JAK1 / JAK2 / TYK2 inhibitors for the topical treatment of skin diseases

Abstract

The provided 4-pyrazolyl-N-heteroarylpyrimidin-2-amine compounds are potent TYK2 / JAK1 / JAK2 inhibitors with low systemic exposure when applied topically. Thus, these compounds and compositions are useful as topical treatments for JAK1 / JAK2 / TYK2-associated skin disorders, such as atopic dermatitis, psoriasis, urticaria, alopecia areata, vitiligo, hidradenitis pustulosa, hand eczema, lipoid necrolysis, chronic graft-versus-host disease of non-sclerosing skin, digital dermatitis, or lichen planus.

Description

Detailed Description of the Invention

[0001] 〔background〕 The Janus kinase family consists of four known family members: JAK1, JAK2, JAK3, and JAK tyrosine kinase 2 (TYK2). These cytoplasmic tyrosine kinases associate with membrane cytokine receptors, such as the common gamma chain receptor and glycoprotein 130 (gp130) (Murray, J. Immunol. 178(5):2623-2629, 2007). Approximately 40 cytokine receptors signal through a combination of these four JAK family members and seven downstream substrates, namely, signal transduction and activator of transcription (STAT) family members (Ghoreschi et al., Immunol Rev. 228(1):273-287, 2009). Cytokine binding to the receptor initiates JAK activation through transphosphorylation and autophosphorylation. JAK family kinases then phosphorylate cytokine receptor residues, forming binding sites for proteins containing sarcoma homology 2 (SH2), such as STAT factors and other regulatory factors, which are subsequently activated by JAK phosphorylation. Activated STATs enter the nucleus and initiate the expression of survival factors, cytokines, chemokines, and molecules that promote leukocyte trafficking (Schindler et al., J. Biol. Chem. 282(28):20059-20063, 2007). JAK activation also leads to cell proliferation via pathways mediated by phosphoinositide 3-kinase (PI3K) and protein kinase B.

[0002] Tofacitinib, a JAK1 / JAK3 / JAK2 inhibitor, was the first JAK inhibitor approved by the FDA for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. Recently, the JAK1-selective compounds upadacitinib and abrocitinib have been approved for the treatment of atopic dermatitis (Nakashima et al. Allergol Int. 2022 Jan; 71(1):40-46). The TYK2-selective inhibitor deuclavacitinib has shown favorable phase 2 and 3 results in patients with psoriasis (Papp et al. N Engl J Med. 2018, 379; 14) and is FDA-approved for the treatment of psoriasis. Ruxolitinib (Opzelura), a selective JAK1 / JAK2 inhibitor, is also approved. TM Topical formulations of JAK inhibitors have also been approved for the treatment of mild to moderate atopic dermatitis and are in clinical development for the treatment of psoriasis, alopecia areata, vitiligo, hidradenitis pustules, hand eczema, lipoid necrolysis, chronic graft-versus-host disease (CVS), digital dermatitis, and lichen planus. Therefore, JAK inhibitors are useful for the treatment of various skin diseases, such as atopic dermatitis, psoriasis, urticaria, alopecia areata, vitiligo, hidradenitis pustules, hand eczema, lipoid necrolysis, chronic graft-versus-host disease (CVS), digital dermatitis, or lichen planus (Zhang et al. J Inflamm Res. 2022 Mar 18; 15:1935-1941).

[0003] However, the approved oral agents, upadacitinib and abrocitinib, carry black box warnings regarding risks such as serious infections, non-melanoma skin cancer, thrombosis, and thrombocytopenia. Interestingly, topical formulations of ruxolitinib pose similar risks, likely due to high systemic exposure, with doses of 1.2 g to 37.6 g applied topically twice daily (FDA-approved Medication Guide, September 2021), reaching a Cmax of 449 ± 883 nM and an IC of 100 for JAK1 and JAK2 inhibition in biochemical assays. 50(3.3 nM and 2.8 nM, respectively) or by far exceeding the inhibition of cellular assays involving JAK1 and JAK2 (maximal effect at ≤300 nM, ruxolitinib FDA pharmacology review 2011).

[0004] Many of the reported JAK inhibitors, including tofacitinib, abrocitinib, ruxolitinib, baricitinib, and oclacitinib, share a pyrrolopyrimidine core structure, as shown below: [ka]

[0005] WO2009 / 064835 discloses compounds represented by D1 and D2 as JAK2 inhibitors. WO2012 / 062704 and WO2020 / 119819 disclose compounds represented by D3 as JAK1 / JAK2 / TYK2 inhibitors. WO2014 / 111037 discloses compounds represented by D4 as JAK1 / JAK2 / JAK3 inhibitors. WO2021 / 078022 discloses compounds represented by D5 as JAK1 / JAK2 / TYK2 inhibitors. [ka]

[0006] The present invention discloses novel 4-pyrazolyl-N-heteroarylpyrimidin-2-amine compounds as potent TYK2 / JAK1 / JAK2 inhibitors with low systemic exposure upon topical application. These compounds, and compositions containing the disclosed compounds, are therefore useful as topical treatments for JAK1 / JAK2 / TYK2-associated skin disorders, such as atopic dermatitis, psoriasis, urticaria, alopecia areata, vitiligo, hidradenitis pustulosa, hand eczema, lipoid necrolysis, chronic graft-versus-host disease of the non-sclerosing skin, digital dermatitis, or lichen planus.

[0007] 〔summary〕 The present disclosure provides novel 4-pyrazolyl-N-heteroarylpyrimidin-2-amine compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, as TYK2 / JAK1 / JAK2 kinase inhibitors with advantageous properties such as being rapidly degraded by liver microsomes, making them suitable as topical treatments for use in treating skin disorders. The present disclosure also provides compositions comprising the disclosed compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. The present disclosure further provides methods of using such compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof, or such compositions, to treat diseases associated with TYK2, JAK1, JAK2, including skin disorders such as atopic dermatitis, psoriasis, urticaria, alopecia areata, vitiligo, hidradenitis pustulosa, hand eczema, lipoid necrolysis, chronic graft-versus-host disease of the non-scleroderma, digital dermatitis, or lichen planus.

[0008] In one embodiment, a compound of formula (I): [ka] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, comprising: R 1 is C 1~3 Alkyl, C 3~4 cycloalkyl, or halo; R 2 teeth, [ka] and R 4 is C 1~3 Alkyl, C 3~8 cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is R 5, oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R and S(O)NRR'; 5 is C 1~3 alkyl, or 4- to 7-membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R, and S(O)NRR'; Each R, R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 1~3

[0023] Provided are compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof, wherein:

[0009] In another embodiment, the compound of formula (II): [ka] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, comprising: R 1 is C 1~3 Alkyl, C 3~4 cycloalkyl, or halo; R 2 teeth, [ka] and R 4 is C 1~3 Alkyl, C 3~8 cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is R5 , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R and S(O)NRR'; 5 is C 1~3 alkyl, or 4- to 7-membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R, and S(O)NRR'; Each R, R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 1~3

[0023] Provided are compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof, wherein:

[0010] In another embodiment, a compound of formula (III): [ka] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, comprising: R 1 is C 1~3 Alkyl, C 3~4 cycloalkyl, or halo; R 2 teeth, [ka] and R 4 is C 1~3 Alkyl, C 3~8cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is R 5 , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R and S(O)NRR'; 5 is C 1~3 alkyl, or 4- to 7-membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R, and S(O)NRR'; Each R, R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 1~3

[0023] Provided are compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof, wherein:

[0011] The compounds of the present invention and compositions comprising them are useful for treating or lessening the severity of diseases, disorders or symptoms thereof modulated by TYK2, JAK1 and JAK2.

[0012] Accordingly, one aspect of the present disclosure relates to a method for treating a skin disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of Formulas (I)-(III) herein, or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, optionally formulated into a composition. In some examples, the composition may be a pharmaceutical composition, which may further comprise a pharmaceutically acceptable carrier.

[0013] In some embodiments, the skin disorder is atopic dermatitis, psoriasis, urticaria, alopecia areata, vitiligo, hidradenitis pustulosis, hand eczema, lipoid necrolysis, chronic graft-versus-host disease of the non-sclerosing skin, digital dermatitis, or lichen planus.

[0014] In some embodiments, the skin disorder may be any of the skin disorders regulated by TYK2, JAK1, and JAK2. In certain embodiments, the skin disorder is atopic dermatitis, psoriasis, urticaria, alopecia areata, vitiligo, hidradenitis pustulosa, hand eczema, lipoid necrolysis, chronic graft-versus-host disease with non-sclerosing skin, digital dermatitis, or lichen planus.

[0015] The present disclosure also includes: (i) a pharmaceutical composition for use in treating a targeted skin disorder described herein, comprising a compound of Formula (I)-(III), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, and a pharmaceutically acceptable carrier; and (ii) the use of a compound of Formula (I)-(III), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, for the manufacture of a medicament for use in treating any of the targeted skin disorders.

[0016] The recitation of a list of chemical groups in any definition of a variable herein includes defining that variable as any single group or combination of listed groups. The recitation of an embodiment of a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0017] The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the invention will be apparent from the following drawings and detailed description of certain embodiments, as well as from the appended claims.

[0018] [Definition] Definitions of certain chemical terms are detailed below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and certain functional groups are generally defined as set forth therein. Additionally, general principles of organic chemistry, as well as specific functional groups and reactivities, are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7th Ed. th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0019] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods well known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725(1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds as individual isomers, substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0020] The compounds herein may also contain bonds (e.g., carbon-carbon bonds) where bond rotation is restricted relative to that particular bond, for example, restrictions due to the presence of a ring or double bond. Accordingly, all cis / trans and E / Z isomers are expressly included in the present disclosure. The compounds herein may also be represented in multiple tautomeric forms; in such cases, even if only a single tautomer may be represented, the present disclosure expressly includes all tautomeric forms of the compounds described herein. All isomeric forms of such compounds herein are expressly included in the present disclosure. The term "isomer" is intended to include diastereomers, enantiomers, positional isomers, structural isomers, rotamers, tautomers, and the like. For compounds containing one or more stereoisomeric centers, e.g., chiral compounds, the methods of the present disclosure can be practiced using enantiomerically enriched compounds, racemates, or mixtures of diastereomers. All isomers of the compounds defined herein are expressly included in the present disclosure.

[0021] In the formula, the bond [ka] is a single bond, and the dashed line [ka] is a single bond or is absent, and [ka] is a single or double bond.

[0022] Unless otherwise specified, formulas and structures depicted herein include compounds that do not contain isotopically enriched atoms, as well as compounds that contain isotopically enriched atoms, e.g., replacement of hydrogen with deuterium or tritium, 19 F 18 Substitution by F or carbon 13 C- or 14Compounds having this structure except for the C-enriched carbon substitution are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0023] The term "isotope" refers to varieties of a particular chemical element such that all isotopes of the element have the same number of protons in each atom of the element, but the isotopes differ in the number of neutrons.

[0024] When a range of values ​​("range") is described, the range includes each value and subrange within the range. Unless otherwise specified, a range includes both endpoints of the range.

[0025] As used herein, the term "salt" refers to any salt, including pharmaceutically acceptable salts. Salts include ionic compounds resulting from the neutralization reaction of an acid and a base. Salts are composed of one or more cations (positively charged ions) and one or more anions (negatively charged ions) so that they are electrically neutral (have no net charge). Salts of the compounds of the present invention include those derived from inorganic and organic acids and bases. Examples of acid addition salts include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed using other methods known in the art, such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfonate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobacillus acid salt, and benzoate. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-2-hydroxybenzoates, such as benzoates, ... + (C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Additional salts include ammonium salts, quaternary ammonium salts, and amine cation salts formed with counterions such as halide salts, hydroxide salts, carboxylate salts, sulfate salts, phosphate salts, nitrate salts, lower alkyl sulfonates, and aryl sulfonates.

[0026] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, and the like, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts of amino groups formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfonate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium salts, quaternary ammonium salts, and amine cation salts formed with counterions such as halide salts, hydroxide salts, carboxylate salts, sulfate salts, phosphate salts, nitrate salts, lower alkyl sulfonates, and aryl sulfonates.

[0027] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0028] Stereoisomers that are not mirror images of one another are called "diastereomers," while isomers whose mirror images are non-superimposable are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, it can have a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light, designating it as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0029] The term "prodrug" refers to a compound having a cleavable group that, upon solvation or under physiological conditions, becomes a compound described herein and has in vivo pharmaceutical activity. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein are active in both their acid and acid-derivative forms, but the acid-sensitive forms often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with an appropriate alcohol, amides prepared by reacting the parent acid with a substituted or unsubstituted amine, acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from the acidic groups appended to the compounds described herein are particularly suitable prodrugs. In some cases, it may be desirable to prepare double ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. C1-C8 alkyl esters, C2-C8 alkenyl esters, C2-C8 alkynyl esters, aryl esters, C7-C12 substituted aryl esters, and C7-C12 arylalkyl esters of the compounds described herein may be preferred.

[0030] The terms "composition" and "formulation" are used interchangeably.

[0031] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, child, or adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)), or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird (e.g., a commercially relevant bird, e.g., a chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be male or female, at any stage of development. The non-human animal may be a genetically modified or engineered animal. The term "patient" refers to a human subject in need of treatment for a disorder or disease.

[0032] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into or onto a subject.

[0033] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disorder or disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disorder. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., based on a history of symptoms and / or exposure to a pathogen). Treatment may also be continued after symptoms have resolved, e.g., to delay or prevent recurrence.

[0034] The terms "condition," "disease," and "disorder" are used interchangeably. An "effective amount" of a compound described herein refers to an amount sufficient to elicit a desired biological response. The effective amount of a compound described herein can vary depending on factors such as the desired biological endpoint, side effects, severity of the disease or disorder, the identity of the specific compound, pharmacokinetics and pharmacodynamics, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age, and health or general condition of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment. In certain embodiments, the effective amount is a single dose of a compound described herein. In certain embodiments, the effective amount is the total amount of a compound described herein in multiple administrations. In certain embodiments, the desired dosage is delivered three times a day, twice a day, once a day, every other day, every other day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dose is delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations).

[0035] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic effect in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effect of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to inhibit TYK2 / JAK1 / JAK2 kinase. In certain embodiments, a therapeutically effective amount is an amount sufficient to treat a skin disorder. In certain embodiments, a therapeutically effective amount is an amount sufficient to inhibit TYK2 / JAK1 / JAK2 kinase and treat a skin disorder.

[0036] Detailed Description of the Invention The present disclosure is based, at least in part, on the unexpected finding that compounds of Formulas (I)-(III) are selective TYK2 / JAK1 / JAK2 kinase inhibitors and exhibit good exposure in the skin but low exposure in plasma.

[0037] In one embodiment, a compound of formula (I): [ka] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, comprising: R 1 is C 1~3 Alkyl, C 3~4 cycloalkyl, or halo; R 2 teeth, [ka] and R 4 is C 1~3 Alkyl, C 3~8 cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is R 5 , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R and S(O)NRR'; 5 is C 1~3 alkyl, or 4- to 7-membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R, and S(O)NRR'; Each R, R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 1~3

[0023] Provided are compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof, wherein:

[0038] In another embodiment, the compound of formula (II): [ka] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, comprising: R 1 is C 1~3 Alkyl, C 3~4 cycloalkyl, or halo; R 2 teeth, [ka] and R 4 is C 1~3 Alkyl, C 3~8 cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is R 5 , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R and S(O)NRR'; 5 is C 1~3alkyl, or 4- to 7-membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R, and S(O)NRR'; Each R, R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 1~3

[0023] Provided are compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof, wherein:

[0039] In another embodiment, a compound of formula (III): [ka] or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, comprising: R 1 is C 1~3 Alkyl, C 3~4 cycloalkyl, or halo; R 2 teeth, [ka] and R 4 is C 1~3 Alkyl, C 3~8 cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is R 5 , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R and S(O)NRR'; 5is C 1~3 alkyl, or 4- to 7-membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R, and S(O)NRR'; Each R, R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 1~3

[0023] Provided are compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives or prodrugs thereof, wherein:

[0040] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein: R 2 teeth, [ka] and R 4 is C 1~3 Alkyl, C 3~8 cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is R 5 , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R and S(O)NRR'; 5 is C 1~3alkyl, or 4- to 7-membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R, and S(O)NRR'; Each R, R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 1~3 It is alkyl.

[0041] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 2 teeth, [ka] is.

[0042] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 2 teeth, [ka] is.

[0043] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 Alkyl, C 3~4 It is cycloalkyl, or halo.

[0044] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 It is alkyl.

[0045] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 1 is CH3.

[0046] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3~4 It is cycloalkyl.

[0047] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl.

[0048] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 1 is a halo.

[0049] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 1 is Cl.

[0050] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein: R 4 is C 1~3 alkyl, and R 5 , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R and S(O)NRR'; 5 is C 1~3alkyl, or 4- to 7-membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R, and S(O)NRR'; Each R, R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 1~3 It is alkyl.

[0051] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 4 is CH2CH2OH.

[0052] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 4 is isopropyl.

[0053] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 4 is CH3.

[0054] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 4 is CH2R 5 and R 5 is a 4- to 6-membered heterocyclyl.

[0055] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 4 is CH2R 5 and R 5 teeth, [ka] is.

[0056] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein: R 4 are 4- to 7-membered heterocyclyl, and R 5 , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R and S(O)NRR'; 5 is C 1~3 alkyl, or 4- to 7-membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O)R', S(O)R, and S(O)NRR'; Each R, R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 1~3 It is alkyl.

[0057] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R 4 teeth, [ka] is.

[0058] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein the compound is depicted in Table 1: Table 1: [ka] to provide. Representative compounds of the present invention include: 2-(3-(4-(5-cyclopropyl-2-(isoxazol-4-ylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (1); 2-(3-(4-(5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (2); 2-(1-(ethylsulfonyl)-3-(4-(2-(isoxazol-4-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (3); 2-(1-(ethylsulfonyl)-3-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (12); 2-(3-(4-(5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (13); 2-(1-(ethylsulfonyl)-3-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (17); 2-(1-(ethylsulfonyl)-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (18); 2-(1-(ethylsulfonyl)-3-(4-(5-methyl-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (26); 2-(3-(4-(5-chloro-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (27).

[0059] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein the compound is depicted in Table 2: [ka] to provide. Representative compounds of the present invention include: (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (4); (R)-3-cyclopentyl-3-(4-(2-(isoxazol-4-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (5); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (6); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (7); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (8); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (9); (R)-3-(4-(5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (10); ((R)-3-(4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (11); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (15); (R)-3-cyclopentyl-3-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (16); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (23); (R)-3-cyclopentyl-3-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (24); (R)-3-(4-(5-chloro-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (25).

[0060] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein the compound is: (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (4); [ka]

[0061] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein the compound is: (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (23); [ka]

[0062] In some embodiments, the present invention provides a compound of any one of Formulas (I)-(III), or a pharmaceutically acceptable salt thereof, wherein the compound is: (R)-3-cyclopentyl-3-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (24); [ka]

[0063] In another embodiment, the present invention provides crystalline form A of compound (4), [ka] Here, the powder X-ray diffraction pattern of said crystalline form exhibits characteristic peaks at 2θ angles of 10.3°±0.2°, 14.5°±0.2° and 16.7°±0.2°.

[0064] In some embodiments, the present invention provides crystalline form A of Compound (4), whose X-ray powder diffraction pattern exhibits characteristic peaks at 2θ angles of 10.3°±0.2°, 14.5°±0.2°, 16.7°±0.2°, 19.8°±0.2°, 23.3°±0.2°, and 23.5°±0.2°.

[0065] In some embodiments, the present invention provides crystalline form A of Compound (4), wherein the powder X-ray diffraction pattern of said crystalline form exhibits characteristic peaks at 2θ angles of 10.3°±0.2°, 14.5°±0.2°, 16.7°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 23.3°±0.2°, 23.5°±0.2°, 27.2°±0.2°, and 28.1°±0.2°.

[0066] Accordingly, disclosed herein are methods of treating skin disorders, such as those described herein, with an effective amount of a compound of Formula (I)-(III), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, or a composition comprising a compound of Formula (I)-(III), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof.

[0067] BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Ear thickness in the hIL-23-induced psoriasis model for compound 4.

[0068] Figure 2: Ear thickness in the DNFB-induced atopic dermatitis model for compound 4.

[0069] Figure 3: XRPD of Form A of Compound 4.

[0070] Figure 4: TGA and DSC curves of Form A of Compound 4.

[0071] [Composition] The present disclosure provides pharmaceutical compositions comprising a compound of Formula (I)-(III), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein comprise a compound of Formula (I)-(III), or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0072] The pharmaceutical compositions described herein can be prepared by any method well known in the art of pharmacy. Generally, such methods of preparation include bringing into association a compound described herein (i.e., the "active ingredient") with the carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dosage unit.

[0073] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and flavoring agents may also be present in the compositions.

[0074] The pharmaceutical compositions of the present invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. In certain embodiments, the compounds of the formulations herein are administered transdermally (for example, using a transdermal patch). Other formulations can be conveniently presented in unit dosage forms, such as tablets and sustained-release capsules, and liposomes, and can be prepared by any method well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).

[0075] Such preparative methods include the step of bringing into association with the molecule a component to be administered, such as a carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0076] In certain preferred embodiments, compound is orally administered.The composition of the present invention suitable for oral administration can be presented in the form of individual units such as capsules, sachets or tablets, each containing a predetermined amount of active ingredient; as powder or granules; as a solution or suspension in aqueous liquid or non-aqueous liquid; or as oil-in-water liquid emulsion or water-in-oil liquid emulsion, or as liposome encapsulation, and as bolus.Soft gelatin capsules are useful for containing such suspensions, and can advantageously increase the absorption rate of compound.

[0077] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent, in a suitable machine. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets can optionally be coated or scored and can be molded to provide a slow or controlled release of the active ingredient therein. Methods for formulating such sustained- or controlled-release compositions of pharmaceutically active ingredients, such as the compounds described herein and other compounds known in the art, are well known in the art and are described in several issued U.S. patents, some of which include, but are not limited to, U.S. Pat. Nos. 4,369,172 and 4,842,866, and the references cited therein. Coatings can be used to deliver compounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, 6,569,457, 6,461,631, 6,528,080, and 6,800,663, and references cited therein). A useful formulation of the compounds of the invention is in the form of enteric-coated pellets, in which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.

[0078] For oral tablets, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also commonly added.For oral administration in capsule form, useful diluents include lactose and dry corn starch.For oral administration of aqueous suspension, active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners and / or flavorings and / or colorings can be added.

[0079] Compositions suitable for topical administration include lozenges, which typically contain the ingredient in a flavored base, such as sucrose and acacia or tragacanth; and tablets, which contain the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia.

[0080] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the preparation isotonic with the patient's blood; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents.The preparations can be stored in single-dose or multi-dose containers, such as sealed ampoules and vials, in a lyophilized (freeze-dried) state, and only require the addition of sterile liquid carriers, such as water for injection, immediately before use.Extemporaneous injection solutions and suspensions can also be prepared from sterile powders, granules, and tablets.

[0081] Such injections may be in the form of, for example, a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated using suitable dispersants or wetting agents (e.g., Tween 80, etc.) and suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among acceptable vehicles and solvents, mannitol, water, Ringer's solution, and isotonic sodium chloride solution can be used. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be employed, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injections, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0082] The pharmaceutical composition of the present invention can be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the active ingredient.Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycol.

[0083] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents well known in the art.

[0084] Topical administration of the pharmaceutical compositions of the present invention is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated in a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention can also be applied topically to the lower intestinal tract via a rectal suppository or suitable enema. Topical transdermal patches and iontophoretic administration are also included in the present invention.

[0085] Particularly preferred derivatives and prodrugs are those that increase the bioavailability of the compounds of the invention when such compounds are administered to a mammal (e.g., by making an orally administered compound more readily absorbed into the blood) or that enhance delivery of the parent compound to a biological compartment (e.g., the brain or central nervous system) relative to the parent species. Preferred prodrugs include derivatives in which groups that enhance water solubility or active transport across the intestinal membrane have been added to the structures of the formulas described herein. For example, Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H. Design of Prodrugs', Elsevier: Amsterdam, 1985; pp 1-92; Bundgaard, H.; Nielsen, NM Journal of Medicinal Chemistry 1987, 30, 451-454; Bundgaard, H.A. Textbook of Drug Design and Development, Harwood Academic Publ.: Switzerland, 1991; pp 113-191; Digenis, GA et al. Handbook of Experimental Pharmacology 1975, 28, 86-112; Friis, GJ; Bundgaard, H. A TextbookofDrugDesignandDevelopment, 2 ed.; OverseasPubl.: Amsterdam, 1996; See pp 351-385; Pitman, IH Medicinal Research Reviews 1981, 1, 189-214.

[0086] The therapeutic application of the subject may be local, such that the composition is administered to the desired site. Various techniques can be used to provide the composition to the subject at the desired site, such as injection using a catheter, trocar, projectile, pluronic gel, stent, sustained drug release polymer, or other device that provides internal access.

[0087] According to another embodiment, the present invention provides a method of impregnating an implantable drug release device, including but not limited to, biodegradable polymer capsules or bullets, non-degradable diffusible polymer capsules, and biodegradable polymer wafers, comprising the step of contacting said drug release device with a compound or composition of the present invention.

[0088] According to another embodiment, the present invention provides an implantable medical device coated with a compound or composition comprising a compound of the present invention, such that said compound is therapeutically active.

[0089] In another embodiment, the composition of the present invention further comprises a second therapeutic agent. The second therapeutic agent includes any compound or therapeutic agent known to have or exhibiting advantageous properties when administered alone or together with a compound of any of the formulas herein. Agents that can be usefully combined with these compounds include other kinase inhibitors and / or other therapeutic agents for the treatment of the above-mentioned diseases and disorders.

[0090] Such agents are described in detail in the art. Preferably, the second therapeutic agent is an agent useful for treating or preventing a disease or condition selected from cancer and neoplastic diseases or disorders, autoimmune and inflammatory diseases or disorders, and neurodegenerative diseases or disorders.

[0091] In another embodiment, the present invention provides separate dosage forms of a compound of the present invention and a second therapeutic agent that are associated with each other. As used herein, the term "associated with each other" refers to the separate dosage forms being packaged together or otherwise attached to each other in a manner that makes it readily apparent that the separate dosage forms are intended to be sold together and administered together (within 24 hours of each other, sequentially or simultaneously).

[0092] In the pharmaceutical compositions of the present invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount that, when administered in a proper dosage regimen, is sufficient to reduce or ameliorate the severity, duration, or progression of the disorder being treated, prevent the progression of the disorder being treated, cause regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effects of other therapies.

[0093] The correlation of dosages for animals and humans (based on milligrams per square meter of body surface area) is described in Freireich et al. (1966) Cancer Chemother Rep 50:219. Body surface area can be roughly determined from the patient's height and weight. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, NY, 1970, 537. Effective amounts of the compounds of the present invention may range from about 0.001 mg / kg to about 500 mg / kg, more preferably 0.01 mg / kg to about 50 mg / kg, and even more preferably 0.1 mg / kg to about 2.5 mg / kg. As recognized by those skilled in the art, effective dosages will also vary depending on the disease being treated, the severity of the disease, the route of administration, the patient's sex, age, and general health, the amount of excipients used, the possibility of concurrent use of other therapeutic treatments, such as the use of other drugs, and the judgment of the treating physician.

[0094] In pharmaceutical compositions containing a second therapeutic agent, the effective amount of the second therapeutic agent is about 20% to 100% of the dosage typically used in monotherapy using only that agent. Preferably, the effective amount is about 70% to 100% of the typical monotherapy dose. Typical monotherapy doses of these second therapeutic agents are well known in the art. See, for example, Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), the entire contents of each of which are incorporated herein by reference.

[0095] [Treatment Method] As generally described herein, the present disclosure provides a method for treating a skin disorder (or a symptom thereof), comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, or a composition comprising an effective amount of a compound of the present disclosure, or a salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof. Such a method can be performed in vivo (i.e., by administration to a subject) or in vitro (e.g., by contact with tissue or cell culture). As used herein, treating includes therapeutic treatment. In certain embodiments, the subject is identified as a subject in need thereof. In certain embodiments, the method further comprises treating the subject; i.e., improving the disease, disorder, or its symptoms.

[0096] In certain embodiments, the effective amount is a therapeutically effective amount. For example, in certain embodiments, the method slows the progression of a skin disorder in a subject. In certain embodiments, the method improves the condition of a subject suffering from a skin disorder. In certain embodiments, the subject is suspected or confirmed to have a skin disorder.

[0097] Exemplary skin disorders include, but are not limited to, atopic dermatitis, psoriasis, urticaria, alopecia areata, vitiligo, hidradenitis pustulosis, hand eczema, lipoid necrolysis, chronic graft-versus-host disease of the non-sclerosing skin, digital dermatitis, or lichen planus.

[0098] In certain embodiments, the skin disorder is regulated by the JAK-STAT pathway. In certain embodiments, the skin disorder is regulated by JAK1. In certain embodiments, the skin disorder is regulated by JAK2. In certain embodiments, the skin disorder is regulated by TYK2. In certain embodiments, the skin disorder is regulated by any combination of TYK2, JAK1, and JAK2.

[0099] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intracavitary, subcutaneous, intraventricular / intraventricular, transdermal, interdermal, rectal, vaginal, intraperitoneal, topical (by powder, ointment, cream, and / or drops), mucosal, nasal, submucosal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as oral spray, nasal spray, and / or aerosol. Particularly contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), local administration via the blood supply and / or lymphatic supply, and / or direct administration to the affected area. Generally, the most appropriate administration route depends on various factors, including the properties of the drug (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In certain embodiments, the compounds or pharmaceutical compositions described herein are suitable for topical administration to the subject's eye.

[0100] [Example] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate particular embodiments and are not intended to limit the scope of the disclosure. Furthermore, it should be understood that various other embodiments, modifications, and equivalents thereof may be suggested to those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0101] The compounds of the present disclosure can be prepared by methods well known in the art of organic synthesis. It is understood that in any method, protecting groups for sensitive or reactive groups can be employed as necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (TW Green and PGM Wuts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage in the compound synthesis using methods readily apparent to those skilled in the art.

[0102] Unless otherwise stated, reagents and solvents were used as obtained from commercial suppliers.

[0103] Temperatures are given in degrees Celsius. Unless otherwise noted, all evaporations were carried out under reduced pressure. The structure of final products, intermediates, and starting materials was confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

[0104] Example 1: Preparation of 2-(3-(4-(5-cyclopropyl-2-(isoxazol-4-ylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (1) [ka] Step 1: A mixture of 1a (9.2 g, 33.5 mmol, 1.0 eq), cyclopropylboronic acid (3.7 g, 43.5 mmol, 1.3 eq), Pd(OAc) (1.5 g, 6.7 mmol, 0.2 eq), PCy (3.7 g, 13.4 mmol, 0.4 eq), and KPO (56.7 g, 267.6 mmol, 8.0 eq) in toluene (460 mL) / HO (92 mL) was stirred at 105 °C overnight and then cooled to room temperature. The resulting mixture was concentrated, and the residue was purified by silica gel column flash chromatography (PE / EA = 10 / 1) to give 1b (700 mg, 11.0% yield) as a yellow oil. LC / MS: [M+H] + :189.2.

[0105] Step 2: A mixture of 1b (388 mg, 2.06 mmol, 2.0 eq), 2-(1-(ethylsulfonyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile 1c (390 mg, 1.03 mmol, 1.0 eq), Pd(PPh) (115 mg, 0.10 mmol, 0.05 eq), and NaCO (164 mg, 1.55 mmol, 1.5 eq) in dioxane (6 mL) / HO (1 mL) was stirred at 80 °C overnight and then cooled to room temperature. The resulting mixture was concentrated, and the residue was purified by silica gel column flash chromatography (PE / EA = 1 / 1) to give 1d (300 mg, 71.8% yield) as a yellow solid. LC / MS: [M+H] + :407.1.

[0106] Step 3: A mixture of 1d (100 mg, 0.25 mmol, 1.0 eq), isoxazol-4-amine (31 mg, 0.37 mmol, 1.5 eq), Brettfos PdG (23 mg, 0.025 mmol, 0.1 eq), and KPO (104 mg, 0.50 mmol, 2.0 eq) in dioxane (5 mL) was stirred overnight at 100 °C under N. The resulting mixture was concentrated and purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to give the crude product (50 mg). The crude product was then purified by prep-HPLC (0.1% NHH0) to give 1 (9.60 mg, 0.021 mmol, 8.5% yield) as a white solid. Rt: 1.525 min. LCMS: [M+H] + : 455.1. 1 H NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1 H), 9.13 (s, 1 H), 8.76 (s, 1 H), 8.61 (s, 1 H), 8.40 (s, 1 H), 8.32 (s, 1 H), 4.56 (d, J= 9.2 Hz, 2 H), 4.25 (d, J=9.2 Hz, 2 H), 3.69 (s, 2 H), 3.27-3.21 (m, 2 H), 2.03-1.99 (m, 1 H), 1.25 (t, J=7.6 Hz, 3 H), 1.05-1.00 (m, 2 H), 0.64-0.61 (m, 2 H).

[0107] Example 2: Preparation of 2-(3-(4-(5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (2) [ka] Step 1: A mixture of 1a (9.2 g, 33.5 mmol, 1.0 eq), cyclopropylboronic acid (3.7 g, 43.5 mmol, 1.3 eq), Pd(OAc) (1.5 g, 6.7 mmol, 0.2 eq), Pcy (3.7 g, 13.4 mmol, 0.4 eq), and KPO (56.7 g, 267.6 mmol, 8.0 eq) in toluene (460 mL) / HO (92 mL) was stirred at 105 °C overnight and then cooled to room temperature. The resulting mixture was concentrated, and the residue was purified by silica gel column flash chromatography (PE / EA = 10 / 1) to give 1b (700 mg, 11.0% yield) as a yellow oil. LC / MS: [M+H] + :189.2.

[0108] Step 2: A mixture of 1b (388 mg, 2.06 mmol, 2.0 eq), 2-(1-(ethylsulfonyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile 1c (390 mg, 1.03 mmol, 1.0 eq), Pd(PPh) (115 mg, 0.10 mmol, 0.05 eq), and NaCO (164 mg, 1.55 mmol, 1.5 eq) in dioxane (6 mL) / HO (1 mL) was stirred at 80 °C overnight and then cooled to room temperature. The resulting mixture was concentrated, and the residue was purified by silica gel column flash chromatography (PE / EA = 1 / 1) to give 1d (300 mg, 71.8% yield) as a yellow solid. LC / MS: [M+H] + :407.1.

[0109] Step 3: A mixture of 1d (100 mg, 0.25 mmol, 1.0 eq), 1-methyl-1H-pyrazol-4-amine (36 mg, 0.37 mmol, 1.5 eq), Brettfos PdG (23 mg, 0.025 mmol, 0.1 eq), and KPO (104 mg, 0.50 mmol, 2.0 eq) in dioxane (5 mL) was stirred overnight at 100 °C under N. The resulting mixture was concentrated and purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to give the crude product (120 mg). The crude product was then purified by prep-HPLC (0.1% NHHO) to give 2 (19.8 mg, 0.042 mmol, 17.2% yield) as a white solid. Rt: 1.348 min. LCMS: [M+H] + : 468.3. 1 H NMR (400 MHz, DMSO-d6): δ 9.26 (s, 1 H), 8.73 (s, 1 H), 8.37 (s, 1 H), 8.23 ​​(s, 1 H), 7.92 (s, 1 H), 7.47 (s, 1 H), 4.55 (d, J= 9.2 Hz, 2 H), 4.24 (d, J=9.6 Hz, 2 H), 3.82 (s, 3 H), 3.69 (s, 2 H), 3.27-3.21 (m, 2 H), 2.00-1.96 (m, 1 H), 1.25 (t, J=7.2 Hz, 3 H), 1.03-0.98 (m, 2 H), 0.61-0.57 (m, 2 H).

[0110] Example 3 Preparation of 2-(1-(ethylsulfonyl)-3-(4-(2-(isoxazol-4-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (3) [ka] Step 1: A mixture of 1c (500 mg, 1.32 mmol, 1.0 eq), 2,4-dichloro-5-methylpyrimidine (643 mg, 3.96 mmol, 3.0 eq), Pd(PPh3)4 (150 mg, 0.13 mmol, 0.1 eq), and Na2CO3 (280 mg, 2.64 mmol, 2.0 eq) in dioxane (10 mL) and HO (1 mL) was stirred at 80 °C for 16 h and then cooled to room temperature. The resulting mixture was concentrated, and the residue was purified by silica gel column flash chromatography (PE / EA = 1 / 1) to give 3a (505 mg, crude) as a white solid. LC / MS: [M+H] + :381.0.

[0111] Step 2: A mixture of 3a (100 mg, 0.26 mmol, 1.0 eq), isoxazol-4-amine (44 mg, 0.52 mmol, 2.0 eq), Brettfos PdG (24 mg, 0.026 mmol, 0.1 eq), and KPO (138 mg, 0.65 mmol, 2.5 eq) in dioxane (5 mL) was stirred overnight at 100 °C under N. The resulting mixture was concentrated and purified by column chromatography on silica gel (DCM / MeOH = 20 / 1) to give the crude product, which was then purified by prep-HPLC (0.1% NHH0) to give 3 (9.23 mg, 0.022 mmol, 8.2% yield) as a white solid. Rt: 1.168 min. LCMS: [M+H] + : 429.2. 1 H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1 H), 9.13 (s, 1 H), 8.66 (s, 1 H), 8.60 (s, 1 H), 8.37 (s, 1 H), 8.28 (s, 1 H), 4.57 (d, J= 9.2 Hz, 2 H), 4.25 (d, J=9.2 Hz, 2 H), 3.67 (s, 2 H), 3.26-3.23 (m, 2 H), 2.35 (s, 3 H), 1.26-1.23 (m, 3 H).

[0112] Example 4: Preparation of (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (4) [ka] Step 1: Compound 4a (15.2 g, 48.2 mmol, 1.0 eq), 2,4-dichloro-5-methylpyrimidine (23.6 g, 145 mmol, 3.0 eq), and anhydrous Na2CO3 (15.4 g, 145 mmol, 2.0 eq) were added to a mixture of dioxane (400 mL) and HO (40 mL) at room temperature. Pd(PPh3)4 (5.57 g, 4.82 mmol) was then added quickly and purged with nitrogen three times. The reaction mixture was heated at 95 °C under a N2 atmosphere for 18 h. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The residue was purified by column chromatography on silica gel (PE / EA = 3 / 1) to give compound 4b (18 g) as an oil. Rt: 1.820 min. LCMS: [M+H] + : 316.0.

[0113] Step 2: Compound 4b (16.8 g, 53.2 mmol, 1.0 eq), 1-methyl-1H-pyrazol-4-amine (25.8 g, 266 mmol), and p-toluenesulfonic acid monohydrate (30.3 g, 160 mmol) were added to isopropanol (1000 mL), and the mixture was stirred at 90 °C for 18 h under a N atmosphere. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give the crude product. The crude product was further purified by Prep-HPLC to give compound 4 (12 g, 60% yield) as a white solid. Rt: 1.569 min. LCMS: [M+H] + : 377.2. 1H NMR (400 MHz, DMSO) δ 9.17 (s, 1 H), 8.48 (s, 1 H), 8.24 (s, 1 H), 8.17 (s, 1 H), 7.90 (s, 1 H), 7.48 (s, 1 H), 4.59-4.54 (m, 1 H), 3.82 (s, 3 H), 3.27-3.15 (m, 2 H), 2.45-2.38 (m, 1 H), 2.29 (s, 3 H), 1.84-1.80 (m, 1 H), 1.62-1.44 (m, 4 H), 1.35-1.16 (m, 3 H).

[0114] The solid was confirmed to be Form A of the free base of the present disclosure. The XRPD pattern was substantially as depicted in Figure 3, and the XRPD data is presented in Table 3. The TGA curve for Form A of the present disclosure showed a weight loss of about 0.07% when heated to 120°C, substantially as depicted in Figure 4. The DSC curve for Form A of the present disclosure is also depicted in Figure 4 and shows a single endothermic peak at about 143°C, corresponding to the melting endothermic peak. Without intending to be limiting in any way, Form A is anhydrous.

[0115] Table 3. XRPD peak list [Table 1]

[0116] Example 5 Preparation of (R)-3-cyclopentyl-3-(4-(2-(isoxazol-4-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (5) [ka] Step 1: To a mixture of 4a (500 mg, 1.59 mmol, 1.0 eq) and 2,4-dichloro-5-methylpyrimidine (778 mg, 4.77 mmol, 3.0 eq) in dioxane (20 mL) and HO (2 mL) was added NaCO (337 mg, 3.18 mmol, 2.0 eq) and Pd(PPh) (185 mg, 0.16 mmol, 0.1 eq). After the addition, the mixture was degassed under N three times and stirred at 80 °C under N for 16 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 4 / 1) to give 4b (771 mg, crude) as a brown solid. Rt: 1.575 min. LCMS: [M+H] + : 316.2.

[0117] Step 2: 4b (450 mg, 1.43 mmol, 1.0 eq), isoxazol-4-amine (239 mg, 2.86 mmol, 2.0 eq), Brettfos PdG (65 mg, 0.072 mmol, 0.05 eq), and KPO (758 mg, 3.58 mmol, 2.5 eq) in dioxane (20 mL) were stirred at 100 °C for 16 h under a N atmosphere. The resulting mixture was concentrated and purified by column chromatography on silica gel (DCM / MeOH = 10 / 1) to give the crude product (110 mg). The crude product was then purified by prep-HPLC (0.1% NHHO) to give 5 (36.6 mg, 0.10 mmol, 7.1% yield) as a white solid. Rt: 1.891 min. LCMS: [M+H] + : 364.2. 1 H NMR (400 MHz, DMSO) δ 9.49 (s, 1 H), 9.13 (s, 1 H), 8.60 (s, 1 H), 8.56 (s, 1 H), 8.33 (s, 1 H), 8.18 (s, 1 H), 4.61-4.56 (m, 1 H), 3.27-3.16 (m, 2 H), 2.49-2.39 (m, 1 H), 2.33 (s, 3 H), 1.84-1.80 (m, 1 H), 1.63-1.43 (m, 4 H), 1.35-1.18 (m, 3 H).

[0118] Example 6 Preparation of (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (6) [ka] Step 1: To a mixture of 4a (500 mg, 1.59 mmol, 1.0 eq) and 2,4-dichloro-5-methylpyrimidine (778 mg, 4.77 mmol, 3.0 eq) in dioxane (20 mL) and HO (2 mL) was added NaCO (337 mg, 3.18 mmol, 2.0 eq) and Pd(PPh) (185 mg, 0.16 mmol, 0.1 eq). After the addition, the mixture was degassed under N three times and stirred at 80 °C under N for 16 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 4 / 1) to give 4b (771 mg, crude) as a brown solid. Rt: 1.575 min. LCMS: [M+H] + : 316.2.

[0119] Step 2: 4b (130 mg, 0.41 mmol, 1.0 eq), 1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-amine (149 mg, 0.82 mmol, 2.0 eq), Brettfos PdG (36 mg, 0.041 mmol, 0.1 eq), and KPO (218 mg, 1.03 mmol, 2.5 eq) in dioxane (10 mL) were stirred at 120 °C for 16 h under a N atmosphere. The resulting mixture was filtered, and the residue was concentrated and purified by prep-HPLC (0.1% NHHO) to give 6 (14.72 mg, 0.032 mmol, 7.7% yield) as a white solid. Rt: 1.514 min. LCMS: [M+H] + : 461.3. 1H NMR (400 MHz, DMSO) δ 9.18 (s, 1 H), 8.48 (s, 1 H), 8.24 (s, 1 H), 8.16 (s, 1 H), 7.93 (s, 1 H), 7.50 (s, 1 H), 4.57-4.56 (m, 1 H), 3.99-3.97 (m, 2 H), 3.84-3.80 (m, 2 H), 3.27-3.19 (m, 4 H), 2.45-2.38 (m, 1 H), 2.29 (s, 3 H), 2.06-1.98 (m, 1 H), 1.85-1.78 (m, 1 H), 1.65-1.39 (m, 6 H), 1.35-1.13 (m, 5 H).

[0120] Example 7 Preparation of (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (7) [ka] Step 1: To a mixture of 4a (500 mg, 1.59 mmol, 1.0 eq) and 2,4-dichloro-5-methylpyrimidine (778 mg, 4.77 mmol, 3.0 eq) in dioxane (20 mL) and HO (2 mL) was added NaCO (337 mg, 3.18 mmol, 2.0 eq) and Pd(PPh) (185 mg, 0.16 mmol, 0.1 eq). After the addition, the mixture was degassed under N three times and stirred at 80 °C under N for 16 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 4 / 1) to give 4b (771 mg, crude) as a brown solid. Rt: 1.575 min. LCMS: [M+H] + : 316.2.

[0121] Step 2: A mixture of 4b (130 mg, 0.41 mmol, 1.0 eq), 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (138 mg, 0.82 mmol, 2.0 eq), Brettfos PdG (36 mg, 0.041 mmol, 0.1 eq), and KPO (218 mg, 1.03 mmol, 2.5 eq) in dioxane (10 mL) was stirred at 120 °C for 16 h under a N atmosphere. The resulting mixture was filtered, and the residue was concentrated and purified by prep-HPLC (0.1% NHHO) to give 7 (21.47 mg, 0.048 mmol, 11.6% yield) as a white solid. Rt: 1.484 min. LCMS: [M+H] + : 447.2. 1 H NMR (400 MHz, DMSO) δ 9.17 (s, 1 H), 8.48 (s, 1 H), 8.24 (s, 1 H), 8.15 (s, 1 H), 7.98 (s, 1 H), 7.54 (s, 1 H), 4.57-4.56 (m, 1 H), 4.39-4.36 (m, 1 H), 3.98-3.95 (m, 2 H), 3.50-3.43 (m, 2 H), 3.29-3.19 (m, 2 H), 2.44-2.38 (m, 1 H), 2.29 (s, 3 H), 1.96-1.81 (m, 5 H), 1.62-1.32 (m, 4 H), 1.30-1.18 (m, 3 H).

[0122] Example 8 Preparation of (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (8) [ka] Step 1: To a mixture of 4a (500 mg, 1.59 mmol, 1.0 eq) and 2,4-dichloro-5-methylpyrimidine (778 mg, 4.77 mmol, 3.0 eq) in dioxane (20 mL) and HO (2 mL) was added NaCO (337 mg, 3.18 mmol, 2.0 eq) and Pd(PPh) (185 mg, 0.16 mmol, 0.1 eq). After the addition, the mixture was degassed under N three times and stirred at 80 °C under N for 16 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 4 / 1) to give 4b (771 mg, crude) as a brown solid. Rt: 1.575 min. LCMS: [M+H] + : 316.2.

[0123] Step 2: A mixture of 4b (130 mg, 0.41 mmol, 1.0 eq), 1-(oxetan-3-yl)-1H-pyrazol-4-amine (115 mg, 0.82 mmol, 2.0 eq), Brettfos PdG (36 mg, 0.041 mmol, 0.1 eq), and KPO (218 mg, 1.03 mmol, 2.5 eq) in dioxane (10 mL) was stirred at 120 °C for 16 h under a N atmosphere. The resulting mixture was filtered, and the residue was concentrated and purified by prep-HPLC (0.1% NHHO) to give 8 (47.39 mg, 0.113 mmol, 27.4% yield) as a white solid. Rt: 1.433 min. LCMS: [M+H] + : 419.2. 1 H NMR (400 MHz, DMSO) δ 9.27 (s, 1 H), 8.49 (s, 1 H), 8.25 (s, 1 H), 8.18 (s, 1 H), 8.08 (s, 1 H), 7.66 (s, 1 H), 5.62-5.55 (m, 1 H), 4.93-4.87 (m, 4 H), 4.59-4.53 (m, 1 H), 3.27-3.19 (m, 2 H), 2.45-2.41 (m, 1 H), 2.30 (s, 3 H), 1.86-1.78 (m, 1 H), 1.61-1.44 (m, 4 H), 1.34-1.18 (m, 3 H).

[0124] Example 9 Preparation of (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (9) [ka] Step 1: To a mixture of 4a (500 mg, 1.59 mmol, 1.0 eq) and 2,4-dichloro-5-methylpyrimidine (778 mg, 4.77 mmol, 3.0 eq) in dioxane (20 mL) and HO (2 mL) was added NaCO (337 mg, 3.18 mmol, 2.0 eq) and Pd(PPh) (185 mg, 0.16 mmol, 0.1 eq). After the addition, the mixture was degassed under N three times and stirred at 80 °C under N for 16 h. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 4 / 1) to give 4b (771 mg, crude) as a brown solid. Rt: 1.575 min. LCMS: [M+H] + : 316.2.

[0125] Step 2: A mixture of 4b (130 mg, 0.41 mmol, 1.0 eq), 1-(oxetan-3-ylmethyl)-1H-pyrazol-4-amine (125 mg, 0.82 mmol, 2.0 eq), Brettfos PdG (36 mg, 0.041 mmol, 0.1 eq), and KPO (218 mg, 1.03 mmol, 2.5 eq) in dioxane (10 mL) was stirred at 120 °C for 16 h under a N atmosphere. The resulting mixture was filtered, and the residue was concentrated and purified by prep-HPLC (0.1% NHHO) to give 9 (29.0 mg, 0.066 mmol, 16.2% yield) as a white solid. Rt: 1.391 min. LCMS: [M+H] + : 433.2. 1H NMR (400 MHz, DMSO) δ 9.18 (s, 1 H), 8.48 (s, 1 H), 8.24 (s, 1 H), 8.17 (s, 1 H), 7.95 (s, 1 H), 7.50 (s, 1 H), 4.65-4.62 (m, 2 H), 4.58-4.55 (m, 1 H), 4.44-4.39 (m, 4 H), 3.42-3.38 (m, 1 H), 3.22-3.18 (m, 2 H), 2.42-2.40 (m, 1 H), 2.20 (s, 3 H), 1.83-1.81 (m, 1 H), 1.61-1.44 (m, 4 H), 1.34-1.19 (m, 3 H).

[0126] Example 10: Preparation of (R)-3-(4-(5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (10) [ka] Step 1: A mixture of 4a (600 mg, 1.90 mmol), 10a (1.06 g, 5.80 mmol), Pd(PPh) (100 mg), and NaCO (615 mg, 5.80 mmol) in dioxane (50 mL) and HO (5 mL) was stirred overnight at 80 °C under N. The resulting mixture was filtered, and the residue was concentrated and purified by silica gel column flash chromatography (PE / EA = 1 / 1) to give 10b (600 mg, 94% yield) as a brown solid. LC / MS: [M+H] + :336.

[0127] Step 2: A mixture of 10b (410 mg, 1.23 mmol), 10c (280 mg, 2.21 mmol), Brettfos PdG (111 mg, 0.123 mmol), and KPO (391 mg, 1.85 mmol) in dioxane (20 mL) was stirred overnight at 100 °C under N. The resulting mixture was filtered, and the residue was concentrated and purified by Prep-HPLC to give 10 (9.35 mg, 2% yield) as a yellow solid. LC / MS: [M+H] + :427.2. 1 H NMR (400 MHz, DMSO) δ 9.60 (s, 1H), 8.79 - 8.63 (m, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 7.99 (s, 1H), 7.52 (s, 1H), 4.94 (s, 1H), 4.61-4.63 (m, 1H), 4.14 (s, 2H), 3.73 (dd, J = 10.8, 5.6 Hz, 2H), 3.28 - 3.13 (m, 2H), 2.50 (dd, J = 3.2 Hz, 1.6 Hz, 1H), 1.79-1.84 (m, 1H), 1.42 - 1.69 (m, 4H), 1.11 - 1.38 (m, 3H).

[0128] Example 11: Preparation of ((R)-3-(4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (11) [ka] Step 1: A mixture of 4a (600 mg, 1.90 mmol), 10a (1.06 g, 5.80 mmol), Pd(PPh) (100 mg), and NaCO (615 mg, 5.80 mmol) in dioxane (50 mL) and HO (5 mL) was stirred overnight at 80 °C under N. The resulting mixture was filtered, and the residue was concentrated and purified by silica gel column flash chromatography (PE / EA = 1 / 1) to give 10b (600 mg, 94% yield) as a brown solid. LC / MS: 336 [M+H] + .

[0129] Step 2: A mixture of 10b (200 mg, 0.59 mmol), 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (199 mg, 1.19 mmol), Brettfos PdG (54 mg, 0.059 mmol), and KPO (375 mg, 1.77 mmol) in dioxane (20 mL) was stirred overnight at 100 °C under N. The resulting mixture was filtered, and the residue was concentrated and purified by Prep-HPLC to give 11 (14.38 mg, 5.2% yield) as a yellow solid. LC / MS: [M+H] + : 467.3. 1 H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.97 (s, 1H), 7.56 (s, 1H), 4.40 - 4.63 (m, 1H), 4.35 - 4.36 (m, 1H), 3.95 - 3.98(m, 2H), 3.43 - 3.50 (m, 2H), 3.16 - 3.27 (m, 2H), 2.39 - 2.41 (m, 1H), 1.92 - 1.98 (m, 4H), 1.79 -1.82 (m, 1H), 1.44 -1.63 (m, 4H), 1.26 -1.43 (m, 3H).

[0130] Example 12: Preparation of 2-(1-(ethylsulfonyl)-3-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (12) [ka] Step 1: A mixture of 1c (1 g, 2.63 mmol), 2,4-dichloro-5-methylpyrimidine (1.28 g, 7.89 mmol), Pd(PPh) (300 mg), and NaCO (558 mg, 5.26 mmol) in dioxane (100 mL) and HO (10 mL) was stirred overnight at 80 °C under N. The resulting mixture was filtered, and the filtrate was extracted three times with EA (100 mL). The residue was concentrated and purified by silica gel column flash chromatography (DCM / MeOH = 10 / 1) to give 3a (1 g, 100% yield) as a yellow solid. LC / MS: [M+H] + :382.

[0131] Step 2: A mixture of 3a (300 mg, 0.789 mmol), 10c (180 mg, 1.42 mmol), Brettfos PdG (71 mg, 0.08 mmol), and KPO (251 mg, 1.18 mmol) in dioxane (20 mL) was stirred overnight at 100 °C under N. The resulting mixture was filtered, and the residue was concentrated and purified by prep-HPLC to give 12 (62.90 mg, 17% yield) as a yellow solid. LC / MS: [M+H] +: 472.0. 1H NMR (400 MHz, DMSO) δ 9.21 (s, 1H), 8.60 (s, 1H), 8.27 (s, 2H), 8.00 (s, 1H), 7.49 (s, 1H), 4.90 (s, 1H), 4.56 (d, J = 8.8 Hz, 2H), 4.24 (d, J = 8.8 Hz, 2H), 4.12 (s, 2H), 3.72 (d, J = 4.8 Hz, 2H), 3.66 (s, 2H), 3.26 - 3.19 (m, 2H), 2.32 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H).

[0132] Example 13: Preparation of 2-(3-(4-(5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (13) [ka] Step 1: A mixture of 1c (676 mg, 1.78 mmol), 10a (979 mg, 5.34 mmol), Pd(PPh) (100 mg), and NaCO (580 mg, 5.47 mmol) in dioxane (30 mL) and HO (3 mL) was stirred overnight at 80 °C under N. The resulting mixture was filtered, and the residue was concentrated and purified by silica gel column flash chromatography (PE / EA = 1 / 1) to give 13a (600 mg, 84% yield) as a brown solid. LC / MS: [M+H] + : 401.

[0133] Step 2: A mixture of 13a (360 mg, 0.9 mmol), 10c (206 mg, 1.62 mmol), Brettfos PdG (81 mg, 0.09 mmol), and KPO (286 mg, 1.35 mmol) in dioxane (10 mL) was stirred overnight at 100 °C under N. The resulting mixture was filtered, and the residue was concentrated and purified by prep-HPLC to give 13 (30 mg, 6% yield) as a yellow solid. LC / MS: [M+H] + : 492.1. 1 H NMR (400 MHz, DMSO) δ 9.66 (s, 1H), 8.86 (s, 1H), 8.44 (d, J = 28.4 Hz, 2H), 8.01 (s, 1H), 7.51 (s, 1H), 4.91 (s, 1H), 4.54 (d, J = 12 Hz, 2H), 4.24 (d, J = 9.2 Hz, 2H), 4.13 (d, J = 5.6 Hz, 2H), 3.68-3.73 (m, 2H), 3.68 (s, 2H), 3.21-3.26 (m, 2H), 1.24 (t, J = 8.0 Hz, 3H).

[0134] Example 14: Preparation of 2-(1-(ethylsulfonyl)-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (14) [ka] Step 1: A mixture of 1c (1 g, 2.63 mmol), 2,4-dichloro-5-methylpyrimidine (1.28 g, 7.86 mmol), Pd(PPh) (300 mg), and NaCO (558 mg, 5.26 mmol) in dioxane (100 mL) and HO (10 mL) was stirred overnight at 80 °C under N. The resulting mixture was filtered and extracted three times with EA (100 mL). The organic phase was concentrated and purified by silica gel column flash chromatography (DCM / MeOH = 10 / 1) to give 3a (1 g, 100% yield) as a yellow solid. LC / MS: [M+H] + :381.

[0135] Step 2: A mixture of 3a (200 mg, 0.526 mmol), 1-methyl-1H-pyrazol-3-amine (102 mg, 1.05 mmol), Brettfos PdG (48 mg, 0.053 mmol), and KPO (167 mg, 0.789 mmol) in dioxane (20 mL) was stirred overnight at 100 °C under N. The resulting mixture was filtered, and the organic phase was concentrated and purified by Prep-HPLC to give 14 (53.06 mg, 21% yield) as a yellow solid. LC / MS: [M+H] + : 442.1. 1 H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 8.73 (s, 1H), 8.33 (d, J = 22.8 Hz, 2H), 7.66 (d, J = 2.0 Hz, 1H), 6.45 (s, 1H), 4.55 (d, J = 9.2 Hz, 2H), 4.26 (d, J = 9.2 Hz, 3H), 3.68 (s, 4H), 3.21-3.26 (m, 3H), 2.36 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H).

[0136] Example 15: Preparation of (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (15) [ka] Step 1: A mixture of 15a (280 mg, 2.48 mmol), 15b (808 mg, 4.94 mmol), KCO (1.02 g, 7.38 mmol), and TBAI (183 mg, 0.49 mmol) in MeCN (10 mL) was stirred at 80 °C for 2 h. The mixture was concentrated and purified by silica gel column flash chromatography (PE / EA = 3 / 1) to give 15c (500 mg, 83.9%) as a brown solid. LC / MS: [M+H] + :241.

[0137] Step 2: A mixture of 15c (500 mg, 2.08 mmol) and Pd / C (50 mg) in MeOH (10 mL) was stirred under H at 50 °C for 2 h. The resulting mixture was filtered. The filtrate was concentrated and purified by silica gel column flash chromatography (PE / EA = 1 / 1) to give 15d (400 mg, 91.5% yield) as a brown solid. LC / MS: [M+H] + :211.

[0138] Step 3: A mixture of 4b (170 mg, 0.54 mmol), 15d (136 mg, 0.65 mmol), KPO (172 mg, 0.81 mmol), and Brettfos PdG (49 mg, 0.054 mmol) in dioxane (10 mL) was stirred overnight at 100 °C under N. The mixture was concentrated and purified by Prep-HPLC to give 15 (16 mg, 6.1% yield) as a yellow solid. LC / MS: [M+H] + :490.2. 1 H NMR (400 MHz, DMSO) δ 9.21 (s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.50 (s, 1H), 5.11 (s, 2H), 4.55 (td, J = 9.2, 4.8 Hz, 1H), 3.59 (dd, J = 12.4, 4.8 Hz, 4H), 3.53 - 3.41 (m, 4H), 3.25 - 3.13 (m, 2H), 2.30 (s, 3H), 1.80 (dd, J = 12.0, 7.2 Hz, 1H), 1.68 - 1.42 (m, 4H), 1.39 - 1.11 (m, 4H).

[0139] Example 16: Preparation of (R)-3-cyclopentyl-3-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (16) [ka] Step 1: To a solution of 4a (400 mg, 1.27 mmol), 2,4-dichloro-5-methylpyrimidine (617 mg, 3.79 mmol), and NaCO (269 mg, 2.54 mmol) in dioxane / HO (30 ml / 3 ml), Pd(PPh) (150 mg, 0.127 mmol) was added, and the mixture was stirred at 80 °C under N for 16 h. Dilution with EA, extraction with EA, concentration, and purification by SGC (PE:EA = 2:1) gave 4b (530 mg, 100% yield) as a yellow oil. LC / MS: [M+H] + :316.

[0140] Step 2: To a solution of 4b (170 mg, 0.54 mmol), 17c (81 mg, 0.648 mmol), and KPO (172 mg, 0.81 mmol) in dioxane (10 mL) was added Brettfos PdG (49 mg, 0.054 mmol), and the mixture was stirred at 100 °C under N for 16 h. Dilution, filtration, and concentration purification by SGC (DCM:MeOH = 10:1) afforded 16 (20.02 mg, 9.18% yield) as a yellow solid. LC / MS: [M+H] + :405.3. 1H NMR (400 MHz, DMSO) δ 9.15 (s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.51 (s, 1H), 4.56 (td, J = 9.6, 4.8 Hz, 1H), 4.46 (dd, J = 13.2, 6.8 Hz, 1H), 2.46 - 2.36 (m, 1H), 2.29 (s, 3H), 1.82 (dd, J = 11.6, 4.8 Hz, 1H), 1.64 - 1.50 (m, 3H), 1.39-1.41 (m, 6H), 1.38 - 1.12 (m, 4H).

[0141] Example 17: Preparation of 2-(1-(ethylsulfonyl)-3-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (17) [ka] Step 1: To a solution of 17a (3 g, 26.5 mmol), 2-iodopropane (9 g, 53 mmol), and K2CO3 (7.3 g, 53 mmol) in DMA (30 mL), the mixture was stirred at 70 °C for 2 h. EA (100 mL) was added, washed with HO, brine (100 mL) was added, and the organic phase was concentrated to give 17b (4 g, 97.6% yield). LC / MS: [M+H] + :156.

[0142] Step 2: To a solution of 17b (2 g, 12.9 mmol) in MeOH (20 mL) was added Pd / C (400 mg), and the mixture was stirred under H atmosphere at room temperature for 3 h, diluted, filtered, and concentrated to give 17c (1.8 g, 100% yield). LC / MS: [M+H] + :126.

[0143] Step 3: To a solution of 3a (150 mg, 0.395 mmol), 17c (59 mg, 0.474 mmol), and KPO (126 mg, 0.592 mmol) in dioxane (10 mL) was added Brettfos PdG (36 mg, 0.04 mmol), and the mixture was stirred at 100 °C under N for 16 h. Dilution, filtration, and concentration purification by SGC (DCM:MeOH = 13:1) afforded 17 (27.9 mg, 15.1% yield) as a yellow solid. LC / MS: [M+H] + :470.3. 1H NMR (400 MHz, DMSO) δ 9.20 (s, 1H), 8.61 (s, 1H), 8.26 (d, J = 11.2 Hz, 2H), 7.95 (s, 1H), 7.50 (s, 1H), 4.56 (d, J = 9.2 Hz, 2H), 4.48 (dd, J = 13.2, 6.4 Hz, 1H), 4.24 (d, J = 9.2 Hz, 2H), 3.67 (s, 2H), 3.22 (t, J = 7.2 Hz, 2H), 2.32 (s, 3H), 1.41 (d, J = 6.8 Hz, 6H), 1.24 (t, J = 7.2 Hz, 3H).

[0144] Example 18: Preparation of 2-(1-(ethylsulfonyl)-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (18) [ka] Step 1: A mixture of 1c (20.0 g, 52.63 mmol), 2,4-dichloro-5-methylpyrimidine (25.6 g, 157.89 mmol), Pd(PPh) (6.0 g), and NaCO (22.3 g, 210.52 mmol) in dioxane (400 mL) and HO (50 mL) was stirred at 80 °C under N overnight. The resulting mixture was triturated with ethyl acetate and filtered. The filter cake was triturated with water to give 3a (16.1 g, 80.5% yield) as a pale yellow solid. LC / MS: [M+H] + :380.9.

[0145] Step 2: A mixture of 3a (16.1 g, 42.37 mmol), 1-methyl-1H-pyrazol-4-amine (12.3 g, 127.11 mmol), Brettfos PdG (3.8 g, 4.24 mmol), and KPO (35.9 g, 169.47 mmol) in dioxane (300 mL) was stirred at 100 °C under N for 24 h. The reaction mixture was concentrated and triturated with DCM. After filtration, trituration with water gave 18 (8.31 g, 44.4% yield) as a yellow solid. LCMS: Rt: 1.361 min; MS m / z (ESI): [M+H] + : 442.1. 1 H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1 H), 8.61 (s, 1 H), 8.27 (s, 2 H), 7.93 (s, 1 H), 7.46 (s, 1 H), 4.56 (d, J=9.2 Hz, 1 H), 4.24 (d, J=9.2 Hz, 2 H), 3.82 (s, 3 H), 3.68 (s, 2 H), 3.21-3.26 (m, 2 H), 2.32 (s, 3 H), 1.25 (t, J=7.2 Hz, 3 H).

[0146] Example 19: Preparation of 2-(1-(ethylsulfonyl)-3-(4-(5-methyl-2-((1-methyl-1H-1,2,3-triazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (19) [ka] Step 1: A mixture of 3a (120 mg, 0.32 mmol), 1-methyl-1H-1,2,3-triazol-4-yl)amine (62 mg, 0.63 mmol), Brettfos PdG (10 mg), and KPO (167 mg, 0.79 mmol) in dioxane (10 mL) was stirred at 110 °C overnight. The resulting mixture was filtered, and the residue was concentrated and purified by Prep-HPLC to give TLL-117 (20.1 mg, 14%) as a pale yellow solid. LC / MS: [M+H] +:443.4. 1 H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 8.65 (s, 1H), 8.33 (s, 2H), 8.16 (s, 1H), 4.57 (d, J = 9.1 Hz, 2H), 4.24 (d, J = 9.1 Hz, 2H), 4.05 (s, 3H), 3.68 (s, 2H), 3.23 (dd, J = 14.6, 7.3 Hz, 2H), 2.35 (s, 3H), 1.25 (t, J = 7.3 Hz, 3H).

[0147] Example 20 Preparation of N-((1s,3s)-3-(methyl(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide (20) [ka] Step 1: A mixture of 20a (300 mg, 0.90 mmol), 1-methyl-1H-pyrazol-4-amine (175 mg, 1.81 mmol), Brettfos PdG (25 mg), and KPO (478 mg, 2.26 mmol) in dioxane (20 mL) was stirred at 100 °C overnight. The resulting mixture was filtered, and the residue was concentrated and purified by Prep-HPLC to give 20 (94.3 mg, 27%) as a pale yellow solid. LC / MS: [M+H] + :394.3. 1 H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.79 (s, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 7.43 (s, 1H), 4.03-4.02 (m, 1H), 3.78 (s, 3H), 3.52 - 3.46 (m, 1H), 2.93 - 2.89 (m, 5H), 2.57 - 2.55 (m, 2H), 2.12 - 2.08 (m, 5H), 1.69 - 1.62 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H).

[0148] Example 21: Preparation of N-methyl-1-((1r,4r)-4-(methyl(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide (21) [ka] Step 1: To a mixture of 21a (5.0 g, 20.6 mmol) in THF (100 mL) was added LiAlH (3.9 g, 103 mmol) at 0 °C, and the reaction mixture was stirred at 75 °C for 16 h. The reaction was quenched with HO (3.9 mL), 15% NaOH (3.9 × 3 mL), and HO (3.9 mL). The resulting mixture was then filtered, and the filtrate was concentrated to give 21b (3.1 g, >99%) as a yellow solid. LC / MS: [M+H] + :144.6.

[0149] Step 2: A mixture of 21b (2.6 g, 18.2 mmol), 2,4-dichloro-5-methylpyrimidine (8.9 g, 54.6 mmol), and DIEA (9.4 g, 72.8 mmol) in dioxane (100 mL) was stirred at 105 °C overnight and then cooled to room temperature. The resulting mixture was concentrated, and the residue was purified by silica gel column flash chromatography (PE / EA = 1 / 1) to give 21c (1.9 g, 38%) as a yellow solid. LC / MS: [M+H] + :270.4.

[0150] Step 3: To a mixture of 21c (1.9 g, 7.1 mmol) and EtN (2.9 g, 28.2 mmol) in DCM (50 mL) was added TsCl (4.0 g, 21.3 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel column flash chromatography (PE / EA = 1 / 1) to give 21d (2.8 g, 93%) as a yellow solid. LC / MS: [M+H] + :424.1.

[0151] Step 4: A mixture of 21d (2.8 g, 6.6 mmol) and potassium ethanethiolate (1.5 g, 13.2 mmol) in DMSO (50 mL) was stirred at 55 °C overnight and then cooled to room temperature. The resulting mixture was diluted with EA (50 mL), washed with HO (20 mL × 3), and extracted with EA. The organic phase was washed with brine, dried over NaSO, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column flash chromatography (PE / EA = 1 / 1) to give 21e (1.0 g, 46%) as a yellow solid. LC / MS: [M+H] + : 328.4.

[0152] Step 5: To a mixture of 21e (800 mg, 2.4 mmol) in HCOOH (2 mL) was added HO (408 mg, 12.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with NaSO, and the residue was purified by flash chromatography (0.1% TFA) to give 21f (350 mg, 42%) as a white solid. LC / MS: [M+H] + : 334.4.

[0153] Step 6: To a mixture of 21f (350 mg, 1.1 mmol) in DCM (10 mL) was added DMF (2 drops) and SOCl2 (625 mg, 5.5 mmol). The reaction mixture was stirred at 45 °C for 2 h. The reaction was concentrated to give 21g (385 mg, >99%) as a yellow oil. LC / MS: [M+H] + :352.3.

[0154] Step 7: A mixture of 21g (385 mg, 1.1 mmol) and 2M CH3NH2 (2.75 mL, 5.5 mmol) in THF (5 mL) was stirred at room temperature overnight. The resulting mixture was concentrated, and the residue was purified by silica gel column flash chromatography (DCM / MeOH = 20 / 1) to give 21h (300 mg, 79%) as a yellow solid. LC / MS: [M+H] + :347.1.

[0155] Step 8: A mixture of 21h (150 mg, 0.43 mmol), 1-methyl-1H-pyrazol-4-amine (84 mg, 0.86 mmol), Brettfos PdG (10 mg), and KPO (228 mg, 1.1 mmol) in dioxane (10 mL) was stirred at 100 °C overnight. The resulting mixture was filtered, and the residue was concentrated and purified by Prep-HPLC to give 21 (55 mg, 31%) as a white solid. LC / MS: [M+H] + :408.1. 1 H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1 H), 7.81 (s, 1 H), 7.70 (s, 1 H), 7.52 (s, 1 H), 6.90 (d, J = 4.8 Hz, 1 H), 4.33 - 4.32 (m, 1 H), 3.84 (s, 3 H), 3.12 (s, 3 H), 2.94 (d, J = 6.4 Hz, 2 H), 2.58 (d, J = 4.4 Hz, 3 H), 2.25 (s, 3 H), 2.07 - 2.04 (m, 2 H), 1.86 - 1.84 (m, 1 H), 1.72 - 1.69 (m, 4 H), 1.26 - 1.16 (m, 2 H).

[0156] Example 22: Preparation of 3-((3R,4R)-4-methyl-3-(methyl(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (22) [ka] Step 1: A mixture of 22a (600 mg, 1.74 mmol), 1-methyl-1H-pyrazol-4-amine (338 mg, 3.48 mmol), Bretophos PdG3 (10 mg), and K3PO4 (922 mg, 4.35 mmol) in dioxane (10 mL) was stirred at 100 °C overnight. The resulting mixture was filtered, and the residue was concentrated and purified by silica gel column flash chromatography (DCM / MeOH = 10 / 1) to give 22b (800 mg, >99%) as a brown solid. LC / MS: [M+H] + :406.2.

[0157] Step 2: To a mixture of 22b (405 mg, 1.0 mmol) in MeOH (10 mL), Pd / C (200 mg) and HOAc (10 drops) were added, and the reaction mixture was stirred at 50 °C for 16 h. The resulting mixture was filtered, and the residue was concentrated and purified by silica gel column flash chromatography (DCM / MeOH = 10 / 1) to give 22c (140 mg, 44%) as a brown solid. LC / MS: [M+H] + :316.2.

[0158] Step 3: To a mixture of 22c (100 mg, 0.32 mmol) and 2-cyanoacetic acid (54 mg, 0.64 mmol) in DCM (10 mL) was added EtN (97 mg, 0.96 mmol) and T3P (204 mg, 0.64 mmol). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was filtered, and the residue was concentrated and purified by Prep-HPLC to give 22 (19.4 mg, 16%) as a white solid. LC / MS: [M+H] + : 383.3. 1H NMR (400 MHz, DMSO-d6): δ 8.75 - 8.74 (m, 1 H), 7.80 (d, J = 7.2 Hz, 1 H), 7.72 (s, 1 H), 7.42 - 7.38 (m, 1 H), 4.23 - 4.02 (m, 1 H), 3.86 (d, J = 4.0 Hz, 2 H), 3.83 - 3.82 (m, 1 H), 3.77 (d, J = 3.6 Hz, 3 H), 3.74 - 3.70 (m, 1 H), 3.59 - 3.14 (m, 2 H), 2.96 (s, 3 H), 2.51 - 2.50 (m, 1 H), 2.12 (d, J = 6.0 Hz, 3 H), 1.76 - 1.51 (m, 2 H), 1.00 (t, J = 6.8 Hz, 3 H).

[0159] Example 23: Preparation of (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (23) [ka] Step 1: To a flask containing dioxane (600 mL) and water (60 mL) were added 4a (25 g, 79.3 mmol), 2,4-dichloro-5-methylpyrimidine (38.8 g, 238 mmol), and Na2CO3 (25.2 g, 238 mmol) at room temperature. Pd(PPh3)4 (9 g, 23.8 mmol) was added quickly. The resulting mixture was purged with nitrogen three times, and the mixture was stirred under N2 at 80 °C for 18 h. The reaction mixture was filtered, and the filtrate was concentrated. The crude residue was purified by column chromatography to give 4b (20 g, 80% yield) as a yellow oil. LC / MS: [M+H] + :316.

[0160] Step 2: To a flask containing dioxane (500 mL) was added 4b (10 g, 31.7 mmol), 1-methyl-1H-benzo[d]imidazol-6-amine (14 g, 95.1 mmol), and KPO (33.6 g, 158.5 mmol) at room temperature. Brettfos PdG (2.88 g, 3.17 mmol) was added quickly. The resulting mixture was purged with nitrogen three times, and the mixture was stirred at 110 °C under a nitrogen atmosphere for 48 h. The reaction mixture was filtered, and the filtrate was concentrated. The crude residue was purified by column chromatography (DCM:MeOH = 30:1) to remove impurities. The residue was purified again by prep-HPLC to give 23 (5 g, yield = 37%) as a red solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.47 (s, 1 H), 8.55 (s, 1 H), 8.36 (d, J= 1.6 Hz, 1 H), 8.33 (s, 1 H), 8.22 (s, 1 H), 8.04 (s, 1 H), 7.54-7.51 (m, 1 H), 7.38-7.35 (m, 1 H), 4.59-4.55 (m, 1 H), 3.81(s, 3 H), 3.29-3.16 (m, 2 H), 2.43-2.40 (m, 1 H), 2.34 (s, 3 H), 1.83-1.80 (m, 1 H), 1.63-1.44 (m, 4 H), 1.35-1.18 (m, 3 H). LCMS: Rt: 1.143 min; MS m / z (ESI): 427.3[M+H] + .

[0161] Example 24: Preparation of (R)-3-cyclopentyl-3-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (24) [ka] Step 1: To a flask containing dioxane (500 mL) were added 4b (10 g, 31.7 mmol), 10c (12 g, 95.1 mmol), and KPO (33.6 g, 158.5 mmol) at room temperature. Brettfos PdG (2.88 g, 3.17 mmol) was added quickly. The resulting mixture was purged with nitrogen three times, and the mixture was stirred at 110 °C under a nitrogen atmosphere for 48 h. The reaction mixture was filtered, and the filtrate was concentrated. The crude residue was purified by column chromatography (DCM:MeOH = 50:1) to obtain the impurity. The impurity was triturated with methanol to give 24 (4.52 g, yield = 35%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 1 H), 8.47 (s, 1 H), 8.24 (s, 1 H), 8.17 (s, 1 H), 7.98 (s, 1 H), 7.50 (s, 1 H), 4.91 (t, J= 4.8 Hz, 1 H), 4.57-4.53 (m, 1 H), 4.12 (t, J=5.2 Hz, 2 H), 3.75-3.71 (m, 2 H), 3.32-3.18 (m, 2 H), 2.42-2.40 (m, 1 H), 2.29 (s, 3 H), 1.83-1.80 (m, 1 H), 1.62-1.32 (m, 4 H), 1.29-1.18 (m, 3 H). LCMS: Rt: 1.407 min; MS m / z (ESI): [M+H] + :407.2.

[0162] Compounds 25, 26 and 27 were prepared by the procedure previously described for the preparation of compounds 13, 18 and 23.

[0163] Example 1b. Biochemical testing of TYK2, JAK1, JAK2, and JAK3 The test was performed by Reaction Biology Corp, Malvern, PA (Anastassiadis et al. Nat Biotechnol. 2011; 29(11):1039-45). A brief description of the procedure is as follows.

[0164] reagent: Basic reaction buffer: 20 mM Hepes (pH 7.5), 10 mM MgCl, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM NaVO, 2 mM DTT, and 1% DMSO. Cofactors required for each kinase reaction were added separately.

[0165] Reaction steps: 1. Prepare the desired substrate in a freshly prepared basic reaction buffer; 2. Transfer the necessary cofactors into the matrix solution described above; 3. Transfer the designated kinase to the substrate solution and mix carefully and slightly; 4. Transfer the compound of formula I-III in DMSO to the kinase reaction mixture by sonication (Echo550; nanoliter range) and incubate at room temperature for 20 minutes; 5. 33 P-ATP (specific activity: 10 μCi / μl) was introduced into the reaction mixture to induce the reaction; 6. Incubate at room temperature and allow the kinase reaction to proceed for 2 hours; 7.P81 Plot the reaction on ion exchange paper; 8. Examine kinase activity using a filter binding assay.

[0166] The test results are as follows (IC 50 , in nM): [Table 2]

[0167] The above data demonstrate that compounds of Formula II and III (Examples 2, 4, 5, 6, 7, 8, 9, 11, 18, 23, 24, and 26) are potent TYK2 / JAK1 / JAK2 inhibitors. In comparison, the 2-((pyrazol-3-yl)amino) compound (Example 14, D2) and the 2-((triazol-4-yl)amino) compound (Example 19) are more than 10-fold less potent than their 2-((pyrazol-4-yl)amino) analogs (Example 18). Compounds using 4-pyrimidine substituents based on abrocitinib (Example 20), tofacitinib (Example 22), and oclacitinib (Example 21) are more than 10-fold, more than 100-fold, and more than 100-fold less potent TYK2 / JAK1 / JAK2 inhibitors than their analogs of Formula II (Example 4) and Formula III (Example 18), respectively.

[0168] Example 2b. TYK2 Cell ELISA Assay Using NK92 Cells Objective: To investigate cellular TYK2 activity using IL-12 and IL-18 stimulated IFNγ excretion assays of NK92 cells.

[0169] procedure: 1. Replace the NK92 cell medium containing IL-2 with medium without IL-2 and leave overnight; 2. NK92 cells are plated in a 96-well plate at a density of 150,000 cells / well or less; 3. Different concentrations of test substances are added to the wells and placed in an incubator at 37°C and 5% CO2 for 1 hour; 4. Add IL-12 (final concentration: 2 ng / ml) and IL-18 (final concentration: 5 ng / ml) and stimulate in the above incubator for 24 hours; 5. After 24 hours, centrifuge at 2000 rpm for 5 minutes, collect the supernatant and analyze it according to the instructions of the ELISA kit.

[0170] In this assay, the IC of compound 4 50 was less than 10 nM.

[0171] Example 3b. JAK1 Cellular ELISA Assay Using PBMC Cells Objective: To investigate cellular JAK1 activity using an IL-6 stimulated STAT3 phosphorylation assay in PBMC cells.

[0172] procedure: 1. PBMC cells are plated in a 96-well plate at a density of 300,000 cells / well or less; 2. Different concentrations of test substances are added to the wells and placed in an incubator at 37°C and 5% CO2 for 1 hour; 3. Add IL-6 (final concentration: 100 ng / ml) and stimulate for 25 minutes in the incubator; 4. After stimulation, transfer the suspension to a 1.5mL tube and centrifuge at 200g for 5 minutes to collect the cells. Add 100μL of 1X lysis solution and lyse on ice for 1 hour; Centrifuge at 5.4°C and 12,000 rpm for 10 minutes, remove the supernatant and analyze according to the ELISA kit instructions.

[0173] In this assay, the IC 50 was less than 500 nM.

[0174] Example 4b. Human Liver Microsome Stability Assay The assay was carried out as follows: 1. Eight 96-well sample plates were prepared and named T0, T3, T6, T9, T15, T30, NCF30 and blank. 2. 100 μl / well of human microsomes was dispensed onto each plate. 3. 2 μL of compound or control working solution was dispensed into each well of each plate (T0, T3, T6, T9, T15, T30, NCF30) except for the matrix blank, and incubated at 37°C for approximately 10 minutes. The final concentration of the test compound was 1 μM. 600 μL of cold stop solution was immediately added to T0 plates. 4. 98 μL / well of 100 mM potassium phosphate buffer was added to the NCF30 plate, and the plate was incubated at 37° C., after which the reaction was initiated. 5. After preheating, the NADPH regenerating system was dispensed into a 96-well plate as a reservoir according to the plate map. Then, 98 μL / well was added to each plate (blank, T30, T15, T9, T6, T3, T0) to start the reaction. 6. The reaction was stopped by adding 600 μl of cold stop solution at 0, 3, 6, 9, 15, and 30 min. The samples were shaken for 10 min and then centrifuged at 3220 g for 20 min. The supernatant from each well was taken, diluted with diluent solution, and analyzed by LC / MS / MS. 7. The peak area ratio of the analyte / internal standard was converted to the remaining percentage (% Remaining) using the following formula:

number

[0175] Example 5b. Minipig transdermal pharmacokinetic study The purpose of this study was to obtain the distribution of the test article in minipigs after topical administration. The test article was formulated as an ointment and then applied to two female Guangxi Bama minipigs (8 kg - 12 kg) (Wujiang Tianyu Biological Technology). Briefly, a total area estimated to be approximately 10% of the total body surface area was shaved using electric clippers before treatment. Test article 15 mg / cm 2 The test substance was uniformly applied to the skin at 0, 8, and 24 hours. The test product was removed before the next administration. Blood and skin samples were collected at 24 hours (pre-dose), 25 hours, 28 hours, 32 hours, 48 ​​hours, and 96 hours. Blood was collected from a peripheral vein of each animal into pre-chilled tubes containing potassium (K2) EDTA as an anticoagulant. Prior to skin sample collection, the exposed skin was washed with ethanol and then wiped with a dry cotton swab. Eight treated skin samples were collected at each time point using a biopsy punch (0.7 cm diameter). The epidermis and dermis were separated, and eight samples from the same time point were pooled and homogenized. All samples and homogenates were quantified by LC-MS / MS analysis.

[0176] This study demonstrated that topical administration of compound 4 resulted in minimal systemic exposure and concentration in the dermis and epidermis.

[0177] The results of the example are as follows: [Table 3]

[0178] Example 6b. Efficacy Study in a hIL-23-Induced Psoriasis Model C57BL / 6J mice (Beijing Vital River Laboratory) were randomly assigned to normal, vehicle, and treatment groups based on body weight and ear thickness on day 0. The vehicle and treatment groups were immunized with hIL-23 (Sigma) to induce psoriasis-like inflammation, while the normal group was immunized with PBS in parallel. Human IL-23-immunized animals were topically administered with vehicle and test article, respectively, once daily from days 1 to 9. Ear thickness was assessed using a digital micrometer (QuantuMike, 293-185) before injection of hIL-23 or PBS on days 0, 2, 4, 6, 8, and 10. Ear thickness was used to evaluate the efficacy of the test article. As shown in Figure 1, data are presented as mean ± SEM and statistical analysis was performed using two-way ANOVA. * p<0.05, *** p<0.0001 compared with the vehicle group.

[0179] Example 7b. Efficacy test in a 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis model Approximately 8-week-old BALB / c mice (Beijing Vital River Laboratory) were randomly assigned to normal, vehicle, and treatment groups according to their body weight and ear thickness at the start of the study. Animals in the vehicle and treatment groups received 0.15% DNFB stimulation on days 1, 8, 15, 22, and 29, and were administered vehicle and test products (0.1%, 0.25%, 0.5%, and 1% ointment of Compound 4) once daily, respectively. Ear thickness was assessed using a digital micrometer (QuantuMike, 293-185) immediately before and 24 hours after each DNFB stimulation. As shown in Figure 2, data are presented as mean ± SEM, and were analyzed using two-way ANOVA. * p<0.05, *** p<0.0001 compared with the vehicle group.

[0180] [Incorporation by Reference] This application references various issued patents, published patent applications, scientific journal articles, and other publications, all of which are incorporated herein by reference. The details of one or more embodiments of the invention are described herein. Other features, objects, and advantages of the invention will become apparent from the detailed description, drawings, examples, and claims.

[0181] [Equivalents and Scope] In the claims, articles such as "a," "an," and "the" may mean one or more than one, unless indicated to the contrary or otherwise clear from the context. A claim or description including "or" between one or more members of a group is deemed to be satisfied when one, more than one, or all group members are present in, used in, or otherwise involved in a given product or process, unless indicated to the contrary or otherwise clear from the context. The invention includes embodiments in which exactly one member of a group is present in, used in, or otherwise involved in a given product or process. The invention also includes embodiments in which more than one or all group members are present in, used in, or otherwise involved in a given product or process.

[0182] Furthermore, the present disclosure encompasses all variations, combinations, and permutations that introduce one or more limitations, elements, clauses, and descriptive language from one or more enumerated claims into another claim. For example, any claim that depends on another claim may be modified to include one or more limitations found in any other claim that depends on the same base claim. When elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. In general, when the present disclosure or aspects of the present disclosure refer to including particular elements and / or features, it is understood that certain embodiments of the present disclosure or aspects of the present disclosure include or essentially include such elements and / or features. For brevity, those embodiments are not specifically referred to in this specification in this language. Note that the terms "comprise" and "contain" are intended to be open-ended, allowing for the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or clearly dictated otherwise by the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the ranges set forth in different embodiments of this disclosure, down to the tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0183] This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated documents and this specification, this specification shall control. In addition, certain embodiments of the present disclosure that fall within the prior art may be expressly excluded from any one or more claims. Such embodiments may be excluded even if the exclusion is not expressly provided for herein because they are deemed to be well known to those skilled in the art. Any particular embodiment of the present disclosure may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0184] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but rather is as defined in the appended claims. Those skilled in the art will appreciate that various changes and modifications can be made to this specification without departing from the spirit or scope of the present disclosure, as defined in the following claims. [Brief explanation of the drawings]

[0185] [Figure 1] Ear thickness in the hIL-23-induced psoriasis model for compound 4. [Figure 2] Ear thickness in DNFB-induced atopic dermatitis model for compound 4. [Figure 3] XRPD of Form A of Compound 4. [Figure 4] TGA and DSC curves of Form A of Compound 4.

Claims

1. Compounds of formula (I): 【Chemical 1】 or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof: R １ is C １～３ Alkyl, C ３～４ cycloalkyl, or halo; R ３ teeth, 【Chemistry 2】 and R ２ teeth, 【Chemistry 3】 and R ４ is C １～３ Alkyl, C ３～８ cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is R ５ , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ NRR′ is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: ５ is C １～３ alkyl, or 4- to 7-membered heterocyclyl, each of which is halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of NRR'; Each of R and R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. １～３ The compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, wherein:

2. Compound of formula (II): 【Chemistry 4】 or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof: R １ is C １～３ Alkyl, C ３～４ cycloalkyl, or halo; R ２ teeth, 【Chemistry 5】 and R ４ is C １～３ Alkyl, C ３～８ cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is R ５ , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ NRR′ is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: ５ is C １～３ alkyl, or 4- to 7-membered heterocyclyl, each of which is halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of NRR'; Each of R and R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. １～３ The compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, wherein:

3. Compounds of formula (III): 【Chemistry 6】 or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof: R １ is C １～３ Alkyl, C ３～４ cycloalkyl, or halo; R ２ teeth, 【Chemistry 7】 and R ４ is C １～３ Alkyl, C ３～８ cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is R ５ , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ NRR′ is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: ５ is C １～３ alkyl, or 4- to 7-membered heterocyclyl, each of which is halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of NRR'; Each of R and R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. １～３ The compound, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative or prodrug thereof, wherein:

4. R ２ teeth, 【Chemistry 8】 and R ４ is C １～３ Alkyl, C ３～８ cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is R ５ , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ NRR′ is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: ５ is C １～３ alkyl, or 4- to 7-membered heterocyclyl, each of which is halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of NRR'; Each of R and R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. １～３ 4. The compound of claim 1, 2, or 3, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

5. R ２ teeth, 【Chemistry 9】 4. The compound of claim 1, 2 or 3, wherein:

6. R ２ teeth, 【Chemistry 10】 4. The compound of claim 1, 2 or 3, wherein:

7. R １ is C １～３ Alkyl, C ３～４ 7. The compound of any one of claims 1 to 6, which is cycloalkyl, or halo, or a pharmaceutically acceptable salt thereof.

8. R １ is C １～３ The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

9. R １ is CH ３ 9. The compound according to any one of claims 1 to 8, wherein:

10. R １ is C ３～４ The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

11. R １ The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein is halo.

12. R １ 12. The compound of claim 1, wherein R is Cl, or a pharmaceutically acceptable salt thereof.

13. R ４ is C １～３ alkyl, and R ５ , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ NRR′ is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: ５ is C １～３ alkyl, or 4- to 7-membered heterocyclyl, each of which is halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of NRR'; Each of R and R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. １～３ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, which is alkyl.

14. R ４ is CH ２ R ５ and R ５ teeth, 【Chemistry 11】 14. The compound according to any one of claims 1 to 13, wherein:

15. R ４ are 4- to 7-membered heterocyclyl, and R ５ , oxo, halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ NRR′ is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: ５ is C １～３ alkyl, or 4- to 7-membered heterocyclyl, each of which is halo, OH, CN, OR, NHR, NRR', N(R)C(O)R', N(R)C(O)OR', OC(O)NRR', C(O)R, C(O)NRR', N(R)S(O) ２ R', S(O) ２ R and S(O) ２ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of NRR'; Each of R and R' is independently H or C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. １～３ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, which is alkyl.

16. R ４ teeth, 【Chemistry 12】 16. The compound according to any one of claims 1 to 15, wherein:

17. 2-(3-(4-(5-cyclopropyl-2-(isoxazol-4-ylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (1); 2-(3-(4-(5-cyclopropyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (2); 2-(1-(ethylsulfonyl)-3-(4-(2-(isoxazol-4-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (3); 2-(1-(ethylsulfonyl)-3-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (12); 2-(3-(4-(5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (13); 2-(1-(ethylsulfonyl)-3-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (17); 2-(1-(ethylsulfonyl)-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (18); 2-(1-(ethylsulfonyl)-3-(4-(5-methyl-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (26); 2-(3-(4-(5-chloro-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (27) 4. The compound of claim 1 or 3, wherein:

18. (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (4); (R)-3-cyclopentyl-3-(4-(2-(isoxazol-4-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (5); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (6); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (7); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (8); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (9); (R)-3-(4-(5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (10); ((R)-3-(4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (11); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (15); (R)-3-cyclopentyl-3-(4-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (16); (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (23); (R)-3-cyclopentyl-3-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (24); (R)-3-(4-(5-chloro-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (25) 3. The compound of claim 1 or 2, wherein:

19. The compound is (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (4); 【Chemistry 13】 3. The compound of claim 1 or 2, wherein:

20. The compound is (R)-3-cyclopentyl-3-(4-(5-methyl-2-((1-methyl-1H-benzo[d]imidazol-6-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (23); 【Chemistry 14】 3. The compound of claim 1 or 2, wherein:

21. The compound is (R)-3-cyclopentyl-3-(4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (24); 【Chemistry 15】 3. The compound of claim 1 or 2, wherein:

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

23. A pharmaceutical composition for topical administration comprising a therapeutically effective amount of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

24. Compounds of the present invention and compositions comprising them are useful for treating or lessening the severity of diseases, disorders or conditions modulated by TYK2, JAK1 and JAK2.

25. 22. A method of treating a skin disorder, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising the compound of any one of claims 1 to 21, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

26. 26. The method of claim 25, wherein the skin disorder can be any of the skin disorders regulated by TYK2, JAK1 and JAK2.

27. 27. The method of claim 25 or 26, wherein the skin disorder is atopic dermatitis, psoriasis, urticaria, alopecia areata, vitiligo, hidradenitis pustulosa, hand eczema, lipoid necrolysis, chronic graft-versus-host disease of the non-sclerosing skin, digital dermatitis, or lichen planus.

28. 27. The method of claim 25 or 26, wherein the skin disorder is atopic dermatitis, psoriasis, hives, alopecia areata, or vitiligo.

29. Crystalline form A of compound (4), 【Chemistry 16】 Crystalline form A of compound (4), wherein the powder X-ray diffraction pattern of said crystalline form shows characteristic peaks at 2θ angles of 10.3°±0.2°, 14.5°±0.2° and 16.7°±0.2°.

30. 30. The crystalline form A of compound (4) according to claim 29, wherein the powder X-ray diffraction pattern of the crystalline form exhibits characteristic peaks at 2θ angles of 10.3°±0.2°, 14.5°±0.2°, 16.7°±0.2°, 19.8°±0.2°, 23.3°±0.2° and 23.5°±0.2°.

31. Crystalline form A of compound (4) according to any one of claims 29 to 30, wherein the powder X-ray diffraction pattern of the crystalline form shows characteristic peaks at 2θ angles of 10.3°±0.2°, 14.5°±0.2°, 16.7°±0.2°, 19.8°±0.2°, 20.7°±0.2°, 23.3°±0.2°, 23.5°±0.2°, 27.2°±0.2°, and 28.1°±0.2°.

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