Pyridazine ring derivative and use thereof

Abstract

Disclosed in the present invention are a pyridazine ring derivative and a use thereof. Particularly, disclosed in the present invention are a compound as represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The pyridazine ring derivative of the present invention has good inhibitory activity against NLRP3, and can better inhibit the secretion of IL-1β in THP-1 cells.

Description

Pyridazine ring derivatives and their applications

[0001] This application claims priority to Chinese Patent Application No. 2024102231644 filed on February 28, 2024, Chinese Patent Application No. 2024103294814 filed on March 21, 2024, Chinese Patent Application No. 2024103954640 filed on April 2, 2024, Chinese Patent Application No. 2024104408210 filed on April 12, 2024, Chinese Patent Application No. 2024105318989 filed on April 29, 2024, and Chinese Patent Application No. 2024107239568 filed on June 5, 2024. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to pyridazine ring derivatives and applications thereof. Background Art

[0003] The NLRP3 inflammasome is a multiprotein complex consisting of the sensor NLRP3, the adaptor 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.

[0004] Currently, no NLRP3 inhibitors are available on the market. However, several NLRP3 inhibitors, including OLT-1177, DFV-890, and Selnoflast, are in various stages of clinical research. The development of NLRP3 inhibitors holds broad potential for application. Summary of the Invention

[0005] The present invention aims to overcome the shortage of NLRP3 inhibitors in the prior art by providing novel pyridazine ring derivatives and their applications. These pyridazine ring derivatives exhibit excellent inhibitory activity against NLRP3 and are capable of effectively inhibiting IL-1β secretion in THP-1 cells.

[0006] The present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0007] Among them, R 1 For one or more R 4 Substituted naphthyl, one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl;

[0008] R 4 and R 5 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl, substituted by one or more R c Substituted C1-C6 alkyl, one or more R d’ Substituted C1-C6 alkoxy or one or more R d substituted 5-6 membered heteroaryl;

[0009] R c are independently deuterium, halogen or hydroxyl;

[0010] R d’ are independently halogen;

[0011] R d are independently halogen or C1-C6 alkyl;

[0012] Or, two adjacent R 4 The atoms to which they are attached together form a C3-C7 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C3-C7 ... e Substituted C3-C7 cycloalkenyl or one or more R f substituted 3-7 membered heterocycloalkenyl;

[0013] Or, two adjacent R 5 The atoms to which they are attached together form a C3-C7 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C3-C7 ... e Substituted C3-C7 cycloalkenyl or one or more R f substituted 3-7 membered heterocycloalkenyl;

[0014] R e and R f Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl, substituted by one or more R c Substituted C1-C6 alkyl, one or more R d’ Substituted C1-C6 alkoxy or one or more R d substituted 5-6 membered heteroaryl;

[0015] R 2is hydrogen, CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, 2-1 Substituted C1-C6 alkoxy or one or more R 2-2 Substituted C1-C6 alkyl;

[0016] R 2-1 and R 2-2 are each independently halogen;

[0017] A 1 、A 2 、A 3 and A 4 Each is independently a connecting bond, CR a R b NR c , O or S;

[0018] A 1 、A 2 、A 3 and A 4 The number of connecting bonds in is 0, 1, 2 or 3;

[0019] R a 、R b and R c Each independently represents hydrogen, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl or is replaced by one or more R a-1 Substituted C1-C6 alkyl or R a and R b Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group;

[0020] R a-1 are independently halogen;

[0021] R 3 is a C3-C7 monocyclic cycloalkyl, a C5-C 12 Bicyclic cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocycloalkyl, one or more R 3-1 substituted 3-7 membered monocyclic heterocycloalkyl, substituted by one or more R 3-1 substituted 5-12 membered bicyclic heterocycloalkyl, substituted by one or more R 3-2 Substituted C1-C6 alkyl, one or more R 3-3 Substituted C3-C7 monocyclic cycloalkyl or one or more R 3-3 Substituted C5-C 12 bicyclic cycloalkyl;

[0022] R 3-1 and R 3-3Each is independently hydroxy, halogen, oxo (=O), -COOH, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, 3-1-1 Substituted C1-C6 alkyl, one or more R 3-1-2 Substituted C3-C7 cycloalkyl or one or more R 3-1-3 substituted 3-7 membered heterocycloalkyl;

[0023] R 3-1-1 are independently OH, halogen, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl;

[0024] R 3-1-2 and R 3-1-3 Each is independently a C1-C6 alkyl group;

[0025] R 3-2 is independently a 3-7 membered heterocycloalkyl group or is replaced by one or more R 3-2-1 substituted 3-7 membered heterocycloalkyl;

[0026] R 3-2-1 are independently C1-C6 alkyl;

[0027] In the above groups, each "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S; the number of heteroatoms is 1, 2 or 3;

[0028] Each "3-7 membered heterocycloalkyl" is independently a 3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0029] Each "3-7 monocyclic heterocycloalkyl" is independently a 3-7 membered monocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0030] Each "5-12 membered bicyclic heterocycloalkyl" is independently a 5-12 membered bicyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0031] Each "5-6 membered heteroaryl" is independently a 5-6 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0032] Each "3- to 7-membered heterocycloalkenyl group" is independently a 3- to 7-membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of the heteroatoms is 1, 2 or 3.

[0033] In a certain embodiment of the present invention, the compound represented by formula (I) is not the following compound and its stereoisomers:

[0034] In certain preferred embodiments of the present invention, certain groups in the compound of formula (I), its pharmaceutically acceptable salt or solvate of any of the foregoing are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention").

[0035] In one embodiment of the present invention,

[0036] R 1 For one or more R 4 Substituted naphthyl, one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl;

[0037] R 4 and R 5 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl, substituted by one or more R c Substituted C1-C6 alkyl, one or more R d’ Substituted C1-C6 alkoxy or one or more R d substituted 5-6 membered heteroaryl;

[0038] R c are independently deuterium, halogen or hydroxyl;

[0039] R d’ are independently halogen;

[0040] Rd are independently halogen or C1-C6 alkyl;

[0041] Or, two adjacent R 4 The atoms to which they are attached together form a C3-C7 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C3-C7 ... e Substituted C3-C7 cycloalkenyl or one or more R f substituted 3-7 membered heterocycloalkenyl;

[0042] Or, two adjacent R 5 The atoms to which they are attached together form a C3-C7 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C3-C7 ... e Substituted C3-C7 cycloalkenyl or one or more R f substituted 3-7 membered heterocycloalkenyl;

[0043] R e and R f Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl, substituted by one or more R c Substituted C1-C6 alkyl, one or more R d’ Substituted C1-C6 alkoxy or one or more R d substituted 5-6 membered heteroaryl;

[0044] R 2 is hydrogen, CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, 2-1 Substituted C1-C6 alkoxy or one or more R 2-2 Substituted C1-C6 alkyl;

[0045] R 2-1 and R 2-2 are each independently halogen;

[0046] A 1 、A 2 、A 3 and A 4 Each is independently a connecting bond, CR a R b NR c , O or S;

[0047] A 1 、A 2 、A 3 and A 4 The number of connecting bonds in is 0, 1, 2 or 3;

[0048] Ra 、R b and R c Each independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or substituted by one or more R a-1 Substituted C1-C6 alkyl or R a and R b Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group;

[0049] R a-1 are independently halogen;

[0050] R 3 is a C3-C7 monocyclic cycloalkyl, a C5-C 12 Bicyclic cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocycloalkyl, one or more R 3-1 substituted 3-7 membered monocyclic heterocycloalkyl, substituted by one or more R 3-1 substituted 5-12 membered bicyclic heterocycloalkyl, substituted by one or more R 3-2 Substituted C1-C6 alkyl, one or more R 3-3 Substituted C3-C7 monocyclic cycloalkyl or one or more R 3-3 Substituted C5-C 12 bicyclic cycloalkyl;

[0051] R 3-1 and R 3-3 Each is independently hydroxy, halogen, oxo (=O), -COOH, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl or substituted by one or more R 3-1-1 Substituted C1-C6 alkyl;

[0052] R 3-1-1 are independently OH, halogen, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl;

[0053] R 3-2 is independently a 3-7 membered heterocycloalkyl group or is replaced by one or more R 3-2-1 substituted 3-7 membered heterocycloalkyl;

[0054] R 3-2-1 are independently C1-C6 alkyl;

[0055] In the above groups, each "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S; the number of heteroatoms is 1, 2 or 3;

[0056] Each "3-7 membered heterocycloalkyl" is independently a 3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0057] Each "3-7 monocyclic heterocycloalkyl" is independently a 3-7 membered monocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0058] Each "5-12 membered bicyclic heterocycloalkyl" is independently a 5-12 membered bicyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0059] Each "5-6 membered heteroaryl" is independently a 5-6 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0060] Each "3- to 7-membered heterocycloalkenyl group" is independently a 3- to 7-membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of the heteroatoms is 1, 2 or 3.

[0061] In one embodiment of the present invention, each "5-10 membered heteroaryl" is independently a 8-10 membered bicyclic heteroaryl group having one heteroatom selected from N, O and S, for example

[0062] In a certain embodiment of the present invention, each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; for example, methyl, ethyl or isopropyl, further for example, methyl.

[0063] In one embodiment of the present invention, each "halogen" is independently fluorine, chlorine, bromine or iodine; for example, fluorine or chlorine, further for example fluorine.

[0064] In one embodiment of the present invention, each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; for example, methoxy.

[0065] In one embodiment of the present invention, each "C3-C6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; for example, cyclopropyl, cyclobutyl or cyclohexyl.

[0066] In one embodiment of the present invention, each "5-6 membered heteroaryl group" is independently a 5-membered heteroaryl group in which the heteroatoms are S and N and the number of heteroatoms is 3; for example,

[0067] In one embodiment of the present invention, each "C3-C7 cycloalkenyl" is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, for example, cyclopentenyl.

[0068] In one embodiment of the present invention, each "3-7 membered heterocycloalkenyl" is independently a "4-6 membered heterocycloalkenyl" wherein the heteroatom is O and the number of heteroatoms is 1 or 2, for example, dihydrofuranyl.

[0069] In one embodiment of the present invention, each "C3-C7 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0070] In one embodiment of the invention, each "3-7 membered heterocycloalkyl" is independently a 4-9 membered heterocycloalkyl group in which the heteroatom is O or N and the number of heteroatoms is 1 or 2, for example, any of the following:

[0071] Case 1: oxetanyl or tetrahydropyranyl, further example,

[0072] Case 2: Oxetane, further example,

[0073] In one embodiment of the present invention, each "C3-C7 membered monocyclic cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, Among them, the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; for example,

[0074] In one embodiment of the present invention, each "3-7 membered monocyclic heterocycloalkyl" is independently a "4-7 membered monocyclic heterocycloalkyl" wherein the heteroatom is N and / or O, and the number of heteroatoms is 1 or 2, for example, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl; for example, Among them, the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof, and X is O, NH or CH2; for example,

[0075] In one embodiment of the present invention, each "5-12 membered bicyclic heterocycloalkyl" is independently an "8-10 membered bicyclic heterocycloalkyl" wherein the heteroatom is N and the number of heteroatoms is 1; for example, Among them, the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; for example,

[0076] In a certain embodiment of the present invention, each "C5-C 12 The bicyclic cycloalkyl groups are independently C5-C12 Cycloalkyl, C5-C 12 Bridged cycloalkyl or C5-C 12 Spirocyclic cycloalkyl.

[0077] In one embodiment of the present invention, R 1 For one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl; preferably substituted by one or more R 4 Substituted phenyl.

[0078] In one embodiment of the present invention, R 4 and R 5 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, 5-6 membered heteroaryl, c Substituted C1-C6 alkyl or one or more R e substituted 5-6 membered heteroaryl;

[0079] Or, two adjacent R 4 Together with the atoms to which they are attached, they form a C3-C7 cycloalkenyl or a 3-7 membered heterocycloalkenyl.

[0080] In one embodiment of the present invention, R 4 and R 5 Each independently represents hydrogen, hydroxy, C1-C6 alkyl or is replaced by one or more R c Substituted C1-C6 alkyl.

[0081] In one embodiment of the present invention, R c are independently halogen.

[0082] In one embodiment of the present invention, R e are independently C1-C6 alkyl.

[0083] In one embodiment of the present invention, R 2 is hydrogen, C1-C6 alkyl or 3-7 membered heterocycloalkyl; preferably hydrogen.

[0084] In one embodiment of the present invention, A 1 、A 2 、A 3 and A 4 The number of connecting bonds in is 0 or 1; preferably 1.

[0085] In one embodiment of the present invention, R a 、R b and R c are each independently H, hydroxyl or C1-C6 alkyl; or, R a and Rb Together with the carbon atom to which they are attached, they form a C3-C6 cycloalkyl group.

[0086] In one embodiment of the present invention, R a 、R b and R c are each independently H or C1-C6 alkyl; or, R a and R b Together with the carbon atom to which they are attached, they form a C3-C6 cycloalkyl group.

[0087] In one embodiment of the present invention, R 3 is a 5-12 membered bicyclic heterocycloalkyl group, 3-1 substituted 3-7 membered monocyclic heterocycloalkyl, substituted by one or more R 3-2 Substituted C1-C6 alkyl or one or more R 3-3 Substituted C3-C7 monocyclic cycloalkyl; preferably substituted by one or more R 3-1 Substituted 3-7 membered monocyclic heterocycloalkyl.

[0088] In one embodiment of the present invention, R 3-1 and R 3-3 Each independently represents a hydroxyl group, a halogen group, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a 3-7 membered heterocycloalkyl group, a 3-1-1 Substituted C1-C6 alkyl or one or more R 3-1-2 Substituted C3-C7 cycloalkyl.

[0089] In one embodiment of the present invention, R 3-1-1 are independently C3-C7 cycloalkyl.

[0090] In one embodiment of the present invention, R 3-1-2 are independently C1-C6 alkyl.

[0091] In one embodiment of the present invention, R 3-1 and R 3-3 Each is independently hydroxy, halogen or C1-C6 alkyl; preferably C1-C6 alkyl.

[0092] In one embodiment of the present invention, R 3-2 Independently by one or more R 3-2-1 Substituted 3-7 membered heterocycloalkyl.

[0093] In one embodiment of the present invention, R 3-2-1 are independently C1-C6 alkyl.

[0094] In one embodiment of the present invention, R 1 for

[0095] In one embodiment of the present invention, R 1 for Preferably

[0096] In one embodiment of the present invention, R 2 is hydrogen, methyl or For example, hydrogen.

[0097] In one embodiment of the present invention, R 3 for (For example, ), R 3a and R 3b Together with the carbon atoms to which they are attached, they form a C3-C7 monocyclic cycloalkyl group, a C5-C 12 Bicyclic cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocycloalkyl, one or more R 3-1 substituted 3-7 membered monocyclic heterocycloalkyl, substituted by one or more R 3-1 substituted 5-12 membered bicyclic heterocycloalkyl, substituted by one or more R 3-3 Substituted C3-C7 monocyclic cycloalkyl or one or more R 3-3 Substituted C5-C 12 Bicyclic cycloalkyl, R 3c and R 3d Together with the carbon atoms to which they are attached, they form a 3-2-1 Substituted 3-7 membered heterocycloalkyl, wherein the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof, R 3-1 、R 3-3 and R 3-2-1 The definition of is as described in any one of the present invention.

[0098] In one embodiment of the present invention, R 3 for (For example, ), wherein the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-1 、R 3-3 and R 3-2-1 The definition of is as described in any one of the present invention.

[0099] In one embodiment of the invention, R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-1The definition of is as described in any one of the present invention.

[0100] In one embodiment of the invention, R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-1 The definition of is as described in any one of the present invention.

[0101] In one embodiment of the invention, R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-1 The definition of is as described in any one of the present invention.

[0102] In one embodiment of the invention, R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-2-1 The definition of is as described in any one of the present invention.

[0103] In one embodiment of the invention, R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-3 The definition of is as described in any one of the present invention.

[0104] In one embodiment of the invention, R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-3 The definition of is as described in any one of the present invention.

[0105] In one embodiment of the invention, R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-3 The definition of is as described in any one of the present invention.

[0106] In one embodiment of the invention, R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-3 The definition of is as described in any one of the present invention.

[0107] In one embodiment of the invention, R3 is (For example, Further example ), where m is 0 or 1; R 3-1 、R 3-3 and R 3-2-1 The definition of is as described in any one of the present invention.

[0108] In one embodiment of the present invention, R 3 for Preferably

[0109] In a certain embodiment of the present invention, R3 is Preferably

[0110] In one embodiment of the present invention, for Among them, R a 、R b and R c The definition of is as described in any one of the present invention; for example For example, Preferred

[0111] In one embodiment of the present invention, for Among them, R a 、R b and R c The definition of is as described in any one of the present invention; for example For example,

[0112] In one embodiment of the present invention, for Among them, R a and R b The definition of is as described in any one of the present invention.

[0113] In one embodiment of the present invention, for

[0114] In one embodiment of the present invention, for

[0115] In one embodiment of the present invention, for Among them, R c The definition of is as described in any one of the present invention.

[0116] In one embodiment of the present invention, for Among them, R c The definition of is as described in any one of the present invention.

[0117] In one embodiment of the present invention, for Among them, R a and R b The definition of is as described in any one of the present invention.

[0118] In one embodiment of the present invention, for Among them, R a and R b The definition of is as described in any one of the present invention.

[0119] In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0120] The present invention also provides a pharmaceutical composition comprising a substance X and a pharmaceutically acceptable excipient, wherein the substance X is a compound as represented by formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0121] The present invention also provides a use of the above-mentioned pharmaceutical composition or the above-mentioned substance X in the preparation of an NLRP3 inhibitor.

[0122] The present invention also provides a use of the above-mentioned pharmaceutical composition or the above-mentioned substance X in the preparation of a drug for preventing and / or treating diseases related to NLRP3;

[0123] Preferably, the NLRP3-related disease is a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease).

[0124] The present invention also provides a pharmaceutical composition or substance X for use in the preparation of a method for preventing and / or treating neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease).

[0125] The present invention also provides a method for preventing and / or treating a disease associated with NLRP3, comprising administering a therapeutically effective amount of the substance X or the pharmaceutical composition to an individual in need thereof. The NLRP3-associated disease is preferably a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease).

[0126] The present invention also provides a method for preventing and / or treating a disease, comprising: administering a therapeutically effective amount of the aforementioned substance X or the aforementioned pharmaceutical composition to an individual in need thereof, wherein the disease is a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease).

[0127] The present invention also provides a method for inhibiting NLRP3, comprising administering to an individual in need thereof a therapeutically effective amount of a compound as represented by 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 the above-mentioned pharmaceutical composition.

[0128] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0129] Unless otherwise specified, the terms used in this invention have the following meanings:

[0130] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0131] As used herein, a substituent may be preceded by a single dash "-" to indicate that the named substituent is bonded to the parent moiety through a single bond.

[0132] The term "plurality" refers to two or three.

[0133] The term "halogen" refers to F, Cl, Br or I.

[0134] The term "alkyl" refers to a straight or branched chain 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 the like.

[0135] The term "alkoxy" refers to a group R X -O-, R X The same definition is given to the term "alkyl".

[0136] The term "heterocycloalkyl" refers to a monocyclic or bicyclic saturated cyclic group having a specified number of ring atoms (e.g., 3-7 members, 5-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S).

[0137] The term "heterocycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon radical having a specified number of ring atoms (e.g., 3-7 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), and having one or more (e.g., 1 or 2) carbon-carbon sp 2 Double bond, which is not aromatic. (The term "heteroaryl" refers to a cyclic, aromatic, monovalent group with a specified number of ring atoms (e.g., 5-6, 5-10 members), 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 is a single ring or multiple rings, with two atoms and one bond shared between the single rings. A heteroaryl group is attached to the rest of the molecule through a carbon atom or a heteroatom; a heteroaryl group is attached to the rest of the molecule through a ring with a heteroatom or a ring without a heteroatom.

[0138] The term "cycloalkyl" refers to a saturated cyclic group having a specified number of ring carbon atoms (e.g., C3-C6 or C3-C7) and wherein the ring atoms consist solely of carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0139] The term "cycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C3-C7) and having one or more (e.g., 1 or 2) carbon-carbon sp 2 double bond, which is not aromatic. c ) When a variable appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definition at the remaining positions, and their meanings are independent of each other and do not affect each other.

[0140] The term "pharmaceutically acceptable salt" refers to salts prepared from compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. 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 neat solution or in 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 neat solution or in a suitable inert solvent.

[0141] The term "solvate" refers to a compound of the present invention combined with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or non-ordered arrangement.

[0142] The term "pharmaceutically acceptable salt" and "solvate" in the term "pharmaceutically acceptable salt solvate" as described above refer to substances prepared by the compounds of the present invention with relatively non-toxic, pharmaceutically acceptable acids or bases; and formed in combination with stoichiometric or non-stoichiometric solvents.

[0143] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These excipients are all substances, other than the active ingredient, contained in a pharmaceutical preparation. For more information, see Part IV of the Pharmacopoeia of the People's Republic of China (2020 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0144] In the present invention, the "inhibitor" can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art.

[0145] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating 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 progression of the condition or one or more biological manifestations of the condition.

[0146] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0147] The reagents and raw materials used in the present invention are commercially available.

[0148] The positive progress of the present invention is that the present invention has one or more of the following effects: ① The pyridazine ring derivatives of the present invention have good inhibitory activity against NLRP3 and can effectively inhibit the secretion of IL-1β in THP-1 cells: IC 50 The value is 1-160nM; ② The compound of the present invention has good pharmacokinetic properties: the bioavailability F is 35%-130%; ③ The compound of the present invention has the characteristics of high permeability and low efflux: the efflux ratio is 0.5-1.4; ④ The compound of the present invention can effectively inhibit the secretion of IL-1β in PBMC cells: IC50 The value is 1-12nM; ⑤ The compound of the present invention can significantly reduce the serum IL-1β concentration in the mouse inflammation model, showing a good anti-inflammatory effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0149] Figure 1 shows the effect of the compound in the inflammatory model induced by intraperitoneal injection of LPS (lipopolysaccharide) in mice DETAILED DESCRIPTION

[0150] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0151] Example 1

[0152] Synthesis route:

[0153] first step

[0154] Compound 1-1 (5.00 g, 33.6 mmol), 4-[N-(tert-butoxycarbonyl)amino]butyric acid (20.5 g, 101 mmol), and silver nitrate (570 mg, 3.36 mmol) were dissolved in water (250 mL). The reaction solution was heated to 70°C, and a solution of ammonium persulfate (13.8 g, 60.4 mmol) in water (20 mL) was added. The reaction solution was stirred at 25°C for 12 hours. The reaction solution was cooled to room temperature (room temperature: 20-30°C), the pH was adjusted to 9 with aqueous ammonia solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-10 mmol / L 0.1% formic acid aqueous solution, gradient: 0-5%, retention time: 17 min) to obtain the monoformate of compound 1-2. 1 H NMR (400MHz, DMSO-d6): δ8.43(s,1H),8.04(s,1H),2.87-2.80(m,4H),1.99-1.791(m,2H).

[0155] Step 2

[0156] The monoformate salt of compound 1-2 (1.00 g, 4.85 mmol), N-tert-butyloxycarbonyl-3-piperidone (967 mg, 4.85 mmol), and acetic acid (580 mg, 9.70 mmol) were dissolved in methanol (10 mL), and sodium cyanoborohydride (914 mg, 14.6 mmol) was added. The reaction mixture was stirred at 30°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target compound. The residue was purified by high-performance liquid chromatography (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-10 mmol / L 0.1% formic acid in water, gradient: 25-35%, retention time: 17 min) to obtain compound 1-3. ESI-MS calculated value: [M+H] + =389.14, measured value 389.0.

[0157] Step 3

[0158] Compound 1-3 (800 mg, 2.05 mmol) was dissolved in dimethyl sulfoxide (15 mL), and N,N-diisopropylethylamine (1.32 g, 10.3 mmol) was added. Under nitrogen, the reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride aqueous solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to obtain compound 1-4. ESI-MS theoretical value: [M+H] + =353.17, measured value 353.0.

[0159] Step 4

[0160] Compound 1-4 (300 mg, 0.85 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). Compound 1-5 (459 mg, 1.27 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (72.0 mg, 0.085 mmol), and potassium carbonate (235 mg, 1.70 mmol) were added. Under nitrogen, the reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and extraction was performed with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain compound 1-6. ESI-MS theoretical calculation value: [M+H] +=551.28, measured value 551.7.

[0161] Step 5

[0162] Compound 1-6 (300 mg, 0.54 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1.23 g, 10.8 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the mixture was concentrated and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (30 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield compound 1-7. ESI-MS theoretical value: [M+H] + =393.18, measured value 393.5.

[0163] Step 6

[0164] Compound 1-7 (200 mg, 0.51 mmol) and 37% aqueous formaldehyde solution (153 mg, 5.10 mmol) were dissolved in methanol (2 mL). Sodium cyanoborohydride (96.2 mg, 1.53 mmol) was added, and the reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (30 mL x 3). The organic phase was washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-10 mmol / L 0.1% aqueous formic acid, gradient: 20-35%, retention time: 17 min) to obtain the monoformate salt of compound 1. 1 H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 8.15 (s, 1H), 7.10 (s, 1H), 7.05 (s, 2H), 5.08-5.03 (m, 1H), 3.45-3.38 (m, 2H), 2.96-2.90 (m, 2H), 2.77-2.70 (m, 2H), 2.36 (s, 3H), 2.34-2.28 (m, 1H), 2.14 (s, 3H), 2.13-2.07 (m, 1H), 1.86-1.62 (m, 6H). ESI-MS theoretical value: [M+H] + =407.20, measured value 407.2.

[0165] Example 2

[0166] Synthesis route:

[0167] first step

[0168] Compound 2-iodoethanol (4.92 g, 28.6 mmol) was dissolved in tetrahydrofuran (40 mL). Sodium hydride (1.31 g, 32.7 mmol, 60% purity) was added at 0°C and stirred at 0°C for 30 minutes. Compound 2-1 (5.00 g, 27.3 mmol) was added to the reaction mixture and stirred at 50°C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, and saturated aqueous ammonium chloride (50 mL) was added. The mixture was then extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to afford compound 2-2. 1 H NMR (400 MHz, CDCl3): δ 6.91 (s, 1H), 4.40 (t, J = 8.0 Hz, 2H), 3.51 (t, J = 8.0 Hz, 2H). ESI-MS theoretical calculated value: [M+H] + =318.88, measured value 318.8.

[0169] Step 2

[0170] Compound 2-2 (300 mg, 0.94 mmol) and compound 2-3 (377 mg, 1.88 mmol) were dissolved in dimethyl sulfoxide (5 mL), and N,N-diisopropylethylamine (243 mg, 1.88 mmol) was added. The mixture was stirred at 50°C under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 0 / 1, v / v) to obtain compound 2-4. 1 H NMR (400 MHz, CDCl3) δ 6.95 (s, 1H), 4.25-4.17 (m, 2H), 3.98-3.91 (m, 1H), 3.75-3.68 (m, 1H), 3.20-3.09 (m, 2H), 3.05-2.95 (m, 1H), 2.81-2.74 (m, 1H), 2.70-2.63 (m, 1H), 1.97-1.88 (m, 1H), 1.75-1.65 (m, 1H), 1.46 (s, 9H), 1.40-1.28 (m, 2H). ESI-MS theoretical value: [M+H-56] + =335.12, measured value 335.0.

[0171] Step 3

[0172] Compound 2-4 (250 mg, 0.64 mmol) was dissolved in toluene (5 mL), and cesium carbonate (417 mg, 1.28 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (79.7 mg, 0.13 mmol), and palladium acetate (14.4 mg, 0.064 mmol) were added sequentially. The reaction mixture was stirred at 110°C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was then extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to afford compound 2-5. 1 H NMR (400 MHz, CDCl3): δ 6.55 (s, 1H), 4.34-4.25 (m, 2H), 4.10-4.02 (m, 2H), 3.51-3.39 (m, 2H), 3.33-3.27 (m, 1H), 2.72-2.64 (m, 2H), 1.98-1.91 (m, 1H), 1.86-1.65 (m, 3H), 1.43 (s, 9H). ESI-MS theoretical value: [M+H] + =355.15, actual measured value 355.0.

[0173] Step 4

[0174] Compound 2-5 (240 mg, 0.68 mmol) and compound 1-5 (490 mg, 1.36 mmol) were dissolved in dioxane (6 mL) and water (1.2 mL). Potassium carbonate (282 mg, 2.04 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (57.6 mg, 0.068 mmol) were added sequentially. Under a nitrogen atmosphere, the reaction solution was stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (25 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain compound 2-6. ESI-MS theoretical calculation value: [M+H] + =553.26, measured value 553.1.

[0175] Step 5

[0176] Compound 2-6 (100 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added at room temperature and the reaction mixture was stirred at 25°C for 3 hours. The filtrate was concentrated under reduced pressure to give compound 2-7. ESI-MS theoretical calculated value: [M+H] + =395.16, measured value 395.2.

[0177] Step 6

[0178] Compound 2-7 (70.0 mg, 0.178 mmol) was dissolved in methanol (2 mL), and 37% pure formaldehyde solution (43.8 mg, 0.533 mmol) was added. The mixture was stirred at 25°C for 30 minutes. Sodium cyanoborohydride (33.9 mg, 0.533 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (Waters-Sunfire-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol / L 0.1% formic acid in water, gradient: 15-25%, retention time: 10 minutes) to obtain the monoformate salt of compound 2. 1 H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 8.14 (s, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6.83 (s, 1H), 5.04-4.96 (m, 1H), 4.35-4.28 (m, 2H), 3.62-3.50 (m, 2H), 3.18-3.09 (m, 2H), 2.70-2.65 (m, 1H), 2.55 (s, 3H), 2.46-2.39 (m, 1H), 2.13 (s, 3H), 1.93-1.80 (m, 2H), 1.78-1.65 (m, 2H). ESI-MS calculated value: [M+H] + =409.18, measured value 409.1.

[0179] Example 3

[0180] Synthesis route:

[0181] first step

[0182] Compound 3-1 (5.00 g, 23.8 mmol) was dissolved in tetrahydrofuran (50 mL), and compound 2-3 (9.54 g, 47.6 mmol) and N,N-diisopropylethylamine (9.23 g, 71.4 mmol) were added. The mixture was stirred at 70°C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The mixture was then extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 0 / 1, v / v) to afford compound 3-2. 1 H NMR (400MHz, CDCl3): δ4.17(s,2H),4.10-3.95(m,1H),3.83-3.75(m,1H),3.73-3.58(m,2H),2.98-2.77(m,3H),2.76-2 .49(m,2H),2.44-2.42(m,1H),1.99-1.88(m,1H),1.75-1.64(m,1H),1.63-1.56(m,1H),1.46(s,9H),1.36-1.27(m,1H).

[0183] Step 2

[0184] Compound 3-2 (2.00 g, 7.08 mmol) was dissolved in toluene (100 mL), and 3-3 (1.07 g, 7.08 mmol) was added. The reaction mixture was stirred at 130°C for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain compound 3-4. 1 H NMR (400 MHz, CDCl3): δ7.11 (s, 1H), 4.61-4.52 (m, 1H), 4.46-4.38 (m, 2H), 4.29-4.21 (m, 1H), 4.13-4.05 (m, 1H), 3.94-3.87 (s, 1H), 3.77-3.67 (m, 1H), 3.46-3.12 (m, 2H), 2.92-2.85 (m, 1H), 2.67-2.62 (m, 1H), 2.23-2.15 (m, 1H), 1.80-1.76 (m, 1H), 1.73-1.60 (m, 2H), 1.46 (s, 9H). ESI-MS calculated value: [M+H] + =369.16, measured value 369.2.

[0185] Step 3

[0186] Compound 3-4 (320 mg, 0.87 mmol) and compound 1-5 (470 mg, 1.30 mmol) were dissolved in dioxane (10 mL) and water (2 mL). Potassium carbonate (360 mg, 2.61 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (74.0 mg, 0.087 mmol) were added sequentially. Under a nitrogen atmosphere, the reaction solution was stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (25 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain compound 3-5. ESI-MS theoretical calculation value: [M+H] + =567.27, measured value 567.6.

[0187] Step 4

[0188] Compound 3-5 (200 mg, 0.35 mmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (2 mL) was added at room temperature and the reaction mixture was stirred at 25°C for 1 hour. The filtrate was concentrated under reduced pressure to give compound 3-6. ESI-MS theoretical calculated value: [M+H] + =409.18, measured value 409.3.

[0189] Step 5

[0190] Compound 3-6 (142 mg, 0.347 mmol) was dissolved in methanol (2 mL), and 37% pure formaldehyde solution (43.8 mg, 0.522 mmol) was added. The mixture was stirred at 25°C for 30 minutes. Sodium cyanoborohydride (65.5 mg, 1.04 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (Waters-Sunfire-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol / L 0.1% formic acid in water, gradient: 20-30%, retention time: 17 minutes) to obtain the monoformate salt of compound 3. 1H NMR (400 MHz, DMSO-d6): δ10.19 (s, 1H), 8.14 (s, 1H), 7.34 (s, 1H), 7.14 (s, 1H), 7.07 (s, 1H), 4.78-4.72 (m, 1H), 4.69-4.54 (m, 2H), 3.84-3.75 (m, 2H), 3.56-3.48 (m, 2H), 3.16-3.10 (m, 1H), 2.70-2.53 (m, 4H), 2.44-2.32 (m, 2H), 2.13 (s, 3H), 1.93-1.84 (m, 2H), 1.75-1.64 (m, 2H). ESI-MS calculated value: [M+H] + =423.19, measured value 423.0.

[0191] Example 4

[0192] Synthesis route:

[0193] first step

[0194] 2-1 (4.0 g, 21.81 mmol) and 4-1 (4.54 g, 23.99 mmol) were dissolved in N,N-dimethylformamide (50 mL). Potassium carbonate (9.04 g, 65.43 mmol) was added at 0°C. After 10 minutes, the temperature was raised to 40°C and stirred for 3 hours. The reaction solution was cooled to room temperature, slowly diluted with water (40 mL), and extracted with ethyl acetate (150 mL x 3). The organic layers were combined, 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, 5 / 1, v / v) to obtain 4-2. 1 H NMR (400 MHz, CDCl3): δ 6.82 (s, 1H), 3.83 (t, J = 5.20 Hz, 2H), 3.70 (t, J = 5.20 Hz, 2H), 3.06 (s, 3H), 0.81 (s, 9H), 0.01 (s, 6H). ESI-MS calculated value [M+H] + =336.1, measured value 336.0.

[0195] Step 2

[0196] Dissolve 4-2 (6.5 g, 19.33 mmol) in tetrahydrofuran (80 mL) and slowly add tetrabutylammonium fluoride (23.2 mL, 23.20 mmol, 1.0 mol / L tetrahydrofuran solution) dropwise at 0°C. Stir at 25°C for 12 hours. Dilute the reaction mixture with water (30 mL) and extract with ethyl acetate (150 mL x 3). Combine the organic layers, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to afford 4-3. 1 H NMR (400 MHz, DMSO-d6): δ7.18 (s, 1H), 4.76 (s, 1H), 3.67-3.60 (m, 4H), 3.03 (s, 3H). ESI-MS calculated value [M+H] + =222.0, measured value 222.0.

[0197] Step 3

[0198] 4-3 (1.7 g, 12.61 mmol) was dissolved in dichloromethane (30 mL). Triphenylphosphine (3.31 g, 12.61 mmol) was added at room temperature, followed by iodine (3.20 g, 12.61 mmol) in portions. The mixture was stirred under a nitrogen atmosphere for 3 hours. After the reaction, a saturated aqueous sodium sulfite solution (10 mL) was added dropwise. The mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were combined, 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 / 1, v / v) to afford 4-4. 1 H NMR (400 MHz, CDCl3): δ 6.78 (s, 1H), 3.88 (t, J = 5.20 Hz, 2H), 3.35 (t, J = 5.20 Hz, 2H), 3.04 (s, 3H). ESI-MS calculated value [M+H] + =331.9, measured value 332.0.

[0199] Step 4

[0200] Dissolve 4-4 (1.7 g, 5.12 mmol) and 2-3 (2.05 g, 10.24 mmol) in dimethyl sulfoxide (40 mL). Add N,N-diisopropylethylamine (1.32 g, 10.24 mmol) at room temperature. Under nitrogen, warm the reaction mixture to 50°C and stir for 12 hours. Cool to room temperature, dilute with water (20 mL), and extract with ethyl acetate (100 mL x 3). The combined organic layers are 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, 1 / 1, v / v) to afford 4-5. 1H NMR (400 MHz, CDCl3) δ 6.14 (s, 1H), 4.75-4.65 (m, 1H), 4.15-4.05 (m, 2H), 3.47-3.33 (m, 4H), 3.03-2.93 (m, 1H), 2.91 (s, 3H), 2.76-2.66 (m, 1H), 1.98-1.88 (m, 1H), 1.78-1.63 (m, 3H), 1.45 (s, 9H). ESI-MS calculated value [M+H] + =368.2, measured value 368.2.

[0201] Step 5

[0202] Dissolve 4-5 (400 mg, 1.09 mmol) and 1-5 (589 mg, 1.64 mmol) in 1,4-dioxane (10 mL) and water (2 mL). Add potassium carbonate (452 ​​mg, 3.27 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (92 mg, 0.11 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (52 mg, 0.11 mmol). Under nitrogen, heat the reaction mixture to 110°C and stir for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (methanol / dichloromethane, 1 / 10, v / v) to obtain 4-6. ESI-MS calculated value [M+H] + =566.3, measured value 566.4.

[0203] Step 6

[0204] Dissolve 4-6 (360 mg, 0.64 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure to obtain a crude product containing the target compound 4-7. ESI-MS calculated value [M+H] + =408.20, measured value 408.2.

[0205] Step 7

[0206] 4-7 (255 mg, 0.63 mmol) was dissolved in methanol (3 mL). Aqueous formaldehyde (37%, 76.70 mg, 0.95 mmol) was added at room temperature and stirred for 30 minutes. Sodium cyanoborohydride (119 mg, 1.89 mmol) was then added and stirred for another 3 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters 3767 / QDA Column: SunFire Sunfire C18, 19 x 250 mm, 10 μm, mobile phase: acetonitrile-10 mmol / L 0.1% formic acid in water, gradient: 48-58%, retention time: 9 min) to afford the monoformate salt of 4. 1 H NMR (400 MHz, DMSO-d6): δ8.19 (s, 1H), 7.08 (s, 1H), 7.04 (s, 1H), 6.35 (s, 1H), 4.87-4.80 (m, 1H), 3.57-3.51 (m, 1H), 3.46-3.38 (m, 3H), 2.90-2.84 (m, 4H), 2.83-2.77 (m, 1H), 2.26 (s, 3H), 2.17 (s, 3H), 2.18-2.10 (m, 1H), 1.98-1.90 (m, 1H), 1.79-1.68 (m, 2H), 1.63-1.53 ​​(m, 2H). ESI-MS calculated value [M+H] + =422.2, measured value 422.2.

[0207] Example 5

[0208] Synthesis route:

[0209] first step

[0210] 5-1 (1.0 g, 11.89 mmol) and imidazole (1.6 mg, 0.024 mmol) were dissolved in tetrahydrofuran (15 mL) and cooled to 0°C under nitrogen. Sodium hydride (860 mg, 35.67 mmol, 60% purity) was added, followed by benzyl bromide (2.44 g, 14.27 mmol) 10 minutes later. The mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, 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 afford 5-2. 1H NMR (400MHz, DMSO-d6): δ7.41-7.21(m,5H),4.46(s,2H),3.49(t,J=6.40Hz,2H),2.75(s,1H),2.53-2.21(m,2H),1.74-1.68(m,2H).

[0211] Step 2

[0212] Dissolve 5-2 (1.7 g, 11.26 mmol) and 3-3 (2.94 g, 16.89 mmol) in toluene (15 mL). Heat to 130°C and stir under nitrogen for 16 hours. Cool the reaction mixture to room temperature and extract with ethyl acetate (100 mL x 3). Combine the organic layers, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to yield 5-3. 1 H NMR (400 MHz, CDCl3): δ 7.37-7.13 (m, 6H), 4.42 (s, 2H), 3.44 (t, J = 6.00 Hz, 2H), 2.89-2.65 (m, 2H), 2.03-1.81 (m, 2H). ESI-MS calculated value [M+H] + =297.1, measured value 296.9.

[0213] Step 3

[0214] 5-3 (1.3 g, 4.37 mmol) was dissolved in dichloromethane (15 mL), and boron trichloride (1.28 g, 10.93 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, methanol (1.3 mL) was added to quench the reaction and the mixture was concentrated under reduced pressure. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (100 mL × 3). The organic layers were combined, 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, 1 / 1, v / v) to obtain 5-4. 1 H NMR (400MHz, DMSO-d6): δ7.97 (s, 1H), 4.63 (t, J = 5.20Hz, 1H), 3.49-3.45 (m, 2H), 2.76 (t, J = 6.00Hz, 2H), 1.85-1.69 (m, 2H).

[0215] Step 4

[0216] 5-4 (500 mg, 2.41 mmol) and triphenylphosphine (630 mg, 2.41 mmol) were dissolved in dichloromethane (5 mL), iodine (610 mg, 2.41 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate (50 mL×3). The organic layers were combined, 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, 1 / 1, v / v) to obtain 5-5. 1 H NMR (400 MHz, CDCl3): δ7.43 (s, 1H), 3.29-3.19 (m, 2H), 2.92-2.85 (m, 2H), 2.28-2.12 (m, 2H). ESI-MS calculated value [M+H] + =316.9, measured value 316.7.

[0217] Step 5

[0218] Dissolve 5-5 (400 mg, 2.05 mmol) and 5-6 (380 mg, 3.78 mmol) in dimethyl sulfoxide (5 mL), and add N,N-diisopropylethylamine (810 mg, 6.30 mmol). Heat to 100°C and stir under nitrogen for 8 hours. Cool to room temperature and extract with ethyl acetate (50 mL x 3). Combine the organic layers, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify by silica gel column chromatography (petroleum ether / ethyl acetate, 0 / 1, v / v) to obtain 5-7. 1 H NMR (400 MHz, DMSO-d6): δ7.20 (s, 1H), 5.03 (s, 1H), 4.74-4.56 (m, 1H), 3.46-3.37 (m, 2H), 2.75-2.65 (m, 2H), 2.29-2.11 (m, 4H), 1.87-1.73 (m, 2H), 1.29 (s, 3H). ESI-MS calculated value [M+H] + =254.1, measured value 254.0.

[0219] Step 6

[0220] 5-7 (280 mg, 1.10 mmol), 5-8 (500 mg, 1.65 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (90 mg, 0.11 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (50 mg, 0.11 mmol), and potassium carbonate (610 mg, 4.40 mmol) were dissolved in 1,4-dioxane (6 mL) and water (1.2 mL). The mixture was heated to 100°C and stirred under nitrogen for 12 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with 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-0.1% formic acid aqueous solution, gradient: 20-30%, retention time: 9 min) to obtain 5. 1 H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 7.09 (s, 1H), 7.04 (s, 1H), 7.03 (s, 1H), 5.06-5.00 (m, 1H), 4.97-4.86 (m, 1H), 3.51-3.43 (m, 2H), 2.77-2.67 (m, 2H), 2.30-2.20 (m, 4H), 2.12 (s, 3H), 1.92-1.81 (m, 2H), 1.32 (s, 3H). ESI-MS calculated value [M+H] + =394.2, measured value 394.5.

[0221] Example 6

[0222] Synthesis route:

[0223] first step

[0224] 3-6 (100 mg, 0.21 mmol) and acetaldehyde (0.1 mL, 0.50 mmol, 5.0 mol / L tetrahydrofuran solution) were dissolved in methanol (2 mL). Sodium triacetoxyborohydride (150 mg, 0.72 mmol) was added and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters 3767 / QDA Column: SunFire C18, 19 x 250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid in water, gradient: 20-30%, retention time: 9 min) to yield 6. 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 7.36 (s, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 4.88-4.78 (m, 1H), 4.73-4.57 (m, 2H), 3.87-3.76 (m, 2H), 3.58-3.46 (m, 4H), 2.97-2.85 (m, 3H), 2.72-2.62 (m, 1H), 2.13 (s, 3H), 1.99-1.89 (m, 2H), 1.83-1.73 (m, 2H), 1.20 (t, J = 6.40 Hz, 3H). ESI-MS calculated value [M+H] + =437.2, measured value 437.3.

[0225] Example 7

[0226] Synthesis route:

[0227] first step

[0228] 3-4 (150 mg, 0.41 mmol), 7-1 (103 mg, 0.61 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (20 mg, 0.04 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (35 mg, 0.04 mmol), and potassium carbonate (230 mg, 1.64 mmol) were added to 1,4-dioxane (5 mL) and 1 mL. The mixture was heated to 100°C and stirred for 12 hours under argon protection. After cooling, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 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, 1 / 1, v / v) to obtain 7-2. 1HNMR(400MHz,DMSO-d6)δ9.39(s,1H),7.24(s,1H),6.60-6.58(m,2H),4.65-4.57(m, 2H),4.48-4.40(m,1H),4.20-4.13(m,1H),3.97-3.90(m,1H),3.83-3.73(m,2H),3.5 4-3.44(m,2H),2.93-2.83(m,1H),2.70-2.65(m,1H),2.22(s,3H),2.03(s,3H),2.03-1.96(m,1H),1.80-1.70(m,2H),1.50-1.43(m,1H),1.41(s,9H).ESI-MS calculated value [M+H] + =455.3, measured value 455.5.

[0229] Step 2

[0230] Dissolve 7-2 (170 mg, 0.37 mol) in dichloromethane (3 mL), add trifluoroacetic acid (1.5 mL), and stir at room temperature for 1 hour. After the reaction is complete, concentrate under reduced pressure to obtain a crude product containing 7-3, which is used directly in the next reaction. ESI-MS theoretical calculated value [M+H] + =355.2, measured value 355.2.

[0231] Step 3

[0232] 7-3 (130 mg, 0.37 mmol) was dissolved in methanol (3 mL), and 37% aqueous formaldehyde (0.055 mL, 0.55 mmol) and sodium triacetoxyborohydride (240 mg, 1.11 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 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% aqueous formic acid, gradient: 20-30%, retention time: 9 min) to obtain the formate salt of 7. 1H NMR (400 MHz, DMSO-d6): δ9.67 (s, 1H), 9.39 (s, 1H), 7.30 (s, 1H), 6.59-6.50 (m, 2H), 4.85-4.75 (m, 1H), 4.75-4.55 (m, 2H), 3.85-3.75 (m, 2H), 3.57-3.47 (m, 2H), 3.44-3.34 (m, 2H), 3.16-3.06 (m, 1H), 2.85-2.75 (m, 4H), 2.22 (s, 3H), 2.02 (s, 3H), 2.00-1.90 (m, 2H), 1.82-1.72 (m, 2H). ESI-MS calculated value [M+H] + =369.2, measured value 369.2.

[0233] Example 8

[0234] Synthesis route:

[0235] first step

[0236] Dissolve 1-2 (870 mg, 4.22 mmol) and 8-1 (1.17 g, 6.33 mmol) in methanol (10 mL), add acetic acid (0.1 mL), and stir at 30°C for 1 hour. Then add sodium cyanoborohydride (800 mg, 12.7 mmol), and stir at room temperature overnight. After the reaction is complete, dilute with water (20 mL) and extract with ethyl acetate (50 mL x 3). The combined organic layers are dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to yield 8-2. ESI-MS calculated value [M+H] + =375.1, measured value 375.1.

[0237] Step 2

[0238] 8-2 (550 mg, 1.47 mmol) and N,N-diisopropylethylamine (1.22 mL, 7.35 mmol) were dissolved in dimethyl sulfoxide (10 mL). The mixture was heated to 100°C and stirred for 12 hours under nitrogen. The reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to obtain 8-3. 1H NMR (400 MHz, DMSO-d6): δ7.26 (s, 1H), 5.30-5.23 (m, 1H), 3.50-3.40 (m, 2H), 3.30-3.20 (m, 2H), 3.19-3.16 (m, 2H), 2.74-2.70 (m, 2H), 2.14-2.02 (m, 2H), 1.90-1.70 (m, 2H), 1.40 (m, 9H). ESI-MS calculated value [M+H] + =339.2, measured value 338.9.

[0239] Step 3

[0240] 8-3 (460 mg, 1.36 mmol), 1-5 (588 mg, 1.63 mmol), potassium carbonate (560 mg, 4.08 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (115 mg, 0.14 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The mixture was heated to 90°C and stirred for 12 hours under nitrogen. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, 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, 1 / 1, v / v) to afford 8-4. ESI-MS calculated value [M+H] + =537.3, measured value 537.4.

[0241] Step 4

[0242] Dissolve 8-4 (310 mg, 0.58 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing 8-5, which was used directly in the next reaction. ESI-MS theoretical calculated value [M+H] + =379.2, measured value 379.0.

[0243] Step 5

[0244] 8-5 (220 mg, 0.58 mmol) was dissolved in methanol (2 mL). Aqueous formaldehyde (37%, 71 mg, 0.87 mmol) and acetic acid (0.05 mL) were added dropwise at room temperature. Sodium cyanoborohydride (110 mg, 1.74 mmol) was then added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC (Gilson GX_281 Column: Pursuit Xrs C18, 21.2 x 250 mm, 10 μm; mobile phase: acetonitrile-0.1% aqueous formic acid, gradient: 21-31%; retention time: 10 min) to afford 8. 1 H NMR (400 MHz, DMSO-d6): δ 10.11 (br, 1H), 7.10 (s, 1H), 7.09-7.05 (m, 2H), 5.70-5.60 (m, 1H), 3.54-5.44 (m, 2H), 3.07-2.87 (m, 2H), 2.78-2.68 (m, 3H), 2.52-2.40 (m, 4H), 2.26-2.16 (m, 1H), 2.13 (s, 3H), 1.94-1.80 (m, 3H). ESI-MS calculated value [MH] + =391.2, measured value 390.9.

[0245] Example 9

[0246] Synthesis route:

[0247] first step

[0248] Dissolve 1-2 (946 mg, 4.59 mmol) and 9-1 (914 mg, 4.59 mmol) in methanol (15 mL), add acetic acid (0.05 mL), and stir at 30°C for 1 hour. Then add sodium cyanoborohydride (860 mg, 13.8 mmol), and stir at room temperature for 12 hours. After the reaction is complete, dilute with water (20 mL) and extract with ethyl acetate (50 mL x 3). The combined organic phases are 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, 1 / 1, v / v) to afford 9-2. ESI-MS calculated value [M+H] + =389.1, measured value 389.0.

[0249] Step 2

[0250] 9-2 (1 g, 2.57 mmol) and N,N-diisopropylethylamine (2.13 mL, 12.85 mmol) were dissolved in dimethyl sulfoxide (10 mL), heated to 100°C under nitrogen, and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, 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 / 1, v / v) to obtain 9-3. ESI-MS calculated value [M+H] + =353.2, measured value 353.0.

[0251] Step 3

[0252] 9-3 (300 mg, 0.85 mmol), 1-5 (459 mg, 1.27 mmol), potassium carbonate (352 mg, 2.55 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (40.52 mg, 0.085 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (72 mg, 0.085 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), heated to 110 ° C under nitrogen protection and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, 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 / 1, v / v) to obtain 9-4. ESI-MS calculated value [M+H] + =551.3, measured value 551.2.

[0253] Step 4

[0254] Dissolve 9-4 (169 mg, 0.31 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product containing 9-5, which was used directly in the next reaction. ESI-MS calculated value [M+H] + =393.2, measured value 393.0.

[0255] Step 5

[0256] 9-5 (120 mg, 0.31 mmol) was dissolved in methanol (1.5 mL). Aqueous formaldehyde (37%, 38 mg, 0.46 mmol), acetic acid (0.05 mL), and sodium cyanoborohydride (58 mg, 0.93 mmol) were added dropwise. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters 3767 Column: Boston Uni C18, 21.2 x 250 mm, 10 μm; mobile phase: acetonitrile-0.1% aqueous formic acid, gradient: 23-33%; retention time: 10 min) to yield 9. 1 H NMR (400 MHz, DMSO-d6): δ 10.14 (br, 1H), 7.12-7.09 (m, 2H), 7.06 (s, 1H), 4.07-4.00 (m, 1H), 3.81-3.71 (m, 1H), 3.60-3.50 (m, 3H), 2.83-2.73 (m, 3H), 2.72-2.65 (m, 4H), 2.13 (s, 3H), 2.11-2.02 (m, 1H), 1.93-1.73 (m, 6H). ESI-MS calculated value [M+H] + =407.21, measured value 407.3.

[0257] Example 10

[0258] Synthesis route:

[0259] first step

[0260] 5-5 (470 mg, 1.48 mmol) and 10-1 (535 mg, 4.44 mmol) were dissolved in dimethyl sulfoxide (7 mL), and N,N-diisopropylethylamine (0.51 mL, 2.96 mmol) was added. The mixture was heated to 50°C and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, 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, 0 / 1, v / v) to afford 10-2. ESI-MS calculated value [M+H] + =268.1, measured value 268.2.

[0261] Step 2

[0262] 10-2 (134 mg, 0.87 mmol), 5-8 (165 mg, 0.75 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (24 mg, 0.05 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (42 mg, 0.05 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added to 1,4-dioxane (3 mL) and water (1 mL), heated to 100°C and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 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-0.1% aqueous ammonia, gradient: 20-30%, retention time: 11 min) to obtain 10. 1 H NMR (400 MHz, DMSO-d6): δ 10.18 (br, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 7.00 (s, 1H), 4.78-4.68 (m, 1H), 4.58 (d, J = 4.80 Hz, 1H), 3.70-3.60 (m, 1H), 3.48-3.38 (m, 2H), 2.77-2.67 (m, 2H), 2.15 (s, 3H), 2.00-1.92 (m, 2H), 1.73-1.63 (m, 4H), 1.52-1.42 (m, 1H), 1.35-1.25 (m, 3H). ESI-MS calculated value [M+H] + =408.2, measured value 408.0.

[0263] Example 11

[0264] Synthesis route:

[0265] first step

[0266] Dissolve 3-6 (70 mg, 0.17 mmol) and 11-1 (18 mg, 0.26 mmol) in methanol (2 mL). Add acetic acid (0.05 mL) and stir at 50°C for 1 hour. Then add sodium triacetoxyborohydride (110 mg, 0.51 mmol) and stir at room temperature for 12 hours. After the reaction, concentrate under reduced pressure and purify by high-performance liquid chromatography (Column: C18 spherical, 20-35 μm, 12 g; mobile phase: acetonitrile-0.1% formic acid in water, gradient: 5-45%; retention time: 15 min) to obtain 11. 1 H NMR (400 MHz, DMSO-d6): δδ10.20 (s, 1H), 7.36 (s, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 4.95-4.85 (m, 1H), 4.75-4.55 (m, 1H), 3.91-3.72 (m, 2H), 3.66-3.46 (m, 3H), 2.99-2.79 (m, 3H), 2.34-2.24 (m, 1H), 2.13 (s, 3H), 1.99-1.88 (m, 3H), 1.86-1.74 (m, 2H), 1.13-1.01 (m, 1H), 0.67-0.57 (m, 2H), 0.38-0.28 (m, 2H). ESI-MS calculated value [M+H] + =463.2, measured value 463.2.

[0267] Example 12

[0268] Synthesis route:

[0269] first step

[0270] 3-4 (100 mg, 0.27 mmol), 12-1 (55 mg, 0.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (22 mg, 0.03 mmol), and potassium carbonate (149 mg, 1.09 mmol) were added to 1,4-dioxane (3 mL) and water (1 mL). The mixture was heated to 100°C and stirred for 16 hours under argon. After cooling, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 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, 1 / 1, v / v) to afford 12-2. ESI-MS calculated value [M+H] + =475.2, measured value 475.1.

[0271] Step 2

[0272] Dissolve 12-2 (85 mg, 0.18 mol) in dichloromethane (3 mL), add trifluoroacetic acid (0.5 mL), and stir at room temperature for 1 hour. After the reaction, concentrate under reduced pressure to obtain a crude product containing 12-3, which is used directly in the next reaction. ESI-MS theoretical calculated value [M+H] + =375.2, measured value 375.1.

[0273] Step 3

[0274] 12-3 (75 mg, 0.20 mmol) was dissolved in methanol (3 mL). Aqueous formaldehyde (37%, 410 mg, 5.05 mmol) and sodium triacetoxyborohydride (130 mg, 0.06 mmol) were added sequentially, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 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 in water, gradient: 20-30%, retention time: 8 min) to obtain 12. 1 H NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 7.31 (s, 1H), 6.86 (s, 1H), 6.82 (s, 1H), 4.83-4.73 (m, 1H), 4.73-4.53 (m, 2H), 3.89-3.72 (m, 2H), 3.58-3.39 (m, 3H), 3.26-3.15 (m, 1H), 2.90-2.80 (m, 1H), 2.75-2.60 (m, 4H), 2.05 (s, 3H), 1.97-1.87 (m, 2H), 1.78-1.68 (m, 2H). ESI-MS calculated value [M+H] + =389.2, measured value 389.2.

[0275] Example 13

[0276] Synthesis route:

[0277] first step

[0278] Compound 3-6 (100 mg, 0.24 mmol) and compound 13-1 (34 mg, 0.48 mmol) were dissolved in methanol (2 mL). Acetic acid (0.05 mL) was added and the mixture was stirred at 50°C for 1 hour. Sodium triacetoxyborohydride (203 mg, 0.96 mmol) was then added and stirred at room temperature for 12 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters 3767 / QDA Column: SunFire C18, 19 x 250 mm, 10 μm; mobile phase: acetonitrile-0.05% aqueous ammonia monohydrate, gradient: 52-62%, retention time: 9 min) to afford compound 13. 1 H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 7.27 (s, 1H), 7.13 (s, 1H), 7.07 (s, 1H), 4.66-4.56 (m, 3H), 3.80-3.73 (m, 2H), 3.53-3.47 (m, 2H), 3.03-2.97 (m, 1H), 2.77-2.70 (m, 2H), 2.13 (s, 3H), 2.00-1.93 (m, 2H), 1.90-1.72 (m, 5H), 1.65-1.50 (m, 5H). ESI-MS calculated value [M+H] + =463.2, measured value 463.4.

[0279] Example 14

[0280] Synthesis route:

[0281] first step

[0282] 3-4 (200 mg, 0.54 mmol), 14-1 (271 mg, 0.81 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (26 mg, 0.054 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (46 mg, 0.054 mmol), and potassium carbonate (224 mg, 1.62 mmol) were added to 1,4-dioxane (5 mL) and a mixture of 1 mL. The mixture was heated to 100°C and stirred for 16 hours under argon protection. After cooling, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 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, 1 / 1, v / v) to afford 14-2. ESI-MS calculated value [M+H] + =541.3, measured value 541.4.

[0283] Step 2

[0284] Dissolve 14-2 (280 mg, 0.52 mol) in dichloromethane (6 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 1 hour. After the reaction, concentrate under reduced pressure to obtain a crude product containing 14-3, which is used directly in the next reaction. ESI-MS theoretical calculated value [M+H] + =383.2, measured value 383.3.

[0285] Step 3

[0286] 14-3 (198 mg, 0.52 mmol) was dissolved in methanol (5 mL). Aqueous formaldehyde (37%, 47 mg, 1.56 mmol), acetic acid (0.05 mL), and sodium cyanoborohydride (98 mg, 1.56 mmol) were added sequentially, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 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 in water, gradient: 22-32%, retention time: 9 min) to obtain 14. 1 H NMR (400 MHz, DMSO-d6): δ 14.71 (br, 1H), 8.30 (s, 1H), 7.86 (d, J = 8.80 Hz, 1H), 7.68 (d, J = 5.60 Hz, 1H), 7.59-7.55 (m, 2H), 4.89-4.79 (m, 1H), 4.77-4.66 (m, 2H), 3.88-3.78 (m, 2H), 3.67-3.57 (m, 3H), 3.21-3.11 (m, 2H), 2.72-2.62 (m, 1H), 2.60 (s, 3H), 1.94-1.84 (m, 2H), 1.76-1.66 (m 2H). ESI-MS calculated value [M+H] + =397.2, measured value 397.1.

[0287] Example 15

[0288] Synthesis route:

[0289] first step

[0290] 15-1 (11 g, 35.15 mmol) was dissolved in dimethyl sulfoxide (30 mL) and water (3 mL). Anhydrous copper sulfate (280 mg, 1.76 mmol), potassium hydroxide (9.86 g, 175.75 mmol), and 1,2-ethanedithiol (6.62 g, 70.3 mmol) were added sequentially. The mixture was heated to 90°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, and bromoacetaldehyde diethyl acetal (20.78 g, 105.45 mmol) was slowly added dropwise. Stirring was continued at room temperature for 2 hours. After the reaction, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3). The organic layers were combined, 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 afford 15-2. 1 H NMR (400MHz, CDCl3): δ7.42 (d, J = 8.00Hz, 1H), 6.94 (d, J = 2.00Hz, 1H), 6.85 (dd, J = 8.00, 2.00Hz, 1H), 4.64 (t, J=5.60Hz,1H),3.88(s,3H),3.71-3.66(m,2H),3.61-3.51(m,2H),3.13(d,J=5.60Hz,2H),1.24-1.19(m,6H).

[0291] Step 2

[0292] Polyphosphoric acid (1.71 g, 17.45 mmol) was added to chlorobenzene (60 mL). The temperature was raised to 140°C, and a solution of 15-2 (2 g, 5.97 mmol) in chlorobenzene (12 mL) was slowly added dropwise. The mixture was then heated to 140°C and stirred for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, 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, 30 / 1, v / v) to afford 15-3. 1 H NMR (400MHz, CDCl3): δ7.98 (s, 1H), 7.35 (s, 1H), 7.29 (d, J = 5.40Hz, 1H), 7.18 (d, J = 5.40Hz, 1H), 3.96 (s, 3H).

[0293] Step 3

[0294] 15-3 (400 mg, 1.65 mmol), bis-pinacol boronate (628 mg, 2.47 mmol), potassium acetate (486 mg, 4.95 mmol), and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (121 mg, 0.17 mmol) were dissolved in 1,4-dioxane (8 mL) and stirred at 100°C under nitrogen for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, 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, 30 / 1, v / v) to afford 15-4. 1 H NMR (400MHz, CDCl3): δ8.13(s,1H),7.30(s,1H),7.25-7.20(m,2H),3.89(s,3H),1.38(s,12H).

[0295] Step 4

[0296] Dissolve 15-4 (800 mg, 2.76 mmol) in dichloromethane (8 mL), cool to 0°C under nitrogen, and slowly add boron tribromide (1.73 g, 6.9 mmol) dropwise. Stir at room temperature for 2 hours. After the reaction, slowly add water (20 mL) at 0°C to quench the reaction. Adjust the pH to 9 with saturated sodium carbonate solution, wash the aqueous phase with ethyl acetate (20 mL), and then adjust the pH to 3 with dilute hydrochloric acid (1 mol / L). Extract with ethyl acetate (30 mL x 3). Combine the organic layers, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product containing 15-5, which is used directly in the next reaction. 1 H NMR (400MHz, DMSO-d6): δ8.24(s,1H),7.60(d,J=5.20Hz,2H),7.43(d,J=5.20Hz,1H),7.22(s,1H).

[0297] Step 5

[0298] 1-4 (130 mg, 0.37 mmol), 15-5 (144 mg, 0.74 mmol), potassium carbonate (200 mg, 1.48 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (18 mg, 0.037 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (31 mg, 0.037 mmol) were added to 1,4-dioxane (10 mL) and water (2 mL), the temperature was raised to 100 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, 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, 2 / 1, v / v) to obtain 15-6. ESI-MS calculated value [M+H] + =467.2, measured value 467.2.

[0299] Step 6

[0300] Dissolve 15-6 (61 mg, 0.13 mmol) in dichloromethane (1.2 mL) and slowly add trifluoroacetic acid (0.4 mL) dropwise at 0°C. Stir at room temperature for 2 hours. After the reaction is complete, concentrate under reduced pressure to obtain a crude product containing 15-7, which is used directly in the next reaction. ESI-MS calculated value [M+H] + =367.2, measured value 367.2.

[0301] Step 7

[0302] 15-7 (48 mg, 0.13 mmol) was dissolved in methanol (1 mL). Aqueous formaldehyde (37%, 11.7 mg, 0.39 mmol) and sodium cyanoborohydride (25 mg, 0.39 mmol) were added sequentially, and stirred at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by HPLC (SunFire C18, 19 x 250 mm, 10 μm, mobile phase: acetonitrile-0.1% formic acid in water, gradient: 18-28%; retention time: 9 min) to afford 15. 1H NMR (400 MHz, DMSO-d6): δ 14.05 (s, 1H), 8.38 (s, 1H), 8.06 (s, 1H), 7.50 (d, J = 5.20 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J = 5.20 Hz, 1H), 4.99-4.90 (m, 1H), 3.50-3.40 (m, 2H), 2.97-2.82 (m, 4H), 2.33 (s, 3H), 2.30-2.23 (m, 1H), 2.10-2.00 (m, 1H), 1.94-1.84 (m, 1H), 1.85-1.72 (m, 3H), 1.70-1.60 (m, 2H). ESI-MS calculated value [M+H] + =381.2, measured value 381.2.

[0303] Example 16

[0304] Synthesis route:

[0305] first step

[0306] Dissolve 1-1 (12.5 g, 83.9 mmol) in 16-1 (154 mL, 1.84 μmol). Add tert-butyl hydroperoxide (70% aqueous solution, 32.4 g, 251.7 mmol) and stir for 10 minutes. Then slowly add titanium trichloride (15-20% dissolved in 30% aqueous hydrogen chloride, 194.1 g, 251.7 mmol) dropwise at 0°C. Stir overnight at room temperature under nitrogen. After the reaction, cool to 0°C and slowly add saturated ammonium chloride solution (400 mL) dropwise. Extract with dichloromethane (300 mL x 3). The combined organic phases are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to afford 16-2. 1 H NMR (400MHz, CDCl3): δ7.86(s,1H),5.29-5.19(m,1H),3.92-3.82(m,1H),3. 79-3.73(m,1H),3.43(d,J=4.6Hz,1H),2.32-2.24(m,1H),1.99-1.93(m,1H).

[0307] Step 2

[0308] Dissolve 16-2 (2.00 g, 8.28 mmol) and 2-3 (1.99 g, 9.94 mmol) in N,N-dimethylformamide (20 mL), and add triethylamine (4.60 mL, 33.1 mmol). Under nitrogen, heat to 140°C and stir for 3 hours. Cool the reaction mixture to room temperature, dilute with water (100 mL), and extract with ethyl acetate (40 mL x 3). The combined organic phases are washed three times 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, 1 / 1, v / v) to afford 16-3. 1 H NMR (400 MHz, DMSO-d6): δ7.28 (s, 1H), 5.85-5.75 (m, 1H), 4.70-4.48 (m, 2H), 3.96-3.86 (m, 2H), 3.49-3.33 (m, 2H), 3.02-2.77 (m, 1H), 2.72-2.72 (m, 1H), 1.99-1.89 (m, 1H), 1.87-1.61 (m, 4H), 1.40 (s, 9H). ESI-MS calculated value [M+H] + =369.2, measured value 369.0.

[0309] Step 3

[0310] Dissolve 16-3 (200 mg, 0.54 mmol) and 5-8 (326 mg, 1.08 mmol) in 1,4-dioxane (12 mL) and water (2 mL). Add potassium phosphate (573 mg, 2.70 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (26 mg, 0.05 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (46 mg, 0.05 mmol). Heat to 100°C and stir under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, 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, 1 / 1, v / v) to obtain 16-4. ESI-MS calculated value [M+H] + =509.2, measured value 509.0.

[0311] Step 4

[0312] Dissolve 16-4 (240 mg, 0.47 mmol) in dichloromethane (2.5 mL), add trifluoroacetic acid (0.6 mL), and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound 16-5, which was used directly in the next reaction. ESI-MS calculated value [M+H] + =409.2, measured value 409.1.

[0313] Step 5

[0314] 16-5 (150 mg, 0.37 mmol) was dissolved in methanol (2 mL), and acetaldehyde (5.0 mol / L tetrahydrofuran solution, 0.37 mL, 1.85 mmol) was added. The mixture was stirred at room temperature for 30 minutes, followed by the addition of sodium triacetoxyborohydride (235 mg, 1.11 mmol). After the reaction, saturated aqueous sodium bicarbonate (10 mL) was added dropwise, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by HPLC (Waters 3767 / QDA Column: SunFire C18, 19 x 250 mm, 10 μm; mobile phase: acetonitrile-0.05% ammonia monohydrate, gradient: 37-47%, retention time: 8.5 min) to afford 16. 1 H NMR (400 MHz, DMSO-d6): δ 10.15 (br, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.10-7.05 (m, 2H), 5.71-5.61 (m, 1H), 4.99-4.93 (m, 1H), 4.63-4.53 (m, 1H), 3.52-3.36 (m, 2H), 2.91-2.81 (m, 2H), 2.41-2.31 (m, 2H), 2.14 (s, 3H), 2.08-1.94 (m, 2H), 1.85-1.68 (m, 4H), 1.65-1.55 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =437.2, measured value 437.0.

[0315] Example 17

[0316] Synthesis route:

[0317] first step

[0318] Dissolve 3-4 (2.6 g, 7.05 mmol) in dichloromethane (30 mL), add trifluoroacetic acid (15 mL), and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing the target compound 17-1, which was used directly in the next reaction. ESI-MS calculated value [M+H] + =269.1, measured value 269.1.

[0319] Step 2

[0320] 17-1 (1.8 g, 6.70 mmol) was dissolved in methanol (20 mL). Acetaldehyde (5.0 mol / L tetrahydrofuran solution, 2.68 mL, 13.4 mmol), acetic acid (0.1 mL), and sodium triacetoxyborohydride (4.26 g, 20.1 mmol) were added sequentially and stirred at room temperature for 16 hours. After completion of the reaction, the pH was adjusted to greater than 8 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to afford 17-2. 1 H NMR (400 MHz, DMSO-d6): δ 7.50 (s, 1H), 4.70-4.55 (m, 3H), 3.86-3.69 (m, 2H), 3.52-3.50 (m, 2H), 3.25-3.15 (m, 1H), 3.10-3.00 (m, 1H), 2.71-2.61 (m, 2H), 2.41-2.31 (m, 1H), 2.22-2.12 (m, 1H), 1.88-1.78 (m, 2H), 1.68-1.58 (m, 2H), 1.10 (t, J = 6.8 Hz, 3H). ESI-MS calculated value [M+H] + =297.1, measured value 297.1.

[0321] Step 3

[0322] 17-2 (100 mg, 0.34 mmol), 12-1 (90 mg, 0.51 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (30 mg, 0.03 mmol), and potassium carbonate (190 mg, 1.36 mmol) were added to 1,4-dioxane (10 mL) and water (2 mL). The mixture was heated to 100°C and stirred under nitrogen for 16 hours. After cooling, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by HPLC (Waters 3767 / QDA Column: Boston Uni C18, 21.2 x 250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid in water, gradient: 21-31%, retention time: 7.5 min) afforded 17. 1 H NMR (400 MHz, DMSO-d6): δ 7.24 (s, 1H), 6.87-6.80 (m, 2H), 4.67-4.54 (m, 3H), 3.93-3.64 (m, 2H), 3.61-3.41 (m, 2H), 3.18-3.08 (m, 1H), 2.96-2.86 (m, 1H), 2.51-2.41 (m, 2H), 2.17-2.07 (m, 1H), 2.05 (s, 3H), 2.00-1.84 (m, 2H), 1.82-1.72 (m, 1H), 1.69-1.51 (m, 2H), 1.04 (t, J = 6.8 Hz, 3H). ESI-MS calculated value [M+H] + =403.2, measured value 403.3.

[0323] Example 18

[0324] Synthesis route:

[0325] first step

[0326] Compound 3-6 (150 mg, 0.37 mmol) and compound 18-1 (36 mg, 0.37 mmol) were dissolved in methanol (2 mL). Acetic acid (0.05 mL) was added and the mixture was stirred at 60°C for 1 hour. Sodium triacetoxyborohydride (310 mg, 1.48 mmol) was then added and stirred at room temperature for 12 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters 3767 / QDA Column: SunFire C18, 19 x 250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid in water, gradient: 26-40%, retention time: 8 min) to afford compound 18. 1H NMR (400MHz, DMSO-d6): δ10.19(s,1H),7.28(s,1H),7.13(s,1H),7.07(s,1H),4.72- 4.50(m,3H),3.89-3.71(m,2H),3.55-3.49(m,2H),3.10-3.03(m,1H),2.89-2.77(m, 1H), 2.44-2.29 (m, 2H), 2.28-2.17 (m, 1H), 2.13 (s, 3H), 1.91-1.83 (m, 1H), 1.82-1.67 (m, 5H), 1.65-1.49 (m, 3H), 1.34-1.13 (m, 4H), 1.12-0.99 (m, 1H). ESI-MS calculated value [M+H] + =491.2, measured value 491.4.

[0327] Example 19

[0328] Synthesis route:

[0329] first step

[0330] Compound 3-6 (154 mg, 0.38 mmol) and compound 19-1 (76 mg, 0.76 mmol) were dissolved in methanol (2 mL). Acetic acid (0.05 mL) was added and the mixture was stirred at 50°C for 1 hour. Sodium triacetoxyborohydride (110 mg, 0.51 mmol) was then added and stirred at room temperature for 12 hours. After the reaction, 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-0.05% ammonia monohydrate, gradient: 41-51%, retention time: 9 min) to afford compound 19. 1H NMR (400MHz, DMSO-d6): δ10.16(s,1H),7.27(s,1H),7.13(s,1H),7.07(s,1H),4.70-4.50(m,3 H),3.93-3.85(m,2H),3.84-3.72(m,2H),3.55-3.47(m,2H),3.29-3.21(m,2H),3.13-3.03(m, 1H), 2.90-2.80 (m, 1H), 2.51-2.45 (m, 1H), 2.31-2.21 (m, 1H), 2.13 (s, 3H), 2.11-1.99 (m, 1H), 1.92-1.83 (m, 1H), 1.79-1.63 (m, 3H), 1.61-1.51 (m, 2H), 1.51-1.36 (m, 2H). ESI-MS calculated value [M+H] + =493.2, measured value 493.4.

[0331] Example 20

[0332] Synthesis route:

[0333] first step

[0334] 2-5 (211 mg, 0.63 mmol), 14-1 (150 mg, 0.42 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (20 mg, 0.04 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (36 mg, 0.04 mmol), and potassium carbonate (174 mg, 1.26 mmol) were added to 1,4-dioxane (10 mL) and a mixture of 1,4-dioxane (2 mL). 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) and extracted with ethyl acetate (30 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, 1 / 1, v / v) to obtain 20-1. ESI-MS calculated value [M+H] + =527.2, measured value 527.4.

[0335] Step 2

[0336] Dissolve 20-1 (111 mg, 0.21 mol) in dichloromethane (3 mL) under an ice-water bath, add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. After the reaction is complete, concentrate under reduced pressure to obtain a crude product containing 20-2, which is used directly in the next reaction. ESI-MS calculated value [M+H]+ =369.1, measured value 369.2.

[0337] Step 3

[0338] 20-2 (78 mg, 0.21 mmol) was dissolved in methanol (2 mL). Acetaldehyde (5.0 mol / L tetrahydrofuran solution, 0.12 mL, 0.63 mmol), acetic acid (0.05 mL), and sodium cyanoborohydride (40 mg, 0.63 mmol) were added sequentially, and stirred at room temperature for 16 hours. After completion of the reaction, 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 in water, gradient: 23-33%, retention time: 9 min) to obtain 20. 1 H NMR (400MHz, DMSO-d6): δ15.27(br,1H),7.86(d,J=8.8Hz,1H),7.78(s,1H),7.65(d ,J=5.6Hz,1H),7.54(d,J=5.6Hz,1H),7.49(d,J=8.8Hz,1H),4.99-4.89(m,1H),4.4 4-4.34 (m, 2H), 3.66-3.56 (m, 2H), 3.27-3.17 (m, 2H), 2.86-2.76 (m, 2H), 2.57-2.47 (m, 1H), 2.37-2.28 (m, 1H), 1.95-1.70 (m, 4H), 1.19-1.10 (m, 3H). ESI-MS calculated value [M+H] + =397.2, measured value 397.1.

[0339] Example 21

[0340] Synthesis route:

[0341] first step

[0342] 2-7 (100 mg, 0.28 mmol) and 11-1 (20 mg, 0.42 mmol) were dissolved in methanol (2 mL). Acetic acid (0.05 mL) was added and the mixture was stirred at 50°C for 1 hour. Sodium triacetoxyborohydride (240 mg, 1.11 mmol) was then added and stirred at room temperature for 12 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by HPLC (Waters 3767 / QDA Column: SunFire C18, 19 x 250 mm, 10 μm; mobile phase: acetonitrile-0.05% aqueous ammonia monohydrate, gradient: 54-64%; retention time: 7 min) to afford 21.1 H NMR (400MHz, DMSO-d6): δ10.14(br,1H),7.10-7.02(m,2H),6.78(s,1H),4.92-4.82(m ,1H),4.28(t,J=4.20Hz,2H),3.67-3.59(m,1H),3.56-3.49(m,1H),3.02-2.90(m,2H) ,2.27-2.17(m,2H),2.16-2.10(m,4H),1.98-1.88(s,1H),1.82-1.72(m,2H),1.67-1.57(m,2H),0.90-0.80(m,1H),0.49-0.42(m,2H),0.13-0.03(m,2H).ESI-MS theoretical value [M+H] + =449.2, measured value 449.2.

[0343] Example 22

[0344] Synthesis route:

[0345] first step

[0346] 2-7 (50 mg, 0.13 mmol) was dissolved in methanol (2 mL), and acetaldehyde (5.0 mol / L tetrahydrofuran solution, 0.13 mL, 0.65 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (110 mg, 0.52 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters 3767 / QDA Column: SunFire C18, 19 x 250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid in water, gradient: 13-23%, retention time: 9 min) to afford 22. 1 H NMR (400 MHz, DMSO-d6): δ 10.19 (br, 1H), 7.12-7.03 (m, 2H), 6.82 (s, 1H), 5.04-4.94 (m, 1H), 4.36-4.26 (m, 2H), 3.64-3.51 (m, 2H), 3.20-3.10 (m, 2H), 2.78-2.68 (m, 2H), 2.57-2.47 (m, 1H), 2.38-2.28 (m, 1H), 2.13 (s, 3H), 1.93-1.66 (m, 4H), 1.12 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =423.2, measured value 423.2.

[0347] Example 23

[0348] Synthesis route:

[0349] first step

[0350] Compound 2-7 (150 mg, 0.38 mmol) and compound 13-1 (40 mg, 0.57 mmol) were dissolved in methanol (2 mL). Acetic acid (0.05 mL) was added and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (242 mg, 1.14 mmol) was then added and stirred at room temperature for 12 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters 3767 / QDA Column: Boston Uni C18, 21.2 x 250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid in water, gradient: 20-30%; retention time: 9 min) to afford compound 23. 1 H NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6.80 (s, 1H), 5.02-4.83 (m, 1H), 4.34-4.24 (m, 2H), 3.73-3.45 (m, 2H), 3.04-2.85 (m, 3H), 2.13 (s, 3H), 2.08-1.96 (m, 3H), 1.94-1.75 (m, 5H), 1.67-1.57 (m, 4H). ESI-MS calculated value [M+H] + =449.2, measured value 449.4.

[0351] Example 24

[0352] Synthesis route:

[0353] first step

[0354] Compound 2-7 (150 mg, 0.38 mmol) and compound 19-1 (76 mg, 0.76 mmol) were dissolved in methanol (2 mL). Acetic acid (0.05 mL) was added and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (242 mg, 1.14 mmol) was then added and stirred at 50°C for 12 hours. After the reaction, 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 in water, gradient: 15-25%; retention time: 9 min) to yield compound 24. 1H NMR (400 MHz, DMSO-d6): δ 10.17 (br, 1H), 7.12-7.04 (m, 2H), 6.79 (s, 1H), 4.92-4.82 (m, 1H), 4.29 (t, J = 4.0 Hz, 2H), 3.94-3.84 (m, 2H), 3.63-3.53 (m, 2H), 3.30-3.20 (m, 2H), 3.05-2.90 (m, 2H), 2.71-2.61 (m, 1H), 2.50-2.40 (m, 1H), 2.28-2.09 (m, 1H), 2.13 (s, 3H), 1.89-1.36 (m, 8H). ESI-MS calculated value [M+H] + =479.2, measured value 479.1.

[0355] Example 25

[0356] Synthesis route:

[0357] first step

[0358] Compound 17-1 (200 mg, 1.74 mmol) was dissolved in dichloromethane (5 mL), and acetone (215 mg, 3.70 mmol), acetic acid (0.05 mL), and sodium triacetoxyborohydride (471 mg, 2.22 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the pH was adjusted to greater than 8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 15 / 1, v / v) to afford compound 25-1. 1 H NMR (400 MHz, DMSO-d6): δ7.45 (s, 1H), 4.69-4.50 (m, 2H), 4.50-4.40 (m, 1H), 3.83-3.70 (m, 2H), 3.58-3.48 (m, 2H), 2.96-2.86 (m, 1H), 2.77-2.67 (m, 2H), 2.20-2.02 (m, 2H), 1.81-1.70 (m, 2H), 1.56-1.45 (m, 2H), 0.98-0.96 (m, 6H). ESI-MS calculated value [M+H] + =311.2, measured value 311.1.

[0359] Step 2

[0360] 25-1 (134 mg, 0.43 mmol), 5-8 (260 mg, 0.86 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (20 mg, 0.04 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (36 mg, 0.04 mmol), and potassium carbonate (297 mg, 2.15 mmol) were added to 1,4-dioxane (15 mL) and 2,4-dioxane (3 mL). The mixture was heated to 100°C and stirred for 16 hours under nitrogen protection. After cooling, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 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: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 22-32%; retention time: 9 min) to obtain 25. 1 H NMR (400 MHz, DMSO-d6): δ7.29 (s, 1H), 7.12 (s, 1H), 7.08 (s, 1H), 4.70-4.55 (m, 3H), 3.86-3.70 (m, 2H), 3.58-3.48 (m, 2H), 3.13-3.03 (m, 1H), 2.91-2.84 (m, 2H), 2.46-2.36 (m, 1H), 2.28-2.18 (m, 1H), 2.13 (s, 3H), 1.90-1.75 (m, 2H), 1.65-1.50 (m, 2H), 1.05-1.03 (m, 6H). ESI-MS calculated value [M+H] + =451.2, measured value 451.5.

[0361] Example 26

[0362] Synthesis route:

[0363] first step

[0364] 14-3 (65 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL), and acetaldehyde (5.0 mol / L tetrahydrofuran solution, 0.17 mL, 0.85 mmol) and sodium triacetoxyborohydride (110 mg, 0.52 mmol) were added sequentially. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, 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-0.05% ammonia monohydrate, gradient: 54-54%, retention time: 9 min) to afford 26. 1 H NMR (400MHz, DMSO-d6): δ8.23(s,1H),7.84(d,J=8.8Hz,1H),7.67(d,J=5.6Hz,1H),7 .59-7.52(m,2H),4.81-4.71(m,2H),4.64-4.54(m,1H),3.90-3.73(m,2H),3.64-3.5 3 (m, 2H), 3.09-3.00 (m, 1H), 2.89-2.80 (m, 1H), 2.37 (q, J = 7.2 Hz, 2H), 2.04-1.94 (m, 1H), 1.85-1.75 (m, 3H), 1.63-1.53 ​​(m, 2H), 1.02 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =411.2, measured value 411.1.

[0365] Example 27

[0366] Synthesis route:

[0367] first step

[0368] 17-1 (150 mg, 0.56 mmol) was dissolved in methanol (6 mL) and tetrahydrofuran (6 mL). 27-1 (195 mg, 1.12 mmol), acetic acid (148 mg, 2.8 mmol), and sodium triacetoxyborohydride (180 mg, 0.84 mmol) were added sequentially, and the mixture was stirred at 60°C for 16 hours. After completion of the reaction, the pH was adjusted to greater than 8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 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, 1 / 1, v / v) to afford 27-2. 1H NMR (400 MHz, CDCl3): δ7.07 (s, 1H), 4.57-4.41 (m, 3H), 3.89-3.75 (m, 2H), 3.47-3.29 (m, 2H), 3.27-3.19 (m, 1H), 3.03-2.93 (m, 1H), 2.31-2.21 (m, 1H), 2.18-2.00 (m, 2H), 1.75-1.67 (m, 2H), 1.67-1.62 (m, 1H), 1.52-1.42 (m, 1H), 0.49-0.37 (m, 4H). ESI-MS calculated value [M+H] + =309.2, measured value 309.1.

[0369] Step 2

[0370] 27-2 (115 mg, 0.37 mmol), 5-8 (223 mg, 0.74 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (18 mg, 0.04 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (31 mg, 0.04 mmol), and potassium carbonate (256 mg, 1.85 mmol) were added to 1,4-dioxane (5 mL) and 1 mL. 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) and extracted with ethyl acetate (20 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: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.05% monohydrate aqueous ammonia solution, gradient: 47-57%; retention time: 8 min) to obtain 27. 1 H NMR (400 MHz, DMSO-d6): δ 10.16 (br, 1H), 7.28 (s, 1H), 7.12-7.06 (m, 2H), 4.68-4.47 (m, 3H), 3.79 (t, J = 4.4 Hz, 2H), 3.55-3.47 (m, 2H), 3.18-3.08 (m, 1H), 2.95-2.85 (m, 1H), 2.35-2.25 (m, 1H), 2.15-2.07 (m, 4H), 1.90-1.80 (m, 1H), 1.74-1.64 (m, 2H), 1.60-1.50 (m, 2H), 0.48-0.36 (m, 2H), 0.35-0.24 (m, 2H). ESI-MS calculated value [M+H] +=449.2, measured value 449.1.

[0371] Example 28

[0372] Synthesis route:

[0373] first step

[0374] 2-5 (150 mg, 0.42 mmol), 12-1 (117 mg, 0.63 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (34 mg, 0.04 mmol), and potassium carbonate (232 mg, 1.68 mmol) were added to 1,4-dioxane (10 mL) and water (2 mL). The mixture was heated to 100°C and stirred for 16 hours under nitrogen. After cooling, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 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, 1 / 1, v / v) to afford 28-1. 1 H NMR (400 MHz, DMSO-d6): δ 10.01 (br, 1H), 6.83-6.77 (m, 2H), 6.75 (s, 1H), 4.73-4.63 (m, 1H), 4.30 (t, J = 4.2 Hz, 2H), 4.03-3.85 (m, 2H), 3.61-3.51 (m, 2H), 2.96-2.86 (m, 1H), 2.72-2.62 (m, 1H), 2.05 (s, 3H), 1.85-1.74 (m, 3H), 1.54-1.44 (m, 1H), 1.40 (s, 9H). ESI-MS calculated value [M+H] + =461.2, measured value 461.2.

[0375] Step 2

[0376] Dissolve 28-1 (165 mg, 0.64 mol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. After the reaction, adjust the pH to 8-9 with saturated sodium bicarbonate solution, extract with ethyl acetate (20 mL x 3), combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product containing 28-2, which is used directly in the next reaction. ESI-MS calculated value [M+H] + =361.2, measured value 361.2.

[0377] Step 3

[0378] 28-2 (90 mg, 0.25 mmol) was dissolved in 1,2-dichloroethane (2 mL). Acetaldehyde (5.0 mol / L tetrahydrofuran solution, 0.08 mL, 0.37 mmol) and sodium triacetoxyborohydride (159 mg, 0.75 mmol) were added sequentially, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 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 in water, gradient: 10-20%, retention time: 8 min) to afford 26. 1 H NMR (400 MHz, DMSO-d6): δ 6.83-6.79 (m, 2H), 6.73 (s, 1H), 4.88-4.78 (m, 1H), 4.27 (t, J = 4.2 Hz, 2H), 3.64-3.55 (m, 1H), 3.54-3.47 (m, 1H), 2.95-2.85 (m, 1H), 2.84-2.74 (m, 1H), 2.43-2.33 (m, 2H), 2.11-2.01 (m, 4H), 1.91-1.81 (m, 1H), 1.80-1.70 (s, 2H), 1.66-1.56 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =389.2, measured value 389.2.

[0379] Example 29

[0380] Synthesis route:

[0381] first step

[0382] Dissolve 2-5 (500 mg, 1.41 mol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. After the reaction, adjust the pH to 8-9 with saturated sodium bicarbonate solution. Extract with isopropanol and dichloromethane (1 / 10, v / v, 50 mL x 3). Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product containing 29-1, which is used directly in the next reaction. ESI-MS calculated value [M+H] + =255.1, measured value 255.2.

[0383] Step 2

[0384] 29-1 (350 mg, 1.37 mmol) was dissolved in 1,2-dichloroethane (5 mL). Acetaldehyde (5.0 mol / L tetrahydrofuran solution, 0.08 mL, 0.37 mmol) and sodium triacetoxyborohydride (871 mg, 4.11 mmol) were added sequentially at 0°C, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to afford 29-2. 1 H NMR (400 MHz, DMSO-d6): δ 7.00 (s, 1H), 4.71-4.64 (m, 1H), 4.27 (t, J = 4.2 Hz, 2H), 3.62-3.52 (m, 1H), 3.54-3.44 (m, 1H), 2.87-2.77 (m, 2H), 2.40-2.30 (m, 2H), 2.06-1.96 (m, 1H), 1.89-1.79 (m, 1H), 1.75-1.68 (m, 2H), 1.61-1.51 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =283.1, measured value 283.2.

[0385] Step 3

[0386] 29-2 (70 mg, 0.25 mmol), 29-3 (85 mg, 0.50 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 potassium carbonate (173 mg, 1.25 mmol) were added to 1,4-dioxane (5 mL) and 1 mL. The mixture was heated to 90°C and stirred for 16 hours under nitrogen protection. After cooling, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 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: XBridge C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 20-30%; retention time: 9 min) to obtain 27. 1H NMR (400 MHz, DMSO-d6): δ 6.72 (s, 1H), 6.64-6.51 (m, 2H), 4.90-4.80 (m, 1H), 4.27 (t, J = 4.2 Hz, 2H), 3.61-3.46 (m, 2H), 2.95-2.82 (m, 2H), 2.47-2.35 (m, 2H), 2.17-2.07 (m, 1H), 2.07 (s, 3H), 1.94-1.83 (m, 1H), 1.80-1.70 (m, 2H), 1.66-1.56 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =373.2, measured value 373.0.

[0387] Examples 30 and 31

[0388] Synthesis route:

[0389] first step

[0390] 16 (26 mg, 0.06 mmol) was purified by supercritical fluid chromatography (Waters SFC 150, IE, 250*30mm, 10μm; mobile phase: supercritical CO2-methanol solution containing 0.1% 7mol / L ammonia methanol, gradient: 50%-50%, flow rate: 70ml / min) to separate and purify compound 30 (elution time: 5.0-6.9min) and compound 31 (elution time: 7.4-10.4min).

[0391] Compound 30: 1 H NMR (400MHz, DMSO-d6): δ10.15(br,1H),7.19(s,1H),7.11(s,1H),7.06(s,1H),5.65(d ,J=5.2Hz,1H),5.03-4.93(m,1H),4.64-4.54(m,1H),3.54-3.44(m,1H),3.43-3.32(m, 1H), 2.91-2.81 (m, 2H), 2.41-2.30 (m, 2H), 2.14 (s, 3H), 2.08-2.02 (m, 1H), 1.99-1.89 (m, 1H), 1.86-1.68 (m, 4H), 1.66-1.55 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =437.2, measured value 437.0.

[0392] Compound 31: 1H NMR (400 MHz, DMSO-d6): δ 10.16 (br, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 7.06 (s, 1H), 5.68 (d, J = 5.2 Hz, 1H), 5.01-4.89 (m, 1H), 4.62-4.52 (m, 1H), 3.48-3.38 (m, 2H), 2.91-2.81 (m, 2H), 2.36 (q, J = 7.2 Hz, 2H), 2.14 (s, 3H), 2.06-1.95 (m, 2H), 1.85-1.69 (m, 4H), 1.65-1.55 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =437.2, measured value 437.0.

[0393] Example 32

[0394] Synthesis route:

[0395] first step

[0396] Dissolve 3-1 (610 mg, 2.90 mmol) and 32-1 (410 mg, 2.90 mmol) in acetonitrile (20 mL), add N,N-diisopropylethylamine (2.4 mL, 14.5 mmol), and heat to 70°C with stirring for 18 hours. After the reaction is completed, cool to room temperature, add 3-3 (820 mg, 5.40 mmol) and N,N-diisopropylethylamine (2.2 mL, 13.5 mmol), and continue stirring at room temperature for 18 hours. After the reaction is completed, concentrate under reduced pressure, dilute with water (50 mL), and extract with ethyl acetate (50 mL x 3). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 40 / 1, v / v) to obtain 32-2. ESI-MS calculated value [M+H] + =337.2, measured value 337.0.

[0397] Step 2

[0398] 32-2 (100 mg, 0.30 mmol) was dissolved in toluene (5 mL), heated to 130°C, and stirred for 24 hours. After the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to afford 32-3. ESI-MS calculated value [M+H] + =309.2, measured value 309.0.

[0399] Step 3

[0400] 32-3 (20 mg, 0.06 mmol), 5-8 (39 mg, 0.13 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (3 mg, 6.5 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (5.5 mg, 6.5 μmol), and potassium carbonate (36 mg, 0.26 mmol) were added to 1,4-dioxane (5 mL) and a mixture of 1 mL. 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) and extracted with ethyl acetate (20 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: Agilent C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 25-35%; retention time: 7 min) to obtain 32. 1 H NMR (400MHz, DMSO-d6): δ10.24(br,1H),7.30(s,1H),7.12(s,1H),7.08(s,1H),4.80 -4.70(m,1H),4.50-4.42(m,2H),4.00-3.82(m,1H),3.77-3.69(m,1H),3.67-3.58(m, 1H), 3.35-3.29 (m, 1H), 3.10-2.93 (m, 2H), 2.21-2.15 (m, 2H), 2.13 (s, 3H), 2.06-1.86 (m, 3H), 1.81-1.71 (m, 1H), 1.71-1.58 (m, 3H), 1.58-1.41 (m, 2H). ESI-MS calculated value [M+H] + =449.2, measured value 449.5.

[0401] Example 33

[0402] Synthesis route:

[0403] first step

[0404] 2-5 (131 mg, 0.37 mmol), 33-1 (100 mg, 0.56 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (26 mg, 0.06 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (47 mg, 0.06 mmol), and potassium carbonate (309 mg, 2.24 mmol) were added to 1,4-dioxane (10 mL) and 2 mL. The mixture was heated to 100°C and stirred for 16 hours under nitrogen protection. After cooling, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 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, 1 / 1, v / v) to give 33-2. ESI-MS calculated value [M+H] + =452.2, measured value 452.4.

[0405] Step 2

[0406] Dissolve 33-2 (60 mg, 0.13 mol) in dichloromethane (1 mL), add trifluoroacetic acid (0.3 mL), and stir at room temperature for 2 hours. After the reaction is complete, concentrate under reduced pressure to obtain a crude product containing 33-3, which is used directly in the next reaction. ESI-MS calculated value [M+H] + =352.2, measured value 352.3.

[0407] Step 3

[0408] 33-3 (47 mg, 0.13 mmol) was dissolved in methanol (5 mL). Acetaldehyde (5.0 mol / L tetrahydrofuran solution, 0.04 mL, 0.2 mmol), acetic acid (0.1 mL), and sodium triacetoxyborohydride (83 mg, 0.39 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters 3767 / QDA Column: SunFire C18, 19 x 250 mm, 10 μm; mobile phase: acetonitrile-0.05% ammonia monohydrate, gradient: 34-44%, retention time: 8 min) to afford 33. 1H NMR (400MHz, DMSO-d6): δ10.25(br,1H),7.22(s,1H),7.09(s,1H),6.77(s,1H),4. 88-4.38(m,1H),4.27(t,J=4.2Hz,2H),3.65-3.45(m,2H),2.95-2.85(m,1H),2.84 -2.77 (m, 1H), 2.41-2.30 (m, 2H), 2.10 (s, 3H), 2.09-2.00 (m, 1H), 1.88-1.78 (m, 1H), 1.77-1.70 (m, 2H), 1.65-1.55 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =380.2, measured value 380.1.

[0409] Example 34

[0410] Synthesis route:

[0411] first step

[0412] 34-1 (5.0 g, 71.34 mmol) was dissolved in N,N-dimethylformamide (150 mL). Sodium hydride (60%, 3.71 g, 92.74 mmol) was added portionwise at 0°C. After stirring for 1 hour, 34-2 (25.60 g, 107.01 L) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. After completion of the reaction, water (400 mL) was slowly added to quench the reaction. The mixture was extracted with ethyl acetate / petroleum ether (1 / 4, v / v, 300 mL x 3). The organic phases were combined, washed with saturated brine (600 mL x 3), 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 afford 34-3. 1 H NMR (400MHz, CDCl3): δ4.28-4.18(m,1H),3.86-3.71(m,3H),3.57-3.44(m, 1H), 2.40 (d, J = 2.0Hz, 1H), 1.44 (d, J = 6.4Hz, 3H), 0.90 (s, 9H), 0.07 (s, 6H).

[0413] Step 2

[0414] 34-3 (9.0 g, 39.4 mmol) was dissolved in tetrahydrofuran (90 mL), and tetrabutylammonium fluoride (1.0 mol / L tetrahydrofuran solution, 59.10 mL, 59.10 mmol) was added. The mixture was stirred at 25°C for 12 hours. After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were 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 afford 34-4. 1 H NMR (400MHz, CDCl3): δ4.27-4.17(m,1H),3.89-3.81(m,1H),3.82-3.72(m,2H),3.58-3.49(m,1H),2.45(d,J=2.0Hz,1H),1.47(d,J=6.4Hz,3H).

[0415] Step 3

[0416] 34-3 (4.5 g, 39.43 mmol) was dissolved in tetrahydrofuran (180 mL), and triphenylphosphine (12.41 g, 47.32 mmol) and imidazole (8.05 g, 118.29 mmol) were added. The mixture was cooled to -10°C, and iodine (12.01 g, 47.32 mmol) was added. The mixture was stirred at 25°C for 3 hours. After the reaction, the mixture was diluted with water (250 mL) and extracted with petroleum ether (200 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, 100 / 1, v / v) to obtain 34-5. 1 H NMR (400MHz, CDCl3): δ4.29-4.19(m,1H),4.05-3.90(m,1H),3.74-3.64(m,1H),3.39-3.20(m,2H),2.44(d,J=2.0Hz,1H),1.48(d,J=7.6Hz,3H).

[0417] Step 4

[0418] Compound 34-5 (800 mg, 3.57 mmol) and compound 5-8 (1.07 g, 5.35 mmol) were dissolved in dimethyl sulfoxide (15 mL). N,N-diisopropylethylamine (920 mg, 7.14 mmol) was added, and the mixture was heated to 50°C and stirred for 16 hours. After the reaction, water (50 mL) was slowly added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 0 / 1, v / v) to afford compound 34-6. ESI-MS calculated value [M+H] + =297.2, measured value 297.2.

[0419] Step 5

[0420] Dissolve 34-6 (970 mg, 3.28 mmol) and 3-3 (550 mg, 3.64 mmol) in tetrahydrofuran (20 mL), add N,N-diisopropylethylamine (1.88 g, 14.56 mmol), and stir at 25°C for 16 hours. After the reaction, concentrate under reduced pressure and purify by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 34-7. ESI-MS calculated value [M+H] + =411.2, measured value 411.0.

[0421] Step 6

[0422] 34-7 (380 mg, 0.92 mmol) was dissolved in toluene (15 mL), heated to 130°C, and stirred for 16 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain 34-8. ESI-MS calculated value [M+H] + =383.2, measured value 383.2.

[0423] Step 7

[0424] 34-8 (200 mg, 0.52 mmol), 1-5 (280 mg, 0.78 mmol), potassium carbonate (180 mg, 1.30 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (25 mg, 0.05 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (44 mg, 0.05 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), heated to 110 ° C under nitrogen protection and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, 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, 5 / 1, v / v) to obtain 34-9. ESI-MS calculated value [M+H] + =581.3, measured value 581.0.

[0425] Step 8

[0426] Dissolve 34-9 (100 mg, 0.35 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 2 hours. After the reaction is complete, concentrate under reduced pressure to obtain a crude product containing 34-10, which is used directly in the next reaction. ESI-MS calculated value [M+H] + =423.2, measured value 423.1.

[0427] Step 9

[0428] 34-10 (72 mg, 0.17 mmol) was dissolved in methanol (2 mL), and formaldehyde (37% aqueous solution, 0.05 mL) and sodium cyanoborohydride (32 mg, 0.51 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 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-0.05% ammonia monohydrate, gradient: 44-54%, retention time: 9 min) to afford 34. 1H NMR (400MHz, DMSO-d6): δ10.16(br,1H),7.28-7.18(m,1H),7.13(s,1H),7.07(s,1H),4.87-4 .66(m,1H),4.65-4.49(m,1H),3.92-3.82(m,1H),3.81-3.62(m,2H),3.26-3.20&2.97-2.89( m, 1H), 3.20-3.06 (m, 1H), 2.78-2.68 (m, 1H), 2.21 (s, 3H), 2.13 (s, 3H), 2.05-1.90 (m, 2H), 1.86-1.77 (m, 1H), 1.76-1.69 (m, 1H), 1.68-1.47 (m, 2H), 1.47-1.40 (m, 3H). ESI-MS calculated value [M+H] + =437.2, measured value 437.1.

[0429] Examples 35 and 36

[0430] Synthesis route:

[0431] first step

[0432] 34-9 (220 mg, 0.38 mmol) was separated and purified by high performance liquid chromatography (Waters 3767 / QDA Column: Agilent C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.05% formic acid aqueous solution, gradient: 71-71%, flow rate: 20 ml / min) to obtain 35-1 (peak time: 7.8-9.9 min) and compound 36-1 (peak time: 10.0-11.5 min). Compound 35-1: ESI-MS theoretical calculated value [M+H] + =581.3, found 581.0. Compound 36-1: ESI-MS theoretical calculated value [M+H] + =581.3, measured value 581.0.

[0433] Step 2

[0434] Dissolve 35-1 (100 mg, 0.17 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 1 hour. After the reaction, concentrate under reduced pressure to obtain a crude product containing 35-2, which is used directly in the next reaction. ESI-MS theoretical calculated value [M+H] + =423.2, measured value 423.3.

[0435] Step 3

[0436] 35-2 (72 mg, 0.17 mmol) was dissolved in methanol (2 mL), and formaldehyde (37% aqueous solution, 0.05 mL) and sodium cyanoborohydride (32 mg, 0.51 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Gilson GX_281 Column: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 21-31%, retention time: 8 min) to afford 35. 1 H NMR (400MHz, DMSO-d6): δ10.16(br,1H),7.25(s,1H),7.13(s,1H),7.07(s,1H),4.88-4.78(m, 1H),4.72-4.62(m,1H),3.92-3.82(m,1H),3.81-3.74(s,1H),3.73-3.67(m,1H),3.28-3.23(m ,1H),3.18-3.07(m,1H),2.99-2.88(m,1H),2.52(s,3H),2.45-2.35(m,2H),2.13(s,3H),1.99-1.90(m,1H),1.85-1.75(m,1H),1.70-1.60(m,2H),1.43(d,J=6.4Hz,3H).ESI-MS calculated value [M+H] + =437.2, measured value 437.0.

[0437] Step 4

[0438] Dissolve 36-1 (100 mg, 0.17 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 1 hour. After the reaction, concentrate under reduced pressure to obtain a crude product containing 36-2, which is used directly in the next reaction. ESI-MS calculated value [M+H] + =423.2, measured value 423.1.

[0439] Step 5

[0440] 36-2 (72 mg, 0.17 mmol) was dissolved in methanol (2 mL), and formaldehyde (37% aqueous solution, 0.05 mL) and sodium cyanoborohydride (32 mg, 0.51 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Gilson GX_281 Column: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid in water, gradient: 21-31%, retention time: 8 min) to afford 36.1 H NMR (400MHz, DMSO-d6): δ10.20(br,1H),7.25(s,1H),7.13(s,1H),7.07(s,1H),4.76-4.6 6(m,1H),4.61-4.51(m,1H),3.92-3.82(m,1H),3.77-3.67(m,2H),3.20-3.10(m,2H),2.7 8-2.68 (m, 1H), 2.23 (s, 3H), 2.13 (s, 3H), 2.08-1.98 (m, 1H), 1.89-1.79 (m, 2H), 1.76-1.66 (m, 1H), 1.65-1.58 (m, 1H), 1.57-1.48 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H). ESI-MS calculated value [M+H] + =437.2, measured value 437.0.

[0441] Example 37

[0442] Synthesis route:

[0443] first step

[0444] 2-2 (200 mg, 0.63 mmol) and 37-1 (200 mg, 0.95 mmol) were dissolved in dimethyl sulfoxide (5 mL), and N,N-diisopropylethylamine (0.21 mL, 1.26 mmol) was added. The mixture was stirred at 50°C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / triethylamine, 200 / 1, v / v) to afford 37-2. ESI-MS calculated value: [M+H] + =407.1, measured value 407.2.

[0445] Step 2

[0446] 37-2 (150 mg, 0.37 mmol) was dissolved in toluene (3 mL), and cesium carbonate (360 mg, 1.11 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (35 mg, 0.06 mmol), and palladium acetate (9 mg, 0.03 mmol) were added sequentially. The reaction mixture was stirred at 110°C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated ammonium chloride solution (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / ethyl acetate, 1 / 1, v / v) to afford 37-3. ESI-MS calculated value: [M+H] + =371.2, measured value 371.2.

[0447] Step 3

[0448] 37-3 (40 mg, 0.11 mmol) and 1-5 (59 mg, 0.17 mmol) were dissolved in dioxane (2 mL) and water (0.5 mL). Potassium carbonate (39 mg, 0.28 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (9 mg, 0.01 mmol) were added sequentially. The reaction mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (25 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to afford 37-4. ESI-MS theoretical calculation value: [M+H] + =569.3, measured value 569.0.

[0449] Step 4

[0450] Dissolve 37-4 (200 mg, 0.35 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 1 hour. After the reaction, concentrate under reduced pressure to obtain a crude product containing 37-5, which is used directly in the next reaction. ESI-MS calculated value [M+H] + =411.2, measured value 411.3.

[0451] Step 5

[0452] 37-5 (25 mg, 0.06 mmol) was dissolved in ethanol (5 mL), and acetaldehyde (5.0 mol / L tetrahydrofuran solution, 0.04 mL, 0.18 mmol), acetic acid (0.1 mL), and sodium triacetoxyborohydride (39 mg, 0.18 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 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 in water, gradient: 14-24%, retention time: 7 min) to obtain 37. 1 H NMR (400 MHz, DMSO-d6): δ 7.09 (s, 1H), 7.00 (s, 1H), 6.90 (s, 1H), 5.15-5.01 (m, 1H), 4.50-4.36 (m, 2H), 4.11-3.99 (m, 1H), 3.74-3.66 (m, 1H), 3.65-3.49 (m, 3H), 3.28-3.18 (m, 2H), 3.11-2.94 (m, 1H), 2.74-2.59 (m, 1H), 2.36-2.26 (m, 1H), 2.17 (s, 3H), 2.05-1.84 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =439.2, measured value 439.2.

[0453] Example 38

[0454] Synthesis route:

[0455] first step

[0456] Compound 2-2 (600 mg, 1.88 mmol) and compound 38-1 (620 mg, 2.82 mmol) were dissolved in dimethyl sulfoxide (12 mL), and N,N-diisopropylethylamine (490 mg, 3.76 mmol) was added. The mixture was stirred at 50°C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The mixture was then extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (100 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 0 / 1, v / v) to afford compound 38-2. ESI-MS calculated value: [M+H] + =409.1, measured value 409.2.

[0457] Step 2

[0458] 38-2 (470 mg, 1.15 mmol) was dissolved in toluene (10 mL), and cesium carbonate (940 mg, 2.88 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (110 mg, 0.17 mmol), and palladium acetate (26 mg, 0.11 mmol) were added sequentially. The reaction mixture was stirred at 110°C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated ammonium chloride solution (50 mL) was added, and extraction was performed with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to afford 38-3. ESI-MS calculated value: [M+H] + =373.2, measured value 373.2.

[0459] Step 3

[0460] 38-3 (35 mg, 0.09 mmol) and 1-5 (39 mg, 0.14 mmol) were dissolved in dioxane (10 mL) and water (3 mL). Potassium carbonate (39 mg, 0.28 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (8 mg, 0.01 mmol) were added sequentially. The reaction mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to afford 38-4. ESI-MS calculated value: [M+H] + =571.3, measured value 571.3.

[0461] Step 4

[0462] Dissolve 38-4 (25 mg, 0.04 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 1 hour. After the reaction, concentrate under reduced pressure to obtain a crude product containing 38-5, which was used directly in the next reaction. ESI-MS calculated value [M+H] + =413.2, measured value 413.3.

[0463] Step 5

[0464] 38-5 (18 mg, 0.04 mmol) was dissolved in ethanol (5 mL), and acetaldehyde (5.0 mol / L tetrahydrofuran solution, 0.02 mL, 0.01 mmol), acetic acid (0.1 mL), and sodium triacetoxyborohydride (28 mg, 0.13 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, 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-0.05% ammonia monohydrate, gradient: 44-54%, retention time: 10 min) to afford 38. 1 H NMR (400 MHz, MeOD-d4): δ 7.06 (s, 1H), 6.99 (s, 1H), 6.80 (s, 1H), 5.37-5.25 (m, 1H), 5.06-4.96 (m, 1H), 4.41-4.32 (m, 2H), 3.72-3.53 (m, 2H), 3.26-3.16 (m, 1H), 3.15-3.09 (m, 1H), 2.57 (q, J = 7.2 Hz, 2H), 2.49-2.39 (m, 1H), 2.26-2.15 (m, 5H), 2.13-2.00 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =441.2, measured value 441.2.

[0465] Example 39

[0466] Synthesis route:

[0467] first step

[0468] Dissolve 39-1 (1.0 g, 6.48 mmol) and 3-1 (1.36 g, 6.48 mmol) in acetonitrile (20 mL), add N,N-diisopropylethylamine (2.15 mL, 12.96 mmol), and stir at 70°C for 16 hours. After the reaction, concentrate under reduced pressure to obtain a crude product containing 39-2, which is used directly in the next reaction. ESI-MS theoretical calculated value [M+H] + =237.2, measured value 237.0.

[0469] Step 2

[0470] 39-2 (1.53 g, 6.48 mmol) and 3-3 (640 mg, 4.23 mmol) were dissolved in acetonitrile (20 mL), and N,N-diisopropylethylamine (1.40 mL, 8.46 mmol) was added. The mixture was stirred at 25°C for 16 hours. After the reaction, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to obtain 39-3. ESI-MS calculated value [M+H] + =351.2, measured value 351.0.

[0471] Step 3

[0472] 39-3 (300 mg, 0.86 mmol) was dissolved in toluene (10 mL), heated to 130°C, and stirred for 24 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 39-4. 1 H NMR (400 MHz, DMSO-d6): δ7.45 (s, 1H), 4.66-4.55 (m, 2H), 4.44-4.29 (m, 1H), 3.81-3.72 (m, 2H), 3.58-3.47 (m, 2H), 2.95-2.85 (m, 1H), 2.74-2.64 (m, 1H), 2.49-2.39 (m, 1H), 2.37-2.27 (m, 1H), 1.78-1.68 (m, 2H), 1.54-1.42 (m, 2H), 1.02 (s, 3H), 0.49-0.42 (m, 2H), 0.38-0.22 (m, 2H). ESI-MS calculated value [M+H] + =323.2, measured value 323.0.

[0473] Step 4

[0474] 39-4 (86 mg, 0.27 mmol), 5-8 (163 mg, 0.54 mmol), potassium carbonate (149 mg, 1.08 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (13 mg, 0.03 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (23 mg, 0.03 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), heated to 100 ° C under nitrogen protection and stirred for 2 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (80 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: 24-34%, retention time: 6 min) to obtain 39. 1 H NMR (400MHz, DMSO-d6): δ10.16(br,1H),7.27(s,1H),7.12(s,1H),7.07(s,1H),4.66-4.55(m ,2H),4.54-4.45(m,1H),3.84-3.74(m,2H),3.58-3.48(m,2H),3.04-2.94(m,1H),2.79-2.69 (m, 1H), 2.52-2.42 (m, 1H), 2.41-2.34 (m, 1H), 2.12 (s, 3H), 1.90-1.80 (m, 1H), 1.78-1.68 (m, 1H), 1.61-1.41 (m, 2H), 1.06 (s, 3H), 0.55-0.45 (m, 2H), 0.37-0.30 (m, 2H). ESI-MS calculated value [M+H] + =463.2, measured value 463.5.

[0475] Example 40

[0476] Synthesis route:

[0477] first step

[0478] 16-3 (1.5 g, 4.07 mmol) was dissolved in dichloromethane (20 mL), cooled to 0°C, and Dess-Martin periodinane (1.90 g, 4.48 mmol) was added. The mixture was stirred at 25°C for 1 hour. After the reaction, saturated aqueous sodium bicarbonate (150 mL) was slowly added dropwise, and the mixture was extracted with ethyl acetate (100 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, 1 / 1, v / v) to afford 40-1. 1 H NMR (400MHz, DMSO-d6): δ7.63(s,1H),4.82-4.75(m,1H),4.07-3.86(m,2H),3.72-3.72(m,2H),3.03- 2.90(m,1H),2.82-2.64(m,3H),1.89-1.79(m,2H),1.78-1.70(m,1H),1.60-1.45(m,1H),1.40(s,9H).

[0479] Step 2

[0480] Dissolve 40-1 (1.1 g, 3.0 mmol) in tetrahydrofuran (15 mL), cool to 0°C, and slowly add methylmagnesium bromide (1.0 mol / L tetrahydrofuran solution, 5.4 mL, 5.54 mmol) dropwise under nitrogen. Stirring is continued at 0°C for 3 hours. After completion of the reaction, saturated ammonium chloride solution (20 mL) is added dropwise to quench the reaction. Extraction is then performed with ethyl acetate (20 mL x 3). The organic phases are combined, washed with saturated sodium chloride solution (50 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 afford 40-2. 1 H NMR (400 MHz, DMSO-d6): δ7.37 (s, 1H), 5.58-5.48 (m, 1H), 4.68-4.57 (m, 1H), 3.96-3.86 (m, 2H), 3.54-3.39 (m, 1H), 3.32-3.22 (m, 1H), 2.97-2.83 (m, 1H), 2.80-2.65 (m, 1H), 1.89-1.71 (m, 5H), 1.40-1.35 (m, 13H). ESI-MS calculated value [M+H] + =383.2, measured value 383.0.

[0481] Step 3

[0482] 40-2 (550 mg, 1.44 mmol), 1-5 (778 mg, 2.16 mmol), sodium carbonate (460 mg, 4.32 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (69 mg, 0.14 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (122 mg, 0.14 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), heated to 100 ° C under nitrogen protection and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and 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, 1 / 1, v / v) to obtain 40-3. 1 H NMR (400 MHz, DMSO-d6) δ 7.40-7.26 (m, 3H), 5.43-5.33 (m, 1H), 5.26-5.20 (m, 2H), 4.88-4.78 (m, 1H), 4.11-3.86 (m, 2H), 3.62-3.43 (m, 3H), 3.43-3.33 (m, 1H), 2.99-2.80 (m, 1H), 2.79-2.60 (m, 1H), 2.15 (s, 3H), 1.95-1.68 (m, 5H), 1.60-1.31 (m, 13H), 1.07 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =581.3, measured value 581.0.

[0483] Step 4

[0484] Dissolve 40-3 (200 mg, 0.34 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1.5 mL), and stir at room temperature for 16 hours. After the reaction, concentrate under reduced pressure to obtain a crude product containing 40-4, which was used directly in the next reaction. ESI-MS calculated value [M+H] + =423.2, measured value 423.0.

[0485] Step 5

[0486] 40-4 (150 mg, 0.36 mmol) was dissolved in methanol (5 mL), and acetaldehyde (5.0 mol / L tetrahydrofuran solution, 0.36 mL, 1.80 mmol) and sodium triacetoxyborohydride (229 mg, 1.08 mmol) were added sequentially. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, 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-0.05% ammonia monohydrate, gradient: 38-48%, retention time: 7 min) to obtain 40. 1 H NMR (400MHz, DMSO-d6): δ10.16(br,1H),7.31(s,1H),7.11(s,1H),7.05(s,1H),5. 42-5.32(m,1H),5.04-4.89(m,1H),3.57-3.41(m,1H),3.40-3.33(m,1H),2.93-2. 83 (m, 2H), 2.36 (q, J = 7.2 Hz, 2H), 2.15 (s, 3H), 2.10-2.00 (m, 1H), 1.89-1.71 (m, 5H), 1.68-1.58 (m, 2H), 1.42-1.32 (m, 3H), 1.01 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =451.2, measured value 451.0.

[0487] Examples 41 and 42

[0488] Synthesis route:

[0489] first step

[0490] 40 (65 mg, 0.14 mmol) was purified by supercritical fluid chromatography (Waters SFC 150, IE, 250*30mm, 10μm; mobile phase: supercritical CO2-methanol solution containing 0.1% 7mol / L ammonia methanol, gradient: 30%-30%, flow rate: 150ml / min) to separate and purify compound 41 (elution time: 4.6-5.8min) and compound 42 (elution time: 6.9-10.4min).

[0491] Compound 41: 1H NMR (400 MHz, DMSO-d6): δ 10.17 (br, 1H), 7.30 (s, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 5.36 (s, 1H), 5.05-4.95 (m, 1H), 3.59-3.47 (m, 1H), 3.33-3.23 (m, 1H), 2.93-2.82 (m, 2H), 2.42-2.29 (m, 2H), 2.15 (s, 3H), 2.12-2.02 (m, 1H), 1.90-1.70 (m, 5H), 1.67-1.57 (m, 2H), 1.38 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =451.2, measured value 451.0.

[0492] Compound 42: 1 H NMR (400 MHz, DMSO-d6): δ 10.17 (br, 1H), 7.31 (s, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 5.38 (s, 1H), 5.03-4.93 (m, 1H), 3.52-3.41 (m, 1H), 3.42-3.32 (m, 1H), 2.96-2.81 (m, 2H), 2.37 (q, J = 7.2 Hz, 2H), 2.15 (s, 3H), 2.09-2.00 (m, 1H), 1.86-1.72 (m, 5H), 1.70-1.54 (m, 2H), 1.36 (s, 3H), 1.01 (t, J = 7.2 Hz, 3H). ESI-MS calculated value [M+H] + =451.2, measured value 451.0.

[0493] Example 43

[0494] Synthesis route:

[0495] first step

[0496] 17-1 (200 mg, 0.74 mmol) was dissolved in 1,2-dichloroethane (5 mL), and 43-1 (266 mg, 3.7 mmol) and sodium triacetoxyborohydride (470 mg, 2.22 mmol) were added sequentially. The mixture was stirred at 25°C for 12 hours. After the reaction, the pH was adjusted to greater than 8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to afford 43-2. ​​ESI-MS calculated value [M+H] +=325.2, measured value 325.1.

[0497] Step 2

[0498] 43-2 (220 mg, 0.68 mmol), 5-8 (308 mg, 1.02 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (32 mg, 0.07 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (57 mg, 0.07 mmol), and potassium carbonate (470 mg, 3.40 mmol) were added to 1,4-dioxane (10 mL) and 2 mL. 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) and extracted with ethyl acetate (20 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: XBridge C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.05% monohydrate aqueous ammonia solution, gradient: 38-48%; retention time: 9 min) to obtain 43. 1 H NMR (400 MHz, DMSO-d6): δ 10.16 (br s, 1H), 7.29 (s, 1H), 7.13 (s, 1H), 7.06 (s, 1H), 4.67-4.58 (m, 3H), 4.57-4.50 (m, 2H), 4.49-4.40 (m, 2H), 3.80-3.72 (m, 2H), 3.52-3.40 (m, 3H), 2.95-2.85 (m, 1H), 2.71-2.61 (m, 1H), 2.13 (s, 3H), 1.98-1.88 (m, 2H), 1.80-1.70 (m, 2H), 1.65-1.50 (m, 2H). ESI-MS calculated value [M+H] + =465.2, measured value 465.9.

[0499] Activity Test 1: Evaluation of the compound's ability to inhibit IL-1β secretion from THP-1 cells

[0500] Purpose of the experiment:

[0501] The ELISA kit was used to detect the secretion of IL-1β to evaluate the activity of the compound in inhibiting the secretion of IL-1β by THP-1 cells.

[0502] Experimental Materials:

[0503] Experimental equipment:

[0504] Cell treatment:

[0505] 1. This experiment used THP-1 cells.

[0506] 2. Cell Treatment: THP-1 cells were cultured in 1640 medium supplemented with 10% heat-inactivated fetal bovine serum at 37°C and 5% CO2. The cell suspension was gently shaken and transferred to a centrifuge tube for counting. The required volume was removed and added to fresh subculture medium.

[0507] Experimental operation:

[0508] 1. Add 40 μL of poly-lysine diluted with sterile water (concentration after dilution is 55 μM) to a 96-well plate and incubate at 37°C and 5% CO2 for 30 minutes. Wash twice with 100 μL of sterile water.

[0509] 2. Add 50 ng / mL of PMA (phorbol 12-myristate 13-acetate) to the THP-1 cell suspension and seed 50,000 cells per well in a 96-well plate prepared in step 1 at 37°C and 5% CO2 for 24 hours.

[0510] 3. Remove the culture medium from the 96-well plate and wash the cells once with PBS preheated at 37°C.

[0511] 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.

[0512] 5. Add 5 μL of compounds of different concentrations (DMSO concentration is uniformly 1‰, the final concentration of the compound starts at 300 nM, diluted 3-fold, for a total of 9 concentrations, namely 300 nM, 100 nM, 33 nM, 11 nM, 3.7 nM, 1.2 nM, 0.4 nM, 0.13 nM, 0.05 nM), and continue incubating the cells at 37°C and 5% CO2 for 30 minutes.

[0513] 6. Add 5 μL of diluted Nigericin to a working concentration of 5 μg / mL and continue incubating the cells at 37°C and 5% CO2 for 1 hour.

[0514] 7. Collect the cell supernatant, store it at -80℃, and use ELISA kit to detect the secretion of IL-1β.

[0515] 8. Calculate the IL-1β concentration based on the standard curve, calculate the inhibition rate, fit the compound action curve, and calculate the IC 50 .

[0516] Experimental results:

[0517] Experimental conclusion: The compound of the present invention can effectively inhibit the secretion of IL-1β in THP-1 cells.

[0518] Activity test 2: Evaluation of the pharmacokinetic properties of the compound in mice

[0519] Purpose of the experiment:

[0520] The pharmacokinetic properties of the compounds obtained in the examples of the present invention were evaluated in CD-1 mice.

[0521] Experimental operation:

[0522] The candidate compound was formulated into a clear solution or suspension in a designated solvent and administered intravenously or orally to three mice. Both intravenous and oral administration were performed in 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 over a 24-hour period into commercially available EDTA2K anticoagulant tubes (ethylenediaminetetraacetic acid dipotassium anticoagulant tubes). The supernatant was centrifuged to obtain the upper plasma layer. Protein was precipitated by the addition of acetonitrile containing an internal standard. The supernatant was centrifuged, an equal volume of water was added, and the supernatant was centrifuged again. The supernatant was sampled and injected for quantitative analysis of plasma concentrations and calculation of pharmacokinetic parameters using LCMS / MS.

[0523] Experimental methods:

[0524] Experimental results:

[0525] Experimental conclusion:

[0526] The test samples were prepared according to the corresponding examples, and the results showed that the compounds of the present application have good pharmacokinetic properties.

[0527] Activity test 3: Bidirectional permeability test in MDR1-MDCK II cells

[0528] Cell culture:

[0529] MDR1-MDCK II cells obtained from the Netherlands Cancer Institute will be seeded onto PET membranes in 96-well inserts and cultured for 4-7 days before use in experiments.

[0530] Verification of monolayer cell integrity:

[0531] Verify the integrity of the cell monolayer by performing a Lucifer Yellow exclusion assay.

[0532] Monolayer cell quality verification:

[0533] Validation was performed in duplicate wells by measuring the unidirectional (A→B) permeability of nadolol (low permeability marker), metoprolol (high permeability marker), and the bidirectional permeability of digoxigenin (P-glycoprotein substrate marker).

[0534] Standard test conditions:

[0535] Buffer: HBSS (Hank's balanced salt solution) containing 10 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), pH 7.40 ± 0.05;

[0536] The compound was first dissolved in DMSO solution to 1 mM, then diluted to the test concentration with buffer, and then added to the A side of the cells. Test compound concentration: 2.0 μM;

[0537] Number of repetitions: n = 2;

[0538] Direction: including bidirectional transportation from A to B and from B to A;

[0539] Incubation conditions: 37±1°C, 5% CO2, relative saturated humidity.

[0540] T0 solution preparation:

[0541] 50 μL of the dosing solution (2.0 μM solution of the test compound) was mixed with 100 μL of buffer and 250 μL of a stop solution containing an appropriate internal standard (IS) (usually 250 nM tolbutamide and 100 nM labetalol in methanol or acetonitrile) to serve as the T0 sample.

[0542] Sample processing:

[0543] Add 75 μL (A→B direction) or 250 μL (B→A direction) of dosing solution (2.0 μM solution of the test compound) to the donor well, and add 250 μL (A→B direction) or 75 μL (B→A direction) of blank incubation solution (buffer) to the receptor well; after incubation for 2.5 hours, remove appropriate volumes of solution from the donor well and receptor well as the dosing end sample and the receiving end sample, respectively, and immediately mix with the buffer and stop solution. The sample collection method is shown in the table below:

[0544] Sample analysis:

[0545] All samples (including T0 samples, dosing samples, receiving samples, and blank samples) will be analyzed using LC-MS / MS. The concentration of the test compound will be expressed as the peak area ratio of the analyte to the IS, without the need for a standard curve.

[0546] Experimental results:

[0547] Experimental conclusion:

[0548] The test samples were prepared according to the corresponding examples. The results showed that the compounds of the present application have the characteristics of high permeability and low efflux.

[0549] Activity Test 4: Evaluation of the compound's ability to inhibit IL-1β secretion from PBMCs

[0550] Experimental plan:

[0551] 1. Add 9 mL of pre-warmed complete culture medium (RPMI 1640 + 10% FBS + 1% phosphate buffered saline) to a 15 mL centrifuge tube. Thaw the frozen human PBMC vial in a 37°C water bath. Gently pipette the thawed PBMC suspension into the previously prepared centrifuge tube. Centrifuge at 400 g for 10 minutes at room temperature.

[0552] 2. Aspirate and discard the supernatant, add fresh complete medium to resuspend the PBMC pellet and count the cells, then adjust the cell density to 1×10 6 cells / mL.

[0553] 3. Add 100 μL of PBMC suspension to each well of a 96-well flat-bottom plate and incubate overnight in a 37°C, 5% CO2 incubator.

[0554] 4. The next day, 2×100 ng / mL LPS (lipopolysaccharide) solution was prepared in serum-free RPMI1640 medium, 100 μL LPS was added to each well (final concentration was 100 ng / mL), and stimulation was performed for three hours.

[0555] 5. Three hours later, the experimental plate was centrifuged at 350 g for 5 minutes, the supernatant was discarded, and 100 μL of serum-free RPMI1640 medium and 50 μL of 4× test compound were added to each well and treated for 30 minutes.

[0556] 6. Half an hour later, 50 μL of 4×10 μM Nigericin was added to each well for stimulation for 90 minutes.

[0557] 7. Collect the cell culture supernatant by centrifugation and use ELISA kit to detect the secretion of IL-1β.

[0558] 8. Calculate the IL-1β concentration based on the standard curve, calculate the inhibition rate, fit the compound action curve, and calculate the IC 50 .

[0559] Experimental results:

[0560] Experimental conclusion: The compound of the present invention can effectively inhibit the secretion of IL-1β in PBMC cells.

[0561] Activity test 5: Evaluation of the compound's efficacy in an inflammation model induced by intraperitoneal injection of LPS and ATP in mice

[0562] Experimental purpose: To evaluate the effect of the compound of the present invention in an inflammation model induced by intraperitoneal injection of LPS (lipopolysaccharide) in mice.

[0563] Experimental Materials:

[0564] Experimental operation:

[0565] Male C57BL / 6 mice were randomly divided into 5 groups according to body weight before administration, with 6 mice in each group. Group 1 was the vehicle control group, Group 2 was the model group, and Groups 3 to 5 were the test sample administration groups (Group 3: the test sample was prepared by Example 2; Group 4: the test sample was prepared by Example 6; Group 5: the test sample was prepared by Example 17). The animals in Group 1 were first orally gavaged with the test vehicle (aqueous solution containing 10% sulfobutyl-β-cyclodextrin), and then intraperitoneally injected with phosphate buffered saline one hour later. After another two hours, phosphate buffered saline was injected, and 300 μL of whole blood was collected from the inner canthus half an hour later; the animals in Group 2 were first orally gavaged with the test vehicle (aqueous solution containing 10% sulfobutyl-β-cyclodextrin), and then intraperitoneally injected with LPS (dissolved in phosphate buffered saline) at a dose of 5 mg / kg one hour later. After another two hours, 0.5 mL of LPS was injected. ATP (30 mM phosphate buffer) was administered, and 300 μL of whole blood was collected from the medial canthus half an hour later. Animals in Groups 3 to 5 were first orally gavaged with the test article (dissolved in an aqueous solution containing 10% sulfobutyl-β-cyclodextrin) at a dose of 5 mg / kg. One hour later, they were intraperitoneally injected with 5 mg / kg of LPS (dissolved in phosphate buffer). Two hours later, 0.5 mL of ATP (30 mM phosphate buffer) was injected, and 300 μL of whole blood was collected from the medial canthus half an hour later. After the collected whole blood was allowed to naturally separate into serum, it was centrifuged at 7500 rpm for 5 minutes, and the serum was aspirated and frozen at -80°C. Serum IL-1β concentrations were measured using a mouse IL-1β enzyme-linked immunosorbent assay (ELISA) kit.

[0566] Experimental results:

[0567] The experimental results are shown in Figure 1. One-way ANOVA was used for comparison and Dunnett's method was used for test: ### indicates that there is a significant difference between the vehicle control group and the model group (p < 0.001), *** indicates that there is a significant difference between the model group and the corresponding test article group (p < 0.001)

[0568] Experimental conclusion:

[0569] The compound of the present invention can significantly reduce the IL-1β concentration in the serum of a mouse inflammation model, showing a good anti-inflammatory effect.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: in, R 1 For one or more R 4 Substituted naphthyl, one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl; R 4 and R 5 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl, substituted by one or more R c Substituted C1-C6 alkyl, one or more R d’ Substituted C1-C6 alkoxy or one or more R d substituted 5-6 membered heteroaryl; R c are independently deuterium, halogen or hydroxyl; R d’ are independently halogen; R d are independently halogen or C1-C6 alkyl; Or, two adjacent R 4 The atoms to which they are attached together form a C3-C7 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C3-C7 ... e Substituted C3-C7 cycloalkenyl or one or more R f substituted 3-7 membered heterocycloalkenyl; Or, two adjacent R 5 The atoms to which they are attached together form a C3-C7 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C3-C7 ... e Substituted C3-C7 cycloalkenyl or one or more R f substituted 3-7 membered heterocycloalkenyl; R e and R f Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl, substituted by one or more R c Substituted C1-C6 alkyl, one or more R d’ Substituted C1-C6 alkoxy or one or more R d substituted 5-6 membered heteroaryl; R 2 is hydrogen, CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, 2-1 Substituted C1-C6 alkoxy or one or more R 2-2 Substituted C1-C6 alkyl; R 2-1 and R 2-2 are each independently halogen; A 1 、A 2 、A 3 and A 4 Each is independently a connecting bond, CR a R b NR c , O or S; A 1 、A 2 、A 3 and A 4 The number of connecting bonds in is 0, 1, 2 or 3; R a 、R b and R c Each independently represents hydrogen, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl or is replaced by one or more R a-1 Substituted C1-C6 alkyl or R a and R b Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group; R a-1 are independently halogen; R 3 is a C3-C7 monocyclic cycloalkyl, a C5-C 12 Bicyclic cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocycloalkyl, one or more R 3-1 substituted 3-7 membered monocyclic heterocycloalkyl, substituted by one or more R 3-1 substituted 5-12 membered bicyclic heterocycloalkyl, substituted by one or more R 3-2 Substituted C1-C6 alkyl, one or more R 3-3 Substituted C3-C7 monocyclic cycloalkyl or one or more R 3-3 Substituted C5-C 12 bicyclic cycloalkyl; R 3-1 and R 3-3 Each is independently hydroxy, halogen, oxo (=O), -COOH, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, 3-1-1 Substituted C1-C6 alkyl, one or more R 3-1-2 Substituted C3-C7 cycloalkyl or one or more R 3-1-3 substituted 3-7 membered heterocycloalkyl; R 3-1-1 are independently OH, halogen, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl; R 3-1-2 and R 3-1-3 Each is independently a C1-C6 alkyl group; R 3-2 is independently a 3-7 membered heterocycloalkyl group or is replaced by one or more R 3-2-1 substituted 3-7 membered heterocycloalkyl; R 3-2-1 are independently C1-C6 alkyl; In the above groups, each "5-10 membered heteroaryl group" is independently a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S; the number of heteroatoms is 1, 2 or 3; Each "3-7 membered heterocycloalkyl" is independently a 3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; Each "3-7 monocyclic heterocycloalkyl" is independently a 3-7 membered monocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; Each "5-12 membered bicyclic heterocycloalkyl" is independently a 5-12 membered bicyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; Each "5-6 membered heteroaryl" is independently a 5-6 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; Each "3- to 7-membered heterocycloalkenyl group" is independently a 3- to 7-membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3.

2. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: R 1 For one or more R 4 Substituted naphthyl, one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl; R 4 and R 5 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl, substituted by one or more R c Substituted C1-C6 alkyl, one or more R d’ Substituted C1-C6 alkoxy or one or more R d substituted 5-6 membered heteroaryl; R c are independently deuterium, halogen or hydroxyl; R d’ are independently halogen; R d are independently halogen or C1-C6 alkyl; Or, two adjacent R 4 The atoms to which they are attached together form a C3-C7 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C3-C7 ... e Substituted C3-C7 cycloalkenyl or one or more R f substituted 3-7 membered heterocycloalkenyl; Or, two adjacent R 5 The atoms to which they are attached together form a C3-C7 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C3-C7 ... e Substituted C3-C7 cycloalkenyl or one or more R f substituted 3-7 membered heterocycloalkenyl; R e and R f Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl, substituted by one or more R c Substituted C1-C6 alkyl, one or more R d’ Substituted C1-C6 alkoxy or one or more R d substituted 5-6 membered heteroaryl; R 2 is hydrogen, CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, 2-1 Substituted C1-C6 alkoxy or one or more R 2-2 Substituted C1-C6 alkyl; R 2-1 and R 2-2 are each independently halogen; A 1 、A 2 、A 3 and A 4 Each is independently a connecting bond, CR a R b NR c , O or S; A 1 、A 2 、A 3 and A 4 The number of connecting bonds in is 0, 1, 2 or 3; R a 、R b and R c Each independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or substituted by one or more R a-1 Substituted C1-C6 alkyl or R a and R b Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group; R a-1 are independently halogen; R 3 is a C3-C7 monocyclic cycloalkyl, a C5-C 12 Bicyclic cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocycloalkyl, one or more R 3-1 substituted 3-7 membered monocyclic heterocycloalkyl, substituted by one or more R 3-1 substituted 5-12 membered bicyclic heterocycloalkyl, substituted by one or more R 3-2 Substituted C1-C6 alkyl, one or more R 3-3 Substituted C3-C7 monocyclic cycloalkyl or one or more R 3-3 Substituted C5-C 12 bicyclic cycloalkyl; R 3-1 and R 3-3 Each is independently hydroxy, halogen, oxo (=O), -COOH, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl or substituted by one or more R 3-1-1 Substituted C1-C6 alkyl; R 3-1-1 are independently OH, halogen, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl; R 3-2 is independently a 3-7 membered heterocycloalkyl group or is replaced by one or more R 3-2-1 substituted 3-7 membered heterocycloalkyl; R 3-2-1 are independently C1-C6 alkyl; In the above groups, each "5-10 membered heteroaryl group" is independently a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S; the number of heteroatoms is 1, 2 or 3; Each "3-7 membered heterocycloalkyl" is independently a 3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; Each "3-7 monocyclic heterocycloalkyl" is independently a 3-7 membered monocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; Each "5-12 membered bicyclic heterocycloalkyl" is independently a 5-12 membered bicyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; Each "5-6 membered heteroaryl" is independently a 5-6 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; Each "3- to 7-membered heterocycloalkenyl group" is independently a 3- to 7-membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3.

3. The compound of formula (I) according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein: It meets one or more of the following conditions; (1) Each "5-10 membered heteroaryl" is independently a 8-10 membered bicyclic heteroaryl group having one heteroatom selected from N, O and S, for example (2) each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; for example, methyl, ethyl or isopropyl; (3) Each "halogen" is independently fluorine, chlorine, bromine or iodine; for example, fluorine or chlorine; (4) each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; for example, methoxy; (5) Each "C3-C6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; for example, cyclopropyl, cyclobutyl or cyclohexyl; (6) Each "5-6 membered heteroaryl" is independently a 5-membered heteroaryl group in which the heteroatoms are S and N and the number of heteroatoms is 3; for example, (7) Each "C3-C7 cycloalkenyl" is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, for example, cyclopentenyl; (8) Each "3-7 membered heterocycloalkenyl" is independently a "4-6 membered heterocycloalkenyl" wherein the heteroatom is O and the number of heteroatoms is 1 or 2, for example, dihydrofuranyl; (9) Each "C3-C7 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (10) Each "3-7 membered heterocycloalkyl" is independently a 4-9 membered heterocycloalkyl group in which the heteroatom is O or N and the number of heteroatoms is 1 or 2, for example, oxetanyl or tetrahydropyranyl, and further for example, (11) Each "C3-C7 membered monocyclic cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, Among them, the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; for example, (12) Each "3-7 membered monocyclic heterocycloalkyl" is independently a "4-7 membered monocyclic heterocycloalkyl" wherein the heteroatom is N and / or O and the number of heteroatoms is 1 or 2, for example, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl; for example, Wherein, the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof, and X is O, NH or CH2; for example, (13) Each "5-12 membered bicyclic heterocycloalkyl" is independently an "8-10 membered bicyclic heterocycloalkyl" wherein the heteroatom is N and the number of heteroatoms is 1; for example, Among them, the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; for example, and (14) Each "C5-C 12 The bicyclic cycloalkyl groups are independently C5-C 12 Cycloalkyl, C5-C 12 Bridged cycloalkyl or C5-C 12 Spirocyclic cycloalkyl.

4. The compound of formula (I) according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein: It meets one or more of the following conditions; (1)R 1 For one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl; preferably substituted by one or more R 4 substituted phenyl; (2)R 4 and R 5 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, 5-6 membered heteroaryl, c Substituted C1-C6 alkyl or one or more R e substituted 5-6 membered heteroaryl; Or, two adjacent R 4 Together with the atoms to which they are attached, they form a C3-C7 cycloalkenyl or a 3-7 membered heterocycloalkenyl; Preferably, R 4 and R 5 Each independently represents hydrogen, hydroxy, C1-C6 alkyl or is replaced by one or more R c Substituted C1-C6 alkyl; (3)R c are independently halogen; (4)R e are independently C1-C6 alkyl; (5)R 2 is hydrogen, C1-C6 alkyl or 3-7 membered heterocycloalkyl; preferably hydrogen; (6)A 1 、A 2 、A 3 and A 4 The number of connecting bonds in is 0 or 1; preferably 1; (7)R a 、R b and R c Any of the following: Case 1: R a 、R b and R c are each independently H, hydroxyl or C1-C6 alkyl; or, R a and R b Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group; Case 2: R a 、R b and R c are each independently H or C1-C6 alkyl; or, R a and R b Together with the carbon atoms to which they are attached, they form a C3-C6 cycloalkyl group; (8)R 3 is a 5-12 membered bicyclic heterocycloalkyl group, 3-1 substituted 3-7 membered monocyclic heterocycloalkyl, 3-2 Substituted C1-C6 alkyl or one or more R 3-3 Substituted C3-C7 monocyclic cycloalkyl; preferably substituted by one or more R 3-1 substituted 3-7 membered monocyclic heterocycloalkyl; (9)R 3-1 and R 3-3 Each is independently hydroxy, halogen or C1-C6 alkyl; preferably C1-C6 alkyl; (10)R 3-2 Independently by one or more R 3-2-1 substituted 3-7 membered heterocycloalkyl; and (11)R 3-2-1 are independently C1-C6 alkyl.

5. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1)R 3-1 and R 3-3 Each independently represents a hydroxyl group, a halogen group, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a 3-7 membered heterocycloalkyl group, a 3-1-1 Substituted C1-C6 alkyl or one or more R 3-1-2 substituted C3-C7 cycloalkyl; (2)R 3-1-1 are independently C3-C7 cycloalkyl; (3)R 3-1-2 are independently C1-C6 alkyl.

6. The compound of formula (I) according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein: Any of the following situations: Case 1: for Among them, R a 、R b and R c The definition of is as described in any one of claims 1-5; for example For example, Preferred Case 2: for Among them, R a and R b The definition as described in any one of claims 1 to 5; Case 3: for Case 4: for Case 5: for Among them, R c The definition as described in any one of claims 1 to 5; Case 6: for Among them, R c The definition as described in any one of claims 1 to 5; Case 7: for Among them, R a and R b The definition as described in any one of claims 1 to 5; Case 8: for Among them, R a and R b The definition as described in any one of claims 1 to 5.

7. The compound of formula (I) according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein: It meets one or more of the following conditions; (1)R 1 for Preferably More preferably (2)R 2 is hydrogen, methyl or For example, hydrogen; (3)R 3 for (For example, ), R 3a and R 3b Together with the carbon atoms to which they are attached, they form a C3-C7 monocyclic cycloalkyl group, a C5-C 12 Bicyclic cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocycloalkyl, one or more R 3-1 substituted 3-7 membered monocyclic heterocycloalkyl, 3-1 substituted 5-12 membered bicyclic heterocycloalkyl, substituted by one or more R 3-3 Substituted C3-C7 monocyclic cycloalkyl or one or more R 3-3 Substituted C5-C 12 Bicyclic cycloalkyl, R 3c and R 3d Together with the carbon atoms to which they are attached, they form a 3-2-1 Substituted 3-7 membered heterocycloalkyl, wherein The configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof. 3-1 、R 3-3 and R 3-2-1 as defined in any one of claims 1 to 3; and (4) for Among them, R a 、R b and R c The definition as described in any one of claims 1 to 5; for example For example, 8. The compound of formula (I) according to claim 7, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: R 3 Any of the following situations: Case 1: R 3 for (For example, ), wherein the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-1 、R 3-3 and R 3-2-1 The definition as described in any one of claims 1 to 7; Case 2: R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-1 The definition as described in any one of claims 1 to 7; Case 3: R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-1 The definition as described in any one of claims 1 to 7; Case 4: R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-1 The definition as described in any one of claims 1 to 7; Case 5: R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-2-1 The definition as described in any one of claims 1 to 7; Case 6: R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-3 The definition as described in any one of claims 1 to 7; Case 7: R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-3 The definition as described in any one of claims 1 to 7; Case 8: R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-3 The definition as described in any one of claims 1 to 7; Case 9: R 3 for The carbon atoms marked with "*" are in R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-3 The definition as described in any one of claims 1 to 7.

9. The compound of formula (I) according to claim 8, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: R 3 for (For example, ), where m is 0 or 1; R 3-1 、R 3-3 and R 3-2-1 The definition as described in any one of claims 1 to 7.

10. The compound of formula (I) according to claim 9, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: R 3 for Preferably More preferably More preferably 11. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound represented by formula (I) is any one of the following compounds:

12. The compound of formula (I) according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) is not the following compound and its stereoisomers:

13. A pharmaceutical composition comprising a substance X and a pharmaceutically acceptable excipient, wherein the substance X is a compound of formula (I) according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

14. Use of the pharmaceutical composition according to claim 13 or the compound of formula (I) according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of an NLRP3 inhibitor.

15. Use of a compound of formula (I) according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13 in the preparation of a medicament for preventing and / or treating a disease associated with NLRP3; preferably, the disease associated with NLRP3 is a neurodegenerative disease; the neurodegenerative disease may be Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease.

16. Use of the compound of formula (I) according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13 in the preparation of a method for preventing and / or treating a disease, wherein the disease is a neurodegenerative disease; the neurodegenerative disease may be Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease.

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