Ring-fused compound and application thereof

Abstract

The invention discloses a ring-fused compound and application thereof. Specifically disclosed are a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof. The ring-fused compound provided by the invention has good inhibitory activity on NLRP3.

Description

Cyclic compounds and their applications

[0001] This application claims priority to Chinese Patent Application No. 2023112633752, filed on September 27, 2023, Chinese Patent Application No. 2023116045603, filed on November 28, 2023, Chinese Patent Application No. 2023118097068, filed on December 26, 2023, and Chinese Patent Application No. 2024101713160, filed on February 6, 2024. The entire text of the above-mentioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] The present invention relates to a cyclic compound and application 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 autoimmune diseases, neurodegenerative diseases, and various cardiovascular 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 promise for future applications.

[0005] Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the deficiency of the existing NLRP3 inhibitors and provide a novel cyclic compound and its application. The cyclic compound of the present invention has good inhibitory activity against NLRP3.

[0007] 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:

[0008] in,

[0009] for

[0010] express

[0011] X1, X5, X7 and X 11 Each independently

[0012] X2 and X3 are each independently -CH= or -N=;

[0013] X4 is independently -CH=, -N= or -CR x =;

[0014] R x For-OR x-3 、-CHR x-1 R x-2 , C1-C6 alkyl or one or more R x3 Substituted C1-C6 alkyl;

[0015] R x-3 -CHR x-1 R x-2 , C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, one or more R x1 Substituted C3-C6 cycloalkyl or one or more R x2 substituted 3-7 membered heterocycloalkyl;

[0016] R x-1 and R x-2 Together with the carbon atoms to which they are commonly attached, they form a C3-C6 cycloalkyl group, a 3-7 membered heterocycloalkyl group, a x1 Substituted C3-C6 cycloalkyl or one or more R x2 substituted 3-7 membered heterocycloalkyl;

[0017] R x1 and R x2 Each is independently a C1-C6 alkyl group;

[0018] R x3 are independently C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl;

[0019] X6, X8, X9, X 10 and X 12 Each independently represents -CH=, -N=, -O-, -S- or -NR 1 -, R 1 is H, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0020] L 1 and L2 The following conditions are met:

[0021] When L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 When the 8-10 membered heterocyclic alkyl group is substituted, L 2 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl;

[0022] Or, when L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 When the 5-10 membered heteroaryl group is substituted, L 2 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 substituted 8-10 membered heterocycloalkyl;

[0023] R 2 is C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, or one or more R 2-1 substituted 3-7 membered heterocycloalkyl, 2-2 Substituted C1-C6 alkyl or one or more R 2-3 substituted C3-C6 cycloalkyl;

[0024] R 2-1 and R 2-3 Each is independently hydroxy, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl or substituted by one or more R 2-1-1 Substituted C1-C6 alkyl;

[0025] R 2-1-1 are independently halogen, C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl;

[0026] R 2-2 is independently a 3-7 membered heterocycloalkyl group or is replaced by one or more R 2-2-1 substituted 3-7 membered heterocycloalkyl;

[0027] R 2-2-1 are independently C1-C6 alkyl;

[0028] R 3 are independently C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens;

[0029] R 4 and R 5Each 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, C1-C6 alkoxy substituted by one or more halogens or by one or more R d substituted 5-6 membered heteroaryl;

[0030] R c are independently deuterium, halogen or hydroxyl;

[0031] R d are independently C1-C6 alkyl;

[0032] Or, two adjacent R 4 Together with the atoms to which they are attached, they form a C3-C6 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C3-C6 ... e Substituted C3-C6 cycloalkenyl or one or more R f substituted 3-7 membered heterocycloalkenyl;

[0033] Or, two adjacent R 5 Together with the atoms to which they are attached, they form a C3-C6 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C3-C6 ... e Substituted C3-C6 cycloalkenyl or one or more R f substituted 3-7 membered heterocycloalkenyl;

[0034] 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, C1-C6 alkoxy substituted by one or more halogens or by one or more R d substituted 5-6 membered heteroaryl; each "8-10 membered heterocycloheteroalkyl" is independently 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 8-10 membered heterocycloheteroalkyl;

[0035] 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, and the number of heteroatoms is 1, 2 or 3;

[0036] 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;

[0037] 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;

[0038] Each "3-7 membered heterocycloalkenyl" is independently a 3-7 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;

[0039] The compound of formula (I) satisfies one, two, three, four or five of the following conditions:

[0040] I: for for

[0041] II: for for

[0042] X4 is -CH=, -N= or -CR x =, X6 is -O-, -S- or -NR 1 -;

[0043] L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 Substituted 5-10 membered heteroaryl, L 2 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 substituted 8-10 membered heterocycloalkyl;

[0044] III: for for

[0045] X4 is -CH=, -N= or -CR x =, X6 is -O-, -S- or -NR 1 -;

[0046] L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocyclic alkyl, L 2 For naphthyl, or by one or more R 5A substituted 5-10 membered monocyclic or bicyclic heteroaryl group, wherein each ring of the monocyclic or bicyclic heteroaryl group is aromatic, and R 4-1 and R 4-5 Each is independently hydrogen, halogen, 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, C1-C6 alkoxy substituted by one or more halogens or by one or more R d Substituted 5-6 membered heteroaryl, R 4-2 、R 4-3 and R 4-4 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, C1-C6 alkoxy substituted by one or more halogens or by one or more R d substituted 5-6 membered heteroaryl;

[0047] IV: X4 for -CR x =, R x For-OR x-3 、-CHR x-1 R x-2 or by one or more R x3 Substituted C1-C6 alkyl, R x-1 and R x-2 Together with the carbon atoms to which they are commonly attached, they form a C3-C6 cycloalkyl group, a 3-7 membered heterocycloalkyl group, a x1 Substituted C3-C6 cycloalkyl or one or more R x2 substituted 3-7 membered heterocycloalkyl;

[0048] V:L 2 for Among them, R 4-3 is a 5-6 membered heteroaryl group or is replaced by one or more R d Substituted 5-6 membered heteroaryl, R 4-1 、R 4-2 、R 4-4 and R 4-5 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, C1-C6 alkoxy substituted by one or more halogens or by one or more R d Substituted 5-6 membered heteroaryl, or "R 4-1 and R 4-2 ”, “R 4-2and R 4-3 "Together with the atoms to which they are connected, they form a C3-C6 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a e Substituted C3-C6 cycloalkenyl or one or more R f Substituted 3-7 membered heterocycloalkenyl.

[0049] 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:

[0050] in,

[0051] for

[0052] express

[0053] X1, X5, X7 and X 11 Each independently

[0054] X2 and X3 are each independently -CH= or -N=;

[0055] X4 is independently -CH=, -N= or -CR x =;

[0056] R x -CHR x-1 R x-2 , C1-C6 alkyl or one or more R x3 Substituted C1-C6 alkyl;

[0057] R x-1 and R x-2 Together with the carbon atoms to which they are commonly attached, they form a C3-C6 cycloalkyl group, a 3-7 membered heterocycloalkyl group, a x1 Substituted C3-C6 cycloalkyl or one or more R x2 substituted 3-7 membered heterocycloalkyl;

[0058] R x1 and R x2 Each is independently a C1-C6 alkyl group;

[0059] R x3 are independently C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl;

[0060] X6, X8, X9, X 10 and X 12Each independently represents -CH=, -N=, -O-, -S- or -NR 1 -, R 1 is H, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0061] L 1 and L 2 The following conditions are met:

[0062] When L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 When the 8-10 membered heterocyclic alkyl group is substituted, L 2 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl;

[0063] Or, when L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 When the 5-10 membered heteroaryl group is substituted, L 2 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 substituted 8-10 membered heterocycloalkyl;

[0064] R 2 is C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, or one or more R 2-1 substituted 3-7 membered heterocycloalkyl, 2-2 Substituted C1-C6 alkyl or one or more R 2-3 substituted C3-C6 cycloalkyl;

[0065] R 2-1 and R 2-3 Each is independently hydroxy, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl or substituted by one or more R 2-1-1 Substituted C1-C6 alkyl;

[0066] R 2-1-1 are independently halogen, C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl;

[0067] R 2-2 is independently a 3-7 membered heterocycloalkyl group or is replaced by one or more R 2-2-1 substituted 3-7 membered heterocycloalkyl;

[0068] R 2-2-1 are independently C1-C6 alkyl;

[0069] R 3 are independently C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens;

[0070] R 4 and R 5 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens;

[0071] R c are independently deuterium or halogen;

[0072] Each "8-10 membered cycloheterocycloalkyl" is independently an 8-10 membered cycloheterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0073] 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, and the number of heteroatoms is 1, 2 or 3;

[0074] 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;

[0075] The compound of formula (I) satisfies one, two, three or four of the following conditions:

[0076] I: for for

[0077] II: for for

[0078] X4 is -CH=, -N= or -CR x =, X6 is -O-, -S- or -NR 1 -;

[0079] L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 Substituted 5-10 membered heteroaryl, L 2 NHR 2, 8-10 membered heterocyclic alkyl or one or more R 3 substituted 8-10 membered heterocycloalkyl;

[0080] III: for for

[0081] X4 is -CH=, -N= or -CR x =, X6 is -O-, -S- or -NR 1 -;

[0082] L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocyclic alkyl, L 2 For naphthyl, or by one or more R 5 Substituted 5-10 membered heteroaryl, R 4-1 and R 4-5 Each is independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens, R 4-2 、R 4-3 and R 4-4 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens;

[0083] IV: X4 for -CR x =, R x -CHR x-1 R x-2 , R x-1 and R x-2 Together with the carbon atoms to which they are commonly attached, they form a C3-C6 cycloalkyl group, a 3-7 membered heterocycloalkyl group, a x1 Substituted C3-C6 cycloalkyl or one or more R x2 Substituted 3-7 membered heterocycloalkyl.

[0084] 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").

[0085] In one embodiment of the present invention,

[0086] for

[0087] express

[0088] X1, X5, X7 and X 11 Each independently

[0089] X2, X3 and X4 are each independently -CH= or -N=;

[0090] X6, X8, X9, X 10 and X 12 Each independently represents -CH=, -N=, -O-, -S- or -NR 1 -, R 1 is H, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0091] L 1 and L 2 The following conditions are met:

[0092] When L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 When the 8-10 membered heterocyclic alkyl group is substituted, L 2 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl;

[0093] Or, when L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 When the 5-10 membered heteroaryl group is substituted, L 2 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 substituted 8-10 membered heterocycloalkyl;

[0094] R 2 is a 3-7 membered heterocycloalkyl group, 2-1 substituted 3-7 membered heterocycloalkyl or one or more R 2-2 Substituted C1-C6 alkyl;

[0095] R 2-1is independently halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl or is replaced by one or more R 2-1-1 Substituted C1-C6 alkyl;

[0096] R 2-1-1 are independently halogen, C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl;

[0097] R 2-2 is independently a 3-7 membered heterocycloalkyl group or is replaced by one or more R 2-2-1 substituted 3-7 membered heterocycloalkyl;

[0098] R 2-2-1 are independently C1-C6 alkyl;

[0099] R 3 are independently C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens;

[0100] R 4 and R 5 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens;

[0101] R c are independently deuterium or halogen;

[0102] Each "8-10 membered cycloheterocycloalkyl" is independently an 8-10 membered cycloheterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0103] 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, and the number of heteroatoms is 1, 2 or 3;

[0104] 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;

[0105] The compound of formula (I) satisfies one, two or three of the following conditions:

[0106] I: for for

[0107] II: for for

[0108] X4 is -CH= or -N=, and X6 is -O-, -S- or -NR 1 -;

[0109] L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 Substituted 5-10 membered heteroaryl, L 2 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 substituted 8-10 membered heterocycloalkyl;

[0110] III: for for

[0111] X4 is -CH= or -N=, and X6 is -O-, -S- or -NR 1 -;

[0112] L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocyclic alkyl, L 2 For naphthyl, or by one or more R 5 Substituted 5-10 membered heteroaryl, R 4-1 and R 4-5 Each is independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens, R 4-2 、R 4-3 and R 4-4 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens.

[0113] In one embodiment of the present invention, each "C3-C6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0114] In one embodiment of the present invention, each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0115] In one embodiment of the present invention, each "8-10 membered heterocycloalkyl" is independently a 5-membered heterocycloalkyl, a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl, for example R a and R b Together with the N atom to which they are connected, a 5-membered and 5-membered heterocycloalkyl group, a 5-membered and 6-membered heterocycloalkyl group or a 6-membered and 6-membered heterocycloalkyl group is formed. wherein X is independently CH2, NH, O or S, and X' is independently CH2 or NH.

[0116] In one embodiment of the present invention, each "8-10 membered heterocycloalkyl" is independently

[0117] In one embodiment of the present invention, each "5-10 membered heteroaryl" is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, wherein each ring of the 8-10 membered bicyclic heteroaryl is aromatic; preferably, each "5-10 membered heteroaryl" is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, wherein the heteroatom is one or two selected from N, O and S, and the number of heteroatoms is 1, 2 or 3, wherein each ring of the 8-10 membered bicyclic heteroaryl is aromatic, such as pyridyl, indolyl or benzothienyl, and further such as

[0118] In one embodiment of the present invention, each "5-10 membered heteroaryl" is independently a 5-6 membered heteroaryl or an 8-10 membered bicyclic heteroaryl, such as pyridyl, further such as

[0119] In one embodiment of the present invention, each "3-7 membered heterocycloalkyl" is independently a 4-7 membered heterocycloalkyl, such as oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, tetrahydropyranyl or azepanyl, for example

[0120] In one embodiment of the present invention, each "3-7 membered heterocycloalkyl" is independently a 4-7 membered heterocycloalkyl, such as oxetane, tetrahydropyrrolyl, piperidinyl, tetrahydropyranyl or azepanyl, for example

[0121] In one embodiment of the present invention, each "halogen" is independently F, Cl, Br or I, such as F or Cl.

[0122] In one embodiment of the present invention, each "C3-C6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0123] In one embodiment of the present invention, each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.

[0124] In one embodiment of the present invention, each "C3-C6 cycloalkenyl" is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, for example, cyclopentenyl.

[0125] 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.

[0126] In one embodiment of the present invention, in condition 1, for

[0127] In one embodiment of the present invention, in condition II or III, for

[0128] In one embodiment of the present invention, in condition II or III, for For example

[0129] In one embodiment of the present invention, in condition II or III, for

[0130] In one embodiment of the present invention, in condition IV, for For example

[0131] In one embodiment of the present invention, in condition IV, for For example

[0132] In one embodiment of the present invention, in condition V, for For example

[0133] In one embodiment of the present invention, in condition I or II, L 1 for

[0134] In one embodiment of the present invention, in condition I or II, L 1 for

[0135] In one embodiment of the present invention, in condition I or II, L 1 for

[0136] In one embodiment of the present invention, in condition I or II, L 2 for

[0137] In one embodiment of the present invention, in condition I or II, L 2 for

[0138] In one embodiment of the present invention, in condition I, III or IV, L 1 for

[0139] In one embodiment of the present invention, in condition V, L 1 for

[0140] In one embodiment of the present invention, in condition I or III, L 1 for

[0141] In one embodiment of the present invention, in condition I or IV, L 2 for

[0142] In one embodiment of the present invention, in condition I or IV, L 2 for

[0143] In one embodiment of the present invention, in condition I or IV, L 2 for

[0144] In one embodiment of the present invention, in condition III, L 2 for

[0145] In one embodiment of the present invention, in condition III, L 2 for

[0146] In one embodiment of the present invention, in condition III, L 2 for

[0147] In one embodiment of the present invention, in condition V, L 2 for

[0148] In one embodiment of the present invention, the compound represented by formula (I) satisfies condition III, wherein:

[0149] for

[0150] L 1 for R 2-1 is a C1-C6 alkyl group (e.g., a methyl group or an ethyl group);

[0151] L 2 for R 5 is hydrogen or methyl.

[0152] In one embodiment of the present invention, the compound represented by formula (I) satisfies condition IV, wherein:

[0153] for

[0154] X4-CR x =, R x For-OR x-3or -CHR x-1 R x-2 ,

[0155] R x-3 is a 4-6 membered oxygen-containing heterocycloalkyl group, wherein the type of heteroatom is O and the number of heteroatoms is 1;

[0156] R x-1 and R x-2 Together with the carbon atom to which they are commonly attached, they form a 4-6 membered oxygen-containing heterocycloalkyl group or a 5-6 membered nitrogen-containing heterocycloalkyl group substituted with one or more methyl groups, wherein the type of heteroatom in the 4-6 membered oxygen-containing heterocycloalkyl group is O and the number of heteroatoms is 1; and the type of heteroatom in the 5-6 membered nitrogen-containing heterocycloalkyl group is N and the number of heteroatoms is 1;

[0157] L 1 for R 2-1 is a C1-C6 alkyl group (e.g., a methyl group or an ethyl group);

[0158] L 2 for

[0159] In one embodiment of the present invention, the compound represented by formula (I) satisfies condition IV, wherein:

[0160] for

[0161] X4-CR x =, R x -CHR x-1 R x-2 ;

[0162] R x-1 and R x-2 Together with the carbon atom to which they are commonly connected, they form a 4-6 membered oxygen-containing heterocycloalkyl group, wherein the type of heteroatom in the 4-6 membered oxygen-containing heterocycloalkyl group is O and the number of heteroatoms is 1; and the type of heteroatom in the 5-6 membered nitrogen-containing heterocycloalkyl group is N and the number of heteroatoms is 1;

[0163] L 2 for

[0164] In one embodiment of the present invention, the compound represented by formula (I) satisfies condition V, wherein:

[0165] for

[0166] L 1 for R 2-1 is a C1-C6 alkyl group (e.g., a methyl group or an ethyl group);

[0167] L 2 for

[0168] R 4-3 is a 5-6 membered heteroaryl group or is replaced by one or more R d substituted 5-6 membered heteroaryl;

[0169] R d are independently C1-C6 alkyl;

[0170] “R 4-1 and R 4-2 "Together with the atoms to which they are attached, they form a C3-C6 cycloalkenyl group.

[0171] In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0172] 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.

[0173] 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.

[0174] 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.

[0175] Preferably, the NLRP3-related disease is an autoimmune disease (such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-associated periodic syndrome or ulcerative colitis), a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease), a cardiovascular disease or chronic obstructive pulmonary disease, etc.

[0176] The present invention also provides a use of the above-mentioned pharmaceutical composition or the above-mentioned substance X in the preparation of a medicament for preventing and / or treating autoimmune diseases (such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-associated periodic syndrome, or ulcerative colitis), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease), cardiovascular disease, or chronic obstructive pulmonary disease.

[0177] 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 an autoimmune disease (such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-associated periodic syndrome, or ulcerative colitis), a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease), a cardiovascular disease, or chronic obstructive pulmonary disease.

[0178] 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 an autoimmune disease (such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-associated periodic syndrome, or ulcerative colitis), a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease), a cardiovascular disease, or chronic obstructive pulmonary disease.

[0179] 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.

[0180] 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.

[0181] Unless otherwise specified, the terms used in this invention have the following meanings:

[0182] 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.

[0183] 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.

[0184] 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 double bond.

[0185] The term "plurality" refers to 2, 3 or 4.

[0186] The term "halogen" refers to F, Cl, Br or I.

[0187] 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.

[0188] The term "alkoxy" refers to a group R X -O-, R X The same definition is given to the term "alkyl".

[0189] The term "heterocycloalkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 3-7 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).

[0190] The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-10 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), which is monocyclic or polycyclic, with two atoms and one bond shared between the rings, and (at least one or each ring) aromatic. 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 heteroatoms or a ring without heteroatoms; a heteroaryl group is attached to the rest of the molecule through a ring with aromatic properties.

[0191] The term "cycloalkyl" refers to a saturated cyclic group having a specified number of ring carbon atoms (e.g., C3-C6) and the ring atoms consisting only of carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0192] When any variable (such as R 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.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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 contained in pharmaceutical preparations, other than the active ingredient. 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).

[0197] 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.

[0198] 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.

[0199] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0200] The reagents and raw materials used in the present invention are commercially available.

[0201] The positive effects of the present invention are that the cyclopentadiene compounds of the present invention have good inhibitory activity against NLRP3 and can effectively inhibit the secretion of IL-1β in THP-1 cells. DETAILED DESCRIPTION

[0202] 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.

[0203] Example 1

[0204] Synthesis route:

[0205] first step

[0206] Compound 1-1 (1.00 g, 3.93 mmol) and compound 1-2 (0.74 g, 4.52 mmol) were dissolved in acetone (5 mL) and the reaction mixture was stirred at 60°C for 12 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with n-heptane and dried to obtain compound 1-3. 1 HNMR (400 MHz, DMSO-d6): δ 12.39 (s, 1H), 11.89 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.02-8.00 (m, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.58-7.54 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H). ESI-MS theoretical value: [M+H] + =417.92, measured value 418.0.

[0207] Step 2

[0208] Compound 1-3 (500 mg, 1.20 mmol) was dissolved in dioxane (20 mL), and potassium carbonate (332 mg, 2.40 mmol), L-proline (27.6 mg, 0.24 mmol), and cuprous iodide (22.8 mg, 0.12 mmol) were added sequentially. Under a nitrogen atmosphere, the reaction solution was stirred at 80°C for 6 hours. The reaction solution was cooled to room temperature, and water (30 mL) and saturated ammonium chloride solution (30 mL) were slowly added. The mixture was stirred at room temperature for one hour and filtered. The filter cake was washed sequentially with saturated ammonium chloride solution (20 mL x 2) and water (20 mL x 2). The filter cake was dried to obtain compound 1-4. 1H NMR (400 MHz, DMSO-d6): δ13.29 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.2 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H). ESI-MS calculated value: [M+H] + =290.01, measured value 290.0.

[0209] Step 3

[0210] Compound 1-4 (320 mg, 1.10 mmol) was dissolved in 70% sulfuric acid solution (10 mL), and the reaction mixture was stirred at 120°C for 4 hours. The reaction mixture was cooled to room temperature, and ice water (30 mL) was added dropwise. The pH was then adjusted to alkaline with 1 mol / L sodium hydroxide solution. The mixture was filtered, and the filter cake was washed sequentially with 1 mol / L sodium hydroxide solution (10 mL x 2), saturated ammonium chloride solution (20 mL), and water (20 mL x 2). After drying, compound 1-5 was obtained. 1 H NMR (400 MHz, DMSO-d6): δ 8.18 (s, 2H), 8.08 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H). ESI-MS calculated value: [M+H] + =185.98, measured value 186.0.

[0211] Step 4

[0212] Compound 1-5 (1.70 g, 9.16 mmol) was dissolved in acetonitrile (30 mL). Tert-butyl nitrite (1.42 g, 13.74 mmol) was slowly added at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, followed by the addition of copper bromide (2.46 g, 10.99 mmol). The reaction mixture was stirred at 25°C for 6 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to yield compound 1-6. 1 H NMR (400MHz, DMSO-d6): δ8.65 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H).

[0213] Step 5

[0214] Compound 1-6 (600 mg, 2.40 mmol) and compound 1-7 (746 mg, 2.52 mmol) were dissolved in dioxane (10 mL) and water (2 mL). Sodium carbonate (509 mg, 4.80 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (176 mg, 0.24 mmol) were added sequentially at room temperature. Under a nitrogen atmosphere, the reaction solution was stirred at 90°C for 4 hours. The reaction solution was cooled to room temperature, and water (50 mL) was added. The solution was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 1-8. 1 HNMR (400 MHz, DMSO-d6): δ8.71-8.62 (m, 2H), 7.77 (s, 1H), 7.63-7.56 (m, 4H), 7.43-7.38 (m, 3H), 5.61 (s, 2H). ESI-MS theoretical calculated value: [M+H] + =421.03, measured value 421.0.

[0215] Step 6

[0216] Compound 1-8 (80.0 mg, 0.19 mmol) and compound 1-9 (26 mg, 0.23 mmol) were dissolved in toluene (10 mL). Cesium carbonate (186 mg, 0.57 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (16.0 mg, 0.019 mmol) were added sequentially at room temperature. Under a nitrogen atmosphere, the reaction solution was stirred at 110°C for 12 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The solution was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain crude compound 1-10. ESI-MS theoretical calculated value: [M+H] + =499.17, measured value 499.2.

[0217] Step 7

[0218] Compound 1-10 (70.0 mg, 0.14 mmol) was dissolved in anhydrous ethanol (5 mL). Palladium on carbon (29.8 mg, 0.028 mmol, 10% purity) was added at room temperature. The reaction mixture was stirred at 25°C for 4 hours under a hydrogen atmosphere (15 psi). The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude target compound. The crude product was purified by high-performance liquid chromatography (Waters-XBundge-C18-10μm-19*250mm, mobile phase: acetonitrile-7.5 mmol / L aqueous ammonium bicarbonate solution and 0.04% aqueous ammonia, gradient: 55-65%, retention time: 17 min) to obtain compound 1. 1 H NMR (400MHz, CD3OD): δ8.11(d,J=8.0Hz,1H),8.02(d,J=8.8Hz,1H),7.26(s,1 H),7.18(d,J=8.4Hz,1H),6.67(d,J=8.8Hz,1H),4.20-4.18(m,1H),3.17-3.1 5(m,1H),2.80-2.78(m,1H),2.38(s,3H),2.26-2.24(m,1H),2.22-2.19(m,1H ),2.05-2.02(m,1H),1.86-1.84(m,1H),1.78-1.75(m,1H),1.47-1.43(m,1H). ESI-MS theoretical calculation value: [M+H] + =409.12, measured value 409.2.

[0219] Example 2

[0220] Synthesis route:

[0221] first step

[0222] Compound 2-1 (100 mg, 0.49 mmol) and compound 2-2 (92.6 mg, 0.49 mmol) were added to polyphosphoric acid (0.24 mL), and the reaction mixture was stirred at 130°C for 16 hours. The reaction mixture was cooled to room temperature, added to ice water (15 mL), neutralized with saturated sodium bicarbonate solution, and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium bicarbonate solution (20 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-0.01% formic acid solution, gradient: 20-70%, retention time: 15 min) to obtain compound 2-3. ESI-MS calculated value: [M+H] + =358.96, measured value 358.8.

[0223] Step 2

[0224] Compound 2-3 (12.0 mg, 0.033 mmol), compound 1-9 (5.65 mg, 0.050 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (2.77 mg, 0.0033 mmol) and cesium carbonate (53.8 mg, 0.17 mmol) were dissolved in 1,4-dioxane (0.5 mL) and the reaction solution was stirred at 110 ° C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, 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-0.1% formic acid aqueous solution, gradient: 20-70%, retention time: 15 min) to obtain the monoformate salt of compound 2. 1 H NMR (400 MHz, CD3OD): δ8.53 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.35-7.31 (m, 2H), 6.65 (d, J = 9.2 Hz, 1H), 4.23-4.17 (m, 1H), 3.51-3.45 (m, 1H), 3.18-3.10 (m, 1H), 2.72-2.62 (m, 5H), 2.10-1.99 (m, 2H), 1.89-1.84 (m, 1H), 1.61-1.55 (m, 1H). ESI-MS calculated value: [M+H] + =393.15, measured value 393.1.

[0225] Example 3

[0226] Synthesis route:

[0227] first step

[0228] 4-1 (2.0 g, 9.64 mmol) and 4-2 (2.78 g, 17.35 mmol) were added to N,N-dimethylformamide (10 mL) and stirred at 150°C for 4 hours. The reaction solution was cooled to 0°C, diluted with ice water (30 mL), acidified with concentrated hydrochloric acid, and the precipitated solid was filtered and dried to obtain 4-3. ESI-MS calculated value: [M+H] + =202.95, measured value 202.9.

[0229] Step 2

[0230] 4-3 (0.5 g, 2.47 mmol) and potassium carbonate (0.34 g, 2.47 mmol) were added to dry acetonitrile (5.0 mL), followed by iodomethane (0.35 g, 2.47 mmol) and stirred at room temperature for 2 hours. After the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product containing the target compound. Purification by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) afforded 4-4. ESI-MS calculated value: [M+H] + =216.97, measured value 216.9.

[0231] Step 3

[0232] Dissolve 4-4 (0.2 g, 0.92 mmol) in dichloromethane (2.0 mL), add 3-chloroperoxybenzoic acid (0.32 g, 1.84 mmol), and stir at room temperature for 4 hours. After the reaction is complete, concentrate under reduced pressure to obtain a crude product containing 4-5, which is used directly in the next step. ESI-MS theoretical calculated value: [M+H] + =248.96, measured value 248.9.

[0233] Step 4

[0234] Compounds 4-5 (0.3 g, 0.72 mmol) and 3-5 (0.14 g, 1.08 mmol) were added to dimethyl sulfoxide (2.0 mL), followed by triethylamine (0.36 g, 3.60 mmol). The mixture was stirred at 100°C for 1 hour. After the reaction, the mixture was concentrated under reduced pressure and purified by HPLC (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-10 mmol / L 0.1% formic acid aqueous solution, gradient: 10-50%, retention time: 16 min) to afford compound 4-6. ESI-MS calculated value: [M+H] + =297.10, measured value 297.0.

[0235] Step 5

[0236] 4-6 (0.15 g, 0.51 mmol) and 3-7 (0.16 g, 0.77 mmol) were added to 1,4-dioxane (1.0 mL) along with (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (43 mg, 0.05 mmol). Cesium carbonate (0.50 g, 1.53 mmol) and water (0.2 mL) were then added. The mixture was heated to 100°C and stirred for 1 hour. After the reaction, the reaction mixture was filtered and the filtrate was directly purified by HPLC (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-10 mmol / L 0.1% formic acid in water, gradient: 10-50%, retention time: 17 min) to afford 4. 1 H NMR (400 MHz, CD3OD): δ 8.17 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.60-7.51 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 4.33-4.30 (m, 1H), 3.88-3.79 (m, 1H), 3.53-3.48 (m, 1H), 3.20 (q, J = 7.2 Hz, 2H), 3.04-2.94 (m, 2H), 2.41 (s, 3H), 2.24-2.06 (m, 2H), 1.99-1.84 (m, 1H), 1.78-1.70 (m, 1H), 1.35 (t, J = 7.2 Hz, 3H). ESI-MS calculated value: [M+H] + =421.17, measured value 421.4.

[0237] Example 4

[0238] Synthesis route:

[0239] first step

[0240] 4-6 (70 mg, 0.24 mmol) and 5-1 (109 mg, 0.36 mmol) were added to 1,4-dioxane (2.0 mL) and water (0.2 mL). Cesium carbonate (156 mg, 0.48 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (20 mg, 0.02 mmol) were added sequentially. The mixture was heated to 90°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was directly purified by HPLC (C18 spherical 30-35 μm 100A 40 g, mobile phase: acetonitrile-10 mmol / L 0.1% formic acid in water, gradient: 10-50%, retention time: 30 min) to afford the formate salt of 5. 1 H NMR (400MHz, DMSO-d6): δ10.42-9.75(br,1H),8.43(d,J=7.6Hz,1H),8.21(s,1H),8.11(d,J= 8.0Hz,1H),7.11-7.03(m,2H),6.95(d,J=7.6Hz,1H),3.98-3.88(m,1H),2.97-2.89(m,1H),2. 67-2.57 (m, 1H), 2.34-2.39 (m, 2H), 2.10 (s, 3H), 2.07-1.99 (m, 2H), 1.94-1.89 (m, 1H), 1.76-1.69 (m, 1H), 1.54-1.49 (m, 1H), 1.43-1.37 (m, 1H), 1.00 (t, J = 7.2 Hz, 3H). ESI-MS calculated value: [M+H] + =437.15, measured value 437.2.

[0241] Example 5

[0242] Synthesis route:

[0243] first step

[0244] 4-6 (60 mg, 0.20 mmol) and 6-1 (40 mg, 0.24 mmol) were added to 1,4-dioxane (0.5 mL) and water (0.1 mL). Cesium carbonate (195 mg, 0.60 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (17 mg, 0.02 mmol) were added sequentially. The mixture was heated to 85°C and stirred for 12 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then directly purified by HPLC (Waters-XBndge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid in water, gradient: 18-28%, retention time: 17 min) to obtain the formate salt of 6. 1 H NMR (400MHz, DMSO-d6): δ8.44- 8.34(m,1H),8.17(s,1H),8.08(d,J=8.0Hz,1H),7.33(d,J=8.4Hz,1H),7.06(d,J=8.0Hz, 1H),6.89-6.79(m,2H),4.01-3.91(m,1H),3.79(s,3H),3.02-2.92(m,1H),2.72-2.62(m, 1H), 2.38 (d, J = 7.2 Hz, 2H), 2.34 (s, 3H), 2.10-2.00 (m, 2H), 1.95-1.85 (m, 1H), 1.77-1.67 (m, 1H), 1.58-1.48 (m, 1H), 1.41-1.31 (m, 1H), 1.00 (t, J = 7.2 Hz, 3H). ESI-MS calculated value: [M+H] + =383.19, measured value 383.4.

[0245] Example 6

[0246] Synthesis route:

[0247] first step

[0248] 4-6 (60 mg, 0.20 mmol) and 7-1 (37 mg, 0.24 mmol) were added to 1,4-dioxane (0.5 mL) and water (0.1 mL). Cesium carbonate (195 mg, 0.60 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (17 mg, 0.02 mmol) were added sequentially. The mixture was heated to 85°C and stirred for 12 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then directly purified by HPLC (Waters-XBndge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid in water, gradient: 19-29%, retention time: 17 min) to obtain the formate salt of 7. 1 H NMR (400MHz, DMSO-d6): δ8.50-8.40(m,1H),8.16(s,1H),8.12(d,J=8.0Hz,1H),7.44-7.3 8(m,1H),7.17-7.11(m,1H),7.15-7.05(m,2H),3.99-3.92(m,1H),3.02-2.92(m,1H),2.7 2-2.62 (m, 1H), 2.43-2.35 (m, 2H), 2.35 (s, 3H), 2.12-2.02 (m, 2H), 1.96-1.86 (m, 1H), 1.78-1.68 (m, 1H), 1.59-1.49 (m, 1H), 1.43-1.33 (m, 1H), 1.01 (t, J = 7.2 Hz, 3H). Theoretical calculation: [M+H] + =371.17, measured value 371.4.

[0249] Example 7

[0250] Synthesis route:

[0251] first step

[0252] 4-6 (60 mg, 0.20 mmol) and 8-1 (38 mg, 0.24 mmol) were added to 1,4-dioxane (0.5 mL) and water (0.1 mL). Cesium carbonate (195 mg, 0.60 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (17 mg, 0.02 mmol) were added sequentially. The mixture was heated to 85°C and stirred for 12 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and then directly purified by HPLC (Waters-XBndge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid in water, gradient: 18-28%, retention time: 17 min) to obtain the formate salt of 8. 1 H NMR (400MHz, DMSO-d6): δ8.56-8.46(m,1H),8.17(d,J=7.6Hz,2H),7.80(s,1H),7.74(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7.17(d, J = 7.6 Hz, 1H), 4.03-3.93 (m, 1H), 3.01-2.91 (m, 1H), 2.72-2.62 (m, 1H), 2.44-2.34 (m, 5H), 2.11-2.01 (m, 2H), 1.94-1.84 (m, 1H), 1.77-1.67 (m, 1H), 1.59-1.49 (m, 1H), 1.44-1.34 (m, 1H), 1.00 (t, J = 7.2 Hz, 3H). ESI-MS calculated value: [M+H] + =378.18, measured value 378.4.

[0253] Example 8

[0254] Synthesis route:

[0255] first step

[0256] 3-4 (500 mg, 2.04 mmol) and 9-1 (920 mg, 6.12 mmol) were added to dimethyl sulfoxide (5 mL), followed by triethylamine (1.07 mL, 12.24 mmol). The mixture was heated to 100°C and stirred for 12 hours under nitrogen. After the reaction, the reaction mixture was filtered and the filtrate was directly purified by HPLC (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-0.1% formic acid in water, gradient: 20-30%, retention time: 17 min) to obtain 9-2. 1H NMR (400 MHz, CDCl3): δ 8.69-8.59 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 4.59-4.49 (m, 1H), 3.78-3.68 (m, 1H), 3.64-3.54 (m, 1H), 2.40-2.30 (m, 1H), 2.20-2.10 (m, 1H), 1.84-1.74 (m, 2H), 1.52-1.42 (m, 1H), 1.41-1.31 (m, 3H). ESI-MS calculated value: [M+H] + =312.03, measured value 311.9.

[0257] Step 2

[0258] 9-2 (800 mg, 2.56 mmol), 9-3 (626 mg, 0.40 mmol) and methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (216 mg, 0.26 mmol) were added to 1,4-dioxane (10 mL), and potassium phosphate (1.63 g, 7.68 mmol) and water (2 mL) were added. The mixture was heated to 85 ° C and stirred for 12 hours under nitrogen protection. After the reaction, water (20 mL) was added for dilution, and the product was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The reaction solution was filtered, and the filtrate was directly purified by high performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-aqueous solution containing 0.05% ammonia monohydrate, gradient: 47-57%, retention time: 17 min) to obtain 9. 1 H NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 4.80 (d, J = 5.2 Hz, 1H), 3.51-3.41 (m, 1H), 3.40-3.35 (m, 1H), 2.40 (s, 3H), 2.02-1.88 (m, 2H), 1.73-1.63 (m, 2H), 1.38-1.22 (m, 4H). ESI-MS calculated value: [M+H] + =392.15, actual measured value 392.5.

[0259] Example 9

[0260] Synthesis route:

[0261] first step

[0262] 10-1 (10 g, 45.7 mmol) and 3-7 (11.2 g, 54.8 mmol) were dissolved in dioxane (100 mL) and water (20 mL). Sodium carbonate (14.5 g, 137 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.34 g, 4.57 mmol) were added sequentially at room temperature. The mixture was heated to 85°C and stirred under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, the pH was adjusted to 6 with dilute hydrochloric acid, and extracted with ethyl acetate (300 mL). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain 10-2. ESI-MS calculated value: [M+H] + =299.06, measured value 299.2.

[0263] Step 2

[0264] Dissolve 10-2 (5.0 g, 16.8 mmol) in DMF (30 mL) and add N-bromosuccinimide (3.0 g, 16.8 mmol) at 0°C. Stir for 3 hours. After the reaction, extract with ethyl acetate (250 mL). The organic phase is washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain 10-3. ESI-MS calculated value: [M+H] + =376.98, measured value 376.8.

[0265] Step 3

[0266] 10-3 (3.1 g, 8.2 mmol) and iron powder (2.3 g, 41.2 mmol) were dissolved in ethanol (36 mL) and saturated ammonium chloride solution (36 mL). The mixture was heated to 70°C and stirred for 3 hours under nitrogen. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL). The organic phase was washed with saturated brine (150 mL), 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 10-4. ESI-MS calculated value: [M+H] + =347.00, measured value 346.8.

[0267] Step 4

[0268] Dissolve 10-4 (2.1 g, 6.1 mmol) in DMF (20 mL), add 3-2 (1.2 g, 6.7 mmol) at 0°C, and stir at room temperature for 3 hours. After the reaction is complete, extract with ethyl acetate (150 mL). The organic phase is washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain 10-5. ESI-MS theoretical value: [M+H] + =388.96, measured value 388.9.

[0269] Step 5

[0270] 10-5 (1.5 g, 3.9 mmol), potassium carbonate (533 mg, 3.9 mmol), and iodomethane (830 mg, 5.9 mmol) were dissolved in acetonitrile (30 mL) and reacted at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (150 mL). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain 10-6. 1 H NMR (400 MHz, DMSO-d6): δ7.82 (s, 1H), 7.72 (s, 1H), 7.66-7.62 (m, 2H), 2.85 (s, 3H), 2.42 (s, 3H). ESI-MS calculated value: [M+H] + =402.97, measured value 402.6.

[0271] Step 6

[0272] 10-6 (100 mg, 0.25 mmol), 10-7 (103 mg, 0.75 mmol), tris(trimethylsilyl)silane (187 mg, 0.75 mmol), nickel chloride dimethoxyethane (0.6 mg, 2.5 μmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.7 mg, 2.5 μmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]bis[3,5-difluoro-2-(5-fluoro-2-pyridyl)phenyl]iridium hexafluorophosphate (2.8 mg, 2.5 μmol) and sodium carbonate (53 mg, 0.5 mmol) were added to ethylene glycol dimethyl ether (3 mL) and irradiated with a 34 W blue LED (420 nm) under nitrogen protection for 12 hours. After the reaction, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The reaction mixture was filtered, and the filtrate was directly purified by high-performance liquid chromatography (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 55-70%, retention time: 17 min) to obtain 10-8. ESI-MS calculated value: [M+H] + =381.08, measured value 381.0.

[0273] Step 7

[0274] Compound 10-8 (30 mg, 0.08 mmol), compound 1-9 (13 mg, 0.12 mmol), and triethylamine (24 mg, 0.24 mmol) were added to dimethyl sulfoxide (1 mL). The mixture was heated to 100°C and stirred under nitrogen for 4 hours. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product containing the target compound. This product was purified by high-performance liquid chromatography (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 25-40%, retention time: 17 min) to obtain the formate salt of compound 10. 1H NMR (400MHz, DMSO-d6): δ8.62-8.52(m,1H),7.68(s,1H),7.65-7.56(m,2H),7.16 (s,1H),5.02-4.92(m,2H),4.93-4.83(m,2H),4.60-4.50(m,1H),3.85-3.75(m,1H ),2.97-2.87(m,1H),2.67-2.57(m,1H),2.42(s,3H),2.20(s,3H),1.99-1.93(m,3H),1.76-1.70(m,1H),1.59-1.50(m,1H),1.37-1.30(m,1H).ESI-MS theoretical value:[M+H] + =447.19, measured value 447.6.

[0275] Example 10

[0276] Synthesis route:

[0277] first step

[0278] 3-4 (3 g, 12.2 mmol), 1-9 (1.82 g, 15.9 mmol), and triethylamine (10.2 mL, 73.4 mmol) were dissolved in dimethyl sulfoxide (30 mL). The mixture was heated to 100°C and stirred for 12 hours under nitrogen. After the reaction, the reaction solution was added to water (100 mL). The filtered solid was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to afford 11-1. 1 H NMR (400 MHz, DMSO-d6): δ 8.70-8.67 (m, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 3.80-3.70 (m, 1H), 2.92-2.82 (m, 1H), 2.63-2.53 (m, 1H), 2.18 (s, 3H), 1.96-1.86 (m, 3H), 1.76-1.66 (m, 1H), 1.58-1.48 (m, 1H), 1.36-1.26 (m, 1H). ESI-MS calculated value: [M+H] + =311.05, measured value 310.8.

[0279] Step 2

[0280] 11-1 (165 mg, 0.53 mmol), 11-2 (163 mg, 0.64 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (45 mg, 0.05 mmol) were added to 1,4-dioxane (2 mL). Potassium phosphate (337 mg, 1.59 mmol) and water (0.4 mL) were then added. The mixture was heated to 100°C and stirred for 12 hours under nitrogen. After completion of the reaction, the product was concentrated under reduced pressure to obtain a crude product containing the target compound. 11 was purified by HPLC (Waters-XBundge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.05% ammonia monohydrate in water, gradient: 35-45%, retention time: 17 min) to obtain 11. 1 H NMR (400MHz, DMSO-d6): δ11.01(s,1H),8.37(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H ),7.40(s,1H),7.36-7.31(m,2H),7.05(d,J=8.0Hz,1H),6.36(s,1H),3.84-3.74(m ,1H),2.97-2.87(m,1H),2.64-2.54(m,1H),2.35(s,3H),2.19(s,3H),1.99-1.89(m,3H),1.77-1.67(m,1H),1.59-1.49(m,1H),1.37-1.28(m,1H).ESI-MS calculated value:[M+H] + =362.19, measured value 362.0.

[0281] Example 11

[0282] Synthesis route:

[0283] first step

[0284] 11-1 (200 mg, 0.62 mmol), 12-1 (332 mg, 0.93 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (52 mg, 0.06 mmol) were added to 1,4-dioxane (2 mL). Potassium phosphate (263 mg, 1.24 mmol) and water (0.5 mL) were then added. The mixture was heated to 100°C and stirred for 2 hours under nitrogen. After the reaction, the reaction mixture was added to water (20 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The reaction mixture was filtered, and the filtrate was directly purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 12-2. ESI-MS theoretical calculation value: [M+H] + =462.24, measured value 462.3.

[0285] Step 2

[0286] Dissolve 12-2 (50 mg, 0.11 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (0.3 mL) at 0°C, and stir at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a crude product containing the target compound. This was purified by HPLC (C18 spherical 30-35 μm 100A25g, mobile phase: acetonitrile-0.1% formic acid in water, gradient: 15-30%, retention time: 17 min) to afford the formate salt of 12. 1 H NMR (400MHz, DMSO-d6): δ11.23(s,1H),8.48(d,J=7.60Hz,1H),7.79(d,J=8.4Hz,1H),7. 54(d,J=7.6Hz,1H),7.46-7.36(m,2H),7.10(t,J=7.2Hz,1H),6.99(t,J=7.6Hz,1H),3.8 4-3.74(m,1H),2.99-2.89(m,1H),2.65-2.55(m,1H),2.56(s,3H),2.21(s,3H),2.01-1.91(m,3H),1.79-1.89(m,1H),1.64-1.46(m,1H),1.40-1.30(m,1H).ESI-MS calculated value:[M+H] + =362.20, measured value 362.1.

[0287] Example 12

[0288] Synthesis route:

[0289] first step

[0290] 3-4 (6.2 g, 25.3 mmol), (R)-1-tert-butyloxycarbonyl-3-aminopiperidine (7.6 g, 38.0 mmol), and triethylamine (21.0 mL, 151.8 mmol) were dissolved in dimethyl sulfoxide (60 mL). Under nitrogen, the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, and water (200 mL) was added. The mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to afford 13-1. ESI-MS calculated value: [M+H] + =397.08, measured value 396.9.

[0291] Step 2

[0292] 13-1 (1.00 g, 2.52 mmol), hexabutylditin (1.75 g, 3.02 mmol), and bistriphenylphosphine palladium dichloride (176.88 mg, 0.25 mmol) were dissolved in dioxane (10 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to afford 13-2. ESI-MS calculated value: [M+H] + =609.28, measured value 609.0.

[0293] Step 3

[0294] 13-2 (200 mg, 0.33 mmol), 2-bromo-3-methyl-5-(trifluoromethyl)pyridine (95.1 mg, 0.40 mmol), and bistriphenylphosphine palladium dichloride (23.2 mg, 0.033 mmol) were dissolved in dioxane (4 mL). The reaction mixture was stirred at 100°C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, and saturated aqueous potassium fluoride (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to afford 13-3. ESI-MS calculated value: [M+H] + =478.20, measured value 478.2.

[0295] Step 4

[0296] Dissolve 13-3 (100 mg, 0.21 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL, 13.4 mmol), and stir at 25°C for 0.5 hours. The reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 13-4. ESI-MS calculated value: [M+H] + =378.15, measured value 377.9.

[0297] Step 5

[0298] 13-4 (79.0 mg, 0.21 mmol) was dissolved in ethanol (2 mL). Acetaldehyde (74.0 mg, 1.68 mmol) and sodium cyanoborohydride (79.2 mg, 1.26 mmol) were added dropwise at room temperature and stirred at 25°C for 12 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-XBndge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.05% aqueous ammonia, gradient: 42-52%, retention time: 17 min) to afford 13. 1 H NMR (400 MHz, DMSO-d6): δ 8.84 (s, 1H), 8.16 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 3.81-3.74 (m, 1H), 3.05-2.95 (m, 1H), 2.76-2.66 (m, 1H), 2.59 (s, 3H), 2.37 (q, J = 7.2 Hz, 2H), 2.00-1.90 (m, 3H), 1.78-1.68 (m, 1H), 1.55-1.48 (m, 1H), 1.39-1.30 (m, 1H), 1.00 (t, J = 7.2 Hz, 3H). ESI-MS calculated value: [M+H] + =406.18, measured value 406.2.

[0299] Example 13

[0300] Synthesis route:

[0301] first step

[0302] 13-1 (2.27 g, 5.71 mmol), 3-7 (1.4 g, 6.85 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (480 mg, 0.57 mmol) were added to 1,4-dioxane (22 mL). Cesium carbonate (4.65 g, 14.28 mmol) and water (5 mL) were then added. The mixture was heated to 90°C and stirred for 12 hours under nitrogen. After the reaction, the reaction mixture was added to water (80 mL) and extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The reaction mixture was filtered, and the filtrate was directly purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain 14-1. ESI-MS theoretical calculation value: [M+H] + =477.20, measured value 477.1.

[0303] Step 2

[0304] 14-1 (2.2 g, 4.62 mmol) was dissolved in methanol (35 mL). 30% aqueous hydrogen peroxide (2.36 mL, 23.1 mmol) and methyltrioxorhenium (230 mg, 0.92 mmol) were added at 0°C and stirred at room temperature for 12 hours. After the reaction, 10% aqueous sodium persulfate (30 mL) was added dropwise at 0°C. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The reaction mixture was filtered, and the filtrate was directly purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to obtain 14-2. ESI-MS calculated value: [M+H] + =493.20, measured value 493.1.

[0305] Step 3

[0306] 14-2 (500 mg, 1.02 mmol) was dissolved in DMF (20 mL), and oxalyl bromide (1.32 g, 6.12 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with aqueous sodium hydroxide solution (1 mol / L, 10 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The reaction solution was filtered, and the filtrate was directly purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 14-3. ESI-MS theoretical value: [M+H] +=555.10, measured value 554.9.

[0307] Step 4

[0308] 14-3 (56 mg, 0.10 mmol), 14-4 (47 mg, 0.20 mmol), tris(trimethylsilyl)silane (50 mg, 0.20 mmol), nickel chloride dimethoxyethane (1.1 mg, 5 μmol), 4,4'-di-tert-butyl-2,2'-bipyridine (1.35 mg, 5 μmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]bis[3,5-difluoro-2-(5-fluoro-2-pyridyl)phenyl]iridium hexafluorophosphate (2.8 mg, 2.5 μmol) and sodium carbonate (1.12 mg, 1 μmol) were added to ethylene glycol dimethyl ether (0.5 mL) and irradiated with a 34 W blue LED (420 nm) under nitrogen protection for 12 hours. After the reaction, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The reaction mixture was filtered, and the filtrate was directly purified by high-performance liquid chromatography (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 45-60%, retention time: 17 min) to obtain 14-5. ESI-MS calculated value: [M+H] + =632.31, measured value 632.2.

[0309] Step 5

[0310] Dissolve 14-5 (25 mg, 0.04 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL) at 0°C, and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing 14-6, which was used directly in the next reaction. ESI-MS theoretical calculated value: [M+H] + =432.20, measured value 432.0.

[0311] Step 6

[0312] 14-6 (15 mg, 0.04 mmol) was dissolved in methanol (0.5 mL), and formalin (2.1 mg, 0.07 mmol) and sodium cyanoborohydride (7 mg, 0.11 mmol) were added. 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 (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-0.1% formic acid in water, gradient: 13-23%, retention time: 17 min) to obtain the formate salt of 14. 1H NMR (400 MHz, CD3OD): δ7.61 (s, 1H), 7.59-7.51 (m, 2H), 7.12 (s, 1H), 4.48-4.20 (m, 5H), 4.16-4.04 (m, 1H), 3.50-1.40 (m, 1H), 3.18-3.05 (m, 1H), 2.88 (s, 3H), 2.80-2.70 (m, 2H), 2.68 (s, 3H), 2.39 (s, 3H), 2.20-2.08 (m, 1H), 2.08-1.98 (m, 1H), 1.90-1.76 (m, 1H), 1.73-1.63 (m, 1H). ESI-MS calculated value: [M+H] + =460.23, measured value 460.1.

[0313] Example 14

[0314] Synthesis route:

[0315] first step

[0316] 14-3 (50 mg, 0.09 mmol), 15-1 (39 mg, 0.18 mmol), nickel chloride dimethoxyethane (4 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (3.6 mg, 0.01 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]bis[3,5-difluoro-2-(5-fluoro-2-pyridyl)phenyl]iridium hexafluorophosphate (1 mg, 0.9 μmol) and cesium carbonate (59 mg, 0.18 mmol) were added to DMF (0.5 mL) and irradiated with a 34 W blue LED (420 nm) under nitrogen protection for 24 hours. After the reaction, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The reaction mixture was filtered, and the filtrate was directly purified by high-performance liquid chromatography (C18 spherical 30-35 μm 100A25g, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 55-75%, retention time: 17 min) to obtain 15-2. ESI-MS calculated value: [M+H] + =646.31, measured value 646.2.

[0317] Step 2

[0318] Dissolve 15-2 (27 mg, 0.04 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (0.5 mL) at 0°C, and stir at room temperature for 1 hour. Concentrate the reaction mixture under reduced pressure to obtain a crude product containing 15-3, which is used directly in the next reaction. ESI-MS calculated value: [M+H] + =446.22, measured value 446.1.

[0319] Step 3

[0320] 15-3 (15 mg, 0.04 mmol) was dissolved in methanol (0.5 mL), and formalin (1 mg, 0.03 mmol) and sodium cyanoborohydride (6 mg, 0.10 mmol) were added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-0.1% formic acid in water, gradient: 15-25%, retention time: 17 min) to obtain the formate salt of 15. 1 H NMR (400MHz, CD3OD): δ7.61(s,1H),7.57(d,J=8.8Hz,1H),7.54(d,J=8.4Hz,1H),7.21(s,1H),4.15-4.05(m,1H),3.79-3.69(m,1H),3. 66-3.54(m,1H),3.35-3.30(m,1H)2.98-2.88(m,2H),2.81(s,3H),2.59-2.49(m,1H),2.46-2.42(m,1H),2.40(s,3H),2.37(s,3H),2.24 -1.94 (m, 6H), 1.92-1.82 (m, 1H), 1.79-1.69 (m, 1H). ESI-MS calculated value: [M+H] + =474.25, measured value 474.0.

[0321] Example 15

[0322] Synthesis route:

[0323] first step

[0324] 13-1 (200 mg, 0.05 mmol), 16-1 (182 mg, 0.75 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (42 mg, 0.05 mmol) were added to 1,4-dioxane (2 mL). Cesium carbonate (4.65 g, 14.28 mmol) and water (0.4 mL) were then added. The mixture was heated to 90°C and stirred under nitrogen for 12 hours. After the reaction, the reaction mixture was added to water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound. The reaction mixture was filtered, and the filtrate was directly purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 16-2. ESI-MS theoretical calculation value: [M+H] + =434.22, measured value 434.5.

[0325] Step 2

[0326] Dissolve 16-2 (100 mg, 0.21 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL) at 0°C, and stir at room temperature for 1 hour. Concentrate the reaction mixture under reduced pressure to obtain a crude product containing 16-3, which is used directly in the next reaction. ESI-MS theoretical calculated value: [M+H] + =334.17, measured value 334.2.

[0327] Step 3

[0328] 16-3 (115 mg, 0.34 mmol) was dissolved in methanol (2 mL), and formalin (15 mg, 0.51 mmol) and sodium cyanoborohydride (64 mg, 1.02 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by HPLC (Waters-XBndge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.05% ammonia monohydrate, gradient: 37-47%, retention time: 17 min) to obtain 16. 1H NMR (400MHz, DMSO-d6): δ11.22(s,1H),8.43-8.33(m,1H),8.08(s,1H),7.70(d,J=8.4Hz,1H) ,7.67(dd,J=8.4,1.6Hz,1H),7.58(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),7.41-7.38(m,1H) ,6.49-6.40(m,1H),3.83-3.73(m,1H),2.98-2.88(m,1H),2.65-2.55(m,1H),2.20(s,3H),1.99-1.89(m,3H),1.78-1.68(m,1H),1.60-1.50(m,1H),1.38-1.30(m,1H).ESI-MS theoretical value:[M+H] + =348.18, measured value 348.1.

[0329] Example 16

[0330] Synthesis route:

[0331] first step

[0332] 13-1 (2.76 g, 6.95 mmol), 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxinol (3.00 g, 8.34 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (294 mg, 0.35 mmol) and potassium carbonate (2.88 g, 20.9 mmol) were dissolved in dioxane (28 mL) and water (4 mL), and the reaction solution was stirred at 100 ° C for 16 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and water (100 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 17-1. ESI-MS theoretical calculated value: [M+H] + =551.24, measured value 551.4.

[0333] Step 2

[0334] 17-1 (3.66 g, 6.65 mmol) was dissolved in dichloromethane (15 mL). Meta-chloroperbenzoic acid (2.30 g, 13.3 mmol, 85% purity) was added at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was adjusted to pH 8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (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 residue was purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to obtain 17-2. ESI-MS calculated value: [M+H] + =567.24, measured value 567.1.

[0335] Step 3

[0336] 17-2 (1.40 g, 2.47 mmol) was dissolved in N,N-dimethylformamide (20 mL), and oxalyl bromide (3.20 g, 14.8 mmol) was added dropwise at 0°C. The reaction solution was stirred at 25°C for 0.5 hours. The pH of the reaction solution was adjusted to 8 with 2 mol / L aqueous sodium hydroxide solution, and extracted with ethyl acetate (50 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 silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to obtain 17-3. ESI-MS calculated value: [M+H] + =629.15, measured value 629.0.

[0337] Step 4

[0338] 17-3 (130 mg, 0.21 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (66 mg, 0.32 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) methanesulfonate (18 mg, 0.021 mmol), and potassium carbonate (87.0 mg, 0.63 mmol) were dissolved in dioxane (2 mL) and water (0.4 mL). The reaction mixture was stirred at 100°C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give 17-4. ESI-MS theoretical calculated value: [M+H] + =633.28, measured value 633.2.

[0339] Step 5

[0340] 17-4 (130 mg, 0.21 mmol) was dissolved in methanol (3 mL), and palladium / carbon (11.0 mg, 10% purity) was added. The reaction mixture was stirred at 25°C for 12 hours under hydrogen protection. The reaction mixture was filtered through celite and concentrated under reduced pressure to obtain crude product 17-5. ESI-MS calculated value: [M+H] + =635.30, measured value 635.2.

[0341] Step 6

[0342] 17-5 (120 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added at 0°C, and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated aqueous sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 17-6. ESI-MS calculated value: [M+H] + =477.20, measured value 476.9.

[0343] Step 7

[0344] 17-6 (80.0 mg, 0.17 mmol) and 37% aqueous formaldehyde solution (28.0 mg, 0.34 mmol) were dissolved in methanol (2 mL). Sodium cyanoborohydride (32.0 mg, 0.51 mmol) was added to the reaction solution. The reaction solution was stirred at 25°C for 12 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-XBndge-C18-10μm-19*250mm, mobile phase: acetonitrile-0.05% aqueous ammonia, gradient: 31-41%, retention time: 17 min) to obtain 17. 1 H NMR (400 MHz, DMSO-d6): δ9.91 (s, 1H), 8.42 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 7.04 (s, 1H), 6.82 (s, 1H), 4.00-3.91 (m, 2H), 3.79-3.71 (m, 1H), 3.50-3.40 (m, 2H), 3.12-3.00 (m, 1H), 2.96-2.86 (m, 1H), 2.63-2.53 (m, 1H), 2.18 (s, 3H), 2.08 (s, 3H), 1.95-1.65 (m, 8H), 1.60-1.42 (m, 1H), 1.37-1.25 (m, 1H). ESI-MS calculated value: [M+H] + =491.22, measured value 491.2.

[0345] Example 17

[0346] Synthesis route:

[0347] first step

[0348] In a glove box, 17-1 (50.0 mg, 0.08 mmol) was dissolved in ethylene glycol dimethyl ether (3 mL), and 3-bromobutylene oxide (32.4 mg, 0.24 mmol), tris(trimethylsilyl)silane (58.9 mg, 0.24 mmol), sodium carbonate (16.8 mg, 0.16 mmol), nickel chloride dimethoxyethane (0.55 mg, 2.5 μmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.67 mg, 2.5 μmol) and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridylN]phenyl-C]iridium(III)hexafluorophosphate (0.89 mg, 0.8 μmol) were added. The reaction mixture was irradiated with a 34W blue LED (420nm) and stirred at 25°C for 12 hours. Saturated aqueous sodium bicarbonate (10mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10mL x 3). The combined organic phases were washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (C18 spherical 30-35μm 100A25g, mobile phase: acetonitrile-0.1% aqueous formic acid, gradient: 45-60%, retention time: 17min) to afford 18-1. ESI-MS calculated value: [M+H] + =607.27, measured value 607.4.

[0349] Step 2

[0350] Dissolve 18-1 (100 mg, 0.16 mmol) in dichloromethane (2 mL). Add trifluoroacetic acid (1 mL) at 0°C, and stir the reaction mixture at 25°C for 2 hours. Adjust the pH of the reaction mixture to 8 with saturated aqueous sodium bicarbonate solution and extract with ethyl acetate (30 mL x 3). The organic phase is washed with saturated aqueous sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to yield 18-2. ESI-MS calculated value: [M+H] + =449.17, measured value 449.1.

[0351] Step 3

[0352] Compound 18-2 (100 mg, 0.22 mmol) and 37% aqueous formaldehyde solution (39.2 mg, 0.33 mmol) were dissolved in methanol (2 mL). Sodium cyanoborohydride (41.5 mg, 0.66 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (C18 spherical 30-35 μm 100A25g, mobile phase: acetonitrile-0.1% aqueous formic acid, gradient: 20-50%, retention time: 17 min) to obtain the formate salt of compound 18. 1 H NMR (400MHz, DMSO-d6): δ9.92(s,1H),8.67-8.57(m,1H),8.14(s,1H),7.09(s,1H),7. 05(s,1H),6.96(s,1H),5.02-4.92(m,2H),4.89-4.79(m,2H),4.60-4.43(m,1H),3.93- 3.83 (m, 1H), 3.24-3.14 (m, 1H), 2.94-2.84 (m, 1H), 2.45 (s, 3H), 2.38-2.28 (m, 1H), 2.08 (s, 3H), 1.99-1.93 (m, 1H), 1.87-1.80 (m, 1H), 1.67-1.57 (m, 1H), 1.48-1.40 (m, 1H). ESI-MS theoretical value: [M+H] + =463.19, measured value 463.1.

[0353] Example 18

[0354] Synthesis route:

[0355] first step

[0356] 17-1 (200.0 mg, 0.32 mmol), 2,5-dihydrofuran-3-naphthoyl borate (94.1 mg, 0.48 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (27.1 mg, 0.032 mmol), and potassium carbonate (88.5 mg, 0.64 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give 19-1. ESI-MS theoretical calculated value: [M+H] + =619.27, measured value 619.0.

[0357] Step 2

[0358] 19-1 (178 mg, 0.29 mmol) was dissolved in methanol (5 mL), and palladium / carbon (30.0 mg, 10% purity) was added. Under hydrogen protection, the reaction solution was stirred at 25°C for 4 hours. The reaction solution was filtered through celite and concentrated under reduced pressure to obtain crude product 19-2. ESI-MS calculated value: [M+H] + =621.28, measured value 621.3.

[0359] Step 3

[0360] 19-2 (154 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (0.5 mL) was added at 0°C, and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated aqueous sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 19-3. ESI-MS calculated value: [M+H] + =463.19, measured value 463.3.

[0361] Step 4

[0362] 19-3 (140 mg, 0.30 mmol) and 37% aqueous formaldehyde solution (13.5 mg, 0.45 mmol) were dissolved in methanol (2 mL). Sodium cyanoborohydride (56.6 mg, 0.90 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (C18 spherical 30-35 μm 100A25g, mobile phase: acetonitrile-0.1% aqueous formic acid, gradient: 20-40%, retention time: 17 min) to obtain the formate salt of 19. 1 H NMR (400MHz, DMSO-d6): δ9.91(s,1H),8.54-8.44(m,1H),8.15(s,1H),7.08(s,1H),7.04(s,1H),6.86(s,1H),4.15-4.05(m,1H), 4.00-3.91(m,1H),3.89-3.79(m,2H),3.76-3.72(m,1H),3.68-3.54(m,1H),3.10-3.00(m,1H),2.80-2.70(m,1H),2.41-2.34(m, 1H), 2.32(s,3H), 2.21-2.10(m,3H), 2.08(s,3H), 1.99-1.89(m,1H), 1.83-1.73(m,1H), 1.62-1.53(m,1H), 1.46-1.29(m,1H). ESI-MS theoretical calculated value: [M+H] + =477.20, measured value 477.4.

[0363] Example 19

[0364] Synthesis route:

[0365] first step

[0366] 20-1 (7.6 g, 35.67 mmol) was dissolved in acetic acid (55 mL), and concentrated nitric acid (2.36 g, 37.45 mmol) was added at 0°C. The mixture was reacted at 25°C for 2 hours. After the reaction, the mixture was cooled to room temperature and quenched with water (100 mL). The mixture was extracted with dichloromethane (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing 20-2. 1 H NMR (400MHz, DMSO-d6): δ10.62(br s,1H),7.71(s,1H),2.97(t,J=7.2Hz,2H),2.87(t,J=7.2Hz,2H),2.10-2.00(m,2H).

[0367] Step 2

[0368] Dissolve 20-2 (4.6 g, 17.82 mmol) and cesium carbonate (11.61 g, 35.64 mmol) in N,N-dimethylformamide (40 mL). Slowly add iodomethane (3.79 g, 26.73 mmol) dropwise at 0°C. Allow to react at 25°C for 2 hours. After the reaction, dilute with water (200 mL) and extract with ethyl acetate (150 mL x 3). Dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product containing 20-3. 1 HNMR (400MHz, DMSO-d6): δ7.82(s,1H),3.87(s,3H),2.98-2.88(m,4H),2.15-2.05(m,2H).

[0369] Step 3

[0370] 20-3 (5.2 g, 19.11 mmol) and 10% wet palladium on carbon (2.12 g, 19.87 mmol) were dissolved in methanol (100 mL) and stirred under hydrogen (15 psi) for 2 hours. The reaction mixture was filtered, rinsed with methanol, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate / triethylamine, 100 / 5 / 0.1, v / v / v) to afford 20-4. 1 H NMR (400 MHz, DMSO-d6): δ 6.59 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 4.40 (s, 2H), 3.71 (s, 3H), 2.72 (t, J = 7.2 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 2.03-1.89 (m, 2H). ESI-MS calculated value: [M+H] + =164.11, measured value 164.1.

[0371] Step 4

[0372] 20-4 (900 mg, 5.51 mmol) was dissolved in concentrated hydrochloric acid (10 mL) and water (10 mL) and cooled to 0°C. Sodium nitrite (760 mg, 11.02 mmol) was dissolved in water (2 mL) and slowly added dropwise to the reaction mixture at 0°C, with stirring continuing for 2 hours. Potassium iodide (4.57 g, 27.55 mmol) was dissolved in water (2 mL) and slowly added dropwise to the reaction mixture at 0°C, with stirring continuing for 30 minutes. The mixture was then heated to room temperature and stirred for 1 hour, then heated to 60°C and stirred for 1 hour. After the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium sulfite solution (50 mL × 3), 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 afford 20-5. 1 H NMR (400MHz, CDCl3): δ7.08 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.07-2.97 (m, 2H), 2.92-2.82 (m, 2H), 2.17-2.00 (m, 2H).

[0373] Step 5

[0374] 20-5 (600 mg, 2.19 mmol), pinacol diboronate (1.4 g, 10.95 mmol), 2-(dicyclohexylphosphino)biphenyl (150 mg, 0.44 mmol), palladium acetate (49 mg, 0.22 mmol), and triethylamine (1.55 g, 15.33 mmol) were dissolved in 1,4-dioxane (5 mL). The mixture was heated to 80°C and stirred for 16 hours under nitrogen. After the reaction, saturated ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 20-6 was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1) to afford 20-6. 1 H NMR (400MHz, DMSO-d6): δ7.17(d,J=8.0Hz,1H),6.68(d,J=8.0Hz,1H),3.67(s,3H ),2.82(t,J=7.2Hz,2H),2.74(t,J=7.2Hz,2H),2.00-1.90(m,2H),1.27(s,12H).

[0375] Step 6

[0376] Dissolve 20-6 (270 mg, 0.98 mmol) in dichloromethane (5 mL), add boron tribromide (736 mg, 2.94 mmol) at 0°C, and continue stirring for 30 minutes. After the reaction, quench with water (40 mL), adjust the pH to 10 with aqueous sodium hydroxide solution, and wash with ethyl acetate (15 mL). The aqueous phase is adjusted to pH 4 with saturated ammonium chloride solution and extracted with ethyl acetate (50 mL x 3). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing 20-7. ESI-MS calculated value: [M+H] + =179.09, measured value 179.1.

[0377] Step 7

[0378] 11-1 (130 mg, 0.42 mmol), 20-7 (75 mg, 0.42 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 phosphate (267 mg, 1.26 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The mixture was heated to 90°C and stirred for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters 3767 / QDA, Column: Agilent C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% formic acid in water, gradient: 23-33%, retention time: 7 min) to obtain 20. 1 H NMR (400MHz, DMSO-d6): δ10.97(br s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 3.85-3.75 (m, 1H), 2.97-2.87 (m, 3H), 2.80 (t, J = 7.2 Hz, 2H), 2.64-2.54 (m, 1H), 2.20 (s, 3H), 1.98-1.92 (m, 5H), 1.78-1.67 (m, 1H), 1.59-1.49 (m, 1H), 1.38-1.28 (m, 1H). ESI-MS calculated value: [M+H] + =365.20, measured value 365.1.

[0379] Example 20

[0380] Synthesis route:

[0381] first step

[0382] Compound 11-1 (300 mg, 0.96 mmol), compound 21-1 (233 mg, 1.25 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (118 mg, 0.14 mmol), and potassium carbonate (637 mg, 4.61 mmol) were added to 1,4-dioxane (4 mL) and water (2 mL). The mixture was heated to 95°C and stirred for 16 hours under nitrogen. After the reaction, saturated aqueous ammonium chloride (30 mL) was added and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (methanol / dichloromethane, 1 / 9, v / v) to afford compound 21-2. ESI-MS calculated value: [M+H] + =373.15, measured value 373.0.

[0383] Step 2

[0384] 21-2 (200 mg, 0.54 mmol), bis-pinacol boronate (160 mg, 0.65 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (46 mg, 0.05 mmol), and potassium acetate (637 mg, 4.61 mmol) were added to 1,4-dioxane (4 mL) and stirred at 100°C for 16 hours. After the reaction, saturated aqueous ammonium chloride (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing 21-3, which was used directly in the next step. ESI-MS calculated value: [M+H] + =465.27, measured value 465.1.

[0385] Step 3

[0386] 21-3 (200 mg, 0.43 mmol), 21-4 (150 mg, 0.86 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 (180 mg, 1.29 mmol) were added to 1,4-dioxane (4 mL) and water (2 mL), and the temperature was raised to 95 ° C and stirred for 16 hours. After the reaction, saturated aqueous ammonium chloride (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by high-performance liquid chromatography (Waters 3767 / QDA, Column: SunFire C18, 19*250 mm, 10 um; mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 23-33%, retention time: 9 min) to obtain 21. 1 H NMR (400MHz, DMSO-d6): δ9.59 (br s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 3.84-3.74 (m, 1H), 3.00-2.90 (m, 1H), 2.87 (s, 3H), 2.69-2.59 (m, 1H), 2.23 (s, 3H), 2.10 (s, 3H), 2.02-1.92 (m, 3H), 1.79-1.69 (m, 1H), 1.60-1.50 (m, 1H), 1.39-1.29 (m, 1H). ESI-MS calculated value: [M+H] + =437.18, measured value 437.5.

[0387] Example 21

[0388] Synthesis route:

[0389] first step

[0390] Compounds 17-1 (150 mg, 0.24 mmol) and 22-1 (155 mg, 0.72 mmol) were dissolved in N,N-dimethylformamide (1 mL). Cesium carbonate (156 mg, 0.48 mmol), nickel chloride in dimethoxyethane (11 mg, 0.05 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (10 mg, 0.04 mmol), and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (3 mg, 0.3 μmol) were added. The reaction mixture was irradiated with a 34 W blue LED (420 nm) and stirred for 16 hours under nitrogen protection. After the reaction, the mixture was diluted with water (30 mL) 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 (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 45-55%) to obtain 22-2. ESI-MS calculated value: [M+H] + =720.36, measured value 720.3.

[0391] Step 2

[0392] Dissolve 22-2 (57 mg, 0.08 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL) dropwise, and stir at 25°C for 30 minutes. After the reaction, concentrate under reduced pressure to obtain a crude product containing 22-3, which is used directly in the next reaction. ESI-MS theoretical calculated value: [M+H] + =462.21, measured value 462.1.

[0393] Step 3

[0394] 22-3 (37 mg, 0.08 mmol) was dissolved in methanol (1 mL), and a 37% aqueous formaldehyde solution (10 mg, 0.12 mmol) and sodium cyanoborohydride (15 mg, 0.24 mmol) were added. The mixture was stirred at 25°C 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% aqueous ammonia; gradient: 46-56%, retention time: 10 min) to yield 22. 1H NMR (400MHz, DMSO-d6): δ9.79 (br s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 7.03 (s, 1H), 6.90 (s, 1H), 3.82-3.72 (m, 1H), 3.44-3.34 (m, 1H), 3.18-3.08 (m, 1H), 2.96-2.86 (m, 1H), 2.64-2.54 (m, 1H), 2.37-2.22 (m, 2H), 2.18 (s, 3H), 2.16 (s, 3H), 2.08 (s, 3H), 2.02-1.66 (m, 7H), 1.60-1.44 (m, 1H), 1.36-1.25 (m, 1H). ESI-MS calculated value: [M+H] + =490.25, measured value 490.1.

[0395] Example 22

[0396] Synthesis route:

[0397] first step

[0398] 17-1 (150 mg, 0.24 mmol), 23-1 (170 mg, 0.72 mmol), tris(trimethylsilyl)silane (179 mg, 0.72 mmol), sodium carbonate (51 mg, 0.48 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(III) hexafluorophosphate (3 mg, 0.3 μmol), nickel chloride dimethoxyethane (530 μg, 0.3 μmol), and 4,4'-di-tert-butyl-2,2'-bipyridyl (640 μg, 3 μmol) were added to ethylene glycol dimethyl ether (3 mL). The reaction was stirred under nitrogen protection and irradiated with a 34 W blue LED (420 nm) for 16 hours. After the reaction, the mixture was diluted with water (30 mL) 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 (C18 spherical 30-35 μm 100A 25 g, mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 50-60%) to obtain 23-2. ESI-MS calculated value: [M+H] + =706.34, measured value 706.4.

[0399] Step 2

[0400] Dissolve 23-2 (67 mg, 0.09 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (0.4 mL) dropwise, and stir at 25°C for 1 hour. After the reaction, concentrate under reduced pressure to obtain a crude product containing 23-3, which is used directly in the next reaction. ESI-MS calculated value: [M+H] + =448.20, measured value 448.3.

[0401] Step 3

[0402] 23-3 (40 mg, 0.09 mmol) was dissolved in methanol (1 mL), and 37% aqueous formaldehyde (0.1 mL, 0.89 mmol) and sodium triacetoxyborohydride (57 mg, 0.27 mmol) were added. The mixture was stirred at 25°C 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: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.1% aqueous formic acid; gradient: 25-35%, retention time: 9 min) to obtain 23. 1 H NMR (400MHz, DMSO-d6): δ9.88 (br s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 7.04 (s, 1H), 6.90 (s, 1H), 3.85-3.72 (m, 2H), 3.65 (t, J = 7.2 Hz, 2H), 3.23 (t, J = 7.2 Hz, 2H), 2.95-2.85 (m, 1H), 2.64-2.54 (m, 1H), 2.26 (s, 3H), 2.19 (s, 3H), 2.08 (s, 3H), 1.97-1.86 (m, 3H), 1.73-1.70 (m, 1H), 1.54-1.51 (m, 1H), 1.40-1.19 (m, 1H). ESI-MS calculated value: [M+H] + =476.23, measured value 476.1.

[0403] Example 23

[0404] Synthesis route:

[0405] first step

[0406] 17-1 (110 mg, 0.17 mmol), 24-1 (79 mg, 0.26 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 22 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (14 mg, 17 μmol), and potassium carbonate (70 mg, 0.51 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL). The mixture was heated to 100°C and stirred for 16 hours. After the reaction, the mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 1, v / v) afforded 24-2. ESI-MS theoretical calculation value: [M+H] + =732.36, measured value 732.2.

[0407] Step 2

[0408] Dissolve 24-2 (140 mg, 0.19 mmol) in methanol (3 mL), add 10% wet palladium on carbon (140 mg, 0.13 mmol), and stir under a hydrogen atmosphere (15 psi) for 48 hours. After the reaction, filter, rinse with methanol, and concentrate the filtrate under reduced pressure to obtain a crude product containing 24-3, which was used directly in the next reaction. ESI-MS calculated value: [M+H] + =734.38, measured value 734.1.

[0409] Step 3

[0410] Dissolve 24-3 (140 mg, 0.19 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL) dropwise, and stir at 25°C for 1 hour. After the reaction, concentrate under reduced pressure to obtain a crude product containing 24-4, which is used directly in the next reaction. ESI-MS theoretical calculated value: [M+H] + =476.23, measured value 476.0.

[0411] Step 4

[0412] 24-4 (90 mg, 0.19 mmol) was dissolved in methanol (2 mL), and a 37% aqueous formaldehyde solution (23 mg, 0.29 mmol) and sodium cyanoborohydride (36 mg, 0.57 mmol) were added. The mixture was stirred at 25°C 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% aqueous ammonia; gradient: 44-54%, retention time: 8 min) to yield 24. 1 H NMR (400 MHz, DMSO-d6): δ 9.90 (br s, 1H), 8.48-8.38 (m, 1H), 7.08 (s, 1H), 7.04 (s, 1H), 6.81 (s, 1H), 3.83-3.73 (m, 1H), 2.93 (s, 3H), 2.82-2.72 (m, 1H), 2.60-2.50 (m, 2H), 2.39-2.29 (m, 1H), 2.27-2.10 (m, 5H), 2.09-2.00 (s, 4H), 1.98-1.76 (m, 7H), 1.74-1.69 (m, 1H), 1.61-1.51 (m, 1H), 1.38-1.28 (m, 1H). ESI-MS calculated value: [M+H] + =504.26, measured value 504.3

[0413] Example 24

[0414] Synthesis route:

[0415] first step

[0416] 17-1 (50 mg, 0.08 mmol), 25-1 (29 mg, 0.40 mmol), cuprous iodide (30 mg, 0.02 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (8 mg, 0.03 mmol), and cesium carbonate (120 mg, 0.37 mmol) were dissolved in dioxane (2 mL) and stirred at 110°C for 12 hours. After the reaction, the mixture was diluted with ethyl acetate (30 mL) and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 1, v / v) afforded 25-2. ESI-MS calculated value: [M+H] + =623.27, measured value 623.1.

[0417] Step 2

[0418] Dissolve 25-2 (30 mg, 0.05 mmol) in dichloromethane (1.5 mL) and add trifluoroacetic acid (0.5 mL) dropwise. Stir at 25°C for 30 minutes. After the reaction is complete, concentrate under reduced pressure to obtain a crude product containing 25-3, which is used directly in the next reaction. ESI-MS theoretical calculated value: [M+H] + =465.18, measured value 465.0.

[0419] Step 3

[0420] 25-3 (22 mg, 0.05 mmol) was dissolved in methanol (1 mL), and a 37% aqueous formaldehyde solution (6 mg, 0.07 mmol) and sodium cyanoborohydride (9 mg, 0.14 mmol) were added. The mixture was stirred at 25°C 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: SunFire C18, 19*250 mm, 10 μm; mobile phase: acetonitrile-0.05% trifluoroacetic acid in water, gradient: 24-34%, retention time: 7 min) to obtain 25. 1 H NMR (400 MHz, CD3OD): δ7.09 (s, 1H), 7.01 (s, 1H), 6.73-6.63 (m, 1H), 5.71-5.61 (m, 1H), 5.11-5.01 (m, 2H), 4.82-4.72 (m, 2H), 4.16-4.04 (m, 1H), 3.95-3.85 (m, 1H), 3.59-3.50 (m, 1H), 3.05-2.80 (m, 5H), 2.32-2.21 (m, 1H), 2.18 (s, 3H), 2.15-2.05 (m, 1H), 2.01-1.85 (m, 1H), 1.77-1.68 (m, 1H). ESI-MS calculated value: [M+H] + =479.19, measured value 479.0.

[0421] Activity Test 1: Evaluation of the compound's ability to inhibit IL-1β secretion from THP-1 cells

[0422] Purpose of the experiment:

[0423] 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.

[0424] Experimental Materials:

[0425] Experimental equipment:

[0426] Cell treatment:

[0427] 1. This experiment uses THP-1 cells

[0428] 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.

[0429] Experimental operation:

[0430] 1. Add 40 μL of poly-lysine diluted with sterile water to a 96-well plate and incubate at 37°C and 5% CO2 for 30 minutes. Wash twice with 100 μL of sterile water.

[0431] 2. Add 50 nG / mL 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 100 μL per well. Incubate at 37° C. and 5% CO 2 for 24 hours.

[0432] 3. Remove the culture medium from the 96-well plate and wash the cells once with PBS preheated at 37°C.

[0433] 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.

[0434] 5. Add 5 μL of compounds of different concentrations (DMSO concentration is uniformly 1‰) and continue incubating the cells at 37°C and 5% CO2 for 30 minutes.

[0435] 6. Add 5 μL of diluted Nigericin to make the working concentration of Nigericin 5 μG / mL and continue incubating the cells at 37°C and 5% CO2 for 1 hour.

[0436] 7. Collect the cell supernatant, store it in -80, and use ELISA kit to detect the secretion of IL-1β.

[0437] 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 .

[0438] Experimental results:

[0439] Experimental conclusion: The compound of the present invention can effectively inhibit the secretion of IL-1β in THP-1 cells.

[0440] Activity test 2: Evaluation of the pharmacokinetic properties of the compound in mice

[0441] Purpose of the experiment:

[0442] The pharmacokinetic properties of the compounds obtained in the examples of the present invention were evaluated in CD-1 mice.

[0443] Experimental operation:

[0444] The candidate compound was formulated as 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 and 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 injected after further centrifugation. LCMS / MS analysis was used to quantify plasma concentrations and calculate pharmacokinetic parameters.

[0445] Experimental methods:

[0446] Experimental results:

[0447] Experimental conclusion: The test samples were prepared from the corresponding examples, and the results showed that some of the compounds in this application have good pharmacokinetic properties.

[0448] Although specific embodiments of the present invention have been described above, those skilled in the art will appreciate that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof: in, for express X1, X5, X7 and X 11 Each independently X2 and X3 are each independently -CH= or -N=; X4 is independently -CH=, -N= or -CR x =; R x For-OR x-3 、-CHR x-1 R x-2 , C1-C6 alkyl or one or more R x3 Substituted C1-C6 alkyl; R x-3 -CHR x-1 R x-2 , C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, x1 Substituted C3-C6 cycloalkyl or one or more R x2 Substituted 3-7 membered heterocycloalkyl; R x-1 and R x-2 Together with the carbon atoms to which they are commonly attached, they form a C3-C6 cycloalkyl group, a 3-7 membered heterocycloalkyl group, or a x1 Substituted C3-C6 cycloalkyl or one or more R x2 Substituted 3-7 membered heterocycloalkyl; R x1 and R x2 Each is independently a C1-C6 alkyl group; R x3 are independently C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl; X6, X8, X9, X 10 and X 12 Each independently represents -CH=, -N=, -O-, -S- or -NR 1 -, R 1 is H, halogen, C1-C6 alkyl or C1-C6 alkoxy; L 1 and L 2 The following conditions are met: When L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 When the 8-10 membered heterocyclic alkyl group is substituted, L 2 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl; Or, when L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 When the 5- to 10-membered heteroaryl group is substituted, L 2 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocycloalkyl; R 2 is C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, 2-1 substituted 3-7 membered heterocycloalkyl, 2-2 Substituted C1-C6 alkyl or one or more R 2-3 Substituted C3-C6 cycloalkyl; R 2-1 and R 2-3 Each is independently hydroxyl, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl or substituted by one or more R 2-1-1 Substituted C1-C6 alkyl; R 2-1-1 are independently halogen, C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl; R 2-2 is independently a 3-7 membered heterocycloalkyl or is replaced by one or more R 2-2-1 Substituted 3-7 membered heterocycloalkyl; R 2-2-1 are independently C1-C6 alkyl; R 3 are independently C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens; 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, C1-C6 alkoxy substituted by one or more halogens, or C1-C6 alkoxy substituted by one or more R d Substituted 5-6 membered heteroaryl; R c are independently deuterium, halogen or hydroxyl; R d are independently C1-C6 alkyl; Or, two adjacent R 4 The atoms to which they are attached together form a C3-C6 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a e Substituted C3-C6 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-C6 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a e Substituted C3-C6 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, C1-C6 alkoxy substituted by one or more halogens, or C1-C6 alkoxy substituted by one or more R d Substituted 5-6 membered heteroaryl; Each "8-10 membered cycloheterocycloalkyl" is independently 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 8-10 membered cycloheterocycloalkyl; Each "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl 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 membered heterocycloalkyl" is independently a 3-7 membered heterocycloalkyl 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 heteroatom selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-6 membered heteroaryl groups; Each "3-7 membered heterocycloalkenyl group" is independently a 3-7 membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S; the number of heteroatoms is 1, 2 or 3; The compound as shown in formula (I) satisfies one, two, three, four or five of the following conditions: I： for for II: for for X4 is -CH=, -N= or -CR x =, X6 is -O-, -S- or -NR 1 -; L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 Substituted 5-10 membered heteroaryl, L 2 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocycloalkyl; III: for for X4 is -CH=, -N= or -CR x =, X6 is -O-, -S- or -NR 1 -; L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocyclic alkyl, L 2 For naphthyl, or one or more R 5 A substituted 5-10-membered monocyclic or bicyclic heteroaryl group, wherein each ring of the monocyclic or bicyclic heteroaryl group is aromatic, and R 4-1 and R 4-5 Each is independently hydrogen, halogen, 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, C1-C6 alkoxy substituted by one or more halogens, or C1-C6 alkoxy substituted by one or more R d Substituted 5-6 membered heteroaryl, R 4-2 , R 4-3 and R 4-4 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, C1-C6 alkoxy substituted by one or more halogens, or C1-C6 alkoxy substituted by one or more R d Substituted 5-6 membered heteroaryl; IV: X4-CR x =, R x For-OR x-3 、-CHR x-1 R x-2 or one or more R x3 Substituted C1-C6 alkyl, R x-1 and R x-2 Together with the carbon atoms to which they are commonly attached, they form a C3-C6 cycloalkyl group, a 3-7 membered heterocycloalkyl group, or a x1 Substituted C3-C6 cycloalkyl or one or more R x2 Substituted 3-7 membered heterocycloalkyl; V:L 2 for Among them, R 4-3 is a 5-6 membered heteroaryl or is replaced by one or more R d Substituted 5-6 membered heteroaryl, R 4-1 , R 4-2 , R 4-4 and R 4-5 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, C1-C6 alkoxy substituted by one or more halogens, or C1-C6 alkoxy substituted by one or more R d substituted 5-6 membered heteroaryl, or "R 4-1 and R 4-2 ”、"R 4-2 and R 4-3 " and the atoms to which they are connected together form a C3-C6 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a e Substituted C3-C6 cycloalkenyl or one or more R f Substituted 3-7 membered heterocycloalkenyl.

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: for express X1, X5, X7 and X 11 Each independently X2 and X3 are each independently -CH= or -N=; X4 is independently -CH=, -N= or -CR x =; R x -CHR x-1 R x-2 , C1-C6 alkyl or one or more R x3 Substituted C1-C6 alkyl; R x-1 and R x-2 Together with the carbon atoms to which they are commonly attached, they form a C3-C6 cycloalkyl group, a 3-7 membered heterocycloalkyl group, or a x1 Substituted C3-C6 cycloalkyl or one or more R x2 Substituted 3-7 membered heterocycloalkyl; R x1 and R x2 Each is independently a C1-C6 alkyl group; R x3 are independently C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl; X6, X8, X9, X 10 and X 12 Each independently represents -CH=, -N=, -O-, -S- or -NR 1 -, R 1 is H, halogen, C1-C6 alkyl or C1-C6 alkoxy; L 1 and L 2 The following conditions are met: When L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 When the 8-10 membered heterocyclic alkyl group is substituted, L 2 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl; Or, when L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 When the 5- to 10-membered heteroaryl group is substituted, L 2 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocycloalkyl; R 2 is C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, 2-1 substituted 3-7 membered heterocycloalkyl, 2-2 Substituted C1-C6 alkyl or one or more R 2-3 Substituted C3-C6 cycloalkyl; R 2-1 and R 2-3 Each is independently hydroxyl, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl or substituted by one or more R 2-1-1 Substituted C1-C6 alkyl; R 2-1-1 are independently halogen, C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl; R 2-2 is independently a 3-7 membered heterocycloalkyl or is replaced by one or more R 2-2-1 Substituted 3-7 membered heterocycloalkyl; R 2-2-1 are independently C1-C6 alkyl; R 3 are independently C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens; R 4 and R 5 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens; R c are independently deuterium or halogen; Each "8-10 membered cycloheterocycloalkyl" is independently 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 8-10 membered cycloheterocycloalkyl; Each "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl 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 membered heterocycloalkyl" is independently a 3-7 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; The compound as shown in formula (I) satisfies one, two, three or four of the following conditions: I： for for II: for for X4 is -CH=, -N= or -CR x =, X6 is -O-, -S- or -NR 1 -; L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 Substituted 5-10 membered heteroaryl, L 2 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocycloalkyl; III: for for X4 is -CH=, -N= or -CR x =, X6 is -O-, -S- or -NR 1 -; L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocyclic alkyl, L 2 For naphthyl, or one or more R 5 Substituted 5-10 membered heteroaryl, R 4-1 and R 4-5 Each is independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens, R 4-2 , R 4-3 and R 4-4 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens; IV: X4-CR x =, R x -CHR x-1 R x-2 , R x-1 and R x-2 Together with the carbon atoms to which they are commonly attached, they form a C3-C6 cycloalkyl group, a 3-7 membered heterocycloalkyl group, or a x1 Substituted C3-C6 cycloalkyl or one or more R x2 Substituted 3-7 membered heterocycloalkyl.

3. The compound of formula (I) according to claim 1 or 2, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: for express X1, X5, X7 and X 11 Each independently X2, X3 and X4 are each independently -CH= or -N=; X6, X8, X9, X 10 and X 12 Each independently represents -CH=, -N=, -O-, -S- or -NR 1 -, R 1 is H, halogen, C1-C6 alkyl or C1-C6 alkoxy; L 1 and L 2 The following conditions are met: When L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 When the 8-10 membered heterocyclic alkyl group is substituted, L 2 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 substituted 5-10 membered heteroaryl; Or, when L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 When the 5- to 10-membered heteroaryl group is substituted, L 2 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocycloalkyl; R 2 is a 3-7 membered heterocycloalkyl group, 2-1 substituted 3-7 membered heterocycloalkyl or one or more R 2-2 Substituted C1-C6 alkyl; R 2-1 is independently halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl or is replaced by one or more R 2-1-1 Substituted C1-C6 alkyl; R 2-1-1 are independently halogen, C3-C6 cycloalkyl or 3-7 membered heterocycloalkyl; R 2-2 is independently a 3-7 membered heterocycloalkyl or is replaced by one or more R 2-2-1 Substituted 3-7 membered heterocycloalkyl; R 2-2-1 are independently C1-C6 alkyl; R 3 are independently C1-C6 alkyl or C1-C6 alkyl substituted by one or more halogens; R 4 and R 5 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens; R c are independently deuterium or halogen; Each "8-10 membered cycloheterocycloalkyl" is independently 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 8-10 membered cycloheterocycloalkyl; Each "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl 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 membered heterocycloalkyl" is independently a 3-7 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; The compound as shown in formula (I) satisfies one, two or three of the following conditions: Condition I: for for Condition II: for for X4 is -CH= or -N=, and X6 is -O-, -S- or -NR 1 -; L 1 is naphthyl, one or more R 4 Substituted phenyl or one or more R 5 Substituted 5-10 membered heteroaryl, L 2 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocycloalkyl; Condition III: for for X4 is -CH= or -N=, and X6 is -O-, -S- or -NR 1 -; L 1 NHR 2 , 8-10 membered heterocyclic alkyl or one or more R 3 Substituted 8-10 membered heterocyclic alkyl, L 2 For naphthyl, or one or more R 5 Substituted 5-10 membered heteroaryl, R 4-1 and R 4-5 Each is independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens, R 4-2 , R 4-3 and R 4-4 Each is independently hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, c Substituted C1-C6 alkyl or C1-C6 alkoxy substituted by one or more halogens.

4. 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) Each "5-10 membered heteroaryl" is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, wherein each ring of the 8-10 membered bicyclic heteroaryl is aromatic; preferably, each "5-10 membered heteroaryl" is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, wherein the heteroatom is one or two selected from N, O and S, and the number of the heteroatom is 1, 2 or 3, wherein each ring of the 8-10 membered bicyclic heteroaryl is aromatic, such as pyridyl, indolyl or benzothienyl, and further, for example (2) each "C3-C6 cycloalkenyl" is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, for example cyclopentenyl; (3) Each "3-7 membered heterocycloalkenyl" is independently a "4-6 membered heterocycloalkenyl" having 0 heteroatoms and 1 or 2 heteroatoms, for example, dihydrofuranyl.

5. The compound of formula (I) according to claim 1 or 2, 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) each "C3-C6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (2) Each "3-7 membered heterocycloalkyl" is independently a 4-7 membered heterocycloalkyl, such as oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, tetrahydropyranyl or azepanyl, for example 6. The compound of formula (I) according to any one of claims 1 to 3, 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) each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; (2) Each "8-10 membered heterocycloalkyl" is independently a 5-membered heterocycloalkyl, a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl, for example R a and R b Together with the N atom to which they are connected, they form a 5-membered and 5-membered heterocycloalkyl group, a 5-membered and 6-membered heterocycloalkyl group, or a 6-membered and 6-membered heterocycloalkyl group. Wherein, X is independently CH2, NH, O or S, and X' is independently CH2 or NH; Preferably, each "8-10 membered heterocycloalkyl" is independently (3) Each "5-10 membered heteroaryl" is independently a 5-6 membered heteroaryl or an 8-10 membered bicyclic heteroaryl, such as pyridyl, further such as (4) Each "3-7 membered heterocycloalkyl" is independently a 4-7 membered heterocycloalkyl, such as oxetanyl, tetrahydropyrrolyl, piperidinyl, tetrahydropyranyl or azepanyl, for example (5) each "halogen" is independently F, Cl, Br or I, such as F or Cl; (6) each "C3-C6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (7) Each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.

7. 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) In condition II or III, for (2) In condition IV, for For example (3) Under condition V, for For example (4) In condition I or II, L 1 for (5) In condition V, L 1 for (6) In condition IV, L 2 for (7) In condition III, L 2 for For example (8) In condition V, L 2 for 8. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: In condition I, L 2 for 9. 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, characterized in that: It meets one or more of the following conditions: (1) In condition II or III, for For example (2) In condition IV, for For example (3) In condition IV, L 1 for (4) In condition IV, L 2 for For example 10. The compound of formula (I) according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) Under condition I, for (2) In conditions II or III, for 11. 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, characterized in that: In condition I or II, L 2 for 12. The compound of formula (I) according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) In condition I or II, L 1 for Preferably (2) In condition I or II, L 2 for 13. The compound of formula (I) according to claim 1 or 2, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: In condition I or III, L 1 for 14. The compound of formula (I) according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) In condition I or III, L 1 for (2) In condition I, L 2 for For example (3) In condition III, L 2 for 15. 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 as shown in formula (I) is any one of the following: Case 1: The compound as shown in formula (I) satisfies condition III, wherein: for L 1 for R 2-1 is C1-C6 alkyl (e.g. methyl or ethyl); L 2 for R 5 is hydrogen or methyl; Case 2: The compound as shown in formula (I) satisfies condition IV, wherein: for X4-CR x =, R x For-OR x-3 or -CHR x-1 R x-2 , R x-3 is a 4-6 membered oxygen-containing heterocycloalkyl group, wherein the type of heteroatom is O and the number of heteroatoms is 1; R x-1 and R x-2 Together with the carbon atoms to which they are commonly connected, they form a 4-6-membered oxygen-containing heterocycloalkyl group or a 5-6-membered nitrogen-containing heterocycloalkyl group substituted with one or more methyl groups, wherein the type of heteroatom in the 4-6-membered oxygen-containing heterocycloalkyl group is O and the number of heteroatom is 1, and the type of heteroatom in the 5-6-membered nitrogen-containing heterocycloalkyl group is N and the number of heteroatom is 1; L 1 for R 2-1 is C1-C6 alkyl (e.g. methyl or ethyl); L 2 for Case 3: The compound as shown in formula (I) satisfies condition IV, wherein: for X4-CR x =, R x -CHR x-1 R x-2 ; R x-1 and R x-2 Together with the carbon atoms to which they are commonly connected, they form a 4-6-membered oxygen-containing heterocycloalkyl group, wherein the type of heteroatom in the 4-6-membered oxygen-containing heterocycloalkyl group is O and the number of heteroatoms is 1, and the type of heteroatom in the 5-6-membered nitrogen-containing heterocycloalkyl group is N and the number of heteroatoms is 1; L 2 for Case 4: The compound as shown in formula (I) satisfies condition V, wherein: for L 1 for R 2-1 is C1-C6 alkyl (e.g. methyl or ethyl); L 2 for R 4-3 is a 5-6 membered heteroaryl or is replaced by one or more R d Substituted 5-6 membered heteroaryl; R d are independently C1-C6 alkyl; "R 4-1 and R 4-2 "Together with the atoms to which they are attached, they form a C3-C6 cycloalkenyl group.

16. A compound of formula (I), 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 any one of the following compounds:

17. A pharmaceutical composition comprising a substance X and a pharmaceutically acceptable excipient, wherein the substance X is a compound of formula (I) as described in any one of claims 1 to 16, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

18. Use of the compound of formula (I) according to any one of claims 1 to 16, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of an NLRP3 inhibitor.

19. Use of a compound of formula (I) as described in any one of claims 1 to 16, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 17 in the preparation of a medicament for preventing and / or treating a disease associated with NLRP3; preferably, the disease associated with NLRP3 is an autoimmune disease, a neurodegenerative disease, a cardiovascular disease, or chronic obstructive pulmonary disease; the autoimmune disease is, for example, osteoarthritis, gout, Schnitzler syndrome, cryopyrin-associated periodic syndrome, ulcerative colitis; the neurodegenerative disease is, for example, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease.

20. Use of a compound of formula (I) as claimed in any one of claims 1 to 16, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 17 in the preparation of a method for preventing and / or treating a disease, wherein the disease is an autoimmune disease, a neurodegenerative disease, a cardiovascular disease, or chronic obstructive pulmonary disease; the autoimmune disease is, for example, osteoarthritis, gout, Schnitzler syndrome, cryopyrin-associated periodic syndrome, or ulcerative colitis; the neurodegenerative disease is, for example, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease.

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