Quinoline derivative, and preparation method therefor and use thereof

Abstract

A quinoline derivative as represented by formula (I), and a preparation method therefor and the use thereof. The compound is used for treating diseases related to skin wound healing.

Description

Quinoline derivatives, processes for their preparation and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular, the present application relates to a quinoline derivative for treating skin wound healing related diseases. In addition, the present application also provides a preparation method of the quinoline derivative and its use in the preparation of a medicament for treating skin wound healing related diseases. BACKGROUND

[0002] Skin wounds, such as burns, abrasions, lacerations, contusions, incised wounds, puncture wounds, pressure wounds, disease complicated skin ulcers (such as diabetic foot ulcers), bedsores, pressure sores, chronic ulcers, skin necrotic defects and postoperative incisions, and diabetic patients often suffer from impaired wound healing, with a lifetime risk of 15% developing diabetic skin ulcers. Diabetic ulcers have a poor prognosis, and 15-27% of patients require surgical resection. These problems bring inconvenience and pain to the patient's life and spirit, endanger the patient's health, and at the same time increase the economic burden of the healthcare system. Wound healing is a complex process, including inflammation, granulation tissue formation, angiogenesis, re-epithelialization and remodeling of the wound. The repair stage requires the participation of different types of cell networks, including endothelial cells, inflammatory cells, fibroblasts and keratinocytes. The wound healing process is regulated by a variety of cytokines and growth factors, including epidermal growth factor, transforming growth factor-β, hepatocyte growth factor, vascular endothelial growth factor, fibroblast growth factor, keratinocyte growth factor, interleukin family and tumor necrosis factor-α, etc. However, the expression and purification of these proteins and cytokines for the development of therapeutic drugs is difficult. The existing small molecule drugs for wound application on the market are mostly anti-infective drugs or dressings, without inducing wound healing effect. Among the macromolecular drugs, granulocyte colony-stimulating factor, fibroblast growth factor receptor 2 activator (FGFR2), platelet-derived growth factor analogues, fibrinogen mimics, synthetic matrix proteins, etc. can promote wound healing, but are expensive, difficult to store stably for a long time, and inconvenient to use, leading to increased burden on patients. Therefore, it has great clinical value to develop a small molecule drug that is fast, efficient and inexpensive for the treatment of wound healing.

[0003] The present application provides a novel quinoline derivative which has a strong effect of promoting skin wound healing in animal body experiments. In addition, the compound of the present application has the characteristics of low cost, easy synthesis and good storage stability, and has a good clinical application prospect. SUMMARY

[0004] In one aspect, the present application provides a compound having the structure shown in formula (I),

[0005] or a deuterated derivative, a pharmaceutically acceptable salt thereof; wherein

[0006] L1is selected from -CH2-, -O-, -S-, -S(O)-, -S(O)2-, or -CH2O-;

[0007] L2is selected from C 1-6 alkylene;

[0008] R1is selected from hydrogen, halogen, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 haloalkyl, cyano, nitro, carboxyl, sulfonic acid, NR a R b , -C(O)R4; wherein R a and R b are each independently selected from hydrogen and C 1-6 alkyl, R4is selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, or optionally substituted phenyl;

[0009] R2is selected from hydroxyl, thiol, amino, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkanoyloxy, or glycosyl; wherein the alkoxy, alkanoyloxy is optionally substituted with a group selected from halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxyacyl, or C 1-6 alkanoyloxy;

[0010] R3is selected from hydrogen, halogen, hydroxyl, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy;

[0011] R5and R5' are selected from hydrogen or C 1-6 alkyl;

[0012] provided that the compounds 3-(quinolin-2-yloxy)-benzene methanol, 2-[3-(l- hydroxyhexyl)phenoxy]quinoline, 2-[[3-(l-hydroxyhexyl)phenoxy]methyl]quinoline, 3-(quinolin-2-ylmethoxy)-benzene methanol, 3-hydroxy-5-(quinolin-2-ylmethoxy)- benzene methanol, 3-[(7-chloro-quinolin-2-yl)methoxy]-benzene methanol, 3-(quinolin-2-ylamino)-benzene methanol, 3-(quinolin-2-ylamino)-phenyl ethanol, 3-(quinolin-2-ylamino)benzene methoxyphosphonic acid diethyl ester are excluded.

[0013] In another aspect, the present application provides a pharmaceutical composition for treating a skin wound healing related disease, comprising a therapeutically effective amount of a compound represented by formula (I) or a deuterated derivative, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0014] In another aspect, the present application also provides use of a compound represented by formula (I) or a deuterated derivative, a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a skin wound healing related disease. Advantages

[0015] The present inventors have surprisingly found that the compound of the present application and the pharmaceutical composition comprising the same can efficiently promote skin wound healing. BRIEF DESCRIPTION OF DRAWINGS

[0016] FIG. 1A and FIG. 1B show the effect of the compound of the present application on the healing of a rat back skin scald, wherein, ** P < 0.01 vs. matrix gel group / placebo group, ## P < 0.01 vs. human epidermal growth factor group, ▲▲ P < 0.01 vs. Example 1 (5%) gel. DETAILED DESCRIPTION

[0017] DEFINITIONS

[0018] As used in this specification, unless the context dictates the opposite, the following words and phrases are generally intended to have the meanings set forth below.

[0019] As used herein, the term "alkyl" refers to a monovalent branched or unbranched saturated hydrocarbon chain of 1 to 6 carbon atoms (more typically of 1 to 4, or 1 to 3 carbon atoms). The term exemplifies such groups as methyl, ethyl, 1-propyl (normal propyl), 2-propyl (isopropyl), 1-butyl (normal butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (normal pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0020] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0021] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, wherein alkyl is as defined herein. The term illustratively is a group such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, and the like.

[0022] As used herein, the term "alkanoyl" refers to an "alkyl-C(O)-" group, wherein alkyl is as defined herein. The term illustratively is a group such as formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl, and the like.

[0023] As used herein, the term "alkanoyloxy" refers to an "alkyl-C(O)O-" group, wherein alkyl is as defined herein. The term illustratively is a group such as formyloxy, acetyloxy, n-propionyloxy, isopropionyloxy, n-butyryloxy, isobutyryloxy, t-butyryloxy, and the like.

[0024] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, wherein alkyl is as defined herein. The term illustratively is a group such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trichloromethyl, dichloromethyl, chloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1,1,-difluoroethyl, and the like.

[0025] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to effect a treatment as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the subject and disease condition being treated, weight and age of the subject, severity of the disease condition, mode of administration, and the like, which can readily be determined by one of ordinary skill in the art.

[0026] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the given compound and that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts can be acid addition salts and / or base addition salts. Acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloride, hydrobromic, sulfate, nitrate, phosphate, carbonate, bisulfate, hydrogen phosphate, dihydrogen phosphate, bicarbonate, and the like; salts derived from organic acids include formate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartarate, citrate, benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, salicylate, lactate, nicotinate, laurylsulfate, naphthalenesulfonate, camphorsulfonate, gluconate, glucaronate, oleate, palmitate, stearate, pamoate, trifluoroacetate, and the like. Base addition salts can be formed with inorganic and organic bases. Salts derived from inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, lithium, barium, aluminum salts and the like; salts derived from organic bases include salts of various primary, secondary, and tertiary amines, such as ethylamine, diethylamine, n-propylamine, isopropylamine, diethanolamine, meglumine, lysine, piperizine, piperidine, morpholine, tromethamine, choline, and the like.

[0027] As used herein, the term "pharmaceutically acceptable" means the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising a formulation and / or the mammal to which it is administered.

[0028] As used herein, the term "deuterated" means that the compound has the structure depicted herein, except that one or more hydrogen atoms are replaced by deuterium atoms. Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0029] As used herein, "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the described event or circumstance occurs and instances where it does not.

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0031] Compounds

[0032] In one embodiment, the present application provides a compound represented by Formula (I)

[0033] or a deuterated form, a pharmaceutically acceptable salt thereof; wherein L1, L2, R1, R2, R3 are as defined herein;

[0034] with the proviso that the compounds 3-(quinolin-2-yloxy)-benzene carbinol, 2-[3-(1- hydroxyhexyl)phenoxy]quinoline, 2-[[3-(1-hydroxyhexyl)phenoxy]methyl]quinoline, 3-(quinolin-2-ylmethoxy)-benzene carbinol, 3-hydroxy-5-(quinolin-2-ylmethoxy)- benzene carbinol, 3-[(7-chloro-quinolin-2-yl)methoxy]-benzene carbinol, 3-(quinolin-2- ylamino)-benzene carbinol, 3-(quinolin-2-ylamino)-phenyl ethanol, 3-(quinolin-2-ylamino)benzene methoxy diethyl phosphate are excluded.

[0035] In one embodiment, L1is selected from -CH2-, -O-, -S-, -S(O)-, -S(O)2-, or -CH2O-; preferably, L1is selected from -CH2-, -O-, -S-, -S(O)-, or -S(O)2-; more preferably, L1is selected from -CH2-, -O-, or -S-; more preferably, L1is selected from -O- or -S-; most preferably, L1is selected from -O-.

[0036] In one embodiment, L2is selected from C 1-6 alkylene; preferably, L2is selected from C 1-4 alkylene; more preferably, L2is selected from C 1-3 alkylene; more preferably, L2is selected from C 1-2 alkylene.

[0037] In one embodiment, R1is selected from hydrogen, halogen, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, cyano, nitro, carboxyl, sulfonic acid, NR a R b , -C(O)R4; wherein R a and R b are each independently selected from hydrogen and C 1-6 alkyl, R4is selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkyl, or optionally substituted phenyl; preferably, R1is selected from halogen, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, cyano, nitro, carboxyl, sulfonic acid; more preferably, R1is selected from halogen, optionally substituted C 1-6 haloalkyl, cyano; more preferably, R1is selected from optionally substituted C1-3 Halogenated alkyl groups, cyano groups.

[0038] In one embodiment, R2 is selected from hydroxyl, mercapto, amino, or optionally substituted C. 1-6 Alkoxy, optional substituted C 1-6 Alkyloxy, Or a glycosyl group; wherein the alkoxy or alkyloxy group is optionally substituted with a group selected from the following: halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 alkoxy acyl, or C 1-6 Alkyloxy; R5 and R5' are selected from hydrogen or C 1-6 Alkyl; preferably, R2 is selected from hydroxyl, optionally substituted C 1-6 Alkoxy, optional substituted C 1-6 Alkyloxy, Or a glycosyl group; wherein the alkoxy or alkyloxy group is optionally substituted with a group selected from the following: halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 alkoxy acyl, or C 1-6 Alkyloxy; R5 and R5' are selected from hydrogen or C 1-6 Alkyl; more preferably, R2 is selected from hydroxyl, optionally substituted C 1-6 Alkoxy, optional substituted C 1-6 Alkyloxy, Or a glycosyl group; wherein the alkoxy or alkyloxy group is optionally substituted with a group selected from the following: C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 alkoxy acyl, or C 1-6 Alkyloxy; R5 and R5' are selected from hydrogen or C 1-6 The alkyl group, wherein the glycosyl group is selected from monosaccharides, disaccharides, or trisaccharides; preferably, the glycosyl group is selected from pentoses (e.g., ribose, arabinose, xylose, deoxyribose, etc.), hexoses (e.g., fructose, tagatose, allose, arbutinose, glucose, mannose, galactose, rhamnose, glucosamine, galactosamine, glucuronic acid, etc.), or disaccharides (e.g., maltose, kosperidose, cellobiose, isomaltose, gentiobiose, lactose, etc.).

[0039] In one embodiment, the glycosyl group is selected from...

[0040] In one embodiment, R3 is selected from hydrogen, halogen, hydroxyl, or optionally substituted C. 1-6 Alkyl, or optionally substituted C 1-6alkyl, or optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkyl, or optionally substituted C 1-3 alkyl, or C 1-3 alkyl, or C

[0041] In one embodiment, the present application provides a compound of Formula (II)

[0042] or a deuterated form, pharmaceutically acceptable salt thereof, wherein L1, L2, R1, R2, R3 are as defined herein,

[0043] with the proviso that the compounds 3-(quinolin-2-yloxy)-benzene methanol, 2-[3-(1- hydroxyhexyl)phenoxy]quinoline, 2-[[3-(1-hydroxyhexyl)phenoxy]methyl]quinoline, 3- (quinolin-2-ylmethoxy)-benzene methanol, 3-hydroxy-5-(quinolin-2-ylmethoxy)-benzene methanol, 3-[(7-chloro-quinolin-2-yl)methoxy]-benzene methanol, 3-(quinolin-2-ylamino)- benzene methanol, 3-(quinolin-2-ylamino)-benzene ethanol, 3-(quinolin-2-ylamino)benzene methoxy diethyl phosphate are excluded.

[0044] In one embodiment, the present application provides a compound of Formula (I) or a deuterated form, pharmaceutically acceptable salt thereof, wherein,

[0045] L1is selected from -CH2-, -O-, -S-, -S(O)-, or -S(O)2-;

[0046] L2is selected from C 1-6 alkylene;

[0047] R1is selected from hydrogen, halogen, optionally substituted C 1-6 haloalkyl, cyano, nitro, carboxyl, sulfonic acid, -C(O)R4; wherein R4is selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, or optionally substituted phenyl;

[0048] R2is selected from hydroxyl, thiol, amino, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkanoyloxy, or glycosyl; wherein the alkoxy, alkanoyloxy is optionally substituted with a group selected from halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxyacyl, or C 1-6 alkanoyloxy;

[0049] R3is selected from hydrogen, halogen, hydroxyl, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy;

[0050] R5and R5' are selected from hydrogen or C 1-6 alkyl.

[0051] In one embodiment, the present application provides a compound represented by Formula (I)

[0052] L1is selected from -O-;

[0053] L2is selected from C 1-3 alkylene;

[0054] R1is selected from halogen, C 1-3 haloalkyl, cyano, nitro, carboxyl, sulfonic acid group, -C(O)R4; wherein R4is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, and phenyl;

[0055] R2is selected from hydroxyl, thiol, amino, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkanoyloxy, or glycosyl; wherein the alkoxy, alkanoyloxy is optionally substituted with a group selected from halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxyacyl, or C 1-6 alkanoyloxy;

[0056] R3is selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, or optionally substituted C 1-6 alkoxy;

[0057] R5and R5' are selected from hydrogen or C 1-6 alkyl.

[0058] In one embodiment, the present application provides a compound represented by Formula (III)

[0059] or a deuterated form, pharmaceutically acceptable salt thereof, wherein,

[0060] L2is selected from C 1-3 alkylene;

[0061] R1is selected from halogen, C 1-3 haloalkyl, cyano, nitro, carboxyl, or sulfonic acid group;

[0062] R2is selected from the group consisting of hydroxyl, thiol, amino, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkanoyloxy, or glycosyl; wherein the alkoxy, alkanoyloxy is optionally substituted with a group selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxyacyl, or C 1-6 alkanoyloxy;

[0063] R5and R5’are selected from the group consisting of hydrogen or C 1-6 alkyl.

[0064] In one embodiment, the present application provides a compound represented by Formula (I), (II), or (III), or a deuterated isomer, pharmaceutically acceptable salt thereof, wherein the glycosyl is selected from a monosaccharide, disaccharide, or trisaccharide; preferably, the glycosyl is selected from a pentose (e.g., ribose, arabinose, xylose, deoxyribose, etc.), a hexose (e.g., fructose, tagatose, allose, altrose, glucose, mannose, galactose, rhamnose, glucosamine, galactosamine, glucuronic acid, etc.), or a disaccharide (e.g., maltose, kojibiose, cellobiose, isomaltose, gentiobiose, lactose, etc.).

[0065] In one embodiment, the present application provides a compound selected from the group consisting of:

[0066] or a deuterated isomer, pharmaceutically acceptable salt thereof.

[0067] Pharmaceutical compositions and administration

[0068] The pharmaceutical composition provided by the present application comprises a compound of the present application or a stereoisomer, tautomer, solvate, prodrug, isotopically-labeled derivative thereof, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier. Depending on the route of administration of the drug, for example, oral administration, parenteral administration, etc., the pharmaceutical composition of the present application can be prepared into tablets, capsules, pills, granules, powders, suppositories, solutions, suspensions, emulsions, tinctures, syrups, ointments, creams, gels, lotions, liniments, sprays, etc.

[0069] When the pharmaceutical composition of the present application is in a fixed form (e.g., tablet, capsule, pill, etc.), the pharmaceutically acceptable carrier usually includes, but is not limited to, one or more of the following: a) diluent, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, etc.; b) lubricant, such as silicon dioxide, talc, stearic acid, polyethylene glycol, etc.; c) binder, such as magnesium aluminometasilicate, gelatinized starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, etc.; d) disintegrant, such as starch, alginic acid, agar, corn starch; e) stabilizer, such as antioxidant, e.g., ascorbic acid; f) glidant, such as silicon dioxide; g) flavoring agent, such as peppermint, methyl salicylate; sweetener, such as sucrose, saccharin. When the pharmaceutical composition of the present application is in a liquid form (e.g., solution), the pharmaceutically acceptable carrier usually includes one or more of the following: a) diluent, such as water for injection, physiological saline, Ringer's solution, polyethylene glycol, glycerol, propylene glycol, etc.; b) antioxidant, such as propyl gallate, ascorbic acid, or sodium bisulfite; c) buffer, such as acetate, phosphate, etc. When the pharmaceutical composition of the present application is in a form for topical administration (e.g., ointment, gel, etc.), the pharmaceutically acceptable carrier usually includes, but is not limited to, one or more of the following: a) preservative, such as phenylmercuric nitrate, thiomersal, benzalkonium chloride, benzalkonium bromide, cetyltrimethylammonium bromide, cetylpyridinium chloride, etc.; b) antioxidant, such as butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, propyl gallate, sodium metabisulfite, and tocopherol, etc.; c) solubilizer, such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docusate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol, tetrahydrofurfuryl alcohol polyethylene glycol ether, diethylene glycol monoethyl ether, propylene glycol, dimethyl isosorbide, etc.; d) surfactant, such as sodium lauryl sulfate, sodium docusate, sorbitan monooleate, polyoxyethylene polysorbate, poloxamer, bile salt, glyceryl monostearate, copolymer of ethylene oxide and propylene oxide, etc.; e) viscosity modifier, such as methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, polyethylene glycol (e.g., polyethylene glycol having a molecular weight of about 300 to about 6000), alginate, gum arabic, chitosan, etc.

[0070] The weight percentage of the compound of the present application as the active ingredient in the pharmaceutical composition provided by the present application is 0.01-30%; preferably, the weight percentage of the compound of the present application as the active ingredient in the pharmaceutical composition provided by the present application is 0.01-20%; preferably, the weight percentage of the compound of the present application as the active ingredient in the pharmaceutical composition provided by the present application is 0.01-10%; more preferably, the weight percentage of the compound of the present application as the active ingredient in the pharmaceutical composition provided by the present application is 0.05-10%; more preferably, the weight percentage of the compound of the present application as the active ingredient in the pharmaceutical composition provided by the present application is 0.1-10%; more preferably, the weight percentage of the compound of the present application as the active ingredient in the pharmaceutical composition provided by the present application is 0.5-10%. In one embodiment, the weight percentage of the compound of the present application as the active ingredient in the pharmaceutical composition provided by the present application is 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01%.

[0071] The effective dosage of the compound of the present application depends at least on the nature, degree, delivery method and pharmaceutical dosage form of the treated condition, and will be ultimately determined by the clinician. It is contemplated that about 0.0001 to about 100 mg per kilogram body weight per day; typically about 0.01 to about 10 mg per kilogram body weight per day; more typically about 0.01 to about 5 mg per kilogram body weight per day; and most typically about 0.05 to about 0.5 mg per kilogram body weight per day. For example, a candidate daily dosage for an average adult human of about 70 kg body weight will be in the range of 1 mg to 1000 mg, preferably in the range of 5 mg to 500 mg, and can be given in a single dose or in divided doses.

[0072] Indications

[0073] The compound of the present application has therapeutic effects on skin wound healing related diseases. Here, the skin wound healing related diseases are the loss of skin epidermal tissue, including, for example, skin laceration, abrasion, surgical incision, diabetic wound, radiotherapy and chemotherapy wound, skin ulcer, burn, scald, laceration, contusion, incision, puncture, pressure injury, skin ulceration caused by diseases (such as diabetic foot ulcer), pressure sores, skin necrosis defects, post-transplantation wounds, skin wounds caused by vascular diseases, bedsores, frostbite, wounds after mosquito bites, etc.

[0074] Examples

[0075] Example 1 (3-((6-(trifluoromethyl)quinolin-2-yl)oxy)phenyl)methanol

[0076] Step 1 Synthesis of 3-((6-(trifluoromethyl)quinolin-2-yl)oxy)benzaldehyde (Intermediate 3)

[0077] Into a reaction kettle, 2-chloro-6-(trifluoromethyl)quinoline (Compound 1) 1.001 kg, 3-hydroxybenzaldehyde (Compound 2) 0.528 kg, potassium carbonate 1.194 kg, 2.5 L N,N-dimethylformamide, nitrogen replacement for three times, nitrogen protection condition, temperature rise to 110±2℃, stirring reaction for 3h, TLC detection (petroleum ether: ethyl acetate = 10:1) the raw material is basically complete reaction. The reaction system is cooled to 60±5℃, 10L water is added dropwise, and maintained at 60±5℃ for 0.5h, then cooled to room temperature, and filtered under vacuum, and the filter cake is dried under vacuum (55±5℃, P≤-0.08Mpa), to get 1.287 kg of intermediate 3, the yield is 93.9%.

[0078] Step 2 Synthesis of (3-((6-(trifluoromethyl)quinolin-2-yl)oxy)phenyl)methanol (Example 1)

[0079] Into a reaction kettle, 2-methyltetrahydrofuran 7680 mL, intermediate 3 1.280 kg, stirring and cooling to 0-10℃, sodium borohydride aqueous solution (sodium borohydride 62.57g / water 313mL) is added, temperature control 0-10℃ reaction 0.5h. To the reaction liquid, 6400mL water is added, and dilute hydrochloric acid (160mL hydrochloric acid dissolved in 1600mL water) is added to adjust the pH value of the reaction liquid to 2-3. Stand for separation, discard the water phase, and the organic phase is concentrated under reduced pressure (40-50℃, P≤-0.09Mpa). After concentration, isopropyl alcohol 1.28L is added to the residue, heated to reflux until the solution is clear, then 7.86L of n-heptane is added dropwise at 80-105℃, after the addition is completed, the reaction system is cooled to 10±5℃, and stirred for 1h. Filter, the filter cake is washed once with isopropyl alcohol / n-heptane mixed solution (isopropyl alcohol 128mL / n-heptane 780mL), after the filter is finished, the filter cake is dried under vacuum (45±2℃, P≤-0.09Mpa), to get 1204.11g of example 1 compound.

[0080] 1H NMR (400 MHz, DMSO) δ 8.61 (d, J = 8.9 Hz, 1H, ArH), 8.46 (s, 1H, ArH), 7.94 - 7.77 (m, 2H, ArH), 7.45 (dd, J = 16.7, 8.4 Hz, 2H, ArH), 7.28 (d, J = 8.3 Hz, 2H, ArH), 7.18 (d, J = 8.3 Hz, 1H, ArH), 5.35 (s, 1H, OH), 4.61 (s, 2H, ArCH 2- ).

[0081] 13 C NMR (101 MHz, DMSO) δ (ppm): 163.56, 153.44, 147.79, 145.24, 141.72, 129.78, 128.82, 126.37 (d, J = 4.4 Hz), 125.82 (d, J = 3.0 Hz), 125.09, 123.54, 120.39, 119.80, 114.95, 62.94, 40.62, 40.32 (d, J = 18.0 Hz), 40.20 (s), 39.90 (d, J = 18.2 Hz), 39.79, 39.58, 39.37.

[0082] Synthesis of 3-((6-(trifluoromethyl)quinolin-2-yl)oxy)benzyl acetate (Example 2)

[0083] Into a 250 mL single necked flask, the compound of Example 1 (1.25 g, 3.92 mmol), anhydrous dichloromethane (50 mL) were added in turn, under nitrogen protection, and cooled to 0 °C, then triethylamine (990 mg, 9.79 mmol) and acetyl chloride (615 mg, 7.83 mmol) were added dropwise in turn, after 1 h reaction at 0 °C, it was transferred to room temperature for 2 h reaction. TLC (V 石油醚 :V 乙酸乙酯 = 4: 1) was used to monitor the end of the reaction, the reaction system was diluted with dichloromethane (150 mL), washed with 1 N dilute hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate solution (100 mL) and saturated aqueous sodium chloride solution (100 mL) in turn, and the organic phase was collected. Anhydrous sodium sulfate was dried, filtered, concentrated and purified by flash chromatography (20 g, V 石油醚 :V 乙酸乙酯 = 9: 1) to obtain 1.30 g of white solid (compound of Example 2), with a yield of 91.9%.

[0084] 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.62 (d, J = 8.3 Hz, 1 H, ArH), 8.48 (s, 1 H, ArH), 7.92 (dd, J1= 8.9 Hz, J2= 2.2 Hz, 1 H, ArH), 7.81 (d, J = 8.8 Hz, 1 H, ArH), 7.49 (t, J = 8.0 Hz, 1 H, ArH), 7.44 (d, J = 8.9 Hz, 1 H, ArH), 7.31 - 7.29 (m, 2 H, ArH), 7.28 - 7.25 (m, 1 H, ArH), 5.13 (s, 2 H, ArCH2), 2.09 (s, 3 H, COCH3).

[0085] 13 C NMR (101 MHz, DMSO-d6) d (ppm): 170.68, 163.35, 153.39, 147.68, 141.80, 138.61, 130.17, 128.81, 126.44 (q, J C-F = 4.4 Hz), 126.06 (q, J C-F = 32.3 Hz), 125.85 (q, J C-F = 3.2 Hz), 125.12 (d, J C-F = 3.5 Hz), 123.36, 121.86, 121.47, 114.93, 65.38, 21.09.

[0086] Synthesis of (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-((3-((6- (trifluoromethyl)quinolin-2-yl)oxy)benzyl)oxy)tetrahydro-2H-pyran-3,4,5-triol

[0087] Synthesis of (2R,3R,4S,5R,6R)-2-(acetyloxymethyl)-6-((3-((6- (trifluoromethyl)quinolin-2-yl)oxy)benzyl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Intermediate 4)

[0088] Into a 50 mL single necked flask was added the compound of Example 1 (500 mg, 1.57 mmol), toluene (7.5 mL), acetyl bromide-a-D-glucose (773 mg, 1.88 mmol) and silver carbonate (518 mg, 1.88 mmol) sequentially under nitrogen protection, and the reaction was carried out at 75 °C for 19 h in the dark. TLC (V 石油醚 :V 乙酸乙酯 = 3:1) was used to monitor the end of the reaction. The filtrate was concentrated and purified by flash chromatography (80 g, V 石油醚 :V乙酸乙酯 = 3: 1) to give 314 mg of white solid intermediate 4 in 30.8% yield.

[0089] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 8.61 (d, J = 8.9 Hz, 1H, ArH), 8.47 (d, J = 2.1 Hz, 1H, ArH), 7.89 (dd, J1= 8.9 Hz, J2= 2.1 Hz, 1H, ArH), 7.82 (d, J = 8.8 Hz, 1H, ArH), 7.54 - 7.40 (m, 2H, ArH), 7.26 - 7.13 (m, 3H, ArH), 5.28 (t, J = 9.6 Hz, 1H, tetrahydropyran-H), 4.98 - 4.88 (m, 2H, tetrahydropyran-H), 4.88 - 4.78 (m, 2H, ArCH2), 4.66 (d, J = 12.9 Hz, 1H, tetrahydropyran-H), 4.18 (dd, J1= 12.3 Hz, J2= 5.1 Hz, 1H, tetrahydropyran-H), 4.05 - 3.99 (m, 2H, AcOCH2), 2.00 (s, 3H, COCH3), 1.97 (s, 3H, COCH3), 1.92 (s, 3H, COCH3), 1.84 (s, 3H, COCH3).

[0090] Step 2: Synthesis of (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-((3-((6- (trifluoromethyl)quinolin-2-yl)oxy)benzyl)oxy)tetrahydro-2H-pyran-3,4,5-triol (Example 3)

[0091] Into a 50 mL single necked flask, intermediate 4 (314 mg, 0.48 mmol), methanol (3.2 mL), water (3.2 mL) and triethylamine (97 mg, 0.96 mmol) were added sequentially under nitrogen protection. The reaction was monitored by TLC (V 石油醚 :V 乙酸乙酯 = 3: 1) to give 314 mg of white solid intermediate 4 in 30.8% yield. 二氯甲烷 :V 甲醇 = 10: 1) to give 140 mg of white solid (Example 3 compound) in 60.6% yield.

[0092] 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.61 (d, J = 8.9 Hz, 1H, ArH), 8.47 (d, J = 2.1 Hz, 1H, ArH), 7.89 (dd, J1= 8.9 Hz, J2= 2.1 Hz, 1H, ArH), 7.81 (d, J = 8.8 Hz, 1H, ArH), 7.49 - 7.39 (m, 2H, ArH), 7.35 - 7.29 (m, 2H, ArH), 7.23 - 7.16 (m, 1H, ArH), 5.11 (d, J = 4.6 Hz, 1H, H of CHOH), 4.97 - 4.84 (m, 3H, H of ArCH2 and 2H of 2(CHOH)), 4.65 (d, J = 12.6 Hz, 1H, H of ArCH2), 4.49 (t, J = 5.9 Hz, 1H, CH2OH), 4.27 (d, J = 7.7 Hz, 1H, tetrahydropyran-H), 3.73 - 3.63 (m, 1H, tetrahydropyran-H), 3.51 - 3.40 (m, 1H, tetrahydropyran-H), 3.20 - 2.99 (m, 4H, CH2OH and 2H of tetrahydropyran-H).

[0093] 13 C NMR (101 MHz, DMSO-d6) d (ppm): 163.12, 152.93, 147.34, 141.39, 140.31, 129.48, 128.45, 125.99 (q, J C-F = 4.5 Hz), 125.46 (q, J C-F = 3.5 Hz), 125.05 (q, J C-F = 32.1 Hz), 124.32 (q, J C-F = 273.0 Hz), 124.70, 124.26, 120.77, 120.56, 114.54, 102.26, 77.03, 76.75, 73.56, 70.14, 69.00, 61.16.

[0094] HRMS (ESI): m / z [M+H] + C 23 H 22 F3NO7: Calcd: 482.1426; Found: 482.1429.

[0095] Synthesis of (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-((3-((6- (trifluoromethyl)quinolin-2-yl)oxy)benzyl)oxy)tetrahydro-2H-pyran-3,4,5-triol

[0096] Step 1 Synthesis of (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-((3-((6- (trifluoromethyl)quinolin-2-yl)oxy)benzyl)oxy)tetrahydro-2H-pyran-3,4,5-triacetate (Intermediate 5)

[0097] Into a 25 mL single necked flask was added the compound of Example 1 (250 mg, 0.78 mmol), toluene (3.75 mL), 2,3,4,6-tetraacetoxy-a-D- pyranose bromide (387 mg, 0.94 mmol) and silver carbonate (259 mg, 0.94 mmol) successively, under nitrogen protection, and the reaction was carried out at 75 °C for 16 h in the dark. TLC (V 石油 醚 :V 乙酸乙酯 = 3: 1) was monitored for completion of the reaction, filtered under a pad of celite, concentrated and purified by flash chromatography (12 g, V 石油醚 :V 乙酸乙酯 = 3: 1) to give 243 mg of Intermediate 5 as a white solid in 47.9% yield.

[0098] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 8.61 (d, J = 8.9 Hz, 1H, ArH), 8.47 (d, J = 2.1 Hz, 1H, ArH), 7.89 (dd, J1= 8.9 Hz, J2= 2.1 Hz, 1H, ArH), 7.83 (d, J = 8.8 Hz, 1H, ArH), 7.53 - 7.40 (m, 2H, ArH), 7.26 - 7.16 (m, 3H, ArH), 5.26 (d, J = 3.6 Hz, 1H, tetrahydropyran-H), 5.20 - 5.16 (m, 1H, tetrahydropyran-H), 5.01 - 4.07 (m, 1H, tetrahydropyran-H), 4.89 - 4.80 (m, 2H, ArCH2), 4.67 (d, J = 12.9 Hz, 1H, tetrahydropyran-H), 4.22 (t, J = 6.5 Hz, 1H, tetrahydropyran-H), 4.10 - 4.04 (m, 2H, AcOCH2), 2.11 (s, 3H, COCH3), 1.99 (s, 3H, COCH3), 1.90 (s, 3H, COCH3), 1.84 (s, 3H, COCH3).

[0099] Step 2 Synthesis of (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-((3-((6- (trifluoromethyl)quinolin-2-yl)oxy)benzyl)oxy)tetrahydro-2H-pyran-3,4,5-triol (Example 4)

[0100] Into a 50 mL single necked flask, intermediate 5 (485 mg, 0.75 mmol), methanol (4.85 mL), water (4.85 mL) and triethylamine (152 mg, 1.50 mmol) were added successively under nitrogen atmosphere and the reaction was carried out at room temperature for 16 h. The reaction was monitored by TLC (V 石油醚 :V 乙酸乙酯 = 3: 1) and the reaction was completed. The reaction mixture was filtered and the filter cake was washed with mixture of solvents (V 甲 醇 :V 水 = 1: 10, 11 mL) and the cake was washed for 1 h. The filter cake was dried under suction at 48 °C for 11 h to get 160 mg of white solid (compound of example 4) with 44.3% yield.

[0101] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 8.60 (d, J = 8.9 Hz, 1H, ArH), 8.46 (d, J = 2.1 Hz, 1H, ArH), 7.89 (dd, J1= 8.9 Hz, J2= 2.1 Hz, 1H, ArH), 7.81 (d, J = 8.8 Hz, 1H, ArH), 7.50 - 7.39 (m, 2H, ArH), 7.36 - 7.28 (m, 2H, ArH), 7.23 - 7.15 (m, 1H, ArH), 4.96 (d, J = 4.8 Hz, 1H, H of CHOH), 4.87 (d, J = 12.7 Hz, 1H, H of ArCH2), 4.68 (d, J = 5.5 Hz, 1H, H of CHOH), 4.64 (d, J = 12.7 Hz, 1H, H of ArCH2), 4.55 (t, J = 5.7 Hz, 1H, CH2OH), 4.35 (d, J = 4.5 Hz, 1H, H of CHOH), 4.23 (d, J = 7.5 Hz, 1H, tetrahydropyran-H), 3.64 (t, J = 4.0 Hz, 1H, tetrahydropyran-H), 3.58 - 3.46 (m, 2H, CH2OH), 3.41 - 3.33 (m, 2H, tetrahydropyran-H), 3.30 - 3.24 (m, 1H, tetrahydropyran-H).

[0102] 13 C NMR (101 MHz, DMSO-d6) d (ppm): 163.13, 152.93, 147.35, 141.40, 140.44, 129.45, 128.46, 125.99 (q, J C-F = 5.0 Hz), 125.46 (q, J C-F = 2.8 Hz), 125.05 (q, J C-F = 32.3 Hz), 124.32 (q, JC-F = 273.2 Hz), 124.70, 124.25, 120.73, 120.55, 114.53, 102.91, 75.39, 73.45, 70.68, 68.96, 68.24, 60.54.

[0103] HRMS (ESI): m / z [M+H] + C 23 H 22 F3NO7 Theoretical: 482.1426; Found: 482.1419.

[0104] Synthesis of 2-(3-((6-(trifluoromethyl)quinolin-2-yl)oxy)phenyl)ethanol

[0105] Synthesis of 2-(3-((6-(trifluoromethyl)quinolin-2-yl)oxy)phenyl)ethanol (Example 5)

[0106] Into a 250 mL single necked flask, compound 6 (1.49 g, 6.43 mmol), anhydrous DMF (120 mL), compound 7 (898 mg, 6.49 mmol) and potassium carbonate (1.78 g, 12.87 mmol) were added successively under nitrogen protection, and reacted at 110 °C for 16 h. TLC (V 石油醚 :V 乙酸乙酯 = 1:1) was used to monitor the end of the reaction, which was quenched with ethyl acetate (400 mL), washed with saturated aqueous sodium chloride solution (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (40 g, V 石油醚 :V 乙酸乙酯 = 4:1) to give 2.00 g of light yellow solid (compound of Example 5) with a yield of 93.4%.

[0107] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.60 (d, J = 8.9 Hz, 1H, ArH), 8.46 (s, 1H, ArH), 7.90 (dd, J1= 8.8 Hz, J2= 2.2 Hz, 1H, ArH), 7.82 (d, J = 8.8 Hz, 1H, ArH), 7.43-7.34 (m, 2H, ArH), 7.17-7.06 (m, 3H, ArH), 4.66 (t, J = 5.2 Hz, 1H, OH), 3.68-3.61 (m, 2H, ArCH2CH2), 2.78 (t, J = 6.9 Hz, 2H, ArCH2).

[0108] Example 6 Synthesis of (2R, 3S, 4S, 5R, 6R)-2-(hydroxymethyl)-6-(3-((6- (trifluoromethyl)quinolin-2-yl)oxy)phenethoxy)tetrahydro-2H-pyran-3, 4, 5-triol

[0109] Step 1 Synthesis of (2R, 3S, 4S, 5R, 6R)-2-(hydroxymethyl)-6-(3-((6- (trifluoromethyl)quinolin-2-yl)oxy)phenethoxy)tetrahydro-2H-pyran-3, 4, 5-triacetate (Intermediate 9)

[0110] Into a 100 mL single necked flask was added the compound of Example 5 (500 mg, 1.50 mmol), toluene (6 mL), acetyl bromide-a-D-glucose (740 mg, 1.80 mmol) and silver carbonate (496 mg, 1.80 mmol) successively, under nitrogen protection and dark, reacted at 75 °C for 16 h. TLC (V 石油醚 :V 乙酸乙酯 = 1 : 1) showed about 10% of the starting material remained, filtered under a pad of celite, concentrated and purified by flash chromatography (20 g, V 石油醚 :V 乙酸乙酯 = 3 : 1) to give 500 mg of Intermediate 9 as a white solid in 50.2% yield.

[0111] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 8.60 (d, J = 8.9 Hz, 1H, ArH), 8.46 (s, 1H, ArH), 7.90 (dd, J1= 8.9 Hz, J2= 2.1 Hz, 1H, ArH), 7.82 (d, J = 8.8 Hz, 1H, ArH), 7.43 - 7.35 (m, 2H, ArH), 7.17 - 7.10 (m, 3H, ArH), 5.23 (t, J = 9.6 Hz, 1H, H of ArCH2CH2), 4.88 (t, J = 9.5 Hz, 1H, H of ArCH2CH2), 4.83 (d, J = 8.1 Hz, 1H, tetrahydropyran-H), 4.74 (t, J = 9.4 Hz, 1H, tetrahydropyran-H), 4.20 - 4.13 (m, 1H, tetrahydropyran-H), 4.05 - 3.93 (m, 3H, tetrahydropyran-H and AcOCH2), 3.78 - 3.69 (m, 1H, tetrahydropyran-H), 2.96 - 2.80 (m, 2H, ArCH2), 1.99 (s, 3H, COCH3), 1.98 (s, 3H, COCH3), 1.92 (s, 3H, COCH3), 1.87 (s, 3H, COCH3).

[0112] Step 2: Synthesis of (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(3-((6-(trifluoromethyl)quinolin-2-yl)oxy)phenethoxy)tetrahydro-2H-pyran-3,4,5-triol (Example 6)

[0113] Intermediate 9 (100 mg, 0.15 mmol), methanol (2 mL), and sodium methoxide (1 mg, 0.015 mmol) were added sequentially to a 25 mL single-necked flask. The reaction was carried out at room temperature for 1 h under nitrogen protection. TLC (V 二氯甲烷 V 甲醇 =10:1) After monitoring the reaction to completion, water (20 mL) was added to quench the reaction, and the pH was adjusted to 4 with 1M hydrochloric acid. The mixture was stirred in an ice bath for 1 h, and a white solid precipitated out. The mixture was filtered, and the filter cake was collected and dried under reduced pressure at room temperature to obtain 12 mg of white solid (compound of Example 6), with a yield of 16.0%.

[0114] 1 H NMR (400MHz, CD3OD) δ (ppm): 8.42 (d, J = 8.9 Hz, 1H, ArH), 8.24 (s, 1H, ArH), 7.89-7.80 (m, 2H, ArH), 7.38 (t, J = 7. 8Hz,1H,ArH),7.25(d,J=8.9Hz,1H,ArH),7.23-7.16(m,2H,ArH),7.07(dd,J1=8.3Hz,J2=2.3Hz,1H,ArH),4.31( d, J = 7.8 Hz, 1H, tetrahydropyran-H), 4.19-4.10 (m, 1H, tetrahydropyran-H), 3.90-3.77 (m, 2H, ArCH2CH2), 3.68-3.58 (m, 1H, tetrahydropyran-H), 3.37-3.33 (m, 1H, tetrahydropyran-H), 3.28-3.24 (m, 2H, CH2OH), 3.17 (t, J = 9.1 Hz, 1H, tetrahydropyran-H), 3.00 (t, J = 7.1 Hz, 2H, ArCH2).

[0115] HRMS(ESI): m / z[M+H] + C 24 H 24 Theoretical value of F3NO7: 496.1583; Measured value: 496.1538.

[0116] Example 7 Synthesis of 3-((6-(trifluoromethyl)quinoline-2-yl)oxy)phenethyl acetate

[0117] Step 1: Synthesis of 3-((6-(trifluoromethyl)quinolin-2-yl)oxy)phenethyl acetate (Example 7)

[0118] To a 100 mL single necked flask was added the compound of Example 5 (250 mg, 0.75 mmol) and dry dichloromethane (10 mL) and cooled to 0 °C under nitrogen. Triethylamine (190 mg, 1.88 mmol) and acetyl chloride (118 mg, 1.50 mmol) were added dropwise and the reaction was allowed to proceed for 1 h and then allowed to warm to room temperature and continue for 2 h. The reaction was monitored to completion by TLC (V 石油醚 :V 乙酸乙酯 = 4:1) and dichloromethane (100 mL) was added. The organic phase was washed with 1 M hydrochloric acid (50 mL), saturated aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL) and dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (20 g, V 石油醚 :V 乙酸乙酯 = 10:1) to give 249 mg of a colorless oil (compound of Example 7) in 88.4% yield.

[0119] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 8.61 (d, J = 8.9 Hz, 1H, ArH), 8.46 (s, 1H, ArH), 7.90 (dd, J1= 8.9 Hz, J2= 2.1 Hz, 1H, ArH), 7.81 (d, J = 8.8 Hz, 1H, ArH), 7.45-7.37 (m, 2H, ArH), 7.21-7.13 (m, 3H, ArH), 4.25 (t, J = 6.8 Hz, 2H, ArCH2CH2), 2.94 (t, J = 6.8 Hz, 2H, ArCH2), 1.97 (s, 3H, COCH3).

[0120] 13 C NMR (101 MHz, CDC13) d (ppm): 170.73, 163.48, 153.42, 147.77, 141.78, 140.48, 130.05, 128.84, 126.34 (q, J C-F = 4.3 Hz), 126.18, 125.87 (q, J C-F = 3.2 Hz), 125.49 (q, J C-F = 32.1 Hz), 125.12, 124.74 (q, J C-F = 272.9 Hz), 122.45, 120.18, 114.96, 64.57, 34.55, 21.13.

[0121] HRMS (ESI): m / z [M+H] + C 20 H 16F3NO3theoretical value: 376.1161; found: 376.1101.

[0122] Example 8 Synthesis of 2-(3-(hydroxymethyl)phenoxy)quinoline-6-carbonitrile

[0123] Step 1 Synthesis of 2-(3-formylphenoxy)quinoline-6-carbonitrile (Intermediate 11)

[0124] Into a 25 mL single necked flask, was added compound 10 (200 mg, 1.06 mmol), 3- hydroxybenzaldehyde (129 mg, 1.06 mmol), N,N-dimethylformamide (4 mL) and potassium carbonate (439 mg, 3.18 mmol) successively, under nitrogen protection, and reacted at 100 °C for 2 h. TLC (V 石油醚 :V 乙酸乙酯 = 5: 1) was used to monitor the completion of the reaction. After cooling to room temperature, water (30 mL) was added to quench the reaction, and ethyl acetate (50 mL x 2) was used to extract the product. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (12 g, V 石油醚 :V 乙酸乙酯 = 5: 1) to give 250 mg of brown solid intermediate 11 with a yield of 86.2%.

[0125] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.05 (s, 1H, CHO), 8.62 (d, J = 1.9 Hz, 1H, ArH), 8.56 (d, J = 8.9 Hz, 1H, ArH), 7.95 (dd, J1= 8.7 Hz, J2= 1.9 Hz, 1H, ArH), 7.88-7.86 (m, 1H, ArH), 7.82-7.81 (m, 1H, ArH), 7.75-7.71 (m, 2H, ArH), 7.69-7.65 (m, 1H, ArH), 7.51 (d, J = 8.9 Hz, 1H, ArH).

[0126] Step 2 Synthesis of 2-(3-(hydroxymethyl)phenoxy)quinoline-6-carbonitrile (Example 8)

[0127] Into a 25 mL single necked flask, was added intermediate 11 (250 mg, 0.91 mml) and methanol (4 mL), under nitrogen protection, and sodium borohydride (52 mg, 1.37 mml) was added portionwise under ice water bath, and reacted at room temperature for 2 h. TLC (V 石油醚 :V 乙酸乙酯= 3: 1) and the reaction was monitored by TLC (petroleum ether: ethyl acetate = 3: 1). When the reaction was completed, the reaction mixture was added water (30 mL) to quench the reaction, extracted with ethyl acetate (50 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (12 g, V 石油醚 :V 乙酸乙酯 = 3: 1) to give 220 mg of white solid (compound of example 8) with a yield of 87.6%.

[0128] 1 H NMR (400 MHz, DMSO-d6) d (ppm): 8.59 (d, J = 2.0 Hz, 1H, ArH), 8.52 (d, J = 8.9 Hz, 1H, ArH), 7.94 (dd, J1= 8.8 Hz, J2= 2.0 Hz, 1H, ArH), 7.74 (d, J = 8.6 Hz, 1H, ArH), 7.45-7.41 (m, 2H, ArH), 7.24 (d, J = 7.6 Hz, 1H, ArH), 7.20 (s, 1H, ArH), 7.15-7.12 (m, 1H, ArH), 5.27 (t, J = 5.8 Hz, 1H, CH2OH), 4.55 (d, J = 5.8 Hz, 2H, CH2OH).

[0129] 13 C NMR (101 MHz, DMSO-d6) d (ppm): 163.90, 153.29, 147.93, 145.27, 141.32, 134.64, 131.57, 129.84, 128.81, 125.45, 123.67, 120.42, 119.80, 119.24, 115.28, 107.66, 62.90.

[0130] HRMS (ESI): m / z [M+H] + C 17 H 13 N2O2 Theoretical value: 277.0977; Found: 277.0909.

[0131] Example 9 Synthesis of 2-(3-(2-methoxyethyl)phenoxy)-6-(trifluoromethyl)quinoline

[0132] Step 1 Synthesis of (E)-2-(3-(2-methoxyethenyl)phenoxy)-6-(trifluoromethyl)quinoline (Intermediate 12)

[0133] Into a 50 mL single necked flask was placed (methoxymethyl)triphenylphosphonium chloride (596 mg, 1.74 mmol) and tetrahydrofuran (5 mL), under nitrogen protection, a solution of lithium bis(trimethylsilyl)amide (1 M in THF, 1.89 mL, 1.89 mmol) was added dropwise at ice water bath, after 30 min, a solution of intermediate 3 (460 mg, 1.45 mmol) in tetrahydrofuran (3 mL) was added dropwise at room temperature, the reaction was monitored by TLC (V 石油醚 :V 乙酸乙酯 = 5: 1) until the starting material was consumed. The reaction was quenched by the addition of saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (12 g, V 石油醚 :V 乙酸乙酯 = 10: 1) to give 170 mg of white solid intermediate 12 in 28.3% yield.

[0134] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.47 (s, 2H, ArH), 7.90-7.88 (m, 2H, ArH), 7.37-7.33 (m, 2H, ArH), 7.22-7.19 (m, 2H, ArH), 7.04 (dt, Ji = 7.1 Hz, J2= 2.1 Hz, 1H, ArH), 5.88 (d, J = 13.0 Hz, 1H, ArCH=CHOCH3), 5.29 (d, J = 7.0 Hz, 1H, ArCH=CHOCH3), 3.64 (s, 3H, CH3).

[0135] Step 2 Synthesis of 2-(3-(2-methoxyethyl)phenoxy)-6-(trifluoromethyl)quinoline (Example 9)

[0136] Into a 25 mL single necked flask was placed intermediate 12 (170 mg, 0.49 mml), 10% Pd / C (17 mg, 10% wt) and ethanol (4 mL), the reaction was monitored by TLC (V 石油 醚 :V 乙酸乙酯 = 5: 1) until the starting material was consumed, the reaction was filtered through celite, concentrated and purified by flash chromatography (4 g, V 石油醚 :V 乙酸乙酯 = 10: 1) to give 120 mg of white solid Example 9 in 70.5% yield.

[0137] 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.60 (d, J = 8.9 Hz, 1H, ArH), 8.47 (s, 1H, ArH), 7.90 (dd, J1= 8.9 Hz, J2= 2.3 Hz, 1H, ArH), 7.81 (d, J = 8.8 Hz, 1H, ArH), 7.42-7.36 (m, 2H, ArH), 7.17-7.14 (m, 2H, ArH), 7.13-7.11 (m, 1H, ArH), 3.58 (t, J = 6.8 Hz, 2H, OCH2), 3.25 (s, 3H, OCH3), 2.86 (t, J = 6.8 Hz, 2H, OCH2CH2).

[0138] 13 C NMR (101 MHz, DMSO-d6) d (ppm): 163.47, 153.32, 147.78, 141.73, 141.63, 129.80, 128.82, 126.38 (q, J C-F = 4.1 Hz), 126.15, 125.85 (q, J C-F = 3.0 Hz), 125.47 (q, J C- F = 32.1 Hz), 125.10, 124.73 (q, J C-F = 272.8 Hz), 122.34, 119.79, 114.95, 72.91, 58.26, 35.55.

[0139] HRMS (ESI): m / z [M+H] + C 19 H 16 F3NO2 Calc: 348.1211; Found: 348.1137.

[0140] Example 10 Synthesis of sodium 3-((6-(trifluoromethyl)quinolin-2-yl)oxy)benzyl phosphate Step 1 Synthesis of (3-((6-(trifluoromethyl)quinolin-2-yl)oxy)benzyl) diphenyl phosphate (intermediate 13)

[0141] Into a 100 mL single necked flask was added the compound of example 1 (2.00 g, 6.26 mmol), dichloromethane (80 mL), N,N-diisopropylethylamine (2.43 g, 18.8 mmol), tetra-benzyl pyrophosphate (8.09 g, 15.0 mmol) and tetra-tert-butyl titanate (1.28 g, 3.76 mmol) sequentially. The reaction was allowed to proceed at room temperature under nitrogen overnight. TLC (V 石油醚 :V 乙酸乙酯=2:1) ​​Monitor the reaction to completion, concentrate and sequentially perform column chromatography (V 石油 醚 V 乙酸乙酯 =3:1) and rapid preparative chromatography (120g, V 石油醚 V 乙酸乙酯 Purification was performed using a ratio of 4:1 to obtain 2.90 g of white solid intermediate 13, with a yield of 80.1%.

[0142] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.62 (d, J=8.9Hz, 1H, ArH), 8.47 (s, 1H, ArH), 7.84 (dd, J1=8.8Hz, J1=2.2Hz, 1H, ArH), 7.74 (d, J=8.8Hz, 1H, ArH), 7.49(t,J=7.8Hz,1H,ArH),7.44(d,J=8.9Hz,1H,ArH),7.34-7.22(m,13H,ArH),5.09(d,J=8.2Hz,2H,OArCH2O),5.03(d,J=8.1Hz,4H,2ArCH2O).

[0143] Step 2: Synthesis of 3-((6-(trifluoromethyl)quinoline-2-yl)oxy)benzyl dihydrogen phosphate (intermediate 14)

[0144] Intermediate 13 (900 mg, 1.55 mmol), dichloromethane (9 mL), and trifluoroacetic acid (9 mL) were added sequentially to a 100 mL single-necked flask. The reaction was carried out at 50 °C for 3.5 h under nitrogen protection. TLC (V 石油醚 V 乙酸乙酯 =2:1) ​​The reaction was monitored until it ended, and the mixture was concentrated to obtain 617 mg of colorless oily intermediate 14, with a yield of 99.7%.

[0145] 1 H NMR (400MHz, CD3OD) δ (ppm): 8.44 (d, J=8.9Hz, 1H, ArH), 8.25 (s, 1H, ArH), 7.83 (s, 2H, ArH), 7.48 (t ,J=7.8Hz,1H,ArH),7.36-7.26(m,3H,ArH),7.22-7.19(m,1H,ArH),5.06(d,J=7.2Hz,2H,OArCH2O).

[0146] Step 3: Synthesis of sodium 3-((6-(trifluoromethyl)quinoline-2-yl)oxy)benzylphosphate (Example 10)

[0147] Into a 100 mL single necked flask, was added intermediate 14 (617 mg, 1.55 mmol) and aqueous sodium hydroxide (433 mg, 10.8 mmol in 9 mL) successively, stirred at 0 °C for 30 min, and at room temperature for 30 min. The solid was completely dissolved. TLC (V 二氯甲烷 :V 甲醇 = 10: 1) showed no change in polarity, the reaction solution was cooled to 0 °C, and acetone (90 mL) was added, and stirred for 30 min. Filtration was performed, the filter cake was eluted with a mixed solvent (V 丙酮 :V 水 = 10: 1, 11 mL), and the filter cake was collected. The filter cake was slurried in a mixed solvent (V 丙酮 :V 水 = 7.5: 1, 17 mL) at room temperature for 30 min. Filtration was performed, the filter cake was washed with (V 丙酮 :V 水 = 7.5: 1, 8.5 mL), and the filter cake was dried at 48 °C under a blast of air overnight to give 615 mg of Example 10 as a white solid in a yield of 89.5%. HPLC: 99.97%, maximum single impurity: 0.02%.

[0148] 1 H NMR (400 MHz, CD3OD) d (ppm): 8.41 (d, J = 9.0 Hz, 1H, ArH), 8.24 (s, 1H, ArH), 7.86-7.81 (m, 2H, ArH), 7.42-7.35 (m, 3H, ArH), 7.24 (d, J = 8.9 Hz, 1H, ArH), 7.10-7.07 (m, 1H, ArH), 4.96 (d, J = 4.7 Hz, 2H, OArCH2O).

[0149] 13 C NMR (101 MHz, D2O) d (ppm): 163.23, 152.74, 146.38, 141.79 (d, J C-P = 8.0 Hz), 141.21, 130.09, 123.89 (q, J C-F = 272.8 Hz), 126.93, 125.85 (q, J C-F = 32.1 Hz), 125.60 (q, J C-F = 3.6 Hz), 125.28 (q, J C-F = 4.4 Hz), 124.69, 124.02, 120.25, 120.04, 113.52, 65.42 (d, J C-P = 3.6 Hz).

[0150] HRMS (ESI): m / z [M - 2Na + 3H] + C17 H 11 F3NNa2O5P theoretical value: 400.0562; found: 400.

[0151] Synthesis of sodium 4-oxo-4-((3-((6-(trifluoromethyl)quinolin-2-yl)oxy)benzyl)oxy)butanoate

[0152] Synthesis of 4-oxo-4-((3-((6-(trifluoromethyl)quinolin-2-yl)oxy)benzyl)oxy)butanoic acid (Intermediate 15)

[0153] Into a 250 mL single necked flask was added the compound of Example 1 (4.50 g, 14.09 mmol), succinic anhydride (7.05 g, 70.47 mmol), 4-dimethylaminopyridine (172 mg, 1.41 mmol), triethylamine (7.13 g, 70.47 mmol) and dichloromethane (50 mL), protected by nitrogen, and reacted at room temperature for 4 h. TLC (V 石油醚 :V 乙酸乙酯 = 1 : 1) was used to monitor the completion of the reaction. Water (50 mL) was added to the reaction, dichloromethane (100 mL x 2) was used to extract, the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (20 g, V 石油醚 :V 乙酸乙酯 = 1 : 1) to give 5.80 g of white solid Intermediate 15 with a yield of 98.2%.

[0154] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.23 (s, 1H, COOH), 8.61 (d, J = 9.0 Hz, 1H, ArH), 8.47 (s, 1H, ArH), 7.89 (dd, J1= 8.9 Hz, J2= 2.3 Hz, 1H, ArH), 7.81 (d, J = 8.8 Hz, 1H, ArH), 7.50-7.42 (m, 2H, ArH), 7.29-7.24 (m, 3H, ArH), 5.15 (s, 2H, ArCH2), 2.61-2.58 (m, 2H, COOHCH2), 2.52-2.51 (m, 2H, COOHCH2CH2).

[0155] Synthesis of sodium 4-oxo-4-((3-((6-(trifluoromethyl)quinolin-2-yl)oxy)benzyl)oxy)butanoate

[0156] To a 25 mL single necked flask was added intermediate 15 (600 mg, 1.43 mmol) and methanol (10 mL), under nitrogen protection, a solution of sodium hydroxide (60 mg, 1.50 mmol) in water (0.6 mL) was added dropwise, the reaction was allowed to proceed at room temperature for 4 h. When the solution was completely clear, the reaction was concentrated, the resulting crude was dissolved in water (2 mL), added dropwise to 4 mL of ice acetone, a small amount of solid precipitated, filtered, water (10 mL) was added to the filtrate, washed with ethyl acetate (20 mL x 2), the aqueous phase was concentrated and evaporated with t-butyl methyl ether (6 mL x 2), t-butyl methyl ether (4 mL) was slurried for 20 min, filtered and dried to obtain 230 mg of white solid (compound of example 11), yield 36.5%. HPLC: 98.58%, maximum single impurity: 0.59%.

[0157] 1 H NMR (400 MHz, CD3OD) d (ppm): 8.44 (d, J = 8.9 Hz, 1H, ArH), 8.25 (s, 1H, ArH), 7.84 (s, 2H, ArH), 7.46 (t, J = 7.9 Hz, 1H, ArH), 7.32-7.28 (m, 3H, ArH), 7.21-7.18 (m, 1H, ArH), 5.17 (s, 2H, ArCH2), 2.64 (t, J = 7.3 Hz, 2H, H of CH2CH2), 2.54-2.50 (m, 2H, H of CH2CH2).

[0158] 13 C NMR (101 MHz, CD3OD) d (ppm): 179.44, 174.85, 164.80, 154.80, 149.00, 142.27, 139.77, 130.87, 129.46, 127.76 (q, J C-F = 32.8 Hz), 125.67 (q, J C-F = 272.0 Hz), 126.68 (q, J C-F = 4.3 Hz), 126.64 (q, J C-F = 3.6 Hz), 126.20, 125.88, 122.46, 122.26, 115.31, 66.66, 32.62, 31.48.

[0159] HRMS (ESI): m / z [M - Na + 2H] + C 21 H 15 F3NNaO5 theoretical value: 420.1059; found: 420.1040.

[0160] Example 12: Preparation of a pharmaceutical composition (ointment)

[0161] 1. Prescription composition

[0162] 2. Preparation:

[0163] 2.1 Add the above batch of PEG400 into the homogenizer, start stirring and homogenizing. At the same time, start the water bath heating of the homogenizer, set the temperature to 55°C; continue to slowly add the above batch of PEG4000, stir until the solid material is nearly completely melted (if there are material clumps, use clean silica gel to crush the clumps), continue to add the above batch of propyl gallate, stir until the material is completely melted, visually should be colorless or light yellow clear transparent liquid. Stirring speed: not higher than 65 rpm; homogenization speed: about 1000 rpm.

[0164] 2.2 Under the above stirring and homogenizing conditions, add the prescription amount of the compound of Example 1 into the homogenizer. Stir until completely dissolved, visually should be colorless or light yellow clear transparent liquid.

[0165] 2.3 Turn off the heating, slowly cool the homogenizer jacket with cooling water, slowly cool under the above stirring and homogenizing conditions, when the clear liquid begins to become turbid, adjust the homogenization speed to 1500 rpm, continue to stir and homogenize cooling. Stop homogenizing when the base becomes viscous, discharge part of the material from the discharge port, visually observe the properties, and prepare for discharge.

[0166] 2.4 Place a stainless steel bucket at the discharge port, and discharge the material with a double-layer PE bag with tare weight.

[0167] 2.5 Pour the filling material into the hopper, adjust the filling amount to 15 g per piece, and start filling. Take 6 samples every 10 minutes during the filling process, check the filling amount and record. After filling is completed, fill 1 piece per box into a blank small box to obtain the product.

[0168] Note: All process parameters, cleaning verification, etc. during preparation and filling can refer to the relevant operation procedures of the registration batch.

[0169] Preparation of a pharmaceutical composition (gel) of Example 13

[0170] 1. Prescription composition

[0171] 2. Preparation:

[0172] Mix Carbopol 940 with the corresponding prescription amount of water and reserve; add the compound of Example 1, benzalkonium bromide, and the corresponding amount of polyethylene glycol 400 solvent system, stir thoroughly until completely dissolved to obtain a mixed solution, stir thoroughly until uniform, and add an appropriate amount of diethylene glycol monoethyl ether to adjust to obtain a transparent gel with appropriate viscosity.

[0173] Example 14: Rat skin wound healing experiment

[0174] 1. Experimental materials

[0175] SPF level SD male rats, weighing 220-250 g, kept in an environment with room temperature of 22-24℃, relative humidity of 45%-60%, and light for 12 hours.

[0176] 2. Experimental instruments

[0177] Shaver, electronic balance of BS224s type, medical bandage and adhesive tape.

[0178] 3. Reagent configuration

[0179] Example 12 ointment (3%), base ointment (PEG400 79.95%, PEG4000 20.00%, propyl gallate 0.05%), 70% ethanol, normal saline, 10% chloral hydrate.

[0180] 4. Experimental method

[0181] 4.1 Modeling method

[0182] After intraperitoneal injection of 10% chloral hydrate for anesthesia, the hair on the back of each rat was shaved, then the back was wiped with 70% ethanol, and a cut of about 0.5 cm 2 (1 cm*0.5 cm) was carefully made on the skin with scissors, the wound was stopped bleeding with a cotton swab soaked in normal saline, and the rats were put back into the cage according to the grouping (antibiotics were given according to the condition of the rats). The success evaluation index of modeling: after successful modeling, the wound was a 0.5 cm 2 rectangular, with a depth reaching the subcutaneous fascia layer.

[0183] 4.2 Dosing regimen

[0184] The skin was applied with the drug 24 hours after modeling.

[0185] Table 2. Dosing regimen

[0186] 5. Detection index

[0187] 5.1 Wound healing index score

[0188] The wound healing index was evaluated on the 14th day after administration, and the scoring index was two items of exudation at the wound edge and edema at the edge. The scoring criteria were as follows: 0 points: none; 1 point: mild; 2 points: moderate, 3 points: severe. The total score of the two indexes was 6 points.

[0189] 5.2 Wound healing rate

[0190] The wound recovery was photographed by camera on the 14th day after administration, and then the wound area was calculated using Image-J. The calculation formula: wound healing rate (%) = (initial wound area - post-administration wound area) / initial wound area * 100%.

[0191] 6. Statistical analysis

[0192] The data were statistically processed by SPSS22.0 statistical software, and the results were represented by ANOVA was performed between groups, and Tukey HSD test was used for pairwise comparison. P < 0.05 was statistically significant.

[0193] 7. Experimental results

[0194] Table 3. Example 1 promotes rat skin wound healing experiment n = 8 *P < 0.05, **P < 0.01 vs model group; # P < 0.05, ## P < 0.01 vs matrix ointment group;

[0195] According to the results in Table 3, compared with the model group and the matrix ointment group, the ointment of Example 12 (3%) can significantly improve the healing score and healing rate of skin wound damage after 14 days of continuous administration (P < 0.05, P < 0.01), indicating that the ointment of Example 12 has the effect of improving skin wound healing.

[0196] Example 15: Rat skin burn wound healing experiment

[0197] 1. Experimental materials

[0198] SPF level SD male rats, weighing 220-250g, kept in an environment with room temperature of 22-24℃, relative humidity of 45%-60%, and light for 12 hours.

[0199] 2. Experimental consumables

[0200] Chloral hydrate, 10% sodium sulfide, dimethylbenzene, ethanol, physiological saline; electric shaver, cotton swab, beaker, electric stove, gauze, straight forceps, 50g weight with a diameter of 1cm, human epidermal growth factor gel (100μg / 10g / branch, Guilin Huano Wei Gene Pharmaceutical Co., Ltd., National Drug Code S20020111).

[0201] 3. Experimental instruments

[0202] Shaver, BS224s electronic balance, medical bandage and adhesive tape.

[0203] 4. Experimental grouping

[0204] Model group, matrix gel group (PEG400, water, carbomer 940, diethylene glycol monoethyl ether, benzalkonium bromide), solvent control group (DMSO), Example 13 gel (5%, 10%) group, human epidermal growth factor gel group (15 mg / cm 2 ).

[0205] 5. Experimental method

[0206] 5.1 Modeling method

[0207] After intraperitoneal injection of 10% chloral hydrate anesthesia, the long hair on the back was removed with an electric shaver, and 10% sodium sulfide depilatory was evenly applied to the depilated area (3*3 cm) on the back. The water bath was opened in advance and heated to 99℃, a weight was placed in the hot water with tweezers for 10 min, then the weight was taken out with tweezers and placed on the back of the scalded rat for 15 s, during which the position of the weight was stabilized with tweezers, without additional pressure.

[0208] 5.2 Dosing regimen

[0209] The skin was applied with drugs 24 hours after modeling, and the drug administration was continuous for 14 days.

[0210] Table 4 Dosing regimen

[0211] 6. Detection index:

[0212] 6.1 Wound healing rate

[0213] On the 14th day after drug administration, the recovery of the scalded area was photographed with a camera, and then Image-J was used to calculate the wound area. The calculation formula is: wound healing rate (%) = (initial wound area - post-drug wound area) / initial wound area * 100%.

[0214] 7. Statistical analysis

[0215] The data were statistically processed by SPSS 22.0 statistical software, and the results were expressed as x±s. ANOVA was performed between groups, and Tukey HSD test was used for pairwise comparison. P<0.05 was statistically significant.

[0216] 8. Experimental results

[0217] The experimental results are shown in Figures 1A and 1B. Compared with the model group, the Example 13 (5%, 10%) gel group and the human epidermal growth factor group can significantly improve the healing rate of skin scald (P<0.01), indicating that they have significant therapeutic effects. Compared with human epidermal growth factor, Example 13 (10%) gel has a significant advantage (P<0.01). Among the different dose groups of Example 13 gel, the Example 13 (10%) gel group is significantly better than the Example 13 (5%) gel group (P<0.01).

[0218] Example 13 (5%) gel group (P<0.01), suggesting a dose gradient relationship.

[0219] In summary, the compounds of the present application have good effects on improving skin wound healing, and have better clinical application prospects.

[0220] The above examples only express several embodiments of the present application, which are described in more detail and in detail, but cannot be understood as limiting the scope of the patent. It should be noted that for ordinary skilled persons in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of protection of the present application.

Claims

1. Compound of formula (I), or a deuterated form, a pharmaceutically acceptable salt thereof; wherein L1is selected from -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, or -CH2O-; L2is selected from C 1-6 alkylene; R1 is selected from hydrogen, halogen, hydroxyl, or optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optional substituted C 1-6 Halogenated alkyl, cyano, nitro, carboxyl, sulfonic acid, NR a R b -C(O)R4; where R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl group, R4 is selected from hydrogen, optionally substituted C4 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, or optionally substituted phenyl; R2is selected from the group consisting of hydroxy, thiol, amino, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkanoyloxy, Or a glycosyl group; wherein the alkoxy or alkyloxy group is optionally substituted with a group selected from the following: halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 alkoxy acyl, or C 1-6 Alkyloxy; R3is selected from hydrogen, halogen, hydroxyl, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy; R5and R5' are selected from hydrogen or C 1-6 alkyl; with the proviso that the compound 3-(quinolin-2-yloxy)-benzyl alcohol, 2-[3-(1- hydroxyhexyl)phenoxy]quinoline, 2-[[3-(1-hydroxyhexyl)phenoxy]methyl]quinoline, 3- (quinolin-2-ylmethoxy)-benzyl alcohol, 3-hydroxy-5-(quinolin-2-ylmethoxy)-benzyl alcohol, 3-[(7-chloro-quinolin-2-yl)methoxy]-benzyl alcohol, 3-(quinolin-2-ylamino)-benzyl alcohol, 3-(quinolin-2-ylamino)-phenethyl alcohol, 3-(quinolin-2-ylamino)benzyloxy diethyl phosphate is not included.

2. The compound of claim 1, which is a compound of formula (II) or a deuterated form, a pharmaceutically acceptable salt thereof, wherein L1, L2, R1, R2, R3are as defined in claim 1; with the proviso that the compound 3-(quinolin-2-yloxy)-benzyl alcohol, 2-[3-(1- hydroxyhexyl)phenoxy]quinoline, 2-[[3-(1-hydroxyhexyl)phenoxy]methyl]quinoline, 3- (quinolin-2-ylmethoxy)-benzyl alcohol, 3-hydroxy-5-(quinolin-2-ylmethoxy)-benzyl alcohol, 3-[(7-chloro-quinolin-2-yl)methoxy]-benzyl alcohol, 3-(quinolin-2-ylamino)-benzyl alcohol, 3-(quinolin-2-ylamino)-phenethyl alcohol, 3-(quinolin-2-ylamino)benzyloxy diethyl phosphate is not included.

3. The compound according to claim 1 or 2, or a deuterated form, a pharmaceutically acceptable salt thereof, wherein, L1is selected from -CH2-, -O-, -S-, -S(O)-, or -S(O)2-; L2is selected from C 1-6 alkylene; R1is selected from hydrogen, halo, optionally substituted C 1-6 haloalkyl, cyano, nitro, carboxy, sulfonic acid, -C(O)R4; wherein R4is selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, or optionally substituted phenyl; R2is selected from the group consisting of hydroxy, thiol, amino, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkanoyloxy, Or a glycosyl group; wherein the alkoxy or alkyloxy group is optionally substituted with a group selected from the following: halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 alkoxy acyl, or C 1-6 Alkyloxy; R3is selected from hydrogen, halogen, hydroxyl, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy; R5and R5' are selected from hydrogen or C 1-6 alkyl.

4. The compound according to any one of the preceding claims, or a deuterated form, a pharmaceutically acceptable salt thereof, wherein, L1is selected from -O-; L2is selected from C 1-3 alkylene; R1is selected from the group consisting of halogen, C 1-3 haloalkyl, cyano, nitro, carboxyl, sulfonic acid, -C(O)R4; wherein R4is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, and phenyl; R2is selected from the group consisting of hydroxy, thiol, amino, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkanoyloxy, Or a glycosyl group; wherein the alkoxy or alkyloxy group is optionally substituted with a group selected from the following: halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 alkoxy acyl, or C 1-6 Alkyloxy; R3is selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, or optionally substituted C 1-6 alkoxy; R5and R5' are selected from hydrogen or C 1-6 alkyl.

5. The compound according to any one of the preceding claims, which is a compound of formula (III) or a deuterated form, a pharmaceutically acceptable salt thereof, wherein, L2is selected from C 1-3 alkylene; R1is selected from halogen, C 1-3 haloalkyl, cyano, nitro, carboxyl, or sulfonic acid group; R2is selected from the group consisting of hydroxy, thiol, amino, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 alkanoyloxy, Or a glycosyl group; wherein the alkoxy or alkyloxy group is optionally substituted with a group selected from the following: halogen, hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl group, C 1-6 alkoxy acyl, or C 1-6 Alkyloxy; R5and R5' are selected from hydrogen or C 1-6 alkyl.

6. The compound according to any one of the preceding claims or a deuterated form, pharmaceutically acceptable salt thereof, wherein, the sugar group is selected from a monosaccharide group, a disaccharide group, or a trisaccharide group; preferably, the sugar group is selected from a pentose group (e.g., ribose, arabinose, xylose, deoxyribose, etc.), a hexose group (e.g., fructose, tagatose, allose, altrose, glucose, mannose, galactose, rhamnose, glucosamine, galactosamine, glucuronic acid, etc.), or a disaccharide group (e.g., maltose, kojibiose, cellobiose, isomaltose, gentiobiose, lactose, etc.).

7. The compound according to any one of the preceding claims, selected from: or a deuterated form, a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the preceding claims, or a deuterated form, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, wherein, The pharmaceutical composition is an ointment comprising a compound according to any one of claims 1-7, or a deuterated form, a pharmaceutically acceptable salt thereof, a base, an emulsifier, an antioxidant, a humectant, and other pharmaceutically acceptable adjuvants; wherein the weight percentage of the compound according to any one of claims 1-7, or a deuterated form, a pharmaceutically acceptable salt thereof, in the ointment is 0.01% to 30%.

10. The pharmaceutical composition of claim 8, wherein, The pharmaceutical composition is a gel, comprising the compound or deuterated derivative thereof, pharmaceutically acceptable salt thereof, gel base, antioxidant, humectant, penetration enhancer and other pharmaceutically acceptable adjuvants according to any one of claims 1-7; wherein the weight percentage of the compound or deuterated derivative thereof, pharmaceutically acceptable salt thereof according to any one of claims 1-7 in the gel is 0.01%-30%.

11. Use of a compound or deuterated derivative thereof, pharmaceutically acceptable salt thereof according to any one of the preceding claims for the manufacture of a medicament for the treatment of a skin wound healing related disease.

12. Use according to claim 11, wherein the skin wound healing related disease is selected from the group consisting of burn, abrasion, laceration, contusion, incision, puncture, pressure, disease complicated with skin ulcer (such as diabetic foot ulcer), bed sore, pressure sore, chronic ulcer, skin necrotic defect and postoperative incision.

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