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

Abstract

Disclosed in the present invention are a compound as a TRPA1 inhibitor, a pharmaceutical composition thereof, and the use thereof. Moreover, specifically disclosed are a compound of formula I, a racemate thereof, a stereoisomer thereof, a tautomer thereof, an oxynitride thereof, a prodrug thereof, or a pharmaceutically acceptable salt or solvate thereof. The compound has a good inhibitory activity on the TRPA1 and has excellent pharmacokinetic and pharmacodynamic activities.

Description

Compounds, pharmaceutical compositions and applications as TRPA1 inhibitors

[0001] This application claims priority to Chinese Patent Application No. 2024119342983, filed on December 26, 2024, and Chinese Patent Application No. 2025119610074, filed on December 23, 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 TRPA1 inhibitor drugs on the market. Therefore, there is a greater clinical need for inhibitors with high TRPA1 activity to provide patients with more active and safer drug options. Developing TRPA1 inhibitors has great market and medical value. Summary of the Invention

[0009] This invention provides compounds as TRPA1 inhibitors, their racemic forms, their stereoisomers, their tautomers, their nitrides, their prodrugs, or their pharmaceutically acceptable salts or solvates, their pharmaceutical compositions, their preparation methods, and their applications. These compounds exhibit excellent inhibitory activity against TRPA1 and possess 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] Ring A is a 5-10 member heteroaryl group, C 6-10 Aryl, 4-10 membered heterocyclic or C 3-10 Cycloalkyl groups, wherein the heteroatoms in the 5-10 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;

[0013] R 1 For H, deuterium, halogens, C 1-6 Alkyl, C1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, oxo (=O), -NH2, -OH, -COOH, -CN, 3-6 membered heterocyclic alkyl, phenyl, 5-10 membered heteroaryl, -CO-C 1-3 Alkyl, -CONH2, -SO2NH2 or -NHR 1-2 The C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, and 5-10-membered heteroaryl groups are optionally surrounded by one, two, or more R groups. 1-1 replace;

[0014] n is 1, 2, 3 or 4;

[0015] 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;

[0016] 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;

[0017] R 5 H, deuterium, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl groups or -CN;

[0018] R 1-1 and R 1-2 Each can be independently classified as deuterium, halogen, oxo group (=O), -OH, -CN, -COOH, -NH2, -SO2NH2, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl;

[0019] 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 (=O), -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 Cycloalkyl, 5-10-membered heteroaryl, and 4-10-membered heterocyclic groups are optionally surrounded by one, two, or more R groups. 4-1-1 replace;

[0020] Each R 4-1-1 They are the same or different, and independently belong to H, deuterium, halogen, -OH, -CN, -COOH, -SO2NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkyl group.

[0021] In a preferred embodiment of the present invention, the compound represented by Formula I is not one of the following compounds:

[0022] In a preferred embodiment of the present invention, the Not for

[0023] In a preferred embodiment of the present invention, ring A is a 5-10 member heteroaryl group, and C is a 5-10 member heteroaryl group. 6-10 Aryl, 4-10 membered heterocyclic or C 3-10 Cycloalkyl groups, wherein the heteroatoms in the 5-10 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;

[0024] R 1 For H, deuterium, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, oxo (=O), -OH, -COOH, -CN, 3-6 membered heterocyclic alkyl, phenyl, 5-10 membered heteroaryl, -SO2NH2 or -NHR 1-2 The C 1-6 Alkyl, C 1-6Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, and 5-10-membered heteroaryl groups are optionally surrounded by one, two, or more R groups. 1-1 replace;

[0025] n is 1, 2, 3 or 4;

[0026] R 2 and R 3 Each of the following is independent: H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic alkyl;

[0027] 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; 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;

[0028] R 5 H, deuterium, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl groups or -CN;

[0029] R 1-1 and R 1-2 Each can be independently classified as deuterium, halogen, oxo, -OH, -CN, -COOH, -SO2NH2, C. 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, -OH, -COOH, -CN, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl;

[0030] 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-Hydroalkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 5-10-membered heteroaryl, or 4-10-membered heterocyclic group, wherein C1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 3-8 Cycloalkyl, 5-10-membered heteroaryl, and 4-10-membered heterocyclic groups are optionally surrounded by one, two, or more R groups. 4-1-1 replace;

[0031] Each R 4-1-1 They are the same or different, and independently belong to H, deuterium, halogen, -OH, -CN, -COOH, -SO2NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkyl group.

[0032] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula I-0:

[0033] in

[0034] Ring A is a 5-10 member heteroaryl group, C 6-10 Aryl, 4-10 membered heterocyclic or C 3-10 Cycloalkyl groups, wherein the heteroatoms in the 5-10 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;

[0035] R 1 Each is independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2- 6-alkynyl, oxoyl (=O), -NH2, -OH, -COOH, -CN, 3-6-membered heterocyclic alkyl, phenyl, 5-10-membered heteroaryl, -CONH2, -SO2NH2 or -NHR 1-2 The C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, and 5-10-membered heteroaryl groups are optionally surrounded by one, two, or more R groups. 1-1 replace;

[0036] R 0 Each is independently of deuterium, halogen, or has one, two, or more R atoms. 1-1 Replace C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C2-6 alkenyl, C 2-6 Alkyne, oxo (=O), -NH2, -OH, -COOH, -CN, 3-6 membered heterocyclic alkyl, phenyl, 5-10 membered heteroaryl, -CO-C 1-3 Alkyl, -CONH2, -SO2NH2 or -NHR 1-2 The C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, and 5-10-membered heteroaryl groups are optionally surrounded by one, two, or more R groups. 1-1 replace;

[0037] n1 is 0, 1, 2, 3 or 4;

[0038] n2 is 1, 2, 3, or 4.

[0039] And n1+n2 is 1, 2, 3 or 4;

[0040] 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;

[0041] 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;

[0042] R 5 H, deuterium, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl groups or -CN;

[0043] R 1-1 and R 1-2 Each can be independently classified as deuterium, halogen, oxo group (=O), -OH, -CN, -COOH, -NH2, -SO2NH2, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl;

[0044] 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 (=O), -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 Cycloalkyl, 5-10-membered heteroaryl, and 4-10-membered heterocyclic groups are optionally surrounded by one, two, or more R groups. 4-1-1 replace;

[0045] Each R 4-1-1 They are the same or different, and independently belong to H, deuterium, halogen, -OH, -CN, -COOH, -SO2NH2, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkyl group.

[0046] In a preferred embodiment of the present invention, ring A is a 5-6 membered heteroaryl, phenyl, 5-8 membered heterocyclic, or C. 3-8 The cycloalkyl group, wherein the heteroatoms in the 5-6 membered heteroaryl and 5-8 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.

[0047] In a preferred embodiment of the present invention, ring A is a 5-membered heteroaryl, phenyl, or 5-membered heterocyclic group.

[0048] In a preferred embodiment of the present invention, ring A is a 5-10 member heteroaryl or a 4-10 member heterocyclic group; for example, it is a 5-10 member heteroaryl; and for another example, it is a 5 member heteroaryl.

[0049] In a preferred embodiment of the present invention, in ring A, the heteroatom in the heteroaryl group is selected from one or two of N, O and S, and the number of heteroatoms is two.

[0050] In a preferred embodiment of the present invention, ring A is imidazole, triazolyl, pyrrolyl, furanyl, pyrazolyl, thiophenyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dihydrofuranyl, dihydrothiophenyl, dihydropyrrolyl, dioxacyclopentenyl, dihydroimidazolyl, dihydropyrrolyl, dihydroisothiazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydrofuranyl, tetrahydroimidazolyl, tetrahydropyrrolyl, tetrahydropyrrolyl, or tetrahydrothiophenyl; for example, imidazole (e.g.) ), thiazolyl (e.g.) ), dihydroimidazolium (e.g.) ), dihydrooxazolyl (e.g.) ) or pyrazolyl (e.g. ).

[0051] In a preferred embodiment of the present invention, R 1 Each independently can be H, deuterium, or C. 1-6 Alkyl groups; for example, deuterium or C 1-6 alkyl.

[0052] In a preferred embodiment of the present invention, R 1 Each can be H, D, or methyl, for example, methyl.

[0053] In a preferred embodiment of the present invention, n1 is 0, 1, or 2. For example, n1 is 1.

[0054] In a preferred embodiment of the present invention, R 0 Each is independently of deuterium, halogen, or has one, two, or more R atoms. 1-1 Replacement C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, oxo (=O), -NH2, -CN, 3-6 membered heterocyclic alkyl, -CO-C 1-3 Alkyl or -CONH2; for example, R 0 Each is independently of deuterium, halogen, or has one, two, or more R atoms. 1-1 Replacement C 1-6 Alkyl group, -C(O)CH3 or -CONH2; preferably, R 0 It is a halogen.

[0055] In a preferred embodiment of the present invention, R 1-1 Each can be independently a halogen, an oxo group (=O), or -NH2; for example, an oxo group (=O) or -NH2.

[0056] In a preferred embodiment of the present invention, R 0Each can be independently D, methyl, methoxy, oxo (=O), Cl, Br, F, -C(O)CH3, -CHF2, -CH2F, -CH2NH2, -C(O)NH2 or -NH2; for example D, F or Cl, and for example F.

[0057] In a preferred embodiment of the present invention, n2 is 1 or 2.

[0058] In a preferred embodiment of the present invention, R 1 For H, deuterium, halogens, C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-5 cycloalkyl, C 1-3 alkoxy, oxo, -OH, -COOH, -CN or 3-5 membered heterocyclic alkyl, wherein C 1-4 Alkyl, C 1-3 Alkoxy, C 3-5 Cycloalkyl and 3-5 membered heterocyclic alkyl groups are optionally surrounded by one, two or more R groups. 1-1 replace.

[0059] In a preferred embodiment of the present invention, R 1 For H, deuterium, halogens, C 1-4 Alkyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN, or oxecyclobutyl.

[0060] In a preferred embodiment of the present invention, n is 1, 2 or 3.

[0061] In a preferred embodiment of the present invention for R 11 Methyl; R 12 H or deuterium (e.g., R) 12 For H); R 0 Having the definition described in any of the schemes in this application, preferably, R 0 For deuterium or halogen (e.g., R) 0 (Halogen).

[0062] In a preferred embodiment of the present invention for

[0063] In a preferred embodiment of the present invention for

[0064] In a preferred embodiment of the present invention for For example, For example,

[0065] In a preferred embodiment of the present invention, R 5 H, deuterium, C 1-6 Alkyl or C 3-6 Cycloalkyl; for example, R 5 For H.

[0066] In a preferred embodiment of the present invention, R 5 H, deuterium, C 1-3 Alkyl or C 3-4 cycloalkyl; preferably, R 5 It can be H, methyl, ethyl, or cyclopropyl.

[0067] In a preferred embodiment of the present invention, R 2 and R 3 Each can be H, deuterium, or halogen independently.

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

[0069] In a preferred embodiment of the present invention, R 2 and R 3 Each can be independently H, deuterium, halogen, or C. 1-3 Alkyl, and R 2 and R 3 At least one of them is H.

[0070] In a preferred embodiment of the present invention, R 2 For H, R 3 For H or F; or, R 2 For H or F, R 3 For H.

[0071] In a preferred embodiment of the present invention, R 2 For F or H, R 3 For H.

[0072] In a preferred embodiment of the present invention, R 2 and R 3 For H.

[0073] In a preferred embodiment of the present invention, R 4 C 6-10 Aryl, 5-12 membered heteroaryl or 4-10 membered heterocyclic, wherein C 6-10 Aryl, 5-12-membered heteroaryl, and 4-10-membered heterocyclic groups may be selectively coupled with one, two, or more R groups. 4-1 Replace; for example, R 4 C 6-10 Aryl, the C6-10 Aryl groups can be selectively coated with one, two, or more R groups. 4-1 replace.

[0074] In a preferred embodiment of the present invention, R 4 For one or two R 4-1 The substituted phenyl group may be replaced by one or two R groups. 4-1 Substituted naphthyl groups (e.g., with one or two R groups) 4-1 Replacement ).

[0075] In a preferred embodiment of the present invention, each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one, two, or more R groups. 4-1-1 Replace; each R 4-1-1 They are the same or different, and are independent of each other as H, deuterium, or halogen. For example, each R 4-1 They are the same or different, and are independent of each other as H or halogen; for example, they are halogens.

[0076] In a preferred embodiment of the present invention, R 4 The phenyl, dihydroindene, naphthyl, tetrahydronaphthyl, 5-10-membered heteroaryl, or 5-10-membered heterocyclic group is optionally surrounded by one, two, or three R groups. 4-1 replace;

[0077] Each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally surrounded by one, two, or three R groups. 4-1-1 replace;

[0078] Each R 4-1-1 They may be the same or different, and are independent of each other as H, deuterium or halogen.

[0079] In a preferred embodiment of the present invention, R 4 for q can be 0, 1, 2, 3 or 4.

[0080] In a preferred embodiment of the present invention, R 4 for

[0081] In a preferred embodiment of the present invention, R 4 for For example, R 4 for

[0082] In a preferred embodiment of the present invention, q is 0, 1 or 2.

[0083] In a preferred embodiment of the present invention, each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally surrounded by one, two, or more R groups. 4-1-1 replace;

[0084] Each R 4-1-1 They may be the same or different, and are independent of each other as H, deuterium, or halogen;

[0085] q can be 0, 1, 2, 3 or 4.

[0086] In a preferred embodiment of the present invention, R 4 for

[0087] In a preferred embodiment of the present invention, R 4 for For example, R 4 for For example, R 4 for

[0088] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula I-1:

[0089] Among them, rings A, n, and R 1 R 2 R 3 R 4-1 R 5Each of q has the definition described in any of the schemes in this application. When the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration, or a mixture thereof.

[0090] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula II:

[0091] in,

[0092] R 11 For H, C 1-6 Alkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclic alkyl;

[0093] R 12 H, halogen or C 1-6 alkyl;

[0094] R 1 R 2 R 3 R 4 and R 5 Each has its own independent definition as described in any of the schemes in this application.

[0095] In a preferred embodiment of the present invention, R 1 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0096] R 2 and R 3 Each is independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0097] R 4 C 6-10 Aryl, 5-10 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 three R's. 4-1 replace;

[0098] R 5 H, deuterium, C 1-6 Alkyl or C 3-6 cycloalkyl;

[0099] 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-halogenated alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one, two, or more R groups. 4-1-1 replace;

[0100] Each R 4-1-1 They may be the same or different, and are independent of each other as H, deuterium, halogen, -OH, -CN, -COOH or -SO2NH2.

[0101] In a preferred embodiment of the present invention, in formula II, R 11 For H or C 1-6 Alkyl, for example, C 1-6 Alkyl, for example, methyl.

[0102] In a preferred embodiment of the present invention, in formula II, R 12 For H.

[0103] In a preferred embodiment of the present invention, in formula II, R 1 It is a halogen, for example, F or Cl, or F for example.

[0104] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula III:

[0105] Among them, R 1 R 2 R 3 and R 4 Each has its own definition as described in any of the schemes in this application. When the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration, or a mixture thereof.

[0106] In a preferred embodiment of the present invention, in formula III, R 1 It is a halogen, for example, F or Cl, or F for example.

[0107] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula III-1:

[0108] R 1 Halogen, methyl, ethyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or -C(=O)C 1-3 Alkyl, q and R 4-1Each has its own definition as described in any of the embodiments of this application. When the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration, or a mixture thereof.

[0109] In a preferred embodiment of the present invention, in formula III, R 1 It is a halogen, for example, F or Cl, or F for example.

[0110] In a preferred embodiment of the present invention, the compound represented by Formula I has any of the structures shown in formulas III-1-a to III-1-h:

[0111] R 1 q and R 4-1 Each has its own independent definition as described in any of the embodiments of this application.

[0112] In a preferred embodiment of the present invention, R 1 Halogen, methyl, ethyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or -C(=O)C 1-3 alkyl;

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

[0114] R 4-1 Halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl or C 1-3 Halogenated alkoxy groups.

[0115] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula IV:

[0116] Where R 2 R 3 q and R 4-1 Each has its own definition as described in any of the schemes in this application. When the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration, or a mixture thereof.

[0117] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in any of the structural formulas IV-a to IV-h:

[0118] Where R 2 R 3 q and R 4-1 Each has its own independent definition as described in any of the schemes in this application.

[0119] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula IV-1:

[0120] Where R 2 R 3 q and R 4-1 Each has its own definition as described in any of the schemes in this application. When the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, S configuration, or a mixture thereof.

[0121] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in any of the structural formulas IV-1-a to IV-1-h:

[0122] Where R 2 R 3 q and R 4-1 Each has its own independent definition as described in any of the schemes in this application.

[0123] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula V:

[0124] Where q and R 4-1 Each has its own independent definition as described in any of the schemes in this application.

[0125] In a preferred embodiment of the present invention, the compound represented by Formula I has any of the structural formulas shown in Va to Vh:

[0126] Where q and R 4-1 Each has its own independent definition as described in any of the schemes in this application.

[0127] In a preferred embodiment of the present invention, the compound represented by Formula I has the structure shown in Formula V-1:

[0128] Where q and R 4-1 Each has its own independent definition as described in any of the schemes in this application.

[0129] In a preferred embodiment of the present invention, the compound represented by Formula I has any of the structural formulas shown in V-1-a to V-1-h:

[0130] Where q and R 4-1 Each has its own independent definition as described in any of the schemes in this application.

[0131] In a preferred embodiment of the present invention, the compound is any of the following compounds or pharmaceutically acceptable salts thereof:

[0132] In a preferred embodiment of the present invention, the compound has the following structure:

[0133] In a preferred embodiment of the present invention, the compound has the following structure:

[0134] In a preferred embodiment of the present invention, compound 5 has a crystalline form, wherein the crystal system of the crystalline form is orthorhombic, the space group is P212121, and the unit cell parameters are:

[0135] The present invention also provides a method for preparing the compound shown in Formula I, comprising the following steps: in a solvent, in the presence of a condensing agent and an organic base, performing a condensation reaction between the compound shown in Formula IA and the compound shown in Formula I to obtain the compound shown in Formula I.

[0136] Among them, rings A and R 1 R 2 R 3 R 4 R 5 Each of the two elements, n, has its own definition as described in any one of the present invention. When the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, the S configuration, or a mixture thereof.

[0137] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I as described in any one of the present invention, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or a pharmaceutically acceptable salt or solvate thereof.

[0138] In a preferred embodiment of the present invention, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier.

[0139] 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.

[0140] The present invention further provides the use of compounds of Formula I according to any one of the present invention, their racemates, their stereoisomers, their tautomers, their nitrides, their prodrugs, or their pharmaceutically acceptable salts or solvates, or the use of said pharmaceutical compositions as pharmaceuticals.

[0141] 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 a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition thereof in the preparation of a medicament.

[0142] In a preferred embodiment of the present invention, the drug is a drug for diagnosing, preventing and / or treating TRPA1-mediated diseases or conditions.

[0143] In a preferred embodiment of the present invention, the drug is a TRPA1 inhibitor.

[0144] 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, or optionally, in combination with another compound of the present invention and / or at least one other type of therapeutic agent.

[0145] In a preferred embodiment of the present invention, 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.

[0146] According to the present invention, the disease or symptom is a respiratory disease, pain, inflammatory disease, itching, or gastrointestinal disease.

[0147] The respiratory diseases mentioned are: chronic cough, acute cough, subacute cough, bronchitis, asthma, chronic obstructive pulmonary disease (COPD), rhinitis, or idiopathic pulmonary fibrosis.

[0148] The pain referred to includes: acute pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritis pain, osteoarthritis pain, back pain, visceral pain, cancer pain, hyperesthesia, neuralgia, migraine, postherpetic neuralgia, fibromyalgia, sciatica, or postherpetic neuralgia (herpes zoster).

[0149] The inflammatory diseases mentioned include: inflammatory disorders, esophagitis, arthritis (e.g., rheumatoid arthritis), atopic dermatitis, or psoriasis.

[0150] The gastrointestinal disease mentioned is a sensory disorder-related gastrointestinal disease, selected from gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), irritable bowel syndrome, ulcerative colitis, Crohn's disease, or gastroduodenal ulcer.

[0151] In a preferred embodiment of the present invention, the disease or symptom is chronic cough, acute cough, subacute cough, bronchitis, asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, pain, sleep apnea, gastrointestinal disease, itching, or urinary incontinence.

[0152] In a preferred embodiment of the present invention, the TRPA1-mediated diseases or conditions may also include sleep apnea, neuropathy, chemotherapy-induced neuropathy, eye irritation, skin irritation (atopic dermatitis), frostbite, spasms, tension syndrome, generalized rigidity, Parkinson's disease, diabetic neuropathy, HIV-related neuropathy, nerve damage, ischemia, neurodegenerative diseases, stroke, multiple sclerosis, pelvic allergy, cystitis, burns, psoriasis, eczema, or vomiting.

[0153] The compounds of the present invention can be used in combination with other therapeutic agents. Beneficial effects

[0154] The positive and progressive effects of this invention are as follows: This invention provides a TRPA1 inhibitor compound represented by Formula I, which has good TRPA1 inhibitory activity, as well as excellent pharmacokinetic and pharmacodynamic properties.

[0155] Terminology Definitions and Explanations

[0156] 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.

[0157] 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.

[0158] 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.

[0159] "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

[0160] 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 independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0161] In the general formula definition of this application, the term "optional" (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.

[0162] 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.

[0163] The term "n-ary", where n is an integer, usually describes the number of ring atoms in a aryl atom.

[0164] 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.

[0165] 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.

[0166] Unless otherwise stated, “multiple” means three or more, such as 3, 4, 5, 6, 7, 8 or 9.

[0167] 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 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, or their isomers. For example, methyl.

[0168] 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, 1-bromomethyl-2-bromoethyl, etc.

[0169] 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.

[0170] 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, C 3-6 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.

[0171] The term "3-6 heterocyclic alkyl" refers to a saturated cyclic group having 3 to 6 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 groups 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. The 3-6 membered heterocyclic alkyl group includes 3-5 membered heterocyclic alkyl groups, 5 membered heterocyclic alkyl groups, etc., and the heterocyclic alkyl group can be linked to other segments or groups in the compound through cyclic carbon atoms or cyclic heteroatoms. Heterocyclic alkyl groups include, but are not limited to, nitrogen-containing heterocyclic butyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, etc.

[0172] 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.

[0173] The term "5-12-membered heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 5-12 ring atoms, with each ring atom comprising 1-5 heteroatoms independently selected from N, O, and S, and wherein the bicyclic and tricyclic aromatic ring systems can be fused rings. The 5-12-membered heteroaryl includes 5-7-membered, 5-10-membered, 7-12-membered, 9-10-membered, 5-membered, and 9-membered heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, oxazolyl, isoxazolyl, pyrazolyl, pyrroleyl, imidazolyl, triazolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, and pyridazinyl groups. 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.

[0174] The term "4-10 membered heterocyclic group" refers to a saturated or partially unsaturated non-aromatic ring or ring system having 4-10 ring atoms, and whose ring atoms contain 1-5 heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrogen oxides, -S(=O)-, or -S(=O)2- states. The 4-10 membered heterocyclic group includes 4-10 membered heterocyclic alkyl groups and 4-10 membered heterocyclic alkenyl groups, which can be 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, or 10-membered bicyclic, or 10-membered tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include fused rings, bridged rings, or spirocyclic rings. The 4-10 membered heterocyclic group includes 4-8 membered heterocyclic groups, 4-6 membered heterocyclic groups, 4-5 membered heterocyclic groups, etc. The heterocyclic group can be connected to the rest of the molecule through any one carbon or nitrogen atom (if present) on its ring. Examples of heterocyclic groups include, but are not limited to: azirrobutyl, oxacyclobutyl, tetrahydrofuranyl, dioxacyclopentenyl, 2,3-dihydro-1H-imidazolyl, pyrrolyl, imidazolyl, pyrrolinyl, dihydrofuranyl, dihydropyranyl, tetrahydropyranyl, dihydropyridyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, trithiaalkyl, 4,6-dihydro-1H-furano[3,4] -c]pyrazolyl, 2,6-dihydro-4H-furano[3,4-c]pyrazolyl, 5,6-dihydro-1H-furano[3,2-c]pyrazolyl, 5,6-dihydro-2H-furano[3,2-c]pyrazolyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 2,4,5,6-tetracyclopentano[c]pyrazolyl, etc. Optionally, the heterocyclic group may be benzo[d][1,3]m-dioxacyclopentenyl.

[0175] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine, or chlorine, or fluorine.

[0176] The term "halogenation" refers to the replacement of a substance with one, two, or more halogens.

[0177] Unless otherwise stated, the term "hydrogen" refers to the hydrogen atom portion (-H), not H2.

[0178] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0179] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0180] The term "bridged ring" refers to a ring system in which two rings share two or more cyclic atoms.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0191] 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.

[0192] 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).

[0193] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0194] The term "pharmaceutical acceptable" means that salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for patient use.

[0195] 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 and 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] The reagents and raw materials used in this invention are all commercially available. Attached Figure Description

[0200] Figure 1 shows the absolute stereoconfiguration of compound 5. Detailed Implementation

[0201] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0202] The terms used in the following specific experimental descriptions represent (unless otherwise stated) the following reagents or procedures:

[0203] TFA: Trifluoroacetic acid; TBAF: Tetrabutylammonium fluoride; DMF: N,N-Dimethylformamide; MTBE: Methyl tert-butyl ether; DCM: Dichloromethane; EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide 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'-tetrafluoroethylene Methylurea hexafluorophosphate; m-CPBA: m-chloroperoxybenzoic acid; DIEA: N,N-diisopropylethylamine; IPA: isopropanol; PE: petroleum ether; EtOAc / EA: ethyl acetate; PPh3: triphenylphosphine; AIBN: azobisisobutyronitrile; NBS: N-bromosuccinimide; n-BuLi: n-butyllithium; DIPEA: N,N-diisopropylethylamine; TPGS: vitamin E polyethylene glycol succinate; PEG: polyethylene glycol; EDTA: ethylenediaminetetraacetic acid; po: oral; iv: tail vein bolus;

[0204] <Preparation Examples>

[0205] Preparation Example 1: Preparation of Intermediates 1-4

[0206] Step 1: Preparation of Intermediate 1-1

[0207] Cyanamide (15 g, 178.40 mmol, 50% purity) was dissolved in triethyl orthoformate (60 mL, 360.73 mmol) and stirred at 100 °C for 3 hours. The reaction solution was then distilled under reduced pressure (oil bath temperature 150 °C, vapor pressure temperature 112 °C) to give intermediate 1-1 (6 g).

[0208] Step 2: Preparation of intermediates 1-2

[0209] Intermediate 1-1 (6 g, 61.16 mmol) was dissolved in THF (20 mL), and sarcosine methyl ester hydrochloride (6.37 g, 61.77 mmol) and TEA (6.44 g, 63.61 mmol) were added. The mixture was reacted at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated to remove the solvent. An ethanol solution of sodium ethoxide (9.7 g, 53.87 mmol, 30% purity) was added, and the mixture was stirred at room temperature for 1 hour, then stirred overnight at 4°C. The mixture was filtered to obtain a yellow solid, which was then concentrated under reduced pressure to remove the solvent, yielding intermediate 1-2 (0.56 g). LC-MS: [M+H] + =170.05.

[0210] Step 3: Preparation of intermediates 1-3

[0211] 0.52 g (5.04 mmol) of tert-butyl nitrite was dissolved in acetonitrile (10 mL), and cuprous chloride (0.36 g (3.64 mmol) was added. Then, intermediate 1-2 (0.5 g (2.96 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours, followed by stirring at 60 °C for 1 hour. After the reaction solution cooled to room temperature, HCl (20 mL, 2N) and DCM (20 mL) were added. The organic phase was separated, and the aqueous phase was extracted with DCM (40 mL × 2). The organic phases were combined, washed with saturated brine, 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 = 1:1) to obtain intermediate 1-3 (0.04 g). LC-MS: [M+H] + =189.00.

[0212] Step 4: Preparation of intermediates 1-4

[0213] Intermediate 1-3 (0.04 g, 0.21 mmol) was dissolved in methanol (2.5 mL) and water (0.5 mL), and sodium hydroxide (0.025 g, 0.63 mmol) was added. The mixture was stirred at 60 °C for 1 hour. The pH of the reaction solution was adjusted to 5 with HCl (2N), and then water (10 mL) and ethyl acetate (10 mL) were added. The mixture was extracted, and the aqueous phase was extracted again with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 1-4 (0.02 g).

[0214] Preparation Example 2: Preparation of Intermediate 2-2

[0215] Step 1: Preparation of intermediate 2-1

[0216] 4,5-Dibromo-1-methyl-1H-imidazole (900 mg, 3.75 mmol) was weighed into a reaction flask, dissolved in THF (10 mL), and purged with nitrogen three times. At -78 °C, n-butyllithium (2.5 M, 1.65 mL, 4.13 mmol) was added, and the mixture was stirred for 15 min. Then, dimethyl carbonate (371.58 mg, 4.13 mmol) was added, and the mixture was slowly heated to 25 °C and reacted for 2 h. At 0 °C, the reaction solution was quenched by pouring it into a saturated ammonium chloride aqueous solution (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with a saturated sodium chloride aqueous solution (60 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 2-1 (0.1 g). LC-MS: [M+H] + =220.90.

[0217] Step 2: Preparation of intermediate 2-2

[0218] Weigh intermediate 2-1 (0.1 g, 0.46 mmol), dissolve in THF (2 mL), then add lithium hydroxide (0.033 g, 1.38 mmol) and water (1 mL), and react at room temperature for 2 h. Adjust the pH to 4–5 with 4 M hydrogen chloride aqueous solution, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated sodium chloride aqueous solution (20 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 2-2 (0.07 g). LC-MS: [M+H] + =206.90.

[0219] Preparation Example 3: Preparation of Intermediate 3-8

[0220] Step 1: Synthesis of intermediate 3-1

[0221] 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 with 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 3-1 (16 g).

[0222] Step 2: Synthesis of intermediate 3-2

[0223] Weigh 16 g (87.60 mmol) of intermediate 3-1 into a reaction flask, dissolve it in 160 mL of DCM, and add m-chloroperoxybenzoic acid (17.01 g, 98.55 mmol, purity: 85%) 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 3-2 (15 g).

[0224] Step 3: Synthesis of intermediate 3-3

[0225] Intermediate 3-2 (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 solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated sodium chloride 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 3-3 (9 g).

[0226] Step 4: Synthesis of intermediates 3-4

[0227] Intermediate 3-3 (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 give intermediate 3-4 (10 g).

[0228] Step 5: Synthesis of intermediates 3-5

[0229] Weigh intermediate 3-4 (300 mg, 1.53 mmol) into a reaction flask, dissolve in DCM (10 mL), add trimethylsilane (227.69 mg, 2.29 mmol) and boron trifluoride ether (217.15 mg, 1.53 mmol), and react at room temperature for 2 h. Quench the reaction with saturated sodium bicarbonate aqueous solution (20 mL), extract with dichloromethane (20 mL × 3), combine the organic phases, wash with saturated sodium chloride aqueous solution (100 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography. A pair of diastereomers are obtained; the product spotted first is the non-target product, and its R... f =0.4 (dichloromethane: methyl tert-butyl ether = 30:1), the product at the second spot is the target product intermediate 3-5 (250mg), its R f =0.3 (dichloromethane: methyl tert-butyl ether = 30:1).

[0230] Intermediate 3-5 includes 3-5-1 and 3-5-2.

[0231] Step 6: Synthesis of intermediates 3-6

[0232] Weigh intermediate 3-5 (90 mg, 0.40 mmol) into a reaction flask, dissolve it in DCM (3 mL), cool to -78 °C, add diethylaminosulfur trifluoride (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 3-6 (75 mg).

[0233] Intermediate 3-6 includes 3-6-1 and 3-6-2.

[0234] Step 7: Synthesis of intermediates 3-7

[0235] Intermediate 3-6 (0.02 g, 0.089 mmol) was weighed into a reaction flask, dissolved in 2 mL of EtOH, and then reacted with hydroxylamine aqueous solution (0.024 g, 0.36 mmol) 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 to give intermediate 3-7 (0.075 g). LC-MS: [M+H] + =259.00.

[0236] Intermediate 3-7 includes 3-7-1 and 3-7-2.

[0237] Step 8: Synthesis of intermediates 3-8

[0238] Intermediate 3-7 (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. 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 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 3-8 (0.07 g). LC-MS: [M+H] + =317.00.

[0239] Intermediate 3-8 includes 3-8-1 and 3-8-2.

[0240] Preparation Example 4: Preparation of Intermediate 4-8

[0241] Step 1: Preparation of intermediate 4-2

[0242] Weigh liquid bromine (53.88 g, 337.3 mmol) into a reaction flask, add dichloromethane (400 mL), protect under nitrogen atmosphere, cool to -30 °C, and slowly add a dichloromethane solution (400 mL) of intermediate 3-1 (56 g, 306.6 mmol). React at -30 °C for 1 hour, then quench the reaction in a saturated sodium sulfite aqueous solution (1000 mL), extract with dichloromethane (300 mL × 3), combine the organic phases, wash 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 4-2 (100 g).

[0243] Step 2: Preparation of intermediate 4-3

[0244] Weigh 100 g (292 mmol) of intermediate 4-2 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 400 mL of saturated ammonium chloride aqueous solution to the reaction solution, then add water (1000 mL) and extract with ethyl acetate (300 mL × 3). Combine the organic phases, wash with 500 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 to obtain intermediate 4-3 (40 g).

[0245] Step 3: Preparation of intermediate 4-4

[0246] Weigh intermediate 4-3 (40 g, 152.96 mmol) into a reaction flask, add tetrahydrofuran (500 mL), add trimethylcyanosilane (75.88 g, 764.8 mmol), under nitrogen protection, cool to 0 °C, slowly add tetrabutylammonium fluoride (458.9 mL, 1 N, 458.9 mmol), and 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 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 4-4 (10 g).

[0247] Step 4: Preparation of intermediate 4-5

[0248] Weigh 11 g (52.95 mmol) of intermediate 4-4 into a reaction flask, add 100 mL of ethanol and 14 g (211.88 mmol, 50% Wt), and react under nitrogen protection at 80 °C for 16 hours. Pour the reaction mixture into 300 mL of water, extract with ethyl acetate (200 mL × 3), combine the organic phases, wash with 300 mL of saturated sodium chloride solution, dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 11 g of intermediate 4-5. LC-MS: [M+H] + =240.95.

[0249] Step 5: Preparation of intermediates 4-6

[0250] Weigh intermediate 4-5 (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 with saturated sodium chloride aqueous solution (200 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain intermediate 4-6 (12 g). LC-MS: [M+H] + =316.9.

[0251] Step 7: Preparation of intermediates 4-7

[0252] Intermediate 4-6 (12 g, 37.84 mmol) was weighed into a reaction flask, and toluene (100 mL) and 4A molecular sieve (40 g) were added. The 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 4-7 (10 g). LCMS: [M+H] + =298.90.

[0253] Step 8: Preparation of intermediate 4-8

[0254] At room temperature, intermediate 4-7 (150 mg, 0.50 mmol) and an ethanol solution of ammonia (2.5 mL, 2 M) were added to a sealed container, and the reaction mixture was heated to 60 °C and stirred for 16 hours. After the reaction mixture was cooled to room temperature, it was directly concentrated under reduced pressure to obtain intermediate 4-8 (100 mg).

[0255] LC-MS:[M+H] + =279.95.

[0256] Preparation Example 5: Preparation of Intermediate 3-9

[0257] Following the preparation method of intermediate 4-8, intermediate 3-9 can be prepared using intermediate 3-8 as raw material.

[0258] Intermediate 3-8 (120 mg, 0.38 mmol) was added to an isopropanol solution of ammonia (15 mL, 30 mmol) at room temperature, and the reaction was carried out overnight at 50 °C with stirring. The reaction solution was then concentrated directly to dryness under reduced pressure to give intermediate 3-9 (110 mg). LC-MS: [M+H] + =298.00.

[0259] Intermediate 3-9 includes 3-9-1 and 3-9-2.

[0260] Referring to the preparation method for intermediates 4-8 in the above preparation examples, the following compounds were prepared using appropriate steps and starting materials:

[0261] Preparation Example 6: Preparation of Intermediate 6-4

[0262] Step 1: Preparation of intermediate 6-2

[0263] At room temperature, 6-SM-01 (1.00 g, 7.93 mmol) was dissolved in ethanol (10 mL), followed by the addition of methanesulfonic acid (2.06 mL, 31.72 mmol). The reaction mixture was heated to 115 °C in a sealed tube for 16 hours. After cooling to room temperature, the organic solvent ethanol was removed by direct concentration under reduced pressure. Then, saturated sodium bicarbonate solution was slowly added to the reaction mixture until the pH reached 8-9. Ethyl acetate (10 mL × 3) was added for extraction. The organic phases were combined, washed once with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 6-1 (714 mg). LC-MS: [M+H]+=156.05.

[0264] Step 2: Preparation of intermediate 6-2

[0265] At room temperature, intermediate 6-1 (250 mg, 1.61 mmol) was dissolved in fluoroboric acid (8.61 mL, 67.62 mmol), and the solution was cooled to -10 °C. Then, sodium nitrite (555 mg, 8.05 mmol) dissolved in water (1 mL) was slowly added to the reaction solution until the solution turned blue-green. The reaction solution was then placed in a 302 nm light irradiator and left at room temperature overnight. The reaction solution was cooled to 0 °C, and then sodium hydroxide aqueous solution (5 M) was slowly added dropwise until neutral. The solution was extracted with ethyl acetate (30 mL × 3), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 6-2 (200 mg).

[0266] Step 3: Preparation of intermediate 6-3

[0267] Intermediate 6-2 (130 mg, 0.82 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, followed by the addition of methanol (31 mg, 0.98 mmol), triphenylphosphine (279 mg, 1.07 mmol), and diisopropyl azodicarbonate (199 mg, 0.98 mmol). The reaction mixture was allowed to react at room temperature for 0.5 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give intermediate 6-3 (120 mg). LC-MS: [M+H] + =173.05.

[0268] Step 4: Preparation of intermediate 6-4

[0269] Weigh 120 mg (0.70 mmol) of intermediate 6-3 into a reaction flask, dissolve it in 1.50 mL of ethanol, then cool the reaction solution to 0 °C. Slowly add 0.56 mL (2.80 mmol, 5 M) of sodium hydroxide aqueous solution. After the addition is complete, allow the reaction solution to react at room temperature for 1 hour. Concentrate the reaction solution under reduced pressure, then slowly add dilute hydrochloric acid (2 N) to adjust the pH to 3-5. Extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with 10 mL of saturated sodium chloride aqueous solution, dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 80 mg of compound intermediate 6-4. LC-MS: [M+H] + =145.00.

[0270] Preparation Example 7: Preparation of Intermediates 7-8

[0271] Step 1: Preparation of Intermediate 7-1

[0272] 7-SM-01 (5 g, 31.53 mmol) was added to a reaction flask, followed by R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.98 g, 1.58 mmol), allyl acetate (31.57 g, 315.30 mmol), isopropanol (4.83 mL, 63.06 mmol), 4-chloro-3-nitrobenzoic acid (0.64 g, 3.15 mmol), 1,5-cyclooctadiene iridium chloride dimer (0.64 g, 0.95 mmol), and cesium carbonate (2.05 g, 6.31 mmol). Then, 1,4-dioxane (50 mL) was added, and the mixture was purged with nitrogen for 10 minutes. The reaction was carried out at 112 °C for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 19:1) to give compound 7-1 (4.87 g).

[0273] Step 2: Preparation of intermediate 7-2

[0274] Liquid bromine (1.63 mL, 31.76 mmol) was dissolved in dichloromethane (25 mL), nitrogen gas was purged, and the mixture was cooled to -30 °C. A dichloromethane (25 mL) solution of 7-1 (5.31 g, 26.47 mmol) was slowly added, and the reaction mixture was stirred at -30 °C for 1 hour. The reaction mixture was then quenched in a saturated sodium sulfite aqueous solution (100 mL), and extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed with a saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 7-2 (9.66 g).

[0275] Step 3: Preparation of intermediate 7-3

[0276] 7-2 (9.66 g, 26.80 mmol) was dissolved in anhydrous methanol (20 mL), and anhydrous potassium carbonate (14.82 g, 107.20 mmol) was added. The mixture was reacted overnight at room temperature. The reaction solution was poured into a saturated ammonium chloride aqueous solution (100 mL), diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed once with a saturated sodium chloride aqueous solution (500 mL). The mixture was 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 = 19:1) to give compound 7-3 (5.01 g).

[0277] Step 4: Preparation of intermediate 7-4

[0278] 7-3 (5.01 g, 17.92 mmol) was dissolved in tetrahydrofuran (50 mL), and trimethylcyanosilane (9.16 g, 89.60 mmol) was added. The mixture was cooled to 0 °C, and then tetrabutylammonium fluoride (53.76 mL, 53.76 mmol, 1 M) was added. After the addition was complete, the mixture was heated to 50 °C and reacted overnight. The reaction solution was poured into water (100 mL), and extracted with dichloromethane (100 mL × 3). The organic phases were combined and washed once with saturated sodium chloride aqueous solution (100 mL). The solution was 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 = 10:1) to give a pair of diastereomers. The first point R... f =0.29 (petroleum ether: ethyl acetate = 5:1), intermediate 7-4 (1.17 g). Second point R f =0.12 (petroleum ether: ethyl acetate = 5:1), which is a non-target intermediate (1.12 g).

[0279] Step 5: Preparation of intermediate 7-5

[0280] Intermediate 7-4 (1.17 g, 5.19 mmol) was dissolved in anhydrous ethanol (10 mL), and hydroxylamine (1.27 mL, 20.76 mmol, 50% aqueous solution) was added. The reaction mixture was reacted at 80 °C for 2 hours. The reaction solution was poured into water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed once with saturated sodium chloride aqueous solution (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 7-5 (1.37 g). LC-MS: [M+H] + =259.00.

[0281] Step 6: Preparation of intermediate 7-6

[0282] Intermediate 7-5 (1.37 g, 5.30 mmol) was dissolved in methyl tert-butyl ether (13 mL), purged with nitrogen three times, cooled to 0 °C, and chloroacetic anhydride (1.0 g, 5.83 mmol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. A saturated sodium bicarbonate aqueous solution (10 mL) was slowly added dropwise to the reaction mixture, followed by extraction with ethyl acetate (20 mL × 3). The organic phases were combined and washed once with a saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 7-6 (1.68 g). LC-MS: [M+H] + =334.90.

[0283] Step 7: Preparation of intermediate 7-7

[0284] Intermediate 7-6 (1.68 g, 5.01 mmol) was dissolved in toluene (15 mL), and 4A molecular sieve powder (2 g) was added. The mixture was stirred overnight at 100 °C under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give intermediate 7-7 (560 mg). LC-MS: [M+H] + =316.90.

[0285] Step 8: Preparation of intermediates 7-8

[0286] Intermediate 7-7 (200 mg, 0.63 mmol) was dissolved in ammonia in isopropanol (2 mL, 2 M), and the reaction mixture was heated to 60 °C and reacted overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give intermediate 7-8 (97 mg). LC-MS: [M+H] + =297.95.

[0287] Preparation 8: Preparation of intermediates 8-9

[0288] Weigh 8-SM-01 (8 g, 64.46 mmol) into a reaction flask, add 1,4-dioxane (100 mL), 4-chloro-3-nitrobenzoic acid (1.3 g, 6.45 mmol), 1,5-cyclooctadiene iridium chloride dimer (1.3 g, 1.93 mmol), cesium carbonate (4.2 g, 12.89 mmol), R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (2.01 g, 12.78 mmol), allyl acetate (7.1 g, 70.91 mmol), and isopropanol (7.75 g, 128.92 mmol), and react at 112 °C for 20 hours under nitrogen protection. Concentrate the reaction solution under reduced pressure, and purify the residue by silica gel column chromatography to obtain intermediate 8-1 (8.6 g).

[0289] Step 2: Preparation of intermediate 8-2

[0290] Weigh intermediate 8-1 (2 g, 12.03 mmol) into a reaction flask, add dichloromethane (20 mL), protect with nitrogen, cool to 0 °C, slowly add m-chloroperoxybenzoic acid (7.79 g, 36.09 mmol), and after completion, react at room temperature for 2 hours. Quench the reaction in saturated sodium sulfite aqueous solution (60 mL), extract with dichloromethane (100 mL × 3), combine the organic phases, wash once with saturated sodium bicarbonate aqueous solution (100 mL), wash once with saturated sodium chloride aqueous solution (100 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 8-2 (1.6 g).

[0291] Step 3: Preparation of intermediate 8-3

[0292] Weigh intermediate 8-2 (1.6 g, 8.78 mmol) into a reaction flask, add 1,4-dioxane (200 mL) and sulfuric acid (0.86 g, 8.78 mmol), and react at 50 °C for 12 hours. Concentrate the reaction solution under reduced pressure, then adjust the pH to 7-8 with saturated sodium bicarbonate aqueous solution, then extract with water (100 mL) and ethyl acetate (60 mL × 3), combine the organic phases, wash once with saturated sodium chloride aqueous solution (100 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 8-3 (0.9 g).

[0293] Step 4: Preparation of intermediate 8-4

[0294] Carbon tetrabromide (2.29 g, 6.92 mmol) was weighed into a reaction flask, and dichloromethane (20 mL) was added. Under nitrogen protection, the mixture was cooled to 0 °C, and a mixed solution of triphenylphosphine (3.63 g, 13.83 mmol) in dichloromethane (10 mL) was added. After the reaction was completed, the mixture was allowed to react at room temperature for 0.5 hours, and then cooled to 0 °C again. A solution of intermediate 8-3 (0.9 g, 4.94 mmol) in dichloromethane (10 mL) was added, and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was then quenched in water (100 mL), and the mixture was extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed once 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 to obtain intermediate 8-4 (0.7 g).

[0295] Step 5: Preparation of intermediate 8-5

[0296] Weigh intermediate 8-4 (0.7 g, 2.86 mmol) into a reaction flask, add tetrahydrofuran (10 mL), add trimethylcyanosilane (1.42 g, 14.3 mmol), under nitrogen protection, cool to 0 °C, slowly add tetrabutylammonium fluoride (8.58 mL, 1N, 8.58 mmol), and then react at 80 °C for 16 hours. Pour the reaction solution into water (100 mL), extract with ethyl acetate (60 mL × 3), combine the organic phases, wash once with saturated sodium chloride aqueous solution (100 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 8-5 (0.18 g) (R). f =0.23, petroleum ether:ethyl acetate = 3:1).

[0297] Intermediate 8-5 contains a pair of enantiomers, with structures as shown in 8-5-1 and 8-5-2, or as shown in 8-5-3 and 8-5-4.

[0298] Step 6: Preparation of intermediate 8-6

[0299] Weigh intermediate 8-5 (0.18 g, 0.94 mmol) into a reaction flask, add ethanol (1 mL) and hydroxylamine (0.25 g, 3, 76 mmol, 50% wt), and react under nitrogen protection at 80 °C for 2 hours. Pour the reaction solution into water (60 mL), extract with ethyl acetate (60 mL × 3), combine the organic phases, wash once with saturated sodium chloride aqueous solution (100 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound intermediate 8-6 (0.2 g). LC-MS: [M+H] + =225.05.

[0300] Intermediate 8-6 contains a pair of enantiomers, with structures shown in 8-6-1 and 8-6-2, or as shown in 8-6-3 and 8-6-4.

[0301] Step 7: Preparation of intermediate 8-7

[0302] Weigh intermediate 8-6 (0.19 g, 0.83 mmol) into a reaction flask, add methyl tert-butyl ether (3 mL), protect under nitrogen atmosphere, cool to 0 °C, add chloroacetic anhydride (0.13 g, 0.77 mmol), and stir at room temperature for 0.5 hours. Slowly add saturated sodium bicarbonate aqueous solution (10 mL) to the reaction solution, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash once with saturated sodium chloride aqueous solution (60 mL), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound intermediate 8-7 (0.2 g). LC-MS: [M+H] + =300.95.

[0303] Intermediate 8-7 contains a pair of enantiomers, with structures shown in 8-7-1 and 8-7-2, or as shown in 8-7-3 and 8-7-4.

[0304] Step 8: Preparation of intermediate 8-8

[0305] Intermediate 8-7 (0.2 g, 0.67 mmol) was weighed into a reaction flask, and toluene (5 mL) and 4A molecular sieve (1 g) were added. The mixture was reacted at 115 °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 8-8 (0.18 g). LC-MS: [M+H] + =282.90.

[0306] Intermediate 8-8 contains a pair of enantiomers with structures as shown in 8-8-1 and 8-8-2, or as shown in 8-8-3 and 8-8-4.

[0307] Step 9: Preparation of intermediates 8-9

[0308] Intermediate 8-8 (0.2 g, 0.71 mmol) was weighed into a reaction flask, and an isopropanol solution of ammonia (1.42 mL, 2.84 mmol, 2N) was added. The mixture was sealed and reacted at 60 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give intermediate 8-9 (0.15 g). LC-MS: [M+H] + =264.00.

[0309] Intermediate 8-9 contains a pair of enantiomers with structures shown in 8-9-1 and 8-9-2, or as shown in 8-9-3 and 8-9-4.

[0310] Preparation Example 9: Preparation of Intermediate 9-9

[0311] Step 1: Preparation of Intermediate 9-1

[0312] At room temperature, R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.98 g, 1.58 mmol), intermediate 9-SM-01 (5 g, 31.53 mmol), allyl acetate (31.57 g, 315.3 mmol), IPA (3.79 g, 63.06 mmol), 4-chloro-3-nitrobenzoic acid (0.64 g, 3.15 mmol), [Ir(COD)Cl]₂ (0.64 g, 0.95 mmol), and Cs₂CO₃ (2.05 g, 6.31 mmol) were added to 1,4-dioxane (40 mL). The reaction mixture was purged with nitrogen three times and stirred overnight at 112 °C. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain intermediate 9-1 (6.3 g).

[0313] Step 2: Preparation of intermediate 9-2

[0314] At room temperature, intermediate 9-1 (6.3 g, 31.40 mmol) was added to DCM (80 mL), and m-CPBA (11.47 g, 56.52 mmol) was added at 0 °C. After the addition was complete, the reaction was stirred overnight at room temperature. The reaction was quenched by adding saturated Na2SO3 aqueous solution (100 mL), and after stirring for 5 minutes, saturated NaHCO3 aqueous solution (50 mL) was added. The mixture was extracted with DCM (100 mL × 2), the organic phases were combined, dried over anhydrous Na2SO4, 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 = 3:1) to obtain intermediate 9-2 (3.9 g).

[0315] Step 3: Preparation of intermediate 9-3

[0316] At room temperature, intermediate 9-2 (3.9 g, 18.00 mmol) was added to 1,4-dioxane (180 mL), and H2SO4 (1.80 g, 18 mmol) was slowly added. After the addition was complete, the mixture was stirred overnight at 50 °C. The reaction solution was cooled to room temperature, and saturated NaHCO3 aqueous solution (300 mL) was added to adjust the pH to 9-10. The solution was extracted with EtOAc (200 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous Na2SO4, 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 = 3:1) to obtain intermediate 9-3 (1.8 g).

[0317] Step 4: Preparation of intermediate 9-4

[0318] PPh3 (6.10 g, 23.27 mmol) was weighed into a reaction flask, dissolved in DCM (20 mL), and CBr4 (3.86 g, 11.63 mmol) in DCM (20 mL) solution was added at 0 °C. The mixture was stirred for 0.5 hours, and intermediate 9-3 (1.8 g, 8.31 mmol) was added. The mixture was reacted overnight at room temperature. The reaction solution was concentrated directly to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) to obtain intermediate 9-4 (1.2 g).

[0319] Step 5: Preparation of intermediate 9-5

[0320] Weigh intermediate 9-4 (1.2 g, 4.29 mmol) into a reaction flask, add THF (15 mL) and TMSCN (2.13 g, 21.45 mmol), cool to 0 °C, add TBAF (3.92 g, 15 mmol), and stir overnight at 50 °C. Quench the reaction mixture with water (30 mL), extract with DCM (20 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the residue, and purify the residue by silica gel column chromatography (PE:EA = 3:1) to obtain the desired intermediate 9-5 (450 mg), R f =0.6; a non-target product of a diastereomer ((390 mg), R) was also obtained. f =0.5.

[0321] Intermediate 9-5 contains a pair of enantiomers, with structures shown in 9-5-1 and 9-5-2, or as shown in 9-5-3 and 9-5-4.

[0322] Step 6: Preparation of intermediate 9-6

[0323] At room temperature, intermediate 9-5 (450 mg, 1.99 mmol) and NH2OH (0.53 g, 7.96 mmol, purity: 50%) were added to EtOH (8 mL), and the reaction was stirred overnight at 80 °C. The reaction solution was then concentrated to dryness under reduced pressure to obtain intermediate 9-6 (500 mg).

[0324] Intermediate 9-6 contains a pair of enantiomers, with structures shown in 9-6-1 and 9-6-2, or as shown in 9-6-3 and 9-6-4.

[0325] Step 7: Preparation of intermediate 9-7

[0326] 1) At room temperature, intermediate 9-6 (500 mg, 1.93 mmol) was added to MTBE (10 mL), and chloroacetic anhydride (0.66 g, 3.86 mmol) was added at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 1 hour. 10 mL of saturated NaHCO3 aqueous solution was slowly added dropwise to the reaction mixture, followed by extraction with methyl tert-butyl ether (10 mL × 2). The organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 9-7 (580 mg). LC-MS: [M+H] + =334.95.

[0327] Intermediate 9-7 contains a pair of enantiomers, with structures shown in 9-7-1 and 9-7-2, or as shown in 9-7-3 and 9-7-4.

[0328] Step 8: Preparation of intermediate 9-8

[0329] At room temperature, intermediate 9-7 (580 mg, 1.73 mmol) and 4A molecular sieve (500 mg) were added to toluene (10 mL), and the reaction was stirred at 100 °C for 1 hour. The reaction solution was directly concentrated to dryness under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA = 3:1) to obtain intermediate 9-8 (420 mg). LC-MS: [M+H] + =316.90.

[0330] Intermediate 9-8 contains a pair of enantiomers, with structures shown in 9-8-1 and 9-8-2, or as shown in 9-8-3 and 9-8-4.

[0331] Step 9: Preparation of intermediate 9-9

[0332] Intermediate 9-8 (200 mg, 0.63 mmol) was dissolved in an isopropanol solution of ammonia (0.68 g, 40 mmol) at room temperature, and the reaction was carried out overnight with stirring at 70 °C. The reaction solution was then concentrated directly to dryness under reduced pressure to give intermediate 9-9 (180 mg). LC-MS: [M+H] + =297.95.

[0333] Intermediate 9-9 contains a pair of enantiomers with structures shown in 9-9-1 and 9-9-2, or as shown in 9-9-3 and 9-9-4.

[0334] Preparation Example 10: Preparation of Intermediate 10-9

[0335] Step 1: Preparation of intermediate 10-1

[0336] Add 10-SM-01 (4.24 g, 24.23 mmol) to the reaction flask, then add R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (754.36 mg, 1.21 mmol), allyl acetate (24.26 g, 242.3 mmol), isopropanol (3.71 mL, 48.46 mmol), 4-chloro-3-nitrobenzoic acid (488.38 mg, 2.42 mmol), 1,5-cyclooctadiene iridium chloride dimer (488.26 mg, 0.73 mmol), and cesium carbonate (1.58 g, 4.85 mmol). Then add 1,4-dioxane (40 mL), purge with nitrogen for 10 minutes, and react at 112 °C for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give intermediate 10-1 (4.15 g).

[0337] Step 2: Preparation of intermediate 10-2

[0338] Liquid bromine (0.95 mL, 18.49 mmol) was dissolved in dichloromethane (30 mL), nitrogen gas was purged, and the mixture was cooled to -30 °C. A dichloromethane (30 mL) solution of intermediate 10⁻¹ (3.65 g, 16.81 mmol) was slowly added, and the mixture was stirred at -30 °C for 1 hour. The reaction mixture was then quenched in a saturated sodium sulfite aqueous solution (100 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed once with a saturated sodium chloride aqueous solution (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 10⁻² (5.85 g).

[0339] Step 3: Preparation of intermediate 10-3

[0340] Intermediate 10⁻² (5.85 g, 15.52 mmol) was dissolved in anhydrous methanol (60 mL), and anhydrous potassium carbonate (8.58 g, 62.08 mmol) was added. The mixture was reacted overnight at room temperature. The reaction solution was poured into a saturated ammonium chloride aqueous solution (20 mL), diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed once with a saturated sodium chloride aqueous solution (50 mL). The mixture was 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 = 19:1) to give intermediate 10⁻³ (3.5 g).

[0341] Step 4: Preparation of intermediate 10⁻⁴

[0342] Intermediate 10⁻³ (3.5 g, 11.82 mmol) was dissolved in tetrahydrofuran (40 mL), and trimethylcyanosilane (5.86 g, 59.1 mmol) was added. The mixture was cooled to 0 °C, and then tetrabutylammonium fluoride (35.46 mL, 35.46 mmol, 1 M) was added. After the addition was complete, the mixture was heated to 50 °C and reacted overnight. The reaction solution was poured into water (100 mL), and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and washed once with saturated sodium chloride aqueous solution (200 mL). The solution was 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 = 10:1) to give a pair of diastereomers. The first point R... f =0.22 (petroleum ether: ethyl acetate = 7:1), which is 10-4 (680 mg) of the compound intermediate.

[0343] The structure of intermediate 10-4 is shown in 10-4-1 or 10-4-2.

[0344] Step 5: Preparation of intermediate 10-5

[0345] Intermediate 10⁻⁴ (680 mg, 2.81 mmol) was dissolved in anhydrous ethanol (7 mL), and hydroxylamine (0.69 mL, 11.24 mmol, 50% aqueous solution) was added. The mixture was reacted at 80 °C for 3 hours. The reaction solution was poured into water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed once with saturated sodium chloride aqueous solution (50 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 10⁻⁵ (720 mg). LC-MS: [M + H⁺] + =274.95. The structure of intermediate 10-5 is shown in 10-5-1 or 10-5-2.

[0346] Step 6: Preparation of intermediate 10-6

[0347] Intermediate 10⁻⁵ (720 mg, 2.62 mmol) was dissolved in methyl tert-butyl ether (7 mL), purged with nitrogen three times, cooled to 0 °C, and chloroacetic anhydride (492.76 mg, 2.88 mmol) was slowly added. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. A saturated sodium bicarbonate aqueous solution (50 mL) was slowly added dropwise to the reaction mixture, followed by extraction with ethyl acetate (50 mL × 3). The organic phases were combined and washed once with a saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 10⁻⁶ (1 g). LC-MS: [M + H⁺] + =350.95. The structure of intermediate 10-6 is shown in 10-6-1 or 10-6-2.

[0348] Step 7: Preparation of intermediate 10-7

[0349] Intermediate 10⁻⁶ (1 g, 2.84 mmol) was dissolved in toluene (10 mL), and 4A molecular sieve powder (1 g) was added. The mixture was stirred overnight at 100 °C under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give intermediate 10⁻⁷ (660 mg). LC-MS: [M+H] + =332.90. The structure of intermediate 10-7 is shown in 10-7-1 or 10-7-2.

[0350] Step 8: Preparation of intermediate 10-8

[0351] Intermediate 10⁻⁷ (300 mg, 0.90 mmol) was dissolved in ammonia in isopropanol (7 mL, 2 M), and the mixture was heated to 60 °C and reacted overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give intermediate 10⁻⁸ (214 mg). LC-MS: [M+H] + =313.95. The structure of intermediate 10-8 is shown in 10-8-1 or 10-8-2.

[0352] Preparation Example 11: Preparation of Intermediate 11-4

[0353] Step 1: Preparation of Intermediate 11-1

[0354] Intermediate 1-2 (100 mg, 0.59 mmol) was dissolved in chloroform (0.5 mL) at room temperature, followed by the addition of isoamyl nitrite (82.94 mg, 0.71 mmol) and diiodomethane (0.48 mL, 5.90 mmol), respectively. The reaction mixture was reacted at 90 °C for 1 hour. After cooling to room temperature, the reaction mixture was directly concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give intermediate 11-1 (110 mg). LC-MS: [M+H] + =280.90.

[0355] Step 2: Preparation of intermediate 11-2

[0356] Intermediate 11-1 (110 mg, 0.39 mmol) was dissolved in N,N-dimethylformamide (6 mL) at room temperature. Then, bis(triphenylphosphine)palladium dichloride (27.37 mg, 0.04 mmol) and tributyl(1-ethoxyethylene)tin (0.26 mL, 0.78 mmol) were added, purging with nitrogen. The reaction mixture was reacted at 80 °C for 16 hours. After cooling to room temperature, water (30 mL) was slowly added, followed by extraction with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 11-2 (120 mg). LC-MS: [M+H] + =225.10.

[0357] Step 3: Preparation of intermediate 11-3

[0358] Intermediate 11-2 (100 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (2 mL) at room temperature, followed by the addition of hydrochloric acid (3.38 mL, 6.75 mmol, 2 M). The reaction mixture was reacted at room temperature for 3 hours. The reaction mixture was then slowly added to water (10 mL), followed by extraction with ethyl acetate (10 mL × 3). The organic phases were combined, washed once with saturated sodium chloride (20 mL), 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 = 5:1) to obtain intermediate 11-3 (30 mg). LC-MS: [M+H] + =197.05.

[0359] Step 4: Preparation of intermediate 11-4

[0360] Weigh intermediate 11-3 (30 mg, 0.15 mmol) into a reaction flask, dissolve it in ethanol (2 mL), then slowly add sodium hydroxide aqueous solution (0.60 mL, 0.60 mmol, 1 M). After the addition is complete, the reaction solution is reacted at 80 °C for 2 hours. The reaction solution is then cooled to 0 °C, and dilute hydrochloric acid (2 N, 1 mL) is slowly added to adjust the pH to 3-5. Ethyl acetate (10 mL × 3) is added for extraction. The organic phases are combined, washed once with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain intermediate 11-4 (30 mg). LC-MS: [M+H] + =169.00.

[0361] Preparation Example 12: Preparation of Intermediate 12-3

[0362] Step 1: Preparation of Intermediate 12-1

[0363] Intermediate 12-SM-01 (5 g, 30.75 mmol) was dissolved in tetrahydrofuran (120 mL), and di-tert-butyl dicarbonate (7.38 g, 33.83 mmol) and 4-dimethylaminopyridine (338.11 mg, 2.77 mmol) were added. Nitrogen gas was purged, and the reaction mixture was reacted at 60 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 12-1 (7.54 g). LC-MS: [M+H] + =262.95.

[0364] Step 2: Preparation of Intermediate 12-2

[0365] Intermediate 12-1 (7.54 g, 28.70 mmol) was dissolved in dimethyl sulfoxide (150 mL), and cesium fluoride (43.60 g, 287 mmol) was added. Nitrogen gas was then introduced, and the mixture was stirred overnight at 130 °C. The reaction mixture was cooled to room temperature, and 500 mL of saturated sodium bicarbonate aqueous solution, 500 mL of saturated sodium chloride aqueous solution, and 500 mL of ethyl acetate were added. The mixture was stirred for 10 minutes, filtered, and the filtrate was separated into two layers. The aqueous layer was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with saturated brine (500 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give intermediate 12-2 (4.23 g). LC-MS: [M+H] + =247.00.

[0366] Step 3: Preparation of intermediate 12-3

[0367] Intermediate 12-2 (1 g, 4.06 mmol) was dissolved in tert-butanol (10 mL) and water (5 mL). Sodium chlorite (2.11 g, 18.68 mmol, 80%), sodium dihydrogen phosphate (1.36 g, 11.37 mmol), and isopentenene (1.27 g, 16.24 mmol) were added, and the mixture was reacted overnight at room temperature. The pH of the reaction mixture was adjusted to 9-10 with aqueous sodium hydroxide solution. The mixture was washed with ethyl acetate (50 mL × 2). The aqueous layer was adjusted to pH 5-6 with 10% citric acid and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 12-3 (540 mg). LC-MS: [M+H] + =206.95.

[0368] Preparation Example 14: Preparation of Intermediate 16-4

[0369] Step 1: Preparation of Intermediate 16-1

[0370] At room temperature, intermediate 16-SM-01 (1.0 g, 7.93 mmol), pyridine (4.39 g, 55.51 mmol), and p-toluenesulfonyl chloride (3.02 g, 15.86 mmol) were added to n-butanol (10 mL), and the reaction was stirred overnight at room temperature. The reaction solution was directly concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 2:1) to give intermediate 16-1 (1.0 g).

[0371] Step 2: Preparation of Intermediate 16-2

[0372] At room temperature, intermediate 16-1 (1.0 g, 5.49 mmol), NBS (0.98 g, 5.49 mmol), and AIBN (0.18 g, 1.10 mmol) were added to CCl4 (20 mL), and the reaction was stirred overnight at 60 °C. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to give intermediate 16-2 (700 mg). LC-MS: [M+H] + =260.95.

[0373] Step 3: Preparation of Intermediate 16-3

[0374] At room temperature, intermediate 16-2 (0.4 g, 1.53 mmol) and cesium fluoride (1.16 g, 7.65 mmol) were added to DMSO (8 mL), and the reaction was stirred at 100 °C for 48 hours. Water (30 mL) was added to the reaction mixture to dilute it, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to give intermediate 16-3 (200 mg). LC-MS: [M+H] + =201.05.

[0375] Step 4: Preparation of intermediate 16-4

[0376] At room temperature, intermediate 16-3 (150 mg, 0.75 mmol) and TFA (3.07 g, 26.93 mmol) were added to DCM (2 mL), and the reaction was stirred at 40 °C for 1 hour. The reaction solution was then concentrated to dryness under reduced pressure to obtain intermediate 16-4 (100 mg).

[0377] Preparation Example 15: Preparation of Intermediate 17-2

[0378] Step 1: Preparation of Intermediate 17-1

[0379] Intermediate 17-SM-01 (500 mg, 2.69 mmol), triethylamine (816.60 mg, 8.07 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (219.68 mg, 0.27 mmol) were dissolved in N,N-dimethylformamide (13 mL). Methanol (8 mL) was added, carbon monoxide was substituted three times, and the reaction was carried out overnight at 80 psi and 80 °C. The reaction solution was diluted in water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed three times with saturated brine, 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 = 2:1) to give intermediate 17-1 (160 mg). LC-MS: [M+H] + =166.05.

[0380] Step 2: Preparation of Intermediate 17-2

[0381] Intermediate 17-1 (140 mg, 0.85 mmol) was dissolved in water (3.5 mL), and tetraethylammonium hydroxide (511.50 mg, 0.87 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The pH was adjusted to 1-2 with 1 M hydrochloric acid, resulting in the precipitation of a solid. The solid was filtered, the filter cake was washed with water, and dried to obtain intermediate 17-2 (95 mg). LC-MS: [M+H] + =130.15.

[0382] Preparation Example 16: Preparation of Intermediate 19-3

[0383] Step 1: Preparation of Intermediate 19-1

[0384] At room temperature, intermediate 16-3 (300 mg, 1.50 mmol) and NBS (400 mg, 2.25 mmol) were added to ACN (10 mL), and the reaction was stirred overnight at room temperature. The reaction solution was diluted with water (20 mL), extracted with EA (10 mL × 2), the organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to give intermediate 19-1 (180 mg). LC-MS: [M+H] + =280.95.

[0385] Step 2: Preparation of Intermediate 19-2

[0386] At room temperature, intermediate 19-1 (180 mg, 0.64 mmol) was added to TFA (4 mL), and the reaction was stirred at 40 °C for 1 hour. The reaction solution was then concentrated to dryness under reduced pressure to obtain intermediate 19-2 (120 mg).

[0387] Step 3: Preparation of intermediate 19-3

[0388] At room temperature, intermediate 19-3 (50 mg, 0.22 mmol) was added to THF (3 mL). A THF solution of n-BuLi (0.35 mL, 0.88 mmol, 2.5 mol / L) was added dropwise at -78 °C. After the addition was complete, the mixture was stirred at -78 °C for 1 hour. D₂O (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. A saturated ammonium chloride aqueous solution (10 mL) was added to the reaction mixture to quench the reaction. The pH was adjusted to 3-4 with 2N hydrochloric acid. The mixture was extracted with ethyl acetate (10 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 intermediate 19-3 (10 mg). LC-MS: [M+H] + =146.00.

[0389] Example 1: Preparation of 4-chloro-N-((3-(3R,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-methyl-1H-imidazol-5-carboxamide (Compound 1)

[0390] Intermediates 1-4 (0.02 g, 0.12 mmol) and HATU (0.068 g, 0.18 mmol) were dissolved in DMF (2 mL) and stirred for 10 minutes. Then, intermediates 4-8 (0.04 g, 0.14 mmol) and TEA (0.024 g, 0.24 mmol) were added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was directly separated (preparation method: 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 1 (13.2 mg, yield 25.05%). LC-MS: [M+H] + =421.90. Chiral purity: 95.73%, T R = 16.876 min (254 nm) (Chiral purity test method: CHIRALPAKAD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: n-hexane containing 60% isopropanol, flow rate: 0.8 mL / min, column temperature: 30℃).

[0391] 1 H NMR (400MHz, DMSO-d6): δ8.67 (s, 1H), 7.78 (s, 1H), 7.41–7.30 (m, 4H), 5.00 (t, J=7.2Hz, 1H), 4.72 (s, 2 H), 4.39–4.30 (m, 1H), 3.90 (dd, J=8.4, 6.0Hz, 1H), 3.80–3.68 (m, 4H), 2.56 (m, 1H), 2.18–2.08 (m, 1H).

[0392] Example 2: Preparation of 4-bromo-N-((3-(3R,5R)-5-(4-chlorophenyl)tetrahydrofuran-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-1-methyl-1H-imidazol-5-carboxamide (compound 2)

[0393] Intermediate 2-2 (0.1 g, 0.49 mmol) was weighed into a reaction flask, dissolved in 5 mL of DCM, followed by the addition of N,N-diisopropylethylamine (0.19 g, 1.47 mmol) and HATU (0.28 g, 0.73 mmol). The mixture was stirred at 25 °C for 30 min, then intermediate 4-8 (0.16 g, 0.59 mmol) was added, and the mixture was stirred at 25 °C for 2 h. The reaction solution was filtered, and the filtrate was purified by high-performance liquid chromatography (HPLC). Compound 2 (3.2 mg) was obtained. LC-MS: [M+H] + =467.90. Chiral purity: 95.21%, T R = 20.587 min (220 nm) (Chiral purity test method: CHIRALPAKAD-H, 4.6*250 mm, particle size 5 μm, mobile phase: hexane containing 50% isopropanol, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0394] 1 H NMR (400MHz, DMSO-d6): δ8.81 (s, 1H), 7.82 (s, 1H), 7.45–7.36 (m, 4H), 5.03 (t, J=7.2Hz, 1H), 4.75 (s, 2H), 4.41–4.35 (m, 1H), 3.93 (dd, J=8.4, 6.2Hz, 1H), 3.79 (dd, J=14.8, 6.3Hz, 1H), 3.74 (d, J=5.2Hz, 3H), 2.59 (ddd, J=12.4, 7.2, 5.2Hz, 1H), 2.21–2.11 (m, 1H).

[0395] Example 3: Preparation of Compound 3

[0396] Step 1: Preparation of intermediate 3-1-1

[0397] At room temperature, 2-naphthaldehyde (9.00 g, 57.63 mmol), R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.79 g, 2.88 mmol), 4-chloro-3-nitrobenzoic acid (1.16 g, 5.76 mmol), 1,5-cyclooctadiene iridium chloride dimer (1.16 g, 1.73 mmol), and cesium carbonate (3.76 g, 1.15 mmol) were weighed into a reaction flask, and nitrogen gas was purged. Then, allyl acetate (62.18 mL, 576.30 mmol), isopropanol (8.82 mL, 115.26 mmol), and 1,4-dioxane (60 mL) were slowly added. The reaction solution was reacted at 112 °C for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to obtain intermediate 3-1-1 (8.30 g).

[0398] Step 2: Preparation of intermediate 3-1-2

[0399] At room temperature, liquid bromine (0.65 mL, 12.76 mmol) and dichloromethane (12 mL) were added to a reaction flask. After the addition was complete, nitrogen gas was introduced, and the mixture was cooled to -30 °C. Intermediate 3-1-1 (2.30 g, 11.60 mmol) was dissolved in dichloromethane (12 mL) and slowly added dropwise to the reaction mixture. The reaction mixture was reacted at -30 °C for 1 hour. The reaction mixture was then slowly added dropwise to a saturated sodium sulfite solution (50 mL), and extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL). After drying with anhydrous sodium sulfate, the organic phases were concentrated under reduced pressure to obtain compound intermediate 3-1-2 (4.15 g).

[0400] Step 3: Preparation of intermediate 3-1-3

[0401] Intermediate 3-1-2 (4.10 g, 3.59 mmol) was dissolved in methanol (23 mL) at room temperature, followed by the addition of potassium carbonate (6.33 g, 45.80 mmol). The reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was then slowly added to a saturated aqueous solution of ammonium chloride (50 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to give intermediate 3-1-3 (2.30 g).

[0402] Step 4: Preparation of intermediate 3-1-4

[0403] At room temperature, intermediate 3-1-3 (2.30 g, 8.30 mmol) and trimethylcyanosilane (4.12 g, 41.50 mmol) were dissolved in tetrahydrofuran (22 mL). The mixture was cooled to 0 °C, and tetrabutylammonium fluoride (24.90 mL, 1.0 M, 24.90 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was heated to 60 °C and reacted for 16 hours. The reaction mixture was then slowly added to water (80 mL), and extracted with dichloromethane (80 mL × 3). The organic phases were combined and washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to give the desired intermediate 3-1-4 (480 mg, R). f =0.3 (PE:EA = 10:1)); a diastereomer of the non-target product (510 mg, R) was also obtained. f =0.15 (PE:EA = 10:1).

[0404] Step 5: Preparation of intermediate 3-1-5

[0405] Intermediate 3-1-4 (480 mg, 2.15 mmol) was dissolved in ethanol (4 mL) at room temperature, followed by the slow addition of hydroxylamine (0.53 mL, 8.60 mmol). After the addition was complete, the reaction mixture was heated to 80 °C and reacted for 16 hours. The reaction mixture was then slowly added to water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 3-1-5 (450 mg). LC-MS: [M+H] + =257.05.

[0406] Step 6: Preparation of intermediate 3-1-6

[0407] Intermediate 3-1-5 (450 mg, 1.76 mmol) was dissolved in methyl tert-butyl ether (6 mL) at room temperature, purged with nitrogen, and cooled to 0 °C. Chloroacetic anhydride (361 mg, 2.11 mmol) was then slowly added. After the addition was complete, the reaction mixture was allowed to react at room temperature for 0.5 hours. The reaction mixture was then slowly added to a saturated sodium bicarbonate aqueous solution (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 3-1-6 (600 mg). LC-MS: [M+H] + =333.00.

[0408] Step 7: Preparation of intermediate 3-1-7

[0409] At room temperature, intermediate 3-1-6 (600 mg, 1.80 mmol) was dissolved in toluene (6 mL), followed by the addition of 4A molecular sieve (700 mg). After the addition was complete, nitrogen gas was introduced, and the reaction mixture was heated to 100 °C and reacted for 5 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain intermediate 3-1-7 (110 mg).

[0410] Step 8: Preparation of intermediate 3-1-8

[0411] Intermediate 3-1-7 (90 mg, 0.29 mmol) was dissolved in isopropanol solution of ammonia (2.75 mL, 2.0 M, 5.51 mmol) at room temperature. After addition, the reaction solution was heated to 100 °C and reacted for 16 hours. The reaction solution was then concentrated under reduced pressure to give intermediate 3-1-8 (75 mg). LC-MS: [M+H] + =296.50.

[0412] Step 9: Preparation of Compound 3

[0413] Intermediate 1-4 (48 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of triethylamine (76 mg, 0.75 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (143 mg, 0.38 mmol), and intermediate 3-1-8 (75 mg, 0.25 mmol). The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was collected and purified by preparative high-performance liquid chromatography (HPLC) under alkaline conditions (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). The filtrate was then freeze-dried to obtain compound 3 (17.0 mg). LC-MS: [M+H] + =438.00. Chiral purity 94.45%, T R = 11.23 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size 5 μm, mobile phase: hexane containing 50% isopropanol, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0414] 1H NMR (400MHz, DMSO-d6): δ8.74 (s, 1H), 7.91 (dd, J=9.6, 5.2Hz, 4H), 7.83 (s, 1H), 7.51 (dd, J=8.4, 4.8Hz, 3H), 5.21 (t, J=7.2Hz, 1H), 4.77 (s , 2H), 4.46 (t, J=8.0Hz, 1H), 3.99 (dd, J=8.4, 6.4Hz, 1H), 3.89–3.80 (m, 1H), 3.75 (s, 3H), 2.71–2.63 (m, 1H), 2.28 (dt, J=12.8, 8.4Hz, 1H).

[0415] Example 4: Preparation of Compound 4

[0416] Intermediate 7-8 (97 mg, 0.33 mmol) was dissolved in dichloromethane (1 mL), and N,N-diisopropylethylamine (85.30 mg, 0.66 mmol), HATU (163.12 mg, 0.43 mmol), and intermediate 1-4 (50 mg, 0.31 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was purified by preparative high-performance liquid chromatography (under basic conditions) to give compound 4 (92.3 mg). LC-MS: [M+H] + =439.95. Chiral purity: 95.46%, T R = 7.62 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size 5 μm, mobile phase: n-hexane containing 50% isopropanol, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0417] 1 H NMR (400MHz, DMSO-d6): δ8.72(t, 1H), 7.82(s, 1H), 7.59(m, 1H), 7.40(dd, 2H), 5.04(t, 1H), 4. 75 (d, 2H), 4.39 (dd, 1H), 3.92 (dd, 1H), 3.79 (m, 1H), 3.74 (s, 3H), 2.60 (ddd, 1H), 2.18 (m, 1H).

[0418] Example 5: Preparation of Compound 5

[0419] Intermediate 6-4 (70 mg, 0.49 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of triethylamine (150 mg, 1.47 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (280 mg, 0.73 mmol), and intermediate 4-8 (137 mg, 0.49 mmol). The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was collected. The filtrate was purified by preparative high-performance liquid chromatography (HPLC) and then freeze-dried to give compound 5 (32.7 mg). LC-MS: [M+H] + =406.10.

[0420] Chiral purity: 95.92%, T R = 10.12 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size 5 μm, mobile phase: 20% ethanol-30% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0421] 1 H NMR(400MHz,DMSO-d6)δ8.48(s,1H),7.63(s,1H),7.46–7.36(m,4H),5.03(t,J=7.6Hz,1H),4.69(s,2H),4 .38(t,J=8.0Hz,1H),3.92(dd,J=8.4,6.4Hz,1H),3.80–3.74(m,4H),2.61–2.57(m,1H),2.17–2.12(m,1H).

[0422] The single-crystal diffraction pattern of compound 5 is shown in Figure 1, and its configuration is confirmed by its single-crystal diffraction pattern.

[0423] Preparation of single crystals of compound 5

[0424] Weigh approximately 5.0 mg of compound 5 sample, dissolve it in methanol (1.5 mL, AR), add water (0.05 mL), sonicate at room temperature for 2 minutes, and let stand at room temperature for 2 days to obtain needle-shaped colorless crystals.

[0425] Single-crystal diffraction analysis of compound 5

[0426] Testing instrument and model: D8 Venture

[0427] X-ray single crystal diffractometer parameters:

[0428] in conclusion

[0429] The single crystal structure was determined by direct analysis using the SHELXT2014 method, and the Flack constant was obtained as 0.11(2). The absolute configuration of compound 5 was determined, and the configurations of C6 and C8 in the structure were R configurations.

[0430] Table 1 Crystal structure data of compound 5

[0431] Example 6: Preparation of Compound 6

[0432] At room temperature, intermediates 3-9 (110 mg, 0.37 mmol), 1-4 (0.12 g, 0.74 mmol), EDCI (0.11 g, 0.55 mmol), HOBT (0.075 g, 0.55 mmol), and TEA (0.11 g, 1.11 mmol) were added to 3 mL of DMF, and the reaction mixture was stirred overnight at room temperature. The reaction mixture 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 6 (41 mg) was obtained. LC-MS: [M+H] + =439.95.

[0433] 1 H NMR (600MHz, DMSO-d6) δ8.74(t,J=5.4Hz,1H),7.81(s,1H),7.50–7.34(m,4H),5.20–5.11(m,1H),4.78(d,J=5.4Hz,2H) ,4.54(ddd,J=18.6,11.4,1.8Hz,1H),4.06(dd,J=33.6,11.4Hz,1H),3.72(s,3H),3.15-3.13(m,1H),2.43-2.40(m,1H).

[0434] Example 7: Preparation of Compound 7

[0435] Intermediates 1-4 (0.06 g, 0.37 mmol) were weighed into a reaction flask, and N,N-dimethylformamide (3 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.21 g, 70.2 mmol), N,N-diisopropylethylamine (0.14 g, 1.11 mmol), and intermediates 8-9 (0.097 g, 0.37 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction solution was separated 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: pure water (0.1% ammonia) B: preparative acetonitrile) to obtain compound 7 (0.018 g). LC-MS: [M+H] + =406.00.

[0436] Compound 7 includes a pair of enantiomers with structures shown as 7-A-1 and 7-A-2, or as shown as 7-B-1 and 7-B-2.

[0437] Compound 7 underwent chiral purity testing. The chiral purity testing method was as follows: CHIRALPAK AD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: 20% ethanol-30% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃. The test data are as follows:

[0438] Component 1: Chiral purity 44.635%, T R1 = 11.741 min (220 nm);

[0439] Component 2: Chiral purity 55.365%, T R2 = 12.164 min (220 nm).

[0440] 1 H NMR (400MHz, DMSO-d6) δ8.73(t,J=4.0Hz,1H),7.82(s,1H),7.43–7.39(m,2H),7.21–7.15(m,2H),5.02(t,J=8.0Hz,1H),4.75(d ,J=8.0Hz,2H),4.40-4.36(m,1H),3.91(q,J=4.0Hz,1H),3.82–3.77(m,1H),3.74(s,3H),2.60-2.64(m,1H),2.20–2.12(m,1H).

[0441] Example 8: Preparation of Compound 8

[0442] Intermediate 8-SM-01 (33 mg, 0.26 mmol) was weighed into a reaction flask, and N,N-dimethylformamide (2 mL), (7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (170 mg, 0.43 mmol), N,N-diisopropylethylamine (110 mg, 0.87 mmol), and intermediate 4-8 (80 mg, 0.29 mmol) were added. The mixture was stirred at room temperature for 2 hours. Purification by high-performance liquid chromatography (HPLC) (Preparation method: YMC Triart C18 12nm 10μm, 30*250mm, flow rate: 40 mL / min, column temperature: room temperature, mobile phase: A: pure water (0.1% ammonia), B: preparative acetonitrile) yielded compound 8 (31.3 mg). LC-MS: [M+H] + =387.95. Chiral purity 95.681%, T R = 13.711 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size 5 μm, mobile phase: 60% ethanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0443] 1 H NMR (400MHz, DMSO-d6) δ9.15(s,1H),7.79(s,1H),7.68(s,1H),7.44–7.35(m,4H),5.03(t,J=7.4Hz,1H),4.69(s,2H),4.38(t,J=8.0Hz,1H ), 3.93(dd,J=8.4,6.4Hz,1H),3.81(d,J=7.6Hz,3H),3.79–3.71(m,1H),2.60(ddd,J=12.4,6.8,5.4Hz,1H),2.15(dt,J=12.8,8.4Hz,1H).

[0444] Example 9: Preparation of Compound 9

[0445] At room temperature, intermediates 9-9 (90 mg, 0.30 mmol), 1-4 (0.048 g, 0.30 mmol), EDCI (0.086 g, 0.45 mmol), HOBt (0.061 g, 0.45 mmol), and TEA (0.091 g, 0.90 mmol) were added to 3 mL of DMF, and the reaction was stirred at room temperature for 1 hour. The reaction solution was directly filtered, and the filtrate 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: water (1% ammonia) B: preparative acetonitrile) to obtain compound 9 (42.9 mg). LC-MS: [M+H] + =440.00.

[0446] 1 H NMR(400MHz, DMSO-d6)δ8.70(t,J=5.6Hz,1H),7.80(s,1H),7.54(t,J=8.0Hz ,1H),7.39(dd,J=10.4,1.6Hz,1H),7.22(d,J=8.4Hz,1H),5.04(t,J=7.2Hz, 1H),4.72(d,J=5.6Hz,2H),4.37(t,J=7.6Hz,1H),3.91(dd,J=8.4,6.4Hz,1H ),3.81–3.64(m,4H),2.59(ddd,J=12.4,7.2,5.6Hz,1H),2.25–2.07(m,1H).

[0447] Compound 9 (32 mg) was separated (separation method: column: DALCEL CHIRALCEL OJ, 250×30 mm ID, particle size: 10 μm, mobile phase: phase A 60% CO2, phase B 40% EtOH, flow rate: 120 g / min) to obtain two enantiomers, named compound 9-A and compound 9-B, respectively.

[0448] Compound 9-A (5.2 mg), chiral purity: 100%, T R = 8.068 min (220 nm). (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0449] The structures of compounds 9-A and 9-B are shown as one of 9-A-1, 9-A-2, 9-B-1, or 9-B-2. When 9-A is 9-A-1, 9-B is 9-A-2; when 9-A is 9-A-2, 9-B is 9-A-1; when 9-A is 9-B-1, 9-B is 9-B-2; and when 9-A is 9-B-2, 9-B is 9-B-1.

[0450] 1 H NMR (400MHz, DMSO-d6) δ8.69(t,J=5.6Hz,1H),7.79(s,1H),7.53(t,J=8.4Hz,1H),7.38(dd,J=10.4,1.6Hz,1H),7.20(dd,J=8.4,1.6Hz,1H),5.03(t,J =7.2Hz,1H),4.71(d,J=5.6Hz,2H),4.35(dd,J=8.4,7.2Hz,1H),3.90(dd,J =8.4,6.0Hz,1H),3.79–3.69(m,4H),2.60–2.54(m,1H),2.15-2.05(m,1H).

[0451] Compound 9-B (17.4 mg), chiral purity: 100%, T R = 8.963 min (220 nm). (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0452] 1 H NMR (400MHz, DMSO-d6) δ8.69(t,J=5.6Hz,1H),7.79(s,1H),7.53(t,J=8.4Hz,1H),7.38(dd,J=10.4,1.6Hz,1H),7.20(dd,J=8.4,1.6Hz,1H),5.03( t,J=7.2Hz,1H),4.71(d,J=5.6Hz,2H),4.35(dd,J=8.4,7.2Hz,1H),3.90( dd,J=8.4,6.0Hz,1H),3.79–3.66(m,4H),2.58(m,1H),2.20–2.05(m,1H).

[0453] Example 10: Preparation of Compound 10

[0454] Intermediate 10-8 (90 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (4.5 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (83.39 mg, 0.43 mmol), 1-hydroxybenzotriazole (58.78 mg, 0.43 mmol), intermediate 1-4 (69.84 mg, 0.43 mmol), and triethylamine (0.12 mL, 0.87 mmol) were added. The mixture was stirred overnight at room temperature. The reaction solution was purified by preparative high-performance liquid chromatography (under basic conditions) to give compound 10 (54.3 mg). LC-MS: [M+H] + =457.90.

[0455] The structure of compound 10 is shown as 10-A or 10-B.

[0456] Chiral purity: 95.09%, T R = 8.37 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 ℃).

[0457] 1 H NMR(400MHz,DMSO-d6)δ8.72(s,1H),7.82(s,1H),7.62(d,2H),7.37(dd,1H),5.06(t,1H),4.7 5(s,2H),4.39(dd,1H),3.93(dd,1H),3.79(dd,1H),3.74(s,3H),2.62(ddd,1H),2.18(m,1H).

[0458] Example 11: Preparation of Compound 11

[0459] Intermediate 11-4 (25 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of triethylamine (45 mg, 0.45 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (85 mg, 0.22 mmol), and intermediate 4-8 (37 mg, 0.14 mmol). The reaction mixture was reacted at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was collected. The filtrate was purified by preparative high-performance liquid chromatography (under alkaline conditions) and then freeze-dried to give compound 11 (1.3 mg). LC-MS: [M+H] + =430.15.

[0460] Chiral purity: 95.97%, T R= 14.121 min (220 nm) (Chiral purity test method: CHIRALPAK IC, 4.6*250 mm, particle size: 5 μm, mobile phase: 50% ethanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 °C).

[0461] 1 H NMR (400MHz, DMSO-d6) δ10.62(t,J=5.6Hz,1H),7.98(s,1H),7.45–7.36(m,4H),5.03(s,1H),4.84(d,J=5.6Hz,2H),4.38(t,J=8. 0Hz,1H),3.93(dd,J=8.4,6.4Hz,1H),3.84(s,3H),3.77(dt,J=13.6,6.8Hz,1H),2.61–2.57(m,4H),2.15(dt,J=12.8,8.4Hz,1H).

[0462] Example 12: Preparation of Compound 12

[0463] Step 1: Preparation of intermediate 12-4

[0464] Intermediate 12-3 (375.03 mg, 1.43 mmol) and HATU (652.47 mg, 1.72 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (554.44 mg, 4.29 mmol) was added. After stirring at room temperature for 30 minutes, intermediate 4-8 (400 mg, 1.43 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated sodium chloride aqueous solution. The mixture was 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 12-4 (542 mg). LC-MS: [M+H] + =524.10.

[0465] Step 2: Preparation of Intermediate 12-5

[0466] Intermediate 12-4 (542 mg, 1.03 mmol) was dissolved in dichloromethane (30 mL), and zinc bromide (695.93 mg, 3.09 mmol) was added. The mixture was reacted overnight at 40 °C. The reaction solution was dissolved in methanol, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give intermediate 12-5 (1 g). LC-MS: [M+H] + =424.00.

[0467] Step 3: Preparation of Compound 12

[0468] Intermediate 12-5 (1 g, 2.36 mmol) was dissolved in 1,4-dioxane (10 mL), and amyl nitrite (785.52 mg, 6.37 mmol) was added. The mixture was stirred at 80 °C for 1 hour. The reaction solution was purified by high performance liquid chromatography to give compound 12 (110.8 mg). LC-MS: [M+H] + =409.00.

[0469] Chiral purity: 94.499%, T R = 25.600 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: 50% ethanol: n-hexane, flow rate: 0.8 mL / min, column temperature: 30 °C).

[0470] 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),9.01(s,1H),7.40(m,4H),5.03(t,1H),4.7 3(s,2H),4.38(t,1H),3.93(dd,1H),3.77(dt,1H),2.59(ddd,1H),2.15(dt,1H).

[0471] Example 13: Preparation of Compound 13

[0472] Step 1: Preparation of Intermediate 13-1

[0473] At room temperature, intermediate 6-4 (20 mg, 0.14 mmol) was added to THF (1 mL). LDA (60 mg, 0.56 mmol, 2.0 mol / L THF solution) was slowly added at -78 °C. After the addition was complete, the mixture was stirred at -78 °C for 20 minutes, followed by the addition of D2O (11 mg, 0.56 mmol). The mixture was then stirred overnight at room temperature. 2N hydrochloric acid was added to the reaction mixture to adjust the pH to 3-4. The mixture was extracted with EtOAc (5 mL × 2). The organic phases were combined, washed once with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 13-1 (12 mg). LC-MS: [M+H] + =146.00.

[0474] Step 2: Preparation of Compound 13

[0475] At room temperature, intermediates 13-1 (10 mg, 0.069 mmol), 4-8 (19 mg, 0.069 mmol), EDCI (20 mg, 0.10 mmol), HOBt (14 mg, 0.10 mmol), and TEA (21 mg, 0.21 mmol) were added to 2 mL of DMF, and the reaction was stirred at room temperature for 1 hour. The reaction solution was directly filtered, and the filtrate was purified by 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 (0.1% ammonia) B: preparative acetonitrile) to obtain compound 13 (6.7 mg). LC-MS: [M+H] + =407.00.

[0476] Chiral purity: 95.863%, T R = 26.391 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0477] 1 H NMR (600MHz, DMSO-d6) δ8.45(s,1H),7.43–7.35(m,4H),5.01(t,J=7.4Hz,1H),4.68(d,J=5.4Hz,2H),4.36( t,J=8.4Hz,1H),3.91(dd,J=8.4,6.6Hz,1H),3.75(s,4H),2.61–2.55(m,1H),2.14(dt,J=12.6,8.4Hz,1H).

[0478] Example 14: Preparation of Compound 14

[0479] At room temperature, intermediates 14-SM-01 (26 mg, 0.18 mmol), DIEA (70 mg, 0.54 mmol), and HATU (102.6 mg, 0.27 mmol) were added to 2 mL of DMF. After stirring for 5 minutes, intermediate 4-8 (50.0 mg, 0.18 mmol) was added. The mixture was then stirred at room temperature for 1 hour. The reaction solution was purified by high-performance liquid chromatography and lyophilized to give compound 14 (25.4 mg). LCMS: [M+H] + =405.05. Chiral purity: 95.278%, T R= 13.279 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: 50% ethanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0480] 1 H NMR (400MHz, DMSO-d6) δ9.43(s,1H),8.83(d,J=1.6Hz,1H),8.44(d,J=9.2Hz,2H),7.46–7.34(m,4H),5.03(t,J=7.6Hz,1H) ,4.79(d,J=5.2Hz,2H),4.38(t,J=8.0Hz,1H),3.95-3.91((m,1H),3.0-2.97((m,1H),2.63–2.56(m,1H),2.19–2.12(m,1H).

[0481] Example 15: Preparation of Compound 15

[0482] Weigh 15-SM-01 (0.05 g, 0.49 mmol) into a reaction flask, add N,N-dimethylformamide (5 mL), HATU (0.22 g, 0.58 mmol), and DIEA (0.15 g, 1.17 mmol), and react at room temperature for 30 minutes. Then add a solution of intermediate 4-8 (0.14 g, 0.49 mmol) in N,N-dimethylformamide (2 mL), and react at room temperature for 1 hour. The reaction solution is 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 15 (53.7 mg). LC-MS: [M+H] + =391.00.

[0483] Chiral purity: 95.708, T R = 17.736 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0484] 1H NMR (600MHz, DMSO-d6) δ9.62(s,1H),9.28(s,1H),8.54(s,1H),7.42–7.38(m,4H),5.03(t,J=6.0Hz,1H),4.77(s, 2H), 4.38 (t, J = 6.0Hz, 1H), 3.93 (dd, J = 12.0, 6.0Hz, 1H), 3.80-3.75 (m, 1H), 2.62-2.57 (m, 1H), 2.18-2.13 (m, 1H).

[0485] Example 16: Preparation of Compound 16

[0486] At room temperature, intermediates 16-4 (130 mg, 0.90 mmol), 4-8 (250 mg, 0.90 mmol), EDCI (260 mg, 1.35 mmol), HOBt (180 mg, 1.35 mmol), and TEA (360 mg, 3.6 mmol) were added to 5 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, B: preparative acetonitrile) to give compound 16 (30.3 mg). LC-MS: [M+H] + =406.00. Chiral purity: 95.817%, T R = 19.894 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm particle size: 5 μm, mobile phase: 50% ethanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0487] 1 H NMR (600MHz, DMSO-d6) δ9.16(s,1H),7.41–7.37(m,4H),5.01(t,J=7.2Hz,1H),4.68(d,J=5.4Hz,2H),4.36(t,J=8.4H z,1H),3.94–3.89(m,1H),3.76(dd,J=14.4,6.6Hz,1H),3.64(s,3H),2.62–2.56(m,1H),2.14(dt,J=12.6,8.4Hz,1H).

[0488] Example 17: Preparation of Compound 17

[0489] Step 1: Preparation of Intermediate 17-4

[0490] Intermediate 17-3 (99.74 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (139.58 mg, 1.08 mmol) and HATU (205.32 mg, 0.54 mmol) were added. After stirring for 20 minutes, intermediate 4-8 (100 mg, 0.36 mmol) was added, and the mixture was reacted at room temperature for 30 minutes. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed three times with saturated sodium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 17-4 (175 mg). LC-MS: [M+H] + =413.00.

[0491] Step 2: Preparation of Compound 17

[0492] Intermediate 17-4 (175 mg, 0.42 mmol), potassium carbonate (174.14 mg, 1.26 mmol), and hydrogen peroxide (2.06 mL, 20.16 mmol, 30%) were dissolved in dimethyl sulfoxide (3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by high performance liquid chromatography to give compound 17 (44.1 mg). LC-MS: [M+H] + =431.05. Chiral purity: 96.727%, T R = 35.493 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0493] 1 H NMR (400MHz, DMSO-d6) δ12.22(t,1H),8.13(s,1H),7.96(s,2H),7.40(m,4H),5.03(t,1H),4. 82(d,2H),4.37(t,1H),3.93(dd,1H),3.89(s,3H),3.76(dt,1H),2.60(m,1H),2.14(dt,1H).

[0494] Example 18: Preparation of Compound 18

[0495] Intermediate 18-SM-01 (68.63 mg, 0.54 mmol) was weighed and dissolved in DMF (2 mL). HATU (307.99 mg, 0.81 mmol) and DIPEA (209.37 mg, 1.62 mmol) were added, and the mixture was stirred at room temperature for 15 min. Intermediate 4-8 (150 mg, 0.54 mmol) was added, and the reaction was continued at room temperature for 1 h. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), and the organic phase was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (HPLC) to give compound 18 (86.6 mg). LC-MS: [M+H]+ = 389.00. Chiral purity: 95.619%, T R = 10.677 min (220 nm) (Chiral purity test method: CHIRALPAK IC, 4.6*250 mm, particle size: 5 μm, mobile phase: 30% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 °C).

[0496] 1 H NMR (600MHz, DMSO-d6) δ9.34(s,1H),9.28(s,1H),7.50–7.29(m,4H),5.03(t,J=7.4Hz,1H),4.72(s,2H),4.38(t,J=8.0Hz,1H),3.93 (dd,J=8.5,6.3Hz,1H),3.77(dt,J=13.8,6.8Hz,1H),2.59(ddd,J=12.4,7.0,5.2Hz,1H),2.38(s,3H),2.15(dt,J=12.7,8.5Hz,1H).

[0497] Example 19: Preparation of Compound 19

[0498] At room temperature, intermediates 19-3 (10 mg, 0.069 mmol), 4-8 (23 mg, 0.083 mmol), EDCI (20 mg, 0.10 mmol), HOBt (14 mg, 0.10 mmol), and TEA (21 mg, 0.21 mmol) were added to 1 mL of DMF, and the reaction was stirred 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 (0.1% TFA) B: preparative acetonitrile). The preparative solution was adjusted to pH 8-9 with sodium bicarbonate, extracted and concentrated with EA, and the residue was lyophilized with water and acetonitrile to give compound 19 (4.5 mg). LC-MS: [M+H] +=407.05. Chiral purity: 93.856%, T R = 20.716 min (220 nm) (Chiral purity test method: CHIRALPAK AD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: 50% ethanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30℃).

[0499] 1 H NMR (600MHz, DMSO-d) 6) δ9.16(t,J=5.4Hz,1H),7.47–7.30(m,4H),5.01(t,J=7.2Hz,1H),4.68(d,J=5.4Hz,2H),4.36(t,J=8.4Hz,1H), 3.97–3.86(m,1H),3.79–3.72(m,1H),3.65(s,3H),2.58(dd,J=12.6,6.6Hz,1H),2.14(dt,J=12.6,8.4Hz,1H).

[0500] Example 20: Preparation of compound 24:

[0501] Step 1: Preparation of Intermediate 24-1

[0502] Cyclopropylamine (4.10 g, 71.84 mmol) was dissolved in EtOH (30 mL). Intermediate 24-SM-02 (3 g, 17.96 mmol) was added under ice bath conditions, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, and then 50 mL of dichloromethane and 50 mL of water were added to the reaction flask. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 24-1 (2.3 g). LCMS: [M+1] + =144.05.

[0503] Step 2: Preparation of intermediate 24-2

[0504] Intermediate 1-1 (1.3 g, 13.25 mmol) was dissolved in THF (5 mL), and the solution of intermediate 24-1 (1.10 g, 7.68 mmol) dissolved in THF (5 mL) was added dropwise to the reaction mixture. The reaction was carried out at room temperature for 1 hour. The solvent was removed by concentration, and EtOH (5 mL) and potassium tert-butoxide (1.64 g, 14.58 mmol) were added. The mixture was stirred at room temperature for 10 hours. The reaction mixture was evaporated to dryness, and 20 mL of ethyl acetate and 20 mL of sodium bicarbonate were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 24-2 (0.2 g). LCMS: [M+H]+ =196.00.

[0505] Step 3: Preparation of intermediate 24-3

[0506] 0.18 g (1.73 mmol) of tert-butyl nitrite was dissolved in acetonitrile (5 mL), and cuprous chloride (0.12 g (1.25 mmol) was added. Intermediate 24-2 (0.2 g (1.02 mmol) was then slowly added under ice bath conditions. The mixture was stirred at room temperature for 2 hours, followed by stirring at 60 °C for 1 hour. After the reaction solution cooled to room temperature, 20 mL of 2N HCl and 20 mL of DCM were added. The organic phase was separated, and the aqueous phase was extracted twice with 40 mL of DCM. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 1:1) to obtain intermediate 24-3 (0.1 g). LCMS: [M+H] + =214.95.

[0507] Step 4: Preparation of intermediate 2.4

[0508] Intermediate 24-3 (100 mg, 0.47 mmol) was dissolved in methanol (2.5 mL) and water (0.5 mL), and sodium hydroxide (60 mg, 1.5 mmol) was added. The mixture was stirred at 60 °C for 1 hour. The pH of the reaction solution was adjusted to 5 with 2N HCl, and then extracted with 20 mL of ethyl acetate. The aqueous phase was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 24-4 (0.07 g). LCMS: [M+H] + =187.00.

[0509] Step 5: Preparation of compound 24

[0510] Intermediate 24-4 (30 mg, 0.16 mmol) and HATU (0.073 g, 0.19 mmol) were dissolved in DMF (3 mL) and stirred for 10 minutes. Then, intermediate 4-8 (53.71 mg, 0.19 mmol) and TEA (0.032 g, 0.32 mmol) were added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was directly separated (preparation method: 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 24 (6.9 mg). LCMS: [M+H] + =448.00.

[0511] 1H NMR (400MHz, DMSO-d6) δ8.91(t,J=5.6Hz,1H),7.83(s,1H),7.43–7.33(m,4H),5.01(t,J=7.2Hz,1H),4.73(d,J=5.6Hz,2H),4.40–4.31(m,1H) ), 3.90(dd,J=8.4,6.0Hz,1H),3.76(dt,J=13.6,6.8Hz,1H),3.62–3.53(m,1H),2.56(m,1H),2.17–2.08(m,1H),0.89(dd,J=7.2,2.8Hz,4H).

[0512] Example 21: Preparation of compound 36

[0513] Step 1: Preparation of Intermediate 36-1

[0514] Intermediate 4-7 (0.1 g, 0.33 mmol) was dissolved in acetonitrile (3 mL), and cyclopropylamine (0.057 g, 0.99 mmol) and potassium carbonate (0.091 g, 0.66 mmol) were added. The mixture was stirred at 70 °C for 3 hours. The reaction solution was poured into 20 mL of water and 20 mL of ethyl acetate solution, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 36-1 (0.11 g). LCMS: [M+H] + =319.95.

[0515] Step 2: Preparation of Compound 36

[0516] Intermediate 1-4 (59.77 mg, 0.372 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (0.18 g, 0.46 mmol) were dissolved in N,N-dimethylformamide (3 mL) and stirred at room temperature for 10 minutes. Then, intermediate 36-1 (100.0 mg, crude product) and triethylamine (0.094 mg, 0.93 mmol) were added to the reaction solution, and the reaction was continued for 1 hour. The reaction was then stopped, and the reaction solution was purified by 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% TFA), B: preparative acetonitrile). The purified solution was then freeze-dried to obtain compound 36 (14.0 mg). LC-MS: [M+H] + =462.00.

[0517] Chiral purity: 95.758%, retention time: T R= 17.011 min (220 nm) (CHIRALPAK AD-H, 4.6*250 mm, particle size: 5 μm, mobile phase: 50% isopropanol-n-hexane, flow rate: 0.8 mL / min, column temperature: 30 °C).

[0518] 1 H NMR (400MHz, DMSO-d6) δ7.74(s,1H),7.46–7.27(m,4H),4.97(dd,J=18.0,10.4Hz,3H),4.45–4.28(m,1H),3.88(dd,J=8.4,6.8Hz ,1H),3.75(dt,J=8.8,6.8Hz,1H),3.56(s,3H),3.10(s,1H),2.53(ddd,J=17.2,11.2,7.6Hz,1H),2.20–2.05(m,1H),0.61(s,4H).

[0519] Example 22: Preparation of Compound 95

[0520] Compound 5 (50 mg, 0.12 mmol) was weighed into a reaction flask, dissolved in toluene (2 mL), and then Lawson's reagent (53 mg, 0.13 mmol) was added. The reaction mixture was reacted at 110 °C for 6 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC). Compound 95 (12.1 mg) was obtained. LC-MS: [M+H] + =421.90.

[0521] 1 H NMR (600MHz, CDCl3) δ8.33(s,1H),7.34–7.24(m,4H),5.20(d,J=4.8Hz,2H),5.13(t,J=7.2Hz,1H),4.45(t,J=8.4Hz ,1H),4.10–4.06(m,1H),4.04(s,3H),3.75(dd,J=13.6,7.2Hz,1H),2.70(dt,J=12.4,6.4Hz,1H),2.24–2.19(m,1H).

[0522] Using suitable starting materials, the following compounds can be prepared according to the preparation methods shown in Examples 1-16 and Examples 1-19:

[0523] <Biological Activity Testing Test>

[0524] 1. IC of the example compound of the present invention 50 Determine Experiment

[0525] Stable cells expressing human TRPA1 were seeded into 384-well plates and cultured overnight at 37°C with 5% CO2. Afterward, the culture medium was removed, and 20 μL of experimental buffer was added. The plates were centrifuged at 200×g for 3–5 seconds at room temperature and then incubated at 37°C for 2 hours. Using a FLIPR Penta, 10 μL of 6× working solution of the target compound was added to the corresponding well. The cell plate was incubated at room temperature for 30 min, followed by incubation at room temperature for 5 min. Then, using a FLIPR Penta, 10 μL of 6× Cinnamaldehyde working solution was added to all wells. Data was collected every second for a total of 5 min of ROB signal acquisition.

[0526] The FLIPR Calcium 6 calcium ion detection kit was used to detect the release of intracellular calcium ions. 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. When TRPA1 was activated, the intracellular calcium ion concentration increased, and the activated calcium ion indicator bound to it. Under excitation light at 470 / 495 nm, the corresponding fluorescence emission signal could be captured at 515 / 575 nm. The inhibitory effect of the compound on the receptor was then assessed by the intensity of the fluorescence.

[0527] Data Analysis

[0528] Data were collected to calculate the logarithm of inhibition rate versus compound concentration, and IC was calculated using GraphPad Prism software. 50 value.

[0529] 1) PC group: 10 micromolar (μM) Ruthenium Red

[0530] 2) NC group: 0.1% DMSO

[0531] 3) Activity percentage = (Compound reading - Average NC group reading) / (Average PC group reading - Average NC group reading) × 100

[0532] 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|

[0533] 5) CV of the PC group = (Standard deviation of PC group readings / Mean of PC group readings) × 100%

[0534] 6) CV of the NC group = (Standard deviation of NC group readings / Mean of NC group readings) × 100%

[0535] 7) Calculate the signal-to-ground ratio S / B = signal value / background value

[0536] 8) Calculate the compound IC using the GraphPad nonlinear fitting formula. 50 Y = minimum value + (maximum value - minimum value / (1 + 10^(logIC))) 50 -x)×slope factor))

[0537] Where x is the log value of the compound concentration; Y: inhibition rate (%).

[0538] Among them, the maximum value, minimum value, and IC 50 Automatically fitted and generated by GraphPad Prism;

[0539] IC 50 Half-inhibition concentration (WIC) represents the concentration at which a compound inhibits TRPA1 target activity by 50%.

[0540] IC50 of the inhibitory activity of the compounds of this invention against TRPA1 50 The values ​​are shown in Table 2:

[0541] Table 2: Inhibitory activity of the compounds of this invention against human TRPA1 Note: A<50(nM), 50(nM)≤B<200(nM), 200(nM)≤C<500(nM), D≥500(nM).

[0542] Experimental conclusion: The compounds of this invention have good TRPA1 inhibitory activity.

[0543] 2. In vivo pharmacokinetic studies of the example compounds of this invention in rats.

[0544] 2.1 Experimental Preparation

[0545] 2.2.1 Rats: SD rats, SPF grade, 6 males, weighing between 180-200g;

[0546] 2.2.2 Preparation: For oral administration (po), 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 intravenous administration (iv), accurately weigh the compound, add the required volume of 15% dimethyl sulfoxide (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.

[0547] 2.2 Dosing regimen

[0548] 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, blood samples were collected at 0.167 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h; for the iv group, blood samples were collected at 0.033 h, 0.167 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h.

[0549] 2.3 Sample Collection and Preparation

[0550] After administration to rats, blood was collected from the orbital venous plexus at sampling time points. At each time point, approximately 0.2-0.3 mL of blood was collected 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 3000×g for 10 minutes at 4°C. The supernatant was transferred to a labeled EP tube and sent for bioanalytical analysis.

[0551] 2.4 Sample Analysis and Data Analysis

[0552] The data will be analyzed using WinNonlin through 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 bioavailability (F)). Please see Table 3 for specific data.

[0553] Table 3: PK experiment of the compounds of the present invention on SD rats

[0554] Experimental conclusion: The compounds of this invention have excellent pharmacokinetic properties.

[0555] 3. Pharmacokinetic studies of some compounds of this invention in beagle dogs

[0556] 3.1 Experimental Preparation

[0557] 3.1.1 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.

[0558] 3.1.2 Solvent composition: 10% TPGS (v / v) was used as the solvent in the po group; 15% DMSO + 60% PEG400 + 25% physiological saline solution was used as the solvent in the in vitro group.

[0559] Preparation procedure: After accurately weighing the compound for 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.

[0560] After accurate weighing of 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.

[0561] 4.2 Dosing regimen

[0562] 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.

[0563] 4.3 Sample Collection and Preparation

[0564] 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.

[0565] 4.4 Sample Analysis and Data Analysis

[0566] 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.

[0567] Table 4: Beagle PK test of the compounds of the present invention

[0568] Experimental conclusion: The compounds of this invention have excellent pharmacokinetic properties.

[0569] 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, Ring A is a 5-10 member heteroaryl group, C 6-10 Aryl, 4-10 membered heterocyclic or C 3-10 Cycloalkyl groups, wherein the heteroatoms in the 5-10 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; R 1 For H, deuterium, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, oxo (=O), -NH2, -OH, -COOH, -CN, 3-6 membered heterocyclic alkyl, phenyl, 5-10 membered heteroaryl, -CO-C 1-3 Alkyl, -CONH2, -SO2NH2 or -NHR 1-2 The C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, and 5-10-membered heteroaryl groups are optionally surrounded by one, two, or more R groups. 1-1 replace; n is 1, 2, 3 or 4; 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 heterocycloalkyl; 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; R 5 H, deuterium, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl groups or -CN; R 1-1 and R 1-2 Each can be independently classified as deuterium, halogen, oxo group (=O), -OH, -CN, -COOH, -NH2, -SO2NH2, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl; 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 (=O), -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 Cycloalkyl, 5-10-membered heteroaryl, and 4-10-membered heterocyclic groups are optionally surrounded by one, two, or more R groups. 4-1-1 replace; Each R 4-1-1 They are the same or different, and independently belong to H, deuterium, halogen, -OH, -CN, -COOH, -SO2NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy; Wherein, the compound represented by Formula I is not one of the following compounds: Preferably, the Not for 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, The compound represented by Formula I has the structure shown in Formula I-0: in, Ring A is a 5-10 member heteroaryl group, C 6-10 Aryl, 4-10 membered heterocyclic or C 3-10 Cycloalkyl groups, wherein the heteroatoms in the 5-10 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; R 1 Each is independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, oxo (=O), -NH2, -OH, -COOH, -CN, 3-6 membered heterocyclic alkyl, phenyl, 5-10 membered heteroaryl, -CONH2, -SO2NH2 or -NHR 1-2 The C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, and 5-10-membered heteroaryl groups are optionally surrounded by one, two, or more R groups. 1-1 replace; R 0 Each independently is deuterium, halogen, or has one, two, or more R atoms. 1-1 Replace C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne, oxo (=O), -NH2, -OH, -COOH, -CN, 3-6 membered heterocyclic alkyl, phenyl, 5-10 membered heteroaryl, -CO-C 1-3 Alkyl, -CONH2, -SO2NH2 or -NHR 1-2 The C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, and 5-10-membered heteroaryl groups are optionally surrounded by one, two, or more R groups. 1-1 replace; n1 is 0, 1, 2, 3 or 4; n2 is 1, 2, 3 or 4; And n1+n2 is 1, 2, 3 or 4; 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 heterocycloalkyl; 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; R 5 H, deuterium, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl groups or -CN; R 1-1 and R 1-2 Each can be independently classified as deuterium, halogen, oxo group (=O), -OH, -CN, -COOH, -NH2, -SO2NH2, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl; 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 (=O), -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 Cycloalkyl, 5-10-membered heteroaryl, and 4-10-membered heterocyclic groups are optionally surrounded by one, two, or more R groups. 4-1-1 replace; Each R 4-1-1 They are the same or different, and independently belong to H, deuterium, halogen, -OH, -CN, -COOH, -SO2NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkyl group.

3. The compound of Formula I as claimed in claim 1 or 2, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, It is selected from one or more of the following conditions: (1) Ring A is a 5-10 membered heteroaryl or a 4-10 membered heterocyclic group; (2) In ring A, the heteroatom in the heteroaryl group is selected from one or two of N, O and S, and the number of heteroatoms is two; (3)R 1 Each independently can be H, deuterium, or C. 1-6 alkyl; (4) n1 is 0, 1 or 2; for example, n1 is 1; (5)R 0 Each is independently a halogen, and is affected by one, two or more Rs. 1-1 Replacement C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, oxo (=O), -NH2, -CN, 3-6 membered heterocyclic alkyl, -CO-C 1-3 Alkyl or -CONH2; (6)R 1-1 Each can be independently a halogen, an oxo group (=O), or -NH2; for example, an oxo group (=O) or -NH2; (7) n2 is 1 or 2; (8)R 5 H, deuterium, C 1-6 Alkyl or C 3-6 cycloalkyl; (9)R 2 and R 3 Each can be independently H, deuterium, or halogen; (10)R 4 C 6-10 Aryl, 5-12 membered heteroaryl or 4-10 membered heterocyclic, wherein C 6-10 Aryl, 5-12-membered heteroaryl, and 4-10-membered heterocyclic groups may be selectively coupled with one, two, or more R groups. 4-1 replace; (11) Each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one, two, or more R groups. 4-1-1 Replace; each R 4-1-1 They may be the same or different, and are independent of each other as H, deuterium or halogen.

4. The compound of Formula I as claimed in claim 1 or 2, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, It is selected from one or more of the following conditions: (1) Ring A is a 5-10 membered heteroaryl group; for example, it is a 5 membered heteroaryl group; (2)R 1 Each independently is either deuterium or C 1-6 alkyl; (3)R 0 Each is independently a halogen, and is affected by one, two or more Rs. 1-1 Replacement C 1-6 Alkyl group, -C(O)CH3 or -CONH2; preferably, R 0 It is a halogen; (4)R 5 For H; (5)R 2 H or halogen; R 3 For H; (6)R 4 C 6-10 Aryl, the C 6-10 Aryl groups can be selectively coated with one, two, or more R groups. 4-1 replace; (7) Each R 4-1 They are the same or different, and are independent of each other as H or halogens; for example, they are halogens.

5. The compound of Formula I as claimed in claim 1 or 2, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, It is selected from one or more of the following conditions: (1) Ring A is a 5-6 membered heteroaryl, phenyl, 5-8 membered heterocyclic or C 3-8 Cycloalkyl groups, wherein the heteroatoms in the 5-6 membered heteroaryl and 5-8 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; for example, ring A is a 5-membered heteroaryl, phenyl, or a 5-membered heterocyclic group; (2)R 1 For H, deuterium, halogens, C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-5 cycloalkyl, C 1-3 alkoxy, oxo, -OH, -COOH, -CN or 3-5 membered heterocyclic alkyl, wherein C 1-4 Alkyl, C 1-3 Alkoxy, C 3-5 Cycloalkyl and 3-5 membered heterocyclic alkyl groups are optionally surrounded by one, two or more R groups. 1-1 replace; (3) n is 1, 2 or 3; (4)R 5 H, deuterium, C 1-3 Alkyl or C 3-4 cycloalkyl; (5)R 2 and R 3 Each can be independently H, deuterium, halogen, or C. 1-3 Alkyl, and R 2 and R 3 At least one of them is H; (6)R 4 The phenyl, dihydroindenyl, naphthyl, tetrahydronaphthyl, 5-10-membered heteroaryl, or 5-10-membered heterocyclic group is optionally surrounded by one, two, or three 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, C 1-3 Halogenated alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally surrounded by one, two, or three R groups. 4-1-1 replace; Each R 4-1-1 They may be the same or different, and are independent of each other as H, deuterium or halogen.

6. The compound of Formula I as claimed in claim 1 or 2, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, It is selected from one or more of the following conditions: (1) Ring A is imidazole, triazolyl, pyrrolyl, furanyl, pyrazolyl, thienyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dihydrofuranyl, dihydrothiophene, dihydropyrrolyl, dioxacyclopentenyl, dihydroimidazolyl, dihydropyrrolyl, dihydroisothiazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydrofuranyl, tetrahydroimidazolyl, tetrahydropyrrolyl, tetrahydropyrrolyl, or tetrahydrothiophene; for example, imidazole (e.g.) ), thiazolyl (e.g.) ), dihydroimidazolium (e.g.) ), dihydrooxazolyl (e.g.) ) or pyrazolyl (e.g. )； (2)R 1 For H, deuterium, halogens, C 1-4 Alkyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN, or oxecyclobutyl; for example, R 1 Each can be independently H, D, or methyl, for example, methyl; (3)R 0 Each can be independently D, methyl, methoxy, oxo (=O), Cl, Br, F, -C(O)CH3, -CHF2, -CH2F, -CH2NH2, -C(O)NH2 or -NH2; for example D, F or Cl, and for example F; (4)R 5 It can be H, methyl, ethyl, or cyclopropyl; (5)R 2 For H, R 3 For H or F; or, R 2 For H or F, R 3 For example, R. 2 and R 3 For H; (6)R 4 For one or two R 4-1 The substituted phenyl group may be replaced by one or two R groups. 4-1 Substituted naphthyl groups (e.g., with one or two R groups) 4- 1 Replacement )。 7. The compound of Formula I as claimed in claim 1 or 2, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or its pharmaceutically acceptable salt or solvate, characterized in that, It is selected from one or more of the following conditions: (1) for R 11 Methyl; R 12 For H or deuterium; R 0 It is either deuterium or halogen; preferably, for or, for For example, (2)R 2 For F or H, R 3 For H; (3)R 4 for q is 0, 1, 2, 3, or 4; for example, R 4 for Better, R 4 for For example, each R 4-1 They are the same or different, and are independent of each other: H, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally surrounded by one, two, or more R groups. 4-1-1 Replace; each R 4-1-1 They may be the same or different, and are independent of each other as H, deuterium, or halogen; For example, R 4 for For example, R 4 for For example, R 4 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, It is selected from any of the following conditions: (1) The compound shown in Formula I has the structure shown in Formula I-1: Among them, rings A, n, and R 1 R 2 R 3 R 4-1 R 5 Each of q independently has the definition described in any of claims 1-7, and when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, the S configuration, or a mixture thereof; (2) The compound shown in Formula I has the structure shown in Formula II: in, R 11 For H, C 1-6 Alkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclic alkyl; R 12 H, halogen or C 1-6 alkyl; R 1 R 2 R 3 R 4 and R 5 Each of them independently possesses the definition described in any of claims 1-7; For example, R 1 H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy; R 2 and R 3 Each is independently H, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; R 4 C 6-10 Aryl, 5-10 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 three R's. 4-1 replace; R 5 H, deuterium, C 1-6 Alkyl or C 3-6 cycloalkyl; 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-halogenated alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by one, two, or more R groups. 4-1-1 replace; Each R 4-1-1 They may be the same or different, and are independent of each other as H, deuterium, halogen, -OH, -CN, -COOH or -SO2NH2; Preferably, in Formula II, R 11 For H or C 1-6 Alkyl, such as C 1-6 Alkyl groups, such as methyl groups; Preferably, in Formula II, R 12 For H; Preferably, in Formula II, R 1 It is a halogen, for example, F or Cl, or for example, F; (3) The compound shown in Formula I has the structure shown in Formula III: Among them, R 1 R 2 R 3 and R 4 Each has independently the definition described in any of claims 1-7, and when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, the S configuration, or a mixture thereof; Preferably, in formula III, R 1 It is a halogen, for example, F or Cl, or for example, F; (4) The compound represented by Formula I has the structure shown in Formula III-1: Among them, R 1 Halogen, methyl, ethyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or -C(=O)C 1-3 Alkyl, q and R 4-1 Each of the embodiments independently has the definition described in any one of claims 1-7. When the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, the S configuration, or a mixture thereof. Preferably, in formula III, R 1 It is a halogen, for example, F or Cl, or for example, F; (5) The compound shown in Formula I has the structure shown in Formula IV: Among them, R 2 R 3 q and R 4-1 Each has independently the definition described in any of claims 1-7, and when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, the S configuration, or a mixture thereof; (6) The compound shown in Formula I has the structure shown in Formula IV-1: Among them, R 2 R 3 q and R 4-1 Each has independently the definition described in any of claims 1-7, and when the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, the S configuration, or a mixture thereof; (7) The compound shown in Formula I has the structure shown in Formula V: Where q and R 4-1 Each of them independently possesses the definition described in any of claims 1-7; (8) The compound shown in Formula I has the structure shown in Formula V-1: Where q and R 4-1 Each of them independently has the definition described in any of claims 1-7.

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, It is selected from any of the following conditions: (1) The compound represented by Formula I is any of the structures shown in the structural formulas III-1-a to III-1-h: Among them, R 1 q and R 4-1 Each of them independently possesses the definition described in any one of claims 1-7; Better, R 1 Halogen, methyl, ethyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups or -C(=O)C 1-3 alkyl; q is 0, 1, or 2; R 4-1 Halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl or C 1-3 Halogenated alkoxy groups; (2) The compound represented by formula I has the structure shown in any of the structural formulas IV-a to IV-h: Among them, R 2 R 3 q and R 4-1 Each of them independently possesses the definition described in any of claims 1-7; (3) The compound represented by formula I has the structure shown in any of the structural formulas IV-1-a to IV-1-h: Among them, R 2 R 3 q and R 4-1 Each of them independently possesses the definition described in any of claims 1-7; (4) The compound shown in Formula I has the structure shown in any of the structural formulas from Va to Vh: Where q and R 4-1 Each of them independently possesses the definition described in any of claims 1-7; (5) The compound shown in Formula I has the structure shown in any of the structural formulas from V-1-a to V-1-h: Where q and R 4-1 Each of them independently has the definition described in any of claims 1-7.

10. Any of the following compounds, their racemates, stereoisomers, tautomers, nitrides, prodrugs, or pharmaceutically acceptable salts or solvates thereof, Alternatively, the compound may have the following structure: For example, the compound has the following structure: Preferably, compound 5 has a crystalline form, wherein the crystal system of the crystalline form is orthorhombic, the space group is P212121, and the unit cell parameters are:

11. A method for preparing the compound shown in Formula I, characterized in that, Includes the following steps: In a solvent, in the presence of a condensing agent and an organic base, the compound shown in Formula IA is subjected to a condensation reaction with the compound shown in Formula IB to obtain the compound shown in Formula I. Among them, rings A and R 1 R 2 R 3 R 4 R 5 Each of the two elements, n, has the definition as described in any one of claims 1-10. When the carbon atom marked with "*" is a chiral carbon atom, it represents the R configuration, the S configuration, or a mixture thereof.

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound as claimed in any one of claims 1-10, its racemate, its stereoisomer, its tautomer, its nitride, its prodrug, or a pharmaceutically acceptable salt or solvate thereof; for example, the pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

13. The use of the compound, racemate, stereoisomer, tautomer, nitride, prodrug, or pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1-10, in the preparation of a medicament. Preferably, the drug is a drug for treating and / or preventing 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. Preferably, the TRPA1-mediated disease or condition is a respiratory disease, pain, inflammatory disease, pruritus, or gastrointestinal disease; Preferably, the respiratory disease is chronic cough, acute cough, subacute cough, bronchitis, asthma, chronic obstructive pulmonary disease, rhinitis, or idiopathic pulmonary fibrosis. The pain referred to includes acute pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritis pain, osteoarthritis pain, back pain, visceral pain, cancer pain, hyperesthesia, neuralgia, migraine, postherpetic neuralgia, fibromyalgia, sciatica, or postherpetic neuralgia. The inflammatory diseases mentioned are inflammatory disorders, esophagitis, arthritis, atopic dermatitis, or psoriasis; The gastrointestinal diseases mentioned are esophageal reflux disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, Crohn's disease, or gastroduodenal ulcers; 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, idiopathic pulmonary fibrosis, pain, sleep apnea, gastrointestinal disease, pruritus, or urinary incontinence. Preferably, the TRPA1-mediated disease or condition is sleep apnea, neuropathy, chemotherapy-induced neuropathy, eye irritation, skin irritation, frostbite, spasm, tension syndrome, generalized rigidity, Parkinson's disease, diabetic neuropathy, HIV-related neuropathy, nerve damage, ischemia, neurodegenerative diseases, stroke, multiple sclerosis, pelvic allergy, cystitis, burns, psoriasis, or eczema.

14. The use of any compound, racemate, stereoisomer, tautomer, nitride, prodrug, or pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1-10, in the preparation of a TRPA1 inhibitor.

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