CYP11a1 inhibitor, preparation method therefor and use thereof

Abstract

The present application relates to a compound represented by formula (I). The compound can inhibit steroid hormone dependent conditions and diseases of CYP11A1. The present application further comprises a pharmaceutical composition comprising the compound represented by formula (I), and a method for treating a condition related to CYP11A1 activity.

Description

A CYP11A1 inhibitor, its preparation method and application

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application CN202311163184.9 filed on September 8, 2023 and Chinese patent application CN202410733904.9 filed on June 6, 2024, the contents of which are incorporated by reference into this application in their entirety and for all purposes. Technical Field

[0003] The present application relates to the field of medicine, and specifically to a CYP11A1 inhibitor, a preparation method thereof, and applications thereof. Background Art

[0004] Treatment of steroid receptor-dependent diseases, such as androgen receptor (AR)-dependent and estrogen receptor (ER)-dependent cancers, has been extensively studied. For example, prostate cancer is one of the most common cancers in men worldwide. While the five-year survival rate for patients with localized prostate cancer is high, the prognosis for patients who develop castration-resistant prostate cancer (CRPC) within a five-year follow-up period is dismal. The androgen receptor (AR) signaling axis is crucial in all stages of prostate cancer. In CRPC (castration-resistant prostate cancer), the disease is characterized by high AR expression, AR amplification, and persistent activation of the AR signaling axis by residual tissue / tumor androgens, other steroid hormones, and steroid biosynthesis intermediates. Therefore, treatment of advanced prostate cancer involves androgen deprivation therapy (ADT), such as hormonal control using gonadotropin-releasing hormone (GnRH) agonists / antagonists or surgical castration, AR antagonists, or CYP17A1 inhibitors (such as abiraterone acetate in combination with prednisone). Although therapy can initially lead to disease regression, most patients ultimately develop disease that is refractory to currently available therapies. It has been hypothesized that elevated progesterone levels in patients receiving abiraterone acetate represent a mechanism of resistance. Several nonclinical and clinical studies have suggested that enzymes catalyzing steroid biosynthesis are upregulated in the late stages of CRPC. Recently, it has been reported that 11β-OH androstenedione can be metabolized to 11-ketotestosterone (11-KT) and 11-ketodehydrotestosterone (11-K-DHT), which can bind to and activate the AR as effectively as testosterone and dihydrotestosterone. Studies have shown that these steroids are present in high levels in the plasma and tissues of prostate cancer patients, suggesting their role as AR agonists in CRPC. Furthermore, it has been addressed that prostate cancer resistance to CYP17A1 inhibition may still remain steroid-dependent and respond to treatments that can further inhibit de novo intratumoral steroid synthesis upstream of CYP17A1, such as through CYP11A1 inhibition therapy (Cai, C. et al., 1(20), 6503-6513, 2011).

[0005] CYP11A1, also known as cholesterol side-chain cleavage enzyme, is a mitochondrial monooxygenase that catalyzes the conversion of cholesterol to pregnenolone, a precursor of all steroid hormones. By inhibiting CYP11A1, a key enzyme in steroid biosynthesis upstream of CYP17A1, complete blockade of steroid biosynthesis can be achieved. Therefore, CYP11A1 inhibitors may have significant potential for treating steroid hormone-dependent cancers, including prostate cancer, even in advanced stages of the disease, particularly in patients who appear refractory to hormone therapy.

[0006] Summary of the Invention

[0007] The compounds of formula (0) have been found to be potent inhibitors of CYP11A1. Therefore, the compounds of the present invention are particularly useful as drugs for the treatment of steroid hormone-dependent conditions and diseases requiring inhibition of CYP11A1.

[0008] In one aspect, the present invention provides a compound of formula (0), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof:

[0009] Among them: Ring A is C 6-10 Aryl, 5-6 membered heteroaryl, 5-12 membered heterocyclic group; wherein the heteroatom in the 5-6 membered heteroaryl group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; wherein the heteroatom in the 5-12 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0010] L 1 is a direct bond, O, S, -NH-, unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-6 Alkenylene, unsubstituted or substituted with one or more L 1-3 Substituted C 2-6 Alkyne, unsubstituted or substituted with one or more L 1-4 Substituted *-C 1-6 Alkylene-S-, unsubstituted or substituted with one or more L 1-5 Replaced *-SC 1-6 Alkylene-, unsubstituted or substituted by one or more L 1-6 Substituted *-C 1- 6-alkylene-O-, unsubstituted or substituted with one or more L 1-7 Replaced *-OC 1-6 Alkylene-, unsubstituted or substituted by one or more L 1-8 Replaced *-OC 6-10 Arylene-, unsubstituted or substituted by one or more L 1-8 Substituted *-C 6-10 Arylene-O-, unsubstituted or substituted with one or more L 1-9 Substituted *-SO2-C 1-3 Alkylene*-C(=O)-NH-, *-NH-C(=O)-, unsubstituted or substituted with one or more L 1-10 Substituted *-C 1-6 Alkylene-OC 1-6 Alkylene-, unsubstituted or substituted by one or more L1-10 Substituted *-C 1-6 Alkylene-C(O)-; wherein the bond marked with "*" is connected to ring B;

[0011] Preferably, L 1 is a direct bond, O, -NH-, unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-6 Alkenylene, C 2-6 Alkynylidene, *-C 1-6 Alkylene-S-, *-C 1-6 Alkylene-O-, *-OC 1-6 Alkylene-, *-C 6-10 Arylene-O-, *-C 1-6 Alkylene-C(O)-; wherein the bond marked with "*" is connected to ring B;

[0012] Each L 1-1 , L 1-2 , L 1-3 , L 1-4 , L 1-5 , L 1-6 , L 1-7 , L 1-8 , L 1-9 , L 1-10 are independently halogen, OH, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the heteroatom in the 3-6 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; wherein, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by deuterium, halogen, OH, CN or -NH2,

[0013] Ring B is a 5-12 membered heterocyclic group; wherein the heteroatom in the 5-12 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0014] R 1 are independently deuterium, halogen, cyano, hydroxyl, oxo, C 1-6 Alkoxy, R 1-1 、-C(=O)-R 1-1 、-(CR 1-2 R 1-3 ) q -C(=O)-OR 1-4 NR 1-7 R 1-8 、-C(=O)-NR 1-7R 1-8 、-C(=NH)-(R 1- 9 )、-S(O)2-R 1-9 、-S(O)2-NR 1-5 R 1-6 、-NR 1-5 S(O)2-R 1-10 、-R 1-10 -OH, -P(=O)-R 1-2 R 1-3 ;

[0015] Preferably, R 1 are independently cyano, hydroxy, -C(=O)-R 1-1 、-(CR 1-2 R 1-3 ) q -C(=O)-OR 1-4 NR 1-7 R 1-8 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-S(O)2-NR 1- 5 R 1-6 、-NR 1-5 S(O)2-R 1-10 、-R 1-10 -OH, -P(=O)-R 1-2 R 1-3 or two R attached to the same carbon atom 1 Forming an oxo group (=O);

[0016] Preferably, R 1 are each independently -C(=O)-R 1-1 、-(CR 1-2 R 1-3 ) q -C(=O)-OR 1-4 NR 1-7 R 1- 8 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-NR 1-5 S(O)2-R 1-10 、-R 1-10 -OH or -P(=O)-R 1-2 R 1-3or two R attached to the same carbon atom 1 Forming an oxo group (=O);

[0017] R 2 are independently deuterium, OH, NH2, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 1- 6 haloalkyl, C 1-6 Deuterated alkyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 2-6 Alkenyl, -OC 3-10 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-10 Cycloalkyl, -C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 1-6 Alkylene-C 3-10 Cycloalkyl, -C(=O)NR 2-1 R 2-2 、-NR 2-3 -C(=O)-R 2-4 or two R attached to the same carbon atom 2 forming an oxo group (=O); wherein the heteroatoms in the 3-10 membered heterocyclic group or the 5-10 membered heteroaryl group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0018] Optionally, two adjacent R 2 Forming a 5-6 membered heterocyclic group; wherein the heteroatom in the 5-6 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0019] R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 and R 1-8 Each independently is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -CN, -C3-10 Cycloalkyl, or 3-10 membered heterocyclic group; wherein the heteroatoms in the 3-10 membered heterocyclic group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0020] R 1-9 and R 1-10 Each independently is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene -CN, C 2-6 Alkenyl, C 1-6 Halogenated alkyl, C 2-6 Halogenated alkenyl, C 3-10 Cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C 1-6 Alkyl-C 6-10 arylene-;

[0021] R 2-1 、R 2-2 、R 2-3 or R 2-4 are each independently H, halogen or C 1-6 alkyl;

[0022] Ring C is independently a 5-membered nitrogen-containing heterocyclic acene or a 5-membered nitrogen-containing heterocyclic pyridine;

[0023] Each R 3 are independently cyano, hydroxy, halogen, C 1-6 Alkyl or two R attached to the same carbon atom 3 Forming an oxo group (=O);

[0024] R 4 and R 5 are independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, or R 4 and R 5 Together with the atoms they are connected to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0025] Preferably, R 4 and R 5 are independently H, deuterium, halogen, C 1-6 Alkyl; More preferably, R 4 and R 5 All are H or deuterium, or R 4 and R 5 One of them is H and the other is deuterium, halogen, C 1-4 alkyl;

[0026] q is 0 or 1;

[0027] m, t and n are each independently 0, 1, 2, 3 or 4; and

[0028] Wherein: 1) when ring A is a benzene ring, L 1 When *-CH2-O-, the bond marked with "*" is connected to ring B, and the compound of formula (0) is not

[0029] 2) no

[0030] In some embodiments according to the first aspect, the R 1 are each independently an oxo group, -C(=O)-R 1-1 、-(CR 1-2 R 1-3 ) q -C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-NR 1-5 S(O)2-R 1-10 、-R 1-10 -OH, -P(=O)-R 1-2 R 1-3 .

[0031] In some embodiments according to the first aspect, the R 1 are independently oxo, -C(=O)-R 1-1 、-(CR 1-2 R 1-3 ) q -C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-(C=NH)-(C 1-6 Alkyl), -S(O)2-C 1-6 Alkyl, -S(O)2-C 1-6 Halogenated alkyl, -S(O)2-C 6-10 Arylene-C 1-6 Alkyl, -S(O)2-C 3-10 Cycloalkyl, -S(O)2-5-10 membered heteroaryl, -S(O)2-C 2-6 Alkenyl, -NR 1-5 S(O)2-C 1-6 Alkyl, -P(=O)-R 1- 2 R1-3 ; preferably oxo, -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-(C=NH)-(C 1-3 Alkyl), -S(O)2-C 1-3 Alkyl, -S(O)2-C 1-3 Halogenated alkyl, -S(O)2-phenylene-C 1-3 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-5-6 membered heteroaryl, -S(O)2-C 2-3 Alkenyl, -NR 1-5 S(O)2-C 1-3 Alkyl, -P(=O)-R 1-2 R 1-3 More preferably -S(O)2-C 1-3 Alkyl, -C(=O)-OC 1-6 Alkyl, -S(O)2-C 1-3 Halogenated alkyl, -S(O)2-phenylene-C 1-3 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-5-6 membered heteroaryl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkylene-CN, -S(O)2-C 2-3 Alkenyl, -C(=O)-NHC 1-6 Alkyl; most preferably -S(O)2-C 1-3 alkyl.

[0032] In some embodiments according to the first aspect, the R 1-1 、R 1-4 Each independently is H, C 1- 6 alkyl, preferably C 1-3 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-CN, or -C 3-10 Cyclic hydrocarbon group.

[0033] In some embodiments according to the first aspect, the R 1-2 、R 1-3 、R 1-5 、R 1-6 、R 1-7 and R 1- 8 Each independently is H or C 1-6The alkyl group is preferably H or C 1-3 alkyl.

[0034] In some embodiments according to the first aspect, R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1- 7 、R 1-8 、R 1-9 and R 1-10 In the C 1-6 The alkyl groups are independently methyl, ethyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably C 1-4 Alkyl, more preferably methyl or tert-butyl.

[0035] In some embodiments according to the first aspect, R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1- 7 、R 1-8 、R 1-9 and R 1-10 In the -C 1-6 Alkylene-CN is independently -methylene-CN, -ethylene-CN, -isopropylene-CN, -n-butylene-CN, -isobutylene-CN or -tert-butylene-CN, preferably -C 1-4 Alkylene-CN, more preferably -methylene-CN.

[0036] In some embodiments according to the first aspect, R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1- 7 、R 1-8 、R 1-9 and R 1-10 C 3-10 The cycloalkyl groups are independently C 3-10 Cycloalkyl, preferably C 3-6 Cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

[0037] In some embodiments according to the first aspect, the R 1 for

[0038] In some embodiments according to the first aspect, the heteroatoms in ring B are selected from N, O and S in a 5-12 membered heterocyclic group, and the number of heteroatoms is 1, 2, 3 or 4, wherein at least one heteroatom is N, and preferably the number of heteroatoms is 1, 2 or 3.

[0039] In some embodiments according to the first aspect, the ring B is a 5-6 membered monocyclic heterocyclyl, a 6-12 membered (preferably 9-12 membered) fused bicyclic heterocyclyl, or a 9-12 membered spirocyclic heterocyclyl. Preferably, the ring B is a 6 membered monocyclic heterocyclyl (e.g., piperidinyl, piperazinyl).

[0040] In some embodiments according to the first aspect, the ring B is a 5-6 membered monocyclic heterocyclyl or a 9-12 membered fused bicyclic heterocyclyl (eg, a benzo 6-membered heterocycloalkyl or a pyrido 6-membered heterocycloalkyl).

[0041] According to some embodiments of the first aspect, the 5-6 membered monocyclic heterocyclic group in ring B is independently a 5-6 membered monocyclic heterocyclic group, preferably having 1 heteroatom, such as azacyclopentane or azacyclohexane, preferably azacyclohexane.

[0042] According to some embodiments of the first aspect, the 6-12 membered fused and bicyclic heterocyclic group in ring B is independently a 6-10 membered fused and bicyclic heterocyclic group, such as benzazepine, pyridazepine, thienazepine, pyrrolotetrahydropyridinyl, pyrazolotetrahydropyridinyl, imidazotetrahydropyridinyl, indolinyl, indolinone, pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl, Preference is given to benzazepines, pyridazepines or thienoazepines.

[0043] According to some embodiments of the first aspect, the 6-12 membered fused bicyclic heterocyclic group in ring B is independently a 9-12 membered fused bicyclic heterocyclic group, such as benzazacyclopentane, benzazacyclohexane, benzazacycloheptane, pyridazacyclohexane, pyrimidazacyclohexane, thienoazacyclohexane, pyrrolidinocyclopentane; preferably benzazacyclohexane and pyridazacyclohexane.

[0044] According to some embodiments of the first aspect, the 9-12 membered spirocyclic heterocyclic group in ring B is independently a 7-10 membered monospirocyclic heterocyclic group, and optionally the heteroatoms may be N and O, preferably a 3-membered / 4-membered ring system, a 3-membered / 5-membered ring system, a 3-membered / 6-membered ring system, a 4-membered / 4-membered ring system, a 4-membered / 5-membered ring system, a 4-membered / 6-membered ring system, a 5-membered / 5-membered ring system, a 5-membered / 6-membered ring system and a 6-membered / 6-membered ring system, for example For example

[0045] According to some embodiments of the first aspect, the 9-12 membered spirocyclic heterocyclic group in the ring B is independently a 9-12 membered monospirocyclic heterocyclic group, and the heteroatoms are optionally N and O, preferably a 4-membered / 6-membered ring system, a 5-membered / 5-membered ring system, a 5-membered / 6-membered ring system and a 6-membered / 6-membered ring system, for example

[0046] In some embodiments according to the first aspect, the ring B is The bond marked with "a" is connected to R 1 , the bond marked with "b" is connected to L 1 .

[0047] In some embodiments according to the first aspect, the ring B is The bond marked with "a" is connected to R 1 , the bond marked with "b" is connected to L 1 Preferably, ring B is

[0048] According to some embodiments of the first aspect, the ring B is In some embodiments according to the first aspect, the L 1 is a direct bond, O, -NH-, unsubstituted or replaced by one or more L 1-1 Substituted C 1-4 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-4 Alkenylene, C 2-4 Alkynylidene, *-C 1-4 Alkylene-S-, *-C 1-4 Alkylene-O-, *-OC 1-4 Alkylene-, *-phenylene-O-, *-C1-4 Alkylene-C(O)-.

[0049] In some embodiments according to the first aspect, the L 1 is unsubstituted or replaced by one or more L 1- 1 Substituted C 1-4 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-4 Alkenylene.

[0050] In some embodiments according to the first aspect, the unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-6 The plurality of alkenylene groups is 1, 2, 3, or 4, preferably 1 or 2.

[0051] In some embodiments according to the first aspect, the L 1 is a direct bond, unsubstituted or replaced by one or more L 1-1 Substituted C 1-2 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-3 Alkenylene, C 2-3 Alkynylidene, *-C 1-2 Alkylene-S-, *-C 1-2 Alkylene-O-, *-C 1-2 Alkylene-C(O)-.

[0052] In some embodiments according to the first aspect, the L 1 is unsubstituted or replaced by one or more L 1- 1 Substituted C 1-2 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-3 Alkenylene.

[0053] In some embodiments according to the first aspect, each L 1-1 , L 1-2 , L 1-3 , L 1-4 , L 1-5 , L 1-6 , L 1-7 , L 1-8 , L 1-9 , L 1-10 are independently halogen, OH, C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0054] In some embodiments according to the first aspect, each L 1-1 , L 1-2 , L 1-3 , L 1-4 , L 1-5 , L 1-6 , L 1-7 , L 1-8 , L 1-9 , L 1-10 wherein the halogen is independently F, Cl, Br or I, preferably F, Cl, Br, and more preferably F.

[0055] In some embodiments according to the first aspect, each L 1-1 , L 1-2 , L 1-3 , L 1-4 , L 1-5 , L 1-6 , L 1-7 , L 1-8 , L 1-9 , L 1-10 In the C 1-6 The alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, preferably methyl.

[0056] In some embodiments according to the first aspect, each L 1-1 , L 1-2 , L 1-3 , L 1-4 , L 1-5 , L 1-6 , L 1-7 , L 1-8 , L 1-9 , L 1-10 C 3-6 The cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

[0057] In some embodiments according to the first aspect, the unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, *-C 1-6 Alkylene-S-, *-C 1-6 Alkylene-O-, *-OC 1-6 Alkylene- or *-C 1-6 Alkylene-C(O)-C 1-6 Each alkylene group is independently -CH2-, -CH2-CH2-, -C(CH3)-CH2-, -CH(CH3)-CH(CH3)-, -CH2CH2-CH(CH3)-, or -CH2CH(CH3)-CH2-.

[0058] In some embodiments according to the first aspect, 1-2 Substituted C 2-6 In the alkenylene group, the C 2-6 Alkenylene is independently -CH=CH-, -CH=CHCH2-, -CH2CH=CHCH2-, -CH=CHCH2CH2-, -C(CH3)=CHCH2-, -C(CH3)=CHCH2-, -C(CH3)=CH-, or -C(CH3)=C(CH3)-.

[0059] In some embodiments according to the first aspect, the L 1 C 2-6 In the alkynylene group, the C 2-6 Alkynylene is -C≡C-, -CH2-C≡C-, -CH2-C≡C-CH2-, -CH2-CH2-C≡C-, -C≡CC≡C-.

[0060] In some embodiments according to the first aspect, the L 1 *-C 6-10 Arylene-O-, the C 6-10 Arylene is phenyl or naphthyl, preferably phenyl.

[0061] In some embodiments according to the first aspect, the L 1 For *-CH2-O-, -CH2-CH2-, *-CH2-CH2-O-, *-O-CH2-, *-CH2-S-, *-CH2-CH2-S-, -CH=CH-, -CH2-, bond, -N H-, -O-, *-CH=CF-, *-CF=CH-, *-CH=C(CH3)-, *-C(CH3)=CH-, -CF=CF-, -C(CH3)=C(CH3)-, *-CH2-CH F-, *-CHF-CH2-, *-CH2-CH(CH3)-, *-C(CH3)-CH2-, -CHF-CHF-, -CH(CH3)-CH(CH3)-, *-CH2-CF2-, *-CF2-CH2-, *-CH2-CH(cyclopropane)-, *-CH(cyclopropane)-CH2-, *-CH=C(cyclopropane)-, *-C(cyclopropane)=CH-, *-CH2-CH(OH)-, -C≡C-, or *-CH2-C(O)-; wherein the bond identified by "*" is connected to ring B.

[0062] In some embodiments according to the first aspect, the L 1*-CH2-O-, -CH2-CH2-, *-CH2-CHF-, *-CH=CF-, *-CH2-CH(OH)-, *-CH2-S-, *-CH2-CH2-S-, -CH=CH-, bond, -C≡C-, *-CH2-C(O)-.

[0063] In some embodiments according to the first aspect, the L 1 *-CH2-O-, -CH2-CH2-, -CH=CH-; wherein the bond marked with "*" is connected to ring B.

[0064] In some embodiments according to the first aspect, the L 1 It is -CH2-CH2-, -CH=CH-; wherein the bond marked with "*" is connected to ring B.

[0065] In some embodiments according to the first sub-aspect, the R 2 are independently OH, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 2-6 Alkenyl, -OC 3-10 Cycloalkyl, -SC 1-6 Alkyl, -C 3-10 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 1-6 Alkylene-C 3-10 Cycloalkyl, -C(=O)NR 2- 1 R 2-2 or two R attached to the same carbon atom 2 forming an oxo group (=O); wherein the heteroatoms in the 3-10 membered heterocyclic group or the 5-10 membered heteroaryl group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0066] Alternatively, the adjacent R 2 Forming a 5-6 membered heterocyclic group; wherein the heteroatoms in the 5-6 membered heterocyclic group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0067] In some embodiments according to the first sub-aspect, the R 2 Independently OH, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 2-6 Alkenyl, -OC 3-10 Cycloalkyl, -SC 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 1-6 Alkylene-C 3-10 Cycloalkyl, -C(=O)NR 2- 1 R 2-2 or two R attached to the same carbon atom 2 An oxo group (=O) is formed.

[0068] In some embodiments according to the first sub-aspect, each R 2 are independently OH, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -SC 1-4 Alkyl, -OC 2-4 Alkenyl, -OC 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -C(=O)NHC 1-4 Alkyl or two R attached to the same carbon atom 2 An oxo group (=O) is formed.

[0069] In some embodiments according to the first sub-aspect, R 2 wherein the halogen is independently F, Cl, Br or I, preferably F, Cl or Br.

[0070] In some embodiments according to the first sub-aspect, R 2 In the C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 C in the alkyl group 1-6The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, isopropyl, sec-butyl or tert-butyl.

[0071] In some embodiments according to the first sub-aspect, R 2 In the C 2-6 Alkenyl, -OC 2-6 C in alkenyl 2-6 The alkenyl group is independently vinyl, propenyl, isopropenyl, butenyl or isobutenyl, preferably vinyl, propenyl or isopropenyl.

[0072] In some embodiments according to the first sub-aspect, R 2 In the C 1-6 Haloalkyl, -OC 1- 6-Halogenated alkyl C 1-6 The haloalkyl groups are independently C 1-3 Haloalkyl, such as -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Cl, -CH2CH2F, -CHClCH3 or -CH(CH3)CH2F, preferably -CF3.

[0073] In some embodiments according to the first sub-aspect, R 2 In the C 1-6 C in deuterated alkyl 1-6 Deuterated alkyl is preferably C 1-3 Deuterated alkyl, such as -CD3, -CHD2, -CH2D; preferably -CD3.

[0074] In some embodiments according to the first sub-aspect, R 2 In, the -OC 3-10 Cycloalkyl, -SC 3- 10 Cycloalkyl, -C 3-10 Cycloalkyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 1-6 Alkylene-C 3-10 C in the cycloalkyl group 3-10 The cycloalkyl groups are independently C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, preferably C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cyclopropyl. 3-6 Cycloalkenyl is for example cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.

[0075] In some embodiments according to the first sub-aspect, R 2 wherein the 3-10 membered heterocyclic group is independently a 3-6 membered heterocyclic group, and the 3-6 membered heterocyclic group is an oxirane group, an aziridine group, an azetidine group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a dioxolyl group, a pyrrolidinyl group, a pyrrolidonyl group, an oxazolidinyl group, a thiazolidinyl group, a pyrazolidinyl group, an imidazolidinyl group, a pyrrolinyl group, a tetrahydropyranyl group or a piperidinyl group, preferably an oxirane group, an aziridine group, an azetidine group or an oxetanyl group.

[0076] In some embodiments according to the first sub-aspect, R 2 wherein the 5-10 membered heteroaryl is independently pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolyl, indolyl, pyrrolopyridazinyl or benzofuranyl, preferably oxazolyl, furanyl or thiazolyl.

[0077] In some embodiments according to the first sub-aspect, R 2 In the R 2-1 、R 2-2 Each independently is H or C 1-3 Alkyl, preferably H or methyl.

[0078] In some embodiments according to the first sub-aspect, R 2 The adjacent R 2 Forming a 5-6 membered heterocyclic group; wherein the heteroatom in the 5-6 membered heterocyclic group is selected from N or O, the number of heteroatoms is 1 or 2, preferably azetidine, azetidine, azetidine, oxetane, oxhexane or oxetane, more preferably oxetane or oxhexane.

[0079] In some embodiments according to the first sub-aspect, the halogen is independently F, Cl, Br or I, preferably F, Cl or Br.

[0080] In some embodiments according to the first sub-aspect, the R 2 Independently OH, F, Cl, Br, CN, -CH2F, -CHF2, -CF3, -CD3, -S-CH3, -O-CH-(CH3)2, -O-CH(CH3)-CH2CH3, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, isopropenyl, methoxy, ethoxy, cyclopropyl, cyclopropylmethyl-, in The wavy line Indicates the position of fusion with ring A.

[0081] In some embodiments according to the first aspect, m is independently 0, 1, 2 or 3, preferably 0, 1 or 2.

[0082] In some embodiments according to the first aspect, n is independently 0, 1, 2 or 3, preferably 0 or 1.

[0083] In some embodiments according to the first aspect, t is independently 0, 1, 2 or 3, preferably 0 or 1.

[0084] In some embodiments according to the first aspect, Ring A is C 6-10 aryl, 5-6 membered heteroaryl or 6 membered heterocyclic group.

[0085] In some embodiments according to the first aspect, C in Ring A 6-10 Aryl is independently phenyl or naphthyl, preferably phenyl.

[0086] In some embodiments according to the first aspect, the 5-6 membered heteroaryl group in ring A is independently a 5-6 membered nitrogen-containing heteroaryl group, such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, pyranyl, pyrrolyl, furanyl, thienyl or imidazolyl, preferably pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0087] In some embodiments according to the first aspect, the 5-12 membered heterocyclic groups in ring A are independently oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolyl, pyrrolidinyl, pyrrolidonyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrrolinyl, pyranyl, tetrahydropyranyl,

[0088] In some embodiments according to the first aspect, the 5-12 membered heterocyclic group in ring A is tetrahydrofuranyl, tetrahydrothiophenyl, dioxolyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrrolinyl, pyranyl, tetrahydropyranyl,

[0089] In some embodiments according to the first aspect, Ring A is: The bond marked with "c" is connected to L 1 , the key marked with "d" is connected to

[0090] In some embodiments according to the first aspect, Ring A is: Preferably, the ring A is The bond marked with "c" is connected to L 1 , the key marked with "d" is connected to

[0091] In some embodiments according to the first aspect, the Part of it is:

[0092] In some embodiments according to the first aspect, the Part of it is:

[0093] In some embodiments according to the first aspect, the Part of it is:

[0094] In some embodiments according to the first aspect, the Part of it is:

[0095] In some embodiments according to the first aspect, the Part of it is:

[0096] In some embodiments according to the first aspect, the Part of it is:

[0097] In some embodiments according to the first aspect, the Part of it is:

[0098] In some embodiments according to the first aspect, Ring C is independently

[0099] In some embodiments according to the first aspect, the present invention provides a compound of formula (0) as described above, wherein the compound has a structure shown in formula (I):

[0100] In some embodiments according to the first aspect, the present invention provides a compound of formula (0) as described above, wherein the compound has a structure shown in formula (I-20'), formula (I-21') or formula (I-22'):

[0101] In some embodiments according to the first aspect, the present invention provides a compound of formula (I-20'), formula (I-21') or formula (I-22') as described above, wherein the compound has a structure shown in formula (I-20), formula (I-21) or formula (I-22):

[0102] In some embodiments according to the first aspect, the present invention provides a compound (I-20') as described above, wherein the compound has a structure shown in Formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ) or (IR):

[0103] Where m1 is 0, 1, or 2.

[0104] In some embodiments according to the first aspect, the present invention provides the compound (0) as described above, wherein the compound has a structure shown in formula (II-A), (II-B), (II-C) or (II-D):

[0105] In some embodiments according to the first aspect, the present invention provides a compound as described above (0), wherein the compound has a structure shown in formula (II-A-1), (II-B-1), (II-C-1) or (II-D-1):

[0106] In some embodiments according to the first aspect, the present invention provides a compound as described above (0), wherein the compound has a structure shown in formula (II-A-2), (II-B-2), (II-C-2), (II-D-2), (II-A-3), (II-B-3), (II-C-3) or (II-D-3): Where m1 is 0, 1, or 2.

[0107] In some embodiments according to the first aspect, the present invention provides a compound as described above (0), wherein the compound has a structure represented by formula (II'-A-2), (II'-B-2), (II'-C-2), (II'-D-2), (II'-A-3), (II'-B-3), (II'-C-3) or (II'-D-3): wherein m1 is 0, 1 or 2, preferably m1 is 2; m is 0, 1, 2 or 3, preferably m is 1 or 2; L 1-2 Halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, preferably L 1-2 is F, methyl, cyclopropyl; more preferably L 1-2 For F.

[0108] In some embodiments according to the first aspect, the present invention provides a compound of formula (0) as described above, wherein the compound has a structure shown in formula (IH-1):

[0109] Among them, each R 1 and R 1’ are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, R 1-1 、-C(=O)-R 1-1 、-C(=O)-OR 1-4 、-NR 1-7 R 1-8 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-S(O)2-NR 1-5 R 1-6 、-NR 1-5 S(O)2-R 1-10 、-R 1-10 -OH, -P(=O)-R 1-2 R 1-3 ;

[0110] R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 and R 1-8Each independently is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -CN, C 3-10 Cycloalkyl, or 3-10 membered heterocyclic group; wherein the heteroatoms in the 3-10 membered heterocyclic group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; preferably, R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 and R 1-8 Each independently is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl, -C 1-4 Alkylene-OH, -C 1- 4-alkylene-CN, C 3-6 Cycloalkyl, or 3-6 membered heterocyclic group;

[0111] R 1-9 and R 1-10 Each independently is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene -CN, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 3-10 Cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C 1-6 Alkyl-C 6-10 Arylene-; preferably, R 1-9 and R 1-10 Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene -CN, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 3-6 Cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-C 6-10 arylene-;

[0112] Preferably, R 1 -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R1-9 )、-S(O)2-R 1-9 、-S(O)2-NR 1-5 R 1-6 、-NR 1-5 S(O)2-R 1-10 、-P(=O)-R 1-2 R 1-3 , R 1’ For deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, R 1-1 、-NR 1-7 R 1-8 、-R 1-10 -OH;

[0113] Preferably, R 1 -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-S(O)2-R 1-9 , R 1’ For deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, R 1-1 、-NR 1-7 R 1-8 、-R 1-10 -OH;

[0114] Preferably, R 1 -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-S(O)2-R 1-9 , R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -CN, C 3-10 Cycloalkyl, or 3-10 membered heterocyclic group;

[0115] Preferably, R 1 -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)-C 3-10 Cycloalkyl, -C(=O)-C 1-6Alkylene-CN, -C(=O)-OC 1-6 Alkyl, -C(=O)-OC 3-10 Cycloalkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 6-10 Arylene-C 1-6 Alkyl, -S(O)2-C 3-10 Cycloalkyl, -S(O)2-5-10 membered heteroaryl, -S(O)2-C 1-6 Halogenated alkyl, -S(O)2-C 2-6 Alkenyl, -C(=O)-NH(C 1-6 alkyl), R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -CN, C 3-10 Cycloalkyl, or 3-10 membered heterocyclic group;

[0116] Preferably, R 1 -C(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Haloalkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)-C 1-4 Alkylene-CN, -C(=O)-OC 1-4 Alkyl, -C(=O)-OC 3-6 Cycloalkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-phenylene-C 1-4 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-5-6 membered heteroaryl, -S(O)2-C 1-4 Halogenated alkyl, -S(O)2-C 2-4 Alkenyl, -C(=O)-NH(C 1-4 alkyl), R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-4 Alkoxy, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl, -C 1-4Alkylene-OH, -C 1-4 Alkylene -CN, C 3-6 Cycloalkyl, or 3-6 membered heterocyclic group;

[0117] Preferably, R 1 -S(O)2-C 1-4 Alkyl, -S(O)2-C 2-4 Alkenyl, -S(O)2-phenylene-C 1-4 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-5-6 membered heteroaryl, -C(=O)-OC 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Alkylene-CN; R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl;

[0118] n1 is each independently 0, 1, 2, or 3; preferably, n1 is each independently 0, 1 or 2; more preferably, n1 is 0;

[0119] Ring B is a 5-12 membered heterocyclic group; wherein the heteroatoms in the 5-12 membered heterocyclic group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; preferably, ring B is a 5-6 membered monocyclic heterocyclic group, a 9-12 membered fused bicyclic heterocyclic group or a 9-12 membered spirocyclic heterocyclic group; preferably, ring B is Preferably, for

[0120] L 1 is a direct bond, O, -NH-, unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-6 Alkenylene, unsubstituted or substituted with one or more L 1-3 Substituted C 2-6 Alkyne, unsubstituted or substituted with one or more L 1-4 Substituted *-C 1-6 Alkylene-S-, unsubstituted or substituted with one or more L 1-6 Substituted *-C 1-6 Alkylene-O-, unsubstituted or substituted with one or more L 1-7 Replaced *-OC 1- 6 alkylene-, unsubstituted or substituted by one or more L 1-8 Substituted *-C 6-10 Arylene-O-, unsubstituted or substituted with one or more L 1-10 Substituted *-C1-6 Alkylene-C(O)-;

[0121] Preferably, L 1 is a direct bond, O, -NH-, unsubstituted or replaced by one or more L 1-1 Substituted C 1-4 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-4 Alkenylene, unsubstituted or substituted with one or more L 1- 3 Substituted C 2-4 Alkyne, unsubstituted or substituted with one or more L 1-4 Substituted *-C 1-4 Alkylene-S-, unsubstituted or substituted with one or more L 1-6 Substituted *-C 1-4 Alkylene-O-, unsubstituted or substituted with one or more L 1-7 Replaced *-OC 1-4 Alkylene-, unsubstituted or substituted by one or more L 1-8 Substituted *-phenylene-O-, unsubstituted or replaced by one or more L 1-10 Substituted *-C 1-2 Alkylene-C(O)-;

[0122] Each L 1-1 , L 1-2 , L 1-3 , L 1-4 , L 1-6 , L 1-7 , L 1-8 , L 1-10 are independently halogen, OH, C 1- 6 alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the heteroatom in the 3-6 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; wherein, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with deuterium, halogen, OH, CN or -NH2;

[0123] Preferably, L 1 -CH2-CH2-, *-CH2-O-, -CH=CH-;

[0124] More preferably, L 1 -CH2-CH2-, -CH=CH-;

[0125] R 2 are independently deuterium, OH, NH2, halogen, CN, C 1-6 Alkyl, C 2-6Alkenyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 2-6 Alkenyl, -OC 3-10 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-10 Cycloalkyl, C 3- 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C(O)NH(C 1-6 alkyl); optionally, two adjacent R 2 Forming a 5-6 membered heterocyclic group; wherein the heteroatom in the 5-6 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0126] Preferably, R 2 are independently deuterium, OH, NH2, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl, C 2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -OC 2-4 Alkenyl, -OC 3-6 Cycloalkyl, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C(O)NH(C 1-4 alkyl);

[0127] m is 0, 1, 2, 3 or 4; preferably, m is 0, 1, 2 or 3;

[0128] R 4 and R 5 are independently H, deuterium, halogen, C 1-6 Alkyl; preferably, R4 and R 5 All are H or deuterium, or R 4 and R 5 One of them is H and the other is deuterium, halogen, C 1-4 alkyl.

[0129] In some embodiments according to the first aspect, the present invention provides a compound of formula (IH-1) as described above, wherein the compound has the structure shown in formula (IH-1A), (IH-1B), (IH-1C), or (IH-1D):

[0130] In some embodiments according to the first aspect, the present invention provides a compound of formula (I) as described above, wherein the compound has a structure shown in formula (I-1), formula (I-2), formula (I-3), formula (I-4) or formula (I-5):

[0131] In some embodiments, m is independently 0, 1, 2, 3 or 4, preferably 2 or 4.

[0132] In some embodiments, the R 2 are independently OH, CN, halogen, C 1-3 Alkyl, OC 1-3 Alkyl, C 2-4 Alkenyl, C 1-3 Halogenated alkyl, preferably C 1-3 Alkyl, CN, halogen, more preferably methyl or F.

[0133] In some embodiments, the present invention provides a compound of formula (I) as described above, wherein the compound has a structure shown by formula (I-6), formula (I-7), formula (I-8), formula (I-23), formula (I-6') or formula (I-7'):

[0134] In some embodiments, the L 1 is independently a direct bond, O, S, -NH-, unsubstituted or substituted with one or more L 1-1 Substituted C 1-6 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-6 Alkenylene, *-C 1-6 Alkylene-S-, *-SC 1-6 Alkylene-, *-C 1-6 Alkylene-O-, *-OC 1-6Alkylene-, preferably *-CH2-S-, *-CH2CH2-S-, *-CH2-O-, ethylene or vinylene, more preferably *-CH2-O-, ethylene or vinylene, further preferably ethylene or vinylene.

[0135] In some embodiments, the present invention provides a compound of formula (0) as described above, wherein the compound has a structure shown by formula (I-10), formula (I-11), formula (I-12), formula (I-13), formula (I-24), formula (I-25), formula (I-12'), formula (I-13'), formula (I-121), formula (I-131), formula (I-120) or formula (I-130):

[0136] In some embodiments, the ring B is independently a 5-10 membered heterocyclic group, preferably a 5-10 membered nitrogen-containing heterocyclic group, more preferably Best

[0137] In some embodiments, the present invention provides a compound of formula (0) as described above, wherein the compound has a structure shown in formula (I-16), formula (I-17), formula (I-18), formula (I-170), formula (I-171) or formula (I-172):

[0138] When the ring A of the compound of the present invention is phenyl, the substituent R 2 The activity of the compounds with cyclopropyl group (e.g., inhibition of pregnenolone biosynthesis in NCI-H295R cells) was inferior to that of R 2 H, halogen (such as F, Cl, Br), hydroxyl, alkyl (such as C 1-3 Alkyl), alkenyl (e.g. C 2-3 alkenyl), alkoxy (e.g. C 1-3 Alkoxy), alkenyloxy (e.g. C 2-3 Alkenyloxy) and other compounds.

[0139] In some embodiments, the present invention provides a compound of formula (0) as described above, wherein the compound has a structure shown in formula (IB-1):

[0140] Among them, each R 1 and R 1’ are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, R 1-1 、-C(=O)-R 1-1 、-C(=O)-OR 1-4 、-NR1-7 R 1-8 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-S(O)2-NR 1-5 R 1-6 、-NR 1-5 S(O)2-R 1-10 、-R 1-10 -OH, -P(=O)-R 1-2 R 1-3 ;

[0141] R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 and R 1-8 Each independently is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -CN, C 3-10 Cycloalkyl, or 3-10 membered heterocyclic group; wherein the heteroatoms in the 3-10 membered heterocyclic group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; preferably, R 1-1 、R 1-2 、R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 and R 1-8 Each independently is H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl, -C 1-4 Alkylene-OH, -C 1- 4-alkylene-CN, C 3-6 Cycloalkyl, or 3-6 membered heterocyclic group;

[0142] R 1-9 and R 1-10 Each independently is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene -CN, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 3-10Cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C 1-6 Alkyl-C 6-10 Arylene-; preferably, R 1-9 and R 1-10 Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene -CN, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 3-6 Cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-C 6-10 arylene-;

[0143] Preferably, R 1 -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-S(O)2-NR 1-5 R 1-6 、-NR 1-5 S(O)2-R 1-10 、-P(=O)-R 1-2 R 1-3 , R 1’ For deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, R 1-1 、-NR 1-7 R 1-8 、-R 1-10 -OH;

[0144] Preferably, R 1 -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-S(O)2-R 1-9 , R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -CN, C 3-10 Cycloalkyl, or 3-10 membered heterocyclic group;

[0145] Preferably, R 1 -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-10 Cycloalkyl, -C(=O)-OC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkylene-CN; R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, -NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, C 1-6 alkoxy;

[0146] Preferably, R 1 -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Alkylene-CN; R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, -NH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl, C 1-4 alkoxy;

[0147] n1 is each independently 0, 1, 2, or 3; preferably, n1 is each independently 0, 1 or 2; more preferably, n1 is 0;

[0148] Ring B is a 5-12 membered heterocyclic group; wherein the heteroatoms in the 5-12 membered heterocyclic group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; preferably, ring B is a 5-6 membered monocyclic heterocyclic group, a 9-12 membered fused bicyclic heterocyclic group or a 9-12 membered spirocyclic heterocyclic group; preferably, ring B is wherein G1, G2, G3, G4 are CH or N, at least one of which is CH, s and k are each independently 0, 1 or 2; preferably, ring B is wherein G1, G2, G3, G4 are CH or N, at least one of which is CH, and s is 0, 1 or 2; preferably,

[0149] L 1 is a direct bond, unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, unsubstituted or substituted with one or more L 1-2Substituted C 2-6 Alkenylene, unsubstituted or substituted with one or more L 1-3 Substituted C 2-6 Alkyne, unsubstituted or substituted with one or more L 1-4 Substituted *-C 1-6 Alkylene-S-, unsubstituted or substituted with one or more L 1-6 Substituted *-C 1-6 Alkylene-O-, unsubstituted or substituted with one or more L 1-7 Replaced *-OC 1-6 Alkylene-, unsubstituted or substituted by one or more L 1-8 Substituted *-C 6-10 Arylene-O-, unsubstituted or substituted with one or more L 1-10 Substituted *-C 1-6 Alkylene-C(O)-;

[0150] Preferably, L 1 is a direct bond, unsubstituted or replaced by one or more L 1-1 Substituted C 1-4 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-4 Alkenylene, unsubstituted or substituted with one or more L 1-3 Substituted C 2-4 Alkyne, unsubstituted or substituted with one or more L 1-6 Substituted *-C 1-4 Alkylene-O-, unsubstituted or substituted with one or more L 1-10 Substituted *-C 1-2 Alkylene-C(O)-;

[0151] Each L 1-1 , L 1-2 , L 1-3 , L 1-4 , L 1-6 , L 1-7 , L 1-8 , L 1-10 are independently halogen, OH, C 1- 6 alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the heteroatom in the 3-6 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; wherein, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with deuterium, halogen, OH, CN or -NH2;

[0152] Preferably, L 1is a direct bond, -CH2-CH2-, *-CH2-CHF-, *-CH2-CH(OH)-, *-CH2-O-, -CH=CH-, *-CH=CF-, -C≡C-, *-CH2-C(O)-;

[0153] Preferably, L 1 is -CH2-CH2- or -CH=CH-;

[0154] R 2 are independently deuterium, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl;

[0155] Preferably, R 2 are each independently halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl;

[0156] Preferably, R 2 are independently F, Cl, Br, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 deuterated alkyl;

[0157] m1 is 0, 1 or 2, preferably, m1 is 1 or 2; more preferably, m1 is 2;

[0158] R 4 and R 5 are independently H, deuterium, halogen, C 1-6 Alkyl; preferably, R 4 and R 5 All are H or deuterium, or R 4 and R 5 One of them is H and the other is deuterium, halogen, C 1-4 alkyl.

[0159] In some embodiments, the present invention provides a compound of formula (0) as described above, wherein the compound has a structure shown in formula (IB-1A), (IB-1B) or (IB-1C):

[0160] The present invention at least partially 1 The compounds with cyanoacetyl group have advantages over R 1 PK (pharmacokinetic) properties of compounds containing a methylsulfonyl group.

[0161] The present invention is at least partially 1 Compounds that are alkenylene (e.g., -CH=CH-) have advantages over L 1 PK (pharmacokinetic) properties of compounds containing an alkylene group (e.g., -CH2-CH2-).

[0162] When the compound of the present invention for When at least part of the ring N atoms are replaced by non-hydrogen substituents (e.g., methyl, ethyl, -CD3), the compound has better PK (pharmacokinetic) properties than the compound in which the ring N atoms are replaced by hydrogen (i.e., NH); and at least part of the oxo groups are para-positioned ( The compound in which the oxo group (the circled part) is substituted by F has better PK (pharmacokinetic) properties than the compound in which the oxo group is not substituted at the para position.

[0163] In some embodiments, the present invention provides a compound of formula (0) as described above, wherein the compound has a structure shown in formula (IB-1A-1), (IB-1A-2), (IB-1B-1), (IB-1B-2), (IB-1C-1) or (IB-1C-2):

[0164] Among them, R 2 Each independently is C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl; R 2 ' is halogen, preferably, R 2 Each independently is C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Deuterated alkyl; R 2 'For F.

[0165] In some embodiments, the present invention provides a compound of formula (0) as described above, wherein the compound has a structure shown in formula (III-1), (III-2), (III-3), (III-4), (III-5) or (III-6):

[0166] wherein m1 is 0, 1 or 2, preferably, m1 is 1 or 2; more preferably, m1 is 2; M1 and M2 are each independently selected from CH or N, preferably, at least one of M1 and M2 is selected from CH, L 1-1 Selected from halogen, OH, C 1-4Alkyl, preferably F, OH; L 1-2 Selected from halogen, C 1-4 Alkyl, preferably F.

[0167] In some embodiments, the present invention provides a compound of formula (0) as described above, which satisfies the conditions: Part of When the bond marked with "c" is connected to L 1 , the bond marked with "d" is connected to -C(R 4 R 5 )-;L 1 Not *-CH2-O-, wherein the bond identified by "*" is connected to ring B.

[0168] In some embodiments, the present invention provides a compound of formula (0), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0169] In some embodiments, the present invention provides a compound of formula (0), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is not:

[0170] In another aspect, the present invention provides a method for preparing a compound of formula (I):

[0171] Method 1

[0172] wherein Ring A is preferably C 6-10 Aryl; R1 is preferably R 1-1 、-C(=O)-R 1-1 、-(CR1-2 R 1-3 ) q -C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-S(O)2-NR 1-5 R 1-6 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-R 1-10 -OH, -P(=O)-R 1-2 R 1-3 ;

[0173] Preferred

[0174] Method 2

[0175] Ring C is preferably X or Y is independently CH or N;

[0176] Method 3

[0177] Preferred

[0178] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (0) or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;

[0179] Preferably, the pharmaceutical composition comprises the compound of formula (0) and at least one additional active ingredient selected from the following list:

[0180] - Glucocorticoids;

[0181] - Mineralocorticoids;

[0182] - Nonsteroidal androgen receptor antagonists;

[0183] - Steroidogenesis inhibitors;

[0184] - Chemotherapeutic agents;

[0185] -Antiestrogen;

[0186] - epigenetic regulators;

[0187] -mTOR inhibitors (such as everolimus);

[0188] -AKT inhibitors (e.g., AZ5363);

[0189] - Radiopharmaceuticals (e.g. Alpharadin);

[0190] -GnRH / LHRH analogs (such as leuprorelin);

[0191] - PI3K inhibitors; and

[0192] -CDK4 / 6 inhibitors.

[0193] In another aspect, the present invention provides a method for treating steroid receptor-dependent disorders and diseases of a compound of formula (0) or a pharmaceutical composition thereof, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (0) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts or pharmaceutical compositions thereof; wherein the steroid receptor-dependent disease is preferably cancer; the cancer is preferably prostate cancer; the prostate cancer is preferably castration-resistant prostate cancer (CRPC);

[0194] wherein a therapeutically effective amount of a compound of formula (0) or a pharmaceutical composition thereof is administered, preferably a glucocorticoid and / or a mineralocorticoid is also administered, and optionally one or more anticancer drugs are administered;

[0195] Wherein, a therapeutically effective amount of a compound of formula (0) or a pharmaceutical composition thereof is administered together with one or more anticancer drugs, wherein the anticancer drugs are preferably selected from:

[0196] - Nonsteroidal androgen receptor antagonists;

[0197] - Steroidogenesis inhibitors;

[0198] - Chemotherapeutic agents;

[0199] -Antiestrogen drugs;

[0200] - epigenetic regulators;

[0201] -mTOR inhibitors (such as everolimus);

[0202] -AKT inhibitors (e.g., AZ5363);

[0203] - Radiopharmaceuticals (e.g. alpharadin);

[0204] -GnRH / LHRH analogs (e.g., leuprorelin);

[0205] -PI3K inhibitors; and

[0206] -CDK4 / 6 inhibitors.

[0207] Explanation of terms

[0208] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0209] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of and "consisting of").

[0210] As used herein, the term "alkane" means a straight-chain or branched saturated aliphatic hydrocarbon.

[0211] As used herein, the term "alkyl" means a linear or branched monovalent saturated aliphatic hydrocarbon, which can be viewed as a group derived from an alkane by losing one hydrogen atom. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight or branched chain group of 1 to 6 carbon atoms, including "C 2-6 Alkyl", "C 2-5 Alkyl", "C 1-4 Alkyl", "C 1-3 Alkyl" and "C 1-2 Alkyl". "C 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The alkyl is optionally substituted with one or more (such as one to three) suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl", for example CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 The term "alkyl" refers to an alkyl group having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0212] As used herein, the term "alkylene" refers to a linear or branched divalent saturated aliphatic hydrocarbon obtained by further losing 1 H from the "alkyl" described above. In some embodiments, the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0213] As used herein, the term "alkenyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, the alkenyl group has 2-6 carbon atoms ("C 2-6 alkenyl”), for example 2 to 4 carbon atoms (“C 2-4 alkenyl”), or 2 to 3 carbon atoms (“C 2-3 Examples of the alkenyl group include, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compound of the present invention contains an alkenyl group, the compound may exist in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof. The term "alkenylene" is a corresponding divalent group, including, for example, "C 2-6 Alkenylene", "C 2-4 Alkenylene" and "C 2-3 Specific examples include, but are not limited to, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene, etc.

[0214] As used herein, the term "alkynyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, or 6 carbon atoms ("C 2-6 alkynyl”), for example 2 to 4 carbon atoms (“C 2-4 alkynyl”), or 2 to 3 carbon atoms (“C 2-3 The alkynyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The term "alkynylene" is a corresponding divalent group, including, for example, "C 2-6 Alkynylidene", "C 2-4 Alkynylidene" and "C 2-3 Examples include, but are not limited to, The alkynylene group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.

[0215] As used herein, the terms "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" refer to saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., "cycloalkenyl" and "cycloalkenylene") and / or triple bonds within the ring) monocyclic or polycyclic fused hydrocarbon groups having, for example, 3-10 (suitably 3-8, more suitably 3-7, 3-6, 4-6 or 5-6) ring carbon atoms. Cycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc. In some embodiments, cycloalkyl includes aryl-fused cycloalkyl, as long as the entire ring system is non-aromatic.

[0216] As used herein, the term "fused" means that two or more ring structures share two adjacent atoms with each other.

[0217] As used herein, the terms "cycloalkyl" and "cycloalkylene" refer to a saturated monocyclic or polycyclic (such as bicyclic) fused hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring such as ). The cycloalkyl and cycloalkylene groups have 3 to 10 carbon atoms, suitably 3-8, such as 3-7, 3-6, 4-6 or 5-6 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl). The cycloalkyl and "cycloalkylene" groups are optionally substituted by one or more (such as one to three) suitable substituents (for example, methyl or halogen), for example, a methyl-substituted cyclopropyl group.

[0218] As used herein, the terms "cycloalkenyl" and "cycloalkenylene" refer to monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic) having one or more double bonds within the ring. The cycloalkenyl and "cycloalkenylene" have 3 to 10 carbon atoms, suitably 3-8, for example 3-7, 3-6, 4-6 or 5-6. The cycloalkenyl and cycloalkenylene are optionally substituted with one or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopentenyl.

[0219] As used herein, the terms "heterocyclyl," "heterocycle," and "heterocyclylene" refer to a saturated (i.e., "heterocycloalkyl" and "heterocycloalkylene") or partially unsaturated (e.g., having one or more double bonds within the ring (i.e., "heterocycloalkenyl," "heterocycloalkenylene," or "benzoheterocycloalkyl" and "benzoheterocycloalkylene")) monovalent or divalent monocyclic or polycyclic (e.g., bicyclic, tricyclic) ring structure that is non-aromatic overall and has 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, S(O), S(O)2, and NR', wherein R' is a hydrogen atom, C 1-6 Alkyl or C 1-6 One or more ring carbon atoms in the heterocyclic group may be C(O), S(O)2, Substitution. Wherein "*" represents an atom replacing a ring carbon atom. The heterocyclic radical can be connected to the rest of the molecule through any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic radical can be a fused ring, a spirocycle, a bridged ring or a combination thereof. The ring in which the heterocyclic radical comprises a monocyclic group is a non-aromatic ring and at least one of the fused rings comprising a bicyclic or tricyclic group is a non-aromatic ring (e.g., benzoheterocycloalkyl, benzoheterocycloalkenyl, pyridoheterocycloalkyl, etc.). In particular, a 3-10 membered heterocyclic radical is a group having 3-10 (e.g., 3-8, 3-7, 3-6, 4-6 or 5-6) carbon atoms and heteroatoms in the ring. Heterocyclic radicals include nitrogen-containing heterocyclic radicals, oxygen-containing heterocyclic radicals and sulfur-containing heterocyclic radicals. Examples that can be enumerated include, but are not limited to, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolyl, pyrrolidinyl, pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl. The heterocyclic radical is optionally substituted by one or more (such as one to three) suitable substituents (e.g., halogen, OH, NH , C 1-6 Alkyl, C 1-6 haloalkyl) substituted.

[0220] As used herein, the term "nitrogen-containing heterocyclic group" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and at least one nitrogen atom in the ring, which may also optionally contain one or more (e.g., 1, 2, 3 or 4) ring members selected from N, O, C(O), S, S(O) and S(=O)2. One or more ring carbon atoms in the nitrogen-containing heterocyclic group may be replaced by C(O). The nitrogen-containing heterocyclic group may be connected to the rest of the molecule via any one of the carbon atoms or the nitrogen atom. The nitrogen-containing heterocyclic group may be a saturated nitrogen-containing monocyclic ring. In particular, the 3- to 10-membered nitrogen-containing heterocycle is a group having 3-10 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as aziridine), a four-membered nitrogen-containing heterocycle (such as azetidinyl), a five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl), a seven-membered nitrogen-containing heterocycle, etc.

[0221] As used herein, the term "heterocyclic group" includes nitrogen-containing heterocyclic groups, oxygen-containing heterocyclic groups and sulfur-containing heterocyclic groups, and covers fused ring structures, and the connection point of the fused ring structure with other groups can be on any ring in the fused ring structure. Therefore, the heterocyclic group of the present invention also includes but is not limited to heterocyclic and heterocyclic groups, heterocyclic and cycloalkyl groups, monoheterocyclic and monoheterocyclic groups, and monoheterocyclic and monocycloalkyl groups, such as 3-7 membered (mono) heterocyclic groups and 3-7 membered (mono) heterocyclic groups, 3-7 membered (mono) heterocyclic groups and (mono) cycloalkyl groups, 3-7 membered (mono) heterocyclic groups and C 4-6 (Mono)cycloalkyl, examples of which are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl, In some embodiments, heterocyclyl also includes heteroaryl-fused heterocyclyl or cycloalkyl, and aryl-fused heterocyclyl, as long as the entire ring system is non-aromatic. In some embodiments, heterocyclyl includes 5-6 membered monocyclic heteroaryl-fused C 5-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl-fused 5-6 membered monocyclic heterocyclyl, and benzo-fused 5-6 membered monocyclic heterocyclyl, such as pyrrolotetrahydropyridinyl, pyrazolotetrahydropyridinyl, imidazotetrahydropyridinyl, indolyl or indolonyl.

[0222] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-14"Aryl" means an aromatic group containing 6 to 14 (e.g. 6 to 12) carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted by one or more (e.g. 1 to 3) suitable substituents (e.g. halogen, OH, CN, NO2, C 1-6 alkyl, etc.) substituted.

[0223] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and 1, 2, 3, 4, or 5 identical or different heteroatoms independently selected from N, O, S, and S(O). One or more ring carbon atoms in a heteroaryl group may be replaced by C(O). A heteroaryl group may be benzo-fused. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridonyl, pyrimidinyl, pyrimidonyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolinyl, indolyl, pyrrolopyridazinyl, benzo The heteroaryl group may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0224] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0225] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-6 Halogenated alkyl, "C 1-4 Haloalkyl" and "C 1-3 The term "haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms, 1 to 4 carbon atoms, and 1-3 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0226] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0227] If a group is described as being "optionally substituted by" or "optionally substituted", the group may be: (1) unsubstituted or (2) substituted. If a carbon of a group is described as being optionally substituted by one or more of the listed substituents, then one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, by independently selected optional substituents. If a nitrogen of a group is described as being optionally substituted by one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced by an independently selected optional substituent. Optional substituents may be selected from: halogen, OH, SH, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -O-halogenated C 1- 6-alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -SC 1-6 Alkyl, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -C 1-6 Alkylene-OH, -C 1-6 Alkylene -SH, -C 1-6 Alkylene -CN, -C 1-6 Alkylene-NH2, -C 1-6 Alkylene-NH(C 1-6 Alkyl), -C 1-6 Alkylene-N(C 1-6 Alkyl)2, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 0-6 Alkylene-C(O)OH, -C 0-6 Alkylene-C(O)OC 1-6 Alkyl, -C 0-6 Alkylene-C(O)NH2, -C 0-6 Alkylene-C(O)NH(C 1-6 Alkyl), -C 0-6 Alkylene-C(O)N(C 1-6 Alkyl)2, -C 0-6Alkylene-S(O)2C 1- 6-alkyl, -C 0-6 Alkylene-S(O)2NH2, -C 0-6 Alkylene-S(O)2NH(C 1-6 Alkyl), -C 0-6 Alkylene-S(O)2N(C 1-6 Alkyl)2, -NH-C(O)C 1-6 Alkyl, -N(C 1-6 alkyl)-C(O)C 1-6 Alkyl, -NH-C(O)OH, -NH-C(O)OC 1-6 Alkyl, -N(C 1-6 alkyl)-C(O)OC 1-6 Alkyl, -NH-C(O)NH2, -NH-C(O)NH(C 1-6 alkyl), -NH-C(O)N(C 1-6 Alkyl)2, -NH-S(O)2-C 1-6 Alkyl, -N(C 1-6 alkyl)-S(O)2-C 1-6 Alkyl, -C 0-6 Alkylene-C 3-10 Cycloalkyl, -C 0-6 Alkylene-(3-10 membered heterocyclic group), -C 0-6 Alkylene-phenyl and -C 0-6 Alkylene-(5-10 membered heteroaryl).

[0228] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0229] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0230] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0231] When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such substituent may be bonded to any atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown as carrying a substitutable hydrogen atom, such substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is to the available ring member.

[0232] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) can be substituted in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6. In some embodiments, the isotopically labeled compounds of the present invention are deuterated.

[0233] As used herein, the term "oxo" refers to

[0234] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center, which has the same chemical composition but different spatial arrangements of atoms or groups. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0235] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereoisomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

[0236] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0237] The term "chiral" refers to molecules that have the property of non-superimposability of their mirror image pairs, whereas the term "achiral" refers to molecules that are superimposable on their mirror image pairs.

[0238] The compounds of the present invention may be prepared in racemic form, or individual enantiomers may be prepared by enantioselective synthesis or by resolution.

[0239] As used herein, the term "cis-trans isomers" or "geometric isomers" is caused by the inability to rotate freely about double bonds or single bonds of ring-forming carbon atoms. The compounds provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and their corresponding mixtures.

[0240] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0241] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0242] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0243] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0244] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

[0245] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

[0246] For a review of suitable salts see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0247] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0248] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0249] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0250] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GW H Cheeseman and ES G Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0251] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0252] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0253] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0254] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value. Example

[0255] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all commercially available conventional products.

[0256] NMR was measured using a Bruker Avance III 400 NMR spectrometer, and the chemical shift (δ) was measured at 10 -6 The unit is ppm. The solvent is deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS).

[0257] MS was measured using an Agilent (ESI) mass spectrometer (Agilent 1260, Agilent 6125B).

[0258] High-performance liquid chromatography (HPLC) conditions: SUIMADZU HPLC (LC-2030 Plus), Waters Sunfire C18 column (3.5 μm, 4.6×100 mm), UV detection at 220 and 254 nm, elution at 5-95% acetonitrile (containing 0.05%-0.1% v / v formic acid, trifluoroacetic acid, or ammonium bicarbonate), flow rate 1.8 mL / min.

[0259] Reverse phase purification was performed using the Biotage Isolera Rapid Purification System.

[0260] Thin layer chromatography separation and purification were performed using thin layer chromatography silica gel plates (aluminum plates (20 cm x 20 cm x 1 mm) produced by Meck, or GF 254 produced in Yantai).

[0261] Microwave reaction was carried out using Biotage Initiator+ (400W, RT-300°C) microwave reactor.

[0262] Reaction monitoring is usually performed by TLC or LCMS. Common developing solvent systems include: dichloromethane / methanol, n-hexane / ethyl acetate, petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.

[0263] The silica gel used in column chromatography is generally 100-200 mesh. Common eluent systems include dichloromethane / methanol and petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0264] The reagents and solvents of the present invention were purchased from Aldrich Chemical Company, Anage, J&K Technology, Shanghai Bid Pharmaceutical Technology Co., Ltd., Yaoshi Technology, and Shanghai Titan Technology Co., Ltd.

[0265] In conventional synthesis methods and synthesis examples of compounds and intermediates of the present invention, the meanings of the abbreviations are as follows.

[0266] Synthesis Example

[0267] Example 1: Preparation of Compound 1

[0268] Potassium carbonate (193 mg, 0.14 mmol) was added to a solution of compound 1-0 (60 mg, 0.14 mmol) and methylamine hydrochloride (97 mg, 1.43 mmol) in methanol (5 mL) at 25°C, and the temperature was raised to 60°C and stirred for 16 hours. The reaction was monitored by LCMS, and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 1. LCMS: m / z 432.0 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.12-7.25(m,4H),7.03(s,1H),6.49(s,1H),3.94(s,4H),3.86-3.83(m,4H ),3.81(s,3H),3.75(s,2H),2.79(s,3H),2.64-2.76(m,2H),1.99-2.12(m,3H),1.36-1.51(m,2H).

[0269] Example 2: Preparation of Compound 2

[0270] Step 1: Add (1-(methylsulfonyl)piperidin-4-ylmethyl) methanesulfonate (1.10 g, 3.95 mmol) to a solution of compound 2-0 (1.00 g, 3.29 mmol) and potassium carbonate (910 mg, 6.58 mmol) in N,N-dimethylformamide (10 mL), heat to 80 ° C, and stir for 16 hours. The reaction was monitored by LCMS. Water (50 mL) was added to the reaction to dilute it, washed with dichloromethane (50×3 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain intermediate 2-1. LCMS: m / z 419.0 [M+H] + .

[0271] Step 2: Add intermediate 2-1 (750 mg, 1.79 mmol) to a solution of ammonium hydroxide (3 mL, 23.37 mmol, 28%-30%) in methanol (3 mL), heat to 80°C, and stir for 16 hours. The reaction was monitored by LCMS and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography on silica gel (dichloromethane:methanol=10:1) to obtain intermediate 2-2. LCMS: m / z 418.0 [M+H] + .

[0272] Step 3: At 25 ° C, (trimethylsilyl) diazomethane (82 mg, 23.37 mmol) was added dropwise to a solution of intermediate 2-2 (150 mg, 0.36 mmol) in methanol (1 mL) and dichloromethane (3 mL) and stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 2. LCMS: m / z 432.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 8.05 (s, 1H), 7.21 (s, 4H), 7.08-7.16 (m, 1H), 4.00-4.06 (m, 6H), 3.94 (d, J = 6.0Hz, 2H), 3 .91(s,3H),3.85-3.90(m,2H),2.80(s,3H),2.72(td,J=12.1,2.1Hz,2H),1.92-2.09(m,3H),1.53-1.51(m,2H).

[0273] Example 3: Preparation of Compound 3

[0274] Step 1: To a solution of compound 3-0 (1.50 g, 9.40 mmol) and [1-(methyldioxo-λ6-thio)hexahydropyridin-4-yl]methyl methanesulfonate (2.55 g, 9.40 mmol) in dimethyl sulfoxide (10.0 mL) was added potassium carbonate (2.60 g, 18.8 mmol) at 20°C. The mixture was stirred at 80°C for 5 hours. LCMS monitored the reaction completion. Water (150 mL) was added and the mixture was extracted with ethyl acetate (120 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:5) to obtain intermediate 3-1. LCMS: m / z 335.1 [M+H] + .

[0275] Step 2: To a solution of intermediate 3-1 (1.20 g, 3.58 mmol) in toluene (20.0 mL) was added dropwise thionyl chloride (0.39 mL, 5.38 mmol) at 0°C. The mixture was stirred at 20°C for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain intermediate 3-2. LCMS: m / z 353.0 [M+H] + .

[0276] Step 3: To a solution of intermediate 3-2 (100 mg, 0.20 mmol) and 2,3-dihydro-1H-isoindole (0.02 mL, 0.20 mmol) in dimethylformamide (2.00 mL) was added potassium carbonate (82.2 mg, 0.59 mmol) at 25°C. The mixture was stirred at 100°C for 2 hours. LCMS monitored the completion of the reaction, and water (30 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The intermediate 3-3 was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the intermediate 3-3. LCMS: m / z 436.2 [M+H] + .

[0277] Step 4: To a solution of intermediate 3-3 (400 mg, 0.92 mmol) in dimethyl sulfoxide (0.50 mL) was added potassium hydroxide solution (2.00 mL, 10 mol / L) at 25°C. The mixture was stirred at 130°C for 36 hours. Intermediate 3-4 was purified by preparative HPLC. LCMS: m / z 418.2 [M+H]+ .

[0278] Step 5: At -40°C, sodium hydride (2 mg, 0.05 mmol) was added to a solution of intermediate 3-4 (14 mg, 0.04 mmol) in dimethylformamide (0.50 mL). The mixture was stirred at -40°C for 2 minutes, and iodomethane (3 μL, 0.04 mmol) was added to the mixture. The mixture was stirred at -40°C for 30 minutes. The reaction was monitored by LCMS. Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain compound 3. LCMS: m / z 432.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ7.40-7.35(m,2H),7.34-7.29(m,2H),6.64(d,J=7.6Hz,1H),6.42(d,J=7.6Hz,1H),4.50(s,4H),4.28(s,2H),3.86(br d,J=11.8Hz,2H),3.80(br d,J=6.3Hz,2H),3.65(s,3H),2.79(s,3H),2.74-2.66(m,2H),2.03(br d,J=12.1Hz,3H),1.52-1.36(m,2H).

[0279] Example 4: Preparation of Compound 4

[0280] Step 1: Add (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (1.02 g, 3.76 mmol) to compound 4-0 (0.50 g, 3.13 mmol) dissolved in N,N-dimethylformamide (20.0 mL), add potassium carbonate (1.08 g, 7.83 mmol), warm to 70°C, and stir for 12 hours. LCMS monitoring indicates the completion of the reaction, quench with water (100 mL), extract with ethyl acetate (120 mL x 2), combine the organic phases, wash with saturated sodium chloride aqueous solution (120 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 4-1. LCMS: m / z 335.0 [M+H] + .

[0281] Step 2: To a mixture of intermediate 4-1 (0.50 g, 0.30 mmol) in methanol (5 ml) was added sodium methoxide (167 μL, 3.00 mmol) at 25°C, the temperature was raised to 90°C, and the mixture was stirred for 6 hours. LCMS monitored the reaction completion, and the mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:4) to obtain intermediate 4-2. LCMS: m / z 331.1 [M+H] + .

[0282] Step 3: To a mixture of intermediate 4-2 (200 mg, 0.61 mmol) in dichloromethane (10 ml) was slowly added dropwise thionyl chloride (0.44 mL, 6.05 mmol) at 25°C and stirred for 12 hours. LCMS monitored the reaction completion, quenched with water (100 mL), and extracted with ethyl acetate (120 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 4-3. LCMS: m / z 349.1 [M+H] + .

[0283] Step 4: At 25°C, triethylamine (258 μL, 1.86 mmol) was added dropwise to a solution of intermediate 4-3 (130 mg, 0.37 mmol) and 2,3-dihydro-1H-isoindole hydrochloride (64 mg, 0.41 mmol) in acetonitrile (2 ml) and stirred for 3 hours. LCMS monitored the reaction completion, quenched with water (20 mL), and extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound 4. LCMS: m / z 432.2 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ:7.27(d,J=7.9Hz,1H),7.15-7.24(m,4H),6.96(d,J=7.9Hz,1H),3.92(s,4H),3.84-3.89(m, 5H),3.83(s,2H),3.59(d,J=11.8Hz,2H),2.85(s,3H),2.69-2.77(m,2H),1.86(d,J=10.5Hz,3H),1.28-1.41(m,2H).

[0284] Example 5: Preparation of Compound 5 and Compound 6

[0285] Step 1: At 25°C, compound 5-0 (2.00 g, 15.48 mmol) and potassium carbonate (10.70 g, 77.40 mmol) were added to acetonitrile (30.0 mL), followed by the dropwise addition of methylsulfonyl chloride (5.99 mL, 77.40 mmol). Stirring was continued at 25°C for 12 hours. The reaction mixture was poured into water (50.0 mL), extracted with ethyl acetate (200.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford intermediate 5-1. LCMS: m / z 286.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ4.25(t,2H,J=6.4Hz),3.5-3.6(m,2H),3.1-3.2(m,3 H),2.83(s,3H),2.6-2.7(m,2H),1.7-1.8(m,2H),1.6-1.7(m,2H),1.4-1.6(m, 1H),1.1-1.3(m,2H).

[0286] Step 2: At 25°C, thionyl chloride (1.30 mL, 17.98 mmol) was added dropwise to a solution of 4-hydroxymethylpyridin-2(1H)-one (900 mg, 7.19 mmol) in dichloromethane (9.0 mL). The temperature was raised to 50°C and stirred for 1 hour. The reaction was monitored by LCMS to determine completion. The reaction solution was then concentrated under reduced pressure to yield Intermediate 5-2. LCMS: m / z 144.0 / 146.0 [M+H] + .

[0287] Step 3: At 25°C, add intermediate 5-2 (200 mg, 1.39 mmol), isoindoline (200 mg, 1.67 mmol), and potassium carbonate (770 mg, 5.57 mmol) to a solution of N,N-dimethylformamide (3.0 mL). Heat to 80°C and stir for 3 hours. LCMS monitoring indicates the completion of the reaction. The reaction solution is filtered to obtain a solution of intermediate 5-3 in N,N-dimethylformamide. LCMS: m / z 227.1 [M+H] + .

[0288] Step 4: To a solution of intermediate 5-3 in N,N-dimethylformamide at 25°C, 2-(1-(methylsulfonyl)piperidin-4-yl)ethyl methanesulfonate (300 mg, 1.06 mmol) and potassium carbonate (364 mg, 2.64 mmol) were added. The mixture was heated to 85°C and stirred for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography to obtain compound 5. LCMS: m / z 416.2 [M+H] + .1 H NMR (400MHz, DMSO-d6): δ7.64(d,1H,J=7.0Hz),7.1-7.3(m,4H),6.34(s,1H),6.25(dd,1H,J=1.6,7.0Hz),3.90 -3.86(m,6H),3.69(s,2H),3.52(d,2H,J=11.9Hz),2.83(s,3H),2.6-2.7(m,2H ),1.81(d,2H,J=10.9Hz),1.59(d,2H,J=7.6Hz),1.3-1.4(m,1H),1.21(s,2H).

[0289] Compound 6. LCMS: m / z 416.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.10(d,J=5.1Hz,1H),7.1-7.3(m,4H),6.98(d,J=5.1 Hz,1H),6.77(s,1H),4.30(t,J=6.5Hz,2H),3.8-3.9(m,6H),3.53(d,J=11.8Hz ,2H),2.83(s,3H),2.67(dt,2H,J=1.9,11.9Hz),1.80(d,J=11.5Hz,2H),1.68( q, J=6.5Hz, 2H), 1.57 (dd, J=3.8, 6.8, 10.5Hz, 1H), 1.23 (d, J=3.9, 12.2Hz, 2H).

[0290] Example 6: Preparation of Compound 7

[0291] Step 1: At 0°C, a toluene solution of lithium aluminum tetrahydride (11.6 mL, 28.95 mmol, 2.5 M) was slowly added dropwise to a solution of compound 7-0 (2.01 g, 9.65 mmol) in tetrahydrofuran (20 mL) and stirred for 3 hours. The reaction was monitored by LCMS. Ethyl acetate (10 mL) was added to the reaction solution, and the pH was adjusted to 2 with hydrochloric acid (8 mL, 5 M). The mixture was extracted with ethyl acetate (25 mL x 3). The organic phase was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 7-1. LCMS: m / z 194.0 [M+H] + .

[0292] Step 2: Sodium hydride (310 mg, 7.76 mmol) was added to a solution of intermediate 7-1 (500 mg, 2.59 mmol) in tetrahydrofuran (10 mL) at 0°C and stirred for 30 minutes. Ethyl 6-chloronicotinate (577 mg, 3.10 mmol) was then added and stirred for 16 hours. The reaction was monitored by LCMS. Methanol (5 mL) was added to the reaction solution and concentrated under reduced pressure to obtain intermediate 7-2. LCMS: m / z 343.0 [M+H] + .

[0293] Step 3: At 0°C, under a nitrogen atmosphere, intermediate 7-2 (400 mg, 1.17 mmol) was dissolved in toluene (5 mL), and a toluene solution of diisobutylaluminum hydride (2 mL, 2.92 mmol, 1.5 M) was slowly added dropwise and stirred for 16 hours. The reaction was monitored by LCMS. Methanol (5 mL) was added to quench the reaction. After stirring for 30 minutes, potassium sodium tartrate solution (5 mL, 4 M) was added and stirred for 2 hours. The mixture was extracted with dichloromethane (20 × 2 mL), and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (dichloromethane: methanol = 10:1) to obtain intermediate 7-3. LCMS: m / z 301.0 [M+H] + .

[0294] Step 4: Add thionyl chloride (315 mg, 2.64 mmol) dropwise to a solution of intermediate 7-3 (100 mg, 0.33 mmol) in dichloromethane (3 mL) at 25°C and stir for 2 hours. The reaction was monitored by LCMS. Concentrate under reduced pressure to obtain intermediate 7-4. LCMS: m / z 319.0 [M+H] + .

[0295] Step 5: 1H-isoindole hydrochloride (73 mg, 0.47 mmol) was added to a solution of intermediate 7-4 (100 mg, 0.31 mmol) and diisopropylethylamine (203 mg, 1.57 mmol) in acetonitrile (5 mL) at 25°C and stirred for 16 hours. The reaction was monitored by LCMS and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate) to give compound 7. LCMS: m / z 402.0 [M+H] + ; 1H NMR(400MHz, CDCl3)δ:8.09-8.14(m,1H),7.71(dd,J=8.5,2.0Hz,1H),7.19(s,4H),6.74(d,J=8.4Hz,1H),4.20(d,J=6.0Hz,2H),3.94(s,4H),3.88(br d,J=2.5Hz,4H),2.80(s,3H),2.72(td,J=12.0,2.1Hz,2H),1.94-2.00(m,3H),1.51(br dd,J=12.1,2.6Hz,2H).

[0296] Example 7: Preparation of Compound 8

[0297] Step 1: At 25°C, add methyl (1-(methylsulfonyl)piperidin-4-yl)methanesulfonate (1.08 g, 3.98 mmol) to a solution of compound 8-0 (700 mg, 5.69 mmol) and potassium carbonate (1.57 g, 11.37 mmol) in N,N-dimethylformamide (3.00 mL), heat to 100°C, and stir for 1 hour. Add water (15 mL) to the reaction solution, extract with ethyl acetate (10 mL x 3), combine the organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 8-1. LCMS: m / z 299.0 [M+H] + .

[0298] Step 2: At 25°C, sodium triacetylborohydride (530 mg, 2.52 mmol) was added to a solution of intermediate 8-1 (300 mg, crude product) and isoindoline (462 mg, 3.02 mmol) and acetic acid (0.5 mL) in 1,2-dichloroethane (5 mL) and stirred for 2 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain compound 8. LCMS: m / z 402.1 [M+H] + ; 1H NMR (400MHz, CDCl3) δ: 8.26 (d, J = 2.5Hz, 1H), 7.42 (d, J = 8.5Hz, 1H), 7.24-7.08 (m, 5H), 4.10-3.96 (m, 6H), 3.89 (br d,J=5.9Hz,4H),2.84-2.74(m,3H),2.75-2.64(m,2H),2.00-1.91(m,3H),1.59-1.41(m,2H).

[0299] Example 8: Preparation of Compound 9

[0300] Step 1: Dissolve 5-chloropyrazine-2-methanol (1.00 g, 6.92 mmol) and manganese dioxide (6.02 g, 69.2 mmol) in dichloromethane (20 mL) at 50°C and stir for 16 hours. Monitor the reaction by LCMS. The reaction mixture is filtered and concentrated under reduced pressure to obtain Intermediate 9-1. LCMS: m / z 143.0 [M+H] + .

[0301] Step 2: At 25°C, intermediate 9-1 (700 mg, 4.91 mmol), 1H-isoindole hydrochloride (1.14 g, 7.37 mmol), sodium acetate borohydride (3.11 g, 14.73 mmol), and acetic acid (0.28 ml, 4.91 mmol) were dissolved in 1,2-dichloroethane (20 mL) and stirred for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was extracted with dichloromethane (20 ml x 3), and the combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 3:1) to obtain intermediate 9-2. LCMS: m / z 246.1 [M+H] + .

[0302] Step 3: At 0°C, 1-(methylsulfonyl)piperidine-4-methanol (235 mg, 1.22 mmol) and sodium hydride (26 mg, 1.47 mmol) were dissolved in N,N-dimethylacetamide (5 mL) solution and stirred for 30 minutes. Then, intermediate 9-2 (200 mg, 0.81 mmol) was added and stirred for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was extracted with dichloromethane (20 mL x 3), the organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 9. LCMS: m / z 403.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.25(s,1H),8.21(d,J=1.3Hz,1H),7.18-7.25(m,4H),4.23(d,J=6.0Hz,2H),4.14-4.10(br s,6H),3.88(br d,J=11.9Hz,2H),2.80(s,3H),2.72(td,J=12.0,2.2Hz,2H),1.93-2.02(m,3H),1.24-1.51(m,2H).

[0303] Example 9: Compound 10 and Compound 11

[0304] Potassium carbonate (303 mg, 2.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (55 mg, 0.07 mmol) were added to a solution of compound 17 (350 mg, 0.7 mol) and trimethylcyclotriboroxine (370 mg, 2.9 mmol) in dioxane (8.0 mL) and water (1.0 mL) at 25°C. The atmosphere was replaced with nitrogen, and the reaction solution was stirred at 100°C for 16 hours. The reaction was monitored by LCMS to confirm completion. The reaction solution was filtered, the filtrate was dried, and the crude product was purified by preparative HPLC to obtain compound 10. LCMS: m / z 401.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.26 (d, J = 8.0 Hz, 2H), 7.11 (s, 4H), 6.79 (d, J = 8.1 Hz, 2H), 3.98-3 .66(m,10H),2.73(s,3H),2.64(t,J=11.6Hz,2H),2.00-1.84(m,3H),1.48-1.36(m,2H).

[0305] Compound 11. LCMS: m / z 415.1 [M+H]+; 1 H NMR(400MHz, CDCl3)δ:7.26-7.13(m,6H),6.77(d,J=8.0Hz,1H),3.99(s,4H),3.93-3.81(m, 6H), 2.81 (s, 3H), 2.78-2.69 (m, 2H), 2.23 (s, 3H), 1.99 (d, J = 10.5Hz, 3H), 1.62-1.51 (m, 2H).

[0306] Example 10: Compound 12

[0307] Under a nitrogen atmosphere at 25°C, compound 52 (120 mg, 0.28 mmol), 2-bromobutane (0.04 mL, 0.33 mmol), and cesium carbonate (270 mg, 0.83 mmol) were dissolved in N,N-dimethylformamide (2 mL), heated to 75°C, and stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 12. LCMS: m / z 491.3 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.19(s,4H),7.04 -7.00(m,1H),6.62(d,J=11.0Hz,1H),4.18(q,J=6.0Hz,1H),3.96(s,4H), 3.92-3.85(m,4H),3.84(d,J=6.0Hz,2H),2.80(s,3H),2.72(dt,J=2.3,12 .0Hz,2H),2.03-1.94(m,3H),1.77-1.72(m,1H),1.61(ddd,J=6.2,7.3,13 .7Hz,1H),1.56-1.44(m,2H),1.25(d,J=6.1Hz,3H),0.98(t,J=7.5Hz,3H).

[0308] Example 11: Compound 13

[0309] Compound 26 (100 mg, 0.23 mmol) and palladium / carbon (25 mg, 0.23 mmol) were added to tetrahydrofuran (2 mL) and methanol (2 mL) at 25°C under a nitrogen atmosphere. The hydrogen was replaced three times, and the reaction solution was stirred under a hydrogen system for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 13. LCMS: m / z 429.3 [M+H] + ; 1HNMR(400MHz, CDCl3)δ:7.22(d,J=1.9Hz,1H),7.20-7.17(m,5H),6.78(d,J=8.3Hz,1H),3.92(s,4H),3.92-3.90(m,1H),3.88(br s,1H),3.87(s,1H),3.86(s,1H),3.85(s,2H),2.81(s,3H),2.74(dt,J=1.9,12.0Hz,2 H),2.66(q,J=7.5Hz,2H),2.02-1.92(m,3H),1.63-1.49(m,2H),1.22(t,J=7.6Hz,3H)

[0310] Example 12: Compound 14

[0311] Compound 27 (100 mg, 0.23 mmol) and palladium / carbon (10 mg, 0.1 mmol) were added to a methanol (5 mL) solution at 25°C under a nitrogen atmosphere. The hydrogen was replaced three times, and the reaction solution was stirred under a hydrogen system for 8 hours. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 14. LCMS: m / z 443.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.26 (d, J = 1.9 Hz, 1H), 7.19 (s, 5H), 6.79 (d, J = 8.3 Hz, 1H), 3.94 (s, 4H), 3.90 (br d,J=12.1Hz,2H),3.86(s,3H),3.31(quin,J=6.9Hz,1H),2.81(s,3H),2.70 -2.79(m,2H),1.91-2.01(m,3H),1.50-1.63(m,3H),1.24(d,J=6.9Hz,6H).

[0312] Example 13: Compound 15

[0313] Step 1: (1-(Methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (249 mg, 0.92 mmol) was added to a mixture of Intermediate 15-0 (130 mg, 0.76 mmol) in N,N-dimethylformamide (2.5 mL) at room temperature. Potassium carbonate (264 mg, 1.91 mmol) was then added to the mixture, and the temperature was raised and the mixture was stirred at 70°C for 12 hours. LCMS monitoring indicated that the reaction was complete, and the mixture was quenched by the addition of water (20 mL). The mixture was extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was used in the next step without further purification to obtain Intermediate 15-1. LCMS: m / z 316.1 [M+H] + .

[0314] Step 2: Intermediate 15-1 (200 mg, 0.63 mmol) and 2,3-dihydro-1H-isoindole hydrochloride (148 mg, 0.95 mmol) were dissolved in 1,2-dichloroethane (10 ml) at room temperature. Acetic acid (240 μL, 4.20 mmol) and sodium triacetoxyborohydride (334 mg, 1.59 mmol) were added to the mixture and stirred at 25°C for 3 hours. The reaction was monitored by LCMS. Water (20 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse preparative chromatography (trifluoroacetic acid conditions) to obtain the trifluoroacetic acid salt of compound 15. LCMS: m / z 419.1 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ:10.8-11.0(m,1H),7.4-7.5(m,1H),7.3-7.4(m,5H),7.3-7.3(m,1H),4.5-4.6(m,6H),4.0-4.0(m,2H),3.61(br d,J=11.8Hz,2H),2.8-2.9(m,3H),2.7-2.8(m,2H),1.8-1.9(m,3H),1.3-1.4(m,2H); 19 F NMR(376MHz,DMSO-d6)δ:-73.87(s,1F),-134.23(s,1F)

[0315] Example 14: Compound 16

[0316] Step 1: At 25°C, raw material 16-0 was added to a mixture of (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (415 mg, 1.53 mmol) in N,N-dimethylformamide (10 mL). Potassium carbonate (441.36 mg, 3.19 mmol) was then added to the mixture. The temperature was raised and the mixture was stirred at 70°C for 12 hours. LCMS monitoring indicated that the reaction was complete, and water (20 mL) was added to quench the reaction. The reaction was then filtered to obtain intermediate 16-1. LCMS: m / z 332.1 [M+H] + .

[0317] Step 2: At 25°C, intermediate 16-1 (270 mg, 0.81 mmol) and 1H-isoindole hydrochloride (187 mg, 1.22 mmol) were dissolved in 1,2-dichloroethane (3 ml). Acetic acid (200 μL, 3.50 mmol) and sodium triacetoxyborohydride (429 mg, 2.03 mmol) were added to the mixture and stirred at 25°C for 12 hours. The reaction was monitored by LCMS. Water (20 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (60 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by reverse preparative chromatography to give compound 16. LCMS: m / z 435.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ: 7.41 (d, J = 1.9 Hz, 1H), 7.28 (m, J = 8.4, 1.8 Hz, 1H), 7.15-7.24 (m, 4H), 7.12 (d, J = 8.4 Hz, 1H), 3.96 (d, J = 5. 9Hz,2H),3.76-3.84(m,6H),3.60(d,J=11.8Hz,2H),2.86(s,3H),2.75(t,J=11.1Hz,2H),1.89(d,J=11.4Hz,3H),1.33-1.45(m,2H)

[0318] Example 15: Compound 17

[0319] Step 1: Potassium carbonate (3.00 g, 21.67 mmol) was added to a solution of starting material 17-0 (2.20 g, 10.84 mmol) and [1-(methyldioxothio)hexahydropyridin-4-yl]methyl methanesulfonate (4.41 g, 16.25 mmol) in N,N-dimethylformamide (50 mL) at 25°C. The mixture was heated to 80°C and stirred for 16 hours. The reaction was monitored by LCMS. Water (100 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (100 mL x 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. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to provide intermediate 17-1. 1 H NMR (400MHz, CDCl3) δ: 7.47 (d, J = 1.4 Hz, 1H), 7.19-7.13 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.51 (s, 2H), 3.86-3.73 (m, 4H), 2.72 (s, 3H), 2.65 (br t,J=11.4Hz,2H),1.92(br d,J=11.5Hz,3H),1.44(br dd,J=2.6,12.1Hz,2H).

[0320] Step 2: Add thionyl chloride (0.19 mL, 2.64 mmol) dropwise to a solution of intermediate 17-1 (500 mg, 1.32 mmol) in dichloromethane (5 mL) at 25°C and stir for 30 minutes. The reaction is complete after monitoring by LCMS. Add saturated sodium bicarbonate solution (12 mL) to quench the reaction, extract with ethyl acetate (15 mL x 3), and combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 17-2. LCMS: m / z 397.9 [M+H] + .

[0321] Step 3: Add 2,3-dihydro-1H-isoindole (0.84 g, 7.06 mmol) to a solution of triethylamine (4.89 mmol) and intermediate 17-2 (4.20 g, 10.59 mmol) in acetonitrile (50 mL) at 25°C and stir for 18 hours. The reaction mixture was concentrated and the residue was purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to afford compound 17. LCMS: m / z 480.9 [M+H] + ; 1H NMR(400MHz, CDCl3)δ:7.62(d,J=1.8Hz,1H),7.30(dd,J=1.8,8.4Hz,1H),7.19(s,4H),6.85(d,J=8.3Hz,1 H),3.95-3.87(m,8H),3.83(s,2H),2.81(s,3H),2.78-2.69(m,2H),2.08-1.94(m,3H),1.65-1.47(m,2H).

[0322] Example 16: Compound 18

[0323] Compound 17 (200 g, 0.42 mmol), N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (7 mg, 0.02 mmol), and lithium hydroxide (36 mg, 0.88 mmol) were added to a solution of dimethyl sulfoxide (6 mL) and water (2 mL). The temperature was raised to 120°C and stirred for 18 hours. LCMS monitored the completion of the reaction. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions) to obtain compound 18. LCMS: m / z 417.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.28-7.20(m,4H),7.06(br s,1H),6.94(br d,J=8.1Hz,1H),6.83(d,J=8.3Hz,1H),4.24(s,4H),4.04(s,2H),3.94( d,J=6.0Hz,2H),3.92-3.86(m,2H),2.81(s,3H),2.76-2.68(m,2H),2.03 -1.94(m,3H),1.59-1.43(m,2H).

[0324] Example 17: Compound 19

[0325] Step 1: Potassium carbonate (254 mg, 1.84 mmol) was added to a solution of starting material 19-0 (213 mg, 1.38 mmol) and (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (250 mg, 0.92 mmol) in N,N-dimethylformamide (8 mL) at 25°C, the temperature was raised to 80°C, and the mixture was stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain intermediate 19-1. LCMS: m / z 330.1 [M+H] + .

[0326] Step 2: Add thionyl chloride (0.62 mL, 8.50 mmol) dropwise to a solution of Intermediate 19-1 (190 mg, 0.58 mmol) in dichloromethane (10 mL) at 25°C and stir for 6 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give Intermediate 19-2. LCMS: m / z 348.1 [M+H] + .

[0327] Step 3: At 25°C, intermediate 19-2 (190 mg, 0.55 mmol) was added to a solution of 2,3-dihydroisoindole hydrochloride (127 mg, 0.83 mmol) and potassium carbonate (457 mg, 3.3 mmol) in acetonitrile (10 mL) and stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was added with water (15 mL) and extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 19. LCMS: m / z 431.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:7.19(br d,J=9.3Hz,4H),6.94-6.98(m,1H),6.90(s,1H),6.83-6.88(m,1H),3.84-3.77(m,8H),3.75(s ,3H),3.54-3.63(m,2H),2.85(s,3H),2.67-2.78(m,2H),1.81-1.92(m,3H),1.27-1.42(m,2H).

[0328] Example 18: Compound 20

[0329] Step 1: At 25°C, add methyl (1-(methylsulfonyl)piperidin-4-yl)methanesulfonate (645 mg, 2.38 mmol) to a solution of raw material 20-0 (700 mg, 3.40 mmol) and potassium carbonate (938 mg, 6.79 mmol) in N,N-dimethylformamide (3.00 mL), heat to 100°C, and stir for 1 hour. LCMS monitoring of the reaction completion. Add water (15 mL) to the reaction solution, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 20-1. LCMS: m / z 382.1 [M+H] + .

[0330] Step 2: At 25 ° C, sodium triacetyl borohydride (414 mg, 1.97 mmol) was added to a solution of intermediate 20-1 (300 mg), isoindoline (362 mg, 2.36 mmol), and acetic acid (0.5 mL) in 1,2-dichloroethane (5 mL) and stirred for 2 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to the reaction solution, and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain compound 20. LCMS: m / z 485.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.38-7.29 (m, 2H), 7.20 (s, 4H), 6.94 (d, J = 8.3Hz, 1H), 3.93 (s, 3H), 3.91 -3.85(m,7H),2.81(s,3H),2.75(dt,J=1.8,12.0Hz,2H),2.06-1.91(m,3H),1.59-1.45(m,2H).

[0331] Example 19: Compound 21

[0332] At 25°C, diisopropyl azodicarboxylate (32 mg, 0.16 mmol) was added dropwise to a solution of compound 18 (35 mg, 0.08 mmol), triphenylphosphine (42 mg, 0.16 mmol), and isopropanol (24, 0.40 mmol) in dichloromethane (1 mL) and stirred for 18 hours. LCMS monitored the completion of the reaction, and the reaction solution was directly concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonium bicarbonate) to obtain compound 21. LCMS: m / z 459.3 [M+H] + ; 1H NMR(400MHz, CDCl3)δ:7.19(s,4H),7.08-7.02(m,1H),6.96-6.91(m,1H),6.90-6. 82(m,1H),4.57-4.38(m,1H),3.94(s,4H),3.91-3.83(m,6H),2.80(s,3H),2.73(br d,J=1.9Hz,2H),2.06-1.97(m,3H),1.56-1.48(m,2H),1.34(s,3H),1.33(s,3H)

[0333] Example 20: Compound 22

[0334] Step 1: To a solution of starting material 22-0 (1.00 g, 4.52 mmol) and [1-(methyldioxo-λ6-thio)hexahydropyridin-4-yl]methyl methanesulfonate (1.47 g, 5.43 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (1.56 g, 11.31 mmol) at 25°C. The mixture was heated to 70°C and stirred for 12 hours. LCMS monitored the reaction completion. Water (150 mL) was added and the mixture was extracted with ethyl acetate (120 mL x 2). The combined organic phases were washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:4) to obtain intermediate 22-1. LCMS: m / z 396.0 [M+H] + .

[0335] Step 2: At 25°C, intermediate 22-1 (100 mg, 0.25 mmol), bis[5-(diphenylphosphino)cyclopenta-1,3-dienyl]-λ2-iron(II)palladium chloride (10.21 mg, 0.01 mmol), and triethylsilane (161 μL, 1.00 mmol) were dissolved in N,N-dimethylformamide (2 mL). Triethylamine (173 μL, 1.25 mmol) was added to the mixture, and the mixture was heated to 90°C and stirred for 6 hours. The reaction was monitored by LCMS. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 7:3) to provide intermediate 22-2. LCMS: m / z 346.0 [M+H] + .

[0336] Step 3: To a mixture of intermediate 22-2 (40 mg, 0.12 mmol) and isoindoline hydrochloride (27 mg, 0.17 mmol) was added acetic acid (100 μL, 1.75 mmol) and sodium triacetoxyborohydride (61 mg, 0.29 mmol) at 25°C and stirred for 12 hours. LCMS monitored the completion of the reaction, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain compound 22. LCMS: m / z 449.5 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ:7.15-7.24(m,4H),7.00(d,J=7.3Hz,1H),6.89(d,J=11.5Hz,1H),3.85-3.89(m,2H),3.84(m,4H) ,3.81(s,2H),3.74(s,3H),3.58(d,J=11.6Hz,2H),2.85(s,3H),2.68-2.78(m,2H),1.80-1.93(m,3H),1.29-1.39(m,2H); 9 F NMR(DMSO-d6)δ:-128.05--124.13(m,1F).

[0337] Example 21: Compound 23

[0338] Step 1: 1-(Methylsulfonyl)piperidine-4-methanol (1.01 g, 5.68 mmol) and sodium hydride (568 mg, 14.19 mmol) were stirred in N,N-dimethylformamide (5 mL) at 0°C for 30 minutes, then the starting material 23-0 (800 mg, 4.73 mmol) was added and stirred for 16 hours. The reaction was monitored by LCMS. Methanol (10 mL) was slowly added dropwise to the reaction solution at 0°C. After stirring for 30 minutes, the mixture was extracted with dichloromethane (25 mL x 3). The organic phase was washed with saturated sodium chloride solution (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 23-1. LCMS: m / z 343.1 [M+H] + .

[0339] Step 2: Stir a solution of intermediate 23-1 (800 mg, 5.68 mmol) and potassium hydroxide (10 mL, 6 M) in ethanol (30 mL) at 70°C for 16 hours. Monitor the reaction by LCMS. Slowly add hydrochloric acid (10 mL, 6 M) dropwise to the reaction mixture at 0°C until it becomes acidic. Extract the reaction mixture with dichloromethane (40 mL x 3). Wash the organic phase with brine (150 mL). Collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 23-2. LCMS: m / z 362.1 [M+H] + .

[0340] Step 3: Under a nitrogen atmosphere at 60°C, stir a solution of intermediate 23-2 (800 mg, 2.21 mmol) and borane in tetrahydrofuran (8 mL, 1.5 M) in tetrahydrofuran (20 mL) for 4 hours. Slowly add methanol (10 mL) dropwise to the reaction mixture at 25°C, then raise the temperature to 40°C and stir for 1 hour. Finally, cool the reaction mixture to room temperature and extract with dichloromethane (40 mL x 3). The organic phase is washed with saturated sodium chloride solution (150 mL), collected, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain intermediate 23-3.

[0341] Step 4: Stir a solution of intermediate 23-3 (700 mg, 2.01 mmol) and thionyl chloride (2.0 mL, 13.68 mmol) in dichloromethane (10 mL) at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to afford 23-4.

[0342] Step 5: At 25 ° C, intermediate 23-4 (730 mg, 2.0 mmol), 2,3-dihydroisoindole hydrochloride (440 mg, 2.87 mmol), N,N-diisopropylethylamine (1.23 g, 9.55 mmol) were stirred in acetonitrile (15 mL) for 2 hours. The reaction was monitored by LCMS. The reaction solution was extracted with dichloromethane (30 mL x 3), the organic phase was collected, and then washed with saturated sodium chloride solution (100 mL), concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 23. LCMS: m / z 449.2 [M+H] + ; 1HNMR (400MHz, CDCl3) δ7.21(s,1H),7.18(s,4H),6.52(d,J=7.1Hz,1H),3.97(s,4H),3.92(d,J=6.1Hz,2H),3.90(br d,J=1.9Hz,2H),3.86(s,2H),3.83(s,3H),2.81(s,3H),2.67-2.77(m,2H),1.96-2.06(m,3H),1.43-1.58(m,2H).

[0343] Example 22: Compound 24

[0344] Compound 17 (200 g, 0.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (31 mg, 0.04 mmol), triethylamine (211 mg, 2.09 mmol), and methylamine hydrochloride (85 mg, 1.25 mmol) were added to dimethyl sulfoxide (5 mL), the temperature was raised to 80°C, and the mixture was stirred for 18 hours. LCMS monitored the completion of the reaction, and the reaction solution was directly filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate) to obtain compound 24. LCMS: m / z 458.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 8.15 (d, J = 1.9Hz, 1H), 7.68 (br d,J=2.9Hz,1H),7.63-7.52(m,1H),7.18(s,4H),6.95(d,J=8.5Hz,1H),4.04(d,J=6.0Hz,2H),3.99-3.87(m, 8H),3.02(d,J=4.8Hz,3H),2.82(s,3H),2.80-2.68(m,2H),2.09-1.87(m,3H),1.56(dq,J=4.0,12.3Hz,2H).

[0345] Example 23: Compound 25

[0346] Step 1: Add bromine (0.40 mL, 7.85 mmol) to a solution of starting material 25-0 (1.00 g, 7.14 mmol) in acetic acid (32 mL) at 25°C. Heat to 45°C and stir for 6 hours. Completion of the reaction was monitored by LCMS. The reaction solution was directly concentrated under reduced pressure. The residue was eluted by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford intermediate 25-1. LCMS: m / z 216.9 [MH]-.

[0347] Step 2: Dissolve Intermediate 25-1 (600 mg, 2.74 mmol), 2,3-dihydroisoindole hydrochloride (841 mg, 5.48 mmol), sodium triacetoxyborohydride (1.15 g, 5.48 mmol), and acetic acid (0.16 mL, 2.74 mmol) in 1,2-dichloroethane (10 mL) at 25°C and stir for 3 hours. The reaction was monitored for completion by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium bicarbonate (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was eluted with silica gel column chromatography (petroleum ether:ethyl acetate = 5:2) to provide Intermediate 25-2. LCMS: m / z 322.0 [M+H] + .

[0348] Step 3: At 25°C, intermediate 25-2 (300 mg, 0.93 mmol), methyl (1-(methylsulfonyl)piperidin-4-yl)methanesulfonate (303 mg, 1.12 mmol) and potassium carbonate (386 mg, 2.79 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 80°C for 18 hours. The reaction was monitored by LCMS. Dilute with water (20 mL), extract with ethyl acetate (30 mL×3), combine the organic phases, wash with water (30 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 25. LCMS: m / z 497.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.66(d,J=7.9Hz,1H),7.19(s,4H),6.63(d,J=11.1Hz,1H),3.98-3.95(m,4H) ,3.93-3.85(m,6H),2.81(s,3H),2.75(dt,J=2.2,12.1Hz,2H),2.09-1.95(m,3H),1.65-1.48(m,2H).

[0349] Example 24: Compound 26

[0350] At 25°C, compound 17 (300 mg, 0.63 mmol), potassium ethylene trifluoroborate (419 mg, 3.13 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46 mg, 0.06 mmol), and potassium carbonate (259 mg, 1.88 mmol) were added to a mixed solvent of water (1 mL) and 1,4-dioxane (5 mL). The nitrogen atmosphere was replaced three times, the temperature was raised to 100°C, and the mixture was stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 26. LCMS: m / z 427.2 [M+H] +; 1H NMR (400MHz, CDCl3) δ: 7.53 (d, J=2.1Hz, 1H), 7.29-7.26 (dd, J=2.0, 8.4Hz, 1H), 7.20 -7.17(m,4H),7.04(dd,J=11.2,17.8Hz,1H),6.84-6.81(m,1H),5.82-5.76(m,1H),5 .30-5.26(m,1H),3.93(s,4H),3.92-3.90(m,1H),3.90-3.87(m,3H),3.87-3.85(m,2 H),2.81(s,3H),2.73(dt,J=2.2,12.0Hz,2H),2.03-1.96(m,3H),1.61-1.49(m,2H).

[0351] Example 25: Compound 27

[0352] Step 1: Potassium carbonate (6.20 g, 44.77 mmol) was added to a solution of starting material 27-0 (3.00 g, 14.92 mmol) and (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (4.90 g, 17.91 mmol) in N,N-dimethylformamide (10 mL) at 25°C. The mixture was heated to 80°C and stirred for 16 hours. The reaction was monitored for completion by LCMS. The reaction solution was diluted with water (150 mL) and extracted with dichloromethane (100 mL x 3). The organic phase was collected, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:3) to obtain intermediate 27-1. LCMS: m / z 376.0 [M+H] + .

[0353] Step 2: At 25°C, intermediate 27-1 (5.00 g, 13.29 mmol), 2,3-dihydroisoindole hydrochloride (3.10 g, 19.94 mmol), sodium acetate borohydride (8.41 g, 39.87 mmol), and acetic acid (0.8 ml, 13.24 mmol) were stirred in 1,2-dichloroethane (15 mL) for 16 hours. The reaction was monitored by LCMS. The reaction solution was extracted with dichloromethane (40 mL × 3), and the organic phase was collected and washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain intermediate 27-2. LCMS: m / z 479.1 [M+H] + .

[0354] Step 3: At 25°C under a nitrogen atmosphere, bistriphenylphosphine palladium dichloride (91 mg, 0.13 mmol) was added to a solution of intermediate 27-2 (600 mg, 1.25 mmol), 4,4,5,5-tetramethyl-2-propene-2-propenyl-1,3,2-dioxaborolane (315.5 mg, 1.88 mmol), and potassium carbonate (518 mg, 3.75 mmol) in 1,4-dioxane (10 mL) and water (3 mL). The temperature was raised to 90°C and stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was extracted with dichloromethane (40 x 3 mL). The organic phase was collected and washed with saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 3:1) to obtain crude compound 27. 50 mg of the crude product was purified by high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 27. LCMS: m / z 441.3 [M+H] + . 1 H NMR(400MHz, CDCl3)δ:7.20(br d,J=2.3Hz,1H),7.16(d,J=2.1Hz,1H),7.11(s,4H),6.74(d,J=8.3Hz,1H),4.90-5.08(m,2H),3.86(s,4H),3.81-3.83( m,1H),3.76-3.80(m,5H),2.72(s,3H),2.64(td,J=12.1,2.1Hz,2H),2.04(s,3H),1.81-1.93(m,3H),1.35-1.51(m,2H)

[0355] Example 26: Compound 28

[0356] At 25 ° C, compound 25 (100 mg, 0.20 mmol), 4,4,5,5-tetramethyl-2-(propan-2-yl)-1,3,2-dioxaborane (0.11 mL, 0.60 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (15 mg, 0.02 mmol), potassium carbonate (83 mg, 0.60 mmol) were added to water (0.2 mL) and 1,4-dioxane (1 mL), nitrogen was replaced three times, the temperature was raised to 100 ° C, and stirred for 2 hours. LCMS monitoring of the reaction was completed. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 28. LCMS: m / z 459.3 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.29-7.26(d,J=8.8Hz,1H),7.18(s,4H),6.58(d,J=11.8 Hz,1H),5.13-5.11(m,1H),5.06-5.03(m,1H),3.97(s,4H),3.90(s,3H),3.87(br d,J=2.1Hz,1H),3.83(d,J=5.8Hz,2H),2.80(s,3H),2.72(dt,J=2.2,12.1Hz,2H),2.09(s,3H),1.99-1.92(m,3H),1.52(br dd,J=2.9,12.2Hz,2H).

[0357] Example 27: Compound 29

[0358] Compound 18 (300 mg, 0.72 mmol) and bromocyclopropane (871 mg, 7.20 mmol) were added to N,N-dimethylacetamide (5 mL) at 25°C. Potassium carbonate (299 mg, 2.16 mmol) was added, and the reaction solution was stirred at 130°C for 2 hours. LCMS monitored the reaction completion. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions) to obtain compound 29. LCMS: m / z 457.3 [M+H] + ; 1HNMR(400MHz, CDCl3)δ:7.31-7.18(m,4H),7.09(d,J=1.4Hz,1H),6.96-6.90(m ,1H),6.89-6.82(m,1H),6.17-5.97(m,1H),5.43(dd,J=1.2,17.2Hz,1H),5.32 -5.21(m,1H),4.59(d,J=5.1Hz,2H),4.21(s,4H),4.05(s,2H),3.94-3.81(m,4 H),2.80(s,3H),2.77-2.68(m,2H),2.01(d,J=10.3Hz,3H),1.58-1.43(m,2H).

[0359] Example 28: Compound 30

[0360] In a dry 8 mL reaction flask, compound 25 (100 mg, 0.20 mmol), zinc cyanide (24 mg, 0.20 mmol), tris(dibenzylidene indeneacetone)dipalladium(0) (18 mg, 0.02 mmol), 1,1'-bis(diphenylphosphino)ferrocene (23 mg, 0.04 mmol), zinc powder (3 mg, 0.04 mmol) and N,N-dimethylacetamide (1 mL) were added sequentially with stirring. The atmosphere was purged with nitrogen three times. The reaction solution was stirred at 105°C for 2 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 30. LCMS: m / z 444.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.74 (d, J = 7.9 Hz, 1H), 7.20 (s, 4H), 6.68 (d, J = 11.1 Hz, 1H), 3.96 (s, 4H), 3. 93-3.87(m,6H),2.82(s,3H),2.75(dt,J=2.1,12.1Hz,2H),2.10-1.99(m,3H),1.57-1.45(m,2H).

[0361] Example 29: Compound 31

[0362] At 25°C under a nitrogen atmosphere, compound 28 (120 mg, 0.26 mmol) and palladium / carbon (28 mg, 0.26 mmol) were added to methanol (2 mL). The hydrogen was replaced three times, and the reaction solution was stirred under a hydrogen system for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 31. LCMS: m / z 461.3 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.25(d,J=8.5Hz,1H),7.18(s,4H),6.55(d,J=11.8Hz,1H),3.96(s,4H),3.93-3.87(m,4H),3.83(d,J=5.6Hz,2H ),3.24(quin,J=6.9Hz,1H),2.81(s,3H),2.74(dt,J=2.1,12.0Hz,2H),2.03-1.90(m,3H),1.64-1.50(m,2H),1.23(s,3H),1.21(s,3H).

[0363] Example 30: Compound 32

[0364] Step 1: Dissolve the starting material 32-0 (1.00 g, 4.50 mmol) in dichloromethane (10 mL) at 25°C, add boron tribromide (2.26 g, 9.0 mmol), and continue stirring for 18 hours. The reaction is monitored by LCMS for completion. Add saturated sodium bicarbonate solution (50 mL) to adjust the pH of the reaction solution to alkaline. Extract with dichloromethane (50 mL x 3). The organic phases are combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is separated by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford intermediate 32-1.

[0365] Step 2: At 25°C, intermediate 32-1 (750 mg, 3.60 mmol) and methyl (1-(methylsulfonyl)piperidin-4-yl)methanesulfonate (1074 mg, 3.96 mmol) were dissolved in N,N-dimethylformamide (10 mL). Potassium carbonate (1.49 g, 10.79 mmol) was added, the atmosphere was replaced with nitrogen, the temperature was raised to 85°C, and the mixture was stirred for 3 hours. The reaction was monitored by TLC for completion. The mixture was diluted with water (20 mL) and extracted with dichloromethane (20 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. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 32-2. LCMS: m / z 384.0 [M+H] + .

[0366] Step 3: At 25°C, intermediate 32-2 (800 mg, 2.08 mmol) and triethylsilane (1.21 g, 10.43 mmol) were dissolved in dimethyl sulfoxide (8 mL). Triethylamine (1.05 g, 10.39 mmol) and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (152 mg, 0.21 mmol) were added to displace carbon monoxide. The mixture was heated to 85°C and stirred for 3 hours. The reaction was monitored for completion by LCMS. The mixture was quenched with water (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1.5:1) to afford intermediate 32-3. LCMS: m / z 334.1 [M+H] + .

[0367] Step 4: At 25°C, intermediate 32-3 (200 mg, 0.60 mmol) and isoindoline hydrochloride (140 mg, 0.90 mmol) were dissolved in 1,2-dichloroethane (6 mL), and acetic acid (180 mg, 3.00 mmol) and sodium triacetoxyborohydride (255 mg, 1.20 mmol) were added. The mixture was stirred for 18 hours. The reaction was monitored by LCMS. Water (30 mL) was added to quench the mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 32. LCMS: m / z 437.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.29-7.18(m,5H),6.70(dd,J=6.9,10.7Hz,1H),3.98(s,4H),3.94-3 .85(m,6H),2.82(s,3H),2.74(t,J=11.2Hz,2H),2.01(d,J=11.3Hz,3H),1.58-1.46(m,2H).

[0368] Example 31: Compound 33

[0369] At 25°C, compound 25 (100 mg, 0.20 mmol), sodium thiomethoxide (56 mg, 0.80 mmol), tris(dibenzylideneindeneacetone)dipalladium(0) (32 mg, 0.04 mmol), potassium phosphate (171 mg, 0.80 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol) were added to toluene (2 mL). The reaction solution was stirred at 150°C for 5 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 33. LCMS: m / z 465.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.25 (d, J = 7.9 Hz, 1H), 7.19 (s, 4H), 6.58 (d, J = 11.3 Hz, 1H), 3.96 (s, 4H), 3.93-3. 86(m,6H),2.81(s,3H),2.74(dt,J=2.2,12.1Hz,2H),2.42(s,3H),2.06-1.96(m,3H),1.62-1.49(m,2H)

[0370] Example 32: Compound 34

[0371] Step 1: At 25°C, the starting material 34-0 (5.0 g, 29.39 mmol) and liquid bromine (2.82 g, 35.27 mmol) were stirred in acetic acid (20 mL) and dichloromethane (20 mL) for 16 hours. Completion of the reaction was monitored by thin-layer chromatography (ethyl acetate:petroleum ether = 1:10). Aqueous potassium carbonate (20 mL) was added to the reaction solution and stirred for 30 minutes. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was collected and washed with saturated brine (150 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to provide intermediate 34-1.

[0372] Step 2: A solution of Intermediate 34-1 (1.0 g, 4.02 mmol), (1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate (1.31 g, 4.82 mmol), and potassium carbonate (1.94 g, 14.05 mmol) in N,N-dimethylformamide (8 mL) was heated to 80°C and stirred for 16 hours. The reaction was monitored for completion by LCMS. The reaction solution was diluted with water (80 mL), and the mixture was extracted with dichloromethane (80 mL × 3). The organic phase was collected and washed with saturated brine (250 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:3) to obtain Intermediate 34-2. LCMS: m / z 426.0 [M+H] + .

[0373] Step 3: Under a nitrogen atmosphere at 0°C, dissolve Intermediate 34-2 (400 mg, 0.94 mmol) in toluene (5 mL). Slowly add diisobutylaluminum hydride (1.89 mL, 2.83 mmol) in toluene dropwise. Warm to 25°C and stir for 16 hours. Completion of the reaction is monitored by LCMS. Aqueous potassium sodium tartrate (10 mL) is slowly added to the reaction solution and stirred for 2 hours. The mixture is extracted with dichloromethane (30 mL x 3). The organic phase is collected and washed with saturated brine (150 mL). The organic phase is concentrated under reduced pressure to yield Intermediate 34-3.

[0374] LCMS: m / z 396.0 [M+H] + .

[0375] Step 4: Add thionyl chloride (0.25 mL, 3.45 mmol) dropwise to a solution of intermediate 34-3 (175 mg, 0.44 mmol) in dichloromethane (5 mL) at 25°C and stir for 6 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to afford intermediate 34-4. LCMS: m / z 416.0 [M+H] + .

[0376] Step 5: A solution of intermediate 34-4 (175 mg, 0.42 mmol), 2,3-dihydroisoindole hydrochloride (100 mg, 0.65 mmol), and triethylamine (0.3 mL, 2.2 mmol) in acetonitrile (5 mL) was stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The reaction solution was extracted with ethyl acetate (15 mL × 3). The organic phase was collected and washed with saturated brine (40 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain a crude product. The crude product was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 34. LCMS: m / z 497.0 [M+H] + ;1 H NMR (400MHz, CDCl3) δ: 7.39 (s, 1H), 7.21 (s, 4H), 7.16 (dd, J = 1.9, 11.5Hz, 1H), 3.97 (d, J = 6.0Hz, 2H), 3.94 (s, 4H), 3.88 (br d,J=11.9Hz,2H),3.83(s,2H),2.81(s,3H),2.74(dt,J=2.5,12.1Hz,2H),2.05(br d,J=13.4Hz,3H),1.5-1.6(m,2H).

[0377] Example 33: Compound 35

[0378] At 25°C under a nitrogen atmosphere, tetrakistriphenylphosphine palladium (15 mg, 0.01 mmol) was added to a solution of compound 34 (60.0 mg, 0.14 mmol), trimethylcyclotriboroxine (0.04 mL, 0.24 mmol), and potassium carbonate (62.0 mg, 0.45 mmol) in 1,4-dioxane (3 mL) and water (1 mL). The mixture was heated to 90°C and stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was extracted with dichloromethane (10 mL × 3). The organic phase was collected and washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain the crude product. The crude product was then purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 35. LCMS: m / z 433.2 [M+H] + ; 1 H NMR(CDCl3,400MHz)δ:7.19(s,4H),6.96-7.04(m,2H),3.93(s,4H),3.86-3.92(m,4H),3.81(s,2 H),2.81(s,3H),2.73(td,J=12.0,2.4Hz,2H),2.27(s,3H),1.97-2.07(m,3H),1.46-1.59(m,2H).

[0379] Example 34: Compound 36

[0380] Under a nitrogen atmosphere, tetrakistriphenylphosphine palladium (24 mg, 0.02 mmol) was added to a solution of compound 17 (50 mg, 0.10 mmol), potassium carbonate (29 mg, 0.21 mmol), and 2-(2-furyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (20 mg, 0.10 mmol) in dioxane-water (3 mL, 5:1), the temperature was raised to 110°C, and the mixture was stirred for 3 hours. LCMS monitored the completion of the reaction, the reaction solution was directly filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate) to give compound 36. LCMS: m / z 467.2 [M+H] + ; 1 HNMR (400MHz, CDCl3) δ: 7.90 (d, J = 1.6 Hz, 1H), 7.47 (d, J = 0.6 Hz, 1H), 7.30 (dd, J = 1. 6,8.4Hz,1H),7.19(s,4H),6.98-6.87(m,2H),6.50(dd,J=1.7,2.9Hz,1H),3.99(br d,J=5.9Hz,2H),3.96(s,3H),3.94-3.88(m,4H),2.81(s,3H),2.80-2.71(m,2H),2.13-1.95(m,4H),1.67-1.51(m,2H).

[0381] Example 35: Compound 37

[0382] Step 1: Compound 17 (120 mg, 0.25 mmol) and pinacol diboron (0.16 mL, 0.63 mmol) were dissolved in 1-4-dioxane (5.00 mL). Acetic anhydride (0.09 mL, 1.00 mmol) and bis[5-(diphenylphosphino)cyclopenta-1,3-dienyl]-λ2-iron(II) dichloromethanepalladium chloride (18 mg, 0.02 mmol) were added to the mixture. The reaction solution was stirred at 100°C under nitrogen for 3 hours. The reaction was monitored by LCMS and concentrated under reduced pressure. The residue (37-1) was used directly in the next reaction. LCMS: m / z 527.3 [M+H] + ;

[0383] Step 2: Intermediate 37-1 (120 mg, 0.23 mmol), tetrakistriphenylphosphine palladium (263 mg, 0.23 mmol) and 2-iodo-1,3-oxazole (44 mg, 0.23 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL). Sodium carbonate (31 mg, 0.23 mmol) was added to the mixed solution. The mixture was heated to 90°C and stirred for 4 hours under nitrogen protection. LCMS monitoring showed that the reaction was complete, and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse preparative chromatography to obtain compound 37. LCMS: m / z 468.3 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ:8.18(s,1H),7.85(s,1H),7.47(dd,J=8.5,1.6Hz,1H),7.35(s,1H),7.20-7.25(m,2H),7.15-7.19(m,3H),3.99(d ,J=5.8Hz,2H),3.79-3.90(m,6H),3.60(d,J=11.6Hz,2H),2.86(s,3H),2.75(t,J=11.2Hz,2H),1.92(d,J=10.8Hz,3H),1.33-1.45(m,2H).

[0384] Example 36: Compound 38

[0385] Step 1: Potassium acetate (74 mg, 0.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (18 mg, 0.03 mmol) were added to a solution of compound 17 (120 mg, 0.25 mol) and pinacol diboron (159 mg, 0.6 mmol) in dioxane (2.0 mL) at 25°C. The atmosphere was replaced with nitrogen and the reaction mixture was stirred at 90°C for 4 hours. The reaction was monitored by LCMS for completion. The reaction mixture was cooled to 25°C and used directly in the next reaction. LCMS: m / z 527.2 [M+H] + .

[0386] Step 2: At 25°C, dioxane (1.0 mL) and water (0.7 mL) were added to the reaction mixture from Step 1, followed by 2-bromothiazole (48 mg, 0.30 mmol), potassium carbonate (102 mg, 0.70 mmol), and tetrakis(triphenylphosphine)palladium (28 mg, 0.02 mmol). The atmosphere was replaced with nitrogen, and the reaction mixture was heated to 110°C and stirred for 16 hours. The reaction was monitored by LCMS to confirm completion. The reaction mixture was filtered, the filtrate was dried, and the residue was purified by preparative HPLC to yield compound 38. LCMS: m / z 484.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ = 8.41 (s, 1H), 7.93 (d, J = 2.8Hz, 1H), 7.54 (d, J = 8.1Hz, 1H), 7.42 (d, J = 2.6Hz, 1H), 7.19 (s, 4H), 7.02 (d, J = 8.4Hz,1H),4.10(d,J=5.6Hz,2H),4.06-3.88(m,8H),2.82(s,3H),2.81-2.72(m,2H),2.12(d,J=12.8Hz,3H),1.70-1.57(m,2H).

[0387] Example 37: Compound 39

[0388] Compound 17 (150 mg, 0.31 mmol) and potassium cyclopropylfluoroborate (92 mg, 0.62 mmol) were added to dioxane (3 mL) at 25°C. Cesium carbonate (307 mg, 0.94 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (23 mg, 0.03 mmol), and water (0.5 mL) were then added. The atmosphere was replaced with nitrogen. The reaction solution was stirred at 100°C for 18 hours. LCMS monitored the completion of the reaction. The reaction solution was filtered, diluted with water (10 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (40 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid conditions) to obtain the formate salt of compound 39. LCMS: m / z 441.3 [M+H] + ; 1H NMR(400MHz, CDCl3)δ:7.31-7.27(m,2H),7.26-7.17(m,3H),6.95(s,1H), 6.80(d,J=8.1Hz,1H),4.29(s,4H),4.09(s,2H),3.90(d,J=5.8Hz,4H),2.8 1(s,3H),2.74(dt,J=2.0,12.0Hz,2H),2.14(ddd,J=3.3,5.2,8.5Hz,1H),2 .04-1.96(m,3H),1.65-1.53(m,2H),0.98-0.90(m,2H),0.71-0.63(m,2H).

[0389] Example 38: Compound 40

[0390] Step 1: At 80°C under nitrogen atmosphere, the raw material 40-0 (2.00g, 9.85mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (3.09g, 14.78mmol), bistriphenylphosphine palladium dichloride (690mg, 0.98mmol), and cuprous iodide (90mg, 0.49mmol) were dissolved in triethylamine (5mL) and tetrahydrofuran (15mL) and stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was extracted with dichloromethane (30x 3mL), the organic phase was collected, and washed with saturated brine (100mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5:1) to obtain intermediate 40-1. LCMS: m / z 276.1 [M+H] + .

[0391] Step 2: Under nitrogen at 25°C, intermediate 40-1 (1.5 g, 4.53 mmol) and palladium / carbon (150 mg, 4.53 mmol) were dissolved in isopropanol (10 mL). The hydrogen atmosphere was replaced three times and stirred for 8 hours. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give intermediate 40-2. LCMS: m / z 280.1 [M+H] + .

[0392] Step 3: At 25°C, a solution of intermediate 40-2 (1.5 g, 4.47 mmol), 1H-isoindole hydrochloride (1.03 g, 6.71 mmol), sodium acetate borohydride (2.83 g, 13.42 mmol), and acetic acid (0.26 ml, 4.47 mmol) in 1,2-dichloroethane (20 mL) was stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was extracted with dichloromethane (30 x 3 mL), and the organic phase was collected, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 3:1) to obtain intermediate 40-3. LCMS: m / z 437.0 [M+H] + .

[0393] Step 4: Stir intermediate 40-3 (500 mg, 1.15 mmol) and trifluoroacetic acid (1 mL, 13.42 mmol) in dichloromethane (5 mL) at 25°C for 30 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to obtain intermediate 40-4. LCMS: m / z 337.1 [M+H] + .

[0394] Step 5: At 25°C, intermediate 40-4 (385 mg, 1.14 mmol), triethylamine (0.47 mL, 3.42 mmol), and methanesulfonyl chloride (0.44 mL, 5.72 mmol) were dissolved in dichloromethane (5 mL) and stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC (ammonium bicarbonate conditions) to obtain compound 40. LCMS: m / z 417.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.12-7.25(m,7H),4.03(br s,4H),3.93(s,2H),3.81(br d,J=11.6Hz, 2H),2.78(s,3H),2.60-2.71(m,4H),1.88(br d,J=9.9Hz,2H),1.61(br d,J=5.8Hz,2H),1.26-1.49(m,3H).

[0395] Example 39: Compound 41

[0396] Step 1: Add liquid bromine (3.59 g, 22.47 mmol) to a solution of Intermediate 41-0 (3.5 g, 24.97 mmol) in dichloromethane (20 mL) at 25°C and stir for 16 hours. Completion of the reaction was monitored by thin-layer chromatography (ethyl acetate:petroleum ether = 1:10). Aqueous potassium carbonate (20 mL) was added to the reaction solution and stirred for 30 minutes. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was collected and washed with saturated brine (150 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to obtain Intermediate 41-1. 1 H NMR (400MHz, CDCl3) δ: 7.13 (d, J = 8.6Hz, 1H), 6.62 (d, J = 6.8Hz, 1H), 3.8-3.8 (m, 3H), 2.16 (d, J = 2.0Hz, 3H).

[0397] Step 2: Add azobisisobutyronitrile (0.19 g, 1.14 mmol) to a solution of Intermediate 41-1 (2.50 g, 11.41 mmol) and N-bromosuccinimide (2.03 g, 11.41 mmol) in carbon tetrachloride (15 mL) at 60°C and stir for 16 hours. Completion of the reaction was monitored by thin-layer chromatography (ethyl acetate:petroleum ether = 1:10). The reaction solution was extracted with dichloromethane (20 mL x 3). The organic phase was collected and washed with saturated brine (60 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:10) to provide Intermediate 41-2. 1 H NMR (400MHz, CDCl3) δ: 7.23 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 6.5 Hz, 1H), 4.40 (d, J = 0.8 Hz, 2H), 3.8-3.9 (m, 3H).

[0398] Step 3: At 25°C, intermediate 41-2 (2.00 g, 6.71 mmol), 2,3-dihydroisoindole hydrochloride (1.55 g, 10.07 mmol), and triethylamine (2.79 mL, 20.14 mmol) were stirred in acetonitrile (15 mL) for 16 hours. The reaction was monitored by LCMS. The reaction solution was extracted with dichloromethane (30 mL × 3), and the organic phase was collected and washed with saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain intermediate 41-3. LCMS: m / z 338.1 [M+H] + .

[0399] Step 4: At 25°C under a nitrogen atmosphere, bistriphenylphosphine palladium dichloride (104.0 mg, 0.15 mmol) was added to a solution of intermediate 41-3 (500.0 mg, 1.49 mmol), 4-ethynyl-1-(methylsulfonyl)piperidine (1.12 g, 5.96 mmol), and cuprous iodide (28.32 mg, 0.15 mmol) in triethylamine (2 mL) and tetrahydrofuran (6 mL). The mixture was heated to 80°C and stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was extracted with dichloromethane (30 × 3 mL). The organic phase was collected and washed with saturated brine (100 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 5:1) to obtain intermediate 41-4. LCMS: m / z 443.2 [M+H] + .

[0400] Step 5: Under a nitrogen atmosphere at 25°C, palladium / carbon (48.09 mg, 0.45 mmol) was added to a methanol (5 mL) solution of intermediate 41-4 (200.0 mg, 0.45 mmol), the temperature was raised to 50°C, hydrogen was replaced three times, and the mixture was stirred for 8 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 41. LCMS: m / z 447.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 7.20 (s, 4H), 6.96 (d, J = 6.1Hz, 1H), 6.84(d,J=10.1Hz,1H),4.00(s,4H),3.94(s,2H),3.77-3.84(m,5H),2.78(s,3H),2.57-2.69(m,4H),1.88(br d,J=9.8Hz,2H),1.52-1.61(m,2H),1.26-1.42(m,3H).

[0401] Example 40: Compound 42

[0402] Step 1: 1H-isoindole hydrochloride (1.20 g, 8.9 mmol) was added to a solution of raw material 42-0 (1.20 g, 4.63 mmol) and diisopropylethylamine (6.14 mL, 37.04 mmol) in acetonitrile (30 mL) at 25°C and stirred for 16 hours. The reaction was monitored by LCMS to confirm completion. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5:1) to obtain intermediate 42-1. LCMS: m / z 298.2 [M+H] + .

[0403] Step 2: At 0°C, a toluene solution of diisobutylaluminum hydride (5.6 mL, 8.4 mmol, 1.5 M) was slowly added dropwise to a toluene (10 mL) solution of intermediate 42-1 (1 g, 1.17 mmol) and stirred for 16 hours. The reaction was monitored by LCMS. Methanol (10 mL) was added to quench the reaction. After stirring for 30 minutes, potassium sodium tartrate solution (10 mL, 4 M) was added and stirred for 2 hours. The mixture was extracted with dichloromethane (40 mL × 2). The combined organic phases were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography on silica gel (dichloromethane: methanol = 10:1) to obtain intermediate 42-2. LCMS: m / z 270.2 [M+H] + .

[0404] Step 3: Add thionyl chloride (0.68 mL, 9.3 mmol) dropwise to a solution of intermediate 42-2 (500 mg, 1.86 mmol) in dichloromethane (10 mL) at 25°C and stir for 2 hours. The reaction was monitored by LCMS. Concentrate under reduced pressure to obtain intermediate 42-3. LCMS: m / z 288.1 [M+H] + .

[0405] Step 4: Sodium hydride (175 mg, 4.34 mmol) was added to a solution of 1-(methylsulfonyl)piperidin-4-ol (340 mg, 1.81 mmol) in N,N-dimethylformamide (8 mL) at 0°C, stirred for 30 minutes, and intermediate 42-3 (420 mg, 1.46 mmol) was added. Stirring was continued for 16 hours. The reaction was monitored by LCMS. The temperature was lowered to 0°C, and water (10 mL) was slowly added dropwise to quench the reaction. After stirring for 30 minutes, the mixture was extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate) to obtain compound 42. LCMS: m / z 431.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.35(d,J=7.5Hz,1H),7.20(s,4H),7.01(s,1H),6.98(d,J=7.6Hz,1H),4.58(s,2H),3.97(s,4H),3.92( s,2H),3.85(s,3H),3.64-3.72(m,1H),3.39(ddd,J=11.8,8.2,3.9Hz,2H),3.19-3.30(m,2H),2.79(s,3H),1.84-2.00(m,4H).

[0406] Example 41: Compound 43

[0407] Step 1: Add raw material 43-0 (100 mg, 0.58 mmol) and sodium sulfide nonahydrate (84 mg, 0.87 mmol) to dimethyl sulfoxide (5 mL), heat to 80°C, and stir for 30 minutes. LCMS monitoring indicates the completion of the reaction. Add [1-(methyldioxo-λ6-thio)hexahydropyridin-4-yl]methyl methanesulfonate to the reaction solution and continue the reaction for 30 minutes. LCMS monitoring indicates the completion of the reaction. Pour the reaction solution into water (20 mL), extract with ethyl acetate (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 43-1. LCMS: m / z 362.1 [M+H] + .

[0408] Step 2: Dissolve Intermediate 43-1 (150 mg, 0.41 mmol) in toluene (3 mL), cool to 0°C, and add diisobutylaluminum hydride-toluene solution (0.69 mL, 1.04 mmol, 1.5 M) dropwise. Stir for 2 hours. LCMS monitoring indicates the completion of the reaction. Add saturated sodium potassium tartrate solution (10 mL) dropwise to quench the reaction. Extract with ethyl acetate (20 mL x 3). The combined organic phases are washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain Intermediate 43-2. ​​LCMS: m / z 316.1 [M-OH] + .

[0409] Step 3: Dissolve intermediate 43-2 (90 mg, 0.27 mmol) in dichloromethane (2 mL) and add thionyl chloride (64 mg, 0.54 mmol) dropwise. Stir at 25°C for 30 minutes. LCMS monitoring indicates the completion of the reaction. The reaction mixture is concentrated under reduced pressure to obtain intermediate 43-3. LCMS: m / z 352.1 [M+H] + .

[0410] Step 4: Dissolve intermediate 43-3 (105 mg, 0.30 mmol) and 2,3-dihydroisoindole hydrochloride (46 mg, 0.30) in acetonitrile (5 mL), add triethylamine (91 mg, 0.90 mmol) dropwise, and stir at 25°C for 18 hours. The reaction was monitored by LCMS. The reaction solution was directly concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 43. LCMS: m / z 435.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ7.23(t,J=7.9Hz,1H),7.09-7.06(m,4H),7.05-7.01(m,2H),3.83(s,4H),3.77(s,2H),3.69(br d,J=12.0Hz,2H),2.73(d,J=6.9Hz,2H),2.65(s,3H),2.51(dt,J=2.4,12.0Hz,2H),1.93-1.82(m,2H),1.52-1.41(m,1H),1.37-1.24(m,2H).

[0411] Example 42: Compound 44

[0412] Step 1: A solution of compound 50 (200 mg, 0.45 mmol) in trifluoroacetic acid (1 mL) was sonicated at 25°C for 1 minute. LCMS monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure to afford Intermediate 44-1. LCMS: m / z 349.2 [M+H]+.

[0413] Step 2: A solution of intermediate 44-1 (150 mg, 0.43 mmol), methanesulfonyl chloride (0.07 mL, 0.86 mmol), and triethylamine (0.18 mL, 1.29 mmol) in dichloromethane (2 mL) was stirred at 25°C for 2 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 44. LCMS: m / z 427.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.39(d,J=7.8Hz,1H),7.22-7.17(m,4H),6.99(s,1H),6.95(d,J=7 .9Hz,1H),6.75(d,J=16.0Hz,1H),6.14(dd,J=6.9,16.1Hz,1H),3.95(s,4H),3.90(s,2H), 3.86(s,3H),3.85(br s,1H),3.82(br s,1H),2.80(s,3H),2.79-2.71(m,2H),2.35-2.24(m,1H),1.96-1.89(m,2H),1.68-1.56(m,2H).

[0414] Example 43: Compound 45

[0415] Step 1: At 25°C, the starting material 45-0 (2 g, 9.30 mmol) and isoindole (1.66 g, 13.95 mmol) were dissolved in dichloroethane (20 mL). Acetic acid (2.79 g, 46.5 mmol) and sodium triacetoxyborohydride (3.94 g, 18.60 mmol) were added sequentially. The reaction solution was stirred at 25°C for 12 hours. The reaction was monitored by LCMS. The mixture was diluted with water (50 mL) and extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 45-1. LCMS: m / z 318.0 [M+H] + .

[0416] Step 2: At 25°C, intermediate 45-1 (1.20 g, 3.80 mmol) and copper acetylacetonate (100 mg, 0.38 mmol) were dissolved in dimethyl sulfoxide (12 mL) and water (4 mL). Lithium hydroxide monohydrate (400 mg, 9.52 mmol) and N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxamide (120 mg, 0.36 mmol) were added. The atmosphere was replaced with nitrogen. The reaction solution was stirred at 80°C for 6 hours. The reaction was monitored by LCMS. The pH was adjusted to acidic with 2M dilute hydrochloric acid (4 mL), diluted with water (20 mL), and extracted with dichloromethane (40 mL×3). The organic phases were combined, washed with saturated brine (5 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain intermediate 45-2. LCMS: m / z 256.1 [M+H] + .

[0417] Step 3: At 25 ° C, the intermediate 45-2 (100 mg, 0.39 mmol) and tert-butyl 5-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (245 mg, 0.78 mmol) were dissolved in dimethylformamide (2 mL), and cesium carbonate (383 mg, 1.17 mmol), cuprous iodide (8 mg, 0.05 mmol), N1-(2-methyl-1-naphthyl)-N2-(phenylmethyl)-oxalyl were added. Amine (10 mg, 0.03 mmol) was added, nitrogen was replaced, and the reaction mixture was stirred at 120°C for 18 hours. The reaction was completed by LCMS monitoring. The reaction mixture was filtered, the filtrate was diluted with water (10 mL), and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 45-3. LCMS: m / z 487.3 [M+H] + ;

[0418] Step 4: At 25°C, intermediate 45-3 (50 mg, 0.1 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at 25°C for 1 hour. The reaction was completed by LCMS monitoring. The reaction solution was concentrated to obtain intermediate 45-4. LCMS: m / z 387.1 [M+H] + .

[0419] Step 5: At 25°C, intermediate 45-4 (40 mg, 0.1 mmol) and triethylamine (36 mg, 0.3 mmol) were dissolved in dichloromethane (4 mL). Methanesulfonyl chloride (20 mg, 0.17 mmol) was added dropwise. The reaction solution was stirred at 25°C for 2 hours. The reaction was monitored by LCMS. Water (10 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound 45. LCMS: m / z 465.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.22(s,4H),7.17-7.03(m,2H),6.91(d,J =7.9Hz,1H),6.82(dd,J=7.9,12.9Hz,2H),6.64(d,J=8.1Hz,1H),4.50(s,2H),3.99(s,4 H), 3.92 (s, 2H), 3.85 (s, 3H), 3.60 (t, J = 6.0Hz, 2H), 3.03 (t, J = 5.8Hz, 2H), 2.86 (s, 3H).

[0420] Example 44: Compound 46

[0421] Step 1: At 25°C, triethylamine (4.64 g, 45.94 mmol) and methanesulfonyl chloride (2.07 g, 18.15 mmol) were added to a solution of raw material 46-0 (3.00 g, 13.95 mmol) in dichloromethane (30 mL) in one portion. The mixture was stirred for 3 hours. The reaction was monitored by LCMS for completion. The mixture was quenched with water (80 mL) and extracted with dichloromethane (80 mL x 3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 46-1. LCMS: m / z 238.2 [M-55] + ;

[0422] Step 2: At 25°C, intermediate 46-1 (4 g, 13.65 mmol) and 5-bromo-2-fluoro-4-hydroxybenzaldehyde (3.00 g, 13.76 mmol) were dissolved in N,N-dimethylformamide (40 mL). Potassium carbonate (5.7 g, 41.30 mmol) was added and the reaction mixture was stirred at 25°C for 3 hours. The reaction was monitored by LCMS for completion. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). 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. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford intermediate 46-2. LCMS: m / z 360.0 [M-55] + ;

[0423] Step 3: At 25°C, intermediate 46-2 (800 mg, 1.92 mmol) and isoindoline hydrochloride (480 mg, 3.09 mmol) were dissolved in 1,2-dichloroethane (15 mL). Acetic acid (578 mg, 9.63 mmol) and sodium triacetoxyborohydride (817 mg, 3.85 mmol) were added. The reaction solution was stirred at 25°C for 18 hours. The reaction was monitored by LCMS. Water (40 mL) was added to quench the reaction and the mixture was extracted with dichloromethane (40 mL × 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 46. LCMS: m / z 519.2 [M+H] + ; 1HNMR(400MHz, CDCl3)δ:7.66(d,J=7.8Hz,1H),7.19(s,4H),6.62(d,J=11.3Hz,1H),4.19(s,2H),3.98(s,4H),3.89(s,2 H),3.84(d,J=6.4Hz,2H),2.78(t,J=12.3Hz,2H),2.10-1.99(m,1H),1.91-1.83(m,2H),1.48(s,9H),1.39-1.27(m,2H).

[0424] Example 45: Compound 47

[0425] Step 1: At 25°C, the starting material 47-0 (3.00 g, 14.78 mmol), 2,3-dihydroisoindole hydrochloride (2.72 g, 17.73 mmol), acetic acid (0.85 mL, 14.78 mmol), and sodium triacetoxyborohydride (9.35 g, 44.33 mmol) were stirred in 1,2-dichloroethane (20 mL) for 16 hours. The reaction was monitored by LCMS. The reaction mixture was added with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (30 mL x 3). The organic phase was collected, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 3:1) to obtain intermediate 47-1. LCMS: m / z 306.0 [M+H] + .

[0426] Step 2: At 25°C, intermediate 47-1 (660.0 mg, 2.16 mmol), tert-butyl 4-(3-hydroxyphenyl)piperazine-1-carboxylate (500 mg, 1.80 mmol), cuprous iodide (171.2 mg, 0.90 mmol), cesium carbonate (1.76 g, 5.39 mmol), and N-(2-phenyl-4-methylphenyl)-N-benzyloxamide (31.0 mg, 0.09 mmol) were added to N,N-dimethylformamide (5 mL). The atmosphere was purged with nitrogen three times, and the temperature was raised to 120°C and stirred for 16 hours. The reaction was monitored by LCMS. The reaction solution was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phase was collected, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=5:1) to obtain intermediate 47-2. LCMS: m / z 504.3 [M+H] + .

[0427] Step 3: Add trifluoroacetic acid (1 mL, 13.42 mmol) to a solution of intermediate 47-2 (150 mg, 0.30 mmol) in dichloromethane (5 mL) at 25°C and stir for 2 hours. The reaction was monitored by LCMS. The product was concentrated under reduced pressure and the residue was purified by thin layer chromatography (petroleum ether:ethyl acetate = 1:1) to afford intermediate 47-3. LCMS: m / z 404.3 [M+H] + .

[0428] Step 4: At 25°C, triethylamine (0.10 mL, 0.74 mmol) and acetyl chloride (0.02 mL, 0.25 mmol) were added dropwise to a solution of intermediate 47-3 (100 mg, 0.25 mmol) in dichloromethane (5 mL) and stirred for 4 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure and purified by thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 47 (60 mg). The crude product was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to give compound 47. LCMS: m / z 446.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.30 (dd, J = 1.8Hz, 1H), 7.21-7.24 (m, 4H), 7.18-7.21 (m, 1H), 7.16 (br d,J=8.3Hz,1H),7.01-7.07(m,1H),6.66(dd,J=8.3,2.0Hz,1H),6.61(t,J=2.3Hz,1H),6.47(dd,J=8.0,2.1Hz, 1H),4.00(s,4H),3.92(s,2H),3.72-3.81(m,2H),3.58-3.65(m,2H),3.18(dt,J=13.4,5.3Hz,4H),2.14(s,3H).

[0429] Example 46: Compound 48

[0430] Step 1: Dissolve the starting material 48-0 (2.00 g, 9.30 mmol), 1H-isoindole hydrochloride (1.66 g, 13.95 mmol), sodium acetate borohydride (3.92 g, 46.50 mmol), and acetic acid (2.66 ml, 46.50 mmol) in 1,2-dichloroethane (10 mL) at 25°C and stir for 18 hours. Monitor the reaction by LCMS until completion. Add saturated sodium bicarbonate solution (50 mL) to the reaction solution, extract with dichloromethane (50 mL x 3), and combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:petroleum ether = 5:1) to obtain intermediate 48-1. LCMS: m / z 318.1 [M+H] + .

[0431] Step 2: Dissolve Intermediate 48-1 (300 mg, 0.94 mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (373 mg, 1.89 mmol), and potassium carbonate (260 mg, 1.89 mmol) in a mixture of dioxane and water (6 mL, 5:1). Add tetrakis(triphenylphosphine)palladium (109 mg, 0.09 mmol) under a nitrogen atmosphere. Stir at 80°C for 2 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain Intermediate 48-2. LCMS: m / z 310.2 [M+H] + .

[0432] Step 3: Dissolve Intermediate 48-2 in tetrahydrofuran-water (3 mL, 2:1) and add concentrated sulfuric acid (63 mg, 0.65 mmol) dropwise. Stir at 25°C for 18 hours. LCMS monitoring indicates the completion of the reaction. Add saturated sodium bicarbonate solution (10 mL) to the reaction solution, extract with ethyl acetate (10 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain Intermediate 48-3. LCMS: m / z 382.2 [M+H] + .

[0433] Step 4: Dissolve intermediate 48-3 (100 mg, 0.36 mmol) in methanol (3 mL), add sodium borohydride (13 mg, 0.36 mmol), and stir at 25°C for 1 hour. LCMS monitoring of the reaction completion. The reaction solution was added to water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 48-4. LCMS: m / z 284.2 [M+H] + .

[0434] Step 5: Dissolve intermediate 48-4 (80 mg, 0.28 mmol) and triethylamine (114 mg, 1.13 mmol) in dichloromethane (3 mL), add methanesulfonyl chloride (64 mg, 0.56 mmol) dropwise, and stir at 25°C for 1 hour. LCMS monitoring indicates the completion of the reaction. The reaction solution is concentrated under reduced pressure to obtain intermediate 48-5. LCMS: m / z 362.1 [M+H] + .

[0435] Step 6: Dissolve intermediate 48-5 (100 mg, 0.28 mmol) and potassium carbonate (153 mg, 1.11 mmol) in acetonitrile (5 mL), add N-methylsulfonylpiperazine (136 mg, 0.83 mmol), and stir at 80°C for 3 hours. The reaction was monitored by LCMS. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 48. LCMS: m / z 430.3 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ7.19(s,4H),7.10(d,J=7.5Hz,1H),6.97(s,1H),6.91(d,J=7.5Hz,1H),3 .95(s,4H),3.89(s,2H),3.84(s,3H),3.32-3.25(m,4H),2.85-2.76(m,5H),2.71-2.60(m,6H).

[0436] Example 47: Compound 49

[0437] Step 1: Dissolve raw material 49-0 (500 mg, 3.80 mmol) in dichloromethane (5 mL) at 25°C. Cool to 0°C and add acetic anhydride (395 mg, 3.08 mmol) dropwise. Stir the reaction mixture at 0°C for 2 hours. Monitor the reaction completion by TLC. Dilute the reaction mixture with dichloromethane (50 mL) and wash with saturated sodium chloride solution (50 mL). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 49-1.

[0438] Step 2: At 25°C, intermediate 49-1 (600 mg, 3.50 mmol) and triethylamine (800 mg, 7.91 mmol) were added to dichloromethane (8 mL). Methanesulfonyl chloride (480 mg, 4.21 mmol) was added dropwise. The reaction mixture was stirred at 25°C for 2 hours. LCMS monitored the reaction completion. The reaction mixture was diluted with dichloromethane (40 mL), washed with saturated sodium bicarbonate solution (50 mL), and then washed with saturated sodium chloride solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 49-2. LCMS: m / z 250.0 [M+H] + .

[0439] Step 3: Dissolve the starting material 49-3 (500 mg, 2.90 mmol) in dimethyl sulfoxide (8 mL) at 25°C, then add sodium sulfide nonahydrate (837 mg, 3.50 mmol). Stir the reaction at 80°C for 1.5 hours. LCMS monitoring indicates the completion of the reaction. This yields the intermediate 49-4, which is used directly in the next step. LCMS: m / z 373.2 [2M+H] + .

[0440] Step 4: At 25°C, add Intermediate 49-2 (700 mg, 2.80 mmol) and triethylamine (850 mg, 8.40 mmol) to the reaction mixture from Step 3 above. The reaction mixture was stirred at 80°C for 2 hours. The reaction was monitored for completion by LCMS. The reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated sodium chloride solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to obtain Intermediate 49-5. LCMS: m / z 340.1 [M+H] + .

[0441] Step 5: At 25°C, intermediate 49-5 (80 mg, 0.2 mmol) was dissolved in tetrahydrofuran (4 mL). Lithium triethylborohydride in tetrahydrofuran (0.7 mL, 0.6 mmol, 1 M) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. The reaction was monitored by LCMS to determine completion. The reaction mixture was diluted with ethyl acetate (40 mL), quenched with saturated sodium bicarbonate solution (50 mL), and washed with saturated sodium chloride solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 49-6. LCMS: m / z 312.2 [M+H] + .

[0442] Step 6: Dissolve intermediate 49-6 (80 mg, 0.2 mmol) in dichloromethane (3 mL) at 25°C, add thionyl chloride (1 mL), and stir the reaction at 25°C for 1 hour. LCMS monitoring indicates the completion of the reaction. The reaction solution is concentrated under reduced pressure to obtain intermediate 49-7. LCMS: m / z 330.1 [M+H] + .

[0443] Step 7: At 25°C, intermediate 49-7 (90 mg, 0.3 mmol) and isoindoline (51 mg, 0.3 mmol) were dissolved in acetonitrile (4 mL). Triethylamine (83 mg, 0.8 mmol) was added and the reaction mixture was stirred at 25°C for 3 hours. The reaction was monitored by LCMS to determine completion. Water (10 mL) was added to quench the mixture and the mixture was extracted with ethyl acetate (20 mL x 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. The residue was purified by preparative HPLC to obtain compound 49. LCMS: m / z 413.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.34(t,J=7.9Hz,1H),7.25-7.09(m,6H),4.60(td,J=2.0,13.2Hz,1H),3.95(s,4H),3.89(s,2H),3.85-3.69(m,1H),3.03( dt,J=2.4,13.0Hz,1H),2.94(t,J=7.4Hz,2H),2.53(dt,J=2.3,12.9Hz,1 H),2.08(s,3H),1.81-1.65(m,3H),1.63-1.53(m,2H),1.22-1.02(m,2H).

[0444] Example 48: Compound 50

[0445] Step 1: At 25°C, add the raw material 50-0 (1.00 g, 4.78 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.59 mL, 4.06 mmol), and zirconocene hydrochloride (0.12 g, 0.48 mmol) to toluene (15 mL). The nitrogen atmosphere is replaced three times, the temperature is raised to 60°C, and the mixture is stirred for 18 hours. LCMS monitoring indicates that the reaction is complete. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in petroleum ether (20 mL), filtered, and the filtrate is concentrated under reduced pressure to obtain intermediate 50-1. LCMS: m / z 338.2 [M+H] + ;

[0446] Step 2: At 25°C, intermediate 50-1 (1.3 g, 3.77 mmol), intermediate 45-1 (400 mg, 1.26 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (92 mg, 0.13 mmol), and potassium carbonate (521 mg, 3.77 mmol) were added to a mixed solvent of water (1 mL) and 1,4-dioxane (5 mL). The nitrogen atmosphere was replaced three times, the temperature was raised to 100°C, and the mixture was stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 50. LCMS: m / z 449.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.39 (d, J = 7.8Hz, 1H), 7.19 (s, 4H), 6.97 (s, 1H), 6.94 ( d,J=7.9Hz,1H),6.73(d,J=16.0Hz,1H),6.15(dd,J=6.9,16.1Hz,1H),4.13(br d,J=7.1Hz,2H),3.94(s,4H),3.89(s,2H),3.86(s,3H),2.80(br t,J=11.9 Hz,2H),2.37-2.26(m,1H),1.78(br d,J=11.6Hz,2H),1.49(s,9H),1.46-1.35(m,2H)

[0447] Example 49: Compound 51

[0448] Step 1: At 25°C, raw material 51-0 (2.7 g, 13.30 mmol), 2,3-dihydroisoindole hydrochloride (4.09 g, 526.60 mmol), sodium triacetoxyborohydride (5.61 g, 26.60 mmol), and acetic acid (0.76 mL, 13.30 mmol) were added to 1,2-dichloroethane (50 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was directly concentrated under reduced pressure, and the residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium bicarbonate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was eluted by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 51-1. LCMS: m / z 306.0 [M+H] + ;

[0449] Step 2: At 25°C, intermediate 51-1 (508 mg, 1.66 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (500 mg, 1.66 mmol), (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (269 mg, 0.17 mmol), and cesium carbonate (1.6 g, 4.98 mmol) were added to 1,4-dioxane (10 mL). The atmosphere was purged with nitrogen three times, the temperature was raised to 120°C, and the mixture was stirred for 3 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was eluted with silica gel column chromatography (petroleum ether:ethyl acetate=5:2) to give compound 51. LCMS: m / z 466.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ: 7.19 (s, 4H), 7.14-7.07 (m, 2H), 6.94 (q, J = 8.1Hz, 1H), 3.93 (s, 4H), 3.84 (s, 2H), 3.45 (br t, J = 7.0Hz, 1H), 3.40 (br t,J=7.1Hz,1H),3.29(s,1H),3.20(s,1H),3.17-3.07(m,2H),3.04-2.92(m,2H),1.81-1.73(m,6H),1.48(s,9H).

[0450] Example 50: Compound 52

[0451] Compound 25 (200 mg, 0.40 mmol), copper acetylacetonate (10 mg, 0.04 mmol), lithium hydroxide monohydrate (42 mg, 1.01 mmol), N1, N2-bis(4-hydroxy-2,6-dimethylphenyl)oxamide (13 mg, 0.04 mmol), and water (0.4 mL) were dissolved in dimethyl sulfoxide (1.2 mL), replaced with nitrogen three times, heated to 100 ° C, and stirred for 5 hours. The reaction was monitored by LCMS. The reaction solution was adjusted to pH = 4-5 with 3M hydrochloric acid, diluted with water (50 mL), extracted with ethyl acetate (100 mL×3), and the aqueous phase was filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 52. LCMS: m / z 435.2 [M+H] + ; 1HNMR(400MHz, CDCl3)δ:7.17(s,4H),7.00(d,J=7.1Hz,1H),6.60(d,J=10.6Hz,1H),3.96(s,4H),3 .92-3.85(m,6H),2.80(s,3H),2.71(dt,J=2.0,12.1Hz,2H),2.04-1.92(m,4H),1.57-1.45(m,2H).

[0452] Example 51: Compound 53

[0453] Step 1: Combine the starting material 53-0 (200 mg, 0.93 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (583 mg, 2.79 mmol), and bistriphenylphosphine palladium dichloride (65 mg, 0.09 mmol) in triethylamine (1.30 mL) and tetrahydrofuran (1 mL). Heat to 80°C under a nitrogen atmosphere and stir for 1 hour. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 53-1. LCMS: m / z 288.0 [M-55] + .

[0454] Step 2: Under nitrogen at 25°C, dissolve Intermediate 53-1 (175 mg, 0.51 mmol) and palladium / carbon (53 mg, 0.05 mmol, 10%) in isopropanol (5 mL). Replace the hydrogen atmosphere three times and stir for 2 hours. Filter the reaction mixture and concentrate the filtrate under reduced pressure to yield Intermediate 53-2.

[0455] Step 3: Add trifluoroacetic acid (98 mg, 0.86 mmol) to a solution of intermediate 53-2 (1.50 mg, 0.43 mmol) in dichloromethane (3 mL) at 25°C and stir for 2 hours. Monitor the reaction by TLC. Concentrate the reaction mixture under reduced pressure to obtain intermediate compound 53-3.

[0456] Step 4: Methanesulfonyl chloride (246 mg, 2.15 mmol) was added dropwise to a solution of intermediate 53-3 (110 mg, crude product) and triethylamine (0.6 mL, 4.30 mmol) in dichloromethane (5 mL) at 25°C and stirred for 4 hours. The reaction was monitored by LCMS. The reaction solution was diluted with water (10 mL) and 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 intermediate 53-4. LCMS: m / z 310.1 [M-95] + .

[0457] Step 5: Potassium carbonate (103 mg, 0.74 mmol) was added to a solution of intermediate 53-4 (151 mg, crude product) and isoindoline hydrochloride (153 mg, 0.74 mmol) in N,N-dimethylformamide (5 mL) at 25°C, the temperature was raised to 80°C, and the mixture was stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (formic acid conditions) to obtain compound 53. LCMS: m / z 429.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 8.37 (br s, 1H), 7.34-7.25 (m, 4H), 7.15 (s, 1H), 7.11 (d, J = 7.5Hz, 1H), 6.8 (br d,J=7.5Hz,1H),4.38(s,4H),4.19(s,2H),3.85(s,3H),3.84-3.76(m,2H),2.78(s,3H ),2.71-2.59(m,4H),1.88(brd,J=10.1Hz,2H),1.62-1.51(m,2H),1.45-1.26(m,3H).

[0458] Example 52: Compound 54

[0459] Step 1: Dissolve the starting material 54-0 (1.50 g, 7.69 mmol), N-bromosuccinimide (1.50 g, 8.42 mmol), and azobisisobutyronitrile (630 mg, 3.84 mmol) in carbon tetrachloride (15 mL) at 25°C. Heat to 80°C and stir for 2 hours. Completion of the reaction is monitored by TLC. The reaction mixture is quenched with water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phases are combined and washed with saturated sodium chloride solution (50 mL). The organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain intermediate 54-1.

[0460] Step 2: At 25°C, intermediate 54-1 (2.50 g, 9.15 mmol) and isoindoline hydrochloride (1.85 g, 11.85 mmol) were added to N,N-dimethylformamide (20 mL), followed by potassium carbonate (3.79 g, 27.46 mmol). The reaction mixture was stirred at 25°C for 18 hours. LCMS monitored the reaction completion. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (150 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain intermediate 54-2. LCMS: m / z 313.0 [M+H] + .

[0461] Step 3: At 25°C, intermediate 54-2 (700 mg, 2.24 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate (703 mg, 3.36 mmol) were added to tetrahydrofuran (9 mL). Bistriphenylphosphine palladium dichloride (157 mg, 0.22 mmol), cuprous iodide (43 mg, 0.22 mmol), and triethylamine (3 mL) were then added. The reaction mixture was stirred at 80°C for 18 hours. LCMS monitored the reaction completion. The reaction mixture was filtered, the filtrate diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (60 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to afford intermediate 54-3. LCMS: m / z 386.2 [M-55] + .

[0462] Step 4: At 25°C under a nitrogen atmosphere, intermediate 54-3 (500 mg, 1.13 mmol) was dissolved in methanol (10 mL). Pd / carbon (500 mg, 10%) was added and the hydrogen was replaced three times. The reaction mixture was stirred at 25°C for 3 hours. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain intermediate 54-4. LCMS: m / z 446.2 [M+H] + .

[0463] Step 5: At 25°C, intermediate 54-4 (400 mg, 0.89 mmol) was dissolved in dioxane (4 mL). A solution of hydrochloric acid in dioxane (4 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure to obtain intermediate 54-5. LCMS: m / z 346.2 [M+H] + .

[0464] Step 6: At 25°C, intermediate 54-5 (200 mg, 0.58 mmol) and triethylamine (200 mg, 1.98 mmol) were dissolved in dichloromethane (8 mL). Methanesulfonyl chloride (80 mg, 0.70 mmol) was added, and the reaction solution was stirred at 25°C for 3 hours. The reaction was monitored by LCMS to determine completion. Water (20 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 54. LCMS: m / z 424.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.68(d,J=1.4Hz,1H),7.60(dd,J=1.4,8.0Hz,1H),7.30(d,J=8.0Hz,1H),7.21(s,4H),3.95(s,4H),3.92(s,2H ),3.82(d,J=12.1Hz,2H),2.90-2.84(m,2H),2.78(s,3H),2.71-2.61(m,2H),1.94-1.86(m,2H),1.69-1.62(m,2H),1.48-1.32(m,3H).

[0465] Example 53: Compound 55

[0466] At 25°C, intermediate 55-0 (300 mg, 0.71 mmol) and 2-bromo-1-ol (133 mg, 1.07 mmol) were dissolved in N,N-dimethylformamide (8 mL), and potassium carbonate (396 mg, 2.86 mmol) was added. The reaction solution was stirred at 25°C for 18 hours. The reaction was monitored by LCMS for completion. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 55. LCMS: m / z 463.2[M+H]+; 1H NMR(400MHz, CDCl3)δ:7.64(d,J=7.9Hz,1H),7.19(s,4H),6.63(d,J=11.3Hz,1H),3.96(s,4H),3.88(s,2H),3.84(d,J=6.0Hz,2H),3.64(t,J =5.3Hz,2H),3.01(d,J=11.4Hz,2H),2.58(t,J=5.4Hz,2H),2.42-2.29(m,1H),2.21-2.13(m,2H),1.92(d,J=10.3Hz,3H),1.55-1.40(m,2H).

[0467] Example 54: Compound 56

[0468] At 25°C, intermediate 56-0 (100 mg, 0.19 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at 25°C for 1.5 hours. LCMS monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 56. LCMS: m / z 419.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.64(d,J=7.9Hz,1H),7.19(s,4H),6.62(d,J=11.4Hz,1H),3.95(s,4H),3.87 (s,2H),3.83(d,J=6.3Hz,2H),3.22(s,2H),2.73(s,2H),2.14-1.80(m,3H),1.39(d,J=11.8Hz,2H).

[0469] Example 55: Compound 57

[0470] Step 1: At 0°C, sodium triacetoxyborohydride (3.94 g, 18.68 mmol) was added to a solution of starting material 57-0 (2.00 g, 9.34 mmol), 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (3.99 g, 18.69 mmol), and acetic acid (0.56 mL, 9.34 mmol) in 1,2-dichloroethane (30 mL). The mixture was heated to 25°C and stirred for 18 hours. The reaction was monitored by LCMS. The reaction was quenched by addition of saturated sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL x 3), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 2:1) to provide intermediate 57-1. LCMS: m / z 355.1 [M-55] + .

[0471] Step 2: Trifluoroacetic acid (1.58 mL, 21.15 mmol) was added dropwise to a solution of intermediate 57-1 (2.90 g, 7.05 mmol) in dichloromethane (20 mL) at 25°C and stirred for 3 hours. The reaction was monitored by LCMS and the reaction solution was concentrated under reduced pressure to obtain intermediate 57-2. LCMS: m / z 311.1 [M+H] + .

[0472] Step 3: Methanesulfonic anhydride (2.46 g, 14.10 mmol) was added to a solution of intermediate 57-2 (2.20 g) and triethylamine (2.93 mL, 21.15 mmol) in dichloromethane (20 mL) at 25°C and stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 2:1) to obtain intermediate 57-3. LCMS: m / z 389.0 [M+H] + .

[0473] Step 4: A solution of intermediate 57-3 (2.20 g, crude product), triethylamine (4.45 mL, 32.11 mmol), triethylsilane (5.19 mL, 32.11 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (0.47 g, 0.64 mmol) in dimethyl sulfoxide (20 mL) was heated to 80°C under a carbon monoxide atmosphere and stirred for 8 hours. The reaction was monitored by LCMS. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain intermediate 57-4. LCMS: m / z 339.1 [M+H] + .

[0474] Step 5: Sodium triacetoxyborohydride (248 mg, 1.18 mmol) was added to a solution of intermediate 57-4 (200 mg, 0.59 mmol), 2,3-dihydroisoindoline hydrochloride (181 mg, 1.18 mmol), and acetic acid (30 μL, 0.59 mmol) in 1,2-dichloroethane (5 mL) at 25°C and stirred for 18 hours. The reaction was monitored by LCMS. The reaction was quenched by adding saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 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. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to give compound 57. LCMS: m / z 323.2 [M-118] + ; 1 H NMR (400MHz, CDCl3) δ: 7.17 (s, 4H), 6.90-6.83 (m, 2H), 6.55 (d, J = 8.1Hz, 1H), 4.26-4.21 (m, 2H), 3.93 (s, 4H), 3.90-3.83 (m, 2H), 3.7 8(s,2H),3.42-3.33(m,2H),3.13(d,J=6.6Hz,2H),2.78(s,3H),2.64(dt,J=2.0,12.1Hz,2H),1.94-1.84(m,3H),1.46-1.33(m,2H).

[0475] Example 56: Compound 58

[0476] Step 1: In a dry 40 mL single-necked flask, sodium borohydride (0.28 g, 7.39 mmol) was added portionwise to a solution of starting material 58-0 (1.00 g, 4.93 mmol), methanol (5 mL), and tetrahydrofuran (10 mL) with stirring. The reaction mixture was stirred at 25°C for 1 hour. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield intermediate 58-1.

[0477] Step 2: Stir Intermediate 58-1 (900 mg, 4.39 mmol), tert-butyldimethylsilyl chloride (992 mg, 6.58 mmol), and imidazole (896 mg, 13.17 mmol) in N,N-dimethylformamide (10 mL) at 25°C for 1 hour. The reaction was monitored by TLC. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield Intermediate 58-2.

[0478] Step 3: To a dry 40 mL single-necked flask, intermediate 58-2 (500 mg, 1.57 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (377 mg, 1.57 mmol), cesium carbonate (1.53 g, 4.7 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)(2'-methylamino-1,1'-biphenyl-2-yl) palladium(II) (124 mg, 0.16 mmol), and 1,4-dioxane (10 mL) were added sequentially with stirring. The reaction mixture was purged with nitrogen three times, heated to 120°C, and stirred for 5 hours. The reaction was monitored by LCMS for completion. The reaction mixture was concentrated under reduced pressure, and the residue was eluted by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford intermediate 58-3. LCMS: m / z 379.2 [M+H] + .

[0479] Step 4: In a dry 8 mL reaction bottle, tert-butyl 8-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorophenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (100 mg, 0.21 mmol), trifluoroacetic acid (0.1 mL) and dichloromethane (1 mL) were added sequentially with stirring. The reaction solution was stirred at 25 ° C for 5 hours. LCMS monitoring of the reaction completion was performed. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 58-4. LCMS: m / z 265.1 [M+H] + .

[0480] Step 5: To a dry 8 mL reaction vial, add Intermediate 58-4 (50 mg, 0.19 mmol), methanesulfonyl chloride (0.06 mL, 0.76 mmol), triethylamine (0.08 mL, 0.57 mmol), and dichloromethane (2 mL) sequentially with stirring. The reaction mixture was stirred at 25°C for 2 hours. LCMS monitored the reaction completion. The reaction mixture was concentrated under reduced pressure to afford Intermediate 58-5. LCMS: m / z 325.0.

[0481] Step 6: In a dry 8 mL reaction bottle, intermediate 58-5 (50 mg, 0.12 mmol), isoindoline hydrochloride (36 mg, 0.24 mmol), cesium carbonate (116 mg, 0.36 mmol) and N,N-dimethylformamide (2 mL) were added in sequence with stirring. The reaction solution was stirred at 100 ° C for 18 hours. LCMS monitoring of the reaction completion was performed. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 58. LCMS: m / z 444.3 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.19(s,4H),7.15-7.08(m,2H),6.95-6.89(m,1H),3.93(s,4H),3.84(s,2H),3.45(t,J=7.1H z,2H),3.26(s,2H),3.16-3.09(m,2H),3.02-2.95(m,2H),2.87(s,3H),1.90(t,J=7.1Hz,2H),1.81(t,J=5.5Hz,4H).

[0482] Example 57: Compound 59

[0483] Step 1: Stir starting material 59-0 (3.00 g, 14.02 mmol), azobisisobutyronitrile (230 mg, 1.40 mmol), and N-bromosuccinimide (2.74 g, 15.42 mmol) in carbon tetrachloride (15 mL) at 60°C for 4 hours. Cool to 25°C, concentrate the reaction mixture under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 59-1. 1 H NMR (400MHz, CDCl3) δ: 7.75 (d, J = 7.3Hz, 1H), 7.46 (d, J = 8.8Hz, 1H), 4.43 (s, 2H).

[0484] Step 2: At 25°C, intermediate 59-1 (2.30 g, 7.85 mmol), 2,3-dihydroisoindoline hydrochloride (1.45 g, 9.42 mmol), and triethylamine (3.27 mL, 23.56 mmol) were stirred in dichloromethane (15 mL) for 4 hours. The reaction was monitored by LCMS. The reaction solution was extracted with ethyl acetate (30 mL × 3), and the organic phase was collected and washed with saturated brine (100 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 59-2. LCMS: m / z 331.1 [M+H] + .

[0485] Step 3: A solution of intermediate 59-2 (300 mg, 0.91 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (474 ​​mg, 2.26 mmol), bistriphenylphosphine palladium dichloride (64 mg, 0.09 mmol), and cuprous iodide (18 mg, 0.09 mmol) in triethylamine (2 mL) and tetrahydrofuran (6 mL) was stirred at 80°C under a nitrogen atmosphere for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 59-3. LCMS: m / z 404.2 [M-55] + .

[0486] Step 4: Under nitrogen at 25°C, a solution of intermediate 59-3 (200 mg, 0.44 mmol) and palladium / carbon (20 mg, 0.19 mmol) in methanol (5 mL) was replaced with hydrogen three times and stirred at 50°C under a hydrogen atmosphere for 16 hours. The reaction was monitored by LCMS. The temperature was raised to 25°C, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 59-4. LCMS: m / z 464.3 [M+H] + .

[0487] Step 5: At 25°C, trifluoroacetic acid (0.02 mL, 0.32 mmol) was added to a solution of intermediate 59-4 (150 mg, 0.32 mmol) in dichloromethane (5 mL) and stirred for 2 hours. LCMS monitored the reaction completion, and saturated aqueous sodium bicarbonate solution (5 mL) was added and stirred for 30 minutes. The reaction solution was extracted with dichloromethane (10 mL × 3), and the organic phase was collected and washed with saturated brine (30 mL). The organic phase was concentrated under reduced pressure to obtain intermediate 59-5. LCMS: m / z 364.2 [M+H] + .

[0488] Step 6: Methanesulfonic anhydride (143 mg, 0.84 mmol) was added to a solution of intermediate 59-5 (100 mg, 0.28 mmol) and potassium carbonate (114 mg, 0.84 mmol) in acetonitrile (5 mL) at 25°C and stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate) to give compound 59. LCMS: m / z 442.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.83(d,J=7.1Hz,1H),7.21(s,4H),7.03(d,J=10.3Hz,1H),3.93-4.05(m,6H),3.82(br d,J=12.3Hz,2H),2.83-2.90(m,2H),2.78(s,3H),2.61-2.72(m,2H),1.83-1.95(m,2H),1.63-1.75(m,2H),1.32-1.47(m,3H).

[0489] Example 58: Compound 60

[0490] Step 1: Heat a toluene (10 mL) solution of starting material 60-0 (500 mg, 2.39 mmol), pinacol borane (257 mg, 2.03 mmol), and zirconocene hydrochloride (61 mg, 0.24 mmol) to 80°C and stir for 6 hours. Monitor the reaction by TLC. Cool to 25°C, add water (10 mL), and extract with ethyl acetate (10 mL x 3). Collect the organic phase and wash with saturated brine (30 mL). Concentrate the organic phase under reduced pressure to obtain intermediate 60-1.

[0491] Step 2: Add azobisisobutyronitrile (270 mg, 1.63 mmol) to a solution of starting material 60-2 (3.20 g, 16.32 mmol) and N-bromosuccinimide (3.20 g, 17.95 mmol) in carbon tetrachloride (20 mL) at 60°C and stir for 4 hours. Monitor the reaction by TLC. Cool to 25°C. Quench the reaction mixture with water (20 mL) and extract with ethyl acetate (30 mL x 3). Collect the organic phase and wash with saturated brine (100 mL). Concentrate the organic phase under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 60-3. 1 H NMR (400MHz, CDCl3) δ: 7.65-7.70 (m, 2H), 7.49 (dd, J = 8.4, 2.3Hz, 1H), 4.43 (s, 2H).

[0492] Step 3: At 25°C, 2,3-dihydroisoindole hydrochloride (2.01 g, 13.09 mmol) was added to a solution of intermediate 60-3 (3.00 g, 10.91 mmol) and triethylamine (4.54 ml, 32.73 mmol) in dichloromethane (15 mL) and stirred for 4 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water (15 mL) and extracted with ethyl acetate (15 mL × 3). The organic phase was collected and washed with saturated brine (50 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 60-4. LCMS: m / z 313.0 [M+H] + .

[0493] Step 4: Intermediate 60-4 (300 mg, 1.09 mmol), (E)-tert-butyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (552 mg, 1.64 mmol), tetrakistriphenylphosphine palladium (40 mg, 0.05 mmol), and potassium carbonate (452 ​​mg, 3.27 mmol) were added to a mixed solvent of 1,4-dioxane (10 mL) and water (3 mL). The nitrogen atmosphere was replaced three times, the temperature was raised to 80°C, and the mixture was stirred for 16 hours. The reaction was monitored by LCMS. The mixture was extracted with ethyl acetate (20 mL × 3), the organic phase was collected, and washed with saturated brine (60 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 60-5. LCMS: m / z 444.3 [M+H] + .

[0494] Step 5: Trifluoroacetic acid (0.03 mL, 0.45 mmol) was added dropwise to a solution of intermediate 60-5 (200 mg, 0.45 mmol) in dichloromethane (5 mL) at 25°C and stirred for 2 hours. LCMS monitored the reaction completion, and saturated aqueous sodium bicarbonate solution (5 mL) was added and stirred for 30 minutes. The reaction solution was extracted with dichloromethane (10 mL × 3), and the organic phase was collected and washed with saturated brine (30 mL). The organic phase was concentrated under reduced pressure to obtain intermediate 60-6. LCMS: m / z 344.2 [M+H] + .

[0495] Step 6: Methanesulfonic anhydride (228 mg, 1.31 mmol) was added to a solution of intermediate 60-6 (150 mg, 0.44 mmol) and potassium carbonate (182 mg, 1.32 mmol) in acetonitrile (5 mL) at 25°C and stirred for 2 hours. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (ammonium bicarbonate) to give compound 60. LCMS: m / z 422.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.67(s,1H),7.60(s,2H),7.15-7.24(m,4H),6.79(dd, J=15.9,0.9Hz,1H),6.32(dd,J=15.9,7.3Hz,1H),3.90-3.99(m,6H),3.87(br d,J=11.9Hz,2H),2.71-2.83(m,5H),2.38(tdt,J=11.1,7.4,3.6Hz,1H),1.94(br dd,J=13.1,2.2Hz,2H),1.51-1.72(m,2H).

[0496] Example 59: Compound 61

[0497] Step 1: Dissolve the starting material 61-0 (500 mg, 1.51 mmol), tert-butyl (E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (763 mg, 2.26 mmol), tetrakistriphenylphosphine palladium (55 mg, 0.08 mmol), and potassium carbonate (625 mg, 4.53 mmol) in 1,4-dioxane (5 mL) and water (1.5 mL). The atmosphere was purged with nitrogen three times, and the temperature was raised to 80°C. Stir for 16 hours. The reaction was monitored by LCMS. The temperature was lowered to 25°C, and the reaction mixture was extracted with ethyl acetate (8 mL x 3). The organic phase was collected and washed with saturated brine (25 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 61-1. LCMS: m / z 462.3 [M+H] + .

[0498] Step 2: Trifluoroacetic acid (0.5 mL, 6.71 mmol) was added dropwise to a solution of Intermediate 61-1 (250 mg, 0.54 mmol) in dichloromethane (5 mL) at 25°C and stirred for 2 hours. The reaction was monitored by TLC. Saturated aqueous sodium bicarbonate (5 mL) was added and stirred for 30 minutes. The reaction solution was extracted with dichloromethane (10 mL x 3). The organic phase was collected and washed with saturated brine (30 mL). The organic phase was concentrated under reduced pressure to obtain Intermediate 61-2.

[0499] Step 3: Add methanesulfonic anhydride (146 mg, 0.84 mmol) to a solution of intermediate 61-2 (100 mg, 0.28 mmol) and potassium carbonate (116 mg, 0.84 mmol) in acetonitrile (5 mL) at 25°C and stir for 2 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate) to give compound 61. LCMS: m / z 440.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.82(d,J=7.0Hz,1H),7.30(d,J=10.6Hz,1H),7.21(s,4H) ,6.75(d,J=15.8Hz,1H),6.32(dd,J=15.9,7.3Hz,1H),3.93-4.04(m,6H),3.87(br d,J=12.0Hz,2H),2.82(s,3H),2.77(td,J=12.0,2.4Hz,2H),2.38(tdt,J=11.1,7.3,3.6Hz,1H),1.94(br dd,J=13.1,2.4Hz,2H),1.55 -1.70(m,2H).

[0500] Example 60: Compound 62

[0501] Step 1: Add the raw material 62-0 (10.00 g, 46.50 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (14.60 g, 69.75 mmol), bistriphenylphosphine palladium dichloride (3.26 g, 4.65 mmol), cuprous iodide (890 mg, 4.65 mmol), and triethylamine (15 mL) to tetrahydrofuran (50 mL). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 80°C and stirred for 2 hours. The reaction was monitored by LCMS. The temperature was lowered to 25°C, and the mixture was washed with saturated brine (300 mL). The reaction solution was extracted with ethyl acetate (100 mL x 3), and the organic phase was collected. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:10) to obtain intermediate 62-1. LCMS: m / z 244.1 [M-99] + .

[0502] Step 2: Under nitrogen at 25°C, palladium / carbon (200 mg, 0.28 mmol) was added to a solution of intermediate 62-1 (2.00 g, 5.82 mmol) in isopropanol (5 mL). The hydrogen atmosphere was replaced three times and the mixture was stirred for 30 minutes. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated to obtain intermediate 62-2. LCMS: m / z 292.2 [M-55] + .

[0503] Step 3: A solution of intermediate 62-2 (500 mg, 1.44 mmol), 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (416 mg, 2.16 mmol), sodium acetate borohydride (910 mg, 4.32 mmol), and acetic acid (0.08 ml, 1.44 mmol) in 1,2-dichloroethane (10 mL) was stirred at 25°C for 4 hours. The reaction was monitored by LCMS. The reaction solution was washed with saturated brine (30 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was collected. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to obtain intermediate 62-3. LCMS: m / z 452.3 [M+H] + .

[0504] Step 4: Add dioxane hydrochloride (0.83 mL, 3.32 mmol, 4 M) dropwise to a solution of intermediate 62-3 (300 mg, 0.66 mmol) in dioxane (5 mL) at 25°C and stir for 2 hours. LCMS monitoring indicates completion of the reaction. The reaction mixture is concentrated under reduced pressure to yield intermediate 62-4. LCMS: m / z 352.3 [M+H] + .

[0505] Step 5: At 25°C, methanesulfonic anhydride (297 mg, 1.71 mmol) was added to a solution of intermediate 62-4 (200 mg, 2.02 mmol) and potassium carbonate (235 mg, 1.71 mmol) in acetonitrile (5 mL) and stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was washed with saturated brine (30 mL) and extracted with ethyl acetate (10 × 3 mL). The organic phase was concentrated under reduced pressure and purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 62. LCMS: m / z 430.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 8.40 (d, J = 4.8Hz, 1H), 7.48 (d, J = 7.4Hz, 1H), 7.10-7.14 (m, 1H), 7.09 (d, J = 7.8Hz, 1H), 6.98 (br s,1H),6.90(d,J=7.5Hz,1H),4.04(br d,J=17.3Hz,4H),3.94(s,2H),3.74-3.88(m,5H),2.77(s,3H),2.58-2.71(m,4H),1.89(br d,J=9.9Hz,2H),1.50-1.61(m,2H),1.30-1.47(m,3H).

[0506] Example 61: Compound 63

[0507] Step 1: Dissolve Intermediate 62-2 (200 mg, 0.58 mmol), 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine hydrochloride (182 mg, 1.16 mmol), sodium acetate borohydride (244 mg, 1.16 mmol), and acetic acid (34 mg, 0.58 mmol) in 1,2-dichloroethane (10 mL) at 25°C and stir for 18 hours. LCMS monitoring of the reaction was performed. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Intermediate 63-1. LCMS: m / z 452.1 [M+H] + .

[0508] Step 2: Trifluoroacetic acid (0.50 mL, 6.64 mmol) was added dropwise to a solution of Intermediate 63-1 (300 mg, crude) in dichloromethane (10 mL) at 25°C and stirred for 20 minutes. The reaction was monitored by LCMS. Saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain Intermediate 63-2. LCMS: m / z 352.2 [M+H] + .

[0509] Step 3: Methanesulfonic anhydride (267 mg, 1.54 mmol) was added to a solution of intermediate 63-2 (270 mg, crude product) and triethylamine (0.32 mL, 2.30 mmol) in dichloromethane (5 mL) at 25°C and stirred for 30 minutes. The reaction was monitored by LCMS. Saturated ammonium chloride solution (10 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate) to obtain compound 63. LCMS: m / z 430.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:8.50-8.37(m,2H),7.16(d,J=4.9Hz,1H),7.08(d,J=7.5Hz,1H),6.93(s,1H),6.89(d,J=7.5Hz,1H),3.98(br d,J=14.5Hz,4H),3.90(s,2H),3.84(s,3H),3.80(br d,J=12.0Hz,2H),2.77(s,3H),2.71-2.51(m,4H),1.89(br d,J=10.3Hz,2H),1.63-1.54(m,2H),1.44-1.29(m,3H).

[0510] Example 62: Compound 64

[0511] Step 1: At -78°C under a nitrogen atmosphere, slowly add a solution of lithium diisopropylamide in tetrahydrofuran (16.81 mL, 33.63 mmol) dropwise to a solution of starting material 6-0 (3.00 g, 13.45 mmol) in tetrahydrofuran (30 mL). Stir for 1 hour, then slowly add N,N-dimethylformamide (3.14 mL, 40.36 mmol) dropwise and stir for 3 hours. Completion of the reaction was monitored by thin-layer chromatography (petroleum ether:ethyl acetate = 5:1). Quench with saturated aqueous ammonium chloride (20 mL), stir for 30 minutes, warm to 25°C, wash with saturated brine (300 mL), and extract with ethyl acetate (100 mL x 3). The organic phases were combined. The organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to yield intermediate 64-1. 1 H NMR (400MHz, CDCl3) δ: 10.29 (s, 1H), 7.27 (s, 1H), 3.93-4.02 (m, 3H).

[0512] Step 2: Add Intermediate 64-1 (1.60 g, 6.37 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (2.00 g, 9.56 mmol), bis(triphenylphosphine)palladium dichloride (450 mg, 0.64 mmol), cuprous iodide (120 mg, 0.64 mmol), and triethylamine (3 mL) to a tetrahydrofuran (10 mL) solution. The atmosphere was purged with nitrogen three times, the temperature was raised to 80°C, and the mixture was stirred for 2 hours. The reaction was monitored by LCMS. The temperature was lowered to 25°C, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain Intermediate 64-2. LCMS: m / z 324.0 [M-55] + .

[0513] Step 3: Under nitrogen at 25°C, palladium / carbon (100 mg, 0.26 mmol) was added to a solution of intermediate 64-2 (1.00 g, 2.64 mmol) in isopropanol (10 mL). The hydrogen atmosphere was replaced three times and the mixture was stirred for 30 minutes. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated to obtain intermediate 64-3. LCMS: m / z 328.1 [M-55] + .

[0514] Step 4: Sodium acetate borohydride (1.65 g, 7.82 mmol) was added to a solution of intermediate 64-3 (1.00 g, 2.61 mmol), isoindoline hydrochloride (600 mg, 3.91 mmol), and acetic acid (0.15 ml, 2.61 mmol) in 1,2-dichloroethane (10 mL) at 25°C and stirred for 4 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water (10 mL) and extracted with dichloromethane (10 mL × 3). The organic phase was collected and washed with saturated brine (30 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 64-4. LCMS: m / z 487.2 [M+H] + .

[0515] Step 5: Add dioxane hydrochloride (5 mL, 0.32 mmol) dropwise to a solution of intermediate 64-4 (500 mg, 1.03 mmol) in dioxane (5 mL) at 25°C and stir for 2 hours. LCMS monitored the completion of the reaction, and the reaction solution was concentrated under reduced pressure to obtain intermediate 64-5. LCMS: m / z 387.3 [M+H] + .

[0516] Step 6: At 25°C, intermediate 64-5 (300 mg, 0.78 mmol), potassium carbonate (323 mg, 2.34 mmol), and methanesulfonic anhydride (407 mg, 2.34 mmol) were dissolved in acetonitrile (5 mL) and stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was extracted with ethyl acetate (10 mL × 3), and the organic phase was collected and washed with saturated brine (30 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 64. LCMS: m / z 465.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.17(s,4H),6.70(dd,J=9.6,1.8Hz,1H),4.00(s,6H),3.88(d,J=1.1Hz,3H),3.80(br d,J=11.6Hz,2H),2.77(s,3H),2.56-2.68(m,4H),1.86(br d,J=9.8Hz,2H),1.50-1.59(m,2H),1.32-1.44(m,3H).

[0517] Example 63: Compound 65

[0518] Step 1: Add the starting material 65-0 (1.01 g, 4.06 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (1.70 g, 8.13 mmol), bistriphenylphosphine palladium dichloride (290 mg, 0.41 mmol), cuprous iodide (80 mg, 0.41 mmol), and triethylamine (5.6 mL) to tetrahydrofuran (10 mL). The atmosphere was purged with nitrogen three times and stirred at 25°C for 1.5 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 65-1. LCMS: m / z 375.2 [M+H] + .

[0519] Step 2: Under a nitrogen atmosphere at 25°C, intermediate 65-1 (1.34 g, 3.57 mmol) and palladium / carbon (80 mg, 0.71 mmol) were added to methanol (30 mL). The hydrogen atmosphere was replaced three times and the mixture was stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain intermediate 65-2. LCMS: m / z 323.2 [M-55] + .

[0520] Step 3: Add hydrochloric acid-dioxane solution (10 mL, 4 M) to intermediate 65-2 (1.01 g, 2.46 mmol) at 25°C and stir for 10 minutes. LCMS monitoring indicates the completion of the reaction. The reaction solution is concentrated under reduced pressure to obtain intermediate 65-3. LCMS: m / z 279.2 [M+H] + .

[0521] Step 4: At 25°C, add intermediate 65-3 (730 mg, 2.62 mmol), triethylamine (1.09 mL, 7.86 mmol), and methanesulfonic anhydride (685 mg, 3.93 mmol) to dichloromethane (10 mL). Stir for 30 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 65-4. LCMS: m / z 357.2 [M+H] + .

[0522] Step 5: Dissolve intermediate 65-4 (497 mg, 1.39 mmol) in tetrahydrofuran (6 mL) and replace the nitrogen three times. Slowly add diisobutylaluminum hydride (5.58 mL, 8.37 mmol, 1.5 M) in toluene at -78 °C, warm to 25 °C, and stir for 1 hour. LCMS monitoring indicates the completion of the reaction. The reaction solution is quenched with saturated sodium potassium tartrate aqueous solution (100 mL), extracted with ethyl acetate (100 mL × 2), and the organic phases are combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to obtain intermediate 65-5. LCMS: m / z 329.3 [M+H] + .

[0523] Step 6: Add manganese dioxide (634 mg, 7.3 mmol) to a solution of intermediate 65-5 (240 mg, 0.73 mmol) in dichloromethane (5 mL) and stir at 25°C for 16 hours. LCMS monitoring indicates the completion of the reaction. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to afford intermediate 65-6. LCMS: m / z 327.2 [M+H] + .

[0524] Step 7: At 25°C, intermediate 65-6 (238 mg, 0.74 mmol), 2,3-dihydroisoindole hydrochloride (343 mg, 2.21 mmol), and acetic acid (0.04 mL, 0.74 mmol) were added to 1,2-dichloroethane (6 mL) and stirred for 30 min. Sodium acetate borohydride (310 mg, 1.47 mmol) was added and stirring continued for 1 hour. The reaction was monitored by LCMS. The reaction solution was quenched with water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 65. LCMS: m / z 430.3 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.35(d,J=7.3Hz,1H),7.20(s,4H),6.98(d,J=7.3Hz,1H),4.12(s,4H),3.99(s,2H),3.95(s,3H),3.80(br d,J=11.8Hz,2H),2.77(s,3H),2.68-2.56(m,4H),1.87(br d,J=9.9Hz,2H),1.61-1.53(m,2H),1.43-1.33(m,3H).

[0525] Example 64: Compound 66

[0526] Step 1: A solution of starting material 66-0 (2.00 g, 6.71 mmol), 4-fluoroisoindoline hydrochloride (1.75 g, 10.07 mmol), and triethylamine (2.79 mL, 20.14 mmol) in acetonitrile (10 mL) was stirred at 25°C for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford intermediate 66-1. LCMS: 354.0 [M+H]+.

[0527] Step 2: Add Intermediate 66-1 (1.00 g, 2.82 mmol), bistriphenylphosphine palladium dichloride (198 mg, 0.28 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (1.18 g, 5.65 mmol), and cuprous iodide (54 mg, 0.28 mmol) to triethylamine (2 mL) and tetrahydrofuran (15 mL). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 80°C. Stir for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) afforded Intermediate 66-2. LCMS: m / z 483.2 [M+H]+.

[0528] Step 3: Under nitrogen at 25°C, intermediate 66-2 (310 mg, 0.64 mmol) and palladium on carbon (7 mg, 0.05 mmol, 10 wt%) were dissolved in methanol (10 mL). The hydrogen atmosphere was replaced three times, and the temperature was raised to 50°C. Stirring was continued for 18 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford intermediate 66-3. LCMS: m / z 487.3 [M+H].

[0529] Step 4: Trifluoroacetic acid (0.04 mL, 0.51 mmol) was added dropwise to a solution of Intermediate 66-3 (250 mg, 0.51 mmol) in dichloromethane (5 mL) at 25°C and stirred for 1 hour. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, which was extracted with dichloromethane (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford Intermediate 66-4.

[0530] Step 5: Methanesulfonic anhydride (36 mg, 0.21 mmol) was added to a solution of intermediate 66-4 (80 mg, 0.21 mmol) and triethylamine (0.04 mL, 0.31 mmol) in dichloromethane (5 mL) at 25 ° C and stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was added with saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was collected, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (ammonium bicarbonate) to obtain compound 66. LCMS:m / z 465.2[M+H]+; 1H NMR(400MHz, CDCl3)δ:7.18(dt,J=5.2,7.8Hz,1H),6.97(d,J=7.4Hz,1H),6.92(d,J=6.0Hz,1H),6.90-6.87(m,1H),6.84(d,J=10.3Hz,1H),4.03(br d,J=10.8Hz,4H),3.94(d,J=0.8Hz,2H),3.81(s,3H),3.79(br s,2H),2.77(s,3H),2.71-2.57(m,4H),1.88(br d,J=9.8Hz,2H),1.64-1.52(m,2H),1.43-1.33(m,3H).

[0531] Example 65: Compound 67

[0532] Step 1: Add a solution of hydrochloric acid in 1,4-dioxane (1 mL, 4 mol / L) to a solution of 67-0 (150 mg, 0.33 mmol) in dioxane (1 mL) at 25°C. Stir for 1 hour. Completion of the reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to afford intermediate 67-1. LCMS: m / z 351.2 [M+H]+.

[0533] Step 2: At 25 ° C, ethylsulfonyl chloride (64 mg, 0.49 mmol) was added to a solution of intermediate 67-1 (120 mg, 0.31 mmol) and triethylamine (167 mg, 1.65 mmol) in tetrahydrofuran (3 mL), stirred for 2 hours, and the reaction was completed by LCMS. The reaction solution was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 67. LCMS: m / z 443.3 [M+H] +: 1H NMR (400MHz, CDCl3) δ: 7.20 (s, 4H), 7.08 (d, J = 7.5Hz, 1H), 7.02 (s, 1H), 6.90 (d, J =7.4Hz,1H),4.06-3.90(m,6H),3.84(s,3H),3.82(s,1H),3.79(s,1H),2.99-2.91 (m,2H),2.82-2.72(m,2H),2.67-2.59(m,2H),1.86(dd,J=2.0,12.6Hz,2H),1.61 -1.53(m,3H),1.39(s,1H),1.38-1.36(m,2H),1.35(s,1H),1.34(d,J=3.8Hz,1H).

[0534] Example 66: Compound 68

[0535] 2-Cyanoacetic acid (300 mg, 3.53 mmol) and N,N'-carbonyldiimidazole (514 mg, 3.17 mmol) were added to tetrahydrofuran (5 mL) at 25°C and stirred for 1 hour. N,N-dimethylformamide (2 mL) and 2-(3-methoxy-4-(2-(piperidin-4-yl)ethyl)benzyl)isoindoline hydrochloride (200 mg, 0.57 mmol) were added to the reaction solution and stirring continued for 1 hour. LCMS monitored the reaction completion. The reaction solution was washed with water (20 mL) and extracted with dichloromethane (30 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain the crude product, which was then purified by preparative HPLC (ammonium bicarbonate conditions) to yield Compound 68. LCMS: m / z 418.3 [M+H] + ; 1H NMR (400MHz, CDCl3) δ: 7.20 (s, 4H), 7.07 (d, J = 7.5Hz, 1H), 6.97 (s, 1H), 6.91 (d, J=7.5Hz,1H),4.60-4.49(m,1H),3.96(s,4H),3.90(s,2H),3.84(s,3H),3.70(br d,J=13.9Hz,1H),3.49(d,J=1.8Hz,2H),3.14(dt,J=2.6,13.0Hz,1H),2.71-2.61(m,3H),1.88(br t,J=15.0Hz,2H),1.57(br t,J=6.0Hz,3H),1.30-1.20(m,2H).

[0536] Example 67: Compound 69

[0537] 2-(3-methoxy-4-(2-(piperidin-4-yl)ethyl)benzyl)isoindoline hydrochloride (120 mg, 0.34 mmol), triethylamine (0.14 mL, 1.02 mmol) and cyclopropanesulfonyl chloride (0.05 mL, 0.51 mmol) were added to tetrahydrofuran (5 mL) at 25°C and stirred at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 69. LCMS: m / z 455.3 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.19(s,4H),7.08(d,J=7.5Hz,1H),6.97(s,1H),6.91(d,J=7.5Hz,1H),3.96(s,4H),3.90(s,2H),3.84(s,3H),3.80(br d,J=12.1Hz,2H),2.85-2.75(m,2H),2.68-2.59(m,2H),2.26(tt,J=4.8,8.1Hz,1H),1.87(br d,J=11.1Hz,2H),1.57(td,J=6.1,9.5Hz,2H),1.42-1.31(m,3H),1.21-1.14(m,2H),1.01-0.93(m,2H).

[0538] Example 68: Compound 70

[0539] At 25°C, 2-(3-methoxy-4-(2-(piperidin-4-yl)ethyl)benzyl)isoindoline (300 mg, 0.86 mmol), triethylamine (0.36 mL, 2.58 mmol), and acetyl chloride (0.18 mL, 1.29 mmol) were dissolved in dichloromethane (5 mL) and stirred for 3 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was collected and washed with saturated brine (15 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 70. LCMS: m / z 393.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.19 (s, 4H), 7.08 (d, J = 7.5Hz, 1H), 6.95 (s, 1H), 6. 90(d,J=7.5Hz,1H),4.55-4.65(m,1H),3.95(s,4H),3.89(s,2H),3.77-3.8 5(m,4H),3.03(td,J=12.9,2.7Hz,1H),2.60-2.68(m,2H),2.56(td,J=12.8 ,2.7Hz,1H),2.10(s,3H),1.78-1.88(m,2H),1.50-1.60(m,3H),1.07-1.24 (m,2H).

[0540] Example 69: Compound 71

[0541] At 25°C, 2-(3-methoxy-4-(2-(piperidin-4-yl)ethyl)benzyl)isoindoline (100 mg, 0.29 mmol), triethylamine (0.20 mL, 1.43 mmol), and trifluoroacetic anhydride (0.08 mL, 0.58 mmol) were dissolved in dichloromethane (5 mL) and stirred for 3 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was collected and washed with saturated brine (15 mL). The organic phase was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (ammonium bicarbonate) to obtain compound 71. LCMS: m / z 447.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ: 7.19 (s, 4H), 7.07 (d, J = 7.5Hz, 1H), 6.96 (s, 1H), 6.91 (d, J = 7.5Hz, 1H), 4.53 (br d, J = 13.4Hz, 1H), 4.01 (br d,J=13.4Hz,1H),3.95(s,4H),3.89(s,2H),3.84(s,3H),3.06-3.17(m,1H),2.77(br t,J=12.2Hz,1H),2.60-2.69(m,2H),1.91(br d,J=13.4Hz,2H),1.51-1.61(m,2H),1.18-1.33(m,3H).

[0542] Example 70: Compound 72

[0543] Step 1: At 25°C, add concentrated sulfuric acid (0.50 mL) to a solution of intermediate 72-0 (4.40 g, 20.09 mmol) in methanol (30 mL), heat to 80°C, stir for 12 hours, and monitor the reaction completion by LCMS. Cool to 25°C. The reaction solution is concentrated under reduced pressure, neutralized with saturated sodium bicarbonate solution (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases are combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain intermediate 72-1. LCMS: m / z 234.2 [M+H] + .

[0544] Step 2: At 25°C, add hydrogen peroxide (5.30 g, 33 wt%) to a solution of Intermediate 72-1 (4.00 g, 17.16 mmol) and trifluoroacetic anhydride (10.80 g, 51.42 mmol) in dichloromethane (60 mL). Stir for 18 hours. LCMS monitoring indicates the reaction is complete. The reaction mixture is quenched with saturated sodium bicarbonate solution (50 mL) and then saturated sodium sulfite solution (50 mL). The mixture is extracted with dichloromethane (100 mL x 3). The combined organic phases are washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford Intermediate 72-2. LCMS: m / z 249.9 [M+H] + .

[0545] Step 3: At 0°C, trifluoroacetic anhydride (5.06 g, 24.09 mmol) was added to a solution of intermediate 72-2 (3.00 g, 12.04 mmol) in N,N-dimethylformamide (50 mL), the temperature was raised to 50°C, and the mixture was stirred for 1 hour. The reaction was monitored by LCMS to complete. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium bicarbonate solution (100 mL), and then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by solvent slurry (petroleum ether: ethyl acetate = 8:1) to obtain intermediate 72-3. LCMS: m / z 249.8 [M+H] + .

[0546] Step 4: Potassium carbonate (1.66 g, 12.02 mmol) was added to a solution of intermediate 72-3 (1.50 g, 6.02 mmol) and iodomethane (2.56 g, 18.02 mmol) in N,N-dimethylformamide (10 mL) at 25°C. The reaction was stirred at 25°C for 3 hours. The reaction was monitored by LCMS to determine completion. The reaction was quenched with water (50 mL) and 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. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1.5) to obtain intermediate 72-4. LCMS: m / z 263.9 [M+H] + .

[0547] Step 5: At 25°C, intermediate 72-4 (500 mg, 1.89 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (792 mg, 3.79 mmol), cuprous iodide (36 mg, 0.19 mmol), and triethylamine (1.31 mL, 9.47 mmol) were added to tetrahydrofuran (10 mL). Bis(triphenylphosphine)palladium dichloride (133 mg, 0.19 mmol) was added, the atmosphere was replaced with nitrogen three times, and the mixture was stirred for 5 hours. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 72-5. LCMS: m / z 393.2 [M+H] + .

[0548] Step 6: Under nitrogen at 25°C, palladium / carbon (122 mg, 0.11 mmol, 10 wt%) was added to a solution of intermediate 72-5 (450 mg, 1.15 mmol) in methanol (10 mL). The hydrogen atmosphere was replaced three times, and the solution was stirred for 18 hours. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain intermediate 72-6. LCMS: m / z 297.2 [M-99] + .

[0549] Step 7: Stir a solution of intermediate 72-6 (430 mg, 1.08 mmol) in hydrochloric acid-dioxane (10 mL, 4 M / L) at 25°C for 20 minutes. LCMS monitored the completion of the reaction, and the reaction solution was concentrated under reduced pressure to obtain intermediate 72-7. LCMS: m / z 297.2 [M+H] + .

[0550] Step 8: Methanesulfonic anhydride (308 mg, 1.77 mmol) was added to a solution of intermediate 72-7 (350 mg, 1.18 mmol) and triethylamine (0.49 mL, 3.54 mmol) in dichloromethane (10 mL) at 25°C and stirred for 20 minutes. The reaction was monitored by LCMS. Saturated ammonium chloride solution (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 72-8. LCMS: m / z 375.2 [M+H] + .

[0551] Step 9: Sodium borohydride (111 mg, 2.94 mmol) and lithium chloride (124 mg, 2.94 mmol) were added to a solution of intermediate 72-8 (110 mg, 0.29 mmol) in tetrahydrofuran (5 mL) at 25°C and stirred for 4 hours. The reaction was monitored by LCMS. Water (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 72-9. LCMS: m / z 347.0 [M+H] + .

[0552] Step 10: Add thionyl chloride (68 mg, 0.58 mmol) to a solution of intermediate 72-9 (40 mg, 0.12 mmol) in dichloromethane (3 mL) at 25°C and stir for 30 minutes. The reaction was monitored by LCMS and the reaction solution was concentrated to give intermediate 72-10. LCMS: m / z 365 [M+H] + .

[0553] Step 11: A solution of potassium carbonate (33 mg, 0.24 mmol) and intermediate 72-10 (43 mg, 0.12 mmol) in N,N-dimethylformamide (3 mL) was heated to 80°C and stirred for 30 minutes. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (NH4HCO3 conditions) to obtain compound 72. LCMS: m / z 448.2 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.25-7.18(m,4H),7.15(d,J=9.0Hz,1H),3.99(s,4H),3.91(d,J=4.1Hz,2H),3.81(br d,J=12.0Hz,2H),3.73(s,3H),2.78(s,3H),2.71-2.56(m,4H),1.96-1.83(m,2H),1.69-1.55(m,3H),1.42-1.31(m,2H).

[0554] Example 71: Compound 73

[0555] Step 1: Add boron tribromide (176 mg, 0.70 mmol) to a solution of compound 53 (100 mg, 0.23 mmol) in dichloromethane (2 mL) at 25°C and stir for 12 hours. LCMS monitoring indicates the completion of the reaction. The reaction solution was quenched with saturated sodium bicarbonate solution (5 mL) and water (25 mL), extracted with dichloromethane (30 mL x 3), and the combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure to obtain the crude product of compound 73-1. LCMS: m / z 415.2 [M+H] + .

[0556] Step 2: Compound 73-1 (100 mg, 0.24 mmol), anhydrous ethanol (55 mg, 1.19 mmol), diisopropyl azodicarboxylate (98 mg, 0.48 mmol), and triphenylphosphine (126 mg, 0.48 mmol) were added to dichloromethane (2.5 mL). The nitrogen atmosphere was replaced three times. The reaction solution was stirred at 25°C for 18 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 73. LCMS: m / z 443.2 [M+H] + ; 1H NMR(400MHz, CDCl3)δ:7.26-7.17(m,4H),7.09(d,J=7.5Hz,2H),6.88(dd,J=1.3,7.5Hz,1H),4.18-4.00(m,6H),3.97(s,2H),3.79(d,J=11.9Hz,2 H),2.78(s,3H),2.69-2.62(m,4H),1.89(d,J=10.5Hz,2H),1.58(td,J=1 .9,4.0Hz,2H),1.43(s,1H),1.41(s,2H),1.40(s,1H),1.39-1.36(m,2H).

[0557] Example 72: Compound 74

[0558] Step 1: Add borane-tetrahydrofuran complex (6.12 mL, 6.12 mmol, 1 M) dropwise to a solution of 74-0 (500 mg, 2.06 mmol) in tetrahydrofuran (10 mL) at 25°C and stir for 2 hours. Monitor the reaction by TLC. Quench the reaction mixture with methanol (10 mL) and concentrate under reduced pressure to afford 74-1.

[0559] Step 2: Add manganese dioxide (3.40 g, 39.28 mmol) to a solution of 74-1 (450 mg, 1.96 mmol) in dichloromethane (10 mL) at 25°C and stir for 1 hour. Monitor the reaction by TLC. Filter the reaction mixture and concentrate the filtrate under reduced pressure to obtain 74-2.

[0560] Step 3: At 25°C, 74-2 (400 mg, 1.76 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (737 mg, 3.52 mmol), cuprous iodide (34 mg, 0.18 mmol), bistriphenylphosphine palladium dichloride (124 mg, 0.18 mmol), and triethylamine (1.22 mL) were added to tetrahydrofuran (5 mL). The atmosphere was purged with nitrogen three times and stirred for 7 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 74-3. LCMS: m / z 300.1 [M-55] + .

[0561] Step 4: At 25°C, 74-3 (300 mg, 0.84 mmol), 2,3-dihydroisoindole hydrochloride (259 g, 1.69 mmol), and acetic acid (0.05 mL, 0.05 mmol) were added to 1,2-dichloroethane (5 mL) and stirred for 30 min. Sodium acetate borohydride (356 mg, 1.69 mmol) was added and stirring continued for 5 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5:1) to obtain 74-4. LCMS: m / z 459.3 [M+H] + .

[0562] Step 5: At 25°C under nitrogen atmosphere, palladium / carbon (4 mg, 0.039 mmol, 10 wt%) was added to a solution of 74-4 (280 mg, 0.62 mmol) in methanol (4 mL). The hydrogen atmosphere was replaced three times and the mixture was stirred for 1 hour. LCMS monitored the reaction completion. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain 74-5. LCMS: m / z 463.4 [M+H] + .

[0563] Step 6: Add 1.50 mL of 4 M hydrochloric acid-dioxane solution to 74-5 (198 mg, crude) at 25°C and stir for 20 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give 74-6. LCMS: m / z 363.2 [M+H] + .

[0564] Step 7: At 25°C, methanesulfonic anhydride (73 mg, 0.42 mmol) was added to a solution of 74-6 (100 mg, crude) and triethylamine (0.83 mL, 0.83 mmol) in dichloromethane (4 mL) and stirred at 25°C for 20 minutes. The reaction was monitored by LCMS. The reaction solution was quenched with water (15 mL), extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate) to obtain compound 74. LCMS: m / z 441.3 [M+H] + ; 1H NMR(400MHz, CDCl3)δ:7.33(s,1H),7.20(s,4H),7.18-7.18(m,1H),7.18-7.12(m,1H),4.02(s,4H),3.94(s,2H),3.82(br d,J=12.0Hz,2H),3.17-3.10(m,1H),2.78(s,3H),2.71-2.66(m,4H),1.89(br d,J=11.0Hz,2H),1.61-1.53(m,2H),1.45-1.32(m,3H),,1.26(d,J=6.8Hz,6H).

[0565] Example 73: Compound 75

[0566] At 25 ° C, p-toluenesulfonyl chloride (79.45 mg, 0.43 mmol) was added to a solution of 2-(3-methoxy-4-(2-(piperidin-4-yl)ethyl)benzyl)isoindoline hydrochloride (100 mg, crude) and triethylamine (0.12 mL, 0.87 mmol) in dichloromethane (1 mL) and stirred for 1 hour. LCMS monitored the completion of the reaction. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 75. LCMS: m / z 505.2 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ:7.65(d,J=8.1Hz,2H),7.32(br d,J=8.0Hz,2H),7.25-7.14(m,4H),7.03(d,J=7.5Hz,1H),6.98(s,1H),6.87(br d,J=7.4Hz,1H),3.99(s,4H),3.91(s,2H),3.81(s,3H),3.76(br d,J=11.6Hz,2H),2.62-2.53(m,2H),2.44(s,3H),2.29-2.18(m,2H),1.81(br d,J=11.6Hz,2H),1.56-1.47(m,2H),1.42-1.28(m,3H).

[0567] Example 74: Compound 76

[0568] 5-(Isoindolin-2-ylmethyl)-2-(2-(1-(methylsulfonyl)piperidin-4-yl)ethyl)phenol (40 mg, 0.09 mmol), isopropyl alcohol (29 mg, 0.48 mmol), diisopropyl azodicarboxylate (39 mg, 0.19 mmol) and triphenylphosphine (50 mg, 0.19 mmol) were added to dichloromethane (1.5 mL). The atmosphere was replaced with nitrogen three times. The reaction solution was stirred at 25° C. for 18 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 76. LCMS: m / z 457.2 [M+H] + ; 1 H NMR(400MHz, CDCl3))δ:7.21(s,4H),7.08(d,J=7.6Hz,1H),7.01(s,1H),6.87(d,J=7.5Hz,1H),4.70-4.55(m,1H),4.01(s,4H),3.92(s,2H),3 .79(d,J=11.6Hz,2H),2.77(s,3H),2.68-2.59(m,4H),1.89(d,J=9.8H z,2H),1.61-1.55(m,2H),1.42-1.35(m,3H),1.34(s,3H),1.33(s,3H).

[0569] Example 75: Compound 77

[0570] At 25°C, trifluoromethanesulfonic anhydride (146 mg, 0.52 mmol) was added to a solution of 2-(3-methoxy-4-(2-(piperidin-4-yl)ethyl)benzyl)isoindoline hydrochloride (100 mg, 0.26 mmol) and triethylamine (131 mg, 1.29 mmol) in dichloromethane (3 mL) and stirred for 3 hours. The reaction was monitored by LCMS for completion. The reaction solution was quenched with water (30 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 77. LCMS: m / z 483.2 [M+H] + ; 1H NMR(400MHz, CDCl3)δ:7.20(s,4H),7.07(d,J=7.5Hz,1H),7.00(s,1H),6.91(d,J=7.6Hz,1H),4.03-3.95(m,5H),3.95-3.90(m,3H),3.84(s ,3H),3.03(t,J=12.3Hz,2H),2.69-2.58(m,2H),1.90(d,J=11.5Hz,2H),1.63-1.55(m,2H),1.50(dt,J=3.4,7.1Hz,1H),1.40-1.31(m,2H).

[0571] Example 76: Compound 78

[0572] At 25°C, 2-thiophenesulfonyl chloride (79 mg, 0.43 mmol) was added to 2-(3-methoxy-4-(2-(piperidin-4-yl)ethyl)benzyl)isoindoline hydrochloride (100 mg, crude) and triethylamine (0.12 mL, 0.87 mmol) in dichloromethane (1 mL) and stirred at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 78. LCMS: m / z 497.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.52(dd,J=1.1,5.0Hz,1H),7.45(dd,J=1.2,3.7Hz,1H),7.16-7.09(m,3H),7.06(dd,J=3.8,4.9Hz,1H) ,6.97(d,J=7.5Hz,1H),6.90(s,1H),6.79(d,J=7.6Hz,1H),6.83-6.77(m,1H),3.93(s,3H),3.85(s,2H),3.73(s,3H),3.69(br d,J=5.5Hz,2H),2.56-2.47(m,2H),2.27(dt,J=2.1,11.7Hz,3H),1.84-1.73(m,2H),1.50 -1.41(m,2H),1.38-1.26(m,3H).

[0573] Example 77: Compound 79

[0574] Step 1: Carbonyldiimidazole (500 mg, 3.08 mmol) and methylamine hydrochloride (416 mg, 6.17 mmol) were added to acetonitrile (3 mL) and N,N-dimethylformamide (1 mL) at 25°C and stirred for 24 hours. The reaction was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield N-methyl-1H-imidazole-1-carboxamide.

[0575] Step 2: At 25°C, N-methyl-1H-imidazole-1-carboxamide (150 mg, 1.20 mmol) and 2-(3-methoxy-4-(2-(piperidin-4-yl)ethyl)benzyl)isoindoline (100 mg, 0.29 mmol) were dissolved in dichloromethane (10 mL). Triethylamine (0.12 mL, 0.86 mmol) was added dropwise and stirred for 3 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 79. LCMS: m / z 408.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.19 (s, 4H), 7.08 (d, J = 7.6Hz, 1H), 6.97 (s, 1H), 6. 90(d,J=7.5Hz,1H),4.45-4.34(m,1H),3.99-3.96(m,4H),3.95-3.92(m,1H ),3.91-3.88(m,3H),3.83(s,3H),2.84-2.81(m,3H),2.80-2.72(m,2H),2 .66-2.60(m,2H),1.85-1.74(m,3H),1.60-1.49(m,2H),1.25-1.11(m,2H).

[0576] Example 78: Compound 80

[0577] Step 1: At 25°C, a solution of 80-0 (2.20 g, 6.33 mmol), isoindoline hydrochloride (1.46 g, 9.49 mmol), sodium acetate borohydride (4.01 g, 18.99 mmol) and acetic acid (0.36 mL, 6.33 mmol) in 1,2-dichloroethane (15 mL) was stirred for 4 hours. The reaction was monitored by LCMS. Water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was collected and washed with saturated brine (60 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 80-1. LCMS: m / z 451.3 [M+H] + .

[0578] Step 2: At 25°C, add a solution of hydrochloric acid-dioxane (3 mL, 12.00 mmol, 4 M / L) dropwise to a solution of 80-1 (1.00 g, 1.03 mmol) in dioxane (5 mL) and stir for 2 hours. LCMS monitored the completion of the reaction, and the reaction solution was concentrated under reduced pressure to give 80-2. LCMS: m / z 351.2 [M+H] + .

[0579] Step 3: At 25 ° C, dimethyl dicarbonate (58 mg, 0.43 mmol) was added to a solution of 80-2 (100 mg, 0.29 mmol) and triethylamine (0.12 mg, 0.86 mmol) in dichloromethane (5 mL) and stirred for 2 hours. The reaction was monitored by LCMS. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was collected and washed with saturated brine (15 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate) to obtain compound 80. LCMS: m / z 409.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.21 (s, 4H), 7.08 (d, J = 7.5Hz, 1H), 6.99 (s, 1H), 6.89 (dd, J = 7.5, 1.1Hz, 1H), 4.11 (br d,J=10.6Hz,2H),4.01(s,4H),3.93(s,2H),3.84(s,3H),3.70(s,3H),2.76(br t,J=12.3Hz,2H),2.56-2.68(m,2H),1.77(br d,J=12.8Hz,2H),1.41-1.59(m,3H),1.05-1.25(m,2H).

[0580] Example 79: Compound 81

[0581] To a solution of 2-(3-methoxy-4-(2-(piperidin-4-yl)ethyl)benzyl)isoindoline hydrochloride (120 mg, 0.34 mmol) in dichloromethane (5 mL) at 25°C, triethylamine (0.14 mL, 1.02 mmol) and pivaloyl chloride (0.13 mL, 1.02 mmol) were added sequentially and stirred at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a crude product, which was then purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 81. LCMS: m / z 435.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.19 (s, 4H), 7.08 (d, J = 7.5Hz, 1H), 6.97 (s, 1H), 6.90 (dd, J = 1.0, 7.6Hz, 1H), 4.41 (d, J = 12.8Hz, 2H), 3.96 (s, 4H), 3.90 (s,2H),3.84(s,3H),2.78(t,J=12.4Hz,2H),2.67-2.60(m,2H),1.82(d ,J=12.5Hz,2H),1.55(t,J=6.1Hz,3H),1.29(s,9H),1.22-1.11(m,2H).

[0582] Example 80: Compound 82

[0583] At 25°C, triethylamine (0.36 mL, 2.58 mmol) and 2-chloroethane-1-sulfonyl chloride (0.23 mL, 2.15 mmol) were added to a solution of 2-(3-methoxy-4-(2-(piperidin-4-yl)ethyl)benzyl)isoindoline hydrochloride (150 mg, 0.43 mmol) in dichloromethane (4 mL) in sequence, and the mixture was stirred at 25°C for 1.5 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (dichloromethane: methanol = 10:1) to obtain a crude product, which was then purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 82. LCMS: m / z 441.3 [M+H] + ; 1H NMR (400MHz, CDCl3) δ: 7.20 (s, 4H), 7.07 (d, J = 7.5Hz, 1H), 6.99 (s, 1H), 6.90 (dd,J=0.9,7.5Hz,1H),6.48-6.37(m,1H),6.23(d,J=16.6Hz,1H),6.01(d,J= 9.9Hz,1H),3.98(s,4H),3.91(s,2H),3.84(s,3H),3.73(d,J=12.0Hz,2H),2. 66-2.55(m,4H),1.86(d,J=9.8Hz,2H),1.60-1.52(m,2H),1.41-1.31(m,3H).

[0584] Example 81: Compound 83

[0585] Step 1: At 25°C, 83-0 (1.5 g, 8.57 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (1.79 g, 8.57 mmol), bistriphenylphosphine palladium dichloride (600 mg, 0.86 mmol), cuprous iodide (80 mg, 0.43 mmol) and triethylamine (12 mL) were added to tetrahydrofuran (10 mL). The nitrogen atmosphere was replaced three times, and the temperature was raised to 100°C and stirred for 3 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 83-1. LCMS: m / z 204.2 [M-99] + .

[0586] Step 2: At 25°C, sodium acetate borohydride (4.59 g, 21.76 mmol) was added to a solution of 83-1 (2.20 g, 7.25 mmol), isoindoline hydrochloride (2.59 g, 21.76 mmol), and acetic acid (2.0 mL, 36.26 mmol) in 1,2-dichloromethane (25 mL) and stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was quenched with sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 83-2. LCMS: m / z 407.2 [M+H] + .

[0587] Step 3: Under nitrogen atmosphere, 83-2 (1.0 g, 2.46 mmol) and palladium / carbon (0.26 g, 0.25 mmol, 10 wt%) were added to methanol (20 mL), the hydrogen atmosphere was replaced three times, and the mixture was stirred at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 83-3. LCMS: m / z 411.2 [M+H] + .

[0588] Step 4: Stir a solution of 83-3 (300 mg, 0.73 mmol) in hydrochloric acid-dioxane (4 mL, 2 M) at 25°C for 1 hour. LCMS monitored the completion of the reaction, and the reaction solution was concentrated under reduced pressure to give 83-4. LCMS: m / z 311.2 [M+H] + .

[0589] Step 5: Methanesulfonic anhydride (168 mg, 0.97 mmol) was added to a solution of 83-4 (200 mg, 0.64 mmol) and triethylamine (0.27 mL, 1.93 mmol) in dichloromethane (5 mL) at 25°C and stirred for 10 minutes. The reaction was monitored by LCMS. Saturated ammonium chloride solution (20 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 83. LCMS: m / z 389.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.18 (s, 4H), 6.15 (d, J = 3.0Hz, 1H), 5.93 (d, J = 3.0Hz, 1H), 3.99 (s, 4H), 3.87 (s, 2H), 3.77 (br d,J=12.1Hz,2H),2.74(s,3H),2.66(t,J=7.8Hz,2H),2.63-2.55(m,2H),1.81(br d,J=9.9Hz,2H),1.65(br s,2H),1.39-1.29(m,3H).

[0590] Example 82: Compound 84

[0591] Step 1: At 25°C, 84-0 (1.00 g, 2.86 mmol), isoindoline hydrochloride (0.88 g, 5.72 mmol), and acetic acid (0.26 mL, 2.86 mmol) were dissolved in 1,2-dichloroethane (20 mL). The mixture was stirred for 2 hours. Sodium triacetoxyborohydride (1.21 g, 5.72 mmol) was added to the reaction system and stirring continued for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 84-1. LCMS: m / z 453.3 [M+H] + .

[0592] Step 2: At 25°C, replace the hydrogen atmosphere three times with a solution of 84-1 (450 mg, 0.99 mmol) and platinum dioxide (23 mg, 0.10 mmol) in ethyl acetate (5 mL). Stir for 3 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to yield 84-2.

[0593] Step 3: At 25°C, add hydrochloric acid-dioxane solution (2.00 mL, 8.00 mmol, 4 M) dropwise to a solution of 84-2 (450 mg, 0.99 mmol) in dioxane (2 mL) and stir for 2 hours. The reaction mixture was concentrated under reduced pressure to give 84-3. LCMS: m / z 430.2 [M+H] + .

[0594] Step 4: At 25°C, add methanesulfonic anhydride (258 mg, 1.45 mmol) to a solution of 84-3 (350 mg, 0.99 mmol) and triethylamine (0.27 mL, 1.97 mmol) in dichloromethane (2 mL) and stir for 2 hours. The reaction was monitored by LCMS. Water (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 84. LCMS: m / z 433.2 [M+H] + ; 1HNMR(400MHz, CDCl3)δ7.43(s,1H),7.29(s,1H),7.20(s,4H),7.18(s,1H),3.99(s,4H),3.90(s,2H),3.81(br d,J=12.0Hz,2H),2.78(s,3H),2.75(br d,J=2.3Hz,2H),2.67(br t,J=11.5Hz,2H),1.93-1.85(m,2H),1.65-1.57(m,2H),1.49-1.34(m,3H).

[0595] Example 83: Compound 85

[0596] Step 1: Add 85-0 (900 mg, 3.87 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (1.60 g, 7.65 mmol), bistriphenylphosphine palladium dichloride (280 mg, 0.39 mmol), and cuprous iodide (74 mg, 0.38 mmol) to triethylamine (10 mL), replace the nitrogen atmosphere three times, and heat to 80°C and stir for 18 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain 85-1. LCMS: m / z 306.2 [M-55] + .

[0597] Step 2: At 25°C, acetic acid (1.08 g, 18.01 mmol) and sodium triacetoxyborohydride (1.52 g, 7.16 mmol) were added to a solution of 85-1 (1.30 g, 3.60 mmol) and isoindoline hydrochloride (900 mg, 5.78 mmol) in 1,2-dichloroethane (20 mL). The mixture was stirred for 2 hours. The reaction was monitored by LCMS for completion. The reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 85-2. LCMS: m / z 465.2 [M+H] + .

[0598] Step 3: Under a nitrogen atmosphere, 85-2 (700 mg, 1.50 mmol) and palladium / carbon (700 mg, 0.66 mmol) were added to methanol (8 mL), the hydrogen atmosphere was replaced three times, and the temperature was raised to 25°C and stirred for 18 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 85-3. LCMS: m / z 469.2 [M+H] + .

[0599] Step 4: Add hydrochloric acid-dioxane solution (5 mL, 4 M) to 85-3 (90 mg, 0.19 mmol) at 25°C and stir for 1 hour. The reaction is monitored by LCMS. The reaction solution is concentrated under reduced pressure to obtain crude 85-4. LCMS: m / z 369.2 [M+H] + .

[0600] Step 5: At 25°C, methanesulfonic anhydride (51 mg, 0.29 mmol) was added to a solution of 85-4 (71 mg, 0.17 mmol) and triethylamine (98 mg, 0.97 mmol) in dichloromethane (4 mL). The mixture was stirred for 1 hour. The reaction was monitored by LCMS to determine completion. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL x 1). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (ammonium bicarbonate system) to obtain compound 85. LCMS: m / z 447.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.20 (s, 4H), 7.13 (t, J = 7.3Hz, 1H), 6.91 (d, J = 7.9Hz, 1H), 4.03 (s, 4H), 3.98 (s, 2H), 3.92 (d, J = 1.5H z,3H),3.80(d,J=11.8Hz,2H),2.77(s,3H),2.69-2.60(m,4H),1.88(d,J=9.8Hz,2H),1.60-1.54(m,2H),1.43-1.31(m,3H).

[0601] Example 84: Compound 86

[0602] Step 1: Add 86-0 (500 mg, 2.60 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (1.08 g, 5.20 mmol), cuprous iodide (50 mg, 0.26 mmol), bistriphenylphosphine palladium dichloride (182 mg, 0.26 mmol), and triethylamine (3.60 mL) to tetrahydrofuran (10 mL), replace the nitrogen atmosphere three times, and stir at 25°C for 1.5 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 86-1. LCMS: m / z 265.0 [M-55] + .

[0603] Step 2: At 25°C, 86-1 (800 mg, 2.50 mmol), 2,3-dihydroisoindole hydrochloride (1.16 g, 7.49 mmol), and acetic acid (0.14 mL, 2.50 mmol) were added to 1,2-dichloroethane (10 mL) and stirred at 25°C for 30 minutes. Sodium acetate borohydride (1.05 g, 4.99 mmol) was added and stirring continued for 1 hour. The reaction was monitored by LCMS. The reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 3:1) to obtain 86-2. LCMS: m / z 424.2 [M+H] + .

[0604] Step 3: Under nitrogen atmosphere, 86-2 (1 g, 2.36 mmol) and palladium / carbon (0.20 g, 1.88 mmol) were added to methanol (15 mL), the hydrogen atmosphere was replaced three times, and the mixture was stirred at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain crude 86-3. LCMS: m / z 428.2 [M+H] + .

[0605] Step 4: Add hydrochloric acid-dioxane solution (6 mL, 4 M) to 86-3 (562 mg, crude product) at 25°C and stir at 25°C for 20 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give 86-4. LCMS: m / z 328.2 [M+H] + .

[0606] Step 5: At 25°C, 86-4 (400 mg, crude product), triethylamine (0.51 mL, 3.66 mmol) and methanesulfonic anhydride (319 mg, 1.83 mmol) were added to dichloromethane (5 mL) and stirred at 25°C for 20 minutes. The reaction was monitored by LCMS. The reaction solution was quenched with water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 86. LCMS: m / z 406.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.52 (s, 1H), 7.20 (s, 4H), 4.08 (s, 2H), 3.99 (s, 4H), 3.80 (d, J = 11.9Hz, 2 H),3.02(t,J=7.8Hz,2H),2.76(s,3H),2.68-2.60(m,2H),1.91-1.75(m,5H),1.42-1.30(m,2H).

[0607] Example 85: Compound 87

[0608] Step 1: Add 87-0 (1.00 g, 5.21 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (1.64 g, 7.82 mmol), bistriphenylphosphine palladium dichloride (370 mg, 0.52 mmol), and cuprous iodide (100 mg, 0.52 mmol) to a solution of triethylamine (3 mL) and tetrahydrofuran (10 mL). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 80°C and stirred for 2 hours. The reaction was monitored by LCMS. The temperature was lowered to 25°C, and water (40 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (40 mL x 3). The organic phase was collected and washed with saturated brine (150 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 87-1. LCMS: m / z 321.1 [M+1] + .

[0609] Step 2: At 25°C, 87-1 (1.00 g, 3.12 mmol), isoindoline hydrochloride (720 mg, 4.68 mmol), sodium acetate borohydride (1.97 g, 9.36 mmol), and acetic acid (0.18 ml, 3.12 mmol) were added to a 1,2-dichloroethane (10 mL) solution and stirred for 4 hours. The reaction was monitored by LCMS to confirm completion. Water (15 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was collected and washed with saturated brine (100 mL). The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 87-2. LCMS: m / z 424.2 [M+H] + .

[0610] Step 3: Under nitrogen at 25°C, palladium / carbon (50 mg, 0.47 mmol, 10 wt%) was added to a solution of 87-2 (500 mg, 1.18 mmol) in methanol (10 mL). The hydrogen atmosphere was replaced three times, the temperature was raised to 50°C, and the mixture was stirred for 4 hours. The reaction was monitored by LCMS. The mixture was cooled to 25°C, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 87-3. LCMS: m / z 428.2 [M+H] + .

[0611] Step 4: Add dioxane hydrochloride (3.0 mL, 12.00 mmol) dropwise to a solution of 87-3 (400 mg, 1.15 mmol) in dioxane (5 mL) at 25°C and stir for 2 hours. LCMS monitoring indicated the reaction was complete, and the reaction solution was concentrated under reduced pressure to yield 87-4. LCMS: m / z 328.2 [M+H] + .

[0612] Step 5: Dissolve 87-4 (300 mg, 0.92 mmol), potassium carbonate (982 mg, 2.76 mmol), and methanesulfonic anhydride (480 mg, 2.76 mmol) in acetonitrile (5 mL) at 25°C and stir for 2 hours. The reaction was monitored by LCMS. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was collected and washed with saturated brine (30 mL). The organic phase was concentrated under reduced pressure and purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 87. LCMS: m / z 406.1 [M+H] +1; H NMR (400MHz, CDCl3) δ: 7.15 (s, 1H), 7.09 (s, 4H), 4.11 (s, 2H), 4.02 (s, 4H), 3.68 (br d,J=12.0Hz,2H),2.74(t,J=7.7Hz,2H),2.65(s,3H),2.44-2.59(m,2H),1.68-1.71(m,2H),1.45-1.63(m,2H),1.11-1.33(m,3H).

[0613] Example 86: Compound 88

[0614] At 25°C, under a nitrogen atmosphere, 4-((4-(isoindoline-2-methyl)-2-methoxyphenyl)ethynyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (100 mg, 0.25 mmol) and palladium / carbon (3 mg, 0.03 mmol, 10 wt%) were dissolved in methanol (10 mL), the hydrogen atmosphere was replaced three times, and the mixture was stirred for 18 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to give compound 88. LCMS: m / z 400.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.44-7.38(m,2H),7.33(dd,J=3.3,5.3Hz,2H),7.17-7.09(m,2H),6.83(d,J=7.5Hz,1H),4.93(d ,J=14.3Hz,2H),4.45-4.28(m,4H),3.83(s,3H),3.16-2.89(m,4H),2.72-2.55(m,2H),2.19(d,J=13.0Hz,2H),1.92(br d,J=12.3Hz,2H),1.69-1.56(m,3H).

[0615] Example 87: Compound 89

[0616] Step 1: To a solution of 89-0 (1.00 g, 4.00 mmol) in dichloromethane (15 mL) was added trimethyloxonium tetrafluoroboric acid (1.18 g, 8.00 mmol) and stirred at 25°C for 18 hours. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 89-1.

[0617] Step 2: Add 89-1 (600 mg, 2.27 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (950 mg, 4.54 mmol), cuprous iodide (22 mg, 0.11 mmol), bistriphenylphosphine palladium dichloride (159 mg, 0.23 mmol), and triethylamine (1.50 mL) to tetrahydrofuran (10 mL), replace the nitrogen atmosphere three times, and stir at 25°C for 18 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 89-2. LCMS: m / z 393.2 [M+H] + .

[0618] Step 3: Under nitrogen atmosphere, 89-2 (1.07 g, 2.75 mmol) and palladium / carbon (1.01 g, 9.4 mmol, 10 wt%) were added to methanol (15 mL). The hydrogen atmosphere was replaced three times and the mixture was stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 89-3. LCMS: m / z 341.1 [M-55] + .

[0619] Step 4: Add 89-3 (940 mg, crude) to a hydrochloric acid-dioxane solution (6 mL, 4 M) at 25°C and stir at 25°C for 20 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give 89-4. LCMS: m / z 297.1 [M+H] + .

[0620] Step 5: At 25°C, 89-4 (700 mg, crude), triethylamine (0.98 mL, 7.09 mmol), and methanesulfonic anhydride (617 mg, 3.54 mmol) were added to dichloromethane (10 mL) and stirred at 25°C for 30 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 89-5. LCMS: m / z 375.1 [M+H] + .

[0621] Step 6: To a solution of 89-5 (730 mg, 1.95 mmol) in tetrahydrofuran (10 mL), lithium chloride (826 mg, 19.50 mmol) and sodium borohydride (737 mg, 19.50 mmol) were added sequentially and stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water and extracted with dichloromethane (100 mL × 2). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 89-6. LCMS: m / z 347.1 [M+H] + .

[0622] Step 7: To a solution of 89-6 (300 mg, crude) in dichloromethane (4 mL), add thionyl chloride (1 mL) and stir at 25°C for 30 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give 89-7. LCMS: m / z 365.1 [M+H] + .

[0623] Step 8: To a solution of 89-7 (310 mg, crude) in N,N-dimethylformamide (8 mL), potassium carbonate (352 mg, 2.55 mmol) and 2,3-dihydroisoindole hydrochloride (396 mg, 2.55 mmol) were added sequentially and stirred at 80°C for 1.5 hours. The reaction was monitored by LCMS. The reaction solution was added with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 89. LCMS: m / z 448.3 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.22-7.11(m,5H),4.16(s,4H),4.04(d,J=2.6Hz,2H),3.93(s,3H),3.80(d,J=11 .6Hz,2H),2.77(s,3H),2.69-2.53(m,4H),1.86(d,J=9.8Hz,2H),1.60-1.52(m,2H),1.42-1.30(m,3H).

[0624] Example 88: Compound 90

[0625] Step 1: At 25°C, 90-0 (2.01 g, 8.62 mmol), potassium carbonate (2.38 g, 17.24 mmol), and iodomethane (1.61 mL, 25.86 mmol) were added sequentially to N,N-dimethylformamide (25 mL) and stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The reaction solution was added with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 90-1. LCMS: m / z 245.9 [M+H] + .

[0626] Step 2: Add 90-1 (1.18 g, 4.80 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (2.01 g, 9.59 mmol), cuprous iodide (90 mg, 0.48 mmol), bistriphenylphosphine palladium dichloride (340 mg, 0.48 mmol), and triethylamine (6.60 mL) to tetrahydrofuran (20 mL), replace the nitrogen atmosphere three times, and stir at 25°C for 3 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 90-2. LCMS: m / z 375.2 [M+H] + .

[0627] Step 3: Under nitrogen atmosphere, 90-2 (1.69 g, 4.51 mmol) and palladium / carbon (1.25 g, 11.75 mmol, 10 wt%) were added to methanol (15 mL). The hydrogen atmosphere was replaced three times and the mixture was stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 90-3. LCMS: m / z 279.2 [M-99] + .

[0628] Step 4: Add 10 mL of 4 M hydrochloric acid-dioxane solution to 90-3 (1.42 g, crude) at 25°C and stir at 25°C for 30 minutes. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure to give 90-4. LCMS: m / z 279.1 [M+H] + .

[0629] Step 5: At 25°C, 90-4 (1.05 g, crude), triethylamine (1.57 mL, 11.32 mmol), and methanesulfonic anhydride (990 mg, 5.66 mmol) were added to dichloromethane (10 mL) and stirred at 25°C for 30 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 90-5. LCMS: m / z 357.1 [M+H] + .

[0630] Step 6: To a solution of 90-5 (470 mg, 1.32 mmol) in tetrahydrofuran (8 mL) were added lithium chloride (560 mg, 13.2 mmol) and sodium borohydride (500 mg, 13.2 mmol) in sequence and stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water and extracted with dichloromethane (100 mL × 2). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 90-6. LCMS: m / z 329.1 [M+H] + .

[0631] Step 7: To a solution of 90-6 (200 mg, crude) in dichloromethane (4 mL), add thionyl chloride (1 mL) and stir at 25°C for 30 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give 90-7. LCMS: m / z 347.1 [M+H] + .

[0632] Step 8: To a solution of 90-7 (210 mg, crude) in N,N-dimethylformamide (4 mL), potassium carbonate (250 mg, 1.82 mmol) and 2,3-dihydroisoindole hydrochloride (285 mg, 1.83 mmol) were added sequentially and stirred at 80°C for 16 hours. The reaction was monitored by LCMS. The reaction solution was added with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (petroleum ether: ethyl acetate = 1:3) to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 90. LCMS: m / z 430.3 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.24-7.17(m,4H),7.13(d,J=6.9Hz,1H),6.18(d,J=6.9Hz,1H),3.96(s,4H),3.83-3.75(m,4H),3.71( s,3H),2.77(s,3H),2.70-2.61(m,2H),2.60-2.53(m,2H),1.89(dd,J=2.0,12.6Hz,2H),1.62-1.54(m,2H),1.50-1.29(m,3H).

[0633] Example 89: Compound 91

[0634] Step 1: At 25°C, 91-0 (1.01 g, 4.01 mmol), potassium carbonate (1.11 g, 8.02 mmol), and iodomethane (0.94 mL, 12.01 mmol) were added sequentially to N,N-dimethylformamide (10 mL) and stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The reaction solution was added with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 91-1. LCMS: m / z 264.0 [M+H]+ .

[0635] Step 2: Add 91-1 (218 mg, 0.83 mmol), tert-butyl 3-ethynylpiperidine-1-carboxylate (345 mg, 1.65 mmol), cuprous iodide (16 mg, 0.08 mmol), bistriphenylphosphine palladium dichloride (58 mg, 0.08 mmol), and triethylamine (1.15 mL) to tetrahydrofuran (5 mL), replace the nitrogen atmosphere three times, and stir at 25°C for 2 hours. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 91-2. LCMS: m / z 293.1 [M-99] + .

[0636] Step 3: Under nitrogen atmosphere, 91-2 (200 mg, 0.51 mmol) and palladium / carbon (100 mg, 0.94 mmol, 10 wt%) were added to methanol (5 mL), the hydrogen atmosphere was replaced three times, and the mixture was stirred at 25°C for 1 hour. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 91-3. LCMS: m / z 397.2 [M+H] + .

[0637] Step 4: Add 91-3 (200 mg, crude) to a hydrochloric acid-dioxane solution (4 mL, 4 M) at 25°C and stir at 25°C for 30 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to yield 91-4. LCMS: m / z 297.1 [M+H] + .

[0638] Step 5: At 25°C, 91-4 (150 mg, crude), triethylamine (0.21 mL, 1.52 mmol), and methanesulfonic anhydride (132 mg, 0.76 mmol) were added to dichloromethane (4 mL) and stirred at 25°C for 30 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 91-5. LCMS: m / z 375.1 [M+H] + .

[0639] Step 6: To a solution of 91-5 (120 mg, 0.32 mmol) in tetrahydrofuran (4 mL) were added lithium chloride (135 mg, 3.2 mmol) and sodium borohydride (121 mg, 3.2 mmol) in sequence and stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water and extracted with dichloromethane (30 mL × 3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 91-6. LCMS: m / z 347.1 [M+H] + .

[0640] Step 7: To a solution of 91-6 (90 mg, crude) in dichloromethane (3 mL), add thionyl chloride (0.8 mL) and stir at 25°C for 30 minutes. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure to give 91-7. LCMS: m / z 365.1 [M+H] + .

[0641] Step 8: To a solution of 91-7 (95 mg, crude) in N,N-dimethylformamide (3 mL), potassium carbonate (107 mg, 0.78 mmol) and 2,3-dihydroisoindole hydrochloride (121 mg, 0.78 mmol) were added sequentially and stirred at 80°C for 1.5 hours. The reaction was monitored by LCMS. The reaction solution was washed with water and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (petroleum ether: ethyl acetate = 1:2) to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 91. LCMS: m / z 448.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.20 (s, 4H), 7.16 (d, J = 8.9Hz, 1H), 3.98 (s, 4H), 3.90 (d,J=4.3Hz,2H),3.75-3.69(m,4H),3.69-3.62(m,1H),2.77(s,3H),2.69(dt ,J=2.9,11.4Hz,1H),2.65-2.53(m,2H),2.49-2.41(m,1H),1.98-1.90(m,1H) ,1.85-1.77(m,1H),1.77-1.72(m,1H),1.67-1.54(m,3H),1.19-1.06(m,1H).

[0642] Example 90: Compound 92

[0643] Under a nitrogen atmosphere at 25°C, palladium / carbon (22 mg, 0.20 mmol, 10 wt%) was added to a solution of 4-((4-(isoindolin-2-ylmethyl)-2-methoxyphenyl)ethynyl)-1-(methylsulfonyl)piperidin-4-ol (90 mg, 0.20 mmol) in methanol (10 mL) and stirred for 1 hour. LCMS monitored the completion of the reaction. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate conditions) to give compound 92. LCMS: m / z 445.3 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:7.12(s,4H),7.02(d,J=7.5Hz,1H),6.91(s,1H),6.84(d,J=7.4Hz,1H),3.88(s,4H),3.82(s,2H) ,3.78(s,3H),3.52(d,J=11.5Hz,2H),2.99(dt,J=5.2,10.6Hz,2H),2.72(s,3H),2.66-2.61(m,2H),1.74-1.66(m,6H).

[0644] Example 91: Compound 93

[0645] Step 1: Add tetrabutylammonium fluoride (1.09 g, 4.17 mmol) to a solution of 93-0 (700 mg, 2.09 mmol) in tetrahydrofuran (5 mL) at 25°C and stir for 1 hour. The reaction is complete after monitoring by LCMS. The reaction solution is diluted with ethyl acetate (20 mL), washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to afford 93-1. LCMS: m / z 264.0 [M+H] + .

[0646] Step 2: At -78 ° C, n-butyllithium solution (0.36 mL, 0.57 mmol, 1.6 M) was added dropwise to a solution of 93-1 (100 mg, 0.38 mmol) in tetrahydrofuran (4 mL), stirred for 30 minutes, 1-N-methylsulfonyl-4-piperidone (67 mg, 0.38 mmol) was added to the reaction solution, and stirring was continued for 40 minutes. The reaction was monitored by LCMS. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (ammonium bicarbonate conditions) to obtain compound 93. LCMS: m / z 441.2 [M+H] + ; 1H NMR(400MHz, CDCl3)δ:7.32(d,J=7.8Hz,1H),7.20(s,4H),7.04(s,1H),6.94(d,J=7.6Hz,1H),3.96(s,4H),3.91(s,2H),3.89(s ,3H),3.58-3.50(m,2H),3.30(ddd,J=3.3,8.7,11.9Hz,2H),2.81(s,3H),2.14-2.06(m,2H),1.96(ddd,J=3.6,8.8,12.8Hz,3H).

[0647] Example 92: Compound 94

[0648] At 25°C, a hydrobromic acid-acetic acid solution (4 mL, 33 wt%) was added to 2-((3-fluoro-6-methoxy-5-(2-(1-(methylsulfonyl)piperidin-4-yl)ethyl)pyridin-2-yl)methyl)isoindoline (50 mg, 0.11 mmol) and stirred at 60°C for 2 hours. LCMS monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate conditions) to give Compound 94. LCMS: m / z 434.2 [M+H] + ; 1 HNMR(400MHz, CDCl3)δ:7.26-7.14(m,5H),4.05(s,4H),3.93(d,J=2.1Hz,2H),3.79(d,J=11.9Hz,2H),2.77 (s,3H),2.69-2.60(m,2H),2.58-2.51(m,2H),1.87(d,J=12.4Hz,2H),1.62-1.53(m,2H),1.41-1.24(m,3H).

[0649] Example 93: Compound 95

[0650] Step 1: Add 95-0 (1.01 g, 5.23 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (2.19 g, 10.47 mmol), bistriphenylphosphine palladium dichloride (180 mg, 0.26 mmol) and cuprous iodide (100 mg, 0.52 mmol) to triethylamine (3.6 mL) and tetrahydrofuran (10 mL), replace nitrogen three times, and stir at 25°C for 3 hours. The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 95-1. LCMS: m / z 220.0 [M-99] + .

[0651] Step 2: At 25°C under a nitrogen atmosphere, 95-1 (1.00 g, 3.13 mmol) and palladium / carbon (0.33 g, 3.13 mmol, 10 wt%) were added to isopropanol (10 mL). The hydrogen atmosphere was replaced three times and the mixture was stirred for 3 hours. The reaction was monitored by LCMS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude 95-2. LCMS: m / z 268.0 [M-55] + .

[0652] Step 3: Add hydrochloric acid-dioxane solution (5 mL, 4 M) to 95-2 (800 mg, 2.47 mmol) at 25°C and stir for 1 hour. The reaction is monitored by LCMS. The reaction solution is concentrated under reduced pressure to obtain crude 95-3. LCMS: m / z 224.0 [M+H] + .

[0653] Step 4: Methanesulfonic anhydride (780 mg, 4.48 mmol) was added to a solution of 95-3 (500 mg, 2.24 mmol) and triethylamine (1.55 mL, 11.20 mmol) in dichloromethane (5 mL) at 25°C and stirred for 20 minutes. The reaction was monitored by LCMS to determine completion. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to afford 95-4. LCMS: m / z 319.0 [M+NH4] + .

[0654] Step 5: At 25°C, add N-bromosuccinimide (192 mg, 1.07 mmol) and ferric chloride (436 mg, 2.69 mmol) to a solution of 95-4 (270 mg, 0.90 mmol) in acetonitrile (5 mL) and stir at 25°C for 2 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water (30 mL). Extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 95-5. LCMS: m / z 397.1 [M+NH4] + .

[0655] Step 6: At 25°C, acetic acid (0.07 mL, 1.18 mmol) and sodium triacetoxyborohydride (100 mg, 0.47 mmol) were added to a solution of 95-5 (90 mg, 0.24 mmol) and isoindoline hydrochloride (57 mg, 0.47 mmol) in 1,2-dichloroethane (5 mL). The mixture was stirred for 2 hours. The reaction was monitored by LCMS for completion. The reaction solution was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 95. LCMS: m / z 483.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.20 (s, 4H), 6.82 (s, 1H), 4.06-3.97 (m, 6H), 3.80 (br d, J = 12.0Hz, 2H), 2.83-2.75 (m, 5H), 2.68-2.60 (m, 2H), 1.87 (br dd,J=1.7,12.6Hz,2H),1.68-1.60(m,2H),1.44-1.30(m,3H).

[0656] Example 94: Compound 96

[0657] To a solution of compound 95 (40 mg, 0.08 mmol) in N,N-dimethylformamide (1 mL) were added zinc cyanide (7 mg, 0.06 mmol), zinc powder (1 mg, 0.01 mmol), 1,1'-bis(diphenylphosphino)ferrocene (3 mg, 0.01 mmol), and tris(dibenzylideneacetone)dipalladium (8 mg, 0.01 mmol). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 110°C and stirred for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 96. LCMS: m / z 430.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.21 (d, J = 1.3Hz, 4H), 6.99 (s, 1H), 4.04 (s, 2H), 4.01 (s, 4H), 3.81 (br d,J=12.1Hz,2H),3.02(t,J=7.8Hz,2H),2.77(s,3H),2.70-2.61(m,2H),1.90-1.84(m,2H),1.75-1.68(m,2H),1.45-1.34(m,3H).

[0658] Example 95: Compound 97

[0659] Step 1: Add lithium diisopropylamide (2.02 mL, 4.05 mmol, 2 M) in tetrahydrofuran (10 mL) dropwise to tetrahydrothiopyran-4-one 1,1-dioxide 97-0 (0.40 g, 2.70 mmol) at -78°C and stir for 1 hour. Add N-phenylbis(trifluoromethanesulfonyl)imide (1.93 g, 2.00 mmol) in tetrahydrofuran (5 mL) dropwise to the reaction system and continue stirring for 2 hours. Quench the reaction with saturated sodium bicarbonate solution (10 mL) and extract with ethyl acetate (10 mL). Wash the organic phase with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product 97-1.

[0660] Step 2: At 25°C, the crude product of 97-1, 2-(4-ethynyl-3-methoxybenzyl)isoindoline (130 mg), triethylamine (0.34 mL, 2.47 mmol), cuprous iodide (5 mg, 0.02 mmol), and bis(triphenylphosphine)palladium dichloride (35 mg, 0.05 mmol) were dissolved in tetrahydrofuran (5 mL). The atmosphere was replaced with nitrogen three times, the temperature was raised to 100°C, and the mixture was stirred for 18 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (ammonium bicarbonate conditions) to obtain compound 97. LCMS: m / z 394.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.35 (d, J = 7.6Hz, 1H), 7.21 (s, 4H), 7.04 (s, 1H), 6.95 (d, J = 7.6Hz, 1H), 6.06 (ddd, J = 1.4, 3.1,4.5Hz,1H),3.97(s,4H),3.93(s,2H),3.90(s,3H),3.79-3.73(m,2H),3.21-3.16(m,2H),3.08-3.00(m,2H).

[0661] Example 96: Compound 98

[0662] At 80 ° C, potassium carbonate (115 mg, 0.82 mmol) was added to a solution of 6-chloromethyl-5-fluoro-1-methyl-3-(2-(1-methylsulfonyl)piperidin-4-yl)ethyl)pyridin-2(1H)one (100 mg, 0.27 mmol) and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (80 mg, 0.41 mmol) in N,N-dimethylformamide (2 mL) and stirred for 2 hours. LCMS monitored the completion of the reaction. The temperature was lowered to 25 ° C, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phase was collected, and washed with saturated brine (60 mL). Purification by preparative high performance liquid chromatography (ammonium bicarbonate conditions) gave compound 98. LCMS: m / z 449.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 8.41 (d, J = 4.6Hz, 1H), 7.51 (d, J = 7.4Hz, 1H), 7.11- 7.19 (m, 2H), 3.99-4.09 (m, 4H), 3.94 (d, J = 4.1Hz, 2H), 3.81 (br d,J=12.0Hz,2H),3.72(s,3H),2.78(s,3H),2.56-2.72(m,4H),1.85-1.99(m,2H),1.53-1.60(m,2H),1.28-1.44(m,3H).

[0663] Example 97: Compound 99

[0664] At 25°C, 2,3-dihydropyrrolo[3,4-c]pyridine (59 mg, 0.49 mmol) and potassium carbonate (136 mg, 0.99 mmol) were added to a solution of 6-chloromethyl-5-fluoro-1-methyl-3-(2-(1-methylsulfonyl)piperidin-4-yl)ethyl)pyridin-2(1H)one (120 mg, 0.33 mmol) in N,N-dimethylformamide (4 mL). The mixture was heated to 80°C and stirred for 1 hour. The reaction was monitored by LCMS. The temperature was lowered to 25°C. The reaction solution was quenched with water and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain compound 99. LCMS: m / z 449.2 [M+H] + ; 1H NMR(400MHz, CDCl3)δ:8.52-8.43(m,2H),7.20-7.13(m,2H),4.01(br d,J=16.4Hz,4H),3.93(d,J=4.0Hz,2H),3.80(br d,J=12.0Hz,2H),3.70(s,3H),2.77(s,3H),2.70-2.62(m,2H),2.62-2.56( m,2H),1.92-1.87(m,3H),1.61-1.55(m,2H),1.38(dt,J=3.8,12.2Hz,2H).

[0665] Example 98: Compound 100

[0666] At 80 ° C, potassium carbonate (203 mg, 1.47 mmol) was added to a solution of 6-chloromethyl-5-fluoro-1-methyl-3-(2-(1-methylsulfonyl)piperidin-4-yl)ethyl)pyridin-2(1H)one (170 mg, 0.49 mmol) and 4-fluoroisoindoline hydrochloride (128 mg, 0.74 mmol) in N,N-dimethylformamide (2 mL) and stirred for 2 hours. LCMS monitored the completion of the reaction. The temperature was lowered to 25 ° C, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phase was collected, and washed with saturated brine (60 mL). Purification by preparative high performance liquid chromatography (ammonium bicarbonate conditions) gave compound 100. LCMS: m / z 466.1 [M+H] + ; 1 H NMR (400MHz, CDCl3)δ:7.20(td,J=7.8,5.2Hz,1H),7.15(d,J=9.0Hz,1H),6.98(d,J=7.5Hz,1H),6.91(t,J=8.6Hz,1H),4.03(br d,J=12.6Hz,4H),3.92(d,J=4.0Hz,2H),3.81(br d,J=12.0Hz,2H),3.72(s,3H),2.78(s,3H),2.63-2.71(m,2H),2.56-2.62(m,2H),1.85-1.94(m,2H),1.56(br s,2H),1.30-1.51(m,3H).

[0667] Example 99: Compound 101

[0668] At 25°C, 5-fluoroisoindoline (68 mg, 0.49 mmol) and potassium carbonate (136 mg, 0.99 mmol) were added to a solution of 6-chloromethyl-5-fluoro-1-methyl-3-(2-(1-methylsulfonyl)piperidin-4-yl)ethyl)pyridin-2(1H)one (120 mg, 0.33 mmol) in N,N-dimethylformamide (4 mL). The mixture was heated to 80°C and stirred for 1.5 hours. The reaction was monitored by LCMS. The temperature was lowered to 25°C. The reaction solution was quenched with water and extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 101. LCMS: m / z 466.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ: 7.17-7.09 (m, 2H), 6.93-6.85 (m, 2H), 3.94 (br d, J = 10.4Hz, 4H), 3.89 (d, J = 4.1Hz, 2H), 3.79 (br d,J=12.0Hz,2H),3.71(s,3H),2.77(s,3H),2.70-2.61(m,2H),2.61-2.55(m,2H),1.89(br dd,J=1.7,12.6Hz,2H),1.62-1.53(m,2H),1.48-1.29(m,3H).

[0669] Example 100: Compound 102

[0670] Step 1: At 25°C, add 102-0 (500 mg, 1.44 mmol) and manganese dioxide (2.50 g, 28.8 mmol) to a dichloromethane (10 mL) solution, raise the temperature to 60°C, and stir for 3 hours. LCMS monitoring indicates the completion of the reaction. Cool the mixture to 25°C. Concentrate the reaction mixture under reduced pressure to obtain 102-1. LCMS: m / z 345.0 [M+H] + .

[0671] Step 2: Add 102-1 (150 mg, 0.44 mmol) to tetrahydrofuran (4 mL) and replace the nitrogen three times. Cool to -78°C, add methylmagnesium bromide (1.31 mL, 1 M) and stir for 0.5 hours. LCMS monitoring of the reaction completion. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 102-2. LCMS: m / z 361.2 [M+H] + .

[0672] Step 3: To a solution of 102-2 (40 mg, 0.11 mmol) in dichloromethane (2 mL) was added phosphorus tribromide (0.02 mL, 0.17 mmol) at 0°C and stirred for 0.5 hours. The reaction was monitored by LCMS. The reaction solution was quench...

Claims

1. A compound of formula (0), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof: in: Ring A is C 6-10 Aryl, 5-6 membered heteroaryl, 5-12 membered heterocyclic group; wherein the heteroatom in the 5-6 membered heteroaryl group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; wherein the heteroatom in the 5-12 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; L 1 is a direct bond, O, S, -NH-, unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-6 Alkenylene, unsubstituted or substituted with one or more L 1-3 Substituted C 2-6 Alkyne, unsubstituted or substituted with one or more L 1-4 Substituted *-C 1-6 Alkylene-S-, unsubstituted or substituted with one or more L 1-5 Replaced by *-SC 1-6 Alkylene-, unsubstituted or substituted with one or more L 1-6 Substituted *-C 1- 6 alkylene-O-, unsubstituted or substituted with one or more L 1-7 Replaced by *-OC 1-6 Alkylene-, *-OC 2-6 Alkenylene-, unsubstituted or substituted with one or more L 1-8 Replaced by *-OC 6-10 Arylene-, unsubstituted or substituted with one or more L 1-8 Substituted *-C 6-10 Arylene-O-, unsubstituted or substituted with one or more L 1-9 Substituted *-SO2-C 1-3 Alkylene, *-C(=O)-NH-, *-NH-C(=O)-, unsubstituted or substituted with one or more L 1-10 Substituted *-C 1-6 Alkylene-OC 1-6 Alkylene-, unsubstituted or substituted with one or more L 1-10 Substituted *-C 1-6 Alkylene-C(O)-; wherein the bond marked with "*" is connected to ring B; Preferably, L 1 is a direct bond, O, -NH-, unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-6 Alkenylene, C 2-6 Alkynylidene, *-C 1-6 Alkylene-S-, *-C 1-6 Alkylene-O-, *-OC 1-6 Alkylene-, *-C 6-10 Arylene-O-, *-C 1-6 Alkylene-C(O)-; Each L 1-1 , L 1-2 , L 1-3 , L 1-4 , L 1-5 , L 1-6 , L 1-7 , L 1-8 , L 1-9 , L 1-10 are independently halogen, OH, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the heteroatom in the 3-6 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by deuterium, halogen, OH, CN or -NH2, Ring B is a 5-12 membered heterocyclic group; wherein the heteroatom in the 5-12 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Each R 1 are independently deuterium, halogen, cyano, hydroxyl, oxo, C 1-6 Alkoxy, R 1-1 , -C(=O)-R 1-1 、-(CR 1-2 R 1-3 ) q -C(=O)-OR 1-4 、-NR 1-7 R 1-8 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1- 9 )、-S(O)2-R 1-9 、-S(O)2-NR 1-5 R 1-6 、-NR 1-5 S(O)2-R 1-10 , -R 1-10 -OH, -P(=O)-R 1-2 R 1-3 ; Preferably, R 1 are each independently oxo, -C(=O)-R 1-1 、-(CR 1-2 R 1-3 ) q -C(=O)-OR 1-4 NR 1-7 R 1-8 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-NR 1-5 S(O)2-R 1-10 , -R 1-10 -OH, -P(=O)-R 1-2 R 1-3 ; R 2 are independently deuterium, OH, NH2, halogen, CN, NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 1- 6 haloalkyl, C 1-6 Deuterated alkyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 2-6 Alkenyl, -OC 3-10 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-10 Cycloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 1-6 Alkylene-C 3-10 Cycloalkyl, -C(=O)NR 2-1 R 2-2 、-NR 2-3 -C(=O)-R 2-4 or two R attached to the same carbon atom 2 To form an oxo group (=O); wherein the heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Optionally, two adjacent R 2 Form a 5-6 membered heterocyclic group; wherein the heteroatom in the 5-6 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 and R 1-8 Each independently is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene -CN, C 3-10 Cycloalkyl, or 3-10 membered heterocyclic group; wherein the heteroatom in the 3-10 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; R 1-9 and R 1-10 Each independently is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene -CN, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 3-10 Cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C 1-6 Alkyl-C 6-10 Arylene-; R 2-1 , R 2-2 , R 2-3 or R 2-4 are each independently H, halogen or C 1-6 alkyl; Ring C is a 5-membered nitrogen-containing heterocyclic acene or a 5-membered nitrogen-containing heterocyclic pyridine; Each R 3 are independently cyano, hydroxyl, halogen, C 1-6 Alkyl or two R attached to the same carbon atom 3 Forming an oxo group (=O); R 4 and R 5 are each independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, or R 4 and R 5 Together with the atoms they are connected to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; Preferably, R 4 and R 5 are each independently H, deuterium, halogen, C 1-6 More preferably, R 4 and R 5 All are H or deuterium, or R 4 and R 5 One of them is H and the other is deuterium, halogen, C 1-4 alkyl; q is 0 or 1; m, t and n are each independently 0, 1, 2, 3 or 4; and in: 1) When ring A is a benzene ring, L 1 When it is *-CH2-O-, the bond marked with "*" is connected to ring B, and the compound of formula (0) is not 2) no 2. The compound of formula (0) according to claim 1, characterized in that The compound of formula (0) satisfies one or more of the following conditions: (1) R 1 are each independently oxo, -C(=O)-R 1-1 、-(CR 1-2 R 1-3 ) q -C(=O)-OR 1- 4 、-C(=O)-NR 1-7 R 1-8 、-(C=NH)-(C 1-6 Alkyl), -S(O)2-C 1-6 Alkyl, -S(O)2-C 1-6 Halogenated alkyl, -S(O)2-C 6-10 Arylene-C 1-6 Alkyl, -S(O)2-C 3-10 Cycloalkyl, -S(O)2-5-10 membered heteroaryl, -S(O)2-C 2-6 Alkenyl, -NR 1-5 S(O)2-C 1-6 Alkyl, -P(=O)-R 1-2 R 1-3 ; preferably oxo, -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-(C=NH)-(C 1-3 Alkyl), -S(O)2-C 1-3 Alkyl, -S(O)2-C 1-3 Halogenated alkyl, -S(O)2-phenylene-C 1-3 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-5-6 membered heteroaryl, -S(O)2-C 2-3 Alkenyl, -NR 1-5 S(O)2-C 1-3 Alkyl, -P(=O)-R 1-2 R 1-3 More preferably -S(O)2-C 1-3 Alkyl, -C(=O)-OC 1-6 Alkyl, -S(O)2-C 1-3 Halogenated alkyl, -S(O)2-phenylene-C 1-3 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-5-6 membered heteroaryl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)-C 1-6 Alkylene-CN, -S(O)2-C 2-3 Alkenyl, -C(=O)-NHC 1-6 Alkyl; most preferably - S(O)2-C 1-3 alkyl; (2) Ring B is a 5-12 membered heterocyclic group, wherein the heteroatom is selected from N, O and S, the number of heteroatoms is 1, 2, 3 or 4, wherein at least one heteroatom is N, preferably the number of heteroatoms is 1, 2 or 3, preferably, Ring B is a 5-6 membered monocyclic heterocyclic group, a 6-12 membered fused bicyclic heterocyclic group or a 9-12 membered spirocyclic heterocyclic group; more preferably, Ring B is a 5-6 membered monocyclic heterocyclic group or a 9-12 membered fused bicyclic heterocyclic group (e.g., a benzo 6-membered heterocyclic alkyl group or a pyrido 6-membered heterocyclic alkyl group); most preferably, Ring B is a 6-membered monocyclic heterocyclic group (e.g., a piperidinyl group or a piperazinyl group); (3) L 1 is a direct bond, O, -NH-, unsubstituted or replaced by one or more L 1-1 Substituted C 1-4 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-4 Alkenylene, C 2-4 Alkynylidene, *-C 1-4 Alkylene-S-, *-C 1-4 Alkylene-O-, *-OC 1-4 Alkylene-, *-phenylene-O-, *-C 1-4 Alkylene-C(O)-; said unsubstituted or substituted by one or more L 1-1 Substituted C 1-4 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-4 The plurality of alkenylene groups is preferably 1, 2, 3, or 4, more preferably 1 or 2; preferably, the L 1 is a direct bond, unsubstituted or replaced by one or more L 1-1 Substituted C 1-2 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-3 Alkenylene, C 2-3 Alkynylidene, *-C 1-2 Alkylene-S-, *-C 1-2 Alkylene-O-, *-C 1-2 Alkylene-C(O)-; more preferably, the L 1 is unsubstituted or replaced by one or more L 1-1 Substituted C 1-2 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-3 alkenylene; (4) Each R 2 are independently OH, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 2-6 Alkenyl, -OC 3-10 Cycloalkyl, -SC 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3- 10 Cycloalkyl, -OC 1-6 Alkylene-C 3-10 Cycloalkyl, -C(=O)NR 2-1 R 2-2 or two R attached to the same carbon atom 2 To form an oxo group (=O); wherein the heteroatoms in the 3-10 membered heterocyclic group and the 5-10 membered heteroaryl group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; optionally, the adjacent R 2 Form a 5-6 membered heterocyclic group; wherein the heteroatom in the 5-6 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; preferably, each R 2 are independently OH, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -SC 1-4 Alkyl, -OC 2- 4-Alkenyl, -OC 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -OC 1-4 Alkylene-C 3-6 Cycloalkyl, -C(=O)NHC 1-4 Alkyl or two R attached to the same carbon atom 2 Forming an oxo group (=O); (5) m is independently 0, 1, 2 or 3, preferably 0, 1 or 2; n is independently 0, 1, 2 or 3, preferably 0 or 1; t is independently 0, 1, 2 or 3, preferably 0 or 1; (6) Ring A is C 6-10 Aryl, 5-6 membered heteroaryl or 6 membered heterocyclic group; (7) Ring C is 3. The compound of formula (0) according to claim 1 or 2, characterized in that The compound of formula (0) satisfies one or more of the following conditions: (1)R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 and R 1-10 C 1-6 The alkyl group is independently methyl, ethyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably C 1-4 Alkyl, more preferably methyl or tert-butyl; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 and R 1- 10 As described in -C 1-6 Alkylene-CN is independently -methylene-CN, -ethylene-CN, -isopropylene-CN, -n-butylene-CN, -isobutylene-CN or -tert-butylene-CN, preferably -C 1-4 Alkylene-CN, more preferably -methylene-CN; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 and R 1-10 C 3- 10 The cycloalkyl groups are independently C 3-10 Cycloalkyl, preferably C 3-6 Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and for example cyclopropyl; preferably, said R 1-1 , R 1-4 Each independently is H, C 1-6 Alkyl (e.g. C 1-4 Alkyl), C 1-6 Haloalkyl, -C 1-6 Alkylene -CN or -C 3-10 Cycloalkyl; said R 1-2 , R 1-3 , R 1-5 , R 1-6 , R 1-7 and R 1-8 Each independently is H or C 1-6 Alkyl, preferably H or C 1-3 alkyl; (2) The 5-6 membered monocyclic heterocyclic group in the ring B is independently a 5-6 membered monocyclic heterocyclic group, the number of heteroatoms is 1, for example: azacyclopentane or azacyclohexane, preferably azacyclohexane; the 6-12 membered fused bicyclic heterocyclic group in the ring B is independently a 9-12 membered fused bicyclic heterocyclic group, for example: benzazacyclopentane, benzazacyclohexane, benzazacycloheptane, pyridaazacyclohexane, pyrimidaazacyclohexane, thienazacyclohexane, pyrrolidone; preferably benzazacyclohexane, pyridaazacyclohexane; the 9-12 membered spirocyclic heterocyclic group in the ring B is independently a 9-12 membered monocyclic spirocyclic heterocyclic group, optionally the heteroatoms may be N and O, preferably a 4-membered / 6-membered ring system, a 5-membered / 5-membered ring system, a 5-membered / 6-membered ring system and a 6-membered / 6-membered ring system, for example (3) Each L 1-1 , L 1-2 , L 1-3 , L 1-4 , L 1-5 , L 1-6 , L 1-7 , L 1-8 , L 1-9 , L 1-10 are independently halogen, OH, C 1-6 Alkyl or C 3-6 Cycloalkyl; wherein the halogen is independently F, Cl, Br or I, preferably F, Cl, Br, more preferably F; the C 1-6 The alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, preferably methyl; 3-6 The cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl; (4) the unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, *-C 1-6 Alkylene-S-, *-C 1-6 Alkylene-O-, *-OC 1-6 Alkylene- or *-C 1-6 The C in alkylene-C(O)- 1-6 Each alkylene group is independently -CH2-, -CH2-CH2-, -C(CH3)-CH2-, -CH(CH3)-CH(CH3)-, -CH2CH2-CH(CH3)- or -CH2CH(CH3)-CH2-; the unsubstituted or substituted L 1-2 Substituted C 2-6 In the alkenylene group, the C 2-6 Alkenylene is -CH=CH-, -CH=CHCH2-, -CH2CH=CHCH2-, -CH=CHCH2CH2-, -C(CH3)=CHCH2-, -C(CH3)=CH-, or -C(CH3)=C(CH3)-; said L 1 C 2-6 In the alkynylene group, the C 2-6 Alkyne is -C≡C-, -CH2-C≡C-, -CH2-C≡C-CH2-, -CH2-CH2-C≡C-, -C≡CC≡C-; said L 1 For *-C 6-10 Arylene-O-, the C 6-10 Arylene is phenyl or naphthyl, preferably phenyl; (5)R 2 wherein the halogen is independently F, Cl, Br or I, preferably F, Cl or Br; 1- 6-alkyl, -OC 1-6 Alkyl, -SC 1-6 C in the alkyl group 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, isopropyl, sec-butyl or tert-butyl; the C 2-6 Alkenyl, -OC 2-6 C in alkenyl 2-6 The alkenylene group is independently vinyl, propenyl, isopropenyl, butenyl or isobutenyl, preferably vinyl, propenyl or isopropenyl; the C 1-6 Haloalkyl, -OC 1-6 C 1-6 The preferred haloalkyl group is C 1-3 haloalkyl, such as -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Cl, -CH2CH2F, -CHClCH3 or -CH(CH3)CH2F, preferably -CF3; 1-6 Deuterated alkyl C 1-6 Deuterated alkyl is preferably C 1-3 Deuterated alkyl, such as -CD3, -CHD2, -CH2D; preferably -CD3; the -OC 3-10 Cycloalkyl, -SC 3-10 Cycloalkyl, -C 3-10 Cycloalkyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -OC 1-6 Alkylene-C 3-10 C in cycloalkyl 3-10 The cycloalkyl groups are independently C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, preferably C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl; C 3-6 Cycloalkenyl, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl; the 3-10 membered heterocyclic group is a 3-6 membered heterocyclic group, the 3-6 membered heterocyclic group is an oxirane group, an aziridine group, an azetidinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a dioxolyl group, a pyrrolidinyl group, a pyrrolidonyl group, an oxazolidinyl group, a thiazolidinyl group, a pyrazolidinyl group, an imidazolidinyl group, a pyrrolinyl group, a tetrahydropyranyl group or a piperidinyl group, preferably an oxirane group, an aziridine group, an azetidinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a dioxolyl group, a pyrrolidinyl group, a pyrrolidonyl group, an oxazolidinyl group, a thiazolidinyl group, a pyrazolidinyl group, an imidazolidinyl group, a pyrrolinyl group, a tetrahydropyranyl group or a piperidinyl group The 5-10 membered heteroaryl is independently pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolyl, indolyl, pyrrolopyridazinyl or benzofuranyl, preferably oxazolyl, furanyl or thiazolyl; the adjacent R 2 Form a 5-6 membered heterocyclic group; wherein the heteroatom in the 5-6 membered heterocyclic group is selected from N or O, the number of heteroatoms is 1 or 2, preferably azepine, azepine, azetidine, oxacyclopentane, oxhexane or oxetane, more preferably oxacyclopentane or oxhexane; the R 2-1 , R 2-2 Each independently is H or C 1-3 Alkyl, preferably H or methyl; (6) In ring A, the C 6-10 The aryl group is phenyl or naphthyl, preferably phenyl; the 5-6 membered heteroaryl group is a 5-6 membered nitrogen-containing heteroaryl group, such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, pyrrolyl, furanyl, thienyl or imidazolyl, preferably pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; the 5-12 membered heterocyclyl group is tetrahydrofuranyl, tetrahydrothienyl, dioxolyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrrolinyl, pyranyl, tetrahydropyranyl, 4. The compound of formula (0) according to any one of claims 1 to 3, characterized in that The compound of formula (0) satisfies one or more of the following conditions: (1) R 1 for (2) The ring B is The bond marked with "a" is connected to R 1 , the bond marked with "b" is connected to L 1 ;excellent Select, ring B is More preferably, ring B is (3) L 1 For *-CH2-O-, -CH2-CH2-, *-CH2-CH2-O-, *-O-CH2-, *-CH2-S-, *-CH2-CH2-S-, -CH=CH-, -CH2-, bond, -NH -, -O-, *-CH=CF-, *-CF=CH-, *-CH=C(CH3)-, *-C(CH3)=CH-, -CF=CF-, -C(CH3)=C(CH3)-, *-CH2-CHF- 、*-CHF-CH2-、*-CH2-CH(CH3)-、*-C(CH3)-CH2-、-CHF-CHF-、-CH(CH3)-CH(CH3)-、*-CH2-CF2-、*-CF2-CH2-、*-CH2-CH(cyclopropane)-、*-CH(cyclopropane)-CH2-、*-CH=C(cyclopropane)-、*-C(cyclopropane)=CH-、*-CH2-CH(OH)-、-C≡C-、 Or *-CH2-C(O)-; Preferably, the L 1 is *-CH2-O-, -CH2-CH2-, *-CH2-CHF-, *-CH=CF-, *-CH2-CH(OH)-, *-CH2-S-, *-CH2-CH2-S-, -CH=CH-, a bond, -C≡C-, *-CH2-C(O)-; more preferably, the L 1 is *-CH2-O-, -CH2-CH2-, -CH=CH-; more preferably, L 1 -CH2-CH2-, -CH=CH-; wherein the bond marked with "*" is connected to ring B; (4) The ring A is: Preferably, the ring A is The bond marked with "c" is connected to L 1 , the key marked with "d" is connected to (5) R 2 Independently OH, F, Cl, Br, CN, -CH2F, -CHF2, -CF3, -CD3, -S-CH3, -O-CH-(CH3)2, -O-CH(CH3)-CH2CH3, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, isopropenyl, methoxy, ethoxy, cyclopropyl, cyclopropylmethyl-, in The wavy lines Indicates the position of fusion with ring A.

5. The compound of formula (0) according to claim 4, characterized in that The compound of formula (0) satisfies one or more of the following conditions: Parts are: Preferably, the Parts are: Preferably, the Parts are: Preferably, the Parts are: Preferably, the Parts are:

6. The compound of formula (0) according to any one of claims 1 to 5, characterized in that The compound has a structure shown in formula (I):

7. The compound of formula (0) according to any one of claims 1 to 5, characterized in that The compound has a structure shown by formula (I-20'), formula (I-21') or formula (I-22'):

8. The compound of formula (I-20'), formula (I-21') or formula (I-22') according to claim 7, characterized in that: The compound has a structure shown in formula (I-20), formula (I-21) or formula (I-22):

9. The compound of formula (I-20') according to claim 7, characterized in that The compound has a structure shown by formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ) or (IR): Where m1 is 0, 1 or 2.

10. The compound of formula (0) according to any one of claims 1 to 5, characterized in that The compound has a structure shown by formula (II-A), (II-B), (II-C) or (II-D):

11. The compound according to claim 10, characterized in that The compound has a structure shown in formula (II-A-1), (II-B-1), (II-C-1) or (II-D-1):

12. The compound according to claim 10, characterized in that The compound has a structure shown by formula (II-A-2), (II-B-2), (II-C-2), (II-D-2), (II-A-3), (II-B-3), (II-C-3) or (II-D-3): Where m1 is 0, 1 or 2.

13. The compound of claim 12, having the structure shown in (II'-A-2), (II'-B-2), (II'-C-2), (II'-D-2), (II'-A-3), (II'-B-3), (II'-C-3) or (II'-D-3): in, m1 is 0, 1 or 2, preferably m1 is 2; m is 0, 1, 2 or 3, preferably m is 1 or 2; L 1-2 For halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, preferably L 1-2 is F, methyl, cyclopropyl; more preferably L 1-2 For F.

14. The compound according to any one of claims 1 to 9, characterized in that The compound has a structure shown in formula (IH-1): Among them, each R 1 and R 1’ are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, R 1-1 , -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-NR 1-7 R 1-8 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-S(O)2-NR 1-5 R 1-6 、-NR 1-5 S(O)2-R 1-10 , -R 1-10 -OH, -P(=O)-R 1-2 R 1-3 ; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 and R 1-8 Each independently is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene -CN, C 3-10 Cycloalkyl, or 3-10 membered heterocyclic group; wherein the heteroatom in the 3-10 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; preferably, R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 and R 1-8 Each independently is H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, -C 1-4 Alkylene -OH, -C 1- 4-alkylene-CN, C 3-6 Cycloalkyl, or 3-6 membered heterocyclic group; R 1-9 and R 1-10 Each independently is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene -CN, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkyl-C 6-10 Arylene-; preferably, R 1-9 and R 1-10 Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene -CN, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-C 6-10 Arylene-; Preferably, R 1 -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-S(O)2-NR 1-5 R 1-6 、-NR 1-5 S(O)2-R 1-10 、-P(=O)-R 1-2 R 1-3 , R 1’ For deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, R 1-1 、-NR 1-7 R 1-8 , -R 1-10 -OH; Preferably, R 1 -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-S(O)2-R 1-9 , R 1’ For deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, R 1-1 、-NR 1-7 R 1-8 , -R 1-10 -OH; Preferably, R 1 -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-S(O)2-R 1-9 , R 1’ For hydrogen, deuterium, halogen, Cyano, hydroxyl, C 1-6 Alkoxy, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene -CN, C 3-10 Cycloalkyl, or 3-10 membered heterocyclic group; Preferably, R 1 -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Haloalkyl, -C(=O)-C 3-10 Cycloalkyl, -C(=O)-C 1-6 Alkylene -CN, -C(=O)-OC 1-6 Alkyl, -C(=O)-OC 3-10 Cycloalkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 6-10 Arylene-C 1-6 Alkyl, -S(O)2-C 3-10 Cycloalkyl, -S(O)2-5-10 membered heteroaryl, -S(O)2-C 1-6 Halogenated alkyl, -S(O)2-C 2-6 Alkenyl, -C(=O)-NH(C 1-6 Alkyl), R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene -CN, C 3-10 Cycloalkyl, or 3-10 membered heterocyclic group; Preferably, R 1 -C(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Haloalkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)-C 1-4 Alkylene -CN, -C(=O)-OC 1-4 Alkyl, -C(=O)-OC 3-6 Cycloalkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-phenylene-C 1-4 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-5-6 membered heteroaryl, -S(O)2-C 1-4 Halogenated alkyl, -S(O)2-C 2-4 Alkenyl, -C(=O)-NH(C 1-4 Alkyl), R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-4 Alkoxy, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene -CN, C 3-6 Cycloalkyl, or 3-6 membered heterocyclic group; Preferably, R 1 -S(O)2-C 1-4 Alkyl, -S(O)2-C 2-4 Alkenyl, -S(O)2-phenylene-C 1-4 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -S(O)2-5-6 membered heteroaryl, -C(=O)-OC 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Alkylene-CN; R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl; n1 is each independently 0, 1, 2, or 3; preferably, n1 is each independently 0, 1 or 2; more preferably, n1 is 0; Ring B is a 5-12 membered heterocyclic group; wherein the heteroatoms in the 5-12 membered heterocyclic group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; preferably, ring B is a 5-6 membered monocyclic heterocyclic group, a 9-12 membered fused bicyclic heterocyclic group or a 9-12 membered spirocyclic heterocyclic group; preferably, ring B is Preferably, for L 1 is a direct bond, O, -NH-, unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-6 Alkenylene, unsubstituted or substituted with one or more L 1-3 Substituted C 2-6 Alkyne, unsubstituted or substituted with one or more L 1-4 Substituted *-C 1-6 Alkylene-S-, unsubstituted or substituted with one or more L 1-6 Substituted *-C 1-6 Alkylene-O-, unsubstituted or substituted with one or more L 1-7 Replaced by *-OC 1- 6 alkylene-, unsubstituted or substituted with one or more L 1-8 Substituted *-C 6-10 Arylene-O-, unsubstituted or substituted with one or more L 1-10 Substituted *-C 1-6 Alkylene-C(O)-; Preferably, L 1 is a direct bond, O, -NH-, unsubstituted or replaced by one or more L 1-1 Substituted C 1-4 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-4 Alkenylene, unsubstituted or substituted with one or more L 1- 3 Substituted C 2-4 Alkyne, unsubstituted or substituted with one or more L 1-4 Substituted *-C 1-4 Alkylene-S-, unsubstituted or substituted with one or more L 1-6 Substituted *-C 1-4 Alkylene-O-, unsubstituted or substituted with one or more L 1-7 Replaced by *-OC 1-4 Alkylene-, unsubstituted or substituted with one or more L 1-8 Substituted *-phenylene-O-, unsubstituted or replaced by one or more L 1-10 Substituted *-C 1-2 Alkylene-C(O)-; Each L 1-1 , L 1-2 , L 1-3 , L 1-4 , L 1-6 , L 1-7 , L 1-8 , L 1-10 are independently halogen, OH, C 1- 6 alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the heteroatom in the 3-6 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by deuterium, halogen, OH, CN or -NH2; Preferably, L 1 -CH2-CH2-, *-CH2-O-, -CH=CH-; More preferably, L 1 -CH2-CH2-, -CH=CH-; R 2 are independently deuterium, OH, NH2, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 2-6 Alkenyl, -OC 3-10 Cycloalkyl, -SC 1-6 Alkyl, -SC 3-10 Cycloalkyl, C 3- 10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C(O)NH(C 1-6 alkyl); optionally, two adjacent R 2 Forming a 5-6 membered heterocyclic group; wherein the heteroatom in the 5-6 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; Preferably, R 2 are independently deuterium, OH, NH2, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -OC 2-4 Alkenyl, -OC 3-6 Cycloalkyl, -SC 1-4 Alkyl, -SC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C(O)NH(C 1-4 alkyl); m is 0, 1, 2, 3 or 4; preferably, m is 0, 1, 2 or 3; R 4 and R 5 are each independently H, deuterium, halogen, C 1-6 Alkyl; preferably, R 4 and R 5 All are H or deuterium, or R 4 and R 5 One of them is H and the other is deuterium, halogen, C 1-4 alkyl.

15. The compound according to claim 14, characterized in that The compounds have structures shown in formula (IH-1A), (IH-1B), (IH-1C), and (IH-1D):

16. The compound according to any one of claims 1 to 9, characterized in that The compound has a structure shown by formula (I-6), formula (I-7), formula (I-8), formula (I-23), formula (I-6') or formula (I-7'): The L 1 is a direct bond, O, S, -NH-, unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-6 Alkenylene, *-C 1-6 Alkylene-S-, *-SC 1- 6-alkylene-, *-C 1-6 Alkylene-O-, *-OC 1-6 Alkylene-, preferably *-CH2-S-, *-CH2CH2-S-, *-CH2-O-, ethylene or vinylene, more preferably *-CH2-O-, ethylene or vinylene, further preferably ethylene or vinylene.

17. The compound according to any one of claims 1 to 9, characterized in that The compound has a structure represented by formula (I-10), formula (I-11), formula (I-12), formula (I-13), formula (I-12'), formula (I-13'), formula (I-121), formula (I-131), formula (I-120) or formula (I-130): Ring B is preferably a 5-10 membered heterocyclic group, more preferably a 5-10 membered nitrogen-containing heterocyclic group, and further preferably 18. The compound according to any one of claims 1 to 9, characterized in that The compound has a structure shown by formula (I-16), formula (I-17), formula (I-18), formula (I-170), formula (I-171) or formula (I-172):

19. The compound according to any one of claims 1 to 9, characterized in that The compound has a structure shown in formula (IB-1): Among them, each R 1 and R 1’ are independently deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, R 1-1 , -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-NR 1-7 R 1-8 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-S(O)2-NR 1-5 R 1-6 、-NR 1-5 S(O)2-R 1-10 , -R 1-10 -OH, -P(=O)-R 1-2 R 1-3 ; R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 and R 1-8 Each independently is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene -CN, C 3-10 Cycloalkyl, or 3-10 membered heterocyclic group; wherein the heteroatom in the 3-10 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; preferably, R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 and R 1-8 Each independently is H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, -C 1-4 Alkylene -OH, -C 1- 4-alkylene-CN, C 3-6 Cycloalkyl, or 3-6 membered heterocyclic group; R 1-9 and R 1-10 Each independently is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene -CN, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Alkyl-C 6-10 Arylene-; preferably, R 1-9 and R 1-10 Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene -CN, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-4 Alkyl-C 6-10 Arylene-; Preferably, R 1 -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 、-S(O)2-NR 1-5 R 1-6 、-NR 1-5 S(O)2-R 1-10 、-P(=O)-R 1-2 R 1-3 , R 1’ For deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, R 1-1 、-NR 1-7 R 1-8 , -R 1-10 -OH; Preferably, R 1 -C(=O)-R 1-1 、-C(=O)-OR 1-4 、-S(O)2-R 1-9 , R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-6 Alkoxy, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene -CN, C 3-10 Cycloalkyl, or 3-10 membered heterocyclic group; Preferably, R 1 -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-10 Cycloalkyl, -C(=O)-OC 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkylene-CN; R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy; Preferably, R 1 -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-6 Cycloalkyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Alkylene-CN; R 1’ For hydrogen, deuterium, halogen, cyano, hydroxyl, -NH2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy; n1 is each independently 0, 1, 2, or 3; preferably, n1 is each independently 0, 1 or 2; more preferably, n1 is 0; Ring B is a 5-12 membered heterocyclic group; wherein the heteroatoms in the 5-12 membered heterocyclic group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; preferably, ring B is a 5-6 membered monocyclic heterocyclic group, a 9-12 membered fused bicyclic heterocyclic group or a 9-12 membered spirocyclic heterocyclic group; preferably, ring B is Wherein, G1, G2, G3, G4 are CH or N, at least one of which is CH, s and k are each independently 0, 1 or 2; preferably, for L 1 is a direct bond, unsubstituted or replaced by one or more L 1-1 Substituted C 1-6 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-6 Alkenylene, unsubstituted or substituted with one or more L 1-3 Substituted C 2-6 Alkyne, unsubstituted or substituted with one or more L 1-4 Substituted *-C 1-6 Alkylene-S-, unsubstituted or substituted with one or more L 1-6 Substituted *-C 1-6 Alkylene-O-, unsubstituted or substituted with one or more L 1-7 Replaced by *-OC 1-6 Alkylene-, unsubstituted or substituted with one or more L 1-8 Substituted *-C 6-10 Arylene-O-, unsubstituted or substituted with one or more L 1-10 Substituted *-C 1-6 Alkylene-C(O)-; Preferably, L 1 is a direct bond, unsubstituted or replaced by one or more L 1-1 Substituted C 1-4 Alkylene, unsubstituted or substituted with one or more L 1-2 Substituted C 2-4 Alkenylene, unsubstituted or substituted with one or more L 1-3 Substituted C 2-4 Alkyne, unsubstituted or substituted with one or more L 1-6 Substituted *-C 1-4 Alkylene-O-, unsubstituted or substituted with one or more L 1-10 Substituted *-C 1-2 Alkylene-C(O)-; Each L 1-1 , L 1-2 , L 1-3 , L 1-4 , L 1-6 , L 1-7 , L 1-8 , L 1-10 are independently halogen, OH, C 1- 6 alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the heteroatom in the 3-6 membered heterocyclic group is selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; wherein C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by deuterium, halogen, OH, CN or -NH2; Preferably, L 1 is a direct bond, -CH2-CH2-, *-CH2-CHF-, *-CH2-CH(OH)-, *-CH2-O-, -CH=CH-, *-CH=CF-, -C≡C-, *-CH2-C(O)-; Preferably, L 1 is -CH2-CH2- or -CH=CH-; R 2 are independently deuterium, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, -C 1-6 Alkylene-C 3-10 Cycloalkyl; Preferably, R 2 are independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl; Preferably, R 2 are independently F, Cl, Br, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl; m1 is 0, 1 or 2, preferably, m1 is 1 or 2; more preferably, m1 is 2; R 4 and R 5 are each independently H, deuterium, halogen, C 1-6 Alkyl; preferably, R 4 and R 5 All are H or deuterium, or R 4 and R 5 One of them is H and the other is deuterium, halogen, C 1-4 alkyl.

20. The compound according to claim 19, characterized in that The compound has a structure shown by formula (IB-1A), (IB-1B) or (IB-1C):

21. The compound according to claim 20, characterized in that The compound has a structure represented by formula (IB-1A-1), (IB-1A-2), (IB-1B-1), (IB-1B-2), (IB-1C-1) or (IB-1C-2): Among them, R 2 Each independently is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl; R 2 ' is halogen, preferably, R 2 Each independently is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl; R 2 'For F.

22. The compound according to any one of claims 1 to 21, characterized in that The compound has a structure shown in formula (III-1), (III-2), (III-3), (III-4), (III-5) or (III-6): wherein m1 is 0, 1 or 2, preferably, m1 is 1 or 2, more preferably, m1 is 2; M1 and M2 are each independently selected from CH or N, preferably, at least one of M1 and M2 is selected from CH; L 1-1 Selected from halogen, OH, C 1-4 Alkyl, preferably F, OH; L 1-2 Selected from halogen, C 1-4 Alkyl, preferably F.

23. The compound according to any one of claims 1 to 22, with the proviso that: Part of When the bond marked with "c" is connected to L 1 , the bond marked with "d" is connected to -C(R 4 R 5 )-;L 1 It is not *-CH2-O-, wherein the bond marked with "*" is connected to ring B.

24. The compound according to any one of claims 1 to 23, selected from:

25. The compound of formula (I) according to claim 6, characterized in that The preparation method of the compound is shown in any of the following methods: Method 1 Among them, ring A is preferably C 6-10 Aryl; R1 is preferably R 1-1 , -C(=O)-R 1-1 、-(CR 1-2 R 1-3 ) q -C(=O)-OR 1-4 、-C(=O)-NR 1-7 R 1-8 、-S(O)2-NR 1-5 R 1-6 、-C(=NH)-(R 1-9 )、-S(O)2-R 1-9 , -R 1-10 -OH, -P(=O)-R 1-2 R 1-3 ; Best Method 2 Ring C is preferably X or Y is independently CH or N; Method 3 Best 26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; Preferably, the pharmaceutical composition comprises the compound according to any one of claims 1 to 25 and at least one additional active ingredient selected from the following: - Glucocorticoids; - Mineralocorticoids; - Nonsteroidal androgen receptor antagonists; - Steroidogenesis inhibitors; - Chemotherapeutic agents; -Antiestrogen; - epigenetic regulators; - mTOR inhibitors (eg, everolimus); -AKT inhibitors (e.g. AZ5363); - Radiopharmaceuticals (e.g. Alpharadin); -GnRH / LHRH analogs (eg, leuprolide); - PI3K inhibitors; and -CDK4 / 6 inhibitors.

27. A method for treating steroid receptor-dependent disorders and diseases according to any one of claims 1 to 25 or the pharmaceutical composition according to claim 26, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 25 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts or the pharmaceutical composition according to claim 26; wherein the steroid receptor-dependent disease is preferably cancer; the cancer is preferably prostate cancer; the prostate cancer is preferably castration-resistant prostate cancer (CRPC); in, Administration of a therapeutically effective amount of a compound according to any one of claims 1 to 25 or a pharmaceutical composition according to claim 26, preferably also glucocorticoids and / or mineralocorticoids, and optionally one or more anticancer drugs; Wherein, a therapeutically effective amount of the compound according to any one of claims 1 to 25 or the pharmaceutical composition according to claim 26 and one or more anticancer drugs are administered, wherein the anticancer drug is preferably selected from: - Nonsteroidal androgen receptor antagonists; - Steroidogenesis inhibitors; - Chemotherapeutic agents; -Antiestrogen; - epigenetic regulators; - mTOR inhibitors (eg, everolimus); -AKT inhibitors (e.g. AZ5363); - Radiopharmaceuticals (e.g. alpharadin); -GnRH / LHRH analogs (e.g. leuprolide); - PI3K inhibitors; and -CDK4 / 6 inhibitors.

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