Compound as TRPA1 inhibitor, pharmaceutical composition thereof, and use thereof

Abstract

Disclosed herein are a compound as a TRPA1 inhibitor, a pharmaceutical composition thereof, and use thereof. Specifically, disclosed are a compound of formula I, a racemate thereof, a stereoisomer thereof, a tautomer thereof, a nitrogen oxide thereof, or a prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof. The compound has good inhibitory activity against TRPA1 and excellent pharmacokinetic and pharmacodynamic activity.

Description

Compounds, pharmaceutical compositions and applications as TRPA1 inhibitors

[0001] This application claims Chinese patent application 2024116957971, filed on November 25, 2024; Chinese patent application 2025100218616, filed on January 7, 2025; and Chinese patent application 2025117178989, filed on November 21, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to the pharmaceutical field, and more particularly to compounds that can inhibit TRPA1 activity, pharmaceutical compositions thereof, and applications. Background Technology

[0003] Transient receptor potential (TRP) ion channels are a class of channel proteins widely distributed in the peripheral and central nervous systems. To date, more than 30 members of the TRP channel family have been cloned in mammals. TRP ion channels are responsible for various sensory responses, including heat, cold, pain, pressure, vision, and taste. Currently, their most accepted function is mediating the transmission of sensory signals; other functions include regulating cellular calcium homeostasis and influencing development. TRP channels can be regulated by various factors, including temperature, osmotic pressure, pH, mechanical force, and some endogenous and exogenous ligands and intracellular signaling molecules. Based on amino acid sequence homology, the more than 30 members of the TRP channel family can be divided into seven subfamilies: TRPC, TRPV, TRPM, TRPA, TRPP, TRPML, and TRPN.

[0004] TRPA1 is the sole member of the TRPA subfamily, composed of 1119 amino acids. Structurally, it possesses six transmembrane domains (S1-S6) and a characteristic N-terminal ankyrin repeat sequence of 17. TRPA1 is primarily expressed in sensory neurons (both CNS and peripheral cells), fibroblasts, and epithelial cells, with organ-level expression mainly in the bladder and gastrointestinal tract. TRPA1 acts as a sensor for various harmful external stimuli, such as strong cold, irritating compounds, mechanical stimulation, reactive chemicals, and endogenous signals associated with cell damage. Its diverse expression and function in nociceptive nerve fibers, epithelial cells, and various other cells make it associated with a variety of diseases.

[0005] Existing research has shown that TRPA1 is highly expressed in human dorsal root ganglion neurons and peripheral sensory nerves. Many known TRPA1 agonists are stimulants that induce pain, irritation, and neurogenic inflammation in humans and other animals. Therefore, TRPA1 inhibitors, or agents that block the biological effects of TRPA1 channel activators, could be used to treat diseases such as asthma, chronic cough, acute and chronic pain.

[0006] Recently, it has also been shown that products of tissue damage and oxidative stress (e.g., 4-hydroxynonenal and related compounds) activate TRPA1 channels. This finding provides further theoretical justification for the use of small-molecule TRPA1 inhibitors in the treatment of diseases associated with tissue damage, oxidative stress, and bronchial smooth muscle contraction, such as asthma, chronic obstructive pulmonary disease (COPD), occupational asthma, and viral-induced pneumonia.

[0007] GDC-6599 is a small molecule inhibitor of transient receptor potential ankylosing 1 (TRPA1) developed by Genentech for the treatment of chronic cough and asthma, and is currently in Phase II clinical trials. The company has filed a patent for the compound WO2019182925A1, "Oxadiazole transient receptor potential channel inhibitors," dated September 26, 2019, which discloses information about the GDC-6599 compound, its preparation method, and its applications.

[0008] Currently, there are no marketed TRPA1 inhibitor drugs. Therefore, there is a greater clinical need for highly active TRPA1 inhibitors to provide patients with more active and safer drug options. Developing TRPA1 inhibitors has great market and medical value. Summary of the Invention

[0009] The present invention addresses the technical problem of the limited variety of existing TRPA1 inhibitors. To this end, the present invention provides a compound as a TRPA1 inhibitor, its pharmaceutical composition, and its application. This compound exhibits excellent inhibitory activity against TRPA1, as well as superior pharmacokinetic and pharmacodynamic properties.

[0010] This invention provides compounds of Formula I, their racemates, their stereoisomers, their tautomers, their nitrides, their prodrugs, or their pharmaceutically acceptable salts or solvates:

[0011] in,

[0012] R 1 C 6-10aryl, 5-12 membered heteroaryl or 5-13 membered heterocyclic, wherein C 6-10 The aryl, 5-12-membered heteroaryl, and 5-13-membered heterocyclic groups are optionally bounded by one, two, or more R groups. 1-1 replace;

[0013] R 2 and R 3 Each is independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl, and R 2 and R 3 Only one is H or deuterium;

[0014] R 4 C 6-10 aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclic or C 3-10 In the cycloalkyl group, the heteroatoms in the 5-12 membered heteroaryl and 4-10 membered heterocyclic groups are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. 6-10 Aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclic and C 3-10 The cycloalkyl group is optionally surrounded by one, two or more R... 4-1 replace;

[0015] Each R 1-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-6 Alkyl, oxo (=O), -OH, -CN, -COOH, C 1-6 Haloalkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heterocyclic alkenyl, -NR 5-1 R 5-2 -SO2-C 1-6 Alkyl, -C 1-4 Alkyl-CN, C 1-4 Aldehyde group or C 1-4 Ketone group; the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 3-8-membered heterocycloalkyl, 5-10-membered heteroaryl, and 5-10-membered heterocyclic alkenyl groups are optionally surrounded by one, two, or more elements selected from H, deuterium, halogen, -OH, -CN, -COOH, -SO2NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6Substituents of alkoxy groups;

[0016] Each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-6 Alkyl, oxo, -OH, -CN, -COOH, C 1-6 Haloalkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group, wherein C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-8 The cycloalkyl, 5-10-membered heteroaryl, and 4-10-membered heterocyclic groups are optionally surrounded by one, two, or more groups selected from H, deuterium, halogen, -OH, -CN, -COOH, -SO2NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substituents of alkoxy groups;

[0017] R 5-1 and R 5-2 Each independently represents H and C. 1-6 Alkyl or C 1-6 Alkyl group.

[0018] In a preferred embodiment of the present invention, R 1 In the 5-12 membered heteroaryl and 5-13 membered heterocyclic groups, the heteroatoms are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1 to 5.

[0019] In a preferred embodiment of the invention, the invention provides compounds of Formula I, their racemates, their stereoisomers, their tautomers, their nitrides, their prodrugs, or their pharmaceutically acceptable salts or solvates:

[0020] in,

[0021] R 1 C 6-10 aryl, 5-12 membered heteroaryl or 5-13 membered heterocyclic, wherein C 6-10 The aryl, 5-12-membered heteroaryl, and 5-13-membered heterocyclic groups are optionally bounded by one, two, or more R groups. 1-1 The heteroatoms in the 5-12-membered heteroaryl and 5-13-membered heterocyclic groups are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three.

[0022] R 2 and R 3 Each is independently H, deuterium, halogen, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl, and R 2 and R 3 Only one is H or deuterium;

[0023] R 4 C 6-10 aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclic or C 3-10 Cycloalkyl groups, wherein the heteroatoms in the 5-12 membered heteroaryl and 4-10 membered heterocyclic groups are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three, wherein the C 6-10 Aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclic and C 3-10 The cycloalkyl group is optionally surrounded by one, two or more R... 4-1 replace;

[0024] Each R 1-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-6 Alkyl, oxo (=O), -OH, -CN, -COOH, C 1-6 Haloalkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heterocyclic alkenyl, -NR 5-1 R 5-2 -SO2-C 1-6 Alkyl, -C 1-4 Alkyl-CN, C 1-4 Aldehyde group or C 1-4 Ketone group; the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 3-8-membered heterocycloalkyl, 5-10-membered heteroaryl, and 5-10-membered heterocyclic alkenyl groups are optionally surrounded by one, two, or more elements selected from H, deuterium, halogen, -OH, -CN, -COOH, -SO2NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substituents of alkoxy groups;

[0025] Each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-6 Alkyl, oxo, -OH, -CN, -COOH, C 1-6 Haloalkyl, C 1-6 Alkoxy, phenyl, C 3-8Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group, wherein C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-8 The cycloalkyl, 5-10-membered heteroaryl, and 4-10-membered heterocyclic groups are optionally surrounded by one, two, or more groups selected from H, deuterium, halogen, -OH, -CN, -COOH, -SO2NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substituents of alkoxy groups;

[0026] R 5-1 and R 5-2 Each independently represents H and C. 1-6 Alkyl or C 1-6 Alkyl group.

[0027] In a preferred embodiment of the present invention, R 1 C 6-10 Aryl, 5-12 membered heteroaryl, 10-13 membered fused tricyclic heterocyclic group, wherein C 6- 10 Aryl, 5-12-membered heteroaryl, 10-13-membered fused tricyclic heterocyclic group, optionally with one, two or more R groups. 1-1 replace;

[0028] R 2 and R 3 Each is independent of H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclic alkyl, and R 2 and R 3 Only one is H;

[0029] R 4 For not replaced or by one or more R 4-1 Substituted benzene rings, naphthyl rings, 5-12-membered heteroaryl groups, or 5-12-membered heterocyclic alkenyl groups;

[0030] R 1-1 and R 4-1 Each of the following is independent: H, D, halogen, C 1-6 Alkyl, -OH, -CN, -COOH, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heterocyclic alkenyl, -NR 5-1 R 5-2 -SO2-C 1-6 Alkyl, -C 1-4Alkyl-CN, C 1-4 Aldehyde group, or C 1-4 Ketone group; the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 3-8-membered heterocycloalkyl, 5-10-membered heteroaryl, and 5-10-membered heterocyclic alkenyl groups are optionally surrounded by one, two, or more R groups. 4-1-1 replace;

[0031] The R 4-1-1 H, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkyl group.

[0032] In a preferred embodiment of the present invention, R 1 It is a 5-12-membered heteroaryl or a 5-13-membered heterocyclic group, wherein the 5-12-membered heteroaryl and the 5-13-membered heterocyclic group are optionally surrounded by one, two or more R groups. 1-1 replace.

[0033] In a preferred embodiment of the present invention, R 1 It is an 8-12-membered heteroaryl or an 8-13-membered heterocyclic group, wherein the 8-12-membered heteroaryl and the 8-13-membered heterocyclic group are optionally surrounded by one, two or more R groups. 1-1 replace.

[0034] In a preferred embodiment of the present invention, R 1 It consists of 5-12 heteroaryl groups.

[0035] In a preferred embodiment of the present invention, R 1 It consists of 9-10 heteroaryl compounds.

[0036] In a preferred embodiment of the present invention, each R 1-1 Halogen and C are independent of each other. 1-6 Alkyl, oxo (=O), -CN, C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl.

[0037] In a preferred embodiment of the present invention, each R 1-1 They can be halogen, methyl, ethyl, oxo (=O), -CN, cyclopropyl, cyclobutyl, heterocyclobutyl, azirrocyclobutyl, tetrahydropyrrole, or morpholino, independent of each other.

[0038] In a preferred embodiment of the present invention, each R 1-1 C is independent of each other. 1-6 Alkyl or oxo (=O).

[0039] In a preferred embodiment of the present invention, each R1-1 They are either methyl or oxo (=O) independently of each other.

[0040] In a preferred embodiment of the present invention, R 1 for

[0041] in,

[0042] Ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen;

[0043] One to three of X1, X2, X3, X4, X5 and X6 are nitrogen, and the rest are carbon, and one of X1, X2 and X5 can be arbitrarily -C=O or -C=S;

[0044] Alternatively, X2 does not exist, one or three of X1, X3, X4, X5 and X6 are nitrogen, the rest are carbon, and one of X1 and X5 can be arbitrarily -C=O or -C=S;

[0045] Alternatively, X1, X2, X3, X4, X5, and X6 are all carbon.

[0046] m can be 0, 1, 2, or 3;

[0047] p is 0, 1, 2 or 3;

[0048] Each R 1-1-1 Independently, H, deuterium, halogen, C 1-6 Alkyl, -OH, -CN, -COOH, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl;

[0049] Each R 1-1-2 Independently, H, deuterium, halogen, C 1-6 Alkyl, -OH, -CN, or -COOH;

[0050] When there are two adjacent R on the same ring 1-1-1 When, two adjacent R 1-1-1 Together with the ring atoms directly connected to it, they form C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic, or 5-6 membered heteroaryl; wherein the 4-6 membered heterocyclic and 5-6 membered heteroaryl groups have one or two heteroatoms selected from O, S, and N, and the number of heteroatoms is one or two;

[0051] When there are two adjacent R on the same ring 1-1-2 When, two adjacent R 1-1-2 Together with the directly connected ring atoms, they form C 3-6 cycloalkyl, C 3-6Cycloalkenyl, 4-6 membered heterocyclic, or 5-6 membered heteroaryl; wherein the 4-6 membered heterocyclic and 5-6 membered heteroaryl groups have one or two heteroatoms selected from O, S, and N, and the number of heteroatoms is one or two.

[0052] In a preferred embodiment of the present invention, R 1 for

[0053] Where m is 0, 1, 2 or 3;

[0054] p is 0, 1, 2 or 3;

[0055] Each R 1-1-1 Independently, H, deuterium, halogen, C 1-6 Alkyl, -OH, -CN, -COOH, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl;

[0056] Each R 1-1-2 Independently, H, deuterium, halogen, C 1-6 Alkyl, -OH, -CN or -COOH; or

[0057] When there are two adjacent R on the same ring 1-1-1 When, two adjacent R 1-1-1 Together with the ring atoms directly connected to it, they form C 3- 6-cycloalkyl or 4-6-membered heterocyclic groups;

[0058] When there are two adjacent R on the same ring 1-1-2 When, two adjacent R 1-1-2 Together with the ring atoms directly connected to it, they form C 3- 6-cycloalkyl or 4-6-membered heterocyclic group.

[0059] In a preferred embodiment of the present invention, R 1 for For example,

[0060] In a preferred embodiment of the present invention, R 1 for

[0061] In a preferred embodiment of the present invention, R 1 for

[0062] In a preferred embodiment of the present invention, R 2 and R 3 Each is independently H, halogen, C1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, and R 2 and R 3 Only one is H;

[0063] Preferably, the R 2 Or R 3 When the halogen is halogen, the halogen is F, Cl, Br or I, preferably F;

[0064] Preferably, the R 2 Or R 3 C 1-6 When alkyl, the C 1-6 Alkyl group is C 1-4 Alkyl groups, preferably methyl groups;

[0065] Preferably, the R 2 Or R 3 C 1-6 When alkoxy is present, the C 1-6 The alkoxy group is C 1-4 Alkyl groups, preferably methoxy groups;

[0066] Preferably, the R 2 Or R 3 C 3-6 When cycloalkyl, the C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl, preferably cyclopropyl.

[0067] In a preferred embodiment of the present invention, the R 2 For halogens, R 3 For H, or R 2 For H, R 3 It is a halogen.

[0068] In a preferred embodiment of the present invention, the R 2 For halogens, R 3 For H.

[0069] In a preferred embodiment of the present invention, R 2 For F, R 3 For H.

[0070] In a preferred embodiment of the present invention, R 4 The ring is a benzene ring, a naphthalene ring, a 5-10 membered heteroaryl group, or a 5-10 membered heterocyclic group, wherein the benzene ring, naphthalene ring, 5-10 membered heteroaryl group, and 5-10 membered heterocyclic group are optionally surrounded by one, two, or more R groups. 4-1 replace;

[0071] Each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C.1-3 Alkyl, oxo, -OH, -CN, -COOH, C 1-3 Haloalkyl, C 1-3 Alkoxy, phenyl, C 3-6 Cycloalkyl, 5-8 membered heteroaryl or 4-6 membered heterocyclic, wherein C 1-3 Alkyl, C 1-3 Alkoxy, phenyl, C 3-6 Cycloalkyl, 5-8-membered heteroaryl, and 4-6-membered heterocyclic groups are optionally surrounded by one, two, or more elements selected from H, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 The alkoxy group is replaced by a substituent.

[0072] In a preferred embodiment of the present invention, R 4 The phenyl, pyrroloyl, pyrazolyl, imidazoyl, pyrimidinyl, pyrazinyl, thiophenyl, pyridyl, naphthyl, tetrahydronaphthyl, indene, indazole, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, benzo[d]oxazolyl, benzo[2,3-d]pyrimidine, benzodihydropyranyl, or dihydrobenzofuranyl; the phenyl, pyrroloyl... The following groups are optionally represented by one, two, or three R groups: pyrazolyl, pyrazolyl, imidazolyl, pyrimidinyl, thiophene, pyridinyl, naphthyl, tetrahydronaphthyl, indole, indazole, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, benzo[d]oxazolyl, benzo[2,3-d]pyrimidine, benzodihydropyranyl, and dihydrobenzofuranyl. 4-1 Replace; and / or,

[0073] Each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-3 Alkyl, oxo, -OH, -CN, -COOH, C 1-3 Haloalkyl, C 1-3 Alkoxy, phenyl, C 3-6 Cycloalkyl, 5-8 membered heteroaryl or 4-6 membered heterocyclic, wherein C 1-3 Alkyl, C 1-3 Alkoxy, phenyl, C 3-6 Cycloalkyl, 5-8-membered heteroaryl, and 4-6-membered heterocyclic groups are optionally surrounded by one, two, or more elements selected from H, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 The alkoxy group is replaced by a substituent.

[0074] In a preferred embodiment of the present invention, R 4 C 6-10 Aryl, the C6-10 aryl groups are bound by one, two or more R groups. 4-1 Replace; for example, R 4 For not replaced or by one or more R 4-1 Substituted benzene rings; for example, R 4 For one or more R 4-1 Substituted benzene ring.

[0075] In a preferred embodiment of the present invention, R 4-1 It is a halogen on its own.

[0076] In a preferred embodiment of the present invention, R 4 The phenyl group is optionally surrounded by one, two, or three R groups. 4-1 Replace; each R 4- 1 Independently, it is H, halogen, methyl, -CN, -CF3, -OCF3, -OCHF2, phenyl, cyclopropyl, pyrazolyl, or oxazolyl, wherein the phenyl, cyclopropyl, pyrazolyl, or oxazolyl group is optionally selected by one, two, or three from H, halogen, C, ... 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 Substituents of alkoxy groups;

[0077] In a preferred embodiment of the present invention, each R 4-1 Independently, it is H, halogen, methyl, -CN, -CF3, -OCF3, -OCHF2, cyclopropyl, or oxazolyl, wherein the cyclopropyl and oxazolyl groups are optionally selected from H, halogen, C, ... 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkoxy group is replaced by a substituent.

[0078] In a preferred embodiment of the present invention, R 4 for

[0079] Each q is independently 0, 1, 2 or 3;

[0080] Each R 4-1 Independently, it is H, halogen, methyl, -CN, -CF3, -OCF3, -OCHF2, phenyl, cyclopropyl, pyrazolyl, or oxazolyl, wherein the phenyl, cyclopropyl, pyrazolyl, or oxazolyl group is optionally selected by one, two, or three from H, halogen, C, ... 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 The alkoxy group is replaced by a substituent.

[0081] In a preferred embodiment of the present invention, each R4-1 Independently, it is H, halogen, methyl, -CN, -CF3, -OCF3, -OCHF2, cyclopropyl, pyrazolyl, or oxazolyl, wherein the cyclopropyl, pyrazolyl, and oxazolyl groups are optionally selected by one, two, or three from H, halogen, C, ... 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 The alkoxy group is replaced by a substituent.

[0082] In a preferred embodiment of the present invention, R 4 For not replaced or by one, two or more R 4-1 The following groups are substituted: phenyl or pyridyl.

[0083] In a preferred embodiment of the present invention, R 4 for

[0084] In a preferred embodiment of the present invention, R 4 for

[0085] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula II:

[0086] in,

[0087] Ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen;

[0088] One or three of X1, X2, X3, X4 and X6 are nitrogen, and the rest are carbon;

[0089] m is 0, 1, or 2;

[0090] p is 0, 1, or 2;

[0091] R 1-1-1 and R 1-1-2 Each independently possesses the definition described in any of the aforementioned preferred embodiments, R 2 R 3 and R 4 Each has independently the definition described in any of the aforementioned preferred embodiments; when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration, or a mixture thereof.

[0092] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula II-2:

[0093] Among them, rings A, X1, X2, X3, X4, X6, and R 1-1-1R 1-1-2 R 4-1 m, p, q, R 2 and R 3 Each has independently the definition described in any of the aforementioned preferred embodiments.

[0094] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula II-2:

[0095] In this ring, ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen;

[0096] One or three of X1, X2, X3, X4 and X6 are nitrogen, and the rest are carbon;

[0097] m is 0, 1, or 2;

[0098] p is 0, 1, or 2;

[0099] R 1-1-1 R 1-1-2 R 2 and R 3 Each has independently the definition described in any of the aforementioned preferred embodiments; when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration, or a mixture thereof.

[0100] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula II-2-1 or II-2-2:

[0101] in,

[0102] Ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen;

[0103] One or two of X1, X2, X3, and X4 are nitrogen, and the rest are carbon;

[0104] q is 0, 1, 2, or 3;

[0105] m is 0, 1, or 2;

[0106] p is 0, 1, or 2;

[0107] R 1-1-1 and R 1-1-2 Each has independently the definition described in any of the aforementioned preferred embodiments.

[0108] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula II-1:

[0109] in,

[0110] Ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen;

[0111] One or two of X1, X2, X3, and X4 are nitrogen, and the rest are carbon;

[0112] q is 0, 1, 2, or 3;

[0113] m is 0, 1, or 2;

[0114] p is 0, 1, or 2;

[0115] R 1-1-1 and R 1-1-2 Each independently possesses the definition described in any of the aforementioned preferred embodiments, R 4-1 Each has independently the definition described in any of the aforementioned preferred embodiments; when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration, or a mixture thereof.

[0116] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in any of the structural formulas II-1-a to II-1-h:

[0117] in,

[0118] Ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen;

[0119] One or two of X1, X2, X3, and X4 are nitrogen, and the rest are carbon;

[0120] q is 0, 1, 2, or 3;

[0121] m is 0, 1, or 2;

[0122] p is 0, 1, or 2;

[0123] R 1-1-1 and R 1-1-2 Each independently possesses the definition described in any of the aforementioned preferred embodiments, R 4-1 Each has independently the definition described in any of the aforementioned preferred embodiments.

[0124] In a preferred embodiment of the present invention, ring A is a five- or six-membered heteroaryl ring, X1 is carbon, X2 is N, X3 is carbon or N, X4 is carbon, X5 is -C=O, and X6 is N.

[0125] In a preferred embodiment of the present invention, m is 0, 1, or 2; for example, it is 0 or 1.

[0126] In a preferred embodiment of the present invention, R 1-1-1 Halogen, C 1-6Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl; or, when two adjacent Rs exist on the same ring. 1-1-1 When, two adjacent R 1-1-1 Together with the ring atoms directly attached to it, they form 4-6 membered heterocyclic groups; for example, R 1-1-1 C 1-6 alkyl.

[0127] In a preferred embodiment of the present invention, R 1-1-1 Halogen, C 1-3 Alkyl, C 3-4 Cycloalkyl or 4-6 membered heterocyclic alkyl; or, when two adjacent Rs exist on the same ring. 1-1-1 When, two adjacent R 1-1-1 Together with the ring atoms directly attached to it, they form 4-6 membered heterocyclic groups; for example, R 1-1-1 C 1-3 alkyl.

[0128] In a preferred embodiment of the present invention, p is 0, 1 or 2, for example, 1.

[0129] In a preferred embodiment of the present invention, R 1-1-2 C 1-6 Alkyl or -CN, or, when two adjacent Rs are present on the same ring. 1-1-2 When, two adjacent R 1-1-2 Together with the directly attached ring atoms, they form 4-6 membered heterocyclic groups; for example, R 1-1-2 C 1-6 Alkyl; for example, R 1-1-2 C 1-3 alkyl.

[0130] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure represented by Formula III.

[0131] When the carbon atom marked with "*" is a chiral carbon atom, it indicates the R configuration, S configuration, or a mixture thereof;

[0132] q is 0, 1, 2, or 3;

[0133] m is 0, 1, or 2;

[0134] p is 0 or 1; each R 1-1-1 Independently, H, deuterium, halogen, C 1-3 Alkyl, C 3-5 cycloalkyl or 4-6 membered heterocyclic alkyl;

[0135] Each R 1-1-2 Independently, H, deuterium, halogen, C 1-6 Alkyl or -OH;

[0136] Each R 4-1 Independent of H, halogen or C 1-6 alkyl.

[0137] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in III-1 or III-2:

[0138] q is 0, 1, or 2;

[0139] m is 0, 1, or 2;

[0140] p is 0 or 1;

[0141] Each R 1-1-1 Independently, it is H, deuterium, halogen, methyl, cyclopropyl, oxetyl, tetrahydropyrrolyl, or morpholinyl; each R 1-1-2 Independently, it can be H, deuterium, halogen, methyl, or -OH;

[0142] Each R 4-1 It can be H, halogen, or methyl on its own.

[0143] In a preferred embodiment of the present invention, the compound represented by Formula I is any of the following compounds:

[0144] In a preferred embodiment of the present invention, the compound represented by Formula I is any of the following compounds:

[0145] In a preferred embodiment of the present invention, the compound represented by Formula I preferably has the structure represented by Formula 1-A:

[0146] In a preferred embodiment of the present invention, compound 1-A has a crystalline form, wherein the crystal system of the crystalline form is monoclinic, the space group is P21, and the cell parameters are:

[0147] In a preferred embodiment of the present invention, the compound represented by Formula I is preferably any of the following compounds:

[0148] The present invention also provides a method for preparing the compound shown in Formula II-1, comprising the following steps: in a solvent, in the presence of an organic base, subjecting the compound shown in Formula II-1-A to a substitution reaction with the compound shown in Formula II-1-B to obtain the compound shown in Formula II-1:

[0149] Where X is a halogen,

[0150] Ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen;

[0151] One or two of X1, X2, X3 and X4 are nitrogen, and the other X1, X2, X3 and X4 are carbon;

[0152] q is 0, 1, 2, or 3;

[0153] m is 0, 1, or 2;

[0154] p is 0, 1, or 2;

[0155] R 1-1-1 and R 1-1-2 Each independently possesses the definition described in any of the aforementioned preferred embodiments, R 4-1 It independently possesses the definition described in any of the aforementioned preferred embodiments.

[0156] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I of the present invention, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or a pharmaceutically acceptable salt or solvate thereof.

[0157] In a preferred embodiment of the present invention, the pharmaceutical composition of the present invention further comprises a therapeutically effective amount of the compound of formula I of the present invention, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

[0158] The carrier in the pharmaceutical composition is pharmaceutically acceptable, compatible with (and preferably stabilizing) the active ingredient of the composition, and not harmful to the treated subject. One or more pharmaceutical excipients may be used to deliver the active compound.

[0159] The present invention further provides the use of the compound represented by Formula I, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate in the preparation of a medicament, or the use of the pharmaceutical composition of any of the preceding preferred embodiments in the preparation of a medicament.

[0160] In a preferred embodiment of the present invention, the drug is a drug for diagnosing and / or treating TRPA1-mediated diseases or conditions.

[0161] The present invention further provides the use of the compound of Formula I, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, and their pharmaceutically acceptable salts or solvates, or the pharmaceutical composition thereof, in the preparation of a TRPA1 inhibitor medicament.

[0162] In a preferred embodiment of the present invention, the TRPA1-mediated diseases or conditions include respiratory diseases, pain, inflammatory diseases, pruritus, gastrointestinal diseases, metabolic diseases, cardiovascular diseases, kidney diseases, neurodegenerative diseases, central nervous system diseases, fibrotic diseases, urinary system diseases, cancer, or mental disorders.

[0163] The respiratory diseases mentioned include: chronic cough, acute cough, subacute cough, bronchitis, asthma, chronic obstructive pulmonary disease (COPD), rhinitis, chronic pulmonary occlusion, sleep apnea, or idiopathic pulmonary fibrosis (IPF).

[0164] The pain includes: acute pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, inflammatory pain, back pain, endometriosis pain, visceral pain, cancer pain, hyperesthesia, neuralgia, migraine, fibromyalgia, or gout;

[0165] The neuralgia mentioned includes: sciatica, trigeminal neuralgia, and postherpetic neuralgia (shingles);

[0166] The inflammatory pain includes: rheumatoid arthritis pain and osteoarthritis pain;

[0167] The inflammatory diseases mentioned include: inflammatory disorders, esophagitis, cystitis, arthritis (e.g., rheumatoid arthritis), atopic dermatitis, or psoriasis, etc.

[0168] The gastrointestinal diseases mentioned include esophageal reflux disease (GERD), inflammatory bowel disease (IBD), irritable bowel syndrome, ulcerative colitis, Crohn's disease, or gastroduodenal ulcers;

[0169] The metabolic-related diseases include diabetes, obesity, or insulin resistance;

[0170] The cardiovascular-related diseases mentioned include heart failure, myocardial ischemia-reperfusion, myocardial fibrosis, arrhythmia, atherosclerosis, hypertension, myocardial infarction, etc.

[0171] The kidney diseases mentioned include acute kidney injury, diabetic nephropathy, and renal ischemia-reperfusion.

[0172] The neurodegenerative diseases mentioned include Alzheimer's disease, Parkinson's disease, epilepsy, brain injury, etc.

[0173] The cancers mentioned include lung cancer, pancreatic cancer, melanoma, etc.

[0174] In a preferred embodiment of the present invention, the TRPA1-mediated diseases or conditions include respiratory diseases, pain, inflammatory diseases, gastrointestinal diseases, or cardiovascular diseases.

[0175] The respiratory diseases mentioned are chronic cough, acute cough, subacute cough, chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF);

[0176] The pain is acute pain, chronic pain, neuropathic pain, neuralgia, or migraine.

[0177] The inflammatory disease mentioned is atopic dermatitis or psoriasis;

[0178] The gastrointestinal disease mentioned is inflammatory bowel disease (IBD), irritable bowel syndrome, or ulcerative colitis;

[0179] The cardiovascular-related diseases mentioned include heart failure, myocardial ischemia-reperfusion, myocardial fibrosis, arrhythmia, atherosclerosis, hypertension, or myocardial infarction.

[0180] In a preferred embodiment of the present invention, the TRPA1-mediated disease or condition is a respiratory disease, pain, inflammatory disease, pruritus, gastrointestinal disease, or cardiovascular disease.

[0181] In a preferred embodiment of the present invention, the TRPA1-mediated diseases or conditions include chronic cough, acute cough, subacute cough, bronchitis, asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, pain, sleep apnea, gastrointestinal diseases, pruritus, or urinary incontinence.

[0182] In a preferred embodiment of the present invention, the TRPA1-mediated diseases or conditions also include neuropathy (chemotherapy-induced neuropathy, diabetic neuropathy, HIV-related neuropathy), eye irritation, skin irritation (atopic dermatitis), frostbite, spasms, tension syndrome, generalized rigidity, nerve damage, ischemia, stroke, multiple sclerosis, pelvic allergy, burns, psoriasis, eczema, or vomiting, etc.

[0183] In a preferred embodiment of the present invention, the drug is a TRPA1 inhibitor.

[0184] The present invention also provides a method for diagnosing, preventing and / or treating TRPA1-mediated diseases or conditions, the method comprising administering, alone, a therapeutically effective amount of at least one compound of the present invention to a patient requiring such treatment, administering to a patient requiring such treatment a composition of one compound of the present invention and optionally another compound of the present invention, and / or administering to a patient requiring such treatment a composition of one compound of the present invention and at least one other type of therapeutic agent.

[0185] In the method for diagnosing, preventing and / or treating TRPA1-mediated diseases or conditions according to the present invention, the disease or condition is all or part of the specific disease described in any embodiment of the present invention.

[0186] The compounds of the present invention can be used in combination with other therapeutic agents. Beneficial effects:

[0187] The positive and progressive effects of this invention are as follows: This invention provides a compound represented by Formula I, which has excellent TRPA1 inhibitory activity, as well as excellent pharmacokinetic and pharmacodynamic properties.

[0188] Terminology Definitions and Explanations

[0189] The definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the embodiments, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0190] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0191] In this document, a hyphen "-" may be added before the substituents used to indicate that the named substituent is linked to the parent moiety by a single bond. When the linking groups listed in this invention do not specify their linking direction, the linking direction is the same as the reading order from left to right.

[0192] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or groups. Alternatively, it can mean the replacement of the lone pair of electrons on an atom by another atom or group; for example, the lone pair of electrons on a sulfur atom can be replaced by an oxygen atom to form a hydrogen atom. The H atom that is substituted in the molecule can be on a C atom or an N atom. Even if H is drawn on -N-, it can be replaced by other different atoms or groups, such as... Also includes

[0193] When any variable (e.g., R) 1-1 When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by one, two, or three R... 1-1 Group substitution, meaning that the group can be replaced by up to 3 R groups. 1-1 Replace, the position R 1-1 Definition and other positions R 1-1 The definitions are mutually independent. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0194] In the general formula definition of this application, the term "optionally" (or "optionally", "optionally") means that it is substituted by 0, 1, 2 or more substituents. For example, "optionally substituted by 1, 2 or more R" means that it may not be substituted by R (no substitution) or may be substituted by 1, 2 or more R.

[0195] Term "C" n-m "and "C n -C m ", where n and m are integers, representing a group containing n to m carbon atoms. Examples include C 1-6 C 1-4 The term is intended to explicitly disclose each member within that scope, namely C. n C n+1 C n+2 ......C m-2 C m-1 C m For example, C 1-6 The intention is to disclose C1, C2, C3, C4, C5, and C6. "C" n-m The meaning of "C" is the same as "C". n -C m "same.

[0196] The term "n-ary", where n is an integer, usually describes the number of ring atoms in which n are formed.

[0197] The term "nm-aryl" refers to a cyclic ring in which n and m are integers, describing the number of ring-forming atoms in a range from n to m. For example, piperidinyl is an example of a 6-membered heterocyclic alkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, and pyridinyl is an example of a 6-membered heteroaryl ring.

[0198] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-10" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0199] Unless otherwise stated, “multiple” means three or more, such as 3, 4, 5, 6, 7, 8 or 9.

[0200] Term "C" 1-6 "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The C 1-6 Alkyl groups include C 1-3 Alkyl, C 1-4 Alkyl, C 3-4 Alkyl, C 4-6 Alkyl groups, etc. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc., or their isomers.

[0201] Term "C" 1-6 "Halogenated alkyl" refers to an alkyl group as defined above, which is substituted with one, two, or more halogens as defined above. Examples of halogenated alkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, or 1-bromomethyl-2-bromoethyl.

[0202] Term "C" 1-6 "Alkyloxy" indicates a C-type carbon bonded by an oxygen bridge. 1-6 Alkyl; the C 1-6 The definition of alkyl is the same as above. Examples of alkoxy groups include, but are not limited to, methoxy and ethoxy groups.

[0203] Term "C" 3-10 "Cycloalkyl" refers to a monovalent or polyvalent cyclic alkane having 3-10 carbon atoms, including monocyclic, bicyclic, or tricyclic alkanes, wherein the bicyclic and tricyclic alkanes include fused rings, bridged rings, or spirocyclic rings. The C 3-10 Cycloalkyl groups include C 3-8 cycloalkyl, C3-6 cycloalkyl, C 4-6 cycloalkyl, C 3-5 cycloalkyl, C 3-4 cycloalkyl, C 5-6 Cycloalkyl groups, etc. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0204] The term "4-10 membered heterocyclic alkyl" refers to a saturated cyclic group having 4 to 10 ring atoms, wherein the ring atoms include at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. It can be a monocyclic, bicyclic, or tricyclic system, wherein bicyclic and tricyclic systems can be fused rings, bridged rings, or spirocyclic systems. Preferably, the number of heteroatoms in the heterocyclic alkyl group is 1, 2, or 3. The carbon atoms and heteroatoms of the heterocyclic alkyl group may optionally be oxidized to form oxo or sulfide groups or other oxidized bonds (e.g., C(=O), S(=O), S(=O)2, or N-oxides, etc.), or the nitrogen atom may be quaternized. Preferably, N and S may also optionally be oxidized to various oxidation states to form oxyoxides, -S(=O)-, or -S(=O)2- states. The 4-10 membered heterocyclic alkyl groups include 3-6 membered heterocyclic alkyl groups, 3-8 membered heterocyclic alkyl groups, 5-7 membered heterocyclic alkyl groups, 5-10 membered heterocyclic alkyl groups, 9-10 membered heterocyclic alkyl groups, 5 membered heterocyclic alkyl groups, etc. The heterocyclic alkyl groups can be linked to other segments or groups in the compound through cyclic carbon atoms or cyclic heteroatoms.

[0205] The term "4-10 membered heterocyclic alkenyl" refers to a monocyclic, bicyclic, or tricyclic system containing 4-10 ring atoms, comprising a partially unsaturated alkenyl group. The ring atoms include a carbon atom and at least one heteroatom selected from nitrogen, sulfur, and oxygen atoms, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(=O)-, or -S(=O)2- states. The heterocyclic alkenyl group is generally non-aromatic and may be benzofused, such as benzo[d][1,3]m-dioxacyclopentenyl. Unless otherwise stated, the heterocyclic alkenyl group may be carbon-based or nitrogen-based, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocyclic alkenyl group is preferably a 5-9 membered heterocyclic alkenyl group.

[0206] Term "C" 6-10 "Aryl" refers to a monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, or 10 carbon atoms, wherein at least one ring in the bicyclic or tricyclic system is aromatic, such as tetrahydronaphthyl. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, and dihydroindenyl.

[0207] The term "5-12-membered heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 5-12 ring atoms, wherein the ring atoms comprise 1-5 (e.g., 1, 2, or 3) heteroatoms independently selected from N, O, and S, and the bicyclic and tricyclic aromatic ring systems may be fused rings. The 5-12-membered heteroaryl includes 5-7-membered heteroaryl, 5-10-membered heteroaryl, 7-12-membered heteroaryl, 9-10-membered heteroaryl, 5-membered heteroaryl, 9-membered heteroaryl, etc., wherein the 9-membered heteroaryl represents a monocyclic aromatic ring system having 9 ring atoms, wherein the ring atoms comprise 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the bicyclic or tricyclic aromatic ring system may be fused rings. Preferably, the 9-10-membered heteroaryl comprises 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S heteroatoms. Examples of the heteroaryl group include, but are not limited to, oxazolyl, isoxazolyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl. Preferably, the 7-12-membered heteroaryl group contains 1-3 heteroatoms; more preferably, it contains 4 heteroatoms. Additionally, in each case, the 7-12-membered heteroaryl group may be benzofused. Examples of the heteroaryl group include, but are not limited to, imidazo[4,5-d]pyridazinyl, imidazo[5,1-f][1,2,4]triazinyl, imidazo[1,5-a][1,3,5]triazinyl, imidazo[1,2-a][1,3,5]triazinyl, imidazo[1,2-a][1,3,5]triazinyl, imidazo[1,3-]pyridinyl (e.g., imidazo[4,5-c]pyridinyl, imidazo[4,5-b]pyridinyl), pyrazolo[5,1-f][1,2,4]triazinyl (e.g., pyrazolo[5,1-f][1,2,4]triazinyl), and pyridopyridazinyl (e.g., pyrido[2,3- [d]pyridazinyl, pyrido[3,4-d]pyridazinyl, pyrido[4,3-c]pyridazinyl, pyrido[3,4-b]pyrazinyl, [1,2,3]triazolo[4,5-c]pyridinyl, furano[3,4-d]pyrimidinyl, isothiazolo[3,4-d]pyrimidinyl, thiazo[4,5-d]pyrimidinyl, isoxazolo[3,4-d]pyrimidinyl, isoxazolo[5,4-d]pyrimidinyl, benzo[d]imidazolyl, pyrido[2,3-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, etc. When the 5-12 member heteroaryl group is substituted, there are no restrictions on the substitution site. For example, the hydrogen atom bonded to the carbon atom on the heteroaryl ring can be substituted, or the hydrogen atom bonded to the heteroatom on the heteroaryl ring can be substituted.

[0208] The term "4-13 membered heterocyclic group" refers to a saturated or partially unsaturated non-aromatic ring or ring system having 4-13 ring atoms, and whose ring atoms contain 1-5 heteroatoms selected from O, S, and N, wherein N and S can optionally be oxidized to various oxidation states to form nitrides, -S(=O)-, or -S(=O)2- states. The 4-13 membered heterocyclic group includes 5-13 membered heterocyclic groups, 4-10 membered heterocyclic groups, 10-13 membered heterocyclic groups, 12-13 membered heterocyclic groups, etc. The 4-13 membered heterocyclic group includes 4-13 membered heterocyclic alkyl groups and 4-13 membered heterocyclic alkenyl groups, which can be 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, or 10-membered bicyclic, or 10-13 membered tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include fused rings, bridged rings, or spirocyclic. Preferably, the 12-13 membered heterocyclic group comprises 1, 2, 3, or 4 N atoms and 0, 1, or 2 O or S heteroatoms. The heterocyclic group can be connected to the remainder of the molecule via any one carbon or nitrogen atom on its ring (if present). Examples of heterocyclic groups include, but are not limited to: azirrobutyl, oxacyclobutyl, tetrahydrofuranyl, dioxacyclopentenyl, 2,3-dihydro-1H-imidazolyl, pyrrolyl, imidazolyl, pyrazoleyl, pyrrolinyl, dihydrofuranyl, dihydropyranyl, tetrahydropyranyl, dihydropyridyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, trithiaalkyl, 3,5,7,8-tetrahydro-4H-furano[2,3-b]imidazolium. The heterocyclic group may be benzo[4,5-d]pyridinyl, 6,8-dihydro-3H-furano[3,4-b]imidazo[4,5-d]pyridinyl, 3,5,6,7-tetrahydro-4H-furano[3,2-b]imidazo[4,5-d]pyridinyl, 7,8-dihydrofurano[2',3':4,5]pyrido[3,2-d]pyrimidinyl, 8,9-dihydrofurano[3',2':4,5]pyrido[3,2-d]pyrimidinyl, etc. Optionally, the heterocyclic group may be benzo[d][1,3]m-dioxacyclopentenyl.

[0209] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0210] The term "halogenation" refers to the replacement of a substance with one, two, or more halogens.

[0211] Unless otherwise stated, the term "hydrogen" refers to the hydrogen atom portion (-H), not H2.

[0212] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0213] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0214] The term "bridged ring" refers to a ring system in which two rings share two or more cyclic atoms.

[0215] Those skilled in the art will understand that the compounds shown in formula (I) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0216] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0217] The compounds described herein may include all stereoisomers of the compounds. The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule. All stereoisomers of the compounds of this invention constitute a part of this invention, including but not limited to enantiomers, diastereomers, cis-trans isomers, and conformational isomers, as well as mixtures thereof, such as racemic mixtures.

[0218] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key Represents the absolute configuration of the center of a solid. Uses straight solid lines as keys. and straight dashed key It indicates the relative configuration of a stereocenter, such as the cis-trans configuration of alicyclic compounds.

[0219] In this invention, in some cases, the stereochemistry has not been determined or has been provisionally assigned. Depending on their molecular structure, the compounds of this invention can be chiral (having one, two, or more stereocenters), and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of this invention encompass isomers of each chiral carbon in the R or S configuration, or mixtures thereof, or racemates. The compounds of this invention or intermediates thereof can be isolated as enantiomers by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. Racemic mixtures are reacted with optically active resolving agents to yield diastereomers. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0220] In some embodiments, the compounds of the present invention have an (R)-configuration. In other embodiments, the compounds have an (S)-configuration. In compounds having more than one chiral center, each chiral center in the compound may be independently (R) or (S), unless otherwise stated.

[0221] Some compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, regioisomers and individual isomers (e.g., individual enantiomers) are all included within the scope of the present invention.

[0222] The compounds described herein may also include tautomer forms. The term "tautomer" refers to an isomer resulting from the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomer forms include proton-shift tautomers, which are isomeric protonated states having the same empirical formula and total charge. Examples of proton-shift tautomers include keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomer forms can be in equilibrium or spatially locked into one form through appropriate substitution.

[0223] The compounds described herein may also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0224] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0225] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0226] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms).

[0227] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0228] The term "pharmaceutical acceptable" means that salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for patient use.

[0229] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids. The pharmaceutically acceptable acids include organic acids. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts.

[0230] The term "solvent" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in the solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0231] As described above, the terms "pharmaceutically acceptable salt" and "solvent" in the term "solvent of a pharmaceutically acceptable salt" refer to substances formed by combining the compounds of the present invention with 1) a substance prepared with a relatively non-toxic, pharmaceutically acceptable acid or base, or 2) a stoichiometric or non-stoichiometric solvent. The "solvent of a pharmaceutically acceptable salt" includes, but is not limited to, hydrochloric acid monohydrates of the compounds of the present invention.

[0232] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0233] The reagents and raw materials used in this invention are all commercially available. Attached Figure Description

[0234] Figure 1 is a thermo-ellipsoidal diagram of the molecular stereostructure of compound 1-A. Detailed Implementation

[0235] The present invention is further illustrated below by way of examples, but these examples do not limit the invention to the scope of the embodiments described. Experimental methods in the following examples, unless otherwise specified, are performed according to conventional methods and conditions, or as selected in the product instructions. The preparation methods included in the following examples are merely illustrative of the operational procedures for that step; the raw materials used in the next step can be prepared in multiple batches using the same method.

[0236] The terms used in the following specific experimental descriptions represent (unless otherwise stated) the following reagents or procedures:

[0237] TFA: Trifluoroacetic acid; TBAF: Tetrabutylammonium fluoride; DMF: N,N-Dimethylformamide; MTBE: Methyl tert-butyl ether; DCM: Dichloromethane; EDCI: Carbodiimide hydrochloride; TMSCN: Trimethylcyanosilane; TEA: Triethylamine; THF: Tetrahydrofuran; [Ir(COD)Cl]2: 1,5-Cyclooctadiene iridium chloride dimer; HOBt: Hydroxybenzotriazole; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate; m-CPBA: 4-Chloro-3-nitrobenzoic acid; DIEA: N,N-Diisopropylethylamine; IPA: Isopropanol; PE: Petroleum ether; EA: Ethyl acetate; NEU: Neutral; HEX: n-Hexane; po: Oral; iv: Tail vein bolus;

[0238] <Preparation Examples>

[0239] Preparation Example 1: Preparation of Intermediates 1-8

[0240] Step 1: Synthesis of Intermediate 1-1

[0241] Weigh 16 g (113.82 mmol) of 4-chlorobenzaldehyde into a reaction flask, dissolve it in 50 mL of THF, purge with nitrogen three times, add 341.46 mL (341.46 mmol) of propenyl magnesium chloride at 0 °C, and react at room temperature for 2 h. At 0 °C, pour the reaction solution into 100 mL of saturated ammonium chloride aqueous solution, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with 200 mL of saturated sodium chloride aqueous solution, dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (PE:EA = 6:1) to give intermediate 1-1 (16 g).

[0242] Step 2: Synthesis of intermediates 1-2

[0243] Weigh 16 g (87.60 mmol) of intermediate 1-1 into a reaction flask, dissolve it in 160 mL of DCM, and then add 17.01 g (98.55 mmol) of m-chloroperoxybenzoic acid at 0 °C. React at room temperature for 2 h. Quench the reaction mixture in 100 mL of saturated sodium sulfite aqueous solution at 0 °C, extract with ethyl acetate (80 mL × 3), combine the organic phases, wash with 200 mL of saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate 1-2 (15 g).

[0244] Step 3: Synthesis of intermediates 1-3

[0245] Intermediate 1-2 (15 g, 75.51 mmol) was weighed into a reaction flask, dissolved in 1,4-dioxane (1500 mL), and then concentrated sulfuric acid (7.41 g, 75.51 mmol) was slowly added. The reaction mixture was reacted at 50 °C for 16 h. The pH of the reaction mixture was adjusted to approximately 7 by adding saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate 1-3 (9 g).

[0246] Step 4: Synthesis of intermediates 1-4

[0247] Intermediate 1-3 (9 g, 45.31 mmol) was weighed into a reaction flask, dissolved in DCM (100 mL), and then oxidized with Desmartin (38.43 g, 90.61 mmol) at 0 °C. The reaction was allowed to proceed at room temperature for 2 h. At 0 °C, the reaction was quenched by adding saturated sodium sulfite aqueous solution (200 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate 1-4 (10 g).

[0248] Step 5: Synthesis of intermediates 1-5

[0249] Intermediate 1-4 (300 mg, 1.53 mmol) was weighed into a reaction flask, dissolved in DCM (10 mL), followed by the addition of trimethylsilane (227.69 mg, 2.29 mmol) and boron trifluoride diethyl ether (217.15 mg, 1.53 mmol). The reaction was allowed to proceed at room temperature for 2 h. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution (20 mL), and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. A pair of diastereomers were obtained, the first spot being R. f =0.4 (dichloromethane: methyl tert-butyl ether = 30:1) is not the target compound, the second point R f =0.3 (dichloromethane: methyl tert-butyl ether = 30:1) as intermediate 1-5 (250mg).

[0250] Intermediate 1-5 includes 1-5-1 and 1-5-2.

[0251] Step 6: Synthesis of intermediates 1-6

[0252] Weigh intermediate 1-5 (90 mg, 0.40 mmol) into a reaction flask, dissolve it in DCM (3 mL), cool to -78 °C, add diethylaminotrifluoride (0.26 g, 1.6 mmol), maintain the reaction at -78 °C for 1 hour, then react at 0 °C for 1 hour. Quench the reaction with saturated sodium bicarbonate aqueous solution (20 mL), extract with ethyl acetate (200 mL × 3), combine the organic phases, wash with saturated sodium chloride aqueous solution (80 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (PE:EA = 5:1) to obtain intermediate 1-6 (75 mg).

[0253] Intermediate 1-6 includes 1-6-1 and 1-6-2.

[0254] Step 7: Synthesis of intermediates 1-7

[0255] Intermediate 1-7 (0.02 g, 0.089 mmol) was weighed into a reaction flask, dissolved in 2 mL of EtOH, and then reacted with 0.024 g, 0.36 mmol of hydroxylamine aqueous solution at 80 °C for 5 h. The reaction mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with 10 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was used directly in the next step. Intermediate 1-7 (0.075 g) was obtained. LC-MS: [M+H] + =259.00.

[0256] Intermediate 1-7 includes 1-7-1 and 1-7-2.

[0257] Step 8: Synthesis of intermediates 1-8

[0258] Intermediate 1-7 (0.06 g, 0.231 mmol) was weighed into a reaction flask, dissolved in methyl tert-butyl ether (3 mL), and then chloroacetic anhydride (0.012 g, 0.069 mmol) was added at 0 °C. The reaction mixture was reacted at room temperature for 2 h. The reaction solution was quenched by adding saturated sodium bicarbonate aqueous solution (10 mL), and extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was used directly in the next step. Toluene (2 mL) was added to the residue to dissolve it, followed by the addition of 4A molecular sieve (1 g). After purging with nitrogen three times, the reaction mixture was reacted at 100 °C for 5 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain intermediate 1-8 (0.07 g). LC-MS: [M+H] + =317.00.

[0259] Intermediate 1-8 includes 1-8-1 and 1-8-2.

[0260] Preparation Example 2: Preparation of Intermediates 1-9

[0261] Step 1: Synthesis of intermediate S-1

[0262] Sodium bis(trimethylsilyl)amino (161 mL, 161.00 mmol, 1 M) was measured into a reaction flask, and tetrahydrofuran (240 mL) was added to replace the nitrogen atmosphere. The mixture was cooled to 0 °C, and a tetrahydrofuran (240 mL) solution of 4,6-dichloro-2-methylpyrimidin-5-amine (23.90 g, 134.25 mmol) was slowly added to the reaction solution. The mixture was stirred at 0 °C for 1 hour. Then, iodomethane (10 mL, 161.00 mmol) was added dropwise to the reaction solution at 0 °C. After the addition was complete, the reaction solution was allowed to react at room temperature for 2 hours. The reaction solution was quenched by pouring it into a saturated ammonium chloride aqueous solution (100 mL), and then extracted with ethyl acetate (300 mL × 3). The organic phases were combined and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain intermediate S-1 (25.00 g).

[0263] Step 2: Synthesis of intermediate S-2

[0264] Intermediate S-1 (10.50 g, 54.67 mmol) was dissolved in ethanol (40 mL), followed by the addition of ammonium hydroxide (75.20 mL, 546.70 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was then cooled to 0 °C and stirred for 1 hour, resulting in the formation of a large amount of solid. The solid was filtered, and the filter cake was washed with cold ethanol (10 mL). The filter cake was dried to give intermediate S-2 (4.89 g). LC-MS: [M+H] + =173.00.

[0265] Step 3: Synthesis of intermediates 1-9

[0266] Intermediate S-2 (14.10 g, 81.68 mmol) was weighed into a reaction flask, followed by the addition of formic acid (24.65 mL, 653.44 mmol) and triethyl orthoformate (135.86 mL, 816.80 mmol). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate (60 mL) was added to the residue for slurry preparation. The mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL). The filter cake was dried to obtain intermediate 1-9 (12.00 g).

[0267] Example 1: Preparation of Compound 1, Compound 1-A and Compound 1-B

[0268] Step 1: Synthesis of Compound 1

[0269] Intermediates 1-8 (0.07 g, 0.22 mmol) were weighed into a reaction flask and dissolved in DMF (2 mL). Then, intermediates 1-9 (0.054 g, 0.33 mmol) were added. Under nitrogen protection, the mixture was cooled to 0 °C, and potassium carbonate (0.091 g, 0.66 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, filtered, and the filtrate was purified by high-performance liquid chromatography (HPLC). Compound 1 (13.6 mg) (a mixture of stereoisomers) was obtained. LC-MS: [M+H] + =444.95.

[0270] 1 H NMR (400MHz, DMSO-d6): δ8.19 (s, 1H), 7.43 (d, J = 5.6Hz, 4H), 5.68 (s, 2H), 5.16 (d, J = 7.6Hz, 1H), 4.56–4.48 ( m, 1H), 4.12–4.01 (m, 1H), 3.93 (s, 3H), 3.14 (ddd, J=29.6, 14.8, 8.6Hz, 1H), 2.61 (s, 3H), 2.47–2.35 (m, 1H).

[0271] Step 2: Preparation of Compound 1-A and Compound 1-B

[0272] Chiral preparative chromatography was used to separate the chiral isomers of compound 1 (0.14 g, 0.31 mmol) (resolution method: preparative column: CHIRAL ART Amylose-C NEO 10 μm, 30*250 mm, flow rate: 40 mL / min, column temperature: room temperature, mobile phase: A: IPA-ETOH = 1:1 (neutral), B: n-hexane) to obtain compound 1-A and compound 1-B.

[0273] The characterization data of compound 1-A are as follows:

[0274] Compound 1-A: 39.4 mg. Chiral purity: 100%, T R = 22.33 min (wavelength: 220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: n-hexane containing 40% isopropanol, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0275] 1H NMR (400MHz, DMSO-d6): δ8.19 (s, 1H), 7.47–7.36 (m, 4H), 5.68 (s, 2H), 5.19–5.11 (m, 1H), 4.53 (ddd, J=18.8, 11.1, 1.7Hz, 1H ), 4.06 (dd, J=33.2, 11.2Hz, 1H), 3.93 (s, 3H), 3.14 (ddd, J=29.6, 14.8, 8.6Hz, 1H), 2.41 (dddd, J=16.4, 8.2, 6.4, 3.2Hz, 1H).

[0276] The single-crystal diffraction pattern of compound IA is shown in Figure 1 (i.e., the thermal ellipsoid diagram of the molecular stereostructure of compound IA). Its configuration was confirmed by its single-crystal diffraction pattern.

[0277] The characterization data of compound 1-B are as follows:

[0278] Compound 1-B: 41.6 mg. Chiral purity: 99.34%, T R = 32.13 min (wavelength: 220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: n-hexane containing 40% isopropanol, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0279] 1 H NMR (400MHz, DMSO-d6): δ8.19 (s, 1H), 7.49–7.38 (m, 4H), 5.68 (s, 2H), 5.19–5.11 (m, 1H), 4.53 (ddd, J=18.98, 11.2, 1.7Hz, 1H), 4.06 (dd, J=33.2, 11.2Hz, 1H), 3.93 (s, 3H), 3.14 (ddd, J=29.6, 14.8, 8.6Hz, 1H), 2.61 (s, 3H), 2.41 (dddd, J=28.4, 14.8, 6.4, 1.6Hz, 1H).

[0280] Preparation of single crystals of compound 1-A

[0281] Compound 1-A was prepared according to the method in Example 1. 50 mg of compound 1-A was placed in a 10 mL clean sample vial, 2 mL of tetrahydrofuran and 6 mL of dichloromethane were added, and the solution was heated to dissolve it. 1.5 mL of the solution was transferred to an NMR tube and placed in a laboratory fume hood for about 65 hours. No crystals precipitated. The remaining sample solution was sealed with sealing film, and 9 pores were made with a 1 mL syringe needle. After being placed in a laboratory fume hood for about 65 hours, obvious crystals precipitated. The sample was then sealed and sent for testing.

[0282] Single-crystal diffraction analysis of compound 1-A

[0283] Testing instrument and model: D8 Venture

[0284] Instrument parameters:

[0285] Light source: Mo target X-rays Mo-Kα

[0286] Detector: CMOS surface detector; Resolution:

[0287] Current and voltage: 50kV, 1.4mA; Exposure time: 10s

[0288] Distance from surface detector to sample: 40 mm; Test temperature: 100(2) K

[0289] Figure 1 shows the thermo-ellipsoidal diagram of the molecular stereostructure of compound 1-A. The crystal structure data are summarized in Table 1.

[0290] Table 1 Crystal structure data of compound 1-A

[0291] Example 2: Preparation of Compound 5

[0292] Step 1: Preparation of Intermediate 5-1

[0293] 5-SM-01 (ethyl 4-methyl-1H-imidazolium-5-carboxylate) (0.5 g, 3.24 mmol) was dissolved in DMF (50 mL), cooled to 0 °C, and LiHMDS (0.60 g, 3.56 mmol) was slowly added dropwise. The reaction mixture was then kept at this temperature for 20 min. Diphenylphosphonohydroxylamine (0.91 g, 3.89 mmol) was then added to the reaction mixture, stirred for 20 min, and then allowed to react at room temperature for 4 h. 50.0 mL of water was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL × 3). The organic phases were combined, dried, filtered, and the residue was purified by silica gel column chromatography (PE:EA = 3:1 to 1:2) to obtain intermediate 5-1 (210 mg).

[0294] Step 2: Preparation of intermediate 5-2

[0295] Intermediate 5-1 (0.21 g, 1.24 mmol) was dissolved in 10 mL of ACN under nitrogen protection, followed by the addition of 20 mL of hydrogen chloride / 1,4-dioxane solution. The reaction was carried out at 25 °C for 18 h until completion. The solution was then directly incorporated into the next reaction step.

[0296] Step 3: Preparation of intermediate 5-3

[0297] The reaction solution from the previous step was added to EtOH (20 mL) and 5 mL of 5% sodium hydroxide aqueous solution, and the mixture was heated to 65 °C and reacted for 6 h. The reaction solution was purified by high performance liquid chromatography to obtain intermediate 5-3 (100 mg).

[0298] Step 4: Preparation of Compound 5

[0299] Intermediates 1-8 (80 mg, 0.25 mmol) and 5-3 (41.04 mg, 0.25 mmol) were dissolved in DMF (1 mL), followed by the addition of potassium carbonate (103.66 mg, 0.75 mmol) and stirring at room temperature. After 3 hours, a product was formed, and the reaction was stopped. The reaction solution was purified by preparative high-performance liquid chromatography (preparative column: YMC Triart C18 12 nm, 10 μm, 30*250 mm, flow rate: 40 mL / min, column temperature: room temperature, mobile phase: A: pure water (0.1% ammonia), B: preparative acetonitrile) to obtain compound 5 (60 mg) (a mixture of stereoisomers).

[0300] Chiral analysis revealed that compound 5 has two isomers, named compound 5-A and compound 5-B. The configuration of 5-A may be 5-A-1 or 5-A-2, and the configuration of 5-B may be 5-A-2 or 5-A-1. When 5-A is 5-A-1, 5-B is 5-A-2; when 5-B is 5-A-1, 5-A is 5-A-2.

[0301] The characterization data of compound 5-A are as follows:

[0302] Chiral purity: 92.684%, T R = 12.700 min (wavelength: 220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0303] The characterization data for compound 5-B are as follows:

[0304] Chiral purity: 7.316%, T R = 14.473 min (wavelength: 220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0305] 1H NMR(600MHz,DMSO-d6)δ8.34(s,1H),7.48–7.38(m,4H),5.54(s,2H),5.18–5.14(m,1H),4.53(dd,J=18.8,11.2Hz,1 H), 4.07 (dd, J=33.2, 11.2Hz, 1H), 3.16 (ddd, J=29.6, 14.8, 8.6Hz, 1H), 2.48 (s, 3H), 2.46 (s, 3H), 2.45–2.36 (m, 1H).

[0306] Example 3: Preparation of Compound 7

[0307] Step 1: Preparation of Intermediate 7-1

[0308] At room temperature, intermediate 7-SM-01 (1 g, 6.49 mmol) was added to DMF (60 mL), and LiHMDS (7.14 mL, 7.14 mmol) was slowly added dropwise at -10 °C. After the addition was complete, the mixture was stirred at 0 °C for 10 minutes, and then diphenylphosphonohydroxylamine (1.82 g, 7.79 mmol) was added. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated ammonium chloride (300 mL), and extracted with EA (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:1) to obtain intermediate 7-1 (650 mg). LC-MS: [M+H] + =170.05.

[0309] Step 2: Preparation of intermediate 7-2

[0310] At room temperature, intermediate 7-1 (650 mg, 3.84 mmol) was dissolved in ACN (6 mL), and a 1,4-dioxane solution of HCl (0.88 g, 24 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was then concentrated to dryness under reduced pressure. The crude product was dissolved in EtOH (80 mL), and a 5% sodium hydroxide aqueous solution (20 mL) was added. After the addition was complete, the mixture was stirred at 80 °C for 1 hour. The reaction solution was cooled to room temperature, and a white solid precipitated. The solid was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 7-2 (330 mg). LC-MS: [M+H] + =165.05.

[0311] Step 3: Preparation of Compound 7

[0312] At room temperature, intermediates 1-8 (50 mg, 0.16 mmol), 7-2 (0.053 g, 0.32 mmol), and K₂CO₃ (0.088 g, 0.64 mmol) were added to 2 mL of DMF, and the reaction was stirred overnight at room temperature. The reaction solution was directly filtered, and the filtrate was purified by preparative high-performance liquid chromatography (HPLC) (preparative column: YMC Triart C18 12 nm, 10 μm, 30*250 mm, flow rate: 40 mL / min, column temperature: room temperature, mobile phase: A: water (1% ammonia) B: preparative acetonitrile) to give compound 7 (12.2 mg) (a mixture of stereoisomers). LC-MS: [M+H] + =445.00.

[0313] Chirality testing revealed that compound 7 has two isomers, named compound 7-A and compound 7-B.

[0314] The characterization data of compound 7-A are as follows:

[0315] Chiral purity: 49.443%, T R = 12.871 min (wavelength: 220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0316] The characterization data for compound 7-B are as follows:

[0317] Chiral purity: 50.557%, T R = 15.534 min (wavelength: 220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0318] The configuration of 7-A may be 7-A-1 or 7-A-2, and the configuration of 7-B may be 7-A-2 or 7-A-1. When 7-A is 7-A-1, 7-B is 7-A-2; when 7-B is 7-A-1, 7-A is 7-A-2.

[0319] 1H NMR(600MHz,DMSO-d6)δ7.68(s,1H),7.50–7.29(m,4H),5.58(s,2H),5.17–5.10(m,1H),4.51(dd,J=1 8.6,11.6Hz,1H),4.04-4.02(m,1H),3.13-3.10(m,1H),2.53(s,3H),2.44–2.36(m,1H),2.32(s,3H).

[0320] Example 4: Preparation of Compound 8

[0321] Step 1: Preparation of Intermediate 8-1

[0322] Intermediate 8-SM-01 (0.1 g, 0.73 mmol) was weighed into a reaction flask, dissolved in 2 mL of EtOH, followed by the addition of triethyl orthoacetate (0.24 g, 1.46 mmol) and acetic acid (0.13 g, 2.19 mmol). The reaction mixture was reacted at 120 °C for 12 hours. The reaction solution was concentrated under reduced pressure, filtered, and the filter cake was collected. Intermediate 8-1 (0.1 g) was obtained. LC-MS: [M+H] + =162.05.

[0323] Step 2: Preparation of Compound 8

[0324] Intermediate 1-8 (0.06 g, 0.19 mmol) was weighed into a reaction flask, dissolved in DMF (3 mL), followed by intermediate 8-1 (0.034 g, 0.21 mmol) and potassium carbonate (0.079 g, 0.57 mmol). The reaction mixture was reacted at 25 °C for 2 hours. The reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (HPLC). Compound 8 (12.4 mg) (a mixture of stereoisomers) was obtained. LC-MS: [M+H] + =442.15.

[0325] Chirality testing revealed that compound 8 has two isomers, named compound 8-A and compound 8-B.

[0326] The characterization data of compound 8-A are as follows:

[0327] Chiral purity: 49.716%, T R = 15.339 min (wavelength: 220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0328] The characterization data for compound 8-B are as follows:

[0329] Chiral purity: 50.284%, T R = 19.799 min (wavelength: 220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0330] The configuration of 8-A may be 8-A-1 or 8-A-2, and the configuration of 8-B may be 8-A-2 or 8-A-1. When 8-A is 8-A-1, 8-B is 8-A-2, and when 8-B is 8-A-1, 8-A is 8-A-2.

[0331] 1 H NMR(400MHz,DMSO-d6)δ8.99(dd,J=4.4,1.9Hz,1H),8.51(dd,J=7.6,1.6Hz,1 H),7.57(dd,J=7.6,4.4Hz,1H),7.45–7.36(m,4H),5.71(s,2H),5.24–5.06(m ,1H),4.52(dd,J=18.4,11.2Hz,1H),4.05(dd,J=33.2,11.2Hz,1H),3.14(ddd ,J=29.2,14.8,8.8Hz,1H),2.71(s,3H),2.39(ddd,J=26.8,13.6,8.4Hz,1H).

[0332] Example 5: Preparation of Compound 9

[0333] Step 1: Preparation of Intermediate 9-1

[0334] Intermediate 9-SM-01 (0.1 g, 0.73 mmol) was weighed into a reaction flask, dissolved in ethanol (2 mL), and then triethyl orthoacetate (0.24 g, 1.46 mmol) and acetic acid (0.13 g, 2.19 mmol) were added. The reaction solution was reacted at 120 °C for 12 h. The reaction solution was concentrated under reduced pressure, filtered, and the filter cake was collected to obtain intermediate 9-1 (0.1 g). LC-MS: [M+H] + =162.05.

[0335] Step 2: Preparation of Compound 9

[0336] Intermediates 1-8 (0.05 g, 0.16 mmol) were weighed into a reaction flask, dissolved in 2 mL of DMF, followed by potassium carbonate (0.066 g, 0.48 mmol) and compound 9 (0.028 g, 0.18 mmol). The reaction mixture was reacted at room temperature for 2 h. The reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (HPLC) to give compound 9 (23.1 mg) (a mixture of stereoisomers). LC-MS: [M+H] + =442.10.

[0337] Chirality testing revealed that compound 9 has two isomers, named compound 9-A and compound 9-B.

[0338] The characterization data of compound 9-A are as follows:

[0339] Chiral purity: 50.246%, T R = 15.495 min (wavelength: 220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0340] The characterization data for compound 9-B are as follows:

[0341] Chiral purity: 49.754%, T R = 18.402 min (wavelength: 220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0342] The configuration of 9-A may be 9-A-1 or 9-A-2, and the configuration of 9-B may be 9-A-2 or 9-A-1. When 9-A is 9-A-1, 9-B is 8-A-2, and when 9-B is 9-A-1, 9-A is 9-A-2.

[0343] 1 H NMR (600MHz, DMSO-d6) δ9.06(d,J=4.0Hz,1H),8.69(t,J=4.8Hz,1H),7.95(t,J=4.8Hz,1H),7.42(s,4H),5.72(d,J=4.0Hz,2H),5 .14(s,1H),4.57–4.46(m,1H),4.05(ddd,J=33.2,11.2,4.4Hz,1H),3.20–3.06(m,1H),2.71(d,J=4.4Hz,3H),2.44–2.38(m,1H).

[0344] Example 6: Preparation of Compound 18

[0345] Step 1: Preparation of Intermediate 18-1

[0346] Intermediate 18-SM-01 (250.0 mg, 1.61 mmol) was dissolved in acetonitrile (3.5 mL), and nitrogen gas was introduced. A solution of 1,4-dioxane (0.29 mL, 1.18 mmol) of hydrogen chloride was added at 0 °C, and the mixture was reacted overnight at 100 °C. The reaction solution was concentrated under reduced pressure to obtain intermediate 18-1 (270.0 mg), which was directly used in the next reaction. LC-MS: [M+H] + =197.10.

[0347] Step 2: Preparation of intermediate 18-2

[0348] Intermediate 18-1 (270.0 mg) was dissolved in ethanol (8 mL), and an aqueous solution of sodium hydroxide (0.92 mL, 5.52 mmol) was added. The mixture was reacted at 90 °C for 4 hours. After cooling to room temperature, the pH was adjusted to 4-5 with 6N hydrochloric acid aqueous solution. Extraction was performed with a dichloromethane:methanol mixture (10:1, 10 mL * 5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give intermediate 18-2 (85.0 mg). LC-MS: [M+H] + =165.05.

[0349] Step 3: Preparation of Compound 18

[0350] Intermediate 18-2 (40.0 mg) was dissolved in N,N-dimethylformamide (2.5 mL), and anhydrous potassium carbonate (0.066 g, 0.48 mmol) and intermediate 1-8 (0.069 g, 0.22 mmol) were added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was purified by preparative high-performance liquid chromatography (YMC Triart C18 12 nm 10 μm, 30*250 mm, flow rate: 40 mL / min, column temperature: room temperature, mobile phase: A: pure water (0.1% ammonia) B: preparative acetonitrile) to obtain compound 18 (27.0 mg) (a mixture of stereoisomers). LC-MS: [M+H] + =445.15;

[0351] Chirality testing revealed that compound 18 has two isomers, named compound 18-A and compound 18-B.

[0352] The characterization data of compound 18-A are as follows:

[0353] Chiral purity: 49.213%, TR = 15.354 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 °C).

[0354] The characterization data for compound 18-B are as follows:

[0355] Chiral purity: 50.787%, T R = 16.592 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0356] The configuration of 18-A may be 18-A-1 or 18-A-2, and the configuration of 18-B may be 18-A-2 or 18-A-1. When 18-A is 18-A-1, 18-B is 18-A-2. When 18-B is 18-A-1, 18-A is 18-A-2.

[0357] 1 H NMR (600MHz, DMSO-d6) δ7.97(s,1H),7.51–7.32(m,4H),5.69(s,2H),5.18–5.10(m,1H),4.53(ddd,J=18.8,11.2,1.8Hz,1H),4.16( s,3H),4.06(dd,J=33.2,11.2Hz,1H),3.14(ddd,J=29.6,14.8,8.6Hz,1H),2.60(s,3H),2.41(dddd,J=28.8,14.8,6.4,1.6Hz,1H).

[0358] Example 7: Preparation of Compound 57

[0359] Step 1: Preparation of intermediate 4-1

[0360] At room temperature, 4-SM-01 (10 g, 47.13 mmol), K2CO3 (19.54 g, 141.39 mmol), and MeI (26.76 g, 188.52 mmol) were added to DMF (60 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was then added to water (200 mL), lyophilized directly, and the residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain intermediate 4-1 (9.7 g).

[0361] Step 2: Preparation of intermediate 4-2

[0362] At room temperature, intermediate 4-1 (9.7 g, 42.88 mmol) and hydrazine hydrate (8.59 g, 171.52 mmol) were added to EtOH (100 mL), and the reaction was stirred overnight at 80 °C. The reaction solution was then concentrated to dryness under reduced pressure to obtain intermediate 4-2 (7.95 g).

[0363] Step 3: Preparation of intermediate 4-3

[0364] Intermediate 4-2 (7.9 g, 39.86 mmol) was added to hydrochloric acid (120 mL, 4 mol / L, 480 mmol), and the reaction mixture was stirred overnight at 100 °C. The reaction solution was then concentrated to dryness under reduced pressure to obtain intermediate 4-3 (6.0 g). LC-MS: [M+H] + =167.05.

[0365] Step 4: Preparation of intermediate 4-4

[0366] At room temperature, intermediate 4-3 (6 g, 36.11 mmol) and DMF (0.26 g, 3.61 mmol) were added to POCl3 (167.5 g, 1092.42 mmol), and the reaction was stirred overnight at 100 °C. The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. 200 mL of water was added to the residue, and the pH was adjusted to 8-9 with sodium hydroxide. A large amount of yellow solid precipitated. The solid was filtered, and the filter cake was concentrated to dryness under reduced pressure to obtain intermediate 4-4 (4.4 g). LC-MS: [M+H] + =202.95.

[0367] Step 5: Preparation of intermediates 4-5-1 and 4-5-2

[0368] At room temperature, intermediate 4-4 (4.4 g, 21.67 mmol) and sodium methoxide (1.40 g, 26.00 mmol) were added to MeOH (100 mL), and the reaction was stirred at 50 °C for 1 hour. The reaction solution was directly concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 10:1). A mixture of intermediates 4-5-1 and 4-5-2 (2 g) was obtained. LC-MS: [M+H] + =199.00.

[0369] Step 6: Preparation of intermediates 4-6-1 and 4-6-2

[0370] At room temperature, a mixture of intermediates 4-5-1 and 4-5-2 (2 g, 10.07 mmol) and 10% palladium on carbon (2 g, 1.88 mmol) were added to methanol (150 mL), and the reaction was stirred at 30 °C for 2 hours. The reaction solution was directly filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (preparative column: YMC Triart C18 12 nm 10 μm, 30*250 mm, flow rate: 40 mL / min, column temperature: room temperature, mobile phase: A: water (1% TFA), B: preparative acetonitrile) to obtain two isomers: intermediate 4-6-1: 120 mg, and intermediate 4-6-2: 1.0 g. LC-MS: [M+H] + =165.05.

[0371] Step 7: Preparation of intermediate 4-7-1

[0372] At room temperature, intermediate 4-6-1 (70 mg, 0.43 mmol) and hydrochloric acid (2 mL, 8 mmol) were added to 1,4-dioxane (2 mL), and the reaction was carried out overnight at 100 °C with stirring. The reaction solution was then concentrated directly to dryness under reduced pressure to obtain intermediate 4-7-1 (60 mg).

[0373] Step 8: Preparation of intermediate 4-7-2

[0374] At room temperature, intermediate 4-6-2 (100 mg, 0.61 mmol) and hydrochloric acid (4 mL, 16 mmol) were added to 1,4-dioxane (4 mL), and the reaction was carried out overnight at 100 °C with stirring. The reaction solution was then concentrated directly to dryness under reduced pressure to obtain intermediate 4-7-2 (80 mg).

[0375] Step 9: Preparation of Compound 4

[0376] Intermediates 1-8 (55 mg, 0.17 mmol), 4-7-1 (50 mg, 0.33 mmol), and K₂CO₃ (0.094 g, 0.68 mmol) were added to DMF (3 mL) at room temperature, and the reaction mixture was stirred overnight at room temperature. The reaction solution was directly filtered, and the filtrate was purified by high-performance preparative liquid chromatography (preparative column: YMC Triart C18 12 nm 10 μm, 30*250 mm, flow rate: 40 mL / min, column temperature: room temperature, mobile phase: A: water (1% ammonia) B: preparative acetonitrile). Compound 4 (8.2 mg) was obtained. LC-MS: [M+H] + =431.05.

[0377] Chirality testing revealed that compound 4 has two isomers, named compound 4-A and compound 4-B.

[0378] The characterization data of compound 4-A are as follows:

[0379] Chiral purity: 46.358%, T R =18.680 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 °C).

[0380] The characterization data of compound 4-B are as follows:

[0381] Chiral purity: 53.642%, T R = 19.977 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0382] The configuration of 4-A can be 4-A-1 or 4-A-2, and the configuration of 4-B can be 4-A-2 or 4-A-1. When 4-A is 4-A-1, 4-B is 4-A-2, and when 4-B is 4-A-1, 4-A is 4-A-2.

[0383] 1 H NMR (600MHz, DMSO-d6) δ8.62(s,1H),8.32(s,1H),7.50–7.30(m,4H),5.74(s,2H),5.13(t,J=7.6Hz, 1H), 4.51 (dd, J=19.8, 10.8Hz, 1H), 4.06 (s, 1H), 3.91 (s, 3H), 3.12-3.10 (m, 1H), 2.42–2.34 (m, 1H).

[0384] Step 10: Preparation of Compound 57

[0385] At room temperature, intermediates 4-7-2 (40 mg, 0.27 mmol), 1-8 (0.069 g, 0.22 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) were added to 2 mL of DMF, and the reaction was stirred overnight at room temperature. The reaction solution was directly filtered, and the filtrate was purified by high-performance preparative liquid chromatography (preparative column: YMC Triart C18 12 nm 10 μm, 30*250 mm, flow rate: 40 mL / min, column temperature: room temperature, mobile phase: A: water (1% ammonia) B: preparative acetonitrile). Compound 57 (38 mg) was obtained. LC-MS: [M+H] + =431.05.

[0386] The characterization data of compound 57-A are as follows:

[0387] Chiral purity: 48.288%, T R = 32.583 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0388] The characterization data of compound 57-B are as follows:

[0389] Chiral purity 51.712%, T R = 36.101 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0390] The configuration of 57-A may be 57-A-1 or 57-A-2, and the configuration of 57-B may be 57-A-2 or 57-A-1. When 57-A is 57-A-1, 57-B is 57-A-2. When 57-B is 57-A-1, 57-A is 57-A-2.

[0391] 1 H NMR(600MHz,DMSO-d6)δ8.49(s,1H),8.37(s,1H),7.43–7.36(m,4H),5.72(s,2H),5.16– 5.06(m,1H),4.50–4.40(m,1H),4.14–3.93(m,4H),3.15-3.12(m,1H),2.44–2.15(m,1H).

[0392] Comparative Example 1: Preparation of Compound D1

[0393] Step 1: Preparation of Intermediate 1-1

[0394] 4-Chlorobenzaldehyde (60 g, 426.84 mmol) was weighed into a reaction flask, and 1,4-dioxane (420 mL), 4-chloro-3-nitrobenzoic acid (8.58 g, 42.66 mmol), 1,5-cyclooctadiene iridium chloride dimer (8.58 g, 12.78 mmol), cesium carbonate (27.84 g, 85.38 mmol), R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (8.58 g, 12.78 mmol), allyl acetate (427.4 g, 4268.4 mmol), and isopropanol (51.3 g, 853.7 mmol) were added. The reaction mixture was stirred at 112 °C for 20 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain intermediate 1-1 (60 g).

[0395] Step 2: Preparation of intermediate D1-2

[0396] Weigh liquid bromine (53.88 g, 337.3 mmol) into a reaction flask, add dichloromethane (400 mL), and under nitrogen protection, cool to -30 °C. Slowly add a dichloromethane solution (400 mL) of intermediate 1-1 (56 g, 306.6 mmol). React at -30 °C for 1 hour. Quench the reaction in a saturated sodium sulfite aqueous solution (1000 mL), extract with dichloromethane (300 mL × 3), combine the organic phases, wash once with a saturated sodium chloride aqueous solution (500 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate D1-2 (100 g).

[0397] Step 3: Preparation of intermediate D1-3

[0398] Weigh intermediate D1-2 (100 g, 292 mmol) into a reaction flask, add methanol (800 mL) and potassium carbonate (161.44 g, 1168 mmol), and stir at room temperature for 12 hours. Add saturated ammonium chloride aqueous solution (400 mL) to the reaction solution, then add water (1000 mL), extract with ethyl acetate (300 mL × 3), combine the organic phases, wash once with saturated sodium chloride aqueous solution (500 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain intermediate D1-3 (40 g).

[0399] Step 4: Preparation of intermediate D1-4

[0400] Weigh intermediate D1-3 (40 g, 152.96 mmol) into a reaction flask, add tetrahydrofuran (500 mL), and add trimethylcyanosilane (75.88 g, 764.8 mmol). Under nitrogen protection, cool the reaction solution to 0 °C, and slowly add tetrabutylammonium fluoride (458.9 mL, 1 N, 458.9 mmol). After completion, react at 60 °C for 16 hours. Quench the reaction solution in water (300 mL), extract with ethyl acetate (300 mL × 3), combine the organic phases, wash once with saturated sodium chloride aqueous solution (300 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography to obtain intermediate D1-4 (10 g).

[0401] Step 5: Preparation of intermediate D1-5

[0402] Weigh intermediate D1-4 (11 g, 52.95 mmol) into a reaction flask, add ethanol (100 mL) and hydroxylamine (14 g, 211.88 mmol, 50% wt), and react under nitrogen protection at 80 °C for 16 hours. Pour the reaction mixture into water (300 mL), extract with ethyl acetate (200 mL × 3), combine the organic phases, wash once with saturated sodium chloride aqueous solution (300 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate D1-5 (11 g). LC-MS: [M+H] + =240.95.

[0403] Step 6: Preparation of intermediate D1-6

[0404] Weigh intermediate D1-5 (11 g, 45.7 mmol) into a reaction flask, add methyl tert-butyl ether (110 mL), protect under nitrogen atmosphere, cool to 0 °C, add chloroacetic anhydride (7.03 g, 41.13 mmol), and stir at room temperature for 0.5 hours. Slowly add saturated sodium bicarbonate aqueous solution (100 mL) to the reaction solution, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash once with saturated sodium chloride aqueous solution (200 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate D1-6 (12 g). LC-MS: [M+H] + =316.9.

[0405] Step 7: Preparation of intermediate D1-7

[0406] Intermediate D1-6 (12 g, 37.84 mmol) was weighed into a reaction flask, and toluene (100 mL) and 4A molecular sieve (40 g) were added. The reaction mixture was reacted at 100 °C for 5 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain intermediate D1-7 (10 g). LC-MS: [M+H] +=298.90.

[0407] Step 8: Preparation of compound D1

[0408] Intermediate D1-7 (7 g, 23.4 mmol) was weighed into a reaction flask, and intermediate 1-9 (5.76 g, 35.1 mmol) and N,N-dimethylformamide (70 mL) were added. Under nitrogen protection, the reaction solution was cooled to 0 °C, and potassium carbonate (9.7 g, 70.2 mmol) was slowly added. After completion, the mixture was stirred at room temperature for 16 hours. The reaction solution was purified by preparative separation chromatography under alkaline conditions (preparative column: YMC Triart C18 12 nm 10 μm, 30*250 mm, flow rate: 40 mL / min, column temperature: room temperature, mobile phase: A: pure water (0.1% ammonia) B: preparative acetonitrile) to obtain compound D1 (6 g). LC-MS: [M+H] + =426.95.

[0409] Chiral purity: 96.157%, T R = 30.074 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm 5 μm, mobile phase: 40% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0410] 1 H NMR(400MHz, DMSO-d6)δ8.18(s,1H),7.40–7.35(m,4H),5.63(s,2H),5.00(t,J=8.0Hz,1H),4.36-4.32(m, 1H),3.93(s,3H),3.91–3.89(m,1H),3.78-3.71(m,1H),2.60(s,3H),2.59–2.54(m,1H),2.16–2.11(m,1H).

[0411] Comparative Example 2: Preparation of Compound D2

[0412] Step 1: Preparation of intermediate D2-2

[0413] At room temperature, intermediate 1-5 (1.4 g, 6.26 mmol) and aqueous hydroxylamine solution (1.24 g, 18.78 mmol, 50% purity) were added to EtOH (5 mL), and the reaction was stirred at 80 °C for 15 hours. The reaction solution was then concentrated to dryness under reduced pressure to obtain intermediate D2-2 (2.4 g).

[0414] Step 3: Preparation of intermediate D2-3

[0415] Intermediate D2-2 (1.98 g, 7.73 mmol) was weighed into a reaction flask, dissolved in 20 mL of MTBE, and then chloroacetic anhydride (1.98 g, 11.56 mmol) was added at low temperature. The reaction mixture was reacted at room temperature for 2 h. 10 mL of saturated sodium bicarbonate aqueous solution was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (40 mL × 2). The organic phases were combined, washed once with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.4 g of crude product.

[0416] The crude product (2.39 g, 7.16 mmol) was placed in a reaction flask, toluene (30 mL) was added, followed by 5 g of 4A molecular sieve powder. The reaction was carried out at 100 °C for 16 h. After filtration, the filtrate was purified by silica gel column chromatography to obtain intermediate D2-3 (0.495 g).

[0417] Step 4: Preparation of compound D2

[0418] Intermediate 1-9 (0.05 g, 0.30 mmol) was dissolved in DMF (2 mL) at room temperature, followed by the addition of potassium carbonate (0.12 g, 0.90 mmol) and intermediate D2-3 (0.095 g, 0.30 mmol). The reaction mixture was reacted at room temperature for 16 h. The reaction solution was purified by preparative separation chromatography (YMC Triart C18 12 nm 10 μm, 30*250 mm, flow rate: 40 mL / min, column temperature: room temperature, mobile phase: A: pure water (0.1% ammonia) B: preparative acetonitrile). After lyophilization, compound D2 (53.8 mg) was obtained.

[0419] Chirality testing revealed that compound D2 has two isomers, named compound D2-A and compound D2-B, respectively.

[0420] The characterization data of compound D2-A are as follows:

[0421] Chiral purity: 50.115%, T R =18.012 min (wavelength: 220 nm) (Chiral purity detection method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 20% ethanol-30% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 ℃);

[0422] The characterization data of compound D2-B are as follows:

[0423] Chiral purity: 49.885%, T R= 22.428 min (wavelength: 220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, 5 μm, mobile phase: 20% ethanol-30% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0424] The configuration of D2-A can be D2-A-1 or D2-A-2, and the configuration of D2-B can be D2-A-2 or D2-A-1. When D2-A is D2-A-1, D2-B is D2-A-2, and when D2-B is D2-A-1, D2-A is D2-A-2.

[0425] 1 H NMR(600MHz,DMSO-d6)δ8.18(s,1H),7.41–7.34(m,4H),6.31(s,1H),5.63(s,2H),5.19(dd,J=10.2,6.0Hz,1H),4.27(d,J =9.0Hz, 1H), 4.00 (d, J = 9.0Hz, 1H), 3.92 (s, 3H), 2.61 (dd, J = 12.6, 5.4Hz, 1H), 2.58 (s, 3H), 2.16 (dd, J = 12.6, 10.8Hz, 1H).

[0426] The following compounds can be prepared using suitable starting materials and the preparation method shown in Example 1:

[0427] When the carbon atom marked with "*" is a chiral carbon atom, it indicates the R configuration, S configuration, or a mixture thereof.

[0428] <Biological Activity Testing Test>

[0429] 1. IC50 of the example compound 50 Determine Experiment

[0430] Stable transfected cells expressing TRPA1 were seeded into 384-well plates and cultured overnight at 37°C with 5% CO2. Afterward, the culture medium was removed, 20 μL of experimental buffer was added, and the cells were centrifuged at 200g for 3-5 seconds at room temperature, then incubated at 37°C for 2 hours. Using a FLIPR Penta, 10 μL of the 6× working solution of the target compound was added to the corresponding well. The cell plate was incubated at room temperature for 30 minutes, followed by incubation at room temperature for 5 minutes. Then, using a FLIPR Penta, 10 μL of 6× Cinnamaldehyde working solution was added to all wells, and data were collected every second for a total of 5 minutes of ROB signal acquisition.

[0431] The FLIPR Calcium 6 calcium ion detection kit was used to detect the concentration of calcium ions in cells. After co-incubation with the AM group, the calcium ion indicator entered the cytoplasm. Cytoplasmic esterases cleaved the AM group on the indicator, releasing the activated calcium ion indicator. Activation of TRPA1 led to an increase in intracellular calcium ion concentration. If the compound inhibited TRPA1, it reduced the intracellular calcium ion concentration, resulting in a decrease in fluorescence signal amplification. Under excitation light of 470 / 495 nm, the corresponding fluorescence emission signals could be captured at 515 / 575 nm. The degree of inhibition of the receptor by the compound was quantified by recording the changes in the fluorescence signal.

[0432] Data Analysis

[0433] Data were collected to calculate the logarithm of inhibition rate versus compound concentration, and IC was calculated using GraphPad Prism software. 50 value.

[0434] 1) PC group: 10μM Ruthenium Red;

[0435] 2) NC group: 0.1% DMSO;

[0436] 3) Percentage of activity = (Compound reading - Average reading of NC group) / (Average reading of PC group - Average reading of NC group) × 100;

[0437] 4) Z^' factor = 1 - (3 × standard deviation of PC group readings + 3 × standard deviation of NC group readings) / |mean of PC group readings - mean of NC group readings|;

[0438] 5) CV of the PC group = (Standard deviation of PC group readings / Mean of PC group readings) × 100%;

[0439] 6) CV of NC group = (Standard deviation of NC group readings / Mean of NC group readings) × 100%;

[0440] 7) Calculate the signal-to-ground ratio S / B = signal value / background value;

[0441] 8) Calculate the compound IC using the GraphPad nonlinear fitting formula. 50 :

[0442] Y = minimum value + (maximum value - minimum value / (1 + 10^(logIC))) 50 -x)×slope factor))

[0443] Where x is the log value of the compound concentration; Y: inhibition rate (%).

[0444] Among them, the maximum value, minimum value, and IC 50 Automatically fitted and generated by GraphPad Prism;

[0445] IC 50 Half-inhibition concentration (WIC) represents the concentration at which a compound inhibits TRPA1 target activity by 50%.

[0446] The compounds of the present invention exhibit good TRPA1 inhibitory activity; the IC50 of the example compounds for inhibiting TRPA1 is shown in the figure. 50 The values ​​are shown in Table 2:

[0447] Table 2: Inhibitory activity of the compounds of this invention against TRPA1

[0448] Experimental conclusion: As can be seen from the data in Table 2, the compounds of the present invention have good TRPA1 inhibitory activity.

[0449] 2. In vitro hepatic microsomal metabolic stability experiments of some compounds of the present invention

[0450] The in vitro metabolic stability of the compounds in this invention was determined using the liver microsomal incubation method. 416.5 μL of phosphate buffer was mixed with 25 μL of liver microsomes, 3.5 μL of glucose-6-phosphate dehydrogenase (500 U / mL), and 50 μL of cofactor solution (NADP 10 mM, D-6-phosphate glucose 60 mM, MgCl2·6H2O 50 mM). The mixture was shaken twice to mix and then pre-incubated in a 37°C water bath for 5 min. Then, 5 μL of the working solution of the test compound (1 mM, DMSO solvent) was added, and the mixture was shaken twice to mix. The mixture was then incubated in a 37°C water bath to initiate the reaction. After adding the compound and vortexing to mix, 50 μL of the solution was added to centrifuge tubes containing 200 μL of pre-chilled internal standard working solution at 0 min, 2 min, 5 min, 15 min, 30 min, 60 min, 90 min, and 120 min after the reaction, respectively, to terminate the reaction. The mixture was then vortexed for 1 min and centrifuged at 13000 rpm (revolutions per minute) for 10 min in a high-speed centrifuge pre-chilled at 4 °C. The supernatant was collected and analyzed by LC-MS. Semi-quantitative determination was performed using the ratio of the analyte peak area to the internal standard peak area. The retention times of the analyte and internal standard, chromatogram acquisition, and chromatogram integration were processed using Analyst software. The in vitro elimination rate constant k of the test compound and control compound was obtained by converting the ratio of the test compound to the internal standard peak area into a residual rate. The half-life (T) was then calculated according to the following formula. 1 / 2 ).

[0451] Using the above method, various genera of liver microsomes T of some compounds of the present invention were obtained. 1 / 2 The results are shown in Table 3 below.

[0452] Table 3. T obtained from some compounds of the present invention 1 / 2

[0453] Experimental conclusions: The compounds of this invention exhibit excellent metabolic stability in humans, rats, beagles, and cynomolgus monkeys. This invention preferably utilizes the compounds in human liver microsomes (T...). 1 / 2 Compounds with a duration of >30 min, more preferably in human liver microsomes, are more readily metabolized at T... 1 / 2 Compounds with a lifespan of >90 minutes.

[0454] 3. Pharmacokinetic studies of some compounds of this invention in rats

[0455] 3.1 Experimental Preparation

[0456] 3.2.1 Rats: SD rats (Sprague Dawley), specific pathogen-free animals (SPF grade), 6 males, weighing between 180-200g;

[0457] 3.2.2 Preparation: For the oral (PO) group, accurately weigh the compound, add the required volume of 10% vitamin E polyethylene glycol succinate (TPGS), vortex for 10 seconds, and sonicate for 5 minutes to obtain a clear solution. For the intravenous (IV) group, accurately weigh the compound, add the required volume of 15% DMSO, vortex for 10 seconds, then add the required volume of 60% polyethylene glycol 400 (PEG400), vortex for 10 seconds, then add the required volume of 10% physiological saline, and stir magnetically for 1 minute to obtain a clear solution.

[0458] 3.2 Dosing regimen

[0459] Rats were randomly divided into two groups of three based on their body weight. Group 1 received a single dose via gavage (fasting), while Group 2 received a single dose via tail vein injection. Blood samples were collected at the following time points: for the po group, the time points were 0.167h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h; for the iv group, the time points were 0.033h, 0.167h, 1h, 2h, 4h, 6h, 8h, and 24h.

[0460] 3.3 Sample Collection and Preparation

[0461] After administration to rats, blood was collected from the orbital venous plexus at sampling time points. Approximately 0.2-0.3 mL of blood was collected at each time point into an anticoagulant EP tube (containing 4 μL of dipotassium ethylenediaminetetraacetate (EDTA-K2), 375 mg / mL, dried at 50°C). The tube was slowly inverted three times and stored in an ice box (for no more than 30 minutes). The tube was then centrifuged at 3000g for 10 minutes at 4°C. The supernatant was transferred to a labeled EP tube and sent for bioanalytical analysis. If the sample could not be tested on the same day, it should be stored at -80°C until testing (note that repeated freezing / thawing should be avoided).

[0462] 3.4 Sample Analysis and Data Analysis

[0463] The data will be analyzed using Win Nonlin with a non-compartmental model to obtain pharmacokinetic (PK) parameters (peak concentrations (C) selected according to different routes of administration). max Peak time (T) max Half-life (T) 1 / 2 ), Area under the curve (AUC) 0-last (Parameters such as oral bioavailability (F)). Please see Table 4 for specific data.

[0464] Table 4: PK experiment of the compounds of the present invention in SD rats

[0465] Experimental conclusion: The compounds of this invention exhibit superior overall pharmacokinetic properties.

[0466] 4. Pharmacokinetic studies of some compounds of this invention in beagle dogs

[0467] 4.1 Experimental Preparation

[0468] 4.1.1 Beagle: Sourced from Jiangsu Mas Biotechnology Co., Ltd., Certificate No.: B202407290386, 12 dogs in the same batch, male, 6 in group PO and 6 in group IV, weight 10-11kg.

[0469] 4.1.2 Solvent composition: PO group used 10% TPGS (v / v) as solvent; IV group used 15% DMSO + 60% PEG400 + 25% physiological saline solution as solvent.

[0470] Preparation procedure: After accurately weighing the compound in the PO group, add the required volume of 10% TPGS, stir for at least 10 minutes, and sonicate for at least 15 minutes until clear. Prepare and use immediately.

[0471] After accurately weighing the IV group, add the required volume of DMSO, vortex for 10 seconds, then add the required volume of PEG400, vortex for 10 seconds, then add the required volume of physiological saline, and stir magnetically for 1 minute to obtain a clear solution.

[0472] 4.2 Dosing regimen

[0473] Beagles were randomly divided into 4 groups of 3 dogs each based on their weight. Groups 1 and 3 were administered the drug via a single gavage (fasting), while groups 2 and 4 were administered the drug via a single tail vein injection. Blood samples were collected at the following time points for the po group: 0.167h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h. Blood samples were collected at the following time points for the iv group: 0.033h, 0.167h, 1h, 2h, 4h, 6h, 8h, and 24h.

[0474] 4.3 Sample Collection and Preparation

[0475] At each time point, approximately 1 mL of whole blood was collected from the peripheral blood vessels of the non-drug-treated limb of each animal and injected into an EP tube containing EDTA anticoagulant. The EP tube containing whole blood was immediately shaken twice to mix thoroughly and then placed on a tube rack on wet ice or an ice pack. The tube was centrifuged at 3000g at 4℃ for 10 minutes within 1 hour. The supernatant was collected and placed in an environment of -75±15℃ until analysis.

[0476] 4.4 Sample Analysis and Data Analysis

[0477] The data will be analyzed using Win Nonlin with a non-compartmental model to obtain pharmacokinetic (PK) parameters (peak concentrations (C) selected according to different routes of administration). max Peak time (T) max Half-life (T) 1 / 2 ), Area under the curve (AUC) 0-last (Parameters such as oral bioavailability (F)). Please see Table 5 for specific data.

[0478] Table 5: Beagle PK test of the compounds of the present invention

[0479] Experimental conclusion: The compounds of this invention exhibit superior overall pharmacokinetic properties.

[0480] The exemplary embodiments of the present invention have been described above. However, the scope of protection of this application is not limited to the exemplary embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection defined by the claims of this application.

Claims

1. The compound represented by Formula I, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate: in, R 1 C 6-10 aryl, 5-12 membered heteroaryl or 5-13 membered heterocyclic, wherein C 6-10 The aryl, 5-12-membered heteroaryl, and 5-13-membered heterocyclic groups are optionally bounded by one, two, or more R groups. 1-1 replace; R 2 and R 3 Each is independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl, and R 2 and R 3 Only one is H or deuterium; R 4 C 6-10 aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclic or C 3-10 In the cycloalkyl group, the heteroatoms in the 5-12 membered heteroaryl and 4-10 membered heterocyclic groups are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. 6-10 Aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclic and C 3-10 The cycloalkyl group is optionally surrounded by one, two or more R... 4-1 replace; Each R 1-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-6 Alkyl, oxo (=O), -OH, -CN, -COOH, C 1-6 Haloalkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heterocyclic alkenyl, -NR 5-1 R 5-2 -SO2-C 1-6 Alkyl, -C 1-4 Alkyl-CN, C 1-4 Aldehyde group or C 1-4 Ketone group; the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 3-8-membered heterocycloalkyl, 5-10-membered heteroaryl, and 5-10-membered heterocyclic alkenyl groups are optionally surrounded by one, two, or more elements selected from H, deuterium, halogen, -OH, -CN, -COOH, -SO2NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substituents of alkoxy groups; Each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-6 Alkyl, oxo, -OH, -CN, -COOH, C 1-6 Haloalkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group, wherein C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-8 The cycloalkyl, 5-10-membered heteroaryl, and 4-10-membered heterocyclic groups are optionally surrounded by one, two, or more groups selected from H, deuterium, halogen, -OH, -CN, -COOH, -SO2NH2, C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substituents of alkoxy groups; R 5-1 and R 5-2 Each independently represents H and C. 1-6 Alkyl or C 1-6 Alkyl group.

2. The compound of Formula I as claimed in claim 1, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, R 1 In the 5-12 membered heteroaryl and 5-13 membered heterocyclic groups, the heteroatoms are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1 to 5; Preferred, R 1 C 6-10 aryl, 5-12 membered heteroaryl or 5-13 membered heterocyclic, wherein C 6-10 The aryl, 5-12-membered heteroaryl, and 5-13-membered heterocyclic groups are optionally bounded by one, two, or more R groups. 1-1 The heteroatoms in the 5-12-membered heteroaryl and 5-13-membered heterocyclic groups are selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three.

3. The compound of Formula I as claimed in claim 1, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, R 1 C 6-10 Aryl, 5-12 membered heteroaryl, 10-13 membered fused tricyclic heterocyclic group, wherein C 6-10 Aryl, 5-12-membered heteroaryl, 10-13-membered fused tricyclic heterocyclic group, optionally with one, two or more R groups. 1-1 replace; R 2 and R 3 Each is independent of H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclic alkyl, and R 2 and R 3 Only one is H; R 4 For not replaced or by one or more R 4-1 Substituted benzene rings, naphthyl rings, 5-12-membered heteroaryl groups, or 5-12-membered heterocyclic alkenyl groups; R 1-1 and R 4-1 Each of the following is independent: H, D, halogen, C 1-6 Alkyl, -OH, -CN, -COOH, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heterocyclic alkenyl, -NR 5-1 R 5-2 -SO2-C 1-6 Alkyl, -C 1-4 Alkyl-CN, C 1-4 Aldehyde group, or C 1-4 Ketone group; the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocycloalkyl, 5-10-membered heteroaryl and 5-10-membered heterocyclic alkenyl, optionally surrounded by one, two or more R... 4-1-1 replace; The R 4-1-1 H, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 1-6 Alkyl group.

4. The compound of Formula I as described in any one of claims 1-3, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, R 1 for in, Ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen; One or three of X1, X2, X3, X4, X5 and X6 are nitrogen, and the rest are carbon, and one of X1, X2 and X5 can be arbitrarily -C=O or -C=S; Alternatively, X2 does not exist, one or three of X1, X3, X4, X5 and X6 are nitrogen, the rest are carbon, and one of X1 and X5 can be arbitrarily -C=O or -C=S; Alternatively, X1, X2, X3, X4, X5, and X6 are all carbon. m can be 0, 1, 2, or 3; p is 0, 1, 2 or 3; Each R 1-1-1 Independently, H, deuterium, halogen, C 1-6 Alkyl, -OH, -CN, -COOH, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl; Each R 1-1-2 For independent H, deuterium, halogen, C 1-6 Alkyl, -OH, -CN, or -COOH; When there are two adjacent R on the same ring 1-1-1 When, two adjacent R 1-1-1 Together with the ring atoms directly connected to it, they form C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic, or 5-6 membered heteroaryl; wherein the 4-6 membered heterocyclic and 5-6 membered heteroaryl groups have one or two heteroatoms selected from O, S, and N, and the number of heteroatoms is one or two; When there are two adjacent R on the same ring 1-1-2 When, two adjacent R 1-1-2 Together with the directly connected ring atoms, they form C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclic, or 5-6 membered heteroaryl; wherein the 4-6 membered heterocyclic and 5-6 membered heteroaryl groups have one or two heteroatoms selected from O, S, and N, and the number of heteroatoms is one or two.

5. The compound of formula I as claimed in claim 4, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, It meets one or more of the following conditions: (1) Ring A is a five- or six-membered heteroaryl ring, X1 is carbon, X2 is N, X3 is carbon or N, X4 is carbon, X5 is -C=O, and X6 is N; (2) m is 0, 1 or 2; for example, m is 0 or 1; (3)R 1-1-1 Halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic alkyl; or, when two adjacent Rs exist on the same ring. 1-1-1 When, two adjacent R 1-1-1 Together with the ring atoms directly attached to it, they form 4-6 membered heterocyclic groups; for example, R 1-1-1 Halogen, C 1-3 Alkyl, C 3-4 Cycloalkyl or 4-6 membered heterocyclic alkyl; or, when two adjacent Rs exist on the same ring. 1-1-1 When, two adjacent R 1- 1-1 Together with the ring atoms directly attached to it, they form 4-6 membered heterocyclic groups; for example, R 1-1-1 C 1-6 Alkyl; for example, C 1-3 alkyl; (4) p is 0, 1 or 2, for example p is 1; and (5)R 1-1-2 C 1-6 Alkyl or -CN, or, when two adjacent Rs are present on the same ring. 1-1-2 When, two adjacent R 1-1-2 Together with the directly attached ring atoms, they form 4-6 membered heterocyclic groups; for example, R 1-1-2 C 1-6 Alkyl; for example, R 1-1-2 C 1-3 alkyl.

6. The compound of formula I as claimed in claim 4, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, R 1 for m can be 0, 1, 2, or 3; p is 0, 1, 2 or 3; Each R 1-1-1 Independently, H, deuterium, halogen, C 1-6 Alkyl, -OH, -CN, -COOH, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl; Each R 1-1-2 Independently, H, deuterium, halogen, C 1-6 Alkyl, -OH, -CN or -COOH; or When there are two adjacent R on the same ring 1-1-1 When, two adjacent R 1-1-1 Together with the ring atoms directly connected to it, they form C 3- 6-cycloalkyl or 4-6-membered heterocyclic groups; When there are two adjacent R on the same ring 1-1-2 When, two adjacent R 1-1-2 Together with the ring atoms directly connected to it, they form C 3- 6-cycloalkyl or 4-6-membered heterocyclic groups; Preferably, R 1 for 7. The compound of formula I as claimed in claim 6, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, R 1 for Preferably, R 1 for 8. The compound of Formula I as claimed in any one of claims 1-7, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, R 2 and R 3 Each is independently H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, and R 2 and R 3 Only one is H; Preferably, when the R 2 Or R 3 When the halogen is halogen, the halogen is F, Cl, Br or I, preferably F; Preferably, when the R 2 Or R 3 C 1-6 When alkyl, the C 1-6 Alkyl group is C 1-4 Alkyl groups, preferably methyl groups; Preferably, when the R 2 Or R 3 C 1-6 When alkoxy is present, the C 1-6 The alkoxy group is C 1-4 Alkyl groups, preferably methoxy groups; Preferably, when the R 2 Or R 3 C 3-6 When cycloalkyl, the C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl, preferably cyclopropyl; Preferably, the R 2 For halogens, R 3 For H, or R 2 For H, R 3 It is a halogen; Preferably, the R 2 For halogens, R 3 For H; Preferably, the R 2 For F, R 3 For H.

9. The compound of Formula I as claimed in any one of claims 1-7, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, R 4 The ring is a benzene ring, a naphthalene ring, a 5-10 membered heteroaryl group, or a 5-10 membered heterocyclic group, wherein the benzene ring, naphthalene ring, 5-10 membered heteroaryl group, and 5-10 membered heterocyclic group are optionally surrounded by one, two, or more R groups. 4-1 replace; Each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-3 Alkyl, oxo, -OH, -CN, -COOH, C 1-3 Haloalkyl, C 1-3 Alkoxy, phenyl, C 3-6 Cycloalkyl, 5-8 membered heteroaryl or 4-6 membered heterocyclic, wherein C 1-3 Alkyl, C 1-3 Alkoxy, phenyl, C 3-6 Cycloalkyl, 5-8-membered heteroaryl, and 4-6-membered heterocyclic groups are optionally surrounded by one, two, or more elements selected from H, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substituents of alkoxy groups; Preferably, R 4 The phenyl, pyrroloyl, pyrazolyl, imidazoyl, pyrimidinyl, pyrazinyl, thiophenyl, pyridyl, naphthyl, tetrahydronaphthyl, indenyl, indazoleyl, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, benzo[d]oxazolyl, benzo[2,3-d]pyrimidinyl, benzodihydropyranyl, or dihydrobenzofuranyl are used. The following groups are optionally represented by one, two, or three R groups: pyrazolyl, pyrazolyl, imidazolyl, pyrimidinyl, thiophene, pyridinyl, naphthyl, tetrahydronaphthyl, indole, indazole, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, benzo[d]oxazolyl, benzo[2,3-d]pyrimidine, benzodihydropyranyl, and dihydrobenzofuranyl. 4-1 replace; Each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-3 Alkyl, oxo, -OH, -CN, -COOH, C 1-3 Haloalkyl, C 1-3 Alkoxy, phenyl, C 3-6 Cycloalkyl, 5-8 membered heteroaryl or 4-6 membered heterocyclic, wherein C 1-3 Alkyl, C 1-3 Alkoxy, phenyl, C 3-6 Cycloalkyl, 5-8-membered heteroaryl, and 4-6-membered heterocyclic groups are optionally surrounded by one, two, or more elements selected from H, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substituents of alkoxy groups; Preferably, R 4 The phenyl group is optionally surrounded by one, two, or three R groups. 4-1 replace; Each R 4-1 Independently, it is H, halogen, methyl, -CN, -CF3, -OCF3, -OCHF2, phenyl, cyclopropyl, pyrazolyl, or oxazolyl, wherein the phenyl, cyclopropyl, pyrazolyl, or oxazolyl group is optionally selected by one, two, or three from H, halogen, C, ... 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 Substituents of alkoxy groups; Preferably, each R 4-1 Independently, it is H, halogen, methyl, -CN, -CF3, -OCF3, -OCHF2, cyclopropyl, or oxazolyl, wherein the cyclopropyl and oxazolyl groups are optionally selected from H, halogen, C, ... 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 The alkoxy group is replaced by a substituent.

10. The compound of Formula I as claimed in any one of claims 1-7, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, R 4 for Each q is independently 0, 1, 2 or 3; Each R 4-1 Independently, it is H, halogen, methyl, -CN, -CF3, -OCF3, -OCHF2, phenyl, cyclopropyl, pyrazolyl, or oxazolyl, wherein the phenyl, cyclopropyl, pyrazolyl, or oxazolyl group is optionally selected by one, two, or three from H, halogen, C, ... 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substituents of alkoxy groups; Preferably, each R 4-1 Independently, it is H, halogen, methyl, -CN, -CF3, -OCF3, -OCHF2, cyclopropyl, pyrazolyl, or oxazolyl, wherein the cyclopropyl, pyrazolyl, and oxazolyl groups are optionally selected by one, two, or three from H, halogen, C, ... 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Substituents of alkoxy groups; Preferably, R 4 For not replaced or by one, two or more R 4-1 The following groups are substituted: phenyl or pyridyl; Preferably, R 4 for Preferably, R 4 for 11. The compound of Formula I as claimed in claim 1, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, It meets one or more of the following conditions: (1) Each R 1-1 Halogen and C are independent of each other. 1-6 Alkyl, oxo (=O), -CN, C 3-8 Cycloalkyl or 3-8 membered heterocyclic alkyl; preferably, each R 1-1 Each of the following is independently a halogen, methyl, ethyl, oxo (=O), -CN, cyclopropyl, cyclobutyl, heterocyclobutyl, azirrocyclobutyl, tetrahydropyrrole, or morpholino; preferably, each R 1-1 Each is independently methyl or oxo (=O); preferably, each R 1-1 C, independent of each other 1-6 Alkyl or oxo (=O); preferably, each R 1-1 Each can be either methyl or oxo (=O); (2)R 1 It is a 5-12-membered heteroaryl or a 5-13-membered heterocyclic group, wherein the 5-12-membered heteroaryl and the 5-13-membered heterocyclic group are optionally surrounded by one, two or more R groups. 1-1 Replacement; preferred, R 1 It is an 8-12-membered heteroaryl or an 8-13-membered heterocyclic group, wherein the 8-12-membered heteroaryl and the 8-13-membered heterocyclic group are optionally surrounded by one, two or more R groups. 1-1 Replacement; preferably, R 1 It is a 5-12 member heteroaryl group; preferably, R 1 It consists of 9-10 heteroaryl groups; (3)R 4 C 6-10 Aryl, the C 6-10 aryl groups are bound by one, two or more R groups. 4-1 Replacement; preferably, R 4 For not replaced or by one, two or more R 4-1 Substituted benzene ring; preferably, R 4 For one, two or more R 4-1 Substituted benzene ring; and (4)R 4-1 It is a halogen.

12. The compound of Formula I as claimed in any one of claims 1-11, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, The options are as follows: Option 1, Option 2, Option 3, or Option 4: Option 1: The compound represented by Formula I has the structure shown in Formula II: in, Ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen; One or three of X1, X2, X3, X4 and X6 are nitrogen, and the rest are carbon; m is 0, 1, or 2; p is 0, 1, or 2; R 1-1-1 and R 1-1-2 Each independently possesses the definition described in any one of claims 4-7, R 2 R 3 and R 4 Each has its own definition as described in any one of claims 1-11; when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, the S configuration, or a mixture thereof; Option 2: The compound represented by Formula I has the structure shown in Formula II-1: in, Ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen; One or two of X1, X2, X3, and X4 are nitrogen, and the rest are carbon; q is 0, 1, 2, or 3; m is 0, 1, or 2; p is 0, 1, or 2; R 1-1-1 and R 1-1-2 Each independently possesses the definition described in any one of claims 4-7, R 4-1 Each has its own definition as described in any one of claims 1-11; when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, the S configuration, or a mixture thereof; Preferably, the compound represented by Formula I has the structure shown in any of the structural formulas II-1-a to II-1-h: in, Ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen; One or two of X1, X2, X3, and X4 are nitrogen, and the rest are carbon; q is 0, 1, 2, or 3; m is 0, 1, or 2; p is 0, 1, or 2; R 1-1-1 and R 1-1-2 Each independently possesses the definition described in any one of claims 4-7, R 4-1 Each of them independently has the definition described in any one of claims 1-11; Option 3: The compound represented by Formula I has the structure shown in Formula III: When the carbon atom marked with "*" is a chiral carbon atom, it indicates the R configuration, S configuration, or a mixture thereof; q is 0, 1, 2, or 3; m is 0, 1, or 2; p is 0 or 1; Each R 1-1-1 Independently, H, deuterium, halogen, C 1-3 Alkyl, C 3-5 cycloalkyl or 4-6 membered heterocyclic alkyl; Each R 1-1-2 Independently, H, deuterium, halogen, C 1-6 Alkyl or -OH; Each R 4-1 Independent of H, halogen or C 1-6 alkyl; Preferably, the compound represented by Formula I has the structure shown in III-1 or III-2: q is 0, 1, or 2; m is 0, 1, or 2; p is 0 or 1; Each R 1-1-1 Independently, it can be H, deuterium, halogen, methyl, cyclopropyl, oxecyclobutyl, tetrahydropyrrolyl or morpholino; Each R 1-1-2 Independently, it can be H, deuterium, halogen, methyl, or -OH; Each R 4-1 Independently, it can be H, halogen, or methyl; Option 4: The compound represented by Formula I has the structure shown in Formula II-2: In this ring, ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen; One or three of X1, X2, X3, X4 and X6 are nitrogen, and the rest are carbon; m is 0, 1, or 2; p is 0, 1, or 2; R 1-1-1 and R 1-1-2 Each independently possesses the definition described in any one of claims 4-7, R 2 and R 3 Each has its own definition as described in any one of claims 1-11; when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, the S configuration, or a mixture thereof; Preferably, the compound represented by Formula I has the structure shown in Formula II-2-1 or II-2-2: In this ring, ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen; One or three of X1, X2, X3, X4 and X6 are nitrogen, and the rest are carbon; m is 0, 1, or 2; p is 0, 1, or 2; R 1-1-1 and R 1-1-2 Each independently possesses the definition described in any one of claims 4-7, R 2 and R 3 Each of them independently has the definition as described in any one of claims 1-11.

13. The compound of Formula I according to any one of claims 1-12, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, The compound represented by Formula I is any of the following compounds: Preferably, the compound represented by Formula I is any of the following compounds:

14. The compound, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate according to claim 1, characterized in that, The compound has the structure shown in Formula 1-A: Preferably, compound 1-A has a crystalline form, wherein the crystal system of the crystalline form is monoclinic, the space group is P21, and the cell parameters are:

15. A method for preparing the compound of Formula I according to any one of claims 1-14, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or a pharmaceutically acceptable salt or solvate thereof, wherein the method comprises the following steps when the compound of Formula I has the structure shown in Formula II-1: In a solvent and in the presence of an organic base, the compound shown in formula II-1-A is subjected to a substitution reaction with the compound shown in formula II-1-B to obtain the compound shown in formula II-1: Wherein, X is a halogen, preferably Cl; Ring A is a five- or six-membered heteroaryl ring, in which one of the ring carbon atoms is optionally replaced by oxygen; One or two of X1, X2, X3, and X4 are nitrogen, and the rest are carbon; q is 0, 1, 2, or 3; m is 0, 1, or 2; p is 0, 1, or 2; R 1-1-1 and R 1-1-2 Each independently possesses the definition described in any one of claims 4-7, R 4-1 It independently possesses the definition as described in any one of claims 1-11.

16. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: a compound of Formula I as described in any one of claims 1-14, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

17. The use of a compound of Formula I as claimed in any one of claims 1-14, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or a pharmaceutically acceptable salt or solvate thereof, or the use of a pharmaceutical composition as claimed in claim 16 in the preparation of a medicament; Preferably, the drug is a drug for treating TRPA1-mediated diseases or conditions; Preferably, the TRPA1-mediated diseases or conditions are respiratory diseases, pain, inflammatory diseases, pruritus, gastrointestinal diseases, metabolic diseases, cardiovascular diseases, kidney diseases, neurodegenerative diseases, central nervous system diseases, fibrotic diseases, urinary system diseases, cancer, or mental disorders. The respiratory diseases mentioned are chronic cough, acute cough, subacute cough, bronchitis, asthma, chronic obstructive pulmonary disease (COPD), rhinitis, sleep apnea, or idiopathic pulmonary fibrosis (IPF). The pain described includes acute pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, inflammatory pain, back pain, endometriosis pain, visceral pain, cancer pain, hyperesthesia, neuralgia, migraine, fibromyalgia, or gout. The preferred types of neuralgia include: Sciatica, trigeminal neuralgia, or postherpetic neuralgia (shingles); The inflammatory pain includes: rheumatoid arthritis pain or osteoarthritis pain; The inflammatory diseases mentioned are inflammatory disorders, esophagitis, cystitis, arthritis (e.g., rheumatoid arthritis), atopic dermatitis, or psoriasis; The gastrointestinal diseases mentioned are esophageal reflux disease (GERD), inflammatory bowel disease (IBD), irritable bowel syndrome, ulcerative colitis, Crohn's disease, or gastroduodenal ulcers; The metabolic-related diseases mentioned are diabetes, obesity, or insulin resistance; The cardiovascular-related diseases mentioned are heart failure, myocardial ischemia-reperfusion, myocardial fibrosis, arrhythmia, atherosclerosis, hypertension, or myocardial infarction; The kidney disease referred to is acute kidney injury, diabetic nephropathy, or renal ischemia-reperfusion injury; The neurodegenerative diseases mentioned are Alzheimer's disease, Parkinson's disease, epilepsy, or brain injury; The cancer in question is lung cancer, pancreatic cancer, or melanoma; Preferably, the TRPA1-mediated disease or condition is a respiratory disease, pain, inflammatory disease, pruritus, gastrointestinal disease, or cardiovascular disease. Preferably, the TRPA1-mediated disease or condition is chronic cough, acute cough, subacute cough, bronchitis, asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, sleep apnea, gastrointestinal disease, pain, itching, or urinary incontinence. Preferably, the TRPA1-mediated diseases or conditions also include neuropathy (chemotherapy-induced neuropathy, diabetic neuropathy, HIV-related neuropathy), eye irritation, skin irritation (atopic dermatitis), frostbite, spasms, tension syndrome, generalized rigidity, nerve damage, ischemia, stroke, multiple sclerosis, pelvic allergy, burns, psoriasis, or eczema.

18. The use of the compound of Formula I as claimed in any one of claims 1-14, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition as claimed in claim 16, in the preparation of a TRPA1 inhibitor medicament.

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