells were passaged regularly and cells in the logarithmic growth phase were used for plating.

[0284] Cell plating

[0285] Cells were stained with trypan blue and viable cells were counted.

[0286] Adjust the cell concentration to an appropriate level.

[0287] 135 μL of cell suspension was added to each well of the ULA culture plate, and the same volume of culture medium without cells was added to the blank control well.

[0288] Immediately after plating, centrifuge the ULA plate at room temperature for 10 minutes at 1000 rpm. Note: After centrifugation, be careful to avoid unnecessary agitation during subsequent operations.

[0289] The culture plate was incubated overnight in an incubator at 37°C, 5% CO2, and 100% relative humidity.

[0290] Preparation of 10X compound working solution and compound treatment of cells (Day 1)

[0291] 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 the DMSO-cell culture medium mixture to the vehicle control and blank control.

[0292] The 96-well cell plate was returned to the incubator and cultured for 120 hours.

[0293] The cell sphere formation was observed every day until the end of the experiment.

[0294] CellTiter-Glo luminescence cell activity assay (day 5)

[0295] The following steps were performed according to the instructions of the Promega CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega #G9683).

[0296] Add 150 μL of CellTiter-Glo 3D reagent (equal to the volume of cell culture medium in each well) to each well. Wrap the cell plate with aluminum foil to protect it from light.

[0297] The plate was shaken on an orbital shaker for 5 minutes.

[0298] Carefully pipette up and down 10 times to mix the mixture. Ensure that the cell spheroids are fully dissociated before proceeding to the next step.

[0299] The solution in the ULA culture plate was then transferred to a black bottom culture plate (#655090) and placed at room temperature for 25 minutes to stabilize the luminescent signal.

[0300] Luminescent signals were detected on a 2104 EnVision plate reader.

[0301] Data Analysis

[0302] The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1-(RLU compound-RLU blank control) / (RLU vehicle control-RLU blank control)) × 100%. The inhibition rate of the compound at different concentrations was calculated in Excel, and then the inhibition curve was plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC, were calculated using GraphPad Prism software.50 .

[0303] Technical Effects

[0304] The compound of the present invention has good inhibitory activity against various KRAS mutation and KRAS amplification cells and exhibits good tumor inhibition effect in GP2D and Panc0403 cell lines.

[0305] Related definitions

[0306] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0307] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0308] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases, having specific substituents. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0309] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. 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 of the two.

[0310] Unless otherwise indicated, the term "treatment" is intended to refer to all procedures in which the progression of the disease may be slowed, interrupted, stopped or prevented, but does not necessarily imply the complete elimination of all symptoms.

[0311] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0312] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0313] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0314] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as 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. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be any on a chemically feasible basis.

[0315] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0316] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0317] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0318] When the listed linking groups do not specify their linking direction, their linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0319] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0320] Unless otherwise indicated, in some embodiments of the invention, when Ring B is selected from described Each independently 1, 2, 3, 4, 5 or 6 R e When substituted, the substitution is represented by a hexahydro-1H-pyrrolizine ring R e replace.

[0321] Unless otherwise indicated, in some embodiments of the present invention, when the structural fragment When substituted by R1, the substitution is represented by the piperidine ring Replaced by R1.

[0322] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0323] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as a substituent to which it is connected), if a wavy line is used between the atom on the double bond and its substituent in the compound, When connected, it represents the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound. For example, the following formula (A) represents that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2) or in the form of a mixture of two isomers of formula (A-1) and formula (A-2); the following formula (B) represents that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of a mixture of two isomers of formula (B-1) and formula (B-2). The following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of a mixture of two isomers of formula (C-1) and formula (C-2).

[0324] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is regarded as a substituent to which it is connected), if the atoms on the double bond in the compound and their substituents are separated by a If denoted as , it represents the (Z) isomer, the (E) isomer, or a mixture of both isomers of the compound. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can rapidly interconvert into each other. If tautomerism is possible (such as in solution), then chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0325] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including 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 , 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 、C 6-9 、C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0326] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0327] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0328]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0329] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1- Examples of 3-alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0330] Unless otherwise specified, the term “C 1-4 "Alkoxy" refers to those alkyl groups containing 1 to 4 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-4 Alkoxy groups include C 1-3 、C 1-2 、C 2-4 , C4 and C3 alkoxy, etc. 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), and the like.

[0331] Unless otherwise specified, “C 2-4"Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-4 Alkenyl groups include C 2-3 , C4, C3 and C2 alkenyl, etc.; the C 2-4 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-4 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, butadienyl, and the like. Unless otherwise specified, “C 2-3 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0332] Unless otherwise specified, “C 2-4 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-4 Alkynyl groups include C 2-3 , C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.

[0333] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0334] Unless otherwise specified, the term "5-12 membered heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 5 to 12 ring atoms containing 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 rest are carbon atoms, wherein the carbon atoms are optionally oxoed (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spirocyclic, fused and bridged rings, and any ring of such system is non-aromatic. In addition, with respect to the "5-12 membered heterocycloalkenyl", a heteroatom may occupy the position at which the heterocycloalkenyl group is connected to the rest of the molecule. The 5-12 membered heterocycloalkenyl group includes 5-10 membered, 5-8 membered, 5-6 membered, 4-5 membered, 4 membered, 5 membered and 6 membered heterocycloalkenyl groups, etc.

[0335] Unless otherwise specified, the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing 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 rest are carbon atoms, wherein the carbon atoms are optionally oxoed (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings, and any ring of this system is non-aromatic. In addition, with respect to the "5-6 membered heterocycloalkenyl", a heteroatom may occupy the position where the heterocycloalkenyl group connects to the rest of the molecule. The 5-6 membered heterocycloalkenyl group includes 5-membered and 6-membered heterocycloalkenyl groups. Examples of 5-6 membered heterocycloalkenyl groups include but are not limited to

[0336] Unless otherwise specified, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxo (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "4-6 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyls, etc. Examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, etc.

[0337] Unless otherwise specified, the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxo (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the term "5-6 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is attached to the rest of the molecule. The term "5-6 membered heterocycloalkyl" includes 5-membered and 6-membered heterocycloalkyl. Examples of 5-6 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

[0338] Unless otherwise specified, the term "7-12 membered tricyclic heterocycloalkyl" by itself or in combination with other terms refers to a tricyclic saturated cyclic group consisting of 7 to 12 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxoed (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). The 7-12 membered tricyclic heterocycloalkyl group includes spiro, fused, and bridged rings. Furthermore, with respect to the term "7-12 membered tricyclic heterocycloalkyl group," a heteroatom may occupy the position at which the heterocycloalkyl group is attached to the remainder of the molecule. The 7-12 membered tricyclic heterocycloalkyl group includes 7-10 membered, 7-8 membered, 8-10 membered, 8-12 membered, 9-10 membered, 9-12 membered, 10-12 membered, 9 membered, and 10 membered heterocycloalkyl groups, among others.

[0339] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" are used interchangeably. 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 rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5-10 membered heteroaryl group may be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, and 6 membered heteroaryl groups. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4- thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, 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, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0340] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). 5-6 yuan of heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 yuan of heteroaryl includes 5 yuan and 6 yuan of heteroaryl. The example of the 5-6 yuan of heteroaryl includes but is not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0341] Unless otherwise specified, the terms "5-6 membered nitrogen-containing heteroaromatic ring" and "5-6 membered nitrogen-containing heteroaryl" are used interchangeably. The term "5-6 membered nitrogen-containing heteroaryl" refers to a monocyclic group consisting of 5 to 6 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, wherein at least one heteroatom is N and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or carbon atom. The 5-6 membered heteroaryl includes 5- and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2H-1, 2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0342] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0343] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0344] The solvents used in the present invention are commercially available. The present invention uses the following abbreviations: DMF stands for N,N-dimethylformamide; DIPEA stands for N,N-diisopropylethylamine; DCM stands for dichloromethane; m-CPBA stands for u-chloroperoxybenzoic acid; NBS stands for N-bromosuccinimide; HATU stands for 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; NCS stands for N-chlorosuccinimide; and Dess-Martin reagent stands for (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzidoyl-3(1H)-one.

[0345] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0346] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, 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 of the present invention.

[0347] Example 1

[0348] Step 1: Synthesis of compound 1-2

[0349] Compound 1-1 (1 g, 1.31 mmol) and 1-1A (444.20 mg, 2.63 mmol) were weighed and dissolved in DMF (50 mL). DIPEA (1.70 g, 13.13 mmol, 2.29 mL) was added and the mixture was heated to 100°C for 2 hours. Water (50 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL x 2), washed with water (30 mL), and concentrated. Compound 1-2 was obtained, with MS m / z = 781.5 [M+H]. + .

[0350] Step 2: Synthesis of Compounds 1-3

[0351] Compound 1-2 (1.06 g, 1.36 mmol) was weighed and dissolved in DCM (30 mL). m-CPBA (276.34 mg, 1.36 mmol, 85% purity) was added at 0°C and reacted at 25°C for 1 hour. The product was concentrated to obtain compound 1-3. MS m / z = 797.5 [M+H] + .

[0352] Step 3: Synthesis of Compounds 1-4

[0353] Compound 1-2A (847.12 mg, 5.32 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), sodium tert-butoxide (511.38 mg, 5.32 mmol) was added, and the temperature was lowered to 0°C for 30 minutes. Compound 1-3 (1.06 g, 1.33 mmol) was added and the reaction was continued at 25°C for 1 hour. 20 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 2), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 1-4. MS m / z = 892.6 [M+H] + .

[0354] Step 4: Synthesis of hydrochloride salts of compounds 1A and 1B

[0355] Compound 1-4 (0.7 g, 784.82 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at 25° C. for 2 hours. After completion of the reaction, the mixture was directly concentrated and purified by high performance liquid chromatography (Phenomenex C18 150×40mm×5μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 10%-30%) to obtain the hydrochloride salt of compound 1A and the hydrochloride salt of compound 1B. Analytical method: Chromatographic column: ChromCore 120 C18 3 μm, 3.0 × 30 mm; mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)]; gradient: acetonitrile (0.02% trifluoroacetic acid) %: 10%-80%, 7 min (220 × 254 nm), retention time: 1A (Rt = 2.694 min), MS m / z = 652.3 [M+H] + , 1B (Rt=2.848min), MS m / z=652.2[M+H] + .

[0356] 1A: 1 H NMR (400MHz, CD3OD) δ6.90-6.66 (m, 1H), 5.75-5.45 (m, 1H), 5.39-5.22 (m, 1H), 5.00-4.9 4(m, 2H), 4.79-4.63(m, 3H), 4.24-4.07(m, 1H), 4.02-3.81(m, 3H), 3.71-3.62(m, 1H), 3.6 1-3.54(m, 1H), 3.51-3.44(m, 1H), 3.42-3.35(m, 1H), 3.17-3.04(m, 1H), 2.71-2.46(m, 3H ), 2.27-2.17(m, 1H), 2.23(dt, J=4.1, 13.1Hz, 6H), 2.10-1.99(m, 1H), 1.96-1.78(m, 2H).

[0357] 1B: 1H NMR (400MHz, CD3OD) δ7.43-7.34(m, 1H), 7.06-6.90(m, 1H), 6.88-6.76(m, 1H), 5.74-5.50(m, 1H), 5.35-5.20(m, 1H), 5.02-4.96(m, 1H), 4.78-4.72( m, 2H), 4.52-4.39 (m, 1H), 4.20-4.07 (m, 1H), 4.05-3.77 (m, 4H), 3.53-3.3 8(m, 3H), 3.13-2.99(m, 1H), 2.78-2.58(m, 2H), 2.53-2.43(m, 1H), 2.40(br d, J=3.8Hz, 3H), 2.37-2.31(m, 2H), 2.28-2.15(m, 1H), 2.12-2.01(m, 1H), 2.00-1.89(m, 2H).

[0358] Example 2

[0359] Step 1: Synthesis of compound 2-1

[0360] Compound 1-1 (800 mg, 1.05 mmol) and 2-1A (175.18 mg, 1.16 mmol) were weighed and added to DMF (10 mL). DIPEA (407.21 mg, 3.15 mmol, 548.80 μL) and the mixture was heated to 100°C for 2 hours. The mixture was quenched with water (50 mL), extracted with ethyl acetate (50 mL x 2), washed with water (30 mL), concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2-1. MS m / z = 727.3 [M+H] + .

[0361] Step 2: Synthesis of compound 2-2

[0362] Compound 2-1 (620 mg, 853.03 μmol) was weighed and dissolved in DCM (20 mL). m-CPBA (173.18 mg, 853.03 μmol, 85% purity) was added and reacted at 25°C for 1 hour. The reaction solution was diluted with 50 mL of dichloromethane, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol=20:1) to obtain compound 2-2. MS m / z=743.3 [M+H] + .

[0363] Step 3: Synthesis of compound 2-3

[0364] Compound 1-2A (128.59 mg, 807.73 μmol) was dissolved in anhydrous tetrahydrofuran (10 mL), sodium tert-butoxide (77.62 mg, 807.73 μmol) was added, and the mixture was reacted at 25°C for 30 minutes. Compound 2-2 (300 mg, 403.87 μmol) was added, and the mixture was reacted at 25°C for 1 hour. The reaction solution was diluted with 60 mL of ethyl acetate, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2-3. MS m / z = 838.4 [M+H] + .

[0365] Step 4: Synthesis of the hydrochloride salt of compound 2

[0366] Compound 2-3 (0.3 g, 358.03 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The mixture was reacted at 25°C for 2 hours. After completion of the reaction, the mixture was directly concentrated and purified by high-performance liquid chromatography (Phenomenex C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 5%-35%, 10 min) to obtain the hydrochloride salt of compound 2. MS m / z = 598.4 [M+H] + . 1 H NMR (400MHz, CD3OD) δppm 6.85-6.67(m, 1H), 5.69-5.52(m, 1H), 5.32-5.22(m, 1H), 5.00-4.94(m, 1H), 4.80 -4.74(m, 3H), 4.61-4.34(m, 1H), 4.06-3.83(m, 4H), 3.55-3.36(m, 3H), 3.25-3.1 0(m, 1H), 3.07-2.95(m, 1H), 2.82-2.61(m, 2H), 2.54-2.44(m, 1H), 2.42-2.30(m, 5H), 2.30-2.17(m, 1H), 2.14-1.98(m, 1H), 1.89-1.65(m, 3H), 1.34-1.25(m, 3H).

[0367] Example 3

[0368] Step 1: Synthesis of compound 3-1

[0369] Compound 1-1 (300 mg, 0.39 mmol) and 3-1A (144.57 mg, 0.59 mmol) were weighed and added to DMF (5 mL). DIPEA (152.70 mg, 1.18 mmol, 205.80 μL) was added and the mixture was heated to 100°C for 1 hour. The mixture was directly concentrated and separated by column chromatography (petroleum ether:ethyl acetate = 4:1-1:1) to obtain compound 3-1. MS m / z = 820.5 [M+H].

[0370] Step 2: Synthesis of compound 3-2

[0371] Compound 3-1 (320 mg, 390.29 μmol) was weighed and dissolved in DCM (5 mL). m-CPBA (79.24 mg, 390.29 μmol, 85% purity) was added and reacted at 25°C for 0.5 h. The reaction solution was diluted with 40 mL of dichloromethane, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol=20:1) to obtain compound 3-2. MS m / z=836.5 [M+H] + .

[0372] Step 3: Synthesis of compound 3-3

[0373] Compound 1-2A (91.42 mg, 574.23 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), sodium tert-butoxide (55.19 mg, 574.23 μmol) was added, and the mixture was reacted at 25°C for 30 minutes. Compound 3-2 (300 mg, 358.89 μmol) was added, and the mixture was reacted at 25°C for 1 hour. The reaction solution was diluted with 40 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3-3. MS m / z = 931.7 [M+H] + .

[0374] Step 4: Synthesis of the hydrochloride salt of compound 3

[0375] Compound 3-3 (310 mg, 332.97 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The mixture was reacted at 25°C for 1 hour. After completion of the reaction, the mixture was concentrated and purified by high-performance liquid chromatography (Phenomenex C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 13%-43%, 10 min) to obtain the hydrochloride salt of compound 3. MS m / z = 691.4 [M+H]+. 1H NMR (400MHz, CD3OD) δppm 7.08-6.91(m, 1H), 6.87-6.71(m, 1H), 5.77-5.47(m, 1H), 5.35-5.15(m, 2H) , 4.99(brs, 3H), 4.89-4.81(m, 1H), 4.78-4.69(m, 1H), 4.67-4.55(m, 1H), 4 .53-4.43(m, 1H), 4.21-4.05(m, 2H), 4.03-3.80(m, 3H), 3.53-3.34(m, 5H), 3.20-2.99(m, 4H), 2.80-2.61(m, 2H), 2.60-2.51(m, 1H), 2.50-2.17(m, 8H).

[0376] Example 4

[0377] Step 1: Synthesis of compound 4-2

[0378] Compound 4-1 (480 g, 2.53 mol) was weighed and added to DMF (2500 mL). 4-methoxybenzyl chloride (5.18 mol, 702.79 mL), potassium carbonate (872.82 g, 6.32 mol), and potassium iodide (419.35 g, 2.53 mol) were added and reacted at 65°C for 2 hours. Water (1000 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (1000 mL × 3). The organic phase was concentrated under reduced pressure to obtain compound 4-2, MS m / z = 430.0 [M+H] + .

[0379] Step 2: Synthesis of compound 4-3

[0380] Compound 2,2,6,6-tetramethylpiperidine (220.59 g, 1.56 mol, 265.13 mL) was weighed and added to THF (3000 mL). n-Butyl lithium (2.5 M, 499.73 mL) was added at -5°C and stirred for 0.5 hour. The temperature was then lowered to -60°C and 4-2 (280 g, 624.67 mmol) was added. The mixture was stirred for 0.5 hour, and finally DMF (228.28 g, 3.12 mol, 240.30 mL) was added. The reaction was continued for 0.5 hour. The reaction solution was poured into water (1000 mL) to quench the reaction. Hydrochloric acid was added to adjust the pH to 7, and the mixture was extracted with ethyl acetate (1000 mL × 3). The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 4-3.

[0381] Step 3: Synthesis of compound 4-4

[0382] 4-3 (370 g, 807.30 mmol) was weighed, and toluene (1500 mL), dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium (2.86 g, 4.04 mmol, 2.86 mL), and tributyl(1-propynyl)tin (265.69 g, 807.30 mmol) were added. The mixture was reacted at 120°C under nitrogen for 2 hours. The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 4-4. MS m / z = 418.1 [M+H] + .

[0383] Step 4: Synthesis of compound 4-5

[0384] 4-4 (450 g, 970.13 mmol) was weighed and added to DMF (100 mL). N-bromosuccinimide (189.93 g, 1.07 mol) was added and the mixture was allowed to react at 25°C for 2 hours. N-bromosuccinimide (17.27 g, 97.01 mmol) was added and the reaction continued for 3 hours. The product was directly dried and separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 4-5. MS m / z = 496.0 [M+H] + .

[0385] Step 5: Synthesis of Compounds 4-6

[0386] Compound 4-5 (55 g, 110.81 mmol) was weighed and added to DMF (300 mL). Methyl fluorosulfonyldifluoroacetate (42.57 g, 221.61 mmol, 28.19 mL) and cuprous iodide (42.21 g, 221.61 mmol) were added and reacted at 110°C under nitrogen for 2 hours. The mixture was quenched by adding 500 mL of water and extracted with ethyl acetate (600 mL × 3). The combined organic phases were washed sequentially with water (800 mL × 2) and saturated brine (800 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 4-6 was obtained by column chromatography (petroleum ether: ethyl acetate = 10:1). MS m / z = 485.9 [M+H] + .

[0387] Step 6: Synthesis of Compounds 4-7

[0388] To a solution of sodium hydroxide (6.34 g, 158.61 mmol, 60% purity) in tetrahydrofuran (350 mL) at 0°C was added methyl acetoacetate (18.42 g, 158.61 mmol, 17.10 mL) dropwise. The mixture was allowed to react for 15 minutes. After cooling to -20°C, n-butyl lithium (2.5 M, 63.44 mL) was added dropwise. Stirring was continued for 15 minutes after the addition was complete. A solution of 4-6 (35 g, 72.10 mmol) in tetrahydrofuran (350 mL) was then added. The reaction was allowed to react for 0.5 hours. The reaction was quenched by adding 200 mL of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (300 mL x 2). The combined organic phases were washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 4-7 was obtained by column chromatography (petroleum ether:ethyl acetate = 10:1-1:1). MS m / z=624.2[M+Na] + .

[0389] Step 7: Synthesis of Compounds 4-8

[0390] 4-7 (38 g, 63.17 mmol) was weighed, dichloromethane (300 mL) was added, and then N,N-dimethylformamide dimethyl acetal (9.03 g, 75.80 mmol) was added. The reaction was carried out at 25°C for 16 hours. The mixture was cooled to 0°C, and boron trifluoride etherate (10.76 g, 75.80 mmol, 9.32 mL) was added. The system was stirred at 0°C for 1 hour. 200 mL of saturated sodium bicarbonate solution was added to the system, and the organic phase was separated. The aqueous phase was extracted with 200 mL of dichloromethane. The combined organic phases were washed with 250 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether: ethyl acetate = 10:1-1:1) was used to obtain compound 4-8. MS m / z = 612.1 [M+H] + .

[0391] Step 8: Synthesis of Compounds 4-9

[0392] 4-8 (30 g, 49.05 mmol) was weighed and tetrahydrofuran (300 mL) was added. Lithium tri-sec-butylborohydride (1 M, 53.96 mL) was then added at -60°C. The reaction was allowed to react at -60°C for 1 hour. 200 mL of water was added to the system to quench the reaction. The mixture was extracted with ethyl acetate (300 mL x 2). The combined organic phases were washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 4-9 was obtained by column chromatography (petroleum ether:ethyl acetate = 10:1-5:1). MS m / z = 614.1 [M+H] + .

[0393] Step 9: Synthesis of Compounds 4-10

[0394] 4-9 (20 g, 32.59 mmol) was weighed, ethanol (200 mL) was added, 2-methyl-2-thioisourea sulfate (27.22 g, 97.78 mmol) and sodium carbonate (6.91 g, 65.19 mmol) were added, and the mixture was reacted at 50°C for 13 hours. The reaction solution was concentrated to dryness, 40 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with 60 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain compound 4-10. MS m / z = 654.3 [M+H] + .

[0395] Step 10: Synthesis of Compounds 4-11

[0396] 4-10 (21 g, 32.13 mmol) was weighed and added to DMF (200 mL). N,N-diisopropylethylamine (12.46 g, 96.38 mmol, 16.79 mL) and N-phenylbis(trifluoromethanesulfonyl)imide (13.77 g, 38.55 mmol) were then added and reacted at 25°C for 1 hour. 300 mL of water was added to the system, and the mixture was extracted with ethyl acetate (300 mL x 3). The mixture was washed sequentially with water (400 mL x 2) and saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 4-11 was obtained by column chromatography (petroleum ether:ethyl acetate = 10:1).

[0397] Step 11: Synthesis of Compounds 4-12

[0398] Compound 4-11 (5 g, 6.36 mmol) and 3-1A (2.34 g, 9.55 mmol) were weighed, and DMF (15 mL) and DIPEA (2.47 g, 19.09 mmol, 3.33 mL) were added. The mixture was reacted at 100°C for 1 hour. The mixture was directly concentrated and separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 4-12. MS m / z = 844.3 [M+H] + .

[0399] Step 12: Synthesis of Compounds 4-13

[0400] Compound 4-12 (5.3 g, 6.28 mmol) was weighed and dissolved in DCM (60 mL). m-CPBA (1.27 g, 6.28 mmol, 85% purity) was added and reacted at 25°C for 0.5 h. The reaction solution was diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-13. MS m / z = 860.5 [M+H] + .

[0401] Step 13: Synthesis of Compounds 4-14

[0402] Compound 1-2A (1.30 g, 8.16 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), sodium tert-butoxide (784.51 mg, 8.16 mmol) was added, and the mixture was allowed to react at 25°C for 30 minutes. Compound 4-13 (5.4 g, 6.28 mmol) was then added and the mixture was allowed to react at 25°C for 0.5 hours. The reaction solution was diluted with 300 mL of ethyl acetate, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 4-14. MS m / z = 955.8 [M+H] + .

[0403] Step 14: Synthesis of compounds 4A and 4B

[0404] Compound 4-14 (3.4 g, 3.56 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the mixture was reacted at 20° C. for 1 hour. The reaction solution was concentrated, the pH was adjusted to 9-11 with saturated sodium carbonate solution, and extracted with dichloromethane (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane: methanol = 20:1) to obtain compound 4, which was then separated by SFC (chromatographic column: DAICEL CHIRALCEL OD (250 mm×50 mm, 10 μm); mobile phase: [supercritical CO2-methanol (0.1% ammonia)]; methanol (0.1% ammonia)%: 40%-40%) to obtain compound 4A and compound 4B. Chiral SFC analysis (chromatographic column: DAICEL CHIRALCEL OD-3 (150 mm × 4.6 mm, 3 μm); mobile phase: [supercritical CO2-methanol (0.05% diethylamine)]; (methanol (0.05% diethylamine))%: 40%-40%), compound 4A, Rt = 3.084 minutes, ee value 99%; compound 4B, Rt = 5.110 minutes, ee value 98%.

[0405] Compound 4A: MS m / z = 715.4 [M+H] + , 1H NMR (400MHz, CD3OD) δppm 6.98-6.86(m, 1H), 6.73-6.58(m, 1H), 5.40-5.21(m, 1H), 5.20-5.12(m, 1H), 4. 84(brs, 4H), 4.58-4.40(m, 2H), 4.15-4.04(m, 2H), 4.00-3.82(m, 2H), 3.34(s, 6H), 3.37-3.17 (m, 1H), 3.12-3.06 (m, 3H), 3.06-2.98 (m, 1H), 2.90-2.80 (m, 1H), 2.35-2.21 (m, 2H), 2.20-2.06 (m, 3H), 2.05-2.02 (m, 3H), 2.01-1.84 (m, 3H). Compound 4B: MS m / z = 715.4 [M+H] + .

[0406] Example 5

[0407] Step 1: Synthesis of Intermediate 5-1A

[0408] Compound 5-1 was subjected to SFC analysis (chromatographic column: Chiralpak IH-3, 100×4.6mm ID, 3μm; mobile phase: A (supercritical CO2) and B (EtOH, containing 0.1% isopropylamine); gradient: B% = 10-50%, run time 3.7min), and the peak times were 1.266min and 1.521min, of which the peak at 1.521min was compound 5-1A. Preparative supercritical fluid chromatography (SFC) purification was then performed (chromatographic column: ChiralPak IH, 250×50 mm, 10 μm; mobile phase: [supercritical CO2-ethanol (0.1% ammonia)]; ethanol (0.1% ammonia)%: 20%-20%) to obtain compound 5-1A. SFC analysis (chromatographic column: Chiralpak IH-3, 100×4.6 mm ID., 3 μm; mobile phase: A (supercritical CO2) and B (EtOH, containing 0.1% isopropylamine); gradient: B% = 10-50%, 4 min; flow rate: 3.4 mL / min; wavelength: 220 nm; pressure: 2000 psi) gave compound 5-1A, Rt = 1.489 min, ee value 98.8%. 1 H NMR (400MHz, CDCl3) δ = 4.99-4.86 (m, 2H), 4.26-3.95 (m, 3H), 3.59 (m, 1H), 3.01-2.88 (m, 1H), 2.88-2.15 (m, 4H), 1.91 (s, 1H), 1.20-1.09 (m, 3H).

[0409] Step 2: Synthesis of intermediate 5-2

[0410] Lithium aluminum tetrahydride (1.55 g, 40.15 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to 0°C, and a solution of compound 5-1A (2.8 g, 13.38 mmol) in anhydrous tetrahydrofuran (20 mL) was added under nitrogen. The mixture was reacted at 70°C for 1 hour. 1.5 mL of water was added to the reaction solution at 0°C, followed by 1.5 mL of 15% sodium hydroxide solution and 4.5 mL of water. The mixture was stirred for 20 minutes, filtered, and the filter cake was washed with 10 mL of tetrahydrofuran. The filtrate was concentrated to obtain compound 5-2. 1 H NMR (400MHz, CDCl3) δ = 4.99-4.86 (m, 2H), 4.28-3.95 (m, 3H), 3.61-3.59 (m, 1H), 3.00-2.88(m, 1H), 2.74-2.27(m, 4H), 1.91(s, 1H), 1.20-1.08(m, 3H).

[0411] Step 3: Synthesis of compound 5-3

[0412] Compound 5-2 (88.20 mg, 575.63 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), sodium tert-butoxide (55.32 mg, 575.63 μmol) was added, and the mixture was reacted at 25°C for 30 minutes. Compound 4-13 (330 mg, 383.75 μmol) was added, and the mixture was reacted at 25°C for 0.5 hours. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5-3. MS m / z = 949.1 [M+H] + .

[0413] Step 4: Synthesis of compounds 5A and 5B

[0414] Compound 5-3 (360 mg, 379.33 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was reacted at 25°C for 1 hour. The reaction solution was concentrated and separated by HPLC (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile %: 10%-40%, 10 min) to obtain the hydrochloride salt of compound 5. SFC separation (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm); mobile phase: [supercritical CO2-ethanol (0.1% ammonia)]; ethanol (0.1% ammonia) %: 40%-40%) was performed to obtain compounds 5A and 5B. Chiral SFC analysis (chromatographic column: DAICEL CHIRALCEL OD-3 (150 mm × 4.6 mm, 3 μm); mobile phase: [supercritical CO2-ethanol (0.05% diethylamine)]; ethanol (0.05% diethylamine)%: 40%-40%), compound 5A, Rt = 0.848 min, ee value 100%; compound 5B, Rt = 2.371 min, ee value 99%.

[0415] Compound 5A: MS m / z = 709.3 [M+H] + , 1 H NMR (400MHz, CD3Cl) δppm 6.93-6.85(m, 1H), 6.84-6.77(m, 1H), 5.36-5.22(m, 2H), 5.20-5.11(m, 1H), 4.89-4.41(m, 10H), 4.18-3.99(m, 3H), 3.97-3.77(m, 2H), 3.61-3.48(m, 1H) , 3.42-3.26 (m, 4H), 3.17-3.04 (m, 4H), 3.01-2.88 (m, 2H), 2.73-2.61 (m, 1H), 2.56-2.42 (m, 1H), 2.35-2.23 (m, 2H), 2.21-2.12 (m, 2H), 2.10-2.04 (m, 3H). Compound 5B: MS m / z=709.3 [M+H] + .

[0416] Example 6

[0417] Step 1: Synthesis of intermediate 6-2

[0418] Compound 6-1 (20 g, 56.53 mmol) was dissolved in hydrochloric acid / ethyl acetate (4 M, 120 mL) and reacted at 25°C for 2 hours. The reaction solution was directly concentrated to obtain crude product 6-2, which was used directly in the next step.

[0419] Step 2: Synthesis of Intermediate 6-3

[0420] Dissolve the crude product 6-2 (20 g) in DMF (65 mL) and add potassium carbonate (14.2 g, 102 mmol). React at 25°C for 12 hours. Dilute the reaction solution with 500 mL of ethyl acetate, wash with 300 mL of water (2 x 300 mL), then with 300 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 6-3.

[0421] Step 3: Synthesis of Intermediate 6-4

[0422] Compound 6-3 (7 g, 32.23 mmol) was dissolved in 2-methyltetrahydrofuran (75 mL), replaced with nitrogen three times, and then red aluminum (37.2 g, 129 mmol, 35.8 mL, 70% purity) was slowly added at 10 ° C under nitrogen protection. The reaction was carried out at 25 ° C for 12 hours. The reaction solution was added dropwise to 26.0% sodium tartrate aqueous solution to quench, extracted with 2-methyltetrahydrofuran (200 mL), and the aqueous phase was extracted with 2-methyltetrahydrofuran (50 mL x 3). The combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 6-4.

[0423] Step 4: Synthesis of Intermediate 6-5

[0424] Compound 6-4 (2.2 g, 13 mmol) was dissolved in DCM (30 mL), and imidazole (3.5 g, 53 mmol), 4-dimethylaminopyridine (160 mg, 1.3 mmol) and tert-butyldiphenylsilyl chloride (7.2 g, 25 mmol) were added. The mixture was reacted at 45° C. for 12 hours. Water (50 mL) was added to the reaction solution, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (40 mL). The organic phases were combined, washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Methyl tert-butyl ether (10 mL), n-heptane (21 mL) and hydrochloric acid solution (2M, 21 mL) were added thereto, the aqueous phase was separated, washed with a mixed solvent of methyl tert-butyl ether: n-heptane = 1:2 (20 mL×3), and then adjusted to pH = 7 with sodium carbonate aqueous solution, extracted with 200 mL of ethyl acetate, the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to separate the first spot (R f=0.6, another isomer R f =0.5) to give crude intermediate 6-5.

[0425] Step 5: Synthesis of Intermediate 6-6

[0426] Compound 6-5 (2 g, 4.6 mmol) was subjected to SFC analysis (chromatographic column: Chiralpak IC-3 50×4.6 mm ID, 3 μm; mobile phase: A (supercritical CO2) and B (methanol, containing 0.05% diethylamine); gradient: B% = 5-10%, flow rate: 3 mL / min). The peak times were 2.117 min and 2.980 min, of which the sample at 2.117 min was intermediate 6-6. Chiral SFC separation and purification were then performed (chromatographic column: DAICEL CHIRALPAK IC (250 mm×30 mm, 10 μm); mobile phase: [supercritical CO2-methanol (0.1% ammonia)]; methanol (0.1% ammonia)%: 25%-25%, 4.5 min) to obtain compound 6-6. SFC analysis (Chromatographic column: Chiralpak IC-3 50×4.6mm ID, 3μm; Mobile phase: A (supercritical CO2) and B (methanol containing 0.05% diethylamine); Gradient: B% = 5-10%, Flow rate: 3mL / min), Rt = 2.014min, ee value 98%. MS m / z = 410.3 [M+H] + .

[0427] Step 6: Synthesis of Intermediate 6-7

[0428] Dissolve compound 6-6 (1.2 g, 2.93 mmol) in 24 mL of 1,4-dioxane and add concentrated hydrochloric acid (12 M, 7.20 mL). React at 95°C for 12 hours. After cooling, dilute the reaction solution with 10 mL of water, wash with 10 mL of ethyl acetate, and lyophilize the aqueous phase to obtain the hydrochloride salt of compound 6-7. Dissolve the solution in methanol (20 mL), add 2 g of potassium carbonate, filter, concentrate, and dissolve in tetrahydrofuran (20 mL). Filter and concentrate to obtain compound 6-7.

[0429] Step 7: Synthesis of Compounds 6-8

[0430] Compound 6-7 (92.58 mg, 540.74 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), sodium tert-butoxide (51.97 mg, 540.74 μmol) was added, and the mixture was reacted at 25°C for 30 minutes. Compound 4-13 (310 mg, 360.49 μmol) was added, and the mixture was reacted at 25°C for 0.5 hours. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 6-8. MS m / z = 967.3 [M+H] + .

[0431] Step 8: Synthesis of compounds 6A and 6B

[0432] Compound 6-8 (345 mg, 356.76 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at 25°C for 1 hour. The reaction solution was concentrated and separated by high performance liquid chromatography (chromatographic column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 10%-40%, 10 min) to obtain the hydrochloride salt of compound 6. SFC separation (chromatographic column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm); mobile phase: [supercritical CO2-methanol (0.1% ammonia)]; methanol (0.1% ammonia)%: 40%-40%) was performed to obtain compounds 6A and 6B. Chiral SFC analysis (chromatographic column: DAICEL CHIRALCEL OD-3 (150 mm × 4.6 mm, 3 μm); mobile phase: [supercritical CO2-methanol (0.05% diethylamine)]; (methanol (0.05% diethylamine))%: 40%-40%), compound 6A, Rt = 3.658 minutes, ee value 99.9%; compound 6B, Rt = 7.041 minutes, ee value 99.9%.

[0433] Compound 6A: MS m / z = 727.3 [M+H] + , 1H NMR (400MHz, CD3OD) δppm 6.90-6.64(m, 2H), 6.60-6.55(m, 1H), 5.13-5.01(m, 1H), 4.84(brs, 2H), 4.69- 4.57(m, 2H), 4.47-4.38(m, 2H), 4.37-4.26(m, 3H), 4.06-3.96(m, 1H), 3.90-3. 75 (m, 2H), 3.72-3.62 (m, 1H), 3.26-3.23 (m, 3H), 3.19-3.10 (m, 2H), 3.04-2.93 (m, 3H), 2.88-2.62 (m, 3H), 2.36-2.23 (m, 1H), 2.02 (s, 5H), 1.93-1.87 (m, 3H). Compound 6B: MS m / z = 727.3 [M+H] + .

[0434] Example 7

[0435] Step 1: Synthesis of Intermediate 4-11B

[0436] Compound 4-11 was subjected to preparative SFC separation (chromatographic column: DAICEL CHIRALPAK IG (250 mm × 50 mm, 10 μm); mobile phase: [supercritical CO2-ethanol (0.1% ammonia)]; ethanol (0.1% ammonia)%: 25%-25%) to obtain compound 4-11B and its isomers. Chiral SFC analysis (chromatographic column: ChiralPak IG-3 (100 mm × 4.6 mm, 3 μm); mobile phase: [supercritical CO2-ethanol (0.05% diethylamine)]; (ethanol (0.05% diethylamine))%: 5%-40%), compound 4-11B, Rt = 3.055 minutes, ee value 99%; its isomer, Rt = 2.574 minutes, ee value 99%;

[0437] Step 2: Synthesis of Intermediate 7-2

[0438] Compound 4-11B (0.4 g, 509.07 μmol) was weighed and dissolved in DMF (15 mL). 7-1 (125.62 mg, 610.88 μmol) was added, followed by DIPEA (197.38 mg, 1.53 mmol) and the reaction mixture was heated at 100°C for 1 hour. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 7-2, MS m / z = 805.6 [M+H]. + .

[0439] Step 3: Synthesis of Intermediate 7-3

[0440] Compound 7-2 (381.80 mg, 474.37 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (96.31 mg, 474.37 μmol, 85% purity) was added and reacted at 25°C for 1 hour. Water (15 mL) was added to the reaction solution, which was diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7-3. MS m / z = 821.6 [M+H] + .

[0441] Step 4: Synthesis of Intermediate 7-4

[0442] Compound 5-2 (286.64 mg, 1.87 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium tert-butoxide (179.79 mg, 1.87 mmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 7-3 (383.90 mg, 467.69 μmol) was added and reacted at 0°C for 1 hour. Water (15 mL) was added to the reaction solution, which was diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 7-4. MS m / z = 910.5 [M+H] + .

[0443] Step 5: Synthesis of compounds 7A and 7B

[0444] Compound 7-4 (0.2833 g, 311.33 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (4.33 g, 38.01 mmol, 2.82 mL) was added. The mixture was reacted at 20°C for 1 hour. The reaction solution was concentrated, the pH was adjusted to 10 with saturated sodium carbonate solution, and the mixture was extracted with dichloromethane (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by preparative HPLC (column: Phenomenex C18 80 × 40 mm × 3 μm; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile percentage: 41%-71% over 8 min) to obtain Compound 7A and Compound 7B. Chiral SFC analysis (column: DAICEL CHIRALCEL AS-3 (100 mm × 4.6 mm, 3 μm); mobile phase: [supercritical CO₂-methanol (0.05% diethylamine)]; (methanol (0.05% diethylamine))%: 40%-40%), compound 7A, Rt = 1.445 min, ee value 97.4%, MS m / z = 670.3 [M+H] + Compound 7B, Rt = 0.863 min, ee value 94.9%, MS m / z = 670.3 [M+H] + .

[0445] Example 8

[0446] Step 1: Synthesis of Intermediate 8-2

[0447] Compound 8-1 (0.2 g, 710.86 μmol) was weighed and dissolved in DMF (5 mL). O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (351.38 mg, 924.12 μmol), DIPEA (367.50 mg, 2.84 mmol, 495.28 μL) and dimethylamine hydrochloride (173.90 mg, 2.13 mmol) were added to the reaction system and reacted at room temperature (18°C) for 2 hours. Water (20 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-2, MS m / z = 295.2 [M+H] + .

[0448] Step 2: Synthesis of the hydrochloride salt of intermediate 8-3

[0449] Compound 8-2 (209 mg, 674.54 μmol) was weighed and a 4M hydrochloric acid / ethyl acetate solution (5 mL) was added. The reaction system was reacted at room temperature (18°C) for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 8-3. MS m / z = 195.1 [M+H] + .

[0450] Step 3: Synthesis of Intermediate 8-4

[0451] Compound 4-11B (0.2 g, 254.53 μmol) was weighed and dissolved in DMF (8 mL). The hydrochloride of 8-3 (59.33 mg) was added, and DIPEA (98.69 mg, 763.60 μmol) was added to the reaction system. The mixture was reacted at 100°C for 1 hour. Water (20 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (30 mL), dried over anhydrous sodium sulfate, and concentrated under low pressure by rotary evaporation. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 8-4, MS m / z = 830.6 [M+H] + .

[0452] Step 4: Synthesis of Intermediate 8-5

[0453] Compound 8-4 (0.099 g, 119.29 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (24.22 mg, 119.29 μmol, 85% purity) was added and reacted at 25°C for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The product was purified by column chromatography (dichloromethane: methanol = 20:1) to obtain compound 8-5. MS m / z = 846.6 [M+H] + .

[0454] Step 5: Synthesis of Intermediate 8-6

[0455] Compound 5-2 (46.73 mg, 305.00 μmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and sodium tert-butoxide (29.31 mg, 305.00 μmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 8-5 (129 mg, 152.50 μmol) was added and reacted at 0°C for 1 hour. Water (20 mL) was added to the reaction solution, which was diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol=20:1) to obtain compound 8-6. MS m / z=935.5 [M+H] + .

[0456] Step 6: Synthesis of the hydrochloride salt of compound 8

[0457] Compound 8-6 (0.142 g, 151.87 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (2.11 g, 18.54 mmol, 1.38 mL) was added. The mixture was reacted at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to preparative HPLC (column: Xtimate C18 150 × 40 mm × 5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 10%-40%, 10 min) to obtain the hydrochloride salt of compound 8. MS m / z = 695.2 [M+H]+. 1H NMR (400MHz, MeOD) δ = 6.96 (d, J = 8.5Hz, 1H), 6.69-6.47 (m, 1H), 5.39-5.32 (m, 2H), 5.30-5.21 (m, 1H), 5.13-5.04 (m, 2H), 4.95 (br d, J=5.0Hz, 2H), 4.69-4.56 (m, 2H), 4.55-4.42 (m, 2H), 4.41-4.31 (m, 2H), 4.06-3.98 (m, 1H), 3.98-3.91 (m, 1H), 3.87-3.77 (m, 1H) ), 3.47-3.36(m, 3H), 3.30-3.22(m, 2H), 3.20-2.98(m, 5H), 2.91-2.81(m, 1H), 2.51-2.40(m, 1H), 2.33-2.12(m, 3H), 2.04(s, 3H).

[0458] Example 9

[0459] Step 1: Synthesis of Intermediate 9-2

[0460] Compound 4-11B (0.2 g, 254.53 μmol) was weighed and dissolved in DMF (15 mL). 9-1 (61.59 mg, 305.44 μmol) was added, followed by DIPEA (98.69 mg, 763.60 μmol, 133.00 μL). The mixture was reacted at 100°C for 1 hour. Water (20 mL) was added to the reaction solution to quench the mixture, which was diluted with 100 mL of ethyl acetate, 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 = 1:1) to give compound 9-2, MS m / z = 801.6 [M+H] + .

[0461] Step 2: Synthesis of intermediate 9-3

[0462] Compound 9-2 (158.80 mg, 198.29 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (40.26 mg, 198.29 μmol, 85% purity) was added and reacted at room temperature (25°C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 9-3. MS m / z = 817.4 [M+H] + .

[0463] Step 3: Synthesis of Intermediate 9-4

[0464] Compound 5-2 (60.44 mg, 394.44 μmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and sodium tert-butoxide (37.91 mg, 394.44 μmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 9-3 (0.1611 g, 197.22 μmol) was added and reacted at 0°C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 9-4. MS m / z = 906.7 [M+H] + .

[0465] Step 4: Synthesis of the hydrochloride salt of compound 9

[0466] Compound 9-4 (127.44 mg, 140.66 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (1.96 g, 17.17 mmol, 1.28 mL) was added. The mixture was reacted at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to preparative HPLC separation (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 20%-50%, 10 min) to obtain the hydrochloride salt of compound 9. MS m / z = 666.3 [M+H] + .

[0467] Example 10

[0468] Step 1: Synthesis of Intermediate 10-2

[0469] Compound 4-11B (0.205 g, 260.90 μmol) was weighed and dissolved in DMF (15 mL). 10-1 (55.29 mg, 313.08 μmol) was added, followed by DIPEA (101.16 mg, 782.69 μmol, 136.33 μL). The mixture was reacted at 100°C for 1 hour. The reaction solution was quenched with water (20 mL), diluted with 100 mL of ethyl acetate, 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 = 1:1) to obtain compound 10-2, MS m / z = 776.3 [M+H] + .

[0470] Step 2: Synthesis of Intermediate 10-3

[0471] Compound 10-2 (0.202 g, 260.37 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (52.86 mg, 260.37 μmol, 85% purity) was added and reacted at room temperature at 25°C for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 10-3. MS m / z = 792.5 [M+H] + .

[0472] Step 3: Synthesis of Intermediate 10-4

[0473] Compound 5-2 (79.34 mg, 517.80 μmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and sodium tert-butoxide (49.76 mg, 517.80 μmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 10-3 (0.1611 g, 197.22 μmol) was added and reacted at 0°C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane: methanol = 20:1) to obtain compound 10-4. MS m / z = 881.7 [M+H] + .

[0474] Step 4: Synthesis of the hydrochloride salt of compound 10

[0475] Compound 10-4 (0.1338 g, 151.89 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was reacted at 20°C for 1 hour, and the reaction solution was concentrated to obtain a crude product. The crude product was separated by preparative HPLC (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 20%-50%, 10 min) to obtain the hydrochloride salt of compound 10. MS m / z = 641.1 [M+H] + .

[0476] Example 11

[0477] Step 1: Synthesis of Intermediate 11-2

[0478] Compound 4-11B (0.48 g, 610.88 μmol) was weighed and dissolved in DMF (15 mL). 11-1 (96.16 mg, 733.06 μmol) was added, followed by DIPEA (236.85 mg, 1.83 mmol, 319.21 μL). The mixture was reacted at 100 °C for 1 hour. The reaction solution was quenched with water (20 mL), diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 11-2, MS m / z = 767.4 [M+H] + .

[0479] Step 2: Synthesis of Intermediate 11-3

[0480] Compound 11-2 (452.40 mg, 589.95 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (119.77 mg, 589.95 μmol, 85% purity) was added and reacted at room temperature (25°C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 11-3. MS m / z = 783.5 [M+H] + .

[0481] Step 3: Synthesis of Intermediate 11-4

[0482] Compound 5-2 (180.46 mg, 1.18 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium tert-butoxide (113.19 mg, 1.18 mmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 11-3 (0.461 g, 588.88 μmol) was added and reacted at 0°C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 11-4. MS m / z = 872.5 [M+H] + .

[0483] Step 4: Synthesis of the hydrochloride salts of compounds 11A and 11B

[0484] Compound 11-4 (0.2 g, 229.37 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3.19 g, 28.00 mmol, 2.08 mL) was added. The mixture was reacted at 20°C for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to preparative high-performance liquid chromatography (column: Xtimate C18 150 × 40 mm × 5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 20%-50%, 10 min) to obtain the hydrochloride salts of compounds 11A and 11B. Analytical method: (Chromatographic column: ChromCore 120 C18 3μm, 3.0×30mm; mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)]; acetonitrile (0.02% trifluoroacetic acid)%: 10%-80%, 7 min), retention time: 11A (Rt=2.902 min), MS m / z=632.2 [M+H] + ;11B(Rt=3.020min), MS m / z=632.2[M+H] + .

[0485] Example 12

[0486] Step 1: Synthesis of Intermediate 12-2

[0487] Compound 4-11B (0.2 g, 254.53 μmol) was weighed and dissolved in DMF (15 mL). 12-1 (54.27 mg, 305.44 μmol) was added, followed by DIPEA (98.69 mg, 763.60 μmol, 133.00 μL), and the mixture was reacted at 100°C for 1 hour. The reaction solution was quenched with water (20 mL), diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 12-2, MS m / z = 777.4 [M+H] + .

[0488] Step 2: Synthesis of Intermediate 12-3

[0489] Compound 12-2 (0.1976 g, 254.35 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (51.67 mg, 254.35 μmol, 85% purity) was added and reacted at room temperature (25°C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 12-3. MS m / z = 793.6 [M+H] + .

[0490] Step 3: Synthesis of Intermediate 12-4

[0491] Compound 5-2 (77.68 mg, 507.01 μmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium tert-butoxide (48.73 mg, 507.01 μmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 12-3 (0.201 g, 253.51 μmol) was added and reacted at 0°C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 12-4. MS m / z = 882.5 [M+H] + .

[0492] Step 4: Synthesis of the hydrochloride salt of compound 12

[0493] Compound 12-4 (0.221 g, 250.57 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3.49 g, 30.59 mmol, 2.27 mL) was added. The mixture was reacted at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to preparative HPLC separation (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 20%-50%, 10 min) to obtain the hydrochloride salt of compound 12. MS m / z = 642.4 [M+H] + .

[0494] Example 13

[0495] Step 1: Synthesis of Intermediate 13-2

[0496] Compound 4-11B (0.35 g, 445.44 μmol) was weighed and dissolved in DMF (15 mL). 13-1 (121.72 mg, 534.52 μmol) was added, followed by DIPEA (172.70 mg, 1.34 mmol, 232.76 μL). The mixture was reacted at 100° C. for 1 hour. The reaction solution was quenched with water (20 mL), diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 13-2, MS m / z = 827.4 [M+H] + .

[0497] Step 2: Synthesis of Intermediate 13-3

[0498] Compound 13-2 (0.4165 g, 503.68 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (102.26 mg, 503.68 μmol, 85% purity) was added and reacted at room temperature (25°C) for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 13-3. MS m / z = 843.5 [M+H] + .

[0499] Step 3: Synthesis of Intermediate 13-4

[0500] Compound 5-2 (154.33 mg, 1.01 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium tert-butoxide (96.80 mg, 1.01 mmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 13-3 (0.4245 g, 503.61 μmol) was added and reacted at 0°C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 13-4. MS m / z = 932.4 [M+H] + .

[0501] Step 4: Synthesis of hydrochloride salts of compounds 13A and 13B

[0502] Compound 13-4 (0.293 g, 314.26 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (4.37 g, 38.36 mmol, 2.85 mL) was added. The mixture was reacted at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance liquid chromatography (HPLC column: Xtimate C18 150 × 40 mm × 5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 20%-50%, 10 min) to obtain the hydrochloride salts of compounds 13A and 13B. Analytical method: (Chromatographic column: ChromCore 120 C18 3 μm, 3.0 × 30 mm; mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)]; acetonitrile (0.02% trifluoroacetic acid) %: 10%-80%, 7 min), retention time: 13A (Rt = 2.891 min), MS m / z = 692.2 [M+H] + ; 13B (Rt=3.126min), MS m / z=692.2[M+H] + .

[0503] Example 14

[0504] Step 1: Synthesis of Intermediate 14-2

[0505] Compound 4-11B (200.00 mg, 254.53 μmol) was weighed and dissolved in DMF (10 mL). The hydrochloride salt of 14-1 (106.21 mg) was added, followed by DIPEA (98.69 mg, 763.60 μmol, 133.01 μL). The mixture was reacted at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=10:1) to obtain compound 14-2. MS m / z=878.6 [M+H] + .

[0506] Step 2: Synthesis of Intermediate 14-3

[0507] Compound 14-2 (200.23 mg, 227.95 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (39.34 mg, 227.95 μmol, 85% purity) was added and reacted at room temperature (25°C) for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 14-3, MS m / z = 894.3 [M+H] + .

[0508] Step 3: Synthesis of Intermediate 14-4

[0509] Compound 5-2 (61.67 mg, 402.52 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and sodium tert-butoxide (38.68 mg, 402.52 μmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 14-3 (180 mg, 201.26 μmol) was added and reacted at 0°C for 1 hour. The reaction solution was quenched with water (10 mL), adjusted to pH 6 with 1N dilute hydrochloric acid, and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 14-4. MS m / z=983.8 [M+H] + .

[0510] Step 4: Synthesis of Compound 14 and its hydrochloride

[0511] Compound 14-4 (118 mg, 119.98 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative HPLC (column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile percentage: 52%-82% over 8 min) to obtain compound 14. MS m / z = 743.2 [M+H] + .

[0512] The crude product was separated by preparative HPLC under hydrochloric acid conditions (column: Xtimate C18 150×40mm×5μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 17%-47%; 10 min) to obtain the hydrochloride salt of compound 14. Chiral SFC analysis (column: DAICEL CHIRALCEL OD-3 (50mm×4.6mm, 3μm); mobile phase: [supercritical CO2-ethanol (0.05% diethylamine)]; ethanol (0.05% diethylamine) percentage: 40%-40%) showed Rt = 0.745 min. MS m / z = 743.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ = 7.00-6.93 (m, 1H), 5.34 (br d, J = 5.9Hz, 2H), 5.27-5.15 (m, 2H), 5.09 (br d, J = 14.0Hz, 1H), 5.00-4.93 (m, 2H), 4.83 (br d, J=11.8Hz, 1H), 4.65(br d, J=11.9Hz, 1H), 4.59-4.51(m, 1H), 4.37-4.27(m, 2H), 4.17(br d, J=13.4Hz, 1H), 3.96-3.89(m, 2H), 3.85-3.76(m, 1H), 3.35-3.31(m, 1H), 3 .29-3.19(m, 1H), 3.16(s, 3H), 3.13-3.09(m, 3H), 3.08-2.97(m, 2H), 2.83(br d, J=16.3Hz, 1H), 2.62-2.48(m, 1H), 2.47-2.33(m, 2H), 2.31-2.13(m, 3H), 2.04(s, 3H).

[0513] Example 15

[0514] Step 1: Synthesis of Intermediate 15-2

[0515] Compound 4-11B (200.00 mg, 254.53 μmol) was weighed and dissolved in DMF (10 mL). The hydrochloride salt of 15-1 (92.29 mg, 381.80 μmol) was added, followed by DIPEA (98.69 mg, 763.60 μmol), and the mixture was reacted at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=10:1) to obtain compound 15-2, MS m / z=841.6 [M+H] + .

[0516] Step 2: Synthesis of Intermediate 15-3

[0517] Compound 15-2 (150.00 mg, 178.37 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (30.78 mg, 178.37 μmol, 85% purity) was added and reacted at room temperature (25°C) for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 15-3, MS m / z = 857.6 [M+H] + .

[0518] Step 3: Synthesis of Intermediate 15-4

[0519] Compound 5-2 (46.49 mg, 303.41 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and sodium tert-butoxide (29.16 mg, 303.41 μmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 15-3 (130 mg, 151.71 μmol) was added and reacted at 0°C for 1 hour. The reaction solution was quenched with water (10 mL), adjusted to pH 6 with 1N dilute hydrochloric acid, and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 15-4. MS m / z=946.8 [M+H] + .

[0520] Step 4: Synthesis of the hydrochloride salt of compound 15

[0521] Compound 15-4 (100 mg, 105.70 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative HPLC (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 20%-50%, 10 min) to obtain the hydrochloride salt of compound 15. MS m / z = 706.3 [M+H] + .

[0522] Example 16

[0523] Step 1: Synthesis of Intermediate 16-2

[0524] Compound 16-1 (500 mg, 1.78 mmol) was weighed and dissolved in DMF (5 mL). O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (810.99 mg, 2.13 mmol) and triethylamine (539.57 mg, 5.33 mmol, 742.18 μL) were added. After stirring at 25°C for 1 hour, 2-(2-fluorophenyl)acetohydrazide hydrochloride (235.78 mg, 2.13 mmol) was added and the mixture was allowed to react at 25°C for 16 hours. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 16-2. MS m / z = 338.2 [M+H] + .

[0525] Step 2: Synthesis of Intermediate 16-3

[0526] Triphenylphosphine (777.45 mg, 2.96 mmol) and elemental iodine (752.31 mg, 2.96 mmol) were weighed and dissolved in dichloromethane (10 mL) at 0°C. After dissolution was complete, DIPEA (766.17 mg, 5.93 mmol) was added, followed by a tetrahydrofuran solution (10 mL) of compound 16-2 (500 mg, 1.48 mmol). The mixture was stirred and reacted at 20°C for 6 hours. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 16-3. MS m / z = 320.2 [M+H] + .

[0527] Step 3: Synthesis of the hydrochloride salt of intermediate 16-4

[0528] Compound 16-3 (1 g, 1.41 mmol) was weighed and dissolved in 4 M hydrochloric acid / ethyl acetate solution (10 mL), stirred at 25° C. for 1 hour, and concentrated under reduced pressure to obtain the hydrochloride salt of compound 16-4.

[0529] Step 4: Synthesis of Intermediate 16-5

[0530] Compound 4-11B (200.00 mg, 254.53 μmol) was weighed and dissolved in DMF (10 mL). The hydrochloride salt of 16-4 (97.63 mg) was added, followed by DIPEA (148.03 mg, 1.15 mmol, 199.50 μL). The mixture was reacted at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 16-5. MS m / z = 855.5 [M+H] + .

[0531] Step 5: Synthesis of Intermediate 16-6

[0532] Compound 16-5 (120 mg, 140.37 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (24.22 mg, 140.37 μmol, 85% purity) was added and reacted at room temperature (25°C) for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 16-6, MS m / z = 871.4 [M+H] + .

[0533] Step 6: Synthesis of Intermediate 16-7

[0534] Compound 5-2 (35.19 mg, 229.64 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and sodium tert-butoxide (22.07 mg, 229.64 μmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 16-6 (100 mg, 114.82 μmol) was added and reacted at 0°C for 1 hour. The reaction solution was quenched with water (10 mL), adjusted to pH 6 with 1N dilute hydrochloric acid, and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 16-7. MS m / z=960.8 [M+H] + .

[0535] Step 7: Synthesis of compound 16

[0536] Compound 16-7 (70 mg, 72.91 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative HPLC (column: Phenomenex C18 80 × 40 mm × 3 μm; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile percentage: 52%-82% over 8 min) to obtain compound 16. MS m / z = 720.2 [M+H] + .

[0537] Example 17

[0538] Step 1: Synthesis of Intermediate 17-1

[0539] Compound 16-1 (500 mg, 1.78 mmol) was weighed and dissolved in dichloromethane (10 mL). Oxalyl chloride (451.22 mg, 3.55 mmol, 311.18 μL) and DMF (12.99 mg, 177.74 μmol, 13.67 μL) were added, and the mixture was reacted at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 17-1. MS m / z = 300.1 [M+H] + .

[0540] Step 2: Synthesis of Intermediate 17-2

[0541] Compound 17-1 (400 mg, 1.33 mmol) was weighed and dissolved in acetonitrile (10 mL). DIPEA (517.39 mg, 4.00 mmol, 697.29 μL) and N-hydroxyacetamidine (118.63 mg, 1.60 mmol) were added, and the mixture was reacted at 150°C under microwave conditions for 0.5 hours. The reaction solution was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 17-2. MS m / z = 320.2 [M+H] + .

[0542] Step 3: Synthesis of the hydrochloride salt of intermediate 17-3

[0543] Compound 17-2 (260 mg, 814.13 μmol) was weighed and dissolved in 4 M hydrochloric acid / ethyl acetate solution (10 mL), and stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 17-3.

[0544] Step 4: Synthesis of Intermediate 17-4

[0545] Compound 4-11B (300 mg, 381.80 μmol) was weighed and dissolved in DMF (10 mL). The hydrochloride salt of 17-3 (146.44 mg) was added, followed by DIPEA (148.03 mg, 1.15 mmol, 199.50 μL). The mixture was reacted at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 17-4. MS m / z = 855.4 [M+H] + .

[0546] Step 5: Synthesis of Intermediate 17-5

[0547] Compound 17-4 (150 mg, 175.46 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (30.28 mg, 175.46 μmol, 85% purity) was added and reacted at room temperature (25°C) for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 17-5, MS m / z = 871.3 [M+H] + .

[0548] Step 6: Synthesis of Intermediate 17-6

[0549] Compound 5-2 (52.78 mg, 344.47 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and sodium tert-butoxide (33.10 mg, 344.47 μmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 17-5 (150.00 mg, 172.23 μmol) was added and reacted at 0°C for 1 hour. The reaction solution was quenched with water (10 mL), adjusted to pH 6 with 1N dilute hydrochloric acid, and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 17-6. MS m / z=960.5 [M+H] + .

[0550] Step 7: Synthesis of compound 17

[0551] Compound 17-6 (130 mg, 135.41 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative HPLC (column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile percentage: 52%-82% over 8 min) to obtain compound 17. MS m / z = 720.3 [M+H] + .

[0552] Example 18

[0553] Step 1: Synthesis of Intermediate 18-1

[0554] Compound 4-11B (0.15 g, 190.90 μmol) was weighed and dissolved in DMF (15 mL). 2-1A (34.74 mg, 229.08 μmol) was added, followed by DIPEA (74.02 mg, 572.70 μmol, 99.75 μL), and the mixture was reacted at 100°C for 1 hour. The reaction solution was quenched with water (20 mL), diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 18-1, MS m / z = 751.5 [M+H] + .

[0555] Step 2: Synthesis of Intermediate 18-2

[0556] Compound 18-1 (106.5 mg, 141.84 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (28.80 mg, 141.84 μmol, 85% purity) was added and reacted at room temperature at 25°C for 1 hour. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 18-2. MS m / z = 767.5 [M+H] + .

[0557] Step 3: Synthesis of Intermediate 18-3

[0558] Compound 5-2 (86.32 mg, 563.35 μmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium tert-butoxide (54.14 mg, 563.35 μmol) was added. The reaction system was reacted at 0°C for 1 hour. Compound 18-2 (0.108 g, 140.84 μmol) was added and reacted at 0°C for 1 hour. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 18-3. MS m / z = 856.7 [M+H] + .

[0559] Step 4: Synthesis of the hydrochloride salt of compound 18

[0560] Compound 18-3 (120.4 mg, 140.66 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1.96 g, 17.17 mmol, 1.28 mL) was added. The mixture was reacted at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance liquid chromatography (HPLC column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 10%-40%, 10 min) to obtain the hydrochloride salt of compound 18. MS m / z = 616.3 [M+H] + .

[0561] Example 19

[0562] Step 1: Synthesis of Intermediate 19-2

[0563] Compound 4-11B (150 mg, 190.90 μmol) was weighed and dissolved in DMF (5 mL). 19-1 (40 mg, 152.26 μmol) was added, followed by DIPEA (74.02 mg, 572.70 μmol, 99.75 μL). The mixture was reacted at 100°C for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (dichloromethane:methanol=10:1) to obtain compound 19-2. MS m / z=862.6 [M+H] + .

[0564] Step 2: Synthesis of Intermediate 19-3

[0565] Compound 19-2 (120 mg, 139.22 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (24.03 mg, 139.22 μmol, 85% purity) was added and reacted at room temperature (25°C) for 0.5 hours. The reaction solution was quenched with water (15 mL), diluted with 100 mL of dichloromethane, washed with 80 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 19-3, MS m / z = 878.3 [M+H] + .

[0566] Step 3: Synthesis of Intermediate 19-4

[0567] Compound 5-2 (41.89 mg, 273.37 μmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium tert-butoxide (26.27 mg, 273.37 μmol) was added at 0°C. The reaction system was allowed to react at 0°C for 1 hour. A solution of compound 19-3 (120 mg, 136.69 μmol) in 5 mL of tetrahydrofuran was added and allowed to react at 0°C for 1 hour. The reaction solution was quenched with water (20 mL), adjusted to pH 6 with dilute hydrochloric acid, extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol=10:1) to obtain compound 19-4. MS m / z=967.5 [M+H] + .

[0568] Step 4: Synthesis of compound 19

[0569] Compound 19-4 (80 mg, 82.73 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added, and the mixture was reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance liquid chromatography (HPLC column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile percentage: 53%-83%, 9 min) to obtain compound 19. MS m / z = 727.2 [M+H] + .

[0570] Example 20

[0571] Step 1: Synthesis of Intermediate 20-2

[0572] Compound 20-1 (400 mg, 1.30 mmol) was weighed and dissolved in DMF (10 mL). NBS (346.30 mg, 1.95 mmol) was added and reacted at 25°C for 1 hour. The mixture was extracted with ethyl acetate (30 mL × 3), washed with water (30 mL × 3), and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 20-2. MS m / z = 387.0, 389.0 [M+H] + .

[0573] Step 2: Synthesis of the hydrochloride salt of intermediate 20-3

[0574] Compound 20-2 (250 mg, 645.54 μmol) was dissolved in hydrogen chloride / ethyl acetate (4 M, 10 mL) and reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 20-3. MS m / z = 287.0, 289.1 [M+H] + .

[0575] Step 3: Synthesis of Intermediate 20-4

[0576] Compound 4-11B (200 mg, 254.53 μmol) was weighed and dissolved in DMF (5 mL). The hydrochloride salt of 20-3 (123.56 mg) was added, followed by DIPEA (98.69 mg, 763.60 μmol), and the mixture was allowed to react at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=10:1) to obtain compound 20-4. MS m / z=922.1, 924.0 [M+H] + .

[0577] Step 4: Synthesis of Intermediate 20-5

[0578] Compound 20-4 (180 mg, 195.05 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (33.66 mg, 195.05 μmol, 85% purity) was added and reacted at room temperature (25°C) for 0.5 hours. The reaction solution was quenched with water (15 mL), diluted with 20 mL of dichloromethane, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 20-5. MS m / z = 938.2, 940.15 [M+H] + .

[0579] Step 5: Synthesis of Intermediate 20-6

[0580] Compound 5-2 (39.17 mg, 255.64 μmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium tert-butoxide (24.57 mg, 255.64 μmol) was added at 0°C. The reaction system was reacted at 0°C for 1 hour. A solution of compound 20-5 (120 mg, 127.82 μmol) in 5 mL of tetrahydrofuran was added and the reaction was continued at 0°C for 1 hour. The reaction solution was quenched with water (20 mL), the pH was adjusted to about 6 with dilute hydrochloric acid, and the solution was extracted with ethyl acetate (30 mL × 3), washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 20-6. MS m / z = 1027.4, 1029.5 [M+H] + .

[0581] Step 6: Synthesis of compound 20

[0582] Compound 20-6 (100 mg, 97.28 μmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (column: Phenomenex C18 80×40 mm×3 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile percentage: 45%-75%, 8 min) to obtain compound 20. MS m / z = 787.1, 789.05 [M+H] + .

[0583] Example 21

[0584] Step 1: Synthesis of Intermediate 21-1

[0585] Compound 1-2A (291.78 mg, 1.83 mmol) and sodium tert-butoxide (140.91 mg, 1.47 mmol) were dissolved in anhydrous tetrahydrofuran (3 mL) and reacted at -15°C for 15 minutes. A solution of compound 20-5 (0.35 g, 366.56 μmol) in tetrahydrofuran (2 mL) was added dropwise and reacted at -15-0°C for 1 hour. 5 mL of saturated ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 21-1 was obtained. MS m / z = 1033.2, 1035.2 [M+H] + .

[0586] Step 2: Synthesis of the hydrochloride salt of compound 21

[0587] Compound 21-1 (100 mg, 96.7 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (771.96 mg, 6.77 mmol) was added. The mixture was allowed to react at 18°C ​​for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance liquid chromatography (HPLC column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 15%-45%, 8 min) to obtain the hydrochloride salt of compound 21. MS m / z = 793.1, 795.1 [M+H] + .

[0588] Example 22

[0589] Step 1: Synthesis of Intermediate 22-1

[0590] Compound 1-2A (35.60 mg, 223.62 μmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and sodium tert-butoxide (21.49 mg, 223.62 μmol) was added. The mixture was reacted at 0°C for 60 minutes. A solution of compound 14-3 (0.1 g, 111.81 μmol) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was reacted at 0°C for 1 hour. The reaction mixture was quenched by adding 5 mL of saturated ammonium chloride and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed twice with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. Compound 22-1 was obtained. MS m / z = 989.4 [M+H] + .

[0591] Step 2: Synthesis of the hydrochloride salt of compound 22

[0592] Compound 22-1 (0.077 g, 77.82 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (1.08 g, 9.50 mmol) was added. The mixture was reacted at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance liquid chromatography (HPLC column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 20%-50%, 10 min) to obtain the hydrochloride salt of compound 22. MS m / z = 749.2 [M+H] + .

[0593] Example 23

[0594] Step 1: Synthesis of Intermediate 23-1

[0595] Compound 1-2A (15.41 mg, 96.82 μmol) was dissolved in anhydrous tetrahydrofuran (0.5 mL) under nitrogen protection, cooled to -15°C, and sodium tert-butoxide (7.44 mg, 77.46 μmol) was added. The mixture was reacted at -15°C for 0.25 hours. A solution of compound 19-3 (17 mg, 19.36 μmol) in tetrahydrofuran (0.5 mL) was added dropwise, and the mixture was reacted at -15°C for 1 hour. The reaction solution was quenched by adding 3 mL of saturated ammonium chloride and extracted with ethyl acetate (2 mL × 3). The organic phases were combined, washed twice with 5 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. Compound 23-1 was obtained. MS m / z = 973.2 [M+H] + .

[0596] Step 2: Synthesis of the hydrochloride salt of compound 23

[0597] Compound 23-1 (23 mg, 23.64 μmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (539.04 mg, 4.73 mmol) was added at -10°C and allowed to react at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 20%-50%, 8 min) to obtain the hydrochloride salt of compound 23. MS m / z = 733.2 [M+H] + . 1 H NMR (400MHz, MeOD) δppm 6.93 (d, J=8.4Hz, 1H) 5.68-5.51 (m, 1H), 5.17-5.12 (m, 3H), 4.97-4.95 (m, 1H), 4 .75-4.72(m, 1H), 4.64(s, 3H), 4.44-4.36(m, 1H), 4.05(s, 2H), 3.97-3.84(m, 3H) , 3.51-3.42(m, 2H), 3.31-3.27(m, 3H), 3.08(s, 3H), 2.99-2.94(m, 1H), 2.71-2. 58(m, 2H), 2.53-2.44(m, 1H), 2.43-2.28(m, 3H), 2.27-2.07(m, 2H), 2.02(s, 3H).

[0598] Example 24

[0599] Step 1: Synthesis of Intermediate 24-1

[0600] Compound 20-2 (0.1 g, 258.22 μmol), water (0.3 mL), 1,4-dioxane (1.5 mL), isopropenylboronic acid xanaxyl ester (56.41 mg, 335.68 μmol), and potassium carbonate (178.44 mg, 1.29 mmol) were added to a reaction flask under nitrogen protection. Bis(tri-tert-butylphosphine)palladium (13.20 mg, 25.82 μmol) was added and reacted at 80°C for 12 hours. The reaction solution was cooled to room temperature, 2 mL of water was added, and the mixture was extracted with ethyl acetate (2 mL × 2). The organic phase was dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure. It was purified by thin-layer chromatography (dichloromethane: methanol = 10:1). Compound 24-1 was obtained. MS m / z = 349.0 [M+H] + .

[0601] Step 2: Synthesis of Intermediate 24-2

[0602] Under argon, methanol (2 mL), wet palladium hydroxide on carbon (20 mg, 14.24 μmol, 10% purity), and compound 24-1 (39 mg, 111.93 μmol) were added to the reaction flask. Hydrogen was introduced at 15 psi and the reaction was allowed to proceed at 20°C for 16 hours. The reaction mixture was filtered, the filter cake was washed with 10 mL of methanol, and the filtrate was collected and concentrated under reduced pressure to obtain compound 24-2. MS m / z = 351.2 [M+H] + .

[0603] Step 3: Synthesis of the hydrochloride salt of intermediate 24-3

[0604] Compound 24-2 (0.04 g, 114.14 μmol) and hydrochloric acid / methanol (4 M, 0.5 mL) were added to the reaction flask and reacted at 20°C for 0.5 h. The reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride salt of compound 24-3. MS m / z = 251.2 [M+H] + .

[0605] Step 4: Synthesis of Intermediate 24-4

[0606] Compound 4-11B (60 mg, 76.36 μmol) was weighed and dissolved in DMF (1 mL). The hydrochloride salt of 24-3 (32.85 mg) was added, followed by DIPEA (1 mL), and the mixture was allowed to react at 50°C for 1 hour. The reaction mixture was cooled to room temperature, 2 mL of water was added, and the mixture was extracted with ethyl acetate (3 mL x 4). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure. Purification was performed using thin-layer chromatography (dichloromethane:methanol = 10:1). Compound 24-4 was obtained. MS m / z = 886.3 [M+H] + .

[0607] Step 5: Synthesis of Intermediate 24-5

[0608] Compound 24-4 (68 mg, 76.75 μmol) was weighed and dissolved in DCM (1 mL). m-CPBA (10.91 mg, 53.72 μmol, 85% purity) was added and reacted at room temperature at 20°C for 1 hour. The reaction solution was diluted with 5 mL of dichloromethane, washed twice with 3 mL of 5% sodium thiosulfate solution and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by thin-layer chromatography (dichloromethane: methanol = 10: 1) gave compound 24-5, MS m / z = 902.2 [M+H] + .

[0609] Step 6: Synthesis of Intermediate 24-6

[0610] Compound 5-2 (19.53 mg, 127.49 μmol) was dissolved in anhydrous tetrahydrofuran (0.5 mL), sodium tert-butoxide (9.80 mg, 101.99 μmol) was added at -15 ° C, and the reaction system was reacted at -15 ° C for 0.25 hours. A solution of compound 24-5 (23 mg, 25.50 μmol) in 0.5 mL of tetrahydrofuran was added and reacted at 0 ° C for 1 hour. 3 mL of saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (2 mL × 3). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by thin plate chromatography (dichloromethane: methanol = 10: 1) gave compound 24-6, MS m / z = 991.3 [M + H] + .

[0611] Step 7: Synthesis of compound 24

[0612] Compound 24-6 (22 mg, 22.20 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (253.10 mg, 2.22 mmol) was added at -10°C. The mixture was allowed to react for 2 hours at -10°C. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (column: Waters Xbridge BEH C18 100×30 mm 5 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile percentage: 30%-60%, 8 min) to obtain compound 24. MS m / z = 751.3 [M+H] + . 1 H NMR (400MHz, MeOD) δppm 6.90-6.80 (d, J=8.4Hz, 1H), 5.34-5.25 (m, 1H), 5.21-5.13 (m, 1H), 4.98-4.78 (m, 3H), 4.63 (d, J= 13.6Hz, 1H), 4.50-4.39 (m, 3H), 4.10 (s, 2H), 3.99 (d, J=14.4Hz, 1H), 3.75-3.57 (m, 2H), 3.23-3.1 1(m, 1H), 3.00-3.17(m, 6H), 2.93(s, 3H), 2.84-2.78(m, 1H), 2.66-2.77(m, 2H), 2.44-2.34(m, 1H) , 2.26-2.04 (m, 3H), 2.02 (s, 3H), 1.98-1.77 (m, 3H), 1.22 (d, J = 7.2Hz, 3H), 1.17 (d, J = 6.8Hz, 3H).

[0613] Example 25

[0614] Step 1: Synthesis of Intermediate 25-1

[0615] Compound 20-2 (0.15 g, 387.33 μmol), N,N-dimethylformamide (3 mL), and cuprous cyanide (104.07 mg, 1.16 mmol) were added to a dry reaction flask under nitrogen protection. 1,1-Bis(diphenylphosphino)ferrocenepalladium chloride (28.34 mg, 38.73 μmol) and tris(dibenzylideneacetone)dipalladium (35.47 mg, 38.73 μmol) were added and heated to 120°C for 12 hours. The reaction solution was cooled to room temperature, 10 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 4). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed using plate chromatography (dichloromethane: methanol = 10:1). Compound 25-1 was obtained, with MS m / z = 333.9 [M+H]. + .

[0616] Step 2: Synthesis of the hydrochloride salt of intermediate 25-2

[0617] Compound 25-1 (80 mg, 239.96 μmol) and hydrochloric acid / ethyl acetate (4 M, 2 mL) were added to the reaction flask and reacted at 20°C for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride salt of compound 25-2. MS m / z = 234.2 [M+H] + .

[0618] Step 3: Synthesis of Intermediate 25-3

[0619] Compound 4-11B (120 mg, 152.72 μmol) was weighed and dissolved in DMF (2 mL). The hydrochloride of 25-2 (82.39 mg) was added, followed by DIPEA (59.21 mg, 458.16 μmol), and the mixture was allowed to react at 50°C for 1 hour. The reaction mixture was cooled to room temperature, 2 ml of water was added, and the mixture was extracted with ethyl acetate (3 mL x 4). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated under reduced pressure. Purification was performed using thin-layer chromatography (dichloromethane: methanol = 10:1). Compound 25-3 was obtained. MS m / z = 869.2 [M+H] + .

[0620] Step 4: Synthesis of Intermediate 25-4

[0621] Compound 25-3 (90 mg, 103.57 μmol) was weighed and dissolved in DCM (2 mL). m-CPBA (14.72 mg, 72.50 μmol, 85% purity) was added and reacted at room temperature at 20°C for 1 hour. The reaction solution was diluted with 5 mL of dichloromethane, washed twice with 3 mL of 5% sodium thiosulfate solution and 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by thin-layer chromatography (dichloromethane:methanol=10:1) gave compound 25-4, MS m / z=885.1 [M+H] + .

[0622] Step 5: Synthesis of Intermediate 25-5

[0623] Compound 5-2 (65.79 mg, 429.41 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL), sodium tert-butoxide (33.01 mg, 343.53 μmol) was added at -15°C, and the reaction system was reacted at -15°C for 0.25 hours. A solution of compound 25-4 (76 mg, 85.88 μmol) in 1 mL of tetrahydrofuran was added and the reaction was continued for 1 hour. 5 mL of saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 25-5, MS m / z = 974.2 [M+H] + .

[0624] Step 6: Synthesis of compound 25

[0625] Compound 25-5 (96 mg, 98.56 μmol) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (2.25 g, 19.71 mmol, 1.46 mL) was added at -10°C and allowed to react at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (column: Waters Xbridge BEH C18 100×30 mm 5 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile percentage: 25%-55%, 8 min) to obtain compound 25. MS m / z = 734.2 [M+H] + . 1H NMR (400MHz, CDCl3) δppm 6.87(d, J=8.38Hz, 1H), 5.20-5.18(m, 1H), 5.07-4.77(m, 4H), 4.75-4.64(m, 2H), 4. 60-4.47(m, 1H), 4.41-4.31(m, 1H), 4.06(s, 3H), 4.01-3.56(m, 4H), 3.36-3.22(m, 4H ), 3.19-3.04(m, 4H), 2.97-2.90(m, 1H), 2.78-2.69(m, 1H), 2.65-2.61(m, 1H), 2.41 -2.25 (m, 2H), 2.21-2.13 (m, 2H), 2.04 (s, 3H), 1.96-1.84 (m, 2H), 1.79-1.65 (m, 2H).

[0626] Example 26

[0627] Step 1: Synthesis of Intermediate 26-1

[0628] Compound 21-1 (50 mg, 48.36 μmol) and tributyl(trimethylsilylethynyl)tin (112.37 mg, 290.16 μmol) were dissolved in anhydrous toluene (2 mL). Tetrakis(triphenylphosphine)palladium (11.18 mg, 9.67 μmol) was added under nitrogen and reacted at 130°C for 16 hours. The reaction solution was concentrated, 5 mL of water was added, and the mixture was extracted with 3 mL × 2 of ethyl acetate. The mixture was washed with 3 mL × 2 of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 26-1. MS m / z = 1051.3 [M+H] + .

[0629] Step 2: Synthesis of the trifluoroacetate salt of intermediate 26-2

[0630] Compound 26-1 (50 mg, 47.56 μmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (612.82 mg, 5.37 mmol) was added. The mixture was reacted at 15°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 26-2. MS m / z = 811.2 [M+H] + .

[0631] Step 3: Synthesis of compound 26

[0632] The trifluoroacetic acid salt of compound 26-2 (0.1 g) was dissolved in anhydrous methanol (2.5 mL), potassium carbonate (34.09 mg, 246.63 μmol) was added, and the mixture was allowed to react at 18°C ​​for 2 hours. The reaction solution was concentrated, and water (10 mL) and ethyl acetate (5 mL × 2) were added for separation. The organic phases were combined, washed with 5 mL × 2 saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by high-performance liquid chromatography (HPLC column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 20%-50%, 8 min). The pH of the separating solution was adjusted to 9 with saturated sodium bicarbonate solution. The organic phase was removed by concentration under reduced pressure, extracted with ethyl acetate (5 mL × 2), concentrated under reduced pressure, and lyophilized. Compound 26 was obtained. MS m / z = 739.2 [M+H] + .

[0633] Example 27

[0634] Step 1: Synthesis of Intermediate 27-1

[0635] Compound 20-2 (0.2 g, 516.43 μmol), N,N-dimethylformamide (2.5 mL), methyl fluorosulfonyldifluoroacetate (496.07 mg, 2.58 mmol), and cuprous iodide (196.71 mg, 1.03 mmol) were added to a dry reaction flask and reacted at 100°C for 10 hours. 5 mL of water was added to the reaction solution, and the mixture was extracted with 5 mL × 2 of ethyl acetate, washed with 5 mL × 2 of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by high-performance liquid chromatography (HPLC column: Phenomenex luna C18, 100 × 40 mm × 3 μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 30%-60%, 18.0 min). The pH was adjusted to 8-9 by liquid separation. The organic phase was removed by concentration under reduced pressure, and the aqueous phase was extracted with ethyl acetate (5 mL × 2). The combined organic phases were washed with 3 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 27-1. MS m / z = 377.1 [M+H] + .

[0636] Step 2: Synthesis of the hydrochloride salt of intermediate 27-2

[0637] Compound 27-1 (90 mg, 239.12 μmol) and hydrochloric acid / ethyl acetate (4 M, 2.5 mL) were added to the reaction flask and reacted at 18°C ​​for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 27-2. MS m / z = 277.1 [M+H] + .

[0638] Step 3: Synthesis of Intermediate 27-3

[0639] Compound 4-11B (100 mg, 127.27 μmol) was weighed and dissolved in DMF (1 mL). The hydrochloride of 27-2 (42.19 mg) was added, followed by DIPEA (49.34 mg, 381.80 μmol), and the mixture was allowed to react at 50°C for 1 hour. The reaction mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were separated, combined, and extracted with saturated brine (5 mL × 2). The organic phases were separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 27-3. MS m / z = 912.1 [M+H] + .

[0640] Step 4: Synthesis of Intermediate 27-4

[0641] Compound 27-3 (0.14 g, 153.52 μmol) was weighed and dissolved in DCM (2.5 mL). m-CPBA (46.57 mg, 230.28 μmol, 85% purity) was added and reacted at room temperature at 18°C ​​for 1 hour. The reaction solution was quenched with 20 mL of 5% sodium sulfite solution and extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain compound 27-4, MS m / z = 944.1 [M+H] + .

[0642] Step 5: Synthesis of Intermediate 27-5

[0643] Compound 5-2 (113.63 mg, 741.58 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL), sodium tert-butoxide (57.01 mg, 593.27 μmol) was added at -15°C, and the reaction system was reacted at -15°C for 0.25 hours. A solution of compound 27-4 (0.14 g, 148.32 μmol) in 2 mL of tetrahydrofuran was added and the reaction was continued for 1 hour. 5 mL of saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 27-5, MS mn / z = 1017.6 [M+H] + .

[0644] Step 6: Synthesis of the hydrochloride salt of compound 27

[0645] Compound 27-5 (0.12 g, 117.99 μmol) was dissolved in dichloromethane (2.5 mL). Trifluoroacetic acid (766.83 mg, 6.73 mmol) was added at 18°C ​​and allowed to react for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 20%-50%, 8 min) to obtain the hydrochloride salt of compound 27. MS m / z = 777.2 [M+H] + . 1 H NMR (400MHz, MeOD) δ = 7.00-6.90 (m, 1H), 5.31-5.06 (m, 4H), 5.02-4.80 (m, 2H), 4.79-4.61 (m, 2H), 4.59-4.30 (m, 4H), 4.10-3. 70 (m, 4H), 3.52-3.40 (m, 2H), 3.24-3.08 (m, 2H), 3.02-2.93 (m, 6H), 2.49-2.40 (m, 1H), 2.38-2.27 (m, 3H), 2.13-1.84 (m, 6H).

[0646] Example 28

[0647] Step 1: Synthesis of Intermediate 28-2

[0648] Compound 4-11B (0.22 g, 279.99 μmol) was weighed and dissolved in DMF (20 mL). Compound 28-1 (0.1 g, 449.87 μmol) was added, followed by DIPEA (180.93 mg, 1.40 mmol), and the mixture was allowed to react at 100°C for 1 hour. The reaction mixture was cooled to room temperature and quenched by the addition of saturated ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3), separated, and the organic phases were combined and extracted with saturated brine (10 mL). The organic phases were separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 28-2. MS m / z = 858.3 [M+H] + .

[0649] Step 2: Synthesis of Intermediate 28-3

[0650] Compound 28-2 (0.154 g, 179.50 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (36.44 mg, 179.50 μmol, 85% purity) was added and reacted at room temperature at 25°C for 1 hour. The mixture was quenched with water (10 mL). The mixture was extracted with 10 mL × 2 dichloromethane. The organic phases were combined and washed with 20 mL × 2 saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 28-3. MS m / z = 874.3 [M+H] + .

[0651] Step 3: Synthesis of Intermediate 28-4

[0652] Compound 5-2 (56.50 mg, 368.76 μmol) was dissolved in anhydrous tetrahydrofuran (10 mL), sodium tert-butoxide (35.44 mg, 368.76 μmol) was added at 0°C, and the reaction system was reacted at 0°C for 1 hour. Compound 28-3 (161.14 mg, 184.38 μmol) was added and the reaction was continued for 1 hour. 5 mL of aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). 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 obtain compound 28-4, MS m / z = 963.4 [M+H] + .

[0653] Step 4: Synthesis of the hydrochloride salt of compound 28

[0654] Compound 28-4 (0.173 g, 179.63 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (2.50 g, 21.93 mmol) was added at 20°C. The mixture was allowed to react for 1 hour at 20°C. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 20%-50%, 10 min) to obtain the hydrochloride salt of compound 28. MS m / z = 723.2 [M+H] + . 1H NMR (400MHz, MeOH) δ = 6.99-6.90 (m, 1H), 5.38-5.29 (m, 2H), 5.26-5.11 (m, 2H), 5.10-4 .95(m, 2H), 4.75-4.66(m, 2H), 4.55-4.47(m, 1H), 4.38-4.28(m, 2H), 4.20-4.07(m, 1H) , 4.00-3.90(m, 2H), 3.85-3.69(m, 2H), 3.42-3.35(m, 1H), 3.28-3.20(m, 2H), 3.20-3. 07 (m, 6H), 3.05-2.95 (m, 2H), 2.91-2.79 (m, 1H), 2.43-2.16 (m, 8H), 2.08-2.01 (m, 3H).

[0655] Example 29

[0656] Step 1: Synthesis of Intermediate 29-1

[0657] Compound 20-6 (0.15 g, 145.92 μmol) and tributyl(1-propynyl)tin (384.20 mg, 1.17 mmol) were dissolved in anhydrous toluene (6 mL). Dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium (31.00 mg, 43.78 μmol) was added under nitrogen protection. The nitrogen was replaced 5 times and the reaction was carried out at 120°C for 24 hours. 5 mL of water was added to quench the mixture, and the mixture was filtered through celite. The filter cake was washed with ethyl acetate and extracted with ethyl acetate (10 mL × 2). The mixture was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 29-1. MS m / z = 987.7 [M+H] + .

[0658] Step 2: Synthesis of compound 29

[0659] Compound 29-1 (67.2 mg, 68.08 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (212.92 mg, 1.87 mmol) was added at 20°C. The mixture was allowed to react for 1 hour at 20°C. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (column: Welch Xtimate C18 150×25mm×5μm; mobile phase: [water (0.05% ammonia + 10mM ammonium bicarbonate)-acetonitrile]; acetonitrile percentage: 40%-70%, 9 min) to obtain compound 29. MS m / z = 747.3 [M+H] + .

[0660] Example 30

[0661] Step 1: Synthesis of Intermediate 30-2

[0662] Compound 30-1 (0.25 g, 844.27 μmol) was weighed and dissolved in DMF (5 ml). HATU (417.32 mg, 1.10 mmol), DIPEA (436.46 mg, 3.38 mmol, 588.22 μL), and dimethyl-d6-amine hydrochloride (314.18 mg, 2.53 mmol) were added to the solution. The mixture was reacted at room temperature (18°C) for 1 hour. The reaction mixture was quenched by adding 5 mL of water and extracted with ethyl acetate (10 mL × 3). The mixture was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 30-2. MS m / z = 315.2 [M+H] + .

[0663] Step 2: Synthesis of compound 30-3

[0664] Compound 30-2 (264.97 mg, 800.60 μmol) was weighed and dissolved in DMF (3 mL). NCS (160.36 mg, 1.20 mmol) was added to the reaction system and reacted at 55°C for 2 hours. 5 mL of water was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (10 mL × 3), washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 30-3. MS m / z = 349.2 [M+H] + .

[0665] Step 3: Synthesis of the hydrochloride salt of compound 30-4

[0666] Compound 30-3 (0.27 g, 735.26 μmol) was weighed, and hydrogen chloride / ethyl acetate (15 mL) was added. The mixture was reacted at 18°C ​​for 1 hour, and concentrated under reduced pressure to obtain the hydrochloride salt of compound 30-4. MS m / z = 249.2 [M+H] + .

[0667] Step 4: Synthesis of compound 30-5

[0668] Compound 4-11B (0.2 g, 254.53 μmol) was weighed and dissolved in DMF (5 mL). The hydrochloride salt of 30-4 (145.19 mg) was added, followed by DIPEA (98.69 mg, 763.60 μmol), and the mixture was allowed to react at 100°C for 1 hour. The reaction mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were separated, combined, and extracted with saturated brine (5 mL × 2). The organic phases were separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 30-5. MS m / z = 884.3 [M+H] + .

[0669] Step 5: Synthesis of Intermediate 30-6

[0670] Compound 30-5 (0.214 g, 241.97 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (49.13 mg, 241.97 μmol, 85% purity) was added and reacted at room temperature (18°C) for 1 hour. 10 mL of water was added to quench the reaction. The mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 30-6. MS m / z = 900.3 [M+H] + .

[0671] Step 6: Synthesis of Intermediate 30-7

[0672] Compound 5-2 (71.47 mg, 466.45 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and sodium tert-butoxide (44.83 mg, 466.45 μmol) was added at 0°C. The reaction system was reacted at 0°C for 1 hour. A solution of compound 30-6 (0.21 g, 233.23 μmol) in 5 mL of tetrahydrofuran was added and the reaction was continued for 1 hour. 5 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography purification (dichloromethane: methanol = 10: 1) gave compound 30-7, MS m / z = 989.4 [M+H] + .

[0673] Step 7: Synthesis of the hydrochloride salt of compound 30

[0674] Compound 30-7 (0.22 g, 222.33 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (5.65 g, 49.53 mmol) was added at 20°C. The mixture was allowed to react for 1 hour at 20°C. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by HPLC (column: Xtimate C18 150×40 mm×5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 17%-47%, 14 min) to obtain the hydrochloride salt of compound 30. MS m / z = 749.3 [M+H] + . 1 H NMR (400MHz, MeOD) δ = 7.01-6.91 (m, 1H), 5.39-5.29 (m, 2H), 5.26-5.19 (m, 1H) ), 5.16-5.00(m, 4H), 4.76-4.69(m, 1H), 4.59-4.44(m, 2H), 4.41-4.21(m, 2H) ,4.17-4.06(m,1H),4.01-3.85(m,2H),3.84-3.73(m,1H),3.30-3.20(m,2H) , 3.09-2.95(m, 2H), 2.86-2.72(m, 1H), 2.56-2.10(m, 6H), 2.08-1.97(m, 3H).

[0675] Example 31

[0676] Step 1: Synthesis of Intermediate 31-2

[0677] Compound 30-1 (0.25 g, 844.27 μmol) was weighed and dissolved in DMF (5 ml). HATU (417.32 mg, 1.10 mmol), DIPEA (436.46 mg, 3.38 mmol, 588.22 μL), and azetidine hydrochloride (236.96 mg, 2.53 mmol) were added to the solution. The mixture was reacted at room temperature at 18°C ​​for 2 hours. 5 mL of water was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (10 mL × 3), washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 31-2. MS m / z = 321.2 [M+H] + .

[0678] Step 2: Synthesis of compound 31-3

[0679] Compound 31-2 (0.27 g, 800.60 μmol) was weighed and dissolved in DMF (3 mL). NCS (160.36 mg, 1.20 mmol) was added to the reaction system and reacted at 55°C for 2 hours. The reaction solution was quenched by adding 5 mL of water and extracted with ethyl acetate (10 mL × 3). The mixture was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 31-3. MS m / z = 355.2 [M+H] + .

[0680] Step 3: Synthesis of trifluoroacetate salt of compound 31-4

[0681] Compound 31-3 (0.06 g, 160.64 μmol) was weighed, trifluoroacetic acid (18.32 mg, 160.64 μmol) was added, and the mixture was reacted at 18°C ​​for 1 hour. The mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 31-4. MS m / z = 255.1 [M+H] + .

[0682] Step 4: Synthesis of compound 31-5

[0683] Compound 4-11B (0.05 g, 63.63 μmol) was weighed and dissolved in DMF (5 mL). The trifluoroacetic acid salt of 31-4 (28.16 mg) was added, followed by DIPEA (24.67 mg, 190.90 μmol), and the mixture was allowed to react at 100°C for 1 hour. The reaction mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were separated, combined, and extracted with saturated brine (5 mL × 2). The organic phases were separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 31-5. MS m / z = 890.3 [M+H] + .

[0684] Step 5: Synthesis of Intermediate 31-6

[0685] Compound 31-5 (0.278 g, 312.22 μmol) was weighed and dissolved in DCM (10 mL). m-CPBA (63.39 mg, 312.23 μmol, 85% purity) was added and reacted at room temperature (18°C) for 1 hour. 10 mL of water was added to quench the reaction. The mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 31-6. MS m / z = 906.3 [M+H] + .

[0686] Step 6: Synthesis of Intermediate 31-7

[0687] Compound 5-2 (81.14 mg, 529.58 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and sodium tert-butoxide (50.89 mg, 529.58 μmol) was added at 0°C. The reaction system was reacted at 0°C for 1 hour. A solution of compound 31-6 (0.24 g, 264.79 μmol) in 5 mL of tetrahydrofuran was added and the reaction was continued for 1 hour. 5 mL of water was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (dichloromethane: methanol = 10: 1) gave compound 31-7, MS m / z = 995.4 [M+H] + .

[0688] Step 7: Synthesis of the hydrochloride salt of compound 31

[0689] Compound 31-7 (0.05 g, 50.23 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (157.08 mg, 1.38 mmol) was added at 20°C. The mixture was allowed to react for 1 hour at 20°C. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance liquid chromatography (HPLC column: Phenomenex C18 80 × 40 mm × 3 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile percentage: 57%-87%, 8 min) to obtain the hydrochloride salt of compound 31. MS m / z = 755.2 [M+H] + .

[0690] Example 32

[0691] Step 1: Synthesis of Intermediate 32-2

[0692] Compound 3,5-dicarboxylic acid methyl pyrazole (6.5 g, 35.30 mmol) and compound 32-1 (10.56 g, 35.30 mmol) were added to N,N-dimethylformamide (60 mL), followed by potassium carbonate (9.76 g, 70.59 mmol). The resulting reaction solution was heated to 100°C under nitrogen and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. 500 mL of ethyl acetate was added to the crude product, stirred for 5 minutes, filtered, and the filtrate was decompressed to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 32-2. HNMR: (400MHz, CDCl3) δ: 7.34 (m, 1H), 4.69 (t, J=6.8Hz, 2H), 4.49 (br s, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.83-3.64 (m, 1H), 2.12-2.05 (m, 1H), 1.99-1.83 (m, 1H), 1.44 (s, 9H), 1.17 (d, J=6.4Hz, 3H).

[0693] Step 2: Synthesis of Intermediate 32-3

[0694] Compound 32-2 (11.5 g, 32.36 mmol) was dissolved in DCM (10 mL), and then hydrogen chloride / ethyl acetate (4 M, 40.45 mL) was added. The resulting reaction solution was stirred at 15° C. under nitrogen protection for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. 30 mL of water and 50 mL of dichloromethane were added to the residue, and the pH was adjusted to 9 with 2M sodium hydroxide solution. The organic phase was separated, and the aqueous phase was extracted with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 32-3.

[0695] Step 3: Synthesis of Intermediate 32-4

[0696] Compound 32-3 (8.3 g, 32.51 mmol) was dissolved in anhydrous methanol (50 mL), and sodium methoxide (3.51 g, 65.03 mmol) was added. The reaction mixture was stirred at 60°C under nitrogen for 15 hours. The reaction mixture was cooled to room temperature, filtered, and the solid was collected and dried under vacuum for 0.5 hours to obtain compound 32-4. HNMR: (400MHz, CDCl3) δ: 7.34 (s, 1H), 6.10 (br s, 1H), 4.65 (ddd, J=3.6, 6.8, 14.3Hz, 1H), 4.49 (ddd, J=5.9, 10.3, 14.3Hz, 1H), 3.95 ( s, 3H), 3.68-3.52 (m, 1H), 2.46-2.33 (m, 1H), 2.09-1.95 (m, 1H), 1.37 (d, J=6.4Hz, 3H).

[0697] Step 4: Synthesis of Intermediate 32-5

[0698] Compound 32-4 (4.05 g, 18.14 mmol) was dissolved in tetrahydrofuran (80 mL), and lithium aluminum hydride (2.75 g, 72.57 mmol) was slowly added portionwise. After addition, the mixture was stirred at 20°C for 2 hours, then slowly heated to 60°C for 15 hours. The reaction solution was cooled to 0°C, and then 2.8 mL of water and 2.8 mL of 15% sodium hydroxide solution were slowly added dropwise to quench the reaction. The mixture was stirred for 10 minutes, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain compound 32-5. (400MHz, CDCl3) δ: 6.07 (s, 1H), 4.61 (s, 2H), 4.53-4.40 (m, 1H), 4.25-4.05 (m, 2H), 3.72 (d, J =15.6Hz, 1H), 3.10-2.96 (m, 1H), 1.98-1.90 (m, 1H), 1.57-1.45 (m, 1H), 1.20 (d, J = 6.5Hz, 3H).

[0699] Step 5: Synthesis of Intermediate 32-6

[0700] Compound 32-5 (2.80 g, 15.45 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of tert-butyloxycarbonyl anhydride (3.37 g, 15.45 mmol, 3.55 mL). The reaction mixture was stirred at 15°C under nitrogen for 15 hours. The reaction mixture was concentrated under reduced pressure, and 20 mL of methanol and 20 mL of water were added to the residue, followed by the addition of potassium carbonate (4.27 g, 30.90 mmol). The resulting mixture was heated to 80°C and stirred for 8 hours. The reaction solution was concentrated under reduced pressure, and then extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude compound 32-6. 1H NMR: (400 MHz, CDCl3) δ: 6.07 (br s, 1H), 5.12-4.67 (m, 1H), 4.60 (s, 2H), 4.46-4.34 (m, 1H), 4.17-3.89 (m, 2H), 2.45 (br s, 1H), 2.26-2.12 (m, 1H), 2.04-1.79 (m, 1H), 1.50-1.30 (m, 9H), 1.24 (d, J=5.8 Hz, 3H).

[0701] Step 6: Synthesis of Intermediate 32-7

[0702] Compound 32-6 (4.3 g, 15.28 mmol) was dissolved in dichloromethane (100 mL). The resulting solution was cooled to 0°C, and Dess-Martin reagent (6.48 g, 15.28 mmol) was slowly added. After the addition, the ice bath was removed, the temperature was raised to 20°C, and the reaction was stirred for 3 hours. The reaction solution was quenched with 30 mL of saturated sodium bicarbonate solution. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (30 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 32-7. 1 H NMR: (400MHz, CDCl3) δ: 9.92-9.85 (m, 1H), 6.62 (br s, 1H), 5.17-4.33 (m, 3H), 4.24 (dd, J=10.1, 14.1Hz, 1H), 4.02 (br d, J=16.6Hz, 1H), 2.33-2.19 (m, 1H), 2.03-1.89 (m, 1H), 1.39 (br s, 9H), 1.30-1.26 (m, 3H).

[0703] Step 7: Synthesis of Intermediate 32-8

[0704] Compound 32-7 (2.0 g, 7.16 mmol) was dissolved in dimethyl sulfoxide (25 mL), and then a solution of potassium dihydrogen phosphate (2.53 g, 18.62 mmol) in water (5 mL) was added, followed by dropwise addition of a solution of sodium chlorite (1.36 g, 15.04 mmol) in water (5 mL). After the addition was complete, the reaction was stirred at 20°C for 2 hours. The reaction solution was diluted with 200 mL of ethyl acetate, then washed with water (40 mL×2) and 40 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 32-8. 1H NMR: (400 MHz, CDCl3) δ: 6.69 (br s, 1H), 5.18-4.34 (m, 3H), 4.24 (br dd, J=10.3, 14.1 Hz, 1H), 4.03 (br d, J=16.6 Hz, 1H), 2.32-2.18 (m, 1H), 2.00 (br s, 1H), 1.40 (br s, 9H), 1.27 (d, J=6.8 Hz, 3H).

[0705] Step 8: Synthesis of Intermediate 32-9

[0706] Compound 32-8 (1.0 g, 3.39 mmol) was dissolved in tetrahydrofuran (15 mL), followed by the addition of carbonyldiimidazole (823.56 mg, 5.08 mmol). The mixture was stirred at 10°C under nitrogen for 1 hour. A dimethylamine / tetrahydrofuran solution (2 M, 5.08 mL) was then added, and the resulting reaction mixture was stirred under nitrogen for another 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a crude product. Ethyl acetate (50 mL) was added to the crude product to dissolve the product, followed by washing with water (10 mL x 3). The organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, compound 32-9. 1 H NMR: (400MHz, CDCl3) δ: 6.46 (s, 1H), 5.18-4.30 (m, 3H), 4.22-4.10 (m, 1H), 4.00 (d, J=16.8Hz, 1H), 3.32 (br s, 3H), 3.08 (s, 3H), 2.29-2.16 (m, 1H), 2.03-1.88 (m, 1H), 1.50-1.31 (m, 9H), 1.26 (d, J=6.8Hz, 3H).

[0707] Step 9: Synthesis of Intermediate 32-10

[0708] Compound 32-9 (1.03 g, 3.19 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then nitrogen chlorosuccinimide (853.21 mg, 6.39 mmol) was added. The resulting reaction solution was stirred at 55°C under nitrogen for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 32-10, MS m / z = 357.0 [M+H] + .

[0709] Step 10: Synthesis of the hydrochloride salt of intermediate 32-11

[0710] Compound 32-10 (300 mg, 622.12 μmol) was dissolved in dichloromethane (0.5 mL), and then a hydrogen chloride / ethyl acetate solution (4 M, 1.56 mL) was added. The resulting reaction mixture was stirred at 20°C under nitrogen for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude hydrochloride salt of compound 32-11. MS m / z = 257.0 [M+H] + .

[0711] Step 11: Synthesis of Intermediate 32-12

[0712] Compound 4-11B (200 mg, 254.53 μmol) was weighed and dissolved in DMF (1.5 mL). The hydrochloride salt of 32-11 (217.00 mg) was added, followed by DIPEA (164.48 mg, 1.27 mmol), and the mixture was allowed to react at 100°C for 1 hour. The reaction mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were separated, combined, and extracted with saturated brine (5 mL × 2). The organic phases were separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 32-12. MS m / z = 892.4 [M+H] + .

[0713] Step 12: Synthesis of Intermediate 32-13

[0714] Compound 32-12 (58 mg, 64.99 μmol) was dissolved in DCM (1 mL), and m-CPBA (13.19 mg, 64.99 μmol, 85% purity) was added. The mixture was reacted at room temperature (18°C) for 1 hour, and then concentrated under reduced pressure to obtain compound 32-13. MS m / z = 908.3 [M+H] + .

[0715] Step 13: Synthesis of Intermediate 32-14

[0716] Compound 5-2 (39.13 mg, 255.39 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL). Sodium tert-butoxide (24.54 mg, 255.39 μmol) was added at 0°C. The reaction system was allowed to react at 0°C for 1 hour. Compound 32-13 (58 mg, 63.85 μmol) was added and the reaction continued for 1 hour. The reaction solution was quenched by adding 0.5 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (dichloromethane:methanol=10:1) gave compound 32-14, MS m / z=997.4 [M+H] + .

[0717] Step 14: Synthesis of hydrochloride salts of compounds 32A and 32B

[0718] Compound 32-14 (36 mg, 36.09 μmol) was dissolved in trifluoroacetic acid (0.5 mL) and reacted at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high-performance liquid chromatography (HPLC column: Xtimate C18 150 × 40 mm × 5 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile percentage: 30%-60%) to obtain the hydrochloride salts of compounds 32A and 32B. Analytical liquid phase: Chromatographic column: ChromCore 120 C18 3 μm, 3.0 × 30 mm; mobile phase: [water (0.04% trifluoroacetic acid)-acetonitrile (0.02% trifluoroacetic acid)]; acetonitrile (0.02% trifluoroacetic acid) percentage: 10%-80%, 7 min (220 × 254 nm), retention time: 32 Å (Rt = 3.484 min), MS m / z = 757.1 [M+H] + , 32B (Rt=3.606min), MS m / z=757.2[M+H] + .

[0719] Biological test data:

[0720] Experimental Example 1. Anti-cell proliferation effect of the compound in the tumor cell line AsPC-1

[0721] Study Objectives

[0722] This study investigated the inhibitory effect of compounds on cell proliferation by detecting their effects on in vitro cell activity in the KRASG12D mutant tumor cell line AsPC-1.

[0723] Experimental Materials

[0724] The cell line is AsPC-1, the tumor type is pancreatic cancer, the cells grow adherently, and the culture method is RPMI 1640 + 10% FBS.

[0725] Ultra Low Cluster-96 well plate (Corning-7007)

[0726] Greiner CELLSTAR 96-well plates (#655090)

[0727] Promega CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega-G9683)

[0728] 2104-10 EnVision plate reader, PerkinElmer

[0729] RPMI 1640, DMEM, PBS (phosphate buffered saline), FBS (fetal bovine serum), Antibiotic-antimycotic (antibiotic-antifungal), L-glutamine (L-glutamine), DMSO (dimethyl sulfoxide)

[0730] Experimental methods and steps

[0731] Cell culture

[0732] Tumor cell lines were cultured in an incubator at 37°C and 5% CO2 according to the culture conditions indicated in the culture method. Cells were passaged regularly and cells in the logarithmic growth phase were used for plating.

[0733] Cell plating

[0734] Cells were stained with trypan blue and viable cells were counted.

[0735] Adjust the cell concentration to an appropriate level.

[0736] The cell line was AsPC-1, and the density (per well) was 7000 cells.

[0737] 135 μL of cell suspension was added to each well of the ULA culture plate, and the same volume of culture medium without cells was added to the blank control well.

[0738] Immediately after plating, centrifuge the ULA plate at room temperature for 10 minutes at 1000 rpm. Note: After centrifugation, be careful to avoid unnecessary agitation during subsequent operations.

[0739] The culture plate was incubated overnight in an incubator at 37°C, 5% CO2, and 100% relative humidity.

[0740] Preparation of 10X compound working solution and compound treatment of cells (Day 1)

[0741] 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 the DMSO-cell culture medium mixture to the vehicle control and blank control.

[0742] The 96-well cell plate was returned to the incubator and cultured for 120 hours.

[0743] The cell sphere formation was observed every day until the end of the experiment.

[0744] CellTiter-Glo luminescence cell activity assay (day 5)

[0745] The following steps were performed according to the instructions of the Promega CellTiter-Glo 3D Luminescent Cell Viability Assay Kit (Promega #G9683).

[0746] Add 150 μL of CellTiter-Glo 3D reagent (equal to the volume of cell culture medium in each well) to each well. Wrap the cell plate with aluminum foil to protect it from light.

[0747] The plate was shaken on an orbital shaker for 5 minutes.

[0748] Carefully pipette up and down 10 times to mix the mixture. Ensure that the cell spheroids are fully dissociated before proceeding to the next step.

[0749] The solution in the ULA culture plate was then transferred to a black bottom culture plate (#655090) and placed at room temperature for 25 minutes to stabilize the luminescent signal.

[0750] Luminescent signals were detected on a 2104 EnVision plate reader.

[0751] Data Analysis

[0752] The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1-(RLU compound-RLU blank control) / (RLU vehicle control-RLU blank control)) × 100%. The inhibition rate of the compound at different concentrations was calculated in Excel, and then the inhibition curve was plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC, were calculated using GraphPad Prism software. 50 .

[0753] Experimental results

[0754] The results are shown in Table 1.

[0755] Table 1 IC of compounds against AsPC-1 cells 50 value

[0756] Experimental conclusion: The compound of the present invention has excellent KRAS G12D Antiproliferative effect of mutant AsPC-1 cells.

[0757] Experimental Example 2. AsPC-1 cell proliferation test

[0758] 1. Purpose

[0759] Through the 3D-CTG method, the effective inhibitors of KRAS were screened. G12D Compounds that inhibit the proliferation of mutant AsPC-1 cells.

[0760] 2. Experimental Materials:

[0761] ASPC-1 cells were purchased from ATCC; RPMI-1640 medium was purchased from ATCC; fetal bovine serum was purchased from Ausgenex; 3D assay kit (3D-CTG) was purchased from Promega; CellCarrier-96 Spheroid ULA / CS was purchased from PE.

[0762] 3. Experimental methods:

[0763] 1) ASPC-1 cells were seeded in a transparent 96-well cell culture plate with 195 μL of cell suspension per well, containing 2000 cells per well;

[0764] 2) Dilute the test compound to 10 mM as the first concentration with 100% DMSO. Then, pipette a further 5-fold dilution to the eighth concentration, from 10 mM to 0.13 μM. Add 2 μL of the serially diluted compound to 48 μL of cell culture medium for a second dilution. After mixing, add 5 μL of the second diluted compound to the corresponding 195 μL well of the cell plate. Return the cell plate to the CO2 incubator and incubate for 7 days. At this point, the compound concentration ranges from 10 μM to 0.128 nM, and the DMSO concentration is 0.1%.

[0765] 3) After incubation, discard 100 μL of cell supernatant and add 60 μL of 3D-CTG to each well. Incubate at room temperature with shaking at 200 rpm for 20 minutes. Place in an incubator and incubate at room temperature for 1 hour.

[0766] 4) 100 μL of the supernatant from the well plate was transferred to a 96-well black bottom plate and luminescence was read in a BMG.

[0767] 4. Data Analysis:

[0768] The raw data were converted into inhibition rate, IC using the equation Inhibition% = (Ave_H-Sample) / (Ave_H-Ave_L). 50 The value can be obtained by four-parameter curve fitting (obtained by log(inhibitor) vs.response--Variable slope mode in GraphPad Prism).

[0769] H well: reading value of DMSO well

[0770] L hole: Medium reading

[0771] 5 Experimental results

[0772] The results are shown in Table 2.

[0773] Table 2 IC of compounds against AsPC-1 cells 50 value

[0774] Experimental conclusion: The compound of the present invention has excellent KRAS G12D Antiproliferative effect of mutant AsPC-1 cells.

[0775] Experimental Example 3. H727 cell proliferation test

[0776] 1. Purpose

[0777] Through the 3D-CTG method, the effective inhibitors of KRAS were screened. G12V Compounds that inhibit the proliferation of mutant H727 cells.

[0778] 2. Experimental Materials:

[0779] H727 cells were purchased from ATCC; RPMI-1640 medium was purchased from ATCC; fetal bovine serum was purchased from Ausgenex; 3D assay kit (3D-CTG) was purchased from Promega; CellCarrier-96 Spheroid ULA / CS was purchased from PE.

[0780] 3. Experimental methods:

[0781] 5) Multiple cells were seeded in a transparent 96-well cell culture plate, with 195 μL of cell suspension per well, and each well contained 2000 cells;

[0782] 6) Dilute the test compound to 10 mM as the first concentration with 100% DMSO. Then, pipette a further 5-fold dilution to the eighth concentration, from 10 mM to 0.13 μM. Add 2 μL of the serially diluted compound to 48 μL of cell culture medium for a second dilution. After mixing, add 5 μL of the second diluted compound to the corresponding 195 μL well of the cell plate. Return the cell plate to the CO2 incubator and incubate for 7 days. At this point, the compound concentration ranges from 10 μM to 0.128 nM, and the DMSO concentration is 0.1%.

[0783] 7) After incubation, discard 100 μL of cell supernatant and add 60 μL of 3D-CTG to each well. Incubate at room temperature with shaking at 200 rpm for 20 minutes. Place in an incubator and incubate at room temperature for 1 hour.

[0784] 8) 100 μL of the supernatant from the well plate was transferred to a 96-well black bottom transparent plate and luminescence was read in a BMG.

[0785] 4. Data Analysis:

[0786] The raw data were converted to inhibition using the equation Inhibition % = (Ave_H - Sample) / (Ave_H - Ave_L). The IC50 value was then obtained by four-parameter curve fitting (using the variable slope mode in GraphPad Prism using log(inhibitor) vs. response).

[0787] H well: reading value of DMSO well

[0788] L hole: Medium reading

[0789] 5 Experimental results

[0790] The results are shown in Table 3.

[0791] Table 3 IC of compounds against H727 cells 50 value

[0792] Experimental conclusion: The compound of the present invention has excellent KRAS G12V Antiproliferative effect of mutant H727 cells.

[0793] Experimental Example 4. In vitro proliferation test of SW620 cells

[0794] Experimental Materials:

[0795] RPMI1640 medium and penicillin / streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Hyclone. 3D CellTiter-Glo (a chemiluminescent cell viability assay) reagent was purchased from Promega. SW620 (KRAS G12V mutation) cell line was purchased from ATCC, and the Envision Multi-label Analyzer was purchased from PerkinElmer.

[0796] Experimental methods:

[0797] Each cell type was seeded in a 96-well ultra-low attachment U-shaped plate, with 80 μL of cell suspension per well, containing 1000 cells. The cell plate was incubated overnight in a CO2 incubator.

[0798] The compound to be tested was diluted 5-fold into 8 concentrations, from 2mM to 25.6nM, using a dispenser, and a double-well experiment was set up. 78μL of culture medium was added to the middle plate, and then 2μL of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 20μL of each well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10μM to 0.128nM. The cell plate was placed in a carbon dioxide incubator and cultured for 10 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.

[0799] Add 100 μL of cell viability chemiluminescent detection reagent to the cell plate and incubate at room temperature for 30 minutes to allow the luminescent signal to stabilize. Read the results using a multi-label analyzer.

[0800] Data Analysis:

[0801] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)×100%. 50 The value can be obtained by four-parameter curve fitting (obtained using the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Table 4 provides the inhibitory activity of the compounds of the present invention on SW620 cell proliferation.

[0802] Table 4: Results of in vitro screening tests of compounds of the present invention

[0803] Experimental conclusion: The compound of the present invention has excellent KRAS G12V Antiproliferative effect of mutant SW620 cells.

[0804] Experimental Example 5. LU99 cell proliferation test in vitro

[0805] Experimental Materials:

[0806] RPMI1640 medium and penicillin / streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Hyclone. 3D CellTiter-Glo (a chemiluminescent cell viability assay) reagent was purchased from Promega. LU99 (KRAS G12C mutation) cells were purchased from JCRB, and the Envision multi-label analyzer was purchased from PerkinElmer.

[0807] Experimental methods:

[0808] Each cell type was seeded in a 96-well ultra-low attachment U-shaped plate, with 80 μL of cell suspension per well, containing 1000 cells. The cell plate was incubated overnight in a CO2 incubator.

[0809] The compound to be tested was diluted 5-fold into 8 concentrations, from 2mM to 25.6nM, using a dispenser, and a double-well experiment was set up. 78μL of culture medium was added to the middle plate, and then 2μL of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 20μL of each well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10μM to 0.128nM. The cell plate was placed in a carbon dioxide incubator and cultured for 10 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.

[0810] Add 100 μL of cell viability chemiluminescent detection reagent to the cell plate and incubate at room temperature for 30 minutes to allow the luminescent signal to stabilize. Read the results using a multi-label analyzer.

[0811] Data Analysis:

[0812] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)×100%. 50 The value can be obtained by four-parameter curve fitting (obtained using the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Table 5 provides the inhibitory activity of the compounds of the present invention on LU99 cell proliferation.

[0813] Table 5: Results of in vitro screening tests of compounds of the present invention

[0814] Experimental conclusion: The compound of the present invention has excellent KRAS G12C Antiproliferative effect of mutant LU99 cells.

[0815] Experimental Example 6. In vitro proliferation test of MKN-1 cells

[0816] Experimental Materials:

[0817] RPMI1640 medium and penicillin / streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Hyclone. 3D CellTiter-Glo (a chemiluminescent cell viability assay) reagent was purchased from Promega. MKN-1 (KRASWT amplified) cells were purchased from JCRB, and the Envision multi-label analyzer was purchased from PerkinElmer.

[0818] Experimental methods:

[0819] Each cell type was seeded in a 96-well ultra-low attachment U-shaped plate, with 80 μL of cell suspension per well, containing 1000 cells. The cell plate was incubated overnight in a CO2 incubator.

[0820] The compound to be tested was diluted 5-fold into 8 concentrations, from 2mM to 25.6nM, using a dispenser, and a double-well experiment was set up. 78μL of culture medium was added to the middle plate, and then 2μL of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 20μL of each well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10μM to 0.128nM. The cell plate was placed in a carbon dioxide incubator and cultured for 10 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.

[0821] Add 100 μL of cell viability chemiluminescent detection reagent to the cell plate and incubate at room temperature for 30 minutes to allow the luminescent signal to stabilize. Read the results using a multi-label analyzer.

[0822] Data Analysis:

[0823] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)×100%. 50 The value can be obtained by four-parameter curve fitting (obtained using the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Table 6 provides the inhibitory activity of the compounds of the present invention on MKN-1 cell proliferation.

[0824] Table 6: Results of in vitro screening tests of compounds of the present invention

[0825] Note: / represents not tested.

[0826] Experimental conclusion: The compound of the present invention has excellent KRAS WT Amplify the anti-proliferative effect of MKN-1 cells.

[0827] Experimental Example 7. In vivo pharmacodynamic study

[0828] Experimental methods:

[0829] A human colon cancer GP2D cell subcutaneous xenograft tumor model was established in Balb / cnude mice. 0.2 mL (2 × 10 6 GP2D cells (with Matrigel, volume ratio of 1:1) were subcutaneously inoculated on the right back of each mouse. When the average tumor volume reached 270 mm 3 Dosing began at 4:00 AM, with groups of 6 or 4 animals per group. On the day of the experiment, animals were administered the corresponding drugs according to their groups. Group 1 (G1) was designated as the vehicle group and received 5% DMSO + 95% (10% HP-β-CD) by gavage alone. Group 2 (G2) was administered the hydrochloride salt of compound 14 (vehicle: 5% DMSO + 95% (10% HP-β-CD)). The dosage and schedule are shown in Table 7.

[0830] Table 7 Study on the effect of the test substances on animal tumor size in the human colon cancer GP2D mouse xenograft tumor model Note: PO means oral administration, QD means once daily, and BID means once daily.

[0831] During the experiment, the body weight and tumor size of the animals were measured twice a week. The clinical symptoms of the animals were observed and recorded every day. The weight of the animals measured most recently was used as a reference for each administration.

[0832] Tumors were measured using a digital vernier caliper to measure length (a) and width (b). Tumor volume (TV) was calculated using the following formula: TV = a × b 2 / 2.

[0833] Experimental results:

[0834] The hydrochloride of compound 14 had a significant inhibitory effect on human colon cancer GP2D mouse xenograft tumors. After 28 days of administration, the tumor volume inhibition rate TGI (%) of the second group G2 (150 mg / kg, PO, BID) was 97.2 on day 28. The detailed results are shown in Table 8.

[0835] Table 8 Effects of the test substances on animal tumor size in the human colon cancer GP2D mouse xenograft tumor model Note: N / A means not tested.

[0836] Experimental conclusion: In terms of in vivo efficacy, the compounds of the present invention exhibited good tumor inhibition effects in the GP2D cell line.

[0837] Experimental Example 8. In vivo pharmacodynamics study

[0838] Experimental methods:

[0839] A subcutaneous xenograft tumor model of human pancreatic cancer Panc0403 cells was established in Balb / cnude mice. 0.2 mL (5 × 10 6 Panc0403 cells were subcutaneously inoculated on the right back of each mouse. When the average tumor volume reached 190 mm 3 Dosing began at 4:00 AM, with groups of 6 or 4 animals per group. On the day of the experiment, animals were administered the corresponding drugs according to their groups. Group 1, G1, was designated as the vehicle group and received 5% DMSO + 95% (10% HP-β-CD) by gavage alone. Group 2, G2, was administered compound 4A (vehicle: 5% DMSO + 95% (10% HP-β-CD). The dosing schedule is shown in Table 9.

[0840] Table 9 Study on the effect of the test substances on the tumor size in the human pancreatic cancer Panc0403 mouse xenograft tumor model Note: PO means oral administration, QD means once daily, and BID means once daily.

[0841] During the experiment, the body weight and tumor size of the animals were measured twice a week. The clinical symptoms of the animals were observed and recorded every day. The weight of the animals measured most recently was used as a reference for each administration.

[0842] Tumors were measured using a digital vernier caliper to measure length (a) and width (b). Tumor volume (TV) was calculated using the following formula: TV = a × b 2 / 2.

[0843] Experimental results:

[0844] Compound 4A had a significant inhibitory effect on human pancreatic cancer Panc0403 mouse xenograft tumors. After 28 days of administration, the second group G2 (150 mg / kg, PO, BID) had a tumor volume inhibition rate TGI (%) of 113.7 on day 28. The detailed results are shown in Table 10.

[0845] Table 10 Effects of the test substances on the tumor size in the human pancreatic cancer Panc0403 mouse xenograft tumor model Note: N / A means not tested.

[0846] Experimental conclusion: In terms of in vivo efficacy, the compound of the present invention exhibited good tumor inhibition effect in the Panc0403 cell line.

Claims

1. A compound represented by formula (VII) or a pharmaceutically acceptable salt thereof, in, Ring B is selected from 5-12 membered heterocycloalkenyl and 7-12 membered tricyclic heterocycloalkyl, said 5-12 membered heterocycloalkenyl and 7-12 membered tricyclic heterocycloalkyl are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R e Substituted, Ring A is selected from Alternatively, Ring B is selected from Ring A is selected from Ring C is selected from 5-6 membered nitrogen-containing heteroaryl groups; Each R1 is independently selected from F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -SH, -C(=O)-NR a R b 、-C(=O)-R c 、 C 3-6 Cycloalkyl and 5-6 membered heteroaryl Base, the C 1-3 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 1-3 Alkyl-OC 1-3 Alkyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R; Alternatively, R1 on two adjacent atoms and the atom to which they are attached form a 5-6 membered heterocycloalkenyl, and the 5-6 membered heterocycloalkenyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R; R2 is selected from phenyl, naphthyl and 5-10 membered heteroaryl, wherein the phenyl, naphthyl and 5-10 membered heteroaryl are independently optionally substituted by 1, 2, 3, 4 or 5 R d replace; R6 and R7 are independently selected from H, C 1-3 Alkyl, F, Cl, Br and I; T1 is selected from CH2 and O; T2 is selected from O and S; R a Selected from H and C 1-3 Alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 R0; R b Selected from H and C 1-3 Alkyl, the C 1-3 Alkyl is optionally substituted with 1, 2, 3, 4 or 5 R0; R c Selected from H, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R; Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl and C 2-4 Alkynyl, the C 1-3 Alkyl and C 2-4 Alkynyl is each independently optionally substituted with 1, 2, 3, 4 or 5 R0; Each R e Each independently selected from H, F, Cl, Br, I, CN, CH3 and OCH3; Each R is independently selected from F, Cl, Br, I and C 1-3 alkyl; Each R0 is independently selected from D, F, Cl, Br and I; m is selected from 0, 1, 2, 3, 4 and 5; n is selected from 0, 1 and 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from F and CH3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R a Selected from H, CH3, CD3 and CH(CH3)2.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R b Selected from H, CH3, CD3 and CH(CH3)2.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R c is selected from H, cyclopropyl, tetrahydropyrrolyl and morpholinyl; or, R c Selected from tetrahydropyrrolyl and morpholinyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R d Each is independently selected from F, Cl, NH2, OH, CH3, CF3, CH2CH3, -C≡CH and -C≡CCH3.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R e are independently selected from H and F.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R1 is independently selected from F, Cl, Br, OH, NH2, CN, CH3, CH(CH3)2, Cyclopropyl, CF3, 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are each independently selected from H.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrazinyl and pyrimidinyl; alternatively, Ring C is selected from pyrazolyl and imidazolyl.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from and a 5-12 membered heterocycloalkenyl group, and 5-12 membered heterocycloalkenyl are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R e Substituted; or; Ring B is selected from 13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from Ring A is selected from 14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from Structural unit Selected from 15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: The R1 on the two adjacent atoms and the atoms to which they are connected form a 5-6 membered heterocycloalkenyl group, wherein the 5-6 membered heterocycloalkenyl group is independently optionally substituted by 1, 2, 3, 4 or 5 R, so that the structural unit Selected from 16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from Ring A is selected from 17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from Structural unit Selected from 18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: T2 is selected from O.

19. The compound according to claim 1 to 18 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the formula (P-1), in, Ring B is selected from and 5-12 membered heterocycloalkenyl and described and 5-12 membered heterocycloalkenyl are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 R e replace; R1, R2, R6, R7, each R e , Ring C and m are as defined in claims 1 to 18; The carbon atom marked with "*" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer.

20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the formula (P-2), in, Ring B is selected from described Each independently optionally replaced by 1, 2, 3, 4, 5 or 6 R e replace; p is selected from 1, 2, 3, 4 or 5; R1, each R e , each R d and m as defined in claim 19; The carbon atom marked with "*" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer.

21. The following compound or a pharmaceutically acceptable salt thereof:

22. The compound according to claim 21 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of 23. Use of the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pan-KRAS-related diseases.

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