Pyridazine ring compound, and pharmaceutical composition and use thereof

Abstract

Disclosed in the present invention are a pyridazine ring compound, and a pharmaceutical composition and the use thereof. Specifically, disclosed in the present invention are a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof. The pyridazine ring compound of the present invention has a good inhibitory activity against NLRP3.

Description

Pyridazine cyclic compounds, their pharmaceutical compositions and their applications

[0001] This application claims priority to the following Chinese patent applications:

[0002] Chinese patent application 2024106908606, filed on May 30, 2024;

[0003] Chinese patent application 2024108942974, filed on July 4, 2024;

[0004] Chinese patent application 2024109662519, filed on July 18, 2024;

[0005] Chinese patent application 2024111289146, filed on August 16, 2024;

[0006] Chinese patent application 2024113742126, filed on September 29, 2024;

[0007] Chinese patent application 2024114214090, filed on October 12, 2024;

[0008] Chinese patent application 2025101090380, filed on January 23, 2025;

[0009] Chinese patent application 2025101403366, filed on February 8, 2025.

[0010] This application incorporates the full text of the aforementioned Chinese patent application. Technical Field

[0011] This invention relates to pyridazine cyclic compounds, pharmaceutical compositions thereof, and their applications. Background Technology

[0012] The NLRP3 inflammasome is a multi-protein complex comprising the sensor NLRP3, the adapter ASC, and the effector caspase 1. Cytokines, pathogen-associated molecular patterns (PAMPs), or damage-associated molecular patterns (DAMPs) can activate the NLRP3 inflammasome, further activating caspase 1 and promoting the cleavage of pro-IL-1β and pro-IL-18, as well as the release of the cytokines IL-1β and IL-18. The NLRP3 inflammasome plays a crucial role in neurodegenerative diseases.

[0013] Currently, there are no NLRP3 inhibitors on the market. NLRP3 inhibitors such as OLT-1177, DFV-890, and Selnoflast are in different stages of clinical research. Developing NLRP3 inhibitors has broad application prospects. Summary of the Invention

[0014] The technical problem to be solved by this invention is to overcome the deficiency of insufficient types of NLRP3 inhibitors in the prior art, and to provide a novel pyridazine cyclic compound, its pharmaceutical composition, and its application. The compound of this invention exhibits good inhibitory activity against NLRP3.

[0015] The present invention solves the above-mentioned technical problems through the following solutions.

[0016] This invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0017] in,

[0018] n is 1, 2, 3 or 4;

[0019] R 1 Independently, it can be hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 heteroaryl, -S(=O)2C1-C6 alkyl, by one or more R a Substituted C1-C6 alkyl groups, with one or more R b Substituted C1-C6 alkoxy groups or those with one or more R groups c Substituted 5-6 heteroaryl, wherein the 5-6 heteroaryl and "is replaced by one or more R c In the 5-6 heteroaryl group of the substituted 5-6 heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0020] R a Independently, it can be deuterium, halogen, or hydroxyl;

[0021] R b Halogens are independent of each other;

[0022] R c It is independently a halogen or a C1-C6 alkyl group;

[0023] Or, two adjacent R 1 The atoms bonded to them together form C3-C7 cycloalkenyl groups, 3-7 membered heterocyclic alkenyl groups, and are bonded by one or more R groups. d The substituted C3-C7 cycloalkenyl group or the group with one or more R eSubstituted 3-7-membered heterocyclic alkenyl groups, wherein the 3-7-membered heterocyclic alkenyl group and "substituted by one or more R groups" e In the substituted 3-7 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0024] R d and R e Each of the following groups is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 heteroaryl, or surrounded by one or more R groups. a Substituted C1-C6 alkyl groups, with one or more R b Substituted C1-C6 alkoxy groups or those with one or more R groups c Substituted 5-6 heteroaryl, wherein the 5-6 heteroaryl and "is replaced by one or more R c In the 5-6 heteroaryl group of the substituted 5-6 heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0025] R f It is a C1-C6 alkyl group;

[0026] R 4 It is hydrogen, deuterium, or C1-C6 alkyl;

[0027] R 3 for

[0028] Ring A is arbitrarily controlled by one or more R 3-2 The substituted 3-12 member nitrogen-containing saturated heterocycle, wherein the heteroatom or heterogroup, in addition to containing N, may be selected from one or more of O, S, C(=O), S(=O) and S(=O)2, and the number of heteroatoms is one or more.

[0029] R 3-2 Independently, it is cyano, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, C6-C 10 Aryl, 5-10 heteroaryl, -C(=O)C1-C6 alkyl, -C1-C6 alkyl-C6-C 10 Aryl, -C1-C6 alkyl-5-10 heteroaryl, -C1-C6 alkyl-C3-C6 cycloalkyl, -C1-C6 alkyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C3-C6 cycloalkyl, -C2-C6 alkenyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C6-C 10aryl, -C2-C6 alkenyl-5-10 heteroaryl, -C2-C6 ynynyl-C3-C6 cycloalkyl, -C2-C6 ynynyl-3-6 heterocycloalkyl, -C2-C6 ynynyl-C6-C 10 Aryl, -C2-C6 ynyl-5-10 heteroaryl, -(CH2) p -O-C1-C6 alkyl, -(CH2) p -O-C2-C6 alkenyl, -(CH2) p -O-C2-C6 ynyl group, -(CH2) p -O-C3-C6 cycloalkyl, -(CH2) p -O-3-6-membered heterocyclic alkyl group, -(CH2) p -O-C6-C 10 Aryl, -(CH2) p -O-5-10-membered heteroaryl, -C1-C6 alkoxy-C3-C6 cycloalkyl, -C1-C6 alkoxy-3-6-membered heterocycloalkyl, -C1-C6 alkoxy-C6-C 10 Aryl, -C1-C6 alkoxy-5-10 heteroaryl, -(CH2) p -S(=O)2R 32-1 -(CH2) p -S(=O)2N(R 32-2 )2 or -(CH2) p N(R 32-2 )2, wherein the 5-10 heteroaryl group, the 5-10 heteroaryl group in "-C1-C6 alkyl-5-10 heteroaryl group", and the "-C2-C6 alkenyl-C6-C 10 The 5-10 membered heteroaryl in "aryl", the 5-10 membered heteroaryl in "-C2-C6 ynyl-5-10 membered heteroaryl", and "-(CH2)" p In "-O-5-10 heteroaryl", the 5-10 heteroaryl group and the 5-10 heteroaryl group in "-C1-C6 alkoxy-5-10 heteroaryl" are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; the 3-6 heterocyclic alkyl group, the 3-6 heterocyclic alkyl group in "-C1-C6 alkyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "-C2-C6 alkenyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "C2-C6 ynyl-3-6 heterocyclic alkyl", and the 3-6 heterocyclic alkyl group in "-(CH2)" are all selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3. p In the 3-6-membered heterocyclic alkyl group in "-O-3-6-membered heterocyclic alkyl group" and the 3-6-membered heterocyclic alkyl group in "-C1-C6alkoxy-3-6-membered heterocyclic alkyl group", the type of heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0030] The R mentioned 3-2 Optional substitution by one or more groups selected from the following: halogen, -CF3, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0031] p can be 0, 1, 2, 3, 4, 5, or 6 independently;

[0032] R 32-1 It is a C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more of the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy;

[0033] R 32-2 Independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more groups selected from the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy;

[0034] R 2 Hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -C1-C6 alkyl, -O-C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic alkyl, NR m R n , by one or more R 2-1 Substituted C3-C7 cycloalkyl groups, with one or more R 2-2 Substituted 3-7 membered heterocyclic alkyl groups, with one or more R 2-3 Substituted C1-C6 alkyl groups, wherein the 3-7 membered heterocyclic alkyl group and "substituted with one or more R 2-2 In the substituted 3-7 membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0035] R m and R n Each is independently hydrogen or C1-C6 alkyl;

[0036] R 2-1 R 2-2 and R 2-3 Each of the following can be independently classified as C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, or -OR. s1 -NR s2 R s3 -S(=O)2R s4 or -C(=O)NR s5 Rs6 ;

[0037] R s1 R s2 R s3 R s4 R s5 and R s6 Each is independently hydrogen or C1-C6 alkyl;

[0038] Or, R 2 and R 4 The carbon atoms bonded to them together form ring B, wherein ring B is a C5-C6 cycloalkenyl, a 5-6 membered heterocyclic alkenyl, a 5 membered heteroaryl, or is bonded by one or more R 2a1 Substituted C5-C6 cycloalkenyl groups, with one or more R 2a2 Substituted 5-6 membered heterocyclic alkenyl groups or those with one or more R groups 2a3 Substituted 5-membered heteroaryl, said 5-6-membered heterocyclic alkenyl and "substituted by one or more R 2a2 In the substituted 5-6 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3. The 5-membered heteroaryl group and the "substituted 5-6 membered heterocyclic alkenyl group" are further specified. 2a3 In the 5-membered heteroaryl group of the substituted 5-membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0039] R 2a1 R 2a2 and R 2a3 Each is independently a hydroxyl group, a C1-C6 alkyl group, or a halogen;

[0040] Or, R 2 and R 3 The carbon atoms connected to them together form That is to say for Wherein, ring C is a 5-6 membered heterocyclic alkenyl group, Z is CH, and in the 5-6 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1.

[0041] In certain preferred embodiments of the present invention, certain groups in the compound represented by formula (I), its pharmaceutically acceptable salt, its solvate or a solvate of a pharmaceutically acceptable salt thereof are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention").

[0042] In one embodiment of the present invention, n is 1, 2, 3 or 4;

[0043] R 1Independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 heteroaryl, -S(=O)2C1-C6 alkyl, or with one or more R a Substituted C1-C6 alkyl groups, with one or more R b Substituted C1-C6 alkoxy groups or those with one or more R groups c Substituted 5-6 heteroaryl, wherein the 5-6 heteroaryl and "is replaced by one or more R c In the 5-6 heteroaryl group of the substituted 5-6 heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0044] R a Independently, it can be deuterium, halogen, or hydroxyl;

[0045] R b Halogens are independent of each other;

[0046] R c It is independently a halogen or a C1-C6 alkyl group;

[0047] Or, two adjacent R 1 The atoms bonded to them together form C3-C7 cycloalkenyl groups, 3-7 membered heterocyclic alkenyl groups, and are bonded by one or more R groups. d The substituted C3-C7 cycloalkenyl group or the group with one or more R e Substituted 3-7-membered heterocyclic alkenyl groups, wherein the 3-7-membered heterocyclic alkenyl group and "substituted by one or more R groups" e In the substituted 3-7 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0048] R d and R e Each of the following groups is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 heteroaryl, or surrounded by one or more R groups. a Substituted C1-C6 alkyl groups, with one or more R b Substituted C1-C6 alkoxy groups or those with one or more R groups c Substituted 5-6 heteroaryl, wherein the 5-6 heteroaryl and "is replaced by one or more R c In the 5-6 heteroaryl group of the substituted 5-6 heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0049] R 4 It is hydrogen, deuterium, or C1-C6 alkyl;

[0050] R 3 for

[0051] Ring A is arbitrarily controlled by one or more R 3-2 The substituted 3-12 member nitrogen-containing saturated heterocycle, wherein the heteroatom or heterogroup, in addition to containing N, may be selected from one or more of O, S, C(=O), S(=O) and S(=O)2, and the number of heteroatoms is one or more.

[0052] R 3-2 Independently, it is cyano, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, C6-C 10 Aryl, 5-10 heteroaryl, -C(=O)C1-C6 alkyl, -C1-C6 alkyl-C6-C 10 Aryl, -C1-C6 alkyl-5-10 heteroaryl, -C1-C6 alkyl-C3-C6 cycloalkyl, -C1-C6 alkyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C3-C6 cycloalkyl, -C2-C6 alkenyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C6-C 10 aryl, -C2-C6 alkenyl-5-10 heteroaryl, -C2-C6 ynynyl-C3-C6 cycloalkyl, -C2-C6 ynynyl-3-6 heterocycloalkyl, -C2-C6 ynynyl-C6-C 10 Aryl, -C2-C6 ynyl-5-10 heteroaryl, -(CH2) p -O-C1-C6 alkyl, -(CH2) p -O-C2-C6 alkenyl, -(CH2) p -O-C2-C6 ynyl group, -(CH2) p -O-C3-C6 cycloalkyl, -(CH2) p -O-3-6-membered heterocyclic alkyl group, -(CH2) p -O-C6-C 10 Aryl, -(CH2) p -O-5-10-membered heteroaryl, -C1-C6 alkoxy-C3-C6 cycloalkyl, -C1-C6 alkoxy-3-6-membered heterocycloalkyl, -C1-C6 alkoxy-C6-C 10 Aryl, -C1-C6 alkoxy-5-10 heteroaryl, -(CH2) p -S(=O)2R 32-1 -(CH2) p -S(=O)2N(R 32-2 )2 or -(CH2) p N(R32-2 )2, wherein the 5-10 heteroaryl group, the 5-10 heteroaryl group in "-C1-C6 alkyl-5-10 heteroaryl group", and the "-C2-C6 alkenyl-C6-C 10 The 5-10 membered heteroaryl in "aryl", the 5-10 membered heteroaryl in "-C2-C6 ynyl-5-10 membered heteroaryl", and "-(CH2)" p In "-O-5-10 heteroaryl", the 5-10 heteroaryl group and the 5-10 heteroaryl group in "-C1-C6 alkoxy-5-10 heteroaryl" are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; the 3-6 heterocyclic alkyl group, the 3-6 heterocyclic alkyl group in "-C1-C6 alkyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "-C2-C6 alkenyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "C2-C6 ynyl-3-6 heterocyclic alkyl", and the 3-6 heterocyclic alkyl group in "-(CH2)" are all selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3. p In the 3-6-membered heterocyclic alkyl group in "-O-3-6-membered heterocyclic alkyl group" and the 3-6-membered heterocyclic alkyl group in "-C1-C6alkoxy-3-6-membered heterocyclic alkyl group", the type of heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0053] The R mentioned 3-2 Optional substitution by one or more groups selected from the following: halogen, -CF3, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0054] p can be 0, 1, 2, 3, 4, 5, or 6 independently;

[0055] R 32-1 It is a C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more of the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy;

[0056] R 32-2 Independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more groups selected from the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy;

[0057] R 2 Hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -C1-C6 alkyl, -O-C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic alkyl, NR m R n , by one or more R2-1 Substituted C3-C7 cycloalkyl groups, with one or more R 2-2 Substituted 3-7 membered heterocyclic alkyl groups or substituted with one or more R 2-3 Substituted C1-C6 alkyl groups, wherein the 3-7 membered heterocyclic alkyl group and "substituted with one or more R 2-2 In the substituted 3-7 membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0058] R m and R n Each is independently hydrogen or C1-C6 alkyl;

[0059] R 2-1 R 2-2 and R 2-3 Each can be independently C1-C6 alkyl, C2-C6 alkynyl, halogen, or -OR s1 -NR s2 R s3 -S(=O)2R s4 or -C(=O)NR s5 R s6 ;

[0060] R s1 R s2 R s3 R s4 R s5 and R s6 Each is independently hydrogen or C1-C6 alkyl;

[0061] Or, R 2 and R 4 The carbon atoms bonded to them together form ring B, wherein ring B is a C5-C6 cycloalkenyl, a 5-6 membered heterocyclic alkenyl, a 5 membered heteroaryl, or is bonded by one or more R 2a1 Substituted C5-C6 cycloalkenyl groups, with one or more R 2a2 Substituted 5-6 membered heterocyclic alkenyl groups or those with one or more R groups 2a3 Substituted 5-membered heteroaryl, said 5-6-membered heterocyclic alkenyl and "substituted by one or more R 2a2 In the substituted 5-6 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3. The 5-membered heteroaryl group and the "substituted 5-6 membered heterocyclic alkenyl group" are further specified. 2a3 In the 5-membered heteroaryl group of the substituted 5-membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0062] R 2a1 R2a2 and R 2a3 Each is independently a hydroxyl group, a C1-C6 alkyl group, or a halogen;

[0063] Or, R 2 and R 3 The carbon atoms connected to them together form That is to say for Wherein, ring C is a 5-6 membered heterocyclic alkenyl group, Z is CH, and in the 5-6 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1.

[0064] In one embodiment of the present invention, n is 1, 2, 3 or 4;

[0065] R 1 Independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 heteroaryl, or surrounded by one or more R groups. a Substituted C1-C6 alkyl groups, with one or more R b Substituted C1-C6 alkoxy groups or those with one or more R groups c Substituted 5-6 heteroaryl, wherein the 5-6 heteroaryl and "is replaced by one or more R c In the 5-6 heteroaryl group of the substituted 5-6 heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0066] R a Independently, it can be deuterium, halogen, or hydroxyl;

[0067] R b Halogens are independent of each other;

[0068] R c It is independently a halogen or a C1-C6 alkyl group;

[0069] Or, two adjacent R 1 The atoms bonded to them together form C3-C7 cycloalkenyl groups, 3-7 membered heterocyclic alkenyl groups, and are bonded by one or more R groups. d The substituted C3-C7 cycloalkenyl group or the group with one or more R e Substituted 3-7-membered heterocyclic alkenyl groups, wherein the 3-7-membered heterocyclic alkenyl group and "substituted by one or more R groups" e In the substituted 3-7 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0070] R d and R eEach of the following groups is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 heteroaryl, or surrounded by one or more R groups. a Substituted C1-C6 alkyl groups, with one or more R b Substituted C1-C6 alkoxy groups or those with one or more R groups c Substituted 5-6 heteroaryl, wherein the 5-6 heteroaryl and "is replaced by one or more R c In the 5-6 heteroaryl group of the substituted 5-6 heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0071] R 4 It is hydrogen, deuterium, or C1-C6 alkyl;

[0072] R 3 for

[0073] Ring A is arbitrarily controlled by one or more R 3-2 The substituted 3-12 member nitrogen-containing saturated heterocycle, wherein the heteroatom or heterogroup, in addition to containing N, may be selected from one or more of O, S, C(=O), S(=O) and S(=O)2, and the number of heteroatoms is one or more.

[0074] R 3-2 Independently, it is cyano, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, C6-C 10 Aryl, 5-10 heteroaryl, -C(=O)C1-C6 alkyl, -C1-C6 alkyl-C6-C 10 Aryl, -C1-C6 alkyl-5-10 heteroaryl, -C1-C6 alkyl-C3-C6 cycloalkyl, -C1-C6 alkyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C3-C6 cycloalkyl, -C2-C6 alkenyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C6-C 10 aryl, -C2-C6 alkenyl-5-10 heteroaryl, -C2-C6 ynynyl-C3-C6 cycloalkyl, -C2-C6 ynynyl-3-6 heterocycloalkyl, -C2-C6 ynynyl-C6-C 10 Aryl, -C2-C6 ynyl-5-10 heteroaryl, -(CH2) p -O-C1-C6 alkyl, -(CH2) p -O-C2-C6 alkenyl, -(CH2) p -O-C2-C6 ynyl group, -(CH2) p-O-C3-C6 cycloalkyl, -(CH2) p -O-3-6-membered heterocyclic alkyl group, -(CH2) p -O-C6-C 10 Aryl, -(CH2) p -O-5-10-membered heteroaryl, -C1-C6 alkoxy-C3-C6 cycloalkyl, -C1-C6 alkoxy-3-6-membered heterocycloalkyl, -C1-C6 alkoxy-C6-C 10 Aryl, -C1-C6 alkoxy-5-10 heteroaryl, -(CH2) p -S(=O)2R 32-1 -(CH2) p -S(=O)2N(R 32-2 )2 or -(CH2) p N(R 32-2 )2, wherein the 5-10 heteroaryl group, the 5-10 heteroaryl group in "-C1-C6 alkyl-5-10 heteroaryl group", and the "-C2-C6 alkenyl-C6-C 10 The 5-10 membered heteroaryl in "aryl", the 5-10 membered heteroaryl in "-C2-C6 ynyl-5-10 membered heteroaryl", and "-(CH2)" p In "-O-5-10 heteroaryl", the 5-10 heteroaryl group and the 5-10 heteroaryl group in "-C1-C6 alkoxy-5-10 heteroaryl" are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; the 3-6 heterocyclic alkyl group, the 3-6 heterocyclic alkyl group in "-C1-C6 alkyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "-C2-C6 alkenyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "C2-C6 ynyl-3-6 heterocyclic alkyl", and the 3-6 heterocyclic alkyl group in "-(CH2)" are all selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3. p In the 3-6-membered heterocyclic alkyl group in "-O-3-6-membered heterocyclic alkyl group" and the 3-6-membered heterocyclic alkyl group in "-C1-C6alkoxy-3-6-membered heterocyclic alkyl group", the type of heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0075] The R mentioned 3-2 Optional substitution by one or more groups selected from the following: halogen, -CF3, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy.

[0076] p can be 0, 1, 2, 3, 4, 5, or 6 independently;

[0077] R 32-1It is a C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more of the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy;

[0078] R 32-2 Independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more groups selected from the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy;

[0079] R 2 Hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -C1-C6 alkyl, -O-C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic alkyl, NR m R n , by one or more R 2-1 Substituted C3-C7 cycloalkyl groups, with one or more R 2-2 Substituted 3-7 membered heterocyclic alkyl groups or substituted with one or more R 2-3 Substituted C1-C6 alkyl groups, wherein the 3-7 membered heterocyclic alkyl group and "substituted with one or more R 2-2 In the substituted 3-7 membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0080] R m and R n Each is independently hydrogen or C1-C6 alkyl;

[0081] R 2-1 R 2-2 and R 2-3 Each is independently C1-C6 alkyl, halogen, -OR s1 -NR s2 R s3 -S(=O)2R s4 or -C(=O)NR s5 R s6 ;

[0082] R s1 R s2 R s3 R s4 R s5 and R s6 Each is independently hydrogen or C1-C6 alkyl.

[0083] In one aspect of the invention, each "halogen" is independently F, Cl, Br or I, for example F.

[0084] In one embodiment of the invention, each “C1-C6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.

[0085] In one embodiment of the present invention, each “C1-C6 alkoxy” is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy.

[0086] In one embodiment of the present invention, each “C3-C6 cycloalkyl” or “C3-C7 cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl.

[0087] In one embodiment of the invention, each “C3-C6 cycloalkyl” or “C3-C7 cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl.

[0088] In one embodiment of the invention, each "3-6-membered heterocyclic alkyl" or "3-7-membered heterocyclic alkyl" is independently a 4-6-membered heterocyclic alkyl with one or two heteroatoms selected from N and O, such as azacyclobutane or tetrahydrofuran, and further for example...

[0089] In one embodiment of the present invention, each "5-6 heteroaryl group" is independently pyrroleyl, furanyl, thiopheneyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, or pyrimidinyl.

[0090] In each embodiment of the present invention, each "5-membered heteroaryl group" is independently a 5-membered heteroaryl group with N and / or O heteroatoms, and the number of heteroatoms is 1, 2, or 3, such as pyrrole, oxazolyl, isoxazolyl, pyrazolyl, imidazole, or triazolyl, and further for example...

[0091] In one aspect of the invention, each "C3-C7 cycloalkenyl" is independently a C4-C6 cycloalkenyl, for example...

[0092] In one embodiment of the present invention, each "C5-C6 cycloalkenyl group" is independently...

[0093] In one embodiment of the invention, each "3-7 membered heterocyclic alkenyl group" is independently a 5-6 membered heterocyclic alkenyl group with one or two heteroatoms selected from N, O, and S, such as dihydrofuranyl, and further for example...

[0094] In one embodiment of the present invention, each "5-6 membered heterocyclic alkenyl group" is independently a 5-6 membered heterocyclic alkenyl group with one heteroatom (O), for example...

[0095] In one aspect of this invention, each "3-12 member nitrogen-containing saturated heterocycle" is independently... Further examples

[0096] In one aspect of this invention, each "3-12 member nitrogen-containing saturated heterocycle" is independently composed of heteroatoms selected from one or both of N and O, and the number of heteroatoms is one or two, forming a "5-6 member nitrogen-containing saturated heterocycle" or a "7-12 member fused ring, bridged ring, or spiro ring nitrogen-containing saturated heterocycle", for example... Further examples

[0097] In one embodiment of the invention, each “C2-C6 alkenyl” is independently a C2-C4 alkenyl, such as vinyl, allyl, or propenyl.

[0098] In one aspect of the present invention, each “C2-C6 ynyl group” is independently a C2-C4 ynyl group, such as ethynyl, propynyl, or propynyl.

[0099] In one embodiment of the present invention, each "C6-C" 10 Each aryl group can be either aryl or naphthyl.

[0100] In one embodiment of the present invention, each "5-10 member heteroaryl" is independently one or two of the heteroatoms N, O and S, and the number of heteroatoms is one or two 5-6 member monocyclic heteroaryl or 8-10 member bicyclic heteroaryl.

[0101] In one embodiment of the present invention, n is 1, 2 or 3.

[0102] In one embodiment of the present invention, n is 2 or 3.

[0103] In one embodiment of the present invention, n is 1 or 2.

[0104] In one aspect of the present invention, R 1 Independently cyano, C1-C6 alkyl, -S(=O)2C1-C6 alkyl, Or C1-C6 alkyl groups substituted with one or more halogens;

[0105] R f It is a C1-C6 alkyl group;

[0106] Or, two adjacent R 1 The atoms connected to them together form 5-6 membered heterocyclic alkenyl groups.

[0107] In one aspect of the present invention, R 1 Independently, it can be CN, -CF3, -CH3, -S(=O)2CH3 or Or, two adjacent R 1 The atoms connected to them together form

[0108] In one aspect of the present invention, for

[0109] In one aspect of the present invention, R 1 It is independently a cyano, C1-C6 alkyl, -S(=O)2C1-C6 alkyl or a C1-C6 alkyl substituted with one or more halogens;

[0110] Or, two adjacent R 1 The atoms connected to them together form 5-6 membered heterocyclic alkenyl groups.

[0111] In one aspect of the present invention, R 1 Independently CN, -CF3, -CH3, or -S(=O)2CH3, or two adjacent R 1 The atoms connected to them together form

[0112] In one aspect of the present invention, for

[0113] In one step of the present invention, R 1 It is independently a cyano, C1-C6 alkyl, or a C1-C6 alkyl substituted with one or more halogens;

[0114] Or, two adjacent R 1 The atoms connected to them together form 5-6 membered heterocyclic alkenyl groups.

[0115] In one aspect of the present invention, R 1 Independently CN, -CF3, or -CH3;

[0116] Or, two adjacent R 1The atoms connected to them together form

[0117] In one aspect of the present invention, for

[0118] In one aspect of the present invention, R 1 Independently, it is cyano, C1-C6 alkyl, -S(=O)2C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens, or C1-C6 alkoxy substituted with one or more halogens; or, two adjacent R 1 The atoms connected to them together form a 5-membered heterocyclic alkenyl group.

[0119] In one aspect of the present invention, R 1 Independently, it can be CN, -CF3, -CH3, -S(=O)2CH3 or Or, two adjacent R 1 The atoms connected to them together form

[0120] In one aspect of the present invention, for

[0121] In one aspect of the present invention, for For example Further examples

[0122] In one aspect of the present invention, R 3 for For example Further examples

[0123] In one aspect of the present invention, for R 3-2 It is independently a C1-C6 alkyl group or an alkyl group substituted with one or more hydroxyl groups; For example,

[0124] In one aspect of the present invention, for For example

[0125] In one aspect of the present invention, R 3 for For example Further examples

[0126] In one aspect of the present invention, R 3 for For example

[0127] In one aspect of the present invention, R 2 for Or 4-6 membered heterocyclic alkyl groups, R 2-3 It is a hydroxyl group;

[0128] R a1 and R a2 Each can be independently hydrogen, CF3, methyl, ethyl, ethynyl, vinyl, isopropyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl;

[0129] or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, C3-C6 cycloalkyl substituted with one or more halogens, or 3-6 membered heterocyclic alkyl substituted with one or more halogens.

[0130] or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or two R atoms on the same carbon atom. a2 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or, R a1 and R a2 The carbon atoms connected to them together form C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl groups.

[0131] In one aspect of the present invention, R 2 -CH2OH,

[0132] In one aspect of the present invention, R 2 for Or 4-6 membered heterocyclic alkyl groups, R 2-3 It is a hydroxyl group;

[0133] R a1 and R a2 Each can be independently hydrogen, CF3, methyl, ethyl, or ethynyl;

[0134] or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl groups.

[0135] or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or two R atoms on the same carbon atom. a2 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or, R a1 and R a2 The carbon atoms connected to them together form C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl groups.

[0136] In one aspect of the present invention, R 2 -CH2OH,

[0137] In one aspect of the present invention, R 2 for Or 4-6 membered heterocyclic alkyl groups, R 2-3 It is a hydroxyl group;

[0138] R a1 and R a2 Each can be independently hydrogen, methyl, or ethyl;

[0139] or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl groups.

[0140] or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or two R atoms on the same carbon atom. a2 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or, R a1 and R a2 The carbon atoms connected to them together form C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl groups.

[0141] In one aspect of the present invention, R 2 -CH2OH,

[0142] In one aspect of the present invention, R 4 It is hydrogen.

[0143] In one aspect of the present invention, R 2 and R 4 The carbon atoms connected to them together form a 5-6 membered heterocyclic alkenyl group, which is then bonded by one or more R groups. 2a1 Substituted C5-C6 cycloalkenyl or 5-membered heteroaryl.

[0144] In one aspect of the present invention, R 2 and R 4 The carbon atoms connected to them together form

[0145] In one aspect of the present invention, R 2 and R 4 The carbon atoms connected to them together form

[0146] In one aspect of the present invention, R 2 and R 4 The carbon atoms bonded to them together form ring B, wherein ring B is a 5-6 membered heterocyclic alkenyl group containing one oxygen atom or is bonded by one or more R atoms. 2a2 Substituted 5-6 membered heterocyclic alkenyl groups, R 2a2 Independently hydroxyl or halogen, for example

[0147] In inventing a certain solution, R 2 and R 4 The carbon atoms bonded to them together form ring B, which is a 5-6 membered heterocyclic alkenyl group containing one oxygen atom, for example...

[0148] In one aspect of the present invention, R 2 for R 2-3 The carbon atom marked with "*" has an R configuration, an S configuration, or a mixture thereof.

[0149] One of the R a1 It is hydrogen, C1-C6 alkyl, CF3, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, or a C1-C6 alkyl substituted with one or more halogens; another R a1 It is hydrogen.

[0150] In one aspect of the present invention, R 2 for

[0151] In one aspect of the present invention, R 2 and R 4 The carbon atoms bonded to them together form a ring B, wherein the ring B is a C5-C6 cycloalkenyl, a 5-membered heteroaryl, or bonded by one or more R atoms. 2a1 Substituted C5-C6 cycloalkenyl groups or those with one or more R groups 2a2 Substituted 5-6 membered heterocyclic alkenyl groups;

[0152] R 2a1 and R 2a2 Independently, it is a hydroxyl group.

[0153] In one aspect of the present invention, R 2 and R 4 The carbon atoms bonded to them together form ring B, wherein ring B is

[0154] In one aspect of the present invention, R 2 and R 3 The carbon atoms connected to them together form For example

[0155] In one aspect of the present invention, the compound represented by formula (I) is a compound represented by formula (I-1), (I-2), or (I-3):

[0156] In one aspect of the present invention, in the compound represented by formula (I-1),

[0157] R 2 for

[0158] R a1 and R a2 Each can be independently hydrogen, methyl, or ethyl;

[0159] R 2-3 It is a hydroxyl group;

[0160] R 4 It is hydrogen;

[0161] for R 3-2 It is a C1-C6 alkyl group;

[0162] for

[0163] R 1 It is independently a C1-C6 alkyl or a C1-C6 alkyl substituted with one or more F.

[0164] In one aspect of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0165] In one aspect of the present invention, the compound represented by formula (I) is selected from any one of the following compounds:

[0166] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound A1, wherein compound A1 is... The compound that elutes first under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 40-50%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 40% gradient for 1 min, and then linearly increased at 40%-50% over the next 10 min. Preferably, under the above conditions, the retention time of the compound that elutes first is 6.2-7.2 min.

[0167] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound A2, wherein compound A2 is... Compounds that elute later under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 40-50%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 40% gradient for 1 min, and then linearly increased at 40%-50% over the next 10 min. Preferably, under the conditions described, the retention time of the compounds that elute later is 8.7-10.3 min.

[0168] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound B1, wherein compound B1 is... The compound that elutes first under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 40-50%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 40% gradient for 1 min, and then linearly increased at 40%-50% over the next 10 min. Preferably, under the conditions described, the retention time of the compound that elutes first is 6.8-7.7 min.

[0169] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound B2, wherein compound B2 is... Compounds that elute later under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 40-50%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 40% gradient for 1 min, and then linearly increased at 40%-50% over the next 10 min. Preferably, under the conditions described, the retention time of the compounds that elute later is 9.1-10.3 min.

[0170] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound S1, wherein compound S1 is The compounds were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v);

[0171] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound S2, wherein compound S2 is The compounds were separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v);

[0172] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound C1, wherein compound C1 is The compounds were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v);

[0173] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound C2, wherein compound C2 is... The compounds were obtained by separation under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v);

[0174] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound D1, wherein compound D1 is The compounds were separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v);

[0175] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound E1, wherein compound E1 is... The compounds were obtained by separation under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v);

[0176] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound F1, wherein compound F1 is The compounds obtained were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v);

[0177] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound F2, wherein compound F2 is The compounds were separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v);

[0178] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound G1, wherein compound G1 is The compound that elutes first under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 35-45%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 35% gradient for 1 min, and then linearly increased at 35%-45% over the next 10 min. Preferably, under the conditions described, the retention time of the compound that elutes first is 6.9-7.8 min.

[0179] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound G2, wherein compound G2 is Compounds eluting later under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 35-45%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 35% gradient for 1 min, and then linearly increased at 35%-45% over the next 10 min. Preferably, under the conditions described, the retention time of the compounds eluting later is 8.1-9.1 min.

[0180] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound H1, wherein compound H1 is... The compound that elutes first under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 42-52%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a gradient of 42% for 1 min, and then linearly increased at 42%-52% over the next 10 min. Preferably, under the separation conditions, the retention time of the compound that elutes first is 7.0-7.7 min.

[0181] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound H2, wherein compound H2 is Compounds eluting later under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 42-52%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 42% gradient for 1 min, and then linearly increased at 42%-52% over the next 10 min. Preferably, under the separation conditions, the retention time of the compounds eluting later is 7.9-9.0 min.

[0182] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound I1, wherein compound I1 is The compounds were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v);

[0183] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound I2, wherein compound I2 is The compounds were obtained by separation under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v);

[0184] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound J1, wherein compound J1 is... The compound that elutes first under the following conditions: column: C18 spherical, 20-35 μm, 100A, 80 g; mobile phase: acetonitrile-0.1% trifluoroacetic acid aqueous solution; flow rate: 20 mL / min; gradient: 5-45%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a gradient of 5% for 10 min, and then linearly increased at 5%-45% over the next 20 min. Preferably, under the conditions described, the retention time of the compound that elutes first is 19.0-20.0 min.

[0185] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as that of the chiral carbon atom bonded to OH in compound J2, wherein compound J2 is... Compounds eluting later under the following conditions: column: C18 spherical, 20-35 μm, 100A, 80 g; mobile phase: acetonitrile-0.1% trifluoroacetic acid aqueous solution; flow rate: 20 mL / min; gradient: 5-45%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 5% gradient for 10 min, and then linearly increased at 5%-45% over the next 20 min. Preferably, under the conditions described, the retention time of the compounds eluting later is 20.5-23.0 min. One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH and the position of the OH atom are the same as those of the chiral carbon atom bonded to OH and the position of the OH atom in compound K1, wherein compound K1 is... The first compound obtained under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH and the position of the OH atom are the same as those of the chiral carbon atom bonded to OH and the position of the OH atom in compound K2, wherein compound K2 is... The second compound obtained under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH and the position of the OH atom are the same as those of the chiral carbon atom bonded to OH and the position of the OH atom in compound K3, wherein compound K3 is The third compound obtained under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH and the position of the OH atom are the same as those of the chiral carbon atom bonded to OH and the position of the OH atom in compound K4, wherein compound K4 is The fourth compound obtained under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v);

[0186] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound L1, wherein compound L1 is... The compounds obtained were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v);

[0187] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound L2, wherein compound L2 is... The compounds were separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v);

[0188] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound D1, wherein compound D1 is The compounds were separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v);

[0189] One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound C1, wherein compound C1 is The compounds were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v);

[0190] The compound that elutes first under the following conditions: Waters 3767 / Qda Column: XBridge C18, 19*250mm, 10µm; mobile phase: acetonitrile-0.05% ammonia monohydrate aqueous solution; flow rate: 20mL / min; gradient: 22-36%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a gradient of 22% for 1 min, and then linearly increased from 22% to 36% over the next 10 min. Preferably, the retention time of the compound that elutes first is 6.5-7.2 min.

[0191] The compound that elutes first under the following conditions: Waters 3767 / Qda Column: XBridge C18, 19*250mm, 10µm; mobile phase: acetonitrile-0.05% ammonia monohydrate aqueous solution; flow rate: 20mL / min; gradient: 22-36%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is first maintained at a gradient of 22% for 1 min, and then linearly increased at 22%-36% over the next 10 min. Preferably, the retention time of the compound that elutes first is 9.0-9.8 min.

[0192] The above retention time test conditions are not a limitation on the compound. As long as the above test conditions are used to determine the retention time, and the obtained retention time is the same as or within the error range described above, and the compound is a stereoisomer of the compound limited by the retention time described above, then it falls within the protection scope of this invention.

[0193] The present invention also provides a pharmaceutical composition comprising substance X and a pharmaceutically acceptable excipient, wherein substance X is a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0194] The present invention also provides the use of the above-described pharmaceutical composition or the above-described substance X in the preparation of NLRP3 inhibitors.

[0195] The present invention also provides the use of the above-described pharmaceutical composition or the above-described substance X in the preparation of a medicament for the prevention and / or treatment of diseases related to NLRP3;

[0196] Preferably, the NLRP3-related diseases are neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease).

[0197] The present invention also provides the use of the above-mentioned pharmaceutical composition or the above-mentioned substance X in the preparation of a drug for the prevention and / or treatment of neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease).

[0198] The present invention also provides a method for preventing and / or treating diseases associated with NLRP3, comprising: administering a therapeutically effective amount of the substance X or the pharmaceutical composition thereof to an individual in need, wherein the disease associated with NLRP3 is preferably a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease).

[0199] The present invention also provides a method for preventing and / or treating a disease, comprising: administering a therapeutically effective amount of the substance X or the pharmaceutical composition described above to an individual in need, wherein the disease is a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease).

[0200] The present invention also provides a method for inhibiting NLRP3, comprising: administering to an individual in need a therapeutically effective amount of a compound of formula (I) as described in any embodiment of the present invention, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0201] Unless otherwise specified, the terms used in this invention have the following meanings:

[0202] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0203] In this article, the substituents used may be preceded by a single dash "-" to indicate that the named substituent is connected to the parent moiety by a single bond.

[0204] The term "multiple" refers to 2, 3, or 4.

[0205] The term "halogen" refers to F, Cl, Br, or I.

[0206] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1-C6). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and similar alkyl groups.

[0207] The term "alkoxy" refers to the group R. X -O-,R X The definition is the same as the term "alkyl".

[0208] The term "cycloalkyl" refers to a saturated cyclic group having a specified number of carbon atoms in the ring (e.g., C3-C6 or C3-C7) and whose ring atoms consist solely of carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0209] The term "heterocyclic alkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 3-6, 3-7, 5-12), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (1, 2, or 3 of N, O, and S).

[0210] The term "cycloalkenyl" refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3-C7) and having one or more (e.g., 1 or 2) carbon-carbon sp groups. 2 It has a double bond and is not aromatic.

[0211] The term "heterocyclic alkenyl" refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of ring atoms (e.g., 3-7), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom type (one or more of N, O, and S), having one or more (e.g., 1 or 2) carbon-carbon sp groups. 2 It has a double bond and is not aromatic.

[0212] The term "heteroaryl" refers to a cyclic, aromatic monovalent group having a specified number of ring atoms (e.g., 5-6, 5-10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, with monocyclic rings sharing two atoms and one bond. When polycyclic, each ring is aromatic. The heteroaryl group is attached to the rest of the molecule via a carbon atom or a heteroatom. The heteroaryl group is attached to the rest of the molecule via a ring with heteroatoms or a ring without heteroatoms.

[0213] The term "nitrogen-containing saturated heterocycle" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 3-12 members), in addition to containing N, which may be selected from one or more of O, S, C(=O), S(=O) and S(=O)2, and the number of heteroatoms is one or more. It is a monocyclic, bicyclic or tricyclic ring, and when it is a bicyclic or tricyclic ring, it may be connected by fused rings or spirocyclic rings.

[0214] In this invention, "cycloalkenyl," "heterocyclic alkenyl," "heteroaryl," or "aryl" can be linked to other parts of the molecule via one bond or two bonds. When linked via two bonds, it shares two atoms and one bond with the other parts of the molecule. The connection between the "cycloalkenyl," "heterocyclic alkenyl," "heteroaryl," or "aryl" and other parts of the molecule depends on the substituents they contain. For example, when "heteroaryl" is a substituent R... 1 When referring to "heteroaryl" compounds, due to R 1 If a "heteroaryl" group is connected to the rest of the molecule via a single bond, then the "heteroaryl" group is also connected to the rest of the molecule via a single bond; when the "cycloalkenyl" group is "two adjacent R groups..." 1 When the atoms connected to them together form the cycloalkenyl group in "C3-C7 cycloalkenyl", the "cycloalkenyl" here means that it is connected to the other parts of the molecule through two bonds.

[0215] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be located at any position within the alkenyl group. For example, C2-C6 alkenyl refers to an alkenyl group having 2-6 carbon atoms.

[0216] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond can be located at any position within the alkynyl group. For example, C2-C6 alkynyl refers to an alkynyl group having 2-6 carbon atoms.

[0217] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C36, C46, ​​C56, C66). 6- C 10 An aryl group is a cyclic, unsaturated monovalent hydrocarbon group, which can be monocyclic or polycyclic (e.g., two or three). When polycyclic, the monocyclic rings share two atoms and one bond, and each ring is aromatic. The aryl group is attached to the rest of the molecule through an aromatic or non-aromatic ring.

[0218] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.

[0219] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement.

[0220] As described above, "pharmaceutical-acceptable salt" and "solvent" in the term "pharmaceutical-acceptable salt solvate" refer to substances prepared from compounds of the present invention with relatively non-toxic, pharmaceutically acceptable acids or bases, and formed in combination with stoichiometric or non-stoichiometric solvents.

[0221] The term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances included in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0222] In this invention, the "inhibitor" can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art.

[0223] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0224] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0225] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0226] The reagents and raw materials used in this invention are all commercially available.

[0227] The positive and progressive effects of this invention are as follows: the pyridazine cyclic compounds of this invention have one or more of the following advantages:

[0228] (1) It has good inhibitory activity against NLRP3 and good activity in inhibiting the secretion of IL-1β by THP-1 cells;

[0229] (2) The risk of inhibiting hERG potassium ion channels is small;

[0230] (3) It has good pharmacokinetic properties. Detailed Implementation

[0231] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0232] The compounds of the present invention can be prepared by conventional methods in the art.

[0233] Intermediate A

[0234] Synthesis route:

[0235] first step

[0236] A-1 (10 g, 51.8 mmol) was dissolved in dichloromethane (150 mL) and cooled to 0 °C. N,N-diisopropylethylamine (34.3 mL, 207.3 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (39.4 g, 103.6 mmol), and A-2 (7.1 g, 72.6 mmol) were added. The mixture was stirred at 0 °C for 1 hour, then brought to room temperature and stirred for another 16 hours. After the reaction was complete, water (300 mL) was added, followed by extraction with ethyl acetate (300 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 2, v / v) to obtain A-3. 1 ¹H NMR (400MHz, CDCl₃) δ 7.46 (s, 1H), 3.55 (s, 3H), 3.39 (s, 3H). ESI-MS theoretical calculation [M+H] + =236.0, measured value 236.0.

[0237] Step 2

[0238] A-3 (100 mg, 0.42 mmol) and A-4 (160 mg, 0.44 mmol) were dissolved in 1,4-dioxane (6 mL) and water (2 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (34 mg, 0.04 mmol) and potassium carbonate (116 mg, 0.84 mmol) were added. The mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After cooling, the mixture was diluted with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain intermediate A. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.18 (s, 1H), 7.46–7.42 (m, 2H), 5.25 (s, 2H), 3.54 (s, 3H), 3.47 (q, J = 7.2Hz, 2H), 3.34 (s, 3H), 2.14 (s, 3H), 1.03 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculations [M+H] + =434.1, measured value 433.9.

[0239] Intermediate B

[0240] Synthesis route:

[0241] first step

[0242] B-1 (14.4 g, 46.02 mmol), tetrabutylammonium bromide (16.32 g, 50.62 mmol), o-phenanthroline (1.24 g, 6.90 mmol), potassium metabisulfite (20.46 g, 92.04 mmol), triphenylphosphine (1.81 g, 6.90 mmol), sodium formate (7.20 g, 105.85 mmol), and palladium acetate (0.52 g, 2.30 mmol) were dissolved in dimethyl sulfoxide (85 mL). The mixture was heated to 70 °C and stirred for 2 hours under nitrogen protection. After cooling to room temperature, iodomethane (13.06 g, 92.04 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was diluted with water (300 mL), extracted with ethyl acetate (300 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (600 mL), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain B-2. 1 H NMR (400MHz, CDCl3): δ7.78-7.72(m,1H),7.46-7.36(m,2H),3.99(s,3H),3.06(s,3H).

[0243] Step 2

[0244] B-2 (4.7 g, 17.73 mmol) was dissolved in dichloromethane (45 mL), and boron tribromide (1.0 mol / L dichloromethane solution, 35.46 mL, 35.46 mmol) was slowly added dropwise. The mixture was stirred at 0 °C for 8 hours. After the reaction was complete, methanol was added dropwise until no more bubbles were produced. The mixture was diluted with water (100 mL), extracted with dichloromethane (100 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing B-3, which was directly used in the next reaction. 1 H NMR (400MHz, CDCl3): δ7.69 (d, J = 8.4Hz, 1H), 7.57 (d, J = 2.0Hz, 1H), 7.38 (dd, J = 8.4, 2.0Hz, 1H), 6.14 (s, 1H), 3.06 (d, J = 5.60Hz, 3H).

[0245] Step 3

[0246] B-3 (1.75 g, 6.97 mmol) was dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (2.89 g, 20.91 mmol) was added, and chloromethyl ethyl ether (1.16 g, 10.46 mmol) was slowly added dropwise. The mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain B-4. 1 H NMR (400MHz, CDCl3): δ7.75(d,J=8.0Hz,1H),7.69(d,J=2.0Hz,1H),7.45(dd,J=8.0 ,2.0Hz,1H),5.37(s,2H),3.78(q,J=7.2Hz,2H),3.05(s,3H),1.23(t,J=7.2Hz,3H).

[0247] Step 4

[0248] B-4 (2.14 g, 6.92 mol), bis-pinacolborate (2.64 g, 10.38 mmol), potassium acetate (2.04 g, 20.76 mmol), and 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (510 mg, 0.69 mmol) were dissolved in 1,4-dioxane (40 mL). The mixture was heated to 100 °C and stirred for 3 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain intermediate B. 1 H NMR (400MHz, CDCl3): δ7.82(d,J=7.6Hz,1H),7.58-7.51(m,2H),5.30(s,2H),3.77(q,J=7.2Hz,2H),3.02(s,3H),1.35(s,12H),1.20(d,J=7.2Hz,3H).

[0249] Intermediate C

[0250] Synthesis route:

[0251] first step

[0252] C-1 (3.79 g, 19.14 mmol) was dissolved in N,N-dimethylformamide (40 mL), potassium carbonate (2.71 g, 19.64 mmol) was added, and chloromethyl ethyl ether (3.73 g, 22.97 mmol) was slowly added dropwise. The mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain C-2. 1 H NMR (400MHz, CDCl3): δ7.65(d,J=8.0Hz,1H),7.45(d,J=1.6Hz,1H),7.16(dd,J=8.0,1.6Hz,1H),5.32(s,2H),3.77(m,2H),1.24(t,J=7.2Hz,3H).

[0253] Step 2

[0254] C-2 (1.0 g, 3.90 mol), bis-pinacolborate (1.49 g, 5.85 mmol), potassium acetate (960 mg, 9.75 mmol), and 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (290 mg, 0.39 mmol) were dissolved in 1,4-dioxane (15 mL). The mixture was heated to 110 °C and stirred for 3 hours under nitrogen protection. After the reaction was completed, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain intermediate C. 1 H NMR (400MHz, CDCl3): δ7.72(d,J=7.6Hz,1H),7.32(s,1H),7.29-7.26(m,1H),5.25(s,2H),3.75(q,J=6.8Hz,2H),1.35(s,12H),1.22(t,J=6.8Hz,3H).

[0255] Intermediate D

[0256] Synthesis route:

[0257] first step

[0258] A-3 (500 mg, 2.12 mmol), 1-1 (456 mg, 2.01 mmol), and N,N-diisopropylethylamine (820 mg, 6.36 mmol) were dissolved in tetrahydrofuran (15 mL), and the mixture was heated to 60 °C and stirred for 8 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain intermediate D. ESI-MS theoretical calculation value [M+H] + =426.3, measured value 426.1.

[0259] Intermediate E

[0260] Synthesis route:

[0261] first step

[0262] E-1 (20.0 g, 161.1 mmol) was dissolved in N,N-dimethylformamide (600 mL) and water (100 mL). Cesium carbonate (105.0 g, 322.2 mmol) and E-2 (29.5 g, 193.3 mmol) were added, and the mixture was heated to 100 °C and stirred for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, and extracted with water (1.5 L) and ethyl acetate (1.0 L × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane, 5 / 1, v / v) to obtain E-3. 1 H NMR (400MHz, DMSO-d6): δ9.67(s,1H),7.13(t,J H-F =74.4Hz,1H),6.45-6.40(m,2H),6.34(t,J=2.0Hz,1H),2.21(s,3H).

[0263] Step 2

[0264] E-3 (1.45 g, 8.33 mmol) was dissolved in toluene (20 mL), cooled to 0 °C, and sodium hydride (60%, 670 mg, 16.66 mmol) was added. The mixture was stirred for 30 minutes, followed by the addition of elemental iodine (1.48 g, 5.83 mmol), and stirring continued for 2 hours. After the reaction was complete, the pH was adjusted to 5 with 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain E-4. 1H NMR (400MHz, DMSO-d6): δ10.66(s,1H),7.15(t,J H-F =74.0Hz,1H),6.66(d,J=2.4Hz,1H),6.51(d,J=2.4Hz,1H),2.36(s,3H).

[0265] Step 3

[0266] E-4 (1.48 g, 4.93 mmol) and potassium carbonate (2.73 g, 19.72 mmol) were dissolved in N,N-dimethylformamide (20 mL), and E-5 (560 mg, 5.92 mmol) was added dropwise. The mixture was stirred at 25 °C for 3 hours. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain E-6. 1 H NMR (400MHz, CDCl3): δ6.74(s,2H),6.48(t,J H- F =73.8Hz,1H),5.27(s,2H),3.76(q,J=7.2Hz,2H),2.47(s,3H),1.23(t,J=7.2Hz,3H).

[0267] Step 4

[0268] E-6 (1.27 g, 3.55 mol), pinacol borane (2.27 g, 17.75 mmol), palladium acetate (80 mg, 0.35 mmol), 2-(dicyclohexylphosphino)biphenyl (248 mg, 0.71 mmol), and triethylamine (2.51 g, 24.85 mmol) were dissolved in 1,4-dioxane (15 mL). The mixture was heated to 80 °C and stirred for 16 hours under nitrogen protection. After the reaction was completed, the solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain intermediate E. 1 H NMR (400MHz, DMSO-d6): δ7.22(t,J H-F =74.0Hz,1H),6.64(d,J=1.6Hz,1H),6.62-6.60(m,1H),5.17(s,2H),3.65(q,J=7.2Hz,2H),2.26(s,3H),1.30(s,12H),1.12(t,J=7.2Hz,3H).

[0269] intermediate F

[0270] Synthesis route:

[0271] first step

[0272] Intermediate D (700 mg, 1.65 mol) was dissolved in dichloromethane (7 mL), cooled to -78 °C, and a solution of diisobutylaluminum hydride in n-hexane (1.0 mol / L, 2.47 mL, 2.47 mmol) was added dropwise. The mixture was stirred at -78 °C for 1 hour. After the reaction was complete, saturated ammonium chloride aqueous solution (20 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain intermediate F. 1 ¹H NMR (400MHz, CDCl₃): δ 10.11 (s, 1H), 7.59 (s, 1H), 4.56–4.46 (m, 1H), 4.43–4.33 (m, 1H), 3.99–3.91 (m, 2H), 3.31–3.23 (m, 1H), 3.21–3.17 (m, 1H), 3.01–2.88 (m, 1H), 2.58–2.47 (m, 1H), 2.05–1.97 (m, 1H), 1.88–1.73 (m, 2H), 1.71–1.56 (m, 1H), 1.19 (s, 9H). ESI-MS theoretical calculation [M+H] + =367.2, measured value 367.2.

[0273] intermediate G

[0274] Synthesis route:

[0275] first step

[0276] G-1 (25 g, 146.9 mmol) was dissolved in acetic acid (250 mL), and selenium dioxide (17.93 g, 161.57 mmol) was added at 25 °C. The mixture was heated to 110 °C and stirred for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain G-2. 1 ¹H NMR (400MHz, CDCl₃): δ 10.21 (s, 1H), 4.28 (q, J = 7.2Hz, 2H), 4.21–4.09 (m, 2H), 2.53 (t, J = 6.4Hz, 2H), 1.98–1.88 (m, 2H), 1.33 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculations [M+H] + =185.1, measured value 185.0.

[0277] Step 2

[0278] G-2 (20.5 g, 111.3 mmol) was dissolved in tert-butanol (400 mL) and water (80 mL), followed by the sequential addition of sodium dihydrogen phosphate monohydrate (23.0 g, 166.95 mmol), 2-methyl-2-butene (58.5 g, 834.8 mmol), and sodium chlorite (25.2 g, 278.2 mmol). The mixture was stirred under nitrogen protection for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the pH was adjusted to 3-4 with dilute hydrochloric acid (1 mol / L). The mixture was extracted with ethyl acetate (200 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing G-3, which was directly used in the next reaction. ESI-MS theoretical calculation [M+H] + =201.1, measured value 201.0.

[0279] Step 3

[0280] G-3 (19.2 g, 95.9 mmol) was dissolved in methanol (300 mL), cooled to 0 °C, and then thionyl chloride (34.2 g, 287.7 mmol) was added. The mixture was heated to 70 °C and stirred for 2 hours. After the reaction was complete, the methanol was removed by concentration under reduced pressure. Water (100 mL) and a saturated aqueous solution of sodium bicarbonate (200 mL) were added, followed by extraction with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain G-4. ESI-MS theoretical calculation value [M+H] + =215.1, measured value 215.0.

[0281] Step 4

[0282] G-4 (13.5 g, 63.0 mmol) was dissolved in ethanol (200 mL), and hydrazine hydrate (47.3 g, 945.3 mmol) was slowly added. The mixture was heated to 85 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product containing G-5, which was used directly in the next reaction. ESI-MS theoretical calculation value [M+H] + =169.1, measured value 169.0.

[0283] Step 5

[0284] Phosphorus oxychloride (209.7 g, 1368 mmol) was added to G-5 (11.5 g, 68.4 mmol) at 0 °C, followed by the slow addition of N,N-diisopropylethylamine (26.5 g, 205.2 mmol). The mixture was heated to 85 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product containing the target compound. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain G-6. 1 ¹H NMR (400MHz, CDCl₃): δ 4.50–4.36 (m, 2H), 2.79 (t, J = 6.4 Hz, 2H), 2.25–2.07 (m, 2H). ESI-MS theoretical values ​​[M+H] + =205.0, measured value 204.9.

[0285] Step 6

[0286] G-6 (2.3 g, 11.2 mmol) was dissolved in 1,2-dichloroethane (80 mL), and azobisisobutyronitrile (370 mg, 2.24 mmol) and N-bromosuccinimide (2.4 g, 13.46 mmol) were added sequentially. The mixture was heated to 80 °C and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and extracted with 0.5 mol / L sodium hydroxide aqueous solution (50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain G-7. 1 ¹H NMR (400MHz, CDCl₃): δ 5.24 (t, J = 2.4Hz, 1H), 4.85–4.79 (m, 2H), 2.59–2.49 (m, 2H). ESI-MS theoretical values ​​[M+H] + =284.9, measured value 284.8.

[0287] Step 7

[0288] G-7 (2.8 g, 9.86 mmol) was dissolved in ethylene glycol dimethyl ether (50 mL) and water (5 mL). Silver perchlorate monohydrate (3.3 g, 14.79 mmol) was added at 25 °C, and the mixture was heated to 60 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain intermediate G.1 ¹H NMR (400MHz, CDCl₃): δ 4.98–4.93 (m, ¹H), 4.70–4.63 (m, ¹H), 4.53–4.43 (m, ¹H), 2.93–2.83 (m, ¹H), 2.35–2.25 (m, ¹H), 2.15–2.02 (m, ¹H). ESI-MS theoretical calculations [M+H] + =221.0, measured value 220.9.

[0289] intermediate H

[0290] Synthesis route:

[0291] first step

[0292] H-1 (25 g, 164.27 mmol) was dissolved in tetrahydrofuran (135 mL), cooled to 0 °C, and N,N,N',N'-tetramethylethylenediamine (22.91 g, 197.12 mmol) was added. The mixture was stirred for 30 minutes, and then n-butyllithium (2.5 mol / L n-hexane solution, 78.85 mL, 197.12 mmol) was added dropwise. The mixture was stirred for 3 hours, and then ethylene oxide (14.47 g, 328.54 mmol) was added dropwise. The mixture was then heated to room temperature and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to obtain H-2. 1 HNMR (400MHz, CDCl3): δ 6.38 (s, 2H), 3.85–3.77 (m, 6H), 3.74 (t, J = 6.4Hz, 2H), 2.93 (t, J = 6.4Hz, 2H), 2.34 (s, 3H). ESI-MS theoretical calculations [M+H] + =197.1, measured value 197.0.

[0293] Step 2

[0294] H₂ (10.5 g, 53.51 mmol) was dissolved in dichloromethane (200 mL), cooled to 0 °C, and boron tribromide (11.34 mL, 117.72 mmol) was added. The mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to 0 °C, quenched dropwise with methanol (20 mL), concentrated under reduced pressure to remove methanol, diluted with water (100 mL), extracted with dichloromethane (100 mL × 3), and the organic layers were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing H₂. This crude product required no purification and was used directly in the next reaction. ESI-MS theoretical calculation value [M+H] + =233.0, measured value 232.9.

[0295] Step 3

[0296] H-3 (11 g, 47.60 mmol) was dissolved in acetone (510 mL), and potassium carbonate (32.89 g, 238.00 mmol) was added. The mixture was heated to 70 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure to remove acetone, diluted with saturated ammonium chloride solution (150 mL), extracted with dichloromethane (100 mL × 3), and the organic layers were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 3, v / v) to obtain H-4. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 9.24 (br s, 1H), 6.10 (s, 1H), 6.05 (s, 1H), 4.44 (t, J = 8.8Hz, 2H), 2.96 (t, J = 8.8Hz, 2H), 2.13 (s, 3H). ESI-MS theoretical calculations [M+H] + =151.1, measured value 151.1.

[0297] Step 4

[0298] H-4 (7.7 g, 51.28 mmol) was dissolved in toluene (150 mL), cooled to 0 °C, and N-iodosuccinimide (11.54 g, 51.28 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 3, v / v) to obtain H-5. ESI-MS theoretical calculation [M+H] + =277.0, measured value 277.0.

[0299] Step 5

[0300] H-5 (11.5 g, 41.66 mmol) and potassium carbonate (23.03 g, 166.64 mmol) were dissolved in N,N-dimethylformamide (115 mL), and H-6 (6.95 g, 62.49 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic layers were combined. The layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1, v / v) to obtain H-7. 1 H NMR (400MHz, DMSO-d6): δ6.60(s,1H),5.16(s,2H),4.52(t,J=8.8Hz,2H),3.7 8(q,J=7.2Hz,2H),3.28(t,J=8.8Hz,2H),2.34(s,3H),1.16(t,J=7.2Hz,3H).

[0301] Step 6

[0302] H-7 (7.25 g, 21.70 mmol) was dissolved in tetrahydrofuran (75 mL), and H-8 (12.49 g, 65.1 mmol) was added. The mixture was cooled to -78 °C, and n-butyllithium (2.5 mol / L n-hexane solution, 21.7 mL, 54.25 mmol) was added dropwise. The mixture was stirred at -78 °C for 1 hour. After the reaction was complete, saturated ammonium chloride (200 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL × 3), and the organic layers were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1, v / v) to obtain intermediate H. 1 H NMR (400MHz, DMSO-d6): δ6.34(s,1H),5.06(s,2H),4.47(t,J=8.8Hz,2H),3.70(d,J= 7.2Hz,2H),3.17(t,J=8.80Hz,2H),2.21(s,3H),1.28(s,12H),1.13(t,J=7.2Hz,3H).

[0303] Intermediate I

[0304] Synthesis route:

[0305] first step

[0306] I-1 (4.5 g, 33.05 mmol) was dissolved in methanol (60 mL) and cooled to -50 °C under nitrogen protection. I-2 (10.57 g, 33.05 mmol) was dissolved in methanol (30 mL) and added dropwise to the above reaction system. The mixture was stirred for 30 minutes and then heated to room temperature and stirred for 16 hours. After the reaction was completed, the mixture was diluted with saturated sodium chloride aqueous solution (300 mL), the pH was adjusted to 5 with dilute hydrochloric acid (1 mol / L), and extracted with ethyl acetate (300 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain I-3. 1 H NMR (400MHz, CDCl3): δ7.18 (d, J = 8.4Hz, 1H), 6.32 (d, J = 8.4Hz, 1H), 5.54 (s, 1H), 4.62 (t, J = 8.8Hz, 2H), 3.22 (t, J = 8.8Hz, 2H).

[0307] Step 2

[0308] I-3 (3.79 g, 17.62 mmol) was dissolved in N,N-dimethylformamide (45 mL), and potassium carbonate (9.74 g, 70.48 mmol) and H-6 (2.94 g, 26.43 mmol) were added. The mixture was stirred at room temperature for 12 hours under nitrogen protection. After the reaction was complete, the solution was diluted with saturated sodium chloride aqueous solution (150 mL), extracted with ethyl acetate (150 mL × 3), and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate 20 / 1, v / v) to obtain I-4. 1 H NMR (400MHz, CDCl3): δ7.24(d,J=8.0Hz,1H),6.44(d,J=8.4Hz,1H),5.16(s,2H),4.56 (t,J=8.8Hz,2H),3.83(q,J=7.2Hz,2H),3.31(t,J=8.8Hz,2H),1.23(t,J=7.2Hz,3H).

[0309] Step 3

[0310] I-4 (3.8 g, 13.91 mmol), pinacol diborate (5.3 g, 20.87 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (1.02 g, 1.39 mmol), and potassium acetate (4.10 g, 41.73 mmol) were dissolved in 1,4-dioxane (60 mL). The mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic layers were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain intermediate I. 1 H NMR (400MHz, CDCl3): δ7.57(d,J=8.0Hz,1H),6.57(d,J=8.0Hz,1H),5.15(s,2H),4.58(t,J= 8.4Hz,2H),3.83-3.78(m,2H),3.25(t,J=8.8Hz,2H),1.31(s,12H),1.23(t,J=7.20Hz,3H).

[0311] Intermediate J

[0312] Synthesis route:

[0313] first step

[0314] J-1 (10.0 g, 52.9 mmol) was dissolved in acetone (150 mL), followed by the addition of potassium carbonate (21.94 g, 158.7 mmol) and p-toluenesulfonyl chloride (11.1 g, 58.2 mmol). The mixture was heated to 56 °C and stirred for 20 hours under nitrogen protection. After the reaction was complete, saturated sodium chloride solution (300 mL) was added, the pH was adjusted to 5 with dilute hydrochloric acid (6 mol / L), and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 1, v / v) to obtain J-2. 1 H NMR (400MHz, DMSO-d6): δ10.76(s,1H),7.74(d,J=8.0Hz,2H),7.48(d,J=800Hz,2 H),7.45(s,1H),6.64(d,J=2.4Hz,1H),6.37(dd,J=8.0,2.4Hz,1H),2.42(s,3H).

[0315] Step 2

[0316] J-2 (8.0 g, 23.3 mmol) was dissolved in DMF (80 mL), and potassium carbonate (12.89 g, 93.24 mmol) and chloromethyl ethyl ether (85% purity, 3.11 g, 27.97 mmol) were added. The mixture was stirred for 2 hours under nitrogen protection. After the reaction was complete, saturated sodium chloride aqueous solution (300 mL) was added, followed by extraction with ethyl acetate (300 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane, 3 / 2, v / v) to obtain J-3. 1 H NMR (400MHz, CDCl3): δ7.72(d,J=8.0Hz,2H),7.42(d,J=8.0Hz,1H),7.32(d,J=8.0Hz,2H),6.83(d,J= 2.4Hz,1H),6.57-6.54(m,1H),5.15(s,2H),3.69(q,J=6.4Hz,2H),2.44(s,3H),1.18(t,J=6.4Hz,3H).

[0317] Step 3

[0318] J-3 (9.3 g, 23.18 mmol) was dissolved in ethanol (35 mL) and water (5 mL), and potassium carbonate (7.8 g, 139.08 mmol) was added. The mixture was heated to 100 °C and stirred for 2 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (100 mL), and the pH was adjusted to 4 with saturated citric acid aqueous solution. The mixture was extracted with ethyl acetate (300 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 1, v / v) to obtain J-4. 1 H NMR (400MHz, CDCl3): δ7.35 (d, J = 8.0Hz, 1H), 6.73 (d, J = 2, 4Hz, 1H), 6.40 (m, 1H), 5.26 (s, 2H), 3.78 (q, J = 6.4Hz, 2H), 1.24 (t, J = 6.4Hz, 3H).

[0319] Step 4

[0320] J-4 (500 mg, 2.02 mmol) and potassium hydroxide (2.27 g, 40.4 mmol) were dissolved in acetonitrile (10 mL) and water (10 mL). The mixture was cooled to -78 °C under nitrogen protection, and diethyl bromofluoromethylphosphonate (1.08 g, 4.04 mmol) was added. The mixture was gradually heated to 25 °C and stirred for 30 minutes. After the reaction was complete, the mixture was extracted successively with diethyl ether (10 mL) and ethyl acetate (10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 95 / 5, v / v) to obtain J-5. 1 H NMR (400MHz, CDCl3): δ7.50(d,J=8.8Hz,1H),6.99(d,J=2.8Hz,1H),6.68(dd,J=8.8,2.4Hz,1H),6.48(t,J H-F =72.0Hz, 1H), 5.29 (s, 2H), 3.77 (q, J = 6.8Hz, 2H), 1.23 (t, J = 7.2Hz, 3H).

[0321] Step 5

[0322] J-5 (1.20 g, 4.04 mmol), triethylamine (1.20 g, 24.85 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (300 mg, 0.40 mmol), pinacol diboronate (1.54 g, 6.06 mmol), and potassium acetate (790 mg, 8.08 mmol) were added to 1,4-dioxane (30 mL), and the mixture was heated to 100 °C and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate (50 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 95 / 5, v / v) to obtain intermediate J. 1 H NMR (400MHz, CDCl3): δ7.68(d,J=8.0Hz,1H),6.80(d,J=4.0Hz,1H),6.74(dd,J=8.0,4.0Hz,1H),6.52(t,J H-F =76.0Hz,1H),5.23(s,2H),3.77(q,J=6.4Hz,2H),1.33(s,12H),1.22(t,J=6.4Hz,3H).

[0323] Example 1

[0324] Synthesis route:

[0325] first step

[0326] Intermediate A (150 mg, 0.35 mmol), 1-1 (119 mg, 0.52 mmol), and N,N-diisopropylethylamine (226 mg, 1.75 mmol) were dissolved in n-butanol (4 mL), and the mixture was heated to 110 °C and stirred for 2 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 1-2. ESI-MS theoretical calculation value [M+H] + =624.3, measured value 624.4.

[0327] Step 2

[0328] Dissolve 1-2 (290 mg, 0.46 mmol) in dichloromethane (6 mL), cool to 0 °C, add diisobutylaluminum hydride (1 mol / L n-hexane solution, 0.92 mL, 0.92 mmol), stir for 2 hours, and quench the reaction successively with water (0.2 mL) and 15% sodium hydroxide solution (0.2 mL), dry with anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain a crude product containing 1-3, which is directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =565.3, measured value 565.4.

[0329] Step 3

[0330] Dissolve 1-3 (250 mg, 0.44 mmol) in methanol (5 mL), cool to 0 °C, add sodium borohydride (25 mg, 0.66 mmol), stir for 1 hour, quench the reaction with water (50 mL) after the reaction is complete, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, concentrate under reduced pressure to obtain crude product, and purify by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 1-4. ESI-MS theoretical calculation value [M+H] + =567.3, measured value 567.2.

[0331] Step 4

[0332] Dissolve 1-4 (95 mg, 0.17 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (0.4 mL) dropwise, stir for 1 hour, and concentrate under reduced pressure after the reaction to obtain a crude product containing 1-5, which can be directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =409.2, measured value 409.1.

[0333] Step 5

[0334] Dissolve 1-5 (68 mg, 0.17 mmol) in methanol (2 mL), then add formaldehyde aqueous solution (37%, 0.08 mL, 0.85 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (108 mg, 0.61 mmol) sequentially. Stir at room temperature for 8 hours. After the reaction is complete, concentrate under reduced pressure and purify by high performance liquid chromatography (Agilent C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 20-30%; elution time: 7.2-8.5 min) to obtain 1. 1 ¹H NMR (400MHz, DMSO-d6): δ 10.22 (br s, 1H), 7.48 (s, 1H), 7.15–7.11 (m, 1H), 7.10–7.06 (s, 1H), 4.68–4.61 (m, 1H), 4.59–4.48 (m, 2H), 3.84–3.74 (m, 1H), 3.41–3.36 (m, 2H), 3.06 (s, 1H), 2.94–2.85 (m, 2H), 2.66–2.57 (m, 1H), 2.43 (s, 3H), 2.40–2.30 (m, 1H), 2.13 (s, 3H), 2.02–1.65 (m, 4H). ESI-MS theoretical calculations [M+H] + =423.2, measured value 423.0.

[0335] Example 2

[0336] Synthesis route:

[0337] first step

[0338] Intermediate A (200 mg, 0.46 mmol), 2-1 (156 mg, 0.69 mmol), N,N-diisopropylethylamine (180 mg, 1.38 mmol), and cesium fluoride (70 mg, 0.46 mmol) were dissolved in n-butanol (3 mL), and the mixture was heated to 110 °C and stirred for 16 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 2-2. ESI-MS theoretical calculation value [M+H] + =624.3, measured value 624.5.

[0339] Step 2

[0340] 2-2 (110 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 1.08 mL, 1.08 mmol) was added. The mixture was stirred for 5 hours. After the reaction was completed, the reaction was quenched successively with water (0.5 mL) and 15% sodium hydroxide solution (0.5 mL). The mixture was dried over anhydrous magnesium sulfate, and the resulting oily substance was concentrated under reduced pressure and dissolved in methanol (2 mL). Sodium borohydride (11 mg, 0.31 mmol) was added at 0 °C, stirred for 1 hour, concentrated under reduced pressure, and purified by high performance liquid chromatography (Agilent C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 20-30%; elution time: 7.2-8.2 min) to obtain 2. 1 HNMR (400MHz, DMSO-d6): δ 7.53 (s, 1H), 7.13 (s, 1H), 7.10 (s, 1H), 4.56–4.41 (m, 2H), 4.27–4.17 (m, 1H), 3.23–3.20 (m, 1H), 3.03–2.95 (m, 2H), 2.27 (s, 3H), 2.24–2.18 (m, 2H), 2.10 (s, 3H), 2.06–1.99 (m, 1H), 1.81–1.77 (m, 2H), 1.71–1.50 (m, 3H). ESI-MS theoretical calculations [M+H] + =423.2, measured value 423.2.

[0341] Example 3

[0342] Synthesis route:

[0343] first step

[0344] Intermediate A (200 mg, 0.46 mmol), 3-1 (156 mg, 0.69 mmol), N,N-diisopropylethylamine (297 mg, 2.30 mmol), and cesium fluoride (70 mg, 0.46 mmol) were dissolved in n-butanol (3 mL), and the mixture was heated to 110 °C and stirred for 16 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 3-2. ESI-MS theoretical calculation value [M+H] + =624.3, measured value 624.4.

[0345] Step 2

[0346] 3-2 (140 mg, 0.22 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 1.32 mL, 1.32 mmol) was added. The mixture was stirred for 5 hours. After the reaction was completed, the reaction was quenched successively with water (0.5 mL) and 15% sodium hydroxide solution (0.5 mL). The mixture was dried over anhydrous magnesium sulfate, and the resulting oily substance was concentrated under reduced pressure and dissolved in methanol (2 mL). Sodium borohydride (14 mg, 0.36 mmol) was added at 0 °C, stirred for 1 hour, concentrated under reduced pressure, and purified by high performance liquid chromatography (Agilent C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 20-30%; elution time: 6.8-8.0 min) to obtain 3. 1 ¹H NMR (400MHz, DMSO-d6): δ 7.55 (s, 1H), 7.13 (s, 1H), 7.10 (s, 1H), 4.59–4.41 (m, 2H), 4.29–4.18 (m, 1H), 3.25–3.20 (m, 1H), 3.06–2.96 (m, 2H), 2.64–2.54 (m, 1H), 2.33 (s, 3H), 2.29–2.27 (m, 1H), 2.10 (s, 3H), 2.06–2.02 (m, 1H), 1.84–1.79 (m, 2H), 1.71–1.48 (m, 3H). ESI-MS theoretical values ​​[M+H] + =423.2, measured value 423.5.

[0347] Example 4

[0348] Synthesis route:

[0349] first step

[0350] Intermediate A (200 mg, 0.46 mmol), 4-1 (150 mg, 0.69 mmol), and N,N-diisopropylethylamine (297 mg, 2.30 mmol) were dissolved in n-butanol (5 mL), and the mixture was heated to 110 °C and stirred for 16 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 4-2. ESI-MS theoretical calculation [M+H] + =610.3, measured value 610.0.

[0351] Step 2

[0352] 4-2 (270 mg, 0.44 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 1.32 mL, 1.32 mmol) was added. The mixture was stirred for 3 hours. After the reaction was completed, the reaction was quenched successively with water (0.3 mL) and 15% sodium hydroxide solution (0.3 mL). The product was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing 4-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =551.3, measured value 551.4.

[0353] Step 3

[0354] Dissolve 1-3 (250 mg, 0.44 mmol) in methanol (4 mL), cool to 0 °C, add sodium borohydride (26 mg, 0.68 mmol), stir for 1 hour, quench the reaction with water (40 mL) after the reaction is complete, extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure to obtain crude product, and purify by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 4-4. ESI-MS theoretical calculation value [M+H] + =553.3, measured value 553.1.

[0355] Step 4

[0356] 4-4 (140 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added dropwise. The mixture was stirred for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 4-5, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =395.2, measured value 395.1.

[0357] Step 5

[0358] Dissolve 4-5 (99 mg, 0.25 mmol) in methanol (1 mL), then add formaldehyde aqueous solution (37%, 0.25 mL, 2.50 mmol) and sodium triacetoxyborohydride (156 mg, 0.75 mmol) sequentially, and stir at room temperature for 3 hours. After the reaction is complete, concentrate under reduced pressure and purify by high performance liquid chromatography (XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 19-29%; elution time: 7.0-9.2 min) to obtain 4. 1¹H NMR (400MHz, DMSO-d6): δ 10.18 (br s, 1H), 7.46 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H), 5.64–5.54 (m, 1H), 4.89–4.79 (m, 1H), 4.69–4.53 (m, 2H), 3.85–3.75 (m, 1H), 3.71–3.61 (m, 1H), 3.19–3.11 (m, 2H), 3.10–3.02 (m, 3H), 2.61 (s, 3H), 2.12 (s, 3H), 2.12–2.02 (m, 1H), 1.97–1.87 (m, 1H). ESI-MS theoretical calculation [M+H] + =409.2, measured value 409.1.

[0359] Example 5

[0360] Synthesis route:

[0361] first step

[0362] Intermediate A (100 mg, 0.23 mmol), 5-1 (98 mg, 0.46 mmol), cesium fluoride (35 mg, 0.23 mmol), and triethylamine (70 mg, 0.69 mmol) were dissolved in n-butanol (5 mL), and the mixture was heated to 110 °C and stirred for 4 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 5-2. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.39 (s, 1H), 7.38–7.36 (m, 2H), 5.21 (s, 2H), 3.75–3.68 (s, 2H), 3.60–3.42 (m, 7H), 3.40–3.30 (m, 2H), 3.26 (s, 3H), 3.22–3.12 (m, 2H), 3.05–2.95 (m, 2H), 2.15 (s, 3H), 1.40 (s, 9H), 1.04 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculations [M+H] + =610.3, measured value 610.0.

[0363] Step 2

[0364] 5-2 (110 mg, 0.18 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 0.54 mL, 0.54 mmol) was added. The mixture was stirred for 3 hours. After the reaction was completed, the reaction was quenched successively with water (0.1 mL) and 15% sodium hydroxide solution (0.1 mL). The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing 5-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =551.3, measured value 551.4.

[0365] Step 3

[0366] 5-3 (100 mg, 0.18 mmol) was dissolved in methanol (2 mL), cooled to 0 °C, and sodium borohydride (11 mg, 0.27 mmol) was added. The mixture was stirred for 1 hour. After the reaction was complete, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 5-4. ESI-MS theoretical calculation [M+H] + =553.3, measured value 553.1.

[0367] Step 4

[0368] 5-4 (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 5-5, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =395.2, measured value 395.2.

[0369] Step 5

[0370] 5-5 (45 mg, 0.11 mmol) was dissolved in methanol (1 mL), and formaldehyde aqueous solution (37%, 0.05 mL, 0.55 mmol) and sodium triacetoxyborohydride (70 mg, 0.33 mmol) were added sequentially. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.05% ammonia monohydrate aqueous solution, gradient: 30-40%; elution time: 8.3-9.7 min) to obtain 5. 1¹H NMR (400MHz, DMSO-d6): δ 10.17 (br s, 1H), 7.45 (s, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 5.59–5.49 (m, 1H), 4.58–4.53 (m, 2H), 3.64–3.54 (m, 2H), 3.39–3.31 (m, 2H), 2.89–2.80 (m, 2H), 2.69–2.58 (m, 2H), 2.39–2.33 (m, 2H), 2.23 (s, 3H), 2.11 (s, 3H). ESI-MS theoretical calculation [M+H] + =409.2, measured value 408.9.

[0371] Example 6

[0372] Synthesis route:

[0373] first step

[0374] Intermediate A (200 mg, 0.46 mmol), 6-1 (156 mg, 0.69 mmol), cesium fluoride (35 mg, 0.23 mmol), and N,N-diisopropylethylamine (297 mg, 2.30 mmol) were dissolved in n-butanol (5 mL), and the mixture was heated to 110 °C and stirred for 16 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 6-2. ESI-MS theoretical calculation [M+H] + =624.3, measured value 624.0.

[0375] Step 2

[0376] 6-2 (227 mg, 0.44 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 1.08 mL, 1.08 mmol) was added. The mixture was stirred for 3 hours. After the reaction was completed, the reaction was quenched successively with water (0.2 mL) and 15% sodium hydroxide solution (0.2 mL). The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing 6-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =565.3, measured value 565.4.

[0377] Step 3

[0378] 6-3 (210 mg, 0.37 mmol) was dissolved in methanol (4 mL), cooled to 0 °C, and sodium borohydride (21 mg, 0.55 mmol) was added. The mixture was stirred for 1 hour. After the reaction was complete, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 6-4. ESI-MS theoretical calculation [M+H] + =567.3, measured value 567.1.

[0379] Step 4

[0380] 6-4 (125 mg, 0.22 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (1.5 mL) was added dropwise. The mixture was stirred for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 6-5, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =409.2, measured value 409.0.

[0381] Step 5

[0382] Dissolve 6-5 (90 mg, 0.22 mmol) in methanol (1 mL), then add formaldehyde aqueous solution (37%, 0.22 mL, 2.20 mmol) and sodium triacetoxyborohydride (140 mg, 0.66 mmol) sequentially, and stir at room temperature for 3 hours. After the reaction is complete, concentrate under reduced pressure and purify by high performance liquid chromatography (XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 18-28%; elution time: 7.6-9.2 min) to obtain 6. 1 ¹H NMR (400MHz, DMSO-d6): δ 10.20 (br s, 1H), 7.49 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H), 5.59–5.49 (m, 1H), 4.66–4.48 (m, 2H), 4.46–4.40 (m, 1H), 3.81–3.73 (m, 1H), 3.12–3.03 (m, 2H), 2.79–2.68 (m, 3H), 2.62–2.55 (s, 4H), 2.12 (s, 3H), 2.12–2.02 (m, 1H), 2.05–1.95 (m, 2H), 1.83–1.73 (m, 1H). ESI-MS theoretical calculation [M+H] + =423.2, measured value 423.1.

[0383] Example 7

[0384] Synthesis route:

[0385] first step

[0386] Intermediate A (200 mg, 0.46 mmol), 7-1 (156 mg, 0.69 mmol), cesium fluoride (70 mg, 0.46 mmol), and N,N-diisopropylethylamine (297 mg, 2.30 mmol) were dissolved in n-butanol (4 mL), and the mixture was heated to 110 °C and stirred for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 7-2. 1 ¹H NMR (400MHz, CDCl₃): δ 7.32 (s, 1H), 7.23 (s, 1H), 7.18 (s, 1H), 5.11 (s, 2H), 4.07–3.97 (m, 2H), 3.90–3.23 (m, 12H), 3.15–2.95 (m, 1H), 2.54–2.44 (m, 1H), 2.25 (s, 3H), 2.17–2.07 (m, 1H), 2.02–1.92 (m, 2H), 1.83–1.73 (m, 1H), 1.51–1.41 (m, 9H), 1.15 (t, J = 7.2 Hz, 3H). ESI-MS theoretical calculation [M+H] + =624.3, measured value 624.4.

[0387] Step 2

[0388] 7-2 (250 mg, 0.40 mmol) was dissolved in tetrahydrofuran (6 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 2.0 mL, 2.0 mmol) was added. The mixture was stirred for 3 hours. After the reaction was completed, the reaction was quenched successively with water (0.6 mL) and 15% sodium hydroxide solution (0.6 mL). The product was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing 7-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =565.3, measured value 565.4.

[0389] Step 3

[0390] 7-3 (300 mg, 0.53 mmol) was dissolved in methanol (5 mL), cooled to 0 °C, and sodium borohydride (30 mg, 0.80 mmol) was added. The mixture was stirred for 1 hour. After the reaction was complete, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 7-4. ESI-MS theoretical calculation [M+H] + =567.3, measured value 567.4.

[0391] Step 4

[0392] 7-4 (160 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 7-5, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =409.2, measured value 409.2.

[0393] Step 5

[0394] 7-5 (115 mg, 0.28 mmol) was dissolved in methanol (4 mL), and formaldehyde aqueous solution (37%, 0.28 mL, 2.8 mmol) and sodium triacetoxyborohydride (178 mg, 0.84 mmol) were added sequentially. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Agilent C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 20-30%; elution time: 7.5-8.8 min) to obtain 7. 1 ¹H NMR (400MHz, DMSO-d6): δ 10.29 (br s, 1H), 7.58 (s, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 4.79–4.42 (m, 2H), 3.90–3.80 (m, 1H), 3.65–3.55 (m, 1H), 3.54–3.44 (m, 3H), 3.04–2.95 (m, 1H), 2.94–2.87 (m, 1H), 2.75 (s, 3H), 2.55–2.47 (m, 1H), 2.20–2.13 (m, 1H), 2.11 (s, 3H), 1.88–1.76 (m, 1H), 1.72–1.60 (m, 2H). ESI-MS theoretical calculation [M+H] + =423.2, measured value 423.0.

[0395] Example 8

[0396] Synthesis route:

[0397] first step

[0398] Intermediate A (200 mg, 0.46 mmol), 8-1 (208 mg, 0.92 mmol), cesium fluoride (70 mg, 0.46 mmol), and N,N-diisopropylethylamine (297 mg, 2.30 mmol) were dissolved in n-butanol (5 mL), and the mixture was heated to 110 °C and stirred for 16 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 8-2. ESI-MS theoretical calculation value [M+H] + =624.3, measured value 624.4.

[0399] Step 2

[0400] 8-2 (240 mg, 0.38 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 0.76 mL, 0.76 mmol) was added. The mixture was stirred for 3 hours. After the reaction was completed, the reaction was quenched successively with water (0.3 mL) and 15% sodium hydroxide solution (0.3 mL). The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing 8-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =587.3, measured value 587.2.

[0401] Step 3

[0402] 8-3 (217 mg, 0.38 mmol) was dissolved in methanol (3 mL), cooled to 0 °C, and sodium borohydride (22 mg, 0.57 mmol) was added. The mixture was stirred for 1 hour. After the reaction was complete, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 8-4. ESI-MS theoretical calculation [M+H] + =567.3, measured value 567.6.

[0403] Step 4

[0404] 8-4 (130 mg, 0.23 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (1.5 mL) was added dropwise. The mixture was stirred for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 8-5, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =409.2, measured value 409.5.

[0405] Step 5

[0406] Dissolve 8-5 (94 mg, 0.23 mmol) in methanol (2 mL), then add formaldehyde aqueous solution (37%, 0.23 mL, 2.3 mmol) and sodium triacetoxyborohydride (146 mg, 0.69 mmol) sequentially, and stir at room temperature for 3 hours. After the reaction is complete, concentrate under reduced pressure and purify by high performance liquid chromatography (XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.05% ammonia monohydrate aqueous solution, gradient: 31-31%; elution time: 6.2-9.1 min) to obtain 8. 1 H NMR (400MHz, DMSO-d6): δ10.20 (br s, 1H), 7.55(s, 1H), 7.14(s, 1H), 7.09(s, 1H), 5.63-5.53(m, 1H), 4.61-4.50(m, 2H), 3.45-3.35(m, 1H), 3.28-3.20(m, 1H), 3.19-3.14(m, 1H), 3.12-3.01(m, 2H), 2.90-2.80(m, 1H), 2.22(s, 3H), 2.10(s, 3H), 1.99-1.91(m, 1H), 1.92-1.82(m, 2H), 1.82-1.72(m, 1H), 1.71-1.62(m, 2H). ESI-MS theoretical calculation values ​​[M+H] + =423.2, measured value 423.0.

[0407] Example 9

[0408] Synthesis route:

[0409] first step

[0410] Intermediate A (138 mg, 0.32 mmol), 9-1 (65 mg, 0.48 mmol), cesium fluoride (49 mg, 0.32 mmol), and N,N-diisopropylethylamine (248 mg, 1.92 mmol) were dissolved in n-butanol (3 mL), and the mixture was heated to 110 °C and stirred for 16 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 3, v / v) to obtain 9-2. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.43 (s, 1H), 7.43–7.35 (m, 2H), 5.22 (s, 2H), 4.77–4.70 (m, 2H), 3.85–3.65 (m, 4H), 3.56 (s, 3H), 3.55–3.45 (m, 2H), 3.27 (s, 3H), 3.19–3.09 (m, 1H), 2.17 (s, 3H), 1.95–1.85 (m, 1H), 1.05 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculations [M+H] + =497.2, measured value 497.5.

[0411] Step 2

[0412] 9-2 (126 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 1.5 mL, 1.5 mmol) was added. The mixture was stirred for 2 hours. After the reaction was completed, the reaction was quenched successively with water (0.5 mL) and 15% sodium hydroxide solution (0.5 mL). The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing 9-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =438.2, measured value 438.1.

[0413] Step 3

[0414] 9-3 (110 mg, 0.25 mmol) was dissolved in methanol (2 mL), cooled to 0 °C, and sodium borohydride (14 mg, 0.38 mmol) was added. The mixture was stirred for 1 hour. After the reaction was complete, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 9-4. ESI-MS theoretical calculation [M+H] + =440.2, measured value 440.4.

[0415] Step 4

[0416] Dissolve 9-4 (45 mg, 0.10 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (0.25 mL) dropwise, stir for 1 hour, concentrate under reduced pressure after the reaction is complete, and purify by high performance liquid chromatography (XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.05% ammonia monohydrate aqueous solution, gradient: 35-35%; elution time: 7.2-8.0 min) to obtain 9. 1 ¹H NMR (400MHz, DMSO-d6): δ 10.17 (br s, 1H), 7.47 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H), 5.57 (t, J = 5.20Hz, 1H), 4.72–4.62 (m, 4H), 3.97–3.87 (m, 4H), 3.16–3.06 (m, 1H), 2.14 (s, 3H), 2.12–2.02 (m, 1H). ESI-MS theoretical calculations [M+H] + =382.1, measured value 382.4.

[0417] Example 10

[0418] Synthesis route:

[0419] first step

[0420] Intermediate A (200 mg, 0.46 mmol), 10⁻¹ (150 mg, 0.69 mmol), cesium fluoride (70 mg, 0.46 mmol), and N,N-diisopropylethylamine (297 mg, 2.30 mmol) were dissolved in n-butanol (4 mL), and the mixture was heated to 110 °C and stirred for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 10⁻². 1 ¹H NMR (400MHz, CDCl₃): δ 7.32 (s, 1H), 7.23 (s, 1H), 7.20 (s, 1H), 5.12 (s, 2H), 4.25–3.92 (m, 3H), 3.58–3.51 (m, 5H), 3.35 (s, 3H), 3.14–3.03 (m, 1H), 2.93–2.78 (m, 4H), 2.25 (s, 3H), 1.95–1.68 (m, 4H), 1.46 (s, 9H), 1.16 (t, J = 7.2 Hz, 3H). ESI-MS theoretical calculations [M+H] +=612.3, measured value 612.4.

[0421] Step 2

[0422] 10⁻² (216 mg, 0.35 mmol) was dissolved in tetrahydrofuran (6 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 1.7 mL, 1.7 mmol) was added. The mixture was stirred for 2 hours. After the reaction was complete, the reaction was quenched successively with water (0.3 mL) and 15% sodium hydroxide solution (0.3 mL). The product was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing 10⁻³, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =553.3, measured value 553.4.

[0423] Step 3

[0424] 10⁻³ (300 mg, 0.54 mmol) was dissolved in methanol (5 mL), cooled to 0 °C, and sodium borohydride (31 mg, 0.81 mmol) was added. The mixture was stirred for 1 hour. After the reaction was complete, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 10⁻⁴. ESI-MS theoretical calculation [M + H] + =555.3, measured value 555.4.

[0425] Step 4

[0426] 10⁻⁴ (152 mg, 0.27 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 10⁻⁵, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =397.2, measured value 397.2.

[0427] Step 5

[0428] 10⁻⁵ (108 mg, 0.27 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.27 mL, 2.7 mmol) and sodium triacetoxyborohydride (172 mg, 0.81 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.05% ammonia monohydrate aqueous solution, gradient: 34-34%; elution time: 5.0-9.0 min) to obtain 10. 1¹H NMR (400MHz, DMSO-d6): δ 10.20 (br s, 1H), 7.54 (s, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 5.61–5.51 (m, 1H), 4.55–4.45 (m, 2H), 3.71–3.61 (m, 1H), 3.52–3.42 (m, 1H), 2.85–2.63 (m, 2H), 2.47–2.37 (m, 1H), 2.25 (s, 6H), 2.10 (s, 3H), 2.03–1.93 (m, 1H), 1.88–1.78 (m, 1H), 1.67–1.57 (m, 1H), 1.42–1.32 (m, 1H). ESI-MS theoretical calculation [M+H] + =411.2, measured value 411.0.

[0429] Example 11

[0430] Synthesis route:

[0431] first step

[0432] Intermediate A (150 mg, 0.35 mmol), 11-1 (110 mg, 0.52 mmol), cesium fluoride (53 mg, 0.35 mmol), and N,N-diisopropylethylamine (136 mg, 1.05 mmol) were dissolved in dimethyl sulfoxide (4 mL), and the mixture was heated to 130 °C and stirred for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 11-2. ESI-MS theoretical value [M+H] + =624.3, measured value 624.2.

[0433] Step 2

[0434] 11-2 (110 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 0.36 mL, 0.36 mmol) was added. The mixture was stirred for 3 hours. After the reaction was completed, the reaction was quenched successively with water (0.2 mL) and 15% sodium hydroxide solution (0.2 mL). The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing 11-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =565.3, measured value 565.4.

[0435] Step 3

[0436] 11-3 (100 mg, 0.18 mmol) was dissolved in methanol (2 mL), cooled to 0 °C, and sodium borohydride (10 mg, 0.27 mmol) was added. The mixture was stirred for 1 hour. After the reaction was complete, water (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 11-4. ESI-MS theoretical calculation [M+H] + =567.3, measured value 567.1.

[0437] Step 4

[0438] 11-4 (60 mg, 0.11 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 11-5, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =409.2, measured value 409.1.

[0439] Step 5

[0440] 11-5 (63 mg, 0.15 mmol) was dissolved in methanol (1 mL), and formaldehyde aqueous solution (37%, 0.11 mL, 1.5 mmol) and sodium triacetoxyborohydride (95 mg, 0.45 mmol) were added sequentially. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.05% ammonia monohydrate aqueous solution, gradient: 31-41%; elution time: 6.8-9.0 min) to obtain 11. 1 ¹H NMR (400MHz, DMSO-d6): δ 10.13 (br s, 1H), 7.54 (s, 1H), 7.14 (s, 1H), 7.09 (s, 1H), 5.65–5.55 (m, 1H), 4.59–4.42 (m, 2H), 4.28–4.18 (m, 1H), 3.15–2.98 (m, 2H), 2.86–2.76 (m, 1H), 2.63–2.53 (m, 3H), 2.35–2.25 (m, 1H), 2.26 (s, 3H), 2.10 (s, 3H), 1.83–1.68 (m, 3H), 1.67–1.54 (m, 1H). ESI-MS theoretical calculation [M+H] + =423.2, measured value 423.0.

[0441] Example 12

[0442] Synthesis route:

[0443] first step

[0444] Intermediate A (180 mg, 0.41 mmol), 12-1 (160 mg, 0.82 mmol), cesium fluoride (62 mg, 0.41 mmol), and N,N-diisopropylethylamine (260 mg, 2.05 mmol) were dissolved in n-butanol (5 mL), and the mixture was heated to 110 °C and stirred for 16 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 3, v / v) to obtain 12-2. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.32 (s, 1H), 7.23 (s, 1H), 7.14 (s, 1H), 5.11 (s, 2H), 4.90–4.80 (s, 1H), 3.82–3.72 (m, 2H), 3.65–3.48 (m, 7H), 3.33 (s, 3H), 2.84 (s, 3H), 2.27 (s, 3H), 2.21–2.06 (m, 2H), 1.48 (s, 9H), 1.16 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculations [M+H] + =598.3, measured value 598.4.

[0445] Step 2

[0446] 12-2 (220 mg, 0.37 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 1.85 mL, 1.85 mmol) was added. The mixture was stirred for 3 hours. After the reaction was completed, the reaction was quenched successively with water (0.3 mL) and 15% sodium hydroxide solution (0.3 mL). The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing 12-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =539.3, measured value 539.2.

[0447] Step 3

[0448] 12-3 (198 mg, 0.37 mmol) was dissolved in methanol (2 mL), cooled to 0 °C, and sodium borohydride (21 mg, 0.55 mmol) was added. The mixture was stirred for 1 hour. After the reaction was complete, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 12-4. ESI-MS theoretical calculation [M+H] + =541.3, measured value 541.6.

[0449] Step 4

[0450] 12-4 (118 mg, 0.22 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (1.5 mL) was added dropwise. The mixture was stirred for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 12-5, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =383.2, measured value 383.0.

[0451] Step 5

[0452] 12-5 (83 mg, 0.22 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.22 mL, 2.2 mmol) and sodium triacetoxyborohydride (140 mg, 0.66 mmol) were added sequentially. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.05% ammonia monohydrate aqueous solution, gradient: 34-34%; elution time: 6.0-9.0 min) to obtain 12. 1 ¹H NMR (400MHz, DMSO-d6): δ 10.16 (br s, 1H), 7.37 (s, 1H), 7.12 (s, 1H), 7.06 (s, 1H), 5.53–5.43 (m, 1H), 4.74–4.64 (m, 1H), 4.60–4.50 (m, 1H), 3.84–3.77 (m, 1H), 3.75–3.65 (m, 2H), 3.48–3.42 (m, 1H), 2.78–2.67 (m, 1H), 2.22 (s, 6H), 2.18–2.09 (m, 4H), 1.83–1.73 (m, 1H). ESI-MS theoretical calculation [M+H] + =397.2, measured value 397.1.

[0453] Example 13

[0454] Synthesis route:

[0455] first step

[0456] 1-3 (60 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL), cooled to 0 °C under nitrogen protection, and methylmagnesium bromide (1 mol / L tetrahydrofuran solution, 0.17 mL, 0.17 mmol) was added. The mixture was stirred for 3 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride aqueous solution (15 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 13-1. ESI-MS theoretical calculation [M+H] + =581.3, measured value 581.1.

[0457] Step 2

[0458] 13-1 (22 mg, 0.04 mmol) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid (0.5 mL) was added dropwise. The mixture was stirred for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 13-2, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =423.2, measured value 423.0.

[0459] Step 3

[0460] 13-2 (16 mg, 0.04 mmol) was dissolved in methanol (1 mL), and formaldehyde aqueous solution (37%, 0.04 mL, 0.38 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) were added sequentially. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, gradient: 34-35%; elution time: 7.3-10.0 min) to obtain 13-2. 1H NMR (400MHz, DMSO-d6): δ10.19(br s,1H),7.55(s,1H),7.12(s,1H),7.08(s,1H),5.47(d,J=4.8Hz,1H),5.01-4.90(m,1H ),4.47-4.40(m,1H),3.83-3.73(m,1H),3.29-3.19(m,1H),2.79-2.70(m,1H),2.48-2. 44 (m, 1H), 2.30–2.21 (m, 2H), 2.12 (s, 3H), 2.08 (s, 3H), 2.06–2.00 (m, 1H), 1.99–1.90 (m, 1H), 1.86–1.69 (m, 2H), 1.66–1.57 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H). ESI-MS theoretical calculation [M+H] + =437.2, measured value 437.1.

[0461] Example 14

[0462] Synthesis route:

[0463] first step

[0464] 14-1 (13.0 g, 82.20 mmol) and N,N-diisopropylethylamine (27.24 mL, 164.4 mmol) were dissolved in dichloromethane (80 mL). After cooling to 0 °C, trifluoromethanesulfonic anhydride (27.83 g, 98.64 mmol) was added dropwise. The mixture was stirred for 10 minutes, then heated to 25 °C and stirred for 1 hour. After the reaction was complete, saturated sodium bicarbonate aqueous solution was slowly added dropwise. The organic phase was washed twice with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 20, v / v) to obtain 14-2. 1 H NMR (400MHz, CDCl3): δ4.48-4.41(m,2H),3.92-3.86(m,2H),3.82(s,3H),2.58-2.49(m,2H).

[0465] Step 2

[0466] 14-2 (44.0 g, 0.37 mmol) and N,N-diisopropylethylamine (58.78 g, 454.83 mmol) were dissolved in methanol (500 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (12.38 g, 15.16 mmol) was added. The mixture was heated to 60 °C and stirred for 12 hours under a carbon monoxide atmosphere. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain 14-3. 1 ¹H NMR (400MHz, CDCl₃): δ 4.33 (t, J = 2.8Hz, 2H), 3.83–3.74 (m, 8H), 2.49–2.39 (m, 2H). ESI-MS theoretical calculation: [M+H] + =201.08, measured value 201.2.

[0467] Step 3

[0468] 14-3 (2.0 g, 9.99 mmol) and sodium hydroxide (2.40 g, 59.94 mmol) were dissolved in methanol and water (40 mL, 1 / 1, v / v), and the mixture was heated to 50 °C and stirred for 1 hour. After the reaction was complete, the methanol was removed by concentration under reduced pressure. The aqueous phase was washed with dichloromethane (20 mL × 2), and the pH of the aqueous phase was adjusted to 2 with hydrochloric acid (3 mol / L). Most of the water was removed by concentration under reduced pressure. The mixture was then slurried twice with dichloromethane / methanol (500 mL, 20 / 1, v / v), filtered, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 14-4, which was directly used in the next reaction. ESI-MS theoretical calculation: [M+H] + =173.05, measured value 173.1.

[0469] Step 4

[0470] 14-4 (200 mg, 0.35 mmol) was dissolved in acetic anhydride (30 mL), and the mixture was heated to 100 °C and stirred for 4 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 14-5, which was directly used in the next reaction step. 1 H NMR (400MHz, CDCl3): δ4.56-4.50(m,2H), 3.95-3.88(m,2H), 2.65-2.55(m,2H).

[0471] Step 5

[0472] 14-5 (1.3 g, 8.43 mmol) was dissolved in tetrahydrofuran (30 mL), and hydrazine hydrate (1.69 g, 33.72 mmol) was added. The mixture was heated to 70 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, and the crude product was added to ethanol (100 mL), stirred for 30 minutes, filtered, and dried to obtain 14-6. ESI-MS theoretical calculation: [M+H] + =169.06, measured value 169.0.

[0473] Step 6

[0474] 14-6 (1.3 g, 7.73 mmol) was dissolved in phosphorus oxychloride (25 mL), and N,N-diisopropylethylamine (5.0 g, 38.65 mmol) was added dropwise. The mixture was heated to 100 °C and stirred for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and dichloromethane (50 mL) was added. After cooling to 0 °C, N,N-diisopropylethylamine and saturated sodium bicarbonate aqueous solution were slowly added to adjust the pH to 8. The mixture was extracted with dichloromethane and methanol (80 mL × 2, 10 / 1, v / v), and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 14-7. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 4.66 (s, 2H), 3.95 (t, J = 5.6Hz, 2H), 2.77 (t, J = 5.6Hz, 2H). ESI-MS theoretical calculation: [M+H] + =205.00, measured value 205.1.

[0475] Step 7

[0476] 14-7 (800 mg, 3.9 mmol) and 1-1 (1.32 g, 5.85 mmol) were dissolved in dimethyl sulfoxide (8 mL), and potassium carbonate (1.34 g, 9.75 mmol) was added. The mixture was heated to 110 °C (microwave) and stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic layers were combined. The layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 2, v / v) to obtain 14-8A and 14-8B, respectively. 14-8A: ESI-MS theoretical value: [M+H] + =395.19, measured value 395.0. 14-8B: ESI-MS theoretical calculation value: [M+H] + =395.19, measured value 395.2.

[0477] Step 8

[0478] 14-8A (100 mg, 0.25 mmol), 14-9 (77 mg, 0.38 mmol), and potassium carbonate (140 mg, 1.01 mmol) were added to 1,4-dioxane (10 mL) and water (2 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (21 mg, 25 μmol). The mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 1, v / v) to obtain 14-10. ESI-MS theoretical value: [M+H] + =521.24, measured value 520.9.

[0479] Step 9

[0480] 14-10 (120 mg, 0.23 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a crude product containing 14-11, which was directly used in the next reaction. ESI-MS theoretical calculation: [M+H] + =421.19, measured value 421.0.

[0481] Step 10

[0482] Dissolve 14-11 (95 mg, 0.23 mmol) and 37% formaldehyde solution (28 mg, 0.35 mmol) in methanol (5 mL), then add sodium triacetoxyborohydride (150 mg, 0.69 mmol) and stir at 25 °C for 12 hours. After the reaction is complete, add saturated sodium bicarbonate solution (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic layers, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.04% ammonia + 7.5 mmol / L ammonium bicarbonate aqueous solution; gradient: 22-32%, retention time: 8.0-12.0 min) to obtain 14. 1H NMR (400MHz, DMSO-d6): δ10.55(br s,1H),7.41(d,J=7.6Hz,1H),7.27-7.17(m,2H),4.50-4.29(m,3H),4.08-3.99(m,1 H),3.94-3.84(m,1H),3.63-3.52(m,1H),3.47-3.37(m,1H),3.02-2.90(m,1H),2.7 5-2.64(m, 1H), 2.59-2.50(m, 1H), 2.47-2.39(m, 1H), 2.37-2.30(m, 1H), 2.29-2.19(m, 1H), 212-2.03(m, 4H), 1.95-1.85(m, 1H), 1.84-1.61(m, 3H). ESI-MS theoretical calculation: [M+H] + =435.20, measured value 435.1.

[0483] Example 15

[0484] Synthesis route:

[0485] first step

[0486] 14-8B (100 mg, 0.25 mmol), 14-9 (77 mg, 0.38 mmol), and potassium carbonate (140 mg, 1.01 mmol) were added to 1,4-dioxane (10 mL) and water (2 mL), followed by methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (21 mg, 25 μmol). The mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 1, v / v) to obtain 15-1. ESI-MS theoretical calculation: [M+H] + =521.24, measured value 520.9.

[0487] Step 2

[0488] 15-1 (95 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a crude product containing 15-2, which was directly used in the next reaction step. ESI-MS theoretical calculation: [M+H] + =421.19, measured value 420.9.

[0489] Step 3

[0490] 15-2 (70 mg, 0.17 mmol) and 37% formaldehyde solution (21 mg, 0.26 mmol) were dissolved in methanol (5 mL), and sodium triacetoxyborohydride (140 mg, 0.68 mmol) was added. The mixture was stirred at 25 °C for 12 hours. After the reaction was completed, saturated sodium bicarbonate solution (30 mL) was added, followed by extraction with ethyl acetate (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Waters 3767 / Qda Column: Pursuit Xrs C18, 21.2*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 18-28%, retention time: 7.2-8.7 min) to obtain 15. 1 H NMR (400MHz, DMSO-d6): δ10.65(br s, 1H), 7.40 (d, J=7.6Hz, 1H), 7.27-7.20 (m, 2H), 4.74-4.56 (m, 2H), 4.44-4.37 (m, 1H), 4.03-3.90 (m, 1H), 3.77-3.70 (m, 2H), 3.32-3.29 (m, 2H), 2.92-2.82 (m, 1H), 2.67-2.58 (m, 1H), 2.57-2.53 (m, 1H), 2.46-2.37 (m, 1H), 2.31-2.23 (m, 2H), 2.21 (s, 3H), 1.98-1.83 (m, 1H), 1.82-1.62 (m, 3H). ESI-MS theoretical calculation: [M+H] + =435.20, measured value 435.1.

[0491] Example 16

[0492] Synthesis route:

[0493] first step

[0494] Intermediate A (240 mg, 0.55 mmol), 16-1 (151 mg, 0.66 mmol), cesium carbonate (358 mg, 1.10 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.011 mmol) were added to 1,4-dioxane (3 mL). The mixture was heated to 110 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 16-2. ESI-MS theoretical calculation [M+H] + =626.3, measured value 626.0.

[0495] Step 2

[0496] 16-2 (150 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 0.48 mL, 0.48 mmol) was added. The mixture was stirred for 3 hours. After the reaction was completed, the reaction was quenched successively with water (0.2 mL) and 15% sodium hydroxide solution (0.2 mL). The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing 16-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =567.3, measured value 566.9.

[0497] Step 3

[0498] 16-3 (120 mg, 0.21 mmol) was dissolved in methanol (3 mL), cooled to 0 °C, and sodium borohydride (13 mg, 0.32 mmol) was added. The mixture was stirred for 1 hour. After the reaction was complete, saturated ammonium chloride aqueous solution (10 mL) and water (20 mL) were added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 16-4. ESI-MS theoretical calculation [M+H] + =569.3, measured value 569.1.

[0499] Step 4

[0500] 16-4 (80 mg, 0.14 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.4 mL) was added dropwise. The mixture was stirred for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 16-5, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =411.2, measured value 411.0.

[0501] Step 5

[0502] 16-5 (63 mg, 0.15 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.12 mL, 1.5 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (95 mg, 0.45 mmol) were added sequentially. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.04% ammonia aqueous solution; gradient: 30-40%; retention time: 6.2-8.1 min) to obtain 16-5. 1 H NMR (400MHz, DMSO-d6): δ10.18(br s, 1H), 7.56(s, 1H), 7.14(s, 1H), 7.08(s, 1H), 5.60(t, J = 5.2 Hz, 1H), 4.57-4.47(m, 2H), 4.11-4.01(m, 2H), 3.90-3.80(m, 1H), 3.71-3.61(m, 1H), 3.49-3.39(m, 1H), 3.38-3.33(m, 1H), 3.08-3.00(m, 1H), 2.94-2.84(m, 1H), 2.78-2.68(m, 1H), 2.52-2.42(m, 1H), 2.31(s, 3H), 2.11(s, 3H). ESI-MS theoretical calculation values ​​[M+H] + =425.2, measured value 425.0.

[0503] Example 17

[0504] Synthesis route:

[0505] first step

[0506] Intermediate A (240 mg, 0.55 mmol), 17-1 (150 mg, 0.66 mmol), cesium carbonate (358 mg, 1.10 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 0.011 mmol) were added to 1,4-dioxane (3 mL). The mixture was heated to 110 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 16-2. ESI-MS theoretical calculation [M+H] + =626.3, measured value 626.9.

[0507] Step 2

[0508] 17-2 (170 mg, 0.27 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 °C, and diisobutylaluminum hydride (1 mol / L n-hexane solution, 0.54 mL, 0.54 mmol) was added. The mixture was stirred for 3 hours. After the reaction was completed, the reaction was quenched successively with water (0.2 mL) and 15% sodium hydroxide solution (0.2 mL). The solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product containing 17-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =567.3, measured value 567.4.

[0509] Step 3

[0510] 16-3 (150 mg, 0.26 mmol) was dissolved in methanol (3 mL), cooled to 0 °C, and sodium borohydride (15 mg, 0.39 mmol) was added. The mixture was stirred for 1 hour. After the reaction was complete, saturated ammonium chloride aqueous solution (10 mL) and water (20 mL) were added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 17-4. ESI-MS theoretical calculation [M+H] + =569.3, measured value 569.0.

[0511] Step 4

[0512] 17-4 (130 mg, 0.23 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.4 mL) was added dropwise. The mixture was stirred for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 17-5, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =411.2, measured value 411.1.

[0513] Step 5

[0514] 17-5 (90 mg, 0.22 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.12 mL, 1.5 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (140 mg, 0.45 mmol) were added sequentially. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.04% ammonia + 7.5 mmol / L ammonium bicarbonate aqueous solution; gradient: 27-37%; retention time: 8.5-9.5 min) to obtain 17. 1 ¹H NMR (400MHz, DMSO-d6): δ 10.36 (br s, 1H), 7.61 (s, 1H), 7.12 (s, 1H), 7.08 (s, 1H), 5.63–5.53 (m, 1H), 4.71–4.49 (m, 2H), 4.02–3.92 (m, 1H), 3.90–3.80 (m, 1H), 3.79–3.69 (m, 1H), 3.55–3.45 (m, 1H), 3.30–3.20 (m, 2H), 3.19–3.11 (m, 1H), 2.97–2.87 (m, 1H), 2.75–2.65 (m, 2H), 2.39–2.29 (m, 4H), 2.08 (s, 3H). ESI-MS theoretical calculation [M+H] + =425.2, measured value 425.0.

[0515] Example 18

[0516] Synthesis route:

[0517] first step

[0518] 18-1 (190 mg, 1.01 mmol), 1-1 (274 mg, 1.21 mmol), and N,N-diisopropylethylamine (419 mg, 3.03 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the mixture was heated to 120 °C and stirred for 2 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 18-2. ESI-MS theoretical calculation [M+H] + =379.2, measured value 379.0.

[0519] Step 2

[0520] 18-2 (150 mg, 0.40 mmol), 14-9 (124 mg, 0.60 mmol), potassium carbonate (221 mg, 1.6 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34 mg, 0.4 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (19 mg, 0.004 mmol) were added to 1,4-dioxane (15 mL) and water (3 mL), and the mixture was heated to 110 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 18-3. ESI-MS theoretical calculation value [M+H] + =505.2, measured value 505.3.

[0521] Step 3

[0522] 18-3 (140 mg, 0.28 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 18-4, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =405.2, measured value 405.4.

[0523] Step 4

[0524] 18-4 (112 mg, 0.28 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.28 mL, 2.8 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (297 mg, 1.40 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 27-37%; retention time: 7.7-10.1 min) to obtain 18-4. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.18 (br s, 1H), 7.65 (d, J=8.0Hz, 1H), 7.27–7.20 (m, 2H), 4.57–4.47 (m, 1H), 3.92–3.87 (m, 1H), 3.74–3.60 (m, 1H), 3.28–3.17 (m, 2H), 3.17–2.97 (m, 3H), 2.96–2.79 (m, 3H), 2.57 (s, 3H), 2.47–2.37 (m, 1H), 2.19–2.03 (m, 1H), 2.02–1.87 (m, 4H), 1.83–1.78 (m, 1H). ESI-MS theoretical calculations [M+H] + =419.2, measured value 419.5.

[0525] Example 19

[0526] Synthesis route:

[0527] first step

[0528] 19-1 (7.38 g, 53.00 mmol) was dissolved in dichloromethane (210 mL), and 19-2 (8 g, 53.00 mmol) was added at 0 °C, and the mixture was stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain 19-3. 1 ¹H NMR (400MHz, CDCl₃) δ 5.23 (s, 4H). ESI-MS theoretical calculation [M+H] + =191.0, measured value 190.9.

[0529] Step 2

[0530] 19-3 (200 mg, 1.05 mmol), 1-1 (285 mg, 1.26 mmol), and N,N-diisopropylethylamine (407 mg, 3.15 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the mixture was heated to 120 °C and stirred for 2 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 19-4. ESI-MS theoretical calculation [M+H] + =381.2, measured value 381.0.

[0531] Step 3

[0532] 19-4 (100 mg, 0.26 mmol), 14-9 (80 mg, 0.39 mmol), potassium carbonate (144 mg, 1.04 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (20 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (12 mg, 0.03 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 110 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 19-5. ESI-MS theoretical calculation value [M+H] + =507.2, measured value 507.1.

[0533] Step 4

[0534] 19-5 (108 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 19-6, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =407.2, measured value 407.2.

[0535] Step 5

[0536] 19-6 (86 mg, 0.21 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.1 mL, 1.0 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (222 mg, 1.05 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: Pursuit Xrs C18, 21.2*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 23-33%; retention time: 8.0-9.6 min) to obtain 19. 1 H NMR (400MHz, DMSO-d6): δ12.62(br s, 1H), 7.49 (d, J=8.0Hz, 1H), 7.28-7.18 (m, 2H), 5.43-5.33 (m, 2H), 5.20-5.05 (m, 2H), 4.37-4.25 (m, 1H), 3.85-3.75 (m, 1H), 3.69-3.59 (m, 1H), 3.03-2.93 (m, 1H), 2.52-2.42 (m, 1H), 2.40-2.26 (m, 1H), 2.16 (s, 3H), 2.12-2.02 (m, 2H), 1.97-1.84 (m, 3H), 1.73-1.63 (m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =421.2, measured value 421.2.

[0537] Example 20

[0538] Synthesis route:

[0539] first step

[0540] 18-2 (100 mg, 0.26 mmol), intermediate B (120 mg, 0.34 mmol), potassium carbonate (144 mg, 1.04 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (22 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (12 mg, 0.03 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 7, v / v) to obtain 20-1. ESI-MS theoretical calculation value [M+H] + =573.3, measured value 573.6.

[0541] Step 2

[0542] 20-1 (136 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 20-2, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =415.2, measured value 415.1.

[0543] Step 3

[0544] 20-2 (98 mg, 0.24 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.12 mL, 1.2 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (305 mg, 1.44 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: Pursuit Xrs C18, 21.2*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 14-24%; retention time: 7.5-9.6 min) to obtain 20. 1H NMR (400MHz, DMSO-d6): δ12.14(br s, 1H), 8.14(s, 1H), 7.87-7.56(m, 1H), 7.49-7.39(m, 2H), 4.56-4.46(m, 1H), 3.95-3.85(m, 1H), 3.73-3.63(m, 1H), 3.24(s, 3H), 3.25-3.15(m, 2H), 3.18-2.96(m, 3H), 2.92-2.74(m, 3H), 2.52(s, 3H), 2.46-2.36(m, 1H), 2.14-2.03(m, 1H), 2.03-1.87(m, 4H), 1.84-1.74(m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =429.2, measured value 429.2.

[0545] Example 21

[0546] Synthesis route:

[0547] first step

[0548] 14-8A (90 mg, 0.23 mmol), intermediate B (310 mg, 0.35 mmol), potassium carbonate (130 mg, 0.92 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (11 mg, 0.03 mmol) were added to 1,4-dioxane (15 mL) and water (3 mL), and the mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 21-1. ESI-MS theoretical calculation [M+H] + =589.3, measured value 589.2.

[0549] Step 2

[0550] 21-1 (120 mg, 0.20 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 21-2, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =431.2, measured value 431.1.

[0551] Step 3

[0552] 21-2 (92 mg, 0.21 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.12 mL, 1.2 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (130 mg, 0.63 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 10-30%; retention time: 7.2-9.2 min) to obtain 21-2. 1 H NMR (400MHz, DMSO-d6): δ10.68(br s,1H),7.49-7.37(m,3H),4.55-4.47(m,1H),4.46-4.36(m,1H),4.33-4.27(m,1H),4.10-3 .98(m,1H),3.94-3.84(m,1H),3.63-3.52(m,1H),3.47-3.39(m,1H),3.24(s,3H),3.03-2. 88 (m, 1H), 2.75-2.66 (m, 1H), 2.59-2.49 (m, 1H), 2.48-2.41 (m, 1H), 2.38-2.30 (m, 1H), 2.29-2.20 (m, 1H), 2.18-2.02 (m, 4H), 1.96-1.84 (m, 1H), 1.84-1.58 (m, 3H). ESI-MS theoretical calculation values ​​[M+H] + =445.2, measured value 445.0.

[0553] Examples 22 and 23

[0554] Synthesis route:

[0555] first step

[0556] 18-1 (1 g, 5.29 mmol) was dissolved in 1,2-dichloroethane (50 mL), and azobisisobutyronitrile (87 mg, 0.53 mmol) and N-bromosuccinimide (998 mg, 5.61 mmol) were added. The mixture was heated to 80 °C and stirred for 3 hours. After the reaction was complete, sodium hydroxide aqueous solution (0.5 mol / L, 50 mL) was added, followed by extraction with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain 22-1. 1¹H NMR (400MHz, CDCl₃): δ 5.40 (d, J = 8.0Hz, 1H), 3.39–3.30 (m, 1H), 3.16–3.03 (m, 1H), 2.82–2.59 (m, 2H). ESI-MS theoretical values ​​[M+H] + =266.9 and 268.9, actual values ​​266.7 and 268.7.

[0557] Step 2

[0558] 22-1 (1.1 g, 4.11 mmol) was dissolved in ethylene glycol dimethyl ether (22 mL) and water (1.5 mL), and silver perchlorate monohydrate (1.39 g, 6.17 mmol) was added at 25 °C. Under nitrogen protection, the reaction mixture was heated to 60 °C and stirred for 3 hours. After the reaction was completed, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 22-2. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 5.86 (d, J = 8.0Hz, 1H), 5.29–5.24 (m, 1H), 3.17–3.09 (m, 1H), 2.95–2.87 (m, 1H), 2.44–2.38 (m, 1H), 1.99–1.91 (m, 1H). ESI-MS theoretical calculations [M+H] + =205.0, measured value 204.9.

[0559] Step 3

[0560] 22-2 (570 mg, 2.78 mmol), 1-1 (755 mg, 3.34 mmol), and N,N-diisopropylethylamine (1.08 g, 8.34 mmol) were dissolved in dimethyl sulfoxide (10 mL), and the mixture was heated to 120 °C and stirred for 8 hours. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 22-3A and 22-3B, respectively. 22-3A: ESI-MS theoretical calculation value [M+H] + =395.2, measured value 395.1. 22-3B: ESI-MS theoretical calculation value [M+H] + =395.2, measured value 395.1.

[0561] Step 4

[0562] 22-3B (225 mg, 0.57 mmol), 14-9 (235 mg, 1.14 mmol), potassium carbonate (315 mg, 2.28 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (48 mg, 0.06 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (27 mg, 0.06 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection. After the reaction, water (50 mL) and ethyl acetate (50 mL × 3) were added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified sequentially by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) and high-performance liquid chromatography (Waters 3767 / Qda Column: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; flow rate: 20 mL / min; gradient: 40-50%, where the ratio is the volume ratio of acetonitrile in the mobile phase; the gradient elution was initially maintained at a 40% gradient for 1 min, then linearly increased to 40%-50% over the next 10 min) to obtain 22-4 (retention time: 6.2-7.2 min) and 23-4 (retention time: 8.7-10.3 min). 22-4: ESI-MS theoretical calculated value [M+H] + =521.2, measured value 521.1. 23-4: ESI-MS theoretical calculation value [M+H] + =521.2, measured value 521.5.

[0563] Step 5

[0564] 22-4 (93 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour and concentrated under reduced pressure to obtain an oily substance. This oily substance was then dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.09 mL, 0.9 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (153 mg, 0.72 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: Pursuit Xrs C18, 21.2*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 18-28%; retention time: 8.2-9.1 min) to obtain 22-4. 1H NMR (400MHz, DMSO-d6): δ7.99 (d, J = 8.4Hz, 1H), 7.25-7.15 (m, 2H), 5.28-5.18 (m, 1H), 4.47 -4.37(m,1H),3.96-3.85(m,1H),3.81-3.71(m,1H),3.36-3.24(m,2H),3.15-3.05(m,1H),2 .98-2.88(m, 1H), 2.50-2.40(m, 1H), 2.37-2.28(m, 1H), 2.26-2.18(m, 1H), 2.16(s, 3H), 2.14-2.07(m, 1H), 2.06-1.97(m, 2H), 1.95-1.82(m, 3H), 1.73-1.63(m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =435.2, measured value 435.1.

[0565] Starting with 23-4 (119 mg, 0.23 mmol), 23 was purified by a similar reaction procedure and high performance liquid chromatography (Waters 3767 / Qda Column: Pursuit Xrs C18, 21.2*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 18-28%, retention time: 8.5-9.2 min). 1 ¹H NMR (400MHz, DMSO-d⁶): 8.14 (d, J = 8.0Hz, 1H), 7.27–7.17 (m, 2H), 5.13 (d, J = 5.2Hz, 1H), 4.47–4.37 (m, 1H), 4.01–3.92 (m, 1H), 3.71–3.61 (m, 1H), 3.40–3.34 (m, 1H), 3.11–3.01 (m, 1H), 2.82–2.72 (m, 1H), 2.40–2.30 (m, 2H), 2.19–2.07 (m, 6H), 2.04–1.95 (m, 2H), 1.94–1.84 (m, 2H), 1.72–1.62 (m, 1H). ESI-MS theoretical calculations [M+H] + =435.2, measured value 435.1.

[0566] Examples 24 and 25

[0567] Synthesis route:

[0568] first step

[0569] 22-3A (200 mg, 0.51 mmol), 14-9 (136 mg, 0.66 mmol), potassium carbonate (315 mg, 2.28 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (43 mg, 0.05 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (24 mg, 0.05 mmol) were added to 1,4-dioxane (15 mL) and water (3 mL), and the mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection. After the reaction, water (50 mL) and ethyl acetate (50 mL × 3) were added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified sequentially by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) and high-performance liquid chromatography (Waters 3767 / Qda Column: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; flow rate: 20 mL / min; gradient: 40-50%, where the ratio is the volume ratio of acetonitrile in the mobile phase; the gradient elution was initially maintained at a 40% gradient for 1 min, then linearly increased to 40%-50% over the next 10 min) to obtain 24-1 (retention time: 6.8-7.7 min) and 25-1 (retention time: 9.1-10.3 min). 24-1: ESI-MS theoretical calculated value [M+H] + =521.2, measured value 521.6. 25-1: ESI-MS theoretical calculation value [M+H] + =521.2, measured value 521.5.

[0570] Step 2

[0571] 24-1 (82 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour and concentrated under reduced pressure to obtain an oily substance. This oily substance was then dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.08 mL, 0.8 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (135 mg, 0.64 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 20-30%; retention time: 7.9-10.6 min) to obtain 24-1. 1H NMR (400MHz, DMSO-d6): δ12.18(br s,1H),7.65(d,J=8.4Hz,1H),7.27-7.17(m,2H),5.48-5.39(m,1H),5.34-5.26(m,1H),4.64 -4.56(m,1H),4.15-4.06(m,1H),3.71-3.61(m,1H),3.14-3.04(m,1H),2.99-2.90(m,1H),2 .87-2.77(m, 1H), 2.56-2.46(m, 1H), 2.41-2.31(m, 1H), 2.30-2.18(m, 1H), 2.16(s, 3H), 2.13-2.01(m, 2H), 2.00-1.85(m, 3H), 1.85-1.78(m, 1H), 1.75-1.65(m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =435.2, measured value 435.2.

[0572] Starting with 25-1 (123 mg, 0.24 mmol), 25 was obtained by a similar reaction procedure and purification by high performance liquid chromatography (Waters 3767 / Qda Column: Pursuit Xrs C18, 21.2*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 20-30%, retention time: 7.5-8.9 min). 1 H NMR(400MHz,DMSO-d6):12.28(br s, 1H), 7.64 (d, J=8.4Hz, 1H), 7.26-7.16 (m, 2H), 5.39-5.29 (m, 2H), 4.57-4.47 (m, 1H), 4.13-4.03 (m, 1H), 3.87-3.77 (m, 1H), 3.21-3.11 (m, 2H), 2.81-2.71 (m, 1H), 2.52-2.42 (m, 1H), 2.34-2.22 (m, 1H), 2.15 (s, 3H), 2.14-2.04 (m, 3H), 1.99-1.90 (m, 3H), 1.89-1.81 (m, 1H), 1.73-1.63 (m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =435.2, measured value 435.2.

[0573] Example 26

[0574] Synthesis route:

[0575] first step

[0576] 19-4 (50 mg, 0.13 mmol), intermediate B (60 mg, 0.17 mmol), potassium carbonate (72 mg, 0.52 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (11 mg, 0.013 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6 mg, 0.013 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 26-1. ESI-MS theoretical calculation [M+H] + =575.3, measured value 575.6.

[0577] Step 2

[0578] 26-1 (150 mg, 0.26 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 26-2, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =417.2, measured value 417.2.

[0579] Step 3

[0580] 26-2 (108 mg, 0.26 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.26 mL, 2.6 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (330 mg, 1.56 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: Pursuit Xrs C18, 21.2*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 14-24%; retention time: 7.5-9.6 min) to obtain 26-2. 1H NMR (400MHz, DMSO-d6): δ12.27(br s, 1H), 7.57 (d, J=8.0Hz, 1H), 7.50-7.40 (m, 2H), 5.41-5.33 (m, 2H), 5.20-5.07 (m, 2H), 4.57-4.47 (m, 1H), 3.84-3.74 (m, 1H), 3.71-3.60 (m, 1H), 3.50-3.40 (m, 1H), 3.37-3.27 (m, 1H), 3.24 (s, 3H), 3.11-2.88 (m, 2H), 2.65 (s, 3H), 2.48-2.39 (m, 1H), 2.19-1.92 (m, 3H), 1.86-1.83 (m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =431.2, measured value 431.0.

[0581] Examples 27 and 28

[0582] Synthesis route:

[0583] first step

[0584] Dissolve 1-3 (110 mg, 0.19 mmol) in tetrahydrofuran (2 mL), cool to -78 °C under nitrogen protection, add isopropyl magnesium chloride-lithium chloride (1.3 mol / L tetrahydrofuran solution, 0.15 mL, 0.19 mmol), stir for 2 hours, quench the reaction with saturated ammonium chloride aqueous solution (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure to obtain crude product, and purify by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 27-1 and 28-1. 27-1: ESI-MS theoretical value [M+H] + =609.3, measured value 609.3. 28-1: ESI-MS theoretical calculation value [M+H] + =609.3, measured value 609.3.

[0585] Step 2

[0586] 27-1 (12 mg, 0.02 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour and concentrated under reduced pressure to obtain an oily substance. This oily substance was then dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.01 mL, 0.1 mmol) and sodium triacetoxyborohydride (17 mg, 0.08 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: Agilent C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 27-37%; retention time: 8.0-9.4 min) to obtain 27-1. 1 H NMR (400MHz, DMSO-d6): δ10.19(br s,1H),7.51(s,1H),7.13(s,1H),7.06(s,1H),5.40-5.30(m,1H),4.77-4.37(m,1 H),4.60-4.50(m,1H),3.84-3.78(m,1H),3.27-3.17(m,1H),2.94-2.84(m,1H),2. 75-2.65(m,2H), 2.43-2.20(m,5H), 2.11(s,3H), 2.05-1.95(m,2H), 1.93-1.78(m,2H), 1.75-1.57(m,1H), 0.99-0.89(m,3H), 0.62-0.52(m,3H). ESI-MS theoretical calculation values ​​[M+H] + =465.3, measured value 465.1.

[0587] Starting with 28-1 (53 mg, 0.09 mmol), 28 was purified by a similar reaction procedure and high performance liquid chromatography (Waters 3767 / Qda Column: Agilent C18, 21.2*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 24-34%, retention time: 7.0-8.1 min). 1H NMR(400MHz,DMSO-d6):10.22(br s, 1H), 7.46(s, 1H), 7.13(s, 1H), 7.07(s, 1H), 4.78-4.68(m, 1H), 4.58-4.54(m, 1H), 3.73-3.68(m, 1H), 3.59-3.53(m, 1H), 3.32-3.22(m, 1H), 2.78-2.67(m, 3H), 2.48(s, 3H), 2.40-2.33(m, 1H), 2.14(s, 3H), 2.05-1.89(m, 4H), 1.83-1.78(m, 1H), 1.02-0.92(m, 3H), 0.84-0.74(m, 3H). ESI-MS theoretical calculation values ​​[M+H] + =465.3, measured value 465.1.

[0588] Example 29

[0589] Synthesis route:

[0590] first step

[0591] 19-4 (100 mg, 0.26 mmol), intermediate C (160 mg, 0.52 mmol), potassium carbonate (90 mg, 0.65 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (22 mg, 0.026 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (12 mg, 0.026 mmol) were added to 1,4-dioxane (12 mL) and water (3 mL), and the mixture was heated to 100 °C and stirred for 2 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 29-1. ESI-MS theoretical calculation value [M+H] + =522.3, measured value 522.2.

[0592] Step 2

[0593] 29-1 (126 mg, 0.24 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 29-2, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =364.2, measured value 364.1.

[0594] Step 3

[0595] 29-2 (87 mg, 0.24 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.04 mL, 0.4 mmol) and sodium triacetoxyborohydride (150 mg, 0.72 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 14-24%; retention time: 7.1-9.3 min) to obtain 29-2. 1 ¹H NMR (400MHz, DMSO-d6): δ 12.80 (br s, 1H), 7.47–7.41 (m, 1H), 7.36–7.31 (m, 2H), 5.41–5.31 (m, 2H), 5.21–5.09 (m, 2H), 4.37–4.26 (m, 1H), 3.84–3.75 (m, 1H), 3.69–3.60 (m, 1H), 3.02–2.92 (m, 1H), 2.52–2.42 (m, 1H), 2.36–2.30 (m, 1H), 2.16 (s, 3H), 2.10–2.00 (m, 2H), 1.97–1.83 (m, 3H), 1.71–1.64 (m, 1H). ESI-MS theoretical calculation [M+H] + =378.2, measured value 378.1.

[0596] Examples 30 and 31

[0597] Synthesis route:

[0598] first step

[0599] Intermediate F (150 mg, 0.41 mmol) was dissolved in tetrahydrofuran (7 mL), cooled to -78 °C under nitrogen protection, and vinyl magnesium bromide (1.0 mol / L tetrahydrofuran solution, 0.82 mL, 0.82 mmol) was added. The mixture was stirred for 1 hour, then heated to 25 °C and stirred for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 30-1 and 31-1. 30-1: ESI-MS theoretical value [M+H] +=395.2, measured value 395.0. 31-1: ESI-MS theoretical calculation value [M+H] + =395.2, measured value 395.1.

[0600] Step 2

[0601] Add 31-1 (50 mg, 0.13 mmol), A-4 (70 mg, 0.20 mmol), potassium carbonate (45 mg, 0.33 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (11 mg, 0.013 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6 mg, 0.013 mmol) to 1,4-dioxane (3 mL) and water (1 mL), heat to 100 °C and stir for 1 hour under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 31-2. ESI-MS theoretical calculation [M+H] + =593.3, measured value 593.3.

[0602] Step 3

[0603] 31-2 (66 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour and concentrated under reduced pressure to obtain an oily substance. This oily substance was then dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.02 mL, 0.2 mmol) and sodium triacetoxyborohydride (76 mg, 0.36 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 32-42%; retention time: 6.6-8.2 min) to obtain 31. 1H NMR (400MHz, DMSO-d6): δ10.18(br s,1H),7.45(s,1H),7.11(s,1H),7.06(s,1H),6.15-6.05(m,1H),5.82(d,J=5.2Hz,1H),5.43-5.33( m,1H),5.32-5.23(m,1H),5.14-5.08(m,1H),4.51-4.42(m,1H),3.92-3.80(m,1H),3.50-3.41(m,1H ), 2.62-2.52(m,1H), 2.45-2.35(m,2H), 2.32-2.22(m,1H), 2.17-2.12(m,1H), 2.11(s,3H), 2.10(s,3H), 1.99-1.90(m,1H), 1.89-1.81(m,1H), 1.80-1.70(m,1H), 1.67-1.55(m,1H). ESI-MS theoretical calculation values ​​[M+H] + =449.2, measured value 449.0.

[0604] Starting with 30-1 (25 mg, 0.06 mmol), 30 was obtained by purification through similar reaction steps and high performance liquid chromatography (Column: C18 spherical, 20-35 μm, 100 A, 20 g; mobile phase: acetonitrile-0.03% ammonia aqueous solution; gradient: 10-30%, retention time: 7.0-12.0 min). 1 H NMR(400MHz,DMSO-d6):10.19(br s,1H),7.35(s,1H),7.12(s,1H),7.05(s,1H),6.22-6.10(m,1H),5.79-5.69(m,1H),5.37 -5.32(m,1H),5.31-5.25(m,1H),5.24-5.20(m,1H),4.50-4.42(m,1H),3.96-3.85(m,1H) ,3.52-3.42(m,1H),2.54-2.48(m,2H),2.44-2.37(m,1H),2.30-2.22(m,1H),2.21-2.15(m,1H),2.14(s,3H),2.11(s,3H),1.97-1.74(m,3H),1.74-1.65(m,1H). ESI-MS theoretical calculation values ​​[M+H] + =449.2, measured value 449.1.

[0605] Example 32

[0606] Synthesis route:

[0607] first step

[0608] Dissolve 1-3 (60 mg, 0.11 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL) dropwise, stir for 1 hour, and concentrate under reduced pressure after the reaction to obtain a crude product containing 32-1, which is directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =407.2, measured value 407.5.

[0609] Step 2

[0610] 32-1 (45 mg, 0.11 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.02 mL, 0.2 mmol) and sodium triacetoxyborohydride (47 mg, 0.22 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution (5 mL) was added, followed by extraction with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 32-2. ESI-MS theoretical calculation value [M+H] + =421.2, measured value 421.2.

[0611] Step 3

[0612] 32-2 (20 mg, 0.05 mmol) was dissolved in dry tetrahydrofuran (3 mL), cooled to -78 °C under nitrogen protection, and a tetrahydrofuran solution of magnesium acetylene bromide (0.5 mol / L, 0.29 mL, 0.14 mmol) was added dropwise. The mixture was stirred at -78 °C for 1 hour. After the reaction was complete, 10 mL of saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The mixture was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Waters 3767 / Qda Column: SunFire C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 40-55%, retention time: 6.5-7.8 min) to obtain 32. 1H NMR (400MHz, DMSO-d6): δ10.22(br s, 1H), 7.59(s, 1H), 7.13(s, 1H), 7.08(s, 1H), 6.52-6.42(m, 1H), 5.62-5.52(m, 1H), 4.57-4.48(m, 1H), 4.03-3.93(m, 1H), 3.74-3.65(m, 1H), 3.66-3.56(m, 1H), 2.72-2.63(m, 1H), 2.35-2.23(m, 4H), 2.14(s, 3H), 2.13(s, 3H), 1.99-1.89(m, 2H), 1.89-1.78(m, 1H), 1.73-1.63(m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =447.2, measured value 447.1.

[0613] Example 33

[0614] Synthesis route:

[0615] first step

[0616] Intermediate F (600 mg, 1.64 mmol) was dissolved in tetrahydrofuran (8 mL) and cooled to 0 °C under nitrogen protection. A tetrahydrofuran solution of lanthanum(III) chloride bis(lithium chloride) complex (0.6 mol / L, 2.73 mL, 1.64 mmol) and a tetrahydrofuran solution of methylmagnesium bromide (3 mol / L tetrahydrofuran solution, 1.09 mL, 3.28 mmol) were added. The mixture was stirred for 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution (15 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 33-1A and 33-1B. 33-1A: ESI-MS theoretical calculation value [M+H] + =383.2, measured value 383.1. 33-1B: ESI-MS theoretical calculation value [M+H] + =383.2, measured value 383.2.

[0617] Step 2

[0618] 33-1B (100 mg, 0.26 mmol), intermediate E (170 mg, 0.39 mmol), potassium carbonate (108 mg, 0.78 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (22 mg, 0.026 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (12 mg, 0.026 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 33-2. ESI-MS theoretical calculation value [M+H] + =579.3, measured value 579.4.

[0619] Step 3

[0620] 33-2 (90 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 33-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =421.2, measured value 421.1.

[0621] Step 4

[0622] 33-3 (65 mg, 0.15 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.15 mL, 1.5 mmol) and sodium triacetoxyborohydride (95 mg, 0.45 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Waters 3767 / Qda Column: Agilent C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 12-22%, retention time: 8.7-10.3 min) to obtain 33. 1 H NMR (400MHz, DMSO-d6): δ10.03(br s,1H),7.55(s,1H),7.22(t,J H-F=72.0Hz, 1H), 6.73-6.45(m, 2H), 5.50-5.40(m, 1H), 4.99-4.55(m, 1H), 4.55-4.52(m, 1H), 3.82-3.76(m, 1H), 3.25-3.03(m, 2H), 2.87-2.77(m, 1H), 2.73-2.63(m, 1H), 2.50-2.40(m, 1H), 2.39-2.30(m, 4H), 2.07(s, 3H), 2.02-1.95(m, 1H), 1.85-1.81(m, 2H), 1.76-1.63(m, 1H), 1.29(d, J = 6.4Hz, 3H). ESI-MS theoretical calculation values ​​[M+H] + =435.2, measured value 435.2.

[0623] Example 34

[0624] Synthesis route:

[0625] first step

[0626] Intermediate F (150 mg, 0.41 mmol) was dissolved in tetrahydrofuran (7 mL), cooled to -78 °C under nitrogen protection, and vinyl magnesium bromide (1.0 mol / L tetrahydrofuran solution, 0.82 mL, 0.82 mmol) was added. The mixture was stirred for 1 hour, then heated to 25 °C and stirred for another 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 30-1 and 31-1. 30-1: ESI-MS theoretical value [M+H] + =395.2, measured value 395.0. 31-1: ESI-MS theoretical calculation value [M+H] + =395.2, measured value 395.1.

[0627] Step 2

[0628] 31-1 (80 mg, 0.20 mmol), intermediate E (107 mg, 0.31 mmol), potassium carbonate (69 mg, 0.50 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (17 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 0.02 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 34-1. ESI-MS theoretical calculation value [M+H] + =591.3, measured value 591.5.

[0629] Step 3

[0630] 34-1 (100 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 34-2, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =433.2, measured value 433.1.

[0631] Step 4

[0632] 34-2 (73 mg, 0.16 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.16 mL, 1.6 mmol) and sodium triacetoxyborohydride (102 mg, 0.48 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution; gradient: 37-47%, retention time: 6.7-8.2 min) to obtain 34. 1 H NMR (400MHz, DMSO-d6): δ9.98(br s,1H),7.42(s,1H),7.21(t,J H-F=72.0Hz,1H),6.59-6.56(m,2H),6.09(dd,J=17.2,10.3Hz,1H),5.85-5.70(m,1H),5.41-5.31(m,1H) ,5.28(d,J=17.2Hz,1H),5.10(d,J=10.3Hz,1H),4.47-4.43(m,1H),3.87-3.81(m,1H),3.52-3.38(m, 1H), 2.61-2.56(m,1H), 2.46-2.40(m,1H), 2.38-2.34(m,1H), 2.28-2.23(m,1H), 2.15-2.12(m,1H), 2.10(s,3H), 2.05(s,3H), 1.99-1.92(m,1H), 1.88-1.71(m,2H), 1.66-1.58(m,1H). ESI-MS theoretical calculation values ​​[M+H] + =447.2, measured value 447.2.

[0633] Examples 35 and 36

[0634] Synthesis route:

[0635] first step

[0636] Intermediate F (50 mg, 0.14 mmol) was dissolved in tetrahydrofuran (3 mL), cooled to 0 °C under nitrogen protection, and then lanthanum(III) chloride bis(lithium chloride) complex (0.6 mol / L tetrahydrofuran solution, 0.23 mL, 0.14 mmol) and cyclopropylmagnesium bromide (0.5 mol / L tetrahydrofuran solution, 0.56 mL, 0.28 mmol) were added sequentially, and the mixture was stirred for 2 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 35-1 and 36-1. 35-1: ESI-MS theoretical value [M+H] + =409.2, measured value 409.2. 36-1: ESI-MS theoretical calculation value [M+H] + =409.2, measured value 409.2.

[0637] Step 2

[0638] 36-1 (39 mg, 0.10 mmol), A-4 (51 mg, 0.14 mmol), potassium carbonate (40 mg, 0.29 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (8.0 mg, 9.5 μmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (4.5 mg, 9.5 μmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (20 mL) and ethyl acetate (20 mL × 3) were added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 36-2. ESI-MS theoretical calculation value [M+H] + =607.3, measured value 607.3.

[0639] Step 3

[0640] 36-2 (49 mg, 0.08 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 2 hours and concentrated under reduced pressure to obtain an oily substance. This oily substance was then dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.08 mL, 0.8 mmol) and sodium triacetoxyborohydride (51 mg, 0.24 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-7.5 mmol / L ammonium bicarbonate aqueous solution containing 0.4% ammonia; gradient: 45-55%; retention time: 8.2-9.2 min) to obtain 36-2. 1H NMR (400MHz, DMSO-d6): δ10.23(br s,1H),7.52(s,1H),7.12(s,1H),7.07(s,1H),5.44-5.34(m,1H),4.78-4.68(m,1H),4.54-4.44(m, 1H),3.93-3.83(m,1H),3.46-3.36(m,1H),2.60-2.52(m,1H),2.44-2.34(m,2H),2.33-2.23(m,1H) ,2.20-2.15(m,1H),2.13(s,3H),2.09(s,3H),1.96-1.91(m,1H),1.89-1.84(m,1H),1.79-1.74(m,1H),1.65-1.58(m,1H),1.21-1.16(m,1H),0.41-0.37(m,1H),0.32-0.22(m,3H). ESI-MS theoretical calculation values ​​[M+H] + =463.2, measured value 463.2.

[0641] Starting with 35-1 (19 mg, 0.05 mmol), 35 was purified by a similar reaction procedure and high performance liquid chromatography (Column: C18 spherical, 20-35 μm, 100 A, 20 g; mobile phase: acetonitrile-0.03% ammonia aqueous solution; gradient: 50-65%; elution time: 7.2-9.0 min). 1 H NMR(400MHz,DMSO-d6):7.53(s,1H),7.06-6.95(m,2H),4.59-4.50(m,1H),4.49-4 .44(m,1H),3.95-3.85(m,1H),3.59-3.49(m,1H),2.69-2.59(m,1H),2.35-2.18(m ,4H), 2.13(s,3H), 2.10(s,3H), 1.95-1.90(m,2H), 1.84-1.78(m,1H), 1.70-1.63(m,1H), 1.32-1.12(m,1H), 0.50-0.41(m,3H), 0.34-0.30(m,1H). ESI-MS theoretical calculation values ​​[M+H] + =463.2, measured value 463.1.

[0642] Examples 37 and 38

[0643] Synthesis route:

[0644] first step

[0645] 22-3A (295 mg, 0.75 mmol), intermediate C (341 mg, 1.13 mmol), potassium carbonate (259 mg, 1.88 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (63 mg, 0.08 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (36 mg, 0.08 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction, water (50 mL) and ethyl acetate (50 mL × 3) were added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was first purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v), and then purified by high-performance liquid chromatography (Waters 3767 / Qda Column: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; flow rate: 20 mL / min; gradient: 35-45%, where the ratio is the volume ratio of acetonitrile in the mobile phase; the gradient elution was initially maintained at 35% for 1 min, and then linearly increased to 35%-45% over the next 10 min). The crude product was then purified sequentially to obtain 37-1 (peak time: 6.9-7.8 min) and 38-1 (peak time: 8.1-9.1 min). 37-1: ESI-MS theoretical calculated value [M+H] + =536.3, measured value 536.2. 38-1: ESI-MS theoretical calculation value [M+H] + =536.3, measured value 536.3.

[0646] Step 2

[0647] 37-1 (136 mg, 0.25 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 37-2, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =378.2, measured value 378.1.

[0648] Step 3

[0649] 37-2 (95 mg, 0.25 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.25 mL, 2.5 mmol) and sodium triacetoxyborohydride (106 mg, 0.50 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: Agilent C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-water solution containing 0.1% formic acid; gradient: 15-25%; retention time: 8.0-9.6 min) to obtain 37. 1 ¹H NMR (400MHz, DMSO-d6): δ 12.08 (br s, 1H), 7.65–7.55 (m, 1H), 7.39–7.29 (m, 2H), 5.42–5.36 (m, 2H), 4.79–4.69 (m, 1H), 4.21–4.11 (m, 1H), 3.73–3.63 (m, 1H), 3.35–3.25 (m, 2H), 3.10–2.98 (m, 2H), 2.85–2.77 (m, 2H), 2.56 (s, 3H), 2.47–2.40 (m, 1H), 2.28–2.12 (m, 2H), 2.10–2.00 (m, 1H), 1.99–1.78 (m, 3H). ESI-MS theoretical calculation [M+H] + =392.2, measured value 392.2.

[0650] Starting with 38-1 (170 mg, 0.32 mmol), 38 was purified by a similar reaction procedure and high performance liquid chromatography (Column: Agilent C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-water solution containing 0.1% formic acid; gradient: 13-23%, elution time: 7.6-9.2 min). 1H NMR(400MHz,DMSO-d6):12.12(br s,1H),7.61(d,J=8.0Hz,1H),7.44-7.16(m,2H),5.51-5.41(m,1H),5.39-5.29(m, 1H),4.70-4.60(m,1H),4.19-4.09(m,1H),3.88-3.84(m,1H),3.63-3.53(m,1H),3 .25-3.11(m, 1H), 3.05-2.96(m, 1H), 2.90-2.82(m, 1H), 2.76-2.70(m, 2H), 2.60(s, 3H), 2.45-2.38(m, 1H), 2.13-1.94(m, 5H), 1.87-1.84(m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =392.2, measured value 392.1.

[0651] Examples 39 and 40

[0652] Synthesis route:

[0653] first step

[0654] 22-3A (200 mg, 0.51 mmol), A-4 (367 mg, 1.02 mmol), potassium carbonate (282 mg, 2.04 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (43 mg, 0.05 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (24 mg, 0.05 mmol) were added to 1,4-dioxane (10 mL) and water (3 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction, water (50 mL) and ethyl acetate (50 mL × 3) were added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was first purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v), and then purified by high-performance liquid chromatography (Waters 3767 / Qda Column: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; flow rate: 20 mL / min; gradient: 42-52%, where the ratio is the volume ratio of acetonitrile in the mobile phase; the gradient elution was initially maintained at 42% for 1 min, and then linearly increased from 42% to 52% over the next 10 min) to obtain 39-1 (peak time: 7.0-7.7 min) and 40-1 (peak time: 7.9-9.0 min). 39-1: ESI-MS theoretical calculated value [M+H] + =593.3, measured value 593.2. 40-1: ESI-MS theoretical calculation value [M+H] + =593.3, measured value 593.3.

[0655] Step 2

[0656] 39-1 (147 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 39-2, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =435.2, measured value 435.1.

[0657] Step 3

[0658] 39-2 (107 mg, 0.25 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.25 mL, 2.5 mmol) and sodium triacetoxyborohydride (159 mg, 0.75 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: Agilent C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-water solution containing 0.1% formic acid; gradient: 19-29%; retention time: 7.9-9.2 min) to obtain 39. 1 H NMR (400MHz, DMSO-d6): δ10.14(br s,1H),7.17-7.10(m,1H),7.09-7.00(m,1H),5.50-5.25(m,2H),4.81-4.55(m,1 H),4.21-3.93(m,1H),3.69-3.61(m,2H),3.33-3.14(m,1H),2.92-2.80(m,2H), 2.64–2.53 (m, 1H), 2.49–2.45 (m, 1H), 2.42–2.36 (m, 4H), 2.34–2.11 (m, 3H), 2.08 (s, 1H), 2.05–1.99 (m, 1H), 1.97 (s, 1H), 1.96–1.74 (m, 3H). ESI-MS theoretical calculations [M+H] + =449.2, measured value 449.2.

[0659] Starting with 40-1 (164 mg, 0.28 mmol), 40 was obtained by purification through similar reaction steps and high performance liquid chromatography (Column: Agilent C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-water solution containing 0.1% formic acid; gradient: 17-27%, elution time: 7.5-8.8 min). 1H NMR (400MHz, DMSO-d6): δ10.11(br s, 1H), 7.17-7.10 (m, 1H), 7.06 (s, 1H), 5.41-5.35 (m, 2H), 4.67-4.62 (m, 1H), 4.16-4.09 (m, 1H), 3.85-3.78 (m, 1H), 3.63-3.53 (m, 1H), 3.05-2.85 (m, 1H), 2.80-2.70 (m, 1H), 2.69-2.59 (m, 1H), 2.56-2.54 (m, 3H), 2.47-2.30 (m, 2H), 2.23-2.12 (m, 2H), 2.10-1.94 (m, 6H), 1.92-1.82 (m, 2H). ESI-MS theoretical calculation values ​​[M+H] + =449.2, measured value 449.2.

[0660] Examples 41 and 42

[0661] Synthesis route:

[0662] first step

[0663] Intermediate F (260 mg, 0.71 mmol) was dissolved in tetrahydrofuran (3 mL), cooled to 0 °C under nitrogen protection, and ethyl magnesium bromide (2.0 mol / L tetrahydrofuran solution, 0.71 mL, 1.42 mmol) was added. The mixture was stirred for 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 41-1 and 42-1. 41-1: ESI-MS theoretical value [M+H] + =397.2, measured value 397.2. 42-1: ESI-MS theoretical calculation value [M+H] + =397.2, measured value 397.1.

[0664] Step 2

[0665] 42-1 (33 mg, 0.08 mmol), A-4 (60 mg, 0.17 mmol), potassium carbonate (46 mg, 0.33 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (7.0 mg, 8.3 μmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (4.0 mg, 8.3 μmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (20 mL) was added, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 42-2. ESI-MS theoretical calculation value [M+H] + =595.3, measured value 595.4.

[0666] Step 3

[0667] 42-2 (27 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 2 hours and concentrated under reduced pressure to obtain an oily substance. This oily substance was then dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.04 mL, 0.44 mmol) and sodium triacetoxyborohydride (28 mg, 0.13 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-7.5 mmol / L ammonium bicarbonate aqueous solution containing 0.4% ammonia; gradient: 45-55%; retention time: 7.3-9.0 min) to obtain 42-2. 1H NMR (400MHz, DMSO-d6): δ7.53(s,1H),6.85(s,1H),6.80(s,1H),5.42-5.32(m,1H),4.82-4.72 (m,1H),4.47-4.37(m,1H),3.82-3.72(m,1H),3.28-3.17(m,1H),2.75-2.65(m,1H),2.47-2.43 (m, 1H), 2.29–2.17 (m, 2H), 2.07 (s, 3H), 2.06 (s, 3H), 2.03–2.00 (m, 1H), 2.00–1.88 (m, 1H), 1.85–1.68 (m, 3H), 1.66–1.55 (m, 1H), 1.45–1.38 (m, 2H), 0.79 (t, J = 8.0 Hz, 3H). ESI-MS theoretical calculations [M+H] + =451.2, measured value 451.1.

[0668] Starting with 41-1 (20 mg, 0.05 mmol), 41 was purified by a similar reaction procedure and high performance liquid chromatography (Column: Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-7.5 mmol / L ammonium bicarbonate aqueous solution containing 0.4% ammonia; gradient: 45-58%; retention time: 8.5-9.7 min). 1 H NMR (400MHz, DMSO-d6): δ7.46(s,1H),6.83(s,1H),6.76(s,1H),5.39-5.29(m,1H),4.72- 4.62(m,1H),4.43-4.34(m,1H),3.82-3.72(m,1H),3.52-3.39(m,1H),2.60-2.50(m,1H),2 0.44-2.32(m,2H), 2.29-2.14(m,2H), 2.10(s,3H), 2.09(s,3H), 2.02-1.84(m,2H), 1.83-1.74(m,2H), 1.72-1.62(m,1H), 1.61-1.46(m,1H), 0.97(t,J=8.0Hz,3H). ESI-MS theoretical calculation [M+H] + =451.2, measured value 451.1.

[0669] Examples 43 and 44

[0670] Synthesis route:

[0671] first step

[0672] 43-1 (300 mg, 1.60 mmol), 1-1 (362 mg, 1.60 mmol) and N,N-diisopropylethylamine (1.32 mL, 8.0 mmol) were dissolved in dimethyl sulfoxide (10 mL), and the mixture was heated to 150 °C and stirred for 2 hours. After the reaction was completed and cooled to room temperature, the mixture was diluted with water (30 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high-performance liquid chromatography (HPLC) (Column: C18 spherical, 20-35 μm, 100A, 80 g; mobile phase: acetonitrile-0.1% trifluoroacetic acid aqueous solution; flow rate: 20 mL / min; gradient: 5-45%, where the ratio is the volume ratio of acetonitrile in the mobile phase; the gradient elution was initially maintained at a 5% gradient for 10 min, then linearly increased from 5% to 45% over the next 20 min) to obtain 43-2 (retention time: 19.0-20.0 min) and 44-2 (retention time: 20.5-23.0 min). 43-2: ESI-MS theoretical value [M+H] + =378.2, measured value 378.0. 44-2: ESI-MS theoretical calculation value [M+H] + =378.2, measured value 378.2.

[0673] Step 2

[0674] 43-2 (66 mg, 0.17 mmol), A-4 (92 mg, 0.26 mmol), potassium carbonate (59 mg, 0.43 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14 mg, 17 μmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (8.1 mg, 17 μmol) were added to 1,4-dioxane (4 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (20 mL) was added, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 43-3. ESI-MS theoretical calculation value [M+H] + =576.3, measured value 576.3.

[0675] Step 3

[0676] 43-3 (28 mg, 0.05 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour and concentrated under reduced pressure to obtain an oily substance. This oily substance was then dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.01 mL, 0.10 mmol) and sodium triacetoxyborohydride (31 mg, 0.15 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-10.0 mmol / L ammonium bicarbonate aqueous solution; gradient: 35-55%; retention time: 6.5-8.5 min) to obtain 43. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.40 (br s, 1H), 9.96 (s, 1H), 7.31 (d, J = 2.8Hz, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 6.67 (d, J = 3.2Hz, 1H), 4.57–4.48 (m, 1H), 4.00–3.90 (m, 1H), 3.88–3.76 (m, 1H), 3.15–3.03 (m, 1H), 2.43–2.25 (m, 2H), 2.17 (s, 3H), 2.15–2.05 (m, 2H), 2.03 (s, 3H), 2.01–1.90 (m, 3H), 1.75–1.68 (m, 1H). ESI-MS theoretical calculations [M+H] + =432.2, measured value 432.0.

[0677] Starting with 44-2 (64 mg, 0.17 mmol), 44 was purified by a similar reaction procedure and high performance liquid chromatography (Waters 3767 / Qda Column: SunFire C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-10.0 mmol / L ammonium bicarbonate aqueous solution; gradient: 36-46%, retention time: 8.0-10.2 min). 1¹H NMR (400MHz, DMSO-d6): δ 11.51 (br s, 1H), 9.87 (s, 1H), 7.40 (s, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 6.04 (s, 1H), 4.63–4.53 (m, 1H), 4.18–4.08 (m, 1H), 3.85–3.75 (m, 1H), 2.97–2.87 (m, 1H), 2.45–2.35 (m, 2H), 2.22–2.17 (m, 1H), 2.15 (s, 3H), 2.13–2.05 (m, 2H), 2.01 (s, 3H), 2.00–1.90 (m, 2H), 1.75–1.67 (m, 1H). ESI-MS theoretical calculation [M+H] + =432.2, measured value 432.0.

[0678] Examples 45, 46, 47 and 48

[0679] Synthesis route:

[0680] first step

[0681] Intermediate G (248 mg, 1.12 mmol), 1-1 (250 mg, 1.12 mmol), potassium fluoride (65 mg, 1.12 mmol), and N,N-diisopropylethylamine (724 mg, 5.60 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the mixture was heated to 130 °C and stirred for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain a mixture of 45-1A and 45-1B. ESI-MS theoretical calculation [M+H] + =411.2, measured value 411.0.

[0682] Step 2

[0683] A mixture of 45-1A and 45-1B (300 mg, 0.73 mmol), 14-9 (225 mg, 1.09 mmol), potassium carbonate (303 mg, 2.19 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (62 mg, 73 μmol) were added to 1,4-dioxane (12 mL) and water (3 mL), and the mixture was heated to 100 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 45-2A, 45-2B, 45-2C, and 45-2D sequentially. 45-2A: ESI-MS theoretical value [M+H] + =537.2, measured value 537.1. 45-2B: ESI-MS theoretical calculation value [M+H] + =537.2, measured value 537.1. 45-2C: ESI-MS theoretical calculation value [M+H] + =537.2, measured value 537.0. 45-2D: ESI-MS theoretical calculation value [M+H] + =537.2, measured value 537.0.

[0684] Step 3

[0685] 45-2C (68 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour and concentrated under reduced pressure to obtain an oily substance. This oily substance was then dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.02 mL, 0.20 mmol) and sodium triacetoxyborohydride (83 mg, 0.39 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (C18 spherical 20-30 μm 100A 20 g, mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 5-45%, retention time: 6.5-8.5 min) to obtain 45. 1H NMR (400MHz, DMSO-d6): δ11.55(br s,1H),7.71(d,J=8.0Hz,1H),7.18(d,J=8.4Hz,1H),7.16(s,1H),4.91-4.86(m,1H),4.61- 4.54(m,1H),4.36-4.28(m,1H),4.27-4.18(m,1H),4.17-4.09(m,1H),3.71-3.61(m,1H),2. 93-2.85(m, 1H), 2.45-2.40(m, 1H), 2.32-2.27(m, 1H), 2.27-2.17(m, 1H), 2.17(s, 3H), 2.10-2.00(m, 3H), 2.02-1.92(m, 1H), 1.91-1.85(m, 2H), 1.77-1.67(m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =451.2, measured value 451.0.

[0686] Starting with 45-2D (58 mg, 0.11 mmol), 46 was obtained by similar reaction steps and purification by high performance liquid chromatography (C18 spherical 20-30 μm 100A 20 g, mobile phase: acetonitrile-10.0 mmol / L ammonium bicarbonate aqueous solution; gradient: 20-26%, retention time: 8.0-10.2 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.41 (d, J = 7.2Hz, 1H), 7.03–6.93 (m, 2H), 4.44–4.38 (m, 2H), 4.37–4.32 (m, 1H), 4.31–4.25 (m, 1H), 3.85–3.78 (m, 1H), 3.65–2.55 (m, 1H), 2.73–2.63 (m, 1H), 2.58–2.48 (m, 1H), 2.36–2.26 (m, 2H), 2.20–2.11 (m, 5H), 1.90–1.77 (m, 5H), 1.69–1.61 (m, 1H). ESI-MS theoretical calculations [M+H] + =451.2, measured value 451.0.

[0687] Starting with 45-2A (68 mg, 0.13 mmol), 47 was obtained by purification through similar reaction steps and high performance liquid chromatography (C18 spherical 20-30 μm 100A 20 g, mobile phase: acetonitrile-0.1% ammonia aqueous solution; gradient: 36-46%, retention time: 8.0-10.2 min). 1¹H NMR (400MHz, DMSO-d⁶): δ 11.53 (br s, 1H), 7.72 (d, J = 8.0Hz, 1H), 7.22–14 (m, 2H), 5.63 (d, J = 5.2Hz, 1H), 4.84–4.78 (m, 1H), 4.64–4.54 (m, 1H), 4.40–4.28 (m, 2H), 4.15–4.05 (m, 1H), 4.01–3.92 (m, 1H), 2.72–2.63 (m, 1H), 2.35–2.21 (m, 4H), 2.11 (s, 3H), 2.00–1.76 (m, 5H), 1.71–1.60 (m, 1H). ESI-MS theoretical calculations [M+H] + =451.2, measured value 451.0.

[0688] Starting with 45-2B (70 mg, 0.13 mmol), 48 was obtained by similar reaction steps and purification by high performance liquid chromatography (C18 spherical 20-30 μm 100A 20 g, mobile phase: acetonitrile-0.1% ammonia aqueous solution; gradient: 36-46%, retention time: 8.0-10.2 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.62 (d, J = 8.0Hz, 1H), 7.23–7.16 (m, 2H), 4.48–4.39 (m, 2H), 4.38–4.34 (m, 1H), 4.33–4.28 (m, 1H), 3.89–3.80 (m, 1H), 3.64–3.54 (m, 1H), 3.28–3.18 (m, 1H), 2.75–2.65 (m, 1H), 2.41–2.22 (m, 2H), 2.23–2.07 (m, 5H), 1.96–1.78 (m, 5H), 1.70–1.60 (m, 1H). ESI-MS theoretical calculations [M+H] + =451.2, measured value 451.0.

[0689] Example 49

[0690] Synthesis route:

[0691] first step

[0692] 14-8A (44 mg, 0.11 mmol), intermediate J (57 mg, 0.17 mmol), potassium carbonate (46 mg, 0.33 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (9 mg, 11 μmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5 mg, 11 μmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 49-1. ESI-MS theoretical calculation value [M+H] + =577.3, measured value 577.6.

[0693] Step 2

[0694] 49-1 (67 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 49-2, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =419.2, measured value 419.1.

[0695] Step 3

[0696] 49-2 (49 mg, 0.12 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.06 mL, 0.60 mmol) and sodium triacetoxyborohydride (102 mg, 0.48 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 21.2*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 15-25%; retention time: 8.0-9.0 min) to obtain 49-2. 1 H NMR (400MHz, DMSO-d6): δ10.31(br s,1H),7.26(t,J H-F=72.0Hz,1H),7.22-7.20(m,1H),6.72(s,1H),6.71(s,1H),4.54-4.47(m,2H),4.36-4.26 (m,1H),4.10-4.06(m,1H),3.89-3.82(m,1H),3.56-3.51(m,1H),3.46-3.38(m,1H),3.12 -3.09(m, 1H), 2.95-2.83(m, 2H), 2.73-2.70(m, 1H), 2.60-2.55(m, 1H), 2.46-2.43(m, 1H), 2.36(m, 3H), 2.33-2.29(m, 1H), 1.98-1.91(m, 1H), 1.82-1.68(m, 3H). ESI-MS theoretical calculation values ​​[M+H] + =433.2, measured value 433.2.

[0697] Examples 50 and 51

[0698] Synthesis route:

[0699] first step

[0700] Intermediate F (200 mg, 0.55 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C under nitrogen protection, and then trifluoromethyltrimethylsilane (88 mg, 0.61 mmol) and tetrabutylammonium fluoride (1.0 mol / L tetrahydrofuran solution, 0.06 mL, 0.06 mmol) were added. The mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 50-1 and 51-1, respectively. 50-1: ESI-MS theoretical value [M+H] + =437.2, measured value 437.0. 51-1: ESI-MS theoretical calculation value [M+H] + =437.2, measured value 437.1.

[0701] Step 2

[0702] 51-1 (138 mg, 0.32 mmol), intermediate E (172 mg, 0.48 mmol), potassium carbonate (133 mg, 0.96 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (27 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (15 mg, 0.03 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 51-2. ESI-MS theoretical calculation value [M+H] + =633.3, measured value 633.2.

[0703] Step 3

[0704] 51-2 (151 mg, 0.24 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour and concentrated under reduced pressure to obtain an oily substance. This oily substance was then dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.12 mL, 1.20 mmol) and sodium triacetoxyborohydride (203 mg, 0.96 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-10.0 mmol / L ammonium bicarbonate aqueous solution; gradient: 28-38%; retention time: 8.1-9.5 min) to obtain 51. 1 H NMR (400MHz, DMSO-d6): δ9.97(s,1H),7.54(s,1H),7.22(t,J H-F=72.0Hz, 1H), 7.22-7.18(m, 1H), 6.62-6.55(m, 2H), 5.48-5.40(m, 1H), 4.50-4.46(m, 1H), 3.94-3.88(m, 1H), 3.43-3.47(m, 1H), 2.47-2.45(m, 2H), 2.43-2.35(m, 1H), 2.33-2.25(m, 1H), 2.21-2.24(m, 1H), 2.11(s, 3H), 2.05(s, 3H), 1.98-1.87(m, 2H), 1.81-1.74(m, 1H), 1.71-1.61(m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =489.2, measured value 489.2.

[0705] Starting with 50-1 (72 mg, 0.16 mmol), 50 was obtained by similar reaction steps and purification by high performance liquid chromatography (Waters 3767 / Qda Column: Agilent C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 27-37%, retention time: 7.6-9.1 min). 1 H NMR (400MHz, DMSO-d6): δ10.01(br s,1H),7.50(s,1H),7.22(t,J H-F =72.0Hz, 1H), 7.26-7.16(m, 1H), 6.62-6.55(m, 1H), 5.63-5.45(m, 1H), 4.44-4.40(m, 1H), 3.80-3.75(m, 1H), 3.54-3.48(m, 1H), 2.74-2.61(m, 1H), 2.39-2.21(m, 4H), 2.12(s, 3H), 2.08(s, 3H), 2.04-1.92(m, 2H), 1.85-1.78(m, 1H), 1.73-1.67(m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =489.2, measured value 489.2.

[0706] Example 52

[0707] Synthesis route:

[0708] first step

[0709] 33-1B (50 mg, 0.13 mmol), 52-1 (35 mg, 0.20 mmol), potassium carbonate (90 mg, 0.65 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (11 mg, 0.013 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6 mg, 0.013 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 52-2. ESI-MS theoretical calculation value [M+H] + =480.3, measured value 480.2.

[0710] Step 2

[0711] 52-2 (73 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 52-3, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =380.2, measured value 380.0.

[0712] Step 3

[0713] 52-3 (57 mg, 0.15 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.15 mL, 1.5 mmol) and sodium triacetoxyborohydride (96 mg, 0.45 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-7.5 mmol / L ammonium bicarbonate aqueous solution; gradient: 20-34%, retention time: 7.5-10.5 min) to obtain 52. 1H NMR (400MHz, DMSO-d6): δ10.44(br s,1H),7.54(s,1H),7.23(s,1H),7.12(s,1H),5.53-5.43(m,1H),4.99-4.91(m,1H),4.5 1-4.41(m,1H),3.80-3.74(m,1H),3.27-3.21(m,1H),2.75-2.71(m,1H),2.47-2.45(m,1H ), 2.28-2.22 (m, 2H), 2.10-2.07 (m, 6H), 2.04-2.01 (m, 1H), 1.99-1.90 (m, 1H), 1.84-1.79 (m, 1H), 1.78-1.70 (m, 1H), 1.63-1.55 (m, 1H), 1.26 (d, J = 6.40 Hz, 3H). ESI-MS theoretical calculation values ​​[M+H] + =394.2, measured value 394.1.

[0714] Example 53

[0715] Synthesis route:

[0716] first step

[0717] 30-1 (50 mg, 0.13 mmol), intermediate E (70 mg, 0.20 mmol), potassium carbonate (54 mg, 0.39 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (11 mg, 0.013 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6 mg, 0.013 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 53-1. ESI-MS theoretical calculation value [M+H] + =591.3, measured value 591.6.

[0718] Step 2

[0719] 53-1 (64 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 53-2, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =433.2, measured value 433.1.

[0720] Step 3

[0721] 53-2 (46 mg, 0.10 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.10 mL, 1.0 mmol) and sodium triacetoxyborohydride (64 mg, 0.30 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Waters 3767 / Qda Column: Agilent C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 21-31%, retention time: 7.9-8.8 min) to obtain 53. 1 H NMR (400MHz, DMSO-d6): δ10.02(br s, 1H), 7.36(s, 1H), 7.21(t, J=72.0Hz, 1H), 6.60-6.57(m, 2H), 6.21-6.13(m, 1H), 5.35-5.22(m, 3H), 4.55-4.51(m, 1H), 3.90-3.84(m, 2H), 3.43-3.37(m, 1H), 2.88-2.75(m, 3H), 2.51-2.41(m, 1H), 2.35(s, 3H), 2.32-2.28(m, 1H), 2.08(s, 3H), 1.97-1.90(m, 1H), 1.86-1.78(m, 2H), 1.77-1.67(m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =447.2, measured value 447.3.

[0722] Example 54

[0723] Synthesis route:

[0724] first step

[0725] 14-11 (185 mg, 0.44 mmol) was dissolved in methanol (3 mL), and 54-1 (383 mg, 2.20 mmol) and sodium triacetoxyborohydride (280 mg, 1.32 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution (5 mL) was added, followed by extraction with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Waters 3767 / Qda Column: SPherical C18, 19*250 mm, 20-35 μm, mobile phase: acetonitrile-0.1% ammonia monohydrate aqueous solution; gradient: 30-40%, retention time: 14.0-20.0 min) to obtain 54-2. ESI-MS theoretical calculation value [M+H] + =579.3, measured value 579.2.

[0726] Step 2

[0727] 54-2 (80 mg, 0.14 mmol) was dissolved in tetrahydrofuran (3 mL), and trifluoroacetic acid (0.5 mL) was added dropwise. The mixture was stirred for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767 / Qda Column: SPherical C18, 19*250 mm, 20-35 μm, mobile phase: acetonitrile-0.01% ammonia monohydrate aqueous solution; gradient: 20-30%, retention time: 19.0-24.0 min) to obtain 54. 1 H NMR (400MHz, DMSO-d6): δ10.75(br s,1H),7.40(d,J=8.0Hz,1H),7.23-7.16(m,2H),4.56-4.41(m,2H),4.33-4.19(m,2 H),4.04-4.00(m,1H),3.93-3.87(m,1H),3.67-3.52(m,1H),3.49-3.38(m,3H),3.0 6-2.85(m, 1H), 2.65-2.57(m, 2H), 2.58-2.50(m, 1H), 2.49-2.43(m, 1H), 2.41-2.27(m, 4H), 1.94-1.81(m, 2H), 1.80-1.72(m, 1H), 1.68-1.59(m, 1H). ESI-MS theoretical calculation values ​​[M+H] + =465.2, measured value 465.1.

[0728] Example 55

[0729] Synthesis route:

[0730] first step

[0731] 14-8A (250 mg, 0.63 mmol), 55-1 (325 mg, 0.95 mmol), potassium carbonate (261 mg, 1.89 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (55 mg, 0.063 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (30 mg, 0.063 mmol) were added to 1,4-dioxane (10 mL) and water (2 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 55-2. ESI-MS theoretical calculation value [M+H] + =577.3, measured value 577.4.

[0732] Step 2

[0733] 55-2 (361 mg, 0.63 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 55-3, which was directly used in the next reaction. ESI-MS theoretical calculation value [M+H] + =419.2, measured value 419.6.

[0734] Step 3

[0735] 55-3 (247 mg, 0.59 mmol) was dissolved in methanol (3 mL), and 54-1 (552 mg, 2.95 mmol) and sodium triacetoxyborohydride (375 mg, 1.77 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate solution (25 mL) was added, followed by extraction with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (C18 spherical 20-30 μm 100A 40 g, mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 16-21%, retention time: 20.2-25.3 min) to obtain 55-4. ESI-MS theoretical calculation value [M+H] + =577.3, measured value 577.7.

[0736] Step 4

[0737] 55-4 (102 mg, 0.18 mmol) was dissolved in tetrahydrofuran (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (C18 spherical 20-30 μm 100A 20 g, mobile phase: acetonitrile-0.1% ammonia monohydrate aqueous solution; gradient: 20-26%, retention time: 41.5-55.4 min) to obtain 55. 1 H NMR (400MHz, DMSO-d6): δ10.24(br s,1H),7.26(t,J H-F =72.0Hz 1H), 7.23-7.21(m,1H), 6.71-6.70(m,2H), 4.50-4.42(m,2H), 4.32-4.28(m,2H), 4.04-3.99(m,1H), 3.92-3.86(m,1H), 3.61-3.55(m,1H), 3.44-3.39(m,3H), 2.96-2.88(m,1H), 2.63-2.56(m,3H), 2.51-2.45(m,1H), 2.40-2.26(m,4H), 1.93-1.82(m,2H), 1.78-1.70(m,1H), 1.68-1.60(m,1H). ESI-MS theoretical calculation values ​​[M+H] + =463.2, measured value 463.1.

[0738] Example 56

[0739] Synthesis route:

[0740] first step

[0741] Intermediate F (150 mg, 0.41 mmol) was dissolved in methanol (3 mL), and sodium borohydride (22 mg, 0.61 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing 56-1. This crude product required no further purification and was used directly in the next reaction. ESI-MS theoretical calculation [M+H] + =369.2, measured value 369.1.

[0742] Step 2

[0743] 56-1 (140 mg, 0.38 mmol), 56-2 (116 mg, 0.57 mmol), potassium carbonate (158 mg, 1.14 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (32 mg, 0.038 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (18 mg, 0.038 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 56-3. ESI-MS theoretical calculation value [M+H] + =493.2, measured value 493.5.

[0744] Step 3

[0745] 56-3 (190 mg, 0.39 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 56-4, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =393.2, measured value 393.4.

[0746] Step 4

[0747] 56-4 (151 mg, 0.38 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.19 mL, 1.9 mmol) and sodium triacetoxyborohydride (242 mg, 1.14 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Waters 3767 / Qda Column: SPherical C18, 19*250 mm, 20-35 μm, mobile phase: acetonitrile-0.1% ammonia monohydrate aqueous solution; gradient: 62-70%, retention time: 42.0-61.0 min) to obtain 56. 1H NMR (400MHz, DMSO-d6): δ7.71 (s, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.64-7.62 (m, 1H), 7.61-7.58 (m, 1H), 5.52(t,J=4.0Hz,1H),4.67-4.62(m,1H),4.55-4.44(m,2H),3.89-3.83(m,1H),3.61-3.45(m,1H), 2.57-2.52 (m, 1H), 2.51-2.45 (m, 1H), 2.42 (s, 3H), 2.39-2.31 (m, 1H), 2.30-2.25 (m, 1H), 2.24-2.17 (m, 1H), 2.11 (s, 3H), 1.96-1.85 (m, 2H), 1.84-1.75 (m, 1H), 1.71-1.63 (m, 1H). ESI-MS theoretical calculations [M+H] + =407.2, measured value 407.2.

[0748] Example 57

[0749] Synthesis route:

[0750] first step

[0751] 14-8A (170 mg, 0.43 mmol), intermediate I (551 mg, 1.72 mmol), potassium carbonate (178 mg, 1.29 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (37 mg, 0.043 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (21 mg, 0.043 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 57-1. ESI-MS theoretical calculation value [M+H] + =553.3, measured value 553.6.

[0752] Step 2

[0753] 57-1 (150 mg, 0.27 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing 57-2, which was directly used in the next reaction step. ESI-MS theoretical calculation value [M+H] + =395.2, measured value 395.1.

[0754] Step 3

[0755] 57-2 (80 mg, 0.20 mmol) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (37%, 0.2 mL, 2.0 mmol) and sodium triacetoxyborohydride (127 mg, 0.60 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Waters 3767 / Qda Column: XBridge C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.04% ammonia monohydrate aqueous solution; gradient: 28-38%, retention time: 6.5-7.2 min) to obtain 57. 1 H NMR (400MHz, DMSO-d6): δ6.91(d,J=8.0Hz,1H),6.35(d,J=8.0Hz,1H),4.58-4.56(m,3H),4.42-4. 39(m,1H),4.35-4.31(m,1H),4.08-3.98(m,1H),3.93-3.84(m,1H),3.64-3.51(m,1H),3.44-3.34 (m, 2H), 3.14 (t, J = 8.8 Hz, 2H), 2.99-2.88 (m, 1H), 2.72-2.67 (m, 1H), 2.47-2.43 (m, 2H), 2.35-2.20 (m, 2H), 2.08 (s, 3H), 2.06-2.04 (m, 1H), 1.96-1.84 (m, 1H), 1.82-1.58 (m, 3H). ESI-MS theoretical calculations [M+H] + =409.2, measured value 409.1.

[0756] Example 58

[0757] Synthesis route:

[0758] first step

[0759] 57-2 (123 mg, 0.25 mmol) was dissolved in ethanol (3 mL), and acetaldehyde (552 mg, 2.95 mmol) and sodium triacetoxyborohydride (197 mg, 0.93 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (25 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Waters 3767 / Qda Column: SunFire C18, 19*250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid aqueous solution; gradient: 5-20%, retention time: 8.6-9.2 min) to obtain 58. 1 H NMR (400MHz, DMSO-d6): δ9.64 (br s,1H),6.91(d,J=7.6Hz,1H),6.36(d,J=7.6Hz,1H),4.60-4.50(m,3H),4.49-4.40(m,1H) ,4.38-4.30(m,1H),4.06-3.96(m,1H),3.92-3.82(m,1H),3.64-3.54(m,1H),3.42-3.32( (m, 3H), 3.19-3.09 (m, 2H), 2.96-2.86 (m, 1H), 2.63-2.53 (m, 2H), 2.39-2.30 (m, 1H), 2.30-2.23 (m, 2H), 1.81-1.72 (m, 3H), 1.71-1.61 (s, 1H), 0.98-0.88 (s, 3H). ESI-MS theoretical calculation values ​​[M+H] + =423.2, measured value 423.1.

[0760] Examples 59 and 60

[0761] Synthesis route:

[0762] first step

[0763] 14-8A (100 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The mixture was stirred for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain an oily substance, which was then dissolved in methanol (2 mL). Formaldehyde aqueous solution (37%, 0.17 mL, 1.7 mmol) and sodium triacetoxyborohydride (159 mg, 0.75 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing 59-1. This crude product did not require purification and was used directly in the next reaction. ESI-MS theoretical calculation value [M+H] + =309.2, measured value 309.0.

[0764] Step 2

[0765] 59-1 (130 mg, 0.42 mmol), intermediate H (140 mg, 0.42 mmol), potassium carbonate (174 mg, 1.26 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36 mg, 0.042 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (21 mg, 0.043 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL), and the mixture was heated to 100 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain 59-2. ESI-MS theoretical calculation value [M+H] + =481.3, measured value 481.2.

[0766] Step 3

[0767] 59-2 (63 mg, 0.13 mmol) was dissolved in 1,4-dioxane (3 mL), and hydrochloric acid (4.0 mol / L 1,4-dioxane solution, 0.3 mL, 1.2 mmol) was slowly added dropwise. The mixture was stirred for 16 hours. After the reaction was complete, the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane / methanol (v / v, 10 / 1, 20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to high performance liquid chromatography (Waters 3767 / Qda Column: XBridge). C18, 19*250mm, 10um, mobile phase: acetonitrile-0.05% ammonia monohydrate aqueous solution; flow rate: 20mL / min; gradient: 22-36%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is first maintained at a gradient of 22% for 1min, and then linearly increased at 22%-36% over the next 10min. The purification yielded 59 (retention time: 6.5-7.2min) and 60 (retention time: 9.0-9.8min) sequentially.

[0768] 59: 1 H NMR (400MHz, DMSO-d6): δ8.92 (br s, 1H), 6.25(s, 1H), 4.52(t, J=8.8Hz, 2H), 4.47-4.38(m, 1H), 4.37-4.30(m, 1H), 4.08-3.98(m, 2H), 3.95-3.85(m, 1H), 3.58-3.48(m, 1H), 3.43-3.33(m, 1H), 3.14-3.04(m, 2H), 2.99-2.90(m, 1H), 2.45-2.36(m, 2H), 2.32-2.21(m, 2H), 2.13-2.03(m, 4H), 1.91-1.81(m, 4H), 1.78-1.68(m, 4H). ESI-MS theoretical calculation values ​​[M+H] + =423.2, measured value 423.1.

[0769] 60: 1H NMR (400MHz, DMSO-d6): δ8.95 (br s,1H),6.24(s,1H),4.52(t,J=8.8Hz,2H),4.46-4.38(m,1H),4.35-4.28(m,1H),4.13- 4.05(m,2H),3.91-3.82(m,1H),3.61-3.52(m,1H),3.48-3.40(m,1H),3.15-3.06(m,2H ), 2.95-2.89(m,1H), 2.45-2.36(m,2H), 2.30-2.20(m,1H), 2.14-2.04(m,4H), 1.93-1.85(m,2H), 1.84-1.81(m,1H), 1.80-1.72(m,4H), 1.71-1.53(m,2H). ESI-MS theoretical calculation values ​​[M+H] + =423.2, measured value 423.1.

[0770] Activity Test 1: Evaluation of the compound's activity in inhibiting IL-1β secretion from THP-1 cells

[0771] Experimental objective:

[0772] The activity of the compound in inhibiting IL-1β secretion by THP-1 cells was evaluated by detecting the amount of IL-1β secreted using an ELISA kit.

[0773] Experimental materials:

[0774] Experimental instruments:

[0775] Cell treatment:

[0776] 1. This experiment used THP-1 cells.

[0777] 2. Cell treatment: THP-1 cells were cultured in 1640 medium containing 10% heat-inactivated fetal bovine serum at 37°C and 5% carbon dioxide. The cell suspension was gently shaken and transferred to centrifuge tubes for counting. The required volume was then removed and added to fresh passage medium.

[0778] Experimental procedure:

[0779] 1. Add 40 μL of polylysine diluted with sterile water to a 96-well plate and incubate at 37°C and 5% CO2 for 30 minutes, then wash twice with 100 μL.

[0780] 2. After adding 50 ng / mL of PMA (phorbol 12-tetradecanoate 13-acetate) to the THP-1 cell suspension, seed 50,000 cells per well (100 μL per well) into the 96-well plate from step 1 and incubate at 37°C and 5% CO2 for 24 hours.

[0781] 3. Remove the culture medium from the 96-well plate and wash the cells once with PBS preheated to 37°C.

[0782] 4. Add 85 μL of serum-free culture medium containing 25 ng / mL LPS and incubate the cells at 37°C and 5% CO2 for 3 hours.

[0783] 5. Add 5 μL of different concentrations of the compound (DMSO concentration is uniformly 1‰), and continue to incubate the cells at 37℃ and 5% CO2 for 30 minutes.

[0784] 6. Add 5 μL of diluted Nigericin to make the working concentration of Nigericin 5 μG / mL, and continue to incubate the cells at 37℃ and 5% CO2 for 1 hour.

[0785] 7. Collect the cell supernatant, store it at -80℃, and then use an ELISA kit to detect the amount of IL-1β secreted.

[0786] 8. Calculate the IL-1β concentration based on the standard curve, calculate the inhibition rate, fit the compound's action curve, and calculate the IC50. 50 .

[0787] Experimental results:

[0788] Experimental conclusion: The compound of this invention can effectively inhibit the secretion of IL-1β in THP-1 cells.

[0789] Activity Test 2: Evaluation of the compound's inhibitory activity on hERG potassium ion channels

[0790] Experimental objective:

[0791] The inhibitory effect of the compounds obtained in the embodiments of the present invention on the potassium ion channel of hERG (human ether-à-go-go related gene) was tested using fully automated patch-clamp Qpatch technology.

[0792] Cell preparation:

[0793] Chinese hamster ovary cells stably expressing the hERG receptor (purchased from the Cell Bank of the Chinese Academy of Sciences) were cultured in culture flasks. Once the cell density reached 60-80%, the culture medium was removed, and the cells were washed once with 7 mL of phosphate-buffered saline (PFS). Then, 3 mL of cell dissociation reagent (trade name: Detachin) was added.TM The cells (purchased from Genlantis, catalog number: T100100) were digested. After complete digestion, 3 mL of culture medium was added for neutralization, followed by centrifugation. The supernatant was removed, and the cells were resuspended in 5 mL of culture medium to ensure a cell density of 2–5 × 10⁻⁶ cells / mL. 6 / mL.

[0794] Patch clamp testing:

[0795] In whole-cell recording mode, the cell membrane was clamped at -80 mV. Before a 5-second +40 mV depolarization stimulus, a 50-millisecond -50 mV pre-voltage was applied, followed by repolarization to -50 mV for 5 seconds, and then back to -80 mV. This voltage stimulus was applied every 15 seconds, and after 2 minutes of recording, extracellular fluid was administered for 5 minutes of recording, before the drug delivery process began. Compound concentrations were started from the lowest test concentration, and each test concentration was administered for 2.5 minutes.

[0796] Experimental results:

[0797] Experimental conclusion:

[0798] The test samples were prepared according to the corresponding examples. The results of the inhibitory effect of the present invention on hERG potassium ion channels are shown in the table above. It can be seen that the compounds of the present invention have a low risk of inhibiting hERG potassium ion channels.

[0799] Activity Test 3: Evaluation of the Pharmacokinetic Properties of the Compound in Mice

[0800] Experimental objective:

[0801] The pharmacokinetic properties of the compounds obtained in the embodiments of the present invention in CD-1 mice were evaluated.

[0802] Experimental procedure:

[0803] Candidate compounds were prepared into clear solutions or suspensions using designated solvents and administered to three mice via single intravenous injection and oral administration, respectively. The solvent for both intravenous and oral administration was an aqueous solution containing 10% sulfobutyl-β-cyclodextrin. The drug concentration was 0.4 mg / ml for intravenous administration and 0.5 mg / ml for oral administration. Whole blood samples were collected within 24 hours into commercially available EDTA2K anticoagulant tubes. After centrifugation, the supernatant plasma sample was obtained. Acetonitrile solution containing an internal standard was added to precipitate proteins. After centrifugation, the supernatant was collected, and an equal volume of water was added. After further centrifugation, the supernatant was injected into the plasma. Blood drug concentrations were quantitatively analyzed and pharmacokinetic parameters were calculated using LCMS / MS.

[0804] Experimental methods:

[0805] Experimental results:

[0806] Experimental conclusion:

[0807] The test samples were prepared according to the corresponding examples, and the results showed that some compounds in this application have good pharmacokinetic properties.

[0808] Activity Test 4: Evaluation of the compound's activity in inhibiting IL-1β secretion by peripheral blood mononuclear cells (PBMCs)

[0809] Experimental plan:

[0810] 1. Add 9 mL of preheated complete culture medium (RPMI 1640 + 10% FBS + 1% phosphate buffer) to a 15 mL centrifuge tube for later use. Thaw the frozen human PBMC peripheral blood mononuclear cell cryovial tube rapidly in a 37°C water bath, gently blow the thawed PBMC suspension and transfer it to the aforementioned centrifuge tube, centrifuge at 400g at room temperature for 10 minutes.

[0811] 2. Discard the supernatant, resuspend the PBMC pellet in fresh complete culture medium, count the cells, and adjust the cell density to 1×10⁻⁶. 6 cells / mL.

[0812] 3. Add 100 μL of PBMC suspension to each well of a 96-well plate and incubate overnight at 37°C in a 5% CO2 incubator.

[0813] 4. The next day, prepare a 2×100ng / mL LPS (lipopolysaccharide) solution using serum-free RPMI 1640 medium, add 100μL LPS to each well (final concentration 100ng / mL), and stimulate for three hours.

[0814] 5. Three hours later, centrifuge the experimental plate at 350g for 5 minutes, discard the supernatant, add 100μL of serum-free RPMI 1640 medium and 50μL of 4× test compound to each well, and process for 30 minutes.

[0815] 6. Half an hour later, add 50 μL of 4×10 μM Nigericin to each well and stimulate for 90 minutes.

[0816] 7. Collect the cell culture supernatant by centrifugation and use an ELISA kit to detect the amount of IL-1β secreted.

[0817] 8. Calculate the IL-1β concentration based on the standard curve, calculate the inhibition rate, fit the compound's action curve, and calculate the IC50. 50 .

[0818] Experimental results:

[0819] Experimental conclusion: The compound of this invention can effectively inhibit the secretion of IL-1β in PBMC cells.

[0820] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: in, n is 1, 2, 3 or 4; R 1 Independently, it can be hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 heteroaryl, -S(=O)2C1-C6 alkyl, substituted C1-C6alkyl, substituted C1-C6alkoxy, or substituted 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl in the substituted 5-6 membered heteroaryl is substituted with one or more R a substituted C1-C6alkyl, substituted C1-C6alkoxy, or substituted 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl in the substituted 5-6 membered heteroaryl is substituted with one or more R b substituted C1-C6alkyl, substituted C1-C6alkoxy, or substituted 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl in the substituted 5-6 membered heteroaryl is substituted with one or more R c substituted C1-C6alkyl, substituted C1-C6alkoxy, or substituted 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl in the substituted 5-6 membered heteroaryl is substituted with one or more R c substituted C1-C6alkyl, substituted C1-C6alkoxy, or substituted 5-6 membered heteroaryl, R a independently deuterium, halogen, or hydroxyl; R b independently halogen; R c independently halogen or Ci-C6alkyl; or two R 1 with the atom to which they are attached form a C3-C7cycloalkenyl, 3-7 membered d substituted C3-C7cycloalkenyl or a 3-7 membered e substituted heterocycloalkenyl, wherein the 3-7 membered heterocycloalkenyl in the 3-7 membered e heterocycloalkenyl in the 3-7 membered heterocycloalkenyl substituted by one or more R e heterocycloalkenyl in the 3-7 membered heterocycloalkenyl substituted by one or more R R d and R e each independently is hydrogen, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, 5-6 membered heteroaryl, C1-C6alkyl substituted with one or more R a substituents, C1-C6alkoxy substituted with one or more R b substituents, or 5-6 membered heteroaryl substituted with one or more R c substituents, wherein in the 5-6 membered heteroaryl and "5-6 membered heteroaryl substituted with one or more R c substituents" in the 5-6 membered heteroaryl, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R f It is a C1-C6 alkyl group; R 4 It is hydrogen, deuterium, or C1-C6 alkyl; R 3 for Ring A is arbitrarily controlled by one or more R 3-2 The substituted 3-12 member nitrogen-containing saturated heterocycle, wherein the heteroatom or heterogroup, in addition to containing N, may be selected from one or more of O, S, C(=O), S(=O) and S(=O)2, and the number of heteroatoms is one or more. R 3-2 Independently, it is cyano, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, C6-C 10 Aryl, 5-10 heteroaryl, -C(=O)C1-C6 alkyl, -C1-C6 alkyl-C6-C 10 Aryl, -C1-C6 alkyl-5-10 heteroaryl, -C1-C6 alkyl-C3-C6 cycloalkyl, -C1-C6 alkyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C3-C6 cycloalkyl, -C2-C6 alkenyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C6-C 10 aryl, -C2-C6 alkenyl-5-10 heteroaryl, -C2-C6 ynynyl-C3-C6 cycloalkyl, -C2-C6 ynynyl-3-6 heterocycloalkyl, -C2-C6 ynynyl-C6-C 10 Aryl, -C2-C6 ynyl-5-10 heteroaryl, -(CH2) p -O-C1-C6 alkyl, -(CH2) p -O-C2-C6 alkenyl, -(CH2) p -O-C2-C6 ynyl group, -(CH2) p -O-C3-C6 cycloalkyl, -(CH2) p -O-3-6-membered heterocyclic alkyl group, -(CH2) p -O-C6-C 10 Aryl, -(CH2) p -O-5-10-membered heteroaryl, -C1-C6 alkoxy-C3-C6 cycloalkyl, -C1-C6 alkoxy-3-6-membered heterocycloalkyl, -C1-C6 alkoxy-C6-C 10 Aryl, -C1-C6 alkoxy-5-10 heteroaryl, -(CH2) p -S(=O)2R 32-1 -(CH2) p -S(=O)2N(R 32-2 )2 or -(CH2) p N(R 32-2 )2, wherein the 5-10 heteroaryl group, the 5-10 heteroaryl group in "-C1-C6 alkyl-5-10 heteroaryl group", and the "-C2-C6 alkenyl-C6-C 10 The 5-10 membered heteroaryl in "aryl", the 5-10 membered heteroaryl in "-C2-C6 ynyl-5-10 membered heteroaryl", and "-(CH2)" p In "-O-5-10 heteroaryl", the 5-10 heteroaryl group and the 5-10 heteroaryl group in "-C1-C6 alkoxy-5-10 heteroaryl" are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; the 3-6 heterocyclic alkyl group, the 3-6 heterocyclic alkyl group in "-C1-C6 alkyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "-C2-C6 alkenyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "C2-C6 ynyl-3-6 heterocyclic alkyl", and the 3-6 heterocyclic alkyl group in "-(CH2)" are all included. p In the 3-6-membered heterocyclic alkyl group in "-O-3-6-membered heterocyclic alkyl group" and the 3-6-membered heterocyclic alkyl group in "-C1-C6alkoxy-3-6-membered heterocyclic alkyl group", the type of heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. The R mentioned 3-2 Optional substitution by one or more groups selected from the following: halogen, -CF3, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy. p can be 0, 1, 2, 3, 4, 5, or 6 independently; R 32-1 It is a C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more of the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy; R 32-2 Independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more groups selected from the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy; R 2 Hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -C1-C6 alkyl, -O-C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic alkyl, NR m R n , by one or more R 2-1 Substituted C3-C7 cycloalkyl, with one or more R 2-2 Substituted 3-7 membered heterocyclic alkyl groups, with one or more R 2-3 Substituted C1-C6 alkyl groups, wherein the 3-7 membered heterocyclic alkyl group and "substituted with one or more R 2-2 In the substituted 3-7 membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R m and R n Each is independently hydrogen or C1-C6 alkyl; R 2-1 R 2-2 and R 2-3 Each of the following can be independently classified as C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic alkyl, halogen, or -OR. s1 -NR s2 R s3 -S(=O)2R s4 or -C(=O)NR s5 R s6 ; R s1 R s2 R s3 R s4 R s5 and R s6 Each is independently hydrogen or C1-C6 alkyl; Or, R 2 and R 4 The carbon atoms bonded to them together form ring B, wherein ring B is a C5-C6 cycloalkenyl, a 5-6 membered heterocyclic alkenyl, a 5 membered heteroaryl, or is bonded by one or more R 2a1 Substituted C5-C6 cycloalkenyl groups, with one or more R 2a2 Substituted 5-6 membered heterocyclic alkenyl groups or those with one or more R groups 2a3 Substituted 5-membered heteroaryl, said 5-6-membered heterocyclic alkenyl and "substituted by one or more R 2a2 In the substituted 5-6 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3. The 5-membered heteroaryl group and "substituted with one or more R..." 2a3 In the 5-membered heteroaryl group of the substituted 5-membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R 2a1 R 2a2 and R 2a3 Each is independently a hydroxyl group, a C1-C6 alkyl group, or a halogen; Or, R 2 and R 3 The carbon atoms connected to them together form Also for Wherein, ring C is a 5-6 membered heterocyclic alkenyl group, Z is CH, and in the 5-6 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1.

2. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, n is 1, 2, 3 or 4; R 1 Independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 heteroaryl, -S(=O)2C1-C6 alkyl, or with one or more R a Substituted C1-C6 alkyl groups, with one or more R b Substituted C1-C6 alkoxy groups or those with one or more R groups c Substituted 5-6 heteroaryl, wherein the 5-6 heteroaryl and "is substituted with one or more R c In the 5-6 membered heteroaryl group of the substituted 5-6 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R a Independently, it can be deuterium, halogen, or hydroxyl; R b Halogens are independent of each other; R c It is independently a halogen or a C1-C6 alkyl group; Or, two adjacent R 1 The atoms connected to them together form C3-C7 cycloalkenyl groups, 3-7 membered heterocyclic alkenyl groups, and are bonded by one or more R groups. d The substituted C3-C7 cycloalkenyl group or the group with one or more R e Substituted 3-7-membered heterocyclic alkenyl groups, wherein the 3-7-membered heterocyclic alkenyl group and "is substituted with one or more R e In the substituted 3-7 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R d and R e Each of the following groups is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 heteroaryl, or surrounded by one or more R groups. a Substituted C1-C6 alkyl groups, with one or more R b Substituted C1-C6 alkoxy groups or those with one or more R groups c Substituted 5-6 heteroaryl, wherein the 5-6 heteroaryl and "is replaced by one or more R c In the 5-6 membered heteroaryl group of the substituted 5-6 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R 4 It is hydrogen, deuterium, or C1-C6 alkyl; R 3 for Ring A is arbitrarily controlled by one or more R 3-2 The substituted 3-12 member nitrogen-containing saturated heterocycle, wherein the heteroatom or heterogroup, in addition to containing N, may be selected from one or more of O, S, C(=O), S(=O) and S(=O)2, and the number of heteroatoms is one or more. R 3-2 Independently, it is cyano, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, C6-C 10 Aryl, 5-10 heteroaryl, -C(=O)C1-C6 alkyl, -C1-C6 alkyl-C6-C 10 Aryl, -C1-C6 alkyl-5-10 heteroaryl, -C1-C6 alkyl-C3-C6 cycloalkyl, -C1-C6 alkyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C3-C6 cycloalkyl, -C2-C6 alkenyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C6-C 10 aryl, -C2-C6 alkenyl-5-10 heteroaryl, -C2-C6 ynynyl-C3-C6 cycloalkyl, -C2-C6 ynynyl-3-6 heterocycloalkyl, -C2-C6 ynynyl-C6-C 10 Aryl, -C2-C6 ynyl-5-10 heteroaryl, -(CH2) p -O-C1-C6 alkyl, -(CH2) p -O-C2-C6 alkenyl, -(CH2) p -O-C2-C6 ynyl group, -(CH2) p -O-C3-C6 cycloalkyl, -(CH2) p -O-3-6-membered heterocyclic alkyl group, -(CH2) p -O-C6-C 10 Aryl, -(CH2) p -O-5-10-membered heteroaryl, -C1-C6 alkoxy-C3-C6 cycloalkyl, -C1-C6 alkoxy-3-6-membered heterocycloalkyl, -C1-C6 alkoxy-C6-C 10 Aryl, -C1-C6 alkoxy-5-10 heteroaryl, -(CH2) p -S(=O)2R 32-1 -(CH2) p -S(=O)2N(R 32-2 )2 or -(CH2) p N(R 32-2 )2, wherein the 5-10 heteroaryl group, the 5-10 heteroaryl group in "-C1-C6 alkyl-5-10 heteroaryl group", and the "-C2-C6 alkenyl-C6-C 10 The 5-10 membered heteroaryl in "aryl", the 5-10 membered heteroaryl in "-C2-C6 ynyl-5-10 membered heteroaryl", and "-(CH2)" p In "-O-5-10 heteroaryl", the 5-10 heteroaryl group and the 5-10 heteroaryl group in "-C1-C6 alkoxy-5-10 heteroaryl" are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; the 3-6 heterocyclic alkyl group, the 3-6 heterocyclic alkyl group in "-C1-C6 alkyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "-C2-C6 alkenyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "C2-C6 ynyl-3-6 heterocyclic alkyl", and the 3-6 heterocyclic alkyl group in "-(CH2)" are all included. p In the 3-6-membered heterocyclic alkyl group in "-O-3-6-membered heterocyclic alkyl group" and the 3-6-membered heterocyclic alkyl group in "-C1-C6alkoxy-3-6-membered heterocyclic alkyl group", the type of heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. The R mentioned 3-2 Optional substitution by one or more groups selected from the following: halogen, -CF3, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy. p can be 0, 1, 2, 3, 4, 5, or 6 independently; R 32-1 It is a C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more of the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy; R 32-2 Independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more groups selected from the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy; R 2 Hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -C1-C6 alkyl, -O-C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic alkyl, NR m R n , by one or more R 2-1 Substituted C3-C7 cycloalkyl, with one or more R 2-2 Substituted 3-7 membered heterocyclic alkyl groups or substituted with one or more R 2-3 Substituted C1-C6 alkyl groups, wherein the 3-7 membered heterocyclic alkyl group and "substituted with one or more R 2-2 In the substituted 3-7 membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R m and R n Each is independently hydrogen or C1-C6 alkyl; R 2-1 R 2-2 and R 2-3 Each can be independently C1-C6 alkyl, C2-C6 alkynyl, halogen, or -OR s1 -NR s2 R s3 -S(=O)2R s4 or -C(=O)NR s5 R s6 ; R s1 R s2 R s3 R s4 R s5 and R s6 Each is independently hydrogen or C1-C6 alkyl; Or, R 2 and R 4 The carbon atoms bonded to them together form ring B, wherein ring B is a C5-C6 cycloalkenyl, a 5-6 membered heterocyclic alkenyl, a 5 membered heteroaryl, or is bonded by one or more R 2a1 Substituted C5-C6 cycloalkenyl groups, with one or more R 2a2 Substituted 5-6 membered heterocyclic alkenyl groups or those with one or more R groups 2a3 Substituted 5-membered heteroaryl, said 5-6-membered heterocyclic alkenyl and "substituted by one or more R 2a2 In the substituted 5-6 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3. The 5-membered heteroaryl group and "substituted with one or more R..." 2a3 In the 5-membered heteroaryl group of the substituted 5-membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R 2a1 R 2a2 and R 2a3 Each is independently a hydroxyl group, a C1-C6 alkyl group, or a halogen; Or, R 2 and R 3 The carbon atoms connected to them together form Also for Wherein, ring C is a 5-6 membered heterocyclic alkenyl group, Z is CH, and in the 5-6 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1.

3. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, n is 1, 2, 3 or 4; R 1 Independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 heteroaryl, or surrounded by one or more R groups. a Substituted C1-C6 alkyl groups, with one or more R b Substituted C1-C6 alkoxy groups or those with one or more R groups c Substituted 5-6 heteroaryl, wherein the 5-6 heteroaryl and "is substituted with one or more R c In the 5-6 membered heteroaryl group of the substituted 5-6 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R a Independently, it can be deuterium, halogen, or hydroxyl; R b Halogens are independent of each other; R c It is independently a halogen or a C1-C6 alkyl group; Or, two adjacent R 1 The atoms connected to them together form C3-C7 cycloalkenyl groups, 3-7 membered heterocyclic alkenyl groups, and are bonded by one or more R groups. d The substituted C3-C7 cycloalkenyl group or the group with one or more R e Substituted 3-7-membered heterocyclic alkenyl groups, wherein the 3-7-membered heterocyclic alkenyl group and "is substituted with one or more R e In the substituted 3-7 membered heterocyclic alkenyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R d and R e Each of the following groups is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 heteroaryl, or surrounded by one or more R groups. a Substituted C1-C6 alkyl groups, with one or more R b Substituted C1-C6 alkoxy groups or those with one or more R groups c Substituted 5-6 heteroaryl, wherein the 5-6 heteroaryl and "is replaced by one or more R c In the 5-6 membered heteroaryl group of the substituted 5-6 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R 4 It is hydrogen, deuterium, or C1-C6 alkyl; R 3 for Ring A is arbitrarily controlled by one or more R 3-2 The substituted 3-12 member nitrogen-containing saturated heterocycle, wherein the heteroatom or heterogroup, in addition to containing N, may be selected from one or more of O, S, C(=O), S(=O) and S(=O)2, and the number of heteroatoms is one or more. R 3-2 Independently, it is cyano, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, C6-C 10 Aryl, 5-10 heteroaryl, -C(=O)C1-C6 alkyl, -C1-C6 alkyl-C6-C 10 Aryl, -C1-C6 alkyl-5-10 heteroaryl, -C1-C6 alkyl-C3-C6 cycloalkyl, -C1-C6 alkyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C3-C6 cycloalkyl, -C2-C6 alkenyl-3-6 heterocyclic alkyl, -C2-C6 alkenyl-C6-C 10 aryl, -C2-C6 alkenyl-5-10 heteroaryl, -C2-C6 ynynyl-C3-C6 cycloalkyl, -C2-C6 ynynyl-3-6 heterocycloalkyl, -C2-C6 ynynyl-C6-C 10 Aryl, -C2-C6 ynyl-5-10 heteroaryl, -(CH2) p -O-C1-C6 alkyl, -(CH2) p -O-C2-C6 alkenyl, -(CH2) p -O-C2-C6 ynyl group, -(CH2) p -O-C3-C6 cycloalkyl, -(CH2) p -O-3-6-membered heterocyclic alkyl group, -(CH2) p -O-C6-C 10 Aryl, -(CH2) p -O-5-10-membered heteroaryl, -C1-C6 alkoxy-C3-C6 cycloalkyl, -C1-C6 alkoxy-3-6-membered heterocycloalkyl, -C1-C6 alkoxy-C6-C 10 Aryl, -C1-C6 alkoxy-5-10 heteroaryl, -(CH2) p -S(=O)2R 32-1 -(CH2) p -S(=O)2N(R 32-2 )2 or -(CH2) p N(R 32-2 )2, wherein the 5-10 heteroaryl group, the 5-10 heteroaryl group in "-C1-C6 alkyl-5-10 heteroaryl group", and the "-C2-C6 alkenyl-C6-C 10 The 5-10 membered heteroaryl in "aryl", the 5-10 membered heteroaryl in "-C2-C6 ynyl-5-10 membered heteroaryl", and "-(CH2)" p In "-O-5-10 heteroaryl", the 5-10 heteroaryl group and the 5-10 heteroaryl group in "-C1-C6 alkoxy-5-10 heteroaryl" are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; the 3-6 heterocyclic alkyl group, the 3-6 heterocyclic alkyl group in "-C1-C6 alkyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "-C2-C6 alkenyl-3-6 heterocyclic alkyl", the 3-6 heterocyclic alkyl group in "C2-C6 ynyl-3-6 heterocyclic alkyl", and the 3-6 heterocyclic alkyl group in "-(CH2)" are all included. p In the 3-6-membered heterocyclic alkyl group in "-O-3-6-membered heterocyclic alkyl group" and the 3-6-membered heterocyclic alkyl group in "-C1-C6alkoxy-3-6-membered heterocyclic alkyl group", the type of heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. The R mentioned 3-2 Optional substitution by one or more groups selected from the following: halogen, -CF3, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy. p can be 0, 1, 2, 3, 4, 5, or 6 independently; R 32-1 It is a C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more of the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy; R 32-2 Independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl is optionally substituted by one or more groups selected from the following groups: halogen, -CF3, hydroxyl and C1-C6 alkoxy; R 2 Hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, -C1-C6 alkyl, -O-C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic alkyl, NR m R n , by one or more R 2-1 Substituted C3-C7 cycloalkyl, with one or more R 2-2 Substituted 3-7 membered heterocyclic alkyl groups or substituted with one or more R 2-3 Substituted C1-C6 alkyl groups, wherein the 3-7 membered heterocyclic alkyl group and "substituted with one or more R 2-2 In the substituted 3-7 membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R m and R n Each is independently hydrogen or C1-C6 alkyl; R 2-1 R 2-2 and R 2-3 Each is independently C1-C6 alkyl, halogen, -OR s1 -NR s2 R s3 -S(=O)2R s4 or -C(=O)NR s5 R s6 ; R s1 R s2 R s3 R s4 R s5 and R s6 Each is independently hydrogen or C1-C6 alkyl.

4. The compound of formula (I) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) Each "5-membered heteroaryl group" is independently a 5-membered heteroaryl group with N and / or O heteroatoms, and the number of heteroatoms is 1, 2 or 3, such as pyrrole, oxazolyl, isoxazolyl, pyrazolyl, imidazole or triazolyl, further for example (2) Each "C5-C6 cycloalkenyl group" is independently... (3) Each "5-6 membered heterocyclic alkenyl group" is independently a 5-6 membered heterocyclic alkenyl group with one heteroatom (O), for example... (4) Each "3-12 member nitrogen-containing saturated heterocycle" is independently... Further examples 5. The compound of formula (I) as described in any one of claims 1-3, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) Each "halogen" is independently F, Cl, Br or I, for example F; (2) Each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl; (3) Each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy; (4) Each “C3-C6 cycloalkyl” or “C3-C7 cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl, further for example cyclobutyl; (5) Each "3-6 membered heterocyclic alkyl" or "3-7 membered heterocyclic alkyl" is independently a 4-6 membered heterocyclic alkyl with one or two heteroatoms selected from N and O, such as aza-butane or tetrahydrofuranyl, and further for example... (6) Each "5-6 heteroaryl group" is independently pyrrole, furanyl, thiophene, imidazolyl, pyrazolyl, thiazolyl, pyridinyl or pyrimidinyl; (7) Each "C3-C7 cycloalkenyl" is independently a C4-C6 cycloalkenyl, for example (8) Each "3-7 membered heterocyclic alkenyl group" is independently a 5-6 membered heterocyclic alkenyl group with one or two heteroatoms selected from N, O and S, such as dihydrofuranyl, and further for example... (9) Each "3-12 member nitrogen-containing saturated heterocycle" is independently selected from one or two types of N and O heteroatoms, and the number of heteroatoms is 1 or 2. This is used for "5-6 member nitrogen-containing saturated heterocycles" or "7-12 member fused, bridged, or spirocyclic nitrogen-containing saturated heterocycles", for example... Further examples (10) Each "C2-C6 alkenyl" is independently a C2-C4 alkenyl, such as vinyl, allyl or propenyl; (11) Each "C2-C6 ynyl group" is independently a C2-C4 ynyl group, such as ethynyl, propynyl or propynyl; (12) Each "C6-C 10 Each aryl group can be either aryl or naphthyl. (13) Each "5-10 member heteroaryl" is independently composed of one or two heteroatoms of N, O and S, and the number of heteroatoms is one or two 5-6 member monocyclic heteroaryl or 8-10 member bicyclic heteroaryl.

6. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) n is 1, 2 or 3; (2)R 1 Independently cyano, C1-C6 alkyl, -S(=O)2C1-C6 alkyl, Or C1-C6 alkyl groups substituted with one or more halogens; R f It is a C1-C6 alkyl group; Or, two adjacent R 1 The atoms connected to them together form 5-6 membered heterocyclic alkenyl groups; R 1 For example, CN, -CF3, -CH3, -S(=O)2CH3 or Or, two adjacent R 1 The atoms connected to them together form (3) for (4)R 3 for (5)R 2 for Or 4-6 membered heterocyclic alkyl groups, R 2-3 It is a hydroxyl group; R a1 and R a2 Each can be independently hydrogen, CF3, methyl, ethyl, ethynyl, vinyl, isopropyl, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl; or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, C3-C6 cycloalkyl substituted with one or more halogens, or 3-6 membered heterocyclic alkyl substituted with one or more halogens. or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or two R atoms on the same carbon atom. a2 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or, R a1 and R a2 The carbon atoms connected to them together form C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl groups.

7. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) for (2) for (3)R 3 for (4)R 2 -CH2OH, 8. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It satisfies any of the following conditions: Case 1: R 2 and R 4 The carbon atoms connected to them together form Case 2: R 2 and R 4 The carbon atoms bonded to them together form ring B, wherein ring B is a 5-6 membered heterocyclic alkenyl group containing one oxygen atom or is bonded by one or more R atoms. 2a2 Substituted 5-6 membered heterocyclic alkenyl groups, R 2a2 Independently hydroxyl or halogen, for example 9. The compound of formula (I) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 It is independently a cyano, C1-C6 alkyl, -S(=O)2C1-C6 alkyl or a C1-C6 alkyl substituted with one or more halogens; Or, two adjacent R 1 The atoms connected to them together form 5-6 membered heterocyclic alkenyl groups; (2) for For example (3)R 3 for For example (4)R 2 for Or 4-6 membered heterocyclic alkyl groups, R 2-3 It is a hydroxyl group; R a1 and R a2 Each can be independently hydrogen, CF3, methyl, ethyl, or ethynyl; or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl groups. or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or two R atoms on the same carbon atom. a2 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or, R a1 and R a2 The carbon atoms connected to them together form C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl groups.

10. The compound of formula (I) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 Independently CN, -CF3, -CH3, or -S(=O)2CH3, or two adjacent R 1 The atoms connected to them together form (2) for (3)R 3 for (4)R 2 -CH2OH, 11. The compound of formula (I) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, for 12. The compound of formula (I) as claimed in any one of claims 1-5, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) n is 2 or 3; or n is 1 or 2; (2)R 1 It is independently a cyano, C1-C6 alkyl, or a C1-C6 alkyl substituted with one or more halogens; Or, two adjacent R 1 The atoms connected to them together form 5-6 membered heterocyclic alkenyl groups; (3)R 3 for For example (4)R 2 for Or 4-6 membered heterocyclic alkyl groups, R 2-3 It is a hydroxyl group; R a1 and R a2 Each can be independently hydrogen, methyl, or ethyl; or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl groups. or, In the middle, two R on the same carbon atom a1 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or two R atoms on the same carbon atom. a2 The carbon atoms bonded to them together form C3-C6 cycloalkyl or 3-6 membered heterocycloalkyl, or, R a1 and R a2 The carbon atoms connected to them together form C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl groups.

13. The compound of formula (I) as claimed in any one of claims 1-5, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 Independently CN, -CF3, or -CH3; Or, two adjacent R 1 The atoms connected to them together form (2)R 3 for (3)R 2 -CH2OH, (4)R 4 It is hydrogen.

14. The compound of formula (I) as claimed in any one of claims 1-5, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, for 15. The compound of formula (I) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, R 2 and R 4 The carbon atoms connected to them together form a 5-6 membered heterocyclic alkenyl group, which is then bonded by one or more R groups. 2a1 Substituted C5-C6 cycloalkenyl or 5-membered heteroaryl, for example Ideally, R 2 and R 4 The carbon atoms bonded to them together form a 5-6 membered heterocyclic alkenyl group containing one oxygen atom, for example...

16. The compound of formula (I) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, R 2 and R 3 The carbon atoms connected to them together form For example 17. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 Independently, it is cyano, C1-C6 alkyl, -S(=O)2C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogens, or C1-C6 alkoxy substituted with one or more halogens; or, two adjacent R 1 The atoms connected to them together form a 5-membered heterocyclic alkenyl group; Ideally, R 1 Independently, it can be CN, -CF3, -CH3, -S(=O)2CH3 or Or, two adjacent R 1 The atoms connected to them together form Better, for (2) for R 3-2 It is independently a C1-C6 alkyl group or an alkyl group substituted with one or more hydroxyl groups; For example, (3)R 2 for R 2-3 The carbon atom marked with "*" has an R configuration, an S configuration, or a mixture thereof. One of the R a1 It is hydrogen, C1-C6 alkyl, CF3, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, or a C1-C6 alkyl substituted with one or more halogens; another R a1 It is hydrogen; Or, R 2 and R 4 The carbon atoms bonded to them together form a ring B, wherein the ring B is a C5-C6 cycloalkenyl, a 5-membered heteroaryl, or bonded by one or more R atoms. 2a1 Substituted C5-C6 cycloalkenyl groups or those with one or more R groups 2a2 Substituted 5-6 membered heterocyclic alkenyl groups; R 2a1 and R 2a2 Independently, it is a hydroxyl group; Ideally, R 2 for Or, R 2 and R 4 The carbon atoms bonded to them together form ring B, wherein ring B is 18. The compound of formula (I) as claimed in any one of claims 1-17, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is a compound represented by formula (I-1), (I-2), or (I-3): Preferably, in the compound shown in formula (I-1), R 2 for R a1 and R a2 Each can be independently hydrogen, methyl, or ethyl; R 2-3 It is a hydroxyl group; R 4 It is hydrogen; for R 3-2 It is a C1-C6 alkyl group; for R 1 It is independently a C1-C6 alkyl or a C1-C6 alkyl substituted with one or more F.

19. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is any one of the following compounds:

20. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is selected from any one of the following compounds: One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound A1, wherein compound A1 is... The compound that elutes first under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 40-50%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 40% gradient for 1 min, and then linearly increased at 40%-50% over the next 10 min. Preferably, under the above conditions, the retention time of the compound that elutes first is 6.2-7.2 min. One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound A2, wherein compound A2 is... Compounds that elute later under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 40-50%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 40% gradient for 1 min, and then linearly increased at 40%-50% over the next 10 min. Preferably, under the conditions described, the retention time of the compounds that elute later is 8.7-10.3 min. One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound B1, wherein compound B1 is... The compound that elutes first under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 40-50%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 40% gradient for 1 min, and then linearly increased at 40%-50% over the next 10 min. Preferably, under the conditions described, the retention time of the compound that elutes first is 6.8-7.7 min. One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound B2, wherein compound B2 is... Compounds that elute later under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 40-50%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 40% gradient for 1 min, and then linearly increased at 40%-50% over the next 10 min. Preferably, under the conditions described, the retention time of the compounds that elute later is 9.1-10.3 min. One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound S1, wherein compound S1 is The compounds were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound S2, wherein compound S2 is The compounds were separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound C1, wherein compound C1 is The compounds were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound C2, wherein compound C2 is... The compounds were obtained by separation under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound D1, wherein compound D1 is The compounds were separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound E1, wherein compound E1 is... The compounds were obtained by separation under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound F1, wherein compound F1 is The compounds obtained were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound F2, wherein compound F2 is The compounds were separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound G1, wherein compound G1 is The compound that elutes first under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 35-45%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 35% gradient for 1 min, and then linearly increased at 35%-45% over the next 10 min. Preferably, under the conditions described, the retention time of the compound that elutes first is 6.9-7.8 min. One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound G2, wherein compound G2 is Compounds eluting later under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 35-45%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 35% gradient for 1 min, and then linearly increased at 35%-45% over the next 10 min. Preferably, under the conditions described, the retention time of the compounds eluting later is 8.1-9.1 min. One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound H1, wherein compound H1 is... The compound that elutes first under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 42-52%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a gradient of 42% for 1 min, and then linearly increased at 42%-52% over the next 10 min. Preferably, under the separation conditions, the retention time of the compound that elutes first is 7.0-7.7 min. One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound H2, wherein compound H2 is Compounds eluting later under the following conditions: Column: Waters 3767 / Qda; Column: SunFire C18, 19*250mm, 10µm; Mobile phase: acetonitrile-0.05% trifluoroacetic acid aqueous solution; Flow rate: 20mL / min; Gradient: 42-52%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 42% gradient for 1 min, and then linearly increased at 42%-52% over the next 10 min. Preferably, under the separation conditions, the retention time of the compounds eluting later is 7.9-9.0 min. One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound I1, wherein compound I1 is The compounds were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound I2, wherein compound I2 is The compounds were obtained by separation under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound J1, wherein compound J1 is... The compound that elutes first under the following conditions: column: C18 spherical, 20-35 μm, 100A, 80 g; mobile phase: acetonitrile-0.1% trifluoroacetic acid aqueous solution; flow rate: 20 mL / min; gradient: 5-45%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a gradient of 5% for 10 min, and then linearly increased at 5%-45% over the next 20 min. Preferably, under the conditions described, the retention time of the compound that elutes first is 19.0-20.0 min. One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as that of the chiral carbon atom bonded to OH in compound J2, wherein compound J2 is... Compounds eluting later under the following conditions: column: C18 spherical, 20-35 μm, 100A, 80 g; mobile phase: acetonitrile-0.1% trifluoroacetic acid aqueous solution; flow rate: 20 mL / min; gradient: 5-45%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a 5% gradient for 10 min, and then linearly increased at 5%-45% over the next 20 min. Preferably, under the conditions described, the retention time of the compounds eluting later is 20.5-23.0 min. One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH and the position of the OH atom are the same as those of the chiral carbon atom bonded to OH and the position of the OH atom in compound K1, wherein compound K1 is... The first compound obtained under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH and the position of the OH atom are the same as those of the chiral carbon atom bonded to OH and the position of the OH atom in compound K2, wherein compound K2 is... The second compound obtained under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH and the position of the OH atom are the same as those of the chiral carbon atom bonded to OH and the position of the OH atom in compound K3, wherein compound K3 is The third compound obtained under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH and the position of the OH atom are the same as those of the chiral carbon atom bonded to OH and the position of the OH atom in compound K4, wherein compound K4 is The fourth compound obtained under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound L1, wherein compound L1 is... The compounds obtained were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH is the same as that of the chiral carbon atom bonded to OH in compound L2, wherein compound L2 is... The compounds were separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound D1, wherein compound D1 is The compounds were separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v); One of the compounds, wherein the configuration of the chiral carbon atom bonded to OH in the compound is the same as the configuration of the chiral carbon atom bonded to OH in compound C1, wherein compound C1 is The compounds were first separated under the following conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v); The compound that elutes first under the following conditions: Waters 3767 / Qda Column: XBridge C18, 19*250mm, 10µm; mobile phase: acetonitrile-0.05% ammonia monohydrate aqueous solution; flow rate: 20mL / min; gradient: 22-36%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is initially maintained at a gradient of 22% for 1 min, and then linearly increased from 22% to 36% over the next 10 min. Preferably, the retention time of the compound that elutes first is 6.5-7.2 min. The compound that elutes first under the following conditions: Waters 3767 / Qda Column: XBridge C18, 19*250mm, 10um; mobile phase: acetonitrile-0.05% ammonia monohydrate aqueous solution; flow rate: 20mL / min; gradient: 22-36%, where the ratio is the volume ratio of acetonitrile in the mobile phase. The gradient elution is first maintained at a gradient of 22% for 1 min, and then linearly increased at 22%-36% over the next 10 min. Preferably, the retention time of the compound that elutes first is 9.0-9.8 min.

21. A pharmaceutical composition comprising substance X and a pharmaceutically acceptable excipient, wherein substance X is a compound of formula (I) as described in any one of claims 1-20, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

22. The use of a compound of formula (I) as claimed in any one of claims 1-20, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 21 in the preparation of an NLRP3 inhibitor.

23. The use of a compound of formula (I) as described in any one of claims 1-20, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 21 in the preparation of a medicament for the prevention and / or treatment of NLRP3-related diseases, preferably, wherein the NLRP3-related diseases are neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease.

24. The use of a compound of formula (I) as described in any one of claims 1-20, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 21 in the preparation of a drug for the prevention and / or treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease.

Images