Compounds and their use in treating Treg-associated diseases - Patent application

Abstract

The present invention provides a compound and its use in the treatment of Treg-related diseases, particularly in the prevention and / or treatment of diseases in which increasing the number of Treg cells would be beneficial for the prevention or treatment of the disease. Experiments have shown that O-1602 can effectively promote the proliferation of Tregs and increase the number of Tregs, and that increasing the number of Tregs is expected to be beneficial for the prevention or treatment of certain diseases, such as autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), and inflammatory diseases. Furthermore, a series of novel compounds have been prepared that can effectively promote the proliferation of Tregs and increase the number of Tregs, have good physical and chemical properties such as solubility and stability, can be administered via various routes, and are highly valuable for use and research.

Description

[Technical Field]

[0001] The present invention relates to the field of biomedical science, and more particularly to compounds and their use in the treatment of Treg-associated diseases, in particular in the prevention and / or treatment of diseases in which increasing the amount of Treg cells would be beneficial for the prevention or treatment of diseases such as autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), and inflammatory diseases. [Background technology]

[0002] Regulatory T cells (Tregs) are a subpopulation of T cells characterized by the expression of Foxp3, CD25, and CD4. They are capable of suppressing the immune responses of other cells and are the primary regulator of self-tolerance. For example, when encountering harmful substances such as bacteria or viruses, immune cells such as T cells, B cells, and NK cells initiate an immune response to identify and eliminate the harmful substances, protecting the body from attack. After the battle between these cells and the harmful substances is over, Treg cells signal the end of the attack. When immune cells are constantly in an abnormal state of reaction, they attack normal tissues, resulting in damage to the body and, for example, autoimmune diseases. Tregs actively regulate and suppress the activation and proliferation of potentially autoreactive T cells present in normal tissues, thereby exerting their properties related to immunosuppression and immune homeostasis, thereby playing an important role in patients with autoimmune diseases.

[0003] Traditionally, autoimmune diseases have been treated primarily with immunosuppressants (e.g., prednisone, cyclosporine, azathioprine) to suppress or block the body's pathological autoimmune response. However, these substances are associated with various systemic side effects and interactions. Therefore, researchers have attempted to develop new drugs that specifically affect the mechanisms involved in disease events. Examples of such drugs include natalizumab and infliximab. Natalizumab is a monoclonal antibody and selective inhibitor of IgG4 (an adhesion molecule located on the surface of leukocytes). Natalizumab inhibits leukocyte migration into inflammatory lesions and is used to treat a specific aggressive form of plaque progressive multiple sclerosis. Infliximab is a chimeric monoclonal antibody against tumor necrosis factor alpha (TNFα), which plays an important role in autoimmune inflammatory responses. Infliximab is used to treat rheumatoid arthritis, Crohn's disease, Bechterew disease, and psoriasis. Although these recently introduced drugs can function specifically, they can cause serious side effects, such as progressive multifocal leukoencephalopathy. For these reasons, natalizumab was withdrawn from the market only three months after its initial registration in the United States. Furthermore, these new active ingredients are associated with very high costs. Therefore, there is a continuing need to develop new drugs that are inexpensive, effective, and have fewer side effects. Summary of the Invention [Problem to be solved by the invention]

[0004] To overcome the shortcomings of the prior art, the present invention provides compounds and their use in the treatment of Treg-related diseases, particularly in the prevention and / or treatment of diseases in which increasing the amount of Treg cells would be beneficial for the prevention or treatment (e.g., autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), inflammatory diseases). [Means for solving the problem]

[0005] In a first aspect of the present invention, there is provided a compound having the structure: [ka] Formula (I) wherein R1 has the following structure: [ka] where X1 is a single bond, -C(O)-, -C(O)O-, -C(O)N(R 103 )-, [ka] , -S(O)2-, and X2 is a single bond, -O-, -S-, -SS-, -N(R 104 )-, -S(O)2-, -S(O)2N(R 104 )-, -S(O)-, -S(O)N(R 104 )-, -C(O)-, -C(O)O-, -C(O)N(R 104 )-, -OC(O)-, -OC(O)N(R 104 )-, -N(R 104 )C(O)O-, -N(R 104 )C(O)-, -N(R 104 )S(O)2-, [ka] Selected from R 101 represents a single bond, an alkylene group, an alkenylene group, a phenylene group (e.g., [ka] ), [ka] , amino acid residues, oligopeptide residues, polypeptide residues, monosaccharide residues, oligosaccharide residues, polysaccharide residues (for example, [ka] ), n is an integer from 1 to 100, and R 102 is selected from H, alkyl groups, cycloalkyl groups, phenyl groups, and heterocyclyl groups (especially saturated heterocyclyl groups), and R 103 and R 104 are independently selected from H and alkyl groups, wherein said alkylene, alkenylene, phenylene, alkyl, cycloalkyl, phenyl, and heterocyclyl groups are optionally substituted by one or more independent R'; R2, R4, and R5 are independently selected from H, halogen, a hydroxy group, a mercapto group, an amino group, a cyano group, an azide group, an isocyanate group, a sulfonyl chloride group, a sulfonyl fluoride group, an amide group, a sulfonamide group, a formyloxy group, a nitro group, a formaldehyde group, a trifluoromethyl group, a sulfonic acid group, a phosphorous acid group, a trialkyltin group, a trialkylsilyl group, an alkyl group, an alkenyl group, and an alkynyl group; R3 has the following structure: [ka] In the formula, Y1 is a single bond, —C(O)—, —C(O)O—, —C(O)N(R 303 )-, [ka] , -S(O)2-, and Y2 is selected from a single bond, -O-, -S-, -SS-, -N(R 304 )-, -S(O)2-, -S(O)2N(R 304 )-, -S(O)-, -S(O)N(R 304 )-, -C(O)-, -C(O)O-, -C(O)N(R 304)-, -OC(O)-, -OC(O)N(R 304 )-, -N(R 304 )C(O)O-, -N(R 304 )C(O)-, -N(R 304 )S(O)2-, [ka] Selected from R 301 represents a single bond, an alkylene group, an alkenylene group, a phenylene group (e.g., [ka] ), [ka] , amino acid residues, oligopeptide residues, polypeptide residues, monosaccharide residues, oligosaccharide residues, polysaccharide residues (e.g., [ka] ), m is an integer of 1 to 100, and R 302 is selected from H, an alkyl group, a cycloalkyl group, a phenyl group, and a heterocyclyl group; R 303 and R 304 are independently selected from H, alkyl groups, and alkylene groups, each of which is optionally substituted with one or more independent R's; or R4 and R5 together with the carbon atoms connected thereto form a cyclic group (particularly a saturated cyclic group, e.g., a cycloalkyl group, a heterocyclyl group), wherein said cyclic group is optionally substituted by one or more independent R'; W is selected from the following structures: [ka] During the ceremony, [ka] represents a single bond or a double bond, Each R6 independently has the structure: [ka] In the formula, L1 and L2 are each a single bond, -O-, -S-, -N(R 603 )-, -S(O)2-, -S(O)2N(R 603 )-, -S(O)-, -S(O)N(R 603 )-, -C(O)-, -C(O)O-, -C(O)N(R 603 )-, -OC(O)-, -OC(O)N(R 603 )-, -N(R 603 )C(O)O-, -N(R 603 )C(O)-, -N(R 603 )S(O)2- are independently selected, and R 601 is selected from a single bond and an alkylene group, and R 602 is selected from H and alkyl groups, and R 603 is selected from H, an alkyl group, and the alkyl, alkylene group is optionally substituted by one or more independent R's; each R7 is independently selected from H, an alkyl group, an alkenyl group, and an alkynyl group, wherein said alkyl group, alkenyl group, and alkynyl group are optionally substituted with one or more independent R'; Each R' is a halogen, a hydroxy group, a mercapto group, an amino group, a cyano group, an azide group, an isocyanate group, a sulfonyl chloride group, a sulfonyl fluoride group, an amide group, a sulfonamide group, a formyloxy group, a nitro group, a formaldehyde group, a trifluoromethyl group, a sulfonic acid group, a phosphorous acid group, a trialkyltin group, a trialkylsilyl group, -CH=NH, [ka] , an alkoxy group, an alkylamine group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heterocyclyl group, and a substituted or unsubstituted heterocyclylalkyl group; In addition, the compound represented by general formula (I) is not the following: [ka]

[0006] Specifically, X1 is a single bond, —C(O)—, —C(O)O—, —C(O)N(H)—, [ka] , -S(O)2-.

[0007] In some embodiments of the present invention, X1 is -C(O)-.

[0008] In some embodiments of the present invention, X1 is -C(O)O-.

[0009] In some embodiments of the present invention, X1 is -C(O)N(H)-.

[0010] Specifically, the amino acids in the amino acids and oligopeptides and polypeptides may be selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and ornithine.

[0011] Specifically, the monosaccharides and the monosaccharides in the oligosaccharides and polysaccharides may be selected from glyceraldehyde, erythrose, arabinose, ribose, xylose, lyxose, glucose, mannose, fructose, galactose, N-acetylgalactosamine, N-acetylglucosamine, fucose, and N-acetylaspartic acid.

[0012] In one embodiment of the invention, the monosaccharide residue is a glucuronic acid residue.

[0013] In one embodiment of the invention, the polysaccharide residue is a hyaluronic acid residue.

[0014] Specifically, R 101 is a single bond, C 1~6 alkylene groups (e.g., methylene, ethylene, propylene, butylene); [ka] wherein the alkylene group is optionally substituted by one or more independent R', specifically R' is selected from hydroxy, mercapto, amino, amido, sulfonamido, formyloxy, nitro, formaldehyde, trifluoromethyl, [ka] , ethenyl group, ethynyl group, substituted or unsubstituted phenyl group (e.g., [ka] ), heterocyclyl groups (e.g., [ka] ) may be selected from.

[0015] Specifically, n may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, and in some embodiments of the present invention, n is an integer from 1 to 10.

[0016] In some embodiments of the present invention, R 101 represents a single bond, a methylene group, an ethylene group, [ka] Selected from.

[0017] Specifically, X2 is a single bond, -O-, -S-, -SS-, -N(R 104)-, -S(O)2-, -S(O)2N(R 104 )-, -C(O)O-, -C(O)N(R 104 )-, where R 104 is H, C 1~6 It may be selected from alkyl groups.

[0018] Specifically, R 102 is H, C 1~6 Alkyl groups (especially C 1~3 alkyl groups, for example, methyl, ethyl, n-propyl, and isopropyl groups; 4- to 12-membered saturated heterocyclyl groups (including monocyclic and polycyclic heterocyclyl groups (particularly, bicyclic heterocyclyl groups); and polycyclic heterocycles include fused, spiro, and bridged polycyclic heterocycles, for example, [ka] wherein the alkyl group or heterocyclyl group is optionally substituted with one or more independent R', and specifically, R' is selected from the group consisting of C 1~3 Alkyl groups (methyl, ethyl, n-propyl, isopropyl, etc.), hydroxyl groups, mercapto groups, amino groups, amide groups, sulfonamide groups, formyloxy groups, nitro groups, formaldehyde groups, trifluoromethyl groups, [ka] , ethenyl group, ethynyl group, substituted or unsubstituted phenyl group (e.g., [ka] ), heterocyclyl groups (e.g., [ka] ) may be selected from.

[0019] In one embodiment of the present invention, R1 has the structure: [ka] In the formula, R 105 H, [ka] , 4- to 12-membered substituted or unsubstituted saturated heterocyclyl groups (including monocyclic and polycyclic heterocyclyl groups (particularly bicyclic heterocyclyl groups), and polycyclic heterocycles include fused, spiro and bridged polycyclic heterocycles, for example, [ka] (particularly, a 4- to 6-membered monocyclic saturated heterocyclyl group), and R 106 and R 107 is H, C 1~6 Alkyl groups (especially C 1~3 alkyl groups, for example, methyl, ethyl, and n-propyl groups.

[0020] In some embodiments of the present invention, R 105 is H, amino group, [ka] may be selected from

[0021] In some embodiments of the present invention, R1 is H.

[0022] In some embodiments of the present invention, R1 is selected from the following: [ka]

[0023] In some embodiments of the present invention, R2 is H.

[0024] Specifically, Y1 is a single bond, -C(O)-, -C(O)O-, -C(O)N(H)-, [ka] , -S(O)2-.

[0025] In some embodiments of the present invention, Y1 is -C(O)-.

[0026] In some embodiments of the present invention, Y1 is -C(O)O-.

[0027] In some embodiments of the present invention, Y1 is -C(O)N(H)-.

[0028] Specifically, R 301 is a single bond, C 1~6 alkylene groups (e.g., methylene, ethylene, propylene, butylene); [ka] wherein the alkylene group is optionally substituted by one or more independent R', specifically R' is selected from hydroxy, mercapto, amino, amido, sulfonamido, formyloxy, nitro, formaldehyde, trifluoromethyl, [ka] , ethenyl group, ethynyl group, substituted or unsubstituted phenyl group (e.g., [ka] ), heterocyclyl groups (e.g., [ka] ) may be selected from.

[0029] Specifically, m may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, and in some embodiments of the present invention, m is an integer from 1 to 10.

[0030] In some embodiments of the present invention, R 301represents a single bond, a methylene group, an ethylene group, [ka] Selected from.

[0031] Specifically, Y2 is a single bond, -O-, -S-, -SS-, -N(R 304 )-, -S(O)2-, -S(O)2N(R 304 )-, -C(O)O-, -C(O)N(R 304 )-, where R 304 is H, C 1~6 It may be selected from alkyl groups.

[0032] Specifically, R 302 is H, C 1~6 Alkyl groups (especially C 1~3 alkyl groups, for example, methyl, ethyl, n-propyl, and isopropyl groups; 4- to 12-membered saturated heterocyclyl groups (including monocyclic and polycyclic heterocyclyl groups (particularly, bicyclic heterocyclyl groups); and polycyclic heterocycles include fused, spiro, and bridged polycyclic heterocycles, for example, [ka] wherein the alkyl group or heterocyclyl group is optionally substituted with one or more independent R', and specifically, R' is selected from the group consisting of C 1~3 Alkyl groups (methyl, ethyl, n-propyl, isopropyl, etc.), hydroxyl groups, mercapto groups, amino groups, amide groups, sulfonamide groups, formyloxy groups, nitro groups, formaldehyde groups, trifluoromethyl groups, [ka] , ethenyl group, ethynyl group, substituted or unsubstituted phenyl group (e.g., [ka] ), heterocyclyl groups (e.g., [ka] ) may be selected from.

[0033] In one embodiment of the present invention, R3 has the structure: [ka] where R 305 H, [ka] , 4-12-membered substituted or unsubstituted saturated heterocyclyl groups (including monocyclic and polycyclic heterocyclyl groups (particularly bicyclic heterocyclyl groups), and polycyclic heterocycles include fused, spiro and bridged polycyclic heterocycles, for example, [ka] (particularly, a 4- to 6-membered monocyclic saturated heterocyclyl group), and R 306 and R 307 is H, C 1~6 Alkyl groups (especially C 1~3 alkyl groups, for example, methyl, ethyl, and n-propyl groups.

[0034] In some embodiments of the present invention, R 305 is H, amino group, [ka] may be selected from

[0035] In some embodiments of the present invention, R3 is H.

[0036] In some embodiments of the present invention, R3 is selected from the following: [ka]

[0037] In some embodiments of the present invention, R4 is H.

[0038] In some embodiments of the present invention, R4 is C 1~6 Alkyl groups, especially C 1~3 and alkyl groups, wherein the alkyl groups are optionally substituted by one or more independent R', and specifically R' may be selected from fluorine, chlorine, bromine, iodine, hydroxy, mercapto, amino, formyloxy, nitro, formaldehyde, trifluoromethyl, ethenyl, and ethynyl groups. In one embodiment of the present invention, R4 is a methyl group.

[0039] In some embodiments of the present invention, R5 is H.

[0040] In some embodiments of the present invention, R5 is C 1~6 Alkyl groups, especially C 1~3 and alkyl groups, wherein the alkyl groups are optionally substituted by one or more independent R', and specifically R' may be selected from fluorine, chlorine, bromine, iodine, hydroxy, mercapto, amino, formyloxy, nitro, formaldehyde, trifluoromethyl, ethenyl, and ethynyl groups. In one embodiment of the present invention, R5 is a methyl group.

[0041] Specifically, R 601 is a single bond, C 1~6 Alkylene groups (especially C 1~3 alkylene groups, for example, methylene groups, ethylene groups).

[0042] Specifically, R 602 is H, C 1~6 Alkyl groups (especially C 1~3 The alkyl group may be selected from alkyl groups such as methyl, ethyl, n-propyl, and isopropyl groups.

[0043] Specifically, R 603 is H, C 1~6It may be selected from alkyl groups, in particular H.

[0044] Specifically, L1 and L2 may be independently selected from a single bond, -O-, -S-, -N(H), -S(O)2-, -S(O)2N(H)-, -C(O)-, -C(O)O-, -C(O)N(H)-, -OC(O)-, and -N(H)C(O)-.

[0045] Specifically, each R6 is H, an alkyl group, [ka] More specifically, each R6 may be independently selected from H, C 1~6 alkyl groups, [ka] where R 601 is C 1~6 is an alkylene group, and R 602 is H, C 1~6 It is selected from alkyl groups.

[0046] In some embodiments of the present invention, each R6 is independently selected from the group consisting of C 1~6 Alkyl groups, especially C 1~3 It is an alkyl group, for example a methyl group, an ethyl group, an n-propyl group, an isopropyl group, in particular a methyl group.

[0047] In some embodiments of the present invention, each R7 is independently selected from the group consisting of C 2~6 Alkenyl groups, especially C 2~3 Alkenyl groups include, for example, ethenyl, propenyl, allyl, and prop-1-en-2-yl ( [ka] ), in particular: [ka]

[0048] In some embodiments of the present invention, [ka] represents a single bond.

[0049] In some embodiments of the present invention, [ka] represents a double bond.

[0050] In some embodiments of the present invention, W is: [ka]

[0051] In one embodiment of the invention, the compound has the structure: [ka] Formula (II) wherein R1, R3, and R4 have the corresponding definitions as defined above in the present invention.

[0052] In one embodiment of the invention, R1 is H and R3 is not H, for example, the compound may have the following structure: [ka]

[0053] In another embodiment of the invention, R1 is not H and R3 is H, for example, the compound may have the following structure: [ka]

[0054] In another embodiment of the invention, R1 and R3 are not both H, for example, the compound may have the structure: [ka]

[0055] In some embodiments of the present invention, the compound has the following structure: [ka] [ka]

[0056] In a second aspect of the present invention, there is provided a compound according to the first aspect, a stereoisomer of the compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate complex, or crystal of the compound (or composition).

[0057] Specifically, the stereoisomer may be selected from the following structures: [ka] In particular, the following: [ka]

[0058] wherein R1 to R7 have the corresponding definitions as described in the first aspect of the present invention.

[0059] More specifically, the stereoisomer may be selected from the following structures: [ka] In particular, the following: [ka]

[0060] wherein R1, R3, R4 have the corresponding definitions as described in the first aspect of the present invention.

[0061] In some embodiments of the present invention, the stereoisomer has the following structure: [ka]

[0062] Isotopic derivatives according to the present invention include those in which at least one atom is a stable radioisotope of an atom having the same atomic number but a different atomic mass, such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, specifically 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N, 17 O. 18 O, preferably compounds substituted with deuterium.

[0063] In a third aspect of the present invention, there is provided a method for producing the compound according to the first aspect, a stereoisomer of the compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate complex, or crystal thereof, comprising the steps of: [ka] and, [ka] and / or [ka] or [ka] First, [ka] wherein Z and Z′ may be independently selected from H, halogen (e.g., Cl), a hydroxy group, an OC(O)-alkyl group, etc.; Z and Z may be independently selected from halogen (e.g., Cl), a hydroxy group, etc.; and R 102 ' and R 302 ' are R 102 and R 302 or a protected form of R 102 and R 302 (e.g., a protected hydroxy group, an amino group, in which case the method further comprises a deprotection step).

[0064] In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect, a stereoisomer of the compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate complex, or crystal of the compound (or composition), together with one or more pharmaceutically acceptable excipients.

[0065] Specifically, the pharmaceutically acceptable additive may be one or more selected from disintegrants, binders, lubricants, suspending agents, stabilizers, fillers, absorption enhancers, surfactants, flavoring agents, antioxidants, preservatives, etc.

[0066] Specifically, any suitable route of administration may be used for the pharmaceutical composition, for example, a gastrointestinal (e.g., oral, sublingual, rectal) or non-gastrointestinal (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory, etc.) route, preferably a gastrointestinal route, and in particular an oral route.

[0067] Specifically, the pharmaceutical composition may be in any suitable dosage form, such as gastrointestinal dosage forms including, but not limited to, tablets, pills, powders, granules, capsules, tablets, syrups, liquids, emulsions, suspensions, etc., and non-gastrointestinal dosage forms, such as injectable dosage forms (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal injections), respiratory dosage forms such as sprays, aerosols, and powder aerosols, dermal dosage forms such as topical solutions, lotions, ointments, plasters, pastes, and patches, mucosal dosage forms such as eye drops, ophthalmic ointments, nasal drops, and mouthwashes, and intracavitary dosage forms such as vaginal, urethral, ​​nasal, and ear canal suppositories, aerosols, effervescent tablets, drops, and drop pills.

[0068] Specifically, the various dosage forms of the above-mentioned pharmaceutical compositions can be produced by conventional production methods in the pharmaceutical field, for example, by mixing an active ingredient with one or more pharmaceutically acceptable additives and then producing the desired dosage form.

[0069] Specifically, in the above pharmaceutical composition, the weight percentage of the compound according to the first aspect, a stereoisomer of this compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate complex, or crystal of the compound (or composition) is, for example, 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%, and may be 0.1 to 99.5%.

[0070] In a fifth aspect of the present invention, there is provided use of a compound according to the first aspect, a stereoisomer of this compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate complex or crystal of said compound (or composition), in the manufacture of a medicament for the prevention and / or treatment of a disease.

[0071] In particular, the diseases are, for example, autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), and inflammatory diseases, the prevention or treatment of which is beneficial when the amount of Treg cells is increased.

[0072] Specifically, the autoimmune diseases include, for example, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, immune nephropathy, antiphospholipid antibody syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, acute motor axonal neuropathy, Baro's disease (also called concentric sclerosis), Behcet's disease, benign mucous membrane pemphigoid (cicatricial pemphigoid), and the like. (also called eosinophilic granulomatous vasculitis or eosinophilic granulomatosis with polyangiitis), bullous pemphigoid, Castleman's disease, food allergies and related disorders (e.g., celiac disease), Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing polymyelitis, Churg-Strauss syndrome (also called allergic granulomatous vasculitis or eosinophilic granulomatosis with polyangiitis), Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (also called neuromyelitis optica), discoid lupus erythematosus, Dressler's syndrome, uterine Endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (also called anaphylactoid purpura), herpes gestationis or pemphigoid gestationis, hidradenitis suppurativa, hypogammaglobulinemia, IgG4-related sclerosing disease (also called IgG4-related systemic disease, hyperIgG4emia, or IgG4-related disease) (also known as acute pityriasis lichenoides), autoimmune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis (also known as allergic vasculitis), lichen planus, lichen sclerosing and atrophicus, lignified conjunctivitis, linear IgA disease, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, keratotic ulcer, Much-Habermann disease (also known as acute pityriasis lichenoides), multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neutropenia, ocular pemphigoid,Optic neuritis, relapsing rheumatism, PANDAS disease, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis (also called peripheral uveitis), Parsonage-Turner syndrome (also called brachial plexitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndrome types I, II, and III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, rogesterone-induced dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy (also called pain syndrome), recurrent inflammatory bowel disease ... These include, but are not limited to, organ-specific and systemic autoimmune diseases such as progressive polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome (also known as autoimmune polyglandular syndrome type 2), scleritis, scleroderma, Sjogren's syndrome, autoimmune sperm-testicular disorders, stiff-person syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, thyroid eye disease, Tolosa-Hunt syndrome, type 1 diabetes (also known as autoimmune diabetes, insulin-dependent diabetes mellitus), ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada disease. In some embodiments of the present invention, the autoimmune disease is selected from systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, food allergies and related diseases (e.g., celiac disease), ulcerative colitis, and Crohn's disease.

[0073] Specifically, the immune renal diseases include, but are not limited to, anti-glomerular basement membrane nephritis, glomerulonephritis, IgA nephropathy, purpura nephritis, or lupus nephritis.

[0074] Specifically, the allergic diseases include, but are not limited to, allergic conjunctivitis, allergic rhinitis, allergic asthma, allergic bronchopulmonary aspergillosis (ABPA), allergic gastroenteritis, atopic dermatitis, allergic urticaria, allergic angioedema, allergic immediate contact reaction, anaphylactic shock, or food allergy and its related diseases (e.g., celiac disease).

[0075] Specifically, in the case of transplant rejection and graft-versus-host disease (GvHD), the transplant may be a cell transplant (e.g., hematopoietic stem cell transplant), a tissue transplant (e.g., skin transplant, bone marrow transplant, corneal transplant), or an organ transplant (e.g., kidney transplant, heart transplant, liver transplant, pancreas / islet transplant, parathyroid transplant, lung transplant, small intestine transplant), especially an organ transplant.

[0076] Specifically, the inflammatory disease is a disease having inflammation caused by an immune response, and includes, but is not limited to, interstitial lung disease, inflammatory bowel disease (including chronic colitis, acute colitis, ulcerative colitis (UC) and Crohn's disease (CD)), chronic obstructive pulmonary disease (COPD), acute lung injury, neuroinflammation, pyemia, asthma, allergies, etc.

[0077] In one embodiment of the present invention, the use is of a compound according to the first aspect, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, stereoisomer, solvate (e.g. hydrate), prodrug, metal chelate complex, crystal, in the manufacture of a medicament for the prevention and / or treatment of a disease.

[0078] Specifically, any suitable route of administration may be used for the drug, for example, gastrointestinal (e.g., oral, sublingual, rectal) or non-gastrointestinal (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory, etc.) routes, preferably gastrointestinal routes, and especially oral routes.

[0079] In one embodiment of the present invention, the disease is inflammatory bowel disease and the route of administration of the drug is a gastrointestinal route, in particular an oral route.

[0080] Specifically, the dosage, when calculated based on body weight, is, for example, 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.033 mg / kg, 0.1 mg / kg, 0.15 mg / kg, 0.2 mg / kg, 0.25 mg / kg, 0.3 mg / kg, 0.35 mg / kg, 0.4 mg / kg, 0.407 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 ... 0.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.1mg / kg, 4.2mg / kg, 4.3mg / kg, 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, and 0.01 to 5.0mg / kg.

[0081] Specifically, the administration frequency is once a day.

[0082] In a specific embodiment of the present invention, the subject is a non-human mammal, and the dosage, calculated by body weight, is preferably, for example, 0.4 mg / kg, 0.407 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg g, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.1mg / kg, 4.2mg / kg, 4.3mg / kg, 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, and 0.4 to 5.0mg / kg.

[0083] In a specific embodiment of the present invention, the subject is a human, and the administration dose, when calculated by body weight, is preferably, for example, 0.033 mg / kg, 0.1 mg / kg, 0.15 mg / kg, 0.2 mg / kg, 0.25 mg / kg, 0.3 mg / kg, 0.35 mg / kg, 0.4 mg / kg, or 0.407 mg / kg, i.e., 0.033 to 0.407 mg / kg.

[0084] In a sixth aspect of the present invention, there is provided use of a compound according to the first aspect, a stereoisomer of the compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate complex or crystal of the compound (or composition), in the manufacture of a reagent for inducing or promoting the expansion of Tregs.

[0085] In one embodiment of the present invention, the expansion of Tregs is carried out in vivo.

[0086] In another embodiment of the present invention, the expansion of Tregs is carried out in vitro.

[0087] In some embodiments of the present invention, when the increase in Tregs in the above-mentioned uses is carried out in vivo, any suitable administration route may be used for the reagent, for example, a gastrointestinal administration route (e.g., oral, sublingual, rectal administration) or a non-gastrointestinal administration route (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory administration, etc.), preferably a gastrointestinal administration route, and in particular an oral administration route.

[0088] In a seventh aspect of the present invention, there is provided a reagent for inducing or promoting the increase of Tregs, comprising the compound according to the first aspect, a stereoisomer of the compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate complex, or crystal of the compound (or composition).

[0089] In one embodiment of the present invention, the expansion of Tregs is carried out in vivo.

[0090] In another embodiment of the present invention, the expansion of Tregs is carried out in vitro.

[0091] In particular, the reagent may be in any suitable form, for example, solid, liquid, etc.

[0092] In an eighth aspect of the present invention, there is provided a method for preventing and / or treating a disease, comprising the step of administering to a subject in need thereof a compound according to the first aspect or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, stereoisomer, solvate (e.g., hydrate), prodrug, metal chelate complex, crystal, or a pharmaceutical composition comprising same.

[0093] In particular, said disease has the definition set out in the fifth aspect of the invention.

[0094] In particular, the subject is a mammal, especially a human.

[0095] Specifically, in the method, the compound according to the first aspect, a stereoisomer of this compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, prodrug, or solvate of the compound (or composition) may be used alone or in combination with other types of pharmaceutical preparations and / or treatment methods.

[0096] Specifically, the route of administration may be any suitable route, for example, gastrointestinal (e.g., oral, sublingual, rectal) or non-gastrointestinal (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory, etc.) route.

[0097] In one embodiment of the invention, the method comprises administering to a subject in need thereof a compound according to the first aspect or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, stereoisomer, solvate (e.g., hydrate), prodrug, metal chelate complex, crystal, or a pharmaceutical composition comprising same, wherein the route of administration may be any suitable route, for example a gastrointestinal (e.g., oral, sublingual, rectal) or non-gastrointestinal (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory, etc.) route, preferably a gastrointestinal route, and in particular an oral route.

[0098] Specifically, the dosage, when calculated based on body weight, is, for example, 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.033 mg / kg, 0.1 mg / kg, 0.15 mg / kg, 0.2 mg / kg, 0.25 mg / kg, 0.3 mg / kg, 0.35 mg / kg, 0.4 mg / kg, 0.407 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 ... 0.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.1mg / kg, 4.2mg / kg, 4.3mg / kg, 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, and 0.01 to 5.0mg / kg.

[0099] Specifically, the administration frequency is once a day.

[0100] In a specific embodiment of the present invention, the subject is a non-human mammal, and the dosage, calculated by body weight, is preferably, for example, 0.4 mg / kg, 0.407 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg g, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.1mg / kg, 4.2mg / kg, 4.3mg / kg, 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, and 0.4 to 5.0mg / kg.

[0101] In a specific embodiment of the present invention, the subject is a human, and the administration dose, when calculated by body weight, is preferably, for example, 0.033 mg / kg, 0.1 mg / kg, 0.15 mg / kg, 0.2 mg / kg, 0.25 mg / kg, 0.3 mg / kg, 0.35 mg / kg, 0.4 mg / kg, or 0.407 mg / kg, i.e., 0.033 to 0.407 mg / kg.

[0102] In a ninth aspect of the present invention, there is provided a method for modulating an immune response comprising administering to a subject in need thereof a compound according to the first aspect, a stereoisomer of the compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate complex, crystal, or pharmaceutical composition comprising same.

[0103] In particular, the subject is a mammal, especially a human.

[0104] Specifically, the regulation is a negative regulation of the body's immune response, ie, suppression of the body's immune response.

[0105] In one embodiment of the invention, the method comprises administering to a subject in need thereof a compound according to the first aspect, a stereoisomer of this compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate complex, crystal of the compound (or composition), or a pharmaceutical composition comprising same, by any suitable route of administration, for example, gastrointestinal (e.g., oral, sublingual, rectal) or non-gastrointestinal (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory, etc.) route, preferably a gastrointestinal route, and in particular an oral route.

[0106] In a tenth aspect of the present invention, there is provided a method for increasing Tregs, comprising the step of using a compound according to the first aspect, a stereoisomer of the compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate complex, crystal of the compound (or composition), or a pharmaceutical composition comprising same.

[0107] In one embodiment of the invention, the method is performed in vivo.

[0108] In another embodiment of the invention, the method is carried out in vitro.

[0109] In some embodiments of the present invention, the method is carried out in vivo and comprises the step of administering to a subject a compound according to the first aspect, a stereoisomer of the compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate complex, crystal of the compound (or composition), or a pharmaceutical composition comprising same, by any suitable route of administration, for example, gastrointestinal (e.g., oral, sublingual, rectal) or non-gastrointestinal (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory, etc.) route, preferably a gastrointestinal route, and in particular an oral route.

[0110] In some embodiments of the invention, the method is carried out in vitro and comprises the step of culturing Tregs in vitro using a medium comprising a compound according to the first aspect, a stereoisomer of the compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate complex, or crystal of the compound (or composition).

[0111] In an eleventh aspect of the present invention, there is provided a population of Treg cells produced (in vitro) by a method according to the tenth aspect.

[0112] Specifically, the Treg cell population can be used to regulate (suppress) the body's immune response or to prevent or treat diseases such as autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), and inflammatory diseases (specifically those described in the fifth aspect of the present invention). [Effects of the Invention]

[0113] The present invention has found through experiments that O-1602 can effectively promote the proliferation of Tregs and increase the amount of Tregs, and that increasing the amount of Tregs is expected to be beneficial in the prevention or treatment of certain diseases, such as autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), and inflammatory diseases. Furthermore, the present invention also provides a series of novel compounds that can effectively promote the proliferation of Tregs and increase the amount of Tregs, have good physical and chemical properties such as solubility and stability, can be administered via various routes, and are of great value for use and research. [Brief explanation of the drawings]

[0114] [Figure 1] 1. Relief of mild to moderate psoriasis induced in mice by O-1602 derivatives. [Figure 2] Effect of different compounds on body weight change during treatment of TNBS-induced acute enteritis. In the figure, TOFACITINIB is tofacitinib. [Figure 3] Scores after treatment with different compounds for acute enteritis induced by TNBS. In the figure, TOFACITINIB is tofacitinib. [Figure 4] 1 shows the effect of treatment with different compounds on TNBS-induced acute enteritis on colon length after dissection. [Figure 5] The effect of treatment with different compounds on the length and appearance of the colon after dissection in TNBS-induced acute enteritis is shown. From the left, compounds 1 to 13, control, and tofacitinib, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0115] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0116] The term "alkyl group" refers to a straight or branched hydrocarbon chain radical containing no unsaturated bonds and connected to the rest of the molecule by a single bond. Typical alkyl groups may contain 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 10) carbon atoms, particularly 1 to 10 carbon atoms, and preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, and isohexyl. When an alkyl group is substituted with a cycloalkyl group, it is a "cycloalkylalkyl group," such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl. When an alkyl group is substituted with an aryl group, it is an "aralkyl group", for example, a benzyl group, a diphenylmethyl group, or a phenethyl group. When an alkyl group is substituted with a heterocyclyl group, it is a "heterocyclylalkyl group".

[0117] The term "alkylene group" refers to a hydrocarbon group formed by an alkane molecule losing two hydrogen atoms (a divalent alkyl group), which may be straight or branched and connected to the rest of the molecule by a single bond. As used herein, typical alkylene groups have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, and include, for example, methylene (-CH2-), ethylene, propylene, and butylene groups.

[0118] The term "cycloalkyl group" refers to an alicyclic hydrocarbon having, for example, 1 to 4 monocyclic and / or fused rings and 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms, such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, or adamantyl group.

[0119] The term "alkoxy group" refers to a substituent in which the hydrogen in a hydroxy group is replaced by an alkyl group, and is, for example, an alkoxy group containing 1 to 10 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, or a butoxy group.

[0120] The term "alkylamine group" refers to a substituent in which one or two hydrogen atoms in an amino group (-NH2) are replaced by an alkyl group, such as an alkylamine group containing 1 to 10 carbon atoms, [ka] And so on.

[0121] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0122] The term "haloalkyl group" refers to a group in which one or more hydrogen atoms in an alkyl group have been replaced by a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), e.g., -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0123] The term "aryl group" refers to a monocyclic or polycyclic free radical, including polycyclic free radicals containing single aryl groups and / or fused aryl groups, e.g., containing 1 to 3 single or fused rings and 6 to 18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, and is a C6-C6 alkyl group according to the present invention. 12 The aryl group refers to an aryl group containing 6 to 12 carbon ring atoms, such as a phenyl group, a naphthyl group, a biphenyl group, an indenyl group, and the like.

[0124] The term "heterocyclyl group" refers to a 3- to 18-membered ring group containing 2 to 17 carbon atoms and 1 to 10 heteroatoms selected from N, O, or S atoms. Heterocyclyl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic, or other polycyclic ring systems, including fused (two rings sharing two ring atoms), spiro (two rings sharing one ring atom), or bridged (two rings sharing three or more ring atoms) systems (excluding linked rings). Heterocyclyl groups can be partially saturated (heteroaryl groups) or fully saturated (heterocycloalkyl groups). Suitable heteroaryl groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms, and the heteroaryl groups include coumarin (including 8-coumarin), quinolinyl (including 8-quinolinyl and isoquinolinyl), pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, and the like. Examples of such groups include a pyridyl group, a pteridinyl group, a purinyl group, an oxadiazolyl group, a thiadiazolyl group, a furazanyl group, a pyridazinyl group, a triazinyl group, a cinnolinyl group, a benzimidazolyl group, a benzofuryl group, a benzofurazanyl group, a benzothienyl group, a benzothiazolyl group, a benzoxazolyl group, a quinazolinyl group, a quinoxalinyl group, a naphthyridinyl group, a furopyridyl group, a pyridoxazepinyl group, a pyridazepinyl group, a pyridodiazepinyl group, a pyridoxepanyl group, a pyridocycloheptanyl group, a benzoxazepinyl group, a benzazepinyl group, a benzodiazepinyl group, and a benzoxepanyl group.Suitable heterocycloalkyl groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms, and the heterocycloalkyl groups include, for example, pyrrolidinyl, tetrahydrofuryl, dihydrofuran, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, azepanyl, oxiranyl, thiorenyl, azepinyl, oxepanyl, oxathian ... Examples of such groups include azepinyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinolizidinyl.

[0125] The term "amino acid" refers to an organic compound containing a basic amino group and an acidic carboxy group. Depending on the position of the amino group attached to the carbon chain, amino acids can be classified as α-, β-, γ-, or w-amino acids, with α-amino acids being particularly prominent. The term "amino acid residue" refers to a structural moiety obtained by the loss of one hydrogen atom from the amino group and one hydroxyl group from the carboxy group of an amino acid. The term "oligopeptide" refers to a compound formed by the condensation of 2 to 10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, particularly 2 to 6) amino acids. The term "polypeptide" refers to a compound formed by the condensation of 10 to 50 (e.g., 10, 15, 20, 25, 30, 35, 40, 45, 50) amino acids. In the present invention, the amino acids and amino acids in the oligopeptides and polypeptides may be selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and ornithine.

[0126] The term "monosaccharide" refers to a molecule that cannot be hydrolyzed into further sugars. Depending on the position of the carbonyl group, monosaccharides are broadly classified into two types: aldoses and ketoses. Furthermore, monosaccharides can be further classified into trioses, tetroses, pentoses, hexoses, and heptoses depending on the number of carbon atoms in the monosaccharide. Examples include glyceraldehyde, a triose; erythrose, a tetraose; arabinose, ribose, xylose, and lyxose, all of which are pentoses; and glucose, mannose, fructose, and galactose, all of which are hexoses. In the present invention, monosaccharides further include N-acetylgalactosamine, N-acetylglucosamine, fucose, and N-acetylaspartic acid. The term "oligosaccharide" refers to a compound containing 2 to 10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, particularly 2 to 6) glycosidic bonds formed by polymerization. A glycosidic bond is formed by dehydration condensation between a glycosidic hydroxyl group of one monosaccharide and a hydroxyl group of another monosaccharide. The term "polysaccharide" refers to a sugar chain formed by glycosidic bonds, a high molecular weight carbohydrate consisting of at least 10 monosaccharides. Polysaccharides consisting of the same monosaccharides are called homopolysaccharides, such as starch, cellulose, and glycogen, while polysaccharides consisting of different monosaccharides are called heteropolysaccharides, such as hyaluronic acid and chondroitin sulfate. In one embodiment of the present invention, the monosaccharide residue is a glucuronic acid residue. In another embodiment of the present invention, the polysaccharide residue is a hyaluronic acid residue.

[0127] The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

[0128] The term "acid addition salts" includes, but is not limited to, salts made from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, and salts made from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted open-chain alkanoic acids, hydroxy open-chain alkanoic acids, open-chain alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Thus, these salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate salts, and further include salts of amino acids, e.g., arginate, gluconate, galacturonate, etc. Acid addition salts can be prepared by conventional means by contacting the free base with a sufficient amount of the desired acid to form the salt. The salt can be contacted with a base to regenerate the free base, which can then be isolated in a conventional manner.

[0129] The term "base addition salt" refers to salts formed with metals or amines, such as those formed with alkali and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by conventional methods by contacting the free acid with a sufficient amount of the desired base to form the salt. The salt can be contacted with an acid to regenerate the free acid, which can then be isolated by conventional methods.

[0130] The term "stereoisomer" includes enantiomers, diastereomers, and geometric isomers. Some of the compounds of the present invention contain cyclic hydrocarbon groups, which may be substituted at one or more carbon atoms, and in this case, all geometric isomers thereof, including cis and trans isomers and mixtures thereof, are within the scope of the present invention.

[0131] The term "solvate" refers to a physical combination of a compound of the present invention with one or more solvent molecules. Such physical combinations include varying degrees of ionic and covalent bonding, such as hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the lattice of a solid crystal, the compound can be separated as a solvate. Solvates include solution-phase and separable solvates. Representative solvates include hydrates, ethanolates, methanolates, etc.

[0132] The term "prodrug" refers to acetal, ester and zwitterionic forms of compounds of formula (I) that are suitable for administration to a patient and effective for their intended use without undue toxicity, irritation, allergic reaction, etc. Prodrugs are transformed in the body, for example, by hydrolysis in the blood to the parent compound.

[0133] The term "metal chelate complex", also known as a metal chelate compound, refers to a stable compound with a larger molecular weight obtained by incorporating a metal ion into a chelating agent molecule through a strong binding action between the chelating agent molecule and the metal ion.

[0134] The term "crystal" refers to a substance in a crystalline state in which the molecules, atoms, and ions of the constituent substances are regularly arranged in three-dimensional space, resulting in a periodic arrangement.

[0135] The terms "patient" or "subject," etc., are used interchangeably herein to refer to any animal or cells thereof that are treated by the methods described herein, whether in vitro or in situ. Specifically, the animal includes mammals, such as rats, mice, guinea pigs, rabbits, cats, dogs, cows, pigs, goats, horses, monkeys, or humans, and particularly humans.

[0136] The term "treatment" refers to preventing, curing, ameliorating, alleviating, minimizing, suppressing, arresting and / or halting one or more clinical symptoms of a disease after the onset of the disease.

[0137] The term "prevention" refers to preventing, minimizing, or making it harder for a disease to develop or progress by treatment before the disease develops.

[0138] The terms "Treg," "regulatory T cells," and "regulatory T cells" are used interchangeably and are a type of T cell subpopulation that controls autoimmune responses in the body and have the role of suppressing immune responses, and were previously called suppressor T cells.

[0139] The term "Treg-associated disease" primarily refers to diseases associated with abnormal or deficient Treg function, particularly autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), inflammatory diseases, etc., for which increasing the amount of Tregs is beneficial for prevention and / or treatment.

[0140] The term "autoimmune disease" refers to diseases resulting from the body's own tissue damage resulting from its immune response to its own antigens, and can be classified into organ-specific autoimmune diseases (which primarily affect a single organ) and systemic autoimmune diseases (which affect multiple tissues or organs throughout the body). The American Autoimmune Related Diseases Association has compiled a comprehensive list of autoimmune diseases, which includes, in alphabetical order without regard to incidence, the following: achalasia, Addison's disease, Adult Still's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, immune-mediated kidney diseases (e.g., glomerulonephritis, IgA nephropathy), antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, and autoimmune encephalomyelitis. encephalomyelitis), autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy (autoimmune retinopathy), autoimmune urticaria, acute motor axonal neuropathy (AMAN), Barrow disease JPEG2025540166000074.jpg31153 (also called concentric sclerosis), Behcet's disease (also called vasculitis, a chronic multisystem autoimmune disease with systemic vasculitis), benign mucosal pemphigoid (also called cicatricial pemphigoid), bullous pemphigoid, Castleman disease (CD), food allergies and related disorders (e.g., celiac disease), Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CHS), Syndrome (CSS) (also called allergic granulomatous vasculitis or eosinophilic granulomatosis with polyangiitis), Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome (a collective term for calcification (C), Raynaud's phenomenon (R), esophageal dysfunction (E), sclerosis (S), and telangiectasia (T)), Crohn's disease, Dermatitis herpetiformis (also associated with small intestinal gluten sensitivity (celiac disease)), dermatomyositis, Devic's disease disease (also called neuromyelitis optica), Discoid lupus erythematosus (Disco dlupus), Dressler's syndrome, Endometriosis, Eosinophilic esophagitisOther conditions include eosinophilic esophagitis (EoE) (possibly related to food allergies), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA), Graves' disease, Guillain-Barré syndrome, and Hashimoto's thyroiditis. thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP) (also called anaphylactoid purpura), Herpes gestationis or pemphigoid gestationis, Hidradenitis suppurativa, Hypogammaglobulinemia, IgG4-related sclerosing disease (also called IgG4-related systemic disease, hyperIgG4emia, or IgG4-related disease), Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis arthritis, Juvenile myositis, Kawasaki disease, Lambert-Eaton syndromesyndrome, Leukocytoclastic vasculitis (also called allergic vasculitis), Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease, Chronic Lyme disease, Meniere's disease, Microscopic polyangiitis, Mixed connective tissue disease, Mooren's ulcer, Mucha-Habermann disease (also called acute pityriasis lichenoides), Multifocal Motor Neuropathy, Multiple sclerosis, Myasthenia gravis gravis, myositis, narcolepsy, neonatal lupus, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, PANDAS disease (an abbreviation for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis planitis (also called peripheral uveitis), Parsonage-Turner syndromesyndrome (also called brachial plexitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndromes type I, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy (also called pain syndrome), relapsing polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome syndrome (also called polyglandular autoimmune syndrome type 2), scleritis, scleroderma, Sjögren's syndrome JPEG2025540166000075.jpg26147 Sperm & testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis, Susac's syndrome, Sympathetic ophthalmia, Systemic lupus erythematosus, Takayasu's arteritis, Temporal arteritis, Thyroid eye disease, Tolosa-Hunt syndrome, Type 1 diabetes (also called autoimmune diabetes, insulin-dependent diabetes), Ulcerative colitis, Undifferentiated connective tissue disease The list includes: ulcerative colitis, uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada disease. Common autoimmune diseases include systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, food allergies and related disorders (e.g., celiac disease), ulcerative colitis, and Crohn's disease.

[0141] The term "allergic disease" refers to an abnormal immune response caused by an allergen (antigen) resulting in tissue inflammation or organ dysfunction. Allergic diseases most commonly affect the skin, respiratory system, and gastrointestinal tract. Allergic diseases in the broad sense include diseases caused by all types of allergic reaction, while allergic reactions in the narrow sense generally refer to IgE-mediated immediate-type (type I) allergic reactions. Diseases caused by type I allergic reactions include allergic conjunctivitis in the eyes, allergic rhinitis in the nose, allergic asthma and allergic bronchopulmonary aspergillosis (ABPA) in the trachea and lungs, allergic gastroenteritis in the gastrointestinal tract, atopic dermatitis, allergic urticaria, allergic angioedema, and allergic immediate-type contact reactions, as well as severe systemic hypersensitivity reactions and anaphylactic shock. Food allergies manifest in many different ways, most commonly as a red rash on the face, around the mouth, and often on the trunk, which may be accompanied by itching, scaling, and pigmentation, and may also cause nausea, diarrhea, and abdominal pain.

[0142] The term "allergic reaction," also known as hypersensitivity, refers to an abnormal and excessive immune response. Sensitized lymphocytes or specific antibodies, which are produced when the body interacts with an antigen under certain conditions, bind to the antigen again, resulting in a pathological immune response that disrupts the body's physiological functions and damages tissues. Depending on how quickly the reaction appears, allergies are classified as immediate-type and delayed-type. The Gell and Coombs classification divides allergic reactions into four types. Type I allergies, also known as immediate-type allergies, are characterized by a rapid reaction and recovery. Common types of Type I allergies include anaphylactic shock, drug-induced drug rash, food-induced allergic gastroenteritis, and pollen- or dust-induced allergic rhinitis. Type II allergy, also known as cytolytic or cytotoxic allergy, is a pathological allergic reaction characterized by cell lysis or tissue damage, which occurs when IgG or IgM antibodies bind to the corresponding antigen on the surface of target cells, with the involvement of complement, phagocytes, and NK cells. Examples of type II allergy include transfusion reactions due to blood type incompatibility, hemolytic disease of the newborn, and drug-induced hemolytic anemia. Type III allergy, also known as immune complex or vasculitis, is an inflammatory reaction and tissue damage characterized by hyperemia, edema, local necrosis, and neutrophil infiltration, which occurs when moderately sized soluble antigen-antibody complexes deposited on the basement membrane of local or systemic capillaries are activated by complement and with the involvement of platelets, basophils, and neutrophils, such as extrinsic asthma. Type IV allergy, also known as delayed allergy, is mediated by T cells, and includes organ transplant rejection and post-vaccination encephalomyelitis.

[0143] The term "transplantation" refers to the transplantation of autologous or allogeneic cells, tissues, and organs into a body part to restore the anatomical structure and function of a damaged organ or tissue. Blood transfusion was the first cell transplant, and has since evolved into tissue transplantation, which includes transplants of skin, mucous membranes, retina, bone marrow, fat, fascia, muscle, tendon, blood vessels, nerves, bone, and cartilage. Organ transplants primarily include transplants of kidney, heart, liver, pancreas and pancreatic islets, parathyroid gland, lung, small intestine, etc.

[0144] The term "transplant rejection" refers to the process in which, after transplantation of an allogeneic tissue or organ into a recipient, the graft, i.e., foreign tissue or organ, is recognized by the recipient's immune system as a "foreign component," and the latter mounts an immune response to attack, destroy, and eliminate the graft.

[0145] The term "graft-versus-host disease (GvHD)" refers to damage to various organs in the body that occurs after transplantation when transplanted cells compete with the recipient's cells. Depending on the time it occurs after transplantation, GvHD is classified into hyperacute GvHD (often occurring within 10 days after transplantation), acute GvHD (often occurring within 3 months after transplantation), and chronic GvHD (often occurring 3 months after transplantation).

[0146] The term "inflammation" refers to the body's defense response to stimuli, manifesting as redness, swelling, heat, pain, and functional impairment. It can refer to either infectious inflammation caused by infection or non-infectious inflammation caused by factors other than infection, such as inflammation caused by an immune response, including various types of allergic reactions and some autoimmune diseases. The term "inflammatory disease" refers to diseases involving inflammation, particularly diseases involving inflammation caused by an immune response, such as interstitial lung disease, inflammatory bowel disease (idiopathic inflammatory bowel disease occurring in the ileum, rectum, and colon, including chronic colitis, acute colitis, ulcerative colitis (UC), and Crohn's disease (CD)), chronic obstructive pulmonary disease (COPD), acute lung injury, neuroinflammation, pyemia, asthma, and allergies.

[0147] Various publications, patents and disclosed patent specifications cited herein are hereby incorporated by reference in their entireties.

[0148] The following examples of the present invention will be used to clearly and completely describe the technical solutions of the present invention. It is obvious that the described examples are only some of the examples of the present invention, not all of the examples of the present invention. Any other examples that a person skilled in the art can obtain based on the examples of the present invention without any inventive work are all within the scope of protection of the present invention.

[0149] The chemicals used during the experiments in the following examples are 3,5-dihydroxytoluene, (1S,4R)-1-methyl-4-(1-propylene-2-yl)-2-cyclohexen-ol, p-toluenesulfonic acid, N,N'-dimethylformyl chloride, sodium hydride, acetyl chloride, 4,7,10,13-tetraoxatetradecanoic acid, Boc-DL-valine, 3-N,N'-dimethylaminopropionic acid, N-tert-butoxycarbonyl-L-glutamate-1-tert-butyl, triphosgene, diethylaminoethanol, 3-(4-morpholine)-1-propanol, 1,4-butanediamine, D,L-tert-leucine, N,N'-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, dichloromethane, diethyl ether, petroleum ether, ethyl acetate, methanol, acetonitrile, and n-hexane, and all of the chemicals are chemically pure.

[0150] The following are synthesis examples. 1. Synthesis of Compound 1 The synthetic route is as follows: [ka] The operating procedure is as follows: Triphosgene (1.15 g, 3.88 mmol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to -10°C. In another reaction flask, compound O-1602 (1 g, 3.88 mmol) and triethylamine (1.18 g, 11.64 mmol) were dissolved in dichloromethane (5 mL) and slowly added dropwise to the triphosgene solution. The reaction was carried out at -10°C for 2 hours, and then the temperature was raised to room temperature and the reaction was carried out overnight. The dichloromethane in the system was concentrated under reduced pressure to obtain the crude product of compound 1-1. The residue Dry tetrahydrofuran was added to precipitate a solid, which was then filtered off. The filtrate was transferred to a reaction flask, and compound 1-2 (2.27 g, 19.4 mmol) was added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure to give a pale yellow oil. The oil was purified by reverse phase column chromatography (2.5 μm octadecylsilyl silica gel, 0.25% aqueous trifluoroacetic acid:acetonitrile = 4:6). The product solution was collected and directly lyophilized to give compound 1 (400 mg, 19% yield) as an oil. The product was characterized. LCMS: MS=545(M+1) 1 H NMR(400MHz,CDCl3)δ 7.02(d,2H),5.01(d,1H),4.5(d,2H),4.4(s,2H),3.52-3.76(m,2H),3.11-3.26(m,10H),2.77-2.89(m ,2H),1.65-1.75(m,3H),1.69(t.2H),1.61(s,2H),1.54(s,3H),1.18-1.22(t,12H),1.13-1.80(m,3H).

[0151] 2. Synthesis of Compound 2 The synthetic route is as follows: [ka] The operating procedure is as follows: O-1602 (645 mg, 2.5 mmol) was dissolved in 25 mL of anhydrous THF, and under nitrogen protection, NaH (250 mg, 6.25 mmol) was added at -5°C. After completion, the mixture was stirred constantly at -5°C for 30 minutes and the temperature was maintained. Then, acetyl chloride (488 mg, 6.25 mmol, dissolved in 10 mL of anhydrous THF) was added dropwise to the reaction mixture. The addition was completed within 5 minutes. After the addition was completed, the mixture was reacted at -5°C for 1 hour. The reaction was quenched with 10 mL of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure (water temperature 40°C) to remove the solvent to obtain the crude product. The residue was first purified by normal-phase column chromatography (200-300 mesh silica gel (A: petroleum ether, B: ethyl acetate, 0% A-30% B, 60 min, 7% B in A)), followed by reverse-phase column chromatography (2.5 μm octadecylsilanized silica gel (A: 5 mmol / L aqueous ammonium bicarbonate solution, B: acetonitrile, 0% B-100% B, 45 min, approximately 80% B in A)), followed by normal-phase column chromatography (A: petroleum ether, B: ethyl acetate, 0% A-30% B, 60 min, 5% B in A) to give compound 2 as a pale yellow oil (330 mg, 0.965 mmol, 38.6% yield, 97.28% purity, 254 nm). Product 2 LCMS:[M+1] + =343,[M+18] + =360,[M+Na] + =365 product 2 1 H NMR(400MHz,CDCl3)δ 6.71(s,1H),6.67(d,J=2.0Hz,1H),5.25(d,J=24Hz,1H),4.60(d,J=20.0Hz,1H),4.49(d,J=32Hz,1H),3.70-3.56(m,1H),2.74(t, J=8.0Hz,1H),2.26(s,3H),2.24(s,3H),2.14(s,3H),2.06-2.02(m,1H),1.81-1.71(m,2H),1.68(m,3H),1.60(m,1H),1.54(s,3H).

[0152] 3. Synthesis of Compound 3 The synthetic route is as follows: [ka] The operating procedure is as follows: In step 1, triphosgene (2.54 g, 8.55 mmol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to -10°C. In a separate reaction flask, compound 3-1 (1 g, 8.55 mmol) and triethylamine (2.59 g, 25.65 mmol) were dissolved in dichloromethane (5 mL) and slowly added dropwise to the triphosgene solution. The reaction was allowed to proceed at -10°C for 2 hours, and then warmed to room temperature and allowed to proceed overnight. The dichloromethane was then concentrated from the system, and dry tetrahydrofuran was added to the residue to precipitate a solid, which was then filtered off. The filtrate was concentrated under reduced pressure to obtain the crude product of compound 3-2, which was used directly in the synthesis of the next step without further purification.

[0153] In step 2, compound 3-2 (528 mg, 2.05 mmol) was dissolved in tetrahydrofuran, cooled to 0 °C, and NaH (205 mg, 5.13 mmol) was added for 30 min. Compound O-1602 (1.1 g, 6.15 mmol) was added and the mixture was allowed to react at room temperature overnight. The mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated to give the crude product, which was purified by reverse-phase column chromatography (2.5 μm octadecylsilanized silica gel, eluent: 0.25% aqueous trifluoroacetic acid:acetonitrile = 3:7). The product solution was collected and directly lyophilized to give compound 3 (180 mg, 16% yield) as a yellow solid. Its structure was confirmed by LCMS and H NMR. LCMS: MS=545[M+1] + 1H NMR(400MHz,CDCl3)δ 8.71(d,2H),6.25(d,J=2.4Hz,1H),6.23(d,J=2.4Hz,1H),5.11(d,1H),4.5(s,2H),3.61-4.19(m,2H),2.78-3.21(m,1H),2.15- 2.22(d,1H),2.01-2.17(m,6H),1.80-1.97(m,3H),1.35-1.76(m,14H),1.20-1.32(d,2H),1.01-1.18(m,1H),0.76-0.99(m,2H).

[0154] 4. Synthesis of Compound 4 The synthetic route is as follows: [ka] The operating procedure is as follows: To a flask containing compound O-1602 (500 mg, 1.94 mmol), compound 4-1 (895 mg, 5.82 mmol), and DMAP (289 mg, 2.33 mmol), anhydrous dichloromethane (20 mL) was added and stirred for 5 minutes. DCC (1.2 g, 5.82 mmol) was added and the mixture was allowed to react at room temperature overnight. After adding n-hexane to the mixture, a solid precipitated and was removed by filtration. The filtrate was directly mixed with silica gel and purified using a normal phase column (eluent: 10% ethyl acetate / petroleum ether solution). The product was collected and concentrated under reduced pressure to give a colorless oil (250 mg, 36% yield). The structure was confirmed by LCMS and H NMR. LCMS: MS=358.2[M+1] + 1 H NMR(400MHz,CDCl3)δ 9.26(s,1H),6.25(d,J=2.4Hz,1H),6.23(d,J=2.4Hz,1H),5.11(d,1H),4.5(d,2H),3.0(s,1H),2.37(s ,4H),2.18-2.25(m,9H),2.13(s,3H),1.96(d,1H),1.69(t,2H),1.57-1.65(m,3H),1.47-1,53(d,3H).

[0155] 5. Synthesis of Compound 5 The synthetic route is as follows: [ka] The operating procedure is as follows: Compound O-1602 (300 mg, 1.16 mmol), compound 5-1 (686 mg, 2.90 mmol), and DMAP (50 mg) were dissolved in anhydrous dichloromethane (20 mL), and DCC (717 mg, 3.48 mmol) was added. After stirring overnight at room temperature, n-hexane was added, resulting in the formation of a large amount of solid. The solid was removed by filtration, and the filtrate was directly mixed with silica gel and purified by normal phase column chromatography (eluent: 10% ethyl acetate / petroleum ether solution). The product was collected and concentrated under reduced pressure to give a colorless oily product (320 mg, 39% yield). LCMS and 1 The chemical structure was verified by 1 H NMR. LCMS: MS=695.41[M+1] + 1 H NMR(400MHz,CDCl3)δ 6.25(d,J=2.4Hz,1H),6.23(d,J=2.4Hz,1H),5.09(d,1H),4.5(m,2H),3.71(t,14H),3.23(d,6H),2.76(t,3H),2 .52-2.65(m,2H),2.21-2.37(d,2H),2.10-2.18(s,1H),1.94-2.04(d,1H),1.67-1.75(2,2H),1.47-1.67(m,6H).

[0156] 6. Synthesis of Compound 6 The synthetic route is as follows: [ka] The operating procedure is as follows: Triphosgene (576 mg, 1.94 mmol) was dissolved in anhydrous dichloromethane (10 mL) and cooled to -10 ° C. In another reaction flask, compound O-1602 (500 mg, 1.94 mmol) and triethylamine (588 mg, 5.82 mmol) were dissolved in dichloromethane (5 mL) and slowly added dropwise to the triphosgene solution. The reaction was carried out at -10 ° C. for 2 hours, and then the temperature was raised to room temperature and the reaction was carried out overnight. The dichloromethane was concentrated under reduced pressure from the system to obtain the crude product of compound 6-1. Dry tetrahydrofuran was added to precipitate the solid, which was then filtered off. The filtrate was transferred to a reaction flask, and compound 6-1 (1.094 g, 5.82 mmol) was added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure to give a pale yellow oil. The oil was purified by reverse-phase column chromatography (2.5 μm octadecylsilanized silica gel, 0.25% aqueous trifluoroacetic acid:acetonitrile=4:6) and the product solution was collected and directly lyophilized to give compound 6 (270 mg, 37% yield) as a white powder. LCMS: MS=373.21[M+1] + 1 H NMR(400MHz,CDCl3)δ 9.21(s,1H),6.25(d,J=2.4Hz,1H),6.16(d,J=2.4Hz,1H)5.98(d,1H),4.52-4.41(d,2H),3.20-3.04(m,2H),3.03-2.92(q,3H), 2.76(s,1H),2.26-2.15(m,2H),2.16-2.04(m,3H),1.74-1.65(m,3H),1.52-1.44(m,7H),1.47-1.35(m,2H),1.29-1.16(m,2H).

[0157] 7. Synthesis of Compound 7 [ka] The operating procedure is as follows: Synthesis of compound 7-2: Compound O-1602 (516 mg, 2.0 mmol), compound 7-1 (1085 mg, 5.0 mmol), and DMAP (24.4 mg, 0.2 mmol) were dispersed in 25 mL of anhydrous dichloromethane. DCC (1030 mg, 5.0 mmol) was added at room temperature under nitrogen protection. Upon completion, the mixture was stirred continuously at room temperature for 3 h. The reaction mixture was diluted with 60 mL of dichloromethane and washed with saturated ammonium chloride solution (50 mL x 2) and then with saturated brine (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal phase column chromatography (200-300 mesh silica gel (A: petroleum ether, B: ethyl acetate, 0% A-50% B, 60 min)) to obtain a white foamy solid product 7-2s (950 mg, 1.547 mmol, 77.4% yield). LCMS: MS=615.21[M+1] + 1 H NMR(400MHz,CDCl3)δ 6.77(s,1H),6.64(d,J=24.0Hz,1H),5.22(s,1H),5.06(d,J=12.0Hz,1H),4.59-4.35(m,4H),3.70-3.62(m,1H),2. 56-2.51(m,1H),2.38-2.28(m,6H),2.14-1.99(m,2H),1.79-1.66(m,8H),1.62-1.43(m,21H),1.06-0.96(m,12H).

[0158] Synthesis of compound 7: The product 3-1 (350 mg, 0.57 mmol) was dissolved in 15 mL of anhydrous dichloromethane and, under nitrogen protection, hydrochloric acid in dioxane (4.0 M, 7.5 mL) was added at room temperature. Upon completion, the mixture was stirred continuously at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure (water temperature 40 °C) to remove the solvent and obtain a crude product as a white solid. The crude product was purified by slurrying in a 1:5 mixture of dichloromethane and petroleum ether for 3 hours to obtain the hydrochloride product, compound 7 (260 mg, 0.684 mmol, 86.6% yield), as a white solid. LCMS: MS=457.40[M+1] + 1 H NMR(400MHz,CDCl3)δ 6.77(s,1H),6.64(d,J=24.0Hz,1H),5.22(s,1H),5.06(d,J=12.0Hz,1H),4.59-4.35(m,4H),3.70-3.62 (m,1H),2.56-2.51(m,1H),2.38-2.28(m,6H),2.14-1.99(m,2H),1.79-1.66(m,8H),1.06-0.96(m,12H).

[0159] 8. Synthesis of Compound 8 [ka] The operating procedure is as follows: O-1602 (645 mg, 2.5 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran, and under nitrogen protection, NaH (250 mg, 6.25 mmol) was added at -5 °C. After completion, the mixture was stirred constantly at -5 °C for 30 minutes and the temperature was maintained. N,N-dimethylformyl chloride (669 mg, 6.25 mmol, dissolved in 10 mL of anhydrous tetrahydrofuran) was then added dropwise to the reaction mixture. The addition was completed within 10 minutes. After the addition was completed, the mixture was allowed to react at -5 °C for 1 hour. The reaction was quenched with 10 mL of saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layers were combined and washed with saturated brine (50 mL × 1). Anhydrous sodium sulfate was added. The crude product was dried at 77°C, filtered under suction, and concentrated under reduced pressure (water temperature 40°C) to remove the solvent. The crude product was then purified by normal-phase column chromatography (200-300 mesh silica gel (A: petroleum ether, B: ethyl acetate, 0% A-30% B, 60 min, 10% B in A)) and then by reverse-phase column chromatography (2.5 μm octadecylsilanized silica gel (A: 5 mmol / L aqueous ammonium bicarbonate solution, B: acetonitrile, 0% B-100% B, 50 min, 75% B in A)). The target peak was collected, concentrated, and lyophilized to give product 8 as a white solid (540 mg, 1.35 mmol, 54% yield). LCMS: MS=401[M+1] + 1 H NMR(400MHz,CDCl3)δ 6.76(d,J=2.4Hz,1H),6.69(d,J=2.4Hz,1H),5.31(s,1H),4.60(d,J=20.0Hz,1H),4.51(d,J=20.0Hz,1H),3.56(d,J=8.0Hz,1H), 3.02(s,6H),2.96(s,6H),2.61-2.54(m,1H),2.24(s,3H),2.05-1.81(m,2H),1.79-1.75(m,2H),1.68-1.63(m,3H),1.54(s,3H).

[0160] 9. Synthesis of Compound 9 [ka] The operating procedure is as follows: O-1602 (516 mg, 2.0 mmol), compound 9-1 (725 mg, 5.0 mmol), and triphenylphosphine (1031 mg, 5.0 mmol) were dispersed in 25 mL of anhydrous THF, and diisopropyl azodicarboxylate (1.01 g, 5.0 mmol) was added dropwise at 0°C under nitrogen protection. Upon completion, the mixture was stirred constantly at room temperature for 16 hours, and the solvent was removed from the reaction solution by concentration under reduced pressure (water temperature 40°C) to obtain the crude product. The crude product was diluted with 80 mL of dichloromethane and then saturated ammonium chloride. The organic layer was dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure (water temperature 40°C) to obtain a crude product. The crude product was purified by reverse-phase column chromatography (packing material: 2.5 μm octadecylsilylated silica gel (A: 5 mmol / L ammonium bicarbonate solution, B: acetonitrile, 0% B to 100% B, 60 min)) to obtain a pale yellow waxy product 9 (350 mg, 0.684 mmol, yield 34.2%). LCMS: MS=513[M+1] + ,MS=257[M / 2+1] + 1H NMR(400MHz,CDCl3)δ 6.27(d,J=8.0Hz,2H),5.24(d,J=12.0Hz,1H),4.46(t,J=36Hz,2H),3.99-3.89(m,4H),3.79-3.75(m,8H),2 .63-2.53(m,13H),2.31-2.20(m,3H),2.14-1.97(m,7H),1.80-1.79(m,2H),1.78(s,3H),1.67-1.51(m,3H).

[0161] 10. Synthesis of Compound 10 The synthetic route is as follows: [ka] The operating procedure is as follows: Triphosgene (1.15 g, 3.88 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran. Under nitrogen protection, a mixed solution of O-1602 (1.0 g, 3.88 mmol) and triethylamine (1.18 g, 11.64 mmol) was added at 0°C under dropwise addition within 5 minutes. After the dropwise addition was completed, the mixture was reacted at 0°C for 2 hours, and then at room temperature for 18 hours. The solvent was removed by concentration under reduced pressure (water temperature 30°C) to obtain the crude product of compound 10-1. The residue was dissolved again in 15 mL of anhydrous tetrahydrofuran and then suction filtered. The filtrate was transferred to a separatory funnel and obtained compound 10-2 (1.02 g, The mixture was added dropwise to a mixture of 11.64 mmol) and triethylamine (1.18 g, 11.64 mmol). The addition was completed within 5 minutes. After the addition was completed, the mixture was allowed to react at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure (water temperature 30 °C) to obtain the crude product, which was purified twice by reverse phase column chromatography (2.5 μm octadecylsilyl silica gel packing (A: 0.1% trifluoroacetic acid aqueous solution, B: acetonitrile, 0% B-100% B, 60 min, approximately 50% B in A solution)). The target peak was collected, concentrated, and lyophilized to obtain solid product 10 (360 mg, 0.741 mmol, 19.1% yield). LCMS: MS=487[M+1] + ,MS=244[M / 2+1] + 1 H NMR(400MHz,CDCl3)δ 7.290(s,1H),6.968(s,1H),6.753(s,1H),6.714(s,1H),5.123(d,J= 21.6Hz,1H),4.553(s,1H),4.405(s,1H),3.689-3.441(m,5H),3.204( s,4H),2.793(s,12H),2.339(s,1H),2.227(s,3H)2.001-1.956(m,1H ),1.763-1.605(m,4H),1.530(s,3H),1.311-1.255(d,J=22.4Hz,2H).

[0162] 11. Synthesis of Compound 11 The synthetic route is as follows: [ka] The operating procedure is as follows: Triphosgene (1.15 g, 3.88 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran. Under nitrogen protection, a mixed solution of O-1602 (1.0 g, 3.88 mmol) and triethylamine (1.18 g, 11.64 mmol) (O-1602 and triethylamine dissolved in 10 mL of anhydrous tetrahydrofuran) was added at 0 °C. The dropwise addition was completed within 5 minutes. After the dropwise addition was completed, the reaction was continued at 0 °C for 2 hours, and then at room temperature for 18 hours. The solvent was removed by concentration under reduced pressure (water temperature 30 °C) to obtain the crude product of compound 11-1. The residue was dissolved again in 15 mL of anhydrous tetrahydrofuran and filtered with suction. The filtrate was transferred to a separatory funnel and added to compound 11-2 (1.66 g, 1 The crude product was purified three times by reverse phase column chromatography (2.5 μm octadecylsilyl silica gel packing (A: 0.1% trifluoroacetic acid aqueous solution, B: acetonitrile, 0%B-100%B, 60 min, approximately 48% B in solution A)) and concentrated. The target peak was collected, concentrated, and lyophilized to give solid product 11 (330 mg, 0.554 mmol, 14.3% yield). LCMS: MS=597[M+1] + Sum MS=299[M / 2+1] + 1 H NMR(400MHz,DMSO-d6)δ 7.979(brs,1H),7.730(brs,1H),6.795(s,2H),5.131-5.014(m,1H),4.451-4.012(m,2H),3.489-3.476(m,24H), 2.829(s,6H),2.319(m,1H),2.208(s,3H),1.926-1.886(m,1H),1.686-1.662(m,4H),1.576(s,3H),1.527(s,3H).

[0163] 12. Synthesis of Compound 12 The synthetic route is as follows: [ka] The operating procedure is as follows: Triphosgene (856 mg, 2.91 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. Under nitrogen protection, a mixed solution of O-1602 (1.0 g, 3.88 mmol) and triethylamine (588 mg, 5.82 mmol) (O-1602 and triethylamine dissolved in 10 mL of anhydrous tetrahydrofuran) was added at 0°C. The dropwise addition was completed within 5 minutes. After the dropwise addition was completed, the reaction continued at 0°C for 2 hours, and then at room temperature for 18 hours. The solvent was removed by concentration under reduced pressure (water temperature 30°C) to obtain a residue. The residue was dissolved again in 15 mL of anhydrous tetrahydrofuran and then suction filtered. The filtrate was collected and transferred to a separatory funnel. At ℃, compound 12-2 (681 mg, 5.82 mmol) and triethylamine (588 mg, 5.82 mmol) were added dropwise to a mixture, and the addition was completed within 5 minutes. After the addition was completed, the mixture was allowed to react at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure (water temperature 30 ° C) to obtain the crude product, which was purified twice by reverse phase column chromatography (2.5 μm octadecylsilyl silica gel packing (A: 0.1% trifluoroacetic acid aqueous solution, B: acetonitrile, 0% B-100% B, 60 min, approximately 62% B in A solution)). The target peak was collected, concentrated, and lyophilized to obtain solid product 12 (290 mg, 0.723 mmol, 18.6% yield). LCMS: MS=402[M+1] + 1H NMR(400MHz,CDCl3)δ 11.61(d,J=13.3Hz,1H),6.56(d,J=2.0Hz,1H),6.44(d,J=12.9Hz,1H),6.02(d,J=2.4Hz,1H),5. 14(t,J=14.1Hz,1H),4.58(d,J=7.8Hz,2H),4.54-4.33(m,2H),3.56(d,J=67.0Hz,1H),3.43-3.33 (m,2H),3.20(d,J=6.2Hz,1H),2.70-2.40(m,1H),2.38-2.27(m,1H),2.19(s,3H),2.17-2.13(m,1 H),2.12-1.91(m,1H),1.86-1.66(m,3H),1.60(s,3H),1.58(s,3H),1.29(dd,J=15.9,9.1Hz,8H).

[0164] 13. Synthesis of Compound 13 The synthetic route is as follows: [ka] The operating procedure is as follows: O-1602 (645 mg, 2.5 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran, and under nitrogen protection, NaH (150 mg, 3.75 mmol) was added at 0°C. After completion, the mixture was stirred constantly at 0°C for 30 minutes and the temperature was maintained. Then, N,N-dimethylacetyl chloride (454 mg, 3.75 mmol, dissolved in 10 mL of anhydrous tetrahydrofuran) was added dropwise to the reaction mixture. The addition was completed within 10 minutes. After the addition was completed, the mixture was allowed to react at 0°C for 1 hour. The reaction was quenched with 10 mL of saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with saturated brine (50 mL × 1), and dried over anhydrous sodium sulfate. The crude product was then dried, suction filtered, and concentrated under reduced pressure (water temperature 40 °C) to remove the solvent, and the crude product was first purified by normal-phase column chromatography (200-300 mesh silica gel (A: petroleum ether, B: ethyl acetate, 0% A-30% B, 60 min, 15% B in A)) to obtain the crude product. The crude product was then purified by reverse-phase column chromatography (2.5 μm octadecylsilyl silica gel (A: 0.1% aqueous trifluoroethyl acetate, B: acetonitrile, 0% B-100% B, 60 min, approximately 55% B in A)). The target peak was collected, concentrated, and lyophilized to obtain product 13 as a white solid (310 mg, 36.2% yield). LCMS: MS=344[M+1] + 1 H NMR(400MHz,CDCl3)δ 6.587(s,1H),6.432(s,1H),5.185(d,J=20.0Hz,1H),4.577(d,J=30.0Hz,1H),4.441(s,1H),4.180(d,J=16.4Hz,1H),3.694(d,J=17.2Hz,1H) ),3.510(d,J=9.2Hz,1H),2.994(s,6H),2.505-2.456(m,1H),2.258(s ,3H),2.197-1.979(m,2H),1.787(s,2H),1.651(s,3H),1.488(s,3H).

[0165] 14. Synthesis of Compound 14 The synthetic route is as follows: [ka] The operating procedure is as follows: In step 1, compound O-1602 (1 g, 3.88 mmol), compound 14-1 (3.5 g, 11.63 mmol), and DMAP (100 mg) were added to dichloromethane and stirred for 5 min. DCC (1.99 g, 9.70 mmol) was added and the mixture was stirred overnight at room temperature. n-Hexane was added to form a solid. The solid was removed by filtration, and the filtrate was directly mixed with silica gel and subjected to normal phase column chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 1:9). The product was collected and concentrated under reduced pressure to give 900 mg of a white solid (target compound 14-2, 28% yield). LCMS: MS=729 [M-99] + This is the molecular weight of compound 14 after losing one tert-butyl carbonate.

[0166] In step 2, compound 14-2 (830 mg, 1 mmol) was dissolved in 1,4-dioxane (10 mL), and a 5 mol / L solution of hydrochloric acid in 1,4-dioxane was added. The mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure to remove the solvent, and the mixture was slurried with ethyl acetate to precipitate a solid. The solid was filtered to obtain 310 mg of a white powder (hydrochloride salt of compound 14, 60% yield). LCMS: MS=517[M+1] + 1 H NMR(400MHz,D2O)δ 6.80(d,J=2.4Hz,1H),6.70(d,J=2.4Hz,1H),5.02(d,1H),4.44(d,2H),3.912-.3.879(m,2H),3.52-3.50(m,1H),2.62-2.52 (m,4H),2.33(s,1H),2.23(s,3H),2.00-1.95(m,3H),1.87-1.82(m,2H),1.71-1.60(m,4H),1.52(s,3H),1.45-1.33(m,9H).

[0167] Example 1: O-1602 release experiments of O-1602 derivatives under different pH conditions Experimental equipment: electronic balance, high-performance liquid chromatograph, pH meter Experimental reagents: distilled water, phosphoric acid, sodium dihydrogen phosphate, sodium hydroxide, concentrated hydrochloric acid, acetonitrile Experimental sample: O-1602 derivative Chromatography conditions: Chromatography column: Shimnex CS C18 5 μm, 4.6 × 250 mm; Mobile phase A: 0.1% phosphoric acid / water; Mobile phase B: acetonitrile (see Table 1). [Table 1] Wavelength: 210 nm Flow rate: 1.0 mL / min Column temperature: 30°C Injection volume: 10 μL

[0168] The experimental process is as follows: Prepare the buffer as follows: A 0.2 mol / L hydrochloric acid solution was prepared by accurately measuring 18.0 mL of concentrated hydrochloric acid, diluting it to 1000 mL with water, and shaking it by hand to make it homogenous. A 0.2 mol / L sodium dihydrogen phosphate solution was obtained by weighing 6.8 g of potassium dihydrogen phosphate, adding 250 mL of water, dissolving, and shaking by hand to make the solution homogenous. A 0.2 mol / L sodium hydroxide solution was prepared by weighing out 1.6 g of sodium hydroxide, adding 200 mL of water, dissolving, and shaking by hand to make the solution homogenous. Prepare a buffer solution of pH 1.6 to 8.0 as follows: The buffer solution (pH 1.6) was prepared by accurately measuring 32.4 mL of 0.2 mol / L hydrochloric acid, diluting it to 200 mL with water, and shaking it by hand to make it homogenous. Phosphate buffer solution (pH 5.0) was obtained by taking a certain amount of 0.2 mol / L sodium dihydrogen phosphate solution and adjusting the pH to 5.0 with 0.2 mol / L sodium hydroxide solution. Phosphate buffer solution (pH 6.8) was obtained by taking a certain amount of 0.2 mol / L sodium dihydrogen phosphate solution and adjusting the pH to 6.8 with 0.2 mol / L sodium hydroxide solution. Phosphate buffer solution (pH 7.2) was obtained by taking a certain amount of 0.2 mol / L sodium dihydrogen phosphate solution and adjusting the pH to 7.2 with 0.2 mol / L sodium hydroxide solution. Phosphate buffer solution (pH 8.0) was obtained by taking a certain amount of 0.2 mol / L sodium dihydrogen phosphate solution and adjusting the pH to 8.0 with 0.2 mol / L sodium hydroxide solution. Prepare the sample solution as follows: Approximately 1 mg of O-1602 derivative was placed in a 2 mL centrifuge tube, dissolved in 1 mL of acetonitrile, and then 1 mL of buffer solution was added. The mixture was then homogenized by hand shaking and incubated at 37°C for 2 and 4 hours, after which samples were taken and measured (O-1602 release was examined under conditions of pH 1.6, pH 5.0, pH 6.8, pH 7.2, and pH 8.0, respectively). The content of O-1602 is calculated using the area percentage method.

[0169] The experimental results are as follows: 1. Among the O-1602 derivatives, compounds 1 to 13, only compounds 12 and 13 released trace amounts of O-1602 after incubation at 37°C for 4 hours in an acidic buffer solution (pH 1.6), while all other samples were stable. 2. Compounds 2, 8, and 9, which are O-1602 derivatives, were stable and did not release O-1602 when incubated at 37°C for 2 and 4 hours under conditions of pH 1.6 to 8.0. 3. Compounds 1, 6, 7, 10, 11, 12, and 13, which are O-1602 derivatives, all released O-1602 to varying degrees. As time and pH increased, the amount of O-1602 released tended to increase. Compounds 6, 11, and 13 released small amounts of O-1602, while compounds 1, 7, 10, and 12 released the most. Compound 12 released only O-1602, while compounds 1, 7, and 10 released some O-1602 and some decomposed into other impurities. 4. For specific data, please refer to Table 2. [Table 2]

[0170] Example 2: Relief of mild to moderate psoriasis induced in mice by low doses of O-1602 derivatives 1. Induction of mild to moderate psoriasis Female C57BL / 6 mice, 6-8 weeks old, were used. On the seventh day of the experiment, the experimental animals were weighed and randomly assigned to cages according to their weight. The animals were allowed to adapt to the environment in the animal room, which was maintained at a constant temperature (23°C ± 3°C) and humidity (50% relative humidity). The animals were fed standard laboratory food and had unlimited access to water. On the second day of the experiment, mice were injected with an anesthetic (tribromoethanol, 300-375 mg / kg), and the hair from the shoulders to the rump was removed using a depilator. The shaved area was then covered with ample hair removal cream. After waiting 3-5 minutes, the hair on the back was wiped away to expose the skin. On day 0 of the experiment, mice were placed on the experimental bench after anesthesia injection. An appropriate amount of IMQ was applied evenly to the dorsal skin of each mouse (the amount of IMQ applied to each mouse was as close to the same as possible, e.g., 80 mg per mouse). Each mouse was then weighed and scored. On days 1–4 of the experiment, intradermal injections of rIL-23 were performed. Mouse rIL-23 stock solution was diluted in sterile PBS to a working concentration of 25 ng / μL. After aspirating the diluted rIL-23 into a 0.5 mL syringe, the needle was inserted into the skin and slowly injected 25 μL of the rIL-23-containing solution (1 μg per mouse per day) at a small upward angle. Avoid aspirating to avoid puncturing a blood vessel. If the intradermal injection was performed properly, a small, round blister was formed.

[0171] 2. Administration of O-1602 derivatives The solid O-1602 derivative was dissolved in DMSO to a concentration of 2 mg / mL. The solution was diluted to 0.1 mg / mL with PBS. The solution was administered intragastrically at 2:00 PM every day, with a volume of 200 μL. The treatment period with the O-1602 derivative was from days 2 to 8 of the experiment. Clobetasol propionate (TEMOVATE) was used as a positive control.

[0172] 3. Daily observation indicators The body weight and skin condition of the mice were observed daily, and the condition of the back skin was given a score using the PASI score.

[0173] 4. Observation Endpoints The experiment was terminated on day 8. Mice were euthanized by cervical dislocation while under isoflurane anesthesia. Mice were dissected to obtain dorsal skin for H&E staining and histological evaluation.

[0174] 5. Experimental Results At a dose of 1 mg / kg, the O-1602 derivative effectively alleviated mild to moderate psoriasis in mice and reduced the PASI score, a result supported by the pathological score (Figure 1).

[0175] Example 3: Alleviation of acute enteritis induced in mice by 2,4,6-trinitrobenzene sulfonic acid (TNBS) by O-1602 derivatives 1. Induction of acute colitis with TNBS Male and female C57BL / 6 mice, 6-10 weeks old, were used. On day 7 of the experiment, the experimental animals were weighed and randomly assigned to cages according to their weight. The animals were allowed to adapt to the environment in the animal room, which was maintained at a constant temperature (23°C ± 3°C) and humidity (50% relative humidity). The animals were fed standard laboratory food and had unlimited access to water. On day 0, colitis was induced in mice by intrarectal injection of TNBS. The dose of TNBS was 125 mg / kg, and the vehicle was 30% alcohol. Each mouse received a volume of 100 μL. After rectal injection, the mice were held upside down for 1 minute to prevent drug spillage.

[0176] 2. Administration of O-1602 derivatives The solid O-1602 derivative was dissolved in DMSO to a concentration of 2 mg / mL. The solution was diluted to 0.1 mg / mL with PBS. Mice with TNBS-induced colitis were intragastrically administered once daily at 11:00 AM in a volume of 200 μL. The O-1602 derivative was administered at a dose of 1 mg / kg. The treatment period for the O-1602 derivative was from days 0 to 4 of TNBS administration. Control mice were intragastrically administered an equal volume of vehicle. The anti-colitis drug, JAK inhibitor tofacitinib, was used as a positive control to compare the results of the O-1602 derivative in this model experiment. The O-1602 derivative was dissolved in the same solution as above, at a concentration of 1.5 mg / mL, in a volume of 200 μL, and administered at a dose of 15 mg / kg.

[0177] 3. Daily observation indicators The body weight and anal bleeding status of the mice were observed daily, and the disease activity index (DAI) was calculated and recorded daily.

[0178] 4. Observation Endpoints The experiment was terminated on the fifth day after TNBS administration. Mice were euthanized by cervical dislocation while still anesthetized with isoflurane. Mice were dissected and the entire colon was removed. The length of the colon was measured and photographed.

[0179] 5. Experimental Results When O-1602 derivatives were used, compounds 1, 3, 6, and 7 significantly reduced weight loss in model animals (see Figure 2), and compounds 3, 6, 7, and 11 significantly reduced the DAI index (see Figure 3), prolonged colon length (see Figures 4 and 5), and reduced colon tissue damage (see Figure 5), and their effects were superior to those of tofacitinib.

[0180] The above is not intended to limit the present invention, but is merely a preferred embodiment of the present invention, and any modifications, equivalent substitutions, etc. made without departing from the spirit and rules of the present invention shall be considered to be within the protection scope of the present invention.

[0181] The embodiments and methods described herein may vary depending on the ability, experience, and preferences of those skilled in the art.

[0182] Although the present invention describes method steps in a certain order, it does not constitute any limitation on the order of method steps.

Claims

1. A compound having the structure: 【Chemistry 1】 Formula (I) In the formula, R １ has the following structure: 【Chemistry 2】 Here, X １ represents a single bond, —C(O)—, —C(O)O—, —C(O)N(R １０３ ) -, 【Transformation 3】 , -S(O) ２ - is selected from X ２ represents a single bond, -O-, -S-, -S-S-, -N(R １０４ ) -, -S(O) ２ -, -S(O) ２ N (R １０４ )-, -S(O)-, -S(O)N(R １０４ )-, -C(O)-, -C(O)O-, -C(O)N(R １０４ )-, -OC(O)-, -OC(O)N(R １０４ ) -, -N(R １０４ )C(O)O-,-N(R １０４ )C(O)-,-N(R １０４ ) S (O) ２ -, 【Chemistry 4】 Selected from R １０１ represents a single bond, an alkylene group, an alkenylene group, a phenylene group, 【Transformation 5】 , an amino acid residue, an oligopeptide residue, a polypeptide residue, a monosaccharide residue, an oligosaccharide residue, and a polysaccharide residue, n is an integer of 1 to 100, R １０２ is selected from H, alkyl groups, cycloalkyl groups, phenyl groups, and heterocyclyl groups (especially saturated heterocyclyl groups), and R １０３ and R １０４ are independently selected from H and alkyl groups, wherein said alkylene, alkenylene, phenylene, alkyl, cycloalkyl, phenyl, and heterocyclyl groups are optionally substituted by one or more independent R'; R ２ , R ４ , R ５ are independently selected from H, halogen, a hydroxy group, a mercapto group, an amino group, a cyano group, an azide group, an isocyanate group, a sulfonyl chloride group, a sulfonyl fluoride group, an amido group, a sulfonamide group, a formyloxy group, a nitro group, a formaldehyde group, a trifluoromethyl group, a sulfonic acid group, a phosphorous acid group, a trialkyltin group, a trialkylsilyl group, an alkyl group, an alkenyl group, and an alkynyl group; R ３ has the following structure: 【Transformation 6】 In the formula, Y １ represents a single bond, —C(O)—, —C(O)O—, —C(O)N(R ３０３ ) -, 【Transformation 7】 , -S(O) ２ - is selected from Y ２ represents a single bond, -O-, -S-, -S-S-, -N(R ３０４ ) -, -S(O) ２ -, -S(O) ２ N (R ３０４ )-, -S(O)-, -S(O)N(R ３０４ )-, -C(O)-, -C(O)O-, -C(O)N(R ３０４ )-, -OC(O)-, -OC(O)N(R ３０４ ) -, -N(R ３０４ )C(O)O-,-N(R ３０４ )C(O)-,-N(R ３０４ ) S (O) ２ -, 【Transformation 8】 Selected from R ３０１ represents a single bond, an alkylene group, an alkenylene group, a phenylene group, 【Chemistry 9】 , an amino acid residue, an oligopeptide residue, a polypeptide residue, a monosaccharide residue, an oligosaccharide residue, and a polysaccharide residue; m is an integer of 1 to 100; R ３０２ is selected from H, an alkyl group, a cycloalkyl group, a phenyl group, and a heterocyclyl group; R ３０３ and R ３０４ are independently selected from H, alkyl groups, and alkylene groups, each of which is optionally substituted with one or more independent R's; Or, R ４ and R ５ together with the carbon atom attached thereto form a cyclic group (particularly a saturated cyclic group, e.g., a cycloalkyl group, a heterocyclyl group), wherein said cyclic group is optionally substituted by one or more independent R'; W is selected from the following structures: 【Chemistry 10】 During the ceremony, 【Chemistry 11】 represents a single bond or a double bond, Each R ６ independently have the structure: 【Chemistry 12】 In the ceremony, L １ and L ２ represents a single bond, —O—, —S—, —N(R ６０３ ) -, -S(O) ２ -, -S(O) ２ N (R ６０３ )-, -S(O)-, -S(O)N(R ６０３ )-, -C(O)-, -C(O)O-, -C(O)N(R ６０３ )-, -OC(O)-, -OC(O)N(R ６０３ ) -, -N(R ６０３ )C(O)O-,-N(R ６０３ )C(O)-,-N(R ６０３ ) S (O) ２ - are independently selected from R ６０１ is selected from a single bond and an alkylene group, and R ６０２ is selected from H and alkyl groups, and R ６０３ is selected from H, an alkyl group, and wherein said alkyl, alkylene group is optionally substituted by one or more independent R's; Each R ７ are independently selected from H, alkyl, alkenyl, and alkynyl groups, wherein said alkyl, alkenyl, and alkynyl groups are optionally substituted by one or more independent R'; Each R' is a halogen, a hydroxy group, a mercapto group, an amino group, a cyano group, an azide group, an isocyanate group, a sulfonyl chloride group, a sulfonyl fluoride group, an amide group, a sulfonamide group, a formyloxy group, a nitro group, a formaldehyde group, a trifluoromethyl group, a sulfonic acid group, a phosphorous acid group, a trialkyltin group, a trialkylsilyl group, -CH=NH, 【Chemistry 13】 , an alkoxy group, an alkylamine group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heterocyclyl group, and a substituted or unsubstituted heterocyclylalkyl group; and the compound represented by general formula (I) is not: 【Chemistry 14】 a compound, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition, characterized in that:

2. X １ and / or Y １ represents a single bond, —C(O)—, —C(O)O—, —C(O)N(H)—, 【Chemistry 15】 , -S(O) ２ - The compound of claim 1, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition.

3. R １０１ is a single bond, C １～６ an alkylene group, 【Chemistry 16】 wherein said alkylene group is optionally substituted by one or more independent R'; Preferably, R' is a hydroxy group, a mercapto group, an amino group, an amide group, a sulfonamide group, a formyloxy group, a nitro group, a formaldehyde group, a trifluoromethyl group, 【Chemistry 17】 , ethenyl group, ethynyl group, substituted or unsubstituted phenyl group (e.g., [Chemistry 18] ), heterocyclyl groups (e.g., 【Chemistry 19】 ) are selected from More preferably, R １０１ represents a single bond, a methylene group, an ethylene group, 【Chemistry 20】 Selected from The compound according to claim 1, wherein n is preferably an integer from 1 to 10, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition.

4. R ３０１ is a single bond, C １～６ an alkylene group, 【Chemistry 21】 wherein said alkylene group is optionally substituted by one or more independent R'; Preferably, R' is a hydroxy group, a mercapto group, an amino group, an amide group, a sulfonamide group, a formyloxy group, a nitro group, a formaldehyde group, a trifluoromethyl group, 【Chemistry 22】 , ethenyl group, ethynyl group, substituted or unsubstituted phenyl group (e.g., 【Chemistry 23】 ), heterocyclyl groups (e.g., 【Chemistry 24】 ) are selected from More preferably, R ３０１ represents a single bond, a methylene group, an ethylene group, 【Chemistry 25】 Selected from The compound according to claim 1, wherein m is preferably an integer from 1 to 10, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition.

5. X ２ represents a single bond, -O-, -S-, -S-S-, -N(R １０４ ) -, -S(O) ２ -, -S(O) ２ N (R １０４ )-, -C(O)O-, -C(O)N(R １０４ ) - selected from and / or Y ２ represents a single bond, -O-, -S-, -S-S-, -N(R ３０４ ) -, -S(O) ２ -, -S(O) ２ N (R ３０４ )-, -C(O)O-, -C(O)N(R ３０４ ) - selected from Preferably, R １０４ is H, C １～６ selected from alkyl groups, Preferably, R ３０４ is H, C １～６ The compound of claim 1, a stereoisomer of said compound, a composition of any of said compounds and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition, wherein said compound or composition is selected from the group consisting of alkyl groups.

6. R １０２ is H, C １～６ Alkyl groups (especially C １～３ alkyl groups, for example, methyl, ethyl, n-propyl, and isopropyl groups; 4- to 12-membered saturated heterocyclyl groups (including monocyclic and polycyclic heterocyclyl groups (particularly, bicyclic heterocyclyl groups), and polycyclic heterocycles include fused, spiro, and bridged polycyclic heterocycles, for example, 【Chemistry 26】 wherein the alkyl, heterocyclyl groups are optionally substituted by one or more independent R's; and / or R ３０２ is H, C １～６ Alkyl groups (especially C １～３ alkyl groups, for example, methyl, ethyl, n-propyl, and isopropyl groups; 4- to 12-membered saturated heterocyclyl groups (including monocyclic and polycyclic heterocyclyl groups (particularly, bicyclic heterocyclyl groups), and polycyclic heterocycles include fused, spiro, and bridged polycyclic heterocycles, for example, 【Chemistry 27】 and wherein the alkyl group, heterocyclyl group is optionally substituted by one or more independent R', a stereoisomer of the compound, a composition of any of the compounds and stereoisomers, a composition of any of the stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of the compound or composition.

7. R １ is H, or R １ is selected from the following: 【Chemistry 28】 and / or R ３ is H, or R ３ is chosen from the following: 【Chemistry 29】 The compound of claim 1, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition.

8. R ２ is H; a stereoisomer of said compound; a composition of any of said compound and stereoisomers; a composition of any of said stereoisomers; or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition.

9. R ４ is H, C １～６ alkyl groups, wherein said alkyl groups are optionally substituted by one or more independent R'; Preferably, R' is selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, mercapto, amino, formyloxy, nitro, formaldehyde, trifluoromethyl, ethenyl, and ethynyl; More preferably, R ４ is a methyl group, a stereoisomer of the compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of the compound or composition.

10. R ５ is H, C １～６ alkyl groups, wherein said alkyl groups are optionally substituted by one or more independent R'; Preferably, R' is selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxy, mercapto, amino, formyloxy, nitro, formaldehyde, trifluoromethyl, ethenyl, and ethynyl; More preferably, R ５ is H; a compound according to any one of claims 1 to 9, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition.

11. L １ and L ２ represents a single bond, -O-, -S-, -N(H), -S(O) ２ -, -S(O) ２ independently selected from —N(H)—, —C(O)—, —C(O)O—, —C(O)N(H)—, —OC(O)—, and —N(H)C(O)—; Preferably, R ６ is H, C １～６ alkyl groups, 【Transformation 30】 The compound according to any one of claims 1 to 10, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition, wherein said compound or composition is selected from the group consisting of

12. R ６０１ is a single bond, C １～６ alkylene groups, R ６０２ is H, C １～６ selected from alkyl groups, R ６０３ is H, C １～６ selected from alkyl groups, Preferably, R ６ is a methyl group, a stereoisomer of the compound, a composition of any of the compound and stereoisomers, a composition of any of the stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of the compound or composition.

13. R ７ is C ２～６ is an alkenyl group, Preferably, R ７ is selected from ethenyl, propenyl, allyl, and prop-1-en-2-yl; More preferably, R ７ is the following: 【Chemistry 31】 The compound according to any one of claims 1 to 12, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition.

14. W is: 【Chemistry 32】 Preferably, the compound has the following structure: 【Transformation 33】 Formula (II) More preferably, in the compound, R １ is H and R ３ is not H or R １ is H and R ３ is not H or R １ and R ３ and n are not H. The compound according to any one of claims 1 to 13, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition.

15. A compound selected from the following structures: 【Transformation 34】 【Chemistry 35】 The compound of claim 1, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition.

16. The stereoisomer is selected from the following structures: 【Transformation 36】 Preferably, it is: 【Chemistry 37】 Preferably, the stereoisomer is selected from the following structures: 【Transformation 38】 Preferably, it is: 【Chemistry 39】 More preferably, the stereoisomer is selected from the following structures: 【Chemistry 40】 The compound according to any one of claims 1 to 13, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition.

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, stereoisomer, solvate, prodrug, metal chelate complex, or crystal, and one or more pharmaceutically acceptable additives.

18. Use of the compound according to any one of claims 1 to 16, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate, prodrug, metal chelate complex or crystal of said compound or composition in the manufacture of a medicament for the prevention and / or treatment of a disease, comprising: Preferably, the disease is, for example, an autoimmune disease, an allergic disease, a transplant rejection, a graft-versus-host disease (GvHD), or an inflammatory disease, the prevention or treatment of which is beneficial when the amount of Treg cells is increased.

19. The autoimmune diseases include achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, immune nephropathy, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, acute motor axonal neuropathy, Baro's disease, Behcet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease, food allergies, and related diseases. Diseases (e.g., celiac disease), Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing polymyelitis, Churg-Strauss syndrome, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, Crest syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease, discoid lupus erythematosus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans' syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, Goodpascha syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes gestationis or pemphigoid of gestationis, hidradenitis suppurativa, hypogammaglobulinemia, IgG4-related sclerosing disease, autoimmune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing and atrophic bladder disease, lignified conjunctivitis, linear IgA disease, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, erythematous corneal ulcer, Habermann's disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neutropenia, ocular pemphigoid, optic neuritis, relapsing rheumatism, PANDAS disease, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis, Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, type II, type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome,selected from primary biliary cirrhosis, primary sclerosing cholangitis, rogesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, autoimmune sperm and testicular disorders, stiff-person syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, thyroid eye disease, Tolosa-Hunt syndrome, type 1 diabetes, ulcerative colitis, unclassifiable connective tissue disease, uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada disease; Preferably, the immune renal disease is selected from anti-glomerular basement membrane nephritis, glomerulonephritis, IgA nephropathy, purpura nephritis or lupus nephritis; 19. The use according to claim 18, wherein the autoimmune disease is preferably selected from systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, food allergies and related diseases (e.g., celiac disease), ulcerative colitis, and Crohn's disease.

20. The use according to claim 18, characterized in that the allergic disease is selected from allergic conjunctivitis, allergic rhinitis, allergic asthma, allergic bronchopulmonary aspergillosis, allergic gastroenteritis, atopic dermatitis, allergic urticaria, allergic angioedema, allergic immediate contact reaction, anaphylactic shock or food allergy and its related diseases (e.g., celiac disease).

21. In the case of transplant rejection or graft-versus-host disease (GvHD), the transplant is one or more selected from cell transplantation, tissue transplantation, and organ transplantation, preferably organ transplantation; Preferably, the cell transplantation is a hematopoietic stem cell transplantation; Preferably, the tissue transplant is selected from a skin transplant, a bone marrow transplant, and a corneal transplant; 19. The use according to claim 18, wherein the organ transplant is preferably selected from kidney transplant, heart transplant, liver transplant, pancreas / pancreatic islet transplant, parathyroid transplant, lung transplant, and small intestine transplant.

22. The inflammatory disease is a disease having inflammation caused by an immune response, Preferably, the inflammatory disease is selected from interstitial lung disease, inflammatory bowel disease, chronic obstructive pulmonary disease, acute lung injury, neuroinflammation, pyemia, asthma, and allergy; 19. The use according to claim 18, wherein the inflammatory bowel disease is preferably selected from chronic colitis, acute colitis, ulcerative colitis or Crohn's disease.

23. The use according to any one of claims 18 to 22, characterized in that the disease is inflammatory bowel disease and the route of administration of the drug is a gastrointestinal route, in particular an oral route.

24. The use according to any one of claims 18 to 23, characterized in that the subject of the drug is a mammal, particularly a human, the administered dose is 0.033 to 0.407 mg / kg when calculated by body weight, and the administration frequency is once a day.

25. Use of the compound according to any one of claims 1 to 16, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition in the manufacture of a reagent for inducing or promoting the increase of Tregs, Preferably, the increase in Tregs is carried out in vivo or in vitro.

26. A method for increasing Tregs, comprising: The method comprises using a compound according to any one of claims 1 to 16, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, crystal of said compound or composition, or a pharmaceutical composition comprising the same, Preferably, the method is carried out in vitro.

27. 1. A method for preventing and / or treating a disease, comprising:

17. The method of claim 1, further comprising administering to a subject in need thereof a compound according to any one of claims 1 to 16, a stereoisomer of said compound, a composition of any of said compound and stereoisomers, a composition of any of said stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate complex, or crystal of said compound or composition; Preferably, the disease is, for example, an autoimmune disease, an allergic disease, a transplant rejection reaction, a graft-versus-host disease (GvHD), or an inflammatory disease, and is a disease for which increasing the amount of Treg cells would be beneficial for prevention or treatment.

28. The autoimmune diseases include achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, immune nephropathy, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, acute motor axonal neuropathy, Baro's disease, Behcet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease, food allergies, and related diseases. Diseases (e.g., celiac disease), Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing polymyelitis, Churg-Strauss syndrome, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, Crest syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease, discoid lupus erythematosus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans' syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, Goodpascha syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes gestationis or pemphigoid of gestationis, hidradenitis suppurativa, hypogammaglobulinemia, IgG4-related sclerosing disease, autoimmune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing and atrophic bladder disease, lignified conjunctivitis, linear IgA disease, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, erythematous corneal ulcer, Habermann's disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neutropenia, ocular pemphigoid, optic neuritis, relapsing rheumatism, PANDAS disease, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis, Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, type II, type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome,selected from primary biliary cirrhosis, primary sclerosing cholangitis, rogesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, autoimmune sperm and testicular disorders, stiff-person syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, thyroid eye disease, Tolosa-Hunt syndrome, type 1 diabetes, ulcerative colitis, unclassifiable connective tissue disease, uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada disease; Preferably, the immune renal disease is selected from anti-glomerular basement membrane nephritis, glomerulonephritis, IgA nephropathy, purpura nephritis or lupus nephritis; 28. The method of claim 27, wherein the autoimmune disease is selected from systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, food allergies and related diseases (e.g., celiac disease), ulcerative colitis, and Crohn's disease.

29. The method of claim 27, wherein the allergic disease is selected from allergic conjunctivitis, allergic rhinitis, allergic asthma, allergic bronchopulmonary aspergillosis, allergic gastroenteritis, atopic dermatitis, allergic urticaria, allergic angioedema, allergic immediate contact reaction, anaphylactic shock, or food allergy and its related diseases (e.g., celiac disease).

30. In the case of transplant rejection or graft-versus-host disease (GvHD), the transplant is one or more selected from cell transplantation, tissue transplantation, and organ transplantation, preferably organ transplantation; Preferably, the cell transplantation is a hematopoietic stem cell transplantation; Preferably, the tissue transplant is selected from a skin transplant, a bone marrow transplant, and a corneal transplant; 28. The method of claim 27, wherein the organ transplant is selected from kidney transplant, heart transplant, liver transplant, pancreas / pancreatic islet transplant, parathyroid transplant, lung transplant, and small intestine transplant.

31. The inflammatory disease is a disease having inflammation caused by an immune response, Preferably, the inflammatory disease is selected from interstitial lung disease, inflammatory bowel disease, chronic obstructive pulmonary disease, acute lung injury, neuroinflammation, pyemia, asthma, and allergy; 28. The method of claim 27, wherein the inflammatory bowel disease is selected from chronic colitis, acute colitis, ulcerative colitis or Crohn's disease.

32. 32. The method according to any one of claims 27 to 31, wherein the disease is inflammatory bowel disease and the method is for preventing or treating the disease by a gastrointestinal administration route, in particular by the oral route.

33. The method according to any one of claims 27 to 32, characterized in that the subject is a mammal, in particular a human, the dosage is 0.033 to 0.407 mg / kg calculated by body weight, and the administration frequency is once a day.

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