Uses of Azetidine Derivatives and Methods of Treatment

Abstract

Provided is the use of the compound of formula I, its pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug, or their composition in the preparation of the medicine for treating alopecia such as alopecia areata.Azetidine derivative has a clear mechanism of action and pharmacodynamic effect, good pharmacokinetic properties and good safety, and greatly improves patient's compliance with medication.

Description

[Technical field]

[0001] The present invention relates to the use of azetidine derivatives as Janus kinase (JAK) inhibitors and pharmaceutical compositions containing same in the treatment of alopecia, such as alopecia areata. [Background technology]

[0002] Alopecia areata (AA) is a common inflammatory non-scarring alopecia. Clinically, it presents as a sudden appearance of circular, sharply demarcated bald patches on the scalp. Mild cases are often self-limited, but about half of patients experience recurrences that can last for years or even decades. In severe cases, the entire scalp or body hair may be affected. AA can occur at any age, but is more prevalent in young and middle-aged people and affects both sexes.

[0003] The pathogenesis of AA is not fully understood. It is currently believed that in AA patients, the immune privilege of hair follicles is disrupted by upregulation of MHC I and NKG2D on hair follicle epithelial cells, leading to the activation of CD8+ NKG2D+ T cells, which attack hairless follicles. IL-15 secreted from hair follicles activates T cells through binding to JAK1 and JAK3, stimulating the production of IFN-γ. IFN-γ binds to receptors on hair follicle cells and further induces the secretion of IL-15, forming a positive feedback loop that fosters the excessive proliferation of T cells and promotes autoimmune attacks on hair follicles. Subsequently, AA occurs.

[0004] The goals of AA treatment are to control the progression of the disease, promote hair growth, prevent and reduce recurrence, and improve the patient's quality of life. Current treatments include: local therapies such as topical corticosteroids, local corticosteroid injections, local immunotherapy, and topical minoxidil; and systemic therapies such as corticosteroids and immunosuppressants. In recent years, domestic and international studies have reported that several new drugs and treatments, such as oral JAK inhibitors, antihistamines (ebastine, fexofenadine, etc.), glycyrrhizin compounds, topical prostaglandin analogs, psoralen combined with long-wave ultraviolet ray irradiation (PUVA), narrowband ultraviolet B irradiation (UVB), 308 nm excimer laser, low-energy laser, and local cryotherapy, have shown certain efficacy in AA.

[0005] Therefore, there is a demand for the development of more effective and safer drugs for treating alopecia such as alopecia areata. Summary of the Invention

[0006] In view of the deficiencies of the prior art and the practical needs, the object of the present invention is to provide the use of the compound of formula I, its pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug in the manufacture of medicine for treating alopecia, such as alopecia areata, which has a clear mechanism, a reliable pharmacological effect, and good pharmacokinetic and safety properties, and greatly improves patient compliance.

[0007] To achieve this objective, the present invention adopts the following technical solutions:

[0008] The present invention provides the use of a compound of formula I, a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite, or prodrug thereof, in the manufacture of a medicament for treating alopecia, such as alopecia areata, the compound having a structure represented by formula I: [ka] During the ceremony: R 1 is C(O)R8 and S(O) 2 R 9 Selected from; R 2 H, CN, halogens and C 1-6 alkyl; R 3 and R 4 are each independently selected from H, halogen, and CN; R 5 , R 6 and R 7 are each independently H, halogen, CN, or C 1-6 Alkyl, C 1-6 Alkoxy, and C(O)NR 10 R 11 Selected from; R 8 and R 9 are each independently 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 7-20 Arylalkyl, and NR 10 R 11 Selected from; R 10 and R 11 each, if present, independently represents H and C 1-6 alkyl; The alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are independently selected from halogen, CN, and C. 1-4 Each is optionally substituted with 1, 2 or 3 substituents selected from alkyl.

[0009] In some embodiments, in the compound of formula I, R 2 is selected from H, CN, F, and methyl.

[0010] In a preferred embodiment, in the compound of formula I, R 2 is selected from H and methyl.

[0011] In some embodiments, in the compound of formula I, R 3 and R 4 are each independently selected from H, F, Cl, and CN.

[0012] In a preferred embodiment, in the compound of formula I, R 3 and R 4 is H.

[0013] In some embodiments, in the compound of formula I, R 5 , R 6 and R 7 are each independently H, F, Cl, CN, methyl, ethyl, methoxy, and C(O)NH 2 is selected from.

[0014] In a preferred embodiment, in the compound of formula I, R 5 is H, F, Cl, CN, methyl or C(O)NH 2 and; R 6 is H, Cl, CN, methyl or methoxy; and R 7 is H.

[0015] In some embodiments, in the compound of formula I, R 8 and R 9 are each independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, aziridinyl, pyrrolidinyl, phenyl, benzyl, and N(CH 3 ) 2 each of said groups is optionally substituted with 1, 2 or 3 substituents independently selected from F, CN and methyl.

[0016] In some embodiments, in the compound of formula I, R 10 and R 11 is independently selected from H, methyl, and ethyl, at each occurrence.

[0017] In the uses encompassed by the present invention, any combination of the preferred groups described above can be implemented to obtain compounds of formula I.

[0018] In some embodiments, the present invention provides the use of a compound, a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite, or prodrug thereof, in the manufacture of a medicament for treating alopecia, such as alopecia areata, wherein the compound is selected from:

[0019] [ka]

[0020] [ka]

[0021] In some embodiments, the compound of formula I is: [ka] It is.

[0022] In some embodiments, the medicament of the present invention further comprises a pharma- ceutically acceptable excipient.

[0023] In some embodiments, the medicament of the invention further comprises one or more additional therapeutic agents.

[0024] In a preferred embodiment, the excipient comprises a combination of any two or more of an excipient, diluent, carrier, flavoring agent, binder, or filler; preferably, the carrier comprises a liposome, micelle, microsphere, or microcapsule, or the like.

[0025] In some embodiments, the pharmaceutical dosage form of the present invention includes tablets, capsules, granules, powders, or injections. Each dosage form can be prepared according to conventional methods in the pharmaceutical field.

[0026] In some embodiments, the pharmaceutical dosage form of the present invention is a capsule.

[0027] In some embodiments, the pharmaceutical dosage form of the present invention is a capsule, and the capsule dosage (i.e., the amount of the compound of formula I, its pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug in each capsule) is 0.1-50 mg, such as 0.1-20 mg, such as 0.2-10 mg, such as 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg or 6 mg, such as 0.5 mg, 1 mg or 2 mg.

[0028] In some embodiments, the medicaments of the present invention can be administered via a suitable route, such as by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or transdermal administration; or orally, buccal, nasally, transmucosally, topically, in the form of an ophthalmic formulation, or by inhalation.

[0029] In some embodiments, the alopecia of the present invention is inflammatory non-scarring alopecia.

[0030] In some embodiments, the alopecia of the present invention is alopecia areata, preferably severe alopecia areata.

[0031] The present invention provides a compound of formula I, a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof, or a composition comprising the compound, a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof, for use in the treatment of alopecia, preferably for use in the treatment of alopecia areata, more preferably for use in the treatment of severe alopecia areata.

[0032] The present invention provides a method for treating alopecia, which comprises administering to subject a therapeutically effective amount of the compound of above-mentioned formula I, its pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug, or the composition comprising said compound, its pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug.Preferably, this method is for treating alopecia areata, more preferably for treating severe alopecia areata.

[0033] In some embodiments, the method includes restoring the normal growth cycle of hair follicles, inducing hair follicle stem cell proliferation and differentiation, and / or promoting hair follicle stem cell proliferation and differentiation and angiogenesis.

[0034] In some embodiments, the method comprises administering to the subject a compound of Formula I, a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite, or prodrug thereof, or a composition comprising the compound, a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite, or prodrug thereof, once or multiple times daily for 1 to 60 consecutive weeks, e.g., 12, 24, 36 weeks, preferably once daily for 36 consecutive weeks.

[0035] In some embodiments, at screening or baseline, the subject has alopecia areata as measured by the Severity of Alopecia Tool (SALT) and has hair loss of 50% or more of the entire scalp, including alopecia totalis and alopecia universalis, has not had natural improvement in the past 6 months (i.e., a natural decrease in SALT score of 10% or less), and has had alopecia areata for a duration of 8 years or less (time from last free of scalp hair loss to randomization).

[0036] In some embodiments, the subject's SALT score (degree of alopecia) at 24 or 36 weeks after initiation of treatment is ≦20, such as ≦10.

[0037] In some embodiments, the subject's SALT score (degree of alopecia) at 24 or 36 weeks after initiation of treatment shows at least a 50%, e.g., 70%, 75%, 80%, 85% or 90% improvement compared to baseline.

[0038] In some embodiments, the subject's Eyebrow Assessment (EBA) and Eyelash Assessment (ELA) at 24 or 36 weeks after initiation of treatment show at least a 2 grade improvement compared to baseline, or a score of 3.

[0039] In some embodiments, the subject's Alopecia Scale (Clinician-Reported Outcome, ClinRO) score at 24 or 36 weeks after initiation of treatment is 0 or 1, and the improvement is 2 points or more.

[0040] In some embodiments, the subject's Global Impression of Disease Change scale (Patient-Reported Outcomes, PRO) score is 0 or 1 at 24 or 36 weeks after initiation of treatment.

[0041] In some embodiments, the plasma drug concentration in the subject before the first administration is max It is less than 5% of the total.

[0042] In some embodiments, a subject should not have any of the following characteristics prior to the first administration: (1) Hemoglobin < 11.0 g / dL (110.0 g / L); (2) Neutrophil count (NEUT#), white blood cell count (WBC) <lower limit of normal (LLN); (3) alanine aminotransferase (ALT), aspartate aminotransferase (AST) > 2 times the upper limit of normal (2ULN), total bilirubin (TBIL) > 1.5 times the upper limit of normal (1.5ULN); or (4) eGFR calculated according to Cockcroft-Gault is ≦60 ml / min or currently undergoing regular hemodialysis.

[0043] Definition of Terms Unless otherwise defined in the context, all technical and scientific terms used in the present invention are intended to have the same meaning as commonly understood by those skilled in the art. Reference to the technology employed in this specification is intended to refer to the technology commonly understood in the art, including the variants of those technologies or equivalent replacements that would be obvious to those skilled in the art. Although it is believed that the following terms are easily understood by those skilled in the art, the following definitions are nevertheless presented to better explain the present invention.

[0044] All patents, published patent applications, publications, references, and other materials mentioned herein are incorporated by reference in their entirety.

[0045] Unless otherwise clearly indicated by context, the term "or" as used herein means, and can be used interchangeably with, the term "and / or."

[0046] As used herein, the term "alkyl" is defined to include saturated aliphatic hydrocarbons, including straight and branched chains. In some embodiments, alkyl has 1 to 6, such as 1 to 4 carbon atoms. For example, as used herein, "C 1-6 The term "alkyl" refers to straight or branched chain groups having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), which may optionally contain one or more (e.g., 1 to 3) suitable substituents such as halogen (e.g., CF 3 , C 2 F 5 , CHF 2 , C.H. 2 F, C.H. 2 CF3 , C.H. 2 Cl or -CH 2 CH 2 CF 3 etc.) are arbitrarily replaced by "C 1-4 The term "alkyl" refers to a straight or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0047] As used herein, the term "alkoxy" refers to a linear, branched or cyclic saturated monovalent hydrocarbon residue of the formula -O-alkyl, where "alkyl" is as defined above or "cycloalkyl" as defined below, such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, cyclobutoxy, pentoxy, isopentoxy or n-hexyloxy, or their isomers.

[0048] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc., or bicyclic, such as spiro, fused or bridged ring systems (e.g., bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthalene, etc.), which is optionally substituted with one or more (e.g., 1-3) suitable substituents. Cycloalkyl has 3 to 15 carbon atoms. For example, "C 3-10The term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic mono- or polycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 10 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[1.1.1]pentyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

[0049] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated, monovalent, monocyclic or bicyclic residue having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, as well as C(=O), O, S, S(=O), S(=O) 2 , and N.R. a wherein R a represents a hydrogen atom in the ring, C 1-6 Alkyl group, or C 1-6 It represents a haloalkyl group. Heterocycloalkyl may be linked to the remainder of the molecule through any one of the carbon atoms or the nitrogen atom (if present). In particular, 3-10 membered heterocyclyl refers to groups having 3 to 10 carbon atoms and heteroatoms in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0050] As used herein, the term "aryl" refers to a carbocyclic or fused polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, "C 6-14 The term "aryl" refers to an aromatic group containing 6 to 14 carbon atoms, such as phenyl or naphthyl. Aryl is optionally substituted with one or more (eg, 1 to 3) suitable substituents.

[0051] As used herein, the term "heteroaryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, which may be the same or different, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and containing at least one heteroatom (e.g. O, N or S). Furthermore, in each case, the "heteroaryl" may be benzo-fused. In particular, the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.

[0052] The term "aralkyl" preferably refers to aryl-substituted alkyl, where aryl and alkyl are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0053] As used herein, the term “halo” or “halogen” is defined to include F, Cl, Br, or I.

[0054] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the specified atom are replaced with a group selected from the indicated, provided that the replacement does not exceed the normal valences for the specified atom under the existing circumstances, and that the replacement results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0055] The term "optionally substituted" means that a compound is optionally substituted at the specified groups, radicals or moieties.

[0056] When a bond to a substituent is shown to cross the bond between two atoms in a ring, then such substituent may be bonded to any of the substitutable ring-forming atoms in that ring.

[0057] The compounds of the invention may also contain one or more (e.g., 1, 2, 3, or 4) isotopes. For example, in the compounds of the invention, hydrogen or H is: 1 H, 2 H (D or deuterium) and 3 H (T or tritium) in any isotopic form; carbon or C 12 C. 13 C and 14 and oxygen or O may be in the form of any isotopic atom, including C; 16 O and 18 It may be in any isotopic form, including O.

[0058] "Stereoisomer" refers to an isomer formed due to the presence of at least one asymmetric center. Compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers can give rise to racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Certain individual molecules can exist as geometric isomers (cis / trans). Similarly, compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is understood that all such isomers and mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) are within the scope of the present invention.

[0059] The present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as a single polymorph or as a mixture of two or more polymorphs, in any ratio.

[0060] It should also be understood that certain compounds of the present invention can be used in therapy in free form or, where appropriate, in the form of a pharma- ceutically acceptable derivative. In the present invention, a pharma- ceutically acceptable derivative includes, but is not limited to, a pharma- ceutically acceptable salt, solvate, metabolite or prodrug that can directly or indirectly provide the compound of the present invention or a metabolite or residue thereof after administration to a patient in need thereof.

[0061] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base salts thereof.

[0062] Suitable acid addition salts are formed from acids which form non-toxic salts, such as aspartate, bicarbonate / carbonate, bisulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, esylate, fumarate, glucaptate, gluconate, glucuronate, hexafluorophosphate, hydroiodide / iodide, isethionate, lactate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, tannate, and xinafoate.

[0063] Suitable base addition salts are formed from bases which form non-toxic salts, examples of which include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0064] For a review of suitable salts, see "Hand book of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharma- ceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0065] The compounds of the invention may exist in the form of hydrates or solvates, for example containing polar solvents, in particular water, methanol or ethanol, as structural elements of the crystal lattice of the compounds. The polar solvents, in particular water, may be present in stoichiometric or non-stoichiometric amounts.

[0066] The present invention further includes metabolites of the compounds of the invention, that is, compounds produced in vivo upon administration of the drug.

[0067] Prodrugs of the compounds of the invention can be formed by replacing appropriate functional groups in the compounds of formula I with functional groups known in the art, such as the "pro-moieties" described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985).

[0068] As used herein, the term "pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered, which is, within the scope of sound medical judgment, suitable for contact with the tissues of human and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and is commensurate with a reasonable benefit / risk ratio.

[0069] Pharmaceutically acceptable carriers that may be employed in the compositions / medicines of the present invention include sterile liquids such as water and oils, including, but not limited to, those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Pharmaceutical compositions may contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Oral formulations may contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutical carriers are described, for example, in Remington's Pharmaceutical Sciences (1990).

[0070] The compounds / compositions / medicaments of the present invention may act systemically and / or locally.To this end, they may be administered via any suitable route, such as injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal, or may be administered orally, bucally, nasally, transmucosally, topically, as an ophthalmic formulation, or via inhalation.

[0071] For these administration routes, the compounds / compositions / medicaments of the present invention can be administered in appropriate dosage forms.

[0072] Such dosage forms include, but are not limited to, tablets, capsules, troches, hard candies, powders, sprays, creams, ointments, salves, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.

[0073] As used herein, the term "therapeutically effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.

[0074] Dosage regimen can be adjusted to obtain optimal desired response.For example, a single bolus can be administered, or several divided doses can be administered over time, or the dose can be proportionally reduced or increased according to the exigencies of the treatment situation.It should be noted that dosage values ​​vary according to the type and severity of the condition to be alleviated, and can include single or multiple administrations.Furthermore, it should be understood that for any particular subject, a particular dosage regimen should be adjusted over time according to individual need and the professional judgment of the person administering or supervising the administration of the composition.

[0075] The dosage of the compounds of the present invention will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the pharmacokinetics of the compound, and the discretion of the prescribing physician. In general, an effective amount will range from about 0.0001 to about 50 mg per kg of body weight per day, e.g., about 0.01 to about 10 mg / kg / day, administered in a single dose or in divided doses. For a human weighing 70 kg, this corresponds to about 0.007 mg to about 3500 mg / day, e.g., about 0.7 mg to about 700 mg / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, even larger doses may be employed without causing adverse side effects, but such larger doses are first divided into several smaller doses for administration throughout the day.

[0076] The content or dosage of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1 to 500 mg, preferably 0.1 to 300 mg, more preferably 0.1 to 150 mg, particularly preferably 0.3 to 50 mg, for example, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0077] Unless otherwise indicated, the terms "treating" or "treatment" as used herein mean to reverse, alleviate, inhibit the progression of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0078] As used herein, the term "subject" includes humans or non-human animals. Exemplary human subjects include human subjects (referred to as patients) with diseases (such as those described herein) or normal subjects. As used herein, the term "non-human animals" includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, e.g., non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.). When referring to a subject, the terms "subject" and "patient" are used interchangeably herein.

[0079] "Weeks..." refers to a period including 5 days before and after the specified number of weeks (e.g., 4 weeks ±3 days, 28th day ±3 days, 253rd day ±5 days).

[0080] "Baseline" refers to a given parameter or patient condition prior to treatment.

[0081] "One or more additional therapeutic agents" refers to therapeutically active agents that are administered (including simultaneous (concurrent) administration in any order or sequential administration) other than the active ingredients of the invention.

[0082] An adverse event (AE) is a medical occurrence in a subject following administration of an investigational drug that manifests as a symptom, sign, illness, or laboratory abnormality that is not necessarily causally related to the investigational drug.

[0083] A serious adverse event (SAE) is an adverse event that meets any of the following criteria: 1) Leading to death; 2) life-threatening, meaning that the subject is at immediate risk of death at the time the adverse event occurs, but not that future progression may result in death; 3) those requiring hospitalization or extended hospitalization; 4) results in permanent or significant impairment / disability; 5) those resulting in congenital anomalies / birth defects; 6) Other significant medical events. Any event that is not immediately life-threatening, fatal, or requiring hospitalization, but that, based on sound medical judgment, may endanger the subject or require medical intervention to prevent any of the outcomes listed above, is also generally considered a serious adverse event. EXAMPLES

[0084] The examples and embodiments described herein are for illustrative purposes only, and those skilled in the art will suggest various modifications or changes based on these examples and embodiments, all of which are within the spirit and scope of the present application.

[0085] The preparation of the compound of formula I (e.g., compound 8) involved in the present invention can be carried out according to patent application WO2017 / 097224A1. A certain amount of compound 8 was prepared in a capsule together with suitable excipients.

[0086] Potential subjects were screened and randomly assigned prior to dosing on Day 1 (D1) and completed the following: 1) inclusion / exclusion criteria; 2) clinical examination; 3) randomization; 4) AA disease assessment: SALT assessment (photograph required), nail assessment (photograph of affected nail), eyebrow assessment (photograph required), eyelash assessment (photograph required), ClinRO severity assessment, QOL assessment (SF-36); these assessments served as baseline information for the disease; 5) PK sampling, etc.

[0087] At randomization, a randomization stratification factor was set based on the severity of alopecia to ensure balance between groups: one stratum for alopecia totalis or alopecia universalis and another for alopecia non-totalis and non-universalis.

[0088] The subjects were randomly assigned to a treatment group (test group) of capsules of the compound 8 of the present invention at doses of 0.5 mg, 1 mg, and 2 mg, and a placebo group (control group), with 44 subjects in each group. All subjects orally took a capsule of the compound 8 (or a placebo) once a day on an empty stomach, and treatment period A and treatment period B were continued for a total of 36 weeks.

[0089] Treatment Period A: Subjects in the test or placebo groups orally ingested 8 capsules of the compound or placebo once daily on an empty stomach for 24 consecutive weeks.

[0090] Treatment period B: All subjects in the placebo control group in treatment period A were randomly assigned to the Compound 8 capsule treatment group (test group) in treatment period B in a ratio of approximately 1:1:1 at doses of 0.5 mg, 1 mg, and 2 mg. Subjects orally took Compound 8 capsules once a day on an empty stomach for 12 consecutive weeks. The treatment plan for patients in the test group in treatment period A was continued for 12 weeks without change in treatment period B.

[0091] Follow-up surveys were performed at week 2 / 15 ± 3 days, week 4 / 29 ± 3 days, week 8 / 57 ± 3 days, week 12 / 85 ± 3 days, week 16 / 127 ± 3 days, week 20 / 141 ± 3 days, week 24 / 169 ± 3 days, week 28 / 197 ± 3 days, week 32 / 225 ± 3 days, and week 36 / 253 ± 5 days.

[0092] Test Example 1: Evaluation of Alopecia Severity SALT is an assessment based on the state of scalp hair loss and is a method to quantitatively evaluate the severity of AA. SALT score = 0.18 × left side score + 0.18 × right side score + 0.4 × vertex score + 0.24 × occipital score. The Alopecia Severity Tool (SALT) was referenced from Olsen 2004 (Olsen EA, Hordinsky MK, Price VH, et al. Alopecia areata investigational assessment guidelines Part II [J]. J Am Acad Dermatol, 2004, 51(3): 440-447) and Olsen 2011 (Olsen EA. Investigative guidelines for alopecia areata [J]. Dermatol Ther, 2011, 24: 311-319). Subjects had a SALT score of ≥50 at screening and baseline and underwent scalp photographs without wigs for SALT assessment at each visit.

[0093] Test Example 2: Evaluation of nails affected by alopecia areata The number of nails affected by AA was counted for all subjects at baseline and subsequent visits. Nails with any of the following changes were recorded: pitting, onycholysis (rough surface of the nail), vertical furrows or stripes, lunate erythema, leukoonychia (white lines or spots on the nail plate), onycholysis (detachment of the nail plate from the nail bed), brittle nails (nails that break easily), etc. Photographs of affected nails were taken at baseline and during study treatment.

[0094] Test Example 3: Global Impression Scale (ClinRO) A Global Impression Scale score (ClinRO) was derived by rating the severity of alopecia on the subjects' scalp based on the following criteria: none (no alopecia) = 0, mild alopecia = 1, moderate alopecia = 2, severe alopecia = 3, and very severe or complete alopecia = 4.

[0095] Test Example 4: Global Impression Scale (PRO) of changes in disease in subjects The Global Impression Scale of change in subjects' AA status was rated according to the following criteria: 0 for significant improvement, 1 for moderate improvement, 2 for slight improvement, 3 for no change, 4 for slight worsening, 5 for moderate worsening, and 6 for significant worsening.

[0096] Test Example 5: Eyelash Assessment (ELA) The eyelash assessment is a numerical rating scale (NRS) used to characterize eyelash loss. The numerical rating scale ranges from 0 (absent) to 3 (normal) as follows:

[0097] [Table 1]

[0098] Test Example 6: Eyebrow Evaluation (EBA) Eyebrow rating is a numerical rating scale used to characterize eyebrow hair loss. The numerical rating scale ranges from 0 (absent) to 3 (normal) as follows:

[0099] [Table 2]

[0100] Test Example 7: Blocking effect of compounds on the JAK / STAT signal pathway The inhibitory effect of compound 8 on STAT5 phosphorylation induced by cytokine IL-2 stimulation in CD4+ T cells in human whole blood, as well as the inhibitory effect of compound 8 on STAT3 phosphorylation induced by cytokine IL-6 stimulation in CD4+ T cells in human whole blood, were detected using flow cytometry.

[0101] The results showed that compound 8 inhibited STAT5 phosphorylation induced by IL-2 stimulation in human whole blood CD4+ T cells and STAT3 phosphorylation induced by IL-6 stimulation in human whole blood CD4+ T cells. The IC 50 was 0.46 ± 0.03 μM, and the IC 50 was 1.51±0.06 μM.

[0102] Test Example 8: In vivo kinase inhibitory activity test The inhibitory effect of compound 8 on specific kinase targets was tested using an in vitro enzyme assay system, and the results showed that compound 8 showed 67% inhibition of p70S6K (p70 ribosomal protein S6 kinase) and 75% inhibition of PKA (protein kinase A) at a concentration of 200 nM.

[0103] The above description is merely related to the preferred embodiments of the present invention and is not intended to limit the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention. In addition, the technical solutions in various embodiments can be combined, but it should be based on what those skilled in the art can implement. If the combination of technical solutions results in a contradiction or cannot be realized, such combination should not exist and should not be considered to be included in the protection scope claimed by the present invention.

Claims

1. 1. Use of a compound of Formula I, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite, or prodrug thereof, in the manufacture of a medicament for treating alopecia, such as alopecia areata, wherein the compound has the structure of Formula I: 【Chemistry 1】 During the ceremony: R 1 is C(O)R 8 and S(O) 2 R 9 and selected from; R 2 H, CN, halogens and C 1-6 alkyl; R 3 and R 4 are each independently selected from H, halogen, and CN; R 5 , R 6 and R 7 are each independently H, halogen, CN, or C 1-6 Alkyl, C 1-6 Alkoxy, and C(O)NR 10 R 11 Selected from: R 8 and R 9 are each independently 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, C 7-20 Arylalkyl, and NR 10 R 11 selected from the group consisting of: R 10 and R 11 each, if present, independently represents H and C 1-6 alkyl; and The alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are independently selected from halogen, CN, and C 1-4 each optionally substituted with 1, 2 or 3 substituents selected from alkyl, use.

2. R 2 is selected from H, CN, F and methyl; Preferably, R 2 The use according to claim 1, wherein is selected from H and methyl.

3. R 3 and R 4 are each independently selected from H, F, Cl, and CN; Preferably, R 3 and R 4 The use according to claim 1 or 2, wherein is H.

4. R 5 , R 6 and R 7 are each independently H, F, Cl, CN, methyl, ethyl, methoxy, and C(O)NH 2 Selected from: Preferably, R 5 is H, F, Cl, CN, methyl or C(O)NH 2 and R 6 is H, Cl, CN, methyl or methoxy; and R 7 The use according to claim 1, wherein is H.

5. R 8 and R 9 are each independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, aziridinyl, pyrrolidinyl, phenyl, benzyl, and N(CH 3 ) 2 2. The method of claim 1, wherein the group is selected from the group consisting of: wherein the group is optionally substituted with one, two or three substituents independently selected from F, CN and methyl.

6. R 10 and R 11 10. The use of claim 1, wherein each occurrence is independently selected from H, methyl, and ethyl.

7. 1. Use of a compound, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof, in the manufacture of a medicament for treating alopecia, such as alopecia areata, wherein the compound is selected from: 【Chemistry 2】 【Transformation 3】

8. 10. The use according to claim 1 or 7, wherein the medicament further comprises a pharmaceutically acceptable excipient.

9. The use according to claim 1 or 7, wherein the pharmaceutical dosage form comprises a tablet, a capsule, a granule, a powder, or an injection, preferably the pharmaceutical dosage form is a capsule.

10. 10. The use according to claim 9, wherein the capsule has a dosage of 0.1 to 50 mg, such as 0.1 to 20 mg, for example, 0.2 to 10 mg, for example, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg or 6 mg, for example, 0.5 mg, 1 mg or 2 mg.

11. 8. The use according to claim 1 or 7, wherein the alopecia is alopecia areata, preferably severe alopecia areata.

12. 10. The use of claim 1 or 7, further comprising administering the compound or a composition comprising same to a subject in a single or multiple daily dosing regimen for 1 to 60 consecutive weeks, e.g., 12, 24, or 36 weeks, preferably once daily for 36 consecutive weeks.

13. At screening or baseline, the subject's alopecia areata is measured by the Severity of Alopecia Tool (SALT), and the hair loss area is 50% or more of the entire scalp, including alopecia totalis and alopecia universalis, and there has been no spontaneous improvement in the past 6 months (i.e., a spontaneous decrease in SALT score of 10% or less), and the duration of alopecia areata (the time from the last time there was no scalp hair loss to the randomization group) is 8 years or less; or, at 24 or 36 weeks after the start of treatment, the subject's SALT score (degree of hair loss) is ≦20, for example ≦10; or, at 24 or 36 weeks after the start of treatment, the subject's SALT score (degree of hair loss) is ≦20, for example ≦10; or the subject's Eyebrow Assessment (EBA) and Eyelash Assessment (ELA) at 24 or 36 weeks show an improvement of at least 2 grades or a score of 3 compared to baseline; or the subject's ClinRO score at 24 or 36 weeks after the start of treatment is 0 or 1 and an improvement of 2 or more points; or the subject's Global Impression of Disease (PRO) score at 24 or 36 weeks after the start of treatment is 0 or 1; or the subject's plasma drug concentration before the first dose is C max or the subject should not have any of the following characteristics prior to the first administration: (1) hemoglobin <11.0 g / dL (110.0 g / L); (2) neutrophil count (NEUT#), white blood cell count (WBC) < lower limit of normal (LLN); (3) Alanine aminotransferase (ALT), aspartate aminotransferase (AST) > 2 times the upper limit of normal (2ULN), total bilirubin (TBIL) > 1.5 times the upper limit of normal (1.5ULN); or (4) eGFR calculated according to Cockcroft-Gault is ≦60 ml / min or currently undergoing regular hemodialysis.

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