Use of nitrogen‑containing heterocyclic derivative in preparation of drug for treating skin diseases

Abstract

The present invention relates to the technical field of medicine, and relates to a use of a nitrogen-containing heterocyclic derivative in the preparation of a drug for treating skin diseases. Specifically, disclosed in the present invention are a compound represented by formula (I), a stereoisomer, tautomer, polymorph, solvate, or pharmaceutically acceptable salt thereof, and a use of a pharmaceutical composition comprising same as an active ingredient in the preparation of a drug for preventing, alleviating and / or treating skin diseases. The compound represented by formula (I) in the present invention exhibits a significant therapeutic effect and has a good application prospect.

Description

Uses of nitrogen-containing heterocyclic derivatives in the preparation of drugs for treating skin diseases Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to the use of a nitrogen-containing heterocyclic derivative, its stereoisomers, tautomers, crystal forms, solvates or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the prevention, improvement and / or treatment of skin-related diseases. Background Technology

[0002] Acne is a common chronic inflammatory skin disease that predominantly affects adolescents. It has a high incidence rate and recurs frequently, impacting over 85% of adolescents and persisting into adulthood, making it the eighth leading cause of chronic disease worldwide. Acne commonly occurs on the face, neck, chest, and back—areas with a high density of sebaceous glands. Skin lesions include non-inflammatory lesions (open and closed comedones) and inflammatory lesions (papules, pustules, nodules, and cysts). After the inflammatory lesions subside, they often leave behind pigmentation, persistent erythema, and atrophic or hypertrophic scars, making it difficult to cure. This severely affects the patient's appearance, causing significant psychological stress and financial burden, easily leading to low self-esteem, anxiety, depression, and even social difficulties.

[0003] The pathogenesis of acne is complex, involving four main factors: excessive and imbalanced sebum secretion, excessive keratinization of sebaceous follicles, microbial colonization (especially Propionibacterium acnes), and inflammatory response. Inflammation plays a crucial role throughout the pathogenesis, development, and resolution of acne. Most anti-acne medications have anti-inflammatory effects, and Propionibacterium acnes is a key factor in inducing inflammatory responses in acne. Propionibacterium acnes triggers TLR-2 and TLR-4 on sebaceous gland cells and keratinocytes, thereby inducing the release of pro-inflammatory cytokines such as IL-6, IL-8, and IL-12 from monocytes, thus activating the Th1 response. Propionibacterium acnes also induces CD4+... + T cells simultaneously secrete IL-17 and IFN-γ to promote Th17 and Th17 / Th1 combined responses. The Th17 pathway has been shown to play a central role in acne inflammation. Furthermore, *Propionibacterium acnes* activates AP1 and NF-κB, leading to the production of MMPs, TNFα, IL-1β, and IL-8. These factors contribute to the formation of a complex inflammatory pathway network, exacerbating the severity of acne. Multiple studies have shown significantly elevated levels of IL-17, IL-23, and TNFα in acne lesions.

[0004] The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway regulates intracellular signal transduction of a range of pro-inflammatory cytokines, including interleukins (ILs) and interferons (IFNs), and is involved in the development of various inflammatory and autoimmune diseases. The JAK family includes JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2). TYK2 primarily mediates the signal transduction of pro-inflammatory cytokines such as IFN-α / β, IL-12, IL-23, IL-10, IL-22, IL-6, and IL-13 in the JAK-STAT pathway. For example, IL-12 promotes Th1 cell differentiation, inducing the production of IFNγ and TNFα; IL-23 promotes Th17 cell proliferation, differentiation, and maturation, inducing the production of IL-17. TYK2 is highly involved in immune and inflammatory processes by positively regulating the IL-12 / Th1 and IL-23 / Th17 axes.

[0005] WO2022233286A1 discloses a class of nitrogen-containing heterocyclic pyridine derivatives with significant TYK2 inhibitory activity, which can be developed for the treatment of autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, neurodermatitis, psoriasis, psoriatic arthritis, and Sjögren's syndrome. However, the therapeutic use of this class of compounds for acne has not yet been disclosed. This invention is the first to discover that this class of compounds exhibits significant anti-acne activity and has very good prospects for clinical application. Summary of the Invention

[0006] This invention provides the use of a TYK2 inhibitor in the preparation of products for the prevention, improvement, and / or treatment of acne. The TYK2 inhibitor provided by this invention has a significant and effective anti-acne effect in animal models of acne and has important application prospects.

[0007] This invention provides the use of a TYK2 inhibitor in the preparation of a medicament or cosmetic for the prevention, improvement and / or treatment of acne.

[0008] In some embodiments of the uses described in this invention, the TYK2 inhibitor is selected from compounds of formula (A), their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof.

[0009] L represents alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino;

[0010] Ring B is aryl, heteroaryl, or heterocyclic, and ring B is preferably derived from the following groups:

[0011] Among them, T, G, Y, Z, and M are each independently selected from oxygen atoms, and CRA1 CR A2 nitrogen atom or NR B ;

[0012] E can be a nitrogen atom or a carbon atom;

[0013] R A1 R A2 Selected from hydrogen, deuterium, and C 1-6 Alkyl, halogen, and the following structures:

[0014] R B Selected from hydrogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkyl-C(O)-, C 1-6 Haloalkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, substituted amino-C(O)-, C 1-6 Alkyl-S(O)2-, alkenyl, deuterated alkenyl, ynyl, deuterated ynyl, and the following structures:

[0015] Q represents a chemical bond or -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -C(NR)2-. 8 )-, that is:

[0016] P can be an oxygen atom or a sulfur atom;

[0017] X represents a chemical bond, an oxygen atom, or NH or NR. A ;

[0018] R A It is an alkyl group, a deuterated alkyl group, or a haloalkyl group;

[0019] U can be a nitrogen atom or a carbon atom;

[0020] Ring A is aryl, heteroaryl, or heterocyclic, and ring A is preferably derived from the following groups:

[0021] C is an alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, or heterocyclic group, preferably from the following groups:

[0022] Among them, R 1 R 2 R 3 R 4 R 5 R 7 R 8Each is independently selected from hydrogen, deuterium, halogen, amino, alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkenyl carbonyl, deuterated alkenyl carbonyl, alkyl, deuterated alkyl, alkyl carbonyl, deuterated alkyl carbonyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl are arbitrarily substituted by halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl;

[0023] n = 1, 2, 3, 4, 5, 6.

[0024] In some embodiments of the uses described in this invention, the TYK2 inhibitor is selected from compounds of formula (A-1), their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof.

[0025] Among them, ring B is aryl, heteroaryl, or heterocyclic;

[0026] X1, E is a nitrogen atom or a carbon atom;

[0027] L represents alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino;

[0028] R 10 It can be hydrogen, deuterium, alkyl, deuterated alkyl, or halogen;

[0029] E1 can be hydrogen, deuterium, alkyl, or deuterated alkyl.

[0030] Q represents a chemical bond or -C(O)-, -C(S)-, -S(O)-, -S(O)2-, that is:

[0031] C is an alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, or heterocyclic group, preferably selected from the following groups:

[0032] Among them, R 1 R 2 R 3 R 4 R 5 R 7 Each is independently selected from hydrogen, deuterium, halogen, amino, alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl are arbitrarily substituted by halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl;

[0033] R 9Selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -(CH2). n1 R aa ,-(CH2) n1 OR aa -SR aa ,-(CH2) n1 C(O)R aa -(CD2) n1 R aa -(CD2) n1 OR aa -SR aa -(CD2) n1 C(O)R aa -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa ,-(CH2) n1 S(O) m1 R aa -(CD2) n1 S(O) m1 R aa -NR aa R bb , -C(O)NR aa R bb -NR aa C(O)R bb -NR aa S(O) m1 R bb ;

[0034] R aa R bb Each is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally further substituted by one or more substituents selected from hydrogen, deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

[0035] n = 1, 2, 3, 4;

[0036] n1 = 0, 1, 2, 3, 4;

[0037] m1 = 0, 1, 2, 3, 4.

[0038] In some embodiments of the uses described in this invention, the TYK2 inhibitor is selected from compounds of formula (II-1B), their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof.

[0039] Among them, ring B is aryl, heteroaryl, or heterocyclic;

[0040] X1, E is a nitrogen atom or a carbon atom;

[0041] L represents alkyl, deuterated alkyl, haloalkyl, amino, alkylamino, deuterated alkylamino, cycloalkyl, cycloalkylamino, deuterated cycloalkylamino;

[0042] R 10 It can be hydrogen, deuterium, alkyl, deuterated alkyl, or halogen;

[0043] E1 can be hydrogen, deuterium, alkyl, or deuterated alkyl.

[0044] C is an alkyl, cycloalkyl, amino, substituted amino, aryl, heteroaryl, or heterocyclic group, preferably selected from the following groups:

[0045] Among them, R 1 R 2 R 3 R 4 R 5 R 7 Each is independently selected from hydrogen, deuterium, halogen, amino, alkynyl, deuterated alkynyl, alkenyl, deuterated alkenyl, alkyl, deuterated alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl are arbitrarily substituted by halogen, alkyl, hydroxyl, amino, cycloalkyl, aryl, heteroaryl;

[0046] R 9a R 9b R 9c Each is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, cycloalkyl, deuterated cycloalkyl, alkynyl, deuterated alkynyl, or R. 9a and R 9b Together with the attached carbon atom, it forms a cycloalkyl group;

[0047] n = 1, 2, 3.

[0048] In some embodiments of the uses described in this invention, the TYK2 inhibitor is selected from compounds of formula (I), their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof.

[0049] Wherein, L is selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, deuterated C 1-6 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkylamino or deuterated C 3-6 Cycloalkylamino;

[0050] R 10 R 11 R D1 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl or halogen;

[0051] E1 is selected from hydrogen, deuterium, and C. 1-6 Alkyl or deuterated C 1-6 alkyl;

[0052] Q is selected from chemical bonds or carbonyl groups;

[0053] C is selected from the following groups:

[0054] Among them, R 1 R 2 R 3 R 4 R 5 R 7 Each is independently selected from hydrogen, deuterium, halogen, amino, C 2-6 alkynyl group, deuterated C 2-6 alkynyl group, C 2-6 Alkenyl, deuterated C 2-6 alkenyl, C 1-6 Alkyl or deuterated C 1-6 Alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl, optionally halogenated, C 1-6 Alkyl, hydroxyl, amino, C 3-6 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl substitutions;

[0055] R 9a R 9b R 9c Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3- 6-cycloalkyl, deuterated C 3-6 cycloalkyl, C 2-6 alkynyl group, deuterated C 2-6 alkynyl group, or R 9a and R 9b Together with the attached carbon atom, they form C 3-6 cycloalkyl;

[0056] n = 1, 2, 3.

[0057] In some embodiments of the uses described in this invention, the TYK2 inhibitor is selected from compounds of formula (II), their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof.

[0058] Among them, R 12 For deuterium, hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, deuterated C 1-6 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkylamino or deuterated C 3-6 Cycloalkylamino;

[0059] R 10 R 11 R D1 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl or halogen;

[0060] E1 is hydrogen, deuterium, and C. 1-6 Alkyl or deuterated C 1-6 alkyl;

[0061] Q represents a chemical bond or a carbonyl group;

[0062] C is selected from the following groups:

[0063] Among them, R 1 R 2 R 3 R 4 R 5 R 7 Each is independently selected from hydrogen, deuterium, halogen, amino, C 2-6 alkynyl group, deuterated C 2-6 alkynyl group, C 2-6 Alkenyl, deuterated C 2-6 alkenyl, C1-6 Alkyl, deuterated C 1-6 Alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl, optionally halogenated, C 1-6 Alkyl, hydroxyl, amino, C 3-6 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl substitutions;

[0064] R 9a R 9b R 9c Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3- 6-cycloalkyl, deuterated C 3-6 cycloalkyl, C 2-6 alkynyl group, deuterated C 2-6 alkynyl group, or R 9a and R 9b Together with the attached carbon atom, they form C 3-6 cycloalkyl;

[0065] n = 1, 2, 3.

[0066] In some embodiments of the uses described in this invention, the TYK2 inhibitor is selected from compounds of formula (III), their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof.

[0067] Among them, R 12 For deuterium, hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, deuterated C 1-6 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkylamino or deuterated C 3-6 Cycloalkylamino;

[0068] R 10 R 11 R D1 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl or halogen;

[0069] E1 is hydrogen, deuterium, and C. 1-6 Alkyl or deuterated C 1-6 alkyl;

[0070] Among them, R 1 R2 R 3 R 4 R 5 R 7 Each is independently selected from hydrogen, deuterium, halogen, amino, C 2-6 alkynyl group, deuterated C 2-6 alkynyl group, C 2-6 Alkenyl, deuterated C 2-6 alkenyl, C 1-6 Alkyl or deuterated C 1-6 Alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl, optionally halogenated, C 1-6 Alkyl, hydroxyl, amino, C 3-6 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl substitutions;

[0071] R 9a R 9b R 9c Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3- 6-cycloalkyl, deuterated C 3-6 cycloalkyl, C 2-6 alkynyl group, deuterated C 2-6 alkynyl group, or R 9a and R 9b Together with the attached carbon atom, they form C 3-6 cycloalkyl;

[0072] n1 = 1, 2, 3;

[0073] n2 = 1, 2, 3.

[0074] In some embodiments of the uses described in this invention, the TYK2 inhibitor is selected from the following compounds: their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof.

[0075] In some embodiments of the uses described in this invention, the TYK2 inhibitor is selected from the following compounds: their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof.

[0076] The aforementioned TYK2 inhibitor is a compound disclosed in patent WO2022233286A1, the full text of which is incorporated herein by reference.

[0077] In some embodiments of the uses described in this invention, the pharmaceutically acceptable salt is selected from propionate, methanesulfonate, acetate, citrate, D-tartrate, benzenesulfonate, phosphate, aspartate, L-tartrate, maleate, fumarate, benzoate, lactate, hydrochloride, formate, hydrobromide, sulfate, nitrate, phosphate, trifluoroacetate, succinate, mandelate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, citrate, glutamate, cinnamate, p-toluenesulfonate, benzenesulfonate, ethanesulfonate, or trifluoromethanesulfonate.

[0078] In some embodiments of the uses described in this invention, the medicament optionally further comprises at least one other anti-acne treatment agent.

[0079] Preferably, the other anti-acne treatment agents are selected from benzoyl peroxide, nicotinamide, salicylic acid, azelaic acid, retinoids, antibiotics, dapsone, or hormones, etc.

[0080] In some embodiments of the uses described in this invention, the dosage of the TYK2 inhibitor is 0.01-500 mg / kg, preferably 0.1-300 mg / kg.

[0081] In some embodiments of the uses described in this invention, the route of administration of the drug is selected from topical administration, oral administration, transdermal administration, injection administration, skin application, subcutaneous administration, nasal administration, inhalation administration, sublingual administration, or rectal administration.

[0082] Preferably, it can be administered topically, subcutaneously, transdermally, or orally.

[0083] In some embodiments of the uses described in this invention, the dosage form of the drug can be solid, liquid, or gaseous; including powders, tablets, granules, pills, hard capsules or soft capsules, creams, ointments, plasters, gels, pastes, powders, patches, plasters, solutions, suspensions, lotions, injections, syrups, liniments, emulsions, tinctures, elixirs, aerosols, or sprays. Preferably, the dosage form of the drug is selected from tablets, capsules, pills, granules, powders, oral liquids, injections, aerosols, sprays, nasal drops, gels, emulsions, ointments, creams, pastes, powders, patches, plasters, or lotions.

[0084] In some embodiments of the use described in this invention, the acne is selected from acne vulgaris, comedonal acne, papular acne, pustular acne, nodular acne, cystic acne, conglobate acne, acne fulminans, fungal acne, acne infected with Propionibacterium acnes, refractory acne, hormonal acne, or secondary acne. The acne selected from acne vulgaris is selected from facial acne vulgaris.

[0085] The present invention also provides a pharmaceutical or cosmetic composition for the prevention, improvement and / or treatment of acne, wherein the pharmaceutical or cosmetic composition contains the TYK2 inhibitor described herein, and one or more pharmaceutically or cosmetically acceptable carriers.

[0086] In some embodiments of the pharmaceutical or cosmetic compositions of the present invention, they are administered via a topical route, subcutaneous route, transdermal route, or oral route.

[0087] In some embodiments of the pharmaceutical or cosmetic compositions of the present invention, the topical or oral dosage form may be solid, liquid, or gaseous; including powders, tablets, granules, pills, hard capsules or soft capsules, creams, ointments, plasters, gels, pastes, powders, patches, plasters, solutions, suspensions, lotions, injections, syrups, liniments, emulsions, tinctures, elixirs, aerosols, or sprays.

[0088] The present invention also provides a topical formulation for the prevention, improvement and / or treatment of acne, wherein the topical formulation contains the TYK2 inhibitor described herein, and one or more pharmaceutically acceptable carriers.

[0089] In some embodiments of the topical formulation of the present invention, the content of the TYK2 inhibitor is 0.01%-20% of the total weight of the topical formulation, preferably 0.1%-10%, more preferably 0.3%-8%.

[0090] In some embodiments of the topical preparations described in this invention, the preparations include gels, emulsions, ointments, creams, pastes, patches, or plasters.

[0091] The present invention also provides a medicament for the prevention, improvement and / or treatment of acne, wherein the medicament contains the TYK2 inhibitor described herein, and one or more pharmaceutically acceptable carriers.

[0092] In some embodiments of the pharmaceutical or cosmetic composition or pharmaceutical or topical preparation of the present invention, the dosage of the TYK2 inhibitor is 0.01-500 mg, preferably 0.1-300 mg.

[0093] The present invention also provides a method for preventing, ameliorating, and / or treating acne, the method comprising administering to a patient in need thereof a TYK2 inhibitor according to the present invention, or a pharmaceutical or cosmetic composition thereof, or a drug thereof, or a topical preparation thereof.

[0094] In some embodiments of the use according to the present invention, the cosmetic is a skin care product.

[0095] In some embodiments of the use according to the present invention, the skin care products include facial cleanser, toner, lotion, emulsion, facial mask, cream, essence, essential oil, sunscreen, etc.

[0096] Detailed Description of the Invention:

[0097] All technical and scientific terms used in this specification and the claims have the meanings commonly understood by those of ordinary skill in the art.

[0098] The term "hydrogen" herein refers to -H.

[0099] The term "deuterium" herein refers to -D.

[0100] The term "hydroxyl" herein refers to -OH.

[0101] The term "halogen" in the text refers to -F, -Cl, -Br and -I.

[0102] The term "carbonyl" herein refers to C=O.

[0103] The term "chemical bond" means that the strong interaction existing between adjacent atoms or ions within a substance molecule or crystal is called a chemical bond, including ionic bonds, covalent bonds, and metallic bonds, etc. In the present invention, it especially refers to covalent bonds.

[0104] The term "amino" or "amine" herein may interchangeably refer to the -NR2 group, where each R is, for example, H or a substituent. In some embodiments, the amino group is further substituted to form an ammonium ion, for example, NR 3+ . The ammonium moiety is specifically included in the definition of "amino" or "amine". The substituent may be, for example, an alkyl group, a deuterated alkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an amide or a carboxylic acid ester. The R group may be further substituted by one or more (for example, 1 to 4) groups selected from the following: halogen, cyano, alkenyl, alkynyl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl, carboxylic acid ester, amine, and amide.

[0105] The term "alkyl" herein refers to a saturated aliphatic hydrocarbon group having multiple carbon atoms, preferably having 1 - 10 carbon atoms, more preferably having 1 - 6 carbon atoms, and the term includes straight-chain and branched-chain hydrocarbon groups. When a carbon atom number limit is present before the alkyl group, such as C1-6 Alkyl means having 1-6 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. Alkyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, oxo, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, heterocyclic, cycloalkenyl, heterocyclic alkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocyclic alkyloxy, aryloxy, heteroaryloxy, aryl or heteroaryl.

[0106] The term "deuterated alkyl" as used herein refers to an alkyl group obtained by substituting a "alkyl" group by deuterium. Non-limiting examples of deuterated alkyl groups include deuterated methyl, deuterated ethyl, etc.

[0107] The term “halogenated alkyl” in this document refers to an alkyl group obtained by substituting an alkyl group (as defined above) with a halogen, including fluorine, chlorine, bromine, iodine, etc.

[0108] The terms "alkylamino" or "deuterated alkylamino" as used herein refer to an amino or amine group obtained by substituting the aforementioned "amino" with the aforementioned "alkyl" or "deuterated alkyl". Non-limiting examples of alkylamino or deuterated alkylamino groups include -NH-CH3, -NH-CD3, -N(CH3)2, -N(CD3)2, etc.

[0109] The term "aryl" herein refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent core structure is an aryl ring. The aryl group described herein may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, sulfonyl, sulfinyl, cycloalkyl, heterocyclic, cycloalkenyl, alkenyl, alkynyl, heterocyclic, cycloalkoxy, aryl, and heteroaryl.

[0110] An alkynyl group is an unsaturated hydrocarbon group containing a carbon-carbon triple bond. The term "alkynyl" herein refers to an alkyl group containing a carbon-carbon triple bond in a molecule, wherein the alkyl group, as defined above, has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms. When the alkynyl group is preceded by a carbon number qualifier, such as C... 2-6The alkynyl group refers to a group containing 2-6 carbon atoms. The alkynyl group may optionally be substituted by one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, oxo, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, silyl, phosphono, deuterated alkyl, heterocyclic, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, etc.

[0111] The term "deuterated alkynyl" in this document refers to the alkynyl group obtained by substituting "alkynyl" as defined above with deuterium. Non-limiting examples of deuterated alkynyl groups include deuterated propynyl, deuterated propynyl, etc.

[0112] An alkenyl group is an unsaturated hydrocarbon group containing a carbon-carbon double bond. The term "alkenyl" herein refers to an alkyl group containing a carbon-carbon double bond in a molecule, wherein the alkyl group, as defined above, has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms. When the alkenyl group is preceded by a carbon atom number qualifier, such as C... 2-6 Alkenyl refers to an alkenyl group containing 2-6 carbon atoms. The alkenyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, oxo, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, silyl, phosphono, deuterated alkyl, heterocyclic, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl. Non-limiting examples of alkenyl groups include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc.

[0113] The term "deuterated alkenyl" in this document refers to the alkenyl group obtained by substituting a "alkenyl" group as defined above with deuterium. Non-limiting examples of deuterated alkenyl groups include deuterated vinyl groups, deuterated propenyl groups, etc.

[0114] The term "cycloalkyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms. It can include fused ring systems, spirocyclic systems, or bridged ring systems, and has 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms. It is saturated or unsaturated and can be linked to the rest of the molecule via a single bond through any suitable carbon atom. When the cycloalkyl group is preceded by a carbon number limitation, such as C... 3-6A cycloalkyl group is defined as having 3-6 carbon atoms. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl groups described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, oxo, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, heterocyclic, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkoxy, aryl, and heteroaryl.

[0115] The term "deuterated cycloalkyl" as used herein refers to the cycloalkyl obtained by substituting "cycloalkyl" as defined above with deuterium. Non-limiting examples of deuterated cycloalkyl include deuterated cyclopropyl, deuterated cyclobutyl, etc.

[0116] The terms “cycloalkylamino” or “deuterated cycloalkylamino” as used herein refer to the amino or amine group obtained by substituting the aforementioned “amino” with the aforementioned “cycloalkyl” or “deuterated cycloalkyl”.

[0117] The term "heteroaryl" herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S. The term may have a single ring (non-limiting examples include furan, thiophene, imidazole, triazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), wherein the fused ring may or may not be an aromatic group containing a heteroatom, assuming the connecting point is through an atom of the aromatic heteroaryl group. The heteroaryl group described herein may optionally be substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, amino, oxo, alkyl, alkoxy, acyl, acyloxy, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, alkenyl, alkynyl, heterocyclic, cycloalkoxy, aryl, and heteroaryl.

[0118] The term "heterocyclic group" refers to a substituted or unsubstituted aromatic ring or non-aromatic ring containing at least 1 to 5 heteroatoms selected from N, O, or S. The aromatic or non-aromatic ring can be a 3- to 10-membered monocyclic ring, a 4- to 20-membered spirocyclic ring, a fused ring, or a bridged ring. The selectively substituted N and S in the heterocyclic group can be oxidized to various oxidation states. Preferably, it is a 3- to 12-membered heterocyclic ring. Non-limiting embodiments include oxetane, oxetane, oxetane, oxetane, oxetane, oxetane, oxetane, octyl, azirne, azirne, azirne, azirnepentyl, azirnehexyl, azirnepropenyl, 1,3-dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dioxocyclopentyl, 1,3-dioxocyclohexyl, 1,3-dithiocyclohexyl, azirneheptenyl, morpholinyl, piperazine, pyridinyl, furanyl, thiophene, pyrroleyl, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazineyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, 1,4-dioxetanedienyl, etc.

[0119] The terms "optional" or "optionally" mean that the event or situation described below may, but is not necessarily, occur, and the description includes both the occurrence and non-occurrence of said event or situation. For example, "optionally halogen-substituted alkyl" means that the alkyl group may, but is not necessarily, be substituted with a halogen, including both cases where the alkyl group is substituted with a halogen and cases where the alkyl group is not substituted with a halogen.

[0120] The term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with the other components constituting the formulation and / or the mammals to which it is treated.

[0121] The term "stereoisomer" in this text refers to compounds with different chiralities having one or more stereocenters. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, blocked isomers, and so on.

[0122] The term "pharmaceutically acceptable salt" includes, but is not limited to, propionates, methanesulfonates, acetates, citrates, D-tartrates, benzenesulfonates, phosphates, aspartate, L-tartrates, maleates, fumarates, benzoates, lactates, hydrochlorides, formates, hydrobroms, sulfates, nitrates, phosphates, trifluoroacetates, succinates, mandelates, malonates, malates, 2-hydroxypropionates, oxalates, glycolate, salicylates, citrates, glutamates, cinnamates, p-toluenesulfonates, benzenesulfonates, ethanesulfonates, or trifluoromethanesulfonates.

[0123] The terms “prevention,” “treatment,” or “improvement” of disease include: (1) preventing disease, which means causing the absence of clinical symptoms or signs of disease in humans or mammals who are exposed to or susceptible to the disease but have not yet experienced or exhibited symptoms or signs of disease; (2) suppressing disease, which means stopping or reducing the occurrence of disease or its clinical symptoms or signs; or (3) alleviating disease, which means causing the disappearance of disease or its clinical symptoms or signs.

[0124] The term "effective amount" or "effective therapeutic amount" refers to an amount sufficient to provide therapeutic benefit or delay or minimize one or more symptoms associated with a disease or condition in the treatment or control of that disease or condition. For compound therapies, the "effective amount" refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment or control of a disease or condition.

[0125] The term "acne" as used in this invention includes, but is not limited to, acne vulgaris, comedonal or polymorphic acne, papular acne, pustular acne, nodular acne, cystic acne, fungal acne, hormonal acne, premenstrual acne, acne caused by Propionibacterium acnes, neonatal acne, infantile acne, acne lesions (scratching acne), chloracne, congestive acne, rosacea, lesional acne, mechanical acne, senile acne, conglobate acne, fulminant acne, necrotic acne, atrophic acne, or secondary acne. Secondary acne includes, but is not limited to, photoacne, drug-induced acne, cosmetic acne, or occupational acne. Attached Figure Description

[0126] Figure 1 shows the inflammatory symptom scores of the auricle and cheek in a mouse acne model induced by croton oil.

[0127] Figure 2 shows the ear thickness of mice in a croton oil-induced mouse acne model.

[0128] Figure 3 shows the skin erythema scores of animals in each group treated with compound 7 in a DNFB-induced acne inflammation model.

[0129] Figure 4 shows the skin erythema scores of animals in each group treated with compound 11 in a DNFB-induced mouse acne inflammation model.

[0130] Figure 5 shows the TNF-α content in the skin tissue of animals in each group treated with compound 11 in a DNFB-induced mouse acne inflammation model. Detailed Implementation

[0131] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0132] Unless otherwise specified, the instruments and equipment involved in the following embodiments are all conventional instruments and equipment; unless otherwise specified, the reagents and raw materials involved are all from conventional commercial channels; unless otherwise specified, the detection, testing and methods involved are all conventional methods.

[0133] Synthesis Examples

[0134] Synthesis Example 1

[0135] Preparation of compound 7: 6-(cyclopropaneformamido)-4-((3-methoxy-4-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (refer to the preparation of compound 7 in WO2022233286A1).

[0136] Step 1

[0137] Add 3.0 g of 2-aminopyridine compound and 50 ml of N,N-dimethylformamide to the reaction flask, cool to 0°C, and add sodium hydride (1.5 g) in portions. After the addition is complete, stir for 20 min, then slowly raise the temperature to room temperature and stir for another 30 min. Cool the reaction solution to 0°C, and slowly add 40 ml of tetrahydrofuran solution of 3.9 g of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide, controlling the temperature to be below 5°C. Stir overnight after the addition is complete. Add 20 ml of ammonium chloride aqueous solution and 40 ml of water to the reaction solution, stir for 30 min, filter, wash the filter cake twice with water, and dry to obtain 3.95 g of grayish-white solid. 1 H NMR (400MHz, CDCl3): δ12.53(s,1H),9.39(s,1H),8.38(s,1H),8.34(s,1H),8.22(d,J=5.2Hz,1H),7.65(d ,J=5.2Hz,1H),5.62(s,2H),4.04(s,3H),3.74(t,J=8.2Hz,2H),0.98(t,J=8.2Hz,2H),0.02(s,9H).MS:m / z 494.2[M+H] + .

[0138] Step 2

[0139] The product from the previous step (2.4 g), DCPF (1.1 g), palladium acetate (111 mg), cesium carbonate (8 g), and DME (90 ml) were added sequentially to the reaction flask. After purging with nitrogen, the mixture was heated to 90 °C and reacted for 1 hour. The reaction solution was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 2.76 g of a pale yellow solid compound. MS: m / z 543.3 [M+H] + .

[0140] Step 3

[0141] Add the product from the previous step (2.7 g) and trifluoroacetic acid (60 ml) sequentially to the reaction flask, stir overnight at 70°C, concentrate under reduced pressure to dryness, add toluene (100 ml) and concentrate again to dryness. Add tetrahydrofuran (100 ml) to the concentrate, slowly add sodium bicarbonate at room temperature to adjust the pH to 7-8, filter under vacuum to remove solids, concentrate the filtrate and use it directly in the next step.

[0142] Step 4

[0143] Add N,N-dimethylformamide (50 ml) and bromopropyne (3.6 g) to the product from the previous step, and stir at room temperature for 30 min. Add potassium carbonate (2.8 g) in portions, and after the addition is complete, react at room temperature for 2 h. Add water (100 ml) to the reaction solution, extract three times with methyl tert-butyl ether, combine the organic phases, concentrate to dryness, and purify by silica gel column chromatography to give 450 mg of a pale yellow solid, compound 7. 1 HNMR (400MHz, DMSO-d6): δ12.46(s,1H),11.36(s,1H),9.89(s,1H),9.25(s,1H),8.79(s,1H),8.16(d,J=5.2Hz,1H),7.50 (d,J=5.2Hz,1H),5.29(d,J=2.5Hz,2H),3.91(s,3H),3.63(t,J=2.5Hz,1H),2.19–2.08(m,1H),0.98–0.81(m,4H).MS:m / z 451.2[M+H] + .

[0144] Synthesis Example 2

[0145] Preparation of Compound 11: 6-(cyclopropane-1-formamido-1-d)-4-((3-methoxy-4-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (refer to the preparation of Compound 11 in WO2022233286A1).

[0146] Step 1

[0147] Triazole compound (1.20 g), cyclopropane-1-d-1-carboxamide (0.42 g), Xanthpos (0.28 g), Cs₂CO₃ (1.58 g), Pd₂(dba)₃ (0.22 g), and 1,4-dioxane (30 mL) were added sequentially to a reaction flask. Under nitrogen protection, the mixture was heated to 100 °C and stirred. After the reaction was complete, the mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, concentrated under reduced pressure to obtain an oily substance, and purified by silica gel column chromatography to give 0.74 g of a yellow solid. MS: m / z 544.3 [M+H] + .

[0148] Step 2

[0149] The product from the previous step (0.72 g), dichloromethane (2.2 ml), and tetraethylammonium fluoride (2.16 g) were added sequentially to the reaction flask. Trifluoroacetic acid (5.04 ml) was added dropwise while stirring. After the addition was complete, the reaction was stirred at room temperature. After the reaction was complete, the mixture was concentrated, water was added, and impurities were extracted with methyl tert-butyl ether. The aqueous phase was collected, and the pH was adjusted with saturated sodium bicarbonate. The precipitated solid was filtered, dried, and yielded 0.44 g of a pale yellow solid. MS: m / z 414.2 [M+H] + .

[0150] Step 3

[0151] The product from the previous step (0.43 g), N,N-dimethylacetamide (20 ml), and bromopropyne (0.99 g) were added sequentially to the reaction flask. The mixture was stirred until dissolved, and potassium carbonate (1.01 g) was added in portions. The reaction was carried out at room temperature. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, dried, and concentrated under reduced pressure to obtain a yellow oily substance. The substance was purified by silica gel column chromatography to obtain 81 mg of a white solid. 1 H NMR (400MHz, DMSO-d6): δ12.47(s,1H),11.37(s,1H),9.90(s,1H),9.26(s,1H),8.80(s,1H),8.16(d,J=5.2 Hz, 1H), 7.51 (d, J = 5.2Hz, 1H), 5.29 (d, J = 2.6Hz, 2H), 3.91 (s, 3H), 3.64 (t, J = 2.5Hz, 1H), 0.94-0.83 (m, 4H).

[0152] Formulation Examples

[0153] Formulation Example 1: Preparation of Ointment

[0154] Ointment formulation composition:

[0155] Ointment preparation: (Refer to a similar method for ointment preparation in Example 7 of WO2022233286A1)

[0156] (1) Homogenization: Put the prescribed amount of petroleum jelly into the main pot, heat it at 70℃~90℃ until it is completely melted, and control it at 75±5℃ for later use; add compound 7 or compound 11, antioxidant BHA (butylated hydroxyanisole) and benzyl alcohol to about 1 / 2 of the light liquid paraffin, and mechanically stir it to disperse it evenly to obtain mixture 1; add mixture 1, the remaining light liquid paraffin and the melted petroleum jelly solution into the main pot, turn on the wall-scraping stirring at 30~60 rpm, the homogenization stirring speed is 1000~2800 rpm, the vacuum degree is -50~-100Kpa, the temperature is 70±5℃, and homogenize for 20~30 min; then slowly cool down to below 35℃ to obtain the paste.

[0157] (2) Filling: The prepared ointment was filled into the specified size using a filling machine. During the process, the temperature of the feeding funnel jacket was controlled at 25℃~30℃, and the sealing temperature was 450±20℃. According to the above formula and ointment preparation scheme, compound 7 ointment and compound 11 ointment were prepared.

[0158] Biological test cases

[0159] Test Example 1: Efficacy test in a mouse acne model induced by Propionibacterium acnes

[0160] Experimental animals: female ICR mice.

[0161] Experimental Methods: Female ICR mice were shaved from the back and randomly divided into three groups: a blank control group (applied with blank ointment), a model control group (applied with blank ointment), and a treatment group (applied with compound 11 ointment (3%, 100 mg / mouse)), with 6 mice in each group. Mice in the model control group and treatment group were injected intradermally with 20 μL of Propionibacterium acnes bacterial solution on the back, while the blank control group was injected with an equal volume of physiological saline. Ointment administration began 24 hours later, once daily for 7 consecutive days. Blood was collected from the mice 4 hours after the last administration to detect the plasma TNF-α level.

[0162] Experimental results: The levels of the inflammatory factor TNF-α in animal plasma are shown in the table below.

[0163] Where A represents a TNF-α content range of less than 12 pg / mL;

[0164] B represents a TNF-α content range of 12–25 pg / mL;

[0165] C represents a TNF-α content range greater than 25 pg / mL;

[0166] The results showed that in a mouse acne model induced by Propionibacterium acnes, treatment with compound 11 ointment for 7 consecutive days significantly reduced the level of the inflammatory factor TNF-α in the mouse plasma, bringing it close to the level of normal mice.

[0167] Test Example 2: Efficacy test in a mouse acne model induced by Propionibacterium acnes and oleic acid.

[0168] Experimental animals: female ICR mice.

[0169] Experimental methods: After shaving the back of mice, mice in the blank control group were injected intradermally with physiological saline and then coated with liquid paraffin. The other mice were injected intradermally with Propionibacterium acnes and then coated with oleic acid to create the model. The treatment was carried out once a day for 7 days. On the 7th day, the mice were scored and then randomly divided into blank control group, model control group, compound 11 ointment group (3%, 33mg / mouse) and benzoyl peroxide gel group (100mg / mouse), with 8 mice in each group.

[0170] On the first day after grouping (D1), mice in the blank control group were treated with 80 μl of liquid paraffin for 2 hours, followed by 33 mg of blank ointment; mice in the other groups were treated with 80 μl of oleic acid for 2 hours, followed by the corresponding test substance ointment / gel. Treatment was administered once daily for 14 days. On D7 and D14, the skin condition on the backs of the mice was observed and photographed. A comprehensive score was calculated based on five symptoms: erythema, keratosis, papules, crusting, and scaling, to evaluate the severity of acne symptoms on the backs of the mice; higher scores indicated more severe symptoms. On D14, skin samples were collected from the affected areas to detect the levels of inflammatory factors TNF-α and IL-17.

[0171] Experimental results: The acne symptom scores on the back skin of D14 mice are shown in the table below.

[0172] Where "+" represents a score ≥ 10; "++" represents a score greater than 8 and less than 10; and "+++" represents a score greater than 6 and less than or equal to 8.

[0173] "++++" represents a score of ≤6.

[0174] The results of TNF-α and IL-17 content in the dorsal skin of D14 mice are shown in the table below.

[0175] Where A represents a TNF-α content range of less than 600 pg / g and an IL-17 content range of less than 150 pg / g;

[0176] B represents a TNF-α content range of 600–900 pg / g and an IL-17 content range of 150–200 pg / g;

[0177] C represents the TNF-α content range of 900–1300 pg / g and the IL-17 content range of 200–300 pg / g;

[0178] D represents a TNF-α content range greater than 1300 pg / g and an IL-17 content range greater than 300 pg / g.

[0179] The results showed that in a mouse acne model induced by Propionibacterium acnes and oleic acid, continuous application of compound 11 ointment and benzoyl peroxide gel for 14 days significantly improved acne symptoms and significantly reduced the levels of inflammatory factors TNF-α and IL-17 in the skin. Compound 11 ointment was more effective than benzoyl peroxide gel.

[0180] Test Example 3: Efficacy test in a croton oil-induced mouse acne model

[0181] Experimental animal: KM mouse.

[0182] Experimental Methods: After removing hair from the skin around the ears and cheeks of KM mice, they were randomly divided into 6 groups: a blank control group, a model control group, a low-dose compound 11 group (3%, 17 mg / mouse), a medium-dose compound 11 group (3%, 33 mg / mouse), a high-dose compound 11 group (3%, 100 mg / mouse), and an adapalene gel group (100 mg / mouse), with 8 mice in each group. The blank control group and the model group were treated with the blank ointment, while the other groups were treated with the corresponding test substance ointment / gel. One hour after application, the blank control group had 20 μl of anhydrous ethanol applied to their ears and cheeks, while the other groups had 20 μl of 5% croton oil applied to their ears and cheeks. This treatment and modeling continued for 7 days. Three hours after modeling on day 7, the inflammation status of the mice's ears and cheeks was observed, photographed, and scored. The thickness of the ear flaps was also measured and recorded. Higher scores and thicker ear flaps indicated more severe symptoms.

[0183] Experimental Results: The scores of inflammatory symptoms in the mouse auricle and cheek are shown in Figure 1, and the ear thickness is shown in Figure 2. The results indicate that in a croton oil-induced mouse acne model, treatment with different doses of compound 11 ointment for 7 consecutive days significantly improved acne / inflammatory symptoms in mice.

[0184] Test Example 4: Efficacy test in a 2,4-dinitrofluorobenzene (DNFB)-induced mouse acne inflammation model

[0185] Experimental animals: female Balb / c mice.

[0186] Experimental groups: blank control group (applied with blank solvent and blank ointment), model control group (applied with DNFB and blank ointment), low-dose administration group (applied with DNFB and compound 7 ointment (3%, 67 mg / animal)), high-dose administration group (applied with DNFB and compound 7 ointment (3%, 250 mg / animal)), 6 animals in each group.

[0187] Experimental Procedure: Mice were shaved on the back and neck and divided into groups. Starting from Day 1, the model control group and the drug treatment group had 50 μL of 0.5% DNFB (dissolved in acetone / olive oil) applied to the shaved area on the back and neck of the mice. One hour later, blank ointment and compound 7 ointment were applied, respectively. The blank control group had blank ointment applied one hour after the blank solvent was applied. The above procedure was followed for 7 consecutive days. The erythema area and severity of the mice were scored (based on erythema area and severity into 4 levels: 0 points - asymptomatic, 1 point - mild, 2 points - moderate, 3 points - severe).

[0188] Experimental results: The skin erythema scores of each group of animals are shown in Figure 3. The results indicate that in the DNFB-induced mouse acne inflammation model, all doses of compound 7 ointment can effectively improve the skin erythema in mice, and the high-dose group shows a significant improvement in skin erythema.

[0189] Test Example 5: Efficacy test in a 2,4-dinitrofluorobenzene (DNFB)-induced mouse acne inflammation model.

[0190] Experimental animals: female Balb / c mice.

[0191] Experimental groups: blank control group (applied with blank solvent and blank ointment), model control group (applied with DNFB and blank ointment), low-dose administration group (applied with DNFB and compound 11 ointment (3%, 67 mg / animal)), medium-dose administration group (applied with DNFB and compound 11 ointment (3%, 167 mg / animal)), high-dose administration group (applied with DNFB and compound 11 ointment (3%, 250 mg / animal)), 7 animals in each group.

[0192] Experimental Procedure: Mice were shaved on the back and neck and divided into groups. Starting from Day 1, the model control group and the drug treatment group had 50 μL of 0.5% DNFB (dissolved in acetone / olive oil) applied to the shaved area on the back and neck of the mice. One hour later, blank ointment and compound 11 ointment were applied, respectively. The blank control group had blank ointment applied one hour after the blank solvent was applied. The above procedure was followed for 4 consecutive days. The erythema area and severity of the mice were scored (divided into 4 levels according to the erythema area and severity: 0 points - asymptomatic, 1 point - mild, 2 points - moderate, 3 points - severe); and the content level of the inflammatory factor TNF-α in the skin tissue was detected.

[0193] Experimental Results: The skin erythema scores of each group of animals are shown in Figure 4, and the content of the inflammatory factor TNF-α in the skin tissue is shown in Figure 5. The results indicate that in the DNFB-induced mouse acne inflammation model, treatment with different doses of compound 11 ointment effectively improved skin erythema in mice, with the high-dose group showing a significant improvement. Both medium and high-dose groups effectively reduced the content of the inflammatory factor TNF-α in mouse skin tissue, with the high-dose group showing a significant reduction.

[0194] This article uses specific examples to illustrate the principles and implementation methods of the present invention. The descriptions of the above embodiments are only for the purpose of helping to understand the technical solutions and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. Use of a TYK2 inhibitor in the preparation of a medicament or cosmetic for the prevention, improvement and / or treatment of acne.

2. The use according to claim 1, wherein the TYK2 inhibitor is selected from compounds of formula (I), their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof. in, L is selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, deuterated C 1-6 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkylamino or deuterated C 3-6 Cycloalkylamino; R 10 R 11 R D1 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl or halogen; E1 is selected from hydrogen, deuterium, and C. 1-6 Alkyl or deuterated C 1-6 alkyl; Q is selected from chemical bonds or carbonyl groups; C is selected from the following groups: Among them, R 1 R 2 R 3 R 4 R 5 R 7 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 2-6 alkynyl group, deuterated C 2-6 alkynyl group, C 2-6 Alkenyl, deuterated C 2-6 alkenyl, C 1-6 Alkyl or deuterated C 1-6 Alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl, optionally halogenated, C 1-6 Alkyl, hydroxyl, amino, C 3-6 cycloalkyl, C 6-10 Aryl or 5-10 heteroaryl substitutions; R 9a R 9b R 9c Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3- 6-cycloalkyl, deuterated C 3-6 cycloalkyl, C 2-6 alkynyl group, deuterated C 2-6 alkynyl group, or R 9a and R 9b Together with the attached carbon atom, they form C 3-6 cycloalkyl; n＝1，2，3。 3. The use according to claim 2, wherein the TYK2 inhibitor is selected from compounds of formula (II), their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof. in, R 12 For deuterium, hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, deuterated C 1-6 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkylamino or deuterated C 3-6 Cycloalkylamino; R 10 R 11 R D1 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl or halogen; E1 is hydrogen, deuterium, and C. 1-6 Alkyl or deuterated C 1-6 alkyl; Q represents a chemical bond or a carbonyl group; C is selected from the following groups: Among them, R 1 R 2 R 3 R 4 R 5 R 7 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 2-6 alkynyl group, deuterated C 2-6 alkynyl group, C 2-6 Alkenyl, deuterated C 2-6 alkenyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl, optionally halogenated, C 1-6 Alkyl, hydroxyl, amino, C 3-6 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl substitutions; R 9a R 9b R 9c Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3- 6-cycloalkyl, deuterated C 3-6 cycloalkyl, C 2-6 alkynyl group, deuterated C 2-6 alkynyl group, or R 9a and R 9b Together with the attached carbon atom, they form C 3-6 cycloalkyl; n＝1，2，3。 4. The use according to claim 3, wherein the TYK2 inhibitor is selected from compounds of formula (III), their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof. in, R 12 For deuterium, hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, C 1-6 Alkylamino, deuterated C 1-6 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkylamino or deuterated C 3-6 Cycloalkylamino; R 10 R 11 R D1 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl or halogen; E1 is hydrogen, deuterium, and C. 1-6 Alkyl or deuterated C 1-6 alkyl; Among them, R 1 R 2 R 3 R 4 R 5 R 7 Each element is independently selected from hydrogen, deuterium, halogen, amino, and C. 2-6 alkynyl group, deuterated C 2-6 alkynyl group, C 2-6 Alkenyl, deuterated C 2-6 alkenyl, C 1-6 Alkyl or deuterated C 1-6 Alkyl; wherein, alkynyl, alkenyl, deuterated alkynyl, deuterated alkenyl, alkyl and deuterated alkyl, optionally halogenated, C 1-6 Alkyl, hydroxyl, amino, C 3-6 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl substitutions; R 9a R 9b R 9c Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, deuterated C 3-6 cycloalkyl, C 2-6 alkynyl group, deuterated C 2-6 alkynyl group, or R 9a and R 9b Together with the attached carbon atom, they form C 3-6 cycloalkyl; n1＝1，2，3； n2＝1，2，3。 5. The use according to claim 1, wherein the TYK2 inhibitor is selected from the following compounds, their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof.

6. The use according to claim 5, wherein the TYK2 inhibitor is selected from the following compounds, their stereoisomers, tautomers, crystal forms, solvates, or pharmaceutically acceptable salts thereof.

7. The use according to any one of claims 1-6, wherein the medicament optionally further comprises at least one other anti-acne treatment agent.

8. The use according to claim 7, wherein the other anti-acne treatment agent is selected from benzoyl peroxide, nicotinamide, salicylic acid, azelaic acid, retinoids, antibiotics, dapsone, hormones, etc.

9. The use according to any one of claims 1-8, wherein the dosage of the TYK2 inhibitor is 0.01-500 mg / kg, preferably 0.1-300 mg / kg.

10. The use according to any one of claims 1-9, wherein the route of administration of the medicament is selected from oral administration, transdermal administration, transdermal administration, injection administration, subcutaneous administration, topical administration, nasal administration, inhalation administration, sublingual administration, or rectal administration.

11. The use according to any one of claims 1-9, wherein the route of administration of the drug is topical application.

12. The use according to any one of claims 1-11, wherein the dosage form of the medicament is selected from tablets, capsules, pills, granules, powders, oral liquids, injections, sprays, aerosols, nasal drops, gels, emulsions, ointments, creams, pastes, powders, patches, plasters, or lotions.

13. The use according to any one of claims 1-12, wherein the acne is selected from acne vulgaris, comedonal acne, papular acne, pustular acne, nodular acne, cystic acne, conglobate acne, fulminant acne, fungal acne, Propionibacterium acnes infection acne, refractory acne, hormonal acne or secondary acne.

14. The use according to claim 13, wherein the acne vulgaris is selected from facial acne vulgaris.

15. A pharmaceutical or cosmetic composition for the prevention, improvement and / or treatment of acne, wherein the pharmaceutical or cosmetic composition contains a TYK2 inhibitor as described in any one of claims 1-6, and one or more pharmaceutically or cosmetically acceptable carriers.

16. The pharmaceutical composition or cosmetic composition according to claim 15, which is to be administered via a topical route, subcutaneous route, transdermal route, or oral route.

17. A topical formulation for the prevention, improvement and / or treatment of acne, wherein the topical formulation contains a TYK2 inhibitor as described in any one of claims 1-6, and one or more pharmaceutically acceptable carriers.

18. The topical formulation according to claim 17, wherein the content of the TYK2 inhibitor in the topical formulation is 0.01%-20% of the total weight of the topical formulation, preferably 0.1%-10%, more preferably 0.3%-8%.

19. The topical preparation according to claim 17 or 18, wherein the topical preparation comprises a gel, emulsion, ointment, cream, lotion, paste, patch, or plaster.

20. A method for preventing, improving, and / or treating acne, characterized in that, The method comprises administering to a patient in need an effective amount of the TYK2 inhibitor of any one of claims 1-6, or the pharmaceutical composition or cosmetic composition of claim 15, or the topical preparation of claim 17.

21. The use according to any one of claims 1-6, characterized in that, The cosmetics in question are skincare products.

22. The use according to claim 21, characterized in that, The skincare products include facial cleansers, toners, lotions, face masks, face creams, serums, essential oils, and sunscreens.

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