Tricyclic compound, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a tricyclic compound, and a preparation method therefor and the use thereof. The tricyclic compound of the present invention is a compound as represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The compound of the present invention exhibits a good inhibitory activity on NLRP3, and has good pharmaceutical prospects.

Description

Tricyclic compounds, their preparation methods, and applications

[0001] This application claims priority to Chinese patent application 2024119547057, filed on December 27, 2024, and its filing date is [not specified].

[0002] Priority is claimed in Chinese patent application 2025101265417, dated January 27, 2025. The full text of the aforementioned Chinese patent application is incorporated herein by reference. Technical Field

[0003] This invention relates to a tricyclic compound, its preparation method, and its application. Background Technology

[0004] The NLRP3 inflammasome is a multi-protein complex comprising the sensor NLRP3, the adapter ASC, and the effector caspase 1. Cytokines, pathogen-associated molecular patterns (PAMPs), or damage-associated molecular patterns (DAMPs) can activate the NLRP3 inflammasome, further activating caspase 1 and promoting the cleavage of pro-IL-1β and pro-IL-18, as well as the release of the cytokines IL-1β and IL-18. The NLRP3 inflammasome plays a crucial role in neurodegenerative diseases.

[0005] Currently, there are no NLRP3 inhibitors on the market. NLRP3 inhibitors such as OLT-1177, DFV-890, and Selnoflast are in different stages of clinical research. Developing NLRP3 inhibitors has broad application prospects. Summary of the Invention

[0006] The technical problem this invention aims to solve is to overcome the deficiency of insufficient types of NLRP3 inhibitors in the prior art, and to provide a novel tricyclic compound, its preparation method, and its applications. The tricyclic compound of this invention exhibits good inhibitory activity against NLRP3.

[0007] The present invention solves the above-mentioned technical problems through the following solutions.

[0008] This invention provides a compound as shown in Formula I.

[0009] Its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt.

[0010] Where n is 1, 2, 3 or 4;

[0011] Each R 1 Independently hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, the C 1-6 alkoxy groups and the C 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R R1-1 Instead, the 5-6 aryl group is optionally replaced by one or more R groups. R1-2 replace;

[0012] Or, two adjacent R 1 Linkage forms -(CH2) q -, q is 1, 2, 3 or 4, any 1, 2, 3 or 4 -CH2- in -(CH2)q- can be optionally replaced by -O- and -CR R1-3 R R1-3 - One or two substitutions in the text;

[0013] Each R R1-3 Independently hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, the C 1-6 alkoxy groups and the C 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R R1-3a The 5-6 member heteroaryl group may optionally be replaced by one or more R groups. R1-3b replace;

[0014] Each R R1-1 and each R R1-3a Independently, it can be deuterium, halogen, or hydroxyl;

[0015] Each R R1-2 and each R R1-3b Independent of halogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0016] Y is

[0017] Each R 2 Hydrogen, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy or 3-6 membered heterocyclic alkyl groups;

[0018] R 3 and R 4 Independently hydrogen, halogen, C 1-6 Alkyl, C1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne or 3-6 membered heterocyclic alkyl, or R 3 and R 4 Together with the carbon atoms it is attached to, they form C 3-6 Cycloalkanes or 3-6 membered heterocyclic alkyl groups;

[0019] R 6 For H, or R 6 and R 2 Linkage forms -(CH2) p -, p It can be 1, 2, 3, or 4, -(CH2) p Any 1, 2, 3, or 4 of the -CH2- can be optionally replaced by -O- and -CR. R6-1 R R465-2 - One or two substitutions in the text;

[0020] R R6-1 and R R6-2 Independently hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy;

[0021] -L- is the key for connection or -CR L1 R L2 -;

[0022] R L1 and R L2 Independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkyl groups, C atoms substituted with one or more halogens 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 Alkoxy;

[0023] Ring A is a 3-6 membered heterocyclic alkyl group, a 5-12 membered bicyclic bridged heterocyclic alkyl group, or a 5-12 membered bicyclic spirocyclic heterocyclic alkyl group;

[0024] m can be 1, 2, 3, or 4;

[0025] Each R 5 Independently hydrogen, halogen, cyano, oxo (=O), hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 aryl, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-C3-6 cycloalkyl, -C 1-6 Alkyl-3-6-membered heterocyclic alkyl groups, -C 1-6 Alkyl-C 6-10 Aryl, -C 1-6 Alkyl-5-10-membered heteroaryl, -OC 1-6 Alkyl-C 3-6 cycloalkyl, -OC 1-6 Alkyl-3-6-membered heterocyclic alkyl groups, -OC 1-6 Alkyl-C 6-10 Aryl, -OC 1-6 Alkyl-5-10-membered heteroaryl, -C 2-6 alkenyl-C 3-6 cycloalkyl, -C 2-6 alkenyl-3-6-membered heterocyclic alkyl groups, -C 2-6 alkenyl-C 6-10 Aryl, -C 2-6 Alkenyl-5-10-membered heteroaryl, -C 2-6 alkynyl-C 3-6 cycloalkyl, -C 2-6 alkynyl-3-6-membered heterocyclic alkyl groups, -C 2-6 alkynyl-C 6-10 Aryl, -C 2-6 Alkyne-5-10 quinone heteroaryl groups, -(CH2) p -OC 1-6 Alkyl group, -(CH2) p -OC 1-6 Alkyl group, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkyne group, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -O-3-6-membered heterocyclic alkyl groups, -(CH2) p -OC 6-10 Aryl, -(CH2) p -O-5-10 aryl groups, -(CH2) p -S(=O)2R 5a -(CH2) p -S(=O)2N(R 5b )2 or -(CH2) p -N(R 5c )2;

[0026] Each p is independently 0, 1, 2, 3, 4, 5, or 6;

[0027] Each R5a Each R 5b and each R 5c Independently for C 1-6 Alkyl, C 3-6 Alkyl or 3-6 membered heterocyclic alkyl, wherein the C 1-6 Alkyl, the C 3-6 The alkyl group and the 3-6 membered heterocyclic alkyl group are independently and optionally associated with one or more R groups. R5 replace;

[0028] Each R R5 Independently halogen, hydroxyl, C 1-6 Alkyl, C1-C6 alkoxy, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more halogens 1-6 Alkoxy;

[0029] The heteroatoms in the heteroaryl group, the heterocyclic alkyl group, the bridged heterocyclic alkyl group, and the spirocyclic heterocyclic alkyl group are independently one or more of N, O, and S, and the number of heteroatoms is one, two, or three.

[0030] In some schemes, Y is

[0031] In some schemes, R L1 and R L2 Independently, C is a C substituted with one or more hydroxyl groups. 1-6 alkyl.

[0032] In some embodiments, the compound represented by Formula I is Formula I-1 or Formula I-2;

[0033] Its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt.

[0034] Where n is 1, 2, 3 or 4;

[0035] m1 is 1, 2, 3 or 4; m2 is 1, 2 or 3;

[0036] Each R 1 Independently hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, the C 1-6 alkoxy groups and the C 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R R1-1 Instead, the 5-6 aryl group is optionally replaced by one or more R groups. R1-2 replace;

[0037] Or, two adjacent R 1 Linkage forms -(CH2) q -, q can be 1, 2, 3 or 4, -(CH2) q Any 1, 2, 3, or 4 of the -CH2- can be optionally replaced by -O- and -CR. R1-3 R R1-3 - One or two substitutions in the text;

[0038] Each R R1-3 Independently hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, the C 1-6 alkoxy groups and the C 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R R1-3a The 5-6 member heteroaryl group may optionally be replaced by one or more R groups. R1-3b replace;

[0039] Each R R1-1 and each R R1-3a Independently, it can be deuterium, halogen, or hydroxyl;

[0040] Each R R1-2 and each R R1-3b Independent of halogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0041] R 2 Hydrogen, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy or 3-6 membered heterocyclic alkyl groups;

[0042] R 3 and R 4 Independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne or 3-6 membered heterocyclic alkyl, or R 3 and R 4 Together with the carbon atoms it is attached to, they form C 3-6 Cycloalkanes or 3-6 membered heterocyclic alkyl groups;

[0043] -L- is the key for connection or -CR L1 R L2 -;

[0044] R L1 and R L2Independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkyl groups, C atoms substituted with one or more halogens 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 Alkoxy;

[0045] Ring A is a 3-6 membered heterocyclic alkyl group, a 5-12 membered bicyclic bridged heterocyclic alkyl group, or a 5-12 membered bicyclic spirocyclic heterocyclic alkyl group;

[0046] m can be 1, 2, 3, or 4;

[0047] Each R 5 Independently hydrogen, halogen, cyano, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 aryl, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-3-6-membered heterocyclic alkyl groups, -C 1-6 Alkyl-C 6-10 Aryl, -C 1-6 Alkyl-5-10-membered heteroaryl, -OC 1-6 Alkyl-C 3-6 cycloalkyl, -OC 1-6 Alkyl-3-6-membered heterocyclic alkyl groups, -OC 1-6 Alkyl-C 6-10 Aryl, -OC 1-6 Alkyl-5-10-membered heteroaryl, -C 2-6 alkenyl-C 3-6 cycloalkyl, -C 2-6 alkenyl-3-6-membered heterocyclic alkyl groups, -C 2-6 alkenyl-C 6-10 Aryl, -C 2-6 Alkenyl-5-10-membered heteroaryl, -C 2-6 alkynyl-C 3-6 cycloalkyl, -C 2-6 alkynyl-3-6-membered heterocyclic alkyl groups, -C 2-6 alkynyl-C 6-10 Aryl, -C 2-6 Alkyne-5-10 quinone heteroaryl groups, -(CH2) p -OC 1-6 Alkyl group, -(CH2) p -OC1-6 Alkyl group, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkyne group, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -O-3-6-membered heterocyclic alkyl groups, -(CH2) p -OC 6-10 Aryl, -(CH2) p -O-5-10 aryl groups, -(CH2) p -S(=O)2R 5a -(CH2) p -S(=O)2N(R 5b )2 or -(CH2) p -N(R 5c )2;

[0048] Each p is independently 0, 1, 2, 3, 4, 5, or 6;

[0049] Each R 5a Each R 5b and each R 5c Independently for C 1-6 Alkyl, C 3-6 Alkyl or 3-6 membered heterocyclic alkyl, wherein the C 1-6 Alkyl, the C 3-6 The alkyl group and the 3-6 membered heterocyclic alkyl group are independently and optionally associated with one or more R groups. R5 replace;

[0050] Each R R5 Independently halogen, hydroxyl, C 1-6 Alkyl, C1-C6 alkoxy, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more halogens 1-6 Alkoxy;

[0051] The heteroaryl group, the heterocyclic alkyl group, the bridged heterocyclic alkyl group, and the spirocyclic heterocyclic alkyl group are independently one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4.

[0052] In some embodiments, the compound represented by Formula I is Formula I-3 or Formula I-4;

[0053] Its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt.

[0054] Where, n, R1 R 2 R 5 R 6 The definitions of rings A, L, and m1 are as described above.

[0055] In some schemes, in equation I-1,

[0056] n is 1, 2, 3, or 4; m1 is 1, 2, 3, or 4; each R 1 Independently for C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R R1-1 Replace; each R R1-1 It is a halogen; or, two adjacent Rs 1 Linkage forms -(CH2) q -, q can be 1, 2, 3 or 4, -(CH2) q Any 1, 2, 3, or 4 -CH2- in - are replaced by -O-; R 2 It is hydrogen; R 3 and R 4 Independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group, or R 3 and R 4 Together with the carbon atoms it is attached to, they form C 3-6 cycloalkyl; -L- is a linking bond or -CR L1 R L2 -;R L1 and R L2 Independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 Alkyl group; ring A is a 3-6 membered heterocyclic alkyl group or a 5-12 membered bicyclic bridged heterocyclic alkyl group; m is 1, 2, 3 or 4; each R 5 Independently hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy group; the heterocyclic alkyl group and the bridged heterocyclic alkyl group are independently one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0057] Better place,

[0058] m1 is 1 or 2; each R 1 Independently for C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R R1-1 replace;

[0059] Each R R1-1Halogens are independent of each other; R 3 and R 4 Independently hydrogen or C 1-6 alkyl;

[0060] R L1 and R L2 Independently hydrogen or C 1-6 alkyl;

[0061] Ring A is a 3-6 membered heterocyclic alkyl group;

[0062] Each R 5 Independently for C 1-6 Alkyl or C 1-6 Alkoxy;

[0063] Better,

[0064] R 3 and R 4 Independently hydrogen;

[0065] R L1 and R L2 Independently hydrogen;

[0066] Each R 5 Independently for C 1-6 alkyl.

[0067] In some schemes, in Equation I-2,

[0068] n is 1, 2, 3 or 4;

[0069] m2 is 1, 2, or 3;

[0070] Each R 1 Independently for C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 alkyl groups and the C 1-6 The alkoxy group is independently and optionally surrounded by one or more R groups. R1-1 replace;

[0071] Each R R1-1 It is a halogen;

[0072] R 2 It is hydrogen;

[0073] R 6 For H, or R 6 and R 2 Linkage forms -(CH2) p -, p It can be 1, 2, 3, or 4, -(CH2) p Any 1, 2, 3 or 4 -CH2- in - are replaced by -O-;

[0074] -L- is for -CR L1 R L2 -;

[0075] R L1 and R L2 Independently hydrogen;

[0076] Ring A is a 3-6 membered heterocyclic alkyl group;

[0077] Each R 5 Independently hydroxyl or C 1-6 alkyl;

[0078] Better place,

[0079] n is 1, 2, or 3;

[0080] m2 is 1, 2, or 3;

[0081] Each R 1 Independently for C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R R1-1 replace;

[0082] Each R R1-1 Halogens are independent of each other;

[0083] R 2 It is hydrogen;

[0084] R 6 For H.

[0085] In some schemes, in Equation I-3,

[0086] n is 1 or 2;

[0087] m1 is 1 or 2;

[0088] Each R 1 Independently for C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R R1-1 replace;

[0089] Each R R1-1 Halogens are independent of each other;

[0090] R 2 C 1-6 alkyl;

[0091] R 6 For H;

[0092] Ring A is a 3-6 membered heterocyclic alkyl group;

[0093] Each R 5 Independently for C1-6 alkyl.

[0094] In some schemes, in Equation I-4,

[0095] n is 1 or 2;

[0096] m1 is 1 or 2;

[0097] Each R 1 Independently for C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R R1-1 replace;

[0098] Each R R1-1 Halogens are independent of each other;

[0099] R 2 C 1-6 alkyl;

[0100] -L- is for -CR L1 R L2 -;

[0101] R L1 and R L2 Independently hydrogen;

[0102] Ring A is a 3-6 membered heterocyclic alkyl group;

[0103] Each R 5 Independently for C 1-6 alkyl.

[0104] Some of the groups in the compounds shown in Formula I can be defined as follows, and groups not mentioned are as described in any embodiment of the present invention.

[0105] In some schemes, each R 1 Each R R1-3 Each R R1-2 Each R R1-3b R 2 R 3 R 4 R L1 R L2 Each R 5 R 5a R 5b R 5c and each R R5 In, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, such as methyl or ethyl.

[0106] In some schemes, each R 1 Each R R1-3 RR1-1 Each R R1-3a Each R R1-2 Each R R1-3b R 2 R 3 R 4 R L1 R L2 Each R 5 and each R R5 In this context, the halogen is F, Cl, Br, or I, for example, F.

[0107] In some schemes, each R 1 Each R R1-3 Each R R1-2 Each R R1-3b R 2 R 3 R 4 R L1 R L2 Each R 5 and each R R5 In, the C 1-6 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy.

[0108] In some schemes, R L1 and R L2 In the context, the C substituted with one or more halogens 1-6 The halogen in the alkyl group and the C group substituted with one or more halogens 1-6 The halogen in the alkoxy group is independently F, Cl, Br or I, for example F.

[0109] In some schemes, R L1 and R L2 In the context, the C substituted with one or more halogens 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, such as methyl.

[0110] In some schemes, R L1 and R L2 In the context, the C substituted with one or more halogens 1-6 C in alkoxy 1-6 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy, such as methoxy.

[0111] In some schemes, R 3 and R 4 In, the C 2-6 The alkenyl group is vinyl or propenyl.

[0112] In some schemes, R 3 and R 4 In, the C 2-6 The alkynyl group is either ethynyl or propynyl.

[0113] In some schemes, when R 3 and R 4 Together with the carbon atoms it is attached to, they form C 3-6 In the case of cycloalkanes, the C 3-6 Cycloalkanes are cyclopropanes (e.g., cyclopropanes) * is marked as the carbon atom it connects to, cyclobutane, cyclopentane, or cyclohexane.

[0114] In some schemes, the 5-6 membered heterocyclic alkyl group in ring A is piperidinyl or morpholinyl.

[0115] In some schemes, in ring A, the heterocyclic alkyl group of the 5-12 membered bicyclic fused ring is a 5-membered heterocyclic alkyl and a 6-membered heterocyclic alkyl or a 5-membered cycloalkyl and a 6-membered heterocyclic alkyl, and the heteroatom is one or two of N and O, and the number is one or two. It can also be octahydroindolazinyl or octahydro-1H-cyclopent[c]pyridyl.

[0116] In some schemes, each R 5 In, there is at least one R 5 It is attached to ring A by heteroatoms.

[0117] In some schemes, each R 1 Independently for C 1-6 Alkyl group, or two adjacent R groups 1 Linkage forms -(CH2) q -, q can be 1, 2, 3 or 4, -(CH2) q Any 1, 2, 3, or 4 of the -CH2- can be optionally replaced by -O- and -CR. R1-3 R R1-3 - One or two substitutions in the text;

[0118] The C 1-6 Alkyl groups are optionally surrounded by one or more R R1-1 Replace, each R R1-1 The substituted element is independently a halogen or a hydroxyl group.

[0119] In some schemes, each R 1 Independently -CH3 or -CF3, or two adjacent R 1 The connection forms -O(CH2)2-.

[0120] In some schemes, for Preferred

[0121] In some schemes, for Preferred More preferably For example

[0122] In some schemes, R 2 It is hydrogen.

[0123] In some schemes, R 2 It is hydrogen or C 1-6 alkyl.

[0124] In some schemes, R 2 It can be hydrogen or methyl.

[0125] In some schemes, R 3 and R 4 Independently hydrogen, halogen, C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group, or R 3 and R 4 Together with the carbon atoms it is attached to, they form C 3-6 Cycloalkanes.

[0126] In some schemes, R 3 and R 4 Independently hydrogen, F, -CH3, vinyl or ethynyl, or R 3 and R 4 Together with the carbon atom it is attached to, they form cyclopropane.

[0127] In some schemes, Preferred

[0128] In some schemes, Y is Preferred

[0129] In some schemes, Y is Preferred More preferably For example

[0130] In some schemes, R L1 and R L2 Independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkyl groups or C atoms substituted with one or more halogens1-6 alkyl.

[0131] In some schemes, R L1 and R L2 Independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkyl groups, C atoms substituted with one or more halogens 1- 6-alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 Alkyl; preferably hydrogen, C 1-6 Alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl.

[0132] In some schemes, R L1 and R L2 It can be hydrogen, F, -CH3, -CF3 or -OCH3 independently.

[0133] In some schemes, -L- is a linker, -(CH2)-, -(CF2)-, -CH(-CH3))-, -(CH(-CF3))-, or -(CH(-OCH3))-.

[0134] In some schemes, -L- is a linking bond, -(CH2)-, -(CF2)-, -CH(-CH3))-, -(CH(-CF3))-, -(CH(-OCH3))-, or -CH(-CH2OH))-; preferably -(CH2)-, -CH(-CH3))-, or -CH(-CH2OH))-; for example, -(CH2)-.

[0135] In some schemes, each R 5 Independently hydrogen, C 1-6 Alkyl or C 1-6 Alkyl group.

[0136] In some schemes, each R 5 Independently hydrogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkyl group.

[0137] In some schemes, each R 5 It can be hydrogen, -CH3, or -OCH3 independently.

[0138] In some schemes, each R 5 It can be hydrogen, hydroxyl, -CH3, -CH2CH3 or -OCH3 independently.

[0139] In some schemes, R 6 For H, or R 6 and R 2 Linkage forms -(CH2) p -,p It can be 1, 2, 3, or 4, -(CH2) p Any one of the -CH2- in - can be optionally replaced by -O-.

[0140] In some schemes, R 6 For H, or R 6 and R 2 Connection formation This indicates that in some schemes, a ring-forming mechanism is formed at this position with a pyridazine ring. for Preferred More preferably For example

[0141] In some schemes, general formula I is general formula Ia or Ib:

[0142] In general formula Ia or Ib, the carbon atom marked with * is an S-configuration, R-configuration, or achiral carbon atom.

[0143] Better place, for Each R 1 Independently for C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by one or more R R1-1 Replace, each R R1-1 Replacement for halogens independently, or for two adjacent Rs. 1 Linkage forms -(CH2) q -, q can be 1, 2, 3 or 4, -(CH2) q Any one of the -CH2- in - can be optionally replaced by -O-.

[0144] Preferably, ring A is piperidinyl, morpholinyl, octahydroindolazinyl, or octahydro-1H-cyclopenta[c]pyridinyl.

[0145] In some embodiments, the compound represented by Formula I is any of the following compounds

[0146] Its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt.

[0147] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound represented by Formula I, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0148] The present invention also provides a kit for detecting NLRP3 inflammasomes, comprising a pharmaceutically acceptable salt of the compound represented by Formula I, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0149] The present invention also provides the use of a pharmaceutically acceptable salt of the compound represented by Formula I, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof in the preparation of a medicament for the prevention and / or treatment of diseases dependent on NLRP3 inflammasomes.

[0150] The NLRP3 inflammasome-dependent diseases are preferably neuroinflammatory diseases or neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease).

[0151] The present invention also provides a compound represented by formula II-1, II-2 or II-3:

[0152] In formulas II-1, II-2 and II-3: R 6 Independently protected by H or amino groups (-Boc); R 7 Independently protected by H or hydroxyl groups (e.g. );

[0153] n, R 1 R 2 R 3 R 4 R L1 and R L2 The definitions are the same as those described above.

[0154] The compound represented by Formula II-1 is preferably the following compound:

[0155] The compound represented by Formula II-1 is preferably an enantiomer. In the following separation conditions, the compounds that elute first and the compounds that elute later were obtained;

[0156] Separation conditions: Supercritical fluid chromatography; stationary phase: REGIS(S,S)WHELK-O1; mobile phase: A is supercritical carbon dioxide, B is isopropanol containing 0.1% 7.0 mol / L ammonia-methanol; gradient: mobile phase B is 20-20%...

[0157] The preferred separation conditions are as follows: supercritical fluid chromatography; column: Waters SFC 150, REGIS(S,S)WHELK-O1; mobile phase: A is supercritical carbon dioxide, B is isopropanol containing 0.1% 7.0 mol / L ammonia-methanol; gradient: mobile phase B is 20-20%, flow rate: 120 mL / min.

[0158] Preferably, the retention time of the first eluting compound is 4.4-5.2 min, and the retention time of the later eluting compound is 5.6-7.5 min.

[0159] Unless otherwise specified, the terms used in this invention have the following meanings:

[0160] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0161] In this article, the substituents used may be preceded by a single dash "-" to indicate that the named substituent is connected to the parent moiety by a single bond.

[0162] The term "multiple" refers to 2, 3, or 4.

[0163] The term "halogen" refers to F, Cl, Br, or I.

[0164] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms (e.g., C1-C6). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and similar alkyl groups.

[0165] The term "alkoxy" refers to the group R. X -O-,R X The definition is the same as the term "alkyl".

[0166] The term "cycloalkyl" refers to a ring with a specified number of carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ... 3-6 Cycloalkyl groups are cyclic groups consisting of a saturated monocyclic ring composed solely of carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0167] The term "heterocyclic alkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 3-6, 3-7, 5-12), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (1, 2, or 3 of N, O, and S).

[0168] The term "bridged heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 5-12), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is polycyclic (e.g., 2 or 3 rings) and shares two or more carbon atoms and / or heteroatoms among the monocyclic rings. Bridged heterocyclic alkyl groups are attached to the remainder of the molecule via a ring having heteroatoms or a ring without heteroatoms; they are attached to the remainder of the molecule via carbon atoms or heteroatoms. Bridged heterocyclic alkyl groups include, but are not limited to: wait.

[0169] The term "spirocyclic heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 5-12), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is polycyclic (e.g., 2 or 3 rings) and shares a carbon atom between the rings. Spirocyclic heterocyclic alkyl groups are attached to the remainder of the molecule via a ring having a heteroatom or a ring without a heteroatom; spirocyclic heterocyclic alkyl groups are attached to the remainder of the molecule via a carbon atom or a heteroatom. Spirocyclic heterocyclic alkyl groups include, but are not limited to: wait.

[0170] The term "heteroaryl" refers to a cyclic, aromatic monovalent group having a specified number of ring atoms (e.g., 5-6), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), and is monocyclic.

[0171] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be located at any position within the alkenyl group. For example, C2-C6 alkenyl refers to an alkenyl group having 2-6 carbon atoms.

[0172] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond can be located at any position within the alkynyl group. For example, C2-C6 alkynyl refers to an alkynyl group having 2-6 carbon atoms.

[0173] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C36, C46, ​​C56, C66). 6- C 10 An aryl group is a cyclic, unsaturated monovalent hydrocarbon group, which can be monocyclic or polycyclic (e.g., two or three). When polycyclic, the monocyclic rings share two atoms and one bond, and each ring is aromatic. The aryl group is attached to the rest of the molecule through an aromatic or non-aromatic ring.

[0174] The term "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5-10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, with the monocyclic rings sharing two atoms and one bond, and (at least one ring / each ring) is aromatic. Heteroaryl groups are attached to the rest of the molecule via carbon atoms or heteroatoms; they can be attached to the rest of the molecule via a ring with or without heteroatoms; or they can be attached to the rest of the molecule via an aromatic ring or a non-aromatic ring. Heteroaryl groups include, but are not limited to:

[0175] wait.

[0176] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.

[0177] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement.

[0178] As described above, "pharmaceutical-acceptable salt" and "solvent" in the term "pharmaceutical-acceptable salt solvate" refer to substances prepared from compounds of the present invention with relatively non-toxic, pharmaceutically acceptable acids or bases, and formed in combination with stoichiometric or non-stoichiometric solvents.

[0179] The term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances included in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0180] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0181] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0182] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0183] The reagents and raw materials used in this invention are all commercially available.

[0184] The positive and progressive effects of this invention are that the tricyclic compounds of this invention have good inhibitory activity against NLRP3.

[0185] Abbreviations:

[0186] PMB: 4-Methoxybenzyl.

[0187] Boc: tert-Butoxycarbonyl.

[0188] Bn: Benzyl.

[0189] NBS: N-bromosuccinimide.

[0190] DIEA: N,N-diisopropylethylamine.

[0191] DMF: N,N-dimethylformamide.

[0192] Et: Ethyl.

[0193] Me: Methyl group.

[0194] i-Pr: Isopropyl.

[0195] DMSO: Dimethyl sulfoxide.

[0196] THF: Tetrahydrofuran.

[0197] TEA: Triethylamine.

[0198] XPhos-Pd-G3: Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II).

[0199] Cata CXium A-Pd-G3: Methanesulfonyloxy(dadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II).

[0200] Xphos: 2-Dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.

[0201] LiAlH4: Lithium aluminum hydride.

[0202] MOE: Ethoxymethyl.

[0203] TBS: tert-butyldimethylsilyl.

[0204] DMAP: 4-Dimethylaminopyridine.

[0205] TMP: 2,2,6,6-Tetramethylpiperidinyl. Detailed Implementation

[0206] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0207] Intermediate A

[0208] Synthesis route:

[0209] first step

[0210] A-1 (10 g, 51.8 mmol) was dissolved in dichloromethane (150 mL) and cooled to 0 °C. N,N-diisopropylethylamine (34.3 mL, 207.3 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (39.4 g, 103.6 mmol), and A-2 (7.1 g, 72.6 mmol) were added. The mixture was stirred at 0 °C for 1 hour, then brought to room temperature and stirred for another 16 hours. After the reaction was complete, water (300 mL) was added, followed by extraction with ethyl acetate (300 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 2, v / v) to obtain A-3. 1 ¹H NMR (400MHz, CDCl₃) δ 7.46 (s, 1H), 3.55 (s, 3H), 3.39 (s, 3H). ESI-MS theoretical calculation [M+H] + =236.0, measured value 236.0.

[0211] Step 2

[0212] A-3 (100 mg, 0.42 mmol) and A-4 (160 mg, 0.44 mmol) were dissolved in 1,4-dioxane (6 mL) and water (2 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (34 mg, 0.04 mmol) and potassium carbonate (116 mg, 0.84 mmol) were added. The mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After cooling, the mixture was diluted with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain intermediate A. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.18 (s, 1H), 7.46–7.42 (m, 2H), 5.25 (s, 2H), 3.54 (s, 3H), 3.47 (q, J = 7.2Hz, 2H), 3.34 (s, 3H), 2.14 (s, 3H), 1.03 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculations [M+H] + =434.1, measured value 433.9.

[0213] Intermediate B

[0214] Synthesis route:

[0215] first step

[0216] Trimethylsulfonium iodide (12.29 g, 60.24 mmol) was dissolved in THF (40 mL), cooled to -10 °C, and n-butyllithium (2.5 mol / L n-hexane solution, 22.29 mL, 55.72 mmol) was added dropwise under nitrogen protection. After the addition was complete, the mixture was stirred for 30 minutes. Then, B-1 (3.00 g, 15.06 mmol) was dissolved in THF (8 mL) and added dropwise to the above reaction system. The mixture was stirred at 25 °C for 16 hours. After the reaction was completed, methyl tert-butyl ether (60 mL) and water (60 mL) were added, and the mixture was extracted with methyl tert-butyl ether (150 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain B-2. 1H NMR (400MHz, DMSO-d6): δ5.22(d,J=4.0Hz,1H),4.98(s,1H),4.79(s,1H),3.84-3.82(m,2H ),3.73-3.68(m,1H),2.87-2.80(m,1H),2.51-2.49(m,1H),2.33-2.28(m,1H),1.40(s,9H).

[0217] Step 2

[0218] B-2 (2.95 g, 13.83 mmol) was dissolved in dichloromethane (60 mL), cooled to 0 °C, and DMAP (422 mg, 3.46 mmol), TEA (2.80 g, 27.66 mmol), and tert-butyldimethylchlorosilane (4.17 g, 27.66 mmol) were added under nitrogen protection. The mixture was stirred at 25 °C for 16 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1, v / v) to obtain B-3. 1 H NMR (400MHz, DMSO-d6): δ4.90(s,1H),4.81(s,1H),4.25-4.15(m,1H),4.09-3.99(m,1H),3.64-3.54(m ,2H),3.17-3.07(m,1H),1.81-1.64(m,1H),1.40-1.32(m,1H),1.30(s,9H),0.79(s,9H),0.00(s,6H).

[0219] Step 3

[0220] B-3 (500 mg, 1.53 mmol) was dissolved in THF (10 mL), cooled to 0 °C, and 1-2 (0.5 mol / L tetrahydrofuran solution, 3.06 mL, 1.53 mmol) was added dropwise under nitrogen protection. After stirring for 10 minutes, the temperature was raised to 70 °C and stirred for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product containing intermediate B, which could be used directly for the next reaction without further purification.

[0221] Intermediate C

[0222] Synthesis route:

[0223] first step

[0224] Trifluoroacetic anhydride (34.00 g, 161.88 mmol) was dissolved in dichloromethane (150 mL) under ice-cold ethanol bath conditions. C-1 (11.65 g, 161.88 mmol) and pyridine (12.8 g, 161.88 mmol) were dissolved in dichloromethane (30 mL) and then slowly added dropwise to the above solution. The mixture was slowly heated to 25 °C and stirred for 16 hours. After the reaction was complete, the organic phase was washed successively with dilute hydrochloric acid (1 mol / L, 70 mL × 1), saturated sodium bicarbonate aqueous solution (70 mL × 1), and water (70 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain C-2, which was directly used in the next reaction step. 1 H NMR (400MHz, CDCl3): δ5.68(s,1H),3.80(s,3H),2.41(s,3H).

[0225] Step 2

[0226] C-2 (50.00 g, 297.48 mmol) was dissolved in C-3 (148.92 g, 1.49 mol), and TEA (30.10 g, 297.48 mmol) was added. The mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water (100 mL), the pH was adjusted to 6 with acetic acid, and the mixture was extracted with toluene (250 mL × 2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain C-4. 1 H NMR (400MHz, CDCl3): δ7.09(s,1H),6.96(s,1H),2.69(s,3H),2.64(s,3H).

[0227] Step 3

[0228] C-5 (105.20 g, 1.43 mol) was dissolved in water (200 mL) under an ice-cold ethanol bath. C-4 (50.00 g, 229.18 mmol) was added to a potassium hydroxide aqueous solution (2 mol / L, 401 mL, 802 mmol), followed by the addition of another potassium hydroxide aqueous solution (2 mol / L, 366 mL, 732 mmol) under an ice-cold ethanol bath. The resulting solution was added to the C-5 aqueous solution, and the mixture was slowly heated to 25 °C and stirred for 16 hours. After the reaction was complete, the pH was adjusted to 10 with acetic acid, washed with dichloromethane (300 mL × 1), and the aqueous phase was further adjusted to pH 6 with acetic acid, then to pH 9 with ammonia. Hydrazine hydrate (29.27 g, 572.95 mmol) was added, and the mixture was heated to 100 °C and stirred for 20 hours. After the reaction was completed and cooled, the pH was adjusted to 6 with acetic acid. The mixture was then extracted with 2-methyltetrahydrofuran (400 mL × 1), concentrated to 200 mL, and then crystallized by adding n-hexane (200 mL). The precipitated solid was filtered, and methanol (200 mL) and water (400 mL) were added and stirred. The mixture was filtered again, and the solid was dried to obtain C-6. 1 HNMR (400MHz, DMSO-d6): δ 13.18 (s, 1H), 10.35 (s, 1H), 7.40 (d, J = 9.6Hz, 1H), 7.12 (s, 1H), 7.05 (s, 1H), 6.92 (d, J = 9.6Hz, 1H), 2.18 (s, 3H). ESI-MS theoretical calculation: [M+H] + =271.1, measured value 271.0.

[0229] Step 4

[0230] C-6 (8.60 g, 31.83 mmol) was dissolved in acetonitrile (60 mL), and tetraethylammonium chloride (10.55 g, 63.66 mmol) was added. After the solution clarified, phosphorus oxychloride (7.32 g, 47.74 mmol) was slowly added dropwise, and the mixture was stirred for 16 hours. After the reaction was complete, the reaction solution was slowly poured into 50 °C water (100 mL) and stirred for another 2 hours. The mixture was filtered, and the solid was washed with water (20 mL × 1). The solid was then suspended in water (70 mL), and the pH was adjusted to 8 with ammonia. After stirring, the mixture was filtered again, and the solid was washed with water (10 mL × 2) and dried to obtain C-7. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.43 (s, 1H), 8.02 (d, J = 8.8Hz, 1H), 7.85 (d, J = 8.8Hz, 1H), 7.18 (s, 1H), 7.11 (s, 1H), 2.11 (s, 3H). ESI-MS theoretical calculation: [M+H] + =289.0, measured value 288.9.

[0231] Step 5

[0232] C-7 (1.72 g, 5.96 mmol) was dissolved in acetonitrile (20 mL), and cesium carbonate (2.33 g, 7.15 mmol) was added. The mixture was stirred at 50 °C for 30 minutes, and benzyl chloride (830 mg, 6.56 mmol) was slowly added dropwise. The mixture was stirred at 50 °C for 16 hours. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic layers were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 1 / 0, v / v) to obtain C-8. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 8.05 (d, J = 8.8Hz, 1H), 7.93 (d, J = 8.8Hz, 1H), 7.45–7.35 (m, 2H), 7.34–7.20 (m, 5H), 5.20 (s, 2H), 2.13 (s, 3H). ESI-MS theoretical calculation: [M+H] + =379.1, measured value 379.2.

[0233] Step 6

[0234] C-8 (1.88 g, 4.96 mmol) was dissolved in dry THF (50 mL) under a nitrogen atmosphere and cooled to -78 °C. TMPMgCl-LiCl (1 mol / L tetrahydrofuran solution, 5.95 mL, 5.95 mmol) was added, and the mixture was heated to -40 °C and stirred for 2 hours. DMF (1.09 g, 14.88 mmol) was added dropwise, and the mixture was stirred for 1 hour. After the reaction was complete, saturated ammonium chloride solution (50 mL) and water (50 mL) were added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain C-9. 1 ¹H NMR (400MHz, DMSO-d6): δ 10.25 (s, 1H), 8.18 (s, 1H), 7.45 (s, 1H), 7.41 (s, 1H), 7.33–7.23 (m, 5H), 5.22 (s, 2H), 2.17 (s, 3H). ESI-MS theoretical calculation: [M+H] + =407.1, measured value 406.9.

[0235] Step 7

[0236] C-9 (900 mg, 2.21 mmol) was dissolved in THF (50 mL), cooled to 0 °C, and sodium borohydride (84 mg, 2.21 mmol) was added. The mixture was stirred for 30 minutes. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v). 50 mL of water was slowly added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain intermediate C. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.84 (s, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.35–7.22 (m, 5H), 5.89 (t, J = 5.2Hz, 1H), 5.22 (s, 2H), 4.65 (d, J = 5.2Hz, 2H), 2.13 (s, 3H). ESI-MS theoretical calculation: [M+H] + =409.1, measured value 409.0.

[0237] Intermediate D

[0238] Synthesis route:

[0239] first step

[0240] D-1 (25 g, 164.27 mmol) was dissolved in tetrahydrofuran (135 mL), cooled to 0 °C, and N,N,N',N'-tetramethylethylenediamine (22.91 g, 197.12 mmol) was added. The mixture was stirred for 30 minutes, and then n-butyllithium (2.5 mol / L n-hexane solution, 78.85 mL, 197.12 mmol) was added dropwise. The mixture was stirred for 3 hours, and then ethylene oxide (14.47 g, 328.54 mmol) was added dropwise. The mixture was then heated to room temperature and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to obtain D-2. 1 ¹H NMR (400MHz, CDCl₃): δ 6.38 (s, 2H), 3.85–3.77 (m, 6H), 3.74 (t, J = 6.4Hz, 2H), 2.93 (t, J = 6.4Hz, 2H), 2.34 (s, 3H). ESI-MS theoretical values ​​[M+H] + =197.1, measured value 197.0.

[0241] Step 2

[0242] D-2 (10.5 g, 53.51 mmol) was dissolved in dichloromethane (200 mL), cooled to 0 °C, and then boron tribromide (11.34 mL, 117.72 mmol) was added. The mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to 0 °C, quenched dropwise with methanol (20 mL), concentrated under reduced pressure to remove the methanol, diluted with water (100 mL), extracted with dichloromethane (100 mL × 3), and the organic layers were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing D-3. This crude product was used directly in the next reaction without further purification. ESI-MS theoretical calculation value [M+H] + =233.0, measured value 232.9.

[0243] Step 3

[0244] D-3 (11 g, 47.60 mmol) was dissolved in acetone (510 mL), and potassium carbonate (32.89 g, 238.00 mmol) was added. The mixture was heated to 70 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure to remove acetone, diluted with saturated ammonium chloride solution (150 mL), extracted with dichloromethane (100 mL × 3), and the organic layers were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 3, v / v) to obtain D-4. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 9.24 (br s, 1H), 6.10 (s, 1H), 6.05 (s, 1H), 4.44 (t, J = 8.8Hz, 2H), 2.96 (t, J = 8.8Hz, 2H), 2.13 (s, 3H). ESI-MS theoretical calculations [M+H] + =151.1, measured value 151.1.

[0245] Step 4

[0246] D-4 (7.7 g, 51.28 mmol) was dissolved in toluene (150 mL), cooled to 0 °C, and N-iodosuccinimide (11.54 g, 51.28 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane, 1 / 3, v / v) to obtain D-5. ESI-MS theoretical calculation [M+H] + =277.0, measured value 277.0.

[0247] Step 5

[0248] D-5 (11.5 g, 41.66 mmol) and potassium carbonate (23.03 g, 166.64 mmol) were dissolved in N,N-dimethylformamide (115 mL), and D-6 (6.95 g, 62.49 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic layers were combined. The layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1, v / v) to obtain D-7. 1 H NMR (400MHz, DMSO-d6): δ6.60(s,1H),5.16(s,2H),4.52(t,J=8.8Hz,2H),3.7 8(q,J=7.2Hz,2H),3.28(t,J=8.8Hz,2H),2.34(s,3H),1.16(t,J=7.2Hz,3H).

[0249] Step 6

[0250] D-7 (7.25 g, 21.70 mmol) was dissolved in tetrahydrofuran (75 mL), and D-8 (12.49 g, 65.1 mmol) was added. The mixture was cooled to -78 °C, and n-butyllithium (2.5 mol / L n-hexane solution, 21.7 mL, 54.25 mmol) was added dropwise. The mixture was stirred at -78 °C for 1 hour. After the reaction was complete, saturated ammonium chloride (200 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL × 3), and the organic layers were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1, v / v) to obtain intermediate D. 1 H NMR (400MHz, DMSO-d6): δ6.34(s,1H),5.06(s,2H),4.47(t,J=8.8Hz,2H),3.70(d,J= 7.2Hz,2H),3.17(t,J=8.80Hz,2H),2.21(s,3H),1.28(s,12H),1.13(t,J=7.2Hz,3H).

[0251] Examples 1 and 2

[0252] Synthesis route:

[0253] first step

[0254] Dissolve 1-1 (2.0 g, 10.14 mmol) in dry tetrahydrofuran (10 mL), cool to 0 °C under nitrogen protection, add 1-2 (0.5 mol / L tetrahydrofuran solution, 20.28 mL, 10.14 mmol), heat to 25 °C and stir for 10 minutes, then heat to 70 °C and stir for 1 hour. After the reaction is complete, cool to room temperature and concentrate under reduced pressure to obtain a crude product containing 1-3, which can be used directly in the next reaction without purification.

[0255] Step 2

[0256] Intermediate A (600 mg, 1.43 mmol), 1-3 (2.28 g, 7.15 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl (68 mg, 0.14 mmol), and sodium carbonate (450 mg, 4.29 mmol) were added to 1,4-dioxane (15 mL) and water (3 mL). Under nitrogen protection, methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (120 mg, 0.14 mmol) was added, and the mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete and cooled to room temperature, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 5 / 1, v / v) to obtain 1–4. ESI-MS theoretical calculation: [M+H] + =597.3, measured value 597.3.

[0257] Step 3

[0258] Dissolve 1-4 (850 mg, 1.42 mmol) in dry dichloromethane (8 mL), cool to -78 °C, and then add diisobutylaluminum hydride (1.0 mol / L n-hexane solution, 4.26 mL, 4.26 mmol) dropwise. Stir for 2 hours, then dilute the reaction solution with ether (10 mL), raise the temperature to 0 °C, and then add water (0.17 mL), 15% sodium hydroxide aqueous solution (0.17 mL), and water (0.5 mL) sequentially. Stir for 15 minutes, then add anhydrous sodium sulfate, dry, filter, and concentrate under reduced pressure to obtain a crude product containing 1-5. No purification is required; this product can be used directly in the next reaction. ESI-MS theoretical calculation: [M+H] + =538.3, measured value 538.4.

[0259] Step 4

[0260] Dissolve 1-5 (700 mg, 1.30 mmol) in dry tetrahydrofuran (10 mL), cool to 0 °C under nitrogen protection, add sodium borohydride (70 mg, 1.95 mmol) in batches, raise the temperature to 25 °C and stir for 1 hour. After the reaction, the mixture was diluted with water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 3 / 1, v / v) to obtain a mixture of 1-6A and 1-6B. This mixture was then purified by supercritical fluid chromatography (column: Waters SFC 150, REGIS(S,S)WHELK-O1, 250*25mm 10μm; mobile phase: A was supercritical carbon dioxide, B was isopropanol (containing 0.1% 7.0 mol / L ammonia-methanol); gradient: mobile phase B was 20-20%; flow rate: 120 mL / min). The purification yielded 1-6A and 1-6B sequentially. 1-6A: retention time 4.4-5.2 min, ESI-MS theoretical value: [M+H] + =540.3, measured value 540.1. 1-6B: Retention time is 5.6-7.5 min, ESI-MS theoretical calculation value: [M+H] + =540.3, measured value 540.2.

[0261] Step 5

[0262] Dissolve 1-6A (70 mg, 0.13 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (0.5 mL), and stir at 25 °C for 2 hours. Concentrate the reaction solution under reduced pressure and dissolve it in methanol (1 mL). Add formaldehyde (37% aqueous solution, 0.13 mL) and sodium triacetoxyborohydride (83 mg, 0.39 mmol) sequentially, and stir at 25 °C for 2 hours. After the reaction is complete, concentrate under reduced pressure and purify by high-performance liquid chromatography (HPLC) (column: C18 spherical 20-30 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 15-25%; flow rate: 20 mL / min) to obtain 1 (retention time 32-40 min). 1¹H NMR (400MHz, DMSO-d⁶): δ 10.32 (br s, 1H), 7.57 (s, 1H), 7.18–7.09 (m, 2H), 4.63 (s, 2H), 3.01–2.86 (m, 2H), 2.83 (d, J = 8.0Hz, 2H), 2.34 (s, 3H), 2.29–2.20 (m, 2H), 2.14–2.12 (m, 1H), 2.07 (s, 3H), 1.72–1.69 (m, 2H), 1.58–1.49 (m, 1H), 1.16–1.08 (m, 1H). ESI-MS theoretical calculation: [M+H] + =396.2, measured value 396.4.

[0263] Using 1-6B (60 mg, 0.11 mmol) as raw material, 2 was obtained by high performance liquid chromatography (HPLC) under similar synthesis conditions (column: C18 spherical 20-30 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 15-25%; flow rate: 20 mL / min) (retention time 30-40 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.32 (br s, 1H), 7.57 (s, 1H), 7.16–7.10 (m, 2H), 4.63 (s, 2H), 3.00–2.87 (m, 2H), 2.83 (d, J = 8.0Hz, 2H), 2.35 (s, 3H), 2.29–2.21 (m, 2H), 2.15–2.10 (m, 1H), 2.07 (s, 3H), 1.72–1.69 (m, 2H), 1.59–1.49 (m, 1H), 1.16–1.08 (m, 1H). ESI-MS theoretical calculation: [M+H] + =396.2, measured value 396.1.

[0264] Examples 3, 4, 5 and 6

[0265] Synthesis route:

[0266] first step

[0267] Dissolve 3-2 (10.01 g, 60.5 mmol) in DMF (100 mL), cool to 0 °C, and add sodium hydride (60% in diatomaceous earth, 4.84 g, 121.1 mmol) in portions under nitrogen protection. Stir for 30 minutes, then add 3-1 (11.84 g, 72.6 mmol), raise the temperature to 25 °C, and stir for 2 hours. After the reaction is complete, dilute with saturated sodium chloride solution (300 mL), extract with ethyl acetate (300 mL × 3), combine the organic layers, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 3-3. 1 ¹H NMR (400MHz, CDCl₃): δ 8.55 (d, J = 2.0Hz, 1H), 8.50 (dd, J = 4.8, 1.6Hz, 1H), 7.73–7.65 (m, 1H), 7.35 (d, J = 0.8Hz, 1H), 7.27–7.19 (m, 1H), 5.36 (s, 1H), 4.24–4.14 (m, 2H), 2.32 (s, 3H), 1.20 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H] + =292.1, measured value 291.9.

[0268] Step 2

[0269] 3-3 (5.02 g, 17.1 mmol), 3-4 (7.60 g, 25.7 mmol), XPhos (408 mg, 0.86 mmol), and potassium phosphate (9.10 g, 42.8 mmol) were added to 1,4-dioxane (250 mL) and water (30 mL). Under nitrogen protection, XPhos-Pd-G3 (725 mg, 0.86 mmol) was added, and the mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (300 mL), extracted with ethyl acetate (200 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 1, v / v) to obtain 3-5. ESI-MS theoretical value: [M+H] + =508.2, measured value 508.3.

[0270] Step 3

[0271] Dissolve 3-5 (4.01 g, 7.88 mmol) in THF (80 mL), cool to 0 °C, and add LiAlH4 (1 mol / L tetrahydrofuran solution, 3.94 mL, 3.94 mmol) under nitrogen protection. Stir for 30 minutes. After the reaction is complete, dilute with saturated ammonium chloride solution (200 mL), extract with ethyl acetate (150 mL × 3), combine the organic layers, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 3-6. ESI-MS theoretical calculation: [M+H] + =466.2, measured value 466.3.

[0272] Step 4

[0273] Dissolve 3-6 (1.60 g, 3.44 mmol) in methanol (50 mL) and water (5 mL), add platinum dioxide (625 mg, 2.75 mmol) and di-tert-butyl dicarbonate (901 mg, 4.13 mmol), and stir at 25 °C for 16 hours after purging with hydrogen gas. After the reaction is complete, filter with diatomaceous earth. Concentrate the filtrate under reduced pressure and purify by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 3-7. ESI-MS theoretical calculation: [M+H] + =572.3, measured value 572.4.

[0274] Step 5

[0275] 3-7 (700 mg, 1.22 mmol) was subjected to supercritical fluid chromatography (column: Waters SFC 150). AD, 250*30mm 10μm; Mobile phase: A is supercritical carbon dioxide, B is isopropanol (containing 0.1% 7.0mol / L ammonia methanol); Gradient: mobile phase B is 75-75%; Flow rate: 140mL / min) Separation and purification yielded three components: 3-8A (retention time 5.0-6.4min), 3-8B (retention time 6.8-8.7min), and a mixture of 3-8C and 3-8D (retention time 9.5-13.8min). The mixture of 3-8C and 3-8D was then subjected to supercritical fluid chromatography (column: Waters SFC 150, 250*30mm 10μm); IC, 250*30mm 10μm; mobile phase: A is supercritical carbon dioxide, B is methanol (containing 0.1% 7.0mol / L ammonia methanol); gradient: mobile phase B is 75-75%; flow rate: 140mL / min) to separate and purify 3-8C (retention time 3.6-4.3min) and 3-8D (retention time 4.7-6.0min).

[0276] Step 6

[0277] 3-8A (180 mg, 0.31 mmol) was dissolved in methanol (50 mL), and wet palladium on carbon (10%, 20 mg, 0.02 mmol) was added. Hydrogen gas was bubbled through the solution, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain a crude product containing 3-9A, which could be used directly in the next reaction without further purification. ESI-MS theoretical calculation: [M+H] + =482.2, measured value 482.1.

[0278] Step 7

[0279] 3-9A (70 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain an oily substance, which was dissolved in methanol (5 mL). Formaldehyde (37% aqueous solution, 0.15 mL) and sodium triacetoxyborohydride (95 mg, 0.45 mmol) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 15-25%; flow rate: 20 mL / min) to obtain 3 (retention time 10.0-20.0 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.47 (s, 1H), 7.46 (d, J = 7.6Hz, 1H), 7.28 (s, 1H), 7.27 (d, J = 7.6Hz, 1H), 3.83 (d, J = 6.4Hz, 2H), 3.21–3.19 (m, 1H), 3.01–2.96 (m, 1H), 2.89–2.87 (m, 1H), 2.40 (s, 3H), 2.25–2.12 (m, 6H), 1.69–1.58 (m, 1H), 1.50–140 (m, 1H), 1.34–1.31 (m, 1H), 0.94–0.85 (m, 1H). ESI-MS theoretical calculation: [M+H] + =396.2, measured value 396.4.

[0280] Similarly, using 3-8B (90 mg, 0.16 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-30 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 5-45%; flow rate: 20 mL / min) to obtain 4 (retention time 21.5-29.5 min). 1 H NMR (400MHz, DMSO-d6): δ7.49(s,1H),7.47(d,J=8.0Hz,1H),7.29(s,1H),7.27(d,J= 8.0Hz,1H),7.28-7.25(m,1H),3.92-3.78(m,2H),3.00-2.88(m,2H),2.69-2.59(m,1 2.30 (s, 3H), 2.40-2.19 (m, 1H), 2.19-2.12 (m, 4H), 2.10-2.00 (m, 1H), 1.97-1.90 (m, 1H), 1.79-1.68 (m, 1H), 1.63-1.49 (m, 1H), 1.15-1.00 (m, 1H). ESI-MS theoretical calculation: [M+H] + =396.2, measured value 396.4.

[0281] Similarly, using 3-8C (130 mg, 0.23 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (chromatographic column: C18 spherical 20-35 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 15-20%; flow rate: 20 mL / min) to obtain 5 (retention time 10.0-18.0 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.48 (s, 1H), 7.46 (d, J = 8.0Hz, 1H), 7.28 (s, 1H), 7.27 (d, J = 8.0Hz, 1H), 3.83 (d, J = 8.0Hz, 2H), 3.22–3.21 (m, 1H), 3.01–2.96 (m, 1H), 2.91–2.88 (m, 1H), 2.41 (s, 3H), 2.26–2.11 (m, 6H), 1.67–1.58 (m, 1H), 1.53–1.38 (m, 1H), 1.35–1.32 (m, 1H), 0.95–0.87 (m, 1H). ESI-MS theoretical calculation: [M+H] + =396.2, measured value 396.1.

[0282] Similarly, using 3-8D (120 mg, 0.21 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-30 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 5-45%; flow rate: 20 mL / min) to obtain 6 (retention time 18.5-26.5 min). 1 H NMR (400MHz, DMSO-d6): δ10.58(br s,1H),7.48(s,1H),7.46(d,J=8.0Hz,1H),7.27(d,J=8.0Hz,1H),7.26(s,1H),4 .68-4.58(m,1H),3.90-3.75(m,2H),2.96-2.84(m,1H),2.69-2.60(m,1H),2.32- 2.24 (m, 1H), 2.17 (s, 3H), 2.09–1.99 (m, 4H), 1.97–1.87 (m, 1H), 1.82–1.73 (m, 1H), 1.69–1.61 (m, 1H), 1.57–1.42 (m, 2H), 1.06–0.92 (m, 1H). ESI-MS theoretical calculation: [M+H] + =396.2, measured value 396.1.

[0283] Examples 7, 8, 9 and 10

[0284] Synthesis route:

[0285] first step

[0286] 7-1 (2.20 g, 7.91 mmol), 7-2 (1.77 g, 11.87 mmol), and potassium carbonate (2.19 g, 15.82 mmol) were added to 1,4-dioxane (300 mL) and water (40 mL). XPhos-Pd-G3 (320 mg, 0.40 mmol) was added under nitrogen protection, and the mixture was heated to 100 °C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (500 mL), extracted with ethyl acetate (500 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 3, v / v) to obtain 7-3. 1¹H NMR (400MHz, CDCl₃): δ 7.59 (d, J = 8.8Hz, 1H), 7.46 (d, J = 8.8Hz, 1H), 7.36 (s, 1H), 7.26 (s, 1H), 5.15 (s, 2H), 3.57 (q, J = 7.2Hz, 2H), 2.21 (s, 3H), 1.16 (t, J = 6.8Hz, 3H). ESI-MS theoretical calculation: [M+H] + =347.1, measured value 346.9.

[0287] Step 2

[0288] 7-3 (300 mg, 0.87 mmol), intermediate B (782 mg, 1.74 mmol), and potassium carbonate (301 mg, 2.17 mmol) were added to 1,4-dioxane (15 mL) and water (3 mL). XPhos-Pd-G3 (74 mg, 87 μmol) was added under nitrogen protection, and the mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 4, v / v) to obtain 7-4A and 7-4B, respectively. 7-4A: ESI-MS theoretical value: [M+H] + =640.3, measured value 640.6. 7-4B: ESI-MS theoretical calculation value: [M+H] + =640.3, measured value 640.4.

[0289] Step 3

[0290] 7-4A (300 mg, 0.47 mmol) was dissolved in THF (5 mL), and tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 0.70 mL, 0.70 mmol) was added dropwise. The mixture was stirred for 2 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate on the organic layer, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 7-5A. ESI-MS theoretical calculation: [M+H] + =526.3, measured value 526.1.

[0291] Similarly, using 7-4B (240 mg, 0.47 mmol) as the starting material, 7-5B was obtained through the corresponding reaction steps and purification by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v). ESI-MS theoretical calculation: [M+H] +=526.3, measured value 526.1.

[0292] Step 4

[0293] 7-5A (170 mg, 0.32 mmol) was subjected to supercritical fluid chromatography (column: Waters SFC 150). IC, 250*40mm 10μm; Mobile phase: A is supercritical carbon dioxide, B is ethanol (containing 0.1% 7.0mol / L ammonia-methanol); Gradient: Mobile phase B is 85-85%; Flow rate: 150mL / min) Separation and purification yielded 7-6A (retention time 9.9-11.0min) and 7-6B (retention time 11.5-13.2min). 7-6A: ESI-MS theoretical calculation value: [M+H] + =526.3, measured value 526.1. 7-6B: ESI-MS theoretical calculation value: [M+H] + =526.3, measured value 526.2.

[0294] 7-5B (140 mg, 0.27 mmol) was subjected to supercritical fluid chromatography (column: Waters SFC 150). IC, 250*40mm 10μm; Mobile phase: A is supercritical carbon dioxide, B is methanol (containing 0.1% 7.0mol / L ammonia methanol); Gradient: Mobile phase B is 85-85%; Flow rate: 150mL / min) Separation and purification yielded 7-6C (retention time 9.9-11.2min) and 7-6D (retention time 11.8-12.9min). 7-6C: ESI-MS theoretical calculation value: [M+H] + =526.3, measured value 526.2. 7-6D: ESI-MS theoretical calculation value: [M+H] + =526.3, measured value 526.1.

[0295] Step 5

[0296] 7-6A (48 mg, 0.09 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure and dissolved in methanol (1 mL). Formaldehyde (37% aqueous solution, 0.60 mL) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda XBridge C18 19*250 mm, 10 μm; mobile phase: A was an aqueous solution containing 0.05% ammonia monohydrate, B was acetonitrile; gradient: mobile phase B was 20-30%; flow rate: 20 mL / min) to obtain 7 (retention time 6.5-8.3 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.27 (br s, 1H), 7.62 (d, J = 8.4Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 4.64–4.54 (m, 1H), 3.72–3.62 (m, 1H), 3.08–2.98 (m, 1H), 2.96–2.86 (m, 1H), 2.38–2.28 (m, 2H), 2.21–2.11 (m, 3H), 2.10 (s, 3H), 2.08 (s, 3H), 1.68–1.58 (m, 2H). ESI-MS theoretical calculation: [M+H] + =382.2, measured value 382.1.

[0297] Similarly, using 7-6B (45 mg, 0.09 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda XBridge C18 19*250 mm, 10 μm; mobile phase: A is an aqueous solution containing 0.05% ammonia monohydrate, B is acetonitrile; gradient: mobile phase B is 20-30%; flow rate: 20 mL / min) to obtain 8 (retention time 6.0-8.0 min). 1¹H NMR (400MHz, DMSO-d⁶): δ 10.34 (br s, 1H), 7.61 (d, J = 8.4Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.15 (s, 1H), 7.10 (s, 1H), 4.64–4.54 (m, 1H), 3.72–3.62 (m, 1H), 3.08–2.98 (m, 1H), 2.96–2.86 (m, 1H), 2.37–2.27 (m, 2H), 2.21–2.11 (m, 3H), 2.11 (s, 3H), 2.08 (s, 3H), 1.68–1.58 (m, 2H). ESI-MS theoretical calculation: [M+H] + =382.2, measured value 382.1.

[0298] Similarly, using 7-6C (48 mg, 0.09 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda XBridge C18 19*250 mm, 10 μm; mobile phase: A is an aqueous solution containing 0.05% ammonia monohydrate, B is acetonitrile; gradient: mobile phase B is 19-29%; flow rate: 20 mL / min) to obtain 9 (retention time 7.1-8.6 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.26 (br s, 1H), 7.62–7.58 (m, 2H), 7.15 (s, 1H), 7.10 (s, 1H), 4.81 (d, J = 5.4Hz, 1H), 3.45–3.35 (m, 1H), 3.22–3.07 (m, 1H), 2.73–2.58 (m, 2H), 2.57–2.50 (m, 1H), 2.08 (s, 3H), 2.06 (s, 3H), 1.98–1.86 (m, 2H), 1.85–1.75 (m, 1H), 1.74–1.65 (m, 1H), 1.57–1.40 (m, 1H). ESI-MS theoretical calculation: [M+H] + =382.2, measured value 382.0.

[0299] Similarly, using 7-6D (50 mg, 0.10 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda XBridge C18 19*250 mm, 10 μm; mobile phase: A is an aqueous solution containing 0.05% ammonia monohydrate, B is acetonitrile; gradient: mobile phase B is 24-34%; flow rate: 20 mL / min) to obtain 10 (retention time 4.7-6.6 min). 1¹H NMR (400MHz, DMSO-d⁶): δ 10.29 (br s, 1H), 7.62–7.58 (m, 2H), 7.15 (s, 1H), 7.09 (s, 1H), 4.82 (d, J = 5.4Hz, 1H), 3.46–3.36 (m, 1H), 3.21–3.09 (m, 1H), 2.74–2.59 (m, 2H), 2.56–2.49 (s, 1H), 2.08 (s, 3H), 2.07 (s, 3H), 1.95–1.86 (m, 2H), 1.85–1.76 (m, 1H), 1.75–1.66 (m, 1H), 1.53–1.43 (m, 1H). ESI-MS theoretical calculation: [M+H] + =382.2, measured value 382.1.

[0300] Examples 11, 12, 13 and 14

[0301] Synthesis route:

[0302] first step

[0303] Dissolve 1-5 (440 mg, 0.82 mmol) in THF (5 mL), cool to -78 °C, and add methyl magnesium bromide (1 mol / L tetrahydrofuran solution, 1.64 mL, 1.64 mmol) dropwise under nitrogen protection. Stir at -78 °C for 1 hour. After the reaction is complete, quench the reaction with saturated ammonium chloride solution (50 mL), raise the temperature to 25 °C, extract with ethyl acetate (50 mL × 3), combine the organic layers, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 11-1. ESI-MS theoretical calculation: [M+H] + =554.3, measured value 554.3.

[0304] Step 2

[0305] 11-1 (411 mg, 0.74 mmol) was subjected to supercritical fluid chromatography (column: Waters SFC 150). AD, 250*30mm 10μm; Mobile phase: A is supercritical carbon dioxide, B is isopropanol (containing 0.1% 7.0mol / L ammonia methanol); Gradient: mobile phase B is 90-90%; Flow rate: 140mL / min) Separation and purification yielded three components: a mixture of 11-2A and 11-2B (retention time 12.5-18.0min), 11-2C (retention time 20.5-24.0min), and 11-2D (retention time 26.0-35.0min). The mixture of 11-2A and 11-2B was then subjected to supercritical fluid chromatography (column: Waters SFC 150, 250*30mm 10μm); IG, 250*30mm 10μm; mobile phase: A is supercritical carbon dioxide, B is isopropanol (containing 0.1% 7.0mol / L ammonia methanol); gradient: mobile phase B is 80-80%; flow rate: 140mL / min) to separate and purify 11-2A (retention time 2.5-3.3min) and 11-2B (retention time 3.8-4.8min).

[0306] Step 3

[0307] 11-2A (64 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure and dissolved in methanol (3 mL). Formaldehyde (37% aqueous solution, 0.80 mL) and sodium triacetoxyborohydride (68 mg, 0.32 mmol) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 12 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 20-26%; flow rate: 15 mL / min) to obtain 11 (retention time 16.0-28.0 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.60 (s, 1H), 7.14 (s, 1H), 7.12 (s, 1H), 4.95 (q, J = 6.4Hz, 1H), 2.97–2.81 (m, 2H), 2.72–2.62 (m, 2H), 2.27–2.18 (m, 1H), 2.15 (s, 3H), 2.07 (s, 3H), 2.02–1.92 (m, 1H), 1.86–1.76 (m, 1H), 1.71–1.61 (m, 2H), 1.52–1.42 (m, 1H), 1.34 (d, J = 6.4Hz, 3H), 1.15–1.05 (m, 1H). ESI-MS theoretical calculation: [M+H] +=410.2, measured value 410.1.

[0308] Similarly, using 11-2B (90 mg, 0.16 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 12 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 18-21%; flow rate: 15 mL / min) to obtain 12 (retention time 17.0-30.0 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.61 (s, 1H), 7.15 (s, 1H), 7.12 (s, 1H), 4.95 (q, J = 6.4Hz, 1H), 2.99–2.82 (m, 2H), 2.82–2.65 (m, 2H), 2.31–2.21 (m, 1H), 2.20 (s, 3H), 2.08 (s, 3H), 2.05–1.96 (m, 1H), 1.96–1.84 (m, 1H), 1.73–1.63 (m, 2H), 1.54–1.44 (m, 1H), 1.34 (d, J = 6.4Hz, 3H), 1.19–1.01 (m, 1H). ESI-MS theoretical calculation: [M+H] + =410.2, measured value 410.1.

[0309] Similarly, using 11-2C (108 mg, 0.20 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda SunFire C18 19*250 mm, 10 μm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 15-35%; flow rate: 20 mL / min) to obtain 13 (retention time 8.0-9.5 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.28 (br s, 1H), 7.61 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 5.56 (s, 1H), 4.94 (q, J = 6.4Hz, 1H), 2.96–2.89 (m, 3H), 2.88–2.80 (m, 1H), 2.37–2.27 (m, 4H), 2.24–2.14 (m, 1H), 2.16–2.06 (m, 1H), 2.08 (s, 3H), 1.75–1.65 (m, 2H), 1.61–1.44 (m, 1H), 1.34 (d, J = 6.4Hz, 3H), 1.16–1.06 (m, 1H). ESI-MS theoretical calculation: [M+H]+ =410.2, measured value 410.1.

[0310] Similarly, using 11-2D (104 mg, 0.19 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda SunFire C18 19*250 mm, 10 μm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 15-35%; flow rate: 20 mL / min) to obtain 14 (retention time 8.3-9.4 min). 1 H NMR (400MHz, DMSO-d6): δ10.28(br s, 1H), 7.61(s, 1H), 7.16(s, 1H), 7.11(s, 1H), 5.55-5.45(m, 1H), 4.94(q, J = 6.4 Hz, 1H), 2.95-2.87(m, 3H), 2.86-2.78(m, 1H), 2.35-2.25(m, 4H), 2.21-2.11(m, 1H), 2.08(s, 3H), 2.08-1.98(m, 1H), 1.74-1.64(m, 2H), 1.57-1.47(m, 1H), 1.34(d, J = 6.4 Hz, 3H), 1.16-1.06(m, 1H). ESI-MS theoretical calculation: [M+H] + =410.2, measured value 410.1.

[0311] Examples 15 and 16

[0312] Synthesis route:

[0313] first step

[0314] Dissolve 1-6A (77 mg, 0.14 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure and dissolve it in ethanol (3 mL). Add acetaldehyde (0.02 mL) and sodium triacetoxyborohydride (85 mg, 0.40 mmol) sequentially, and stir at 25 °C for 1 hour. After the reaction is complete, concentrate under reduced pressure and purify by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda XBridge C18 19*250 mm, 10 μm; mobile phase: A is an aqueous solution containing 0.05% ammonia monohydrate, B is acetonitrile; gradient: mobile phase B is 17-37%; flow rate: 20 mL / min) to obtain 15 (retention time 8.5-10.0 min). 1H NMR (400MHz, DMSO-d6): δ10.23(br s, 1H), 7.56(s, 1H), 7.15(s, 1H), 7.10(s, 1H), 5.63-5.53(m, 1H), 4.67-4.58(m, 2H), 2.87-2.76(m, 2H), 2.77-2.68(m, 2H), 2.27(q, J = 7.2Hz, 2H), 2.18-2.09(m, 1H), 2.06(s, 3H), 1.93-1.83(m, 1H), 1.80-1.70(m, 1H), 1.69-1.60(m, 2H), 1.49-1.40(m, 1H), 1.14-1.00(m, 1H), 0.94(t, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H] + =410.2, measured value 410.1.

[0315] Similarly, using 1-6B (98 mg, 0.26 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda XBridge C18 19*250 mm, 10 μm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 17-25%; flow rate: 20 mL / min) to obtain 16 (retention time 9.0-10.3 min). 1 H NMR (400MHz, DMSO-d6): δ10.33(br s, 1H), 7.57(s, 1H), 7.16(s, 1H), 7.11(s, 1H), 4.67-4.60(m, 2H), 2.94-2.84(m, 2H), 2.85-2.77(m, 2H), 2.45(d, J = 7.2Hz, 2H), 2.28-2.19(m, 1H), 2.18-2.10(m, 1H), 2.07(s, 3H), 2.05-1.95(m, 1H), 1.74-1.64(m, 2H), 1.55-1.47(m, 1H), 1.17-1.07(m, 1H), 1.01(t, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H] + =410.2, measured value 410.1.

[0316] Examples 17, 18, 19 and 20

[0317] Synthesis route:

[0318] first step

[0319] Lithium bis(trimethylsilyl)amino (1 mol / L tetrahydrofuran solution, 48.39 mL, 48.39 mmol) was dissolved in THF (110 mL) and cooled to -78 °C. 17-1 (10.00 g, 43.99 mmol) was dissolved in THF (20 mL) and added dropwise to the above solution, with stirring continued at -78 °C for 90 minutes. N-Phenylbis(trifluoromethanesulfonyl)imide (17.29 g, 48.39 mmol) was dissolved in THF (20 mL) and added dropwise to the above reaction solution, with stirring at 25 °C for 3 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (100 mL) was added, followed by extraction with ethyl acetate (500 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain 17-2. 1 H NMR (400MHz, CDCl3): δ5.17-5.07(m,1H),4.99-4.89(m,1H),4.14-4.00(m,1H),3.89-3.79(m,1H) ,2.84-2.71(m,2H),2.39-2.29(m,1H),1.99-1.89(m,1H),1.70-1.60(m,1H),1.48-1.32(m,11H).

[0320] Step 2

[0321] 17-2 (7.65 g, 21.29 mmol) was dissolved in toluene (80 mL), and pinacol diboronate (8.11 g, 31.93 mmol), triphenylphosphine (560 mg, 2.13 mmol), potassium phenolate (4.22 g, 31.93 mmol), and palladium dichloride bis(triphenylphosphine) (750 mg, 1.06 mmol) were added. The mixture was heated to 55 °C and stirred for 3 hours under nitrogen protection, then cooled to 25 °C and stirred for 8 hours. After the reaction was complete, the mixture was diluted with saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (500 mL × 3), and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate 20 / 1, v / v) to obtain the crude product. The crude product was dissolved in diethyl ether (50 mL), washed with sodium hydroxide solution (1 mol / L, 150 mL × 3), concentrated under reduced pressure, and dried to obtain 17-3. 1H NMR (400MHz, CDCl3): δ5.83(d,J=2.4Hz,1H),5.64(d,J=1.8Hz,1H),4.15-4.00(m,2H),2.65-2.55(m, 2H),2.28-2.20(m,1H),1.86-1.78(m,1H),1.68-1.59(m,1H),1.53-1.37(m,11H),1.29-1.19(m,12H).

[0322] Step 3

[0323] 17-3 (560 mg, 1.66 mmol), intermediate C (340 mg, 0.83 mmol), and potassium phosphate (704 mg, 3.32 mmol) were added to 1,4-dioxane (10 mL) and water (2 mL). Cata CXium A-Pd-G3 (60 mg, 0.08 mmol) was added under nitrogen protection, and the mixture was heated to 110 °C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 2, v / v) to obtain 17-4. ESI-MS theoretical value: [M+H] + =584.3, measured value 584.2.

[0324] Step 4

[0325] 17-4 (453 mg, 0.78 mmol) was dissolved in methanol (30 mL), and wet palladium on carbon (10%, 45 mg, 0.04 mmol) was added. Hydrogen gas was bubbled through the solution, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 2, v / v) to obtain 17-5. ESI-MS theoretical calculation: [M+H] + =496.2, measured value 496.2.

[0326] Step 5

[0327] 17-5 (270 mg, 0.54 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure and dissolved in methanol (3 mL). Formaldehyde (37% aqueous solution, 0.54 mL) and sodium triacetoxyborohydride (343 mg, 1.62 mmol) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 18-23%; flow rate: 15 mL / min) to obtain three components: 17 (retention time 2.1-2.7 min), a mixture of 18 and 19 (retention time 3.0-4.0 min), and 20 (retention time 6.0-8.0 min). The mixture of 18 and 19 was subjected to supercritical fluid chromatography (column: Waters SFC 150). IG, 250*30mm 10μm; mobile phase: A is supercritical carbon dioxide, B is ethanol (containing 0.1% 7.0mol / L ammonia methanol); gradient: mobile phase B is 20-20%; flow rate: 140mL / min) to separate and purify to obtain 18 (retention time 3.1-4.0min) and 19 (retention time 4.2-6.5min).

[0328] 17: 1 H NMR (400MHz, DMSO-d6): δ10.24(br s, 1H), 7.54(s, 1H), 7.15(s, 1H), 7.11(s, 1H), 5.58(t, J = 4.8 Hz, 1H), 4.68-4.58(m, 2H), 2.95-2.90(m, 2H), 2.64-2.61(m, 1H), 2.18(s, 3H), 2.14-2.08(m, 1H), 2.06(s, 3H), 1.87-1.71(m, 2H), 1.59-1.47(m, 1H), 1.41-1.32(m, 1H), 1.28(d, J = 6.8 Hz, 3H), 1.26-1.16(m, 1H), 0.90-0.80(m, 1H). ESI-MS theoretical calculation: [M+H] + =410.2, measured value 410.3.

[0329] 18: 1¹H NMR (400MHz, DMSO-d⁶): δ 7.54 (s, 1H), 7.04–6.94 (m, 2H), 5.65–5.55 (m, 1H), 4.67–4.57 (m, 2H), 2.99–2.84 (m, 1H), 2.59–2.49 (m, 1H), 2.18–2.13 (m, 2H), 2.04 (s, 3H), 1.97 (s, 3H), 1.90–1.86 (m, 2H), 1.70–1.65 (m, 1H), 1.57–1.46 (m, 2H), 1.28 (d, J = 6.8Hz, 3H), 1.17–1.01 (m, 1H). ESI-MS theoretical calculation: [M+H] + =410.2, measured value 410.1.

[0330] 19: 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.54 (s, 1H), 7.07–6.97 (m, 2H), 5.67–5.57 (m, 1H), 4.71–4.48 (m, 2H), 3.01–2.84 (m, 2H), 2.63–2.60 (m, 1H), 2.18 (s, 3H), 2.11–2.09 (m, 1H), 2.05 (s, 3H), 1.83–1.72 (m, 2H), 1.56–1.47 (m, 1H), 1.39–1.36 (m, 1H), 1.28 (d, J = 6.8Hz, 3H), 1.26–1.16 (m, 1H), 0.91–0.74 (m, 1H). ESI-MS theoretical calculation: [M+H] + =410.2, measured value 410.1.

[0331] 20: 1 ¹H NMR (400MHz, DMSO-d6): δ 10.47 (br s, 1H), 7.54 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 5.66–5.56 (m, 1H), 4.69–4.59 (m, 2H), 3.01–2.83 (m, 1H), 2.57–2.54 (m, 1H), 2.20–2.11 (m, 2H), 2.06 (s, 3H), 1.98 (s, 3H), 1.92–1.84 (m, 2H), 1.75–1.63 (m, 1H), 1.61–1.41 (m, 2H), 1.29 (d, J = 6.8Hz, 3H), 1.18–1.01 (m, 1H). ESI-MS theoretical calculation: [M+H] + =410.2, measured value 410.0.

[0332] Examples 21, 22, 23 and 24

[0333] Synthesis route:

[0334] first step

[0335] 21-1 (4.0 g, 18.8 mmol) was dissolved in THF (40 mL), cooled to 0 °C under nitrogen protection, and sodium hydride (60% by mass, 900 mg, 22.5 mmol) was added. After stirring for 30 minutes, iodomethane (5.33 g, 37.5 mmol) was added, and stirring was continued at 0 °C for 1 hour. After the reaction was complete, the mixture was diluted with water (200 mL), extracted with ethyl acetate (150 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 15, v / v) to obtain 21-2. 1 H NMR(400 MHz, DMSO-d6): δ5.04-4.96(m,2H),3.94-3.85(m,1H),3.81-3.67(m,2H),3.51-3.41(m, 1H),3.39-3.30(m,1H),3.20(s,3H),1.80-1.70(m,1H),1.66-1.57(m,1H),1.40(s,9H).

[0336] Step 2

[0337] 21-2 (1.47 g, 6.47 mmol) was dissolved in dry THF (20 mL), cooled to 0°C, and 1-2 (0.5 mol / L tetrahydrofuran solution, 12.94 mL, 6.47 mmol) was added. The mixture was heated to 25°C and stirred for 10 minutes, then heated to 70°C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product containing 21-3. This crude product was used directly in the next reaction without further purification.

[0338] Step 3

[0339] 21-3 (2.31 g, 6.60 mmol), intermediate C (900 mg, 2.20 mmol), and potassium phosphate (1.40 g, 6.60 mmol) were added to 1,4-dioxane (20 mL) and water (4 mL). XPhos-Pd-G3 (160 mg, 220 μmol) was added under nitrogen protection, and the mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 2, v / v) to obtain mixture 21-4, which was directly used for the next purification step.

[0340] Step 4

[0341] 21-4 was separated by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda XBridge C18 19*250mm, 10μm; mobile phase: A was an aqueous solution containing 0.05% ammonia monohydrate, B was acetonitrile; gradient: mobile phase B was 65-65%; flow rate: 20mL / min) to obtain two components: a mixture of 21-4A and 21-4B (retention time 8.4-9.1min) and a mixture of 21-4C and 21-4D (retention time 9.2-10.2min).

[0342] The mixture of 21-4A and 21-4B was subjected to supercritical fluid chromatography (column: Waters SFC 150). IC, 250*30mm 10μm; Mobile phase: A is supercritical carbon dioxide, B is methanol (containing 0.1% 7.0mol / L ammonia methanol); Gradient: mobile phase B is 15-15%; Flow rate: 140mL / min) Separation and purification yielded 21-4A (retention time 6.2-7.5min) and 21-4B (retention time 8.6-11.2min). 21-4A: ESI-MS theoretical calculation value: [M+H] + =602.3, measured value 602.5. 21-4B: ESI-MS theoretical calculation value: [M+H] + =602.3, measured value 602.5.

[0343] The mixture of 21-4C and 21-4D was subjected to supercritical fluid chromatography (column: Waters SFC 150). IC, 250*30mm 10μm; Mobile phase: A is supercritical carbon dioxide, B is methanol (containing 0.1% 7.0mol / L ammonia methanol); Gradient: mobile phase B is 20-20%; Flow rate: 140mL / min) Separation and purification yielded 21-4C (retention time 3.2-4.1min) and 21-4D (retention time 4.6-6.5min). 21-4C: ESI-MS theoretical value: [M+H] + =602.3, measured value 602.2. 21-4D: ESI-MS theoretical calculation value: [M+H] + =602.3, measured value 602.6.

[0344] Step 5

[0345] 21-4A (117 mg, 0.19 mmol) was dissolved in methanol (20 mL), and wet palladium on carbon (10%, 15 mg, 14 μmol) was added. Hydrogen gas was bubbled through the solution, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain a crude product containing 21-5A, which could be used directly in the next reaction without further purification. ESI-MS theoretical calculation: [M+H] + =512.2, measured value 512.2.

[0346] Step 6

[0347] 21-5A (64 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was added. The mixture was stirred at 25 °C for 30 minutes. After the reaction, the solution was concentrated under reduced pressure to obtain an oily substance, which was redissolved in dichloromethane (2 mL), and the pH was adjusted to 7 with triethylamine. The solution was then concentrated again under reduced pressure at 0 °C to obtain an oily substance, which was further dissolved in methanol (5 mL). Formaldehyde (37% aqueous solution, 0.10 mL) and sodium triacetoxyborohydride (55 mg, 0.26 mmol) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. After the reaction, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 15-20%; flow rate: 15 mL / min) to obtain 21 (retention time 30.0-38.0 min). 1¹H NMR (400MHz, DMSO-d6): δ 10.23 (br s, 1H), 7.56 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 4.63 (s, 2H), 3.27 (s, 3H), 3.27–3.17 (m, 1H), 3.10–3.00 (m, 1H), 2.88–2.79 (m, 2H), 2.74–2.64 (m, 1H), 2.25 (s, 3H), 2.26–2.18 (m, 1H), 2.17–2.09 (m, 2H), 2.08 (s, 3H), 2.05–1.95 (m, 1H), 1.46–1.36 (m, 1H). ESI-MS theoretical calculation: [M+H] + =426.2, measured value 426.1.

[0348] Similarly, using 21-4B (72 mg, 0.12 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 18-21%; flow rate: 15 mL / min; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 16-19%; flow rate: 15 mL / min), 22 was obtained (retention time 28.0-36.0 min). 1 H NMR (400MHz, DMSO-d6): δ10.25(br s, 1H), 7.56(s, 1H), 7.16(s, 1H), 7.11(s, 1H), 4.63(s, 2H), 3.26(s, 3H), 3.23-3.18(m, 1H), 3.05-2.95(m, 1H), 2.77-2.70(m, 1H), 2.69-2.62(m, 2H), 2.19-2.14(m, 1H), 2.13(s, 3H), 2.12-2.09(m, 1H), 2.07(s, 3H), 2.06-1.98(m, 1H), 1.93-1.83(m, 1H), 1.43-1.33(m, 1H). ESI-MS theoretical calculation: [M+H] + =426.2, measured value 426.1.

[0349] Similarly, using 21-4C (96 mg, 0.16 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 15-20%; flow rate: 15 mL / min) to obtain 23 (retention time 25.0-36.0 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 10.24 (br s, 1H), 7.57 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 4.64 (s, 2H), 3.39–3.30 (m, 2H), 3.25 (s, 3H), 2.99–2.90 (m, 1H), 2.89–2.82 (m, 1H), 2.58 (s, 3H), 2.57–2.47 (m, 1H), 2.33 (s, 3H), 2.07 (s, 3H), 2.01–1.89 (m, 1H), 1.69–1.60 (m, 1H). ESI-MS theoretical calculation: [M+H] + =426.2, measured value 426.1.

[0350] Similarly, using 21-4D (116 mg, 0.19 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda XBridge C18 19*250 mm, 10 μm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 15-20%; flow rate: 15 mL / min) to obtain 24 (retention time 25.0-34.0 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 10.34 (br s, 1H), 7.57 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 4.64 (s, 2H), 3.37–3.32 (m, 2H), 3.25 (s, 3H), 2.99–2.90 (m, 1H), 2.89–2.82 (m, 1H), 2.59 (s, 3H), 2.56–2.47 (m, 1H), 2.35 (s, 3H), 2.07 (s, 3H), 2.01–1.89 (m, 1H), 1.69–1.59 (m, 1H). ESI-MS theoretical calculation: [M+H] + =426.2, measured value 426.1.

[0351] Examples 25, 26, 27 and 28

[0352] Synthesis route:

[0353] first step

[0354] A-3 (2.0 g, 5.98 mmol), intermediate D (2.12 g, 8.97 mmol), and potassium carbonate (1.65 g, 11.96 mmol) were added to 1,4-dioxane (120 mL) and water (30 mL). XPhos-Pd-G3 (488 mg, 600 μmol) was added under nitrogen protection, and the mixture was heated to 100 °C and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with saturated ammonium chloride solution (300 mL), extracted with ethyl acetate (300 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 3, v / v) to obtain 25-1. 1 H NMR (400MHz, DMSO-d6): δ7.99(s,1H),6.58(s,1H),4.96(s,2H),4.57(t,J=8. 8Hz,2H),3.53(s,3H),3.31-3.22(m,4H),2.01(s,3H),0.95(t,J=7.2Hz,3H).

[0355] Step 2

[0356] 25-1 (200 mg, 0.49 mmol), 17-3 (248 mg, 0.73 mmol), and potassium carbonate (260 mg, 1.23 mmol) were added to 1,4-dioxane (10 mL) and water (2 mL). XPhos-Pd-G3 (36 mg, 49 μmol) was added under nitrogen protection, and the mixture was heated to 110 °C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, diluted with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 3, v / v) to obtain 25-2. ESI-MS theoretical value: [M+H] + =583.3, measured value 583.3.

[0357] Step 3

[0358] 25-2 (650 mg, 1.12 mmol) was dissolved in methanol (15 mL), and wet palladium on carbon (10%, 65 mg, 0.61 mmol) was added. Hydrogen gas was bubbled through the solution, and the mixture was stirred at 45 °C for 2 hours. After the reaction was complete, the solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain a crude product containing 25-3, which could be used directly in the next reaction without further purification. ESI-MS theoretical calculation: [M+H] +=585.3, measured value 585.3.

[0359] Step 4

[0360] 25-3 (550 mg, 0.94 mmol) was dissolved in dry dichloromethane (15 mL), cooled to -70 °C, and then diisobutylaluminum hydride (1.0 mol / L n-hexane solution, 1.13 mL, 1.13 mmol) was added dropwise. The mixture was stirred for 1 hour, then saturated ammonium chloride solution (30 mL) was added, followed by extraction with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 5, v / v) to obtain 25-4. ESI-MS theoretical calculation: [M+H] + =526.3, measured value 526.2.

[0361] Step 5

[0362] 25-4 (350 mg, 1.30 mmol) was dissolved in dry THF (10 mL), cooled to 0 °C, and sodium borohydride (74 mg, 1.95 mmol) was added. The mixture was heated to 25 °C and stirred for 1 hour. Then, it was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 1, v / v) to obtain 25-5.

[0363] Step 6

[0364] 25-5 was subjected to supercritical fluid chromatography (column: Waters SFC 150). IH, 250*30mm 10μm; Mobile phase: A is supercritical carbon dioxide, B is isopropanol (containing 0.1% 7.0mol / L ammonia methanol); Gradient: mobile phase B is 10-10%; Flow rate: 140mL / min) Separation and purification yielded three components: 25-5A (retention time 11.5-13.0min), a mixture of 25-5B and 25-5C (retention time 14.0-16.2min), and 25-5D (retention time 18.0-22.0min).

[0365] The mixture of 25-5B and 25-5C was subjected again to supercritical fluid chromatography (column: Waters SFC 150). IG, 250*30mm 10μm; mobile phase: A is supercritical carbon dioxide, B is isopropanol (containing 0.1% 7.0mol / L ammonia methanol); gradient: mobile phase B is 35-35%; flow rate: 140mL / min) to separate and purify 25-5B (retention time 3.3-5.0min) and 25-5C (retention time 5.7-9.6min).

[0366] 25-5A: ESI-MS theoretical calculation value: [M+H] + =528.3, measured value 528.2. 25-5B: ESI-MS theoretical calculation value: [M+H] + =528.3, measured value 528.5. 25-5C: ESI-MS theoretical calculation value: [M+H] + =528.3, measured value 528.5. 25-5D: ESI-MS theoretical calculation value: [M+H] + =528.3, measured value 528.1.

[0367] Step 7

[0368] 25-5A (47 mg, 0.13 mmol) was dissolved in 1,4-dioxane (3 mL), and a 1,4-dioxane solution of hydrochloric acid (4.0 mol / L, 1 mL) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to obtain an oily substance, which was dissolved in dichloromethane (3 mL). The pH was adjusted to 7 with triethylamine, and the solution was concentrated under reduced pressure again to obtain an oily substance. The solution was then dissolved in methanol (5 mL), and formaldehyde (37% aqueous solution, 0.10 mL) and sodium triacetoxyborohydride (55 mg, 0.26 mmol) were added sequentially. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda SunFire C18 19*250mm, 5μm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 5-20%; flow rate: 20mL / min) to obtain 25 (retention time 10.0-10.5min). 1HNMR (400MHz, DMSO-d6): δ7.51(s,1H),6.29(s,1H),4.62(s,2H),4.55(t,J=8.8Hz,2 H),3.11(t,J=8.8Hz,2H),2.96-2.88(m,1H),2.68-2.61(m,1H),2.31-2.22(m,1H),2 .21-2.12 (m, 1H), 2.04 (s, 3H), 2.01-1.95 (m, 4H), 1.92-1.85 (m, 1H), 1.74-1.64 (m, 2H), 1.55-1.45 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H), 1.15-1.05 (m, 1H). ESI-MS theoretical calculation: [M+H] + =384.2, measured value 384.1.

[0369] Similarly, using 25-5B (25 mg, 0.05 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 12 g; mobile phase: A is 10 mmol / L ammonium bicarbonate aqueous solution, B is acetonitrile; gradient: mobile phase B is 5-40%; flow rate: 12 mL / min) to obtain 26 (retention time 35.0-45.0 min). 1 H NMR (400MHz, DMSO-d6): δ9.45 (br s, 1H), 7.51(s, 1H), 6.28(s, 1H), 5.58(s, 1H), 4.62(s, 2H), 4.55(t, J = 8.8 Hz, 2H), 3.11(t, J = 8.8 Hz, 2H), 2.97-2.86(m, 1H), 2.61-2.51(m, 1H), 2.21-2.11(m, 2H), 2.03-1.93(m, 6H), 1.91-1.82(m, 2H), 1.73-1.63(m, 1H), 1.57-1.51(m, 1H), 1.50-1.41(m, 1H), 1.28(d, J = 6.8 Hz, 3H), 1.14-1.04(m, 1H). ESI-MS theoretical calculation: [M+H] + =384.2, measured value 384.0.

[0370] Similarly, using 25-5C (43 mg, 0.08 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: Waters 3767 / Qda SunFire C18 19*250 mm, 5 μm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 10-30%; flow rate: 20 mL / min) to obtain 27 (retention time 7.5-7.8 min). 1 H NMR (400MHz, DMSO-d6): δ7.51(s,1H),6.28(s,1H),4.61(s,2H),4.55(t,J=8.8Hz,2H), 3.11(t,J=8.8Hz,2H),3.06-2.96(m,1H),2.93-2.87(m,1H),2.72-2.66(m,1H),2.23(s, 3H), 2.17-2.07(m,1H), 2.06-1.98(m,1H), 1.98(s,3H), 1.94-1.85(m,2H), 1.55-1.49(m,1H), 1.42-1.34(m,1H), 1.27(d,J=6.8Hz,3H), 0.91-0.81(m,1H). ESI-MS theoretical calculation: [M+H] + =384.2, measured value 384.0.

[0371] Similarly, using 25-5D (60 mg, 0.16 mmol) as the starting material, after the corresponding reaction steps, and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 12 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 15-25%; flow rate: 12 mL / min) to obtain 28 (retention time 7.5-7.8 min). 1H NMR (400MHz, DMSO-d6): δ9.44(br s,1H),7.51(s,1H),6.28(s,1H),5.53(s,1H),4.61(s,2H),4.54(t,J=8.8Hz,2H),3.1 1(t,J=8.8Hz,2H),3.06-2.97(m,1H),2.95-2.85(m,1H),2.74-2.67(m,1H),2.24(s,3H ), 2.16-2.06(m, 1H), 2.03-1.99(m, 1H), 1.98(s, 3H), 1.94-1.84(m, 2H), 1.57-1.47(m, 1H), 1.41-1.33(m, 1H), 1.27(d, J=6.8Hz, 3H), 0.92-0.83(m, 1H). ESI-MS theoretical calculation values: [M+H] + =384.2, measured value 384.0.

[0372] Example 29

[0373] Synthesis route:

[0374] first step

[0375] A mixture of 7-4A and 7-4B (440 mg, 0.69 mmol) was dissolved in THF (20 mL). After cooling to 0 °C, tetrabutylammonium fluoride (1.0 mol / L THF solution, 1.03 mL) was added, and the mixture was heated to 25 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 1, v / v) to obtain 29-1. ESI-MS theoretical calculation: [M+H] + =526.3, measured value 526.1.

[0376] Step 2

[0377] 29-1 (245 mg, 0.47 mmol) was dissolved in dichloromethane (6 mL), cooled to 0 °C, and then (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodoxapram-3(1H)-one (399 mg, 0.94 mmol) was added. The mixture was heated to 25 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 3, v / v) to obtain 29-2. ESI-MS theoretical calculation: [M+H]+ =524.2, measured value 524.2.

[0378] Step 3

[0379] 29-2 (230 mg, 0.44 mmol) was dissolved in THF (5 mL), cooled to -78 °C, and then methyl magnesium bromide (1.0 mol / L THF solution, 0.66 mL) was added dropwise. The mixture was stirred at -78 °C for 1 hour. After the reaction was complete, saturated ammonium chloride solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 20 g; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 55-60%; flow rate: 20 mL / min) to obtain 29-3 (retention time 35.0-40.0 min).

[0380] Step 4

[0381] 29-3 (38 mg, 0.07 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain an oily substance, which was dissolved in methanol (5 mL). Formaldehyde (37% aqueous solution, 0.10 mL) and sodium triacetoxyborohydride (43 mg, 0.20 mmol) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 16-20%; flow rate: 20 mL / min) to obtain 29 (retention time 30.0-35.0 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 7.71–7.57 (m, 2H), 7.15 (s, 1H), 7.12 (s, 1H), 4.58 (s, 1H), 3.28–3.24 (m, 1H), 2.76–2.73 (m, 1H), 2.72–2.66 (m, 1H), 2.63–2.58 (m, 1H), 2.57–2.50 (m, 1H), 2.44–2.38 (m, 1H), 2.33 (s, 3H), 2.16–2.11 (m, 1H), 2.08 (s, 3H), 1.73–1.59 (m, 2H), 1.25 (s, 3H). ESI-MS theoretical calculation: [M+H] + =396.2, measured value 396.1.

[0382] Example 30

[0383] Synthesis route:

[0384] first step

[0385] 30-1 (5.0 g, 17.85 mmol) was dissolved in DMF (70 mL), and cuprous iodide (340 mg, 1.79 mmol), lithium methoxide (1.36 g, 35.7 mmol), triphenylphosphine (940 mg, 3.57 mmol), and pinacol diboronate (6.8 g, 26.78 mmol) were added. The mixture was heated to 35 °C and stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (500 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 10, v / v) to obtain 30-2. ESI-MS theoretical calculation: [M+H] + =328.2, measured value 327.9.

[0386] Step 2

[0387] Intermediate C (150 mg, 0.37 mmol), 30-2 (605 mg, 1.85 mmol), and potassium phosphate (314 mg, 1.48 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen protection, methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (27 mg, 37 μmol) was added, and the mixture was heated to 90 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 1, v / v) to obtain 30-3. ESI-MS theoretical calculation: [M+H] + =574.3, measured value 574.3.

[0388] Step 3

[0389] 30-3 (70 mg, 0.12 mmol) was dissolved in methanol (3 mL), and wet palladium on carbon (10%, 7 mg) was added. Hydrogen gas was bubbled through the solution, and the mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain a crude product containing 30-4, which could be used directly in the next reaction without further purification. ESI-MS theoretical calculation: [M+H] + =484.2, measured value 484.2.

[0390] Step 4

[0391] 30-4 (59 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain an oily substance, which was dissolved in methanol (5 mL). Formaldehyde (37% aqueous solution, 0.10 mL) and sodium triacetoxyborohydride (76 mg, 0.36 mmol) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 16-20%; flow rate: 20 mL / min) to obtain 30 (retention time 16.0-20.0 min). 1 H NMR (400MHz, DMSO-d6): δ10.27(br s,1H),7.56(s,1H),7.16(s,1H),7.11(s,1H),5.56(s,1H),4.66(s,2H),4.15-3.98(m,1H),3.80-3.77(m,1H),3.52-3.47(m, 1H),3.13-2.98(m,2H),2.97-2.90(m,1H),2.75-2.66(m,1H),2.28(s,3H),2.20-2.10(m,1H),2.07(s,3H),2.03-2.00(m,1H).

[0392] Example 31

[0393] Synthesis route:

[0394] first step

[0395] 31-1 (3.0 g, 10.71 mmol) was dissolved in DMF (60 mL), and cuprous iodide (200 mg, 1.07 mmol), lithium methoxide (810 mg, 21.4 mmol), triphenylphosphine (560 mg, 2.14 mmol), and pinacol diboronate (4.08 g, 16.07 mmol) were added. The mixture was heated to 35 °C and stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (500 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 10, v / v) to obtain 31-2. ESI-MS theoretical calculation: [M+H] + =328.2, measured value 328.0.

[0396] Step 2

[0397] Intermediate C (150 mg, 0.37 mmol), 31-2 (230 mg, 0.70 mmol), and potassium phosphate (314 mg, 1.48 mmol) were added to 1,4-dioxane (5 mL) and water (1 mL). Under nitrogen protection, methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (27 mg, 37 μmol) was added, and the mixture was heated to 90 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether, 1 / 1, v / v) to obtain 31-3. ESI-MS theoretical calculation: [M+H] + =574.3, measured value 574.3.

[0398] Step 3

[0399] 31-3 (65 mg, 0.11 mmol) was dissolved in methanol (3 mL), and wet palladium on carbon (10%, 7 mg) was added. Hydrogen gas was bubbled through the solution, and the mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain a crude product containing 31-4, which could be used directly in the next reaction without further purification. ESI-MS theoretical calculation: [M+H] + =484.2, measured value 484.2.

[0400] Step 4

[0401] 31-4 (54 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain an oily substance, which was dissolved in methanol (5 mL). Formaldehyde (37% aqueous solution, 0.10 mL) and sodium triacetoxyborohydride (70 mg, 0.33 mmol) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 20 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 17-20%; flow rate: 20 mL / min) to obtain 31 (retention time 18.0-22.0 min). 1¹H NMR (400MHz, DMSO-d6): δ 10.30 (br s, 1H), 7.55 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 4.66 (s, 2H), 4.03–3.98 (m, 1H), 3.77–3.74 (m, 1H), 3.50–3.44 (m, 1H), 3.11–2.96 (m, 2H), 2.89–2.80 (m, 1H), 2.66–2.56 (m, 1H), 2.20 (s, 3H), 2.07 (s, 3H), 2.05–1.98 (m, 1H), 1.93–1.84 (m, 1H). ESI-MS theoretical calculation: [M+H] + =398.2, measured value 398.1.

[0402] Activity Test 1: Evaluation of the compound's activity in inhibiting IL-1β secretion from THP-1 cells

[0403] Experimental objective:

[0404] The activity of the compound in inhibiting IL-1β secretion by THP-1 cells was evaluated by detecting the amount of IL-1β secreted using an ELISA kit.

[0405] Experimental materials:

[0406] Table 1

[0407] Experimental instruments:

[0408] Table 2

[0409] Cell treatment:

[0410] 1. This experiment used THP-1 cells.

[0411] 2. Cell treatment: THP-1 cells were cultured in 1640 medium containing 10% heat-inactivated fetal bovine serum at 37°C and 5% carbon dioxide. The cell suspension was gently shaken and transferred to centrifuge tubes for counting. The required volume was then removed and added to fresh passage medium.

[0412] Experimental procedure:

[0413] 1. Add 40 μL of polylysine diluted with sterile water to a 96-well plate and incubate at 37°C and 5% CO2 for 30 minutes, then wash twice with 100 μL.

[0414] 2. After adding 50 ng / mL of PMA (phorbol 12-tetradecanoate 13-acetate) to the THP-1 cell suspension, seed 50,000 cells per well (100 μL per well) into the 96-well plate from step 1 and incubate at 37°C and 5% CO2 for 24 hours.

[0415] 3. Remove the culture medium from the 96-well plate and wash the cells once with PBS preheated to 37°C.

[0416] 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.

[0417] 5. Add 5 μL of different concentrations of the compound (DMSO concentration is uniformly 1‰), and continue to incubate the cells at 37℃ and 5% CO2 for 30 minutes.

[0418] 6. Add 5 μL of diluted Nigericin to make the working concentration of Nigericin 5 μG / mL, and continue to incubate the cells at 37℃ and 5% CO2 for 1 hour.

[0419] 7. Collect the cell supernatant, store it at -80℃, and then use an ELISA kit to detect the amount of IL-1β secreted.

[0420] 8. Calculate the IL-1β concentration based on the standard curve, calculate the inhibition rate, fit the compound's action curve, and calculate the IC50. 50 .

[0421] Experimental results:

[0422] Table 3

[0423] Experimental conclusion:

[0424] The compound of this invention can inhibit the secretion of IL-1β in THP-1 cells.

[0425] Activity Test 2: Evaluation of the compound's inhibitory activity on hERG potassium ion channels

[0426] Experimental objective:

[0427] The inhibitory effect of the embodiments of the present invention on the potassium ion channel of hERG (human ether-à-go-go related gene) was tested using the fully automated patch-clamp Qpatch technique.

[0428] Cell preparation:

[0429] Chinese hamster ovary cells stably expressing the hERG receptor were cultured in culture flasks. Once the cell density reached 60–80%, the culture medium was removed, and the cells were washed once with 7 mL of phosphate-buffered saline (PFS). Then, 3 mL of cell dissociation reagent was added for digestion. After complete digestion, 3 mL of culture medium was added to neutralize the cells, and the cells were centrifuged. The supernatant was removed, and the cells were resuspended in 5 mL of culture medium to ensure a cell density of 2–5 × 10⁶ cells / mL. 6 / mL.

[0430] Patch clamp testing:

[0431] In whole-cell recording mode, the cell membrane was clamped at -80 mV. Before a 5-second +40 mV depolarization stimulus, a 50-millisecond -50 mV pre-voltage was applied, followed by repolarization to -50 mV for 5 seconds, and then back to -80 mV. This voltage stimulus was applied every 15 seconds, and after 2 minutes of recording, extracellular fluid was administered for 5 minutes of recording, before the drug delivery process began. Compound concentrations were started from the lowest test concentration, and each test concentration was administered for 2.5 minutes.

[0432] Experimental results:

[0433] Table 4

[0434] Experimental conclusion:

[0435] The experimental samples (compounds) were prepared according to the corresponding examples. The results of the inhibitory effect of the embodiments of the present invention on the hERG potassium ion channel are shown in the table above. It can be seen that the compounds of the present invention have a low risk of inhibiting the hERG potassium ion channel, even reaching levels above 10 μM.

Claims

1. A compound of formula I, ###0001### I a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein, n is 1, 2, 3, or 4; each R is independently hydrogen, halogen, hydroxyl, cyano, C 1 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-6 cycloalkyl, or 5-6 membered heteroaryl, said C 1-6 alkyl, said C 1-6 alkenyl, said C 3-6 alkynyl, said C R1-1 cycloalkyl, and said 5-6 membered heteroaryl being independently optionally substituted with 1 or more R R1-2 substituents; or, two R 1 connected to form -(CH2) q -; q is 1, 2, 3, or 4, any 1, 2, 3, or 4 -CH2- in -(CH2)q- can be optionally replaced with -O- and -CR R1-3 R R1-3 -; 1 or 2 of which are replaced with -O- and -CR Each R R1-3 Independently hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, the C 1-6 alkoxy groups and the C 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R R1-3a The 5-6 member heteroaryl group may optionally be replaced by one or more R groups. R1-3b replace; each R R1-1 and each R R1-3a is independently deuterium, halogen or hydroxyl; each R R1-2 and each R R1-3b is independently halogen, C 1-6 alkyl or C 1-6 alkoxy; Y is Each R 2 Hydrogen, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy or 3-6 membered heterocyclic alkyl groups; R 3 and R 4 independently are hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or 3-6 membered heterocycloalkyl, or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; R 6 is H, or R 6 and R 2 are joined to form -(CH2) p -, p is 1, 2, 3 or 4, any 1, 2, 3 or 4 of the -CH2- groups in -(CH2) p - can optionally be replaced with -O- and -CR R6-1 R R465-2 -; R R6-1 and R R6-2 are independently hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl or C 1-6 alkoxy; - L is a bond or -CR L1 R L2 -; R L1 and R L2 are independently hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl substituted by one or more halogens, C 1-6 alkoxy substituted by one or more halogens, or C 1-6 alkyl substituted by one or more hydroxy groups; Ring A is a 3-6 membered heterocycloalkyl, a 5-12 membered bicyclic bridged heterocycloalkyl, or a 5-12 membered bicyclic spiro heterocycloalkyl; m is 1, 2, 3, or 4; Each R 5 Independently hydrogen, halogen, cyano, oxo (=O), hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, C 6-10 Aryl, 5-10 aryl, -C(=O)-C 1-6 Alkyl, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Alkyl-3-6-membered heterocyclic alkyl groups, -C 1-6 Alkyl-C 6-10 Aryl, -C 1-6 Alkyl-5-10-membered heteroaryl, -OC 1-6 Alkyl-C 3-6 cycloalkyl, -OC 1-6 Alkyl-3-6-membered heterocyclic alkyl groups, -OC 1-6 Alkyl-C 6-10 Aryl, -OC 1-6 Alkyl-5-10-membered heteroaryl, -C 2- 6-Alkenyl-C 3-6 cycloalkyl, -C 2-6 alkenyl-3-6-membered heterocyclic alkyl groups, -C 2-6 alkenyl-C 6-10 Aryl, -C 2-6 Alkenyl-5-10-membered heteroaryl, -C 2-6 alkynyl-C 3-6 cycloalkyl, -C 2-6 alkynyl-3-6-membered heterocyclic alkyl groups, -C 2-6 alkynyl-C 6-10 Aryl, -C 2-6 Alkyne-5-10 quinone heteroaryl groups, -(CH2) p -OC 1-6 Alkyl group, -(CH2) p -OC 1-6 Alkyl group, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkyne group, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -O-3-6-membered heterocyclic alkyl groups, -(CH2) p -OC 6-10 Aryl, -(CH2) p -O-5-10 membered heteroaryl, -(CH2) p -S(=O)2R 5a , -(CH2) p -S(=O)2N(R 5b )2 or -(CH2) p -N(R 5c )2; Each p is independently 0, 1, 2, 3, 4, 5, or 6; Each R 5a Each R 5b and each R 5c Independently for C 1-6 Alkyl, C 3-6 Alkyl or 3-6 membered heterocyclic alkyl, wherein the C 1-6 Alkyl, the C 3-6 The alkyl group and the 3-6 membered heterocyclic alkyl group are independently and optionally associated with one or more R groups. R5 replace; each R is independently halogen, hydroxyl, C R5 is independently halogen, hydroxyl, C 1-6 alkyl, C1-C6 alkoxy, C 1-6 alkyl, or C 1-6 alkoxy substituted with one or more halogens; The heteroatoms in the heteroaryl, the heterocycloalkyl, the bridged heterocycloalkyl, and the spiro heterocycloalkyl are independently one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

2. The compound of claim 1, having the formula I, wherein which is of formula I-1, formula I-2, formula I-3 or formula I-4; a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , ring A, L, m1and m2are as defined in claim 1 ; Preferably, n is 1, 2, 3, or 4; m1 is 1, 2, 3, or 4; and m2 is 1, 2, or 3; Each R 1 Independently hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, the C 1-6 alkoxy groups and the C 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R R1-1 Instead, the 5-6 aryl group is optionally replaced by one or more R groups. R1-2 replace; or, two R 1 connected to form -(CH2) q -; q is 1, 2, 3 or 4, any 1, 2, 3 or 4 -CH2- in -(CH2) q - can be optionally replaced with -O- and -CR R1-3 R R1-3 -; 1 or 2 of R Each R R1-3 Independently hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, the C 1-6 alkoxy groups and the C 3-6 The cycloalkyl group is independently and optionally surrounded by one or more R R1-3a The 5-6 member heteroaryl group may optionally be replaced by one or more R groups. R1-3b replace; each R is independently hydrogen, deuterium, halogen, or hydroxyl; R1-1 and each R is independently deuterium, halogen, or hydroxyl; R1-3a is independently deuterium, halogen, or hydroxyl; each R R1-2 and each R R1-3b independently halogen, C 1-6 alkyl or C 1-6 alkoxy; R 2 is hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy or 3-6 membered heterocycloalkyl; R 3 and R 4 independently are hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or 3-6 membered heterocycloalkyl, or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; - L is a bond or -CR L1 R L2 -; R L1 and R L2 are independently hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl substituted by one or more halogens or C 1-6 alkoxy substituted by one or more halogens; Ring A is a 3-6 membered heterocycloalkyl, a 5-12 membered bicyclic bridged heterocycloalkyl, or a 5-12 membered bicyclic spiro heterocycloalkyl; m is 1, 2, 3, or 4; each R 5 independently hydrogen, halogen, cyano, oxo (=0), C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(=0)-C 1-6 alkyl, -C 1-6 alkyl-C 3-6 cycloalkyl, -C 1- 6alkyl-3-6 membered heterocycloalkyl, -C 1-6 alkyl-C 6-10 aryl, -C 1-6 alkyl-5-10 membered heteroaryl, -O-C 1-6 alkyl-C 3-6 cycloalkyl, -O-C 1-6 alkyl-3-6 membered heterocycloalkyl, -O-C 1-6 alkyl-C 6-10 aryl, -O-C 1-6 alkyl-5-10 membered heteroaryl, -C 2-6 alkenyl-C 3- 6cycloalkyl, -C 2-6 alkenyl-3-6 membered heterocycloalkyl, -C 2-6 alkenyl-C 6-10 aryl, -C 2-6 alkenyl-5-10 membered heteroaryl, -C 2-6 alkynyl-C 3-6 cycloalkyl, -C 2-6 alkynyl-3-6 membered heterocycloalkyl, -C 2-6 alkynyl-C 6-10 aryl, -C 2-6 alkynyl-5-10 membered heteroaryl, -(CH2) p -O-C 1-6 alkyl, -(CH2) p -O-C 1-6 alkoxy, -(CH2) p -O-C 2-6 alkenyl, -(CH2) p -O-C 2-6 alkynyl, -(CH2) p -O-C 3-6 cycloalkyl, -(CH2) p -O-3-6 membered heterocycloalkyl, -(CH2) p -O-C 6-10 aryl, -(CH2) p -O-5-10 membered heteroaryl, -(CH2) p -S(=O)2R 5a , -(CH2) p -S(=O)2N(R 5b )2 or -(CH2) p -N(R 5c )2; Each p is independently 0, 1, 2, 3, 4, 5, or 6; Each R 5a Each R 5b and each R 5c Independently for C 1-6 Alkyl, C 3-6 Alkyl or 3-6 membered heterocyclic alkyl, wherein the C 1-6 Alkyl, the C 3-6 The alkyl group and the 3-6 membered heterocyclic alkyl group are independently and optionally associated with one or more R groups. R5 replace; each R is independently halogen, hydroxyl, C R5 is independently halogen, hydroxyl, C 1-6 alkyl, C1-C6alkoxy, C 1-6 alkyl, or C 1-6 alkoxy substituted with one or more halogen; The heteroatoms in the heteroaryl, the heterocycloalkyl, the bridged heterocycloalkyl, and the spiro heterocycloalkyl are independently one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4.

3. The compound of claim 2 of formula I, wherein satisfies one or more of the following conditions: (1) in formula I-1, n is 1, 2, 3, or 4; m1 is 1, 2, 3, or 4; each R 1 independently C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with 1 or more R R1-1 substituents; Each R R1-1 It is a halogen; or, two R 1 connected to form -(CH2) q -; q is 1, 2, 3 or 4, any 1, 2, 3 or 4 -CH2- in -(CH2) q - is replaced with -O-; R 2 is hydrogen; R 3 and R 4 are independently hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group; - L is a bond or -CR L1 R L2 -; R L1 and R L2 are independently hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkyl substituted by one or more halogens; Ring A is a 3-6 membered heterocycloalkyl or a 5-12 membered bicyclic bridged heterocycloalkyl; m is 1, 2, 3, or 4; each R is independently hydrogen, C 5 independently hydrogen, C 1-6 alkyl or C 1-6 alkoxy; The heteroatoms in the heterocycloalkyl and the bridged heterocycloalkyl are independently one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, or 4. Preferably, m1 is 1 or 2; each R 1 independently C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with 1 or more R R1-1 substituents; Each R R1-1 Halogens are independent of each other; R 3 and R 4 are independently hydrogen or C 1-6 alkyl; R L1 and R L2 are independently hydrogen or C 1-6 alkyl; Ring A is a 3-6 membered heterocycloalkyl; each R is independently C 5 independently C 1-6 alkyl or C 1-6 alkoxy; More preferably, R 3 and R 4 is independently hydrogen; R L1 and R L2 is independently hydrogen; Each R 5 Independently for C 1-6 alkyl; (2) in formula I-2, n is 1, 2, 3, or 4; m2 is 1, 2, or 3; each R 1 independently C 1-6 alkyl or C 1-6 alkoxy, said C 1-6 alkyl and said C 1-6 alkoxy are independently optionally substituted with 1 or more R R1-1 substituents; Each R R1-1 It is a halogen; R 2 is hydrogen; R 6 is H, or R 6 and R 2 are joined to form -(CH2) p -, p is 1, 2, 3, or 4, any 1, 2, 3, or 4 -CH2- in -(CH2) p - is replaced with -O-; - L is -CR L1 R L2 -; R L1 and R L2 is independently hydrogen; Ring A is a 3- 6 membered heterocycloalkyl; each R is independently hydroxyl or C 5 independently hydroxyl or C 1-6 alkyl; Preferably, n is 1, 2, or 3; m2 is 1, 2, or 3; each R 1 independently C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with 1 or more R R1-1 substituents; Each R R1-1 Halogens are independent of each other; R 2 is hydrogen; R 6 is H; (3) in formula I-3, n is 1 or 2; m1 is 1 or 2; each R 1 independently C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with 1 or more R R1-1 substituents; Each R R1-1 Halogens are independent of each other; R 2 is C 1-6 alkyl; R 6 is H; Ring A is a 3-6 memberedheterocycloalkyl; Each R 5 Independently for C 1-6 alkyl; and (4) in formula I-4, n is 1 or 2; m1 is 1 or 2; each R 1 independently C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with 1 or more R R1-1 substituents; Each R R1-1 Halogens are independent of each other; R 2 is C 1-6 alkyl; - L is -CR L1 R L2 -; R L1 and R L2 is independently hydrogen; RingA is a 3-6 membered heterocycloalkyl; each R is independently C 5 independently C 1-6 alkyl.

4. The compound of formula I as described in claim 1 or 2, characterized in that, satisfies one or more of the following conditions: (1) each R 1 (2) each R R1-3 (3) each R R1-2 (4) each R R1-3b (5) R 2 (6) R 3 (7) R 4 (8) R L1 (9) R L2 (10) each R 5 (11) R 5a (12) R 5b (13) R 5c and each R R5 , the C 1-6 alkyl group is a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, an i-butyl group, or a t-butyl group, for example a methyl group or an ethyl group; (2) each R 1 (2) each R R1-3 (2) each R R1-1 (2) each R R1-3a (2) each R R1-2 (2) each R R1-3b (2) each R 2 (2) each R 3 (2) each R 4 (2) each R L1 (2) each R L2 (2) each R 5 (2) each R R5 , wherein the halogen is F, Cl, Br, or I, for example F; (3) each R 1 (3) each R R1-3 (3) each R R1-2 (3) each R R1-3b (3) each R 2 (3) each R 3 (3) each R 4 (3) each R L1 (3) each R L2 (3) each R 5 (3) each R R5 (3) each R 1-6 alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or t-butoxy; (4) R L1 and R L2 wherein the halogen in said C 1-6 alkyl group and the halogen in said C 1-6 alkoxy group are independently F, Cl, Br, or I; (5)R L1 and R L2 In the context, the C substituted with one or more halogens 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; (6) R L1 and R L2 , said C 1-6 in the C 1-6 alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy; (7) R 3 and R 4 Among them, the C 2-6 Alkylene is ethylene or propylene; (8) R 3 and R 4 Among them, the C 2-6 Alkynyl is ethynyl or propynyl; (9) when R 3 and R 4 together with the carbon atom to which they are attached form a C 3-6 cycloalkane, said C 3-6 cycloalkane is cyclopropane, cyclobutane, cyclopentane or cyclohexane; (10) in Ring A, the 5-6 membered heterocycloalkyl is piperidinyl or morpholinyl; (11) in Ring A, the 5-12 membered bicyclic fused heterocycloalkyl is a 5 membered heterocycloalkyl and a 6 membered heterocycloalkyl or a 5 membered cycloalkyl and a 6 membered heterocycloalkyl, the heteroatoms are one or two of N and O, and the number is 1 or 2, and can also be octahydroindolizine or octahydro-1H-cyclopenta[c]pyridine; and (12) each R 5 wherein at least one R 5 attached to ring A through a heteroatom.

5. The compound according to claim 1 or 2 of formula I, wherein satisfies one or more of the following conditions: (1) each R 1 independently C 1-6 alkyl, or, two adjacent R 1 groups are joined to form -(CH2) q -, q is 1, 2, 3, or 4, any 1, 2, 3, or 4 -CH2- in -(CH2) q - can optionally be replaced with -O- and -CR R1-3 R R1-3 -; 1 or 2; The C 1-6 alkyl is optionally substituted with 1 or more R R1-1 substituted, each R R1-1 substitution is independently halo or hydroxy; (2) R 2 is hydrogen or C 1-6 alkyl; (3) R 3 and R 4 independently are hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R 3 and R 4 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; (4) R L1 and R L2 independently are hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl substituted by one or more halogens or C 1-6 alkyl substituted by one or more hydroxyl groups; (5) each R is independently hydrogen, hydroxyl, C 5 independently hydrogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy; and (6) R 6 is H, or R 6 and R 2 to form -(CH2) p -, p is 1, 2, 3 or 4, any one of the -CH2- groups in -(CH2) p - can optionally be replaced by -O-.

6. The compound of claim 5 of formula I, wherein satisfies one or more of the following conditions: (1) each R 1 independently -CH3or -CF3, or two adjacent R 1 are joined to form -0(CH2)2-; (2) R 3 and R 4 are independently hydrogen, F, -CH3, vinyl, or ethynyl, or, R 3 and R 4 form, together with the carbon atom to which they are attached, a cyclopropane; (3) R L1 and R L2 are independently hydrogen, F, -CH3, -CF3, or -OCH3; (4) Each R 5 It can be independently hydrogen, hydroxyl, -CH3, -CH2CH3 or -OCH3; (6) R 6 is H, or R 6 and R 2 to form represents a pyridazine ring formed by this position and annulation; and (7) R 2 is hydrogen or methyl.

7. The compound of any one of claims 1-5, according to Formula I, wherein satisfies one or more of the following conditions: (1) For Preferably (2) Y is Preferably More preferably For example (3) -L- is a bond, -(CH2)-, -(CF2)-, -(CH(-CH3))-, and (4) For Preferably More preferably For example 8. The compound of claim 1 of formula I, wherein Formula I is Formula la or lb: In general formula Ia or Ib, the carbon atom marked with * is in S configuration, R configuration or achiral carbon atom; Preferably, For each R 1 independently C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with 1 or more R R1-1 each R R1-1 substitution is independently halo, or, two adjacent R 1 connected to form -(CH2) q -, q is 1, 2, 3 or 4, any one of the -CH2- in -(CH2) q - can optionally be replaced with -O-; Preferably, ring A is piperidinyl, morpholinyl, octahydroindolizine or octahydro-1H-cyclopenta[c]pyridinyl.

9. The compound of claim 1 of formula I, wherein The compound as shown in Formula I is any one of the following compounds: a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition, characterized by, a pharmaceutical composition comprising a compound as shown in formula I according to any one of claims 1-9, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. A kit for detecting NLRP3 inflammasome, characterized by, a pharmaceutical composition comprising a compound as shown in formula I according to any one of claims 1-9, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. Use of a compound as shown in formula I according to any one of claims 1-9, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the manufacture of a medicament for the prevention and / or treatment of a NLRP3 inflammasome-dependent disease. Preferably, the NLRP3 inflammasome-dependent disease is a neuroinflammation-related disease or a neurodegenerative disease; and the neurodegenerative disease is preferably Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease.

13. A compound of Formula II-1, II-2, or II-3: ###00010### II-1 II-2 II-3 independently H or a hydroxyl protecting group; and 6 independently H or a hydroxyl protecting group; and 7 independently H or a hydroxyl protecting group; and n, R 1 , R 2 , R 3 , R 4 , R L1 , R L2 are each as defined in any one of claims 1-9; The compound of formula II-1 is preferably a compound selected from the group consisting of Preferably, the compound as shown in formula II-1 is as follows: enantiomers In the separation condition, the compound eluted first and the compound eluted later are obtained as follows: The separation condition is supercritical fluid chromatography, and the column stationary phase is REGIS (S, S) WHELK-O1; the mobile phase is supercritical carbon dioxide for A and isopropanol containing 0.1% 7.0 mol / L of aminomethanol for B; and the gradient is 20-20% for the mobile phase B, and the flow rate is 120 mL / min. The separation condition is supercritical fluid chromatography, and the column stationary phase is REGIS (S, S) WHELK-O1; the mobile phase is supercritical carbon dioxide for A and isopropanol containing 0.1% 7.0 mol / L of aminomethanol for B; and the gradient is 20-20% for the mobile phase B, and the flow rate is 120 mL / min. Preferably, the retention time of the compound eluted first is 4.4-5.2 min, and the retention time of the compound eluted later is 5.6-7.5 min.

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