Topical formulations containing JAK inhibitors, salts or crystalline forms thereof, and methods of manufacture and uses thereof

Abstract

The present application relates to the field of pharmaceutical preparations and to [1,2,4]triazolo[1,5-a]pyridine compounds and their isomers or pharma- ceutically acceptable salts, or crystalline forms, and topical formulations, and their use in skin diseases. In particular, the present application relates to topical formulations of the compound (S)-N-(5-(2-(2,2-difluorocyclopropanecarbonyl)-2-nitrospiro[3.5]non-7-yl)-[1,2,4-triazole[1,5-a]pyridin-2-yl)cyclopropaneformamide and its isomers or pharma-ceutically acceptable salts, or crystalline forms, and their use in skin diseases. Preferred skin diseases include psoriasis, atopic dermatitis, vitiligo, lupus erythematosus, alopecia areata, eczema, contact dermatitis, urticaria, sweat rash, dermatomyositis, scleroderma, acne, and seborrheic dermatitis.

Description

[Technical Field]

[0001] The present application is in the field of pharmaceutical formulations and relates to topical formulations of [1,2,4]triazolo[1,5-a]pyridine compounds and their isomers or pharmaceutically acceptable salts or crystalline forms, and their use in skin disorders. [Background technology]

[0002] In recent years, JAK kinase inhibitors have become a new target for treating skin diseases. JAK kinases are a family of intracellular non-receptor tyrosine kinases consisting of four family members: JAK1, JAK2, JAK3, and TYK2. Among them, JAK1, JAK2, and TYK2 are expressed in various tissues and cells of the human body, while JAK3 is primarily expressed in various hematopoietic tissue cells. JAK inhibitors are involved in many important biological processes, such as cell proliferation, differentiation, apoptosis, and immunoregulation, by inhibiting the JAK-STAT signaling pathway. JAK inhibitors have the advantages of clear therapeutic effects and relatively few side effects, and topical formulations can be used to treat skin-related diseases (such as psoriasis, atopic dermatitis, vitiligo, lupus erythematosus, and alopecia areata). Local administration also reduces side effects, improves safety, and more rapidly alleviates symptoms and / or resolves the underlying cause of the disease. Topical drug formulations are a significant advancement in this field.

[0003] WO2020 / 038457 discloses a compound of formula I:

[0004] [ka]

[0005] The present invention discloses a series of JAK kinase inhibitors that are [1,2,4]triazolo[1,5-a]pyridine compounds and their isomers or pharmaceutically acceptable salts that satisfy the general formula:

[0006] Although it is known to be a small molecule JAK kinase inhibitor with significant JAK kinase inhibitory activity and high selectivity, topical formulations of JAK kinase inhibitors and their therapeutic effects on skin diseases have not yet been disclosed.

[0007] Among these compounds are those shown in Formula II, which has the chemical name (S)—N-(5-(2-(2,2-difluorocyclopropanecarbonyl)-2-nitrospiro[3,5]non-7-yl)-[1,2,4-triazole[1,5-a]pyridin-2-yl)cyclopropaneformamide.

[0008] [ka] [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2020 / 038457 Summary of the Invention [Problem to be solved by the invention]

[0010] Therefore, further research is needed to discover the efficacy and safety of topical external formulations of the above-mentioned small molecule compounds for skin diseases such as psoriasis, atopic dermatitis, vitiligo, lupus erythematosus, alopecia areata, allergic eczema, contact dermatitis, urticaria, dyshidrotic eczema, dermatomyositis, scleroderma, acne, seborrheic dermatitis, etc., and to develop topically applied formulations with stable manufacturing methods and quality.

[0011] The object of the present invention is to provide a safe and effective topical preparation, the preparation of which is simple, has stable quality, and is suitable for industrial large-scale production. [Means for solving the problem]

[0012] The present invention provides a topical formulation containing a JAK inhibitor, the topical formulation comprising a JAK inhibitor, a matrix, and an excipient, wherein the JAK inhibitor comprises a compound of formula (I), an isomer thereof, a pharmaceutically acceptable salt thereof, or crystalline form A thereof.

[0013] [ka]

[0014] (In the formula, E1 and E2 are each independently selected from a single bond, -CH2-, or -(CH2)2-; L1 is a single bond, -(CH2) g -, -c(=O)- or -c(=O)-(CH2) h - selected from m is 1 or 2; n is 1 or 2, g is 1, 2 or 3; h is 1, 2 or 3; R1 is H, CN, C 1~6 alkyl or 3- to 6-membered cycloalkyl; C 1~6 Alkyl and 3- to 6-membered cycloalkyl may have one, two, or three R a and optionally replaced by R2 is H, F, Cl, Br, I or C 1~3 alkyl, C 1~3 Alkyl can be one, two, or three R b and optionally replaced by R3, R4 and R5 are H, F, Cl, Br, I or C, respectively. 1~3 alkyl, and C 1~3 Alkyl can be one, two, or three R c and optionally replaced by R6, R7 and R8 are each H, F, Cl, Br, I or C 1~3 alkyl, and C 1~3Alkyl can be one, two, or three R d and optionally replaced by R a are H, F, Cl, Br, I, CN or C, respectively. 1~3 alkyl, and C 1~3 alkyl is optionally substituted by one, two or three R; R b are each independently selected from F, Cl, Br, or I; R c are each independently selected from F, Cl, Br, or I; R d are each independently selected from F, Cl, Br, or I; Each R is independently selected from F, Cl, Br, or I.

[0015] In one embodiment, the present invention provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R a are each independently selected from H, F, Cl, Br, I, or CN.

[0016] In one embodiment of the present invention, in the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, R1 is H, CN, C 1~3 alkyl or 3- to 5-membered cycloalkyl; C 1~3 The alkyl and 3- to 5-membered cycloalkyl are optionally substituted by 1, 2, or 3 R a .

[0017] In one embodiment of the present invention, in the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, R1 is H, CN, CH3

[0018] [ka]

[0019] CH3

[0020] [ka]

[0021] is optionally substituted by one, two or three Ra.

[0022] In one embodiment of the present invention, in the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, R1 is H, CN, CF3, CHF2

[0023] [ka]

[0024] is selected from.

[0025] In one embodiment of the present invention, in the compounds of formula (I), its isomers or pharmaceutically acceptable salts thereof, R2 is selected from H, F, Cl, Br or I.

[0026] In one embodiment of the present application, in the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, R3, R4 and R5 are independently selected from H, F, Cl, Br or I.

[0027] In one embodiment of the present invention, in the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, R6, R7 and R8 are independently selected from H, F, Cl, Br or I.

[0028] In one embodiment of the present invention, in the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, L1 is selected from a single bond, -CH2-, -(CH2)2-, -C(=O)- or -C(=O)-(CH2)-.

[0029] In one embodiment, the present invention provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structural unit

[0030] [ka]

[0031] [ka]

[0032] is selected from.

[0033] In one embodiment, the present invention provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structural unit

[0034] [ka]

[0035] [ka]

[0036] is selected from.

[0037] In one embodiment, the present invention provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structural unit

[0038] [ka]

[0039] [ka]

[0040] is selected from.

[0041] In one embodiment of the present invention, the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof is

[0042] [ka]

[0043] is selected from. (In the formula, L1 is defined in claim 1 or 9, R1 is defined in claims 1 to 5, R2 is defined in claim 1 or 6, R3, R4 and R5 are defined in claim 1 or 7; R6, R7 and R8 are defined in claim 1 or 8.

[0044] In one embodiment of the present invention, the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof is

[0045] [ka]

[0046] is selected from. (In the formula, L1 is defined in claim 1 or 9, R a is defined in claim 1 or 2, R2 is defined in claim 1 or 6, R3, R4 and R5 are defined in claim 1 or 7; R6, R7 and R8 are defined in claim 1 or 8.

[0047] In one embodiment of the present invention, the JAK inhibitor includes the following compounds, their isomers, or pharmaceutically acceptable salts thereof:

[0048] [ka]

[0049] In one embodiment of the present invention, the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof is

[0050] [ka]

[0051] is selected from.

[0052] In one embodiment, the present invention includes a compound of formula (II), an isomer or a pharmaceutically acceptable salt thereof:

[0053] [ka]

[0054] In this invention, one embodiment is a compound of formula (III), an isomer or a pharmaceutically acceptable salt thereof:

[0055] [ka]

[0056] In one embodiment, the present invention includes a compound of formula (IV), an isomer or a pharmaceutically acceptable salt thereof:

[0057] [ka]

[0058] In one embodiment, the present invention includes a compound of formula (V), an isomer or a pharmaceutically acceptable salt thereof:

[0059] [ka]

[0060] In one embodiment, the present invention includes a compound of formula (VI), an isomer or a pharmaceutically acceptable salt thereof:

[0061] [ka]

[0062] In one embodiment of the present invention, the topical formulation comprises one of the compounds of formula (II), formula (III), formula (IV), formula (V) or formula (VI) disclosed in the present application.

[0063] In one embodiment of the present invention, the topical formulation comprises one or more pharmaceutically acceptable matrices.

[0064] In one embodiment of the present invention, the topical external preparation comprises one or more additives.

[0065] In one embodiment of the present invention, the topical external preparation comprises one or more matrices and one or more additives.

[0066] In one embodiment of the present invention, the matrix is ​​selected from an oil-soluble matrix or a water-soluble matrix.

[0067] In one embodiment of the present invention, the water-soluble matrix is ​​selected from polyethylene glycol 3350 (PEG3350), polyethylene glycol 400 (PEG400), cellulose derivatives, or a combination of two or more thereof.

[0068] In one embodiment of the present invention, the oil-soluble matrix is ​​selected from an oily substance, a hydrocarbon, a lipid, a synthetic (semi-synthetic) oily substance, or a combination of two or more thereof.

[0069] In one embodiment of the present invention, the oily substance is selected from pork fat, sheep fat, beef fat, sesame oil, cottonseed oil, soybean oil, peanut oil, olive oil, vegetable oil, hydrogenated vegetable oil, or a combination of two or more thereof.

[0070] In one embodiment of the present invention, the hydrocarbon is selected from white petrolatum (also called white vaseline), yellow petrolatum (also called yellow vaseline), liquid paraffin (also called mineral oil or paraffinum liquidum), white wax (also called white beeswax or beeswax), paraffin, microcrystalline paraffin, fine wax, sazol paraffin, or a combination of two or more thereof.

[0071] In one embodiment of the present invention, the lipid is selected from lanolin, beeswax, whale wax or a combination of two or more thereof.

[0072] In one embodiment of the present invention, the synthetic (semi-synthetic) oily substance is selected from squalane, lanolin derivatives, lanolin alcohol, acetylated lanolin, polyoxyethylene lanolin, hydrogenated lanolin, silicone, glyceryl behenate, palmitic acid, stearic acid, isostearic acid, octadecanol, cetanol, stearanol, or a combination of two or more thereof.

[0073] In one embodiment of the present invention, the additive comprises one or more antioxidants, preservatives, humectants, solubilizers, or a combination of two or more thereof.

[0074] In one embodiment of the present invention, the antioxidant is selected from a water-soluble antioxidant, an oil-soluble antioxidant, a metal ion complexing agent, or a combination of two or more thereof.

[0075] In one embodiment of the present invention, the water-soluble antioxidant is selected from sodium bisulfite, sodium metabisulfite, sodium thiosulfate, sodium sulfite, vitamin C, cysteine, methionine, or a combination of two or more thereof.

[0076] In one embodiment of the present invention, the oil-soluble antioxidant is selected from tert-butyl p-hydroxyanisole, dibutylhydroxytoluene, propyl gallate, vitamin E, or a combination of two or more thereof.

[0077] In one embodiment of the present invention, the metal ion complex antioxidant is selected from edetic acid (EDTA), citric acid, tartaric acid, or a combination of two or more thereof.

[0078] In one implementation scheme of the present invention, the preservative is selected from trichloro-tert-butanol, benzoic acid, sorbic acid, phenol, cresol, hydroxybenzyl methyl ester, hydroxyphenyl ethyl ester, benzalkonium bromide, benzalkonium chloride, or a combination of two or more thereof.

[0079] In one embodiment of the present invention, the humectant is selected from polyols such as glycerol, propylene glycol, sorbitol, or a combination of two or more thereof.

[0080] In one embodiment of the present invention, the solubilizer is selected from monoglyceryl linoleiate, diethylene glycol monoethyl ether, polyglycerol fatty acid esters, or a combination of two or more thereof.

[0081] The present invention provides topical formulations comprising a JAK inhibitor, one or more matrices, and one or more excipients, wherein the JAK inhibitor is a compound of structural formula (II), structural formula (III), structural formula (IV), structural formula (V), or structural formula (VI), and isomers or pharmaceutically acceptable salts thereof, or crystalline forms thereof:

[0082] [ka]

[0083] In the topical formulations provided by the present invention, the content of the JAK inhibitor is 0.01% to 10%, preferably 0.02% to 9%, more preferably 0.03% to 8%, even more preferably 0.04% to 7%, and most preferably 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.25%, 1.3%, 1.4%, 1.5%, or 1.6% of the total weight of the topical formulation. 1.7%, 1.8%, 1.9%, 2%, 2.25%, 2.5%, 2.8%, 3%, 3.2%, 3.5%, 3.6%, 3.8%, 4%, 4.5%, 5%, 5.5%, 6% or 6.5%.

[0084] In the topical external preparations provided by the present invention, the matrix may include, but is not limited to, PEG 3350, PEG 400, cellulose derivatives, white petrolatum, yellow petrolatum, liquid paraffin, white wax, paraffin, fine wax, glyceryl behenate, microcrystalline paraffin, sazol paraffin, octadecanol, stearic acid, hog fat, lanolin, tallow, sesame oil, cottonseed oil, soybean oil, peanut oil, olive oil, vegetable oil, hydrogenated vegetable oil, lanolin, beeswax, whale wax, squalane, lanolin derivatives, lanolin alcohol, acetylated lanolin, polyoxyethylene lanolin, hydrogenated lanolin, silicone, palmitic acid, stearic acid, isostearic acid, octadecanol, cetyl alcohol, stearic alcohol, and the like. In a preferred embodiment of the invention, the base is selected from one or more of PEG 3350, PEG 400, white petrolatum, yellow petrolatum, liquid paraffin, white wax, paraffin, fine wax, glyceryl behenate, microcrystalline paraffin, sazol paraffin, octadecanol, stearic acid, wool fat, beeswax, whale wax, squalane, octadecanol or stearic alcohol.

[0085] In the topical formulations provided by the present invention, the additives may include, but are not limited to, one or more of sodium bisulfite, sodium metabisulfite, sodium thiosulfate, sodium sulfite, vitamin C, cysteine, methionine, monoglycerides, diethylene glycol monoethyl ether, polyglycerol fatty acid esters, tert-butyl-p-hydroxyanisole, dibutylhydroxytoluene, propyl gallate, vitamin E, edetic acid (EDTA), citric acid, tartaric acid, trichlorotertbutanol, benzoic acid, sorbic acid, phenol, cresol, hydroxyphenylmethyl esters, hydroxyphenylethyl esters, benzalkonium bromide, benzalkonium chloride, polyols (such as glycerol, propylene glycol, sorbitol, etc.).

[0086] In one embodiment of the present invention, the content of white petrolatum is 45% to 96%, preferably 50% to 95%, more preferably 53% to 94%, even more preferably 55% to 93%, even more preferably 56% to 92%, and most preferably 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 80.5%, 81%, or 81.5% of the total weight of the topical preparation. 82%, 82.5%, 83%, 83.5%, 84%, 84.5%, 85%, 85.5%, 86%, 86.5%, 87%, 87.5%, 88%, 88.5%, 89%, 89.5%, 90%, 90.25%, 90.3%, 90.35%, 90.4%, 90.45%, 90.46%, 90.48%, 90.5%, 90.6%, 90.7%, 90.8%, 90.85%, 90.9%, 91%, 91.25%, 91.45% or 91.5%.

[0087] In one embodiment of the present invention, the content of white wax is 0.5% to 10%, preferably 1% to 9%, more preferably 2% to 8%, even more preferably 3% to 6%, more preferably 4% to 5%, and most preferably 4.01%, 4.02%, 4.04%, 4.06%, 4.08%, 4.1%, 4.12%, 4.1% of the total weight of the topical external preparation. 4%, 4.14%, 4.16%, 4.18%, 4.2%, 4.22%, 4.24%, 4.26%, 4.28%, 4.3%, 4.32%, 4.34%, 4.36%, 4.38%, 4.4%, 4.45%, 4.5%, 4.55%, 4.6%, 4.65%, 4.7%, 4.75%, 4.8%, 4.85%, 4.9% or 4.95%.

[0088] In one embodiment of the present invention, the content of liquid paraffin is 0.2% to 50%, preferably 1% to 40%, more preferably 1.5% to 30%, even more preferably 2% to 20%, more preferably 2.5% to 15%, and most preferably 3%, 3.5%, 4%, 4.05%, 4.1%, 4.15%, 4.2%, 4.25%, 4.3%, 4.35%, 4.4%, 4.45%, 4.5%, 5%, 5.02%, 5.04%, 5.05%, 5.1%, 5.15%, 5.2%, 5.25%, 5.3% of the total weight of the topical external preparation. 5.35%, 5.4%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14% or 14.5%.

[0089] In one embodiment of the present invention, the content of paraffin is 1% to 8%, preferably 2% to 7%, and most preferably 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6% or 6.5% of the total weight of the topical formulation.

[0090] In one embodiment of the present invention, the content of Sasol paraffin is 1% to 10%, preferably 1.5% to 9%, more preferably 2% to 8%, even more preferably 2.5% to 7%, more preferably 3% to 6%, and most preferably 3.5%, 4%, 4.5%, 5% or 5.5% of the total weight of the topical external preparation.

[0091] In one embodiment of the present invention, the content of microcrystalline paraffin is 2% to 50%, preferably 4% to 45%, more preferably 5% to 40%, even more preferably 7% to 35%, more preferably 9% to 30%, and most preferably 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, or 21% of the total weight of the topical external preparation. 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 28% or 29%.

[0092] In one embodiment of the present invention, the content of PEG 400 is 50% to 95%, preferably 60% to 90%, more preferably 70% to 85%, and most preferably 71%, 72%, 73%, 74%, 75%, 75.2%, 75.4%, 75.6%, 75.8%, 76%, 76.2%, 76.4%, 76.6%, 77%, 77.2%, 77.4%, 77.4%, 77.6%, 77.8%, 78%, 78.2%, 78.4%, 78.6%, 78.8% or 79% of the total weight of the topical external preparation.

[0093] In one embodiment of the present invention, the content of PEG3350 is 5% to 50%, preferably 8% to 40%, more preferably 10% to 30%, even more preferably 15% to 25%, and most preferably 16%, 16.5%, 17%, 17.5%, 18%, 18.2%, 18.4%, 18.6%, 18.8%, 19%, 19.2%, 19.4%, 19.6%, 19.8%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, or 24.5% of the total weight of the topical external preparation.

[0094] In one embodiment of the present invention, the ratio of the PEG400 content to the PEG3350 content is 1:8 to 1:1, preferably 1:6 to 1:2, more preferably 1:5 to 1:3, and most preferably 1:4.

[0095] In one embodiment of the present invention, the content of octadecanol is 1% to 10%, preferably 2% to 9%, more preferably 3% to 8%, even more preferably 4% to 7%, and most preferably 4.5%, 5%, 5.5%, 6% or 6.5% of the total weight of the topical preparation.

[0096] In one embodiment of the present invention, the content of stearic acid is 1% to 10%, preferably 1.5% to 9%, more preferably 2% to 8%, even more preferably 2.5% to 7%, even more preferably 3% to 6%, and most preferably 3.5%, 4%, 4.5%, 5%, or 5.5% of the total weight of the topical preparation.

[0097] In one embodiment of the present invention, the content of diethylene glycol monoethyl ether is 1% to 10%, preferably 1.5% to 9%, more preferably 2% to 8%, even more preferably 2.5% to 7%, even more preferably 3% to 6%, and most preferably 3.5%, 4%, 4.5%, 5%, or 5.5% of the total weight of the topical preparation.

[0098] In one embodiment of the present invention, the content of polyglycerol fatty acid ester is 1% to 10%, preferably 1.5% to 9%, more preferably 2% to 8%, even more preferably 2.5% to 7%, even more preferably 3% to 6%, and most preferably 3.5%, 4%, 4.5%, 5% or 5.5% of the total weight of the topical external preparation.

[0099] In one embodiment of the present invention, the content of monolinoleic acid glyceride is 1% to 10%, preferably 1.5% to 9%, more preferably 2% to 8%, even more preferably 2.5% to 7%, even more preferably 3% to 6%, and most preferably 3.5%, 4%, 4.5%, 5% or 5.5% of the total weight of the topical external preparation.

[0100] In one embodiment of the present invention, the content of glyceryl behenate is 1% to 10%, preferably 2% to 9%, more preferably 3% to 8%, and most preferably 3.5%, 4%, 4.5%, 5%, 5.5%, 6% or 6.5% of the total weight of the topical external preparation.

[0101] In one embodiment of the present invention, the content of glycerol monostearate is 1% to 10%, preferably 2% to 9%, more preferably 3% to 8%, and most preferably 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7% or 7.5% of the total weight of the topical external preparation.

[0102] The topical formulation of the present invention can be prepared by methods such as grinding and melting. The topical formulation of the present invention has a suitable texture and consistency of a paste, and good compatibility with excipients.

[0103] The topical external preparation of the present invention is subjected to a stability test in an environment with a temperature of 30°C ± 2°C and a relative humidity of 65% ± 5%. After one month, the related substances and contents are determined using HPLC method, and the changes in appearance are observed. The results show that the external preparation provided by the present application is stable in quality, and compared with the 0th day, there is no significant difference in appearance after one month of accelerated testing, and there is no significant difference in related substances and contents.

[0104] The topical formulations provided by the present invention can be in the form of ointments, creams, pastes, gels, films, pastes or patches. The topical preparations provided by the present application are used to prepare drugs for the treatment of skin diseases, and preferred skin diseases include psoriasis, atopic dermatitis, vitiligo, lupus erythematosus, alopecia areata, eczema, contact dermatitis, urticaria, dyshidrotic eczema, dermatomyositis, scleroderma, acne and seborrheic dermatitis.

[0105] The topical topical formulations provided by the present invention have high retention of active substances in the skin, thereby exerting a better therapeutic effect on the skin. The present invention uniquely adopts a transdermal drug delivery method to deliver drugs, thereby increasing the concentration of local active substances in the affected area and minimizing percutaneous absorption into the bloodstream, effectively reducing the risk of systemic drug delivery, thereby achieving the goals of reduced toxicity and increased efficacy.

[0106] Definitions and Explanations Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings: No specific term or phrase should be considered unclear or ambiguous without a specified definition, but should be understood in accordance with its ordinary meaning. Where a product name appears in the text, the name refers to the corresponding product or its active ingredient.

[0107] The term "pharmaceutically acceptable" as used herein refers to compounds, substances, compositions and / or preparations that are within the scope of sound medical judgment and suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0108] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having specific substituents and relatively non-toxic acids or bases found in the present invention. When a compound of the present invention contains a relatively acidic functional group, an alkali addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable alkali addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts, or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphoric acid, and the like, as well as salts of organic acids, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Salts also include salts of amino acids, such as arginine, and salts of organic acids, such as glucuronic acid. Certain compounds of the present invention contain both alkaline and acidic functional groups, which can be converted into any base or acid addition salt.

[0109] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains an acid or base group by conventional chemical methods. Generally, such salts are prepared by reacting the compound in its free acid or base form with the appropriate stoichiometric amount of base or acid in water, an organic solvent, or a mixture of both.

[0110] The compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof (such as enantiomerically or non-enantiomerically enriched mixtures), all of which are included within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are included within the scope of this application.

[0111] Unless otherwise specified, the terms "enantiomer" or "enantiomers" refer to stereoisomers that are mirror images of each other.

[0112] Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" are caused by double bonds or single bonds of cyclic carbon atoms that cannot rotate freely.

[0113] Unless otherwise specified, the term "diastereomeric" refers to stereoisomers in which the molecules have two or more centers of chirality and do not have a mirror-like relationship to one another.

[0114] Unless otherwise specified, "(D)" or "(+)" indicates clockwise rotation, "(L)" or "(-)" indicates counterclockwise rotation, and "(DL)" or "(±)" indicates racemic rotation.

[0115] Unless otherwise specified, the absolute configuration of a stereocenter is indicated by the solid wedge bond (

[0116] [ka]

[0117] ) and dashed wedge bonds (

[0118] [ka]

[0119] ), and the relative configuration of the stereocenters is represented by the solid linear bond (

[0120] [ka]

[0121] ) and dashed straight line combinations (

[0122] [ka] ), and the solid and wavy lines are connected (

[0123] [ka]

[0124] ) is a solid wedge bond (

[0125] [ka]

[0126] ) or dashed wedge bond (

[0127] [ka]

[0128] ) or a combination of solid lines (

[0129] [ka]

[0130] ) and dashed straight line combinations (

[0131] [ka]

[0132] ) is a wavy line (

[0133] [ka]

[0134] )

[0135] Unless otherwise specified, when a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, is present in a compound and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, the lone pair on the nitrogen atom is considered to be one of the connected substituents), the atoms on the double bond in the compound are represented by a wavy line (

[0136] [ka]

[0137] ), the compound represents the (Z) isomer, the (E) isomer, or a mixture of the two isomers of the compound. For example, the following formula (A) indicates that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2), or in the form of a mixture of the two isomers of formula (A-1) and formula (A-2), and the following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2), or in the form of a mixture of the two isomers of formula (B-1) and formula (B-2). The following formula (C) indicates that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2), or in the form of a mixture of the two isomers of formula (C-1) and formula (C-2).

[0138] [ka]

[0139] Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers consisting of different functional groups in dynamic equilibrium and can rapidly convert into each other at room temperature. When tautomerism is possible (such as in solution), a chemical equilibrium of tautomerism can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions that occur via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve recombination of some bonding electrons for interconversion. A specific example of ketone-enol tautomerism is the tautomerism between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0140] Unless otherwise specified, the terms "enriched in one isomer," "enriched isomer," "enriched in one enantiomer," or "enantiomer-enriched" refer to an isomer or enantiomer that is less than 100% abundant, and the abundance of such isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0141] Unless otherwise specified, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between two isomers or the relative percentage of two enantiomers. For example, if one isomer or enantiomer has a 90% abundance and the other isomer or enantiomer has a 10% abundance, the excess of the isomer or enantiomer (ee value) is 80%.

[0142] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. If it is desired to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral additive (in which case the resulting non-enantiomeric mixture is separated and the auxiliary group is cleaved to yield the pure desired enantiomer). Alternatively, if the molecule contains an alkaline (such as an amino) or acidic (such as a carboxyl) functional group, the molecule can be subjected to the formation of a non-enantiomeric salt with an appropriate optically active acid or base using conventional methods known in the art, followed by non-enantiomeric separation and subsequent recovery to yield the pure enantiomer. Furthermore, separation of enantiomers and diastereomers is typically achieved by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (such as the generation of amino formates from amines). The compounds of the present application may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, the compounds may contain tritium ( 3H), iodine-125( 125 I) or C-14( 14 The compounds of the present invention may be radiolabeled with radioactive isotopes such as HCl, HCl, HCl (C), etc. For example, deuterated drugs may be formed by replacing hydrogen with deuterium. The bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon. Deuterated drugs have advantages over non-deuterated drugs, such as reduced toxic side effects, improved drug stability, increased efficacy, and a longer biological half-life of the drug. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this application. "Optional" or "optionally" refers to events or circumstances that may not necessarily be described thereafter, and the description includes situations in which the event or occurrence occurred and situations in which the event or occurrence did not occur.

[0143] The term "substituted" refers to the replacement of any one or more hydrogen atoms on the designated atom by a substituent, which can include deuterium and hydrogen variants, as long as the valence state of the designated atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted," unless otherwise specified, refers to the ability to be substituted or not substituted, and the type and number of substituents can be any based on chemical feasibility.

[0144] When any variable (e.g., R) occurs more than one time in a compound composition or structure, its definition is independent at each occurrence. Thus, for example, if a group is substituted with zero to two R, that group may optionally be replaced with up to two R, and each R has an independent option. Furthermore, combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0145] When the number of linking groups is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0146] When one of the variables is selected from a single bond, it indicates that the two linking groups are directly joined, e.g., in ALZ, L represents a single bond, indicating that the structure is in fact AZ.

[0147] The absence of a substituent indicates that the substituent is not present, e.g., X is absent in AX, indicating that the structure is actually A. If the listed substituents do not indicate which atom they are linked to the substituted group, these substituents may be bonded through any of those atoms. For example, a pyridine such as substituent may be linked to the substituted group through any carbon atom of the pyridine ring.

[0148] When the listed linking group does not indicate the direction of the link, the direction of the link is arbitrary. For example,

[0149] [ka]

[0150] When the linking group L in is -MW-, -MW- is connected to rings A and B in the same direction as they are read from left to right,

[0151] [ka]

[0152] or linked to rings A and B in the opposite order as read from left to right to form:

[0153] [ka]

[0154] Combinations of linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0155] Unless otherwise specified, the number of atoms on a ring is usually defined as the number of elements in the ring. For example, a 5- to 7-membered ring refers to a "ring" containing about 5 to 7 atoms.

[0156] Unless otherwise specified, a "5- or 6-membered ring" refers to a cyclic alkyl group, heterocyclic alkyl group, cyclic alkenyl group, heterocyclic alkenyl group, cyclic alkynyl group, heterocyclic alkynyl group, aryl group, or heteroaryl group consisting of 5 to 6 ring atoms. A ring includes a single ring and two-ring systems such as a spiral ring, a parallel ring, and a bridged ring. Unless otherwise specified, a ring may optionally contain one, two, or three heteroatoms independently selected from O, S, and N. A 5- or 6-membered ring includes a 5-membered ring, a 6-membered ring, etc. A "5- or 6-membered ring" includes, for example, phenyl, pyridine, and a pyridine group. Meanwhile, the term "5- or 6-membered heterocyclic alkyl" includes a pyridine group but not a phenyl group. The term "ring" also includes ring systems containing at least one ring, where each "ring" independently conforms to the above definition.

[0157] Unless otherwise specified, the term "C 1~6 "Alkyl" is used to refer to a saturated hydrocarbon group of 1 to 6 carbon atoms, either straight or branched. 1~6 The alkyl group is C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~4 , C6 and C5 alkyl groups, etc. The alkyl groups can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). 1~6Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.

[0158] Unless otherwise specified, the term "C 1~3 "Alkyl" is used to refer to a saturated hydrocarbon group of 1 to 3 carbon atoms, either straight or branched. 1~3 The alkyl group is C 1~2 Alkyl groups and C 2~3 alkyl groups, etc. The alkyl groups can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). C 1~3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0159] Unless otherwise specified, "C 3~6 "Cycloalkyl" refers to saturated cyclic hydrocarbon groups of 3 to 6 carbon atoms, both monocyclic and bicyclic. 3~6 The cycloalkyl group is C 3~5 , C 4~5 and C 5~6 Cycloalkyl groups and the like. Cycloalkyl groups can be monovalent, divalent or polyvalent. C 3~6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0160] Unless otherwise specified, C n~n+m or C n ~C n+m are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 C, including 1~12 Including cases where any of n to n+m carbons is specified, such as C 1~3 , C 1~6, C 1~9 , C 3~6 , C 3~9 , C 3~12 , C 6~9 , C 6~12 and C 9~12 C, including 1~12 Also includes any range of n to n+m, such as . Similarly, n-membered to n+m-membered rings indicate that the number of atoms in the ring is n to n+m. For example, a 3- to 12-membered ring includes 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered rings, and any range of n to n+m. For example, a 3- to 12-membered ring includes 3-, 3-, 9-, 5-, 6-, 5-, 6-, 7-, 6-, 8-, and 6-10-membered rings.

[0161] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the embodiments with other chemical synthetic methods, and equivalent alternative methods known to those skilled in the art. Preferred embodiments include, but are not limited to, those in the present application.

[0162] The solvents used in the present invention can be commercially available. The following abbreviations are used in the present invention: aq represents water; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate; EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperbenzoic acid; Eq represents equivalents; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl represents azodicarboxylic acid; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, which is an amine protecting group; BOC represents tert-butoxycarbonyl, which is an amine protecting group; HOAc represents acetic acid; NaCNBH3 represents sodium cyanide borohydride; rtrepresents room temperature; O / N represents overnight; THF represents tetrahydrofuran; Boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; SOCl2 represents sulfoxide chloride; CS2 represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N-(benzenesulfonyl)benzenesulfonamide; NCS represents 1-chloropyrrolidine-2,5-dione; N-Bu4NF represents tetrabutylammonium fluoride; IPrOH represents 2-propanol; mp represents melting point; LDA represents lithium diisopropylamine; Pd(dppf)Cl2·CH2Cl2 represents [1,1'-bis(diphenyl (phosphine)ferrocene]palladium dichloride dichloromethane complex; EDCI represents carbodiimide; DIEA represents N,N-diisopropylethylamine; IPA represents isopropanol; HOBt represents 1-hydroxybenzotriazole; LiHMDS represents lithium hexamethyldisilicylamine; TEA represents triethylamine; HEPES represents 4-hydroxyethylpiperazineethanesulfonic acid; LiHMDS represents lithium hexamethyldisilicylamine; EDCI represents carbodiimide; Pd / C represents palladium on carbon; METHANOL represents methanol; KOAc represents potassium acetate; and K2CO3 represents potassium carbonate.

[0163] Compound II refers to the active ingredient compound (S)—N-(5-(2-(2,2-difluorocyclopropanecarbonyl)-2-nitrospiro[3.5]non-7-yl)-[1,2,4-triazole[1,5-a]pyridin-2-yl)cyclopropaneformamide and its isomers or pharmaceutically acceptable salts, or crystalline forms (also known as “Compound (II)” or “Compound (II)”). Compound III in the present invention refers to an isomer or pharmaceutically acceptable salt, or crystalline form of a compound having structural formula III. Compound IV in the present invention refers to an isomer or pharmaceutically acceptable salt, or crystalline form of a compound having structural formula IV. Compound V in the present invention refers to an isomer or pharmaceutically acceptable salt, or crystalline form of a compound having structural formula V. Compound VI in the present invention refers to an isomer or pharmaceutically acceptable salt, or crystalline form of a compound having structural formula VI. Corecim Ointment 0.5% refers to the specification of 0.5% Corecim, also known as Delgocitinib Ointment or Digotinib Ointment, manufactured by Japan® Ointment.

[0164] Compounds were named manually using supplier catalog names in the case of commercially available compounds, or named in ChemDraw® software. [Brief explanation of the drawings]

[0165] [Figure 1] 1 is a graph showing the intracutaneous retention of Compound II in pig skin in Examples 21 to 24. [Figure 2] 1 is a graph showing changes in thickness of the right ear of rats in Experimental Example 3. [Figure 3] 1 is a graph showing the degree of swelling (ear weight) of the right ear of rats in Experimental Example 3. [Figure 4] 1 is a graph showing the scores of an irritation test on intact skin in Experimental Example 4. [Figure 5] 1 is a graph showing the irritation test scores for a single administration to damaged skin in Experimental Example 4. [Figure 6] 1 is a graph showing the rheology curve of Example 21. [Figure 7] 1 is a graph showing the rheology curve of Example 22. [Figure 8] 1 is a graph showing the rheology curve of Example 23. [Figure 9] 1 is a graph showing the rheology curve of Example 24. [Figure 10] 1 is a graph showing blood concentration-time curves in male and female Bama minipigs after a single intravenous injection of 0.2 mg / kg of Compound II in Experimental Example 6. [Figure 11] 1 is a graph showing blood concentration-time curves in male and female Bama minipigs after a single transdermal administration of the ointment prepared in Example 24 in Experimental Example 6. DETAILED DESCRIPTION OF THE INVENTION

[0166] Further details of the present invention are illustrated by the following examples, which are presented for illustrative purposes only and are not intended to limit the scope of the invention.

[0167] (Examples 1 and 2) Polyethylene glycol 3350 (PEG3350), polyethylene glycol 400 (PEG400), white petrolatum, and white wax were heated and stirred in a water bath until completely melted. The prescribed amount of Compound II was added to the matrix solution, stirred homogeneously, and quenched to obtain the formulation. Specific data are shown in Table 1.

[0168] [Table 1]

[0169] Examples 3 to 7 White petrolatum, liquid paraffin, white wax and glyceryl behenate were heated and stirred in a water bath until completely melted according to the ratio in Table 2. The prescribed amount of Compound II was added to the matrix solution, stirred homogeneously and quenched to obtain the formulation.

[0170] [Table 2]

[0171] In Examples 3-7, the effect of the thickening agent glycerol behenate at 2%, 3%, 4% and 6% on the external sensory surface of the ointment was investigated. Examples 5 and 6 had poor extrudability and slightly hard pastes. Examples 3, 4, and 7 had good extrusion performance, and the pastes were moderately soft and hard. After being maintained at a constant temperature of 30°C for 10 days, particles precipitated from the paste, indicating poor excipient compatibility.

[0172] (Examples 8 to 13) White petrolatum, liquid paraffin, paraffin, white wax, microcrystalline wax and Sasol paraffin were heated and stirred until completely melted according to the ratio in Table 3. The prescribed amount of Compound II was added to the matrix solution, stirred homogeneously and quenched to obtain the formulation.

[0173] [Table 3]

[0174] Paraffin, white wax, microcrystalline wax, and Sasol paraffin are primarily used as components of ointments for topical drug prescriptions. They are used in ointments to improve their melting point or hardness. The melting point of Sasol paraffin in Example 12 was very high, and it was still impossible to homogeneously mix Sasol paraffin with other matrix components at high temperatures. The ointments obtained in Examples 8, 9, 10, 11, and 13 had moderate softness and hardness. After being left at a constant temperature of 30°C, an oily substance precipitated, and the melting points of the ointments in Examples 8 and 9 were relatively low. The perceived hardness of the creams in Examples 10, 11, and 13 was acceptable, while the creams in Examples 11 and 13 were smoother and finer. The addition of white wax can effectively adjust the hardness and texture of the ointment matrix.

[0175] (Examples 14 to 16) White petrolatum, liquid paraffin, white wax, octadecanol, and stearic acid were mixed in the proportions shown in Table 4 and continuously stirred in a water bath at 70°C until completely melted. The prescribed amount of Compound II was added to the matrix solution, homogenized at 70°C, dispersed and stirred, and cooled to room temperature to obtain an ointment.

[0176] The pastes in Examples 14, 15 and 16 exhibited relatively good feel consistency, good extrudability, and a uniform, smooth and fine texture.

[0177] [Table 4]

[0178] (Examples 17 to 20) White petrolatum, liquid paraffin, white wax, monoglyceryl linoleate, diethylene glycol monoethyl ether, and polyglycerol fatty acid ester were mixed in the proportions shown in Table 5 and continuously stirred in a water bath at 70°C until completely melted. Compound II in the prescribed amount was added to the matrix solution, homogenized at 70°C, dispersed and stirred, and cooled to room temperature to obtain an ointment.

[0179] Example 17: When preparing an ointment, the matrix was homogenized in a molten state using a high-shear homogenizer at 500 rpm. The active ingredient could not be dissolved, and the resulting ointment still had a granular texture. The matrix was not fine or smooth. The active substance in the ointments of Examples 18, 19, and 20 did not completely dissolve, and the solubilizer did not improve the solubility of the active substance. The active substance remained suspended in a particulate state.

[0180] [Table 5]

[0181] Examples 21 to 24 According to the formulation proportions of Examples 21, 22, 23, and 24 in Table 6, white petrolatum, white wax, and liquid paraffin were added to the emulsifier in order. The lid was closed, and the main pot temperature was kept at 70°C and stirring was performed at a low speed of 20 rpm. After all the matrix components were melted and homogeneously stirred, Compound II was added in the prescribed proportion. The main pot was maintained at a temperature of 65°C and a vacuum of -0.08 MPa, and the mixture was emulsified at a low speed of 40 rpm and a high speed of 3500 rpm for 4 hours. After Compound II was homogeneously dispersed, the paste began to cool for 2.5 hours. During the cooling process, stirring was continued until the matrix turned white and a paste was formed. Next, high-speed emulsification was stopped, and low-speed stirring was performed at 60 rpm. During the cooling period, the low-speed stirring speed was gradually reduced to 20 rpm, and the temperature was lowered to approximately 35°C, yielding an ointment.

[0182] [Table 6]

[0183] Examples 21 to 23 showed an off-white color on the paste surface, while Example 24 showed a white color on the paste surface. Examples 21 to 24 showed that the creams had a medium sensory viscosity, appropriate softness and hardness, and good extrudability. The texture was smooth and fine, and the ointment had good spreadability. It was easy to apply and retain on the skin surface, which facilitates the active ingredients in the topical external preparations to exert their therapeutic effects on the skin surface.

[0184] (Examples 25 to 26) According to the ratio in Table 7, white petrolatum, liquid paraffin, paraffin and monostearate glyceride were heated and stirred in a water bath until completely melted. The prescribed amount of Compound II was added to the matrix solution, stirred homogeneously, and quenched to obtain the formulation.

[0185] [Table 7]

[0186] Examples 25 and 26 were used to examine the effect of adding the thickener glycerol mono- and di-stearate to the external sensory surface of the ointment. Example 25 demonstrated poor extrusion molding performance and a hard paste. After maintaining a constant temperature of 40°C for 5 days, particles precipitated from the paste. Based on Example 25, Example 26 removed paraffin and increased the amount of liquid paraffin, while simultaneously reducing the amount of glycerol mono- and di-stearate. This resulted in particle precipitation from the ointment without a significant improvement in the hardness of the ointment. The compatibility between the excipients in Examples 25 and 26 was poor.

[0187] Examples 27 to 30 According to the formulation proportions of Examples 27-30 in Table 8, white petrolatum, white wax, and liquid paraffin were sequentially added to the emulsifier, covered with a lid, and stirred at a low speed of 20 rpm at a main pot temperature of 70°C. After all the matrix components were melted and homogeneously stirred, Compound III was added in the prescribed proportion. The main pot was maintained at a temperature of 65°C and a vacuum of -0.08 MPa, and emulsified at a low speed of 40 rpm and a high speed of 3500 rpm for 4 hours. After Compound III was homogeneously dispersed, the paste began to cool for 2.5 hours. During the cooling process, stirring was continued until the matrix turned white and a paste was formed. The high-speed emulsification was stopped, and the low-speed stirring speed was adjusted to 60 rpm, and stirring was continued. During the cooling period, the low-speed stirring speed was gradually reduced to 20 rpm, and the temperature was lowered to approximately 35°C, yielding an ointment formulation.

[0188] [Table 8]

[0189] Compound III of Examples 27 to 30 was dispersed in suspension in an off-white matrix, and no particles larger than 180 μm were observed. The ointment had a fine and smooth texture, good spreadability, and good application tendency, and remained on the surface of the skin, forming a uniform oily film.

[0190] Examples 31 to 34 According to the formulation ratios in Table 9, white petrolatum, white wax, and liquid paraffin were added to the emulsifier, covered with a lid, and stirred at a low speed of 20 rpm at a main pot temperature of 70°C. After all the matrix was melted and stirred homogeneously, Compound IV was added in the formulation ratio, and emulsified in the main pot at 65°C with a vacuum of -0.08 MPa, stirring at a low speed of 40 rpm and a high speed of 3500 rpm for 4 hours. After Compound IV was homogeneously dispersed, the paste began to cool for 2.5 hours. During the cooling process of the paste, stirring was continued until the matrix turned white and a paste was formed. The high-speed emulsification was stopped, and the low-speed stirring speed was adjusted to 60 rpm, and then low-speed stirring was continued. During the cooling period, the low-speed stirring speed was gradually reduced to 20 rpm, and the temperature was reduced to approximately 35°C, obtaining an ointment.

[0191] [Table 9]

[0192] Examples 31-34: Particles of Compound IV, an active ingredient, were uniformly dispersed in a matrix without particles exceeding 180 μm. The matrix had good extensibility and could form a uniform oily film on the skin surface, thereby promoting the effectiveness of the active ingredient.

[0193] Examples 35 to 38 According to the formulation ratios in Table 10, white petrolatum, white wax, and liquid paraffin were added to the emulsifier, covered with a lid, and stirred at a low speed of 20 rpm at a main pot temperature of 70°C. After all the matrix components were melted and stirred homogeneously, Compound V was added in the prescribed proportion to the main pot at 65°C, maintained at a vacuum of -0.08 MPa, stirred at a low speed of 40 rpm, and emulsified at a high speed of 3500 rpm for 4 hours. After Compound V was homogeneously dispersed, the paste began to cool for 2.5 hours. During the cooling process of the paste, stirring was continued until the matrix turned white and a paste was formed. The high-speed emulsification was stopped, and the low-speed stirring speed was adjusted to 60 rpm, and then low-speed stirring was continued. During the cooling period, the low-speed stirring speed was gradually reduced to 20 rpm, and the temperature was reduced to approximately 35°C, resulting in an ointment.

[0194] [Table 10]

[0195] The ointments obtained in Examples 35 to 38 were moderately soft and hard, easy to fill, and had excellent extrusion properties. The ointments were smooth and fine, and the active ingredients were evenly dispersed in the matrix. Such oily matrices could be applied evenly to the skin surface, which is beneficial for skin moisture retention.

[0196] (Examples 39 to 42) According to the formulation in Table 11, white petrolatum, white wax, and liquid paraffin were added to the emulsifier, covered with a lid, and stirred at a low speed of 20 rpm at a main pot temperature of 70°C. After all the matrix was melted and homogeneously stirred, Compound VI was added in the prescribed proportion, and emulsified in the main pot at 65°C with a vacuum of -0.08 MPa, stirring at a low speed of 40 rpm and a high speed of 3500 rpm for 4 hours. After the dispersion of Compound VI was homogenized, the paste began to cool for 2.5 hours. During the cooling process of the paste, stirring was continued until the matrix turned white and a paste was formed. The high-speed emulsification was stopped, and the low-speed stirring speed was adjusted to 60 rpm, and then low-speed stirring was continued. During the cooling period, the low-speed stirring speed was gradually reduced to 20 rpm, and the temperature was reduced to approximately 35°C, obtaining an ointment.

[0197] [Table 11]

[0198] In Examples 39 to 42 prepared according to the formulation ratios in Table 11, Examples 41 and 42 had smooth, white, and glossy creams, while Examples 39 and 40 had white and fine creams. Examples 39 to 42 showed no difference in spreadability, were relatively easy to apply to the skin, and formed a transparent oily film that could reduce skin moisture loss and promote the active ingredient to exert its pharmacological action.

[0199] (Experimental Example 1: In vitro percutaneous test of ointment) Ex vivo transdermal studies were conducted on the ointments prepared from Examples 1, 2, 14, 15, 16, 18, 19, 20, 21, 22, 23 and 24 to examine the ability of the active ingredients from the different formulations to remain on the skin surface. Ex vivo skin preparation: The skin from the same area of ​​the pig's ear and back was selected as the experimental model. The pig's hair was removed, and excess subcutaneous fat was stripped off to control the thickness of the pig's skin between 700 and 800 μm. After confirming the integrity of the skin under a microscope to ensure there was no damage to the skin, the skin was thoroughly rinsed with saline, placed in sealed aluminum foil, and stored at -70°C for later use.

[0200] In vitro transdermal experiment: Peeled porcine skin was slowly cooled to room temperature, laid flat, and fixed with clips between two vertical diffusion pools, with the stratum corneum facing the supply pool and the dermis facing the receiving pool. Drugs were supplied to them using an aluminum plate of a fixed thickness, weighed, and then placed in the supply pool. To avoid the generation of air bubbles, a rotor and phosphate buffer solution were added to the receiving pool (phosphate buffer solution was used as the receiving solution, which was confirmed through preliminary studies to meet the requirements of the leakage tank). The temperature of the multifunctional transdermal diffusion device was set to 32±0.1°C, and the rotation speed was set to 600 rpm. The experiment was stopped after 5 hours, and samples were removed from the receiving pool. At the same time, the residual ointment from the supply pool and skin samples on the contact surface of the ointment were collected and extracted using a solvent suitable for ultrasonic extraction. The drug content of the above samples was detected by LC-MS, and the recovery rate was calculated.

[0201] The content of the active ingredient in the skin was the intradermal retention amount, and the content of the active ingredient in the receptor pool was the cumulative permeation amount. The results of the in vitro percutaneous test of the ointment are shown in Table 12.

[0202] [Table 12]

[0203] Example 1 and Example 2 are water-soluble matrix ointments and oil-based matrix ointments, respectively.Compared with Example 1, which uses a water-soluble matrix, Example 2, which uses an oil-based ointment matrix, shows a higher intradermal retention of the active ingredient, which is beneficial for the active ingredient in the topical formulation to exert its pharmacological effect on the skin surface.The oil-based ointment matrix can promote the retention of the active substance in the skin.

[0204] The effect of viscosity modifiers on the intradermal retention properties of active substances in ointments was investigated in Examples 14, 15, and 16. Compared with Example 2, Example 14 showed comparable intradermal retention, while the combination of liquid paraffin and stearic acid did not improve the retention of the active substance. Compared with Example 2, Examples 15 and 16 significantly increased the intradermal retention of the active substance, which is beneficial for the active ingredient in an external preparation to exert its pharmacological action on the skin surface.

[0205] The effect of solubilizers on the ability of active ingredients to remain in the skin was investigated in Examples 18, 19, and 20. The intradermal retention of active substance in Examples 18, 19, and 20 was equivalent, but the intradermal retention was reduced compared to Example 2. The addition of solubilizers did not help the active ingredients in the topical formulations exert their pharmacological effects in the skin.

[0206] The relationship between intradermal retention of the active ingredient and concentrations of the active ingredient of 0.1%, 0.5%, 1%, and 2% was examined in Examples 21 to 24. As shown in Figure 1, as the drug loading increased, the retention of the active substance in pig skin showed an increasing trend, while the increasing trend of high-concentration delayed retention slowed.

[0207] Experimental Example 2 Stability Study The stability of the ointments prepared in Examples 21 to 24 was examined by storing them at 30°C ± 2°C and RH 65% ± 5%, and the changes in appearance, content, and total impurities were examined. The results are shown in Table 13. These results indicate that Examples 21 to 24 exhibited good physical and chemical stability under accelerated conditions.

[0208] [Table 13]

[0209] Experimental Example 3 Pharmacodynamic Evaluation of DNCB-Induced Atopic Dermatitis Model in Rats Using Topical Preparations 1. Purpose of the test: This study investigated the therapeutic effects of Examples 22 to 24 on a specific dermatitis model in Brown North rats (BN rats) induced by application of 2,4-dinitrochlorobenzene (DNCB) in the ears.

[0210] 2. Experimental animals: The animal species were 12-13 week old female Brown Norway (BN) rats with a weight range of 120-200 g and a grade of SPF at the time of animal transfer.

[0211] 3. Preparation of key reagents: Mixed solution of acetone and olive oil (3:1): For example, if 10 mL is taken, 7.5 mL of acetone and 2.5 mL of olive oil are mixed thoroughly to obtain a solution. 0.5% DNCB solution: Take 10mL of preparation as an example, weigh 0.05g of DNCB yellow crystals, add 10mL of acetone and olive oil mixture (3:1), mix well, and store in the dark. It can be prepared as needed and adjusted according to the ratio.

[0212] 4. Dosage and group design of test and control articles (see Table 14):

[0213] [Table 14]

[0214] 5. Summary of experimental method: Modeling: All animals except the negative control group were modeled. The modeling method was as follows: On days 1, 3, 7, 9, 12, 14, 16, 19, 21, and 23, 40 μL of 0.5% DNCB solution (acetone:olive oil = 3:1) was homogenously applied to the backs of the animals and the inner ear shells of the left and right ears. 40 μL of the acetone-olive oil mixed solution was homogenously applied to the backs of the animals in the negative control group and the inner outer ears of the left and right ears. During the modeling period, the animals were housed in a single box. Approximately 6 hours after modeling, the modeled area was gently cleaned with a cotton swab soaked in saline.

[0215] Administration: The right ears of animals in the positive control group, blank matrix group, low concentration group, medium concentration group, and high concentration group were administered according to the settings. Both ears of the negative control group and model control group, and the left ears of other experimental groups were not treated. During the administration period, the animals were housed in single boxes after wearing Elizabethan collars, and after the drug was removed, these animals were housed normally in their groups. On the day of modeling, the drug was administered approximately one hour after modeling and removed approximately five hours after administration. Starting from the first day of modeling, the drug was administered once daily for 23 consecutive days.

[0216] Test parameters: Ear thickness was measured approximately 6 hours after modeling at D0, D1, D3, D7, D9, D12, D14, D16, D19, D21, and D23. After the experiment, the animals were euthanized and an approximately 8 mm ear section from the same area was weighed.

[0217] 6.Test results: The therapeutic effects of Examples 22 to 24 in a Brown Normal rat (BN rat) atopic dermatitis model were examined by comparing changes in ear thickness and ear swelling.

[0218] Ear Thickness: According to the detection results of the change in ear thickness index (shown in Table 15 and Figure 2), Examples 22 to 24 can inhibit the increase in ear thickness with increasing concentration. The change trend of ear thickness in Example 22 is similar to that of the positive drug (0.5% ointment). Example 24 shows a significant advantage in inhibiting the increase in ear thickness.

[0219] Degree of ear swelling: After the experiment, the degree of swelling of the right ear was calculated by measuring the weight of approximately 8 mm ear pieces in the same area (degree of ear swelling = weight of ear piece of measurement group - weight of ear piece of negative control group). These results are shown in Table 16 and Figure 3. The degree of swelling of the right ear corresponds to the change in ear thickness. The ointment preparation from Example 23 showed an advantage in inhibiting ear swelling, while Example 24 showed a significant advantage in inhibiting ear swelling.

[0220] [Table 15]

[0221] [Table 16]

[0222] Experimental Example 4 Local Irritation Test of Preparations 1. Irritation test on intact skin: Approximately 24 hours prior to the test, the long hair on both sides of the rabbit's back spine was shaved using a pet groomer, and then an electric razor was used to remove the short hair without damaging the epidermis. This experiment employed a self-control method, with each white rabbit treated to obtain four administration areas, each with a hair removal area of ​​approximately 3 cm x 3 cm and an administration area of ​​2.5 cm x 2.5 cm. For the ointment preparation group, approximately 0.5 g of the homemade ointment used in Example 24 was applied directly to the skin surface. For the positive control group, approximately 0.5 mL of 10% sodium dodecyl sulfate was applied to the skin surface. For the blank matrix group, approximately 0.5 g of blank matrix was applied to the skin surface. For the saline group, approximately 0.5 mL of saline was applied to the skin surface. Another area was used as a negative control group. After this, the areas were covered with a double layer of gauze and a layer of glass paper (2.5 cm x 2.5 cm) and fixed with medical anti-allergic tape. An occlusive test was performed, and after application, residual test substance on the skin surface was wiped with warm water. After removing the test substance, the skin reaction at the application site was observed at 0, 1, 24, 48 and 72 hours and evaluated according to a skin reaction score in accordance with Table 17. The average score of the skin evaluation of the test animals was used for the global evaluation, and the skin irritation intensity was determined according to Table 18.

[0223] [Table 17]

[0224] [Table 18]

[0225] The results are shown in Table 19 and Figure 4. The skin irritation intensity level of each group was evaluated by comparing Tables 17 and 18 based on the average score of each observation point. The positive control group showed severe irritation, while the ointment preparation group, saline group, and blank matrix group in Example 24 showed no irritation.

[0226] [Table 19]

[0227] 2. Single-dose irritation test on damaged skin: Approximately 24 hours before the test, the long hair on both sides of the rabbit's back spine was shaved using a pet groomer, followed by manual removal of short hair using an electric razor to induce skin damage. This experiment was conducted using a self-control method, with each white rabbit treated to obtain two areas, each with a hair removal area of ​​approximately 3 cm x 3 cm and a 2.5 cm x 2.5 cm administration area. For the administration group, approximately 0.5 g of Example 24 was applied directly to the surface of the damaged skin. Another area was used as a blank control. After this, the areas were covered with a double layer of gauze and a layer of glass paper (2.5 cm x 2.5 cm) and secured with medical anti-allergy tape. An occlusive test was used, and administration was carried out for 5 hours. After application, residual test material on the skin surface was wiped off with warm water. After removal of the test material, the skin irritation response at the application site was observed at 0, 1, 24, 48, and 72 hours. Skin reaction scores were performed according to Table 17, and a comprehensive evaluation was made based on the average score of the skin evaluation of the test animals. Skin irritation intensity was determined according to Table 18.

[0228] As shown in Table 20 and Figure 5, the damaged skin treatment group (Example 24) and the damaged skin control group (skin damaged but not treated) had the same irritation reaction course of erythema and edema. Example 24 did not worsen the erythema and edema of damaged skin, indicating that this ointment is not irritating to damaged skin.

[0229] [Table 20]

[0230] Experimental Example 5 Rheology By using strain scanning in vibration mode, the flow point where the elastic modulus G' interacts with the viscous modulus G' was observed. The corresponding force was the force that could cause the paste to flow. The extensibility of the ointment applied to the skin was tested. The lower the flow point, the better the skin extensibility. The extensibility of the ointment of Example 21 was 0.15 (% strain), which was the same as that of the blank matrix. There was no significant change in the extensibility of the ointments in Examples 22-24, all of which were approximately 0.4 (% train). There was no significant difference. These results are shown in Table 21 and Figures 6, 7, 8 and 9.

[0231] [Table 21]

[0232] Experimental Example 6 Determination of a Single Dose Curve in Bama Minipigs 1. Experimental Objective: To investigate the pharmacokinetic properties of Compound II in Example 24 prepared by single transdermal application or intravenous injection in Bama minipigs, and to calculate the relevant pharmacokinetic parameters.

[0233] 2. Experimental animals: Two normal-grade Bama minipigs (half male and half female) aged 3-4 months, weighing approximately 10-15 kg, with individual body weight values ​​within the range of the mean ± 20%.

[0234] 3. Solution preparation: Solvent: 5% DMSO (dimethyl sulfoxide) / 95% (20% hydroxypropyl)-β-cyclodextrin aqueous solution;

[0235] Preparation method: Weigh out an appropriate amount of Compound II, add a certain amount of DMSO, then slowly add the corresponding amount of 20% hydroxypropyl-β-cyclodextrin, vortex and sonicate to obtain a clear solution, and filter the solution through a 0.22 μM filter membrane.

[0236] 4.Group design: Groups were divided into intravenous injection and transdermal application groups. Two animals were shared between the two groups, and were reused after each elution cycle. Bama minipigs were randomized by sex based on their body weight using the PRISTIMA 7.2.0 data system.

[0237] 5.Dose design: In this experiment, the intravenous injection group received a dose of 0.2 mg / kg (concentration 0.1 mg / mL), while the transdermal application group received the ointment concentration prepared in Example 24. Dose 0.6 mg / cm 2 (based on active ingredient) and the application area was approximately 5% of the body surface area of ​​the Bama minipig, at 0.03 g / cm 2 First, Compound II was administered intravenously to Bama minipigs, and after 7 days of dissolution, the ointment prepared in Example 24 was applied transdermally.

[0238] 6. Administration: 6.1 Intravenous injection group Ear vein injection, single dose (each animal's dose was adjusted based on their most recent body weight).

[0239] 6.2 Transdermal application group A single dose was applied transdermally to the skin of the back.

[0240] Preparation before administration: Before administration, the backs of the minipigs were depilated using an electric razor to prepare the skin. The skin preparation area was more than 5% of the body surface area of ​​each minipigs and marked with a marker pen before administration, during which care was taken to observe the skin condition before administration to avoid damage or redness.

[0241] Formula to calculate body surface area: Body surface area (cm 2 ) = 9.0 x weight (g) 2 / 3 ;

[0242] Administration: The required amount of test substance (Example 24) was accurately weighed and applied evenly to the prepared skin area on the back of the miniature pig. The dose and area for each animal was calculated based on the most recent body weight. The total amount of ointment administered was equal to the administered area multiplied by the dose (calculated as ointment).

[0243] 7. Sample Collection and Processing 7.1 Collection time Sampling times for the intravenous injection group were: 5 minutes (±1 minute), 15 minutes (±1 minute), 30 minutes (±1 minute), 1 hour (±2 minutes), 2 hours (±2 minutes), 4 hours (±5 minutes), 6 hours (±5 minutes), 8 hours (±5 minutes), 12 hours (±10 minutes), 24 hours (±10 minutes), and 48 hours (±10 minutes) before and after administration.

[0244] Sampling times for the transdermal application group were 10 minutes (±1 minute), 30 minutes (±1 minute), 1 hour (±2 minutes), 2 hours (±2 minutes), 4 hours (±5 minutes), 6 hours (±5 minutes), 8 hours (±5 minutes), 12 hours (±10 minutes), 24 hours (±10 minutes), 36 hours (±10 minutes), and 48 hours (±10 minutes) before and after administration.

[0245] 7.2 Sampling methods and processing of blood samples The jugular veins of all surviving Bama minipigs in each group were sampled with a sampling volume of approximately 1.0 mL, using the anticoagulant EDTA-K2.

[0246] Whole blood samples were placed in an icebox and maintained at 2-8°C prior to centrifugation at 1800g for 10 minutes. Plasma was separated and stored below -66°C.

[0247] 8.Results Plasma drug concentrations of Compound II in male and female Bama minipigs after intravenous and transdermal administration are shown in Tables 22 and 23, plasma pharmacokinetic parameters are shown in Tables 24 and 25, and plasma drug concentration curves are shown in Figures 10 and 11.

[0248] The elimination half-life (T) of Compound II was measured after a single intravenous dose of 0.2 mg / kg of Compound II in both male and female Bama minipigs. 1 / 2 ), and the area under the time plasma concentration curve from 0 to the last quantifiable time point (AUC 0-last ) were 4.71 h and 225 h·ng / mL, respectively.

[0249] After a single transdermal application of the ointment prepared in Example 24, the mean peak time (T max ), peak concentration (C max ) and AUC 0-last The values ​​were 12 h, 2.86 ng / mL, and 70 h·ng / mL, respectively.

[0250] After a single dermal application of the ointment prepared in Example 24 to male and female Bama minipigs, the bioavailability of Compound II was 0.60%.

[0251] 9. Conclusion The ointment prepared in Example 24 is barely absorbed into the bloodstream after transdermal administration, and its bioavailability is very low. This ointment effectively reduces the risk of systemic immunosuppression caused by Compound II and increases the local skin concentration of Compound II, thereby achieving the goals of reduced toxicity and improved efficacy.

[0252] [Table 22]

[0253] [Table 23]

[0254] [Table 24]

[0255] [Table 25]

[0256] Note: "-" indicates a fit with uncalculated λ, Rseq (adjusted) < 0.7, in which case the relevant parameters were not calculated.

Claims

1. A topical external preparation containing a JAK inhibitor, characterized by comprising a JAK inhibitor, a matrix and an additive, wherein the JAK inhibitor is a compound represented by formula (I): 【Chemistry 1】 (In the formula, E 1 and E 2 are a single bond and —CH 2 - or - (CH 2 ) 2 - independently selected from the group consisting of L 1 is a single bond, -(CH 2 ) g -, -C(=O)- or -C(=O)-(CH 2 ) h - is selected from, m is 1 or 2; n is 1 or 2; g is 1, 2 or 3; h is 1, 2 or 3; R 1 are H, CN, C 1 ~ 6 alkyl or 3- to 6-membered cycloalkyl; 1 ~ 6 Alkyl and 3- to 6-membered cycloalkyl are substituted with one, two, or three R a and optionally replaced by R 2 is H, F, Cl, Br, I or C 1 ~ 3 alkyl, C 1 ~ 3 Alkyl is one, two or three R b and optionally replaced by R 3 , R 4 and R 5 are H, F, Cl, Br, I or C, respectively. 1 ~ 3 alkyl; 1 ~ 3 Alkyl is one, two or three R c and optionally replaced by R 6 , R 7 and R 8 are H, F, Cl, Br, I or C, respectively. 1 ~ 3 alkyl; 1 ~ 3 Alkyl is one, two or three R d and optionally replaced by R a are each H, F, Cl, Br, I, CN or C 1 ~ 3 alkyl; 1 ~ 3 alkyl is optionally substituted by one, two or three R; R b are each independently selected from F, Cl, Br, or I; R c are each independently selected from F, Cl, Br, or I; R d are each independently selected from F, Cl, Br, or I; Each R is independently selected from F, Cl, Br, or I. a compound of the formula (I), an isomer thereof, a pharmaceutically acceptable salt thereof, or a crystalline form thereof, the content of the JAK inhibitor is 0.01% to 10% of the total weight of the topical external preparation; the matrix is ​​selected from an oil-soluble matrix, a water-soluble matrix, or a combination of two or more thereof; the oil-soluble matrix is ​​selected from white petrolatum, white wax, liquid paraffin, paraffin, sazol paraffin, microcrystalline paraffin, octadecanol, stearic acid, or a combination of two or more thereof; the water-soluble matrix is ​​selected from polyethylene glycol 3350 (PEG3350), polyethylene glycol 400 (PEG400), or a combination thereof; A topical external preparation, wherein the additive is selected from diethylene glycol monoethyl ether, polyglycerol fatty acid ester, monoglyceryl linoleate, glyceryl behenate, glyceryl monostearate, or a combination of two or more thereof.

2. 2. The topical external preparation according to claim 1, wherein the oil-soluble matrix is ​​selected from white petrolatum, white wax, liquid paraffin, octadecanol, stearic acid or a combination of two or more thereof.

3. In the compounds of formula (I), their isomers or pharmaceutically acceptable salts thereof, R a 10. The topical external formulation of claim 1, wherein each of is independently selected from H, F, Cl, Br, I, or CN.

4. In the compounds of formula (I), their isomers or pharmaceutically acceptable salts thereof, R 1 But H, CN, C 1 ~ 3 alkyl or 3- to 5-membered cycloalkyl; 1 ~ 3 3. The topical external preparation according to claim 1 or 2, characterized in that the alkyl and 3- to 5-membered cycloalkyl are optionally substituted by one, two or three Ra.

5. In the compounds of formula (I), their isomers or pharmaceutically acceptable salts thereof, R 1 But H, CN, CH 3 , 【Chemistry 2】 is selected from 3 , 【Transformation 3】 5. The topical external preparation according to claim 4, characterized in that is optionally substituted by one, two or three Ra.

6. In the compounds of formula (I), their isomers or pharmaceutically acceptable salts thereof, R 1 But H, CN, CF 3 , CHF 2 , 【Chemistry 4】 6. The topical external preparation according to claim 5, characterized in that it is selected from:

7. In the compounds of formula (I), their isomers or pharmaceutically acceptable salts thereof, R 2 2. The topical external preparation according to claim 1, characterized in that is selected from H, F, Cl, Br or I.

8. In the compounds of formula (I), their isomers or pharmaceutically acceptable salts thereof, R 3 , R 4 and R 5 2. The topical external preparation of claim 1, wherein is independently selected from H, F, Cl, Br or I.

9. In the compounds of formula (I), their isomers or pharmaceutically acceptable salts thereof, R 6 , R 7 and R 8 2. The topical external preparation of claim 1, wherein is independently selected from H, F, Cl, Br or I.

10. In the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, L 1 is a single bond, -CH 2 -, -(CH 2 ) 2 -, -C(=O)- or -C(=O)-(CH 2 2. The topical external preparation according to claim 1, characterized in that it is selected from the group consisting of:

11. In the compounds of formula (I), their isomers or pharmaceutically acceptable salts thereof, the structural unit 【Transformation 5】 but, 【Transformation 6】 2. The topical external preparation according to claim 1, characterized in that it is selected from:

12. In the compounds of formula (I), their isomers or pharmaceutically acceptable salts thereof, the structural unit 【Transformation 7】 but, 【Transformation 8】 2. The topical external preparation according to claim 1, characterized in that it is selected from:

13. In the compounds of formula (I), their isomers or pharmaceutically acceptable salts thereof, the structural unit 【Chemistry 9】 but, 【Chemistry 10】 2. The topical external preparation according to claim 1, characterized in that it is selected from:

14. The compound of formula (I), its isomer or a pharmaceutically acceptable salt thereof, 【Chemistry 11】 (In the formula, L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 2. The topical external preparation according to claim 1, characterized in that it is selected from the following:

15. The compound of formula (I), its isomer or a pharmaceutically acceptable salt thereof, 【Chemistry 12】 (In the formula, L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are defined as in claim 1) 15. The topical external preparation according to claim 14, characterized in that it is selected from:

16. The JAK inhibitor is the following compound, an isomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 13】 A topical external preparation containing a JAK inhibitor, comprising:

17. The compound of formula (I), its isomer or a pharmaceutically acceptable salt thereof, 【Chemistry 14】 15. The topical external preparation according to claim 14, characterized in that it is selected from:

18. The composition is characterized by comprising a JAK inhibitor, one or more matrices, and one or more additives, wherein the JAK inhibitor is a compound of structural formula (II), structural formula (III), structural formula (IV), structural formula (V), or structural formula (VI), and an isomer thereof or a pharmaceutically acceptable salt thereof, or a crystalline form thereof: 【Chemistry 15】 2. The topical external preparation of claim 1, wherein

19. 19. The topical formulation according to claim 18, wherein the content of the JAK inhibitor is 0.02% to 9% by weight of the total weight of the topical formulation.

20. The topical formulation according to claim 19, wherein the content of the JAK inhibitor is 0.03 to 8% of the total weight of the topical formulation.

21. The topical formulation according to claim 20, wherein the content of the JAK inhibitor is 0.04 to 7% of the total weight of the topical formulation.

22. The topical formulation of claim 21, wherein the JAK inhibitor content is 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.25%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.25%, 2.5%, 2.8%, 3%, 3.2%, 3.5%, 3.6%, 3.8%, 4%, 4.5%, 5%, 5.5%, 6% or 6.5% of the total weight of the topical formulation.

23. 19. The topical formulation according to claim 18, characterized in that the one or more matrices are selected from oil-soluble matrices.

24. 24. The topical external preparation according to claim 23, characterized in that the oil-soluble matrix is ​​selected from white petrolatum, white wax, liquid paraffin, paraffin, sazol paraffin, microcrystalline paraffin, octadecanol, stearic acid or a combination of two or more thereof.

25. The content of white petrolatum is 45 to 96% of the total weight of the topical preparation, The content of white wax is 0.5 to 10% of the total weight of the external preparation; The content of liquid paraffin is 0.2 to 50% of the total weight of the topical preparation, The content of paraffin is 1 to 8% of the total weight of the topical preparation, The content of Sasol paraffin is 1 to 10% of the total weight of the topical preparation, The content of microcrystalline paraffin is 2 to 50% of the total weight of the topical preparation, The content of octadecanol is 1 to 10% of the total weight of the topical preparation; or 25. The topical external preparation according to claim 24, wherein the content of stearic acid is 1-10% of the total weight of the external preparation.

26. The content of white petrolatum is 50 to 95% of the total weight of the topical preparation, The content of white wax is 1 to 9% of the total weight of the topical preparation; The content of liquid paraffin is 1 to 40% of the total weight of the topical preparation, The content of paraffin is 2 to 7% of the total weight of the topical preparation, The content of Sasol paraffin is 1.5 to 9% of the total weight of the topical preparation, The content of microcrystalline paraffin is 4 to 45% of the total weight of the topical preparation; The content of octadecanol is 2 to 9% of the total weight of the topical preparation; or 26. The topical external preparation according to claim 25, characterized in that the content of stearic acid is 1.5-9% of the total weight of the external preparation.

27. ​​The content of white petrolatum is 53 to 94% of the total weight of the topical preparation, The content of white wax is 2 to 8% of the total weight of the topical preparation; The content of liquid paraffin is 1.5 to 30% of the total weight of the topical preparation, The content of paraffin is 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, or 6.5% of the total weight of the topical formulation; The content of Sasol paraffin is 2 to 8% of the total weight of the topical preparation, The content of microcrystalline paraffin is 5 to 40% of the total weight of the topical preparation, The content of octadecanol is 3 to 8% of the total weight of the topical preparation; or 27. The topical external preparation according to claim 26, wherein the content of stearic acid is 2-8% of the total weight of the external preparation.

28. The content of white petrolatum is 55 to 93% of the total weight of the topical preparation, The content of white wax is 3 to 6% of the total weight of the external preparation; The content of liquid paraffin is 2 to 20% of the total weight of the topical preparation, The content of Sasol paraffin is 2.5 to 7% of the total weight of the topical preparation, The content of microcrystalline paraffin is 7 to 35% of the total weight of the topical preparation, The content of octadecanol is 4 to 7% of the total weight of the topical preparation; or 28. The topical external preparation according to claim 27, characterized in that the content of stearic acid is 2.5-7% of the total weight of the external preparation.

29. The content of white petrolatum is 56 to 92% of the total weight of the topical preparation, The content of white wax is 4-5% of the total weight of the external preparation; The content of liquid paraffin is 2.5 to 15% of the total weight of the topical preparation, The content of Sasol paraffin is 3 to 6% of the total weight of the topical preparation, The content of microcrystalline paraffin is 9 to 30% of the total weight of the topical preparation, The octadecanol content is 4.5%, 5%, 5.5%, 6%, or 6.5% of the total weight of the topical formulation; or 29. The topical external preparation according to claim 28, wherein the content of stearic acid is 3-6% of the total weight of the external preparation.

30. The content of white petrolatum is 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 80.5%, 81%, 81.5%, 82%, 82.5%, 83%, 83.5%, 84%, 84.5%, or 85% of the total weight of the topical preparation. , 85.5%, 86%, 86.5%, 87%, 87.5%, 88%, 88.5%, 89%, 89.5%, 90%, 90.25%, 90.3%, 90.35%, 90.4%, 90.45%, 90.46%, 90.48%, 90.5%, 90.6%, 90.7%, 90.8%, 90.85%, 90.9%, 91%, 91.25%, 91.45%, or 91.5%; the white wax content is 4.01%, 4.02%, 4.04%, 4.06%, 4.08%, 4.1%, 4.12%, 4.14%, 4.14%, 4.16%, 4.18%, 4.2%, 4.22%, 4.24%, 4.26%, 4.28%, 4.3%, 4.32%, 4.34%, 4.36%, 4.38%, 4.4%, 4.45%, 4.5%, 4.55%, 4.6%, 4.65%, 4.7%, 4.75%, 4.8%, 4.85%, 4.9%, or 4.95% of the total weight of the topical preparation; the content of liquid paraffin is 3%, 3.5%, 4%, 4.05%, 4.1%, 4.15%, 4.2%, 4.25%, 4.3%, 4.35%, 4.4%, 4.45%, 4.5%, 5%, 5.02%, 5.04%, 5.05%, 5.1%, 5.15%, 5.2%, 5.25%, 5.3%, 5.35%, 5.4%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, or 14.5% of the total weight of the topical preparation; The content of Sasol paraffin is 3.5%, 4%, 4.5%, 5%, or 5.5% of the total weight of the topical preparation; The content of microcrystalline paraffin is 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, and 18.5% of the total weight of the topical preparation. 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 28% or 29%, or 27. The topical external preparation according to claim 26, characterized in that the content of stearic acid is 3.5%, 4%, 4.5%, 5%, or 5.5% of the total weight of the external preparation.

31. 19. The topical formulation according to claim 18, characterized in that the one or more matrices are selected from the water-soluble matrices PEG 400, PEG 3350 or combinations thereof.

32. The topical formulation according to claim 31, wherein the content of PEG 400 is 60% to 90% of the total weight of the topical formulation.

33. The topical formulation according to claim 31, wherein the content of PEG 3350 is 10% to 40% of the total weight of the topical formulation.

34. The topical formulation according to claim 31, characterized in that the content ratio of PEG400 to PEG3350 is 1:8 to 1:

1.

35. The topical formulation according to claim 32, wherein the content of PEG 400 is 65% to 85% of the total weight of the topical formulation.

36. The topical formulation according to claim 33, wherein the content of PEG 3350 is 15% to 30% of the total weight of the topical formulation.

37. The topical formulation according to claim 34, characterized in that the content ratio of PEG400 to PEG3350 is 1:6 to 1:

2.

38. The topical formulation of claim 35, wherein the PEG 400 content is 66%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 78.4%, 78.5%, 79%, 80%, 82%, or 84% of the total weight of the topical formulation.

39. The topical formulation of claim 36, wherein the PEG 3350 content is 16%, 17%, 18%, 18.5%, 19%, 19.5%, 19.6%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, or 28% of the total weight of the topical formulation.

40. The topical formulation described in claim 37, characterized in that the content ratio of PEG400 to PEG3350 is 1:5 to 1:

3.

41. The topical formulation described in claim 40, characterized in that the content ratio of PEG400 to PEG3350 is 1:

4.

42. 19. The topical formulation according to claim 18, wherein the additive comprises diethylene glycol monoethyl ether, polyglycerol fatty acid ester, monoglyceryl linoleate, glyceryl behenate, glyceryl monostearate, or a combination of two or more thereof.

43. The content of diethylene glycol monoethyl ether is 1% to 10% of the total weight of the topical preparation, The content of polyglycerol fatty acid ester is 1% to 10% of the total weight of the topical preparation; The content of monoglyceryl linoleate is 1% to 10% of the total weight of the topical preparation; The content of glyceryl behenate is 1% to 10% of the total weight of the topical preparation, or The external preparation according to claim 42, wherein the content of glyceryl monostearate is 1% to 10% of the total weight of the external preparation.

44. The content of diethylene glycol monoethyl ether is 1.5% to 9% of the total weight of the topical preparation, The content of polyglycerol fatty acid ester is 1.5% to 9% of the total weight of the topical preparation; The content of monoglyceryl linoleate is 1.5% to 9% of the total weight of the topical preparation; The content of glyceryl behenate is 2% to 9% of the total weight of the topical preparation, or The external preparation according to claim 43, characterized in that the content of glyceryl monostearate is 2% to 9% of the total weight of the external preparation.

45. The content of diethylene glycol monoethyl ether is 2% to 8% of the total weight of the topical preparation, The content of polyglycerol fatty acid ester is 2% to 8% of the total weight of the topical preparation; The content of monoglyceryl linoleate is 2% to 8% of the total weight of the topical preparation; The content of glyceryl behenate is 3% to 8% of the total weight of the topical preparation, or The external preparation according to claim 44, characterized in that the content of glyceryl monostearate is 3% to 8% of the total weight of the external preparation.

46. The content of diethylene glycol monoethyl ether is 2.5% to 7% of the total weight of the topical preparation, The content of polyglycerol fatty acid ester is 2.5% to 7% of the total weight of the topical preparation; The content of monoglyceryl linoleate is 2.5% to 7% of the total weight of the topical preparation; The content of glyceryl behenate is 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, or 6.5% of the total weight of the topical formulation; or 46. ​​The topical formulation according to claim 45, characterized in that the content of glyceryl monostearate is 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7% or 7.5% of the total weight of the topical formulation.

47. The content of diethylene glycol monoethyl ether is 3% to 6% of the total weight of the topical preparation, The content of polyglycerol fatty acid ester is 3% to 6% of the total weight of the topical preparation, or The topical preparation according to claim 46, characterized in that the content of monoglyceryl linoleate is 3% to 6% of the total weight of the topical preparation.

48. The content of diethylene glycol monoethyl ether is 3.5%, 4%, 4.5%, 5%, or 5.5% of the total weight of the topical preparation, The content of polyglycerol fatty acid ester is 3.5%, 4%, 4.5%, 5% or 5.5% of the total weight of the topical preparation; or 48. The topical preparation according to claim 47, characterized in that the content of monoglyceryl linoleate is 3.5%, 4%, 4.5%, 5% or 5.5% of the total weight of the topical preparation.

49. 10. A method for producing the topical external preparation of claim 1, selected from a grinding method or a melting method.

50. A method for producing the topical external preparation of claim 49, which is a melting method.

51. 2. The topical formulation according to claim 1, which is an ointment, cream, paste, gel, film, paste or patch.

52. 10. Use of the topical external preparation of claim 1 in the manufacture of a medicament for treating a skin disorder.

53. Use as described in claim 52 in the manufacture of a drug for treating psoriasis, atopic dermatitis, vitiligo, lupus erythematosus, alopecia areata, eczema, contact dermatitis, hives, dyshidrotic eczema, dermatomyositis, scleroderma, acne or seborrheic dermatitis.

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