Treatment of JAK inhibition-responsive disorders with prodrugs of JAK inhibitors

Abstract

A method of treating a JAK inhibition responsive state in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by structural formula (I) or (II) as described herein, or a pharma- ceutical acceptable salt thereof. [Formula 1] TIFF2024532765000052.tif51162

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 232,538, filed August 12, 2021, and U.S. Provisional Patent Application No. 63 / 233,059, filed August 13, 2021, the entire teachings of which are incorporated herein by reference.

[0002] Ruxolitinib phosphate is a heteroaryl-substituted pyrrolo[2,3-d]pyrimidine, also known as 3(R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate, which inhibits the Janus-associated kinases (JAKs) JAK1 and JAK2. These kinases mediate the signal transduction of numerous cytokines and growth factors important for hematopoiesis and immune function. JAK signaling involves the recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus, leading to the regulation of gene expression.

[0003] Ruxolitinib phosphate is approved in the United States and Europe for the treatment of myelofibrosis and for the treatment of polycythemia vera. Ruxolitinib is currently in clinical trials for the treatment of graft-versus-host disease and other conditions.

[0004] The deuterated analog of ruxolitinib, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyclopentyl-2,2,3,3,4,4,5,5-d8)propanenitrile (referred to herein as CTP-543), is a potent selective inhibitor of the Janus kinases JAK1 and JAK2. The compound is disclosed in International Patent Applications WO2013 / 188783A1, WO2017 / 192905A1, and WO2020 / 163653A1. CTP-543 is currently being studied in human clinical trials and has been shown to promote hair growth in patients suffering from alopecia areata at certain doses. Despite the beneficial activity of ruxolitinib and CTP-543, there is a continuing need for new compounds that inhibit JAK1 and JAK2 and can be used to treat the aforementioned diseases and conditions. Summary of the Invention

[0005] In an exemplary embodiment, the invention is a method of treating a JAK inhibition responsive state in a subject in need thereof. The method comprises administering to a subject a compound represented by structural formula (I) or (II): [ka] or a pharma- ceutically acceptable salt thereof, Y 1 is hydrogen or deuterium, Y 2 is also hydrogen or deuterium, Y 3 is also hydrogen or deuterium, R 8 is C1-C6 alkyl, Each R 1 are independently C1-C6 alkyl, or two R 1 together with the oxygen atom to which they are attached form a 5- or 6-membered heterocyclic ring, R 6 and R 7is independently for each occurrence selected from H and a nitrogen protecting group.

[0006] In another exemplary embodiment, the invention is a method of treating a JAK inhibition responsive state in a subject in need thereof. The method includes administering to a subject in need thereof a compound represented by structural formula (I) or (II): [ka] or a pharma- ceutical acceptable salt thereof, wherein, independently for each occurrence, Y 1 is hydrogen or deuterium, and Y 2 is also hydrogen or deuterium, and Y 3 is also hydrogen or deuterium, and R 8 is C1-C6 alkyl, and each R 1 are independently C1-C6 alkyl, or two R 1 together with the oxygen atom to which they are attached form a 5- or 6-membered heterocyclic ring, R 6 and R 7 is independently for each occurrence selected from H and a nitrogen protecting group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] As described herein, a compound represented by formula (I) or (II): [ka] Certain prodrug compounds of ruxolitinib represented by any of the following formulas, and deuterated analogs of ruxolitinib, or pharma- ceutically acceptable salts thereof, upon oral administration to a mammalian subject, can be metabolized in the subject's body (e.g., in the stomach, under acidic conditions) to active metabolites represented by the following formula (III), such as ruxolitinib and its deuterated analogs (e.g., CTP-543). Values ​​and exemplary values ​​of the variables in formulas (I) and (II) are defined below.

[0008] Thus, compounds of formula (I), when orally administered to a mammalian subject, can undergo the following transformation: [ka]

[0009] The compounds of formula (II), when orally administered to a mammalian subject, are capable of undergoing the following transformation: [ka]

[0010] In an exemplary embodiment, the prodrug compound of ruxolitinib and the deuterated analog of ruxolitinib are represented by formula (IV): [ka]

[0011] In formula (IV), R 10 may be any nitrogen protecting group, and in certain embodiments, is a group that can be cleaved in vivo.

[0012] In formula (IV), Y 1 , Y 2 , Y 3 The values ​​of are as described above for Formula (I) and Formula (II), and R 2 and R 3 are each independently C1-C6 alkyl, C 6- C 18 Aryl, (C6-C 18 )aryl-(C1-C3)alkyl, 5-18 membered heteroaryl, C3-C6 cycloalkyl, 5-7 membered heterocyclyl, -O-(C1-C6)alkyl, -N-(mono or di)(C1-C6)alkyl, or -O-(C6-C 18 ) aryl, each of which may be optionally substituted, and R 4 and R 5 are each independently C1-C6 alkyl, C6-C 18 Aryl, (C6-C18 )aryl-(C1-C3)alkyl, 5- to 18-membered heteroaryl, C3-C6 cycloalkyl, or 5- to 7-membered heterocyclyl, each of which may be optionally substituted.

[0013] An exemplary embodiment of the compound of formula (IV) is a compound represented by structural formula (IV A). [ka]

[0014] R 10 R may be any nitrogen protecting group, and in certain embodiments is a group that can be cleaved in vivo. 10 Permitted values ​​of include, but are not limited to, those listed above with respect to formula (IV) as well as protecting groups selected from pivaloyloxymethyl (POM), 2-(trimethylsilyl)ethoxymethyl (SEM), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), 2,4-dimethoxybenzyl, benzenesulfonyl, tosyl (Ts), t-butoxycarbonyl (BOC), methoxycarbonyl (MOC), benzyloxycarbonyl (CBz), 1-naphthalenesulfonate (1-napsyl), 4-nitrobenzenesulfonyl (p-nosyl), and 2,4,6-trimethylphenylsulfonyl.

[0015] definition As used herein, the term "prodrug" refers to a compound that metabolizes under physiological conditions in vivo (e.g., acid conditions, such as physiological conditions with a pH of less than 4), into an active pharmaceutical ingredient, also referred to herein as an "active metabolite". For example, when the compounds of formula (I) and formula (II) are orally administered, they can be metabolized in the mammalian body (e.g., in the stomach) into an active metabolite represented by formula (III). Examples of active metabolites represented by formula (III) include ruxolitinib and CTP-543.

[0016] The term "treat" refers to reducing, inhibiting, attenuating, decreasing, arresting, or stabilizing the onset or progression of a disease (e.g., a disease or disorder detailed herein), reducing the severity of a disease, or ameliorating symptoms associated with a disease. For example, treating a hair loss disorder includes regrowing hair, preventing further hair loss, or reducing the rate of hair loss.

[0017] "Hair loss disorder" means any condition or disorder that results in the loss of hair in one or more areas of the body. Hair loss disorders include, but are not limited to, androgenetic alopecia, alopecia areata, telogen effluvium, alopecia areata, alopecia totalis, and alopecia universalis.

[0018] As used herein, the term "mammal" includes humans, and non-human mammals such as cats, dogs, sheep, cows, pigs, goats, non-human primates (including monkeys and hominins).

[0019] As used herein, an "effective amount" of a prodrug defined by structural formula (I) and formula (II) described herein is an amount sufficient to produce a therapeutically effective amount of its corresponding active metabolite upon oral administration.

[0020] As used herein, a "therapeutically effective amount" is an amount sufficient to treat a target condition or disorder.

[0021] The term "alkyl" refers to a monovalent saturated hydrocarbon group. A C1-C6 alkyl is an alkyl having 1 to 6 carbon atoms. In some embodiments, the alkyl may be linear or branched. In some embodiments, the alkyl may be primary, secondary, or tertiary. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, including n-propyl and isopropyl, butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl, pentyl, including, for example, n-pentyl, isopentyl, and neopentyl, and hexyl, including, for example, n-hexyl and 2-methylpentyl. Non-limiting examples of primary alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Non-limiting examples of secondary alkyl groups include isopropyl, sec-butyl, and 2-methylpentyl. Non-limiting examples of tertiary alkyl groups include t-butyl.

[0022] Nitrogen protecting groups, also referred to as amine protecting groups, are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3, incorporated herein by reference. rdThis includes those described in detail in the following publication, John Wiley & Sons, 1999. For example, nitrogen protecting groups such as amide groups include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanine derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamina)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0023] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as, but not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfa)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthy]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Tro c), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-admantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate , alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthryl methyl carbamate, diphenyl methyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonyl methyl carbamate, Tyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxy Acyl vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate , 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0024] Sulfonamide groups (e.g., -S(=O)R aa Nitrogen protecting groups such as, but not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mtb), ... sulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), -trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0025] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10) acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adducts (STABASE), 5-substituted 1,3-Dimethyl-1,3,5-triazacyclohexan-2-one, 5-Substituted 1,3-Dibenzyl-1,3,5-triazacyclohexan-2-one, 1-Substituted 3,5-dinitro-4-pyridone, N-Methylamine, N-Allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-Acetoxypropylamine, N-(1-Isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, Quaternary ammonium salts, N-Benzylamine, N-Di(4-methoxyphenyl)methylamine, N-5-Dibenzosuberylamine, N-Triphenylmethylamine (Tr), N-[(4-Methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-Phenyl Fluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fern), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl(pyrid1)mesity1)]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N[phenyl(pentaacylcromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys). In certain embodiments, the nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0026] In certain embodiments, the nitrogen protecting group is acid labile. For example, the N-protecting group is a group that is deprotected in the stomach. An example of an acid labile group is a group that is deprotected >80% in 30 minutes at pH 2.0 in aqueous medium. Such groups include t-butoxycarbonyl (Boc), triflyl (Tf, SO2-CF3), trifluoroacetyl (F3-Ac), and trityl (Tr, CPh3). In one exemplary embodiment, the nitrogen protecting group is t-Boc.

[0027] The term "heterocyclic group" refers to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and one to four ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl") or tricyclic systems ("tricyclic heterocyclyl")), may be saturated, or may contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring is fused with one or more carbocyclyl groups, as defined above, and the point of attachment is on either the carbocyclyl ring or the heterocyclyl ring, or in which a heterocyclyl ring is fused with one or more aryl or heteroaryl groups, as defined above, and the point of attachment is on the heterocyclyl ring, in such cases the number of ring members continues to indicate the number of ring members of the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

[0028] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0029] It is recognized that, depending on the origin of the chemicals used in synthesis, some variation in natural isotopic abundance occurs in the synthesized compound.Therefore, preparations of ruxolitinib inherently contain a small amount of deuterated isotope substitution.Despite this variation, the concentration of naturally abundant stable hydrogen and carbon isotopes is small and immaterial compared to the degree of stable isotope substitution of deuterated compounds of the present invention.See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0030] In any compound described herein, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", it is understood that the position has hydrogen at its natural abundance isotopic composition. However, in certain embodiments described, when a position is specifically designated as "H" or "hydrogen", the position has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% hydrogen. In some embodiments, when a position is specifically designated as "H" or "hydrogen", the position incorporates ≦20% deuterium, ≦10% deuterium, ≦5% deuterium, ≦4% deuterium, ≦3% deuterium, ≦2% deuterium, or ≦1% deuterium. Also, unless otherwise noted, when a position is specifically designated as "D" or "deuterium," the position is understood to have deuterium at least 3340 times the natural abundance of deuterium, or 0.015% (i.e., at least 50.1% deuterium incorporation). The amount of deuterium incorporation at a designated position may be measured by analytical methods known to those of skill in the art, for example, by proton NMR.

[0031] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0032] In other embodiments, deuterated compounds of the invention have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0033] In some embodiments, in the compounds of the invention, each designated deuterium position (or atom) has at least 52.5% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 60% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 67.5% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 75% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 80% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 85% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 90% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 95% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 97% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 98% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 99% deuterium incorporation. In some embodiments, in the compounds of the invention, each designated deuterium position has at least 99.5% deuterium incorporation.

[0034] The term "isotopyranoside" refers to a species whose chemical structure differs from any compound described herein only in its isotopic composition.

[0035] The term "compound" when referring to a deuterated compound of the present invention refers to a collection of molecules having the same chemical structure, except that there may be isotopic variations among the constituent molecules of the molecule. Thus, it will be clear to one skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown also contains isotopic substitutions having hydrogen atoms at one or more of the designated deuterium positions in the structure. The relative amount of such isotopic substitutions in the compounds of the present invention depends on several factors, including the isotopic purity of the deuterium reagent used to make the compound, and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound. In certain embodiments, the relative amount of such isotopic substitutions as a whole is less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitutions as a whole is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0036] The present invention also provides any salt of the compounds described herein.The salt of the compound of the present invention is formed between an acid group and a basic group of the compound, such as an amino acid functional group, or a base group and an acid group of the compound, such as a carboxyl functional group.According to another embodiment, the compound is a pharma-ceutically acceptable acid addition salt, such as a phosphate salt.

[0037] As used herein, the term "pharmaceutically acceptable" refers to a composition that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic reaction, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that is capable of providing, directly or indirectly, a compound of the invention upon administration to a recipient. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

[0038] Acids commonly used to form pharma- ceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as paratoluenesulfonic acid, salicylic acid, tartaric acid, bitaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharma- ceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylic acid, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6 ... The pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and in particular those formed with organic acids such as maleic acid.

[0039] In certain embodiments, pharma- ceutically acceptable salts of the compounds represented by structural formulas (I) and (II) are addition salts formed with the following acids: [ka]

[0040] As used herein, the term "stable compound" refers to a compound that has sufficient stability to permit its manufacture and maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into a therapeutic product, an intermediate for use in the manufacture of a therapeutic compound, an isolatable or storable intermediate compound, treatment of a disease or condition responsive to a therapeutic agent).

[0041] "D" and "d" both refer to deuterium. "Stereoisomer" refers to both enantiomers and diastereomers. "Tert" and "t-" each refer to tertiary. "US" means the United States of America.

[0042] "Deuterium substituted" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0043] compound In one aspect, the present invention provides compounds and pharma- ceutically acceptable salts thereof.

[0044] In one embodiment, the present invention provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein, independently for each occurrence: Y 1 is hydrogen or deuterium, and each Y 2 is also hydrogen or deuterium, and each Y 3 is also hydrogen or deuterium, and each R 1 are independently C1-C6 alkyl, or two R 1 together with the oxygen atom to which they are attached form a 5- or 6-membered heterocyclic ring, R 6 and R 7is independently selected for each occurrence from H and a nitrogen protecting group. In certain embodiments, the nitrogen protecting group is an acid labile protecting group. In certain embodiments, the nitrogen protecting group is not t-butoxycarbonyl (Boc), triflyl (Tf, SO2-CF3), trifluoroacetyl (F3-Ac), or trityl (Tr, CPh3). In certain embodiments, Y 2 and Y 3 At least one of Y is deuterium. 2 and Y 3 are deuterium. In certain embodiments, Y 1 is hydrogen, and Y 2 and Y 3 Both are deuterium.

[0045] In certain embodiments, each R 1 are the same. In certain embodiments, at least one R 1 is not methyl. In certain embodiments, at least one R 1 is not ethyl.

[0046] In another embodiment, the present invention provides a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein, independently for each occurrence: Y 1 is hydrogen or deuterium, and Y 2 is also hydrogen or deuterium, and Y 3 is also hydrogen or deuterium, and R 8 is C1-C6 alkyl, R 6 and R 7 is independently for each occurrence independently selected from H and a nitrogen protecting group.

[0047] In certain embodiments, R 8 is not methyl. In certain embodiments, R 8 is not ethyl.

[0048] In another embodiment, the present invention provides a compound of formula (IV): [ka] Y 1 , Y 2 , and Y 3 are as described above for Formula (I) and Formula (II), R 10 is any nitrogen protecting group. In certain embodiments, R 10 is a group that can be cleaved in vivo. In certain embodiments, R 10 is selected from the group: [ka] R 2 and R 3 are each independently C1-C6 alkyl, C6-C 18 Aryl, (C6-C 18 )aryl-(C1-C3)alkyl, 5-18 membered heteroaryl, C3-C6 cycloalkyl, 5-7 membered heterocyclyl, -O-(C1-C6)alkyl, -N-(mono or di)(C1-C6)alkyl, or -O-(C6-C 18 ) aryl, each of which may be optionally substituted, and R 4 and R 5 are each independently C1-C6 alkyl, C6-C 18 Aryl, (C6-C 18) aryl-(C1-C3)alkyl, 5- to 18-membered heteroaryl, C3-C6 cycloalkyl, or 5- to 7-membered heterocyclyl, each of which may be optionally substituted.

[0049] Pharmaceutical Compositions In another aspect, the invention provides pharmaceutical compositions of any of the compounds of formula (I), (II), or (IV).

[0050] In one embodiment, the present invention provides a pharmaceutical composition of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, the pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0051] In one embodiment, the present invention provides a pharmaceutical composition of a compound of formula (II) or a pharma- ceutically acceptable salt thereof, the pharmaceutical composition comprising a compound of formula (II) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. In one embodiment, the present invention provides a pharmaceutical composition of the compound of formula (IV) or a pharma- ceutically acceptable salt thereof, the pharmaceutical composition comprising the compound of formula (IV) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0052] Treatment method In one aspect, the invention provides a method for treating a "JAK inhibition responsive state" (e.g., a disease or disorder that can be treated by a compound that inhibits the activity of JAK (JAK1 and / or JAK2)), the method comprising administering to the patient an effective amount of a compound of formula (I) or a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof to a mammalian subject, Y 1 is hydrogen or deuterium, and Y 2 is also hydrogen or deuterium, and Y 3 is also hydrogen or deuterium, and R 8 is C1-C6 alkyl, and each R 1 are independently C1-C6 alkyl, or two R 1 together with the oxygen atom to which they are attached form a 5- or 6-membered heterocyclic ring, R 6 and R 7 is independently for each occurrence independently selected from H and a nitrogen protecting group.

[0053] In certain embodiments, the method of treatment comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or formula (II) or a pharma- ceutically acceptable salt thereof, as defined above.

[0054] In certain embodiments of formula (I) or formula (II), Y 1 is hydrogen, and Y 2 and Y 3 Each of Y is deuterium. In certain embodiments of Formula (I) or Formula (II), 1 is deuterium, and Y 2 and Y 3 Each of Y is deuterium. In certain embodiments of formula (I) or (II), 1 , Y 2 , and Y 3 Each of R is hydrogen. In certain embodiments of Formula (I), 1 is methyl or ethyl. In certain embodiments of Formula (I), both R 1 is methyl. In certain embodiments of Formula (I), both R 1 is ethyl. In certain embodiments of Formula (I), each R 6 is H. In certain embodiments of formula (I), one R 6 is H and one R 6 is a nitrogen protecting group (NPG). In certain embodiments of formula (I), each R 6 is a nitrogen protecting group. In certain embodiments of formula (II), R 8 is methyl or ethyl. In certain embodiments of formula (II), R 6 and R 7 are H. In certain embodiments of Formula (II), R 6 and R 7 One of them is H and the other is a nitrogen protecting group.

[0055] In certain embodiments, the protecting group of the compounds described herein is selected from t-butoxycarbonyl (Boc), triflyl (Tf, SO2-CF3), trifluoroacetyl (F3-Ac), and trityl (Tr, CPh3). In certain embodiments, the protecting group is a t-butoxycarbonyl group. In certain embodiments, the deuterium incorporation at each position designated as deuterium is at least 90%, at least 95%, or at least 97%.

[0056] In certain embodiments, the compound of formula I is compound (I-1d): [ka] or a pharmaceutically acceptable salt thereof. As described herein, another embodiment of the present invention is a composition comprising compound (I-1d), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. In certain embodiments, the deuterium incorporation at each position designated as deuterium in compound (I-1d) is at least 90%, at least 95%, or at least 97%.

[0057] In certain embodiments, the compound of formula I is compound (I-2d): [ka] or a pharmaceutically acceptable salt thereof. As described herein, another embodiment of the present invention is a composition comprising compound (I-2d), or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier. In certain embodiments, the deuterium incorporation at each position designated as deuterium in compound (I-2d) is at least 90%, at least 95%, or at least 97%.

[0058] In certain embodiments, the compound of formula I is compound (I-1): [ka] or a pharmaceutically acceptable salt thereof. As described herein, another embodiment of the present invention is a composition comprising compound (I-1), or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier. In certain embodiments, the deuterium incorporation at each position designated as deuterium in compound (I-1) is at least 90%, at least 95%, or at least 97%.

[0059] In certain embodiments, the compound of formula I is compound (I-2): [ka] or a pharmaceutically acceptable salt thereof. As described herein, another embodiment of the present invention is a composition comprising compound (I-2), or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier. In certain embodiments, the deuterium incorporation at each position designated as deuterium in compound (I-2) is at least 90%, at least 95%, or at least 97%.

[0060] In certain embodiments, the compound of formula (II) is compound (II-1d): [ka] or a pharmaceutically acceptable salt thereof. As described herein, another embodiment of the present invention is a composition comprising compound (II-1d), or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier. In certain embodiments, the deuterium incorporation at each position designated as deuterium in compound (II-1d) is at least 90%, at least 95%, or at least 97%.

[0061] In certain embodiments, the compound of formula (II) is compound (II-2d): [ka] or a pharmaceutically acceptable salt thereof. As described herein, another embodiment of the present invention is a composition comprising compound (II-2d), or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier. In certain embodiments, the deuterium incorporation at each position designated as deuterium in compound (II-2d) is at least 90%, at least 95%, or at least 97%.

[0062] In certain embodiments, the compound of formula I is compound (II-1): [ka] or a pharma- ceutically acceptable salt thereof, or a composition comprising compound (II-1), or a pharma- ceutically acceptable salt thereof. As described herein, another embodiment of the present invention is a composition comprising compound (II-1), or a pharma- ceutically acceptable salt thereof, optionally with a pharma- ceutically acceptable carrier. In certain embodiments, the deuterium incorporation at each position designated as deuterium in compound (II-1) is at least 90%, at least 95%, or at least 97%.

[0063] In certain embodiments, the compound of formula (II) is compound (II-2): [ka] or a pharmaceutically acceptable salt thereof. As described herein, another embodiment of the present invention is a composition comprising compound (II-2), or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier. In certain embodiments, the deuterium incorporation at each position designated as deuterium in compound (II-2) is at least 90%, at least 95%, or at least 97%.

[0064] In certain embodiments, a "JAK inhibition responsive state" is a condition that is a chronic condition, such as, but not limited to, organ transplant rejection (e.g., allograft rejection and graft-versus-host disease); hair loss disorders such as alopecia (alopecia areata (AA), alopecia totalis, alopecia universalis); autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, autoimmune thyroid disorders; allergic conditions such as asthma, food allergies, atopic dermatitis and rhinitis; Epstein-Barr syndrome, and the like; viral diseases such as EBV, hepatitis B, hepatitis C, HIV, HTLV1, varicella-zoster virus (VZV) and human papillomavirus (HPV); skin disorders such as vitiligo, psoriasis (e.g., plaque psoriasis), atopic dermatitis, hidradenitis suppurativa, skin rash, dermatitis, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis); solid tumors (e.g., prostate cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancer of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, melanoma), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia, or multiple myeloma), and skin cancers such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (examples of which include Sézary syndrome and mycosis fungoides); myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), myelodysplasia with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), and systemic mast cell disease (SMCD); ocular inflammatory diseases (e.g., iritis, uveal tract infections, and inflammatory bowel disease); inflammation and inflammatory diseases such as inflammatory bowel disease, scleritis, conjunctivitis, or related disorders, inflammatory diseases of the respiratory tract (e.g., upper respiratory tract including nose and sinuses such as rhinitis or sinusitis, or lower respiratory tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory myopathies such as myocarditis; systemic inflammatory response syndrome (SIRS) and septic shock; diseases or conditions associated with ischemia-reperfusion injury, or an inflammatory ischemic event such as stroke or cardiac arrest; anorexia; cachexia; fatigue resulting from or associated with cancer; restenosis; scleroderma; fibrosis;conditions associated with hypoxia or astrogliosis, such as diabetic retinopathy, cancer or neurodegeneration; gout; increased prostate size due to benign prostatic hyperplasia or benign prostatic hyperplasia; and diseases involving the immune system, including androgenetic alopecia and other hair loss disorders such as telogen effluvium;

[0065] In certain embodiments, the condition is selected from a hair loss disorder, polycythemia vera (PV), myelofibrosis (MF), or acute graft-versus-host disease (aGVHD).

[0066] Hair loss disorders include, but are not limited to, androgenetic alopecia, alopecia areata, telogen effluvium, alopecia totalis, and alopecia universalis.

[0067] Alopecia areata is an autoimmune disease that causes partial or complete loss of hair on the scalp and body, potentially affecting up to 650,000 Americans at any one time. The scalp is the most commonly affected area, but any hairy site may be affected alone or in combination with the scalp. Onset of the disease can occur throughout life, affecting both women and men. Alopecia areata can be associated with severe psychological consequences, including anxiety and depression. Currently, there are no drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of alopecia areata.

[0068] In certain embodiments, the condition is alopecia areata in a subject, such as a mammalian (e.g., human) patient in need thereof. In certain embodiments, the alopecia areata is moderate to severe alopecia areata (e.g., hair loss of at least 30% of the scalp, hair loss of at least 40% of the scalp, or hair loss of at least 50% of the scalp).

[0069] In a preferred embodiment, the subject is a human. In one embodiment, the subject is a human aged 6 years or older.

[0070] In certain embodiments, the present invention provides a method for treating a disease or disorder (e.g., hair loss disorder such as alopecia areata) that can be treated by a compound that modulates (e.g., inhibits) the activity of JAK (JAK1 and / or JAK2), comprising administering an effective amount of any compound described herein (e.g., a compound of formula (I) or formula (II)) or a pharmaceutically acceptable salt thereof to a mammalian subject once or twice daily, wherein the amount of the compound or a pharmaceutically acceptable salt thereof administered is within the range of about 4 mg / day to about 50 mg / day, e.g., about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, or about 50 mg / day, sufficient to administer an active metabolite of formula (III), e.g., ruxolitinib or CTP-543, to the subject (e.g., a human subject). In certain embodiments, the active metabolite is ruxolitinib. In certain embodiments, the active metabolite is CTP-543. In certain embodiments, for example, when the active metabolite is CTP-543, the amount of the compound or its pharma- ceutically acceptable salt administered is sufficient to provide an amount of the active metabolite that is about 4 mg / day, 8 mg / day, 16 mg / day, 32 mg / day, or 48 mg / day. In certain embodiments, for example, when the active metabolite is CTP-543, the amount of the compound or its pharma- ceutically acceptable salt administered is sufficient to provide an amount of the active metabolite that is about 8 mg / day, 16 mg / day, 24 mg / day, or 32 mg / day. In certain embodiments, for example, when the active metabolite is CTP-543, the amount of the compound or its pharma- ceutically acceptable salt administered is sufficient to provide an amount of the active metabolite that is equivalent to, for example, 10.6 mg / day of the phosphate salt of the active metabolite administered as a twice-daily dose. In certain embodiments, for example, where the active metabolite is CTP-543, the amount of the compound or a pharma- ceutically acceptable salt thereof administered is sufficient to provide an amount of the active metabolite equivalent to, for example, 21.1 mg / day of the phosphate salt of the active metabolite administered as a twice daily dose.

[0071] In certain embodiments, for example, when the active metabolite is CTP-543, the amount of the compound or a pharma- ceutically acceptable salt thereof administered is sufficient to provide an amount of the active metabolite equivalent to, for example, 31.6 mg / day of the phosphate salt of the active metabolite administered as a twice daily dose. In certain embodiments, for example, when the active metabolite is CTP-543, the amount of the compound or a pharma-ceutically acceptable salt thereof administered is sufficient to provide an amount of the active metabolite equivalent to, for example, 42.2 mg / day of the phosphate salt of the active metabolite administered as a twice daily dose.

[0072] In a preferred embodiment, the subject is a human. In one embodiment, the subject is a human aged 6 years or older. Preferably, the administered compound or its pharmaceutically acceptable salt (such as phosphate) is administered orally at any of the doses described above. Preferably, the administered compound or its pharmaceutically acceptable salt is administered orally at any of the doses described above in a pharmaceutical formulation that may be a tablet.

[0073] In one embodiment, the compound is administered orally once daily, hi another embodiment, the compound is administered orally twice daily.

[0074] Effective doses will also vary, as recognized by those of skill in the art, depending on the disease being treated, the severity of the disease, the route of administration, the sex, age, and general health of the subject, the use of excipients, the use of other medications, and the possibility of co-use with other therapeutic treatments, such as the judgment of the treating physician.

[0075] Administration of the compounds described herein or a pharma- ceutically acceptable salt thereof (such as a phosphate salt) can continue for as long as necessary for the disorder, such as a hair loss disorder, for example, one week, two weeks, one month, two months, three months, four months, six months, one year, two years, five years, ten years, or more.

[0076] The effectiveness of the treatment of hair loss disorders such as alopecia areata can be measured in various ways, some of which are known in the art.For example, the "severity of alopecia tool", known as SALT, is a validated assessment scale developed by the working committee of the National Alopecia Areata Foundation to assess the extent of hair loss.See, for example, Olsen EA, Hordinsky MK, Price VH, et al., Alopecia Areata Clinical Trial Assessment Guidelines-Part II.J Am Acad Dermatol 2004:51:440-447 (incorporated herein by reference).SALT score is calculated for a patient by measuring the percentage of hair loss in each of the four areas of the scalp and adding the sum to achieve a composite value.Hair regrowth is reflected by a decrease in SALT score.For example, completely no hair on the scalp has a SALT score of 100, while complete hair regrowth is a SALT score of 0. In certain embodiments, the treatment methods described herein can provide an improvement in the SALT score of at least 10 points after treatment (e.g., from a SALT score of 100 before treatment to a SALT score of 90 after treatment). In further embodiments, the treatment methods described herein can result in an improvement in the SALT score of at least 20 points, 30 points, 40 points, 50 points, 60 points, 70 points, 80 points, 90 points, or 100 points. In certain embodiments, the treatment methods described herein can provide at least a 20% improvement from baseline in the patient's SALT score, or at least a 30% improvement from baseline in the patient's SALT score, or at least a 40% improvement from baseline in the patient's SALT score, or at least a 50% improvement from baseline in the patient's SALT score, or at least a 60% improvement from baseline in the patient's SALT score, or at least a 70% improvement from baseline in the patient's SALT score.

[0077] In certain embodiments, treatment continues for a period of at least four weeks, at least eight weeks, or at least twelve weeks, or at least sixteen weeks, or at least twenty weeks, or at least twenty-four weeks, or at least twenty-eight weeks, or at least thirty-two weeks, or at least thirty-six weeks, or at least forty weeks, or at least forty-four weeks, or at least forty-eight weeks, or at least fifty-two weeks.

[0078] Combination therapy In certain embodiments, the compound described herein or its pharmaceutically acceptable salt can be administered in combination with a second therapeutic agent.Preferably, the second therapeutic agent is an agent useful for treating hair loss disorder or JAK inhibition response disorder such as an inhibitor of JAK1, JAK2 or JAK3 and / or STAT1 or an autoimmune condition.Such inhibitors include ruxolitinib, tofacitinib, baricitinib, filgotinib, etc.Other orally administered second therapeutic agents include agents used for treating alopecia areata, including, for example, oral corticosteroids.

[0079] For pharmaceutical compositions containing a second therapeutic agent, the effective amount of the second therapeutic agent is about 20%-100% of the dose normally used in a monotherapy regimen using only that agent. Preferably, the effective amount is about 70%-100% of the normal monotherapy dose. The normal 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); FDA-approved labeling information for ruxolitinib and tofacitinib; and clinical trial information for baricitinib and filgotinib; each of which is incorporated herein by reference in its entirety.

[0080] Some of the above-mentioned second therapeutic agents are expected to act synergistically with the compounds of the present invention.When synergistic action occurs, the effective dose of the second therapeutic agent and / or any compound described herein, or its pharmaceutically acceptable salt, can be reduced from that required in monotherapy.This has the advantage of minimizing the toxic side effects of either the second therapeutic agent or the compound described herein, or its pharmaceutically acceptable salt, synergistic improvement in efficacy, ease of administration or improvement in use, and / or reduction in the overall cost of preparation or formulation of the compound.

[0081] The selection of the second therapeutic agent may be made from any second therapeutic agent known to be useful in the treatment of hair loss disorders such as alopecia areata.The selection of the second therapeutic agent also depends on the specific disease or condition to be treated.The examples of the second therapeutic agent that can be adopted in the method of the present invention are those described above for use in the combination composition comprising any compound described herein, or its pharma-ceutically acceptable salt, and the second therapeutic agent.The additional therapeutic agent includes, for example, the agent used in the treatment of alopecia areata, including topical minoxidil, injectable corticosteroids, and anthralin cream or ointment.

[0082] As used herein, the term "concomitant" means that the second therapeutic agent can be administered together with any compound described herein, or a pharma- ceutically acceptable salt thereof, as part of a single dosage form (such as the composition of the present invention comprising the compound of the present invention and the second therapeutic agent described above) or as separate multiple dosage forms. Alternatively, the additional agent can be administered before, consecutively, or after the administration of any compound described herein, or a pharma- ceutically acceptable salt thereof. In such combination therapy treatment, both the compound described herein, or a pharma- ceutically acceptable salt thereof, and the second therapeutic agent are administered by conventional methods. The administration of the composition of the present invention comprising both any compound described herein, or a pharma- ceutically acceptable salt thereof, and the second therapeutic agent to a subject does not preclude the separate administration of the same therapeutic agent, any other second therapeutic agent, or any compound described herein, or a pharma- ceutically acceptable salt thereof, to the subject at another time during the course of treatment.

[0083] Effective amounts of these second therapeutic agents are well known to those of skill in the art, and guidance for administration can be found in the patents and published patent applications referenced herein, as well as in 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), and other medical literature. However, determining optimal effective amount ranges for the second therapeutic agents is well within the purview of one of ordinary skill in the art.

[0084] In one embodiment of the present invention, when a second therapeutic agent is administered to a subject, the effective amount of any compound described herein (e.g., a compound of Formula (I) or Formula (II), or a pharma- ceutically acceptable salt thereof) will be less than its effective amount when the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount when any compound described herein, or a pharma- ceutically acceptable salt thereof, is not administered. In this manner, undesirable side effects associated with high doses of either agent can be minimized. Other potential advantages (including, but not limited to, improved dosing regimens and / or reduced drug costs) will be apparent to one of skill in the art.

[0085] In yet another aspect, the present invention provides the use of any of the compounds described herein, or a pharma- ceutically acceptable salt thereof, either alone or together with one or more of the above-mentioned second therapeutic agents in the manufacture of a medicament, in a single composition or in separate dosage forms, for the treatment or prophylaxis in a subject of the above-mentioned diseases, disorders or conditions. Another aspect of the present invention is any of the compounds described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis in a subject of the diseases, disorders or conditions detailed herein.

[0086] Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) or formula (II), or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or diluent. The amount of the compound of formula (I) or formula (II) present in the pharmaceutical composition is an amount sufficient to provide an active metabolite in the range of about 4 mg / day to about 50 mg / day, for example, about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, or about 50 mg / day. In certain embodiments, the amount of the compound or its pharma- ceutically acceptable salt is sufficient to provide an amount of active metabolite that is about 4 mg / day, 8 mg / day, 16 mg / day, 32 mg / day, or 48 mg / day. In certain embodiments, the amount of the compound or its pharma- ceutically acceptable salt is sufficient to provide an amount of active metabolite that is 8 mg / day, 16 mg / day, 24 mg / day, or 32 mg / day. In certain embodiments, the active metabolite is ruxolitinib. In certain embodiments, the active metabolite is CTP-543.

[0087] Another aspect of the present invention is a unit dosage form comprising a compound of formula (I) or formula (II), or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or diluent. The amount of the compound of formula (I) or formula (II) present in the unit dosage form is an amount sufficient to provide an active metabolite in the range of about 4 mg / day to about 50 mg / day, for example, about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, or about 50 mg / day. In certain embodiments, the amount of the compound or its pharma- ceutically acceptable salt is sufficient to provide an amount of active metabolite that is about 4 mg / day, 8 mg / day, 16 mg / day, 32 mg / day, or 48 mg / day. In certain embodiments, the amount of the compound or its pharma- ceutically acceptable salt is sufficient to provide an amount of active metabolite that is about 8 mg / day, 16 mg / day, 24 mg / day, or 32 mg / day. In certain embodiments, the active metabolite is ruxolitinib. In certain embodiments, the active metabolite is CTP-543. In certain embodiments, the unit dosage form is a tablet.

[0088] Synthesis of the Compounds Described Herein I. Synthesis of Compounds Represented by Formula (I) [ka]

[0089] Synthesis of compounds represented by structural formula (I), or a pharma- ceutically acceptable salt thereof (such as a phosphate salt), can be readily accomplished by the methods described in International Patent Application No. PCT / US2020 / 017093, published as WO2020 / 163653, the teachings of which are incorporated herein by reference with appropriate amendment.

[0090] Such synthetic procedures are illustrated by the synthetic scheme that results in compound (I-1) and compound (I-1d), designated in WO2020 / 163653 as compounds (E-6) and (E-6'), respectively. [ka]

[0091] The following synthetic scheme can be used to produce compound (I-1).

[0092] Scheme 1 [ka]

[0093] Synthesis of intermediate E-4 may alternatively be achieved by the methods described in International Patent Application No. PCT / US2021 / 039653, published as WO2022 / 006136, the entire contents of which are incorporated herein by reference.

[0094] Compound 16 of Scheme 1 can be obtained according to the following synthetic scheme.

[0095] Scheme 2 [ka]

[0096] Modification of Scheme 2 (Scheme 2') results in a deuterated analog of compound 16, which can be used to generate a deuterated analog of compound (I-1), such as compound (I-1d), according to Scheme 3.

[0097] Scheme 2' [ka]

[0098] Scheme 3 [ka]

[0099] A similar synthetic route described in WO2020 / 163653 can produce compounds (I-2) and (I-2d). [ka]

[0100] That is, the following scheme 4 can be used to produce compound (I-2).

[0101] Scheme 4 [ka]

[0102] Substitution of compound 16 with compound 16' in Scheme 4 leads to the final product compound (I-2d).

[0103] II. Synthesis of Compounds of Formula (II) [ka]

[0104] Synthesis of a compound represented by structural formula (II), or a pharma- ceutically acceptable salt thereof (such as a phosphate salt), can be readily accomplished by methods known to those of skill in the art, as exemplified by the synthesis of compound (II-1) shown below in Scheme 5.

[0105] Scheme 5 [ka]

[0106] Synthesis of compounds of formula (IV) [ka]

[0107] The synthesis of the compound represented by structural formula (IV) can be easily achieved by those skilled in the art. In particular, a suitable synthetic route for reaching the compound of formula (IV) is described in publication CN107915738A, the teachings of which are incorporated herein by reference in their entirety.

[0108] Such methods may be carried out utilizing the corresponding deuterated, and optionally other isotopically-containing reagents and / or intermediates to synthesize the compounds detailed herein, or by invoking standard synthetic protocols known in the art for introducing isotopic atoms into a chemical structure.

[0109] For example, Scheme 6 can be used. Scheme 6 [ka]

[0110] In Scheme 6,

[0111] R 12 and R 14 are each independently C1-C6 alkyl, C6-C 18 Aryl, (C6-C 18)aryl-(C1-C3)alkyl, 5-18 membered heteroaryl, C3-C6 cycloalkyl, 5-7 membered heterocyclyl, -O-(C1-C6)alkyl, -N-(mono or di)(C1-C6)alkyl, or -O-(C6-C 18 ) aryl, each of which may be optionally substituted;

[0112] R 13 and R 16 are each independently C1-C6 alkyl, C6-C 18 Aryl, (C6-C 18 ) aryl-(C1-C3) alkyl, 5- to 18-membered heteroaryl, C3-C6 cycloalkyl, or 5- to 7-membered heterocyclyl, each of which may be optionally substituted;

[0113] R 11 is, independently for each occurrence, C1-C6 alkyl, C6-C 18 Aryl, (C6-C 18 ) aryl-(C1-C3) alkyl, each of which may be optionally substituted;

[0114] R 15 is defined above, and R 10 and a nitrogen protecting group as exemplified below for

[0115] R 10 is any nitrogen protecting group, and in certain embodiments, is a group that can be cleaved in vivo. In addition to the protecting groups listed above, R 10 Permitted values ​​of include protecting groups selected from pivaloyloxymethyl (POM), 2-(trimethylsilyl)ethoxymethyl (SEM), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), 2,4-dimethoxybenzyl, benzenesulfonyl, tosyl (Ts), t-butoxycarbonyl (BOC), methoxycarbonyl (MOC), benzyloxycarbonyl (CBz), 1-naphthalenesulfonate (1-napsyl), 4-nitrobenzenesulfonyl (p-nosyl), and 2,4,6-trimethylphenylsulfonyl.

[0116] In Scheme 6, X is a suitable leaving group, such as a halide (such as Cl, Br, or I), a mesylate, a triflate, or the like. Those skilled in the art can easily determine the type of protecting group that can be used. See, for example, Peter GMWuts, Theodora W. Greene, "Greene's Protective Groups in Organic Synthesis", Fourth Ed. (2006), Print ISBN: 9780471697541, the relevant teachings of which are incorporated herein by reference. In Scheme 6, XR 10 Some examples of the formula (I) may include protecting groups (e.g., at positions R) to be placed and / or to provide stability throughout the remaining steps of the synthesis. 11 and R 15 In those cases, the protecting group can be removed as a final synthetic step to give the active prodrug (where R 11 and / or R 15 is H).

[0117] Alternatively, such compounds can be prepared by reacting XR 10 Compounds of formula IV can be prepared directly from compounds of formula (III) by reaction with (with or without a protecting group as appropriate). Scheme 7 [ka]

[0118] where X is defined above with respect to Scheme 6.

[0119] In yet another alternative, compounds of formula (IV) may be achieved according to Scheme 8. Scheme 8 [ka]

[0120] The synthesis of compounds of formula (X) can be readily accomplished by one of ordinary skill in the art, for example, by reference to the synthetic schemes disclosed in U.S. Pat. No. 8,410,265, the relevant teachings of which are incorporated herein by reference.

[0121] In formula (X), the group R 10 can be a protecting group selected from pivaloyloxymethyl (POM), 2-(trimethylsilyl)ethoxymethyl (SEM), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), 2,4-dimethoxybenzyl, benzenesulfonyl, tosyl (Ts), t-butoxycarbonyl (BOC), methoxycarbonyl (MOC), benzyloxycarbonyl (CBz), 1-naphthalenesulfonate (1-napsyl), 4-nitrobenzenesulfonyl (p-nosyl), and 2,4,6-trimethylphenylsulfonyl. The hydrogenation catalyst can comprise rhodium and a chiral phosphine ligand (L) according to formula (XX): [ka] In the formula, R 2a , R 2b , R 3a , R 3b , and R 4 are each independently selected from hydrogen, methyl, methoxy, and trifluoromethyl; R 5 is a secondary alkyl, tertiary alkyl, or cycloalkyl.

[0122] Compounds of formula (X) can be prepared from compound 40 using compound 80 according to Scheme 9. Scheme 9 [ka]

[0123] Compound 40 can be prepared in a manner similar to that described in US Pat. No. 9,249,149 and US Pat. No. 8,410,265.

[0124] Pharmaceutical Compositions The present invention also provides a pharmaceutical composition comprising an effective amount of any of the compounds described herein, or its pharma- ceutically acceptable salt, and a pharma- ceutically acceptable carrier.The carrier is "acceptable" in the sense that it is compatible with other components of the formulation, and in the case of a pharma- ceutical acceptable carrier, it is not harmful to the recipient in the amount used in the drug.In certain embodiments, the pharmaceutical composition is provided as a unit dosage form.

[0125] The invention provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier or diluent and any of the compounds described herein, or a pharma- ceutically acceptable salt thereof.

[0126] In another aspect, the invention provides pharmaceutical compositions of any of the compounds of formula (I), (II), or (IV).

[0127] In one embodiment, the present invention provides a pharmaceutical composition of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, the pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0128] In one embodiment, the present invention provides a pharmaceutical composition of a compound of formula (II) or a pharma- ceutically acceptable salt thereof, the pharmaceutical composition comprising a compound of formula (II) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0129] In one embodiment, the present invention provides a pharmaceutical composition of the compound of formula (IV) or a pharma- ceutically acceptable salt thereof, the pharmaceutical composition comprising the compound of formula (IV) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0130] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0131] If necessary, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions can be enhanced by methods well known in the art. One method involves the use of lipid excipients in the formulation. See "Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)" edited by David J.Hauss, Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery:Basic Principles and Biological Examples" edited by Kishor M.Wasan, Wiley-Interscience, 2006.

[0132] Another known method of enhancing bioavailability is the use of amorphous forms of the compounds of the invention, optionally formulated with poloxamers such as LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See U.S. Patent No. 7,014,866, and U.S. Patent Publications 20060094744 and 20060079502.

[0133] The pharmaceutical composition of the present invention includes those suitable for oral administration.Other formulations can be conveniently presented in unit dosage form, such as tablets, sustained release capsules, granules, and liposomes, and can be prepared by any method well known in the art of pharmacy.See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams&Wilkins, Baltimore, MD (20th edition, 2000).

[0134] Such preparative techniques include the step of bringing into association the molecule with the ingredient to be administered, such as the 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.

[0135] In certain embodiments, the compound is administered orally.The composition of the present invention suitable for oral administration can be presented as a discrete unit such as capsule, sachet, or tablet, each containing a predetermined amount of active ingredient, powder or granule, solution or suspension in aqueous or non-aqueous liquid, oil-in-water liquid emulsion, water-in-oil liquid emulsion, liposome-filled, or as a bolus.Soft gelatin capsules can be useful for containing such suspension, which can advantageously increase the absorption rate of the compound.In certain embodiments, the compound is administered orally as tablet.

[0136] For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspension is administered orally, active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. In another embodiment, the composition is in the form of a tablet. In a particular embodiment, an exemplary formulation for tablets is disclosed in U.S. Pat. No. 8,754,224, the teachings of which are incorporated herein by reference.

[0137] In certain embodiments, the tablet formulation contains an effective amount of any compound described herein (e.g., a compound of Formula (I) or Formula (II)) or a pharma- ceutically acceptable salt thereof, the effective amount being sufficient to provide about 4 mg to about 50 mg of an active metabolite, or an equivalent amount of a pharma- ceutically acceptable salt thereof (such as a phosphate salt), and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and povidone. Upon wet granulation followed by compression, a tablet containing a compound of Formula (I) or Formula (II), or a pharma- ceutically acceptable salt thereof, is provided.

[0138] In another embodiment, the composition of the present invention comprising a compound of Formula (I) or Formula (II) or a salt thereof and a pharma- ceutically acceptable carrier further comprises a second therapeutic agent. The second therapeutic agent may be selected from any compound or therapeutic agent known or exhibiting advantageous properties when administered together with a compound having the same mechanism of action as ruxolitinib.

[0139] Preferably, the second therapeutic agent is an agent useful for treating hair loss disorders or autoimmune conditions, including inhibitors of JAK1, JAK2 or JAK3 and / or STAT1.Such inhibitors include ruxolitinib, tofacitinib, baricitinib, filgotinib, etc.Additional therapeutic agents include agents used for treating hair loss disorders, such as alopecia areata, including, for example, topical minoxidil, injectable corticosteroids, oral corticosteroids, and anthralin cream or ointment.

[0140] In another embodiment, the present invention provides separate dosage forms of a compound of Formula (I) or Formula (II), or a pharma- ceutically acceptable salt thereof, and any one or more of the second therapeutic agents described above, wherein the compound of Formula (I) or Formula (II), or a pharma- ceutically acceptable salt thereof, and the second therapeutic agent are associated with each other. As used herein, the term "associated with each other" means that the separate dosage forms are packaged together or sold together and are attached to each other in such a way that it is readily apparent that the separate dosage forms are intended to be administered (within less than 24 hours of each other, either sequentially or simultaneously).

[0141] In the pharmaceutical compositions of the present invention, the compound of formula (I) or formula (II), or a pharma- ceutically acceptable salt thereof, is present in an effective amount. As used herein, an "effective amount" of a prodrug defined by structural formula (I) and formula (II) is an amount sufficient to produce a therapeutically effective amount of its corresponding active metabolite upon oral administration.

[0142] The interrelationship of animal and human doses (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep, 1966, 50:219. Body surface area can be approximately determined from the subject's height and weight. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 1970, 537. EXAMPLES

[0143] Example 1: In vitro testing of the conversion of the compound of formula (I) to its active metabolite, the compound of formula (III) An in vitro study was conducted to examine the conversion of the dibenzoyl-D-tartaric acid (DBTA) salt of compound (I-1d) (compound of formula (I)) to CTP-543 (compound of formula (III)) when subjected to biologically relevant conditions similar to human stomach conditions (0.1 N hydrochloric acid, 37° C.).

[0144] Test conditions: At 37 °C, 28.5 mg of compound (I-1d)·DBTA salt (equivalent to 14.6 mg of compound (I-1d)) was added to 250 mL of 0.1 N HCl with stirring. Samples were removed via syringe at 30, 60, 120, and 240 minutes (times related to human gastric residence time), then filtered through a syringe filter and analyzed by HPLC. The results of the HPLC analysis are shown in the table below. [Table 1]

[0145] Results: Using biologically relevant test conditions, conversion of compound (I-1d) to CTP-543 was observed.

[0146] Without further description, it is believed that one skilled in the art can use the above description and illustrative examples to make and utilize the compounds of the present invention and to practice the claimed methods. It should be understood that the above discussion and examples merely provide detailed descriptions of certain preferred embodiments. It will be apparent to those skilled in the art that various modifications and equivalents can be made without departing from the spirit and scope of the present invention.

Claims

1. 1. Use of a compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a JAK inhibition responsive state in a subject in need thereof, comprising: The compound has structural formula (I) or (II): 【Chemical 1】 wherein, independently for each occurrence: Y １ is hydrogen or deuterium, Y ２ are identical and are hydrogen or deuterium, Y ３ are identical and are hydrogen or deuterium, R ８ is C １ -C ６ is alkyl, Each R １ is independent, C １ -C ６ alkyl or two R １ together with the oxygen atom to which they are attached form a 5- or 6-membered heterocyclic ring, R ６ and R ７ is independently for each occurrence selected from H and a nitrogen protecting group.

2. Y １ is hydrogen, and Y ２ and Y ３ The use according to claim 1 , wherein each of is deuterium.

3. Y １ , Y ２ , and Y ３ The use according to claim 1 , wherein each of is hydrogen.

4. R １ and R ８ The use according to any one of claims 1 to 3, wherein each is independently methyl or ethyl.

5. Each R １ The use according to claim 1, wherein is methyl.

6. Each R １ The use according to any one of claims 1 to 3, wherein is ethyl.

7. R ８ The use according to any one of claims 1 to 3, wherein is methyl.

8. R ８ The use according to any one of claims 1 to 3, wherein is ethyl.

9. R ６ The use of claim 1 , wherein, independently for each occurrence, is H.

10. For each occurrence, R ６ is H and R ７ The use according to claim 1 , wherein is a nitrogen protecting group.

11. The nitrogen protecting group is t-butoxycarbonyl (Boc), triflyl (Tf, SO ２ -CF ３ ), trifluoroacetyl (F ３ -Ac), and trityl (Tr, CPh ３ 2. The use according to claim 1, wherein the compound is selected from the group consisting of:

12. The use according to claim 11, wherein the protecting group is a t-butoxycarbonyl group.

13. The compound of formula (I) is compound (I-1d): 【Chemistry 2】 The use according to any one of claims 1 to 3, wherein

14. The compound of formula (I) is compound (I-2d): 【Chemistry 3】 The use according to any one of claims 1 to 3, wherein

15. The compound of formula (I) is compound (I-1): 【Chemistry 4】 The use according to any one of claims 1 to 3, wherein

16. The compound of formula (I) is compound (I-2): 【Chemistry 5】 The use according to any one of claims 1 to 3, wherein

17. The compound of formula (II) is compound (II-1d): 【Chemistry 6】 The use according to any one of claims 1 to 3, wherein

18. The compound of formula (II) is compound (II-2d): 【Chemistry 7】 The use according to any one of claims 1 to 3, wherein

19. The compound of formula (II) is compound (II-1): 【Chemistry 8】 The use according to any one of claims 1 to 3, wherein

20. The compound of formula (II) is compound (II-2): 【Chemistry 9】 The use according to any one of claims 1 to 3, wherein

21. The JAK inhibition responsive state is selected from the group consisting of hair loss disorders, organ transplant rejection, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type 1 diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, autoimmune thyroid disorders, asthma, food allergies, atopic dermatitis, rhinitis, Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV-1, varicella-zoster virus (VZV), human papillomavirus (HPV), skin rash, dermatitis, skin sensitization, vitiligo, hidradenitis suppurativa, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, and melanoma. , lymphoma, leukemia, cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma, polycythemia vera (PV), essential thrombocythemia (ET), myelodysplasia with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), iritis, uveitis, scleritis, conjunctivitis, rhinitis, sinusitis, bronchitis, chronic obstructive pulmonary disease, myocarditis, systemic inflammatory response syndrome (SIRS), septic shock, ischemia-reperfusion injury, stroke, cardiac arrest, anorexia, cachexia, fatigue, restenosis, scleroderma, fibrosis, diabetic retinopathy, neurodegeneration, gout, benign prostatic hyperplasia and benign prostatic hyperplasia.

22. 22. The use of claim 21, wherein the condition is a hair loss disorder, polycythemia vera (PV), myelofibrosis (MF), or acute graft-versus-host disease (aGVHD).

23. 23. The use according to claim 22, wherein the hair loss disorder is alopecia areata.

24. The use of claim 1 , wherein the compound is administered orally.

25. 10. The use of claim 1, wherein the compound is administered in a pharmaceutical formulation that is a tablet.

26. 10. The use of claim 1, wherein the compound is administered once daily.

27. 10. The use of claim 1, wherein the compound is administered twice daily.

28. 1. Use of a compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for treating a JAK inhibition responsive state in a subject in need thereof, comprising: The compound has structural formula (I) or (II): 【Chemistry 10】 wherein, independently for each occurrence: Y １ is hydrogen or deuterium, Y ２ are identical and are hydrogen or deuterium, Y ３ are identical and are hydrogen or deuterium, R ８ is C １ -C ６ is alkyl, Each R １ is independent, C １ -C ６ alkyl or two R １ together with the oxygen atom to which they are attached form a 5- or 6-membered heterocyclic ring, R ６ and R ７ is independently selected for each occurrence from H and a nitrogen protecting group, and said pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent and said compound or a pharmaceutically acceptable salt thereof.

29. 1. Use of a compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a JAK inhibition responsive state in a subject in need thereof, comprising: The compound has structural formula (IV): 【Chemistry 11】 wherein, independently for each occurrence: Y １ is hydrogen or deuterium, Y ２ are identical and are hydrogen or deuterium, Y ３ are identical and are hydrogen or deuterium, R ８ is C １ -C ６ is alkyl, R １０ is a nitrogen protecting group, used.

30. 1. Use of a compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for treating a JAK inhibition responsive state in a subject in need thereof, comprising: The compound has structural formula (IV): 【Chemistry 12】 wherein, independently for each occurrence: Y １ is hydrogen or deuterium, Y ２ are identical and are hydrogen or deuterium, Y ３ are identical and are hydrogen or deuterium, R ８ is C １ -C ６ is alkyl, R １０ is a nitrogen protecting group, and said pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent and said compound or a pharmaceutically acceptable salt thereof.

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