Macrocyclic compound containing three parallel rings and application thereof

Abstract

The invention discloses a macrocyclic compound containing three parallel rings and application thereof, and particularly discloses a compound shown in a formula (II) and pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Macrocyclic compounds containing tricyclic rings and their applications

[0001] This application claims priority to:

[0002] CN2022108721559, application date: July 22, 2022;

[0003] CN2022113690989, application date: November 03, 2022;

[0004] CN2022116017524, application date: December 13, 2022;

[0005] CN2023102194528, application date: March 8, 2023;

[0006] CN202310562000X, application date: May 16, 2023. Technical Field

[0007] The present invention relates to a class of macrocyclic compounds containing three parallel rings and applications thereof, and in particular to a compound represented by formula (II) and a pharmaceutically acceptable salt thereof. Background Art

[0008] Kinase is related to cell proliferation, metabolism, differentiation and apoptosis. Abnormal activation of multiple kinases can lead to the occurrence of cancer.

[0009] Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that belongs to the insulin receptor family. It is primarily expressed in the central and peripheral nervous systems and plays a role in the development and function of the nervous system.

[0010] ALK was originally discovered in a type of anaplastic large-cell lymphoma (ALCL). The N-terminus of the normally expressed nuclear phosphorylation protein NPM fuses with the kinase domain of ALK to form the fusion protein NPM-ALK. This chromosomal translocation leads to sustained cell activation and ultimately tumor formation. Currently, multiple ALK fusion proteins have been identified. Among them, the EML4-ALK fusion protein is found in 3-7% of NSCLC patients and is considered a potent tumor driver. Therefore, EML4-ALK has been established as an effective target for cancer treatment.

[0011] Currently, several ALK inhibitors have entered clinical trials and have been approved for marketing. Crizotinib and lorlatinib have been approved by the FDA for the treatment of patients with ALK-positive NSCLC. Unfortunately, although ALK inhibitors have proven effective in initial clinical trials, patients who receive treatment can develop acquired ALK resistance and metastatic brain cancer. ALK mutations (EML4-ALK-L1196M, EML4-ALK-L1198F, EML4-ALK-G1202R, EML4-ALK-G1202R-L1198F, and EML4-ALK-G1202R-L1196M, among others) are currently the primary cause of ALK resistance.

[0012] Therefore, for the treatment of NSCLC patients, a new generation of inhibitors that can overcome acquired resistance to existing ALK inhibitors is urgently needed.

[0013] Summary of the Invention

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

[0015] in,

[0016] is selected from single bonds and double bonds;

[0017] T1 is selected from C, T2 is selected from N;

[0018] Alternatively, T1 is selected from N, and T2 is selected from C;

[0019] T3 is selected from O, N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2;

[0020] T4 is selected from N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2;

[0021] L1 is selected from CH2 and C(=O);

[0022] L2 and L3 are independently selected from a single bond and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0023] R1 is selected from O, S and NR4;

[0024] R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2-5 Alkenyl, C2-5 Alkynyl and C 3-6 Cycloalkyl, the C 1-4 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-6 The cycloalkyl group is optionally substituted by 1, 2 or 3 R d replace;

[0025] R3 is selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0026] R4 is selected from OH, CN and -(OCH2CH2) n -C 1-3 alkoxy;

[0027] n is 0 or 1;

[0028] Ring A is selected from phenyl, 5-6 membered heteroaryl and C 5-6 Cycloalkenyl, the phenyl, 5-6 membered heteroaryl and C 5-6 The cycloalkenyl group is optionally substituted by 1, 2 or 3 R c replace;

[0029] Each R a and each R b are independently selected from H, F, Cl, Br, I and OH;

[0030] Alternatively, two R on the same carbon atom a Connect to C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 halogens;

[0031] Alternatively, two R on different carbon atoms a Connect to C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 halogens;

[0032] Each R c are independently selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0033] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, C 1-3 Alkyl and C 3-6 Cycloalkyl, the C1-3 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with 1, 2 or 3 halogens;

[0034] Provided that: when T4 is selected from C(R3)2, T3 is selected from C(R3)2O, T2 is selected from C, T1 is selected from N, L1 is selected from CH2, ring A is selected from optionally 1, 2 or 3 R c When substituted phenyl or 5-6 membered heteroaryl, R1 is selected from O, R2 is selected from F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2- 5-alkenyl, C 2-5 Alkynyl and C 3-6 Cycloalkyl, the C 1-4 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-6 The cycloalkyl group is optionally substituted by 1, 2 or 3 R d replace;

[0035] The "hetero" of the 5- to 6-membered heteroaryl or 4- to 6-membered heterocycloalkyl group represents 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, S(=O), N and C(=O).

[0036] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0037] in,

[0038] is selected from single bonds and double bonds;

[0039] T1 is selected from C, T2 is selected from N;

[0040] Alternatively, T1 is selected from N, and T2 is selected from C;

[0041] T3 is selected from O, N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2;

[0042] T4 is selected from N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2;

[0043] L1 is selected from CH2 and C(=O);

[0044] L2 and L3 are independently selected from a single bond and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0045] R1 is selected from O, S and NR4;

[0046] R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-6 Cycloalkyl, the C 1-4 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-6 The cycloalkyl group is optionally substituted by 1, 2 or 3 R d replace;

[0047] R3 is selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0048] R4 is selected from OH, CN and -(OCH2CH2) n -C 1-3 alkoxy;

[0049] n is 0 or 1;

[0050] Ring A is selected from phenyl, 5-6 membered heteroaryl and C 5-6 Cycloalkenyl, the phenyl, 5-6 membered heteroaryl and C 5-6 The cycloalkenyl group is optionally substituted by 1, 2 or 3 R c replace;

[0051] Each R a and each R b are independently selected from H, F, Cl, Br, I and OH;

[0052] Alternatively, two R on the same carbon atom a Connect to C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 halogens;

[0053] Alternatively, two R on different carbon atoms a Connect to C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 halogens;

[0054] Each R c are independently selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0055] Each Rd are independently selected from H, F, Cl, Br, I, OH, NH2, C 1-3 Alkyl and C 3-6 Cycloalkyl, the C 1-3 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with 1, 2 or 3 halogens;

[0056] Provided that: when T4 is selected from C(R3)2, T3 is selected from C(R3)2O, T2 is selected from C, T1 is selected from N, L1 is selected from CH2, ring A is selected from optionally 1, 2 or 3 R c When substituted phenyl or 5-6 membered heteroaryl, R1 is selected from O, R2 is selected from F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2- 5-alkenyl and C 2-5 Alkynyl, the C 1-4 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl is optionally substituted by 1, 2 or 3 R d replace;

[0057] The "hetero" of the 5-6 membered heteroaryl group represents 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, S(=O), N and C(=O).

[0058] The present invention also provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0059] in,

[0060] is selected from single bonds and double bonds;

[0061] T1 is selected from C, T2 is selected from N;

[0062] Alternatively, T1 is selected from N, and T2 is selected from C;

[0063] T3 is selected from O, N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2;

[0064] T4 is selected from N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2;

[0065] L1 is selected from CH2 and C(=O);

[0066] L2 and L3 are independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0067] R1 is selected from O, S and NR4;

[0068] R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl, the C 1-4 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl is optionally substituted by 1, 2 or 3 R d replace;

[0069] R3 is selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0070] R4 is selected from OH, CN and -(OCH2CH2) n -C 1-3 alkoxy;

[0071] n is 0 or 1;

[0072] Ring A is selected from phenyl, 5-6 membered heteroaryl and C 5-6 Cycloalkenyl, the phenyl, 5-6 membered heteroaryl and C 5-6 The cycloalkenyl group is optionally substituted by 1, 2 or 3 R c replace;

[0073] Each R a and each R b are independently selected from H, F, Cl, Br, I and OH;

[0074] Alternatively, two R on the same carbon atom a Connect to C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 halogens;

[0075] Each R c are independently selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0076] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, C 1-3 Alkyl and C 3-6 Cycloalkyl, the C 1-3 Alkyl and C 3-6The cycloalkyl groups are each independently optionally substituted with 1, 2 or 3 halogens;

[0077] Provided that: when T4 is selected from C(R3)2, T3 is selected from C(R3)2O, T2 is selected from C, T1 is selected from N, L1 is selected from CH2, ring A is selected from optionally 1, 2 or 3 R c When substituted phenyl or 5-6 membered heteroaryl, R1 is selected from O, R2 is selected from F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2- 5-alkenyl and C 2-5 Alkynyl, the C 1-4 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl is optionally substituted by 1, 2 or 3 R d replace;

[0078] The "hetero" of the 5-6 membered heteroaryl group represents 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, S(=O), N and C(=O).

[0079] The present invention also provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0080] in,

[0081] is selected from single bonds and double bonds;

[0082] T1 is selected from C, T2 is selected from N;

[0083] Alternatively, T1 is selected from N, and T2 is selected from C;

[0084] T3 is selected from O, N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2;

[0085] T4 is selected from N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2;

[0086] L1 is selected from CH2 and C(=O);

[0087] L2 and L3 are independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0088] R1 is selected from O, S and NR4;

[0089] R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2-5 Alkenyl and C2-5 Alkynyl, the C 1-4 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl is optionally substituted by 1, 2 or 3 R d replace;

[0090] R3 is selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0091] R4 is selected from OH, CN and -(OCH2CH2) n -C 1-3 alkoxy;

[0092] n is 0 or 1;

[0093] Ring A is selected from phenyl, 5-6 membered heteroaryl and C 5-6 Cycloalkenyl, the phenyl, 5-6 membered heteroaryl and C 5-6 The cycloalkenyl group is optionally substituted by 1, 2 or 3 R c replace;

[0094] Each R a and each R b are independently selected from H, F, Cl, Br, I and OH;

[0095] Alternatively, two R on the same carbon atom a Connect to C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 halogens;

[0096] Each R c are independently selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0097] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, C 1-3 Alkyl and C 3-6 Cycloalkyl, the C 1-3 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with 1, 2 or 3 halogens;

[0098] Provided that: when T4 is selected from C(R3)2, T3 is selected from C(R3)2O, T2 is selected from C, T1 is selected from N, L1 is selected from CH2, ring A is selected from optionally 1, 2 or 3 R cWhen substituted phenyl or 5-6 membered heteroaryl, R1 is selected from O, R2 is selected from F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2- 5-alkenyl and C 2-5 Alkynyl, the C 1-4 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl is optionally substituted by 1, 2 or 3 R d replace;

[0099] The "hetero" of the 5-6 membered heteroaryl group represents 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, S(=O), N and C(=O).

[0100] The present invention also provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0101] in,

[0102] is selected from single bonds and double bonds;

[0103] T1 is selected from C, T2 is selected from N;

[0104] Alternatively, T1 is selected from N, and T2 is selected from C;

[0105] T3 is selected from O, N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2;

[0106] T4 is selected from N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2;

[0107] L1 is selected from -CH 2- and -C(=O)-;

[0108] L2 and L3 are independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0109] R1 is selected from O, S and NR4;

[0110] R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl, the C 1-4 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl is optionally substituted by 1, 2 or 3 R d replace;

[0111] R3 is selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0112] R4 is selected from OH, CN and -(OCH2CH2) n -C 1-3 alkoxy;

[0113] n is 0 or 1;

[0114] Ring A is selected from phenyl, 5-6 membered heteroaryl and C 5-6 Cycloalkenyl, the phenyl, 5-6 membered heteroaryl and C 5-6 The cycloalkenyl group is optionally substituted by 1, 2 or 3 R c replace;

[0115] Each R a and each R b are independently selected from H, F, Cl, Br, I and OH;

[0116] Each R c are independently selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0117] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, C 1-3 Alkyl and C 3-6 Cycloalkyl, the C 1-3 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with 1, 2 or 3 halogens;

[0118] Provided that: when T4 is selected from C(R3)2, T3 is selected from C(R3)2O, T2 is selected from C, T1 is selected from N, L1 is selected from -CH2-, ring A is selected from optionally 1, 2 or 3 R c When substituted phenyl or 5-6 membered heteroaryl, R1 is selected from O, R2 is selected from F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2- 5-alkenyl and C 2-5 Alkynyl, the C 1-4 Alkyl, C 2-5 Alkenyl and C 2-5 Alkynyl is optionally substituted by 1, 2 or 3 R d replace;

[0119] The "hetero" of the 5-6 membered heteroaryl group represents 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -S(=O)-, -N- and -C(=O)-.

[0120] The present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0121] in,

[0122] is selected from single bonds and double bonds;

[0123] T1 is selected from C, T2 is selected from N;

[0124] Alternatively, T1 is selected from N, and T2 is selected from C;

[0125] T3 is selected from -O-, -C(R3)2O- and =CR3-;

[0126] T4 is selected from -C(R3)2-, -N= and -C(=O)-;

[0127] L1 is selected from -CH 2- and -C(=O)-;

[0128] L2 and L3 are independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0129] R1 is selected from O and NR4;

[0130] R2 is selected from H, F, Cl, Br, I, OH, NH2, CN and C 1-4 alkyl;

[0131] R3 is selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0132] R4 is selected from OH, CN and -(OCH2CH2) n -C 1-3 alkoxy;

[0133] n is 0 or 1;

[0134] Ring A is selected from phenyl, 5-6 membered heteroaryl and C 5-6 Cycloalkenyl, the phenyl, 5-6 membered heteroaryl and C 5-6 The cycloalkenyl group is optionally substituted by 1, 2 or 3 R c replace;

[0135] R a and R b are independently selected from F, Cl, Br, I and OH;

[0136] Each R c are independently selected from F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0137] The conditions are:

[0138] When T4 is selected from -C(R3)2-, T3 is selected from -C(R3)2O, T2 is selected from C, T1 is selected from N, L is selected from -CH2-, ring A is selected from phenyl or 5-6 membered heteroaryl, R1 is selected from =O, R2 is selected from F, Cl, Br, I, OH, NH2, CN and C 1-4 alkyl;

[0139] The "hetero" of the 5-6 membered heteroaryl is selected from 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -S(=O)-, -N- and -C(=O)-.

[0140] In some embodiments of the present invention, the two R a Connected to form cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolanyl or pyrrolidinyl, wherein the cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolanyl or pyrrolidinyl is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention.

[0141] In some embodiments of the present invention, the two R a The residues are connected to form cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, and the other variables are as defined in the present invention.

[0142] In some embodiments of the present invention, the two R a Connected to form cyclopropyl or cyclobutyl, said cyclopropyl or cyclobutyl is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention.

[0143] In some embodiments of the present invention, the two R a The other variables are as defined in the present invention.

[0144] In some embodiments of the present invention, the two R a Connected to form cyclopropyl, cyclobutyl or oxetanyl, other variables are as defined in the present invention.

[0145] In some embodiments of the present invention, the two R a Connected to form cyclopropyl or cyclobutyl, said cyclopropyl or cyclobutyl is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention.

[0146] In some embodiments of the present invention, the two R a The other variables are as defined in the present invention.

[0147] In some embodiments of the present invention, the above R c are independently selected from F, Cl, Br, I and CH3, wherein CH3 is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined herein.

[0148] In some embodiments of the present invention, the above R c are independently selected from F, Cl, Br, I, CH3 and CF3, and other variables are as defined in the present invention.

[0149] In some embodiments of the present invention, the above R c are independently selected from H, F, Cl, Br, I and CH3, wherein CH3 is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention.

[0150] In some embodiments of the present invention, the above R c are independently selected from H, F, Cl, Br, I, CH3 and CF3, and other variables are as defined in the present invention.

[0151] In some embodiments of the present invention, the above R d are independently selected from F, OH, NH2, CH3 and cyclopropyl, and other variables are as defined in the present invention.

[0152] In some embodiments of the present invention, the above R d are independently selected from H, F, OH, NH2, CH3 and cyclopropyl, and other variables are as defined in the present invention.

[0153] In some embodiments of the present invention, the above L2 is selected from CH2, CH2CH2 and C(CH3)2, wherein CH2, CH2CH2 and C(CH3)2 are independently optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0154] In some embodiments of the present invention, the above L2 is selected from CH2 and C(CH3)2, and the CH2 and C(CH3)2 are independently optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0155] In some embodiments of the present invention, the above-mentioned L2 is selected from CH2, CF2, C(CH3)2 and C(CF3)2, and other variables are as defined in the present invention.

[0156] In some embodiments of the present invention, L2 is selected from -CH2- and -C(CH3)2-, wherein -CH2- and -C(CH3)2- are independently optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0157] In some embodiments of the present invention, the above-mentioned L2 is selected from -CH2-, -CF2-, -C(CH3)2- and -C(CF3)2-, and other variables are as defined in the present invention.

[0158] In some embodiments of the present invention, the above L2 is selected from CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2, Other variables are as defined in the present invention.

[0159] In some embodiments of the present invention, the above L2 is selected from CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2, Other variables are as defined in the present invention.

[0160] In some embodiments of the present invention, the above L2 is selected from a single bond, CH2, CH2CH2 and C(CH3)2, wherein CH2, CH2CH2 and C(CH3)2 are independently optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0161] In some embodiments of the present invention, the above L2 single bond, CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2, Other variables are as defined in the present invention.

[0162] In some embodiments of the present invention, the above L3 is selected from CH2, CH2CH2 and C(CH3)2, wherein CH2, CH2CH2 and C(CH3)2 are independently optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0163] In some embodiments of the present invention, the above L3 is selected from CH2 and C(CH3)2, and the CH2 and C(CH3)2 are independently optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0164] In some embodiments of the present invention, the above-mentioned L3 is selected from CH2, CF2, C(CH3)2 and C(CF3)2, and other variables are as defined in the present invention.

[0165] In some embodiments of the present invention, L3 is selected from -CH2- and -C(CH3)2-, wherein -CH2- and -C(CH3)2- are independently optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0166] In some embodiments of the present invention, the above-mentioned L3 is selected from -CH2-, -CF2-, -C(CH3)2- and -C(CF3)2-, and other variables are as defined in the present invention.

[0167] In some embodiments of the present invention, the above L3 is selected from CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2, Other variables are as defined in the present invention.

[0168] In some embodiments of the present invention, the above L3 is selected from CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2, Other variables are as defined in the present invention.

[0169] In some embodiments of the present invention, the above L3 is selected from a single bond, CH2, CH2CH2 and C(CH3)2, wherein CH2, CH2CH2 and C(CH3)2 are independently optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0170] In some embodiments of the present invention, the above L3 single bond, CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2, Other variables are as defined in the present invention.

[0171] In some embodiments of the present invention, the structural unit -L2-L3- is selected from -CH2C(CH3)2-, Other variables are as defined in the present invention.

[0172] In some embodiments of the present invention, the structural unit -L2-L3- is selected from -CH2C(CH3)2-, Other variables are as defined in the present invention.

[0173] In some embodiments of the present invention, the structural unit -L2-L3- is selected from -CH2C(CH3)2-, Other variables are as defined in the present invention.

[0174] In some embodiments of the present invention, the above-mentioned R1 is selected from O, S, NOH, NCN, NOCH3, NOCH2CH3 and NOCH2CH2OCH3, and other variables are as defined in the present invention.

[0175] In some embodiments of the present invention, the above R1 is selected from O, NOH, NCN, NOCH3, NOCH2CH3 and NOCH2CH2OCH3, and other variables are as defined in the present invention.

[0176] In some embodiments of the present invention, the above R1 is selected from O and S, and other variables are as defined in the present invention.

[0177] In some embodiments of the present invention, the above R1 is selected from NCN, NOCH3, and other variables are as defined in the present invention.

[0178] In some embodiments of the present invention, the above R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 and The CH3 and Each independently optionally replaced by 1, 2 or 3 R d Substitution, other variables are as defined in the present invention.

[0179] In some embodiments of the present invention, the above R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, Other variables are as defined in the present invention.

[0180] In some embodiments of the present invention, the above-mentioned R2 is selected from H, F, Cl, Br, I, OH, NH2, CN and CH3, and other variables are as defined in the present invention.

[0181] In some embodiments of the present invention, the above R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, cyclopropyl, The CH3, cyclopropyl, Each independently optionally substituted by 1, 2 or 3 R d Substitution, other variables are as defined in the present invention.

[0182] In some embodiments of the present invention, the above R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, Other variables are as defined in the present invention.

[0183] In some embodiments of the present invention, the above R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, Other variables are as defined in the present invention.

[0184] In some embodiments of the present invention, the above R2 is selected from F, Cl, Br, I, OH, NH2, CN, CH3, Other variables are as defined in the present invention.

[0185] In some embodiments of the present invention, the above R2 is selected from C 2-5 Alkynyl, the C 2-5 Alkynyl is optionally substituted by 1, 2 or 3 R d Substitution, other variables are as defined in the present invention.

[0186] In some embodiments of the present invention, the above R2 is selected from ethynyl and propynyl, and the ethynyl and propynyl are independently optionally substituted by 1, 2 or 3 R d In some embodiments of the present invention, R3 is selected from H, F, Cl, Br, I, CH3, CH2F, CHF2, CF3 and Other variables are as defined in the present invention.

[0187] In some embodiments of the present invention, the above R3 is selected from H, CH3 and CHF2, and other variables are as defined in the present invention.

[0188] In some embodiments of the present invention, the above R3 is selected from CHF2, and other variables are as defined in the present invention.

[0189] In some embodiments of the present invention, the above-mentioned T3 is selected from -O-, -CH2O-, =CH- and =CCH3-, and other variables are as defined in the present invention.

[0190] In some embodiments of the present invention, the above T3 is selected from O, CH2O, CH and C(CH3), and other variables are as defined in the present invention.

[0191] In some embodiments of the present invention, the above T4 is selected from -CH(CHF2)-, -N= and -C(=O)-, and other variables are as defined in the present invention.

[0192] In some embodiments of the present invention, the above T4 is selected from CH(CHF2), N and C(=O), and other variables are as defined in the present invention.

[0193] In some embodiments of the present invention, the ring A is selected from phenyl, pyridyl and cyclohexenyl, and the phenyl, pyridyl and cyclohexenyl are independently optionally substituted by 1, 2 or 3 R c Substitution, other variables are as defined in the present invention.

[0194] In some embodiments of the present invention, the ring A is selected from phenyl and pyridyl, and the phenyl and pyridyl are independently optionally substituted by 1, 2 or 3 R c Substitution, other variables are as defined in the present invention.

[0195] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0196] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0197] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0198] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0199] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0200] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0201] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0202] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0203] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0204] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0205] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:

[0206] in,

[0207] R1, R2, R3, T1, T2, L1, L2, L3, Ring A and As defined in the present invention;

[0208] When R3 is not H, 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.

[0209] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:

[0210] in,

[0211] R3 is selected from F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0212] R1, R2, L2, L3, Ring A and each R b As defined in the present invention.

[0213] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:

[0214] in,

[0215] R3 is selected from F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0216] R1, R2, L2, L3, Ring A and each R b As defined in the present invention.

[0217] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:

[0218] in,

[0219] R1 is selected from O, NOH, NCN, NOCH3, NOCH2CH3 and NOCH2CH2OCH3;

[0220] R2 is selected from F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-6 Cycloalkyl, the C 1-4 Alkyl, C 2- 5-alkenyl, C 2-5 Alkynyl and C 3-6 The cycloalkyl group is optionally substituted by 1, 2 or 3 R d replace;

[0221] R3 is selected from F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0222] Ring A is selected from phenyl and pyridyl, and the phenyl and pyridyl are each independently optionally substituted by 1, 2 or 3 R c replace;

[0223] The structural unit -L2-L3- is selected from -CH2C(CH3)2-,

[0224] Each R b are independently selected from H, F, Cl, Br, I and OH;

[0225] Each R c are independently selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0226] Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, C 1-3 Alkyl and C 3-6 Cycloalkyl, the C 1-3 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with 1, 2 or 3 halogens.

[0227] In some embodiments of the present invention, the compound of formula (III-1) or (P-1) or a pharmaceutically acceptable salt thereof, wherein each R d As defined in formula (II) of the present invention.

[0228] In some embodiments of the present invention, the compound of formula (III-1) or (P-1) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from O, and the other variables are as defined in formula (III-1) or (P-1) of the present invention.

[0229] In some embodiments of the present invention, the compound of formula (III-1) or (P-1) or a pharmaceutically acceptable salt thereof, wherein R2 is selected from F, Cl, Br, CN, C 1-4 Alkyl, C 2-5 Alkynyl and C 3-6 Cycloalkyl, the C 1-4 Alkyl, C 2-5 Alkynyl and C 3-6 The cycloalkyl group is optionally substituted by 1, 2 or 3 R d The other variables are as defined in formula (III-1) or (P-1) of the present invention.

[0230] In some embodiments of the present invention, the compound of formula (III-1) or (P-1) or a pharmaceutically acceptable salt thereof, wherein R2 is selected from C 2- 5 alkynyl, the C 2-5 Alkynyl is optionally substituted with 1, 2 or 3 R d The other variables are as defined in formula (III-1) or (P-1) of the present invention.

[0231] In some embodiments of the present invention, the compound of formula (III-1) or (P-1) or a pharmaceutically acceptable salt thereof, wherein R3 is selected from CHF2, and the other variables are as defined in formula (III-1) or (P-1) of the present invention.

[0232] Some other solutions of the present invention are obtained by any combination of the above variables.

[0233] The present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

[0234] The present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

[0235] The present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating ALK inhibitor-related diseases.

[0236] The compounds of the present invention show high kinase inhibitory activity in ALK kinase and its mutants, ROS1 and TRKB kinases, and also have strong inhibitory efficacy on ALK mutant cells and TRKB phenotype cells, among which the inhibition on ALK is stronger and the inhibition on TRKB is relatively weak, with excellent selectivity; the compounds of the present invention are hypertonic and low efflux compounds, have no significant inhibition on different subtypes of P450 isoenzymes, and exhibit good metabolic stability in hepatocytes, and have excellent pharmacokinetic properties.

[0237] Definition and Description

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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 a mixture of two isomers, or a wavy line Indicates a straight solid bond or straight dashed key or a mixture of two isomers.

[0244] 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 denoted by , it represents the (Z) isomer, (E) isomer or a mixture of both isomers of the compound.

[0245] 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%.

[0246] 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%.

[0247] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0248] 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.

[0249] 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.

[0250] 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. When the substituent is =CH2, it means that two hydrogen atoms are replaced.

[0251] The term "optionally substituted" means that the group may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any based on chemical feasibility.

[0252] 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.

[0253] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0254] When the number of a substituent is 0, it means that the substituent does not exist, for example, -A-(R)0 means that the structure is actually -A.

[0255] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0260]

[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.

[0261] Unless otherwise specified, the term “C 1-4 "Alkyl" by itself or in combination with other terms refers to a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C4, C3, C 1-3 、C 1-2 and C 2-3 Alkyl, etc.; it may be monovalent, divalent or polyvalent. 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0262] Unless otherwise specified, the term “C 1-3 "Alkyl" by itself or in combination with other terms refers to a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 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 C3, C 1-2 and C 2-3 Alkyl, etc.; it may be monovalent, divalent or polyvalent. 1-3Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0263] Unless otherwise specified, “C 2-5 "Alkenyl" by itself or in combination with other terms refers to a straight or branched hydrocarbon group consisting of 2 to 5 carbon atoms containing at least one carbon-carbon double bond, which can be located at any position of the group. 2-5 Alkenyl groups include C 2-4 、C 2-3 , C5, C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-5 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, butadienyl, piperyl, and the like.

[0264] Unless otherwise specified, “C 2-5 "Alkynyl" by itself or in combination with other terms refers to a straight or branched hydrocarbon group consisting of 2 to 5 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-5 Alkynyl groups include C 2-4 、C 2-3 , C5, C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. 2-5 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

[0265] Unless otherwise specified, the term “C 1-3 "Alkoxy" by itself or in combination with other terms refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom. It can be monovalent, divalent or polyvalent. The C 1-3 Alkoxy groups include C 1- 2. C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0266] Unless otherwise specified, “C 3-6 "Cycloalkyl" by itself or in combination with other terms refers to a saturated monocyclic hydrocarbon group consisting of 3 to 6 carbon atoms. 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.

[0267] Unless otherwise specified, “C 5-6 "Cycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated monocyclic hydrocarbon group consisting of 5 to 6 carbon atoms containing at least one carbon-carbon double bond. 5-6 The cycloalkenyl group includes C5 or C6 cycloalkenyl groups, etc.; it may be monovalent, divalent or polyvalent. 5-6 Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0268] Unless otherwise specified, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated monocyclic 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 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). In addition, with respect to the "4-6 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is attached to the rest of the molecule. The 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyls. It may be monovalent, divalent, or multivalent. 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.

[0269] 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 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered 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.), 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.).

[0270] 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.

[0271] 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.

[0272] The present invention uses the following abbreviations: aq represents water; DCM represents dichloromethane; PE represents petroleum ether; DMSO represents dimethyl sulfoxide; EA and EtOAc both represent ethyl acetate; EtOH represents ethanol; MeOH represents methanol; DMF represents N,N-dimethylformamide; Boc represents tert-butyloxycarbonyl, which is an amine protecting group; THF represents tetrahydrofuran; Boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; TEA represents triethylamine; HCl represents hydrochloric acid; mp represents melting point; FDPP represents pentafluorophenyl diphenyl phosphate; prep-HPLC represents preparative high performance liquid chromatography; THP represents 2-chloro-tetrahydro-2H-pyran; BRETTPHOS represents 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl; and TBAF represents tetra-n-butylammonium fluoride.

[0273] The solvents used in the present invention can be obtained commercially. Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0274] The present invention is described in detail below by examples, but it is not intended to limit the present invention in any way. 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, the embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement modes well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0275] Reference Example 1: Compound B-1

[0276] Step 1

[0277] Dissolve B-1-1 (90 g, 343.12 mmol) in dichloromethane (700 mL). Add sodium periodate (169.8 g, 793.86 mmol) and 6 mL of saturated sodium bicarbonate solution at 24°C. Add sodium bicarbonate (12 g, 142.85 mmol) 5 minutes later. Remove the water bath after addition. Stir at room temperature for 2 hours before adding magnesium sulfate (180 g, 1.50 mol). Filter the reaction mixture, wash the filter cake with dichloromethane (2 x 180 mL), and collect the filtrate to obtain a crude dichloromethane solution of B-1-2, which is used directly in the next step.

[0278] Step 2

[0279] The crude dichloromethane solution of B-1-2 obtained in step 1 was added dropwise with diethylaminosulfur trifluoride (686.18 mmol, 90.66 mL) at 24 ° C and stirred at 20 ° C for 14 hours. The resulting reaction solution was poured into a sodium bicarbonate solution dissolved in crushed ice in small amounts several times to quench. The liquid was separated, and the organic phase was washed with water (1000 mL) and saturated brine (500 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filter residue was rinsed with dichloromethane (150 mL). The filtrate was concentrated under reduced pressure to obtain compound B-1-3. 1 H NMR (400MHz, CDCl3): δppm 5.88-5.55(m,1H), 4.25-4.22(m,1H), 4.16-4.11(m,1H), 4.10-4.06(m,1H), 1.47(s,3H), 1.39(s,3H).

[0280] Step 3

[0281] Dissolve B-1-3 (22 g, 144.60 mmol) in acetonitrile (190 mL) and H2O (10 mL), add bis(acetonitrile)palladium(II) chloride (750.30 mg, 2.89 mmol), and stir at 60°C under N2 atmosphere for 5 hours. After cooling to room temperature, filter the reaction mixture, and concentrate the filtrate under reduced pressure to obtain crude B-1-4.

[0282] Step 4: Synthesis of B-1-5

[0283] The crude product B-1-4 (22 g) was dissolved in dichloromethane (400 mL), and imidazole (11.81 g, 173.53 mmol) and tert-butyldimethylsilyl chloride (23.97 g, 159.07 mmol) were added sequentially at 0 ° C. The mixture was heated to room temperature and stirred for 2 hours. The reaction solution was diluted with dichloromethane (600 mL) and washed with 400 mL of water. The resulting organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:0-10:1) to obtain compound B-1-5. 1 H NMR (400MHz, DMSO-d6): δppm 5.99-5.67 (m, 1H), 5.57 (d, J = 5.6Hz, 1H), 3.74-3.53 (m, 3H), 0.84 (s, 9H), 0.02 (s, 6H).

[0284] Step 5: Synthesis of B-1-6

[0285] Dissolve B-1-5 (26.2 g, 115.76 mmol) in dichloromethane (400 mL), add pyridine (185.21 mmol, 14.95 mL) and trifluoromethanesulfonic anhydride (138.91 mmol, 22.92 mL) in sequence at -30°C to -20°C, and stir at 0°C for 2 hours. The reaction solution was diluted with dichloromethane (400 mL) and washed with 300 mL of water. The resulting organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:0-10:1) to obtain compound B-1-6. 1 H NMR (400MHz, CDCl3): δppm 6.20-5.85(m,1H), 4.93-4.82(m,1H), 4.03-3.97(m,2H), 0.91(s,9H), 0.11(s,6H).

[0286] Step 6: Synthesis of B-1-7

[0287] Dissolve B-1-6 (28.94 g, 80.75 mmol) in 1,4-dioxane (250 mL), add 4-methoxybenzylamine (96.90 mmol, 12.54 mL) and triethylamine (96.90 mmol, 13.49 mL) in sequence, and stir at 90°C for 8 hours. After the reaction solution cools to room temperature, add water (300 mL) to the reaction solution, extract with ethyl acetate (400 mL*2), combine the organic phases, wash with saturated brine (300 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product. The crude product is separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0-10:1) to obtain compound B-1-7. 1 H NMR (400MHz, CDCl3): δppm 7.22-7.20(m,2H),6.86-6.81(m,2H),5.90-5.58(m,1H),3.87-3.75(m,2H), 3.75(s,3H),3.68-3.64(m,2H),2.89-2.84(m,1H),0.83(s,9H),0.02(s,6H).

[0288] Step 6: Synthesis of B-1

[0289] Dissolve B-1-7 (26.99 g, 78.12 mmol) in tetrahydrofuran (280 mL), then add tetrabutylammonium fluoride solution (1 M, 78.12 mL) and stir at 24°C for 2 hours. The reaction mixture is diluted with ethyl acetate (500 mL x 3) and washed with 300 mL of water. The resulting organic phase is washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. B-1 is then isolated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain B-1. 1 H NMR (400MHz, CDCl3): δppm 7.20-7.16(m,2H),6.86-6.75(m,2H),5.95-5.56(m,1H),3.85-3.75(m,2 H),3.73(s,3H),3.71-3.63(m,1H),3.56-3.49(m,1H),2.98-2.85(m,1H).

[0290] Reference Example 2: Compound B-2

[0291] Step 1: Synthesis of B-2-2

[0292] Dissolve B-2-1 (100 g, 644.52 mmol) in ethanol (1000 mL), then add diethyl 2-fluoromalonate (172.24 g, 966.78 mmol) and sodium ethoxide (109.65 g, 1.61 mol) in sequence, and heat to 90°C and stir for 6 hours. After the reaction solution is cooled to room temperature, add water (1000 mL) to dilute it, adjust the pH to 3 with 2N hydrochloric acid solution, precipitate a solid, filter, collect the filter cake, add 1.5 L of acetonitrile, stir, and filter. Add 1.0 L of acetonitrile to the filter cake, stir, and filter. Collect the filter cake to obtain B-2-2. 1 H NMR (400MHz, DMSO-d6): δppm 7.84 (s, 1H), 4.23 (q, J = 7.0Hz, 2H), 1.27 (t, J = 7.0Hz, 3H); LCMS: m / z = 242.1 [M+1] + .

[0293] Step 2: Synthesis of B-2-3

[0294] Phosphorus oxychloride (11.4 mol, 1.06 L) was added to a reaction flask with a buffer device, and B-2-2 (110 g, 456.1 mmol) was added in batches. After nitrogen was purged, the temperature was lowered to 0 ° C, and N, N-diethylaniline (684.15 mmol, 109.43 mL) was slowly added dropwise. The temperature was raised to 100 ° C and stirred for 3 hours. After the reaction solution was cooled to room temperature, 250 mL of acetonitrile was added to dilute it, and then it was slowly added to 2 L of room temperature water to quench. The resulting solution was placed in an ice-water bath and stirred for 1 hour, filtered, and the filter cake was collected. The filter cake was dissolved in 1 L of dichloromethane, 500 mL of saturated sodium bicarbonate aqueous solution was added, stirred for 1 hour, and separated. The obtained organic phase was concentrated under reduced pressure to obtain B-2-3. 1 H NMR (400MHz, CDCl3): δppm 8.65 (s, 1H), 4.43 (q, J = 7.0Hz, 2H), 1.43 (t, J = 7.0Hz, 3H); LCMS: m / z = 278.0 [M+1] + .

[0295] Step 3: Synthesis of B-2

[0296] B-2-3 (3.9 g, 14.03 mmol) was dissolved in tetrahydrofuran (50.0 mL), water (100.0 mL), and ethanol (150.0 mL), followed by the addition of ammonium chloride (4.05 g, 75.74 mmol). After nitrogen was purged, the temperature was lowered to 0°C, and zinc powder (3.7 g, 56.1 mmol) was added portionwise. The reaction was allowed to react at 0°C for 2 hours. The reaction solution was filtered, and the filtrate was extracted with dichloromethane (50 mL*3). The resulting organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification by column chromatography (eluent PE:EA = 1:0 to 3:1) afforded B-2. 1 H NMR (400MHz, CDCl3): δppm 8.65 (d, J = 3.2Hz, 1H), 8.50 (s, 1H), 4.36 (q, 2H), 1.36 (t, 3H); LCMS: m / z = 244.0 [M+1] + .

[0297] Reference Example 3: Compound B-3

[0298] Step 1: Synthesis of B-3-2

[0299] Dissolve thionyl chloride (74.44 mmol, 5.4 mL) in acetonitrile (35 mL). Slowly add B-3-1 (5.0 g, 26.42 mmol) dissolved in acetonitrile (25 mL) dropwise at -40°C. Stir thoroughly, then add pyridine (142.48 mmol, 11.5 mL). Stir at room temperature (approximately 15°C) for 2 hours. Add 150.0 mL of ethyl acetate to the reaction mixture, filter, and concentrate the filtrate under reduced pressure. The resulting crude product is isolated and purified by column chromatography (PE:EA = 1:1) to obtain compound B-3-2. 1 H NMR (400MHz, CDCl3): δppm 4.77–4.56(m,1H),4.35–4.33(m,1H),1.52(s,6H),1.46(s,9H); LCMS: m / z=258.1[M+Na] + .

[0300] Step 2: Synthesis of B-3

[0301] B-3-2 (1.0 g, 4.25 mmol) and ruthenium trichloride hydrate (4.4 mg, 19.7 μmol) were dissolved in acetonitrile (10.5 mL) under a nitrogen atmosphere. Sodium periodate (5.3 g, 24.8 mmol) dissolved in 10.5 mL of water was added at 0°C, and then the temperature was raised to room temperature (approximately 20°C) and stirred for 16 hours. The reaction solution was diluted with 100 mL of water and extracted with dichloromethane (100 mL*3). The resulting organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (PE:EA=1:1) to obtain B-3. 1 H NMR (400MHz, CDCl3): δppm 4.23 (s, 2H), 1.59 (s, 9H), 1.56 (s, 6H); LCMS: m / z=252.1[M+1] + .

[0302] Reference Example 4: Compound B-4

[0303] Step 1: Synthesis of B-4-2

[0304] Dissolve B-4-1 (0.5 g, 14.03 mmol) and B-3 (0.74 g, 2.94 mmol) in DMF (10.0 mL), then add potassium carbonate (1.02 g, 7.35 mmol). Heat to 50°C and stir for 4 hours. Add 5 mL of dichloromethane to dilute the reaction solution, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is isolated and purified by column chromatography (PE:EA = 10:1) to obtain B-4-2. 1H NMR (400MHz, CDCl3): δppm 7.49-7.44(m,1H),7.12-7.04(m,1H),6.89-6.84(m,1H),3.91(s,2H),3.84(s,3H),1.36(s,6H),1.33(s,9H); LCMS: m / z=364.1[M+Na] + .

[0305] Step 2: Synthesis of B-4-3

[0306] B-4-2 (0.3 g, 0.88 mmol) was dissolved in tetrahydrofuran (4.0 mL). LiBH4 (38.3 mg, 1.76 mmol) was added at 0°C and stirred at room temperature for 18 hours. The reaction was quenched with 5.0 mL of water, followed by the addition of 1 mL of 2M sodium hydroxide solution. The mixture was extracted with dichloromethane (10 mL x 3). The resulting organic phase was washed with 5.0 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by column chromatography (PE:EA = 10:1) to obtain B-4-3. 1 H NMR (400MHz, CDCl3): δppm 7.09-7.05(m,1H),6.97-6.90(m,1H),6.86-6.79(m,1H),4.73-4.71(m,1H),4. 71-4.67(m,2H),4.03(s,2H),1.43(s,6H),1.41(s,9H); LCMS: m / z=336.1[M+Na] + .

[0307] Step 3: Synthesis of B-4

[0308] B-4-3 (0.1 g, 0.32 mmol) was dissolved in dichloromethane (3.0 mL), and N,N-diisopropylethylamine (0.96 mmol, 167 μL) was added. Methanesulfonyl chloride (0.41 mmol, 32.0 μL) was then added at 0°C. The mixture was then warmed to 25°C and stirred for 18 hours. The reaction was quenched by the addition of 3 mL of 2M hydrochloric acid solution at 0°C, diluted with 15 mL of water, and extracted with dichloromethane (15 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by column chromatography (PE:EA = 10:1) to obtain B-4. 1H NMR (400MHz, CDCl3): δppm 7.03-6.98(m,1H),6.93-6.86(m,1H),6.79-6.72(m,1H),4.53(s,2H),3.96(s,2H),1.37(s,6H),1.33(s,9H); LCMS:m / z=354.0[M+Na] + .

[0309] Reference Example 5: Compound B-5

[0310] Step 1: Synthesis of B-5-2

[0311] Dissolve B-5-1 (7.07 g, 43.37 mmol), ethylene glycol methyl ether (3 g, 39.42 mmol), and triphenylphosphine (11.37 g, 43.37 mmol) in tetrahydrofuran (85 mL). Add a solution of diisopropyl azodicarboxylate (51.25 mmol, 9.97 mL) in tetrahydrofuran (15 mL) slowly dropwise to the reaction mixture under an ice bath. The mixture was allowed to react at 0°C for 10 minutes, then slowly warmed to 25°C and stirred for 16 hours. Water (30 mL) was slowly added to the reaction mixture to quench the reaction. The mixture was extracted with EA (200 mL x 2). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 10:1 to 1:1) to obtain B-5-2. 1 H NMR (400MHz, CDCl3) δppm 7.81-7.89(m,2H),7.72-7.79(m,2H),4.30-4.44(m,2H),3.67-3.82(m,2H),3.34-3.45(s,3H); LCMS: m / z=222.0[M+1] + .

[0312] Step 2: Synthesis of B-5

[0313] Dissolve B-5-2 in DCM (10 mL), then add hydrazine hydrate (4.97 mmol, 302.10 μL, 80% purity) and react at 25°C for 16 hours. Filter the reaction solution and concentrate the filtrate under reduced pressure. Add DCM (20 mL) to the residue and stir, filter, and collect the filtrate and concentrate under reduced pressure. Add DCM (5 mL) to the residue and then add ethyl acetate hydrochloride (4 M, 5 mL) solution and stir for 20 minutes. Concentrate the reaction solution under reduced pressure, add ethyl acetate (20 mL) to the residue and concentrate, then add ethyl acetate (20 mL) to the residue and concentrate to obtain B-5.

[0314] Reference Example 6: Compound B-6

[0315] Step 1: Synthesis of B-6-2

[0316] B-6-1 (5 g, 32.23 mmol) and pyridine hydrochloride (14.90 g, 128.93 mmol) were added to a round-bottom flask and heated to 145°C for 1 hour. After the reaction solution cooled to room temperature, water (200 mL) was added to the reaction solution, and then extracted with EA (500 mL*2). The resulting organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain B-6-2. 1 H NMR (400MHz, CDCl3) δppm10.20(s,1H),7.93-8.02(m,1H),7.83-7.87(m,1H).

[0317] Step 2: Synthesis of B-6-3

[0318] B-6-2 (3.0 g, 21.26 mmol) was dissolved in DMF (30 mL), followed by the addition of B-3 (4.86 g, 19.33 mmol) and potassium carbonate (6.68 g, 48.32 mmol). The mixture was heated to 50°C and stirred for 14 hours. The mixture was filtered, the filter cake was rinsed with EA (20 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1-4:1) to obtain B-6-3. LCMS: m / z = 213.1 [M+1-100] + .

[0319] Step 3: Synthesis of B-6-4

[0320] B-6-3 (1.9 g, 6.08 mmol) was dissolved in EtOH (20 mL). Sodium borohydride (1.15 g, 30.42 mmol) was added under a nitrogen atmosphere at 0°C and the mixture was allowed to react at 25°C for 3 hours. Water (10 mL) was added to the reaction mixture at 0°C and stirred for 0.5 hours. After complete quenching, the mixture was extracted with EA (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1-5:1) to obtain B-6-4. 1 H NMR (400MHz, CDCl3) δppm 7.95 (d, J = 3.01Hz, 1H), 7.57 (dd, J = 8.78, 3.01Hz, 1H), 6.62 (brs, 1 H),5.37(t,J=5.52Hz,1H),4.48(d,J=5.52Hz,2H),4.25(s,2H),1.33(s,9H),1.25(s,6H); LCMS: m / z=315.1[M+1] + .

[0321] Step 4: Synthesis of B-6

[0322] B-6-4 (1 g, 3.18 mmol) was dissolved in DCM (20 mL), followed by the addition of N,N-diisopropylethylamine (9.54 mmol, 1.66 mL). The temperature was lowered to 0°C under a nitrogen atmosphere, and methanesulfonyl chloride (6.81 mmol, 527.03 μL) was slowly added dropwise. The mixture was reacted at 0°C for 1 hour, and then raised to 25°C for 2 hours. The reaction solution was slowly added dropwise to an ice-cold solution of saturated sodium bicarbonate (50 mL) and extracted with DCM (200 mL*2). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1-5:1) to obtain B-6. 1 H NMR (400MHz, CDCl3) δppm 7.89-7.96(m,1H),7.45-7.48(m,1H),4.60(s,2H),4.35(s,2H),1.41(s,15H).

[0323] Reference Example 7: Compound B-7

[0324] Compound B-7 was prepared using a synthetic route similar to compound B-2 using B-7-1 as the starting material. LCMS: m / z = 258.1 [M+1] + .

[0325] Reference Example 8: Compound B-8

[0326] B-1-6 (5 g, 13.95 mmol) was dissolved in a 0.4 M ammonia-dioxane solution (100 mL). Triethylamine (2.33 mL, 16.74 mmol) was then added. After replacing the nitrogen atmosphere, the mixture was reacted at 90°C for 12 hours. After cooling the reaction mixture to room temperature, 50 mL of water was added to the mixture, and the mixture was extracted with 50 mL of dichloromethane. After separation, the organic phase was collected and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed sequentially with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 10:1) to obtain B-8. 1 H NMR (400MHz, CDCl3): δppm 5.95-5.55(m,1H), 3.89-3.61(m,2H), 3.13-2.87(m,1H), 0.91(s,9H), 0.08(s,6H).

[0327] Reference Example 9: Compound B-9

[0328] Step 1: Synthesis of B-9-3

[0329] B-4-1 (760 mg, 4.47 mmol) and B-9-2 (899.03 mg, 4.47 mmol) were dissolved in 3 mL of dichloromethane, followed by the addition of triphenylphosphine (1.76 g, 6.70 mmol). The mixture was cooled to 0°C and then diisopropyl azodicarboxylate (7.15 mmol, 1.39 mL) was added. The temperature was slowly raised to 24°C and the reaction mixture was allowed to react for 12 hours. The reaction mixture was quenched with 10 mL of water and extracted with 10 mL of dichloromethane. After separation, the organic phase was collected and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 1:1) to obtain B-9-3. 1 H NMR (400MHz, CDCl3): δppm 7.61(dd,J=3.3,8.9Hz,1H),7.17(ddd,J=3.3,7.5,9.1Hz,1H),6.84(dd,J=4.2,9.2Hz,1H),3.93(s ,3H),3.86(s,2H),3.27(d,J=5.4Hz,2H),1.46(s,9H),0.75-0.68(m,2H),0.65-0.59(m,2H); LCMS: m / z=254.2[M-100+1] + .

[0330] Step 2: Synthesis of B-9-4

[0331] B-9-3 (1.8 g, 3.01 mmol) and calcium chloride (333.52 mg, 3.01 mmol) were added to a reaction flask, followed by tetrahydrofuran (6 mL) and ethanol (12 mL). The mixture was cooled to 0°C under a nitrogen atmosphere, and sodium borohydride (227.38 mg, 6.01 mmol) was slowly added. The reaction mixture was allowed to react at 24°C for 12 hours. The reaction mixture was slowly quenched with 20 mL of water, and the pH was adjusted to 6-7 by adding 2M hydrochloric acid. The mixture was extracted with 20 mL of dichloromethane. After separation, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (2 x 20 mL). The organic phases were combined. The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 2:1) to obtain B-9-4. 1H NMR (400MHz, CDCl3) δppm 7.07 (dd, J=3.1, 8.6Hz, 1H), 6.92 (dt, J=3.2, 8.5Hz, 1H), 6.71 (dd, J=4.3, 8.9Hz, 1H), 6.33 (br s,1H),5.23-5.09(m,1H),4.71(s,2H),3.82(s,2H),3.26(br d,J=4.5Hz,2H),1.39(s,9H),0.67-0.57(m,4H); LCMS: m / z=348.2[M+Na] + .

[0332] Step 3: Synthesis of B-9

[0333] B-9-4 (0.65 g, 2.00 mmol) was dissolved in dichloromethane (13 mL), cooled to 0°C under a nitrogen atmosphere, and thionyl chloride (4.00 mmol, 290.19 μL) was added. The reaction mixture was allowed to react at 20°C for 1 hour. 5 mL of water was added to the reaction mixture to quench the reaction. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and 10 mL of dichloromethane was added for extraction. After separation, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 1:1) to obtain B-9. 1 H NMR (400MHz, CDCl3) δppm 7.10(dd,J=2.9,8.5Hz,1H),6.97(dt,J=3.0,8.4Hz,1H),6.76(dd,J=4.2,8.7Hz,1H),5.15-5.04(m,1H),4.64(s,2H),3.86(s,2H),3.27(br d, J=5.5Hz, 2H), 1.43 (s, 9H), 0.75-0.60 (m, 4H); LCMS: m / z=366.1[M+Na] + .

[0334] Reference Example 10: Compound B-10

[0335] Step 1: Synthesis of B-10-2

[0336] B-4-1 (2.0 g, 11.76 mmol) was dissolved in N,N-dimethylformamide (6.67 mL). 3-Propylene bromide (1.56 g, 12.93 mmol), potassium carbonate (1.79 g, 12.93 mmol), and sodium iodide (1.94 g, 12.93 mmol) were added sequentially under a nitrogen atmosphere. The mixture was allowed to react at 20°C for 12 hours. 30 mL of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (20 mL*3). After separation, the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 6:1) to obtain B-10-2. 1 H NMR (400MHz, CDCl3) δppm 7.53(dd,J=3.2,8.8Hz,1H),7.16–7.15(m,1H),6.93(dd,J=4.0,8.8Hz,1H),6.07–6.03(m,1H),5.50(dd,J=1. 6,17.2Hz,1H),5.32(dd,J=1.6,10.4Hz,1H),4.61(dd,J=1.6,3.2Hz,2H),3.91(s,3H); LCMS: m / z=211.2[M+H] + .

[0337] Step 2: Synthesis of B-10-3

[0338] B-10-2 (2.0 g, 9.51 mmol) was dissolved in toluene (40.0 mL). The mixture was cooled to 0°C under a nitrogen atmosphere, and a toluene solution of diisobutylaluminum hydride (1 M, 28.54 mL) was slowly added dropwise. The mixture was stirred at 0°C for 1 hour. Saturated sodium tartrate (100 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 10:1) to obtain B-10-3. 1 H NMR (400MHz, CDCl3) δppm 7.06 (dd, J=3.2, 8.8Hz, 1H), 6.93 (td, J=3.2, 4.4Hz, 1H), 6.81 (dd,J=4.4,4.8Hz,1H),6.07–6.02(m,1H),5.44(dd,J=1.6,15.6Hz,1H),5.33(d d,J=1.6,10.4Hz,1H),4.70(d,J=2.8Hz,2H),4.57(d,J=5.2Hz,2H),2.25(s,1H).

[0339] Step 3: Synthesis of B-10

[0340] B-10-3 (0.5 g, 2.74 mmol) was dissolved in dichloromethane (10.0 mL). Thionyl chloride (0.3 mL, 4.12 mmol) was added under nitrogen atmosphere and stirred at 20°C for 0.5 h. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (mobile phase: PE:EA = 1:0 to 20:1) to obtain B-10. 1 H NMR (400MHz, CDCl3) δppm 7.13(dd,J=3.2,8.8Hz,1H),6.97(td,J=3.2,4.4Hz,1H),6.83(dd,J=4.4,4.8Hz,1H),6.07–6.02(m,1H ), 5.45 (dd, J = 1.6, 17.2Hz, 1H), 5.33 (dd, J = 1.6, 10.4Hz, 1H), 4.65 (s, 2H), 4.58 (dd, J = 1.6, 3.2Hz, 2H).

[0341] Reference Example 11: Compound B-11

[0342] Step 1: Synthesis of B-11-2

[0343] Imidazole (7.27 g, 106.82 mmol), triethylamine (53.41 mmol, 7.43 mL), and dichloromethane (50 mL) were added to the reaction flask. The mixture was cooled to -65°C under a nitrogen atmosphere. A solution of thionyl chloride (32.05 mmol, 2.33 mL) and B-11-1 (5 g, 26.70 mmol) in dichloromethane (50 mL) was slowly added dropwise. The mixture was then slowly heated to 25°C and stirred for 12 hours. 20 mL of water was added to the reaction solution to quench the reaction. The mixture was extracted with dichloromethane (20 mL*3). After separation, the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude B-11-2. 1 H NMR (400MHz, CDCl3) δppm 5.06(dd,J=1.2,8.8Hz,1H),4.15(d,J=8.8Hz,1H),1.93–1.87(m,1H),1.51–1.50(m,1H),1.41(s,9H),0.77–0.72(m,1H),0.68–0.65(m,1H).

[0344] Step 2: Synthesis of B-11

[0345] B-11-2 (6.2 g, 26.58 mmol), water (31 mL), and acetonitrile (62 mL) were added to the reaction flask. The mixture was cooled to 0°C under a nitrogen atmosphere. Sodium periodate (7.11 g, 33.22 mmol) and ruthenium trichloride (27.56 mg, 132.89 μmol) were then added. The temperature was slowly raised to 20°C and stirred for 2 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (50 mL*3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 3:1) to obtain B-11. 1 H NMR (400MHz, CDCl3) δppm 4.43 (s, 2H), 1.88 (t, J = 6.8 Hz, 2H), 1.54 (s, 9H), 0.77 (t, J = 6.8 Hz, 2H).

[0346] Reference Example 12: Compound B-12

[0347] Step 1: Synthesis of B-12-2

[0348] Imidazole (1.01 g, 14.91 mmol) was dissolved in dichloromethane (16 mL). The mixture was cooled to -5°C and slowly added with a solution of thionyl chloride (0.32 mL, 4.47 mmol) in dichloromethane (5 mL). The mixture was stirred at -5°C for 1 hour. The mixture was then cooled to -10°C and a solution of B-12-1 (0.5 g, 2.48 mmol) in dichloromethane (4 mL) was added. The mixture was returned to room temperature and stirred for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined and washed sequentially with 10% citric acid solution (10 mL) and saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 1:1) to obtain B-12-2. 1 H NMR (400MHz, CDCl3) δppm 4.95 (d, J = 8.8 Hz, 1H), 4.80 (d, J = 8.8 Hz, 1H), 2.12–2.08 (m, 2H), 1.93–1.83 (m, 2H), 1.67–1.64 (m, 2H), 1.58 (s, 9H).

[0349] Step 2: Synthesis of B-12

[0350] B-12-2 (0.51 g, 2.06 mmol) was dissolved in acetonitrile (15 mL) and cooled to 0°C under a nitrogen atmosphere. A solution of sodium periodate (2.56 g, 11.96 mmol) and ruthenium chloride trihydrate (2.7 mg, 10.31 μmol) in water (15 mL) was then added. The temperature was slowly raised to 20°C and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude B-12, which was used directly in the next reaction without purification. 1 H NMR (400MHz, CDCl3) δppm4.82(s,2H),2.89-2.86(m,2H),2.22-2.16(m,2H),1.78-1.73(m,2H),1.51(s,9H).

[0351] Reference Example 13: Compound B-13

[0352] Step 1: Synthesis of B-13-2

[0353] B-13-1 (276.0 mg, 1.97 mmol) and B-12 (415.0 mg, 1.58 mmol) were dissolved in N,N'-dimethylformamide, and cesium carbonate (1.28 g, 3.94 mmol) was added. The mixture was heated to 70°C and stirred for 16 hours. After the reaction mixture was cooled to room temperature, it was quenched with water (50 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 10:0 to 5:1) to obtain B-13-2. 1 H NMR (400MHz, CDCl3) δppm 7.51(dd,J=3.2,8.4Hz,1H),7.25–7.23(m,1H),7.04–7.00(m,1H),4.87(s,1H),4 .27(s,2H),2.30–2.04(m,4H),2.04–2.02(m,1H),1.93–1.88(m,1H),1.42(s,9H).

[0354] Step 2: Synthesis of B-13-3

[0355] B-13-2 (350.0 mg, 1.08 mmol) was dissolved in methanol (5 mL), and sodium borohydride (60.0 mg, 1.59 mmol) was added at 0°C. The mixture was reacted at 24°C for 1 hour. The reaction was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude B-13-3, which was used directly in the next reaction without purification. 1 H NMR (400 MHz, CDCl3) δ ppm 7.05–7.03 (m, 1H), 6.94–6.92 (m, 1H), 6.84 (dd, J = 4.4, 8.8 Hz, 1H), 4.89 (s, 1H), 4.67 (s, 2H), 4.14 (s, 2H), 2.32–2.23 (m, 4H), 1.91–1.89 (m, 1H), 1.86–1.84 (m, 1H), 1.43 (s, 9H). Step 2: Synthesis of B-13

[0356] B-13-3 (345.0 mg, 1.06 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of N,N'-diisopropylethylamine. The temperature was cooled to 0°C, and methylsulfonyl chloride (250.0 μL, 3.23 mmol) was added dropwise. The mixture was allowed to react at 24°C for 16 hours. Water (20 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude B-13. 1 H NMR (400MHz, CDCl3) δppm 7.09(dd,J=3.2,8.4Hz,1H),6.99–6.98(m,1H),6.97–6.87(m,1H),4.97(s,1H),4.61(s, 2H),4.16(s,2H),2.35–2.27(m,4H),1.92–1.89(m,1H),1.87–1.86(m,1H),1.42(s,9H).

[0357] Reference Example 14: Compound B-14

[0358] Step 1: Synthesis of B-14-2

[0359] B-4-1 (5.45 g, 32.05 mmol), B-14-1 (5.0 g, 26.7 mmol), and triphenylphosphine (10.51 g, 40.06 mmol) were added to dichloromethane (60 mL). The temperature was cooled to 0°C, and diisopropyl azodicarboxylate (8.64 g, 42.73 mmol) was added. The mixture was stirred at 20°C for 4 hours. Water (100 mL) was added to the reaction mixture to quench the mixture. The mixture was extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 10:1) to obtain B-14-2. 1 H NMR (400MHz, CDCl3) δppm 7.50(1H,J=3.2Hz,J=8.4Hz,dd),7.15–7.10(m,1H),6.74(1H,J=4.4Hz,J=8.4Hz,dd),4.88–4. 84(m,1H),4.43–4.39(m,1H),3.89(s,3H),2.95–2.94(m,2H),2.09–2.05(m,2H),1.33(s,9H).

[0360] Step 2: Synthesis of B-14-3

[0361] B-14-2 (2.0 g, 5.89 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium borohydride (0.3 g, 13.77 mmol) was added at 0°C. The reaction was allowed to react at 24°C for 30 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 4:1) to obtain B-14-3. LCMS: m / z = 334.2 [M+Na] + .

[0362] Step 3: Synthesis of B-14

[0363] B-14-3 (1.47 g, 4.72 mmol) was dissolved in dichloromethane (30 mL), and then N,N'-diisopropylethylamine (3.29 mL, 18.89 mmol) was added. After cooling to 0°C, methylsulfonyl chloride (763.5 μL, 9.86 mmol) was added dropwise. The reaction was allowed to react at 20°C for 16 hours. Water (50 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with dichloromethane (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 4:1) to obtain B-14. LCMS: m / z = 352.1 [M+Na] + .

[0364] Reference Example 14: Compound B-15

[0365] Step 1: Synthesis of B-15-1

[0366] B-6-2 (3.1 g, 21.97 mmol) and B-11 (6.02 g, 24.17 mmol) were dissolved in DMF (32 mL), and potassium carbonate (7.59 g, 54.93 mmol) was slowly added at 0°C, and the temperature was slowly raised to 20°C and stirred for 10 hours. Saturated brine (30 mL) was added to quench the reaction, and the pH was adjusted to about 3 with 2N hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL), and the aqueous phase was extracted with dichloromethane (20 mL*6). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (developing solvent PE:EA = 1:0 to 1:1) to obtain B-15-1. 1 H NMR (400MHz, CDCl3) δppm 10.39 (d, J = 3.1Hz, 1H), 8.19 (d, J = 3.3Hz, 1H), 7.84 (dd, J = 3.2, 7.4Hz, 1H), 5.04 (br s,1H),4.48(s,2H),1.46–1.36(m,9H),0.95(s,4H); LCMS: m / z=333.1[M+Na] + .

[0367] Step 2: Synthesis of B-15-2

[0368] Dissolve B-15-1 (2.77 g, 8.93 mmol) in tetrahydrofuran (30 mL) and add sodium borohydride (0.47 g, 12.5 mmol) under a nitrogen atmosphere at 0°C. The mixture was allowed to react at 0°C for 1 hour. Water (15 mL) was added to the reaction mixture at 0°C and stirred for 0.5 hours. After complete quenching, 2N hydrochloric acid was added to adjust the pH to 6-7. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined. The organic phases were washed sequentially with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude B-15-2, which was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3) δppm 7.86(d,J=2.9Hz,1H),7.34(brs,1H),5.09(brd,J=2.8Hz,1H),4.61(brs,2H),4.30(s,2H),1.43(s,9H),0.96-0.89(m,4H); LCMS: m / z=313.2[M+1] + .

[0369] Step 4: Synthesis of B-15

[0370] B-15-2 (2.5 g, 8.0 mmol) was dissolved in DCM (25 mL), followed by the addition of N,N-diisopropylethylamine (24.01 mmol, 4.18 mL). The reaction mixture was cooled to 0°C under a nitrogen atmosphere, and methanesulfonyl chloride (16.01 mmol, 1.24 mL) was slowly added dropwise. The temperature was slowly raised to 20°C, and the reaction was allowed to proceed for 12 hours. The solvent was evaporated under reduced pressure, and the crude product was isolated and purified by column chromatography (PE:EA = 9:1 to 1:1) to obtain B-15. 1 H NMR (400MHz, CDCl3) δppm 7.92 (d, J=2.9Hz, 1H), 7.49 (dd, J=2.9, 7.9Hz, 1H), 5.21-4.82 (m, 1H), 4.60 (s, 2H), 4.39 (br s, 2H), 1.44 (br s,9H),0.92(s,4H); LCMS: m / z=331.1[M+1] + .

[0371] Example 1

[0372] Step 1: Synthesis of Compound 001-1

[0373] B-1 (7.26 g, 31.4 mmol) and B-2 (7.65 g, 31.4 mmol) were dissolved in DMSO (140.0 mL), followed by the addition of KF (6.38 g, 109.89 mmol). The reaction mixture was allowed to react at 120°C for 3 hours. The reaction solution was washed with 300 mL of water and extracted with ethyl acetate (500 mL x 3). The resulting organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. 001-1 was isolated and purified by column chromatography (PE:EA = 1:0-1:1) to obtain 001-1. 1 H NMR (400MHz, CDCl3): δppm 8.36-8.30(m,1H),8.23(s,1H),7.17-7.14(m,2H),6.92-6.51(m,3H),4.97-4.86(m,1H),4.66-4.57(m,1H),4.33- 4.20(m,2H),4.10-4.03(m,1H),3.96-3.89(m,1H),3.81-3.70(m,5H),1.26(t,J=7.2Hz,3H); LCMS:m / z=439.1[M+1] + .

[0374] Step 2: Synthesis of Compound 001-2

[0375] Dissolve 001-1 (0.4 g, 0.91 mmol) in DMSO (16 mL), then add cesium carbonate (1.19 g, 3.64 mmol) and stir at 26°C for 1 hour. Wash with 50 mL of water and extract with ethyl acetate (100 mL x 3). The resulting organic phase is washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain the crude product. Purification by column chromatography (PE:EA = 1:0-1:1) affords 001-2. 1 H NMR (400MHz, CDCl3): δppm 8.31(s,1H),8.14(s,1H),7.36(d,J=8.4Hz,2H),6.88(d,J=8.4Hz,2H),6.16-6.08(m,1H),6.08-5.76(m,1H),4.55- 4.47(m,1H),4.41-4.32(m,2H),4.25-4.21(m,1H),3.86-3.72(m,5H),1.38(t,J=7.2Hz,3H); LCMS:m / z=419.0[M+H] + .

[0376] Step 3: Synthesis of Compound 001-3

[0377] 001-2 (0.448 g, 1.07 mmol) was dissolved in trifluoroacetic acid (8 mL) and stirred at 70°C for 7 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (PE:EA=1:0-1:2) to obtain the trifluoroacetic acid salt of 001-3. 1 H NMR (400MHz, CDCl3): δppm8.30-8.24(m,1H),8.17(s,1H),6.09-5.71(m,1H),4.51(dd,J=2.0Hz,J=12.0Hz,1 H),4.34(q,J=7.2Hz,2H),4.26-4.19(m,1H),4.06-3.96(m,1H),1.38(t,J=7.2Hz,3H); LCMS:m / z=299.0[M+H] + .

[0378] Step 4: Synthesis of Compound 001-4

[0379] 001-3 (0.11 g, 0.37 mmol) and B-4 (0.15 g, 0.44 mmol) were dissolved in DMF (3 mL), and cesium carbonate (0.36 g, 1.11 mmol) was added. The mixture was stirred at 26°C for 3 hours. The mixture was washed with 15 mL of water and extracted with ethyl acetate (50 mL*3). The resulting organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. 001-4 was isolated and purified by column chromatography (PE:EA=3:1). LCMS: m / z=594.2 [M+H] + .

[0380] Step 5: Synthesis of Compound 001-5

[0381] Dissolve 001-4 (0.05 g, 84.23 μmol) in tetrahydrofuran (2 mL), ethanol (4 mL), and methanol (2 mL). Then, add lithium hydroxide (2 M, 4.0 mL) and stir at 30°C for 20 hours. The reaction mixture is cooled to -20°C and quenched by the addition of 4.2 mL of 2 M hydrochloric acid solution. Then, dilute with 20 mL of water. Extract with dichloromethane (20 mL x 3). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure. The crude product 001-5 is directly used in the next step without purification. LCMS: m / z = 588.2 [M+Na] + .

[0382] Step 6: Synthesis of Compound 001-6

[0383] Dissolve crude 001-5 (0.045 g) in dichloromethane (4 mL), then add a hydrochloric acid / 1,4-dioxane solution (4 M, 6.85 mL) and stir at 20°C for 1 hour. The reaction mixture is concentrated under reduced pressure to afford the hydrochloride salt of 001-6, which is then used directly in the next step. LCMS: m / z = 466.1 [M+H] + .

[0384] Step 7: Synthesis of Compound 001-7

[0385] 001-6 (38 mg, crude hydrochloride) was dissolved in dichloromethane (4 mL), followed by the addition of N,N-diisopropylethylamine (731.5 μmol, 127.4 μL) and pentafluorophenyl diphenyl phosphate (42.6 mg, 111.0 μmol). The mixture was stirred at 20°C for 3 hours. 10 mL of 2M sodium carbonate solution was added to the reaction solution, which was then extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (mobile phase: DCM:MeOH = 10:1) to obtain 001-7. 1 H NMR (400MHz, CDCl3): δppm9.29–9.24(m,1H),8.26–8.24(m,1H),8.14–8.11(m ,1H),7.03–6.95(m,2H),6.90–6.84(m,1H),6.21–5.93(m,1H),5.92–5.87(m, 1H),4.79–4.67(m,1H),4.40–4.26(m,2H),4.26–4.20(m,1H),4.03–3.96(m,1 H),3.92–3.87(m,1H),1.81–1.76(m,3H),1.62(s,3H); LCMS: m / z=448.1[M+H] + .

[0386] Step 8: Synthesis of Compound 001-8

[0387] 001-7 (0.5 g, 1.12 mmol) was dissolved in 1,2-dimethylbenzene (20 mL), and then Lawesson's reagent (1.81 g, 4.47 mmol) was added and stirred at 140°C for 5 hours. 50 mL of water was added to the reaction solution and extracted with ethyl acetate (60 mL*3). The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was then separated and purified by column chromatography (DCM:MeOH=20:1) to obtain 001-8, LCMS: m / z=464.1[M+H] + .

[0388] Step 9: Synthesis of Compound 001

[0389] 001-8 (0.05 g, 107.9 μmol) was dissolved in DMF (5 mL), followed by the addition of methoxyamine hydrochloride (144.2 mg, 1.73 mmol), mercuric oxide (187.0 mg, 863.05 μmol), and triethylamine (1.51 mmol, 210.22 μL). Stir at 60°C for 3 hours. Dilute the reaction solution with 10 mL of dichloromethane and filter. The filtrate was washed with 10% sodium bicarbonate, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (DCM:MeOH = 20:1) to obtain 001. 1 H NMR (400 MHz, CDCl3): δ ppm 8.52(s,1H),8.08(s,1H),7.08(s,1H),7.02-6.99(m,1H),6.98-6.94(m,1H ),6.89-6.80(m,1H),6.18-6.00(m,1H),5.99-5.96(d,J=12Hz,1H),4.69-4. 66(d,J=12Hz,1H),4.37-4.28(m,1H),4.25-4.19(m,1H),4.17-4.13(d,J=16 Hz,1H),3.99-3.98(m,2H),3.82(s,3H),1.66(s,6H); LCMS:m / z=477.1[M+H] + .

[0390] Example 2

[0391] 001-8 (50 mg, 107.88 μmol) was dissolved in DMF (8 mL), followed by the addition of ethoxylated amine hydrochloride (168.37 mg, 1.73 mmol), mercuric oxide (220 mg, 1.02 mmol), and triethylamine (210.22 μL, 1.51 mmol). The mixture was heated to 60°C and stirred for 3 hours. The reaction mixture was diluted with 40 mL of DCM and filtered. The filtrate was washed with 10% sodium bicarbonate (40 mL) and extracted with DCM (100 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (DCM:MeOH = 20:1) to obtain 002. 1H NMR (400MHz, CDCl3): δppm 8.57(s,1H),8.08(s,1H),7.09(s,1H),6.92-7.03(m,2H),6.85(dd,J=8.76,4.50Hz,1H),5.86-6.18(m,2H),4.67(br d,J=11.63Hz,1H),3.68-4.44(m,6H),1.65(s,7H),1.28-1.35(m,3H); LCMS:m / z=491.0[M+H] + .

[0392] Example 3

[0393] 001-8 (50 mg, 107.88 μmol) and B-5 (137.62 mg, 1.08 mmol) were dissolved in DMF (5 mL). Mercuric oxide (0.4 g, 1.85 mmol) and triethylamine (1.51 mmol, 210.22 μL) were then added sequentially. The mixture was heated to 60°C and stirred for 3 hours under a nitrogen atmosphere. The reaction solution was diluted with 40 mL of dichloromethane and filtered. The filtrate was washed with 10% sodium bicarbonate (40 mL) and extracted with dichloromethane (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (DCM:MeOH = 20:1) to obtain 003. 1 H NMR (400MHz, CDCl3): δppm 8.61 (s, 1H), 8.08 (s, 1H), 7.15 (s, 1H), 6.92-7.05 (m, 2H), 6.85 (dd, J=8.78, 4.52Hz, 1 H),5.84-6.19(m,2H),4.67(d,J=11.80Hz,1H),4.28-4.39(m,1H),4.09-4.25(m,4H), 3.86-4.00(m,2H),3.66-3.80(m,2H),3.41(s,3H),1.64(s,6H); LCMS: m / z=521.1[M+H] + .

[0394] Example 4

[0395] Step 1: Synthesis of Compound 004-1

[0396] B-6 (569.08 mg, 1.71 mmol) and 001-3 (510 mg, 1.71 mmol) were dissolved in DMF (25 mL), followed by the addition of cesium carbonate (2.23 g, 6.84 mmol) and stirring at 5°C for 4 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (100 mL x 2). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by thin-layer chromatography (PE:EA = 2:1) to obtain 004-1. 1 H NMR (400MHz, CDCl3): δppm 8.37 (br d,J=6.00Hz,1H),8.28(d,J=2.25Hz,1H),8.09(d,J=1.50Hz,1H),7.90(dd,J=2.94,1.56Hz,1H),5.78-6.25( m,1H),5.51(d,J=14.51Hz,1H),4.47-4.60(m,4H),4.38-4.46(m,2H),4.12(qd,J=7.13,1.75Hz,1H),3.94(br d, J=11.76Hz, 1H), 1.40 (s, 15H), 1.26 (td, J=7.13, 1.63Hz, 3H); LCMS: m / z=495.1[M+H-100] + .

[0397] Step 2: Synthesis of Compound 004-2

[0398] Dissolve 004-1 (0.8 g, 1.345 mmol) in tetrahydrofuran (30 mL), ethanol (60 mL), and methanol (30 mL). Then, add lithium hydroxide (2 M, 67.3 mL) and stir at 30°C for 20 hours. Cool the reaction mixture to -20°C, add 70.0 mL of 2 M hydrochloric acid solution, and dilute with 200 mL of water. Extract with dichloromethane (200 mL x 3). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure. The resulting crude product 004-2 is directly used in the next step without purification. LCMS: m / z = 489.2 [M+Na-100] + .

[0399] Step 3: Synthesis of Compound 004-3

[0400] Dissolve 004-2 (0.8 g, 1.41 mmol) in DCM (10 mL), then add a solution of hydrochloric acid in 1,4-dioxane (4 M, 10 mL) and stir at 25°C for 1 hour. The resulting reaction solution was concentrated under reduced pressure, and the residue was dissolved in EA (10 mL) and concentrated. Ethyl acetate (10 mL) was then added and dissolved, followed by concentration to afford crude 004-3, which was used directly in the next reaction. LCMS: m / z = 467.1 [M+H] + .

[0401] Step 4: Synthesis of Compound 004-4

[0402] 004-3 was dissolved in DCM (50 mL), followed by the addition of N,N-diisopropylethylamine (11.79 mmol, 2.05 mL) and pentafluorophenyl diphenyl phosphate (679.65 mg, 1.77 mmol). The mixture was stirred at 25°C for 2 hours. Water (20 mL) was added to the reaction solution, which was then extracted with DCM (200 mL x 2). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by thin-layer chromatography (DCM:MeOH = 10:1) to obtain 004-4. 1 H NMR (400MHz, CDCl3): δppm 9.09(s,1H),8.22-8.36(m,1H),8.16(s,1H),8.00(d,J=2.88Hz,1H),7.35(dd,J=7.94 ,2.69Hz,1H),5.83-6.24(m,1H),5.72(dd,J=15.38,1.50Hz,1H),4.83(d,J=10.76Hz,1 H),4.74(d,J=12.38Hz,1H),4.21-4.42(m,3H),3.90(d,J=10.63Hz,1H),1.77(s,3H),1.63(s,3H); LCMS: m / z=449.0[M+H] + .

[0403] Step 5: Synthesis of Compound 004

[0404] 004-4 (0.09 g, 200.71 μmol) and Lawesson's reagent (324.73 mg, 802.86 μmol) were dissolved in 1,2-dimethylbenzene (8 mL) and heated to 140°C under a nitrogen atmosphere for 5 hours. After the reaction solution cooled to room temperature, 50 mL of water was added to the reaction solution, and the mixture was extracted with EA (60 mL*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by thin-layer chromatography (DCM:MeOH = 1:0-20:1) to obtain 004. 1H NMR (400MHz, CDCl3): δppm 10.37(brs,1H),8.54(s,1H),8.13(s,1H),8.02(d,J=3.01Hz,1H),7.41(dd,J=7.91,3.14Hz,1H),6.03-6.19(m,1H),5.69–5 .79(m,1H),4.66–4.81(m,2H),4.17–4.35(m,3H),3.96(d,J=11.04Hz,1H),2.03(s,3H),1.82(s,3H); LCMS:m / z=465.1[M+H] + .

[0405] Example 5

[0406] 004 (90 mg, 193.77 μmol), methoxyamine hydrochloride (258.93 mg, 3.10 mmol), mercuric oxide (0.36 g, 1.66 mmol), and triethylamine (2.71 mmol, 377.59 μL) were dissolved in DMF (8 mL) and stirred at 60°C for 3 hours. The reaction mixture was filtered, and the filtrate was purified by thin-layer chromatography (DCM:MeOH = 20:1) to obtain 005. The filter cake was post-processed by soaking the filter cake in hydrochloric acid (1 M, 50 mL) overnight. The pH was then adjusted to 10 with sodium hydroxide (2 M). Solid sodium sulfide (1 g) was added to form a precipitate. Ferrous sulfate (1 g) was then added as a coprecipitant. The mixture was allowed to stand, then filtered and the filter cake discarded. The filtrate was adjusted to a pH of approximately 7 with hydrochloric acid (1 M) and discarded. 1 H NMR (400MHz, CDCl3): δppm 8.54(s,1H),8.11(s,1H),7.97(d,J=2.89Hz,1H),7.34(dd,J=7.91,2.89Hz,1H),5.86-6.19(m,1H),5.80(dd,J=15.31,1.25H z,1H),4.81(d,J=10.29Hz,1H),4.68(m,1H),4.16-4.32(m,3H),3.87(m,1H),3.83(s,3H),1.67(s,6H); LCMS: m / z=478.1[M+H] + .

[0407] Example 6

[0408] Step 1: Synthesis of Compound 006-1

[0409] B-7 (0.5 g, 1.94 mmol) and B-1 (448.75 mg, 1.94 mmol) were dissolved in DMSO (10 mL), followed by the addition of KF (281.88 mg, 4.85 mmol). The mixture was stirred at 120°C under a nitrogen atmosphere for 5 hours. The reaction mixture was poured into 100 mL of ice water to quench the mixture, resulting in the precipitation of a solid. The resulting solid was filtered, dissolved in dichloromethane (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude product. The crude product was isolated and purified by column chromatography (PE:EA = 1:0 to 1:1) to afford 006-1. 1 H NMR (400MHz, CDCl3) δppm 8.33(d,J=7.8Hz,1H),7.25(s,2H),6.95-6.89(m,2H),6.87-6.67(m,1H),4.96(d,J=16.5Hz,1H),4.70(dd,J=1.9,16.5Hz,1H),4.38(qtd,J =7.1,10.8,17.8Hz,3H),4.16-4.10(m,1H),4.06-3.99(m,1H),3.88-3.75(m,4H),2.61(s,3H),1.39(t,J=7.1Hz,3H); LCMS: m / z=453.1[M+H] + .

[0410] Step 2: Synthesis of Compound 006-2

[0411] Dissolve 006-1 (700 mg, 1.55 mmol) in DMF (49 mL). After replacing the nitrogen atmosphere, add cesium carbonate (1.51 g, 4.64 mmol) and stir at 50°C for 12 hours. After cooling the reaction mixture to room temperature, add 10 mL of water to quench the reaction. Extract with EA (20 mL x 4). The resulting organic phase is washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is separated and purified by thin-layer chromatography (PE:EA = 1:1) to obtain 006-2. 1 H NMR (400MHz, CDCl3) δppm 8.04(s,1H),7.36(d,J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),6.09(d,J=14.8Hz,1H),5.97-5.75(m,1H),4.48(m,1H), 4.43-4.29(m,2H),4.28-4.17(m,1H),3.84-3.69(m,5H),2.62(s,3H),1.38(t,J=7.1Hz,3H); LCMS:m / z=433.1[M+H] + .

[0412] Step 3: Synthesis of Compound 006-3

[0413] 006-2 (440 mg, 1.02 mmol) was dissolved in trifluoroacetic acid (1 mL) and heated to 70°C under a nitrogen atmosphere, stirring for 12 hours. After the reaction solution cooled to room temperature, 50 mL of water was added to quench the reaction. The mixture was extracted with EA (20 mL*4). The resulting organic phase was washed sequentially with saturated sodium bicarbonate (20 mL*3) and saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 006-3, which was used directly in the next reaction. LCMS: m / z = 313.1 [M+H] + .

[0414] Step 4: Synthesis of Compound 006-4

[0415] 006-3 (320 mg, 1.02 mmol), B-4 (340.02 mg, 1.02 mmol), and cesium carbonate (1.00 g, 3.07 mmol) were dissolved in DMF (1 mL) and reacted at 25°C under a nitrogen atmosphere for 3 hours. The reaction was quenched with 10 mL of water and extracted with EA (20 mL x 4). The EA phase was washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by column chromatography (PE:EA = 1:0 to 1:1) to obtain 006-4. 1 H NMR (400MHz, CDCl3) δppm 8.01 (s, 1H), 7.63 (br d,J=7.1Hz,1H),6.99-6.92(m,1H),6.86(dd,J=4.3,8.9Hz,1H),6.12-5.77(m,2H),4. 58-4.46(m,2H),4.45-4.35(m,3H),4.28-4.22(m,1H),4.20(d,J=8.8Hz,1H),3.95(br d,J=8.8Hz,1H),3.84(br d,J=11.4Hz,1H),2.62(s,3H),1.42-1.35(m,18H); LCMS:m / z=608.5[M+H] + .

[0416] Step 5: Synthesis of Compound 006-5

[0417] 006-4 (170 mg, 279.78 μmol) was dissolved in THF (2 mL), EtOH (4 mL), and MeOH (2 mL). Lithium hydroxide monohydrate (2 M, 4 mL) and sodium hydroxide (22.38 mg, 559.56 μmol) were then added and reacted at 25°C under a nitrogen atmosphere for 144 hours. The reaction solution was cooled to -20°C and the pH was adjusted to approximately 3 by adding 2 M hydrochloric acid. The solution was extracted with DCM (20 mL x 4). The resulting 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 the crude product. The crude product was separated and purified by thin-layer chromatography (PE:EA = 1:1) to obtain 006-5. LCMS: m / z = 580.5 [M+H] + .

[0418] Step 6: Synthesis of Compound 006-6

[0419] 006-5 (100 mg, 172.54 μmol) was dissolved in trifluoroacetic acid (0.5 mL) and reacted at 25°C under nitrogen atmosphere for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain crude 006-6. LCMS: m / z = 480.4 [M+H] + .

[0420] Step 7: Synthesis of Compound 006

[0421] 006-6 (83 mg, 173.11 μmol) and pentafluorophenyl diphenyl phosphate (99.78 mg, 259.67 μmol) were dissolved in DCM (2 mL). N,N-diisopropylethylamine (1.73 mmol, 301.53 μL) was added under a nitrogen atmosphere and allowed to react at 25°C for 12 hours. The reaction was quenched with 10 mL of water and extracted with DCM (20 mL*3). The DCM phase was washed sequentially with saturated sodium carbonate (20 mL*3) and saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by thin-layer chromatography (DCM:MeOH=20:1) and then purified by prep-HPLC (chromatographic column: Waters Xbridge BEH C18 100*30mm*10μm, mobile phase: phase A: water (10mM ammonium bicarbonate), phase B: acetonitrile; gradient: phase B ratio increased from 10% to 70% in the first 4.0 minutes, maintained for 1.0 minute, and then decreased to 10% and maintained for 3.0 minutes) to obtain 006. 1H NMR (400MHz, CDCl3) δppm 9.25(s,1H),8.05(s,1H),7.02-6.95(m,2H),6.89-6.82(m,1H),6.18-5.87(m,2H),4.70(m,1H),4.39-4.31(m,1H),4.3 0-4.25(m,1H),4.21(d,J=15.3Hz,1H),3.99-3.89(m,2H),2.64(s,3H),1.80(s,3H),1.63(s,3H); LCMS:m / z=462.2[M+H] + .

[0422] Example 7

[0423] Step 1: Synthesis of Compound 007-2

[0424] 007-1 (3 g, 19.54 mmol), 2-chloro-tetrahydro-2H-pyran (7.14 mL, 78.14 mmol), and 4-methylbenzenesulfonate pyridinium (294.55 mg, 1.17 mmol) were dissolved in 30 mL of toluene. After purging with nitrogen, the reaction was heated at 100°C for 12 hours. The solvent was removed by concentration under reduced pressure, followed by addition of 10 mL of saturated sodium bicarbonate solution and extraction with 15 mL of dichloromethane. After separation, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed sequentially with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 0:1) to obtain 007-2. 1 H NMR (400MHz, CDCl3) δppm 8.28(s,1H),8.02(d,J=8.4Hz,1H),7.28(s,1H),5.85(dd,J=2.2,10.6Hz,1H),4.18(td,J=2.0 ,11.7Hz,1H),3.90-3.74(m,1H),2.21-1.96(m,2H),1.91-1.60(m,4H); LCMS:m / z=238.1[M+H] + .

[0425] Step 2: Synthesis of Compound 007-3

[0426] 007-2 (600 mg, 2.52 mmol) and B-8 (682.64 mg, 3.03 mmol) were dissolved in 10 mL of 1,4-dioxane. After purging with nitrogen, sodium tert-butoxide (485.18 mg, 5.05 mmol), palladium acetate (28.34 mg, 126.22 μmol), and BRETTPHOS (135.50 mg, 252.43 μmol) were added sequentially. The mixture was heated at 80°C for 12 hours. The reaction solution was cooled to room temperature and quenched with 30 mL of water. The solution was extracted with 20 mL of dichloromethane. After separation, the organic phase was collected and the aqueous phase was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA=1:0 to 1:1) to obtain 007-3. 1 H NMR (400MHz, CDCl3) δppm 8.03 (d, J = 2.3Hz, 1H), 7.82 (dd, J = 1.2, 8.6Hz, 1H), 6.46 (dd, J = 2.3, 8.6Hz, 1H), 6.27-5.90 (m, 1H), 5.77-5.62 (m, 1H), 4.89 (br d,J=8.2Hz,1H),4.66-4.43(m,1H),4.22-4.14(m,1H),4.00(td,J=1.8,10.1Hz,1H),3.86-3.73(m,2 H),2.11-2.07(m,2H),1.86-1.75(m,4H),0.93(s,9H),0.11(d,J=7.2Hz,6H); LCMS:m / z=427.2[M+H] + .

[0427] Step 3: Synthesis of Compound 007-4

[0428] 007-3 (490 mg, 1.15 mmol) and sodium acetate (612.50 mg, 7.47 mmol) were dissolved in acetic acid (12.5 mL). The mixture was cooled to 0°C under a nitrogen atmosphere, and pyridinium tribromide (551.06 mg, 1.72 mmol) was added. The mixture was allowed to react at 25°C for 2 hours. The reaction mixture was quenched with 10 mL of saturated sodium thiosulfate (potassium iodide paper did not turn blue), and 10 mL of water was added, stirred for 10 minutes, and extracted with 20 mL of dichloromethane. After separation, the organic phase was collected and the aqueous phase was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product 007-4, which was used directly in the next step without purification. LCMS: m / z = 505.1 [M+H] + .

[0429] Step 4: Synthesis of Compound 007-5

[0430] 007-4 (640 mg, 1.27 mmol) and TBAF (1 M, 1.45 mL) were dissolved in 10 mL of THF and reacted at 25°C under a nitrogen atmosphere for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase: PE:EA = 1:0 to 0:1) to obtain 007-5. 1 H NMR (400MHz, CDCl3) δppm 8.10 (s, 1H), 8.00 (d, J = 4.2Hz, 1H), 6.31-5.96 (m, 1H), 5.69 (br d,J=7.3Hz,1H),5.64-5.54(m,1H),4.69-4.51(m,1H),4.19-4.07(m,2H),4.02-3. 93(m,1H),3.82-3.70(m,1H),3.39(t,J=7.1Hz,1H),2.38(t,J=8.2Hz,1H),2.09(br dd,J=2.8,6.4Hz,3H),2.06-1.98(m,2H).

[0431] Step 5: Synthesis of Compound 007-6

[0432] 007-5 (100 mg, 255.62 μmol) and cesium carbonate (108.27 mg, 332.30 μmol) were dissolved in 2.5 mL of 1,4-dioxane. 2-(Di-tert-butylphosphino)-1,1'-binaphthyl (20.37 mg, 51.12 μmol) and tris(dibenzylideneacetone)dipalladium (23.41 mg, 25.56 μmol) were added sequentially under a nitrogen atmosphere. The temperature was slowly raised to 88°C and the reaction was allowed to proceed for 15 hours. 2-(Di-tert-butylphosphino)-1,1'-binaphthyl (20.37 mg, 51.12 μmol) and tris(dibenzylideneacetone)dipalladium (23.41 mg, 25.56 μmol) were then added, and the reaction was continued at 116°C for 16 hours. The reaction solution was purified by preparative thin-layer chromatography (EA:PE = 2:1) to obtain 007-6. 1 H NMR (400MHz, CDCl3) δppm 7.97 (s, 1H), 7.52-7.29 (m, 1H), 6.04-5.67 (m, 1H), 5.62 (br dd, J = 2.6, 10.3Hz, 1H), 5.20 (br s, 1H), 4.39 (br d,J=11.1Hz,1H),4.22-4.06(m,2H),3.89-3.68(m,2H),2.19-2.07(m,2H),1.90-1.62(m,4H); LCMS:m / z=311.1[M+H]+ .

[0433] Step 6: Synthesis of Compound 007-7

[0434] 007-6 (40 mg, 128.91 μmol), B-4 (85.55 mg, 257.82 μmol), cesium carbonate (126.00 mg, 386.72 μmol) and tetra-n-butylammonium iodide (12.38 mg, 33.52 μmol) were dissolved in 0.8 mL of DMF and heated at 40°C under a nitrogen atmosphere for 16 hours. The reaction solution was quenched with 5 mL of water, extracted with dichloromethane (1 mL*3), and the organic phase was separated to obtain a crude product. The crude product was purified by preparative thin-layer chromatography (EA:PE=10:1) to obtain 007-7. 1 H NMR (400MHz, CDCl3) δppm 7.96(s,1H),7.45(s,1H),7.26-7.18(m,1H),6.97-6.74(m,2H),6.09-5.74(m,1H) ,5.73-5.60(m,2H),4.56-4.38(m,2H),4.24-4.08(m,2H),4.04-3.89(m,2H),3.87- 3.68(m,2H),2.10(br s,2H),1.82-1.58(m,4H),1.45-1.39(m,9H),1.36-1.29(m,6H); LCMS: m / z=606.3[M+H] + .

[0435] Step 7: Synthesis of Compound 007-8

[0436] 007-7 (30 mg, 49.53 μmol) was dissolved in 1.5 mL of dichloromethane, and trifluoroacetic acid (0.5 mL, 6.75 mmol) was added. The mixture was reacted at 25°C for 2 hours. The solvent and trifluoroacetic acid were removed by concentration under reduced pressure to obtain the crude trifluoroacetate salt of 007-8, which was used directly in the next step without purification. 1 H NMR (400MHz, DMSO-d6) δppm 7.95 (s, 1H), 7.38 (s, 1H), 7.04-6.92 (m, 2H), 6.89 (dd, J = 2.7, 9.3Hz, 1H), 6.48-6.08 (m, 1H), 5.25 (br d,J=16.9Hz,1H),4.66(br d,J=16.9Hz,1H),4.49(br d,J=11.5Hz,1H),4.11-3.99(m,2H),3.75-3.66(m,2H),1.15-1.10(m,6H); LCMS:m / z=422.2[M+H] + .

[0437] Step 8: Synthesis of Compound 007

[0438] Dissolve 007-8 (35.36 mg, crude trifluoroacetate) in 2.1 mL of dichloromethane. Add a solution of N,N'-carbonyldiimidazole (25.60 mg, 157.86 μmol) in dichloromethane (0.7 mL) dropwise at 0°C. After thorough stirring, add N,N'-diisopropylethylamine (0.2 mL, 1.15 mmol). Slowly warm the mixture to 25°C and allow to react for 12 hours. Add 5 mL of 10% aqueous citric acid solution to the reaction mixture, adjusting the pH to 6. Extract with dichloromethane (1 mL x 2). Separate the organic phase, concentrate under reduced pressure, and purify by preparative thin-layer chromatography (PE:EA = 1:1). The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: phase A water (10 mM ammonium bicarbonate), phase B acetonitrile; gradient: phase B increased from 10% to 80% in the first 4 minutes, maintained for 2.0 minutes, and then gradually decreased to 10% in the next 2 minutes) to obtain 007. 1 H NMR (400MHz, CDCl3) δppm10.30(br s,1H),8.38(s,1H),7.48(s,1H),7.07-6.92(m,2H),6.83(dd,J=4.4,9.1Hz,1H),6.10-5.80(m,1H),5.76(br d,J=15.5Hz,1H),4.68(br d,J=11.6Hz,1H),4.35-4.16(m,3H),4.07(d,J=8.9Hz,1H),3.93(d,J=8.9Hz,1H),1.77(s,3H),1.67(s,3H); LCMS: m / z=448.1[M+H] + .

[0439] Example 8

[0440] 007-8 (150 mg, 0.33 mmol) was dissolved in dichloromethane (7.5 mL), cooled to 0°C, and then N,N'-thiocarbonyldiimidazole (116.8 mg, 0.66 mmol) was added under a nitrogen atmosphere. The temperature was then slowly raised to 24°C and stirred for 12 hours. 10 mL of 10% aqueous citric acid was slowly poured into the reaction mixture to adjust the pH to 6. Extraction was performed with dichloromethane (10 mL x 2). The organic phase was concentrated under reduced pressure and purified by preparative thin-layer chromatography (PE:EA = 0:1). The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 50 x 2.1 mm x 5 μm; mobile phase: 10 mM aqueous ammonium bicarbonate in phase A, acetonitrile in phase B; gradient: 10% to 80% B in the first 4 minutes, held for 0.9 minutes, then gradually reduced to 10% in the final 0.6 minutes) to afford 008. 1 H NMR (400MHz, CDCl3) δppm 11.67(s,1H),8.91(s,1H),7.46(s,1H),7.09(dd,J=2.8,8.8Hz,1H),6.99(d,J=2.8Hz,1H),6.92(dd,J=4.4,8.8Hz,1H),5.96-5.79(m,2H),4. 67-4.64(m,1H),4.24-4.20(m,1H),4.18-4.17(m,1H),4.05-4.02(m,1 H),3.95–3.92(m,2H),1.98(s,3H),1.84(s,3H); LCMS: m / z=464.3[M+H] + .

[0441] Example 9

[0442] Step 1: Synthesis of Compound 009-2

[0443] 009-1 (5.0 g, 32.23 mmol) was dissolved in ethyl acetate (50 mL), followed by the addition of potassium carbonate (0.23 g, 1.61 mmol). The mixture was cooled to -5°C under a nitrogen atmosphere, and N-bromosuccinimide (7.17 g, 40.28 mmol) was added. The temperature was then gradually raised to 20°C and stirred for 2 hours. The reaction solution was washed with 50 mL of saturated sodium sulfite solution and extracted with ethyl acetate (2*50 mL). The organic phases were combined, washed sequentially with saturated brine (2*50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 1:1) to obtain 009-2. 1H NMR (400MHz, DMSO-d6) δppm 1.26 (t, J = 7.03Hz, 3H), 4.18 (q, J = 7.11Hz, 2H), 6.26 (s, 2H), 12.15 (s, 1H); LCMS: m / z = 233.7, 235.7 [M+H] + .

[0444] Step 2: Synthesis of Compound 009-3

[0445] Dissolve 009-2 (86.0 g, 367.4 mmol), diethyl 2-fluoromalonate (98.2 g, 551.2 mmol), and sodium ethoxide (62.5 g, 918.6 mmol) in ethanol (1000 mL), heat to 78°C, and stir for 6 hours. After cooling to room temperature, concentrate under reduced pressure to remove ethanol. Add 1 M hydrochloric acid solution dropwise to adjust the pH to approximately 3. Stir at 25°C for 1 hour, filter, and dry the resulting filter cake in a vacuum oven. 1 H NMR (400MHz, DMSO-d6) δppm 1.27 (t, J = 7.03Hz, 3H), 4.25 (q, J = 7.11Hz, 2H), 7.84 (s, 1H), 9.63 (br s, 1H); LCMS: m / z = 319.7, 321.7 [M+H] + .

[0446] Step 3: Synthesis of Compound 009-4

[0447] Dissolve 009-3 (43.0 g, 134.3 mmol) in phosphorus oxychloride (454.8 mL, 4.89 mol). Add N,N-diisopropylamine (32.2 mL, 201.5 mmol) dropwise at 0°C. Gradually raise the temperature to 100°C and stir for 3 hours. After the reaction solution cools to room temperature, the phosphorus oxychloride is mostly recovered by distillation under reduced pressure. The resulting solution is slowly added to water (450 mL) to quench the precipitated solid. The solid is filtered and the filter cake is washed with water (3 x 50 mL). The filtrate is neutralized and discarded. The resulting filter cake is redissolved in methyl tert-butyl ether (200 mL), stirred at 25°C for 0.5 hour, and filtered to obtain 009-4. LCMS: m / z = 377.7, 379.7 [M+Na] + .

[0448] Step 4: Synthesis of Compound 009-5

[0449] 009-4 (1.9 g, 5.32 mmol) was dissolved in ethanol (45 mL), tetrahydrofuran (45 mL), and water (30 mL). Ammonium chloride (1.54 g, 28.77 mmol) was then added. Zinc powder (1.39 g, 21.21 mmol) was added portionwise at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. The reaction mixture was filtered, and the filtrate was extracted with dichloromethane (2 x 30 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain the crude product, which was then isolated and purified by column chromatography (mobile phase: PE:EA = 1:0 to 3:1) to obtain 009-5. LCMS: m / z = 321.9 [M+H] + .

[0450] Step 5: Synthesis of Compound 009-6

[0451] 009-5 (5.0 g, 15.5 mmol), B-1 (3.58 g, 15.5 mmol), and potassium fluoride (3.15 g, 54.26 mmol) were dissolved in dimethyl sulfoxide (50 mL), heated to 120°C, and stirred for 1 hour. The reaction solution was washed with 50 mL of water and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed sequentially with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 3:1) to obtain 009-6. LCMS: m / z = 517.1 [M+H] + .

[0452] Step 6: Synthesis of Compound 009-7

[0453] 009-6 (1.4 g, 2.71 mmol) was dissolved in DMF (15 mL). After nitrogen was replaced, cesium carbonate (2.65 g, 8.13 mmol) was added and stirred at 24°C for 2 hours. The reaction was quenched by adding 10 mL of water and extracted with EA (20 mL x 2). The resulting organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by thin-layer chromatography (PE:EA = 1:1) to obtain 009-7. LCMS: m / z = 497.1 [M+H] + .

[0454] Step 7: Synthesis of Compound 009-8

[0455] 009-7 (1.1 g, 2.2 mmol) was dissolved in trifluoroacetic acid (2 mL) and heated to 70°C under a nitrogen atmosphere, with stirring for 12 hours. After the reaction mixture cooled to room temperature, 50 mL of water was added to quench the reaction. The mixture was extracted with EA (20 mL*3). The resulting organic phase was washed sequentially with saturated sodium bicarbonate (20 mL*3) and saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 009-8. LCMS: m / z = 377.1 [M+H] + .

[0456] Step 8: Synthesis of Compound 009-9

[0457] 009-8 (0.9 g, 2.4 mmol) and B-4 (1.2 g, 3.7 mmol) were dissolved in N,N-dimethylformamide (9 mL), followed by the addition of cesium carbonate (2.3 g, 7.2 mmol) and stirring at 24°C for 1.5 hours. The reaction was quenched by the addition of 20 mL of water and extracted with EA (40 mL x 2). The resulting organic phase was washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 2:1) to obtain 009-9. LCMS: m / z = 694.2, 696.2 [M+Na] + .

[0458] Step 9: Synthesis of Compound 009-10

[0459] 009-9 (0.5 g, 0.74 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (5 mL), and ethanol (10 mL), followed by the addition of lithium hydroxide monohydrate (2.5 g, 59.48 mmol) and stirring at 24°C for 72 hours. The pH was adjusted to 7-8 with 2M hydrochloric acid, and the mixture was extracted with dichloromethane (40 mL x 2). The mixture was washed sequentially with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 009-10.

[0460] Step 10: Synthesis of Compound 009-11

[0461] Dissolve 009-10 (0.1 g, 155.2 μmol) in ethyl acetate (1.0 mL). After nitrogen displacement, add hydrochloric acid / ethyl acetate solution (4 M, 0.5 mL) and react at 20°C for 1 hour. The resulting reaction solution is concentrated under reduced pressure to obtain the crude hydrochloride salt of 009-11. LCMS: m / z = 544.0 [M+H] + .

[0462] Step 11: Synthesis of Compound 009

[0463] 009-11 (42 mg, crude hydrochloride) was dissolved in DCM (0.8 mL). After nitrogen purging, pentafluorophenyl diphenyl phosphate (44.47 mg, 115.74 μmol) and N,N-diisopropylethylamine (149.58 mg, 1.16 mmol) were added and stirred at 24°C for 12 hours. The reaction was quenched by adding 10 mL of water and extracted with dichloromethane (20 mL*3). The organic phases were combined, washed sequentially with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel (dichloromethane:methanol = 20:1) and then by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm, mobile phase: [phase A: water (10 mM ammonium bicarbonate); phase B: acetonitrile], gradient: phase B increased from 10% to 80% in the first 3 minutes, held for 0.9 minutes, and then gradually decreased from 80% to 10% in the final 0.6 minutes) to obtain 009. 1 H NMR (400MHz, CDCl3) δppm 9.15(s,1H),8.04(s,1H),7.05-6.94(m,2H),6.86(dd,J=4.5,8.9Hz,1H),6.20-5.86(m,2H),4.73(d,J=12.0Hz,1H),4.43- 4.34(m,1H),4.32-4.26(m,1H),4.24(d,J=15.1Hz,1H),4.00-3.87(m,2H),1.80(s,3H),1.62(s,3H); LCMS: m / z=526.1[M+H] + .

[0464] Example 10

[0465] 009 (40 mg, 76.0 μmol) was dissolved in N,N-dimethylformamide (4.0 mL). After nitrogen was purged, cuprous cyanide (34.03 mg, 380.01 μmol) was added and stirred at 125°C for 16 hours. The reaction was quenched by adding 5 mL of water and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed sequentially with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel (dichloromethane:ethyl acetate:petroleum ether = 1:1:1) and then by prep-HPLC (column: Waters Xbridge BEH C18 2.1*50 mm*5 μm, mobile phase A: 10 mM aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, the proportion of mobile phase B was increased from 10% to 80% in the first 4.5 minutes, maintained for 0.9 minute, and then decreased from 80% to 10% in the next 0.6 minute) to obtain 010. 1 H NMR(400MHz, CDCl3)δppm9.18(s,1H),8.11(s,1H),7.02-6.97(m,2H),6.89-6.86(m,1H),6.21–6.05(m,1H),5.90–5.87(m,1H),4.79-4.76(m,1H) ,4.42-4.35(m,1H),4.32-4.31(m,1H),4.29-4.25(m,1H),4.00-3.98(m, 1H),3.91-3.89(m,1H),1.81(s,3H),1.62(s,3H); LCMS: m / z=473.3[M+H] + .

[0466] Example 11

[0467] Step 1: Synthesis of compound 011-1

[0468] 001-3 (340 mg, 1.14 mmol) and B-9 (391.96 mg, 1.14 mmol) were dissolved in N,N-dimethylformamide (6 mL), followed by the addition of cesium carbonate (1.11 g, 3.42 mmol) and stirring at 24°C under a nitrogen atmosphere for 12 hours. The reaction mixture was quenched with 10 mL of water and extracted with 20 mL of ethyl acetate. After separation, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 1:1) to obtain 011-1. 1H NMR (400MHz, CDCl3) δppm 8.30 (s, 1H), 8.10 (s, 1H), 6.93 (dt, J = 3.3, 8.4Hz, 1H), 6.74 (td,J=4.2,8.9Hz,2H),6.19-5.85(m,1H),5.73(d,J=14.3Hz,1H),4.61-4.51(m,2H),4.43(q,J=7.1Hz,2H),4.39-4.26(m ,2H),3.79-3.74(m,2H),3.33-3.18(m,2H),1.43(t,J=7.1Hz,3H),1.38(s,9H),0.56-0.46(m,4H); LCMS:m / z=606.5[M+H] + .

[0469] Step 2: Synthesis of compound 011-2

[0470] 011-1 (370 mg, 610.96 μmol) was dissolved in tetrahydrofuran (8 mL), ethanol (16 mL), and methanol (8 mL). Lithium hydroxide monohydrate (2M, 16 mL) and sodium hydroxide (48.88 mg, 1.22 mmol) were then added and stirred at 30°C for 12 hours under a nitrogen atmosphere. The reaction mixture was adjusted to pH 3-4 with 2N hydrochloric acid and extracted with 20 mL of dichloromethane. After separation, the organic phase was collected and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed sequentially with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel (PE:EA = 1:1) to obtain 011-2. 1 H NMR (400MHz, CDCl3) δppm 8.32(s,1H),8.17(s,1H),7.18(dd,J=3.1,8.4Hz,1H),6.96(dt,J=3.1,8.4Hz,1H),6.77(dd,J=4.3,9.0Hz,1H),6.23-5.90(m,1H),5.70(br d,J=14.6Hz,1H),4.70(br s,1H),4.64-4.55(m,2H),4.30-4.17(m,1H),4.14-3.99(m,1H),3.86(br d,J=9.5Hz,1H),3.71(br d,J=9.5Hz,1H),3.18-2.94(m,2H),1.36(s,9H),0.56-0.44(m,4H); LCMS:m / z=578.5[M+H] + .

[0471] Step 3: Synthesis of compound 011-3

[0472] Dissolve 011-2 (110 mg, 190.46 μmol) in dichloromethane (2.1 mL), then add trifluoroacetic acid (9.42 mmol, 0.7 mL) and react at 24°C for 1 hour. The resulting reaction solution was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 011-3, which was used directly in the next reaction. LCMS: m / z = 478.4 [M+H] + .

[0473] Step 4: Synthesis of compound 011-4

[0474] 011-3 (80 mg, crude trifluoroacetate) was dissolved in dichloromethane (2 mL). 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (130.80 mg, 251.34 μmol) and N,N-diisopropylethylamine (837.81 μmol, 145.93 μL) were added under a nitrogen atmosphere and stirred at 24°C for 12 hours. The reaction mixture was quenched by adding 5 mL of water and extracted with 10 mL of dichloromethane. The organic phase was separated and collected, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed sequentially with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel (DCM:MeOH = 20:1) to afford 011-4. 1 H NMR (400MHz, CDCl3) δppm 8.59 (br s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 6.97-6.88 (m, 2H), 6.82 (dd, J = 4.4, 8.8Hz, 1H), 6.20-5.83 (m, 2H), 4.73 (br d,J=10.0Hz,2H),4.33-4.30(m,1H),4.18-4.13(m,1H),4.01(br dd,J=1.7,14.1Hz,1H),3.71(d,J=4.3Hz,1H),3.38(br d,J=9.6Hz,1H),2.95(br dd,J=2.6,13.8Hz,1H),0.88-0.65(m,4H); LCMS:m / z=460.4[M+H] + .

[0475] Step 5: Synthesis of compound 011-5

[0476] 011-4 (76 mg, 165.43 μmol) and Lawesson's reagent (267.64 mg, 661.70 μmol) were added to 1,2-dimethylbenzene (2 mL) and stirred at 140°C under a nitrogen atmosphere for 7 hours. The reaction mixture was quenched with 10 mL of water and extracted with 20 mL of dichloromethane. After separation, the organic phase was collected and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed sequentially with saturated sodium carbonate solution (20 mL x 3) and saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel (PE:EA = 1:2) to obtain 011-5. 1 H NMR (400MHz, CDCl3) δppm 10.17 (br s,1H),8.65(s,1H),8.11(s,1H),6.99-6.88(m,2H),6.82(dd,J=4.5,9.0Hz,1H),6.21-5.85(m,2H),4.80(d,J=9.4Hz,1H),4.71(d,J=11.4H z,1H),4.45-4.22(m,3H),4.16(d,J=15.3Hz,1H),3.37-3.27(m,2H),1.00-0.81(m,3H),0.74(td,J=4.8,9.5Hz,1H); LCMS: m / z=476.4[M+H] + .

[0477] Step 6: Synthesis of Compound 011

[0478] Compound 011-5 (35 mg, 73.61 μmol), methoxyamine hydrochloride (1.18 mmol, 89.42 μL), triethylamine (1.03 mmol, 143.44 μL), and mercuric oxide (136.79 mg, 631.56 μmol) were dissolved in N,N-dimethylformamide (3.5 mL) and stirred at 60°C under nitrogen for 3 hours. The reaction mixture was filtered through celite, and the filter cake was rinsed with dichloromethane (20 mL x 3). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18 50 x 2.1 mm x 5 μm, mobile phase A: 10 mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, mobile phase B increased from 10% to 80% in the first 4.5 minutes, maintained for 0.9 minutes, and then gradually decreased to 10% over the final 0.6 minutes) to afford compound 011. The filter cake after filtration of the reaction solution was added to hydrochloric acid (2M, 30mL) and soaked overnight. The pH was then adjusted to 10 with sodium hydroxide (2M), and solid sodium sulfide (1g) was added to form a precipitate. Ferrous sulfate (1g) was then added as a coprecipitant. After standing, the mixture was filtered and the filter cake was discarded. The filtrate was adjusted to pH 7-8 with hydrochloric acid (1M) and then discarded. 1 H NMR (400MHz, CDCl3) δppm 8.85 (br s, 1H), 8.11 (s, 1H), 6.97-6.85 (m, 2H), 6.80 (br d, J = 3.5Hz, 1H), 6.18-5.82 (m, 2H), 4.84-4.61 (m, 2H), 4.29 (br s,2H),4.15-4.04(m,1H),3.99-3.90(m,1H),3.86(s,3H),3.29(br d,J=9.3Hz,1H),2.85-2.66(m,1H),0.93-0.63(m,4H); LCMS:m / z=489.4[M+H] + .

[0479] Example 12

[0480] Step 1: Synthesis of Compound 012-2

[0481] 012-1 (2.5 g, 14.92 mmol), 3,4-dihydro-2H-pyran (5.46 mL, 59.67 mmol), and 4-methylbenzenesulfonate pyridinium (224.9 mg, 0.89 mmol) were added to toluene (25 mL) and stirred at 100°C under a nitrogen atmosphere for 12 hours. 3,4-dihydro-2H-pyran (5.46 mL, 59.67 mmol) and 4-methylbenzenesulfonate pyridinium (112.5 mg, 0.45 mmol) were then added, and the reaction continued for 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was separated by column chromatography (mobile phase PE:EA = 1:0 to 1:1) to obtain 012-2. 1 H NMR (400MHz, CDCl3) δppm 7.85(d,J=8.4Hz,1H),7.19(d,J=8.4Hz,1H),5.89(dd,J=2.8,11.2Hz,1H),4.21-4.17(m,1H),3.80–3.74(m,1H),2.78(s, 3H),2.38–2.34(m,1H),2.08–2.07(m,1H),1.94–1.91(m,1H),1.82–1.77(m,2H),1.76–1.67(m,1H); LCMS: m / z=252.1[M+H] + .

[0482] Step 2: Synthesis of compound 012-3

[0483] 012-2 (1.0 g, 3.97 mmol), B-8 (1.07 g, 4.77 mmol), and sodium tert-butoxide (0.76 g, 7.95 mmol) were added to 1,4-dioxane (15 mL). 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (0.21 g, 0.40 mmol) and palladium acetate (44.6 mg, 0.20 mmol) were added under a nitrogen atmosphere and stirred at 80°C for 12 hours. After the reaction solution was cooled to room temperature, 20 mL of water was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL*3). After separation, the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA=1:0 to 0:1) to obtain 012-3. 1H NMR (400MHz, CDCl3) δppm 7.66(d,J=8.4Hz,1H),6.37(d,J=8.4Hz,1H),6.23-5.92(m,1H),5.69-5.65(m,1 H),4.75(dd,J=5.6,8.4Hz,1H),4.55-4.40(m,1H),4.20-4.17(m,1H),3.97-3.7 9(m,1H),3.78-3.72(m,2H),2.67(s,3H),2.10-2.05(m,1H),1.90-1.87(m,1H), 1.78-1.63(m,3H),0.92(s,9H),0.11(s,3H),0.09(s,3H); LCMS: m / z=441.3[M+H] + .

[0484] Step 3: Synthesis of compound 012-4

[0485] 012-3 (1.05 g, 2.38 mmol) and sodium acetate (1.27 g, 15.49 mmol) were added to acetic acid (25 mL). The mixture was cooled to 0°C under a nitrogen atmosphere. Pyridinium tribromide (1.14 g, 3.57 mmol) was added and the temperature was slowly raised to 25°C with stirring for 2 hours. 200 mL of saturated sodium thiosulfate was added to the reaction solution to quench the reaction, followed by the addition of 50 mL of water and stirring for half an hour. Extraction was performed with dichloromethane (50 mL). After separation, the organic phase was collected and the aqueous phase was extracted with dichloromethane (50 mL*3). The organic phases were combined and washed sequentially with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 012-4. LCMS: m / z = 519.2, 521.2 [M+H] + .

[0486] Step 4: Synthesis of Compound 012-5

[0487] 012-4 (1.2 g, 2.31 mmol) and tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 3.46 mL) were added to tetrahydrofuran (18.75 mL) and stirred at 20°C under a nitrogen atmosphere for 12 hours. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (mobile phase: PE:EA = 1:0 to 1:1) to obtain 012-5. 1H NMR (400MHz, CDCl3) δppm 7.93(d,J=2.4Hz,1H),6.33-6.05(m,1H),5.60-5.53(m,2H),4.55-4.45(m,1H),4.20-4.14(m,2H),4.12-4.00(m,1H),3.7 4-3.68(m,1H),2.65-2.52(m,5H),2.11-2.05(m,1H),1.88-1.85(m,1H),1.77-1.63(m,3H); LCMS: m / z=405.1,407.0[M+H] + .

[0488] Step 5: Synthesis of Compound 012-6

[0489] 012-5 (0.25 g, 0.62 mmol) and cesium carbonate (0.26 g, 0.80 mmol) were added to 1,4-dioxane (6.25 mL). 2-(di-tert-butylphosphino)-1,1'-binaphthyl (0.1 g, 0.25 mmol) and tris(dibenzylideneacetone)dipalladium (0.11 g, 0.12 mmol) were added under a nitrogen atmosphere. The temperature was slowly raised to 88°C and stirred for 1 hour, then to 100°C and stirred for 1 hour, and then to 115°C and stirred for 12 hours. The temperature was slowly cooled to room temperature, and the resulting reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 0:1) to obtain 012-6. LCMS: m / z = 325.1 [M+H] + .

[0490] Step 6: Synthesis of Compound 012-7

[0491] 012-6 (0.10 g, 0.31 mmol), B-4 (0.15 g, 0.46 mmol) and tetrabutylammonium iodide (29.6 mg, 0.08 mmol) were added to N,N-dimethylformamide (2.0 mL). Cesium carbonate (0.30 g, 0.93 mmol) was added under a nitrogen atmosphere and the temperature was raised to 40°C and stirred for 16 hours. After the reaction solution was cooled to room temperature, 10 mL of water was added to the reaction solution to quench the reaction. The reaction was extracted with ethyl acetate (10 mL*3). After separation, the organic phase was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase PE:EA = 1:0 to 0:1) to obtain 012-7. LCMS: m / z = 620.3 [M+H] + .

[0492] Step 7: Synthesis of Compound 012-8

[0493] 012-7 (0.15 g, 0.24 mmol) was added to a 4.0 M solution of hydrochloric acid in ethyl acetate (3.03 mL) and stirred at 20°C for 0.5 h. The resulting reaction solution was concentrated under reduced pressure to afford the crude hydrochloride salt of 012-8, which was used directly in the next step. LCMS: m / z = 436.1 [M+H] + .

[0494] Step 8: Synthesis of Compound 012

[0495] 012-8 (0.07 g, crude hydrochloride) was added to dichloromethane (3.5 mL) and cooled to 0°C under a nitrogen atmosphere. A solution of N,N'-carbonyldiimidazole (48.1 mg, 0.30 mmol) in dichloromethane (0.7 mL) and 4-dimethylaminopyridine (5.4 mg, 0.45 mmol) were then slowly added dropwise. The temperature was slowly raised to 25°C and stirred for 12.0 hours. 10% aqueous citric acid solution (10 mL) was added to the reaction solution to adjust the pH to approximately 6. The solution was extracted with dichloromethane (10 mL x 2). After separation, the organic phase was collected and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel (PE:EA = 0:1) and then by preparative high-performance liquid chromatography (Waters Xbridge Prep OBD C18 column, 150 x 40 mm x 10 μm; mobile phase: phase A (10 mM aqueous ammonium bicarbonate solution), phase B: acetonitrile, gradient elution: phase B from 25% to 65% over 8 minutes) to yield 012. LCMS: m / z = 462.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δppm 10.32(s,1H),7.36(s,1H),7.02–7.00(m,1H),6.95–6.94(m,1H),6.83–6.81(m,1H),6.05–5.77(m,2H),4.67– 4.64(m,1H),4.25–4.20(m,2H),4.16–4.06(m,1H),4.04–3.91(m,2H),2.81(s,3H),1.75(s,3H),1.68(s,3H).

[0496] Example 13

[0497] Step 1: Synthesis of Compound 013-1

[0498] B-6 (0.26 g, 0.77 mmol) and 007-6 (0.12 g, 0.39 mmol) were dissolved in N,N-dimethylformamide (8 mL), followed by the addition of cesium carbonate (0.19 g, 0.58 mmol). The mixture was stirred at 5°C for 4 hours, then heated to 20°C and allowed to react for 12 hours. The reaction mixture was quenched by the addition of 20 mL of water and extracted with dichloromethane (100 mL x 2). The organic phase was separated, collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield the crude product. The crude product was purified by thin-layer chromatography (PE:EA = 0:1) to afford 013-1. 1 H NMR (400MHz, CDCl3) δppm 8.01 (br d, J=8.1Hz, 1H), 7.90 (s, 1H), 7.65 (br d,J=8.1Hz,1H),7.48(s,1H),6.10-5.75(m,1H),5.68-5.55(m,1H),5.31(s,1H),4.58-4.42(m,3H),4.35(s,1H),4.25-4.18(m,1H),3.90(br s,1H),3.77(br s,1H),2.06(s,3H),1.77-1.73(m,1H),1.71(br d,J=2.8Hz,1H),1.67(br s,1H),1.62-1.55(m,2H),1.43(s,9H),1.39(d,J=9.7Hz,6H); LCMS:m / z=607.4[M+H] + .

[0499] Step 2: Synthesis of Compound 013-2

[0500] 013-1 (0.1 g, 0.16 mmol) and methanolic hydrochloric acid solution (4 M, 31.25 mL) were added to the reaction flask and stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude hydrochloride of 013-2, which was used directly in the next step without purification. 1 H NMR (400MHz, CD3OD) δppm 9.04(s,1H),7.93(d,J=2.8Hz,1H),7.57(s,1H),7.44(dd,J=2.3,8.9Hz,1H),6.21(dt,J=4.5,55.2Hz,1H),5.24(br d,J=17.4Hz,1H),4.94(br s,1H),4.70(br d,J=11.8Hz,1H),4.54-4.47(m,1H),4.44-4.38(m,1H),4.28-4.14(m,2H),1.50(d,J=2.6Hz,6H); LCMS: m / z=423.2[M+H] + .

[0501] Step 3: Synthesis of Compound 013

[0502] Dissolve 013-2 (40 mg, crude hydrochloride) in dichloromethane (0.4 mL). Cool to 0°C, then slowly add a solution of N,N'-carbonyldiimidazole (18.43 mg, 113.64 μmol) in dichloromethane (0.2 mL) and 4-dimethylaminopyridine (2.31 mg, 18.94 μmol) dropwise. Stir at 25°C for 3 hours. Quench the reaction mixture with water (10 mL), extract with dichloromethane (10 mL*3), separate the layers, combine the organic phases, wash sequentially with saturated brine (10 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated by thin-layer chromatography (PE:EA=0:1) and then purified by preparative high-performance liquid chromatography [chromatographic column: Phenomenex Luna C18 column, 100*30mm*3μm; mobile phase: phase A (0.2% trifluoroacetic acid aqueous solution), phase B: acetonitrile, gradient elution: phase B gradient from 40% to 70% in 8 minutes] to obtain 013. 1 H NMR (400MHz, CDCl3) δppm 9.95 (br s,1H),8.40(s,1H),7.95(d,J=2.9Hz,1H),7.50(s,1H),7.37(dd,J=2.6,7.9Hz,1H),5.95(dt,J=6.8,55.5Hz,1H),5.58(br d,J=15.8Hz,1H),4.86(d,J=10.6Hz,1H),4.68(br d,J=11.6Hz,1H),4.30-4.17(m,3H),3.97(d,J=10.8Hz,1H),1.77(s,3H),1.68(s,3H); LCMS: m / z=449.1[M+H] + .

[0503] Example 14

[0504] Step 1: Synthesis of Compound 014-1

[0505] 007-6 (0.14 g, 0.45 mmol), B-10 (0.14 g, 0.68 mmol), and cesium carbonate (0.29 g, 0.90 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) and stirred at 20°C for 12 hours. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by thin-layer chromatography (PE:EA = 0:1) to obtain 014-1. LCMS: m / z = 475.2 [M+H] + .

[0506] Step 2: Synthesis of Compound 014-2

[0507] 014-1 (0.16 g, 0.34 mmol) and 1,3-dimethylbarbituric acid (0.11 g, 0.67 mmol) were added to ethanol (3.0 mL). Tetrakis(triphenylphosphine)palladium was added under a nitrogen atmosphere, and the mixture was stirred at 40°C for 12 hours. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by thin-layer chromatography (PE:EA = 0:1) to obtain 014-2. LCMS: m / z = 435.2 [M+H] + .

[0508] Step 3: Synthesis of Compound 014-3

[0509] B-11 (80.3 mg, 0.32 mmol), 014-2 (0.14 g, 0.32 mmol), and cesium carbonate (0.26 g, 0.81 mmol) were added to N,N-dimethylformamide (3.0 mL) and stirred at 70°C for 12 hours. Water (10 mL) was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL x 3). After separation, the organic phases were combined, washed sequentially with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography (ethyl acetate:methanol = 10:1) to obtain 014-3.

[0510] Step 4: Synthesis of Compound 014-4

[0511] 014-3 (80.0 mg, 0.13 mmol) and ethyl acetate solution (4 M, 0.83 mL) were added to ethyl acetate (0.2 mL) and stirred at 20°C for 1 hour. The resulting reaction solution was concentrated under reduced pressure to obtain the crude hydrochloride salt of 014-4, which was directly used in the next step. LCMS: m / z = 420.1 [M+H] + .

[0512] Step 5: Synthesis of Compound 014

[0513] 014-4 (45.0 mg, crude hydrochloride) and dichloromethane (0.5 mL) were added to a reaction flask. The temperature was lowered to 0°C under a nitrogen atmosphere. A solution of N,N'-carbonyldiimidazole (48.0 mg, 0.3 mmol) in dichloromethane (0.1 mL) and 4-dimethylaminopyridine (36.2 mg, 0.3 mmol) were slowly added dropwise at 0°C. The temperature was then slowly raised to 25°C and stirred for 1 hour. Water (2 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with dichloromethane (2 mL*3). After separation, the organic phases were combined, washed sequentially with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography (dichloromethane:ethyl acetate=1:1) and then by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 column, 100*30 mm*10 μm; mobile phase: phase A (10 mM aqueous ammonium bicarbonate solution), phase B: acetonitrile, gradient elution: phase B from 25% to 55% over 8 minutes) to obtain 014. 1 H NMR (400MHz, CDCl3) δppm 10.36(s,1H),8.31(s,1H),7.48(s,1H),6.94–6.90(m,2H),6.76–6.74(m,1H),5.96–5.80(m,2H),4.68(d,J=10.8Hz,1H),4.45(d,J=8.4 Hz,1H),4.26–4.25(m,2H),4.23(d,J=8.4Hz,1H),3.79(d,J=9.2Hz,1H),2.2 7–2.23(m,1H),1.15–1.05(m,2H),0.99–0.96(m,1H); LCMS: m / z=446.2[M+H] + .

[0514] Example 15

[0515] Step 1: Synthesis of compound 015-1

[0516] 006-3 (0.27 g, 0.86 mmol) and B-6 (0.43 g, 1.30 mmol) were dissolved in N,N-dimethylformamide (3.0 mL), followed by the addition of cesium carbonate (0.85 g, 2.59 mmol) and stirring at 25°C for 3 hours. Water (10 mL) was added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate (30 mL x 3). After separation, the organic phases were combined, washed sequentially with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to afford 015-1. 1H NMR (400MHz, CDCl3) δppm8.39-8.32(m,1H),8.01(s,1H),7.91(d,J=3.1Hz,1H),6.17-5.79(m,1H),5.53(d,J=14.5Hz,1H),4.67-4.60(m,1H) ,4.58-4.51(m,2H),4.50-4.39(m,3H),4.37-4.25(m,1H),3.96-3.87(m,1H),2.64-2.58(m,3H),1.45-1.36(m,19H); LCMS: m / z=631.2[M+Na] + .

[0517] Step 2: Synthesis of compound 015-2

[0518] 015-1 (0.36 g, 0.59 mmol), an aqueous solution of lithium hydroxide monohydrate (2M, 20 mL), and sodium hydroxide (47.3 mg, 1.18 mmol) were added to tetrahydrofuran (7.2 mL), methanol (7.2 mL), and ethanol (14.4 mL) and stirred at 30°C for 40 hours. Water (2 mL) was added to the reaction solution, which was washed with ethyl acetate (10 mL) and separated. The resulting aqueous phase was adjusted to a pH of approximately 3 with 2M hydrochloric acid and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 015-2. LCMS: m / z = 581.3 [M+H] + .

[0519] Step 3: Synthesis of Compound 015-3

[0520] 015-2 (80 mg, 137.80 μmol) was added to trifluoroacetic acid (4 mL), stirred at 25°C for 0.5 h, and concentrated under reduced pressure to obtain crude 015-3, which was directly used in the next step. LCMS: m / z = 481.3 [M+H] + .

[0521] Step 4: Synthesis of Compound 015

[0522] 015-3 (80.0 mg, crude product) was dissolved in dichloromethane (2 mL), followed by the addition of N,N-diisopropylethylamine (1.67 mmol, 290.03 μL) and pentafluorophenyl diphenyl phosphate (96.0 mg, 0.25 mmol), and stirred at 25°C for 12 hours. The reaction was quenched with 10 mL of water and extracted with dichloromethane (20 mL). After separation, the organic phase was collected and the aqueous phase was extracted with dichloromethane (20 mL*3). The combined organic phases were washed sequentially with saturated sodium carbonate solution (20 mL*3) and saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by thin-layer chromatography (PE:EA=1:1) and then purified by preparative high-performance liquid chromatography (chromatographic column: Waters Xbridge Prep OBD C18 column 150*40mm*10μm; mobile phase: phase A: 10mM ammonium bicarbonate aqueous solution, phase B: acetonitrile; gradient: phase B gradient increased from 25% to 55% in 8 minutes) to obtain 015. H NMR (400MHz, CDCl3) δ8.95 (br s, 1H), 8.02 (br d, J = 27.9Hz, 2H), 7.39-7.29 (m, 1H), 6.22-5.85 (m, 1H), 5.72 (br d,J=15.4Hz,1H),4.88-4.66(m,2H),4.34-4.20(m,3H),3.88(br d,J=10.1Hz,1H),1.78(br s,3H),1.62(br d, J=11.4Hz, 6H); LCMS: m / z=463.2[M+H] + .

[0523] Example 16

[0524] Step 1: Synthesis of Compound 016-1

[0525] 006-3 (0.27 g, 0.86 mmol) and B-9 (0.31 g, 0.95 mmol) were dissolved in N,N-dimethylformamide (5.4 mL), followed by the addition of cesium carbonate (0.85 g, 2.59 mmol) and stirring at 25°C for 12 hours. Water (10 mL) was added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate (20 mL). The aqueous phase was then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:1) to obtain 016-1. 1H NMR (400MHz, CDCl3) δ8.01 (s, 1H), 7.62 (br d,J=6.3Hz,1H),6.95(dt,J=3.1,8.4Hz,1H),6.76(dd,J=4.3,9.0Hz,1H),6.16-5.91(m,1H),5.88-5.82(m,1H),5.06(br s,1H),4.56-4.47(m,2H),4.43(q,J=7.1Hz,2H),4.33-4.24(m,1H),4.05(d ,J=9.8Hz,1H),3.90-3.78(m,2H),2.62(s,3H),1.45-1.41(m,12H),0.87(br dd,J=5.1,9.8Hz,1H),0.80-0.68(m,3H); LCMS:m / z=606.4[M+H] + .

[0526] Step 2: Synthesis of Compound 016-2

[0527] 016-1 (0.37 g, 0.61 mmol), a 2M aqueous solution of lithium hydroxide monohydrate (24.7 mL), and sodium hydroxide (48.9 mg, 1.22 mmol) were dissolved in tetrahydrofuran (12.3 mL), methanol (12.3 mL), and ethanol (24.7 mL) and stirred at 35°C for 55 hours. Water (2 mL) was added to the reaction solution, which was washed with dichloromethane (20 mL) and separated. The resulting aqueous phase was adjusted to a pH of approximately 3 with 2M hydrochloric acid, extracted with dichloromethane (20 mL x 3), and separated. The organic phases were combined, washed sequentially with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 016-2. 1 H NMR (400MHz, CDCl3) δ10.27-9.95 (m, 1H), 8.11 (s, 1H), 7.10 (dd, J = 2.9, 8.4Hz, 1H), 6.97(dt,J=3.0,8.4Hz,1H),6.80(dd,J=4.3,9.0Hz,1H),6.15-5.86(m,1H),5.66(br d,J=15.1Hz,1H),4.95-4.78(m,2H),4.63-4.51(m,2H),4.15-3.90(m,6H),1.41(br s,9H),0.97(br d, J=6.5Hz, 2H), 0.83-0.80 (m, 2H); LCMS: m / z=578.3[M+H] + .

[0528] Step 3: Synthesis of Compound 016-3

[0529] 016-2 (0.17 g, 0.29 mmol) and TFA (13.5 mmol, 1 mL) were added to dichloromethane (2.0 mL), stirred at 25°C for 0.5 h, and concentrated under reduced pressure to obtain crude 016-3, which was directly used in the next step. LCMS: m / z = 478.3 [M+H] + .

[0530] Step 4: Synthesis of Compound 016

[0531] 016-3 (95.0 mg, crude product) was dissolved in dichloromethane (2 mL), followed by the addition of N,N-diisopropylethylamine (1.99 mmol, 346.6 μL) and pentafluorophenyl diphenyl phosphate (114.7 mg, 0.30 mmol), and stirred at 25°C for 2 hours. 5 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL). After separation, the organic phase was collected and the aqueous phase was further extracted with dichloromethane (10 mL*3). The organic phases were combined and washed sequentially with saturated sodium carbonate solution (20 mL*3) and saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by thin-layer chromatography (PE:EA=0:1) and then purified by preparative high-performance liquid chromatography (chromatographic column: Waters Xbridge Prep OBD C18 column 150*40mm*10μm; mobile phase: phase A: 10mM ammonium bicarbonate aqueous solution, phase B: acetonitrile; gradient: phase B gradient increased from 30% to 65% in 8 minutes) to obtain 016. 1 H NMR (400MHz, CDCl3) δ9.04(s,1H),8.01(s,1H),6.98-6.85(m,2H),6.73(dd,J=4.5,9.0Hz,1H),6.18-5.87(m,2H),4.70(br d,J=11.4Hz,1H),4.43(d,J=9.3Hz,1H),4.33-4.22(m,2H),4.14(d,J=15.3Hz,1H),3.67(d,J=9.3H z,1H),2.58(s,3H),2.28-2.16(m,1H),1.08-0.97(m,2H),0.84-0.74(m,1H)LCMS:m / z=460.2[M+H] + .

[0532] Example 17

[0533] To the reaction flask, 009 (60.0 mg, 114.0 μmol), cyclopropylboronic acid (9.8 mg, 114.0 μmol), cesium carbonate (74.3 mg, 228.0 μmol), 1,4-dioxane (2.5 mL), and water (0.5 mL) were added. After evacuating the nitrogen atmosphere three times, tetrakis(triphenylphosphine)palladium (26.4 mg, 22.8 μmol) was added, and the mixture was reacted at 100°C for 5 hours. The reaction solution was cooled to room temperature and diluted with water (2 mL). Extraction was performed with dichloromethane (5 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel (PE:EA=1:1) and then by preparative high-performance liquid chromatography (column: Waters Xbridge Prep OBD C18 column, 150*40mm*10um; mobile phase: phase A: 10mM aqueous ammonium bicarbonate solution, phase B: acetonitrile; gradient: phase B: 40% to 70% over 8 minutes) to obtain 017. 1 H NMR(400MHz, CDCl3)δ9.26(s,1H),7.99(s,1H),7.02-6.95(m,2H),6.88-6 .83(m,1H),6.18-5.83(m,2H),4.68(brd,J=12.3Hz,1H),4.37-4.23(m,2H) ,4.20(d,J=15.4Hz,1H),3.99-3.90(m,2H),3.04-2.92(m,1H),1.81(s,3H) ,1.64(s,3H),1.27(brs,2H),1.00(d,J=5.4Hz,2H); LCMS:m / z=488.4[M+H] + .

[0534] Example 18

[0535] Step 1: Synthesis of Compound 018-1

[0536] 009-8 (0.3 g, 0.8 mmol) was added to acetonitrile (0.2 mL). The atmosphere was purged with nitrogen three times, followed by the addition of palladium (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate (67.3 mg, 0.08 mmol) and cesium carbonate (0.52 g, 1.6 mmol). The temperature was slowly raised to 80°C, followed by the addition of a solution of propyne (1 M, 2.39 mL) in acetonitrile (0.2 mL). The reaction mixture was allowed to react for 12 hours. After cooling to room temperature, water (5.0 mL) was added to quench the reaction mixture, followed by extraction with dichloromethane (5.0 mL*3). The organic phases were combined, washed sequentially with saturated brine (10.0 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to give 018-1. LCMS: m / z = 337.2 [M+H] + .

[0537] Step 2: Synthesis of Compound 018-2

[0538] 018-1 (0.13 g, 0.39 mmol) and B-4 (0.19 g, 0.58 mmol) were dissolved in N,N'-dimethylformamide (2.0 mL), followed by the addition of cesium carbonate (0.38 g, 1.16 mmol). The mixture was stirred at 25°C for 2 hours under a nitrogen atmosphere. Water (2.0 mL) was added to the reaction mixture to quench the reaction. The mixture was then extracted with ethyl acetate (10.0 mL x 3). The combined organic phases were washed sequentially with saturated brine (10.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 018-2. 1 H NMR(400MHz, CDCl3)δ8.00(s,1H),7.68-7.53(m,1H),7.02-6.91(m,1H),6.90-6.79(m,1H),6.13-5.77(m,2H),4.55-4.36(m,5H),4.28-4.15(m, 2H),4.04-3.93(m,1H),3.91-3.79(m,1H),2.18(s,3H),1.62-1.56(m,3 H),1.41(brs,9H),1.36(brs,3H),1.32(brs,3H); LCMS: m / z=632.3[M+H] + .

[0539] Step 3: Synthesis of Compound 018-3

[0540] 018-2 (0.1 g, 0.16 mmol) was added to a mixture of ethanol (2 mL), tetrahydrofuran (1 mL), and methanol (1 mL), followed by the addition of lithium hydroxide (95.8 mg, 4.0 mmol) and allowed to react at 30°C for 24 hours. Water (5 mL) was added to the reaction mixture to quench the reaction, and the pH was adjusted to approximately 5 with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed sequentially with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (PE:EA = 1:1) to obtain 018-3. LCMS: m / z = 604.3 [M+H] + .

[0541] Step 4: Synthesis of Compound 018-4

[0542] Dissolve 018-3 (55 mg, 91.12 μmol) in dichloromethane (1 mL), then add trifluoroacetic acid (0.3 mL) and react at 20°C for 2 hours. Evaporate the trifluoroacetic acid under reduced pressure to obtain crude 018-4, which was used directly in the next reaction without purification. LCMS: m / z = 504.3 [M+H] + .

[0543] Step 5: Synthesis of Compound 018

[0544] 018-4 (50.0 mg, 99.31 μmol) was dissolved in dichloromethane (0.1 mL), followed by the addition of N,N-diisopropylethylamine (0.5 mmol, 86.5 μL) and pentafluorophenyl diphenyl phosphate (57.2 mg, 0.15 mmol), and the mixture was stirred at 20°C for 3 hours. 5 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL*3). The organic phases were combined, washed sequentially with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (PE:EA=0:1) and then by preparative high-performance liquid chromatography (column: Waters Xbridge Prep OBD C18 column, 150*40 mm*10 μm; mobile phase: phase A: 10 mM aqueous ammonium bicarbonate solution, phase B: acetonitrile; gradient: phase B: 35% to 65% over 8 minutes) to obtain 018. 1H NMR (400MHz, CDCl3) δ9.20(br s,1H),8.03(s,1H),7.03-6.92(m,2H),6.89-6.81(m,1H),6.19-5.85(m,2H),4.72(br d,J=11.9Hz,1H),4.39-4.18(m,3H),3.98-3.86(m,2H),2.17(s,3H),1.81(s,3H),1.61(s,3H); LCMS:m / z=486.3[M+H] + .

[0545] Example 19

[0546] Step 1: Synthesis of Compound 019-1

[0547] 009-8 (0.3 g, 0.8 mmol) was added to acetonitrile (6.0 mL). The atmosphere was purged with nitrogen three times, followed by the addition of (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium (67.3 mg, 0.08 mmol) and cesium carbonate (0.52 g, 1.6 mmol). The temperature was slowly raised to 80°C, followed by the addition of a solution of (triisopropylsilyl)acetylene (535.4 μL, 2.39 mmol) in acetonitrile (6.0 mL). The reaction mixture was allowed to react for 12 hours. The acetonitrile was evaporated under reduced pressure, and the resulting solution was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to afford 019-1. LCMS: m / z = 479.3 [M+H]. + .

[0548] Step 2: Synthesis of Compound 019-2

[0549] 019-1 (0.26 g, 0.54 mmol) and B-4 (0.22 g, 0.65 mmol) were dissolved in N,N-dimethylformamide (2.6 mL), followed by the addition of cesium carbonate (0.53 g, 1.63 mmol) and stirring at 20°C for 2 hours. Water (10 mL) was added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phases were washed sequentially with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 019-2. 1H NMR (400MHz, CDCl3) δppm 8.04(s,1H),7.70-7.56(m,1H),7.00-6.91(m,1H),6.89-6.80(m,1H),6.13-5.78(m,2H),4.53-4.40(m,5H),4.31-4.22(m,1H),4.18(br d,J=9.0Hz,1H),4.00-3.91(m,1H),3.86(br d,J=11.7Hz,1H),1.42-1.38(m,12H),1.37-1.31(m,9H),1.19(s,18H), LCMS: m / z=774.4[M+H] + .

[0550] Step 3: Synthesis of Compound 019-3

[0551] 019-2 (0.13 g, 0.17 mmol) was added to a solution of ethanol (2.6 mL), tetrahydrofuran (1.3 mL), and methanol (1.3 mL), followed by a mixed solvent solution of sodium hydroxide (2 M, 2.6 mL) and stirred at 30°C for 24 hours. The reaction mixture was cooled to 0°C and quenched with water (5 mL). The pH was adjusted to approximately 7 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed sequentially with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 019-3. LCMS: m / z = 590.3 [M+H] + .

[0552] Step 4: Synthesis of Compound 019-4

[0553] Dissolve 019-3 (35.0 mg, 59.4 μmol) in dichloromethane (1 mL), then add trifluoroacetic acid (0.3 mL) and stir at 20°C for 1 hour. Evaporate the trifluoroacetic acid under reduced pressure to obtain crude 019-4, which was used directly in the next reaction without purification. LCMS: m / z = 490.3 [M+H] + .

[0554] Step 5: Synthesis of Compound 019

[0555] 019-4 (25.0 mg, 51.1 μmol) was dissolved in dichloromethane (0.3 mL), followed by the addition of pentafluorophenyl diphenyl phosphate (29.4 mg, 76.6 μmol) and N,N-diisopropylethylamine (33.0 mg, 255.4 μmol), and stirred at 20°C for 3 hours. The reaction was quenched by the addition of water (5 mL), and extracted with dichloromethane (10 mL*3). The organic phases were combined, washed sequentially with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) and then by preparative high-performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 column 100*30mm*10μm; mobile phase: phase A: 10mM ammonium bicarbonate aqueous solution, phase B: acetonitrile; gradient: phase B gradient increased from 35% to 65% in 8 minutes) to obtain 019. 1 H NMR (400MHz, CDCl3) δ9.19(br s,1H),8.06(br s,1H),7.08-6.72(m,3H),6.23-5.79(m,2H),4.73(br d,J=11.3Hz,1H),4.44-4.17(m,3H),4.05-3.82(m,2H),3.46(br s,1H),1.81(br s,3H),1.62(br s,3H); LCMS: m / z=472.3[M+H] + .

[0556] Example 20

[0557] Step 1: Synthesis of compound 020-1

[0558] 009-8 (0.4 g, 1.06 mmol) was added to acetonitrile (4.0 mL). The atmosphere was purged with nitrogen three times, followed by the addition of (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium (89.8 mg, 0.106 mmol) and cesium carbonate (0.69 g, 2.12 mmol). The temperature was slowly raised to 80°C, followed by the addition of a solution of cyclopropylacetylene (263.9 μL, 3.18 mmol) in acetonitrile (2.0 mL). The reaction mixture was allowed to react for 12 hours. The acetonitrile was evaporated under reduced pressure, and the resulting reaction solution was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to afford 020-1. LCMS: m / z = 363.2 [M+H]. + .

[0559] Step 2: Synthesis of compound 020-2

[0560] 020-1 (0.24 g, 0.66 mmol) and B-4 (0.26 g, 0.79 mmol) were dissolved in N,N-dimethylformamide (4.0 mL), followed by the addition of cesium carbonate (0.65 g, 1.99 mmol) and stirring at 20°C for 2 hours. Water (10 mL) was added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phases were washed sequentially with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to afford 020-2. 1 H NMR(400MHz, CDCl3)δ7.99(s,1H),7.72-7.47(m,1H),7.00-6.83(m,2H),6.13-5.68(m,2H),4.67-4.33(m,5H),4.3 2-4.08(m,3H),4.02-3.93(m,1H),3.89-3.78(m,1H),1.44-1.31(m,18H),1.01-0.86(m,4H); LCMS:m / z=658.4[M+H] + .

[0561] Step 3: Synthesis of compound 020-3

[0562] 020-2 (0.17 g, 0.26 mmol) was added to a solution of ethanol (3.4 mL), tetrahydrofuran (1.7 mL), and methanol (1.7 mL). A mixed solvent solution of potassium hydroxide (2 M, 3.4 mL) and sodium fluoride (21.7 mg, 0.52 mmol) was then added, and the mixture was stirred at 30°C for 60 hours. Water (10 mL) was added to the reaction mixture to quench the reaction. The pH was adjusted to 3-4 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed sequentially with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 020-3. LCMS: m / z = 630.3 [M+H] + .

[0563] Step 4: Synthesis of compound 020-4

[0564] 020-3 (80.0 mg, 127.1 μmol) was dissolved in dichloromethane (1.6 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at 20°C for 0.5 h. The trifluoroacetic acid was evaporated under reduced pressure to obtain the crude trifluoroacetate salt of 020-4, which was used directly in the next reaction without purification. LCMS: m / z = 530.3 [M+H] + .

[0565] Step 5: Synthesis of Compound 020

[0566] 020-4 (67.0 mg, crude trifluoroacetate) was dissolved in dichloromethane (1.4 mL), followed by the addition of 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (98.8 mg, 189.8 μmol) and N,N-diisopropylethylamine (110.2 μL, 632.7 μmol). The mixture was stirred at 20°C for 2 hours. The reaction was quenched with water (5 mL) and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate=1:1) and then by preparative high-performance liquid chromatography (chromatographic column: Phenomenex Luna C18 column 75*30mm*3μm; mobile phase: phase A: 0.2% formic acid aqueous solution, phase B: acetonitrile; gradient: phase B gradient increased from 25% to 60% within 8 minutes) to obtain 020. 1 H NMR (400MHz, CDCl3) δ9.18(s,1H),8.01(s,1H),7.04-6.93(m,2H),6.85(br dd,J=4.4,9.5Hz,1H),6.20-5.83(m,2H),4.71(br d,J=12.0Hz,1H),4.40-4.32(m,1H),4.28(td,J=1.8,12.0Hz,1H),4.22(d,J=15.1Hz,1H),3.99-3.92(m,1H),3.91-3 .83(m,1H),1.81(s,3H),1.61(s,3H),1.33-1.22(m,1H),0.98-0.92(m,2H),0.91-0.85(m,2H); LCMS: m / z=512.3[M+H] + .

[0567] Example 21

[0568] Step 1: Synthesis of Compound 021-1

[0569] 009-8 (329.0 mg, 0.87 mmol) and B-13 (299.9 mg, 0.87 mmol) were dissolved in N,N'-dimethylformamide (10 mL), and cesium carbonate (0.85 g, 2.62 mmol) was added and stirred at 20°C for 4 hours. Water (30 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL*4). The organic phases were combined, washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 3:1) to obtain 021-1. LCMS: m / z = 584.1 [M+H-Boc] + .

[0570] Step 2: Synthesis of compound 021-2

[0571] 021-1 (0.54 g, 0.78 mmol) was added to a mixture of methanol (5 mL), tetrahydrofuran (5 mL), and ethanol (10 mL), followed by a mixed solvent solution of sodium hydroxide (2 M, 10.55 mL) and allowed to react at 30°C for 24 hours. 1 M hydrochloric acid was added to the reaction solution to adjust the pH to 3-4, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed sequentially with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by column chromatography (PE:EA = 10:1 to 1:1) to obtain 021-2. LCMS: m / z = 556.3 [M+H-Boc] + .

[0572] Step 3: Synthesis of compound 021-3

[0573] Dissolve 021-2 (320 mg, 487.5 μmol) in ethyl acetate (3.5 mL), then add a 4M solution of hydrochloric acid in ethyl acetate (0.32 mL). The mixture is allowed to react at 20°C for 16 hours. The hydrochloric acid gas is evaporated under reduced pressure to obtain crude 021-3, which is used directly in the next reaction without purification. LCMS: m / z = 556.0 [M+H] + .

[0574] Step 4: Synthesis of Compound 021

[0575] 021-3 (168.0 mg, 283.3 μmol) was dissolved in dichloromethane (8.0 mL), followed by the addition of N,N-diisopropylethylamine (1.42 mmol, 246.8 μL) and pentafluorophenyl diphenyl phosphate (163.3 mg, 0.42 mmol), and the mixture was stirred at 20°C for 3 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 10:1 to 2:1) and then by preparative chiral chromatography (column: DAICEL CHIRALCEL OJ column 250*30 mm*10 μm; mobile phase: phase A: supercritical carbon dioxide, phase B: 0.1% ammonia / ethanol solution, gradient: B: 40%, isobaric elution) to obtain 021. 1 H NMR(400MHz, CDCl3)δ8.97(s,1H),8.03(s,1H),7.02-6.95(m,2H),6.91-6.88(m,1H),6.19-5.92( m,1H),5.85(dd,J=1.2Hz,15.2Hz,1H),4.73(d,J=11.6Hz,1H),4.49(d,J=9.2Hz,1H),4.37-4.35( m,1H),4.30(dm,J=11.6Hz,1H),4.19(d,J=15.2Hz,1H),3.98(d,J=9.2Hz,1H),3.95–3.90(m,1H), 2.66–2.61(m,1H),2.44–2.39(m,1H),2.13–201(m,2H),1.91–1.84(m,1H); LCMS: m / z=538.0[M+H] + ,540.0[M+2+H] + .

[0576] Example 22

[0577] 021 (50 mg, 92.9 μmol) was dissolved in N-methylpyrrolidone (2.0 mL). After nitrogen was purged, cuprous cyanide (16.64 mg, 185.8 μmol) and tetrakis(triphenyl)palladium (21.5 mg, 18.6 μmol) were added and stirred at 120°C for 16 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate (5 mL). Water (20.0 mL) was added to the resulting filtrate, and the mixture was extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 6:4) and then by preparative high-performance liquid chromatography (chromatographic column: Xtimate C18 column 150*40mm*5μm; mobile phase: phase A: 0.1% hydrochloric acid aqueous solution, phase B: acetonitrile; gradient: phase B gradient increased from 43% to 73% over 15 minutes) to obtain 022. 1 H NMR (400 MHz, CDCl3) δ ppm 9.09(s,1H),8.08(s,1H),7.02-6.95(m,2H),6.91-6.89(m,1H),6.23–5.9 5(m,1H),5.86–5.82(m,1H),4.79-4.76(m,1H),4.51-4.49(m,1H),4.42-4 .25(m,2H),4.25-4.22(m,1H),3.99-3.95(m,2H),2.67–2.64(m,1H),2.42 –2.41(m,1H),2.11–1.99(m,2H),1.90–1.85(m,1H); LCMS: m / z=485.3[M+H] + .

[0578] Example 23

[0579] Step 1: Synthesis of Compound 023-1

[0580] 009-8 (0.3 g, 0.80 mmol) and B-14 (262.3 mg, 0.80 mmol) were dissolved in N,N'-dimethylformamide (3.0 mL), and then a solution of cesium carbonate (0.78 g, 2.39 mmol) in N,N'-dimethylformamide (3.0 mL) was added and stirred at 20°C for 3 hours. Water (10 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 4:1 to 2:1) to obtain 023-1. LCMS: m / z = 670.2 [M+H] + ,672.2[M+2+H] + .

[0581] Step 2: Synthesis of Compound 023-2

[0582] 023-1 (0.45 g, 0.67 mmol) was added to a mixture of methanol (5 mL), tetrahydrofuran (5 mL), and ethanol (10 mL), followed by a mixed solvent solution of sodium hydroxide (2 M, 9.06 mL) and allowed to react at 20°C for 30 hours. 2 M hydrochloric acid was added to the reaction solution to adjust the pH to 7-8, and extraction was performed with dichloromethane (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by column chromatography (PE:EA = 1:0 to 3:1) to obtain 023-2. LCMS: m / z = 542.0 [M+H-Boc] + ,m / z=544.0[M+H+2-Boc] + .

[0583] Step 3: Synthesis of Compound 023-3

[0584] Dissolve 023-2 (0.23 g, 358.0 μmol) in dichloromethane (10.0 mL), then add a 1,4-dioxane solution of hydrochloric acid (4 M, 5.75 mL) and react at 20°C for 3 hours. Evaporate the hydrochloric acid under reduced pressure to obtain crude 023-3, which was used directly in the next reaction without purification. LCMS: m / z = 542.0 [M+H] + , m / z=544.0[M+2+H] + .

[0585] Step 4: Synthesis of Compound 023

[0586] 023-3 (209.6 mg, 362.8 μmol) was dissolved in dichloromethane (16.0 mL), followed by the addition of N,N-diisopropylethylamine (1.81 mmol, 316.0 μL) and pentafluorophenyl diphenyl phosphate (209.1 mg, 0.54 mmol), and the mixture was stirred at 20°C for 3 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed sequentially with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA=1:0 to 2:1) and then by preparative chiral chromatography (chromatographic column: DAICEL CHIRALCEL OD column 250*30mm*10μm; mobile phase: phase A: supercritical carbon dioxide, phase B: 0.1% ammonia ethanol solution, gradient: phase B: 40%, isobaric elution) to obtain 023. 1 H NMR (400MHz, CDCl3) δ9.03 (d, J = 10.4Hz, 1H), 8.07 (s, 1H), 6.95-6.87 (m, 2H), 6.48 (dd,J=4.8Hz,J=8.8Hz,1H),6.21-5.92(m,2H),5.00-4.97(m,1H),4.90-4.87(m,1H ),4.78-4.75(m,1H),4.41-4.33(m,2H),4.26-4.22(m,1H),3.13-3.07(m,1H),2.8 5-2.79(m,1H),2.31-2.25(m,1H),1.95-1.90(m,1H); LCMS: m / z=524.0,526.0[M+H] + .

[0587] Example 24

[0588] 023 (85 mg, 162.1 μmol) was dissolved in N-methylpyrrolidone (2.0 mL). After nitrogen was purged, cuprous cyanide (29.04 mg, 324.3 μmol) and tetrakis(triphenyl)palladium (37.5 mg, 32.4 μmol) were added and stirred at 125°C for 16 hours. After the reaction solution was cooled to room temperature, water (10.0 mL) was added to quench the reaction solution and extracted with ethyl acetate (5 mL*3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) and then by chiral chromatography (chromatographic column: ChiralPak IH column 250*30mm*10μm; mobile phase: phase A: supercritical carbon dioxide, phase B: 0.1% ammonia ethanol solution, gradient: phase B 40%, isobaric elution) to obtain 024.1 H NMR (400MHz, CDCl3) δppm 9.02(d,J=10.0Hz,1H),8.14(s,1H),6.98-6.94(m,1H),6.90-6.87(m,1H),6.51 (dd,J=4.0Hz,J=8.8Hz,1H),6.23–5.94(m,2H),4.98-4.95(m,1H),4.91-4.89(m, 1H),4.82-4.79(m,1H),4.46-4.37(m,2H),4.29–4.25(m,1H),3.15–3.08(m,1H) ,2.88–2.82(m,1H),2.31–2.26(m,1H),1.97–1.91(m,1H); LCMS:m / z=471.1[M+H] + .

[0589] Example 25

[0590] Step 1: Synthesis of compound 025-1

[0591] To a reaction flask, 009-8 (1.5 g, 3.02 mmol), cuprous cyanide (540.29 mg, 6.03 mmol), and N-methylpyrrolidone (30 mL) were added, followed by cuprous iodide (574.46 mg, 3.02 mmol). Under a nitrogen atmosphere, the mixture was heated to 125°C for 12 hours. Aqueous ammonia (15.0 mL) was added to the reaction solution and stirred for 10 minutes to quench the reaction. Water (15.0 mL) was added to precipitate a solid. The resulting filter cake was filtered, dissolved in dichloromethane (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 025-1. 1 H NMR (400MHz, CDCl3) δppm 8.11 (br s, 1H), 7.48-7.30 (m, 2H), 6.89 (br d, J = 7.5Hz, 2H), 6.21-5.70 (m, 2H), 4.71-4.12 (m, 4H), 3.81 (br s,5H),1.52-1.33(m,3H), LCMS: m / z=444.3[M+H] + .

[0592] Step 2: Synthesis of compound 025-2

[0593] 025-1 (1.2 g, 2.71 mmol) and trifluoroacetic acid (12 mL) were added to a reaction flask and heated to 90°C under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated under reduced pressure to remove the trifluoroacetic acid, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (20.0 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 0:1) to obtain 025-2. 1 H NMR (400MHz, CDCl3) δppm 8.16 (s, 1H), 7.16 (br s, 1H), 6.03-5.72 (m, 1H), 4.53 (br d, J = 12.6Hz, 1H), 4.42 (q, J = 6.9Hz, 2H), 4.27 (br d,J=12.1Hz,1H),4.10-3.96(m,1H),1.44(t,J=6.8Hz,3H), LCMS:m / z=324.2[M+H] + .

[0594] Step 3: Synthesis of Compound 025-3

[0595] 025-2 (0.3 g, 928.06 μmol) was dissolved in N,N-dimethylformamide (3 mL). The temperature was cooled to 0°C, potassium carbonate (0.38 g, 2.78 mmol) was added, followed by a solution of B-15 (0.46 g, 1.39 mmol) in N,N-dimethylformamide (1 mL). Under a nitrogen atmosphere, the mixture was stirred at 0°C for 1 hour, then slowly warmed to 20°C and stirred for 2 hours. The reaction mixture was quenched with water (6 mL) and extracted with ethyl acetate (6.0 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 1:1) to obtain 025-3. 1H NMR (400MHz, CDCl3) δppm 8.38(dd,J=2.9,8.1Hz,1H),8.05(s,1H),7.87(d,J=2.7Hz,1H),6.25-5.93(m,1H),5.46-5.28(m,1H),5.14-4.79(m,2H),4.66(br d,J=11.5Hz,1H),4.58(d,J=14.2Hz,1H),4.53-4.46(m,2H),4.41-4.34(m,1H),4.33-4.24(m,1H),4.21-4.08 (m,1H),1.48(t,J=7.1Hz,3H),1.45-1.29(m,9H),1.12-1.00(m,1H),0.95-0.78(m,3H), LCMS:m / z=618.3[M+H] + .

[0596] Step 4: Synthesis of Compound 025-4

[0597] 025-3 (0.5 g, 0.81 mmol) was dissolved in ethanol (10 mL), tetrahydrofuran (5 mL), and methanol (5 mL). The mixture was cooled to 0°C and lithium hydroxide monohydrate (2 M, 10 mL) was added. Under a nitrogen atmosphere, the mixture was stirred at 0°C for 1 hour, then heated to 25°C for 5 hours. Water (10 mL) was added to the reaction mixture to quench the reaction. 2N hydrochloric acid was then added to adjust the pH to approximately 4. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 1:1) to obtain 025-4. 1 H NMR (400MHz, CDCl3) δppm 13.32-12.57(m,1H),8.77(d,J=0.9Hz,1H),8.27(dd,J=2.7,8.4Hz,1H),7.96(d,J=2.2Hz,1H),7.30(br s,1H),6.66-6.32(m,1H),5.07(br d,J=14.6Hz,1H),4.90-4.73(m,1H),4.68(br d,J=12.1Hz,1H),4.51(br d,J=14.4Hz,1H),4.40-4.21(m,3H),1.32(br s,9H),0.84-0.67(m,4H), LCMS:m / z=590.3[M+H] + .

[0598] Step 5: Synthesis of Compound 025-5

[0599] Dissolve 025-4 (0.32 g, 0.54 mmol) in dichloromethane (3.0 mL), cool to 0°C, add trifluoroacetic acid (1 mL), slowly warm to 20°C, and stir for 1 hour. Evaporate the reaction mixture under reduced pressure to remove the trifluoroacetic acid, yielding crude 025-5, which was used directly in the next reaction without purification. LCMS: m / z = 490.2 [M+H] + .

[0600] Step 6: Synthesis of Compound 025

[0601] 025-5 (265 mg, 0.54 mmol) was dissolved in dichloromethane (2.6 mL) and cooled to 0°C under a nitrogen atmosphere. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (0.42 g, 0.81 mmol) and N,N-diisopropylethylamine (0.47 mL, 2.71 mmol) were then added. The temperature was slowly raised to 20°C and stirred for 1.0 hour. Water (10.0 mL) was added to the reaction solution to quench the mixture. The mixture was then extracted with dichloromethane (20.0 mL*3). The organic phases were combined, washed sequentially with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 1:1) and then by preparative chromatography (Waters Xbridge Prep OBD C18 150*40mm*10μm column, mobile phase A: 10mM aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient: 25% to 55% phase B over 8.0 minutes). The resulting eluate was concentrated under reduced pressure and freeze-dried to yield 025. SFC chiral analysis (Chromatographic column: Chiralcel OD-3, 50×4.6mm ID, 3μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol [0.2% ammonia in methanol (7M)], gradient: 5% to 50% phase B over 1.2 minutes, held for 1 minute, then 50% to 5% phase B over 0.8 minutes) showed ee = 100% (Rt = 1.609 minutes). 1H NMR (400MHz, CDCl3) δppm 8.94(s,1H),8.79(s,1H),8.06(br s,1H),7.99(br d,J=8.3Hz,1H),6.68-6.33(m,1H),5.47(br d,J=14.8Hz,1H),5.05(br t,J=10.1 Hz,1H),4.91(br d,J=10.9Hz,1H),4.72(br d,J=12.4Hz,1H),4.52-4.38(m,2H),3.74(br d,J=10.9Hz,1H),1.96-1.80(m,1H),1.06-0.96(m,2H),0.89-0.77(m,1H), LCMS:m / z=472.2[M+H] + .

[0602] Example 26

[0603] Step 1: Synthesis of Compound 026-1

[0604] 025-2 (0.3 g, 0.93 mmol) was dissolved in N,N-dimethylformamide (3 mL). After cooling to 0°C, potassium carbonate (0.38 g, 2.78 mmol) was added, followed by a solution of B-6 (463.28 mg, 1.39 mmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at 0°C under a nitrogen atmosphere for 1 hour, then slowly warmed to 20°C and continued to react for 2 hours. The reaction solution was quenched with water (6 mL) and extracted with ethyl acetate (6 mL x 3). The organic phases were combined, washed sequentially with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: PE:EA = 1:0 to 1:1) to obtain 026-1. 1 H NMR (400MHz, CDCl3) δppm 8.37 (br d,J=5.4Hz,1H),8.07(s,1H),7.92(d,J=3.0Hz,1H),6.18-5.85(m,1H),5.47(d,J=14.4Hz,1H),4.68-4.45(m,7H),4.34-4.28(m,1H),4.00(br d,J=11.4Hz,1H),1.50-1.45(m,3H),1.43(s,9H),1.40(br s,3H),1.39(s,3H), LCMS:m / z=620.3[M+H] + .

[0605] Step 2: Synthesis of Compound 026-2

[0606] 026-1 (0.44 g, 0.71 mmol) was dissolved in ethanol (8 mL), tetrahydrofuran (4 mL) and methanol (4 mL), cooled to 0 ° C, and lithium hydroxide monohydrate (2M, 8.80 mL) was added. The reaction was carried out at 0 ° C for 1 hour under a nitrogen atmosphere, and then the temperature was slowly raised to 25 ° C for 5 hours. Water (10 mL) was added to the reaction solution to quench, and 2N hydrochloric acid was added to adjust the pH value to about 4. Ethyl acetate (5 mL * 3) was extracted, and the organic phases were combined and washed with saturated brine (10 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase PE: EA = 1:0 to 1:1) to obtain 026-2. 1 H NMR (400MHz, CDCl3) δppm 13.14-12.54(m,1H),8.81(s,1H),8.23(br d,J=8.4Hz,1H),8.03(br s,1H),6.68(br dd,J=1.1,9.8Hz,1H),6.63-6.34(m,1H),5.23(br d,J=15.0Hz,1H),4.61(br d,J=12.0Hz,1H),4.52(br d,J=14.8Hz,2H),4.40-4.33(m,1H),4.26(br d,J=10.6Hz,2H),1.36(s,9H),1.31(s,3H),1.25(s,3H), LCMS:m / z=592.3[M+H] + .

[0607] Step 3: Synthesis of Compound 026-3

[0608] Dissolve 026-2 (0.27 g, 0.46 mmol) in dichloromethane (3 mL), cool to 0°C under nitrogen atmosphere, add trifluoroacetic acid (1 mL), stir at 0°C for 0.2 hours, warm to 20°C, and react for 0.8 hours. Dichloromethane and trifluoroacetic acid were evaporated under reduced pressure to obtain crude 026-3. LCMS: m / z = 492.3 [M+H] + .

[0609] Step 4: Synthesis of Compound 026

[0610] 026-3 (224 mg, 0.46 mmol) was dissolved in dichloromethane (2.3 mL) and cooled to 0°C under a nitrogen atmosphere. 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (0.36 g, 0.68 mmol) and N,N-diisopropylethylamine (0.40 mL, 2.28 mmol) were then added. The temperature was slowly raised to 20°C and stirred for 1.0 hour. Water (10.0 mL) was added to the reaction solution to quench the mixture. The mixture was then extracted with dichloromethane (20.0 mL*3). The organic phases were combined, washed sequentially with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 1:1) and then by preparative chromatography (column model: Waters Xbridge Prep OBD C18 150*40mm*10μm, mobile phase A: 10mM aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, gradient: phase B 30%-60% over 8.0 minutes). The resulting eluate was concentrated under reduced pressure and freeze-dried to obtain 026. Chiral analysis (chromatographic column: (S,S)-WHELK-O1, 50×4.6 mm ID, 3.5 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: ethanol [0.2% ammonia in methanol (7 M)], gradient: phase B increased from 5% to 50% in the first 1.2 minutes, held for 1 minute, and then decreased from 50% to 5% in the next 0.8 minutes) showed that compound 26 had an ee of 93.86%, Rt = 2.146 minutes, and its enantiomer had an Rt = 1.971 minutes. 1 H NMR (400MHz, CDCl3) δppm 8.91 (s, 1H), 8.80 (s, 1H), 8.11 (brs, 1H), 8.07 (brd, J = 8.8Hz, 1H), 6.35-6.67 (m, 1H), 5.39 (br d,J=14.8Hz,1H),5.00-5.15(m,1H),4.66-4.80(m,2H),4.43-4.55(m,2H),3.94(br d,J=10.8Hz,1H),1.64(s,3H),1.52(s,3H); LCMS:m / z=474.2[M+H] + .

[0611] Example 27

[0612] 009 (20 mg, 38.0 μmol) and 2-methyl-3-butyn-2-ol (37.1 μL, 380.1 μmol) were dissolved in 1,4-dioxane (0.1 mL). A pre-prepared solution of bis(acetonitrile)palladium(II) chloride (0.3 mg, 1.14 μmol), cuprous iodide (0.15 mg, 0.76 μmol), tri-tert-butylphosphine (4.61 mg, 2.28 μmol) and N,N-diisopropylamine (6.4 μL, 45.6 μmol) in 1,4-dioxane (0.2 mL) was added under a nitrogen atmosphere, and the mixture was heated to 96 °C for 12 hours. After cooling to room temperature, 2-methyl-3-butyn-2-ol (37.1 μL, 380.1 μmol) and a pre-prepared solution of bis(acetonitrile)palladium(II) chloride (0.3 mg, 1.14 μmol), cuprous iodide (0.15 mg, 0.76 μmol), tri-tert-butylphosphine (4.61 mg, 2.28 μmol), and N,N-diisopropylamine (6.4 μL, 45.6 μmol) in 1,4-dioxane (0.2 mL) were added. The temperature was raised to 96°C and the reaction was allowed to proceed for an additional 12 hours. After cooling to room temperature, the reaction was quenched by the addition of 10 mL of water. The reaction was then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed sequentially with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:1), and then separated and purified by preparative chromatography (chromatographic column: Waters Xbridge BEH C18 100*30mm*10μm, mobile phase: phase A: 10mM ammonium bicarbonate aqueous solution, phase B: acetonitrile, phase B gradient increasing from 35% to 65% within 8 minutes). The target eluate was concentrated under reduced pressure and then separated and purified by thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:1) to obtain 027. Chiral analysis (chromatographic column: Chiralcel OD-3, 150×4.6 mm ID, 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol [0.2% NH3 / MeOH (7 M)], gradient: phase B increased from 0% to 50% in the first 3.5 minutes, maintained for 1 minute, and then decreased to 10% within 0.5 minutes) showed ee = 98.9%, Rt = 3.491 minutes, and Rt = 3.079 minutes for its enantiomer. 1H NMR (400MHz, CDCl3) δppm 9.22 (s, 1H), 8.04 (s, 1H), 7.03-6.96 (m, 2H), 6.85 (br dd, J = 4.5, 9.6Hz, 1H), 6.21-5.86 (m, 2H), 4.72 (br d,J=12.0Hz,1H),4.42-4.33(m,1H),4.32-4.26(m,1H),4.23(d,J=15.1Hz,1H),3.99-3.93(m,1H),3.89-3.84(m,1H),1.78(s,3H),1.66(br s,3H),1.65(br s,6H), LCMS: m / z=530.3[M+H] + .

[0613] Biological test data

[0614] Experimental Example 1: In vitro kinase inhibitory activity test

[0615] Compounds for ALK, ALK L1196M , ALK G1202R , ALK G1202R / L1196M The kinase inhibitory activity tests of ROS1 and TRKB were completed at Wuhan Heyan Biotechnology Co., Ltd. or Hefei Zhongke Puruisheng Biotechnology Co., Ltd.

[0616] Experimental method 1:

[0617] Experimental materials: ALK Active, ALK(L1196M)Active, ALK(G1202R)Active and ALK(G1202R / L1196M)Active were purchased from Carna; SRC Substrate was purchased from SignalChem; IGF1R tide was purchased from SignalChem; ADP-Glo ​​Kinase Assay was purchased from Promega; Kinase assay buffer III was purchased from SignalChem; Nivo multilabel analyzer (PerkinElmer).

[0618] ALK kinase inhibition assay: Dilute the test compound to 1 mM in 100% DMSO as the first concentration. Then, dilute the compound 5-fold using a pipette to the eighth concentration, from 1 mM to 0.0128 μM. Prepare a 20-fold dilution of each compound concentration point in 1X kinase buffer containing 5% DMSO. Add 1 μL of each compound concentration gradient to a microplate in duplicate. Add 2 μL of ALK enzyme (15 ng per well) and 2 μL of a mixture of substrate and ATP (25 μM ATP, 0.5 μg / μL SRC substrate) to the microplate. The final compound concentration gradient is 10 μM to 0.128 nM, with final ATP and substrate concentrations of 10 μM and 0.2 μg / μL, respectively. Incubate the reaction at 25°C for 1 hour. After the reaction, 5 μL of ADP-Glo ​​reagent was added to each well and the reaction was continued at 25°C for 40 minutes. After the reaction was completed, 10 μL of kinase detection reagent was added to each well. After the reaction was completed at 25°C for 30 minutes, chemiluminescence was read using a PerkinElmer Nivo multi-label analyzer with an integration time of 0.5 seconds.

[0619] ALK (L1196M) kinase inhibition assay: Prepare the working solution of the test compound as for ALK kinase. Add 2 μL of ALK (L1196M) enzyme (4 ng per well) and 2 μL of a mixture of substrate and ATP (125 μM ATP, 0.5 μg / μL IGF1R) to a microplate. The final compound concentration is diluted from 10 μM to 0.128 nM, resulting in final ATP and substrate concentrations of 50 μM and 0.2 μg / μL, respectively. Subsequent steps are the same as for ALK kinase.

[0620] ALK (G1202R) kinase inhibition assay: Prepare the working solution of the test compound as for ALK kinase. Add 2 μL of ALK (G1202R) enzyme (15 ng per well) and 2 μL of a mixture of substrate and ATP (125 μM ATP, 0.5 μg / μL SRC Substrate) to a microplate. The final compound concentration is diluted from 10 μM to 0.128 nM, with final ATP and substrate concentrations of 50 μM and 0.2 μg / μL, respectively. Subsequent steps are the same as for ALK kinase.

[0621] ALK (G1202R / L1196M) kinase inhibition assay: Prepare the working solution of the test compound as for ALK kinase. Add 2 μL of ALK (G1202R / L1196M) enzyme (5 ng per well) and 2 μL of a mixture of substrate and ATP (125 μM ATP, 0.5 μg / μL SRC Substrate) to a microplate. The final compound concentration is diluted from 10 μM to 0.128 nM, with final ATP and substrate concentrations of 50 μM and 0.2 μg / μL, respectively. Subsequent steps are the same as for ALK kinase.

[0622] ROS1 kinase inhibition assay: Prepare the working solution of the test compound as for ALK kinase. Add 2 μL of ROS1 (3.0 ng per well) and 2 μL of a mixture of substrate and ATP (50 μM ATP, 0.2 μg / μL IGF1R tide substrate) to a microplate. The final compound concentration is diluted from 10 μM to 0.128 nM, with final ATP and substrate concentrations of 0.25 μM and 0.2 μg / μL, respectively. Subsequent steps are the same as for ALK kinase.

[0623] TRKB kinase inhibition assay: Prepare the working solution of the test compound as for ALK kinase. Add 2 μL of TRKB (0.5 ng per well) and 4 μL of a mixture of substrate and ATP (5 μM ATP, 0.5 μM SRC substrate) to a microplate. The final compound concentration is diluted from 10 μM to 0.128 nM, with final ATP and substrate concentrations of 0.25 μM and 0.2 μg / μL, respectively. Subsequent steps are the same as for ALK kinase.

[0624] 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 (in GraphPad Prism, log(inhibitor) vs. response--Variable slope mode). The test results of compounds 001-005 are shown in Table 1-1:

[0625] Table 1-1: Kinase half-maximal inhibitory concentration IC 50 (nM)

[0626] Experimental method 2:

[0627] Experimental materials: ALK (G1202R / L1196M) Active and TRKB were purchased from Carna; IGF1 was purchased from GenScript; PolyE4Y1 was purchased from SIGMA; ADP-Glo TMReagent was purchased from Promega; ATP was purchased from Promega; Kinase Detection Reagent was purchased from Promega; and a microplate reader was purchased from PerkinElmer.

[0628] Reaction system: ALK (G1202R / L1196M) reaction concentration 8.63 nM, ATP concentration 5.0 μM, substrate IGF1 concentration 0.2 μg / μL, ALK (G1202R / L1196M) kinase buffer is 40 mM Tris-HCl (pH 7.5) + 20 mM magnesium chloride + 0.1 mg / mL BSA + 50 μM DTT.

[0629] The TRKB reaction concentration was 4.47 nM, the ATP concentration was 5.0 μM, the substrate PolyE4Y1 concentration was 0.2 μg / μL, and the TRKB kinase buffer was 40 mM Tris-HCl (pH 7.5) + 20 mM magnesium chloride + 2.5 mM manganese chloride + 0.1 mg / mL BSA + 50 μM DTT.

[0630] ALK (G1202R / L1196M) and TRKB detection methods: add 2 μL kinase and 1 μL compound to a 384 plate; add 2 μL substrate / ATP mixture and incubate at room temperature in the dark for 60 minutes; add 5 μL ADP-Glo TM Reagent, incubate at room temperature for 40 minutes; add 10 μL Kinase Detection Reagent, incubate at room temperature for 30 minutes; read the plate on a microplate reader and record the luminescence (set the integration time to 0.5 seconds).

[0631] 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 (derived by using the log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). The test results of compound 006-024 are shown in Table 1-2:

[0632] Table 1-2: Kinase half-maximal inhibitory concentration IC 50 (nM)

[0633] Conclusion: The compounds of the present invention show high kinase inhibitory activity against ALK kinase and its mutants, ROS1 and TRKB kinases; among them, they have more efficient inhibition against ALK kinase and its mutants, while the inhibition against TRKB is relatively weak, with good selectivity.

[0634] Experimental Example 2: Cell Permeability Test

[0635] Purpose of the experiment:

[0636] The permeability and efflux ratio of the test compounds were evaluated using the MDCKII-MDR1 monolayer cell assay system to determine the compound's potential to cross the blood-brain barrier and its potential to be effluxed by the P-gp transporter.

[0637] Experimental methods:

[0638] MDCKII-MDR1 cells (from the Netherlands Cancer Institute) were seeded into 96-well cell plates (from Corning) at a cell density of 2.5 x 10 5 cells / ml, cultured for 7 days to form a copolymerized cell monolayer. Hank's balanced salt buffer (pH 7.40 ± 0.05) containing 10mM 4-hydroxyethylpiperazineethanesulfonic acid was used as the transport buffer (wherein, the transport buffer of compound 005 was 1% BSA (bovine serum albumin) added to the transport buffer). The bidirectional transport of the test compound at a concentration of 2μM was tested, and the concentration of DMSO in the incubation system was controlled below 1%. After addition of the sample, the cell plate was placed at 37±1°C, 5% CO2 and saturated humidity and incubated for 150 minutes. All samples were quantitatively analyzed by LC-MS / MS method. The apparent permeability coefficient (P app , cm / s), efflux ratio (ER) and recovery rate.

[0639] Apparent permeability coefficient (P app ,cm / s) is calculated using the following formula: P app =(dC r / d t )×V r / (A×C0). Where, dC r / d t is the cumulative concentration of the compound at the receiving end per unit time (μM / s); V r is the volume of the solution at the receiving end (the volume of the solution at the apical and basal ends is 0.075 mL and 0.250 mL, respectively); A is the relative surface area of ​​the cell monolayer (0.0804 cm 2 ); C0 is the starting concentration of the test sample at the dosing end (nM) or the peak area ratio of the reference sample. The efflux ratio is calculated using the following formula: ER = P app (BA) / P app (AB). The recovery rate was calculated using the following formula: % recovery rate = 100 × [(V r ×C r )+(V d ×C d)] / (V d × C0). Where C0 is the starting concentration (nM) of the test sample at the dosing end or the peak area ratio of the reference sample; V d is the volume of the dosing end (0.075 mL on the apical side and 0.250 mL on the basolateral side); C d and C r are the final concentration (nM) of the test sample at the dosing end and the receiving end or the peak area ratio of the reference sample.

[0640] The test results are shown in Table 2:

[0641] Table 2: MDCKII-MDR1 test results

[0642] Conclusion: The compounds of the present invention are high osmotic and low efflux compounds.

[0643] Experimental Example 3: Antiproliferative Activity Test on Three Ba / F3 Cell Lines: Ba / F3-EML4-ALK-G1202R, Ba / F3-EML4-ALK-G1202R-L1198F, and Ba / F3-EML4-ALK-G1202R-L1196M

[0644] Experimental Materials

[0645] (1) Cell line (established by Hefei Zhongke Puruisheng Biopharmaceutical Technology Co., Ltd.)

[0646] ALK G1202R / L1196M Cell line: Ba / F3-EML4-ALK-G1202R / L1196M; TRKB cell line: Ba / F3-TEL-TRKB.

[0647] (2) Reagents

[0648] RPMI 1640: VivaCell brand, product number C3010-0500; fetal bovine serum: VivaCell brand, product number C04001-500;

[0649] Penicillin-streptomycin solution: Gibco, product number 15140-122; CellTiterGlo: Promega, product number G7573;

[0650] Trypan blue: Solarbio, product number C0040; 96-well white plate: Biosharp, product number BS-MP-96W;

[0651] 96-well plate: Beaver brand, item number 40196.

[0652] (3) Instruments

[0653] Cell counter, manufacturer: Count star, model: IC1000; microplate reader, manufacturer: Molecular Devices, model: SpectraMax Paradigm; carbon dioxide incubator, manufacturer: Thermo, model: HERA cell vios 160i.

[0654] (4) Compound information: The compounds were prepared in DMSO at a working concentration of 1 mM.

[0655] Experimental methods

[0656] (1) Cell culture: The cell lines were cultured in an incubator at 37°C and 5% CO2. Cells were passaged regularly and cells in the logarithmic growth phase were used for plating.

[0657] (2) Compound storage plate preparation: Prepare the test compound into a 10 mM solution (Stock Con.) with DMSO; then prepare the compound into a 1 mM solution (Work Con.) with DMSO; take 1 μL of Stock solution and 9 μL of DMSO to prepare 10 μL of Work solution;

[0658] (3) Prepare 1000× compound storage plates (tubes): dilute the compound three-fold with DMSO from 1 μM to the lowest concentration, for a total of 8 concentrations;

[0659] (4) Preparation of 20× compound working solution: Add 98 μL of cell culture medium to a flat-bottomed 96-well transparent plate. Pipette 2 μL of compound from a 1000× compound storage plate and add it to the cell culture medium in the 96-well transparent plate. Add 2 μL of DMSO to the vehicle control. After adding the compound or DMSO, mix thoroughly by pipetting with a dispenser.

[0660] (5) Stain the cells with trypan blue and count the living cells. The cell viability is required to be above 90%, and the cell concentration is adjusted to an appropriate concentration.

[0661] (6) Add 95 μL of cell suspension (2000 cells / well) to each well of the compound test cell plate, and add culture medium without cells (containing 0.1% DMSO) to the Min control wells;

[0662] (7) Compound assay cell plate dosing: 5 μL of 20× compound working solution was added to the cell culture plate. 5 μL of DMSO-cell culture medium mixture was added to the Max control, with a final DMSO concentration of 0.1%;

[0663] (8) Incubate the culture plate in a 37°C, 5% CO2 incubator for 72 hours;

[0664] (9) Follow the instructions of the Promega CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega-G7573) to perform the following operations: melt the CellTiter-Glo buffer and bring it to room temperature; bring the CellTiter-Glo substrate to room temperature; add CellTiter-Glo buffer to a bottle of CellTiter-Glo substrate to dissolve the substrate, thereby preparing the CellTiter-Glo working solution; slowly vortex to fully dissolve; remove the cell culture plate and let it stand for 10 minutes to equilibrate to room temperature; add 50 μL (equal to half the volume of the cell culture solution in each well) of CellTiter-Glo working solution to each well; shake the culture plate on an orbital shaker for 2 minutes to induce cell lysis; let the culture plate stand at room temperature for 10 minutes to stabilize the luminescent signal; detect the luminescent signal on a SpectraMax Paradigm plate reader; and perform the CellTiter-Glo luminescent cell viability assay.

[0665] Data analysis: SpectraMax Paradigm readings were used to obtain the corresponding fluorescence value RLU per well; the cell proliferation inhibition rate (Inhibition Rate) data were calculated using the formula Inhibition Rate (Inh%) = 100-(RLU Drug -RLU Min ) / (RLU Max -RLU Min )*100%. The inhibition rates corresponding to different concentrations of compounds were calculated in Excel, and then the inhibition rate curve was plotted using GraphPad Prism software and related parameters were calculated, including the maximum and minimum inhibition rates of cells, IC 50 value.

[0666] The experimental results are shown in Table 3.

[0667] Table 3: Half inhibitory concentration IC 50 (nM)

[0668] Conclusion: The compounds of the present invention exhibit potent inhibitory effects on ALK mutant cells and TRKB phenotype cells; among them, compounds 010, 018, 019, and 020 have stronger inhibition on ALK mutant cells and relatively weak inhibition on TRKB phenotype cells, showing excellent selectivity.

[0669] Experimental Example 4: Pharmacokinetic test in mice

[0670] Purpose of the experiment:

[0671] 7-9 week old male CD-1 mice were used as test animals. The pharmacokinetic performance of the compounds of the present invention in mice was studied by measuring the plasma concentrations of the compounds at different time points after single intravenous (IV) and oral (PO) administration of the compounds using LC / MS / MS.

[0672] Experimental methods:

[0673] The drug was administered intravenously (IV) and orally (PO) to two groups of healthy mice (fasted), with two mice in each group.

[0674] The intravenous vehicle for compounds 001, 005, and 006 consisted of 10% dimethyl sulfoxide (DMSO) + 40% polyethylene glycol 400 + 50% water. The test compounds were mixed with the vehicle, vortexed, and sonicated to produce a 0.5 mg / mL clear solution with a pH of 3.3-3.6. The intravenous dose for mice was 1.0 mg / kg. The oral vehicle for compounds 001, 005, and 006 consisted of 0.5% sodium carboxymethyl cellulose + 1% sorbitan monooleate polyoxyethylene ether. The test compounds were mixed with the vehicle, vortexed, and sonicated to produce a 0.5 mg / mL homogeneous suspension containing particles with a pH of 6.8-7.0. The oral dose for mice was 5.0 mg / kg.

[0675] The intravenous vehicle for Compound 010 consisted of 10% dimethylacetamide, 70% polyethylene glycol 400, and 20% (10-hydroxypropyl-β-cyclodextrin aqueous solution). The test compound and the vehicle were mixed, vortexed, and sonicated to produce a 1.0 mg / mL clear solution. The intravenous dose for mice was 1.0 mg / kg. The oral vehicle for Compound 010 consisted of 5% dimethyl sulfoxide, 60% caprylic / capric macrogol glycerides, 30% polyethylene glycol 400, and 5% water. The test compound and the vehicle were mixed, vortexed, and sonicated to produce a 0.5 mg / mL homogeneous suspension containing particles. The oral dose for mice was 5.0 mg / kg.

[0676] The intravenous vehicle for compounds 019 and 020 consisted of 10% dimethyl sulfoxide (DMSO) + 40% polyethylene glycol 400 + 50% water. The test compound was mixed with the vehicle, vortexed, and sonicated to produce a 0.1 mg / mL clear solution. The intravenous dose for mice was 0.5 mg / kg. The oral vehicle for compound 020 consisted of 0.5% sodium carboxymethyl cellulose + 1% sorbitan monooleate polyoxyethylene ether. The test compound was mixed with the vehicle, vortexed, and sonicated to produce a 0.5 mg / mL homogeneous suspension containing particles. The pH was 7.08, and the oral dose for mice was 5.0 mg / kg. After administration, whole blood was collected at 0.083 h, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, 12.0 h, and 24.0 h to prepare plasma. Drug concentrations were analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin 6.3. The experimental results are shown in Table 4.

[0677] Table 4: Pharmacokinetic test results in mice

[0678] Conclusion: The compounds of the present invention have a long half-life, high exposure, high bioavailability in mouse PK and have excellent pharmacokinetic properties.

[0679] Experimental Example 5: HMS CLint (liver) test

[0680] Purpose of the experiment:

[0681] The compounds of the invention were tested for their metabolic stability in human and mouse hepatocytes.

[0682] Experimental Materials:

[0683] (1) Test compound (10 mM); Reference substances: 7-Ethoxycoumarin (30 mM), 7-Hydroxycoumarin (30 mM);

[0684] Mouse hepatocytes, cell viability 73.8%, supplier Cat No.: BioreclamationIVTM005052;

[0685] Human hepatocytes, cell viability 94.6%, supplier Cat No.: Bioreclamation IVTX008001.

[0686] (2) Buffer system:

[0687] Thawing medium: Williams' medium E containing 5% fetal bovine serum and 30% Percoll solution and other supplementary supplies.

[0688] Incubation medium: Williams medium E (without phenol red) containing 2 mM L-glutamine and 25 mM hydroxyethylpiperazineethanesulfonic acid.

[0689] Stop solution: acetonitrile containing 200 ng / mL tosylbutamide and labetalol as internal standard.

[0690] Dilution solution: ultrapure water.

[0691] Experimental methods

[0692] 1) Dissolve an accurate amount of the positive control compound in dimethyl sulfoxide (DMSO) to prepare a 30 mM solution.

[0693] 2) Dilute 10 mM test compound and 30 mM control compound to 1 mM and 3 mM with DMSO in a 96-well plate.

[0694] 3) 1 mM of the test compound and 3 mM of the positive control compound were diluted with acetonitrile to 100 μM and 300 μM quantitative solutions.

[0695] 4) Thaw the frozen cells, separate and suspend them in culture medium, and then dilute them to 0.5×10 6 cells / mL.

[0696] 5) Add 198 μL of pre-warmed cell suspension to a 96-well plate.

[0697] 6) Transfer 100 μL of stop solution (acetonitrile containing 200 ng / mL tosylbutamide and 200 ng / mL labetalol as internal standard) to a pre-labeled 96-well plate.

[0698] 7) Add 2 μL of 100 μM test compound or 300 μM positive control quantification solution in duplicate to each well of a 96-well plate.

[0699] 8) For T0 samples, mix to achieve a uniform suspension for approximately 1 minute, then immediately transfer 20 μL of each sample to a well containing 100 μL of ice-cold stop solution and mix.

[0700] 9) Incubate all plates at 37°C in a 95% humidified incubator with 5% CO2 and start the reaction with constant shaking at approximately 600 rpm.

[0701] 10) At 15, 30, 60, and 90 minutes, mix the samples, then transfer 20 μL of each sample to a well containing 100 μL of ice-cold stop solution at each time point, followed by mixing.

[0702] 11) Prepare medium control (MC) sample plates (labeled T0-MC and T90-MC) at T0 and T90 by adding the same components to each well except for the cell suspension. Generate a table of final concentrations.

[0703] 12) At each corresponding time point, stop the reaction by removing the plate from the incubator and mixing with 100 μL of ice-cold stop solution.

[0704] 13) Immediately vortex the plate at 500 rpm on a plate shaker for 10 minutes. Then, centrifuge all sample plates at 3220×g for 20 minutes at 4°C.

[0705] 14) After centrifugation, transfer 35 μL / well of the supernatant from the sample plate to another set of pre-labeled 96-well plates containing 70 μL of ultrapure water according to the plate map.

[0706] 15) Seal the assay plate and store at 4°C until LC-MS-MS analysis.

[0707] The residual rates of the test compound and the control compound were calculated using the following formula:

[0708] The elimination rate constant k of the test compound and the control compound in the hepatocytes was calculated by plotting the logarithm of the residual rate against the time, and the half-life (T 1 / 2 ) and in vitro intrinsic clearance (CL int ), the formula is as follows:

[0709] T 1 / 2 =0.693 / k;

[0710] CL int(hep) = k / million cells / mL;

[0711] CL int(liver) =CL int(hep) × liver weight to body weight ratio × number of hepatocytes per gram of liver.

[0712] The parameters and test results of the compounds of the present invention in the HMS test are shown in Table 5.

[0713] Table 5 Parameters and test results of HMS test of the compounds of the present invention

[0714] Conclusion: The compound of the present invention is moderately metabolized in human hepatocytes and rapidly metabolized in mice, showing good stability.

[0715] Experimental Example 6: Cytochrome P450 isoenzyme inhibition activity test

[0716] Purpose of the experiment:

[0717] The compounds of the present invention were tested for their inhibitory activity against different isoforms of human liver microsomal cytochrome P450 isoforms.

[0718] Experimental Materials:

[0719] Pooled human liver microsomes (HLM) were purchased from Corning Inc. (Steuben, New York, USA). Diclofenac was used as the probe substrate (10 μM), sulfaphenazole was used as the positive control inhibitor, and 4′-hydroxydiclofenac was used as a metabolite.

[0720] Preparation of the test system working solution: Human liver microsomes: HLM stock solution 20.0 mg / mL, working solution 0.2 mg / mL, final concentration 0.1 mg / mL; potassium phosphate buffer: 100 mM; cofactor working solution: magnesium chloride, NADP (nicotinamide adenine dinucleotide phosphate), G6P (glucose-6-phosphate), G6PDH (glucose-6-phosphate dehydrogenase), and phosphate buffer or magnesium chloride, NADPH (reduced nicotinamide adenine dinucleotide phosphate) powder, and potassium phosphate buffer; prepare the cofactor working solution in appropriate proportions.

[0721] Stop solution: Prepare the isotope internal standard 4′-hydroxydiclofenac-d4 stock solution in methanol, and then prepare the stop solution in acetonitrile.

[0722] Experimental methods:

[0723] Add 100 μL of a mixture of human liver microsomes and potassium phosphate buffer to the substrate-free control sample wells of the reaction plate, and add 98 μL of a mixture of human liver microsomes and potassium phosphate buffer to the zero time point sample wells; add 100 μL of a mixture of human liver microsomes and substrate to the inhibitor-free control (NIC), test sample, and positive control inhibitor sample wells of the reaction plate; take 2 μL of blank solvent, test sample working solution (three parallels), and positive control inhibitor working solution (two parallels) from the dilution plate and add them to the reaction plate; preheat the reaction plate at 37.0°C for 10 minutes; add 98 μL of the cofactor working solution to the reaction plate to start the reaction; after the reaction time of each CYP enzyme is reached, add 200 μL of the stop solution to the reaction plate to stop the reaction; add 4 μL of the zero time point sample wells. 5.0% substrate solution; place the sample plate in a centrifuge and centrifuge at 3220×g for 20 minutes; remove the supernatant and add the appropriate diluent in the appropriate proportion, shake the plate until mixed; use liquid chromatography-tandem mass spectrometry (LC-MS / MS) to determine the concentration of specific metabolites in the sample. Nonlinear regression analysis of the average percentage activity of the test article against the concentration was performed using SigmaPlot (V.11). IC was calculated using a three-parameter or four-parameter sigmoidal logarithmic equation. 50 The experimental results are shown in Table 6.

[0724] Table 6. Inhibition results of the compounds of the present invention on P450 isozymes

[0725] Conclusion: The compounds of the present invention have no significant inhibition on different subtypes of P450 isoenzymes.

[0726] Experimental Example 7: Plasma Protein Binding (PPB) Test

[0727] Purpose of the experiment:

[0728] The protein binding rate of the compound of the present invention in CD-1 mouse and human plasma was determined by equilibrium dialysis.

[0729] Experimental methods:

[0730] Plasma samples of the compound were prepared using CD-1 mouse and human plasma, with the compound concentration at 2.00 μM. The samples were placed in a 96-well equilibrium dialysis apparatus and dialyzed against phosphate buffer at 37°C for 6 hours. Warfarin was used as a control compound in this experiment. The concentrations of the analyte in plasma and dialysis buffer were determined by LC-MS / MS, and the free rate (% Unbound), bound rate (% Bound), and recovery rate (% Recovery) of the compound were calculated using the following formula: % Unbound = 100 * F C / T C;%Bound=100-%Unbound;%Recovery=100*(F C +T C ) / T0, where F C is the concentration of the compound at the buffer end of the dialysis plate; T C is the concentration of the compound at the plasma end of the dialysis plate; T0 is the concentration of the compound in the plasma sample at time zero.

[0731] Experimental conclusion: The compound showed a high degree of binding in both CD-1 mouse and human plasma.

Claims

1. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof, in, is selected from single bonds and double bonds; T1 is selected from C, T2 is selected from N; Alternatively, T1 is selected from N, and T2 is selected from C; T3 is selected from O, N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2; T4 is selected from N, NH, C(═O), C(R3)2O, C(R3) and C(R3)2; L1 is selected from CH2 and C(=O); L2 and L3 are independently selected from a single bond and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace; R1 is selected from O, S and NR4; R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-6 Cycloalkyl, the C 1-4 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-6 The cycloalkyl group is optionally substituted by 1, 2 or 3 R d replace; R3 is selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace; R4 is selected from OH, CN and -(OCH2CH2) n -C 1-3 alkoxy; n is 0 or 1; Ring A is selected from phenyl, 5-6 membered heteroaryl and C 5-6 Cycloalkenyl, the phenyl, 5-6 membered heteroaryl and C 5-6 The cycloalkenyl group is optionally substituted by 1, 2 or 3 R c replace; Each R a and each R b are independently selected from H, F, Cl, Br, I and OH; Alternatively, two R on the same carbon atom a Connect to C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 halogens; Alternatively, two R on different carbon atoms a Connect to C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 halogens; Each R c are independently selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens; Each R d are independently selected from H, F, Cl, Br, I, OH, NH2, C 1-3 Alkyl and C 3-6 Cycloalkyl, the C 1-3 Alkyl and C 3-6 The cycloalkyl groups are each independently optionally substituted with 1, 2 or 3 halogens; Provided that: when T4 is selected from C(R3)2, T3 is selected from C(R3)2O, T2 is selected from C, T1 is selected from N, L1 is selected from CH2, ring A is selected from optionally 1, 2 or 3 R c When substituted phenyl or 5-6 membered heteroaryl, R1 is selected from O, R2 is selected from F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 2- 5-alkenyl, C 2-5 Alkynyl and C 3-6 Cycloalkyl, the C 1-4 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl and C 3-6 The cycloalkyl group is optionally substituted by 1, 2 or 3 R d replace; The “hetero” of the 5- to 6-membered heteroaryl or 4- to 6-membered heterocycloalkyl group represents 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, S(═O), N and C(═O).

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R c are independently selected from H, F, Cl, Br, I and CH3, wherein CH3 is optionally substituted by 1, 2 or 3 halogens; or, each R c Each is independently selected from H, F, Cl, Br, I, CH3 and CF3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R d Each is independently selected from H, F, OH, NH2, CH3 and cyclopropyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L2 and L3 are independently selected from a single bond, CH2, CH2CH2 and C(CH3)2, wherein CH2, CH2CH2 and C(CH3)2 are independently selected from 1, 2 or 3 R a Substituted; or, L2 and L3 are independently selected from a single bond, CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2, 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The structural unit -L2-L3- is selected from -CH2C(CH3)2-, 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from O, NOH, NCN, NOCH3, NOCH2CH3 and NOCH2CH2OCH3.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, cyclopropyl, The CH3, cyclopropyl, Each independently optionally replaced by 1, 2 or 3 R d Substituted; or, R2 is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H, F, Cl, Br, I, CH3, CH2F, CHF2, CF3 and Alternatively, R3 is selected from H, CH3 and CHF2.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein T3 is selected from O, CH2O, CH and C(CH3).

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein T4 is selected from CH(CHF2), N and C(=O).

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from phenyl, pyridyl and cyclohexenyl, wherein the phenyl, pyridyl and cyclohexenyl are each independently optionally substituted by 1, 2 or 3 R c Substituted; or, Ring A is selected from 12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 14. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: in, R1, R2, R3, T1, T2, L1, L2, L3, Ring A and As defined in any one of claims 1 to 13; When R3 is not H, 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.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: in, R3 is selected from F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace; R1, R2, L2, L3, Ring A and each R b As defined in claim 14.

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

17. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ALK inhibitor-related diseases.

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