Furan compound, pharmaceutical composition thereof, and use thereof

Abstract

Disclosed are a furan compound, a pharmaceutical composition thereof, and a use thereof. Specifically, disclosed are a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The compound of the present invention exhibits good inhibitory activity against Naᵥ1.8.

Description

Furan compounds, their pharmaceutical compositions and their applications

[0001] This application claims priority to Chinese patent application 202510350535X, filed March 24, 2025; Chinese patent application 2025105538983, filed April 29, 2025; Chinese patent application 2025109584745, filed July 11, 2025; and Chinese patent application 2026103312883, filed March 17, 2026. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to furan compounds, pharmaceutical compositions thereof, and their applications. Background Technology

[0003] Acute pain is usually a response to external stimuli or tissue damage, caused by the activation of peripheral pain receptors and their specific sensory nerve fibers (nociceptors) located in the skin, subcutaneous tissue, periosteum, joint capsules, and connective tissue surrounding most internal organs. Long-term, repeated activation of these nerve fibers can further lead to chronic pain or neuropathic pain. Besides physical harm, pain can also cause psychological harm, leading to decreased attention, memory loss, and even mental symptoms and illnesses such as depression and anxiety. Clinically used analgesics for pain relief mainly include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, local anesthetics, and opioids. Among these, opioids have numerous adverse reactions and side effects, such as strong addictive properties, constipation, and respiratory depression (Pain Management, 2024, 14, 477-486). Statistics show that the global pain treatment market reached US$8.52 billion in 2024 and is projected to continue increasing at an average annual growth rate of 3.9%, reaching US$12.07 billion by 2033.

[0004] Voltage-gated sodium ion channels (Na v Sodium ion channels are a class of ion channels found in excitable cells, playing a crucial physiological role in the generation and maintenance of action potentials in these nerve cells. Dysfunction of sodium ion channels is closely related to various diseases such as epilepsy, pain, and arrhythmia. Depending on the different α subunits that make up the sodium ion channel, Na... v It can be divided into 9 subtypes (Na) v 1,1-Na v 1.9). Among them, Na v 1.6, Na v 1.7, Na v 1.8 and Na v1.9 It is mainly expressed in the dorsal root ganglia and trigeminal ganglia, which are responsible for transmitting pain signals to the spinal cord. (Pain, 2017, 158, S97-S107).

[0005] Journavx (Suzetrigine, VX-548) is the first FDA-approved oral sodium channel inhibitor with high selectivity. v 1.8 Inhibitors. Following an initial oral dose of 100 mg, 50 mg of Suzetrigine tablets every 12 hours significantly reduced postoperative pain scores in bunion excision and abdominoplasty. In addition, several selective sodium-containing inhibitors, including Suzetrigine, are also mentioned. v 1.8 inhibitors have been used in clinical trials to treat various acute or chronic pain conditions, including painful lumbosacral radiculopathy, diabetic peripheral neuropathy, and peripheral neuropathy caused by chemotherapy for tumors. Therefore, the development of highly active, highly selective Na+ inhibitors with excellent pharmacokinetic properties is crucial. v 1,8 inhibitors can bring new, safer, and faster-acting treatment methods to relieve pain in clinical practice. Summary of the Invention

[0006] The technical problem this invention aims to solve is to address the deficiency in the variety of voltage-gated sodium ion channel 1.8 inhibitors in the prior art, by providing a novel furan compound, its pharmaceutical composition, and its applications. The compound of this invention exhibits good inhibitory activity against voltage-gated sodium ion channels 1.8.

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

[0008] This invention provides a compound as shown in formula (II), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0009] in,

[0010] The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof;

[0011] R 1 and R 2 Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkyl substituted with one or more halogens;

[0012] R 3 and R 8 Each is independently H, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkyl substituted with one or more halogens;

[0013] R9 It is hydrogen or deuterium;

[0014] R 4 H, OH, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C2-C6 alkenyl, C1-C6 alkoxy, -L a -L b -L c -L d -C1-C6 alkylene-OR 4-1 -L d -C1-C6 imidene-OR 4-1 -L d -C1-C6 alkylene-NR a R b , by one or more R 4-2 Substituted C1-C6 alkyl groups or those with one or more R 4- 3 Substituted C1-C6 alkoxy groups;

[0015] L a For connection key or O;

[0016] L b It is a linking bond or a C1-C6 alkylene group;

[0017] L c It is a C3-C8 cycloalkyl, a 3-8 membered heterocycloalkyl, a 5-6 membered heteroaryl, -C(=O)O(C1-C6 alkyl), -C(=O)OH, -C(=O)NR a R b , by one or more R c Substituted C3-C8 cycloalkyl groups, with one or more R d Substituted 3-8 membered heterocyclic alkyl groups or substituted with one or more R e The substituted 5-6-membered heteroaryl group; wherein the 3-8-membered heterocyclic alkyl group or the 5-6-membered heteroaryl group has a heteroatom selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0018] R a and R b Each is independently H, OH, C1-C6 alkyl or 3-8 membered heterocyclic alkyl, wherein the heteroatom in the 3-8 membered heterocyclic alkyl is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0019] R c R d and R eEach of them is independently a halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with one or more halogens, or C1-C6 alkoxy substituted with one or more halogens;

[0020] L d For connection key or O;

[0021] R 4-1 It is H, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens;

[0022] R 4-2 and R 4-3 Independently deuterium, halogen, or C1-C6 alkoxy;

[0023] X 3 For N or CR 5a ;

[0024] X 4 For N or CR 6a ;

[0025] X 5 For N or CR 9a ;

[0026] X 6 For N or CR 10a ;

[0027] R 5a It is H, halogen, C1-C6 alkyl, or formed by one or more R 5a-1 Substituted C1-C6 alkyl; or R 5a With R 4 The atoms between them together form a ring C or are bounded by one or more R atoms. 5a-2 The replaced ring C;

[0028] R 5a-1 It can be halogenated or C1-C6 alkoxy group independently;

[0029] The ring C is a C3-C8 cycloene or a 3-8 heterocyclic cycloene. In the 3-8 membered heterocyclic cycloene, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3. The C3-C8 cycloene and the 3-8 membered heterocyclic cycloene contain only one carbon-carbon double bond, and the carbon-carbon double bond is CR. 4 carbon atoms and CR 5a Carbon-carbon double bonds between carbon atoms in the carbon atoms;

[0030] R 5a-2 Halogens are independent of each other;

[0031] R 6a It is H, halogen, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens;

[0032] R 9a It is H, halogen, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens;

[0033] R 10a It is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 alkyl substituted with one or more halogens;

[0034] R 10 and R 11 Independently H, halogen, or C1-C6 alkyl group substituted with one or more halogens;

[0035] R 7 For CN, C1-C6 alkyl groups or containing one or more R 7 g-substituted C1-C6 alkyl groups;

[0036] R 7a It is H or C1-C6 alkyl;

[0037] R 7b H, C1-C6 alkyl, C3-C6 cycloalkyl, by one or more R 7b - 3 Substituted C1-C6 alkyl groups or those with one or more R 7b- 4 Substituted C3-C6 cycloalkyl groups;

[0038] R 7b-1 and R 7b-2 Each is independently H or C1-C6 alkyl;

[0039] R 7b-3 It is OH;

[0040] R 7b-4 It is OH;

[0041] R 7c It is H or C1-C6 alkyl;

[0042] R 7d For H or R 7d-1 and R 7d-2 Each is independently H or C1-C6 alkyl;

[0043] R 7e It is H or C1-C6 alkyl;

[0044] R 7f It is a C1-C6 alkyl group;

[0045] R 7gIndependently OH;

[0046] X 1 For N or CR X11 R X11 It is H, OH, C1-C6 alkyl, or formed by one or more R X11-1 Substituted C1-C6 alkyl groups;

[0047] R x11-1 Independently OH;

[0048] X 2 It can be O or N;

[0049] L represents C1-C6 alkylene, -C(=O)-C1-C6 alkylene, or... The C1-C6 alkylene and -C(=O)-C1-C6 alkylene- are optionally separated by one or more L 1 replace;

[0050] L 1 Independently OH, C1-C6 alkyl, or surrounded by one or more L 11 Substituted C1-C6 alkyl groups;

[0051] L 11 It is OH on its own.

[0052] This invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0053] in,

[0054] The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof;

[0055] R 1 and R 2 Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkyl substituted with one or more halogens;

[0056] R 3 and R 8 Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkyl substituted with one or more halogens;

[0057] R 4 H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, -L a -L b -L c -L d -C1-C6 alkylene-OR4-1 -L d -C1-C6 imidene-OR 4-1 -L d -C1-C6 alkylene-NR a R b C1-C6 alkyl groups substituted with one or more halogens or C1-C6 alkoxy groups substituted with one or more halogens;

[0058] L a For connection key or O;

[0059] L b It is a linking bond or a C1-C6 alkylene group;

[0060] L c It is a C3-C6 cycloalkyl, a 3-8 membered heterocycloalkyl, a 5-6 membered heteroaryl, -C(=O)O(C1-C6 alkyl), -C(=O)OH, -C(=O)NR a R b , by one or more R c Substituted C3-C6 cycloalkyl groups, with one or more R d Substituted 3-8 membered heterocyclic alkyl groups or substituted with one or more R e The substituted 5-6-membered heteroaryl group; wherein the 3-8-membered heterocyclic alkyl group or the 5-6-membered heteroaryl group has a heteroatom selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0061] R a and R b Each is independently H, OH, C1-C6 alkyl or 3-8 membered heterocyclic alkyl, wherein the heteroatom in the 3-8 membered heterocyclic alkyl is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0062] R c R d and R e Each of them is independently a halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with one or more halogens, or C1-C6 alkoxy substituted with one or more halogens;

[0063] L d For connection key or O;

[0064] R 4-1 It is H, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens;

[0065] X 3 For N or CR 5a ;

[0066] X4 For N or CR 6a ;

[0067] X 5 For N or CR 9a ;

[0068] X 6 For N or CR 10a ;

[0069] R 5a It is H, halogen, C1-C6 alkyl, or formed by one or more R 5a-1 Substituted C1-C6 alkyl groups;

[0070] R 5a-1 It can be halogenated or C1-C6 alkoxy group independently;

[0071] R 6a It is H, halogen, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens;

[0072] R 9a It is H, halogen, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens;

[0073] R 10a It is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 alkyl substituted with one or more halogens;

[0074] Ring A is a five-membered heteroaromatic ring or a six-membered heteroaromatic ring, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0075] When ring A is a five-membered heteroaryl ring, R 7 for C1-C6 alkyl groups or containing one or more R 7g Substituted C1-C6 alkyl groups;

[0076] When ring A is a six-membered heteroaryl ring, R 7 for

[0077] R 7a It is H or C1-C6 alkyl;

[0078] R 7b H, C1-C6 alkyl, C3-C6 cycloalkyl, by one or more R 7b-3 Substituted C1-C6 alkyl groups or those with one or more R 7b- 4 Substituted C3-C6 cycloalkyl groups;

[0079] R 7b' C3-C6 cycloalkyl, by one or more R 7b-3 Substituted C1-C6 alkyl groups or those with one or more R 7b-4 Substituted C3-C6 cycloalkyl groups;

[0080] R 7b-1 and R 7b-2 Each is independently H or C1-C6 alkyl;

[0081] R 7b-3 It is OH;

[0082] R 7b-4 For OH:

[0083] R 7c It is H or C1-C6 alkyl;

[0084] R 7d for R 7d-1 and R 7d-2 Each is independently H or C1-C6 alkyl;

[0085] R 7e It is H or C1-C6 alkyl;

[0086] R 7f It is a C1-C6 alkyl group;

[0087] R 7g Independently OH;

[0088] X 1 For N or CR X11 R X11 It is H, OH, C1-C6 alkyl, or formed by one or more R X11-1 Substituted C1-C6 alkyl groups;

[0089] R x11-1 Independently OH;

[0090] X 2 It can be O or N;

[0091] L represents C1-C6 alkylene, -C(=O)-C1-C6 alkylene, or... The C1-C6 alkylene and -C(=O)-C1-C6 alkylene- are optionally separated by one or more L 1 replace;

[0092] L 1 Independently OH, C1-C6 alkyl, or surrounded by one or more L 11Substituted C1-C6 alkyl groups;

[0093] L 11 Independently OH;

[0094] The compound represented by formula (I) is not any of the following compounds and their stereoisomers:

[0095] In certain preferred embodiments of the present invention, certain groups in the compounds represented by formula (I), the compounds represented by formula (II), their pharmaceutically acceptable salts, their solvates, or solvates of their pharmaceutically acceptable salts are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention").

[0096] In one embodiment of the invention, each “C1-C6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl, ethyl, or isopropyl.

[0097] In one embodiment of the present invention, each “C3-C6 cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopentyl.

[0098] In one aspect of the invention, each "halogen" is independently F, Cl, or Br, for example, F.

[0099] In one embodiment of the invention, each “C2-C6 alkenyl” is independently a C2-C4 alkenyl, such as vinyl, propenyl, or allyl.

[0100] In one embodiment of the present invention, each “C1-C6 alkoxy” is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0101] In one aspect of this invention, each "five-membered heteroaromatic ring" is independently a five-membered heteroaromatic ring with N and / or S heteroatoms, and the number of heteroatoms is one or two, for example...

[0102] In one aspect of this invention, each "six-membered heteroaromatic ring" is independently a six-membered heteroaromatic ring with N heteroatoms and one or two heteroatoms, for example...

[0103] In one embodiment of the present invention, each "C1-C6 alkylene group" is independently...

[0104] In one embodiment of the invention, each “C3-C8 cycloalkyl” is independently a C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and more particularly, cyclopropyl.

[0105] In one embodiment of the present invention, each “C3-C6 cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0106] In one embodiment of the invention, each "3-8 membered heterocyclic alkyl" is independently a 3-6 membered heterocyclic alkyl, such as oxetane, oxetane, azanebutane, tetrahydropyrrole, tetrahydrothiophene, tetrahydrofuranyl, morpholinyl, piperidinyl, tetrahydropyranyl, or piperazine, for example, oxetane, and further for example...

[0107] In one aspect of the invention, each "C3-C8 cycloene" is independently a C3-C6 cycloene, for example...

[0108] In one aspect of the invention, each "3-8 heterocyclic ene" is independently a 3-6 membered heterocyclic ene, such as dihydrofuran, and further for example... In one aspect of the present invention, in the compound represented by formula (II), R 7 For CN, Or by one or more R 7g The substituted C1-C6 alkyl groups; the definitions of the remaining substituents are as described in any embodiment of the present invention.

[0109] In one aspect of the present invention, in the compound represented by formula (II), R 7a For H.

[0110] In one aspect of the present invention, in the compound represented by formula (II), R 7b For H.

[0111] In one aspect of the present invention, in the compound represented by formula (II), R 7c For H.

[0112] In one aspect of the present invention, in the compound represented by formula (II), R 7d For H.

[0113] In one aspect of the present invention, in the compound represented by formula (II), R 7e For H.

[0114] In one aspect of the present invention, in the compound represented by formula (II), R 7f It is a C1-C6 alkyl group;

[0115] In one aspect of the present invention, in the compound represented by formula (II), R 7g It is OH on its own.

[0116] In one aspect of the present invention, in the compound represented by formula (II), R 7 For CN, Or by one or more R 7g Substituted C1-C6 alkyl groups;

[0117] R 7a For H;

[0118] R 7b For H;

[0119] R 7c For H;

[0120] R 7d For H;

[0121] R 7e For H;

[0122] R 7f It is a C1-C6 alkyl group;

[0123] R 7g It is OH on its own.

[0124] In one aspect of the present invention, in the compound represented by formula (II), R 7 for CN Preferred CN Further preferred

[0125] In one embodiment of the present invention, the substituents in the compound shown in formula (I) are defined as in Scheme 1, wherein ring A is a six-membered heteroaromatic ring, R 7 for The definitions of the remaining substituents are as described in any embodiment of the present invention.

[0126] In one embodiment of the present invention, the substituents in the compound shown in formula (I) are defined as in Scheme 2, wherein ring A is a five-membered heteroaromatic ring, and R 7 for C1-C6 alkyl groups or containing one or more R 7g The substituted C1-C6 alkyl groups; the definitions of the remaining substituents are as described in any embodiment of the present invention.

[0127] In one aspect of the present invention, in aspect 1, ring A is... #Terminal and R 7 Connected.

[0128] In one aspect of the present invention, in aspect 2, ring A is... #Terminal and R 7 Connected, preferably

[0129] In one aspect of the present invention, in aspects 1 and 2, R 7a For H.

[0130] In one aspect of the present invention, in aspect 1, R 7b' Cyclopentyl groups substituted with one or more hydroxyl groups, C1-C6 alkyl groups substituted with one or more hydroxyl groups, or... R 7b-1 and R 7b-2 Each is independently H or C1-C6 alkyl.

[0131] In one aspect of the present invention, in aspect 2, R 7b It is H, C1-C6 alkyl, cyclopentyl substituted with one or more hydroxyl groups, or C1-C6 alkyl substituted with one or more hydroxyl groups. R 7b-1 and R 7b-2 Each is independently H or C1-C6 alkyl.

[0132] In one aspect of the present invention, in aspect 1, R 7b' for

[0133] In one aspect of the present invention, in aspect 2, R 7b For H, For example, H.

[0134] In one aspect of the present invention, in aspect 2, R 7f It is a methyl group.

[0135] In one aspect of the present invention, in aspect 2, R 7e For H.

[0136] In one aspect of the present invention, in aspect 2, the R 7 In the context, the one or more R 7g The substituted C1-C6 alkyl groups are

[0137] In one aspect of the present invention, in aspects 1 and 2, R 7c For H.

[0138] In one aspect of the present invention, in aspects 1 and 2, R 7d for

[0139] In one aspect of the present invention, in aspects 1 and 2, R X11 It can be H or OH.

[0140] In one aspect of the present invention, in aspects 1 and 2, L is a C1-C4 alkylene group. #1 -C(=O)-C1-C4 alkylene-or #1 Terminal and X 1 Connected, the C1-C4 alkylene groups and #1 The C1-C4 alkylene group in -C(=O)-C1-C4 alkylene- is optionally surrounded by one or more L 1 Instead, the L 1 It is OH or C1-C4 alkyl.

[0141] In one aspect of the present invention, in aspects 1 and 2, L is... #1 Terminal and X 1 Connected.

[0142] In one aspect of the invention, in the compound represented by formula (II) or formula (I), R 1 and R 2 Each is independently a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one or more halogens.

[0143] In one aspect of the invention, in the compound represented by formula (II) or formula (I), R 1 and R 2 Each can be independently methyl or -CF3.

[0144] In one aspect of the invention, in the compound represented by formula (II) or formula (I), R 1 It is a C1-C6 alkyl group substituted with one or more halogens.

[0145] In one aspect of the invention, in the compound represented by formula (II) or formula (I), R 1 It is -CF3.

[0146] In one aspect of the invention, in the compound represented by formula (II) or formula (I), R 2 It is a C1-C6 alkyl group.

[0147] In one aspect of the invention, in the compound represented by formula (II) or formula (I), R 2 It is a methyl group.

[0148] In one aspect of the invention, in the compound represented by formula (II) or formula (I), R 3 It is a C1-C6 alkyl group.

[0149] In one aspect of the invention, in the compound represented by formula (II) or formula (I), R 3 It is a methyl group.

[0150] In one aspect of the present invention, in the compound represented by formula (II), R 8 It can be H or deuterium.

[0151] In one aspect of the invention, in the compound represented by formula (II) or formula (I), R 8 For H.

[0152] In one aspect of the present invention, in the compound represented by formula (II), R 4 It is a C3-C8 cycloalkyl, C1-C6 alkoxy, -L a -L b -L c , by one or more R 4- 2 Substituted C1-C6 alkyl groups or those with one or more R 4-3 Substituted C1-C6 alkoxy groups.

[0153] In one aspect of the present invention, in the compound represented by formula (II), L a It is O.

[0154] In one aspect of the present invention, in the compound represented by formula (II), L b For connection keys.

[0155] In one aspect of the present invention, in the compound represented by formula (II), L c It is a C3-C8 cycloalkyl or a 3-8 membered heterocyclic alkyl.

[0156] In one aspect of the present invention, in the compound represented by formula (II), R 4-2 and R 4-3 It can be independently deuterium, halogen, or C1-C6 alkoxy.

[0157] In one aspect of the present invention, in the compound represented by formula (II), R 4 It is a C3-C8 cycloalkyl, C1-C6 alkoxy, -L a -L b -L c , by one or more R4- 2 Substituted C1-C6 alkyl groups or those with one or more R 4-3 Substituted C1-C6 alkoxy groups;

[0158] L a It is O;

[0159] L b For connection key;

[0160] L c It is a C3-C8 cycloalkyl or a 3-8 membered heterocyclic alkyl;

[0161] R 4-2 It is a C1-C6 alkoxy group;

[0162] R 4-3 It is deuterium, halogen, or C1-C6 alkoxy.

[0163] In one aspect of the present invention, in the compound represented by formula (II), R 4 It is methoxy, -OCD3, -OCD2CD3, -OCF3, -OCH2CH3, -OCH2CF3, -OCHF2、

[0164] In one aspect of the invention, in the compound represented by formula (II) or formula (I), R 4 It is a C1-C6 alkoxy group.

[0165] In one aspect of the invention, in the compound represented by formula (II) or formula (I), R 4 It is a methoxy group.

[0166] In one aspect of the invention, in the compound represented by formula (II) or formula (I), X 3 For CR 5a .

[0167] In one aspect of the present invention, in the compound represented by formula (II), X 3 For CR 5a R 5a For halogen, or, R 5a With R 4 The atoms between them together form a ring C or are bounded by one or more R atoms. 5a-2 The substituted cyclic C is a C3-C8 cyclic alkene or a 3-8 heterocyclic alkene.

[0168] In one aspect of the present invention, in the compound represented by formula (II), X 3 For CR 5a R 5aFor F, or R 5a With R 4 Together with the atoms between them, they form

[0169] In one aspect of the invention, in the compound represented by formula (II) or formula (I), X 3 For CF.

[0170] In one aspect of the invention, in the compound represented by formula (II) or formula (I), X 4 For CR 6a .

[0171] In one aspect of the invention, in the compound represented by formula (II) or formula (I), X 4 For CF.

[0172] In one aspect of the invention, in the compound represented by formula (II) or formula (I), X 5 For CR 9a .

[0173] In one aspect of the invention, in the compound represented by formula (II) or formula (I), X 5 For CH.

[0174] In one aspect of the invention, in the compound represented by formula (II) or formula (I), X 6 For CR 10a .

[0175] In one aspect of the invention, in the compound represented by formula (II) or formula (I), X 6 For CH.

[0176] In one aspect of the present invention, in the compound represented by formula (II), R 9 It can be hydrogen or deuterium, for example, hydrogen.

[0177] In one aspect of the present invention, in the compound represented by formula (II), R 10 and R 11 It can be H, F, or -CF3 independently.

[0178] In one aspect of the present invention, in the compound represented by formula (II), R 11 It is H or a halogen, such as H or F, further such as H.

[0179] In one aspect of the present invention, in the compound represented by formula (II), R 10 For H.

[0180] In one aspect of the present invention, the compound represented by formula (II) is the compound represented by formula (II-1):

[0181] The definitions of each substituent are as described in any embodiment of the present invention.

[0182] In one aspect of the present invention, the compound represented by formula (II) is a compound represented by formula (II-1'):

[0183] The definitions of each substituent are as described in any embodiment of the present invention.

[0184] In one aspect of the present invention, the compound represented by formula (II) is a compound represented by formula (II-2):

[0185] The definitions of each substituent are as described in any embodiment of the present invention.

[0186] In one aspect of the present invention, in the compound represented by formula (II-2), R 8 For H, R 9 For H.

[0187] In one aspect of the present invention, in the compound represented by formula (II-2), R 8 For H, R 9 For D, or R 9 For H, R 8 The answer is D.

[0188] In one aspect of the present invention, in the compound represented by formula (II-2), R 8 For D, R 9 The answer is D.

[0189] In one aspect of the present invention, the compound represented by formula (I) is a compound represented by formula (I-1):

[0190] The definitions of each substituent are as described in any embodiment of the present invention.

[0191] In one aspect of the present invention, the compound represented by formula (I) is a compound represented by formula (I-2):

[0192] The definitions of each substituent are as described in any embodiment of the present invention.

[0193] In one aspect of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0194] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0195] The present invention also provides the use of a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a voltage-gated sodium channel type 1.8 (Nav1.8) inhibitor.

[0196] The present invention also provides the use of a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for the prevention, relief, and / or treatment of diseases or symptoms associated with voltage-gated sodium channel type 1.8 (Nav1.8), preferably, the disease or symptom associated with voltage-gated sodium channel type 1.8 is pain, such as inflammatory pain, neuropathic pain, postoperative pain, or cancer pain.

[0197] The present invention also provides the use of a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for the prevention, relief, and / or treatment of pain, such as inflammatory pain, neuropathic pain, postoperative pain, or cancer pain.

[0198] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0199] The term "solvate" refers to a substance formed by the combination of a compound and a solvent. Solvates are classified into stoichiometric solvates and non-stoichiometric solvates.

[0200] The term "solvate of a pharmaceutically acceptable salt" refers to a substance formed by the combination of a compound with a pharmaceutically acceptable acid or base and a solvent. The amount of solvent can be stoichiometric or non-stoichiometric.

[0201] The term "alkyl" refers to a straight-chain or branched, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0202] The term "cycloalkyl" refers to a saturated cyclic group having a specified number of carbon atoms in the ring (e.g., C3-C6) and whose ring atoms consist only of carbon atoms. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0203] The term "halogen" refers to F, Cl, Br, and I.

[0204] The term "alkenyl" refers to a straight-chain or branched olefin having a specific number of carbon atoms, containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds. The one or more carbon-carbon double bonds can be internal or terminal. Examples of alkenes include vinyl, allyl, methyl vinyl, propenyl, butenyl, pentenyl, 1,1-dimethyl-2-propenyl, hexenyl, etc.

[0205] The term "alkylene" refers to a saturated divalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6).

[0206] The term "alkenyl" refers to a divalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6) and at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be located at any position within the alkenyl group.

[0207] The term "heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 3-8), 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).

[0208] The term "heteroaryl" refers to a cyclic monovalent aromatic 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).

[0209] The term "alkoxy" refers to an alkyl group that is attached to other parts of a molecule via an oxygen bridge.

[0210] The term "connector" indicates that it does not exist. For example, in ALB, if L is the connector, then the ALB is AB.

[0211] The term "optional" means that an event or condition described subsequently may occur but is not required, and the description includes both the possibility that said event or condition occurs and the possibility that said event or condition does not occur. For example, the term "optionally replaced by..." means that it may or may not be replaced.

[0212] 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).

[0213] 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.

[0214] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0215] In the described applications, the inhibitory drug can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the inhibitory effect of voltage-gated sodium channel type 1.8.

[0216] 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.

[0217] The reagents and raw materials used in this invention are all commercially available.

[0218] The positive and progressive effects of this invention are as follows: the compound of this invention has a novel structure and exhibits good inhibitory activity against voltage-gated sodium ion channels 1.8 (especially human voltage-gated sodium ion channels 1.8). Detailed Implementation

[0219] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the concept and scope of the invention.

[0220] 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.

[0221] Abbreviations:

[0222] Boc: tert-Butoxycarbonyl. DIEA: N,N-Diisopropylethylamine. DMF: N,N-Dimethylformamide. Et: Ethyl. Me: Methyl. i-Pr: Isopropyl. DMSO: Dimethyl sulfoxide. THF: Tetrahydrofuran. TEA: Triethylamine. TCFH: N,N,N′,N′-Tetramethylchloroformamidin hexafluorophosphate. NMI: N-Methylimidazole. HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-Tetramethylurea hexafluorophosphate. DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene. DMB: 2,4-Dimethoxybenzyl. Bn: Benzyl. Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium. Xantphos: 4,5-Bisdiphenylphosphine-9,9-Dimethyloxanthracene. SEM: (trimethylsilyl)ethoxymethyl. XPhosPdG3: methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium. Cbz: benzyloxycarbonyl. TBS: tert-butyldimethylsilyl.

[0223] Example 1

[0224] Synthesis route:

[0225] first step

[0226] 1-1 (1.5 g, 4.23 mmol) and 1-2 (772 mg, 5.08 mmol) were dissolved in dry acetonitrile (30 mL). After cooling to 0 °C, NMI (729 mg, 8.88 mmol) and TCFH (1.3 g, 4.65 mmol) were added sequentially, and the mixture was stirred at 25 °C for 4 hours. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain 1-3. ESI-MS theoretical calculation: [M+H] + =489.2, measured value 489.5.

[0227] Step 2

[0228] Dissolve 1-3 (1.5 g, 3.07 mmol) in dry THF (75 mL) and water (10 mL), add lithium hydroxide monohydrate (193 mg, 4.60 mmol), and stir at 25 °C for 4 hours. After the reaction is complete, adjust the pH of the reaction solution to 4 with dilute hydrochloric acid (0.5 mol / L), extract with ethyl acetate (100 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 40 g; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 10-75%; flow rate: 40 mL / min) to obtain 1-4 (retention time 23.0-32.5 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 12.94 (br s, 1H), 10.75 (s, 1H), 8.56 (d, J = 5.6Hz, 1H), 8.34 (d, J = 2.0Hz, 1H), 7.85 (dd, J = 5.2, 2.0Hz, 1H), 7.25–7.10 (m, 2H), 5.11 (d, J = 10.0Hz, 1H), 4.31–4.21 (m, 1H), 3.95 (d, J = 2.0Hz, 3H), 2.83–2.73 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 5.6Hz, 3H). ESI-MS theoretical calculation: [M+H] + =475.1, measured value 475.1.

[0229] Step 3

[0230] Dissolve 1-4 (30 mg, 63 μmol) and 1-5 (13 mg, 95 μmol) in DMF (1 mL), cool to 0 °C, and then add DIEA (24 mg, 0.19 mmol) and HATU (36 mg, 95 μmol) sequentially. Stir at 25 °C for 1 hour. After the reaction is complete, 1 is purified by high performance liquid chromatography (column: SunFire Prep 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 57-83%; flow rate: 20 mL / min) to obtain 1 (retention time 12.0-12.5 min). 1 H NMR (400MHz, DMSO-d6): δ10.76 (s, 1H), 8.50 (d, J=5.6Hz, 1H), 8.42 (d, J=7.6Hz, 1H), 8.29 (d, J=2.4H z, 1H), 7.85 (dd, J=5.2, 2.0Hz, 1H), 7.22-7.11 (m, 2H), 5.11 (d, J=6.8Hz, 1H), 5.09 (s, 1H), 4.26 (dd, J = 10.0, 7.6 Hz, 1H), 4.06-3.98 (m, 2H), 3.95 (d, J = 2.0 Hz, 3H), 2.83-2.73 (m, 1H), 1.98-1.89 (m, 1H), 1.88-1.78 (m, 1H), 1.79-1.69 (m, 1H), 1.65-1.45 (m, 6H), 0.73 (d, J = 6.4 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =558.2, measured value 558.1.

[0231] Example 2

[0232] Synthesis route:

[0233] first step

[0234] Dissolve 1-4 (25 mg, 53 μmol) and 2-1 (11 mg, 80 μmol) in DMF (1 mL), cool to 0 °C, and then add DIEA (21 mg, 0.16 mmol) and HATU (30 mg, 80 μmol) sequentially. Stir at 0 °C for 1 hour. After the reaction is complete, 2 is purified by high performance liquid chromatography (column: SunFire Prep 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 63-73%; flow rate: 20 mL / min) to obtain 2 (retention time 8.7-9.5 min). 1H NMR (400MHz, DMSO-d6): δ10.75 (s, 1H), 8.50 (d, J=8.8Hz, 1H), 8.42 (d, J=5.6Hz , 1H), 8.25 (d, J=2.0Hz, 1H), 7.86 (dd, J=5.6, 2.4Hz, 1H), 7.22-7.12 (m, 2H), 5.1 0 (d, J = 10.4 Hz, 1H), 4.30-4.20 (m, 1H), 4.03-3.96 (m, 2H), 3.95 (d, J = 2.0 Hz, 3H), 2.81-2.71 (m, 1H), 2.03-1.93 (m, 1H), 1.89-1.79 (m, 1H), 1.69-1.57 (m, 5H), 0.54-1.41 (m, 2H), 0.73 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =558.2, measured value 558.0.

[0235] Example 3

[0236] Synthesis route:

[0237] first step

[0238] Dissolve 1-4 (25 mg, 53 μmol) and 3-1 (11 mg, 80 μmol) in DMF (1 mL), cool to 0 °C, and then add DIEA (21 mg, 0.16 mmol) and HATU (30 mg, 80 μmol) sequentially. Stir at 0 °C for 1 hour. After the reaction is complete, 3 is purified by high performance liquid chromatography (column: Pursuit XRs C18, 21.2*250 mm, 10 μm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 72-85%; flow rate: 20 mL / min) to obtain 3 (retention time 12.0-12.9 min). 1H NMR (400MHz, DMSO-d6): δ10.76 (s, 1H), 8.50 (d, J=5.4Hz, 1H), 8.42 (d, J=7.6Hz, 1H), 8.29 (d, J=2.0H z, 1H), 7.86 (dd, J=5.6, 2.0Hz, 1H), 7.22-7.12 (m, 2H), 5.13-5.07 (m, 2H), 4.30-4.20 (m, 1H), 4.06-3 0.97 (m, 2H), 3.95 (s, 3H), 2.84–2.72 (m, 1H), 1.99–1.89 (m, 1H), 1.87–1.79 (m, 1H), 1.78–1.69 (m, 1H), 1.68–1.58 (m, 4H), 1.57–1.52 (m, 1H), 1.52–1.47 (m, 1H), 0.73 (d, J = 7.6 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =558.2, measured value 558.1.

[0239] Example 4

[0240] Synthesis route:

[0241] first step

[0242] Dissolve 1-4 (25 mg, 53 μmol) and 4-1 (11 mg, 80 μmol) in DMF (1 mL), cool to 0 °C, and then add DIEA (21 mg, 0.16 mmol) and HATU (30 mg, 80 μmol) sequentially. Stir at 0 °C for 1 hour. After the reaction is complete, 4 is purified by high performance liquid chromatography (column: SunFire Prep 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 60-75%; flow rate: 20 mL / min) to obtain 4 (retention time 7.0-7.8 min). 1H NMR (400MHz, DMSO-d6): δ10.81 (s, 1H), 8.50 (d, J=5.6Hz, 1H), 8.46 (d, J=7.6Hz, 1H), 8.26 (d, J=2.0H z, 1H), 7.86 (dd, J=5.6, 2.0Hz, 1H), 7.28-7.05 (m, 2H), 5.11 (d, J=10.0Hz, 1H), 4.85-4.75 (m, 1H), 4. 36-4.13 (m, 1H), 4.00-3.97 (m, 2H), 3.95 (s, 3H), 2.94-2.71 (m, 1H), 2.06-1.93 (m, 1H), 1.89-1.79 (m, 1H), 1.72-1.63 (m, 2H), 1.61 (s, 3H), 1.55-1.39 (m, 2H), 0.73 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =558.2, measured value 558.2.

[0243] Example 5

[0244] Synthesis route:

[0245] first step

[0246] Dissolve 1-4 (25 mg, 53 μmol) and 5-1 (11 mg, 80 μmol) in DMF (1 mL), cool to 0 °C, and then add DIEA (21 mg, 0.16 mmol) and HATU (30 mg, 80 μmol) sequentially. Stir at 0 °C for 1 hour. After the reaction is complete, 5 is purified by high performance liquid chromatography (column: SunFire Prep 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 61-71%; flow rate: 20 mL / min) to obtain 5 (retention time 8.4-9.0 min). 1H NMR (400MHz, DMSO-d6): δ10.75 (s, 1H), 8.68 (d, J=8.8Hz, 1H), 8.48 (d, J=5.6Hz, 1H), 8.26 (d, J=2. 0Hz, 1H), 7.85 (dd, J=5.6, 2.4Hz, 1H), 7.22-7.12 (m, 2H), 5.10 (d, J=10.0Hz, 1H), 4.40-4.31 (m, 1H ), 4.30-4.20 (m, 1H), 4.24-4.14 (m, 1H), 3.95 (d, J = 2.0Hz, 3H), 2.81-2.71 (m, 1H), 2.00-1.90 (m, 2H), 1.74-1.64 (m, 3H), 1.61 (s, 3H), 1.61-1.51 (m, 1H), 0.73 (d, J = 6.4Hz, 3H). ESI-MS theoretical calculation values: [M+H] + =558.2, measured value 558.0.

[0247] Example 6

[0248] Synthesis route:

[0249] first step

[0250] Dissolve 1-4 (25 mg, 53 μmol) and 6-1 (11 mg, 80 μmol) in DMF (1 mL), cool to 0 °C, and then add DIEA (23 mg, 0.19 mmol) and HATU (31 mg, 80 μmol) sequentially. Stir at 0 °C for 1 hour. After the reaction is complete, 6 is purified by high performance liquid chromatography (column: Pursuit XRs C18, 21.2*250 mm, 10 μm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 69-82%; flow rate: 20 mL / min) to obtain 6 (retention time 11.3-12.4 min). 1H NMR (400MHz, DMSO-d6): δ10.75 (s, 1H), 8.68 (d, J = 8.8Hz, 1H), 8.48 (d, J = 5.6Hz, 1H), 8.26 (d, J = 2.0Hz, 1H), 7.84 (dd, J=5.6, 2.0Hz, 1H), 7.22-7.12 (m, 2H), 5.10 (d, J=10.0Hz, 1H), 4.86-4.76 (m, 1H), 4.43-4.31 (m, 1H), 4.30-4 0.22 (m, 1H), 4.21-4.16 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.84-2.71 (m, 1H), 2.01-1.90 (m, 2H), 1.77-1.69 (m, 1H), 1.69-1.65 (m, 1H), 1.64-1.62 (m, 1H), 1.61 (s, 3H), 1.59-1.53 ​​(m, 1H), 0.73 (d, J = 5.6 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =558.2, measured value 558.1.

[0251] Example 7

[0252] Synthesis route:

[0253] first step

[0254] Dissolve 1-4 (25 mg, 53 μmol) and 7-1 (11 mg, 80 μmol) in DMF (1 mL), cool to 0 °C, and then add DIEA (21 mg, 0.16 mmol) and HATU (31 mg, 80 μmol) sequentially. Stir at 0 °C for 1 hour. After the reaction is complete, 7 is purified by high performance liquid chromatography (column: Agilent C18, 21.2*250 mm, 10 μm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 65-75%; flow rate: 20 mL / min) to obtain 7 (retention time 9.2-10.2 min). 1H NMR (400MHz, DMSO-d6): δ10.74 (s, 1H), 8.53 (d, J = 8.4Hz, 1H), 8.49 (d, J = 5.6Hz, 1H), 8.24 (d, J = 2.0Hz, 1H), 7.85 (dd, J=5.6, 2.0Hz, 1H), 7.29-7.02 (m, 2H), 5.10 (d, J=10.4Hz, 1H), 4.50 (d, J=4.0Hz, 1H), 4.48-4.39 (m, 1H), 4.27 -4.23 (m, 1H), 4.21-4.17 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.85-2.72 (m, 1H), 2.12-1.98 (m, 1H), 1.97-1.87 (m, 1H), 1.85-1.80 (m, 1H), 1.76-1.66 (m, 1H), 1.61 (s, 3H), 1.55-1.43 (m, 2H), 0.73 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =558.2, measured value 558.1.

[0255] Example 8

[0256] Synthesis route:

[0257] first step

[0258] Dissolve 1-4 (25 mg, 53 μmol) and 8-1 (11 mg, 80 μmol) in DMF (1 mL), cool to 0 °C, and then add DIEA (21 mg, 0.16 mmol) and HATU (31 mg, 80 μmol) sequentially. Stir at 0 °C for 1 hour. After the reaction is complete, 8 is purified by high performance liquid chromatography (column: SunFire Prep C18, 19*250 mm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 57-82%; flow rate: 20 mL / min) to obtain 8 (retention time 11.3-11.7 min). 1H NMR (400MHz, DMSO-d6): δ10.74 (s, 1H), 8.54 (d, J = 8.4Hz, 1H), 8.49 (d, J = 5.6Hz, 1H), 8.24 (d, J = 2.0Hz, 1H), 7.86 (dd, J=5.6, 2.4Hz, 1H), 7.23-7.10 (m, 2H), 5.10 (d, J=10.4Hz, 1H), 4.55-4.50 (m, 1H), 4.49-4.41 (m, 1H), 4.30-4 0.23 (m, 1H), 4.22-4.16 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.83-2.72 (m, 1H), 2.08-1.98 (m, 1H), 1.98-1.88 (m, 1H), 1.86-1.78 (m, 1H), 1.76-1.68 (m, 1H), 1.61 (s, 3H), 1.56-1.40 (m, 2H), 0.73 (d, J = 6.4 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =558.2, measured value 558.2.

[0259] Example 9

[0260] Synthesis route:

[0261] first step

[0262] 1-4 (20 mg, 42 μmol) and 2-amino-1,3-propanediol (6 mg, 63 μmol) were dissolved in DMF (1 mL). After cooling to 0 °C, DIEA (21 mg, 0.16 mmol) and HATU (31 mg, 80 μmol) were added sequentially, and the mixture was stirred at 0 °C for 1 hour. After the reaction was completed, the solution was purified by high performance liquid chromatography (HPLC) (column: Pursuit XRs C18, 21.2*250 mm, 10 μm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 55-67%; flow rate: 20 mL / min) to obtain 9 (retention time 11.4-12.3 min). 1H NMR (400MHz, DMSO-d6): δ10.76 (s, 1H), 8.50 (d, J=5.6Hz, 1H), 8.33 (d, J=8.8Hz, 1H), 8.29 (d, J=2.0Hz, 1H), 7.86 (dd, J=5.6, 2.0Hz, 1H), 7.22-7.12 (m, 2H), 5.11 (d, J=10.4Hz, 1H), 4.81 (t, J = 5.6 Hz, 2H), 4.30-4.20 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 3.95-3.85 (m, 1H), 3.61-3.51 (m, 2H), 3.52-3.44 (m, 2H), 2.83-2.72 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation values: [M+H] + =548.2, measured value 548.1.

[0263] Example 10

[0264] Synthesis route:

[0265] first step

[0266] 1-4 (25 mg, 53 μmol) and N,N′-carbonyldiimidazole (11 mg, 69 μmol) were dissolved in dry THF (1 mL), heated to 60 °C and stirred for 1 hour. 10-1 (12 mg, 0.11 mmol) and DBU (12 mg, 80 μmol) were added, and stirring continued for 1 hour. After the reaction was complete, water (10 mL) was added for dilution, followed by extraction with dilute hydrochloric acid (0.5 mol / L, 0.5 mL) and ethyl acetate (10 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: SunFire Prep C18, 19*250 mm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 73-88%; flow rate: 20 mL / min) to obtain 10 (retention time 10.0-10.4 min). 1¹H NMR (400MHz, MeOD-d⁴): δ 8.53 (d, J = 5.6Hz, 1H), 8.36 (s, 1H), 7.92 (dd, J = 5.6, 2.0Hz, 1H), 7.16–7.08 (m, 1H), 7.03–6.93 (m, 1H), 5.08 (d, J = 10.4Hz, 1H), 4.37–4.26 (m, 1H), 3.99 (d, J = 2.0Hz, 3H), 2.84–2.74 (m, 1H), 2.67 (s, 3H), 1.66 (s, 3H), 0.87–0.77 (m, 3H). ESI-MS theoretical calculation: [M+H] + =567.1, measured value 567.2.

[0267] Example 11

[0268] Synthesis route:

[0269] first step

[0270] Dissolve 1-4 (25 mg, 53 μmol) and N,N′-carbonyldiimidazole (11 mg, 69 μmol) in dry THF (1 mL), heat to 60 °C and stir for 1 hour. Add 11-1 (13 mg, 0.11 mmol) and DBU (12 mg, 80 μmol), and continue stirring for 1 hour. After the reaction is complete, dilute with water (10 mL), extract with dilute hydrochloric acid (0.5 mol / L, 0.5 mL), and extract with ethyl acetate (10 mL × 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by high performance liquid chromatography (column: SunFire Prep C18, 19*250 mm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 70-80%; flow rate: 20 mL / min) to obtain 11 (retention time 11.5-11.9 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 11.39 (br s, 1H), 10.82 (s, 1H), 8.57 (d, J = 5.6Hz, 1H), 8.34 (s, 1H), 7.92 (dd, J = 5.6, 2.0Hz, 1H), 7.21–7.12 (m, 2H), 5.12 (d, J = 10.4Hz, 1H), 4.29–4.22 (m, 1H), 3.95 (d, J = 2.0Hz, 3H), 2.87 (s, 6H), 2.82–2.74 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 5.6Hz, 3H). ESI-MS theoretical calculation: [M+H] + =581.2, measured value 581.2.

[0271] Example 12

[0272] Synthesis route:

[0273] first step

[0274] 12-1 (1.5 g, 4.23 mmol) was dissolved in ammonia water (30 mL), and the mixture was heated to 60 °C and stirred for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-30 μm 100A 20 g; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 5-10%; flow rate: 20 mL / min) to obtain 12-2 (retention time 10.0-12.0 min). ESI-MS theoretical calculation value: [M+H] + =143.0, measured value 143.0.

[0275] Step 2

[0276] Dissolve 1-1 (25 mg, 71 μmol) and 12-2 (15 mg, 0.11 mmol) in DMF (1 mL), cool to 0 °C, and then add DIEA (31 mg, 0.28 mmol) and HATU (41 mg, 0.11 mmol) sequentially. Stir at 0 °C for 1 hour. After the reaction is complete, 12 is purified by high performance liquid chromatography (column: Agilent C18, 19*250 mm; mobile phase: A is an aqueous solution containing 0.1% formic acid, B is acetonitrile; gradient: mobile phase B is 55-85%; flow rate: 20 mL / min) to obtain 12 (retention time 11.5-12.1 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.62 (s, 1H), 7.77 (s, 1H), 7.51 (d, J = 4.0Hz, 1H), 7.24–7.06 (m, 3H), 6.81 (d, J = 4.0Hz, 1H), 5.12 (d, J = 10.4Hz, 1H), 4.26–4.21 (m, 1H), 3.94 (d, J = 2.0Hz, 3H), 2.79–2.72 (m, 1H), 1.59 (s, 3H), 0.72 (d, J = 6.00Hz, 3H). ESI-MS theoretical calculation: [M+H] + =479.1, measured value 479.0.

[0277] Example 13

[0278] Synthesis route:

[0279] first step

[0280] Dissolve 1-1 (50 mg, 0.14 mmol) in DMF (1 mL), cool to 0 °C, and then add 13-1 (33 mg, 0.21 mmol), DIEA (54 mg, 0.42 mmol), and HATU (80 mg, 0.21 mmol) sequentially. Stir at 0 °C for 1 hour. After the reaction is complete, dilute with water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain 13-2. 1 H NMR (400MHz, DMSO-d6): δ10.65 (s, 1H), 7.95-7.85 (m, 2H), 7.20-7.10 (m, 2H), 5.05 (d, J=10.4Hz, 1H), 4.2 6-4.16 (m, 1H), 3.94 (d, J=2.0Hz, 3H), 3.81 (s, 3H), 2.79-2.69 (m, 1H), 1.60 (s, 3H), 0.72 (d, J=6.0Hz, 3H).

[0281] Step 2

[0282] 13-2 (68 mg, 0.14 mmol) was dissolved in a methanol solution of ammonia (7 mol / L, 30 mL), and the mixture was heated to 60 °C and stirred for 16 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: SunFire Prep C18, 19*250 mm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 55-70%; flow rate: 20 mL / min) to obtain 13 (retention time 8.1-8.6 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 10.64 (s, 1H), 8.05–7.95 (m, 1H), 7.80 (d, J = 1.6Hz, 1H), 7.65 (d, J = 1.6Hz, 1H), 7.43–7.33 (m, 1H), 7.19–7.11 (m, 2H), 5.06 (d, J = 10.4Hz, 1H), 4.28–4.18 (m, 1H), 3.95 (d, J = 2.0Hz, 3H), 2.79–2.69 (m, 1H), 1.59 (s, 3H), 0.72 (d, J = 5.6Hz, 3H). ESI-MS theoretical calculation: [M+H] + =479.1, measured value 479.0.

[0283] Example 14

[0284] Synthesis route:

[0285] first step

[0286] 1-1 (50 mg, 0.14 mmol) was dissolved in DMF (1 mL), cooled to 0 °C, and then 14-1 (33 mg, 0.21 mmol), DIEA (54 mg, 0.42 mmol), and HATU (80 mg, 0.21 mmol) were added sequentially. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 14-2. 1 H NMR (400MHz, DMSO-d6): δ8.11 (s, 1H), 7.25-7.14 (m, 2H), 5.15 (d, J=10.4Hz, 1H), 4.30-4.22 (m , 1H), 3.94 (d, J = 2.0Hz, 3H), 3.81 (s, 3H), 2.81-2.75 (m, 1H), 1.61 (s, 3H), 0.71 (d, J = 6.0Hz, 3H)

[0287] Step 2

[0288] 14-2 (51 mg, 0.10 mmol) was dissolved in a methanol solution of ammonia (7 mol / L, 25 mL), and the mixture was heated to 60 °C and stirred for 16 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: SunFire Prep C18, 19*250 mm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 53-73%; flow rate: 20 mL / min) to obtain 14 (retention time 9.0-9.8 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.64 (s, 1H), 7.78–7.68 (m, 1H), 7.54–7.44 (m, 1H), 7.30 (s, 1H), 7.19–7.14 (m, 2H), 5.15 (d, J = 10.4 Hz, 1H), 4.30–4.20 (m, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.82–2.72 (m, 1H), 1.60 (s, 3H), 0.71 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =480.1, measured value 480.0.

[0289] Example 15

[0290] Synthesis route:

[0291] first step

[0292] Dissolve 1-1 (50 mg, 0.14 mmol) in DMF (1 mL), cool to 0 °C, and then add 15-1 (33 mg, 0.21 mmol), DIEA (54 mg, 0.42 mmol), and HATU (80 mg, 0.21 mmol) sequentially. Stir at 0 °C for 1 hour. After the reaction is complete, 15-2 is purified by high performance liquid chromatography (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 60-67%; flow rate: 20 mL / min) to obtain 15-2 (retention time 15.0-18.0 min). 1 H NMR (400MHz, DMSO-d6): δ11.53 (s, 1H), 7.79 (d, J=1.6Hz, 1H), 7.22-7.10 (m, 3H), 5.13 (d, J=10.4Hz, 1H), 4. 25-4.18 (m, 1H), 3.94 (d, J=2.0Hz, 3H), 3.77 (s, 3H), 2.78-2.71 (m, 1H), 1.60 (s, 3H), 0.72 (d, J=5.6Hz, 3H).

[0293] Step 2

[0294] 15-2 (68 mg, 0.14 mmol) was dissolved in a methanol solution of ammonia (7 mol / L, 30 mL), and the mixture was heated to 60 °C and stirred for 16 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: SunFire Prep C18, 19*250 mm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 43-65%; flow rate: 20 mL / min) to obtain 15 (retention time 10.4-11.0 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.53 (s, 1H), 7.71 (s, 1H), 7.59 (d, J = 1.6Hz, 1H), 7.18–7.11 (m, 4H), 5.11 (d, J = 10.4Hz, 1H), 4.28–4.18 (m, 1H), 3.94 (d, J = 2.0Hz, 3H), 2.81–2.71 (m, 1H), 1.59 (s, 3H), 0.72 (d, J = 6.0Hz, 3H). ESI-MS theoretical calculation: [M+H] + =479.1, measured value 479.0.

[0295] Example 16

[0296] Synthesis route:

[0297] first step

[0298] 1-1 (25 mg, 71 μmol) was dissolved in DMF (1 mL), cooled to 0 °C, and then 16-1 (18 mg, 0.11 mmol), DIEA (27 mg, 0.21 mmol), and HATU (40 mg, 0.11 mmol) were added sequentially. The mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain 16-2. 1 H NMR (400MHz, DMSO-d6): δ11.77 (s, 1H), 8.01 (s, 1H), 7.21-7.16 (m, 2H), 5.12 (d, J=10.4Hz, 1H), 4.35 (q, J=7.2Hz, 2H), 4.30-4.20 (m, 1H), 3.94 (d, J=2.0Hz, 3H), 2.79-2.69 (m, 1H), 1.60 (s, 3H), 1.31 (d, J=7.2Hz, 3H), 0.70 (d, J=6.0Hz, 3H).

[0299] Step 2

[0300] 16-2 (30 mg, 59 μmol) was dissolved in a methanol solution of ammonia (7 mol / L, 20 mL), and the mixture was heated to 60 °C and stirred for 4 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: SunFire Prep C18, 19*250 mm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 60-70%; flow rate: 20 mL / min) to obtain 16 (retention time 8.5-9.4 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.16 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.22–7.12 (m, 2H), 5.22 (d, J = 10.4 Hz, 1H), 4.31–4.21 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.81–2.71 (m, 1H), 1.60 (s, 3H), 0.71 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation: [M+H] +=480.1, measured value 480.0.

[0301] Example 17

[0302] Synthesis route:

[0303] first step

[0304] 17-1 (2.0 g, 8.47 mmol) was dissolved in toluene (50 mL), and tert-butyl carbamate (1.49 g, 12.71 mmol), potassium phosphate (6.29 g, 29.65 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (1.35 g, 1.69 mmol) and tris(dibenzylideneacetone)dipalladium (780 mg, 0.85 mmol) were added sequentially. The mixture was heated to 110 °C and stirred for 12 hours under nitrogen protection. After the reaction was completed, the mixture was diluted with saturated saline (150 mL), extracted with ethyl acetate (150 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain 17-2. 1 H NMR (400MHz, DMSO-d6): δ10.54 (s, 1H), 7.64 (s, 1H), 3.89 (s, 3H), 1.47 (s, 9H).

[0305] Step 2

[0306] 17-2 (100 mg, 0.95 mmol) was dissolved in dichloromethane (3 mL), and hydrochloric acid (1,4-dioxane solution, 4 mol / L, 1 mL) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a crude product containing 17-3, which was directly used in the next reaction. ESI-MS theoretical calculation: [M+H] + =159.0, measured value 159.1.

[0307] Step 3

[0308] Dissolve 1-1 (25 mg, 71 μmol) in DMF (1 mL), cool to 0 °C, and then add 17-3 (17 mg, 0.11 mmol), DIEA (36 mg, 0.28 mmol), and HATU (40 mg, 0.11 mmol) sequentially. Stir at 0 °C for 1 hour. After the reaction is complete, dilute with water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain 17-4.1 H NMR (400MHz, DMSO-d6): δ11.73 (s, 1H), 8.01 (s, 1H), 7.21-7.16 (m, 2H), 5.12 (d, J=10.4Hz, 1H), 4.30-4 .20 (m, 1H), 3.94 (d, J = 2.0Hz, 3H), 3.90 (s, 3H), 2.79-2.69 (m, 1H), 1.60 (s, 3H), 0.70 (d, J = 5.6Hz, 3H).

[0309] Step 4

[0310] 17-4 (27 mg, 55 μmol) was dissolved in a methanol solution of ammonia (7 mol / L, 20 mL), and the mixture was heated to 60 °C and stirred for 4 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: SunFire Prep C18, 19*250 mm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 65-75%; flow rate: 20 mL / min) to obtain 17 (retention time 8.5-9.0 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.16 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.22–7.12 (m, 2H), 5.21 (d, J = 10.4 Hz, 1H), 4.31–4.21 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.81–2.71 (m, 1H), 1.60 (s, 3H), 0.71 (d, J = 6.4 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =480.1, measured value 480.2.

[0311] Example 18

[0312] Synthesis route:

[0313] first step

[0314] Sodium hydride (60% by mass, 2.15 g, 53.82 mmol) was added to dry THF (100 mL), cooled to 0 °C, and then a THF (100 mL) solution of 18-1 (10.0 g, 44.85 mmol) was added. The mixture was stirred for 2 hours under nitrogen protection. After the reaction was completed, water (300 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (500 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain 18-2. 1H NMR (400MHz, CDCl3): δ8.05 (d, J=5.2Hz, 1H), 7.54-7.51 (m, 1H), 7.35 (d, J=7.2Hz, 2H), 7.32-7.26 (m, 2H), 7.25-7.18 (m, 2H), 4.37 (s, 2H).

[0315] Step 2

[0316] 18-2 (1.0 g, 3.06 mmol) was dissolved in dichloromethane (15 mL), cooled to 0 °C, and then acetic acid (2 mL) and water (4 mL) were added. 1,3-Dichloro-5,5-dimethylhydantoin (1.81 g, 9.18 mmol) was then added, and the mixture was stirred for 2 hours under nitrogen protection. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing 18-3. Petroleum ether (30 mL) was added, and the mixture was stirred thoroughly for 2 hours, then filtered to obtain 18-3. ESI-MS theoretical value: [M+H] + =299.9, measured value 299.8.

[0317] Step 3

[0318] 18-3 (520 mg, 1.71 mmol) was dissolved in dichloromethane (25 mL), cooled to 0 °C, and then DIEA (0.86 mL, 5.22 mmol) and bis(2,4-dimethoxybenzyl)amine (270 mg, 0.85 mmol) were added. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with dichloromethane (80 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate, 10 / 1, v / v) to obtain 18-4. 1 H NMR (400MHz, CDCl3): δ8.19 (d, J=5.2Hz, 1H), 7.85 (d, J=1.2Hz, 1H), 7.67 (dd, J=5.2, 1.6Hz, 1H), 7.24 (d, J=8.4Hz, 2H), 6.40 (dd, J=8.4, 2.4Hz, 2H), 6.23 (d, J=2.4Hz, 2H), 4.56 (s, 4H), 3.79 (s, 6H), 3.64 (s, 6H).

[0319] Step 4

[0320] 18-4 (205 mg, 0.35 mmol) was dissolved in N-methylpyrrolidone (6 mL), and ammonium acetate (270 mg, 3.50 mmol), copper(II) acetylacetonate (27.5 mg, 0.10 mmol), 2-acetylcyclohexanone (29.5 mg, 0.21 mmol), and cesium carbonate (342 mg, 1.05 mmol) were added. The mixture was heated to 90 °C and stirred for 16 hours. After cooling, water (20 mL) was added, and the mixture was extracted 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 (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 18-5. 1 H NMR (400MHz, CDCl3): δ8.05 (d, J=5.6Hz, 1H), 7.00 (dd, J=6.4, 2.4Hz, 2H), 6.98 (d, J=2.8Hz, 1H), 6.58 (dd, J=5 .6, 2.4Hz, 1H), 6.55 (s, 2H), 6.42-6.32 (m, 3H), 6.36 (d, J=2.4Hz, 1H), 4.31 (s, 4H), 3.70 (s, 6H), 3.58 (s, 6H).

[0321] Step 5

[0322] 18-5 (159 mg, 0.34 mmol) and 1-1 (100 mg, 0.28 mmol) were dissolved in acetonitrile (3 mL), cooled to 0 °C, and then NMI (48 mg, 0.59 mmol) and TCFH (86 mg, 0.31 mmol) were added sequentially. The mixture was stirred at 25 °C for 4 hours. After the reaction was complete, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 18-6. ESI-MS theoretical calculation: [M+H] + =810.2, measured value 810.0.

[0323] Step 6

[0324] 18-6 (140 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The mixture was then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 15 / 1, v / v) to obtain 18-7. 1H NMR (400MHz, DMSO-d6): δ10.85 (s, 1H), 8.57 (d, J=5.6Hz, 1H), 8.26 (d, J=2.0Hz, 1H), 7.81 (dd, J=5.6, 2.0Hz, 1H), 7.42 (s, 2H), 7.22- 7.12 (m, 2H), 5.12 (d, J=10.0Hz, 1H), 4.30-4.20 (m, 1H), 3.95 (d, J=2.0Hz, 3H), 2.83-2.73 (m, 1H), 1.61 (s, 3H), 0.73 (d, J=6.0Hz, 3H).

[0325] Step 7

[0326] 18-7 (20 mg, 39 μmol) was dissolved in dichloromethane (1 mL), and 4-dimethylaminopyridine (480 μg, 4 μmol), TEA (11 μL, 78 μmol), and methylcarbamoyl chloride (5.5 mg, 58 μmol) were added sequentially. The mixture was stirred at 25 °C for 4 hours. After the reaction was complete, the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (HPLC) (column: XBridge Prep C18, 19*250 mm, 10 μm; mobile phase: A was 10 mmol / L ammonium bicarbonate aqueous solution, B was acetonitrile; gradient: mobile phase B was 35-60%; flow rate: 20 mL / min) to obtain 18 (retention time 6.9-7.7 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 10.85 (s, 1H), 8.53–8.43 (m, 1H), 8.25–8.15 (m, 1H), 7.86–7.76 (m, 1H), 7.27–7.08 (m, 3H), 6.19 (s, 1H), 5.12 (d, J = 10.0Hz, 1H), 4.29–4.19 (m, 1H), 3.95 (s, 3H), 2.82–2.72 (m, 1H), 2.43 (s, 3H), 1.61 (s, 3H), 0.73 (d, J = 5.6Hz, 3H). ESI-MS theoretical calculation: [M+H] + =567.1, measured value 567.1.

[0327] Example 19

[0328] Synthesis route:

[0329] first step

[0330] 19-1 (1.0 g, 5.47 mmol) was added to a thick-walled, pressure-resistant flask, dissolved in concentrated ammonia (~25% by mass, 15 mL), and the mixture was heated to 50 °C and reacted for 12 hours. After cooling, the mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (HPLC) (column: spherical Prep C18, 20-35 μm, 100A 40 g; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 0-5%; flow rate: 40 mL / min) to obtain 19-2 (retention time 10.5-15.0 min). ESI-MS theoretical calculation: [M+H] + =144.0, measured value 144.1.

[0331] Step 2

[0332] 19-2 (16 mg, 110 μmol) and 1-1 (25 mg, 71 μmol) were dissolved in DMF (1 mL), and DIEA (47 μL, 0.28 mmol) and HATU (40 mg, 110 μmol) were added sequentially. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, 19 was purified by high performance liquid chromatography (column: SunFire Prep C18, 19*250 mm, 10 μm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 53-64%; flow rate: 20 mL / min) to obtain 19 (retention time 11.9-12.5 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.72 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.40 (s, 1H), 7.22–7.11 (m, 2H), 5.16 (d, J = 10.4 Hz, 1H), 4.29–4.23 (m, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.82–2.75 (m, 1H), 1.60 (s, 3H), 0.71 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =480.1, measured value 480.0.

[0333] Examples 20 and 21

[0334] Synthesis route:

[0335] first step

[0336] 20-1 (5.0 g, 38.4 mmol) was dissolved in DMF (15 mL), cooled to 0 °C, and then N-bromosuccinimide (7.52 g, 42.2 mmol) was added. The mixture was heated to 25 °C and stirred for 90 minutes. After the reaction was complete, ethyl acetate (100 mL) was added, and the mixture was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing 20-2. This crude product was used directly in the next reaction without further purification. 1 H NMR (400MHz, CDCl3): δ6.91 (d, J=3.6Hz, 1H), 6.87 (d, J=3.6Hz, 1H), 2.46 (s, 3H).

[0337] Step 2

[0338] 20-2 (2.0 g, 9.56 mmol) was dissolved in dichloromethane (50 mL), cooled to -5 °C, and then m-chloroperoxybenzoic acid (85% by mass, 2.13 g, 10.52 mmol) was added. The mixture was stirred for 30 minutes. After the reaction was complete, the mixture was filtered, and the filtrate was washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain 20-3. 1 ¹H NMR (400MHz, CDCl₃): δ 7.23 (d, J = 4.0Hz, 1H), 7.07 (d, J = 4.0Hz, 1H), 2.91 (s, 3H). ESI-MS theoretical calculation: [M+H] + =224.9, measured value 225.0.

[0339] Step 3

[0340] 20-3 (2.0 g, 8.88 mmol) was dissolved in dichloromethane (80 mL), and tert-butyl carbamate (1.56 g, 13.32 mmol), magnesium oxide (1.43 g, 35.52 mmol), rhodium dimer acetate (98 mg, 0.22 mmol), and diacetoxyiodobenzene (4.29 g, 13.32 mmol) were added sequentially. The mixture was heated to 40 °C and stirred for 8 hours. After cooling, water (200 mL) was added, and the mixture was extracted with dichloromethane (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 20-4. 1 H NMR (400MHz, CDCl3): δ7.51 (d, J=4.0Hz, 1H), 7.15 (d, J=4.0Hz, 1H), 3.35 (s, 3H), 1.44 (s, 9H).

[0341] Step 4

[0342] 20-4 (500 mg, 1.47 mmol), benzophenone imine (400 mg, 2.21 mmol), Xantphos (134 mg, 0.15 mmol), and cesium carbonate (1.2 g, 3.67 mmol) were added to 1,4-dioxane (15 mL), followed by Pd2(dba)3 (130 mg, 0.15 mmol). The mixture was heated to 100 °C and stirred for 16 hours under nitrogen protection. After cooling, the mixture was diluted with water (50 mL), 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 (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 20-5. ESI-MS theoretical value: [M+H] + =441.1, measured value 441.3.

[0343] Step 5

[0344] 20-5 (480 mg, 1.09 mmol) was dissolved in THF (10 mL), and dilute hydrochloric acid (2 mol / L, 2.42 mL) was added. The mixture was stirred at 25 °C for 15 minutes. After the reaction was complete, the pH was adjusted to greater than 8 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted 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 (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 20-6. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.29 (d, J = 4.4Hz, 1H), 6.81 (s, 2H), 5.95 (d, J = 4.4Hz, 1H), 3.35 (s, 3H), 1.35 (s, 9H). ESI-MS theoretical calculation: [M+H] + =277.1, measured value 277.1.

[0345] Step 6

[0346] 20-6 (110 mg, 0.40 mmol) was subjected to supercritical fluid chromatography (column: Waters SFC 150). 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 30%; flow rate: 100mL / min) to separate and purify 20-6A (retention time 1.8-2.3min) and 20-6B (retention time 2.4-3.3min).

[0347] Step 7

[0348] Dissolve 1-1 (15 mg, 42 μmol) in DMF (1 mL), add 20-6A (17 mg, 63 μmol), DIEA (21 μL, 130 μmol), and HATU (24 mg, 63 μmol), and stir at 0 °C for 1 hour. After the reaction is complete, dilute with water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (20 mL), 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 20-7A. ESI-MS theoretical calculation: [M+H] + =613.2, measured value 613.3.

[0349] Step 8

[0350] 20-7A (16 mg, 26 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.3 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 and purified by high performance liquid chromatography (HPLC) (column: SunFire Prep C18, 19*250 mm, 10 μm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 62-67%; flow rate: 20 mL / min) to obtain 20 (retention time 6.7-7.7 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.95 (br s, 1H), 7.38 (d, J = 4.2Hz, 1H), 7.20–7.13 (m, 2H), 6.89–6.79 (m, 1H), 5.14 (d, J = 10.0Hz, 1H), 4.39 (s, 1H), 4.23 (dd, J = 1.00, 7.6Hz, 1H), 3.94 (d, J = 2.0Hz, 3H), 3.07 (s, 3H), 2.79–2.72 (m, 1H), 1.59 (s, 3H), 0.72 (d, J = 5.6Hz, 3H). ESI-MS theoretical calculation: [M+H] + =513.1, measured value 513.0.

[0351] Using 20-6B (20 mg, 56 μmol) as a starting material, a similar reaction procedure was followed, and the product was purified by high performance liquid chromatography (HPLC) (column: spherical Prep C18, 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 45-50%; flow rate: 20 mL / min) to obtain 21 (retention time 25.0-28.0 min). 1¹H NMR (400MHz, DMSO-d6): δ 11.92 (br s, 1H), 7.39 (d, J = 4.0Hz, 1H), 7.21–7.13 (m, 2H), 6.88 (d, J = 4.0Hz, 1H), 5.17 (d, J = 10.4Hz, 1H), 4.42 (s, 1H), 4.23 (dd, J = 10.0, 7.6Hz, 1H), 3.94 (d, J = 2.0Hz, 3H), 3.08 (s, 3H), 2.81–2.71 (m, 1H), 1.60 (s, 3H), 0.73 (d, J = 6.0Hz, 3H). ESI-MS theoretical calculation: [M+H] + =513.1, measured value 513.1.

[0352] Example 22

[0353] Synthesis route:

[0354] first step

[0355] 22-1 (1.0 g, 3.35 mmol), benzophenone imine (910 mg, 5.03 mmol), Xantphos (194 mg, 0.34 mmol), and cesium carbonate (2.73 g, 8.38 mmol) were added to 1,4-dioxane (50 mL), followed by Pd2(dba)3 (192 mg, 0.34 mmol). The mixture was heated to 100 °C and stirred for 8 hours under nitrogen protection. After cooling, the mixture was diluted with water (200 mL), extracted with ethyl acetate (200 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 (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain 22-2. ESI-MS theoretical value: [M+H] + =399.1, measured value 399.2.

[0356] Step 2

[0357] 22-2 (1.33 g, 5.68 mmol) was dissolved in THF (10 mL), and dilute hydrochloric acid (2 mol / L, 10 mL) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the pH was adjusted to greater than 8 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 22-3. ESI-MS theoretical calculation: [M+H] + =235.1, measured value 235.0.

[0358] Step 3

[0359] Dissolve 1-1 (13 mg, 37 μmol) in DMF (1 mL), add 22-3 (8 mg, 44 μmol), DIEA (18 μL, 110 μmol), and HATU (21 mg, 55 μmol), and stir at 0 °C for 1 hour. After the reaction is complete, dilute with water (10 mL), extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL), 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 22-4. ESI-MS theoretical calculation: [M+H] + =571.1, measured value 571.2.

[0360] Step 4

[0361] Add 22-4 (18 mg, 32 μmol) to a thick-walled, pressure-resistant bottle, dissolve it in trifluoroacetic acid (2 mL), and heat to 70 °C for 15 minutes. After cooling, concentrate under reduced pressure and purify by high-performance liquid chromatography (HPLC) (column: spherical Prep C18, 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 40-75%; flow rate: 12 mL / min) to obtain 22 (retention time 10.0-12.0 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 11.82 (br s, 1H), 7.45 (s, 2H), 7.31 (d, J = 4.0Hz, 1H), 7.21–7.12 (m, 2H), 6.82 (d, J = 4.0Hz, 1H), 5.16 (d, J = 10.0Hz, 1H), 4.23 (dd, J = 10.0, 8.0Hz, 1H), 3.94 (d, J = 2.0Hz, 3H), 2.82–2.71 (m, 1H), 2.07 (s, 1H), 1.60 (s, 3H), 0.73 (d, J = 6.4Hz, 3H). ESI-MS theoretical calculation: [M+H] + =515.1, measured value 515.0.

[0362] Example 23

[0363] Synthesis route:

[0364] first step

[0365] Dissolve 1-1 (50 mg, 110 μmol) in DMF (1 mL), add 23-1 (21 mg, 170 μmol), DIEA (0.54 mL, 0.33 mmol), and HATU (30 mg, 80 μmol), and stir at 0 °C for 1 hour. After the reaction is complete, 23-1 is purified by high performance liquid chromatography (column: SunFirePrep 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 75-85%; flow rate: 20 mL / min) to obtain 23-1 (retention time 7.3-7.8 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 12.11 (br s, 1H), 7.75 (d, J = 4.4Hz, 1H), 7.17 (t, J = 5.2Hz, 2H), 6.98 (d, J = 4.4Hz, 1H), 5.22 (d, J = 10.4Hz, 1H), 4.24 (dd, J = 10.4, 7.6Hz, 1H), 3.94 (d, J = 2.0Hz, 3H), 2.76 (t, J = 7.6Hz, 1H), 1.60 (s, 3H), 0.72 (d, J = 6.0Hz, 3H). ESI-MS theoretical calculation: [M+H] + =461.1, measured value 460.9.

[0366] Example 24

[0367] Synthesis route:

[0368] first step

[0369] Add 23 (34 mg, 74 μmol) to a thick-walled, pressure-resistant bottle, dissolve it in methanol (1 mL), then add hydroxylamine aqueous solution (50% mass fraction, 20 mg, 0.30 mmol), and heat to 60 °C for 2 hours. After the reaction, 24 was purified by high performance liquid chromatography (column: SunFire Prep 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 40-55%; flow rate: 20 mL / min) to obtain 24 (retention time 8.8-11.5 min). 1¹H NMR (400MHz, DMSO-d6): δ 11.65 (br s, 1H), 7.41–7.31 (m, 1H), 7.21–7.10 (m, 2H), 6.88–6.78 (m, 1H), 5.13 (d, J = 10.4 Hz, 1H), 4.23 (dd, J = 10.4, 7.6 Hz, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.76 (t, J = 7.6 Hz, 1H), 1.59 (s, 3H), 0.72 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =494.1, measured value 493.8.

[0370] Example 25

[0371] Synthesis route:

[0372] first step

[0373] 25-1 (5.0 g, 22.73 mmol) was dissolved in dichloromethane (100 mL), cooled to 0 °C, and then pyridine (3.6 mL, 45.46 mmol) and phenyl chloroformate (8.90 g, 56.83 mmol) were added sequentially. The mixture was stirred for 30 minutes, then heated to 25 °C and stirred for another 2 hours. After the reaction was complete, water (200 mL) was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Petroleum ether (100 mL) was added, and the mixture was stirred for 5 hours. The filtered solid was 25-2. ESI-MS theoretical value: [M+H] + =341.0, measured value 340.8.

[0374] Step 2

[0375] 25-2 (7.2 g, 21.17 mmol) was dissolved in acetonitrile (400 mL), and hydrazine hydrate (80%, 3.2 mL, 52.93 mmol) was added. The mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain the crude product. Petroleum ether (100 mL) was added, and the mixture was stirred for 5 hours. The resulting solid was filtered and was 25-3. ESI-MS theoretical calculation: [M+H] + =279.0, measured value 278.8.

[0376] Step 3

[0377] 25-3 (1.96 g, 7.05 mmol) was dissolved in DMF (80 mL), and formamidine acetate (2.94 g, 28.20 mmol) was added. The mixture was stirred at 25 °C for 30 minutes, followed by the addition of acetic acid (5.25 g, 87.43 mmol). The temperature was raised to 80 °C, and stirring continued for 8 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product. After adding ice water (200 mL), the mixture was stirred thoroughly and filtered to obtain the solid, which was 25-4. 1 H NMR (400MHz, DMSO-d6): δ12.19 (br s, 1H), 8.61 (s, 1H), 8.54 (s, 1H), 8.20 (d, J=5.2Hz, 1H), 7.80 (dd, J=5.2, 1.2Hz, 1H).

[0378] Step 4

[0379] 25-4 (200 mg, 0.69 mmol) was dissolved in DMF (5 mL), and DIEA (0.3 mL, 1.82 mmol) and (trimethylsilyl)ethoxymethyl chloride (0.26 mL, 1.45 mmol) were added sequentially. The mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the mixture was diluted with water (40 mL), extracted with ethyl acetate (40 mL × 3), the organic phases were combined, washed with saturated brine (100 mL), 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 25-5. 1 ¹H NMR (400MHz, DMSO-d6): δ 8.70 (s, 1H), 8.56 (d, J = 1.6Hz, 1H), 8.22 (d, J = 5.2Hz, 1H), 7.83 (dd, J = 5.2, 1.6Hz, 1H), 5.11 (s, 2H), 3.66–3.60 (m, 2H), 0.91–0.85 (m, 2H), 0.03 (s, 9H). ESI-MS theoretical calculation: [M+H] + =419.0, measured value 419.1.

[0380] Step 5

[0381] 25-5 (247 mg, 0.59 mmol) was dissolved in N-methylpyrrolidone (5 mL), and ammonia (3 mL, 77.89 mmol) and cuprous oxide (18 mg, 0.12 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 12 hours. After the reaction was complete, the mixture was diluted with water (40 mL), extracted with ethyl acetate (40 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 25-6.1 ¹H NMR (400MHz, DMSO-d⁶): δ 8.57 (s, 1H), 7.87 (d, J = 5.6Hz, 1H), 7.32 (d, J = 2.0Hz, 1H), 6.49 (s, 2H), 6.44 (dd, J = 5.6, 2.0Hz, 1H), 5.09 (s, 2H), 3.65–3.59 (m, 2H), 0.90–0.84 (m, 2H), 0.03 (s, 9H). ESI-MS theoretical calculation: [M+H] + =308.2, measured value 308.3.

[0382] Step 6

[0383] 25-6 (21 mg, 67 μmol) and 1-1 (20 mg, 56 μmol) were dissolved in dry acetonitrile (1 mL). After cooling to 0 °C, NMI (10 mg, 0.12 mmol) and TCFH (17 mg, 62 μmol) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 25-7. 1 H NMR (400MHz, DMSO-d6): δ10.92(br 8.68(s, 1H), 8.47(s, 1H), 8.36(d, J = 5.6Hz, 1H), 7.68(d, J = 4.0Hz, 1H), 7.20-7.10(m, 2H), 5.10(s, 2H), 4.30-4.20(m, 1H), 3.95(d, J = 2.0Hz, 3H), 3.62(t, J = 8.0Hz, 2H), 2.82-2.74(m, 1H), 1.60(s, 3H), 0.90-0.84(m, 3H), 0.73(d, J = 6.4Hz, 3H), 0.03(s, 9H). ESI-MS theoretical calculation values: [M+H] + =644.2, measured value 644.4.

[0384] Step 7

[0385] 25-7 (20 mg, 31 μmol) was dissolved in dichloromethane (1 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 and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 12 g; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 38-45%; flow rate: 15 mL / min) to obtain 25 (retention time 28.0-37.0 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 12.14 (br s, 1H), 10.94 (s, 1H), 8.52 (s, 1H), 8.48 (d, J = 2.0Hz, 1H), 8.34 (d, J = 5.6Hz, 1H), 7.67 (dd, J = 5.6, 2.0Hz, 1H), 7.21–7.10 (m, 2H), 5.17–5.07 (m, 1H), 4.29–4.22 (m, 1H), 3.96 (d, J = 2.0Hz, 3H), 2.81–2.75 (m, 1H), 1.60 (s, 3H), 0.73 (d, J = 5.6Hz, 3H). ESI-MS theoretical calculation: [M+H] + =514.2, measured value 514.1.

[0386] Example 26

[0387] Synthesis route:

[0388] first step

[0389] Dissolve 26-1 (2.0 g, 8.35 mmol) in DMF (100 mL), then add 26-2 (3.21 g, 25.05 mmol), cuprous iodide (1.59 g, 8.35 mmol), (1S,2S)-N,N′-dimethyl-1,2-cyclohexanediamine (480 mg, 3.34 mmol) and potassium carbonate (2.04 g, 16.7 mmol) in sequence. Under nitrogen protection, heat to 90 °C and stir for 12 hours. After cooling, the reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL × 3), 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 220 g; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 25-30%; flow rate: 100 mL / min) to obtain 26-3 (retention time 25.0-35.0 min). ESI-MS theoretical calculation value: [M+H] +=240.1, measured value 240.1.

[0390] Step 2

[0391] 26-3 (300 mg, 1.25 mmol) was dissolved in 1,4-dioxane (15 mL), and benzophenone imine (339.81 mg, 1.88 mmol), Pd2(dba)3 (72 mg, 0.13 mmol), Xantphos (72 mg, 0.13 mmol), and cesium carbonate (1.0 g, 3.13 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 8 hours under nitrogen protection. After cooling, the mixture was 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 (petroleum ether / ethyl acetate, 1 / 99, v / v) to obtain 26-4. ESI-MS theoretical value: [M+H] + =385.2, measured value 385.1.

[0392] Step 3

[0393] 26-4 (129 mg, 0.34 mmol) was dissolved in THF (5 mL), and dilute hydrochloric acid (2 mol / L, 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 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 0-15%; flow rate: 10 mL / min) to obtain 26-5 (retention time 15.0-17.0 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 8.42 (s, 1H), 7.92 (d, J = 6.0Hz, 1H), 6.50 (dd, J = 5.6, 2.4Hz, 1H), 6.40 (d, J = 2.0Hz, 1H), 6.29 (s, 2H), 1.36 (s, 6H). ESI-MS theoretical calculation: [M+H] + =221.1, measured value 221.0.

[0394] Step 4

[0395] 26-5 (19 mg, 85 μmol) and 1-1 (25 mg, 71 μmol) were dissolved in dry acetonitrile (1 mL). After cooling to 0 °C, NMI (12 mg, 0.15 mmol) and TCFH (22 mg, 78 μmol) were added sequentially, and the mixture was stirred at 25 °C for 4 hours. After the reaction was completed, the mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (HPLC) (column: SunFire Prep C18, 20*250 mm, 10 μm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 55-65%; flow rate: 20 mL / min) to obtain 26 (retention time 13.5-14.5 min). 1 H NMR (400MHz, DMSO-d6): δ7.93 (d, J=6.0Hz, 1H), 7.16-7.08 (m, 1H), 7.03-6.93 ( m, 1H), 6.55 (dd, J=5.6, 2.0Hz, 1H), 6.51 (d, J=2.0Hz, 1H), 6.43 (s, 2H), 5.90 (d , J = 6.4 Hz, 1H), 4.23-4.16 (m, 1H), 3.90 (d, J = 2.0 Hz, 3H), 2.85-2.78 (m, 1H), 1.66 (s, 3H), 1.59 (s, 3H), 1.58 (s, 3H), 0.76 (d, J = 6.4 Hz, 3H). ESI-MS theoretical calculation values: [M+H] + =557.2, measured value 557.2.

[0396] Example 27

[0397] Synthesis route:

[0398] first step

[0399] 27-1 (500 mg, 1.76 mmol) was dissolved in DMF (10 mL), and DIEA (0.87 mL, 5.28 mmol), ammonium chloride (282 mg, 5.28 mmol), and HATU (870 mg, 2.29 mmol) were added sequentially. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 3, v / v) to obtain 27-2. 1¹H NMR (400MHz, DMSO-d6): δ 7.84 (s, 1H), 7.47 (s, 1H), 7.32 (s, 1H), 4.39 (s, 2H), 3.61 (t, J = 5.6Hz, 2H), 2.78 (t, J = 5.6Hz, 2H), 1.42 (s, 9H). ESI-MS theoretical calculation: [M+H] + =283.1, measured value 283.0.

[0400] Step 2

[0401] 27-2 (100 mg, 0.35 mmol) was dissolved in 1,4-dioxane (4 mL), and hydrochloric acid (1,4-dioxane solution, 4 mol / L, 2 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 a crude product containing 27-3, which was directly used in the next reaction. ESI-MS theoretical calculation: [M+H] + =183.1, measured value 183.0.

[0402] Step 3

[0403] 27-3 (15 mg, 84 μmol) and 1-1 (20 mg, 56 μmol) were dissolved in DMF (1 mL), cooled to 0 °C, and then DIEA (37 μL, 0.22 mmol) and HATU (32 mg, 84 μmol) were added sequentially. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, 27 was purified by high performance liquid chromatography (column: C18 spherical 20-35 μm 100A 12 g; mobile phase: A was an aqueous solution containing 0.05% ammonia monohydrate, B was acetonitrile; gradient: mobile phase B was 50-57%; flow rate: 15 mL / min) to obtain 27 (retention time 30.0-35.0 min). 1 H NMR (400MHz, DMSO-d6): δ7.92-7.83(m, 1H), 7.54-7.44(m, 1H), 7.37-7.27(m, 1H) ,7.14-7.04(m,2H),5.52-5.41(m,1H),4.80-4.60(m,1H),4.57-4.45(m,1H),4.4 2-4.30 (m, 1H), 3.99-3.92 (m, 3H), 3.91-3.82 (m, 1H), 3.81-3.61 (m, 1H), 2.99-2.86 (m, 1H), 2.79-2.67 (m, 1H), 1.46 (s, 3H), 0.80-0.70 (m, 3H). ESI-MS theoretical calculation: [M+H] + =519.1, measured value 519.0. Example 28

[0404] Synthesis route:

[0405] first step

[0406] Concentrated sulfuric acid (4 mL) and concentrated nitric acid (3 mL) were slowly mixed at 0 °C, and 28-1 (2.0 g, 13.14 mmol) was added. The mixture was heated to 25 °C and stirred for 16 hours. After the reaction was completed, the reaction solution was slowly added to ice water (200 mL) and stirred for 2 hours. The mixture was extracted with dichloromethane / isopropanol (5 / 1, v / v, 200 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium bicarbonate aqueous solution (300 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain 28-2. 1 ¹H NMR (400MHz, DMSO-d6): δ 13.02 (br s, 1H), 9.35 (s, 1H), 8.37 (s, 1H). ESI-MS theoretical calculation: [M+H] + =198.0, measured value 198.1.

[0407] Step 2

[0408] 28-2 (120 mg, 0.61 mmol) was dissolved in ethanol (15 mL) and water (3 mL), followed by the sequential addition of ammonium chloride (326 mg, 6.10 mmol) and reduced iron powder (341 mg, 6.10 mmol). The mixture was heated to 80 °C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain 28-3. ESI-MS theoretical calculation: [M+H] + =168.0, measured value 168.1.

[0409] Step 3

[0410] 28-3 (16 mg, 98 μmol) and 1-1 (29 mg, 82 μmol) were dissolved in DMF (1 mL), cooled to 0 °C, and then DIEA (32 mg, 0.25 mmol) and HATU (32 mg, 86 μmol) were added sequentially. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, 28 was purified by high performance liquid chromatography (column: SunFire Prep C18, 19*250 mm, 10 μm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 72-72%; flow rate: 20 mL / min) to obtain 28 (retention time 9.2-10.3 min). 1¹H NMR (400MHz, DMSO-d6): δ 12.71 (br s, 1H), 10.14 (s, 1H), 8.29 (s, 1H), 8.28 (d, J = 4.0Hz, 1H), 7.32–7.25 (m, 1H), 7.22–7.12 (m, 1H), 5.51–5.41 (m, 1H), 4.29–4.19 (m, 1H), 3.94 (d, J = 2.0Hz, 3H), 2.80–2.70 (m, 1H), 1.62 (s, 3H), 0.72 (d, J = 5.6Hz, 3H). ESI-MS theoretical calculation: [M+H] + =504.1, measured value 504.1.

[0411] Example 29

[0412] Synthesis route:

[0413] first step

[0414] 29-1 (1.8 g, 8.06 mmol) was dissolved in DMF (20 mL), and DIEA (3.1 g, 23.99 mmol), ammonium chloride (1.3 g, 24.30 mmol), and HATU (3.98 g, 10.48 mmol) were added sequentially. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was diluted with water (250 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 (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 29-2. 1 H NMR (400MHz, DMSO-d6): δ7.70-7.60(m, 2H), 7.55-7.47(m, 2H), 7.46-7.40(m, 2H)

[0415] Step 2

[0416] 29-2 (200 mg, 0.90 mmol) was dissolved in ethanol (10 mL), and wet palladium on carbon (10%, 40 mg) was added. Hydrogen gas was then introduced, and the mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain 29-3. ESI-MS theoretical calculation: [M+H] + =193.1, measured value 193.1.

[0417] Step 3

[0418] 29-3 (27 mg, 140 μmol) and 1-1 (25 mg, 71 μmol) were dissolved in DMF (1 mL). After cooling to 0 °C, DIEA (27 mg, 0.21 mmol) and HATU (35 mg, 92 μmol) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, 29 was purified by high performance liquid chromatography (column: XBridge Prep C18, 19*250 mm, 10 μm; mobile phase: A was 10 mmol / L ammonium bicarbonate aqueous solution, B was acetonitrile; gradient: mobile phase B was 55-85%; flow rate: 20 mL / min) to obtain 29 (retention time 8.5-9.0 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 10.46 (br s, 1H), 8.38 (d, J = 1.6Hz, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.85 (d, J = 8.4Hz, 1H), 7.61–7.51 (m, 2H), 7.25–7.11 (m, 2H), 5.11 (d, J = 10.4Hz, 1H), 4.32–4.23 (m, 1H), 3.96 (d, J = 2.0Hz, 3H), 2.84–2.72 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.0Hz, 3H). ESI-MS theoretical calculation: [M+H] + =529.1, measured value 529.0.

[0419] Example 30

[0420] Synthesis route:

[0421] first step

[0422] 30-1 (300 mg, 1.27 mmol) was dissolved in methanol (15 mL), followed by the sequential addition of anhydrous sodium acetate (156 mg, 1.91 mmol) and wet palladium on carbon (10%, 68 mg), and then hydrogen gas was introduced. The mixture was stirred at 25 °C for 16 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and dissolved in dichloromethane (50 mL). Di-tert-butyl dicarbonate (420 mg, 1.91 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 30-2. 1H NMR (400MHz, DMSO-d6): δ8.49 (s, 1H), 7.92 (s, 1H), 4.66 (s, 2H), 4.47 (q, J=6.8Hz, 2 H), 3.69 (t, J=6.0Hz, 2H), 2.90 (t, J=5.6Hz, 2H), 1.50 (s, 9H), 1.44 (t, J=7.2Hz, 3H).

[0423] Step 2

[0424] 30-2 (300 mg, 0.98 mmol) was dissolved in methanol (5 mL) and water (1 mL), and potassium hydroxide (66 mg, 1.18 mmol) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was cooled to 0 °C, and the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid (2 mol / L). The mixture was extracted with dichloromethane / methanol (v / v, 10 / 1, 10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing 30-3, which was directly used in the next reaction. 1 HNMR (400MHz, CDCl3): δ 8.40 (s, 1H), 8.02 (s, 1H), 4.70 (s, 2H), 3.76–3.66 (m, 2H), 2.99–2.90 (m, 2H), 1.51 (s, 9H). ESI-MS theoretical calculation: [M+H] + =279.1, measured value 279.0.

[0425] Step 3

[0426] 30-3 (200 mg, 0.72 mmol) was dissolved in DMF (2 mL), and DIEA (279 mg, 2.16 mmol), ammonium chloride (77 mg, 1.44 mmol), and HATU (356 mg, 0.94 mmol) were added sequentially. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 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 (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 30-4. ESI-MS theoretical calculation: [M+H] + =278.2, measured value 278.2.

[0427] Step 4

[0428] 30-4 (20 mg, 0.072 mmol) was dissolved in hydrochloric acid (1,4-dioxane solution, 4 mol / L, 1 mL), and stirred at 25 °C for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a crude product containing 30-5, which was directly used in the next reaction. ESI-MS theoretical calculation: [M+H]+ =178.1, measured value 178.2.

[0429] Step 5

[0430] 30-5 (19 mg, 110 μmol) and 1-1 (25 mg, 71 μmol) were dissolved in DMF (1 mL), cooled to 0 °C, and then DIEA (27 mg, 0.21 mmol) and HATU (35 mg, 92 μmol) were added sequentially. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the product was purified by high performance liquid chromatography (column: SunFire Prep C18, 19*250 mm, 10 μm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 62-62%; flow rate: 20 mL / min) to obtain 30 (retention time 11.4-12.3 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 8.47-8.37 (m, 1H), 8.06 (s, 1H), 7.91-7.81 (m, 1H), 7.56 (s, 1H), 7.15-7.05 (m, 2H), 5.52-5.43 (m, 1H), 5.00-4.65 (m, 2H), 4.41-4.32 (m, 1H), 3.99-3.92 (m, 3H), 3.91-3.83 (m, 2H), 3.07-2.97 (m, 2H), 2.90-2.75 (m, 1H), 1.50-1.40 (m, 3H), 0.80-0.70 (m, 3H). ESI-MS theoretical calculation: [M+H] + =514.2, measured value 514.4.

[0431] Example 31

[0432] Synthesis route:

[0433] first step

[0434] 26-3 (700 mg, 2.92 mmol) was dissolved in THF (25 mL), and sodium hydride (60%, 175 mg, 4.38 mmol) was added at 0 °C. The mixture was stirred for 30 minutes, and (trimethylsilyl)ethoxymethyl chloride (974 mg, 5.84 mmol) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain 31-1. 1¹H NMR (400MHz, DMSO-d⁶): δ 8.59 (d, J = 5.2Hz, 1H), 7.75 (d, J = 2.0Hz, 1H), 7.68 (dd, J = 5.2, 2.0Hz, 1H), 4.86 (s, 2H), 3.62–3.54 (m, 2H), 1.49 (s, 6H), 0.92–0.85 (m, 2H), 0.01 (s, 9H). ESI-MS theoretical calculation: [M+H] + =370.1, measured value 370.1.

[0435] Step 2

[0436] 31-1 (200 mg, 0.54 mmol) was dissolved in 1,4-dioxane (15 mL), and benzophenone imine (147 mg, 0.81 mmol), XPhos Pd G3 (46 mg, 54 μmol), and cesium carbonate (440 mg, 1.35 mmol) were added. The mixture was heated to 100 °C and stirred for 3 hours under nitrogen protection. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 31-2. ESI-MS theoretical calculation: [M+H] + =515.3, measured value 515.2.

[0437] Step 3

[0438] 31-2 (186 mg, 0.36 mmol) was dissolved in THF (10 mL), and dilute hydrochloric acid (2 mol / L, 0.1 mL) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain 31-3. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.93 (d, J = 5.6Hz, 1H), 6.52 (dd, J = 5.6, 2.0Hz, 1H), 6.43 (d, J = 2.0Hz, 1H), 6.33 (s, 2H), 4.82 (s, 2H), 3.59–3.51 (m, 2H), 1.44 (s, 6H), 0.93–0.87 (m, 2H), 0.00 (s, 9H). ESI-MS theoretical calculation: [M+H] + =351.2, measured value 351.3.

[0439] Step 4

[0440] Dissolve 1-1 (50 mg, 0.14 mmol) in dichloromethane (5 mL), then add DMF (0.1 mL) and oxaloyl chloride (27 mg, 0.21 mmol) sequentially, and stir at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain an oily substance, which is then redissolved in dichloromethane (1 mL). Dissolve 31-3 (74 mg, 0.21 mmol) and triethylamine (42 mg, 0.42 mmol) in dichloromethane (5 mL), and add the above concentrated dichloromethane solution dropwise, stirring at 25 °C for 1 hour. After the reaction is complete, extract with saturated sodium bicarbonate solution (30 mL), then extract with ethyl acetate (30 mL × 3). Combine the organic phases, dry over 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 31-4. ESI-MS theoretical calculation: [M+H] + =687.3, measured value 687.5.

[0441] Step 5

[0442] 31-4 (50 mg, 73 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 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, and acetonitrile (2 mL) and concentrated ammonia (1 mL) were added. The mixture was stirred for another hour, concentrated under reduced pressure, and purified by high performance liquid chromatography (HPLC) (column: SunFire Prep C18, 19*250 mm, 10 μm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 58-60%; flow rate: 20 mL / min) to obtain 31 (retention time 10.8-12.0 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 10.75 (br s, 1H), 8.57 (s, 1H), 8.43 (d, J = 5.6Hz, 1H), 7.73 (d, J = 1.6Hz, 1H), 7.64 (dd, J = 5.6, 2.0Hz, 1H), 7.21–7.09 (m, 2H), 5.16–5.09 (m, 1H), 4.30–4.19 (m, 1H), 3.95 (d, J = 2.0Hz, 3H), 2.81–2.72 (m, 1H), 1.60 (s, 3H), 1.39 (s, 6H), 0.73 (d, J = 6.4Hz, 3H). ESI-MS theoretical calculation: [M+H] + =557.2, measured value 557.4.

[0443] Examples 32 and 33

[0444] Synthesis route:

[0445] first step

[0446] 32-1 (4.7 g, 21.36 mmol) was dissolved in THF (150 mL). Bistrimethylsilylaminolithium (1 mol / L THF solution, 44.86 mL, 44.86 mmol) was added dropwise at 0 °C. After stirring for 30 minutes, benzyl chloroformate (3.61 mL, 25.63 mmol) was added dropwise, and the mixture was stirred at 25 °C for 8 hours. After the reaction was complete, saturated ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then mixed with petroleum ether / ethyl acetate (v / v, 5 / 1, 50 mL). After stirring for 3 hours, the mixture was filtered to obtain 32-2. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.44 (br s, 1H), 8.27 (d, J = 1.2Hz, 1H), 7.99 (d, J = 5.2Hz, 1H), 7.46 (dd, J = 5.2, 1.2Hz, 1H), 7.44–7.33 (m, 5H), 5.18 (s, 2H). ESI-MS theoretical calculation: [M+H] + =355.0, measured value 355.1.

[0447] Step 2

[0448] 32-2 (1.0 g, 2.82 mmol) was dissolved in DMF (50 mL), and 32-3 (407 mg, 2.82 mmol) and cesium carbonate (1.84 g, 5.64 mmol) were added. The mixture was heated to 90 °C and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (200 mL), extracted with ethyl acetate (150 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 32-4. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 8.50 (s, 1H), 8.09 (d, J = 5.2Hz, 1H), 7.54 (dd, J = 4.4, 1.2Hz, 1H), 5.20 (t, J = 5.6Hz, 1H), 4.77–4.67 (m, 1H), 4.19–4.09 (m, 1H), 3.98–3.88 (m, 1H), 3.73–3.63 (m, 1H), 3.61–3.52 (m, 1H). ESI-MS theoretical calculation: [M+H] + =321.0, measured value 320.9.

[0449] Step 3

[0450] 32-4 (250 mg, 0.78 mmol) was dissolved in DMF (10 mL), and imidazole (106 mg, 1.56 mmol) and tert-butyldimethylchlorosilane (141 mg, 0.94 mmol) were added sequentially. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1, v / v) to obtain 32-5. 1 H NMR (400MHz, DMSO-d6): δ 8.49 (d, J = 1.0Hz, 1H), 8.08 (d, J = 5.2Hz, 1H), 7.52 (dd, J = 5.2, 1.2Hz, 1H), 4.83–4.73 (m, 1H), 4.20–4.10 (m, 1H), 4.00–3.93 (m, 1H), 3.91–3.84 (m, 1H), 3.80–3.70 (m, 1H), 0.75 (s, 9H), 0.02 (s, 6H). ESI-MS theoretical calculation: [M+H] + =435.1, measured value 435.2.

[0451] Step 4

[0452] 32-5 (203 mg, 0.47 mmol), benzophenone imine (128 mg, 0.70 mmol), Xantphos (27 mg, 47 μmol), and cesium carbonate (383 mg, 1.17 mmol) were added to 1,4-dioxane (15 mL), followed by Pd2(dba)3 (27 mg, 47 μmol). The mixture was heated to 100 °C and stirred for 4 hours under nitrogen protection. After cooling, the mixture was 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 (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain 32-6. ESI-MS theoretical value: [M+H] + =488.2, measured value 488.3.

[0453] Step 5

[0454] 32-6 (141 mg, 0.29 mmol) was dissolved in THF (10 mL), and dilute hydrochloric acid (2 mol / L, 72 μL) was added at 0 °C. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the pH was adjusted to greater than 8 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted 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 (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 32-7. ESI-MS theoretical calculation: [M+H] + =324.2, measured value 324.4.

[0455] Step 6

[0456] 1-1 (40 mg, 0.11 mmol) was dissolved in dry acetonitrile (2 mL), cooled to 0 °C, and then 32-7 (43 mg, 0.13 mmol), NMI (19 mg, 0.23 mmol), and TCFH (34 mg, 0.12 mmol) were added sequentially. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 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 (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain 32-8. ESI-MS theoretical calculation: [M+H] + =660.3, measured value 660.3.

[0457] Step 7

[0458] 32-8 (35 mg, 52 μmol) was dissolved in THF (2 mL), and tetrabutylammonium fluoride (1 mol / L THF solution, 53 μL) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, saturated sodium bicarbonate solution (20 mL) was added, followed by extraction with ethyl acetate (20 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: SunFire Prep C18, 19*250 mm, 10 μm; mobile phase: A was an aqueous solution containing 0.1% formic acid, B was acetonitrile; gradient: mobile phase B was 64-64%; flow rate: 20 mL / min) to obtain 32-9 (retention time 10.3-11.3 min). ESI-MS theoretical calculation: [M+H] + =546.2, measured value 546.1.

[0459] Step 8

[0460] 32-9 (14 mg, 25 μmol) was subjected to supercritical fluid chromatography (column: Waters SFC 150). 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 15%; flow rate: 140mL / min) to separate and purify 32 (retention time 3.2-4.0min) and 33 (retention time 4.4-6.0min).

[0461] 32: 1 H NMR (400MHz, DMSO-d6): δ10.75(br s, 1H), 8.35 (d, J=1.6Hz, 1H), 8.22 (d, J=5.6Hz, 1H), 7.45 (dd, J=5.6, 1.6Hz, 1H), 7.24-7.06(m, 2H), 5.25-5.15(m, 1H), 5.13-5.03(m, 1H), 4.74-4.64(m, 1H), 4.30- 4.20 (m, 1H), 4.18-4.10 (m, 1H), 3.99-3.90 (m, 4H), 3.72-3.62 (m, 1H), 3.59-3.52 (m, 1H), 2.73-2.63 (m, 1H), 1.58 (s, 3H), 0.72 (d, J = 6.4 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =546.2, measured value 546.0.

[0462] 33: 1 H NMR (400MHz, DMSO-d6): δ10.79(br s, 1H), 8.35 (d, J=1.6Hz, 1H), 8.22 (d, J=5.6Hz, 1H), 7.45 (dd, J=5.6, 1.6Hz, 1H), 7.21-7.07(m, 2H), 5.27-5.17(s, 1H), 5.14-5.04(m, 1H), 4.73-4.63(m, 1H), 4.26- 4.22 (m, 1H), 4.21-4.11 (m, 1H), 3.99-3.90 (m, 4H), 3.68-3.66 (m, 1H), 3.55-3.55 (m, 1H), 2.82-2.72 (m, 1H), 1.58 (s, 3H), 0.72 (d, J = 6.4 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =546.2, measured value 546.1.

[0463] Example 34

[0464] Synthesis route:

[0465] first step

[0466] Compound 1-1 (1 g, 2.82 mmol) was dissolved in anhydrous methanol (20 mL) at room temperature, followed by the slow addition of thionyl chloride (0.81 g, 6.77 mmol). The reaction mixture was stirred at 60 °C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain compound 34-1. ¹H NMR (400 MHz, DMSO-d6): δ 6.91–6.84 (m, 2H), 4.91 (d, J = 10.4 Hz, 1H), 4.15–4.11 (m, 1H), 4.00 (s, 3H), 3.71 (s, 3H), 2.77–2.68 (m, 1H), 1.62 (s, 3H), 0.80–0.72 (m, 3H).

[0467] Step 2

[0468] Compound 34-1 (1 g, 2.72 mmol) was dissolved in anhydrous dichloromethane (100 mL) at room temperature. Boron tribromide (2.73 g, 10.88 mmol) was slowly added at 0 °C, and the mixture was slowly heated to 25 °C and stirred for 2 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate solution (200 mL). The mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 34-2. 1 H NMR (400MHz, DMSO-d6): δ10.44 (s, 1H), 7.07-7.04 (m, 1H), 6.87-6.80 (m, 1H), 5.13 (d, J=10.4Hz, 1H), 4.14-4.10 (m, 1H), 3.62 (s, 3H), 1.53 (s, 3H), 0.68-0.66 (m, 3H).

[0469] Step 3

[0470] Compound 34-2 (180 mg, 0.51 mmol) and deuterated iodomethane (110 mg, 0.77 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (110 mg, 0.77 mmol) was added at room temperature. The mixture was stirred at 60 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain compound 34-3. 1H NMR (400MHz, DMSO-d6): δ7.25-7.10 (m, 2H), 5.13 (d, J=10.4Hz, 1H), 4.13-4 .09 (m, 1H), 3.62 (s, 3H), 2.77-2.74 (m, 1H), 1.54 (s, 3H), 0.70-0.68 (m, 3H).

[0471] Step 4

[0472] Compound 34-3 (125 mg, 0.34 mmol) was dissolved in tetrahydrofuran / methanol / water (1 mL / 1 mL / 1 mL), and then lithium hydroxide monohydrate (29 mg, 0.68 mmol) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the pH was adjusted to 3 with hydrochloric acid (2 mol / L), and the mixture was extracted with ethyl acetate (8 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 34-4. ESI-MS theoretical value: C 15 H 12 D3F5O4[MH] - =356.10, measured value 355.9.

[0473] Step 5

[0474] Compound 34-4 (50 mg, 0.14 mmol), compound 12-2 (22 mg, 0.15 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (80 mg, 0.21 mmol), and N,N-diisopropylethylamine (110 mg, 0.84 mmol) were sequentially dissolved in anhydrous N,N-dimethylformamide. The reaction mixture was stirred at 20 °C for 1 hour under a nitrogen atmosphere. After the reaction was completed, compound 34 was purified by high performance liquid chromatography (HPLC) (column: Sunfire C18, 19*250 mm, 10 μm; mobile phase: A was 0.1% formic acid aqueous solution, B was 0.1% formic acid / acetonitrile; flow rate: 20 mL / min; gradient: 55-70%) to obtain compound 34 (retention time: 9.2-9.7 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.61 (s, 1H), 7.77 (s, 1H), 7.51 (d, J = 4.0Hz, 1H), 7.23–7.06 (m, 3H), 6.81 (d, J = 4.0Hz, 1H), 5.12 (d, J = 10.4Hz, 1H), 4.28–4.19 (m, 1H), 2.77–2.74 (m, 1H), 1.59 (s, 3H), 0.72–0.71 (m, 3H). ESI-MS theoretical calculations: C 20 H16 D3F5N2O4S[M+H]+=482.13, measured value 481.9.

[0475] Example 35

[0476] Synthesis route:

[0477] first step

[0478] Compound 34-2 (180 mg, 0.51 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of potassium carbonate (105.73 mg, 0.77 mmol) and iodoethane (159.09 mg, 1.02 mmol). The reaction was carried out at 60 °C for two hours under a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, and the reaction was quenched by the slow addition of water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 35-1. 1 H NMR (400MHz, DMSO-d6): δ7.22-7.12 (m, 2H), 5.13 (d, J=10.8Hz, 1H), 4.22-4.10 (m, 3H), 3 .61 (s, 3H), 2.71-2.61 (m, 1H), 1.54 (s, 3H), 1.33 (t, J=7.2Hz, 3H), 0.70 (d, J=5.4Hz, 3H).

[0479] Step 2

[0480] Compound 35-1 (140 mg, 0.37 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (1.2 mL). Lithium hydroxide monohydrate (46.58 mg, 1.11 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the pH of the reaction solution was adjusted to 4-5 by dropwise addition of dilute hydrochloric acid (1 mol / L) under ice bath conditions. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 35-2 (125 mg, 90.32%). ESI-MS theoretical value: C 16 H 17 F5O4[M+H] + =369.11, measured value 369.0.

[0481] Step 3

[0482] Compound 35-2 (100 mg, 0.27 mmol) and compound 12-2 (57.58 mg, 0.41 mmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (139.58 mg, 1.08 mmol) was added. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (153.99 mg, 0.41 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 1 hour. After the reaction was completed, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then purified by high performance liquid chromatography (HPLC) (column: SunFire pre C18 OBD, 19*250 mm, 10 μm; mobile phase: A is 0.1% formic acid aqueous solution, B is 1% formic acid acetonitrile solution; flow rate: 20 mL / min, gradient: 60-70%) to obtain compound 35 (retention time: 9.3-9.8 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.61 (s, 1H), 7.77 (s, 1H), 7.50 (d, J = 4.0Hz, 1H), 7.23–7.06 (m, 3H), 6.80 (d, J = 4.0Hz, 1H), 5.11 (d, J = 10.4Hz, 1H), 4.32–4.22 (m, 1H), 4.21–4.11 (m, 2H), 2.79–2.70 (m, 1H), 1.60 (s, 3H), 1.34 (t, J = 7.2Hz, 3H), 0.72 (d, J = 6.4Hz, 3H). ESI-MS theoretical calculation: C 21 H 21 F5N2O4S[M+H] + =493.12, measured value 492.9.

[0483] Example 36

[0484] Synthesis route:

[0485] first step

[0486] Compound 34-2 (80 mg, 0.23 mmol) and 2-bromoethyl methyl ether (48 mg, 0.35 mmol) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (48 mg, 0.35 mmol) was added at room temperature. The reaction mixture was stirred at 60 °C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water (4 mL). The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain compound 36-1. 1 H NMR (400MHz, DMSO-d6): δ7.25-7.11 (m, 2H), 5.15 (d, J=10.8Hz, 1H), 4.33-4.22 (m, 2H), 4.18-4 .14 ​​(m, 1H), 3.66-3.56 (m, 5H), 3.29 (s, 3H), 2.75-2.71 (m, 1H), 1.54 (s, 3H), 0.68-0.65 (m, 3H).

[0487] Step 2

[0488] Compound 36-1 (70 mg, 0.17 mmol) was dissolved in tetrahydrofuran / methanol / water (1 mL / 1 mL / 1 mL). Lithium hydroxide monohydrate (21 mg, 0.51 mmol) was added to the reaction solution, and the mixture was stirred at 20 °C for 2 hours. After the reaction was complete, the pH was adjusted to 3 with hydrochloric acid (2 mol / L). The mixture was extracted with ethyl acetate (8 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 36-2. ESI-MS theoretical value: C 17 H 19 F5O5[M+H] + =399.13, measured value 399.0.

[0489] Step 3

[0490] Compound 36-2 (52 mg, 0.13 mmol), compound 12-2 (20 mg, 0.14 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (74 mg, 0.20 mmol), and N,N-diisopropylethylamine (100 mg, 0.78 mmol) were sequentially dissolved in anhydrous N,N-dimethylformamide and stirred at 20 °C for 1 hour under a nitrogen atmosphere. After the reaction was completed, compound 36 was purified by high performance liquid chromatography (HPLC) (column: Sunfire C18, 19*250 mm, 10 μm; mobile phase: A was 0.1% formic acid aqueous solution, B was 0.1% formic acid / acetonitrile; flow rate: 20 mL / min; gradient: 55-70%) to obtain compound 36 (retention time: 9.5-10.1 min). 1 H NMR (400MHz, DMSO-d6): 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.57 (s, 1H), 7.77 (s, 1H), 7.50 (d, J = 4.0Hz, 1H), 7.25–7.07 (m, 3H), 6.83 (d, J = 4.0Hz, 1H), 5.14 (d, J = 10.8Hz, 1H), 4.39–4.24 (m, 2H), 4.21–4.18 (m, 1H), 3.61–3.58 (m, 2H), 3.26 (s, 3H), 2.87–2.75 (m, 1H), 1.60 (s, 3H), 0.70–0.68 (m, 3H). ESI-MS theoretical calculation: C 22 H 23 F5N2O5S[M+H] + =523.13, measured value 523.0.

[0491] Example 37

[0492] Synthesis route:

[0493] first step

[0494] Compound 34-2 (200 mg, 0.56 mmol) and compound 37-1 (260 mg, 1.12 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (230 mg, 1.68 mmol) was added at room temperature. The mixture was stirred at 75 °C for 48 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain compound 37-2. ESI-MS theoretical value: C18 H 19 F5O5[M+H]+=411.13, measured value 411.0.

[0495] Step 2

[0496] Compound 37-2 (102 mg, 0.25 mmol) was dissolved in tetrahydrofuran / methanol / water (1 mL / 1 mL / 1 mL). Lithium hydroxide monohydrate (21 mg, 0.50 mmol) was added to the reaction solution, and the mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the pH was adjusted to 3 with hydrochloric acid (2 mol / L). The mixture was extracted with ethyl acetate (7 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 37-3. 1 H NMR (400MHz, DMSO-d6): δ13.00 (s, 1H), 7.27-7.10 (m, 2H), 5.31-5.27 (m, 1H), 5.02 (d, J=10.4Hz, 1H), 4.8 9-4.83 (m, 2H), 4.73-4.63 (m, 2H), 4.14-4.09 (m, 1H), 2.69-2.67 (m, 1H), 1.54 (s, 3H), 0.70-0.68 (m, 3H).

[0497] Step 3

[0498] Compound 37-3 (63 mg, 0.16 mmol), compound 12-2 (25 mg, 0.18 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (91 mg, 0.24 mmol), and N,N-diisopropylethylamine (120 mg, 0.96 mmol) were sequentially dissolved in anhydrous N,N-dimethylformamide (1 mL), and stirred at 20 °C for 1 hour under a nitrogen atmosphere. After the reaction was completed, compound 37 was purified by high performance liquid chromatography (HPLC) (column: Sunfire C18, 19*250 mm, 10 μm; mobile phase: A: 0.1% formic acid aqueous solution, B: 0.1% formic acid / acetonitrile; flow rate: 20 mL / min; gradient: 50-70%) to obtain compound 37 (retention time: 8.9-9.3 min). 1¹H NMR (400MHz, DMSO-d⁶): δ 11.60 (s, 1H), 7.78 (s, 1H), 7.51 (d, J = 4.0Hz, 1H), 7.25–7.10 (m, 3H), 6.82 (d, J = 4.0Hz, 1H), 5.31–5.27 (m, 1H), 5.15 (d, J = 10.4Hz, 1H), 4.88–4.82 (m, 2H), 4.71–4.66 (m, 2H), 4.30–4.21 (m, 1H), 2.79–2.75 (m, 1H), 1.60 (s, 3H), 0.72–0.70 (m, 3H). ESI-MS theoretical calculation: C 22 H 21 F5N2O5S[M+H]+=521.12, measured value 520.9.

[0499] Example 38

[0500] Synthesis route:

[0501] first step

[0502] Compound 34-1 (100 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (2 mL). Sodium difluorochloroacetate (51.23 mg, 0.34 mmol) and potassium carbonate (58.05 mg, 0.42 mmol) were added to the reaction solution, and the reaction solution was stirred at 100 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with water (5 mL). The mixture was extracted with ethyl acetate (5 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 38-1. 1 H NMR (400MHz, CDCl3): δ7.17-7.03 (m, 2H), 6.65 (t, J=74.0Hz, 1H), 4.89 (d, J=10.4Hz, 1H) , 4.27-4.17 (m, 1H), 3.70 (s, 3H), 2.82-2.72 (m, 1H), 1.63 (s, 3H), 0.80 (d, J=7.6Hz, 3H).

[0503] Step 2

[0504] Compound 38-1 (60 mg, 0.15 mmol) was dissolved in tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL). Lithium hydroxide monohydrate (31 mg, 0.75 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (2 mL) was added to dilute the solution, and the pH was adjusted to 4 with hydrochloric acid (1 mol / L). The mixture was extracted with ethyl acetate (5 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 38-2. ESI-MS theoretical value: C 15 H 13 F7O4[MH] - =389.06, measured value 389.2.

[0505] Step 3

[0506] Compound 38-2 (50 mg, 0.13 mmol), compound 12-2 (22.18 mg, 0.16 mmol), and N,N-diisopropylethylamine (33.60 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (59.32 mg, 0.16 mmol) was added in portions to the reaction solution, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, water (5 mL) was added to dilute the mixture. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (HPLC) (column: Boston Green ODS, 30*150 mm, 5 μm, 120 A; mobile phase A was 0.1% formic acid aqueous solution, B was acetonitrile, flow rate: 20 mL / min, gradient: 58-69%) to obtain compound 38 (retention time: 10.53-11.1 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.59 (s, 1H), 7.78 (s, 1H), 7.57–7.01 (m, 5H), 6.83 (d, J = 4.4Hz, 1H), 5.18 (d, J = 10.40Hz, 1H), 4.41–4.31 (m, 1H), 2.81–2.71 (m, 1H), 1.59 (s, 3H), 0.76 (d, J = 6.0Hz, 3H). ESI-MS theoretical calculation: C 20 H 17 F7N2O4S[M+H] + =515.09, measured value 515.2.

[0507] Example 39

[0508] Synthesis route:

[0509] first step

[0510] Compound 34-1 (136 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (157.56 mg, 1.14 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (88.2 mg, 0.38 mmol) were added to the reaction solution. The reaction system was subjected to nitrogen protection at 60 °C for two hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 39-1. 1 H NMR (400MHz, DMSO-d6): δ7.31-7.21(m, 2H), 5.18(d, J=10.8Hz, 1H), 5.01-4.78(m, 2H), 4.20-4.10 (m, 1H), 3.60 (s, 3H), 2.69-2.59 (m, 1H), 1.50 (s, 3H), 0.69 (d, J=5.6Hz, 3H).

[0511] Step 2

[0512] Compound 39-1 (196 mg, 0.55 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (1.5 mL). Lithium hydroxide monohydrate (69.23 mg, 1.65 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the pH was adjusted to 4 to 5 by adding dilute hydrochloric acid (1 mol / L) dropwise under ice bath conditions. The reaction solution was diluted with water (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 39-2. 1 H NMR (400MHz, DMSO-d6): δ13.12 (s, 1H), 7.29-7.19 (m, 2H), 5.02-4.81 (m, 3H ), 4.12-4.01 (m, 1H), 2.69-2.59 (m, 1H), 1.50 (s, 3H), 0.69 (d, J=5.6Hz, 3H).

[0513] Step 3

[0514] Compound 39-2 (35 mg, 0.083 mmol) and compound 12-2 were dissolved in N,N-dimethylformamide (0.6 mL). N,N-diisopropylethylamine (42.91 mg, 0.33 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (47.34 mg, 0.12 mmol) were added to the reaction solution at 0 °C, and the reaction was carried out at 0 °C for 1 hour. After the reaction was completed, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (column: SunFire pre C18 OBD, 19*250 mm, 10 μm; mobile phase: A is 0.1% formic acid aqueous solution, B is acetonitrile; flow rate: 20 mL / min, gradient: 60-69%) to obtain compound 39 (retention time: 9.40-10.10 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.60 (s, 1H), 7.77 (s, 1H), 7.50 (d, J = 4.0Hz, 1H), 7.29–7.19 (m, 3H), 6.82 (d, J = 4.0Hz, 1H), 5.16 (d, J = 10.4Hz, 1H), 4.96–4.86 (m, 2H), 4.30–4.20 (m, 1H), 2.73 (s, 1H), 1.57 (s, 3H), 0.72 (d, J = 6.4Hz, 3H). ESI-MS theoretical calculation: C 21 H 18 F8N2O4S[M+H] + =547.10, measured value 546.9.

[0515] Example 40

[0516] Synthesis route:

[0517] first step

[0518] Compound 34-1 (180 mg, 0.51 mmol) was dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (105.73 mg, 0.77 mmol) and deuterated iodoethane (164.22 mg, 1.02 mmol) were added to the reaction solution. The reaction was carried out under nitrogen protection at 60 °C for two hours. After the reaction was completed, the reaction solution was diluted with water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give compound 40-1. 1 H NMR (400MHz, DMSO-d6): δ7.23-7.18(m, 1H), 7.19-7.09(m, 1H), 5.13(d, J=10.8Hz, 1H ), 4.20-4.10(m, 1H), 3.61(s, 3H), 2.71-2.61(m, 1H), 1.54(s, 3H), 0.72-0.67(m, 3H).

[0519] Step 2

[0520] Compound 40-1 (150 mg, 0.39 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (1 mL). Lithium hydroxide monohydrate (49.09 mg, 1.17 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the pH was adjusted to 4 to 5 by adding dilute hydrochloric acid (1 mol / L) dropwise under ice bath conditions. The reaction solution was diluted with water (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 40-2. 1 H NMR (400MHz, DMSO-d6): δ12.96 (s, 1H), 7.22-7.11 (m, 2H), 4.97 (d, J=10.8Hz, 1H), 4.16-4.06 (m, 1H), 2.68-2.62 (m, 1H), 1.54 (s, 3H), 0.69 (d, J=5.6Hz, 3H).

[0521] Step 3

[0522] Compound 40-2 (60 mg, 0.16 mmol) and compound 12-2 (34.12 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (1 mL). N,N-diisopropylethylamine (82.71 mg, 0.64 mmol) was added to the reaction solution. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (91.26 mg, 0.24 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 1 hour. After the reaction was completed, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) (column: SunFire pre C18 OBD, 19*250 mm, 10 μm; mobile phase: A was 0.1% formic acid aqueous solution, B was acetonitrile; flow rate: 20 mL / min, gradient: 60-70%) to obtain compound 40 (retention time: 9.05-9.70 min of 18 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.60 (s, 1H), 7.76 (s, 1H), 7.49 (d, J = 4.0Hz, 1H), 7.23–7.02 (m, 3H), 6.79 (d, J = 4.0Hz, 1H), 5.10 (d, J = 10.4Hz, 1H), 4.31–4.21 (m, 1H), 2.78–2.68 (m, 1H), 1.59 (s, 3H), 0.71 (d, J = 6.8Hz, 3H). ESI-MS theoretical calculation: C 21 H 16 D5F5N2O4S[M+H] + =498.16, measured value 497.9.

[0523] Example 41

[0524] Synthesis route:

[0525] first step

[0526] Compound 41-1 (200 mg, 1.75 mmol) was dissolved in anhydrous diethyl ether (5 mL), pyridine (152.27 mg, 1.93 mmol) was added, and trifluoromethanesulfonic anhydride (493.75 mg, 1.75 mmol) was added at 0 °C. The reaction was carried out at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was allowed to stand and separate into layers. The supernatant was dissolved in N,N-dimethylformamide (1 mL), and compound 34-1 (60 mg, 0.17 mmol) and potassium carbonate (352.44 mg, 2.55 mmol) were added. After mixing well, the diethyl ether in the reaction solution was removed by distillation. The reaction solution was carried out at 80 °C for two hours. After the reaction was completed, the temperature was lowered to room temperature, and water (20 mL) was slowly added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 93 / 7, v / v) to obtain compound 41-2. 1 H NMR (400MHz, DMSO-d6): δ7.31-7.20 (m, 2H), 5.20 (d, J=10.8Hz, 1H), 5.14-5.04 (m, 1H), 4. 17-4.07 (m, 1H), 3.59 (s, 3H), 2.66-2.56 (m, 1H), 1.56-1.49 (m, 6H), 0.65 (d, J=6.0Hz, 3H).

[0527] Step 2

[0528] Compound 41-2 (111 mg, 0.25 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (0.8 mL). Lithium hydroxide monohydrate (31.47 mg, 0.75 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the pH of the reaction solution was adjusted to 4-5 by dropwise addition of dilute hydrochloric acid (1 mol / L) under ice bath conditions. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated sodium chloride aqueous solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 41-3. ESI-MS theoretical value: C 17 H 16 F8O4[M+H] + =437.10, measured value 436.9.

[0529] Step 3

[0530] Compound 41-3 (90 mg, 0.21 mmol) and compound 12-2 (44.79 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (108.56 mg, 0.84 mmol) was added to the reaction solution. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (119.77 mg, 0.32 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 1 hour. After the reaction was completed, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by high performance liquid chromatography (HPLC) (column: SunFire pre C18 OBD, 19*250 mm, 10 μm; mobile phase: A is 0.1% formic acid aqueous solution, B is acetonitrile; flow rate: 20 mL / min, gradient: 61-73%) to obtain compound 41 (retention time: 9.92-10.87 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 11.57 (s, 1H), 7.76 (s, 1H), 7.50 (d, J = 4.0Hz, 1H), 7.26 (d, J = 8.0Hz, 1H), 7.23–7.12 (m, 2H), 6.81 (d, J = 4.0Hz, 1H), 5.16 (d, J = 10.4Hz, 1H), 5.13–5.06 (m, 1H), 4.24–4.18 (m, 1H), 2.77–2.67 (mm, 1H), 1.57 (s, 3H), 1.52 (d, J = 6.40Hz, 3H), 0.68 (d, J = 6.0Hz, 3H). ESI-MS theoretical calculation: C 22 H 20 F8N2O4S[M+H] + =561.11, measured value 560.8.

[0531] Example 42

[0532] Synthesis route:

[0533] first step

[0534] Compound 42-1 (200 mg, 1.75 mmol) was dissolved in anhydrous diethyl ether (5 mL), and pyridine (152.27 mg, 1.93 mmol) was added. Trifluoromethanesulfonic anhydride (493.75 mg, 1.75 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction mixture was allowed to stand and separate into layers. The supernatant was dissolved in N,N-dimethylformamide (1 mL), and then compound 34-1 (60 mg, 0.17 mmol) and potassium carbonate (352.44 mg, 2.55 mmol) were added. The reaction system was purged with nitrogen three times, and the reaction was carried out at 60 °C for two hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), the mixture was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 42-2. 1 H NMR (400MHz, DMSO-d6): δ7.34-7.24(m, 2H), 5.19-5.12(m, 2H), 4.20-4.10(m, 1H), 3.6 1 (s, 3H), 2.64-2.54 (m, 1H), 1.50 (s, 3H), 1.35 (d, J=6.4Hz, 3H), 0.71 (d, J=5.2Hz, 3H).

[0535] Step 2

[0536] Compound 42-2 (38 mg, 0.084 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (0.5 mL). Lithium hydroxide monohydrate (10.57 mg, 0.25 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the pH was adjusted to 4 to 5 by adding dilute hydrochloric acid (1 mol / L) dropwise under ice bath conditions. The reaction solution was diluted with water (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 42-3. 1 H NMR (400MHz, DMSO-d6): δ13.08 (s, 1H), 7.33-7.21 (m, 2H), 5.18-5.11 (m, 1H), 4.97 (d, J=10.8Hz, 1H ), 4.16-4.06 (m, 1H), 2.58-2.53 (m, 1H), 1.50 (s, 3H), 1.36 (d, J=6.4Hz, 3H), 0.70 (d, J=5.6Hz, 3H).

[0537] Step 3

[0538] Compound 42-3 (96 mg, 0.22 mmol) and compound 12-2 (46.92 mg, 0.33 mmol) were dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (113.73 mg, 0.88 mmol) was added. N,N,N′,N-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (125.48 mg, 0.33 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 1 hour. After the reaction was completed, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: XBridge Prep C18, 19*250 mm, 10 μm; mobile phase: A is 10 mmol / L ammonium bicarbonate aqueous solution, B is acetonitrile solution; flow rate: 20 mL / min, gradient: 60-70%) to obtain compound 42 (retention time: 9.18-9.84 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.64 (s, 1H), 7.77 (s, 1H), 7.50 (d, J = 3.6Hz, 1H), 7.33–7.27 (m, 1H), 7.22 (d, J = 5.6Hz, 1H), 6.80 (d, J = 4.4Hz, 1H), 5.14 (d, J = 10.4Hz, 2H), 4.30–4.24 (m, 1H), 2.68–2.61 (m, 2H), 1.56 (s, 3H), 1.36 (d, J = 6.4Hz, 3H), 0.72 (d, J = 7.2Hz, 3H). ESI-MS theoretical calculation: C 22 H 20 F8N2O4S[M+H] + =561.11, measured value 560.8.

[0539] Example 43

[0540] Synthesis route:

[0541] first step

[0542] Compound 34-1 (100 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (22 mg, 0.56 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Difluorodibromomethane (290 mg, 1.40 mmol) was added to the reaction solution, and the mixture was slowly heated to room temperature for 5 h. After the reaction was complete, the reaction solution was quenched by adding water (1 mL) dropwise at 0 °C. The resulting mixture was extracted with ethyl acetate (5 mL × 3), the organic phases were combined, washed with water (5 mL × 2), washed with saturated sodium chloride solution (5 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 43-1.

[0543] Step 2

[0544] Compound 43-1 (22 mg, 0.046 mmol) and silver tetrafluoroborate (45 mg, 0.23 mmol) were dissolved in 1,2-dichloroethane (1 mL) and stirred at 60 °C for 1 hour. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with 1,2-dichloroethane (3 mL × 2). The filtrates were combined and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 43-2. 1 H NMR (400MHz, DMSO-d6): δ7.24-7.15 (m, 1H), 7.24-7.08 (m, 1H), 4.89 (d, J=10.0Hz, 1H ), 4.22-4.12(m, 1H), 3.70(s, 3H), 2.76-2.68(m, 1H), 1.62(s, 3H), 0.85-0.75(m, 3H).

[0545] Step 3

[0546] Compound 43-2 (15 mg, 0.04 mmol) was dissolved in tetrahydrofuran / water (0.3 mL / 0.15 mL), and lithium hydroxide monohydrate (9 mg, 0.22 mmol) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the pH was adjusted to 3 with hydrochloric acid (2 mol / L). The mixture was extracted with ethyl acetate (2 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 43-3. ESI-MS theoretical value: C 15 H 12 F8O4[MH] - =407.05, measured value 407.0.

[0547] Step 4

[0548] Compound 43-3 (15 mg, 0.037 mmol), compound 12-2 (5.8 mg, 0.041 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (21 mg, 0.055 mmol), and N,N-diisopropylethylamine (57 mg, 0.44 mmol) were sequentially dissolved in anhydrous N,N-dimethylformamide (0.6 mL), and stirred at 20 °C for 1 hour under a nitrogen atmosphere. After the reaction was completed, compound 43 was purified by high performance liquid chromatography (HPLC) (column: Sumfire C18, 19*250 mm, 10 μm; mobile phase: A: 0.1% formic acid aqueous solution, B: 0.1% formic acid / acetonitrile; flow rate: 20 mL / min; gradient: 79-85%) to obtain compound 43 (retention time: 7.4-7.7 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.58 (s, 1H), 7.78 (s, 1H), 7.66–7.59 (m, 1H), 7.50 (d, J = 4.0Hz, 1H), 7.45–7.36 (m, 1H), 7.17 (s, 1H), 6.83 (d, J = 4.0Hz, 1H), 5.20 (d, J = 10.0Hz, 1H), 4.28–4.20 (m, 1H), 2.81–2.72 (m, 1H), 1.59 (s, 3H), 0.77 (d, J = 5.6Hz, 3H). ESI-MS theoretical calculation: C 20 H 16 F8N2O4S[M+H] + =533.08, actual value 532.8.

[0549] Example 44

[0550] Synthesis route:

[0551] first step

[0552] Compound 34-1 (200 mg, 0.56 mmol), cyclopropyl trifluoromethanesulfonate (320 mg, 1.68 mmol), and potassium carbonate (230 mg, 1.68 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 25 °C for 48 hours. The reaction mixture was diluted with water (10 mL) dropwise, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 44-1. 1H NMR (400MHz, CDCl3): δ6.91-6.84 (m, 2H), 4.88 (d, J=10.4Hz, 1H), 4.32-4.27 (m, 1H), 4.05-3.95 (m, 1H) , 3.71 (s, 3H), 2.66-2.57 (m, 1H), 1.59 (s, 3H), 0.87-0.81 (m, 2H), 0.78-0.73 (m, 3H), 0.71-0.60 (m, 2H).

[0553] Step 2

[0554] Compound 44-1 (90 mg, 0.23 mmol) was dissolved in tetrahydrofuran / water (1 mL / 1 mL), and lithium hydroxide monohydrate (29 mg, 0.69 mmol) was added. The mixture was stirred at 20 °C for 2 hours. After the reaction was complete, the pH was adjusted to 3 with hydrochloric acid (1 mol / L), and the mixture was extracted with ethyl acetate (4 mL × 3). The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 44-2. ESI-MS theoretical value: C 17 H 17 F5O4[MH] - =379.09, measured value 379.0.

[0555] Step 3

[0556] Compound 44-2 (33 mg, 0.087 mmol), compound 12-2 (14 mg, 0.096 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (50 mg, 0.13 mmol), and N,N-diisopropylethylamine (110 mg, 0.87 mmol) were sequentially dissolved in anhydrous N,N-dimethylformamide (0.6 mL), and stirred at 20 °C for 1 hour under a nitrogen atmosphere. After the reaction was completed, compound 44 was purified by high performance liquid chromatography (HPLC) (column: Sumfire C18, 19*250 mm, 10 μm; mobile phase: A: 0.1% formic acid aqueous solution, B: 0.1% formic acid / acetonitrile; flow rate: 20 mL / min; gradient: 60-80%) to obtain compound 44 (retention time: 8.5-9.2 min). 1¹H NMR (400MHz, DMSO-d⁶): δ 11.62 (s, 1H), 7.78 (s, 1H), 7.51 (d, J = 4.0Hz, 1H), 7.21–7.09 (m, 3H), 6.80 (d, J = 4.0Hz, 1H), 5.09 (d, J = 10.4Hz, 1H), 4.33–4.29 (m, 1H), 4.14–4.03 (m, 1H), 2.64–2.59 (m, 1H), 1.56 (s, 3H), 0.85–0.56 (m, 7H). ESI-MS theoretical calculations: C 22 H 21 F5N2O4S[M+H] + =505.12, measured value 505.1.

[0557] Example 45

[0558] Synthesis route:

[0559] first step

[0560] Compound 1-1 (0.40 g, 1.13 mmol) was dissolved in dichloromethane (20 mL) and N,N-dimethylformamide (0.01 mL). Oxaloyl chloride (0.19 mL, 2.26 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL). Under nitrogen protection, the mixture was slowly added dropwise to a dichloromethane (20 mL) solution of ammonium chloride (120 mg, 2.26 mmol) and triethylamine (0.47 mL, 3.39 mmol) at 0 °C. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was diluted with saturated sodium bicarbonate solution (20 mL). The resulting mixture was extracted with ethyl acetate (2 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give compound 45-1. ESI-MS theoretical value: C 15 H 16 F5NO3[M+H] + =354.12, measured value 353.9.

[0561] Step 2

[0562] Compound 45-1 (200 mg, 0.57 mmol) and compound 45-2 (204.40 mg, 0.85 mmol) were dissolved in dioxane (10 mL). Bis(dibenzylacetone)palladium (65.55 mg, 0.11 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (65.96 mg, 0.11 mmol), and cesium carbonate (557.15 mg, 1.71 mmol) were added sequentially to the reaction solution. The reaction solution was stirred at 110 °C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 3 / 100, v / v) to obtain compound 45-3. 1 H NMR (400MHz, CDCl3): δ9.04 (s, 1H), 7.09-6.99 (m, 1H), 6.95-6.85 (m, 1H), 6.49 (s, 1H), 5.06 (d, J=10.8Hz, 1H ), 4.12-4.02 (m, 1H), 4.00 (d, J=2.8Hz, 3H), 3.82 (s, 3H), 2.83-2.68 (m, 1H), 1.67 (s, 3H), 0.82-0.74 (m, 3H).

[0563] Step 3

[0564] Compound 45-3 (120 mg, 0.23 mmol) was added to ammonia (20 mL) and ethanol (1 mL), and the reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, filtered, and the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: Sunfire C18, 19*250 mm, 10 μm; mobile phase: A is 0.1% formic acid aqueous solution, B is acetonitrile; flow rate: 20 mL / min; gradient: 55-70%) to obtain compound 45 (retention time: 10.35-11.18 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.77 (s, 1H), 7.45 (s, 1H), 7.22–6.95 (m, 3H), 6.73 (s, 1H), 5.16 (d, J = 10.4Hz, 1H), 4.27–4.17 (m, 1H), 3.94 (t, J = 2.8Hz, 3H), 2.80–2.70 (m, 1H), 1.60 (s, 3H), 0.72 (d, J = 6.4Hz, 3H). ESI-MS theoretical calculation: C20 H 18 F6N2O4S[M+H] + =497.09, measured value 497.0.

[0565] Example 46

[0566] Synthesis route:

[0567] first step

[0568] Compound 46-1 (2.6 g, 17.79 mmol) was dissolved in dichloromethane (18 mL) and N,N-dimethylformamide (0.01 mL). Oxaloyl chloride (1.81 mL, 21.35 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (18 mL). Under nitrogen protection, concentrated ammonia (57 mL) was slowly added dropwise to the reaction solution at 0 °C, and the reaction solution was stirred at 25 °C for 0.5 hours. After the reaction was completed, water (50 mL) was added to dilute the reaction solution. The mixture was extracted with methanol / dichloromethane solution (1 / 10, v / v, 50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain compound 46-2. ESI-MS theoretical calculation value: C5H4FNOS[M+H] + =146.01, measured value 146.0.

[0569] Step 2

[0570] Compound 46-2 (1.70 g, 11.71 mmol) was dissolved in concentrated sulfuric acid (100 mL) under ice bath conditions. Potassium nitrate (7.1 g, 70.26 mmol) was added to the reaction solution in portions. The reaction solution was stirred at 0 °C for 5 minutes and then stirred at room temperature for 1 hour. After the reaction was completed, crushed ice was slowly added to the reaction solution under ice bath conditions to quench the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with saturated sodium bicarbonate (50 mL × 3) and sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 46-3. 1 H NMR (400MHz, DMSO-d6): δ 8.97 (d, J=4.0Hz, 1H), 8.04 (s, 1H), 7.69 (s, 1H).

[0571] Step 3

[0572] Iron powder (734.43 mg, 13.15 mmol) was added in portions to a vigorously stirred acetic acid solution (30 mL) of compound 46-3 (0.50 g, 2.63 mmol). The reaction mixture was stirred at 70 °C for 30 minutes, and then stirred for 1 hour at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and evaporated to dryness. 20 mL of 20% dichloromethane / methanol solution and saturated sodium bicarbonate solution were added to neutralize the reaction mixture. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to obtain compound 46-4. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.54 (s, 1H), 7.16 (s, 1H), 6.30 (d, J = 5.2Hz, 1H), 4.98 (s, 2H). ESI-MS theoretical calculation: C₅H₅FN₂OS[M+H] + =161.02, measured value 161.0.

[0573] Step 4

[0574] At 0 °C, N,N-diisopropylethylamine (20.94 mg, 0.16 mmol) was added to a stirred solution of compound 46-4 (12.97 mg, 0.081 mmol) and compound 40-2 (20 mg, 0.054 mmol) in N,N-dimethylformamide (1.0 mL), followed by N,N-diisopropylethylamine (20.94 mg, 0.16 mmol), and then N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (30.80 mg, 0.081 mmol). The reaction was stirred at room temperature for 1 hour. After the reaction was complete, water (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (column: C18 spherical 20-35 μm 100A 20 g; mobile phase: A is 0.1% formic acid aqueous solution, B is acetonitrile; flow rate: 20 mL / min; gradient: 5-75%) to obtain compound 46 (retention time: 30-35 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.40 (s, 1H), 7.84 (d, J = 4.4Hz, 1H), 7.73 (s, 1H), 7.40 (s, 1H), 7.24–7.08 (m, 2H), 5.22 (d, J = 10.8Hz, 1H), 4.27–4.23 (m, 1H), 2.78–2.68 (m, 1H), 1.59 (s, 3H), 0.71 (d, J = 5.6Hz, 3H). ESI-MS theoretical calculation: C 21 H15 D5F6N2O4S[M+H]+=516.15, actual measurement 516.0.

[0575] Example 47

[0576] Synthesis route:

[0577] first step

[0578] Compound 47-1 (25 g, 173.41 mmol) was dissolved in tetrahydrofuran (1 L). Triethylamine (72.31 mL, 520.23 mmol) and compound 47-2 (49.99 g, 208.09 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. Petroleum ether (500 mL) was added to the solution, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give compound 47-3. 1 H NMR (400MHz, CDCl3): δ4.29 (q, J=7.2Hz, 2H), 2.86 (q, J=7.2Hz, 2H), 1.32 (t, J=7.2Hz, 3H), 1.13 (t, J=7.2Hz, 3H).

[0579] Step 2

[0580] Compound 47-3 (10 g, 58.76 mmol) was dissolved in dichloromethane (100 mL) under an ice-water bath, followed by the sequential addition of triethylamine (16.33 mL, 117.52 mmol) and compound 47-4 (19.59 g, 88.14 mmol). The reaction mixture was stirred at 0 °C for 1 hour. The solution was diluted with petroleum ether (200 mL), quenched with saturated sodium bicarbonate (200 mL), allowed to stand for separation, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Trifluoroacetone (6.31 mL, 70.51 mmol) was added to dichloromethane (100 mL) under a dry ice-acetone bath, and titanium tetrachloride (5.81 mL, 52.88 mmol) was slowly added dropwise. The mixture was then slowly added to the concentrated residue, and the reaction mixture was stirred at -78 °C for 2 hours. After the reaction was completed, the reaction system was quenched with water (200 mL), the mixture was extracted with dichloromethane (200 mL × 2), the organic phases were combined, dried with 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 compound 47-5. 1H NMR (400MHz, CDCl3): δ4.33 (q, J=7.2Hz, 2H), 4.15-4.09 (m, 1H), 4.00 (s, 1H), 1.42 (d, J=0.8Hz, 3H), 1.35 (t, J=7.2Hz, 3H), 1.30 (dd, J=7.2, 1.20Hz, 3H).

[0581] Step 3

[0582] Compound 47-5 (1 g, 3.54 mmol) was slowly added to a mixed solution of rhodium dimer acetate (0.16 g, 0.35 mmol) and toluene (15 mL) at 100 °C. The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain crude product 47-6. 1 H NMR (400MHz, CDCl3): δ4.63 (d, J=1.2Hz, 1H), 4.32-4.20 (m, 2H), 2.62-2.35 (m, 1H), 1.72 (d, J=0.8Hz, 3H), 1.30 (t, J=7.2Hz, 3H), 1.29-1.19 (m, 3H).

[0583] Step 4

[0584] Compound 47-6 (560 mg, 2.20 mmol) was dissolved in dichloromethane (6 mL) under dry ice and acetone bath conditions. N,N-diisopropylethylamine (0.44 mL, 2.64 mmol) and trifluoromethanesulfonic anhydride (0.37 mL, 2.20 mmol) were added sequentially to the reaction solution. The reaction mixture was stirred at -78 °C for 1 hour. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product 47-7.

[0585] Step 5

[0586] Compound 47-8 (1 g, 4.65 mmol) was dissolved in dimethyl sulfoxide (10 mL) under a nitrogen atmosphere. Dipicolinate (1.54 g, 6.05 mmol), potassium acetate (1.37 g, 13.95 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (0.34 g, 0.47 mmol) were added sequentially to the reaction mixture. The reaction system was purged three times with nitrogen, and the mixture was stirred overnight at 70 °C. After the reaction was complete, the reaction system was diluted with water (50 mL), and the resulting mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain compound 47-9. 1 H NMR (400MHz, CDCl3): δ7.74-7.66 (m, 2H), 6.94 (dd, J=9.2, 8.4Hz, 1H), 6.85 (d, J=2.4Hz, 1H), 1.40 (s, 12H).

[0587] Step 6

[0588] Under a nitrogen atmosphere, compound 47-9 (500 mg, 1.91 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL). Compound 47-7 (885.31 mg, 2.29 mmol), potassium carbonate (527.96 mg, 3.82 mmol), and tetraphenylphosphine palladium (0.22 g, 0.19 mmol) were added sequentially to the reaction solution. The gas was purged three times with nitrogen, and the reaction solution was stirred at 100 °C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain compound 47-10. 1 H NMR (400MHz, CDCl3): δ 7.58 (d, J = 2.4Hz, 1H), 7.17 (dd, J = 8.4, 5.2Hz, 1H), 6.94 (dd, J = 9.2, 8.4Hz, 1H), 6.89 (d, J = 2.4Hz, 1H), 4.16–4.03 (m, 2H), 3.71 (d, J = 7.2Hz, 1H), 1.75 (s, 3H), 1.12–1.06 (m, 3H), 1.03 (t, J = 7.2Hz, 3H) ESI-MS theoretical calculation: C 18 H 16 F4O4[M+H] + =373.11, measured value: 373.1.

[0589] Step 7

[0590] Compound 47-10 (477 mg, 1.28 mmol) was dissolved in methanol (10 mL). Wet palladium hydroxide / carbon (10%, 50 mg, 0.036 mmol) and wet palladium on carbon (10%, 50 mg, 0.047 mmol) were added to the reaction solution. The reaction mixture was stirred overnight at 50 °C under a hydrogen balloon atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by high-performance liquid chromatography (HPLC) (column: Ultimate Peptide XB-C18, 30*150 mm, 5 μm; mobile phase: A was 0.1% formic acid aqueous solution, B was acetonitrile; flow rate: 20 mL / min; gradient: 70-80%) to obtain a mixture of compounds 47-11A and 47-11B (retention time: 9.2-10.4 min). 1 ¹H NMR (400MHz, CDCl₃): δ 7.23–7.11 (m, 1H), 6.46 (t, J = 8.4 Hz, 1H), 4.81 (d, J = 6.0 Hz, 1H), 4.57 (t, J = 8.8 Hz, 2H), 4.13–3.94 (m, 3H), 3.28–3.18 (m, 2H), 2.84–2.64 (m, 1H), 1.50 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H), 0.91 (dd, J = 7.2, 1.6 Hz, 3H). ESI-MS theoretical calculations: C 18 H 20 F4O4[M+H] + =377.14, measured value: 376.9.

[0591] Step 8

[0592] Under ice-water bath conditions, a mixture of compounds 47-11A and 47-11B (250 mg, 0.66 mmol) was dissolved in tetrahydrofuran (3 mL), and potassium tert-butoxide tetrahydrofuran solution (1 mol / L, 2.69 mL, 2.69 mmol) was added. The mixture was then slowly stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride (5 mL), and the pH was adjusted to 1 with hydrochloric acid (1 mol / L). The resulting mixture was extracted with dichloromethane (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol, 20 / 1, v / v) to obtain a mixture of compounds 47-12A and 47-12B. ESI-MS theoretical calculation: C 16 H 16 F4O4[M+H] + =349.11, measured value: 348.9.

[0593] Step 9

[0594] At 0 °C, a mixture of compounds 47-12A and 47-12B (50 mg, 0.14 mmol) and compound 12-2 (21.90 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (1.0 mL). N,N-diisopropylethylamine (54.28 mg, 0.42 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (79.85 mg, 0.21 mmol) were added to the reaction solution, and the reaction was stirred at room temperature for 1 hour. After the reaction was complete, water (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate 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 0.1% formic acid aqueous solution, B is acetonitrile; flow rate: 20 mL / min; gradient: 15-75%) to obtain a mixture of compounds 47A and 47B (retention time: 27-31 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 11.64 (s, 1H), 7.78 (s, 1H), 7.51 (d, J = 4.0Hz, 1H), 7.17 (s, 1H), 7.12–7.01 (m, 1H), 6.79 (d, J = 3.6Hz, 1H), 6.67 (t, J = 8.0Hz, 1H), 5.15 (d, J = 10.0Hz, 1H), 4.63 (t, J = 9.2Hz, 2H), 4.13–4.05 (m, 1H), 3.30–3.18 (m, 2H), 2.78–2.71 (m, 1H), 1.56 (s, 3H), 0.75 (s, 3H). ESI-MS theoretical calculation: C 21 H 20 F4N2O4S[M+H]+=473.12, measured value: 472.8.

[0595] Example 48

[0596] Synthesis route:

[0597] At 0 °C, N,N-diisopropylethylamine (36.70 mg, 0.28 mmol) was added to a stirred solution of compound 46-4 (17.06 mg, 0.11 mmol) and compound 1-1 (25 mg, 0.071 mmol) in N,N-dimethylformamide (0.5 mL), followed by N,N-diisopropylethylamine (36.70 mg, 0.28 mmol), and then N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (40.49 mg, 0.11 mmol). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography (column: C18 spherical 20-35 μm 100A 20 g; mobile phase: A is 0.1% formic acid aqueous solution, B is acetonitrile; flow rate: 20 mL / min; gradient: 65-70%) to obtain compound 48 (retention time: 30-45 min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 10.40 (s, 1H), 7.85 (d, J = 4.0Hz, 1H), 7.74 (s, 1H), 7.39 (s, 1H), 7.21–7.11 (m, 2H), 5.22 (d, J = 10.4Hz, 1H), 4.22 (dd, J = 10.0, 7.8Hz, 1H), 3.95 (d, J = 2.0Hz, 3H), 2.82–2.70 (m, 1H), 1.58 (s, 3H), 0.71 (d, J = 6.0Hz, 3H). ESI-MS theoretical calculation: C 20 H 18 F6N2O4S[M+H] + =497.10, actual measurement 496.9.

[0598] Example 49

[0599] Synthesis route:

[0600] first step

[0601] Compound 49-1 (5 g, 21.83 mmol) and 1,2-ethanedithiol (2.5 g, 26.20 mmol) were dissolved in dichloromethane (100 mL). Boron trifluoride diethyl ether (4.6 g, 32.74 mmol) was added dropwise to the reaction mixture at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was poured into an ice-cold saturated sodium bicarbonate aqueous solution (100 mL), stirred for 15 minutes, filtered with diatomaceous earth, and the filter cake was washed with dichloromethane. The resulting filtrate was extracted with dichloromethane (100 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 50 / 1, v / v) to obtain compound 49-2. 1 H NMR (400MHz, DMSO-d6): δ7.52 (dd, J=8.8, 4.4Hz, 1H), 7.04 (t, J=9.6Hz, 1H), 3.63-3.38 (m, 4H), 2.92 (t, J=6.8Hz, 2H), 2.68 (t, J=6.8Hz, 2H).

[0602] Step 2

[0603] Dibromohydantoin (19.5 g, 68.16 mmol) was dissolved in dichloromethane (75 mL). Under a nitrogen atmosphere at -78 °C, a 70% pyridine hydrogen fluoride solution (29 g, 204.48 mmol) was added dropwise. After stirring for 30 minutes, a dichloromethane solution of compound 49-2 (5.2 g, 17.04 mmol) (20 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was poured into a mixture of sodium hydroxide aqueous solution (2 mol / L, 250 mL) and saturated sodium bisulfite aqueous solution (50 mL). The resulting mixture was extracted with dichloromethane (150 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether) to obtain compound 49-3. 1 HNMR (400MHz, CDCl3): δ7.61 (dd, J=8.8, 4.4Hz, 1H), 6.98 (t, J=8.4Hz, 1H), 4.71-4.52 (m, 1H), 3.67-3.57 (m, 1H), 3.28-3.18 (m, 1H).

[0604] Step 3

[0605] Compound 49-3 (4.5 g, 13.64 mmol) was dissolved in dichloromethane (50 mL), and then 1,8-diazabispyrospiro[5.4.0]undec-7-ene (3.1 g, 20.46 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (50 mL), washed with hydrochloric acid (2 mol / L, 50 mL × 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 49-4. 1 H NMR (400MHz, CDCl3): δ7.44 (dd, J=8.8, 4.4Hz, 1H), 6.89-6.78 (m, 2H), 6.27 (d, J=6.0Hz, 1H).

[0606] Step 4

[0607] Compound 49-4 (3.3 g, 13.25 mmol) and o-nitrobenzenesulfonyl chloride (5.9 g, 26.5 mmol) were dissolved in acetonitrile (50 mL), and hydrazine hydrate (2.7 g, 53.0 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with saturated brine (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed with hydrochloric acid (1 mol / L), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether) to obtain compound 49-5. 1 H NMR (400MHz, CDCl3): δ7.56 (dd, J=8.8, 4.4Hz, 1H), 6.92 (t, J=8.4Hz, 1H), 3.09-2.98 (m, 2H), 2.74-2.56 (m, 2H).

[0608] Step 5

[0609] Compound 49-5 (1 g, 3.98 mmol), pinacol diborate (1.52 g, 5.97 mmol), potassium carbonate (1.17 g, 11.94 mmol), and [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (290 mg, 0.40 mmol) were sequentially dissolved in dioxane (5 mL). The mixture was stirred at 80 °C for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound 49-6. 1H NMR (400MHz, CDCl3): δ7.90-7.86 (m, 1H), 6.97 (t, J = 8.8Hz, 1H), 3.29-3.24 (m, 2H), 2.64-2.54 (m, 2H), 1.33 (s, 12H).

[0610] Step 6

[0611] Compounds 49-6 (0.62 g, 2.08 mmol) and 47-7 (1.25 mg, 3.22 mmol) were dissolved in dioxane (12 mL) and water (2 mL). Potassium carbonate (0.86 g, 6.24 mmol) and tetraphenylphosphine palladium (0.24 g, 0.21 mmol) were added sequentially to the reaction solution. The reaction solution was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane, 3 / 100, v / v) to obtain compound 49-7. 1 ¹H NMR (400MHz, CDCl₃): δ 7.21–7.16 (m, 1H), 7.02 (t, J = 8.4 Hz, 1H), 4.20–4.02 (m, 2H), 3.39 (q, J = 7.2 Hz, 1H), 3.03–2.81 (m, 2H), 2.69–2.55 (m, 2H), 1.71 (s, 3H), 1.16–1.10 (m, 3H), 1.07 (t, J = 7.2 Hz, 3H). ESI-MS theoretical calculation: C 19 H 18 F6O3[M+H] + =409.13, measured value: 408.9.

[0612] Step 7

[0613] Compound 49-7 (408 mg, 1.0 mmol) was dissolved in methanol (8 mL), and wet palladium hydroxide / carbon (10%, 50 mg) and wet palladium on carbon (10%, 50 mg) were added. The reaction mixture was stirred at 50 °C for 48 hours under a hydrogen balloon atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by high-performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 330 g; mobile phase: A was 0.1% trifluoroacetic acid aqueous solution, B was acetonitrile; flow rate: 100 mL / min; gradient: 5-75%) to obtain a mixture of compounds 49-8A and 49-8B (retention time: 60-65 min). ESI-MS theoretical calculation: C 19 H20 F6O3[M+H] + =411.14, measured value: 410.9.

[0614] Step 8

[0615] A mixture of compounds 49-8A and 49-8B (140 mg, 0.34 mmol) was dissolved in tetrahydrofuran (1.5 mL) under ice-water bath conditions. A solution of potassium tert-butoxide in tetrahydrofuran (1 mol / L, 1.36 mL, 1.36 mmol) was added to the reaction mixture, and the mixture was slowly stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride (5 mL), and the pH was adjusted to 1 with hydrochloric acid (1 mol / L). The resulting mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude mixture of compounds 49-9A and 49-9B. ESI-MS theoretical value: C 17 H 16 F6O3[MH] - =381.09, measured value: 381.0.

[0616] Step 9

[0617] Under ice-water bath conditions, a mixture of compounds 49-9A and 49-9B (130 mg, 0.34 mmol) and compound 12-2 (53.18 mg, 0.37 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). N,N-diisopropylethylamine (131.82 mg, 1.02 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (193.92 mg, 0.51 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography (HPLC) (column: C18 spherical 20-35 μm 100A 40 g; mobile phase: A is 0.1% formic acid aqueous solution, B is acetonitrile; flow rate: 40 mL / min; gradient: 5-60%) to obtain a mixture of compounds 49A and 49B (retention time: 44-47 min). 1H NMR (400MHz, DMSO-d6): δ11.65 (s, 1H), 7.76 (s, 1H), 7.57 (dd, J=8.8, 4.8Hz, 1H ), 7.50 (d, J = 4.0Hz, 1H), 7.22 (t, J = 9.2Hz, 1H), 7.16 (s, 1H), 6.83 (d, J = 4.0Hz, 1H), 5.23 (d, J = 10.4 Hz, 1H), 4.17-4.06 (m, 1H), 3.15-3.03 (m, 2H), 2.90-2.80 (m, 1H), 2.71-2.60 (m, 2H), 1.61 (s, 3H), 0.69 (d, J = 6.80 Hz, 3H). ESI-MS theoretical calculation: C 22 H 20 F6N2O3S[MH] - =505.10, measured value: 504.9.

[0618] Effect Test Example 1: The effect of the compound on hNa v 1.8 Evaluation of sodium ion channel inhibitory activity

[0619] Experimental objective:

[0620] The effects of the present invention on hNa were tested using the fully automated patch-clamp Syncropatch technique. v Inhibition of 1.8 (human voltage-gated sodium ion channel 1.8).

[0621] Cell preparation:

[0622] Stable expression of hNa v Human embryonic kidney cells (HEK293) with 1.8 sodium ion channels were cultured in culture flasks. When the cell density reached 80-90%, 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, 7 mL of culture medium was added for neutralization, followed by centrifugation, aspiration of the supernatant, and the addition of 2 mL of extracellular fluid for cell counting to ensure a cell density of 5 × 10⁸ cells / year. 5 / mL.

[0623] Patch clamp testing:

[0624] In whole-cell recording mode, cells were clamped at -100 mV. A depolarization step voltage of 30 ms was applied to 0 mV to induce sodium current. This voltage was applied every 10 seconds, and the signal was recorded for 1 minute, followed by extracellular fluid administration and recording of sodium current for another 3 minutes. Then, different concentrations of the test compound (100.00, 33.33, 11.11, 3.70, 1.23, and 0.41 nM, a total of six concentrations) were administered, with each concentration administered for 3 minutes. At least two cells were tested for each concentration. The inhibitory effect of different concentrations of the test compound on sodium ion channels was calculated using the following formula:

[0625] Inhibition level = 1 - (Peak sodium current after drug administration / Peak sodium current before drug administration)

[0626] IC50 of the test compound 50 The concentration of the compound was plotted on the x-axis and the degree of inhibition on the y-axis. The concentration of the compound at which the maximum current of inhibition was 50% was calculated by fitting a dose-response curve.

[0627] The experimental results are shown in Table 1:

[0628] Table 1. Inhibitory activity of the compounds in the embodiments of this application against Nav1.8

[0629] Note: Where 0nM<A≤10nM.

[0630] Experimental conclusion: The compounds in the embodiments of this disclosure have strong inhibitory activity against human voltage-gated sodium ion channels 1.8.

[0631] The comparison results of the inhibitory activities of the compounds in the embodiments of this application against Nav1.8 are shown in Table 2.

[0632] Table 2 Comparison of the inhibitory activities of the compounds in the embodiments of this application against Nav1.8

[0633] As shown in the table above, the compound of Example 12, which has a unique thiophene structure, exhibits significantly better cell activity than other compounds with thiophene or thiazole structures.

[0634] Example 2: Pharmacokinetic Evaluation of the Compound in CD-1 Mice

[0635] Experimental objective: To test the pharmacokinetics of the compound in CD-1 mice.

[0636] Experimental materials: CD-1 mice (male, 7-10 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0637] Experimental Procedure: The pharmacokinetic characteristics of the compounds after intravenous and oral administration were tested in rodents according to the standard protocol. In this experiment, candidate compounds were prepared into clear solutions and administered to mice via single intravenous injection and oral administration. The solvent for both intravenous and oral administration was a mixed solvent consisting of 3% dimethyl sulfoxide, 7% solubilol, and 90% physiological saline.

[0638] In this project, six male CD-1 mice were used in each group. Three mice were administered the drug intravenously (IV), and plasma samples were collected at 0 h (before administration) and 0.0833, 0.25, 0.5, 1, 2, 4, 8, and 24 h after administration. The other two mice were administered the drug orally (PO), and plasma samples were collected at 0 h (before administration) and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. The blood drug concentration was quantitatively analyzed by LC-MS / MS, and pharmacokinetic parameters such as peak concentration (Cmax), clearance (CL), half-life (T12), tissue distribution (Vdss), area under the curve (AUC0-1ast), and bioavailability (F) were calculated.

[0639] The experimental results are shown in Table 3:

[0640] Table 3. Pharmacokinetic results of the compounds in CD-1 mice.

[0641] Conclusion: The compounds of this invention exhibit good pharmacokinetic properties in CD-1 mice, including good oral bioavailability, oral exposure, half-life, and clearance.

[0642] Example 3 of efficacy test: Efficacy experiment of drug on plantar incision pain in 57BL / 6J mice

[0643] 1. Experimental objective: This experiment aims to explore the efficacy of the test substance in a C57BL / 6J mouse paw incision pain model and evaluate the analgesic effect of the candidate compound.

[0644] 2. Experimental Design

[0645] 2.1 Laboratory animals: SPF-grade C57BL / 6 mice (Zhejiang Vital River Laboratory Animal Technology Co., Ltd.)

[0646] 2.2 Compound preparation: Weigh an appropriate amount of the test sample, add an appropriate amount of the test sample solvent 10% sulfobutyl-β-cyclodextrin, stir until dissolved, and prepare a 3 mg / mL test sample solution.

[0647] 2.3 Experimental Methods: Animals were anesthetized with isoflurane. The left hind limb was prepared, routinely disinfected, and a longitudinal incision of approximately 1 cm was made from the heel towards the toe. The skin and subcutaneous fascia were cut, and the exposed toe muscles were bluntly dissected and longitudinally incised, preserving the integrity of the muscle's origin and insertion points. After the incision was completed, the area was disinfected with povidone-iodine and the animals were placed in clean cages. The grasping pressure (g) was measured using a dynamic plantar tactile sensor before modeling, before drug administration, and at 15 min, 1 h, 2 h, 4 h, 6 h, and 8 h after drug administration.

[0648] 2.4 Experimental groups: Group 1 was the sham-operated group, Group 2 was the model control group, Group 3 was given VX-548 (dose of 30 mg / kg), and Group 4 was given the target compound of Example 12 (dose of 30 mg / kg). There were 8 animals in each group.

[0649] 2.5 Data Processing and Analysis: The measurement data collected in this experiment are expressed as mean ± standard deviation. Statistical analysis was performed using Graphpad Prism 8.0 software. Two-way ANOVA was used to compare the claw retraction pressure values ​​before and after modeling between the sham-operated group and the model animals; two-way ANOVA was used to compare the claw retraction pressure values ​​before and after drug administration between the drug-administered group and the model group.

[0650] 3. The experimental results are shown in Table 4.

[0651] Table 4. Statistics on claw retraction pressure (g) before and after drug administration Note: Compared with the model control group, in Two-way ANOVA, *, **, and *** represent P<0.05, P<0.01, and P<0.001, respectively.

[0652] 4. Experimental Conclusions

[0653] In 57BL / 6J mice, the compound of this application showed significant analgesic effect at a dose of 30 mg / kg.

[0654] Example 4: Study on the metabolic stability of the compound in liver microsomes of mice, rats, dogs, monkeys and humans.

[0655] Experimental steps

[0656] 1. Incubation steps

[0657] Test compounds or positive controls (including testosterone, diclofenac, and propafenone) were incubated once at 1.0 μM (solvent: acetonitrile) with liver microsomes (from Corning, Xenotech, or other trusted suppliers, with microsomes from multiple donors for each species) at a final concentration of 0.5 mg / mL (100 mM potassium phosphate buffer (PB Buffer)).

[0658] The mixture will be preheated at 37°C for 10 minutes, and the reaction will be initiated by adding a cofactor system (1.0 mM NADPH). Test compounds incubated with liver microsomes at 37°C without the cofactor system will serve as negative controls.

[0659] 2. Sampling

[0660] Reaction samples will be taken at multiple time points (e.g., 0, 5, 15, 30, 45, and 60 minutes), while samples without the cofactor system (NCF) will be taken at 60 minutes. All samples will be immediately mixed with pre-cooled acetonitrile containing the internal standard (IS) to terminate the reaction.

[0661] 3. Single-point testing

[0662] Each test condition is measured once (n=1).

[0663] 4. Sample Analysis

[0664] The samples will be analyzed using LC-MS / MS; the disappearance of the test compound will be assessed based on the peak area ratio of the analyte to the internal standard (IS) (no standard curve required).

[0665] 5. Data Summary

[0666] Provides an Excel summary of data, including calculated intrinsic clearance rate and half-life (T). 1 / 2 )value.

[0667] 6. Calculation of microparticle clearance rate

[0668] Calculate the microsomal clearance rate using the following formula:

[0669] when

[0670] C t : Indicates the drug concentration at time t;

[0671] C0: Represents the drug concentration at the initial time (t=0);

[0672] e: is the base of the natural logarithm, approximately equal to 2.71828;

[0673] ke : Represents the elimination rate constant, describing the rate at which a drug is eliminated from the body;

[0674] t: Indicates time.

[0675] Liver weight: 40 g / kg (rat), 30 g / kg (monkey), 32 g / kg (dog), 20 g / kg (human) and 88 g / kg (mouse).

[0676] Using CL int(mic) Calculate liver clearance rate:

[0677] Microsomal protein / liver weight: 45 mg / g (applicable to 5 species).

[0678] The experimental results are shown in Table 5:

[0679] Table 5

[0680] " / " indicates that it has not been tested.

[0681] The results showed that the compound of this application has the properties of low clearance rate of human liver microsomes and good metabolic stability.

Claims

1. A compound of formula (II), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: in, The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof; R 1 and R 2 Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkyl substituted with one or more halogens; R 3 and R 8 Each is independently H, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkyl substituted with one or more halogens; R 9 It is hydrogen or deuterium; R 4 H, OH, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C2-C6 alkenyl, C1-C6 alkoxy, -L a -L b -L c -L d -C1-C6 alkylene-OR 4-1 -L d -C1-C6 imidene-OR 4-1 -L d -C1-C6 alkylene-NR a R b , by one or more R 4-2 Substituted C1-C6 alkyl groups or those with one or more R 4-3 Substituted C1-C6 alkoxy groups; L a For connection key or O; L b It is a linking bond or a C1-C6 alkylene group; L c It is a C3-C8 cycloalkyl, a 3-8 membered heterocycloalkyl, a 5-6 membered heteroaryl, -C(=O)O(C1-C6 alkyl), -C(=O)OH, -C(=O)NR a R b , by one or more R c Substituted C3-C8 cycloalkyl groups, with one or more R d Substituted 3-8 membered heterocyclic alkyl groups or substituted with one or more R e The substituted 5-6-membered heteroaryl group; wherein the 3-8-membered heterocyclic alkyl group or the 5-6-membered heteroaryl group has a heteroatom selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R a and R b Each is independently H, OH, C1-C6 alkyl or 3-8 membered heterocyclic alkyl, wherein the heteroatom in the 3-8 membered heterocyclic alkyl is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R c R d and R e Each of them is independently a halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with one or more halogens, or C1-C6 alkoxy substituted with one or more halogens; L d For connection key or O; R 4-1 It is H, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens; R 4-2 and R 4-3 It can be independently deuterium, halogen, or C1-C6 alkoxy; X 3 For N or CR 5a ; X 4 For N or CR 6a ; X 5 For N or CR 9a ; X 6 For N or CR 10a ; R 5a It is H, halogen, C1-C6 alkyl, or composed of one or more R 5a-1 Substituted C1-C6 alkyl; or R 5a With R 4 The atoms between them together form a ring C or are bounded by one or more R atoms. 5a-2 The replaced ring C; R 5a-1 It can be halogenated or C1-C6 alkoxy group independently; The ring C is a C3-C8 cycloene or a 3-8 heterocyclic cycloene. In the 3-8 membered heterocyclic cycloene, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3. The C3-C8 cycloene and the 3-8 membered heterocyclic cycloene contain only one carbon-carbon double bond, and the carbon-carbon double bond is CR. 4 carbon atoms and CR 5a Carbon-carbon double bonds between carbon atoms in the carbon atoms; R 5a-2 Halogens are independent of each other; R 6a It is H, halogen, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens; R 9a It is H, halogen, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens; R 10a It is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 alkyl substituted with one or more halogens; R 10 and R 11 Independently H, halogen, or C1-C6 alkyl group substituted with one or more halogens; R 7 For CN, C1-C6 alkyl groups or containing one or more R 7g Substituted C1-C6 alkyl groups; R 7a It is H or C1-C6 alkyl; R 7b H, C1-C6 alkyl, C3-C6 cycloalkyl, by one or more R 7b-3 Substituted C1-C6 alkyl groups or those with one or more R 7b-4 Substituted C3-C6 cycloalkyl groups; R 7b-1 and R 7b-2 Each is independently H or C1-C6 alkyl; R 7b-3 It is OH; R 7b-4 It is OH; R 7c It is H or C1-C6 alkyl; R 7d For H or R 7d-1 and R 7d-2 Each is independently H or C1-C6 alkyl; R 7e It is H or C1-C6 alkyl; R 7f It is a C1-C6 alkyl group; R 7g Independently OH; X 1 For N or CR X11 R X11 It is H, OH, C1-C6 alkyl, or formed by one or more R X11-1 Substituted C1-C6 alkyl groups; R X11-1 Independently OH; X 2 It can be O or N; L represents C1-C6 alkylene, -C(=O)-C1-C6 alkylene, or... The C1-C6 alkylene and -C(=O)-C1-C6 alkylene- are optionally separated by one or more L 1 replace; L 1 Independently OH, C1-C6 alkyl, or surrounded by one or more L 11 Substituted C1-C6 alkyl groups; L 11 It is OH on its own.

2. A compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: in, The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof; R 1 and R 2 Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkyl substituted with one or more halogens; R 3 and R 8 Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkyl substituted with one or more halogens; R 4 H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, -L a -L b -L c -L d -C1-C6 alkylene-OR 4-1 -L d -C1-C6 imidene-OR 4-1 -L d -C1-C6 alkylene-NR a R b C1-C6 alkyl groups substituted with one or more halogens or C1-C6 alkoxy groups substituted with one or more halogens; L a For connection key or O; L b It is a linking bond or a C1-C6 alkylene group; L c It is a C3-C6 cycloalkyl, a 3-8 membered heterocycloalkyl, a 5-6 membered heteroaryl, -C(=O)O(C1-C6 alkyl), -C(=O)OH, -C(=O)NR a R b , by one or more R c Substituted C3-C6 cycloalkyl groups, with one or more R d Substituted 3-8 membered heterocyclic alkyl groups or substituted with one or more R e The substituted 5-6-membered heteroaryl group; wherein the 3-8-membered heterocyclic alkyl group or the 5-6-membered heteroaryl group has a heteroatom selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R a and R b Each is independently H, OH, C1-C6 alkyl or 3-8 membered heterocyclic alkyl, wherein the heteroatom in the 3-8 membered heterocyclic alkyl is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R c R d and R e Each of them is independently a halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted with one or more halogens, or C1-C6 alkoxy substituted with one or more halogens; L d For connection key or O; R 4-1 It is H, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens; X 3 For N or CR 5a ; X 4 For N or CR 6a ; X 5 For N or CR 9a ; X 6 For N or CR 10a ; R 5a It is H, halogen, C1-C6 alkyl, or composed of one or more R 5a-1 Substituted C1-C6 alkyl groups; R 5a-1 It can be halogenated or C1-C6 alkoxy group independently; R 6a It is H, halogen, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens; R 9a It is H, halogen, C1-C6 alkyl, or C1-C6 alkyl substituted with one or more halogens; R 10a It is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 alkyl substituted with one or more halogens; Ring A is a five-membered heteroaromatic ring or a six-membered heteroaromatic ring, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; When ring A is a five-membered heteroaryl ring, R 7 for C1-C6 alkyl groups or containing one or more R 7g Substituted C1-C6 alkyl groups; When ring A is a six-membered heteroaryl ring, R 7 for R 7a It is H or C1-C6 alkyl; R 7b H, C1-C6 alkyl, C3-C6 cycloalkyl, by one or more R 7b-3 Substituted C1-C6 alkyl groups or those with one or more R 7b-4 Substituted C3-C6 cycloalkyl groups; R 7b' C3-C6 cycloalkyl, by one or more R 7b-3 Substituted C1-C6 alkyl groups or those with one or more R 7b-4 Substituted C3-C6 cycloalkyl groups; R 7b-1 and R 7b-2 Each is independently H or C1-C6 alkyl; R 7b-3 It is OH; R 7b-4 It is OH; R 7c It is H or C1-C6 alkyl; R 7d for R 7d-1 and R 7d-2 Each is independently H or C1-C6 alkyl; R 7e It is H or C1-C6 alkyl; R 7f It is a C1-C6 alkyl group; R 7g Independently OH; X 1 For N or CR X11 R X11 It is H, OH, C1-C6 alkyl, or formed by one or more R X11-1 Substituted C1-C6 alkyl groups; R X11-1 Independently OH; X 2 It can be O or N; L represents C1-C6 alkylene, -C(=O)-C1-C6 alkylene, or... The C1-C6 alkylene and -C(=O)-C1-C6 alkylene- are optionally separated by one or more L 1 replace; L 1 Independently OH, C1-C6 alkyl, or surrounded by one or more L 11 Substituted C1-C6 alkyl groups; L 11 Independently OH; The compound represented by formula (I) is not any of the following compounds and their stereoisomers:

3. The compound as described in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) Each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl; (2) Each "C3-C6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopentyl; (3) Each "halogen" is independently F, Cl or Br, for example F; (4) Each "C2-C6 alkenyl" is independently a C2-C4 alkenyl, such as vinyl, propenyl or allyl; (5) Each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (6) Each "five-membered heteroaromatic ring" is independently a five-membered heteroaromatic ring with N and / or S heteroatoms, and the number of heteroatoms is one or two, for example (7) Each "six-membered heteroaromatic ring" is independently a six-membered heteroaromatic ring with N heteroatoms and either one or two heteroatoms, for example (8) Each "C1-C6 alkylene group" is independently... (9) Each "C3-C8 cycloalkyl" is independently a C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, further such as cyclopropyl; (10) Each "C3-C6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (11) Each "3-8 membered heterocyclic alkyl" is independently a 3-6 membered heterocyclic alkyl, such as oxetane, oxetane, azirne, tetrahydropyrrole, tetrahydrothiophene, tetrahydrofuran, morpholino, piperidinyl, tetrahydropyranyl or piperazine, such as oxetane, further for example (12) Each "3-8 heterocyclic alkene" is independently a 3-6 membered heterocyclic alkene, such as dihydrofuran, and further such as (13) Each "C3-C8 cycloene" is independently a C3-C6 cycloene, for example 4. The compound of claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 7 For CN, Or by one or more R 7g Substituted C1-C6 alkyl groups; (2)R 7a For H; (3)R 7b For H; (4)R 7c For H; (5)R 7d For H; (6)R 7e For H; (7)R 7f It is a C1-C6 alkyl group; (8)R 7g Independently OH: (9)R 1 and R 2 Each is independently a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one or more halogens, such as methyl or -CF3; (10)R 3 It is a C1-C6 alkyl group, such as methyl; (11)R 8 For example, H or deuterium; (12)R 4 It is a C3-C8 cycloalkyl, C1-C6 alkoxy, -L a -L b -L c , by one or more R 4-2 Substituted C1-C6 alkyl groups or those with one or more R 4-3 Substituted C1-C6 alkoxy groups, such as C1-C6 alkoxy groups; (13)L a It is O; (14)L b For connection key; (15)L c It is a C3-C8 cycloalkyl or a 3-8 membered heterocyclic alkyl; (16)R 4-2 and R 4-3 It can be independently deuterium, halogen, or C1-C6 alkoxy; (17)X 3 For CR 5a R 5a For halogen, or, R 5a With R 4 The atoms between them together form a ring C or are bounded by one or more R atoms. 5a-2 The substituted cyclic C is a C3-C8 cyclic alkene or a 3-8 heterocyclic alkene; (18)X 4 For CR 6a ; (19)X 5 For CR 9a ; (20)X 6 For CR 10a ; (21)R 9 It can be hydrogen or deuterium, for example, hydrogen; (22)R 10 and R 11 It can be H, F, or -CF3 independently.

5. The compound of claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 7 for CN、 Preferred CN Further preferred (2)R 1 It is a C1-C6 alkyl group substituted with one or more halogens, such as -CF3; (3)R 2 It is a C1-C6 alkyl group, such as methyl; (4)R 4 It is methoxy, -OCD3, -OCD2CD3, -OCF3, -OCH2CH3, -OCH2CF3, -OCHF2、 For example, methoxy groups; (5)X 3 For CR 5a R 5a For F, or R 5a With R 4 Together with the atoms between them, they form X 3 CF is preferred; (6)X 4 For CF; (7)X 5 For CH; (8)X 6 For CH; (9)R 11 It is H or a halogen, such as H or F, further such as H; (10)R 10 For H.

6. The compound of claim 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It satisfies any of the following conditions: Case 1: The substituents in the compound shown in formula (I) are defined as in Scheme 1, where ring A is a six-membered heteroaromatic ring, and R... 7 for The definitions of the remaining substituents are as described in claim 1; Case 2: The substituents in the compound shown in formula (I) are defined as in Scheme 2, where ring A is a five-membered heteroaromatic ring, and R... 7 for C1-C6 alkyl groups or containing one or more R 7g The substituted C1-C6 alkyl groups; the definitions of the remaining substituents are as described in claim 1.

7. The compound of claim 6, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) In Scheme 1, ring A is #Terminal and R 7 Connected; (2) In Scheme 2, ring A is #Terminal and R 7 Connected, preferably (3) In Scheme 1 and Scheme 2, R 7a For H; (4) In Scheme 1, R 7b' Cyclopentyl groups substituted with one or more hydroxyl groups, C1-C6 alkyl groups substituted with one or more hydroxyl groups, or... R 7b-1 and R 7b-2 Each is independently H or C1-C6 alkyl; (5) In Scheme 2, R 7b It is H, C1-C6 alkyl, cyclopentyl substituted with one or more hydroxyl groups, or C1-C6 alkyl substituted with one or more hydroxyl groups. R 7b-1 and R 7b-2 Each is independently H or C1-C6 alkyl; (6) In Scheme 1 or Scheme 2, L is a C1-C4 alkylene group. #1 -C(=O)-C1-C4 alkylene-or #1 Terminal and X 1 Connected, the C1-C4 alkylene groups and #1 The C1-C4 alkylene group in -C(=O)-C1-C4 alkylene- is optionally surrounded by one or more L 1 Instead, the L 1 It is OH or C1-C4 alkyl; (7) In Scheme 1 or Scheme 2, R 1 A C1-C6 alkyl group substituted with one or more halogens; (8) In Scheme 1 or Scheme 2, R 2 It is a C1-C6 alkyl group; (9) In Scheme 1 or Scheme 2, R 3 It is a C1-C6 alkyl group; (10) In Scheme 1 or Scheme 2, R 4 It is a C1-C6 alkoxy group; (11) In Scheme 1 or Scheme 2, X 3 For CR 5a ; (12) In Scheme 1 or Scheme 2, X 4 For CR 6a ; (13) In Scheme 1 or Scheme 2, X 5 For CR 9a ; (14) In Scheme 1 or Scheme 2, X 6 For CR 10a .

8. The compound of claim 6, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) In Scheme 1, R 7b' for (2) In Scheme 2, R 7b For H, For example, H; (3) In Scheme 2, R 7f It is methyl; (4) In Scheme 2, R 7e For H; (5) In the above scheme 2, the R 7 In the context, the one or more R 7g The substituted C1-C6 alkyl groups are (6) In Scheme 1 and Scheme 2, R 7c For H; (7) In Scheme 1 and Scheme 2, R 7d for (8) In Scheme 1 and Scheme 2, R X11 It is H or OH; (9) In Scheme 1 and Scheme 2, L is #1 Terminal and X 1 Connected; (10) In Scheme 1 and Scheme 2, R 1 -CF3 (11) In Scheme 1 and Scheme 2, R 2 It is methyl; (12) In Scheme 1 and Scheme 2, R 3 It is methyl; (13) In Scheme 1 and Scheme 2, R 8 For H; (14) In Scheme 1 and Scheme 2, R 4 It is a methoxy group; (15) In Scheme 1 and Scheme 2, X 3 For CF; (16) In Scheme 1 and Scheme 2, X 4 For CF; (17) In Scheme 1 and Scheme 2, X 5 For CH; (18) In Scheme 1 and Scheme 2, X 6 For CH.

9. The compound according to at least one of claims 1, 3-5, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (II) is a compound represented by formula (II-1), formula (II-1'), or formula (II-2): In compounds of formula (II-1), formula (II-1'), or formula (II-2), the definitions of each variable are as described in at least one of claims 1, 3-5; Preferably, in the compound shown in formula (II-2), R 8 and R 9 The definition satisfies any of the following schemes: Option 1: R 8 For H, R 9 For H; Option 2: R 8 For H, R 9 For D, or R 9 For H, R 8 The answer is D; Option 3: R 8 For D, R 9 The answer is D.

10. The compound according to at least one of claims 2, 4-8, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is either the compound represented by formula (I-1) or the compound represented by formula (II-2): The definitions of each variable are as described in at least one of claims 2, 4-8.

11. A compound, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound is any one of the following compounds:

12. A pharmaceutical composition comprising a compound as claimed in at least one of claims 1-11, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. The use of a compound as described in at least one of claims 1-11, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9 in the preparation of a voltage-gated sodium channel type 1.8 inhibitor.

14. The use of a compound as described in at least one of claims 1-11, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 12 in the preparation of a medicament for the prevention, relief, and / or treatment of diseases or symptoms associated with voltage-gated sodium channel type 1.8, preferably, wherein the disease or symptom associated with voltage-gated sodium channel type 1.8 is pain, such as inflammatory pain, neuropathic pain, postoperative pain, or cancer pain.

15. The use of a compound as described in at least one of claims 1-11, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 12 in the preparation of a medicament for the prevention, relief, and / or treatment of pain, wherein the pain is, for example, inflammatory pain, neuropathic pain, postoperative pain, or cancer pain.

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