WO2024041397A1 - Inhibiteurs de jak1/jak2/tyk2 pour le traitement topique de maladies dermatologiques - Google Patents

Inhibiteurs de jak1/jak2/tyk2 pour le traitement topique de maladies dermatologiques Download PDF

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WO2024041397A1
WO2024041397A1 PCT/CN2023/112361 CN2023112361W WO2024041397A1 WO 2024041397 A1 WO2024041397 A1 WO 2024041397A1 CN 2023112361 W CN2023112361 W CN 2023112361W WO 2024041397 A1 WO2024041397 A1 WO 2024041397A1
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nrr
pyrazol
amino
methyl
halo
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PCT/CN2023/112361
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Congxin Liang
Shuangjiang Li
Xiaojing Tang
Junmin Huang
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Hangzhou Highlightll Pharmaceutical Co., Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the Janus kinase family comprises 4 known family members: JAK 1, 2, 3, and tyrosine kinase 2 (TYK2) . These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors such as common gamma-chain receptors and the glycoprotein 130 (gp 130) trans-membrane proteins (Murray, J. Immunol. 178 (5) : 2623-2629, 2007) . Almost 40 cytokine receptors signal through combinations of these 4 JAK family members and their 7 downstream substrates: the signal transduction activators of transcription (STAT) family members (Ghoreschi et al., Immunol Rev. 228 (1) : 273-287, 2009) .
  • STAT signal transduction activators of transcription
  • Cytokine binding to its receptor initiates JAK activation via trans-and auto-phosphorylation.
  • the JAK family kinases in turn phosphorylate cytokine receptor residues, creating binding sites for sarcoma homology 2 (SH2) containing proteins, such as the STAT factors and other regulators, which are subsequently activated by JAK phosphorylation.
  • SH2 sarcoma homology 2
  • STATs enter the nucleus initiating expression of survival factors, cytokines, chemokines, and molecules that facilitate leukocyte cellular trafficking (Schindler et al., J. Biol. Chem. 282 (28) : 20059-20063, 2007) .
  • JAK activation also results in cell proliferation via phosphoinositide 3-kinase (PI3K) and protein kinase B-mediated pathways.
  • PI3K phosphoinositide 3-kinase
  • Tofacitinib a JAK1/JAK3/JAK2 inhibitor
  • JAK1 selective compounds upadacitinib and abrocitinib
  • TYK2 selective inhibitor deucravacitinib has shown positive Phase 2 and Phase 3 results in patients with psoriasis (Papp et al. N Engl J Med.
  • ruxolitinib (Opzelura TM ) , a selective JAK1/JAK2 inhibitor, is also approved for the treatment of mild to moderate atopic dermatitis, and is in clinical development for the treatment of psoriasis, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lipoidica, non-sclerotic cutaneous chronic graft-versus-host disease, hand dermatitis, and Lichen Planus.
  • JAK inhibitors are useful in treating various dermatological diseases such as atopic dermatitis, psoriasis, hives, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lipoidica, non-sclerotic cutaneous chronic graft-versus-host disease, hand dermatitis, or Lichen Planus (Zhang et al. J Inflamm Res. 2022 Mar 18; 15: 1935-1941) .
  • the approved oral agents, upadacitinib and abrocitinib carry black box warnings of risks such as serious infections, non-melanoma skin cancers, thrombosis, and thrombocytopenia.
  • the topical formulation of ruxolitinib also carry similar risks, probably because its systemic exposure is also high, with Cmax reaching 449 ⁇ 883 nM when applied, topically, 1.2 –37.6g per application, twice a day (Medication Guide approved by FDA, 09/2021) , well above its IC 50 for JAK1 and JAK2 inhibition in biochemical assay (3.3 nM and 2.8 nM respectively) or inhibition of JAK1, JAK2 related cellular assays (maximum effect at ⁇ 300 nM, ruxolitinib FDA pharmacology review 2011) .
  • JAK inhibitors such as tofacitinib, abrocitinib, ruxolitinib, baricitinib, oclacitinib, share the pyrrolopyrimidine core structure as illustrated below:
  • WO2009/064835 disclosed compounds represented by D1 and D2 as JAK2 inhibitors.
  • WO2012/062704 and WO2020/119819 disclosed compounds as shown in D3 as JAK1/JAK2/TYK2 inhibitors.
  • WO2014/111037 disclosed compounds represented by D4 as JAK1/JAK2/JAK3 inhibitors.
  • WO2021/078022 disclosed compounds represented by D5 as JAK1/JAK2/TYK2 inhibitors.
  • This invention discloses novel 4-pyrazolyl-N-heteroarylpyrimidin-2-amine compounds as potent TYK2/JAK1/JAK2 inhibitors with low systemic exposures when applied topically.
  • these compounds, and compositions comprising a compound of this disclosure are useful as topical treatment of dermatological disorders related to JAK1/JAK2/TYK2 such as atopic dermatitis, psoriasis, hives, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lipoidica, non-sclerotic cutaneous chronic graft-versus-host disease, hand dermatitis, or Lichen Planus.
  • 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 that can be quickly degraded by liver microsomes, and as such advantageous properties suited as a topical agent for use in treating dermatological disorders.
  • the present disclosure also provides compositions comprising a compound of this disclosure or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
  • the present disclosure further provides methods of use of such compounds, or salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, or such compositions, for treating disorders associated with TYK2, JAK1, JAK2, including dermatological diseases such as atopic dermatitis, psoriasis, hives, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lipoidica, non-sclerotic cutaneous chronic graft-versus-host disease, hand dermatitis, or Lichen Planus.
  • dermatological diseases such as atopic dermatitis, psoriasis, hives, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lip
  • R 1 is C 1-3 alkyl, C 3-4 cycloalkyl, or halo
  • R 4 is C 1-3 alkyl, C 3-8 cycloalkyl, or 4 to 7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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’, wherein R 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 (
  • R, R’ each is independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.
  • R 1 is C 1-3 alkyl, C 3-4 cycloalkyl, or halo
  • R 4 is C 1-3 alkyl, C 3-8 cycloalkyl, or 4 to 7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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’, wherein R 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 (
  • R, R’ each is independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.
  • R 1 is C 1-3 alkyl, C 3-4 cycloalkyl, or halo
  • R 4 is C 1-3 alkyl, C 3-8 cycloalkyl, or 4 to 7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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’, wherein R 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 (
  • R, R’ each is independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.
  • the compounds of this invention, and compositions comprising them, are useful for treating or lessening the severity of TYK2, JAK1, and JAK2 modulated diseases, disorders, or symptoms thereof.
  • one aspect of the present disclosure relates to a method for treating a dermatological disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of Formulae (I) - (III) herein, or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, which may be formulated into a composition.
  • the composition may be a pharmaceutical composition, which may further comprise a pharmaceutically acceptable carrier.
  • the dermatological disorder is atopic dermatitis, psoriasis, hives, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lipoidica, non-sclerotic cutaneous chronic graft-versus-host disease, hand dermatitis, or Lichen Planus.
  • the dermatological disorder can be any of those modulated by TYK2 JAK1 and JAK2.
  • the dermatological disorder is atopic dermatitis, psoriasis, hives, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lipoidica, non-sclerotic cutaneous chronic graft-versus-host disease, hand dermatitis, or Lichen Planus.
  • compositions for use in treating the target dermatological disorders as described herein comprising a compound of Formulae (I) - (III) , or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable carrier; and (ii) uses of a compound of Formulae (I) - (III) , or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, for manufacturing a medicament for use in treating any of the target dermatological disorders.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods 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 syntheses.
  • HPLC high pressure liquid chromatography
  • the compounds herein may also contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g., restriction resulting from 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 instances, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. All such isomeric forms of such compounds herein are expressly included in the present disclosure.
  • isomers is intended to include diastereoisomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, and the like.
  • the methods of the present disclosure may be carried out with an enantiomerically enriched compound, a racemate, or a mixture of diastereomers. All isomers of compounds delineated herein are expressly included in the present disclosure.
  • the bond is a single bond
  • the dashed line is a single bond or absent
  • the bond is a single or double bond.
  • formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C-or 14 C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • isotopes refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.
  • range When a range of values ( “range” ) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided.
  • salt refers to any and all salts, and encompasses pharmaceutically acceptable salts.
  • Salts include ionic compounds that result from the neutralization reaction of an acid and a base.
  • a salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge) .
  • Salts of the compounds of this invention include those derived from inorganic and organic acids and bases.
  • acid addition salts are salts of an amino group 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 by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, per
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • pharmaceutically acceptable salt refers to those salts which are, 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 response, and the like, and are 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, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group 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 by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers” .
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is 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 and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers respectively) .
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture” .
  • prodrugs refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985) .
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or (alkoxycarbonyl) oxy) alkylesters.
  • C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein may be preferred.
  • composition and “formulation” are used interchangeably.
  • a “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult) ) or non-human animal.
  • the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey) , commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog) , or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey) ) .
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development.
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • patient refers to a human subject in need of treatment of a disorder or a disease.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disorder or disease described herein.
  • treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disorder.
  • treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen) . Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • an effective amount of a compound described herein refers to an amount sufficient to elicit the desired biological response.
  • An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, 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.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations) .
  • 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 means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for TYK2/JAK1/JAK2 kinase inhibition.
  • a therapeutically effective amount is an amount sufficient for treating a dermatological disorder.
  • a therapeutically effective amount is an amount sufficient for TYK2/JAK1/JAK2 kinase inhibition and treating a dermatological disorder.
  • the present disclosure is based at least in part on the unexpected results that compounds of Formulae (I) - (III) are selective TYK2/JAK1/JAK2 kinase inhibitors that have a good exposure in skin but low in plasma.
  • R 1 is C 1-3 alkyl, C 3-4 cycloalkyl, or halo
  • R 4 is C 1-3 alkyl, C 3-8 cycloalkyl, or 4 to 7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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’, wherein R 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 (
  • R, R’ each is independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.
  • R 1 is C 1-3 alkyl, C 3-4 cycloalkyl, or halo
  • R 4 is C 1-3 alkyl, C 3-8 cycloalkyl, or 4 to 7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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’, wherein R 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 (
  • R, R’ each is independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.
  • R 1 is C 1-3 alkyl, C 3-4 cycloalkyl, or halo
  • R 4 is C 1-3 alkyl, C 3-8 cycloalkyl, or 4 to 7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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’, wherein R 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 (
  • R, R’ each is independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 2 is
  • R 4 is C 1-3 alkyl, C 3-8 cycloalkyl, or 4 to 7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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’, wherein R 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, R’ each is independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 2 is
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 2 is
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 1-3 alky, C 3-4 cycloalkyl, or halo.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 1-3 alky.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 1 is CH 3 .
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 3-4 cycloalkyl.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 1 is cyclopropyl.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 1 is halo.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 1 is Cl.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein:
  • R 4 is C 1-3 alkyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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’, wherein R 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) 2 R’, S
  • R, R’ each is independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 4 is CH 2 CH 2 OH.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 4 is isopropyl.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 4 is CH 3 .
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 4 is CH 2 R 5 , R 5 is 4 to 6 membered heterocyclyl.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein:
  • R 4 is CH 2 R 5 , R 5 is
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein:
  • R 4 is 4 to 7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of 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’, wherein R 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, R’ each is independently H, or C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN.
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein: R 4 is
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein the compound is depicted in Table 1:
  • the invention provides a compound of any one of the Formulae (I) - (III) , or a pharmaceutically acceptable salt thereof, wherein the compound is depicted in Table 2:
  • the invention provides a compound of any one of the Formulae (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) ;
  • the invention provides a compound of any one of the Formulae (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) ;
  • the invention provides a compound of any one of the Formulae (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) ;
  • the invention provides a crystal Form A of compound (4) ,
  • the X-ray powder diffraction pattern of the crystal form shows characteristic peaks at 2theta angles of 10.3° ⁇ 0.2°, 14.5° ⁇ 0.2°, and 16.7° ⁇ 0.2°.
  • the invention provides a crystal Form A of compound (4) , wherein the X-ray powder diffraction pattern of the crystal form shows characteristic peaks at 2theta 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°.
  • the invention provides a crystal Form A of compound (4) , wherein the X-ray powder diffraction pattern of the crystal form shows characteristic peaks at 2theta 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°.
  • a compound of Formulae (I) - (III) or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a composition comprising a compound of Formulae (I) - (III) , or salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
  • Figure 1 Ear thickness in hIL-23 induced psoriasis model for compound 4.
  • Figure 2 Ear thickness in DNFB induced atopic dermatitis model for compound 4.
  • compositions comprising a compound of Formulae (I) - (III) , or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical composition described herein comprises a compound of Formulae (I) - (III) , or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • compositions described herein can be prepared by any method known in the art of pharmaceutics.
  • such preparatory methods include bringing the compound described herein (i.e., the “active ingredient” ) into association with a 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-dose unit.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual) , vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch) .
  • Other formulations may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985) .
  • Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients.
  • ingredients such as the carrier that constitutes one or more accessory ingredients.
  • 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.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or packed in liposomes and as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • compositions of pharmaceutically active ingredients are known in the art and described in several issued US Patents, some of which include, but are not limited to, US Patent Nos. 4,369,172; and 4,842,866, and references cited therein.
  • Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Patent Nos. 6,638,534, 5,217,720, and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and references cited therein) .
  • a useful formulation for the compounds of this invention is the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • 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 solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with 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 this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.
  • Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which 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 where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein. See, e.g., Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H.
  • Application of the subject therapeutics may be local, so as to be administered at the site of interest.
  • Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.
  • the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention.
  • Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.
  • the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.
  • a 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 that demonstrates advantageous properties when administered alone or with a compound of any of the formulae herein.
  • Drugs that could be usefully combined with these compounds include other kinase inhibitors and/or other therapeutic agents for the treatment of the diseases and disorders discussed above.
  • the second therapeutic agent is an agent useful in the treatment or prevention of a disease or condition selected from cancer and neoplastic diseases or disorders, autoimmune and inflammatory diseases or disorders, neurodegenerative disease or disorders.
  • the invention provides separate dosage forms of a compound of this invention and a second therapeutic agent that are associated with one another.
  • association with one another means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously) .
  • the compound of the present invention is present in an effective amount.
  • effective amount refers to an amount which, when administered in a proper dosing regimen, is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect (s) of another therapy.
  • An effective amount of a compound of this invention can range from about 0.001 mg/kg to about 500 mg/kg, more preferably 0.01 mg/kg to about 50 mg/kg, more preferably 0.1 mg/kg to about 2.5 mg/kg.
  • Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.
  • an effective amount of the second therapeutic agent is between about 20%and 100%of the dosage normally utilized in a monotherapy regime using just that agent.
  • an effective amount is between about 70%and 100%of the normal monotherapeutic dose.
  • the normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et ak, 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) , each of which references are entirely incorporated herein by reference.
  • the present disclosure provides methods of treating a dermatological disorder (or symptoms thereof) comprising administering an effective amount of a compound of the present disclosure, or a salt, solvate, hydrate, polymorph, co-crystal, 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, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, to a subject in need thereof.
  • Treating encompasses therapeutic treatment.
  • the subject is identified as in need thereof.
  • the method further comprises wherein the subject is treated; that is, the disease, disorder, or symptom thereof is ameliorated.
  • the effective amount is a therapeutically effective amount.
  • the method slows the progress of a dermatological disorder in the subject.
  • the method improves the condition of the subject suffering from a dermatological disorder.
  • the subject has a suspected or confirmed dermatological disorder.
  • Exemplary dermatological disorders include, but are not limited to, atopic dermatitis, psoriasis, hives, alopecia areata, vitiligo, hidradenitis suppurativa, hand eczema, necrobiosis lipoidica, non-sclerotic cutaneous chronic graft-versus-host disease, hand dermatitis, or Lichen Planus.
  • the dermatological disorder is modulated by the JAK-STAT pathway. In certain embodiments, the dermatological disorder is modulated by JAK1. In certain embodiments, the dermatological disorder is modulated by JAK2. In certain embodiments, the dermatological disorder is modulated by TYK2. In certain embodiments, the dermatological disorder is modulated by any combination of TYK2, JAK1, and JAK2.
  • the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral) , parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops) , mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g., oral
  • parenteral intravenous, intramuscular, intra-arterial, intramedullary
  • intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
  • topical as by powders, ointments, creams, and/or drops
  • Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection) , regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
  • intravenous administration e.g., systemic intravenous injection
  • regional administration via blood and/or lymph supply e.g., via blood and/or lymph supply
  • direct administration e.g., direct administration to an affected site.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract) , and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration) .
  • the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.
  • Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley &Sons) . These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • 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) 2 (1.5 g, 6.7 mmol, 0.2 eq) , PCy 3 (3.7 g, 13.4 mmol, 0.4 eq) and K 3 PO 4 (56.7 g, 267.6 mmol, 8.0 eq) in toluene (460 mL) /H 2 O (92 mL) was stirred at 105 °C overnight, then cooled to room temperature.
  • 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 3 ) 4 (115 mg, 0.10 mmol, 0.05 eq) , and Na 2 CO 3 (164 mg, 1.55 mmol, 1.5 eq) in dioxane (6 mL) /H 2 O (1 mL) was stirred at 80 °C overnight, then cooled to room temperature.
  • 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) , Brettphos Pd G 3 (23 mg, 0.025 mmol, 0.1 eq) and K 3 PO 4 (104 mg, 0.50 mmol, 2.0 eq) in dioxane (5 mL) was stirred at 100 °C overnight under N 2 .
  • 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) 2 (1.5 g, 6.7 mmol, 0.2 eq) , Pcy 3 (3.7 g, 13.4 mmol, 0.4 eq) and K 3 PO 4 (56.7 g, 267.6 mmol, 8.0 eq) in toluene (460 mL) /H 2 O (92 mL) was stirred at 105 °C overnight, then cooled to room temperature.
  • 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 3 ) 4 (115 mg, 0.10 mmol, 0.05 eq) , and Na 2 CO 3 (164 mg, 1.55 mmol, 1.5 eq) in dioxane (6 mL) /H 2 O (1 mL) was stirred at 80 °C overnight, then cooled to room temperature.
  • 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) , Brettphos Pd G 3 (23 mg, 0.025 mmol, 0.1 eq) and K 3 PO 4 (104 mg, 0.50 mmol, 2.0 eq) in dioxane (5 mL) was stirred at 100 °C overnight under N 2 .
  • 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) , Brettphos Pd G 3 (24 mg, 0.026 mmol, 0.1 eq) and K 3 PO 4 (138 mg, 0.65 mmol, 2.5 eq) in dioxane (5 mL) was stirred at 100 °C overnight under N 2 .
  • 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 Na 2 CO 3 (15.4 g, 145 mmol, 2.0 eq) were added to a mixture solvent of dioxane (400 mL) and H 2 O (40 mL) at room temperature. Pd (PPh 3 ) 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 for 18 hours under N 2 atmosphere.
  • the solid was confirmed to be free base Form A of the present disclosure.
  • the XRPD pattern is substantially as depicted in Figure 3, and the XRPD data are listed in Table 3.
  • the TGA curve of Form A in the present disclosure shows about 0.07%weight loss when heated to 120 °C, which is substantially as depicted in Figure 4.
  • the DSC curve of Form A in the present disclosure is also depicted in Figure 4, which shows one endothermic peak at around 143 °C corresponding to the melting endothermic peak. Without any limitation being implied, Form A is an anhydrate.
  • Step 1 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 H 2 O (2 mL) was added Na 2 CO 3 (337 mg, 3.18 mmol, 2.0 eq) and Pd (PPh 3 ) 4 (185 mg, 0.16 mmol, 0.1 eq) . After addition, the mixture was degassed under N 2 for three times and stirred at 80 °C under N 2 atmosphere for 16 hours. The reaction mixture was concentrated.
  • Step 2 A mixture of 4b (450 mg, 1.43 mmol, 1.0 eq) , isoxazol-4-amine (239 mg, 2.86 mmol, 2.0 eq) , Brettphos Pd G 3 (65 mg, 0.072 mmol, 0.05 eq) and K 3 PO 4 (758 mg, 3.58 mmol, 2.5 eq) in dioxane (20 mL) was stirred at 100 °C under N 2 atmosphere for 16 hours.
  • Step 1 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 H 2 O (2 mL) was added Na 2 CO 3 (337 mg, 3.18 mmol, 2.0 eq) and Pd (PPh 3 ) 4 (185 mg, 0.16 mmol, 0.1 eq) . After addition, the mixture was degassed under N 2 for three times and stirred at 80 °C under N 2 atmosphere for 16 hours. The reaction mixture was concentrated.
  • Step 2 A mixture of 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) , Brettphos Pd G 3 (36 mg, 0.041 mmol, 0.1 eq) and K 3 PO 4 (218 mg, 1.03 mmol, 2.5 eq) in dioxane (10 mL) was stirred at 120 °C under N 2 atmosphere for 16 hours.
  • Step 1 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 H 2 O (2 mL) was added Na 2 CO 3 (337 mg, 3.18 mmol, 2.0 eq) and Pd (PPh 3 ) 4 (185 mg, 0.16 mmol, 0.1 eq) . After addition, the mixture was degassed under N 2 for three times and stirred at 80 °C under N 2 atmosphere for 16 hours. The reaction mixture was concentrated.
  • 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) , Brettphos Pd G 3 (36 mg, 0.041 mmol, 0.1 eq) and K 3 PO 4 (218 mg, 1.03 mmol, 2.5 eq) in dioxane (10 mL) was stirred at 120 °C under N 2 atmosphere for 16 hours.
  • Step 1 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 H 2 O (2 mL) was added Na 2 CO 3 (337 mg, 3.18 mmol, 2.0 eq) and Pd (PPh 3 ) 4 (185 mg, 0.16 mmol, 0.1 eq) . After addition, the mixture was degassed under N 2 for three times and stirred at 80 °C under N 2 atmosphere for 16 hours. The reaction mixture was concentrated.
  • 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) , Brettphos Pd G 3 (36 mg, 0.041 mmol, 0.1 eq) and K 3 PO 4 (218 mg, 1.03 mmol, 2.5 eq) in dioxane (10 mL) was stirred at 120 °C under N 2 atmosphere for 16 hours.
  • Step 1 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 H 2 O (2 mL) was added Na 2 CO 3 (337 mg, 3.18 mmol, 2.0 eq) and Pd (PPh 3 ) 4 (185 mg, 0.16 mmol, 0.1 eq) . After addition, the mixture was degassed under N 2 for three times and stirred at 80 °C under N 2 atmosphere for 16 hours. The reaction mixture was concentrated.
  • 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) , Brettphos Pd G 3 (36 mg, 0.041 mmol, 0.1 eq) and K 3 PO 4 (218 mg, 1.03 mmol, 2.5 eq) in dioxane (10 mL) was stirred at 120 °C under N 2 atmosphere for 16 hours.
  • Step 2 A mixture of 10b (410 mg, 1.23 mmol) , 10c (280 mg, 2.21 mmol) , Brettphos Pd G 3 (111 mg, 0.123 mmol) and K 3 PO 4 (391 mg, 1.85 mmol) in dioxane (20 mL) was stirred at 100 °Covernight under N 2 . The resulting mixture was filtered, and the residue was concentrated, purified by Prep-HPLC to afford 10 (9.35 mg, 2%yield) as a yellow solid. LC/MS: [M+H] + : 427.2.
  • 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) , Brettphos Pd G 3 (54 mg, 0.059 mmol) and K 3 PO 4 (375 mg, 1.77 mmol) in dioxane (20 mL) was stirred at 100 °C overnight under N 2 . The resulting mixture was filtered, and the residue was concentrated, purified by Prep-HPLC to afford 11 (14.38 mg, 5.2%yield) as a yellow solid.
  • Step 2 A mixture of 3a (300 mg, 0.789 mmol) , 10c (180 mg, 1.42 mmol) , Brettphos Pd G 3 (71 mg, 0.08 mmol) and K 3 PO 4 (251mg, 1.18 mmol) in dioxane (20 mL) was stirred at 100 °Covernight under N 2 . The resulting mixture was filtered, and the residue was concentrated, purified by Prep-HPLC to afford 12 (62.90 mg, 17%yield) as a yellow solid. LC/MS: [M+H] + : 472.0.
  • 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)
  • Step 2 A mixture of 13a (360 mg, 0.9 mmol) , 10c (206 mg, 1.62 mmol) , Brettphos Pd G 3 (81 mg, 0.09) and K 3 PO 4 (286 mg, 1.35 mmol) in dioxane (10 mL) was stirred at 100 °C overnight under N 2 . The resulting mixture was filtered, and the residue was concentrated, purified by Prep-HPLC to afford 13 (30 mg, 6%yield) as a yellow solid.
  • Step 2 A mixture of 3a (200 mg, 0.526 mmol) , 1-methyl-1H-pyrazol-3-amine (102 mg, 1.05 mmol) , Brettphos Pd G 3 (48 mg, 0.053 mmol) and K 3 PO 4 (167 mg, 0.789 mmol) in dioxane (20 mL) was stirred at 100 °C overnight under N 2 . The resulting mixture was filtered, and the organic phase was concentrated, purified by Prep-HPLC to afford 14 (53.06 mg, 21%yield) as a yellow solid. LC/MS: [M+H] + : 442.1.
  • Step 3 A mixture of 4b (170 mg, 0.54 mmol) , 15d (136 mg, 0.65 mmol) , K 3 PO 4 (172 mg, 0.81 mmol) and Brettphos Pd G3 (49 mg, 0.054) in dioxane (10 mL) was stirred at 100°C overnight under N 2 . The mixture was concentrated, purified by Prep-HPLC to afford 15 (16 mg, 6.1%yield) as a yellow solid. LC/MS: [M+H] + : 490.2.
  • Step1 To a solution of 17a (3 g, 26.5 mmol) , 2-iodopropane (9 g, 53 mmol) , K 2 CO 3 (7.3 g, 53 mmol) in DMA (30 ml) , the mixture was stirred at 70 °C for 2 h. Added EA (100 ml) , washed by H 2 O, Sat brine (100 ml) , the organic phase was concentrated to afford 17b (4 g, 97.6%yield) . LC/MS: [M+H] + : 156.
  • Step2 To a solution of 17b (2 g, 12.9 mmol) in MeOH (20 ml) , Pd/C (400 mg) was added, the mixture was stirred under the H 2 at rt for 3 h. Diluted and filtered it, concentrated to afford 17c (1.8 g, 100%yield) .
  • 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 3 ) 4 (6.0g) and Na 2 CO 3 (22.3 g, 210.52 mmol) in dioxane (400 mL) and H 2 O (50 ml) was stirred at 80 °C overnight under N 2 . The resulting mixture was triturated with ethyl acetate, filtered. The filtered cake was triturated with water to afford 3a (16.1 g, 80.5 %yield) as a light-yellow solid.
  • Step 2 A mixture of 3a (16.1 g, 42.37 mmol) , 1-methyl-1H-pyrazol-4-amine (12.3 g, 127.11 mmol) , Brettphos Pd G 3 (3.8 g, 4.24 mmol) and K 3 PO 4 (35.9 g, 169.47 mmol) in dioxane (300 mL) was stirred at 100 °C for 24 h under N 2 . The reaction mixture was concentrated and triturated with DCM. After filtration, it was triturated with water to afford 18 (8.31 g, 44.4 %yield) as a yellow solid.
  • 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) , Brettphos Pd G 3 (10 mg) and K 3 PO 4 (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, purified by Prep-HPLC to afford TLL-117 (20.1 mg, 14%) as a light-yellow solid. LC/MS: [M+H] + : 443.4.
  • Step 1 A mixture of 20a (300 mg, 0.90 mmol) , 1-methyl-1H-pyrazol-4-amine (175 mg, 1.81 mmol) , Brettphos Pd G 3 (25 mg) and K 3 PO 4 (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, purified by Prep-HPLC to afford 20 (94.3 mg, 27%) as a light-yellow solid. LC/MS: [M+H] + : 394.3.
  • Step 1 To a mixture of 21a (5.0 g, 20.6 mmol) in THF (100 mL) was added LiAlH 4 (3.9 g, 103 mmol) at 0 °C, the reaction mixture was stirred at 75 °C for 16 h. The reaction was quenched by H 2 O (3.9 mL) , 15%of NaOH (3.9*3 mL) and H 2 O (3.9 mL) . Subsequently, the resulting mixture was filtered and the filtrate was concentrated to afford 21b (3.1 g, >99 %) as a yellow solid. LC/MS: [M+H] + : 144.6.
  • Step 5 To a mixture of 21e (800 mg, 2.4 mmol) in HCOOH (2 mL) was added H 2 O 2 (408 mg, 12.0 mmol) . The reaction mixture was stirred at rt for 16 h. The reaction was quenched by Na 2 S 2 O 3 , and the residue was purified by flash chromatography (0.1%TFA) to afford 21f (350 mg, 42 %) as a white solid. LC/MS: [M+H] + : 334.4.
  • Step 6 To a mixture of 21f (350 mg, 1.1 mmol) in DCM (10 mL) was added DMF (two drops) and SOCl 2 (625 mg, 5.5 mmol) . The reaction mixture was stirred at 45 °C for 2 h. The reaction was concentrated to afford 21g (385 mg, >99%) as a yellow oil. LC/MS: [M+H] + : 352.3.
  • Step 8 A mixture of 21h (150 mg, 0.43 mmol) , 1-methyl-1H-pyrazol-4-amine (84 mg, 0.86 mmol) , Brettphos Pd G 3 (10 mg) and K 3 PO 4 (228 mg, 1.1 mmol) in dioxane (10 mL) was stirred at 100 °Covernight. The resulting mixture was filtered, and the residue was concentrated, purified by Prep-HPLC to afford 21 (55 mg, 31%) as a white solid. LC/MS: [M+H] + : 408.1.
  • 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 Et 3 N (97 mg, 0.96 mmol) and T 3 P (204 mg, 0.64 mmol) . The reaction mixture was stirred at rt for 16 h. The resulting mixture was filtered, and the residue was concentrated, purified by Prep-HPLC to afford 22 (19.4 mg, 16%) as white solid. LC/MS: [M+H] + : 383.3.
  • Step 1 To a flask containing dioxane (600 mL) and water (60 mL) was added 4a (25 g, 79.3 mmol) , 2, 4-dichloro-5-methylpyrimidine (38.8 g, 238 mmol) , and Na 2 CO 3 (25.2 g, 238 mmol) at room temperature. Pd (PPh 3 ) 4 (9 g, 23.8 mmol) was added quickly. The resulting mixture was purged with nitrogen 3 times and the mixture was stirred at 80°C for 18 h under N 2 . The reaction mixture was filtered and the filtrate was concentrated. The crude residue was purified by column chromatography to obtain 4b (20 g, 80%yield) as a yellow oil. LC/MS: [M+H] + : 316.
  • 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 K 3 PO 4 (33.6 g, 158.5 mmol) at room temperature.
  • Brettphos Pd G 3 (2.88 g, 3.17 mmol) was added quickly.
  • the resulting mixture was purged with nitrogen 3 times and the mixture was stirred at 110°C for 48 h under nitrogen atmosphere.
  • the reaction mixture was filtered and the filtrate was concentrated.
  • Step 1 To a flask containing dioxane (500 ml) was added 4b (10 g, 31.7 mmol) , 10c (12 g, 95.1 mmol) , and K 3 PO 4 (33.6 g, 158.5 mmol) at room temperature.
  • Brettphos Pd G 3 (2.88 g, 3.17 mmol) was added quickly.
  • the resulting mixture was purged with nitrogen 3 times and the mixture was stirred at 110°C for 48 h under nitrogen atmosphere.
  • the reaction mixture was filtered and the filtrate was concentrated.
  • Compound 25, 26, and 27 are prepared by procedures previously described, as in the preparation of compound 13, 18 and 23.
  • Basic reaction buffer 20 mM Hepes (pH 7.5) , 10mM MgCl 2 , 1 mM EGTA, 0.02%Brij35, 0.02 mg/ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT and 1%DMSO.
  • the required cofactor was added to each kinase reaction respectively.
  • Compounds using the 4-pyrimidine substituents based on abrocitinib (example 20) , tofacitinib (example 22) , and oclacitinib (example 21) are >10x, >100x, >100x, respectively, less potent TYK2/JAK1/JAK2 inhibitors compared to their analogs of Formula II (example 4) and Formular III (example 18) .
  • Example 2b TYK2 Cellular ELISA Assay Using NK92 Cells
  • test article add different concentrations of test article to wells, maintain in incubator at 37 °C and 5%CO2 for 1 hour;
  • compound 4 had IC 50 ⁇ 10 nM.
  • test article add different concentrations of test article to wells, maintain in incubator at 37 °C and 5%CO2 for 1 hour;
  • Example 4b Human liver microsome stability assay
  • the assay was conducted following procedures as below:
  • the reaction was stopped by the addition of 600 ⁇ l of cold stop solution at 0, 3, 6, 9, 15 and 30 minutes. Samples were shaked for 10 min and then centrifuged at 3220 g for 20 min. The supernatant was taken from each well and diluted with dilution solution before being analyzed by LC/MS/MS.
  • the slope value, k was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve.
  • the in vitro CL int (mic) of compound 4 in human liver microsome is 65.9 ⁇ l/min/mg protein, and t 1/2 is 21 min.
  • Example 5b Mini-pig dermal pharmacokinetic study
  • test articles were formulated as ointment and then applied to 2 female Guangxi Bama mini-pigs (8-12 kg) (Wujiang Tian yu Biological Technology) . Briefly, total area estimated to be approximately 10%of the total body surface area were clipped free of hair before treatment using electric clippers. The test article was dosed evenly to the skin with 15 mg/cm 2 at 0 h, 8 h and 24 h. Test articles were removed before next dosing. Blood and skin samples were collected at 24 h (pre-dosing) , 25 h, 28 h, 32 h, 48 h and 96 h.
  • the blood was taken via peripheral vein of each animal into pre-chilled tube containing potassium (K2) EDTA as anticoagulant. Exposed skin was washed using ethanol and then wiped with dry cotton swab before skin sample collection. Eight samples of dosing skin were drilled with a biopsy punch (0.7cm diameter) for each time point. Epidermis and dermis were separated and the eight samples from the same time point were pooled together and homogenized. All the above samples and homogenate were quantified by LC-MS/MS analysis.
  • Example 6b Efficacy study in hIL-23 induced psoriasis model
  • C57BL/6J mice (Beijing Vital River Laboratory) were randomized into normal, vehicle and treatment groups according to bodyweight and ear thickness on day 0. Immunization was conducted using hIL-23 (Sigma) in vehicle and treatment groups to induce a psoriasis-like inflammation, whereas PBS was used as a parallel in normal group. Human IL-23 immunized animals were topically administered vehicle and test articles, respectively, once-daily from day 1 to day 9. Ear thickness was assessed using a digital micrometer (QuantuMike, 293-185) before hIL-23 or PBS injection on day 0, 2, 4, 6, 8 and 10. Ear thickness was used to evaluate the efficacy of test article. Data are shown as Mean ⁇ SEM, using two-way ANOVA statistical analysis, *p ⁇ 0.05, ****p ⁇ 0.0001 compared with vehicle group, as shown in Figure 1.
  • Example 7b Efficacy study in 2, 4-dinitro-fluorobenzene (DNFB) induced atopic dermatitis model
  • BALB/c mice (Beijing Vital River Laboratory) of approximately 8 weeks old were randomized into normal, vehicle and treatment groups according to bodyweight and ear thickness at study initiation. Animals in vehicle and treatment groups received 0.15%DNFB stimulation on day 1, 8, 15, 22 and 29, and were once-daily administered with vehicle and test articles (0.1%, 0.25%, 0.5%and 1%ointment of compound 4) , respectively. Ear thickness was evaluated using a digital micrometer (QuantuMike, 293-185) right before and 24h after each DNFB stimulation. Data were plotted as Mean ⁇ SEM, using two-way ANOVA statistical analysis, *p ⁇ 0.05, ****p ⁇ 0.0001 compared with vehicle group, as shown in Figure 2.
  • the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element (s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and/or features.

Abstract

L'invention concerne des composés de 4-pyrazolyl-N-hétéroarylpyrimidin-2-amine utilisés en tant qu'inhibiteurs puissants de TYK2/JAK1/JAK2 avec de faibles expositions systémiques lorsqu'ils sont appliqués par voie topique. Ainsi, ces composés, et les compositions sont utiles en tant que traitement topique de troubles dermatologiques liés à JAK1/JAK2/TYK2 tels que la dermatite atopique, le psoriasis, l'urticaire, l'alopécie areata, le vitiligo, l'hidradénite suppurée, l'eczéma de la main, la nécrobiose lipoïdique, la maladie du greffon contre l'hôte chronique cutanée non sclérosante, la dermatite de la main, ou le Lichen plan.
PCT/CN2023/112361 2022-08-22 2023-08-10 Inhibiteurs de jak1/jak2/tyk2 pour le traitement topique de maladies dermatologiques WO2024041397A1 (fr)

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WO2014111037A1 (fr) * 2013-01-18 2014-07-24 上海昀怡健康管理咨询有限公司 Composé hétérocyclique à cinq et six chaînons, procédé de préparation, composition pharmaceutique et application associés
CN110862380A (zh) * 2019-10-24 2020-03-06 嘉兴特科罗生物科技有限公司 一种小分子化合物
WO2021078021A1 (fr) * 2019-10-24 2021-04-29 嘉兴特科罗生物科技有限公司 Petit composé moléculaire
CN113227074A (zh) * 2018-12-14 2021-08-06 凌科药业(杭州)有限公司 吡唑基-氨基-嘧啶基衍生物的苯甲酰胺及其组合物和方法
CN114181199A (zh) * 2020-09-15 2022-03-15 成都赜灵生物医药科技有限公司 2，4-二取代嘧啶衍生物及其制备方法和用途
WO2023060202A1 (fr) * 2021-10-06 2023-04-13 Aerie Pharmaceuticals, Inc. Composés de pyrazole inhibiteurs de janus kinase et leurs utilisations

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CN101910152A (zh) * 2007-11-16 2010-12-08 因塞特公司 作为janus激酶抑制剂的4-吡唑基-n-芳基嘧啶-2-胺和4-吡唑基-n-杂芳基嘧啶-2-胺
CN103298794A (zh) * 2010-11-09 2013-09-11 塞尔卓姆有限公司 作为tyk2抑制剂的吡啶化合物及其氮杂类似物
WO2014111037A1 (fr) * 2013-01-18 2014-07-24 上海昀怡健康管理咨询有限公司 Composé hétérocyclique à cinq et six chaînons, procédé de préparation, composition pharmaceutique et application associés
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CN110862380A (zh) * 2019-10-24 2020-03-06 嘉兴特科罗生物科技有限公司 一种小分子化合物
WO2021078021A1 (fr) * 2019-10-24 2021-04-29 嘉兴特科罗生物科技有限公司 Petit composé moléculaire
CN114181199A (zh) * 2020-09-15 2022-03-15 成都赜灵生物医药科技有限公司 2，4-二取代嘧啶衍生物及其制备方法和用途
WO2023060202A1 (fr) * 2021-10-06 2023-04-13 Aerie Pharmaceuticals, Inc. Composés de pyrazole inhibiteurs de janus kinase et leurs utilisations

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