US2022372034A1PendingUtilityA1
Substituted pyrrolopyridines as jak inhibitors
Est. expiryMay 2, 2039(~12.8 yrs left)· nominal 20-yr term from priority
Inventors:Eric Jon JacobsenDavid R. AndersonJames Robert BlinnParamita MukherjeePaul ChangelianCanxin Xu
A61K 45/06A61K 31/437C07D 471/04A61P 1/00A61P 29/00A61K 31/444A61P 1/02A61K 31/506A61K 31/4545A61K 2300/00
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Claims
Abstract
The present invention relates to new pyrrolopyridine compounds having the structures of Formula (I)-(IV), wherein the R groups, A, B, C, D and n are as defined in the detailed description, and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibition of JAK kinase activity in a human or animal subject are also provided for the treatment diseases such as pruritus, alopecia, androgenetic alopecia, alopecia areata, vitiligo and psoriasis.
Claims
exact text as granted — not AI-modified1 . A method of treating a JAK-mediated disease in a subject in need thereof, said method comprising: administering, to a subject having the JAK-mediated disease, a compound, a derivative thereof, or a combination thereof, of Formula (I):
wherein:
R 1 is selected from CN or a heteroaryl group and is optionally substituted at the one or more available nitrogen atoms with a group independently selected from H or C 1 -C 5 alkyl and at one or more available carbon atoms with substituents wherein each substituent is independently selected from H, halogen, CN, —C 1 -C 4 alkyl, —C 0 -C 6 alkylC 3 -C 6 cycloalkyl, —(C 0 -C 6 alkyl)C 3 -C 6 heterocycle, —OH, —SO 2 R 9 , —SOR 9 , —SR 9 , —NHSO 2 R 9 , —OSO 2 R 9 , —C 0 -C 6 alkylSO 2 R 9 , C 0 -C 6 alkylCOR 9 , C 0 -C 6 alkylNR 7 C(O)NR 7 R 8 , C 0 -C 6 alkylOC(O)NR 7 R 8 , C 0 -C 6 alkylNR 7 SO 2 R 9 , —C 0 -C 6 alkylNR 7 COR 9 —OC 1 -C 6 alkyl, —OC 0 -C 6 alkylC 3 -C 6 cycloalkyl, —OC 0 -C 6 alkylC 3 -C 6 heterocycle, —OC 0 -C 6 alkylNR 7 C(O)NR 7 R 8 , —OC 0 -C 6 alkylOC(O)NR 7 R 8 , —OC 0 -C 6 alkylNR 7 SO 2 R 9 , —OC 0 -C 6 alkylNR 7 COR 9 , —NR 7 R 8 , —NR 7 C 0 -C 6 alkylC 1 -C 6 alkyl, —NR 7 C 0 -C 6 alkylC 3 -C 6 cycloalkyl, —NR 7 C 0 -C 6 alkylNR 7 C(O)NR 7 R 8 , —NR 7 C 0 -C 6 alkylOC(O)NR 7 R 8 , —NR 7 C 0 -C 6 alkylNR 7 SO 2 R 9 , —NR 7 C 0 -C 6 alkylNR 7 COR 9 , —NR 7 C 0 -C 6 alkylC 3 -C 6 heterocycle, aryl and heteroaryl wherein each alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl group is optionally substituted with one or more groups selected from: halogen, —OH, —C 0 -C 6 alkylNR 7 R 8 , —C 0 -C 6 alkylOH, —SO 2 R 9 , —SOR 9 , —NHSO 2 R 9 , —C 0 -C 6 alkylNR 7 R 4 , CN, —C 1 -C 5 alkylalkoxy, C 1 -C 5 alkoxy or —O—C 1 -C 5 alkyl;
R 2 is selected from H, —C 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, or —C 1 -C 2 alkyl-C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl groups are optionally substituted with one or more groups selected from halogen, —OH, or —O—C 1 -C 5 alkyl;
n is 2;
Ring A is substituted at one or more carbons with one, two, or three R 3 substituents wherein each R 3 substituent is independently selected from H, halogen, —C 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, —OH, or —O—C 1 -C 5 alkyl wherein each alkyl or cycloalkyl group is optionally substituted with one or more groups selected from: halogen, —OH, —C 1 -C 5 alkylalkoxy, or —O—C 1 -C 5 alkyl;
Two R 3 groups on the same or different carbon atoms of the ring A may be optionally joined to form a spirocyclic or bicyclic ring system with ring A;
R 4 is selected from —C(O)—R 6 , —CH 2 R 6 , —C(O)—C 1 -C 5 alkyl, or —C(O)—C 3 -C 6 cycloalkyl, wherein the alkyl or cycloalkyl groups may be optionally substituted with one or more groups selected from —OH, halogen, alkyne, or —CN;
R 5 is selected from —C 1 -C 5 alkyl, or —C 3 -C 6 cycloalkyl wherein the alkyl or cycloalkyl groups may be optionally substituted by one or more groups selected from halogen, —OH, or —O—C 1 -C 5 alkyl;
R 6 is selected from —C 1 -C 5 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 5 alkyl-C 3 -C 6 cycloalkyl, —NR 7 R 8 , —O-aryl, —O-heteroaryl, aryl, or heteroaryl wherein the alkyl, cycloalkyl, aryl or heteroaryl groups can be optionally substituted by one or more groups selected from halogen, —CN, alkyne, —OH, trifluoromethyl, —O—C 1 -C 5 alkyl, or —O—C 3 -C 6 cycloalkyl;
R 7 and R 8 are independently selected from H, —C 1 -C 5 alkyl, —C 1 -C 5 alkoxy, or —C 3 -C 5 cycloalkyl wherein the alkyl groups may be optionally substituted by one or more groups selected from halogen, —OH, or —CN;
R 7 and R 8 may be optionally joined to form a ring to form a heterocycle such as piperidine, pyrrolidine, or with another heteroatom to form a ring such as morpholine wherein the heterocyclic ring may be optionally substituted by one or more groups selected from halogen, —OH, NH 2 , NHMe, NMe 2 , or —CN; and
R 9 is selected from H, —C 1 -C 5 alkyl, —OC 1 -C 5 alkyl, —C 3 -C 6 cycloalkyl, and NR 7 R 8 wherein the alkyl, heterocycle, or cycloalkyl groups may be optionally substituted by one or more groups selected from halogen, —OH, NH 2 , NHMe, NMe 2 , or —CN;
in an amount effective to treat the JAK-mediated disease.
2 . The method of claim 1 , wherein the compound is selected from the group consisting of:
(R)-3-oxo-3-(3-((5-(thiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
(R)-3-(3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile
(R)-3-(3-((5-(2-methylthiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-oxo-3-(3-((5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
(R)-3-(3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3((5-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
rac-(R)-3-(3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)oxazole-4-carboxamide,
(R)-3-(3-((5-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-oxo-3-(3-((5-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
(R)-3-(3-((5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-oxo-3-(3-((5-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
(R)-3-(3-((5-(5-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-oxo-3-(3-((5-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
(R)-3-oxo-3-(3-((5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
(R)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile,
(R)-3-(3-((5-(3-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((2S,5R)-2-methyl-5-((5-(oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl) amino) piperidin-1-yl)-3-oxopropanenitrile,
2-(4-(((3R,6S)-1-(2-cyanoacetyl)-6-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide,
2-(4-(((3R,5S)-1-(2-cyanoacetyl)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide,
2-(4-(((3S,5R)-1-(2-cyanoacetyl)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide,
(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide,
(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-oxazole-4-carboxamide,
(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylthiazole-4-carboxamide,
(R)-3-(3-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
(R)-3-(3-((5-(1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-5-carboxamide,
3-((3R,5S)-3-((5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile
(R)-3-(3-((5-(1-isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)thiazole-5-carboxylate,
(R)-3-(3-((5(5-(2-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl) amino) piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(6-aminopyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R)-3-((5-(5-(methylsulfinyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
(R)-3-(3-((5-(5-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl) amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(2-(methylthio)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
2-cyano-N-(1-(4-(4-(((R)-1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)pyrrolidin-3-yl)-N-methylacetamide,
(R)-3-(3-((5-(2-aminopyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(2-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylthiazole-5-carboxamide,
(R)—N-(2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl)N,N-dimethyl sulfuric diamide,
(R)-3-(3-((5-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) piperidin-1-yl)-3-oxopropanenitrile,
(R)—N-(2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b] pyridin-5-yl)pyridin-4-yl)methanesulfonamide,
3-((3R,5S)-3-methyl-5-((5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(3-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylisonicotinamide,
(R)-3-(3-((5-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(3-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(6-(hydroxymethyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(5-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
N-((3R,5S)-1-((2,2-difluorocyclopropyl)methyl)-5-methylpiperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine,
3-((3R,5S)-3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(hydroxymethyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(fluoromethyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(4-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(4-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(4-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(4-(methylsulfonyl)oxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
3-((3S,5R)-3-methyl-5-((5-(4-methyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
3-((3R,5S)-3-((5-(4,5-bis(hydroxymethyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(hydroxymethyl)-4-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(hydroxymethyl)isoxazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(fluoromethyl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
3-((3R,5S)-3-((5-(5-acetyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(hydroxymethyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(fluoromethyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-acetylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(4-methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
3-((3S,5R)-3-methyl-5-((5-(4-methylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
(R)-3-(3-((5-(5-acetylthiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,4R)-4-methyl-3-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)isothiazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(2-hydroxypropan-2-yl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(fluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-acetyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)propanenitrile,
3-((2S,5R)-2-methyl-5-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((2S,5R)-5-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-2-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,4R)-4-methyl-3-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,4R)-3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(5-(1-fluorocyclopropyl)-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
N-((3R,5S)-5-methyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-5-(thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine,
3-((3S,5R)-3-methyl-5-((5-(3-methyl-1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(6-acetylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(4-(methylsulfonyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(4-acetylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(6-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(4-(hydroxymethyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(2-(hydroxymethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(2-(fluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(2-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
3-((3R,5S)-3-((5-(2-acetylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile,
(R)-3-(3-((5-(4-(methylsulfonyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(4-(methylsulfonyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile,
3-((3S,5R)-3-methyl-5-((5-(6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile, and
3-((3R,5S)-3-((5-(6-(hydroxymethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile.
3 . The method of claim 2 wherein the compound is
rac-(R)-3-(3-((5-(1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile.
4 . The method of claim 2 wherein the compound is
2-(4-(((3R,5S)-1-(2-cyanoacetyl)-5-methylpiperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyloxazole-4-carboxamide.
5 . The method of claim 2 wherein the compound is
(R)-2-(4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylthiazole-5-carboxamide.
6 . The method of claim 2 wherein the compound is
3-((3S,5R)-3-methyl-5-((5-(5-(methylsulfonyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile.
7 . The method of claim 2 wherein the compound is
3-((3R,5S)-3-((5-(5-acetyloxazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-5-methylpiperidin-1-yl)-3-oxopropanenitrile.
8 . The method of claim 2 wherein the compound is
3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile.
9 . The method of claim 2 wherein the compound is
3-((3S,5R)-3-methyl-5-((5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile
10 . The method of claim 1 further comprising: administering another therapeutic agent.
11 . The method of claim 1 , wherein said JAK-mediated disease is selected from the group consisting of an autoimmune disorders or responses, broad activation of the immune responses, bacterial infection, viral infection, inflammation, a chronic and/or acute inflammatory disorder or condition, and/or auto-inflammatory disorder, fibrotic disorders, metabolic disorders, a neoplasm, or cardiovascular or cerebrovascular disorders, a skin disorder, pruritus, a hair loss disorder, a cancer or malignancy, autoimmune connective tissue diseases and an autoimmune condition; Still's disease, adult-onset Still's disease, Th17-associated inflammation, polychondritis (e.g. relapsing polychondritis); myositis, polymyositis, autoimmune myositis, dermatomyositis, juvenile dermatomyositis; myasthenia gravis; Arthritis (e.g. rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, osteoarthritis, infectious arthritis, inflammatory arthritis, inflammatory bowel disease-associated arthritis, idiopathic arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis), spondylitis/spondyloarthritis/spondyloarthropathy (ankylosing spondylitis), gout, scleroderma (systemic scleroderma, juvenile scleroderma), Reiter's syndrome/reactive arthritis, Lyme disease, lupus/systemic lupus erythematosus (SLE) (lupus erythematosus, pediatric systemic lupus erythematosus, cutaneous lupus (subacute cutaneous lupus, chronic cutaneous lupus/discoid lupus, chilblain lupus erythematosus), polymyalgia rheumatica, enthesitis, mixed connective tissue disease, enthesopathy; carditis, myocarditis, angiogenesis disorders, myelodysplastic syndrome, atherosclerosis, restenosis (restenosis of an atherosclerotic coronary artery), acute coronary syndrome, myocardial infarction, cardiac-allograft vasculopathy, transplant arteriopathy; vasculitis (large vessel vasculitis, small vessel vasculitis, giant-cell arteritis, polyarteritis nodosa, vasculitis syndromes including: Takayasu's arteritis, Wegener's granulomatosis, Behcet's Disease), stimulator of interferon genes (STING) associated vasculopathy with onset in infancy (SAVI); gastrointestinal disorders, enterocolitis, colitis, inflammatory bowel disease (ulcerative colitis, Crohn's disease), irritable bowel syndrome, enteritis syndrome/spastic colon, celiac disease; acute and chronic pancreatitis; primary biliary cirrhosis, primary sclerosing cholangitis, jaundice, cirrhosis (for example, primary biliary cirrhosis or cirrhosis due to fatty liver disease (for example, alcoholic and nonalcoholic steatosis); esophagitis, gastritis, gastric and duodenal ulcers, peritonitis; Nephropathies: immunologically mediated glomerulonephropathy, autoimmune nephropathy, membranous glomerulopathy, chronic progressive nephropathies, diabetic kidney disease/diabetic nephropathy, renal fibrosis, renal ischemic/reperfusion injury, HIV associated nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, a nephropathy is an immunologically mediated nephropathy, autoimmune nephropathy, chronic progressive nephropathies, diabetic nephropathy, renal fibrosis, ischemic/reperfusion injury associated, HIV associated nephropathy, ureteral obstructive nephropathy, glomerulonephritis, chronic kidney disease (for example, diabetic nephropathy), hypertension induced nephropathy, glomerulosclerosis, proteinuria, nephrotic syndrome, polycystic kidney disease, autosomal dominant polycystic kidney disease, diabetic kidney disease, lupus nephritis; interstitial cystitis; periodontitis, gingivitis; pulmonary inflammation, sinusitis, pneumonia, bronchitis, asthma, bronchial asthma, allergic asthma, non-allergic asthma, allergic bronchopulmonary mycosis, aspirin-induced asthma, adult-onset asthma, asthma with fixed airflow obstruction, exercise-induced asthma, cough-variant asthma, work-related asthma, nighttime (nocturnal) asthma, asthma with obesity, eosinophilic asthma, steroid-resistant asthma/severe asthma, extrinsic asthma, intrinsic/cryptogenic asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease (pulmonary fibrosis, idiopathic pulmonary fibrosis), acute lung injury, pulmonary fibrosis (for example, idiopathic pulmonary fibrosis or cystic fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury; Meniere's disease; ocular disorders including, (e.g.), ocular inflammation, uveitis, dry eye/keratoconjunctivitis sicca, scleritis, episcleritis, keratitis/keratopathy, choroiditis, retinal vasculitis, optic neuritis, retinopathy (diabetic retinopathy, immune mediated retinopathy, macular degeneration, wet macular degeneration, dry (age related) macular degeneration); Mastocytosis, iron deficiency anemia, uremia, hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), myelodysplastic syndrome, idiopathic thrombocytic purpura; bone resorption diseases; Neurodegenerative disorders, neurological/neuromuscular disorders (e.g.), multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) (familial ALS, sporadic ALS), Alzheimer's disease, myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barret syndrome, meningitis, encephalitis, traumatic brain injury; nervous system damage, delusional parasitosis, dysregulation of neuronal processes and sensory perception, stroke/neuronal ischemia, spinal cord injury, peripheral neuropathy, tactile hallucinations, spinal cord injury, psychiatric disease; pain (acute pain, chronic pain, neuropathic pain, or fibromyalgia) paresthetica, nerve irritation, peripheral neuropathy; pruritus/itch (atopic pruritus, xerotic pruritus, pruritus associated with psoriasis/psoriatic itch/psoriasis-associated itch), acute pruritus, chronic pruritus, idiopathic pruritus, chronic idiopathic itch, biliary itch, hepatobiliary-associated itch, renal associated itch/renal itch, uremic itch, cholestasis, intrahepatic cholestasis of pregnancy, lichen simplex chronicus associated pruritus, lymphoma-associated itch, leukemia-associated itch, prurigo nodularis, atopic dermatitis-associated itch, atopic itch/atopic pruritus, bullous itch, brachioradial pruritus) neurogenic itch, neuropathic itch, notalgia paresthetica, pruritic popular eruption of HIV, psychogenic itch, swimmer's itch, pruritus or uremic itch, urticarial itch; dermatologic disorders (e.g.), dermatologic drug reactions/drug eruptions, xerosis/dry skin, skin rash, skin sensitization, skin irritation, sunburn, shaving, body louse, head lice/pediculosis, pubic lice, cutaneous larva migrans, scabies, parasitic infection, insect infestation, urticaria/hives, papular urticaria, insect bites, insect stings, dandruff, foreign objects or devices on skin, fungal infection, herpes, varicella/chicken pox, eosinophilic folliculitis, dermatosis of pregnancy/pruritic urticarial papules and plaques of pregnancy (PUPP), inflammatory dermatoses, neutrophilic dermatoses, histiocytoid neutrophilic dermatosis, bowel-bypass syndrome dermatosis, psoriasis/psoriasis vulgaris, lichen planus, lichen sclerosus, acne (acne vulgaris, comedonal acne, inflammatory acne, nodulo-cystic acne, scarring acne, acne keloidalis nuchae), atopies (allergic contact sensitization, allergic dermatitis) dermatitis (atopic dermatitis/eczema, contact dermatitis, photodermatitis, seborrheic dermatitis, stasis dermatitis, acute febrile neutrophilic dermatosis (Sweet's syndrome), chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE Syndrome), hidradenitis suppurativa, hives, pyoderma gangrenosum, alopecia (eyebrow alopecia, intranasal hair alopecia, scarring alopecia (e.g., cicatricial alopecia, central centrifugal cicatricial alopecia, lichen planopilaris, frontal fibrosing alopecia, folliculitis decalvans.), nonscarring alopecia (alopecia areata (AA) (patchy AA, alopecia totalis (AT), alopecia universalis (AU), ophiasis pattern alopecia areata, sisaihpo pattern alopecia areata)), androgenetic/androgenic alopecia (AGA)/male and female pattern AGA), telogen effluvium, tinea capitis, hypotrichosis (hereditary hypotrichosis simplex), lichen planopilaris (frontal fibrosing alopecia), punctate palmoplantar keratoderma, erythema elevatinum diutinum (EED), neutrophilic eccrine hidradenitis, palisading neutrophilic granulomatous dermatitis, neutrophilic urticarial dermatosis, vitiligo including segmental vitiligo (unisegmental vitiligo, bisegmental vitiligo, multisegmental vitiligo) non-segmental vitiligo (acral, facial, or acrofacial vitiligo, centrofacial vitiligo, mucosal vitiligo, confetti vitiligo, trichrome vitiligo, marginal inflammatory vitiligo, quadrichrome vitiligo, blue vitiligo, Koebner phenomenon, vulgaris vitiligo, generalized vitiligo, universal vitiligo), mixed vitiligo/nonsegmental associated with segmental vitiligo, focal vitiligo, solitary mucosal vitiligo or vitiligo with or without leukotricia (involvement of body hair); bullous diseases, immunobullous diseases (bullous pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA disease), gestational pemphigoid, xeroderma pigmentosum; disorders of fibrosis and scarring: fibroids, hepatic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, low grade scarring such as, scleroderma, increased fibrosis, keloids, post-surgical scars; wound healing, surgical scarring, radiation induced fibrosis (for example, head and neck, gastrointestinal or pulmonary), CNS scarring, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis, liver fibrosis (for example, nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cardiac fibrosis (for example, endomyocardial fibrosis or atrial fibrosis), ophthalmic scarring, fibrosclerosis, scar growth, wound or scab healing, keloid, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis/Ormond's disease, progressive massive fibrosis, nephrogenic systemic fibrosis; Sjogren's syndrome, sarcoidosis, familial Mediterranean fever, Cryopyrin associated periodic syndrome (Muckle-Wells syndrome, familial cold auto-inflammatory syndrome/familial cold urticaria/TNF receptor associated periodic syndrome, neonatal-onset multisystem inflammatory disease), hyperoxia induced inflammations, reperfusion injury, post-surgical trauma, tissue injury, elevated temperature syndrome; diabetes (Type I diabetes, Type II diabetes)/diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, Addison's disease, Castleman's disease, hyperparathyroidism, menopause, obesity, steroid-resistance, glucose intolerance, metabolic syndrome, thyroid illness, hypophysitis; systemic immune senescence; autoimmune atrophic gastritis, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, Sjogren's syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia; secondary hematologic manifestations of autoimmune diseases (for example, anemias), autoimmune hemolytic syndromes (autoimmune hemolytic anemia), autoimmune and inflammatory hepatitis, autoimmune ovarian failure, autoimmune thrombocytopenia, silicone implant associated autoimmune disease, drug-induced autoimmunity, HIV-related autoimmune syndromes, metal-induced autoimmunity, autoimmune deafness, autoimmune thyroid disorders; allergy and allergic reactions including hypersensitivity reactions such as Type I hypersensitivity reactions, (e.g. including anaphylaxis), Type II hypersensitivity reactions (e.g. Goodpasture's Disease, autoimmune hemolytic anemia), Type III hypersensitivity reaction diseases (e.g. the Arthus reaction, serum sickness), and Type IV hypersensitivity reactions (e.g. contact dermatitis, allograft rejection); acute and chronic infection, sepsis syndromes (sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, gram negative sepsis, gram positive sepsis, fungal sepsis, toxic shock syndrome); acute and chronic infection, sepsis syndromes (sepsis, septic shock, endotoxic shock, exotoxin-induced toxic shock, gram negative sepsis, gram positive sepsis, fungal sepsis, toxic shock syndrome); a rejection: graft vs. host reaction/graft vs. host disease, allograft rejections (for example, acute allograft rejection or chronic allograft rejection), early transplantation rejection; Malignancy, cancer, lymphoma, leukemia, multiple myeloma, a solid tumor, teratoma, metastatic and bone disorders, internal cancers, cancer of the: bone, mouth/pharynx, esophagus, larynx, stomach, intestine, colon, rectum, lung (for example, non-small cell lung cancer or small cell lung cancer), liver (hepatic), pancreas, nerve, brain (for example, glioma, glioblastoma multiforme, astrocytoma, neuroblastoma, and schwannomas), head and neck, throat, ovary, uterus, prostate, testis, bladder, kidney (renal), breast, gall bladder, cervix, thyroid, prostate, eye (ocular malignancies), and skin (melanoma, keratoacanthoma); as well as fibrotic cancers, fibroma, fibroadenomas, fibrosarcomas, a myeloproliferative disorder, neoplasm (hematopoietic neoplasm, a myeloid neoplasm, a lymphoid neoplasm (myelofibrosis, primary myelofibrosis, polycythemia vera, essential thrombocythemia)), leukemias (acute lymphocytic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia (CMML), or promyelocytic leukemia), multiple myeloma and other myeloid malignancies (myeloid metaplasia with myelofibrosis (MMM), primary myelofibrosis (PMF), idiopathic myelofibrosis (IMF)), lymphomas (Hodgkin's disease, cutaneous lymphomas (cutaneous T-cell lymphoma, mycosis fungoides), lymphomas (for example, B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumors, Hodgkin's disease or non-Hodgkin's disease); Kaposi's sarcoma, rhabdomyosarcoma, seminoma, teratocarcinoma, osteosarcoma, thyroid follicular cancer; increased accumulation of exogenous opioids or synthetic opioids, notalgia paraesthetica, obsessive-compulsive disorders, nostalgia associated with obsessive-compulsive disorders, and a combination thereof.
12 . The method of claim 10 , wherein the other therapeutic agent is selected from a chemotherapeutic agent, an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, an agent for treating immunodeficiency disorders, and a combination thereof.
13 . The method of claim 11 , wherein said JAK-mediated disease is inflammatory bowel disease.
14 . The method of claim 13 , wherein upon said administering the compound inhibits JAK activity in a gut-restricted manner in said subject.Cited by (0)
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