Compound and application thereof in treatment of Treg-related diseases

Abstract

Provided are a compound and its use in the treatment of Treg-related diseases, in particular in the prevention and / or treatment of diseases that are beneficial for its prevention or treatment by increasing the amount of Treg cells. Experiments find that the O-1602 can effectively promote Treg proliferation and increase the amount of Treg, and is expected to be beneficial to prevention or treatment of some diseases such as autoimmune diseases, allergic diseases, transplant rejection, graft versus host disease (GvHD) and inflammatory diseases by increasing the amount of Treg cells. Besides, a series of novel compounds are also prepared, can effectively promote Treg proliferation and increase the amount of Treg, have better physicochemical properties such as solubility and stability, are diversified in expected administration route, and have very good application and research values.

Description

A compound and its use in the treatment of Treg-related diseases Technical Field

[0001] The present invention relates to the field of biopharmaceutical technology, and specifically to a compound and its use in the treatment of Treg-related diseases, especially its use in the prevention and / or treatment of diseases that are beneficial for the prevention or treatment of by increasing the amount of Treg cells (e.g., autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), inflammatory diseases). Background Art

[0002] Regulatory T cells (Tregs) are a subpopulation of T cells with significant immunosuppressive properties, characterized by the expression of Foxp3, CD25, and CD4. They can suppress the immune responses of other cells and are the primary controllers of self-tolerance. For example, when immune cells such as T cells, B cells, and NK cells are faced with invading bacteria, viruses, and other harmful substances, they can generate an immune response to identify and eliminate the harmful substances, thereby protecting the body from attack. Once the battle between these cells and the harmful substances is over, Treg cells signal the body to cease attack. If immune cells remain in a hyperreactive state, they will target normal tissues, causing damage to the body and leading to, for example, autoimmune diseases. Tregs actively regulate the body by inhibiting the activation and proliferation of potentially autoreactive T cells present in normal cells, exerting their immunosuppressive and immune homeostatic properties, and playing a vital role in patients with autoimmune diseases.

[0003] At present, autoimmune diseases mainly adopt the treatment method of suppressing or blocking the pathological autoimmune response in the body, for example, adopt immunosuppressants (such as prednisone, cyclosporine, azathioprine) etc., these substances are characterized by multiple systemic side effects and interactions. Therefore, researchers attempt to develop new drugs that specifically affect the mechanism of participation in disease events, and examples of such drugs include natalizumab and infliximab. Natalizumab is a monoclonal antibody and selective inhibitor of IgG4 (a kind of adhesion molecule located on the surface of leukocytes). Natalizumab inhibits the migration of leukocytes to inflammatory lesions and is used to treat the particularly aggressive form of plaque progressive multiple sclerosis. Infliximab is a chimeric monoclonal antibody against tumor necrosis factor α (TNFα) (which plays a key role in autoimmune inflammatory reactions). Infliximab is used for rheumatoid arthritis, Crohn's disease, Bechterew's disease, and psoriasis. While these newly emerging drugs can be highly effective, they can also cause serious side effects, such as progressive multifocal leukoencephalopathy. For this reason, natalizumab was withdrawn from the market in the United States just three months after its initial registration. Furthermore, the cost of these new active substances is very high. Therefore, there is a continued need to develop new drugs that are low-cost, highly effective, and have fewer side effects.

[0004] Summary of the Invention

[0005] To overcome the deficiencies of the prior art, the present invention provides a compound and its use in the treatment of Treg-related diseases, particularly its use in the prevention and / or treatment of diseases that are beneficial for their prevention or treatment by increasing the amount of Treg cells (e.g., autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), inflammatory diseases).

[0006] In a first aspect of the present invention, a compound is provided, which has the following structure:

[0007] in,

[0008] R1 has the following structure: Wherein, X1 is selected from: single bond, -C(O)-, -C(O)O-, -C(O)N(R 103 )-、 -S(O)2-, X2 is selected from: 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-、 R 101 Selected from: single bond, alkylene, alkenylene, phenylene (e.g. ), Amino acid residues, oligopeptide residues, polypeptide residues, monosaccharide residues, oligosaccharide residues, polysaccharide residues (e.g. ), n is an integer from 1 to 100, R 102 is selected from: H, alkyl, cycloalkyl, phenyl, heterocyclic group (especially saturated heterocyclic group), R 103 and R 104 Independently selected from: H, alkyl; wherein the alkylene, alkenylene, phenylene, alkyl, cycloalkyl, phenyl, heterocyclyl is optionally substituted by one or more independent R';

[0009] R2, R4 and R5 are independently selected from the group consisting of H, halogen, hydroxy, thiol, amino, cyano, azido, isocyanate, sulfonyl chloride, sulfonyl fluoride, amide, sulfonamide, formate, nitro, formaldehyde, trifluoromethyl, sulfonic acid, phosphite, trialkyltin, trialkylsilyl, alkyl, alkenyl, and alkynyl;

[0010] R3 has the following structure: Wherein, Y1 is selected from: single bond, -C(O)-, -C(O)O-, -C(O)N(R 303 )-、 -S(O)2-, Y2 is selected from: 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-、 R 301 Selected from: single bond, alkylene, alkenylene, phenylene (e.g. ), Amino acid residues, oligopeptide residues, polypeptide residues, monosaccharide residues, oligosaccharide residues, polysaccharide residues (e.g. ), m is an integer from 1 to 100, R 302 Selected from: H, alkyl, cycloalkyl, phenyl, heterocyclic group, R 303 and R 304 Independently selected from: H, alkyl; wherein said alkyl, alkylene is optionally substituted by one or more independent R';

[0011] Alternatively, R4 and R5 together with the carbon atom to which they are attached form a cyclic group (particularly a saturated cyclic group, such as a cycloalkyl group, a heterocyclic group); wherein the cyclic group is optionally substituted by one or more independent R';

[0012] W is selected from the following structures:

[0013] in, represents a single bond or a double bond;

[0014] Each R6 independently has the following structure: Wherein, L1 and L2 are independently selected from: 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-,R 601 Selected from: single bond, alkylene, R 602 Selected from: H, alkyl, R 603 Selected from: H, alkyl; wherein said alkyl, alkylene is optionally substituted by one or more independent R';

[0015] Each R7 is independently selected from: H, alkyl, alkenyl, alkynyl, wherein said alkyl, alkenyl, alkynyl is optionally substituted with one or more independent R';

[0016] Each R' is independently selected from the group consisting of halogen, hydroxyl, thiol, amino, cyano, azido, isocyanate, sulfonyl chloride, sulfonyl fluoride, amide, sulfonamide, formate, nitro, formaldehyde, trifluoromethyl, sulfonic acid, phosphite, trialkyltin, trialkylsilyl, -CH=NH, Alkoxy, alkylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl;

[0017] Furthermore, the compound represented by general formula I is not

[0018] Specifically, X1 can be selected from: a single bond, -C(O)-, -C(O)O-, -C(O)N(H)-, -S(O)2-.

[0019] In some embodiments of the present invention, X1 is -C(O)-.

[0020] In other embodiments of the present invention, X1 is -C(O)O-.

[0021] In other embodiments of the present invention, X1 is -C(O)N(H)-.

[0022] Specifically, the amino acids and the amino acids in the oligopeptides and polypeptides can 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.

[0023] Specifically, the monosaccharides in the monosaccharides, oligosaccharides and polysaccharides can be selected from: glyceraldehyde, erythrose, arabinose, ribose, xylose, lyxose, glucose, mannose, fructose, galactose, N-acetylgalactosamine, N-acetylglucosamine, fucose, and N-acetylneuraminic acid.

[0024] In one embodiment of the present invention, the monosaccharide residue is a glucuronic acid residue.

[0025] In one embodiment of the present invention, the polysaccharide residue is a hyaluronic acid residue.

[0026] Specifically, R 101 Can be selected from: single bond, C1-6 alkylene (such as methylene, ethylene, propylene, butylene), wherein the alkylene group is optionally substituted by one or more independent R's; specifically, R' can be selected from: hydroxyl, thiol, amino, amide, sulfonamide, formic acid, nitro, formaldehyde, trifluoromethyl, vinyl, ethynyl, substituted or unsubstituted phenyl (e.g. ), heterocyclic groups (e.g. ).

[0027] Specifically, n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100; in some embodiments of the present invention, n is an integer from 1 to 10.

[0028] In some embodiments of the present invention, R 101 Selected from: single bond, methylene, ethylene,

[0029] Specifically, X2 is selected from: 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 It can be selected from: H, C1-6 alkyl.

[0030] Specifically, R 102 It can be selected from: H, C1-6 alkyl (especially C1-3 alkyl, such as methyl, ethyl, n-propyl, isopropyl), 4 to 12 membered saturated heterocyclic group (including monocyclic, polycyclic heterocyclic group (especially bicyclic heterocyclic group), polycyclic heterocyclic ring including fused, spiro, bridged polycyclic heterocyclic ring, such as ) (especially 4 to 6 membered monocyclic saturated heterocyclic group); wherein the alkyl and heterocyclic groups are optionally substituted by one or more independent R'; specifically, R' can be selected from: C1-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl), hydroxyl, thiol, amino, amide, sulfonamide, formic acid, nitro, formaldehyde, trifluoromethyl, vinyl, ethynyl, substituted or unsubstituted phenyl (e.g. ), heterocyclic groups (e.g. ).

[0031] In one embodiment of the present invention, R1 has the following structure: Among them, R 105 Selected from: H, -OH, 4 to 12 membered substituted or unsubstituted saturated heterocyclic group (including monocyclic, polycyclic heterocyclic group (especially bicyclic heterocyclic group), polycyclic heterocyclic ring including fused, spiro, bridged polycyclic heterocyclic ring, for example )(especially a 4- to 6-membered monocyclic saturated heterocyclic group), R 106 and R 107 Independently selected from: H, C1-6 alkyl (especially C1-3 alkyl, such as methyl, ethyl, n-propyl).

[0032] In some embodiments of the present invention, R 105 Can be selected from: H, amino,

[0033] In some embodiments of the present invention, R1 is H.

[0034] In other embodiments of the present invention, R1 is selected from:

[0035] In some embodiments of the present invention, R2 is H.

[0036] Specifically, Y1 can be selected from: a single bond, -C(O)-, -C(O)O-, -C(O)N(H)-, -S(O)2-.

[0037] In some embodiments of the present invention, Y1 is -C(O)-.

[0038] In other embodiments of the present invention, Y1 is -C(O)O-.

[0039] In other embodiments of the present invention, Y1 is -C(O)N(H)-.

[0040] Specifically, R 301 Can be selected from: single bond, C1-6 alkylene (such as methylene, ethylene, propylene, butylene), wherein the alkylene group is optionally substituted by one or more independent R's; specifically, R' can be selected from: hydroxyl, thiol, amino, amide, sulfonamide, formic acid, nitro, formaldehyde, trifluoromethyl, vinyl, ethynyl, substituted or unsubstituted phenyl (e.g. ), heterocyclic groups (e.g. ).

[0041] Specifically, m can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100; in some embodiments of the present invention, m is an integer from 1 to 10.

[0042] In some embodiments of the present invention, R 301 Selected from: single bond, methylene, ethylene,

[0043] Specifically, Y2 is selected from: 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 It can be selected from: H, C1-6 alkyl.

[0044] Specifically, R 302 It can be selected from: H, C1-6 alkyl (especially C1-3 alkyl, such as methyl, ethyl, n-propyl, isopropyl), 4 to 12 membered saturated heterocyclic group (including monocyclic, polycyclic heterocyclic group (especially bicyclic heterocyclic group), polycyclic heterocyclic ring including fused, spiro, bridged polycyclic heterocyclic ring, such as ) (especially 4 to 6 membered monocyclic saturated heterocyclic group); wherein the alkyl and heterocyclic groups are optionally substituted by one or more independent R'; specifically, R' can be selected from: C1-3 alkyl (such as methyl, ethyl, n-propyl, isopropyl), hydroxyl, thiol, amino, amide, sulfonamide, formic acid, nitro, formaldehyde, trifluoromethyl, vinyl, ethynyl, substituted or unsubstituted phenyl (e.g. ), heterocyclic groups (e.g. ).

[0045] In one embodiment of the present invention, R3 has the following structure: Among them, R 305 Selected from: H, -OH, 4 to 12 membered substituted or unsubstituted saturated heterocyclic group (including monocyclic, polycyclic heterocyclic group (especially bicyclic heterocyclic group), polycyclic heterocyclic ring including fused, spiro, bridged polycyclic heterocyclic ring, for example )(especially a 4- to 6-membered monocyclic saturated heterocyclic group), R 306 and R 307 Independently selected from: H, C1-6 alkyl (especially C1-3 alkyl, such as methyl, ethyl, n-propyl).

[0046] In some embodiments of the present invention, R 305 Can be selected from: H, amino,

[0047] In some embodiments of the present invention, R3 is H.

[0048] In other embodiments of the present invention, R3 is selected from:

[0049] In some embodiments of the present invention, R4 is H.

[0050] In other embodiments of the present invention, R4 is a C1-6 alkyl group, particularly a C1-3 alkyl group, wherein the alkyl group is optionally substituted with one or more independent R' groups; specifically, R' groups can be selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, formate, nitro, formaldehyde, trifluoromethyl, vinyl, and ethynyl. In one embodiment of the present invention, R4 is methyl.

[0051] In some embodiments of the present invention, R5 is H.

[0052] In other embodiments of the present invention, R5 is a C1-6 alkyl group, particularly a C1-3 alkyl group, wherein the alkyl group is optionally substituted with one or more independent R' groups; specifically, R' groups can be selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, formate, nitro, formaldehyde, trifluoromethyl, vinyl, and ethynyl. In one embodiment of the present invention, R5 is methyl.

[0053] Specifically, R 601 It can be selected from: a single bond, a C1-6 alkylene group (particularly a C1-3 alkylene group, such as methylene and ethylene).

[0054] Specifically, R 602 It can be selected from: H, C1-6 alkyl (especially C1-3 alkyl, such as methyl, ethyl, n-propyl, isopropyl).

[0055] Specifically, R 603 It can be selected from: H, C1-6 alkyl, especially H.

[0056] Specifically, L1 and L2 can 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)-, -N(H)C(O)-.

[0057] Specifically, each R6 can be independently selected from: H, alkyl, More specifically, each R6 can be independently selected from: H, C1-6 alkyl, Among them, R 601 is C1-6 alkylene, R 602 Selected from: H, C1-6 alkyl.

[0058] In some embodiments of the present invention, each R6 is independently C1-6 alkyl, especially C1-3 alkyl, such as methyl, ethyl, n-propyl, isopropyl, especially methyl.

[0059] In some embodiments of the present invention, each R7 is independently C2-6 alkenyl, particularly C2-3 alkenyl, such as vinyl, propenyl, allyl, prop-1-en-2-yl, in particular

[0060] In some embodiments of the present invention, Represents a single bond.

[0061] In other embodiments of the present invention, Represents a double bond.

[0062] In some embodiments of the present invention, W is

[0063] In one embodiment of the present invention, the compound has the following structure:

[0064] Wherein, R1, R3, and R4 have the corresponding definitions as defined above in the present invention.

[0065] In one embodiment of the present invention, R1 is H, and R3 is not H. For example, the compound may have the following structure:

[0066] In another embodiment of the present invention, R1 is not H, and R3 is H. For example, the compound may have the following structure:

[0067] In another embodiment of the present invention, R1 and R3 are not H. For example, the compound may have the following structure:

[0068] In some embodiments of the present invention, the compound has the following structure:

[0069] In the second aspect of the present invention, provided are the compound described in the first aspect, a stereoisomer of such a compound, any combination of the compound and a stereoisomer, any combination of the stereoisomer of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, or crystal form of the aforementioned compound (or composition).

[0070] Specifically, the stereoisomers can be selected from the following structures:

[0071] in particular

[0072] Wherein, R1 to R7 have the corresponding definitions described in the first aspect of the present invention.

[0073] More specifically, the stereoisomers may be selected from the following structures:

[0074] in particular

[0075] Wherein, R1, R3, and R4 have the corresponding definitions described in the first aspect of the present invention.

[0076] In some embodiments of the present invention, the stereoisomer has the following structure:

[0077] The isotope derivatives of the present invention include compounds in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass, such as stable and radioactive isotopes of 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, etc., preferably deuterium.

[0078] In the third aspect of the present invention, a method for preparing the compound of the first aspect, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer of the compound, or the aforementioned compound (or composition) or its pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (such as hydrate), prodrug, metal chelate, or crystal form is provided, which comprises: With Z-X1-R 101 -X2-R 102 ' and / or Z'-Y1-R 301 -Y2-R 302 'Steps of reacting, or by Prepare first wherein Z and Z' can be independently selected from: H, halogen (such as Cl), hydroxyl, OC (O) -alkyl, etc., Z1 and Z2 can be independently selected from: halogen (such as Cl), hydroxyl, etc., R 102 ' and R 302 ' can be R 102 and R 302 or protected form of R 102 and R 302 (For example, protected hydroxyl or amino groups, in which case the method further comprises a deprotection step).

[0079] In the fourth aspect of the present invention, a pharmaceutical composition is provided, which comprises a stereoisomer of the compound described in the first aspect, any combination of the compound and the stereoisomer, any combination of the stereoisomer of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (such as hydrate), prodrug, metal chelate, crystal form of the aforementioned compound (or composition), and one or more pharmaceutically acceptable excipients.

[0080] Specifically, the pharmaceutically acceptable excipients may be selected from one or more of: disintegrants, binders, lubricants, suspending agents, stabilizers, fillers, absorption enhancers, surfactants, flavoring agents, antioxidants, preservatives, and the like.

[0081] Specifically, the pharmaceutical composition can be administered by any suitable route, such as gastrointestinal administration (e.g., oral, sublingual, rectal) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.), preferably by the gastrointestinal route, especially by the oral route.

[0082] Specifically, the pharmaceutical composition can be in any suitable dosage form, such as a gastrointestinal dosage form, including but not limited to tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, etc.; a non-gastrointestinal dosage form, for example, an injectable dosage form: such as an injection (for example, for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), a respiratory dosage form: such as a spray, an aerosol, a powder aerosol, etc., a skin dosage form, such as an external solution, a lotion, an ointment, a plaster, a paste, a patch, etc., a mucosal dosage form: such as eye drops, eye ointments, nasal drops, gargles, etc., a cavity dosage form: such as suppositories, aerosols, effervescent tablets, drops, pills, etc., for use in the vagina, urethra, nasal cavity, ear canal, etc.

[0083] Specifically, the various dosage forms of the above-mentioned pharmaceutical composition can be prepared according to conventional production methods in the pharmaceutical field, for example, by mixing the active ingredient with one or more pharmaceutically acceptable excipients and then preparing the mixture into the desired dosage form.

[0084] Specifically, in the above-mentioned pharmaceutical composition, the weight percentage of the compound described in the first aspect, the stereoisomer of such compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer of the compound, or the pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (such as hydrate), prodrug, metal chelate, or crystalline form of the aforementioned compound (or composition) can be 0.1-99.5%, for example, 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%.

[0085] In the fifth aspect of the present invention, there is provided the use of the compound described in the first aspect, a stereoisomer of such a compound, any combination of the compound and a stereoisomer, any combination of the stereoisomer of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, or crystal form of the aforementioned compound (or composition) in the preparation of a drug for preventing and / or treating a disease.

[0086] In particular, the disease is a disease that is beneficial for prevention or treatment by increasing the amount of Treg cells, such as autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), and inflammatory diseases.

[0087] Specifically, the autoimmune diseases include, but are not limited to, organ-specific autoimmune diseases and systemic autoimmune diseases, for example, achalasia, Addison's disease, adult-onset 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 Autoimmune retinopathy, autoimmune urticaria, acute motor and sensory axonal neuropathy, Barlow disease (also known as concentric sclerosis), Behçet disease, benign mucous membrane pemphigoid (also known as cicatricial pemphigoid), bullous pemphigoid, giant lymphadenopathy, food allergies and related disorders (such as Celiac disease), Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome (also known as allergic granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis), Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackievirus myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (also known as neuromyelitis optica), discoid lupus, Dressler syndrome, 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-Schonlein purpura (also known as Henoch-Schonlein purpura), herpes gestationis or pemphigoid gestationis, hidradenitis suppurativa, hypogammaglobulinemia, IgG4-related sclerosing disease (also known as IgG4-related Systemic diseases, high IgG4 disease and IgG4-related diseases), immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis (also known as hypersensitivity vasculitis), lichen planus, lichen sclerosus atrophicus, woody conjunctivitis, linear IgA disease, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Mucha-Habermann disease (also known as acute pityriasis lichenoides vulgaris), multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic diseases, PANDAS, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria,Parry-Romberg syndrome, pars planitis (also known as peripheral uveitis), Parsonage-Turner syndrome (also known as brachial neuritis), 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, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestogen-induced dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy (also known as pain syndrome) Symptoms include: rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome (also known as polyglandular autoimmune syndrome type 2), scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-man syndrome, subacute bacterial endocarditis, Susac syndrome, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, thyroid eye disease, Tolosa-Hunt syndrome, type I diabetes (also known as autoimmune diabetes, insulin-dependent diabetes mellitus), ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, and Koyanagi-Harada disease. In some embodiments of the present invention, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, type I diabetes, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, food allergies and related diseases (e.g., Celiac's disease), ulcerative colitis, and Crohn's disease.

[0088] Specifically, the immune renal disease includes but is not limited to anti-glomerular basement membrane antibody nephritis, glomerulonephritis, IgA nephropathy, purpuric nephritis or lupus nephritis.

[0089] Specifically, the allergic diseases include, but are not limited to, allergic conjunctivitis, allergic rhinitis, allergic asthma, allergic bronchopulmonary aspergillosis (also known as allergic bronchopulmonary aspergillosis), allergic gastroenteritis, atopic dermatitis, allergic urticaria, allergic angioedema, allergic immediate contact reaction, anaphylactic shock or food allergy and related diseases (such as Celiac's disease), etc.

[0090] Specifically, for transplant rejection and graft-versus-host disease (GvHD), the transplant can be cell transplantation (e.g., hematopoietic stem cell transplantation), tissue transplantation (e.g., skin transplantation, bone marrow transplantation, corneal transplantation), organ transplantation (e.g., kidney transplantation, heart transplantation, liver transplantation, pancreas and islet transplantation, parathyroid transplantation, lung transplantation, small intestine transplantation), in particular organ transplantation.

[0091] Specifically, the inflammatory disease is a disease with inflammation caused by an immune response, including, but 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, sepsis, asthma, allergies, etc.

[0092] In one embodiment of the present invention, the application is the use of the compound described in the first aspect or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, stereoisomer, solvate (such as a hydrate), prodrug, metal chelate, or crystal form in the preparation of a drug for preventing and / or treating a disease.

[0093] Specifically, the drug can be administered by any suitable route, such as gastrointestinal administration (e.g., oral, sublingual, rectal) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.), preferably by the gastrointestinal route, especially by the oral route.

[0094] In one embodiment of the present invention, the disease is inflammatory bowel disease, and the administration route of the drug is a gastrointestinal administration route, particularly an oral administration route.

[0095] Specifically, the dosage is 0.01-5.0 mg / kg calculated based on body weight, such as 0.01, 0.02, 0.03, 0.033, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.407, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7 ,1.8,1.9,2.0,2.1,2.2,2.3,2.4,2.5,2.6,2.7,2.8,2.9,3.0,3.1,3.2,3.3,3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0mg / kg.

[0096] Specifically, the administration frequency is once a day.

[0097] In a specific embodiment of the present invention, the subject is a non-human mammal and the dosage is preferably 0.4-5.0 mg / kg calculated on body weight, such as 0.4, 0.407, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0 mg / kg.

[0098] In a specific embodiment of the present invention, the subject is a human, and the dosage is preferably 0.033-0.407 mg / kg, such as 0.033, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.407 mg / kg, calculated based on body weight.

[0099] In the sixth aspect of the present invention, provided is the use of the compound described in the first aspect, a stereoisomer of such a compound, any combination of the compound and a stereoisomer, any combination of the stereoisomer of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, or crystal form of the aforementioned compound (or composition) in the preparation of an agent for inducing or promoting Treg expansion.

[0100] In one embodiment of the present invention, the Treg expansion is performed in vivo.

[0101] In another embodiment of the present invention, the Treg expansion is performed in vitro.

[0102] In some embodiments of the present invention, for the above-mentioned applications, the Treg expansion is performed in vivo, and the reagent can be administered by any suitable route, such as gastrointestinal administration (e.g., oral, sublingual, rectal) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.), preferably a gastrointestinal route, especially an oral route.

[0103] In the seventh aspect of the present invention, a reagent for inducing or promoting Treg expansion is provided, which comprises the compound described in the first aspect, a stereoisomer of such a compound, any combination of the compound and the stereoisomer, any combination of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, or crystal form of the aforementioned compound (or composition).

[0104] In one embodiment of the present invention, the Treg expansion is performed in vivo.

[0105] In another embodiment of the present invention, the Treg expansion is performed in vitro.

[0106] Specifically, the reagent can be in any suitable form, such as solid or liquid.

[0107] In the eighth aspect of the present invention, a method for preventing and / or treating a disease is provided, which comprises the step of administering to a subject in need thereof the compound of the first aspect or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, stereoisomer, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or a pharmaceutical composition comprising the same.

[0108] Specifically, the disease has the definition described in the fifth aspect of the present invention.

[0109] Specifically, the subject is a mammal, especially a human.

[0110] Specifically, in the method, the compound described in the first aspect, the stereoisomer of such compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer of the compound, or the aforementioned compound (or composition) in its pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, prodrug, solvate can be used alone or in combination with other types of pharmaceutical preparations and / or treatment methods.

[0111] Specifically, the administration route can be any suitable route, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0112] In one embodiment of the present invention, the method comprises the step of administering to a subject in need thereof the compound of the first aspect or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, stereoisomer, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or a pharmaceutical composition comprising the same, wherein the administration route can be any suitable route, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, peritoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.), preferably a gastrointestinal administration route, in particular an oral administration route.

[0113] Specifically, the dosage is 0.01-5.0 mg / kg calculated based on body weight, such as 0.01, 0.02, 0.03, 0.033, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.407, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7 ,1.8,1.9,2.0,2.1,2.2,2.3,2.4,2.5,2.6,2.7,2.8,2.9,3.0,3.1,3.2,3.3,3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0mg / kg.

[0114] Specifically, the administration frequency is once a day.

[0115] In a specific embodiment of the present invention, the subject is a non-human mammal and the dosage is preferably 0.4-5.0 mg / kg calculated based on body weight, such as 0.4, 0.407, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0 mg / kg.

[0116] In a specific embodiment of the present invention, the subject is a human, and the dosage is preferably 0.033-0.407 mg / kg, such as 0.033, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.407 mg / kg, calculated based on body weight.

[0117] In the ninth aspect of the present invention, a method for regulating an immune response is provided, which comprises the step of administering to a subject in need thereof the compound of the first aspect, a stereoisomer of such a compound, any combination of the compound and the stereoisomer, any combination of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystal form, or pharmaceutical composition comprising the same of the aforementioned compound (or composition).

[0118] Specifically, the subject is a mammal, especially a human.

[0119] Specifically, the regulation is a negative regulation of the body's immune response, that is, inhibiting the body's immune response.

[0120] In one embodiment of the present invention, the method includes the step of administering to a subject in need thereof the compound of the first aspect, a stereoisomer of such a compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystal form, or a pharmaceutical composition comprising the same, wherein the administration route can be any suitable route, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, peritoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.), preferably a gastrointestinal administration route, especially an oral administration route.

[0121] In the tenth aspect of the present invention, a method for Treg expansion is provided, which includes the steps of using the compound described in the first aspect, a stereoisomer of such a compound, any combination of the compound and the stereoisomer, any combination of the stereoisomers of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (such as a hydrate), prodrug, metal chelate, crystal form, or a pharmaceutical composition comprising the same.

[0122] In one embodiment of the invention, the method is performed in vivo.

[0123] In another embodiment of the present invention, the method is performed in vitro.

[0124] In some embodiments of the present invention, the method is performed in vivo, which includes the step of administering to a subject the compound of the first aspect, a stereoisomer of such a compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystal form, or a pharmaceutical composition comprising the same. The administration route can be any suitable route, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, peritoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.), preferably a gastrointestinal administration route, especially an oral administration route.

[0125] In some embodiments of the present invention, the method is performed in vitro, which includes the step of culturing Tregs in vitro using a culture medium containing the compound of the first aspect, a stereoisomer of such a compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer of the compound, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, or crystalline form of the aforementioned compound (or composition).

[0126] In the eleventh aspect of the present invention, a Treg cell population is provided, which is prepared (in vitro) by the method described in the tenth aspect.

[0127] Specifically, the Treg cell population can be used to regulate (inhibit) the body's immune response, prevent or treat diseases, such as autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), and inflammatory diseases (as specifically described in the fifth aspect of the present invention).

[0128] The present invention has experimentally demonstrated that O-1602 can effectively promote Treg proliferation and increase its number. This increase in Treg cell numbers is expected to be beneficial in the prevention or treatment of several diseases, such as autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), and inflammatory diseases. Furthermore, the present invention has also prepared a series of novel compounds that also effectively promote Treg proliferation and increase its number. These compounds exhibit excellent physicochemical properties, such as solubility and stability, and are expected to have diverse administration routes, demonstrating their potential for application and research. BRIEF DESCRIPTION OF THE DRAWINGS

[0129] Figure 1: O-1602 derivatives alleviate mild to moderate PSORIASIS induced in mice.

[0130] Figure 2: Effects of different compounds on body weight changes in the treatment of TNBS-induced acute enteritis, among which TOFACITINIB is tofacitinib.

[0131] Figure 3: Scores of different compounds after treatment of TNBS-induced acute enteritis, among which TOFACITINIB is tofacitinib.

[0132] Figure 4: Effects of different compounds on colon length after dissection of TNBS-induced acute enteritis.

[0133] Figure 5: Effects of different compounds on the length and appearance of the colon after dissection of TNBS-induced acute enteritis. From left to right are compounds 1 to 13, Control, and TOFACITINIB. DETAILED DESCRIPTION

[0134] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0135] The term "alkyl" refers to a straight or branched hydrocarbon chain radical that does not contain unsaturated bonds and is connected to the rest of the molecule by a single bond. Typical alkyl groups can contain 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 10) carbon atoms, particularly 1 to 10 carbon atoms, 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, isohexyl, etc. If an alkyl group is substituted by a cycloalkyl group, it is correspondingly a "cycloalkylalkyl" group, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If an alkyl group is substituted by an aryl group, it is correspondingly an "aralkyl" group, such as benzyl, benzhydryl, or phenethyl. If an alkyl group is substituted by a heterocyclyl group, it is correspondingly a "heterocyclylalkyl" group.

[0136] The term "alkylene" refers to a hydrocarbon group (divalent alkyl group) formed by losing two hydrogen atoms from an alkane molecule, which can be straight or branched and is connected to the rest of the molecule by a single bond. Typical alkylene groups herein have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, and the like.

[0137] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 single rings and / or condensed rings, containing 3-18 carbon atoms, preferably 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, etc.

[0138] The term "alkoxy" refers to a substituent formed by replacing the hydrogen of a hydroxy group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and the like.

[0139] The term "alkylamino" refers to a substituent formed when one or both hydrogen atoms in an amino group (-NH2) are replaced by an alkyl group, such as an alkylamino group containing 1 to 10 carbon atoms, for example

[0140] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0141] The term "haloalkyl" refers to a group in which one or more hydrogen atoms in an alkyl group are replaced by a halogen atom (e.g., fluorine, chlorine, bromine or iodine), for example, -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0142] The term "aryl" refers to a monocyclic or polycyclic free radical, including a polycyclic free radical containing a monocyclic aromatic group and / or a condensed aromatic group, such as a radical containing 1-3 monocyclic or condensed rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. 12 The aryl group refers to an aryl group containing 6 to 12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc.

[0143] The term "heterocyclyl" refers to a 3- to 18-membered ring radical containing 2- to 17 carbon atoms and 1- to 10 heteroatoms selected from nitrogen, oxygen, or sulfur atoms. A heterocyclyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. Polycyclic ring systems may include fused (two rings share two ring atoms), spiro-connected (two rings share one ring atom), or bridged (two rings share three or more ring atoms) ring systems (excluding linked rings). A heterocyclyl may be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms, and the heteroaryl groups include, for example, coumarin, including 8-coumarin, quinolyl, including 8-quinolyl, isoquinolyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindole, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purine benzoxazolyl, benzodiazepine, benzodiazepine, benzophenone ... Suitable heterocycloalkyl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms, and include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepine, oxepanyl, oxazepine , diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiolanyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinolizinyl.

[0144] The term "amino acid" refers to an organic compound containing a basic amino group and an acidic carboxyl group. According to the different positions of the amino group attached to the carbon chain, amino acids can be divided into α-, β-, γ-, and w-amino acids, especially α-amino acids. The term "amino acid residue" refers to the structural part of an amino acid in which a hydrogen is missing from the amino group and a hydroxyl is missing from the carboxyl group. The term "oligopeptide" refers to a compound formed by the condensation of 2-10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, especially 2-6) amino acids. The term "polypeptide" refers to a compound formed by the condensation of 10-50 (e.g., 10, 15, 20, 25, 30, 35, 40, 45, 50) amino acids. In the present invention, the amino acids and amino acids in oligopeptides and polypeptides can be selected from the group consisting of 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.

[0145] The term "monosaccharide" refers to molecules that cannot be simply hydrolyzed into smaller sugars. Monosaccharides are classified into two main categories: aldoses and ketoses, depending on the position of the carbonyl group. Monosaccharides can also be classified into trioses, tetroses, pentoses, hexoses, and heptoses based on the number of carbon atoms in the monosaccharide, such as the three-carbon sugar glyceraldehyde; the four-carbon sugar erythrose; the five-carbon sugars arabinose, ribose, xylose, and lyxose; and the six-carbon sugars glucose, mannose, fructose, and galactose. In the present invention, monosaccharides also include: N-acetylgalactosamine, N-acetylglucosamine, fucose, and N-acetylneuraminic acid. The term "oligosaccharide" refers to a compound composed of 2-10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, especially 2-6) glycosidic bonds, formed by the dehydration condensation of the glycosidic hydroxyl group of one monosaccharide and a hydroxyl group of another monosaccharide. The term "polysaccharide" refers to a polymeric carbohydrate consisting of at least 10 monosaccharides linked by glycosidic bonds. Polysaccharides composed of identical monosaccharides are called homopolysaccharides, such as starch, cellulose, and glycogen; polysaccharides composed 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.

[0146] The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

[0147] The term "acid addition salt" includes, but is not limited to, salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic and phosphonic acids, and salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids. The present invention relates to the preparation of the present invention and the like.Therefore, these salts include but are not limited to sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, 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 mesylate, also comprise amino acid whose salt such as arginate, gluconate, galacturonate etc.Acid addition salts can be prepared by making free alkali form contact with sufficient amount of required acid in a conventional manner.Free alkali form can be regenerated by making salt form contact with alkali, and separate this free alkali in a conventional manner.

[0148] The term "base addition salt" refers to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with 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 contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.

[0149] The term "stereoisomer" includes the presence of enantiomers, diastereomers and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that may be substituted on more than one carbon atom, in which case all geometric forms, including cis and trans forms, and mixtures thereof, are within the scope of the present invention.

[0150] The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution phases and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

[0151] The term "prodrug" refers to a form of a compound of Formula I that is suitable for administration to a patient without undue toxicity, irritation, allergic reactions, etc., and is effective for its intended use, including acetal, ester, and zwitterion forms. The prodrug is transformed in vivo, for example, by hydrolysis in the blood, to yield the parent compound.

[0152] The term "metal chelate" is also called a metal chelate compound, which refers to a compound in which the metal ions are encapsulated inside the chelate through the strong binding effect between the chelate molecules and the metal ions, thereby becoming a stable compound with a larger molecular weight.

[0153] The term "crystal form" refers to a crystalline substance, which has a periodic arrangement pattern due to the orderly arrangement of the molecules, atoms, and ions that constitute the substance in three-dimensional space.

[0154] The terms "patient" or "subject" and the like are used interchangeably herein and refer to any animal or cell thereof to be treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animals include mammals, e.g., rats, mice, guinea pigs, rabbits, cats, dogs, cows, pigs, sheep, horses, monkeys or humans, particularly humans.

[0155] The term "treating" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, suppressing and / or halting one or more clinical symptoms of a disease after onset of the disease.

[0156] The term "prevent" or "prevent" refers to treating a disease before it occurs to avoid, minimize, or make the onset or development of the disease more difficult.

[0157] The terms "Treg," "regulatory T cells," and "regulatory T cells" have the same meaning and can be used interchangeably. They are a type of T cell subset that controls autoimmune reactivity in the body. Because they have the function of suppressing immune responses, they were also called suppressor T cells in the early days.

[0158] The term "Treg-related diseases" mainly refers to diseases associated with abnormal or missing Treg function, especially diseases that can be beneficially prevented and / or treated by increasing the amount of Treg, such as autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), inflammatory diseases, etc.

[0159] The term "autoimmune disease" refers to a disease caused by the body's immune response to its own antigens, resulting in damage to its own tissues. It can be divided into organ-specific autoimmune diseases (mainly affecting a single organ) and systemic autoimmune diseases (affecting multiple tissues or organs throughout the body). The American Autoimmune Related Diseases Association has compiled a comprehensive list of autoimmune diseases, including (in alphabetical order of disease names, not related to incidence): Achalasia, Addison's disease, Adult Still's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Immune kidney diseases (e.g., glomerulonephritis, IgA nephropathy), Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune dysautonomia, and dysautonomia), autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, acute motor and sensory axonal neuropathy (AMAN), Baló disease (also known as concentric sclerosis), Behçet's disease (a chronic, multisystem autoimmune disease involving systemic vascular inflammation, also known as vasculitis), benign mucous membrane pemphigoid (Benign pemphigoid), and varicose vein ulcer.mucosal pemphigoid (also known as cicatricial pemphigoid), bullous pemphigoid, Castleman disease (CD), food allergies and related disorders (such as Celiac's disease), Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) (also known as allergic granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis), Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackiemyocarditis, CREST syndrome (CREST), and other related diseases. syndrome (an abbreviation for calcinosis (C), Raynaud's phenomenon (R), esophageal dysfunction (E), sclerosis (S), and telangiectasia (T)), Crohn's disease, dermatitis herpetiformis (also associated with gluten sensitivity (Celiac's disease) of the small intestine), dermatomyositis, Devic's disease (also known as neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE) (may be associated with food allergies), eosinophilic fasciitis, erythemanodosum, essential mixed cryoglobulinemiacryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis, Giant cell myocarditis, Goodpasture's syndrome, Granulomatosis with Polyangiitis (GPA), Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis, Hidradenitis suppurativa Suppurativa, hypogammaglobulinemia, IgG4-related sclerosing disease (also known as IgG4-related systemic disease, high IgG4 disease, and IgG4-related disease), immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis (also known as hypersensitivity vasculitis), lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease IgAdisease), chronic Lyme diseasediseasechronic), Meniere's disease, Microscopic polyangiitis, Mixed connective tissue disease, Mooren's ulcer, Mucha-Habermann disease (also known as acute pityriasis lichenoides vulgaris), Multifocal Motor Neuropathy, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neonatal Lupus, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococci). Disorders Associated with Streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmalnocturnal hemoglobinuria, Parry-Romberg syndrome, Pars planitis (also known as peripheral uveitis), Parsonage-Turner syndrome (also known as brachial neuritis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, and IIII, II, III), Polymyalgiarheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia, Pyoderma gangrenosum, Raynaud's phenomenon, Reactive arthritis, Reflex sympathetic dystrophy (also known as pain syndrome), Relapsing polychondritis, Restless legs syndrome legs syndrome), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome (also known as polyglandular autoimmune syndrome type 2), scleritis, scleroderma, Sjögren's syndrome syndrome, Sperm and testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis, Susac's syndrome, Sympathetic ophthalmia, Systemic Lupus erythematosus, Takayasu's arteritis, Temporalarteritis, 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, 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 diseases (such as Celiac's disease), ulcerative colitis, Crohn's disease, etc.

[0160] The term "allergic disease" refers to an abnormal immune response of the body caused by allergens (allergens), resulting in tissue inflammation or organ dysfunction. Allergic diseases most commonly affect the skin, respiratory tract, and digestive tract. Allergic diseases in a broad sense include all diseases caused by allergic reaction mechanisms. Allergic reactions in a narrow sense often refer to rapid-type (type I) allergic reactions mediated by IgE. Diseases caused by type I allergic reactions include: eyes: allergic conjunctivitis, nose: allergic rhinitis, trachea and lungs: allergic asthma, allergic bronchopulmonary aspergillosis (also known as allergic bronchopulmonary aspergillosis), etc., digestive tract: allergic gastroenteritis, skin: atopic dermatitis, allergic urticaria, allergic angioedema, allergic rapid-type contact reactions, etc., severe systemic reactions: anaphylaxis, anaphylactic shock. The symptoms of food allergies can be varied, with rash being the most common. It often occurs as erythema on the face, around the mouth, and on the trunk. It can also cause itching and desquamation, and may also cause pigmentation. Nausea, diarrhea, and abdominal pain may also occur.

[0161] The term "allergic reaction," also known as hypersensitivity, refers to an abnormal, exaggerated immune response. This occurs when the body interacts with an antigenic substance under certain conditions, producing sensitized lymphocytes or specific antibodies. These antibodies, when bound to the re-entering antigen, can cause a pathological immune response that disrupts physiological function and damages tissues. Hypersensitivity reactions are categorized as immediate-type and delayed-type, depending on how quickly they occur. Gail and Coombs divided hypersensitivity reactions into four types: Type I hypersensitivity reaction, also known as immediate hypersensitivity reaction, is characterized by rapid reaction and rapid disappearance. Common type I hypersensitivity reactions include anaphylactic shock, drug rash caused by drugs, allergic gastroenteritis caused by food, allergic rhinitis caused by pollen or dust, etc.; Type II hypersensitivity reaction, also known as cytolytic hypersensitivity reaction or cytotoxic hypersensitivity reaction, is a pathological hypersensitivity reaction characterized by cell lysis or tissue damage caused by the binding of IgG or IgM antibodies to the corresponding antigens on the surface of target cells with the participation of complement, phagocytes and NK cells. For example, blood type incompatible transfusion reaction, neonatal hemolytic reaction and drug-induced hemolytic anemia are all type II hypersensitivity reactions; Type III hypersensitivity reaction, also known as immune complex hypersensitivity reaction or vasculitis hypersensitivity reaction. It is caused by the deposition of medium-sized soluble antigen-antibody complexes into the local or systemic capillary basement membrane, which activates complement and, with the participation of platelets, basophils, and neutrophils, causes inflammatory reactions and tissue damage characterized by congestion, edema, local necrosis, and neutrophil infiltration, such as extrinsic asthma; Type IV hypersensitivity reaction, also known as delayed hypersensitivity reaction, is mediated by T cells, such as organ transplant rejection reaction, encephalomyelitis after vaccination, etc.

[0162] The term "transplantation" refers to the transplantation of autologous or allogeneic cells, tissues, and organs into a specific part of the body to restore the anatomical structure and function of the damaged organ or tissue. Blood transfusion was the earliest form of cell transplantation, followed by tissue transplantation, such as skin, mucosa, omentum, bone marrow, fat, fascia, muscle, tendon, blood vessels, nerves, bone, and cartilage. Organ transplantation primarily includes transplantation of kidneys, hearts, livers, pancreas and islets, parathyroid glands, lungs, and small intestine.

[0163] The term "transplant rejection" refers to the situation where, after an allogeneic tissue or organ transplant, the recipient's immune system recognizes the foreign tissue or organ as a "foreign component", which then initiates an immunological response to attack, destroy and eliminate the transplant.

[0164] The term "graft-versus-host disease (GvHD)" refers to damage to various organs of the body caused by transplanted cells against recipient cells after transplantation. Depending on the time of occurrence of GvHD after transplantation, it can be divided into hyperacute GvHD (usually occurring within 10 days after transplantation), acute GvHD (usually occurring within three months after transplantation), and chronic GvHD (usually occurring three months after transplantation).

[0165] The term "inflammation" is the body's defense response to stimulation, manifested as redness, swelling, heat, pain and functional impairment, etc.; it can be infectious inflammation caused by infection, or non-infectious inflammation not caused by infection, such as inflammation caused by an immune response (such as various types of hypersensitivity reactions, inflammation caused by some autoimmune diseases). The term "inflammatory disease" refers to diseases with inflammation, especially diseases with inflammation caused by an immune response, such as: interstitial lung disease, inflammatory bowel disease (an idiopathic intestinal inflammatory disease involving 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, sepsis, asthma, allergies, etc.

[0166] The disclosures of various publications, patents, and published patent specifications cited herein are incorporated by reference in their entirety.

[0167] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0168] The chemicals used in the experiments described in the following examples include: 3,5-dihydroxytoluene, (1S,4R)-1-methyl-4-(1-propen-2-yl)-2-cyclohexenol, p-toluenesulfonic acid, N,N'-dimethylformyl chloride, sodium hydrogen hydride, acetyl chloride, 4,7,10,13-tetraoxatetradecanoic acid, Boc-DL-valine, 3-N,N'-dimethylaminopropionic acid, N-tert-butyloxycarbonyl-L-glutamic acid-1-tert-butyl ester, triphosgene, diethylaminoethanol, 3-(4-morpholino)-1-propanol, 1,4-butanediamine, D,L-tert-leucine, N'N-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, dichloromethane, ether, petroleum ether, ethyl acetate, methanol, acetonitrile, and n-hexane. All of the above chemicals are chemically pure.

[0169] Synthesis examples are as follows:

[0170] 1. Synthesis of Compound 1

[0171] Synthesis route:

[0172] Operation process:

[0173] Dissolve triphosgene (1.15 g, 3.88 mmol) in anhydrous dichloromethane (10 mL) and cool to -10°C. In another reaction flask, dissolve compound O-1602 (1 g, 3.88 mmol) and triethylamine (1.18 g, 11.64 mmol) in dichloromethane (5 mL). Slowly add dropwise to the triphosgene solution and react at -10°C for 2 hours. Then warm to room temperature and react overnight. Concentrate the dichloromethane in the system under reduced pressure to obtain a crude product of compound 1-1. To the residue was added dry tetrahydrofuran to precipitate a solid, which was removed by filtration. The filtrate was transferred to a reaction flask, and compound 1-2 (2.27 g, 19.4 mmol) was added and stirred at room temperature overnight. The mixture was concentrated under reduced pressure to obtain a light yellow oil, which was purified by reverse phase column with a filler of 2.5 μm octadecylsilane bonded silica gel and an eluent of 0.25% trifluoroacetic acid aqueous solution / acetonitrile = 4:6. The product solution was collected and directly lyophilized to obtain an oily substance, namely compound 1 (400 mg, yield: 19%).

[0174] The product was confirmed by LCMS, MS = 545 (M+1)

[0175] 1 HNMR: (400MHz, CDCl3), δ7.02(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)

[0176] 2. Synthesis of Compound 2

[0177] Synthesis route:

[0178] Operation process:

[0179] O-1602 (645 mg, 2.5 mmol) was dissolved in 25 mL of anhydrous THF. NaH (250 mg, 6.25 mmol) was added at -5°C under nitrogen protection. After the addition, the mixture was stirred at -5°C for 30 min, keeping the temperature constant. Acetyl chloride (488 mg, 6.25 mmol, dissolved in 10 mL of anhydrous THF) was then added dropwise to the reaction solution over 5 min. After the addition was complete, the reaction was continued at -5°C for 1 h. The reaction was quenched with 10 mL of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure (40°C) to remove the solvent to obtain the crude product. The crude product was first chromatographed on a normal phase column using 200-300 mesh silica gel (A: petroleum ether; B: ethyl acetate; 0% A–30% B, 60 min; 7% of B in The product was purified by reverse phase column chromatography using 2.5 μm octadecylsilane bonded silica gel (A: 5 mmol / L aqueous ammonium bicarbonate solution; B: acetonitrile; 0% B–100% B, 45 min; ~80% of B in A). The product was further purified by normal phase column chromatography (A: petroleum ether; B: ethyl acetate; 0% A–30% B, 60 min; 5% of B in A) to obtain compound 2 (330 mg, 0.965 mmol, purification yield: 38.6%; purity: 97.28%, 254 nm) as a light yellow oil.

[0180] LCMS-Product 2: [M+1] + =343, [M+18] + =360 and [M+Na] + =365;

[0181] 1 H-NMR-Product 2: (400MHz, CDCl3) δ6.71 (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).

[0182] 3. Synthesis of Compound 3

[0183] Synthesis route:

[0184] Operation process:

[0185] Step 1: Dissolve triphosgene (2.54 g, 8.55 mmol) in anhydrous dichloromethane (10 mL) and cool to -10°C. In another reaction flask, dissolve compound 3-1 (1 g, 8.55 mmol) and triethylamine (2.59 g, 25.65 mmol) in dichloromethane (5 mL). Slowly add dropwise to the triphosgene solution and react at -10°C for 2 hours. Then warm to room temperature and react overnight. Concentrate the dichloromethane in the system and add dry tetrahydrofuran to the residue. Solid precipitates and is removed by filtration. The filtrate is concentrated under reduced pressure to obtain a crude compound 3-2, which is used directly in the next synthesis without purification.

[0186] 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 and reacted for 30 minutes. Compound O-1602 (1.1 g, 6.15 mmol) was added and reacted at room temperature overnight. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by reverse phase column chromatography using 2.5 μm octadecylsilane bonded silica gel as the filler and 0.25% trifluoroacetic acid aqueous solution / acetonitrile = 3:7 as the eluent. The product solution was collected and directly lyophilized to obtain a yellow solid, namely compound 3 (180 mg, yield: 16%), whose structure was confirmed by LCMS and HNMR.

[0187] LCMS: MS=545[M+1] +

[0188] 1 HNMR: (400MHz, CDCl3) δ8.71(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)

[0189] 4. Synthesis of Compound 4

[0190] Synthesis route:

[0191] Operation process:

[0192] 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) was added anhydrous dichloromethane (20 mL) and stirred for 5 minutes. DCC (1.2 g, 5.82 mmol) was then added and allowed to react at room temperature overnight. After adding n-hexane, a solid precipitated. The solid was removed by filtration, and the filtrate was directly mixed with silica gel and purified using a normal phase column chromatography with 10% ethyl acetate in petroleum ether as eluent. The product was collected and concentrated under reduced pressure to afford 250 mg of a colorless oil (36% yield). The structure was confirmed by LCMS and HNMR.

[0193] LCMS: MS=358.2[M+1] +

[0194] 1 HNMR: (400MHz, CDCl3) δ9.26 (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)

[0195] 5. Synthesis of Compound 5

[0196] Synthesis route:

[0197] Operation process:

[0198] 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. The mixture was stirred at room temperature overnight. After adding n-hexane, a large amount of solid was produced. The solid was removed by filtration. The filtrate was directly mixed with silica gel and purified by normal phase column chromatography with 10% ethyl acetate in petroleum ether as eluent. The product was collected and concentrated under reduced pressure to obtain a colorless oil, which was the product (320 mg, yield: 39%). The product was analyzed by LCMS and 1 HNMR confirmed its chemical structure

[0199] LCMS: MS=695.41[M+1] +

[0200] 1HNMR: (400MHz, CDCl3) δ6.25(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)

[0201] 6. Synthesis of Compound 6

[0202] Synthesis route:

[0203] Operation process:

[0204] Dissolve triphosgene (576 mg, 1.94 mmol) in anhydrous dichloromethane (10 mL) and cool to -10°C. In another reaction flask, dissolve compound O-1602 (500 mg, 1.94 mmol) and triethylamine (588 mg, 5.82 mmol) in dichloromethane (5 mL). Slowly add the mixture dropwise to the triphosgene solution and react at -10°C for 2 hours. Then, warm the temperature to room temperature and react overnight. Concentrate the dichloromethane in the system under reduced pressure to obtain a crude product of compound 6-1. To the residue was added dry tetrahydrofuran to precipitate a solid, which was removed by filtration. The filtrate was transferred to a reaction flask and compound 6-1 (1.094 g, 5.82 mmol) was added and stirred at room temperature overnight. The mixture was concentrated under reduced pressure to obtain a light yellow oil, which was purified using a reverse phase column with a filler of 2.5 μm octadecylsilane bonded silica gel and an eluent of 0.25% trifluoroacetic acid aqueous solution / acetonitrile = 4:6. The product solution was collected and lyophilized directly to obtain a white powder, namely compound 6 (270 mg, yield: 37%).

[0205] LCMS: MS = 373.21M+1] + ;

[0206] 1HNMR: (400MHz, CDCl3) δ9.21 (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).

[0207] 7. Synthesis of Compound 7

[0208] Operation process:

[0209] Synthesis of compound 7-2:

[0210] 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. Under nitrogen protection, DCC (1030 mg, 5.0 mmol) was added at room temperature. After the addition, stirring was continued at room temperature for 3 h. The reaction solution was diluted with 60 mL of dichloromethane and washed with saturated ammonium chloride solution (50 mL x 2) and saturated brine (30 mL x 2) in sequence. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain the crude product, which was purified by normal phase column chromatography using 200-300 mesh silica gel (A: petroleum ether; B: ethyl acetate; 0% A–50% B, 60 min) to obtain the white foamy solid product 7-2s (950 mg, 1.547 mmol, yield: 77.4%).

[0211] LCMS: MS=615.21[M+1] +

[0212] 1 HNMR: (400MHz, CDCl3)δ6.77(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),3.70–3.6 2(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).

[0213] Synthesis of compound 7:

[0214] Product 3-1 (350 mg, 0.57 mmol) was dissolved in 15 mL of anhydrous dichloromethane. Under nitrogen protection, a dioxane hydrochloride solution (4.0 M, 7.5 mL) was added at room temperature. After the addition, stirring was continued at room temperature for 12 h. The reaction solution was concentrated under reduced pressure (40 ° C water temperature) to remove the solvent to obtain a white solid crude product. The crude product was purified by beating with a mixed solution of (dichloromethane / petroleum ether = 1:5) for 3 hours to obtain a white solid hydrochloride product compound 7 (260 mg, 0.684 mmol, yield: 86.6%).

[0215] LCMS: MS=457.40[M+1] +

[0216] 1 HNMR: (400MHz, CDCl3) δ6.77(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).

[0217] 8. Synthesis of Compound 8

[0218] Operation process:

[0219] O-1602 (645 mg, 2.5 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran. Under nitrogen protection, NaH (250 mg, 6.25 mmol) was added at -5°C. After the addition, stirring was continued at -5°C for 30 min, keeping the temperature constant. Then, N,N-dimethylformyl chloride (669 mg, 6.25 mmol, dissolved in 10 mL of anhydrous tetrahydrofuran) was added dropwise to the reaction solution. The addition was completed within 10 minutes. After the addition was completed, the reaction was continued at -5°C for 1 h. The reaction was quenched with 10 mL of saturated ammonium chloride solution. The mixed solution was extracted with ethyl acetate (50 mL x 2). The organic layers were combined and washed with saturated brine (50 mL x 2). 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure (40°C water temperature) to remove the solvent to obtain a crude product, which was first purified by normal column chromatography using 200-300 mesh silica gel (A: petroleum ether; B: ethyl acetate; 0% A–30% B, 60 min; 10% of B in A), and then purified by reverse phase column chromatography using 2.5 μm octadecylsilane bonded silica gel (A: 5 mmol / L aqueous ammonium bicarbonate solution; B: acetonitrile; 0% B–100% B, 50 min; 75% B in A solution). The target peak was collected, concentrated, and lyophilized to obtain a white solid product 8 (540 mg, 1.35 mmol, yield: 54%).

[0220] LCMS: MS=401[M+1] + ;

[0221] 1 H-NMR: (400MHz, CDCl3) δ6.76(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).

[0222] 9. Synthesis of Compound 9

[0223] Operation process:

[0224] 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. Under nitrogen protection, diisopropyl azodicarboxylate (1.01 g, 5.0 mmol) was added dropwise at 0°C. After the addition, stirring was continued at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure (40°C water temperature) to remove the solvent to obtain a crude product. The crude product was diluted with 80 mL of dichloromethane and washed with saturated ammonium chloride solution (50 mL x 2) and saturated brine (30 mL x 4). 2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure (40°C water temperature) to obtain a crude product, which was purified by reverse phase column chromatography (filler: 2.5 μm octadecylsilane bonded silica gel) (A: 5 mmol / L ammonium bicarbonate solution; B: acetonitrile; 0% B–100% B, 60 min;) to obtain a light yellow waxy product 9 (350 mg, 0.684 mmol, yield: 34.2%).

[0225] LCMS: MS=513[M+1] + Sum MS = 257 [M / 2 + 1] + ;

[0226] 1 HNMR: (400MHz, CDCl3) δ6.27(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).

[0227] 10. Synthesis of Compound 10

[0228] Synthesis route:

[0229] Operation process:

[0230] 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 dropwise at 0°C within 5 minutes. After the addition was complete, 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 (30°C water temperature) to obtain a crude product of compound 10-1. The residue was redissolved in 15 mL of anhydrous tetrahydrofuran and filtered. The filtrate was collected and transferred to a separatory funnel and added dropwise to compound 10-2 (1. 02g, 11.64mmol) and triethylamine (1.18g, 11.64mmol) were added dropwise within 5 minutes. After the addition was completed, the reaction was continued at room temperature for 2 hours, and the solvent was removed by concentration under reduced pressure (30°C water temperature) to obtain a crude product, which was purified twice by reverse phase column chromatography (filler: 2.5μm octadecylsilane bonded silica gel) (A: 0.1% trifluoroacetic acid aqueous solution; B: acetonitrile; 0% B–100% B, 60min; ~50% B in A solution). The target peak was collected, concentrated and lyophilized to obtain a solid product 10 (360mg, 0.741mmol, yield: 19.1%).

[0231] LCMS: MS=487[M+1] + Sum MS = 244[M / 2+1] + ;

[0232] 1 HNMR: (400MHz, CDCl3)δ7.290(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).

[0233] 11. Synthesis of Compound 11

[0234] Synthesis route:

[0235] Operation process:

[0236] 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 within 5 minutes (O-1602 and triethylamine were dissolved in 10 mL of anhydrous tetrahydrofuran). After the addition was complete, 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 (30°C water temperature) to obtain a crude product of compound 11-1. The residue was redissolved in 15 mL of anhydrous tetrahydrofuran and filtered. The collected filtrate was transferred to a separatory funnel and added dropwise to compound 11-2 (1.6 The crude product was purified by reverse phase column chromatography (filler: 2.5 μm octadecylsilane bonded silica gel) (A: 0.1% trifluoroacetic acid aqueous solution; B: acetonitrile; 0% B–100% B, 60 min; ~48% B in A solution) for 3 times. The target peak was collected, concentrated and lyophilized to obtain a solid product 11 (330 mg, 0.554 mmol, yield: 14.3%).

[0237] LCMS: MS=597[M+1] + Sum MS = 299[M / 2+1] + ;

[0238] 1 HNMR: (400 MHz, DMSO -d6 )δ7.979(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)

[0239] 12. Synthesis of Compound 12

[0240] Synthesis route:

[0241] Operation process:

[0242] 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) was added at 0°C within 5 minutes (O-1602 and triethylamine were dissolved in 10 mL of anhydrous tetrahydrofuran). After the addition was complete, 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 at 30°C) to obtain a residue. The residue was redissolved in 15 mL of anhydrous tetrahydrofuran and filtered. The filtrate was collected and transferred to a separatory funnel and added dropwise at 0°C to Compound 12-2 (681 mg, 5.82 mmol) and triethylamine (588 mg, 5.82 mmol) were added dropwise within 5 minutes. After the addition was completed, the reaction was continued at room temperature for 2 hours, and the solvent was removed by concentration under reduced pressure (30 ° C water temperature) to obtain a crude product. The crude product was purified twice using a reverse phase column chromatography with a filler of 2.5 μm octadecylsilane bonded silica gel (A: 0.1% trifluoroacetic acid aqueous solution; B: acetonitrile; 0% B–100% B, 60 min; ~62% B in A solution) and the target peak was collected, concentrated, and lyophilized to obtain a solid product 12 (290 mg, 0.723 mmol, yield: 18.6%).

[0243] LCMS: MS=402[M+1] + ;

[0244] 1 HNMR (400MHz, CDCl3) δ11.61(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),2.17-2.1 3(m,1H),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).

[0245] 13 Synthesis of compound 13

[0246] Synthesis route:

[0247] Operation process:

[0248] O-1602 (645 mg, 2.5 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran. Under nitrogen, NaH (150 mg, 3.75 mmol) was added at 0°C. After the addition, stirring was continued at 0°C for 30 minutes, keeping the temperature constant. Then, N,N-dimethylacetyl chloride (454 mg, 3.75 mmol, dissolved in 10 mL of anhydrous tetrahydrofuran) was added dropwise to the reaction solution within 10 minutes. After the addition was complete, the reaction was continued 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 x 2). The combined organic layers were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure (40°C) to remove the solvent to obtain the crude product, which was first chromatographed on a normal column using 200-300 mesh silica gel (A: petroleum ether; B: ethyl acetate; 0% A–30% B, 60 min; 15% of The crude product was purified by reverse phase column chromatography using 2.5 μm octadecylsilane bonded silica gel (A: 0.1% trifluoroethyl acetate in water; B: acetonitrile; 0% B–100% B, 60 min; ~55% of B in A). The target peak was collected, concentrated, and lyophilized to obtain the white solid product 13 (310 mg, yield: 36.2%).

[0249] LCMS: MS=344[M+1] +

[0250] 1 HNMR: (400MHz, CDCl3) δ6.587 (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).

[0251] 14. Synthesis of Compound 14

[0252] Synthesis route:

[0253] Operation process:

[0254] first step:

[0255] 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 minutes. Then, DCC (1.99 g, 9.70 mmol) was added and stirred at room temperature overnight. After adding n-hexane, a solid was generated. The solid was removed by filtration. The filtrate was directly mixed with silica gel and subjected to normal phase column chromatography. The filler was 200-300 mesh silica gel. The eluent was petroleum ether: ethyl acetate = 1:9. The product was collected and concentrated under reduced pressure to obtain 900 mg of a white solid compound, the target compound 14-2, with a yield of 28%.

[0256] LCMS:MS=729[M-99] + The molecular weight of compound 14 is reduced by one tert-butyl carbonate

[0257] Step 2:

[0258] Compound 14-2 (830 mg, 1 mmol) was dissolved in 1,4-dioxane (10 mL), and a 5 mol / L 1,4-dioxane hydrochloride solution was added. The mixture was stirred at room temperature for 3 hours, and the solvent was removed by concentration under reduced pressure. The solid was precipitated by beating with ethyl acetate and filtered to obtain 310 mg of a white powder, i.e., the hydrochloride salt of compound 14. The yield was 60%.

[0259] LCMS: MS=517[M+1] +

[0260] 1 HNMR: (400MHz, D2O) δ6.80(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)

[0261] Example 1: Experiment on the release of O-1602 from O-1602 derivatives under different pH conditions

[0262] Experimental equipment:

[0263] Electronic balance, high performance liquid chromatograph, pH meter

[0264] Experimental reagents:

[0265] Distilled water, phosphoric acid, sodium dihydrogen phosphate, sodium hydroxide, concentrated hydrochloric acid, acetonitrile

[0266] Experimental samples:

[0267] O-1602 derivatives

[0268] Chromatographic conditions:

[0269] Chromatographic column: Shimnex CS C18 5μm, 4.6*250mm

[0270] Mobile phase A: 0.1% phosphoric acid water; Mobile phase B: acetonitrile (see Table 1)

[0271] Table 1: Mobile phase

[0272] Wavelength: 210nm Flow rate: 1.0ml / min Column temperature: 30℃ Injection volume: 10μl

[0273] Experimental process:

[0274] Buffer configuration:

[0275] 0.2mol / L hydrochloric acid solution: Accurately measure 18.0ml of concentrated hydrochloric acid, dilute to 1000ml with water, and shake well to obtain

[0276] 0.2 mol / L sodium dihydrogen phosphate solution: weigh 6.8 g potassium dihydrogen phosphate, add 250 ml water, and shake to dissolve.

[0277] 0.2mol / L sodium hydroxide solution: Weigh 1.6g sodium hydroxide, add 200ml water, and shake to dissolve.

[0278] pH 1.6~8.0 buffer solution configuration:

[0279] Buffer solution (pH 1.6): Accurately measure 32.4 ml of 0.2 mol / L hydrochloric acid, dilute to 200 ml with water, and shake well.

[0280] Phosphate buffer (pH 5.0): Take a certain amount of 0.2 mol / L sodium dihydrogen phosphate solution and adjust the pH to 5.0 with 0.2 mol / L sodium hydroxide solution.

[0281] Phosphate buffer (pH 6.8): Take a certain amount of 0.2 mol / L sodium dihydrogen phosphate solution and adjust the pH value to 6.8 with 0.2 mol / L sodium hydroxide solution.

[0282] Phosphate buffer (pH 7.2) is prepared 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.

[0283] Phosphate buffer (pH 8.0) is prepared 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.

[0284] Sample solution preparation:

[0285] Dissolve approximately 1 mg of an O-1602 derivative in 1 ml of acetonitrile in a 2 ml centrifuge tube. Add 1 ml of buffer, shake well, and incubate at 37°C for 2 and 4 hours. Samples were then taken for analysis. (The release of O-1602 was investigated at pH 1.6, pH 5.0, pH 6.8, pH 7.2, and pH 8.0.)

[0286] Calculation: Calculate the content of O-1602 using area percentage

[0287] Experimental results:

[0288] ① In acidic buffer solution (pH 1.6), only compounds 12 and 13 of O-1602 derivatives released trace amounts of O-1602 after incubation at 37°C for 4 hours, while the other samples were stable.

[0289] ②O-1602 derivatives 2, 8, and 9 showed good stability when incubated at 37°C for 2 h and 4 h at pH 1.6-8.0, and did not release O-1602;

[0290] ③O-1602 derivatives 1, 6, 7, 10, 11, 12, and 13 all released O-1602 to varying degrees. With increasing time and pH, the release of O-1602 increased. Derivatives 6, 11, and 13 released a small amount of O-1602, while derivatives 1, 7, 10, and 12 released a larger amount of O-1602. Derivatives 12 released all of the O-1602, while derivatives 1, 7, and 10 only partially released O-1602, with some degrading into other impurities.

[0291] ④For specific data, please see Table 2.

[0292] Table 2: Specific parameters

[0293] Example 2: Application of low doses of O-1602 derivatives to alleviate mild to moderate PSORIASIS induced in mice

[0294] 1. Induction of mild to moderate PSORIASIS

[0295] Female C57BL / 6 mice, 6-8 weeks old, were used. On day -7 of the experiment, the experimental animals were weighed and randomly divided into cages according to body weight. The animals were allowed to acclimate to the animal room environment. The animal room maintained a constant temperature (23°C ± 3°C) and constant humidity (relative humidity 50%). The animals were fed a standard laboratory chow diet and had free access to water. On day -2 of the experiment, the mice, which had been injected with an anesthetic (tribromoethanol, 300-375 mg / kg), were shaved from the shoulders to the buttocks with a shaver. The shaved area was then thoroughly covered with depilatory cream and left for 3-5 minutes before wiping off the back hair to expose the skin. On day 0 of the experiment, the anesthetic-injected mice were placed on the experimental table, and an appropriate amount of IMQ was evenly applied to the back skin of the mice (the amount of IMQ applied to each mouse was as consistent as possible, e.g., 80 mg / mouse). The mice were weighed and scored. On days 1-4 of the experiment, rIL-23 was injected intradermally. Dilute the mouse rIL-23 stock solution to a working concentration of 25 ng / μl in sterile PBS; after aspirating the diluted rIL-23 into a 0.5 ml syringe, insert the needle into the skin, tilt it upward at the shallowest possible angle, and inject 25 μl (1 μg per mouse per day) of the solution containing rIL-23 in a slow, continuous motion. Do not aspirate and avoid puncturing blood vessels. Proper intradermal injection will result in a small round blister.

[0296] 2. Administration of O-1602 derivatives

[0297] Solid O-1602 derivatives were dissolved in DMSO to a concentration of 2 mg / ml. This solution was diluted to 0.1 mg / ml with PBS. Oral administration was performed daily at 2:00 PM in a volume of 200 μl. Treatment with O-1602 derivatives was performed from days 2 to 8 of the experiment. TEMOVATE served as a positive control.

[0298] 3. Daily observation indicators

[0299] The body weight and skin condition of the mice were observed daily, and the PASI score was used to score the back skin condition.

[0300] 4. Observation endpoint

[0301] The experiment was terminated on day 8. Mice were euthanized by cervical dissection under isoflurane anesthesia. The dorsal skin of the mice was obtained and stained with H&E for histological evaluation.

[0302] 5. Experimental results

[0303] The O-1602 derivative, at a dose of 1 mg / kg, effectively alleviated mild psoriasis in mice and alleviated the PASI score. This result was also confirmed by the pathological score (Figure 1).

[0304] Example 3: Application of O-1602 derivatives to alleviate acute enteritis induced by 2,4,6-Trinitrobenzene sulfonic acid (TNBS) in mice

[0305] 1. Induction of acute enteritis with TNBS

[0306] C57BL / 6 mice, male and female, 6 to 10 weeks old, were used. On day -7 of the experiment, the experimental animals were weighed and randomly divided into cages according to their body weight. The animals were allowed to acclimate to the environment of the animal room. The animal room maintained a constant temperature (23°C ± 3°C) and constant humidity (relative humidity of 50%). The animals were fed with standard laboratory chow and had free access to water. On day 0, TNBS colitis was induced in mice by intrarectal injection. The dose of TNBS was 125 mg / kg; the solvent was 30% alcohol; and the volume received by each mouse was 100 μl. After the rectal injection, the mice were inverted for 1 minute to prevent leakage of the drug solution.

[0307] 2. Administration of O-1602 derivatives

[0308] Solid O-1602 derivatives were dissolved in DMSO to a concentration of 2 mg / ml. This solution was diluted to 0.1 mg / ml using PBS. TNBS-induced colitis mice were gavaged once daily in a volume of 200 μl at 11:00 AM. The dose of the O-1602 derivative was 1 mg / kg. Treatment with the O-1602 derivatives lasted from day 0 to day 4 of the TNBS regimen. A control group of mice received an equal volume of solvent by gavage. The anti-colitis drug, the JAK inhibitor tofacitinib, was used as a positive control to compare the results of the O-1602 derivatives in this model. The O-1602 derivatives were dissolved in the same manner as described above at a concentration of 1.5 mg / mL and administered in a volume of 200 μl at a dose of 15 mg / kg.

[0309] 3. Daily Observation Indicators

[0310] The body weight and anal bleeding of the mice were observed daily, and the daily disease activity index (DAI) was calculated and recorded.

[0311] 4. Observation endpoint

[0312] The experiment ended on day 5 of TNBS. Mice were euthanized by cervical dissection under isoflurane anesthesia. The entire colon was obtained by dissection. The colon length was measured and photographed.

[0313] 5. Experimental Results

[0314] O-1602 derivatives were used, among which compounds 1, 3, 6, and 7 could significantly alleviate the weight loss of model animals (see Figure 2), and compounds 3, 6, 7, and 11 could significantly alleviate the DAI index (see Figure 3), increase the length of the colon (see Figures 4 and 5), and reduce colon tissue damage (see Figure 5), with better efficacy than tofacitinib.

[0315] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

[0316] The aforementioned embodiments and methods described in the present invention may be varied based on the ability, experience, and preference of those skilled in the art.

[0317] In the present invention, merely listing the steps of the method in a certain order does not constitute any limitation on the order of the method steps.

Claims

1. A compound, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: The compound has the following structure: in, R1 has the following structure: Wherein, X1 is selected from: single bond, -C(O)-, -C(O)O-, -C(O)N(R 103 )-、 -S(O)2-, 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-, R 101 Selected from: single bond, alkylene, alkenylene, phenylene, amino acid residue, oligopeptide residue, polypeptide residue, monosaccharide residue, oligosaccharide residue, polysaccharide residue, n is an integer from 1 to 100, R 102 is selected from: H, alkyl, cycloalkyl, phenyl, heterocyclic group (especially saturated heterocyclic group), R 103 and R 104 Independently selected from: H, alkyl; wherein the alkylene, alkenylene, phenylene, alkyl, cycloalkyl, phenyl, heterocyclyl is optionally substituted by one or more independent R'; R2, R4, R5 are independently selected from the group consisting of: H, halogen, hydroxy, thiol, amino, cyano, azido, isocyanate, sulfonyl chloride, sulfonyl fluoride, amide, sulfonamide, formic acid, nitro, formaldehyde, trifluoromethyl, sulfonyl, Acid group, phosphite group, trialkyltin group, trialkylsilyl group, alkyl group, alkenyl group, alkynyl group; R3 has the following structure: Wherein, Y1 is selected from: single bond, -C(O)-, -C(O)O-, -C(O)N(R 303 )-、 -S(O)2-, Y2 is selected from: a single bond, -O-, -S-, -S-S-, -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<从 304 )S(O)2-, R 301 Selected from: single bond, alkylene, alkenylene, phenylene, amino acid residue, oligopeptide residue, polypeptide residue, monosaccharide residue, oligosaccharide residue, polysaccharide residue, m is an integer from 1 to 100, R 302 Selected from: H, alkyl, cycloalkyl, phenyl, heterocyclic group, R 303 and R 304 Independently selected from: H, alkyl; wherein the alkyl, alkylene is optionally substituted by one or more independent R'; Alternatively, R4 and R5 together with the carbon atom to which they are attached form a cyclic group (particularly a saturated cyclic group, such as a cycloalkyl group, a heterocyclic group); wherein the cyclic group is optionally substituted by one or more independent R'; W is selected from the following structures: in, represents a single bond or a double bond; Each R6 independently has the following structure: Wherein, L1 and L2 are independently selected from: 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-,R 601 Selected from: single bond, alkylene, R 602 Selected from: H, alkyl, R 603 Selected from: H, alkyl; wherein said alkyl, alkylene is optionally substituted by one or more independent R'; Each R7 is independently selected from: H, alkyl, alkenyl, alkynyl, wherein said alkyl, alkenyl, alkynyl is optionally substituted with one or more independent R'; Each R' is independently selected from the group consisting of halogen, hydroxyl, thiol, amino, cyano, azido, isocyanate, sulfonyl chloride, sulfonyl fluoride, amide, sulfonamide, formate, nitro, formaldehyde, trifluoromethyl, sulfonic acid, phosphite, trialkyltin, trialkylsilyl, -CH=NH, Alkoxy, alkylamino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl; Furthermore, the compound represented by general formula I is not 2. The compound according to claim 1, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: X1 and / or Y1 are selected from: single bond, -C(O)-, -C(O)O-, -C(O)N(H)-, -S(O)2-.

3. The compound according to claim 1, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: R 101 Selected from: single bond, C1-6 alkylene, wherein said alkylene is optionally substituted with one or more independent R'; Preferably, R' is selected from the group consisting of: hydroxyl, thiol, amino, amide, sulfonamide, formic acid, nitro, formaldehyde, trifluoromethyl, vinyl, ethynyl, substituted or unsubstituted phenyl (e.g. ), heterocyclic groups (e.g. )； More preferably, R 101 Selected from: single bond, methylene, ethylene, Preferably, n is an integer of 1-10.

4. The compound according to claim 1, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: R 301 Can be selected from: single bond, C1-6 alkylene, wherein said alkylene is optionally substituted with one or more independent R'; Preferably, R' is selected from the group consisting of: hydroxyl, thiol, amino, amide, sulfonamide, formic acid, nitro, formaldehyde, trifluoromethyl, vinyl, ethynyl, substituted or unsubstituted phenyl (e.g. ), heterocyclic groups (e.g. )； More preferably, R 301 Selected from: single bond, methylene, ethylene, Preferably, m is an integer of 1-10.

5. The compound according to claim 1, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: X2 is selected from: single bond, -O-, -S-, -SS-, -N(R 104 )-、-S(O)2-、-S(O)2N(R 104 )-、-C(O)O-、-C(O)N(R 104 )-; and / or, Y2 is selected from: single bond, -O-, -S-, -SS-, -N(R 304 )-、-S(O)2-、-S(O)2N(R 304 )-、-C(O)O-、-C(O)N(R 304 )-; Preferably, R 104 Selected from: H, C1-6 alkyl; Preferably, R 304 Selected from: H, C1-6 alkyl.

6. The compound according to claim 1, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: R 102 is selected from: H, C1-6 alkyl (especially C1-3 alkyl, such as methyl, ethyl, n-propyl, isopropyl), 4 to 12 membered saturated heterocyclic group (including monocyclic, polycyclic heterocyclic group (especially bicyclic heterocyclic group), polycyclic heterocyclic ring including fused, spiro, bridged polycyclic heterocyclic ring, such as ), wherein the alkyl group and the heterocyclic group are optionally substituted by one or more independent R'; and / or, R 302 Selected from: H, C1-6 alkyl (especially C1-3 alkyl, such as methyl, ethyl, n-propyl, isopropyl), 4 to 12 membered saturated heterocyclic group (including monocyclic, polycyclic heterocyclic group (especially bicyclic heterocyclic group), polycyclic heterocyclic group Includes fused, spiro, bridged polycyclic heterocycles, e.g. ), wherein the alkyl and heterocyclic groups are optionally substituted by one or more independent R's.

7. The compound according to claim 1, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: R1 is H, or R1 is selected from: and / or, R3 is H, or R3 is selected from:

8. The compound according to any one of claims 1 to 7, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: R2 is H.

9. The compound according to any one of claims 1 to 8, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: R4 is selected from: H, C1-6 alkyl; wherein the alkyl is optionally substituted by one or more independent R'; Preferably, R' is selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, formate, nitro, formaldehyde, trifluoromethyl, vinyl, and ethynyl; More preferably, R4 is methyl.

10. The compound according to any one of claims 1 to 9, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: R5 is selected from: H, C1-6 alkyl; wherein the alkyl is optionally substituted by one or more independent R'; Preferably, R' is selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, mercapto, amino, formate, nitro, formaldehyde, trifluoromethyl, vinyl, and ethynyl; More preferably, R5 is H.

11. The compound according to any one of claims 1 to 10, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: L1 and L2 are 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)-, -N(H)C(O)-; Preferably, R6 is selected from: H, C1-6 alkyl, 12. The compound according to any one of claims 1 to 11, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: R 601 Selected from: single bond, C1-6 alkylene; R 602 Selected from: H, C1-6 alkyl; R 603 Selected from: H, C1-6 alkyl; Preferably, R6 is methyl.

13. The compound according to any one of claims 1 to 12, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: R7 is C2-6 alkenyl; Preferably, R7 is selected from the group consisting of: vinyl, propenyl, allyl, prop-1-en-2-yl; More preferably, R7 is 14. The compound according to any one of claims 1 to 13, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: W is Preferably, the compound has the following structure: More preferably, in the compound, R1 is H and R3 is not H; or, R1 is H and R3 is not H; or, both R1 and R3 are not H.

15. The compound according to claim 1, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: The compound is selected from the following structures:

16. The compound according to any one of claims 1 to 13, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomer, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition, characterized in that: The stereoisomers are selected from the following structures: Preferably Preferably, the stereoisomers are selected from the following structures: Preferably More preferably, the stereoisomer is selected from the following structures:

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, isotopic derivative, stereoisomer, solvate, prodrug, metal chelate, or crystal form thereof, and one or more pharmaceutically acceptable excipients.

18. Use of the compound according to any one of claims 1 to 16, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition in the preparation of a medicament for preventing and / or treating a disease; Preferably, the disease is a disease that is beneficial for prevention or treatment by increasing the amount of Treg cells, such as autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), and inflammatory diseases.

19. The use according to claim 18, characterized in that The autoimmune disease is selected from the group consisting of 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 sensory axonal neuropathy, Barlow's disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, giant lymphadenopathy, food allergies and related diseases (e.g., Celiac's disease), Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackievirus myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease, discoid lupus, Dressler syndrome, 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-Smith syndrome Chonlein purpura, herpes gestationis or pemphigoid gestationis, hidradenitis suppurativa, hypogammaglobulinemia, IgG4-related sclerosing disease, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytic vasculitis, lichen planus, atrophic lichen sclerosus, woody conjunctivitis, linear IgA disease, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal Lupus, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic diseases, PANDAS, 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, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestogen-induced dermatitis, psoriasis, psoriasis 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 syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-man 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 mellitus, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, Koyanagi-Harada disease; Preferably, the immune kidney disease is selected from anti-glomerular basement membrane antibody nephritis, glomerulonephritis, IgA nephropathy, purpuric nephritis or lupus nephritis; Preferably, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, type I diabetes, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, food allergies and related diseases (such as Celiac's disease), ulcerative colitis, and Crohn's disease.

20. The use according to claim 18, wherein The allergic disease is selected from the group consisting of 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 related diseases (such as Celiac's disease).

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

22. The use according to claim 18, wherein The inflammatory disease is a disease with inflammation caused by immune response; Preferably, the inflammatory disease is selected from the group consisting of interstitial lung disease, inflammatory bowel disease, chronic obstructive pulmonary disease, acute lung injury, neuroinflammation, sepsis, asthma, and allergy; Preferably, the inflammatory bowel disease is selected from the group consisting of 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 administration route of the drug is a gastrointestinal administration route, especially an oral administration route.

24. The use according to any one of claims 18 to 23, characterized in that The subjects of the drug are mammals, especially humans, the dosage is 0.033-0.407 mg / kg calculated based on 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 the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystal form of the compound or composition in the preparation of an agent for inducing or promoting Treg expansion; Preferably, the Treg expansion is performed in vivo or in vitro.

26. A method for expanding Tregs, comprising the step of using the compound of any one of claims 1 to 16, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, crystalline form of the compound or composition, or a pharmaceutical composition comprising the same; Preferably, the method is performed in vitro.

27. A method for preventing and / or treating a disease, characterized in that: The method comprises administering to a subject in need thereof the compound of any one of claims 1 to 16, a stereoisomer of the compound, any combination of the compound and the stereoisomer, any combination of the stereoisomers, or a pharmaceutically acceptable salt, ester, ether, optical isomer, isotopic derivative, solvate, prodrug, metal chelate, or crystalline form of the aforementioned compound or composition; Preferably, the disease is a disease that is beneficial for prevention or treatment by increasing the amount of Treg cells, such as autoimmune diseases, allergic diseases, transplant rejection, graft-versus-host disease (GvHD), and inflammatory diseases.

28. The method of claim 27, wherein: The autoimmune disease is selected from the group consisting of achalasia, Addison's disease, adult-onset 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 sensory axonal neuropathy, Barlow's disease, Behcet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, giant lymphadenopathy, food allergies and related diseases (e.g., C eliac disease), Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackievirus myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease, discoid lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, Goodpasture syndrome, granulomatous polycythemia vera angitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis or pemphigoid gestationis, hidradenitis suppurativa, hypogammaglobulinemia, IgG4-related sclerosing disease, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, atrophic lichen sclerosus, woody conjunctivitis, linear IgA disease, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Mucha-Habermas nn disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic diseases, PANDAS, 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, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, postpericardiotomy syndrome, primaryBiliary cirrhosis, primary sclerosing cholangitis, progestogen-induced 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, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-man 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 mellitus, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, Koyanagi-Harada disease; Preferably, the immune kidney disease is selected from anti-glomerular basement membrane antibody nephritis, glomerulonephritis, IgA nephropathy, purpuric nephritis or lupus nephritis; Preferably, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, type I diabetes, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, food allergies and related diseases (such as Celiac's disease), ulcerative colitis, and Crohn's disease.

29. The method of claim 27, wherein: The allergic disease is selected from the group consisting of 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 related diseases (such as Celiac's disease).

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

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

32. The method according to any one of claims 27 to 31, wherein: The disease is inflammatory bowel disease, and the method is used to prevent or treat the disease via a gastrointestinal route, particularly an oral route.

33. The method according to any one of claims 27 to 32, wherein: The subject is a mammal, particularly a human being, the dosage is 0.033-0.407 mg / kg calculated based on body weight, and the administration frequency is once a day.

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