US2019106439A1PendingUtilityA1
Heterocyclic itk inhibitors for treating inflammation and cancer
Est. expiryJan 23, 2035(~8.5 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 37/06A61P 37/08A61P 29/00A61P 35/00A61P 31/18A61P 25/04A61P 35/02A61P 1/00A61K 45/06C07D 519/00A61P 1/04A61P 17/04C07D 487/04A61P 11/06A61K 31/437C07D 471/04A61P 17/06A61P 19/02
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Claims
Abstract
Disclosed herein are heterocyclic compounds and compositions useful in the treatment of ITK mediated diseases, such as inflammation, having the structure of Formula (I): wherein R 1 , R 2 , and X are as defined in the detailed description. Methods of inhibition of ITK activity in a human or animal subject are also provided.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, of Formula (I):
wherein:
R 1 is chosen from mono- and bicyclic aryl and heteroaryl, wherein R 1 may be optionally substituted with one or more R 3 substituents;
R 2 is chosen from heterocycloalkyl, aryl, and heteroaryl, each of which is substituted with one R 4 substituent, and any of which may be further optionally substituted with one or more R 8 substituents, or alternatively R 2 is NR 12 R 13 ;
each R 3 is independently chosen from hydrogen, hydroxyl, cyano, C 1-6 alkyl, hydroxyC 1-4 alkyl, C 1-6 alkoxyalkyl, arylC 1-6 alkyl, arylC 1-6 alkoxy, heteroarylC 1-6 alkyl, heteroarylC 1-6 alkoxy, aryloxyC 1-6 alkyl, heteroaryloxyC 1-6 alkyl, aryloxyC 1-6 alkyl, heteroaryloxyC 1-6 alkyl, cyclopropylC 1-4 alkyl, cyclopropylC 1-4 alkoxy, cyclopropoxyC 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkylarylamino, C 1-4 alkylheteroarylamino, di(C 1-4 alkyl)amino, —C(O)NR 6 R 6′ , C 1-4 alkanoyl, —C(O)aryl, —C(O)heteroaryl, —C(O)NHaryl, —C(O)NHheteroaryl, trifluoromethyl, and halo, wherein aryl and heteroaryl may be optionally substituted with R 9 ;
R 4 is chosen from NR 5 R 6 , —(CH 2 ) n CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) n CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) n CR 7 ═CR 9 CN;
R 5 is chosen from cyano, —C(O)CF 3 , —C(O)CH═CH 2 , —C(O)CR 7 ═CH 2 , —C(O)CH═CHR 7 , —C(O)CR 7 ═CHR 7 , —C(O)CH═CR 7 R 7′ , —C(O)CH═CHCH 2 R 8 , —C(O)CH═CHC(O)CH 2 R 8 , —COC(CN)═CHR 6 , —C(O)(C(O)NH 2 )═CHR 6 , C(O)alkynylR 7 , —S(O) 2 CH═CH 2 , —(CH 2 ) m CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) m CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) m CR 7 ═CR 9 CN;
R 6 and R 6′ are each independently chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, and phenylC 1-4 alkyl;
R 7 and R 7′ are each independently chosen from hydrogen, cyano, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyalkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkylalkyl, (NR 6 R 6′ )C 1-4 alkyl, aryl, and heteroaryl, wherein aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 8 is chosen from hydrogen, halo, cyano, C 1-4 alkyl, arylC 1-4 alkyl, heteroarylC 1-4 alkyl, C 3-7 cycloalkyl, hydroxyC 1-6 alkyl, heterocycloalkylC 1-4 alkyl, C 3-7 heterocycloalkyl, hydroxyl, C 1-4 alkoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkoxyalkyl, heteroaryloxy, aryloxy, (NR 6 R 6′ )alkyl, arylalkoxy, C 1-4 alkoxyC 1-4 alkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, trifluoromethyl, aryl, and heteroaryl, wherein alkyl, heterocycloalkyl, aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 9 is chosen from hydrogen, halo, hydroxyl, C 1-4 alkyl, cyano, trifluoromethyl, alkanoyl, amino, amido, and aryl;
R 10 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo, trifluoromethyl, and cyano;
R 11 is chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, heterocycloalkylalkyl, arylC 1-4 alkyl, and heteroarylC 1-4 alkyl, wherein aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 12 is a nitrogen-containing C 3-7 heterocycloalkyl, wherein said nitrogen is further substituted by R 5 ;
R 13 is chosen from hydrogen, C 1-4 alkyl, and C 3-7 cycloalkylalkyl;
X is N or CR 11 ;
m is an integer chosen from 1, 2 and 3; and
n is an integer chosen from 0, 1, 2, and 3.
2 . A compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 2 is chosen from phenyl and pyridinyl, either of which is substituted with one R 4 substituent, and either of which may be further optionally substituted with one or more R 8 substituents.
3 . A compound of claim 2 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 1 is chosen from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinonyl, pyrrolopyridinyl, and pyrrolopyrimidinyl, any of which may be optionally substituted with one or more R 3 substituents.
4 . A compound according to claim 3 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
when R 1 is phenyl, said phenyl is substituted with one or more R 3 substituents; one R 3 is C(O)NR 6 R 6′ ; R 6 is phenylC 1-4 alkyl; and R 6′ is hydrogen.
5 . A compound according to claim 4 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 4 is chosen from NR 5 R 6 and —(CH 2 ) n CR 7 ═CR 9 CN.
6 . A compound according to claim 5 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 4 is NR 5 R 6 ; R 5 is chosen from C(O)CH═CH 2 and —C(O)CH═CHCH 2 R 8 ; R 6 is hydrogen; and R 8 is di(C 1-4 alkyl)amino.
7 . A compound according to claim 5 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 4 is —(CH 2 ) n CR 7 ═CR 9 CN; n is 0; R 7 is hydrogen; R 9 is amido.
8 . A compound according to claim 3 , chosen from:
N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-2-cyano-3-(3-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-2-cyano-3-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl) acrylamide, N-(3-(3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(5-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)acrylamide, N-(5-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)acrylamide, N-(3-cyano-5-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)acrylamide, N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-methylacrylamide, N-(3-methoxy-5-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-4-morpholino-N-(3-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, (E)-4-(dimethylamino)-N-(3-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, N-(3-(3-(2-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(5-(3-(2-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)acrylamide, N-(5-(3-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)acrylamide, N-(3-(3-(2-methoxy-6-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-(methylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-2-cyano-3-(3-(3-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-4-(dimethylamino)-N-(3-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, (E)-N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-morpholinobut-2-enamide, N-(3-(3-(6-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(6-methoxy-4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)acrylamide, N-(4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-6-morpholinopyridin-2-yl)acrylamide, N-(3-(3-(o-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(5-chloropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(6-isopropoxy-4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)acrylamide, N-(3-(3-(6-fluoropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-(cyclopropylmethoxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-(methylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-methoxy-4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(naphthalen-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(isoquinolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-(methylamino)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-fluoropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl) acrylamide, N-(3-(3-(6-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl) acrylamide, N-(3-(3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)acrylamide, (E)-2-cyano-3-(3-methoxy-5-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)acrylamide, N-(3-(1H,1′H-[3,4′-bipyrrolo[2,3-b]pyridin]-5-yl)phenyl)acrylamide, (E)-2-cyano-3-(3-(3-(6-fluoropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-4-methoxy-N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, N-(3-(3-(1-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, 4-(5-(3-acrylamidophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2,4-dimethylphenyl)benzamide, N-(6-methoxy-4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)methacrylamide, N-(3-(3-(1-oxo-1,2-dihydroisoquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-6-(l-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methacrylamide, N-(3-(3-(1H-indol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(5-(3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)acrylamide, 4-(5-(3-acrylamidophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(4-isopropylphenyl)benzamide, (E)-2-cyano-3-(3-(3-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-4-(dimethylamino)-N-(3-methoxy-5-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, N-(3-(3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-N-(3-(3-(3-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(dimethylamino)but-2-enamide, N-(3-(3-(2-methoxy-5-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acrylamide, N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methacrylamide, N-(3-(3-(benzofuran-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-hydroxypentan-3-yl)-5-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-4-(dimethylamino)-N-(3-(3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, N-(3-(3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methacrylamide, N-(3-(3-(2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-2-cyano-N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-methylpent-2-enamide, N-(3-(3-(6-(cyclopropylmethyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-N-(3-(H, 1′H-[3,4′-bipyrrolo[2,3-b]pyridin]-5-yl)phenyl)-4-(dimethylamino)but-2-enamide, (E)-N-(3-(3-(1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(dimethylamino)but-2-enamide, N-(3-(3-(2-(methylamino)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(3-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-3-(3-(3-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)acrylamide, N-(6-isopropyl-4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)acrylamide, N-(3-(3-(2-cyanopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, 4-(5-(3-acrylamidophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide, and N-(3-(1H, 1′H-[3,5′-bipyrrolo[2,3-b]pyridin]-5-yl)phenyl)acrylamide, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
9 . A compound of claim 2 , wherein the compound has formula (III):
or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 1 is chosen from mono- or bicyclic aryl and heteroaryl, wherein R 1 may be optionally substituted with one or more R 3 substituents;
R 3 is independently chosen from hydrogen, hydroxyl, cyano, C 1-6 alkyl, hydroxyC 1-4 alkyl, C 1-6 alkoxyalkyl, arylC 1-6 alkyl, arylC 1-6 alkoxy, heteroarylC 1-6 alkyl, heteroarylC 1-6 alkoxy, aryloxyC 1-6 alkyl, heteroaryloxyC 1-6 alkyl, cyclopropylC 1-4 alkyl, cyclopropylC 1-4 alkoxy, cyclopropoxyC 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkylarylamino, C 1-4 alkylheteroarylamino, di(C 1-4 alkyl)amino, —CONR 6 R 6′ , C 1-4 alkanoyl, —C(O)aryl, —C(O)heteroaryl, —C(O)NHaryl, —C(O)NHheteroaryl, trifluoromethyl, and halo, wherein aryl and heteroaryl may be optionally substituted with R 9 ;
R 4 is chosen from —NR 5 R 6 , —(CH 2 ) n CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) n CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) n CR 7 ═CR 9 CN;
R 5 is chosen from cyano, —C(O)CF 3 , —C(O)CH═CH 2 , —C(O)CR 7 ═CH 2 , —C(O)CH═CHR 7 , —C(O)CR 7 ═CHR 7 , —C(O)CH═CR 7 R 7′ , —C(O)CH═CHCH 2 R 8 , —C(O)CH═CHC(O)CH 2 R 8 , —COC(CN)═CHR 6 , —C(O)(C(O)NH 2 )═CHR 6 , —C(O)alkynylR 7 , —S(O) 2 CH═CH 2 , —(CH 2 ) m CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) m CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) m CR 7 ═CR 9 CN;
R 6 and R 6′ are each independently chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, and phenylC 1-4 alkyl;
R 7 and R 7′ are each independently chosen from hydrogen, cyano, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyalkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkylalkyl, (NR 6 R 6′ )C 1-4 alkyl, aryl, and heteroaryl where aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 8 is chosen from hydrogen, halo, cyano, C 1-4 alkyl, arylC 1-4 alkyl, heteroarylC 1-4 alkyl, C 3-7 cycloalkyl, hydroxyC 1-6 alkyl, heterocycloalkylC 1-4 alkyl, C 3-7 heterocycloalkyl, hydroxyl, C 1-4 alkoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkoxyalkyl, heteroaryloxy, aryloxy, (NR 6 R 6′ )alkyl, arylalkoxy, C 1-4 alkoxyC 1-4 alkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, trifluoromethyl, aryl, and heteroaryl, wherein alkyl, heterocycloalkyl, aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 9 is chosen from hydrogen, halo, hydroxyl, C 1-4 alkyl, cyano, trifluoromethyl, C(O)CH 3 , amido, and aryl;
R 10 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo, trifluoromethyl and CN;
m is an integer chosen from 1, 2 and 3; and
n is an integer chosen from 0, 1, 2, and 3.
10 . A compound according to claim 9 , chosen from:
N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-2-cyano-3-(3-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-2-cyano-3-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl) acrylamide, N-(3-(3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-cyano-5-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)acrylamide, N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-methylacrylamide, N-(3-methoxy-5-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-4-morpholino-N-(3-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, (E)-4-(dimethylamino)-N-(3-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, N-(3-(3-(2-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-methoxy-6-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-(methylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-2-cyano-3-(3-(3-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-4-(dimethylamino)-N-(3-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, (E)-N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-morpholinobut-2-enamide, N-(3-(3-(6-methoxypyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(6-methoxy-4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)acrylamide, N-(4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-6-morpholinopyridin-2-yl)acrylamide, N-(3-(3-(o-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(5-chloropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-fluoropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-(cyclopropylmethoxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-(methylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-methoxy-4-methylpyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(naphthalen-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(isoquinolin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-(methylamino)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(6-fluoropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl) acrylamide, N-(3-(3-(6-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)acrylamide, N-(3-(3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)acrylamide, (E)-2-cyano-3-(3-methoxy-5-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)phenyl)acrylamide, N-(3-(1H,1′H-[3,4′-bipyrrolo[2,3-b]pyridin]-5-yl)phenyl)acrylamide, (E)-2-cyano-3-(3-(3-(6-fluoropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-4-methoxy-N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, N-(3-(3-(1-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, 4-(5-(3-acrylamidophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2,4-dimethylphenyl)benzamide, N-(3-(3-(1-oxo-1,2-dihydroisoquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(1H-indol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, 4-(5-(3-acrylamidophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(4-isopropylphenyl)benzamide, (E)-2-cyano-3-(3-(3-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-4-(dimethylamino)-N-(3-methoxy-5-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, N-(3-(3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-N-(3-(3-(3-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(dimethylamino)but-2-enamide, N-(3-(3-(2-methoxy-5-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acrylamide, N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methacrylamide, N-(3-(3-(benzofuran-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-hydroxypentan-3-yl)-5-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-4-(dimethylamino)-N-(3-(3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide, N-(3-(3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methacrylamide, N-(3-(3-(2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-2-cyano-N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-methylpent-2-enamide, N-(3-(3-(6-(cyclopropylmethyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-N-(3-(H, 1′H-[3,4′-bipyrrolo[2,3-b]pyridin]-5-yl)phenyl)-4-(dimethylamino)but-2-enamide, (E)-N-(3-(3-(1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(dimethylamino)but-2-enamide, N-(3-(3-(2-(methylamino)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(3-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, (E)-3-(3-(3-(pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, N-(3-(3-(2-cyanopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acrylamide, 4-(5-(3-acrylamidophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide, and N-(3-(1H, 1′H-[3,5′-bipyrrolo[2,3-b]pyridin]-5-yl)phenyl)acrylamide, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
11 . A compound of claim 2 , wherein the compound has formula (IV):
or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 1 is chosen from mono- or bicyclic aryl and heteroaryl, wherein R 1 may be optionally substituted with one or more R 3 substituents;
R 3 is independently chosen from hydrogen, hydroxyl, cyano, C 1-6 alkyl, hydroxyC 1-4 alkyl, C 1-6 alkoxyalkyl, arylC 1-6 alkyl, arylC 1-6 alkoxy, heteroarylC 1-6 alkyl, heteroarylC 1-6 alkoxy, aryloxyC 1-6 alkyl, heteroaryloxyC 1-6 alkyl, cyclopropylC 1-4 alkyl, cyclopropylC 1-4 alkoxy, cyclopropoxyC 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkylarylamino, C 1-4 alkylheteroarylamino, di(C 1-4 alkyl)amino, —CONR 6 R 6′ , C 1-4 alkanoyl, —C(O)aryl, —C(O)heteroaryl, —C(O)NHaryl, —C(O)NHheteroaryl, trifluoromethyl, and halo, wherein aryl and heteroaryl may be optionally substituted with R 9 ;
R 4 is chosen from —NR 5 R 6 , —(CH 2 ) n CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) n CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) n CR 7 ═CR 9 CN;
R 5 is chosen from cyano, —C(O)CF 3 , —C(O)CH═CH 2 , —C(O)CR 7 ═CH 2 , —C(O)CH═CHR 7 , —C(O)CR 7 ═CHR 7 , —C(O)CH═CR 7 R 7′ , —C(O)CH═CHCH 2 R 8 , —C(O)CH═CHC(O)CH 2 R 8 , —COC(CN)═CHR 6 , —C(O)(C(O)NH 2 )═CHR 6 , —C(O)alkynylR 7 , —S(O) 2 CH═CH 2 , —(CH 2 ) m CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) m CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) m CR 7 ═CR 9 CN;
R 6 and R 6′ are each independently chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, and phenylC 1-4 alkyl;
R 7 and R 7′ are each independently chosen from hydrogen, cyano, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyalkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkylalkyl, (NR 6 R 6′ )C 1-4 alkyl, aryl, and heteroaryl where aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 8 is chosen from hydrogen, halo, cyano, C 1-4 alkyl, arylC 1-4 alkyl, heteroarylC 1-4 alkyl, C 3-7 cycloalkyl, hydroxyC 1-6 alkyl, heterocycloalkylC 1-4 alkyl, C 3-7 heterocycloalkyl, hydroxyl, C 1-4 alkoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkoxyalkyl, heteroaryloxy, aryloxy, (NR 6 R 6′ )alkyl, arylalkoxy, C 1-4 alkoxyC 1-4 alkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, trifluoromethyl, aryl, and heteroaryl, wherein alkyl, heterocycloalkyl, aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 9 is chosen from hydrogen, halo, hydroxyl, C 1-4 alkyl, cyano, trifluoromethyl, —C(O)CH 3 , amido, and aryl;
R 10 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo, trifluoromethyl and CN;
m is an integer chosen from 1, 2 and 3; and
n is an integer chosen from 0, 1, 2, and 3.
12 . A compound of claim 11 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 8 is hydrogen.
13 . A compound of claim 12 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 1 is independently chosen from aryl and heteroaryl including phenyl, pyridine, pyrimidine, pyrazine, pyridinone, pyrrolopyridine, pyrrolopyrimidine, wherein each aromatic or heteroaromatic ring may be optionally substituted with one or more R 3 substituents.
14 . A compound according to claim 13 , chosen from:
N-(5-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)acrylamide, N-(5-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)acrylamide, N-(5-(3-(2-fluoropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)acrylamide, N-(5-(3-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)acrylamide, and N-(5-(3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)acrylamide, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
15 . A compound of claim 2 , wherein the compound has formula (V):
or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 1 is chosen from mono- or bicyclic aryl and heteroaryl, wherein R 1 may be optionally substituted with one or more R 3 substituents;
R 3 is independently chosen from hydrogen, hydroxyl, cyano, C 1-6 alkyl, hydroxyC 1-4 alkyl, C 1-6 alkoxyalkyl, arylC 1-6 alkyl, arylC 1-6 alkoxy, heteroarylC 1-6 alkyl, heteroarylC 1-6 alkoxy, aryloxyC 1-6 alkyl, heteroaryloxyC 1-6 alkyl, cyclopropylC 1-4 alkyl, cyclopropylC 1-4 alkoxy, cyclopropoxyC 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkylarylamino, C 1-4 alkylheteroarylamino, di(C 1-4 alkyl)amino, —CONR 6 R 6′ , C 1-4 alkanoyl, —C(O)aryl, —C(O)heteroaryl, —C(O)NHaryl, —C(O)NHheteroaryl, trifluoromethyl, and halo, wherein aryl and heteroaryl may be optionally substituted with R 9 ;
R 4 is chosen from —NR 5 R 6 , —(CH 2 ) n CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) n CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) n CR 7 ═CR 9 CN;
R 5 is chosen from cyano, —C(O)CF 3 , —C(O)CH═CH 2 , —C(O)CR 7 ═CH 2 , —C(O)CH═CHR 7 , —C(O)CR 7 ═CHR 7 , —C(O)CH═CR 7 R 7′ , —C(O)CH═CHCH 2 R 8 , —C(O)CH═CHC(O)CH 2 R 8 , —COC(CN)═CHR 6 , —C(O)(C(O)NH 2 )═CHR 6 , —C(O)alkynylR 7 , —S(O) 2 CH═CH 2 , —(CH 2 ) m CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) m CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) m CR 7 ═CR 9 CN;
R 6 and R 6′ are each independently chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, and phenylC 1-4 alkyl;
R 7 and R 7′ are each independently chosen from hydrogen, cyano, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyalkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkylalkyl, (NR 6 R 6′ )C 1-4 alkyl, aryl, and heteroaryl where aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 8 is chosen from hydrogen, halo, cyano, C 1-4 alkyl, arylC 1-4 alkyl, heteroarylC 1-4 alkyl, C 3-7 cycloalkyl, hydroxyC 1-6 alkyl, heterocycloalkylC 1-4 alkyl, C 3-7 heterocycloalkyl, hydroxyl, C 1-4 alkoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkoxyalkyl, heteroaryloxy, aryloxy, (NR 6 R 6′ )alkyl, arylalkoxy, C 1-4 alkoxyC 1-4 alkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, trifluoromethyl, aryl, and heteroaryl, wherein alkyl, heterocycloalkyl, aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 9 is chosen from hydrogen, halo, hydroxyl, C 1-4 alkyl, cyano, trifluoromethyl, —C(O)CH 3 , amido, and aryl;
R 10 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo, trifluoromethyl and CN;
m is an integer chosen from 1, 2 and 3; and
n is an integer chosen from 0, 1, 2, and 3.
16 . A compound of claim 15 , wherein R 1 is chosen from phenyl, pyridine, pyrimidine, pyrazine, pyridinone, pyrrolopyridine, and pyrrolopyrimidine, any of which may be optionally substituted with one or more R 3 substituents.
17 . A compound according to claim 15 , chosen from:
N-(6-isopropoxy-4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)acrylamide, N-(6-methoxy-4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)methacrylamide, N-(4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methacrylamide, N-(4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)acrylamide, and N-(6-isopropyl-4-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)acrylamide, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
18 . A compound of claim 1 , wherein the compound has formula (VI) or a regioisomer thereof:
or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 1 is chosen from mono- or bicyclic aryl and heteroaryl, wherein R 1 may be optionally substituted with one or more R 3 substituents;
R 3 is independently chosen from hydrogen, hydroxyl, cyano, C 1-6 alkyl, hydroxyC 1-4 alkyl, C 1-6 alkoxyalkyl, arylC 1-6 alkyl, arylC 1-6 alkoxy, heteroarylC 1-6 alkyl, heteroarylC 1-6 alkoxy, aryloxyC 1-6 alkyl, heteroaryloxyC 1-6 alkyl, cyclopropylC 1-4 alkyl, cyclopropylC 1-4 alkoxy, cyclopropoxyC 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkylarylamino, C 1-4 alkylheteroarylamino, di(C 1-4 alkyl)amino, —CONR 6 R 6′ , C 1-4 alkanoyl, —C(O)aryl, —C(O)heteroaryl, —C(O)NHaryl, —C(O)NHheteroaryl, trifluoromethyl, and halo, wherein aryl and heteroaryl may be optionally substituted with R 9 ;
R 4 is chosen from —NR 5 R 6 , —(CH 2 ) n CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) n CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) n CR 7 ═CR 9 CN;
R 5 is chosen from cyano, —C(O)CF 3 , —C(O)CH═CH 2 , —C(O)CR 7 ═CH 2 , —C(O)CH═CHR 7 , —C(O)CR 7 ═CHR 7 , —C(O)CH═CR 7 R 7′ , —C(O)CH═CHCH 2 R 8 , —C(O)CH═CHC(O)CH 2 R 8 , —COC(CN)═CHR 6 , —C(O)(C(O)NH 2 )═CHR 6 , —C(O)alkynylR 7 , —S(O) 2 CH═CH 2 , —(CH 2 ) m CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) m CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) m CR 7 ═CR 9 CN;
R 6 and R 6′ are each independently chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, and phenylC 1-4 alkyl;
R 7 and R 7′ are each independently chosen from hydrogen, cyano, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyalkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkylalkyl, (NR 6 R 6′ )C 1-4 alkyl, aryl, and heteroaryl where aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 8 is chosen from hydrogen, halo, cyano, C 1-4 alkyl, arylC 1-4 alkyl, heteroarylC 1-4 alkyl, C 3-7 cycloalkyl, hydroxyC 1-6 alkyl, heterocycloalkylC 1-4 alkyl, C 3-7 heterocycloalkyl, hydroxyl, C 1-4 alkoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkoxyalkyl, heteroaryloxy, aryloxy, (NR 6 R 6′ )alkyl, arylalkoxy, C 1-4 alkoxyC 1-4 alkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, trifluoromethyl, aryl, and heteroaryl, wherein alkyl, heterocycloalkyl, aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 9 is chosen from hydrogen, halo, hydroxyl, C 1-4 alkyl, cyano, trifluoromethyl, —C(O)CH 3 , amido, and aryl;
R 10 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo, trifluoromethyl and CN;
R 11 is chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, heterocycloalkylalkyl, arylC 1-4 alkyl, and heteroarylC 1-4 alkyl, wherein aryl and heteroaryl may be optionally substituted with one or more R 9 ;
U is O, S or NR 11 ;
V is N or CR 11 ;
W is N or CR 11 ;
m is an integer chosen from 1, 2 and 3; and
n is an integer chosen from 0, 1, 2, and 3.
19 . A compound of claim 18 , wherein R 1 is chosen from phenyl, pyridine, pyrimidine, pyrazine, pyridinone, pyrrolopyridine, and pyrrolopyrimidine, any of which may be optionally substituted with one or more R 3 substituents.
20 . A compound according to claim 16 , chosen from the compounds in Table 3 having a five-membered heteroaryl at R 2 .
21 . A compound of claim 1 , wherein the compound has formula (VII):
or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 1 is chosen from mono- or bicyclic aryl and heteroaryl, wherein R 1 may be optionally substituted with one or more R 3 substituents;
R 3 is independently chosen from hydrogen, hydroxyl, cyano, C 1-6 alkyl, hydroxyC 1-4 alkyl, C 1-6 alkoxyalkyl, arylC 1-6 alkyl, arylC 1-6 alkoxy, heteroarylC 1-6 alkyl, heteroarylC 1-6 alkoxy, aryloxyC 1-6 alkyl, heteroaryloxyC 1-6 alkyl, cyclopropylC 1-4 alkyl, cyclopropylC 1-4 alkoxy, cyclopropoxyC 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkylarylamino, C 1-4 alkylheteroarylamino, di(C 1-4 alkyl)amino, —CONR 6 R 6′ , C 1-4 alkanoyl, —C(O)aryl, —C(O)heteroaryl, —C(O)NHaryl, —C(O)NHheteroaryl, trifluoromethyl, and halo, wherein aryl and heteroaryl may be optionally substituted with R 9 ;
R 4 is chosen from —NR 5 R 6 , —(CH 2 ) n CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) n CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) n CR 7 ═CR 9 CN;
R 5 is chosen from cyano, —C(O)CF 3 , —C(O)CH═CH 2 , —C(O)CR 7 ═CH 2 , —C(O)CH═CHR 7 , —C(O)CR 7 ═CHR 7 , —C(O)CH═CR 7 R 7′ , —C(O)CH═CHCH 2 R 8 , —C(O)CH═CHC(O)CH 2 R 8 , —COC(CN)═CHR 6 , —C(O)(C(O)NH 2 )═CHR 6 , —C(O)alkynylR 7 , —S(O) 2 CH═CH 2 , —(CH 2 ) m CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) m CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) m CR 7 ═CR 9 CN;
R 6 and R 6′ are each independently chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, and phenylC 1-4 alkyl;
R 7 and R 7′ are each independently chosen from hydrogen, cyano, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyalkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkylalkyl, (NR 6 R 6′ )C 1-4 alkyl, aryl, and heteroaryl where aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 8 is chosen from hydrogen, halo, cyano, C 1-4 alkyl, arylC 1-4 alkyl, heteroarylC 1-4 alkyl, C 3-7 cycloalkyl, hydroxyC 1-6 alkyl, heterocycloalkylC 1-4 alkyl, C 3-7 heterocycloalkyl, hydroxyl, C 1-4 alkoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkoxyalkyl, heteroaryloxy, aryloxy, (NR 6 R 6′ )alkyl, arylalkoxy, C 1-4 alkoxyC 1-4 alkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, trifluoromethyl, aryl, and heteroaryl, wherein alkyl, heterocycloalkyl, aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 9 is chosen from hydrogen, halo, hydroxyl, C 1-4 alkyl, cyano, trifluoromethyl, —C(O)CH 3 , amido, and aryl;
R 10 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo, trifluoromethyl and CN;
R 11 is chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, heterocycloalkylalkyl, arylC 1-4 alkyl, and heteroarylC 1-4 alkyl, wherein aryl and heteroaryl may be optionally substituted with one or more R 9 ;
m is an integer chosen from 1, 2 and 3; and
n is an integer chosen from 0, 1, 2, and 3.
22 . A compound of claim 21 , wherein R 1 is chosen from phenyl, pyridine, pyrimidine, pyrazine, pyridinone, pyrrolopyridine, and pyrrolopyrimidine, any of which may be optionally substituted with one or more R 3 substituents.
23 . A compound according to claim 21 , chosen from the compounds in Table 3 having a pyridinone at R 2 .
24 . A compound of claim 1 , wherein the compound has formula (VIII):
or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 1 is chosen from mono- or bicyclic aryl and heteroaryl, wherein R 1 may be optionally substituted with one or more R 3 substituents;
R 3 is independently chosen from hydrogen, hydroxyl, cyano, C 1-6 alkyl, hydroxyC 1-4 alkyl, C 1-6 alkoxyalkyl, arylC 1-6 alkyl, arylC 1-6 alkoxy, heteroarylC 1-6 alkyl, heteroarylC 1-6 alkoxy, aryloxyC 1-6 alkyl, heteroaryloxyC 1-6 alkyl, cyclopropylC 1-4 alkyl, cyclopropylC 1-4 alkoxy, cyclopropoxyC 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkylarylamino, C 1-4 alkylheteroarylamino, di(C 1-4 alkyl)amino, —CONR 6 R 6′ , C 1-4 alkanoyl, —C(O)aryl, —C(O)heteroaryl, —C(O)NHaryl, —C(O)NHheteroaryl, trifluoromethyl, and halo, wherein aryl and heteroaryl may be optionally substituted with R 9 ;
R 4 is chosen from —NR 5 R 6 , —(CH 2 ) n CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) n CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) n CR 7 ═CR 9 CN;
R 5 is chosen from cyano, —C(O)CF 3 , —C(O)CH═CH 2 , —C(O)CR 7 ═CH 2 , —C(O)CH═CHR 7 , —C(O)CR 7 ═CHR 7 , —C(O)CH═CR 7 R 7′ , —C(O)CH═CHCH 2 R 8 , —C(O)CH═CHC(O)CH 2 R 8 , —COC(CN)═CHR 6 , —C(O)(C(O)NH 2 )═CHR 6 , —C(O)alkynylR 7 , —S(O) 2 CH═CH 2 , —(CH 2 ) m CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) m CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) m CR 7 ═CR 9 CN;
R 6 and R 6′ are each independently chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, and phenylC 1-4 alkyl;
R 7 and R 7′ are each independently chosen from hydrogen, cyano, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyalkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkylalkyl, (NR 6 R 6′ )C 1-4 alkyl, aryl, and heteroaryl where aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 8 is chosen from hydrogen, halo, cyano, C 1-4 alkyl, arylC 1-4 alkyl, heteroarylC 1-4 alkyl, C 3-7 cycloalkyl, hydroxyC 1-6 alkyl, heterocycloalkylC 1-4 alkyl, C 3-7 heterocycloalkyl, hydroxyl, C 1-4 alkoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkoxyalkyl, heteroaryloxy, aryloxy, (NR 6 R 6′ )alkyl, arylalkoxy, C 1-4 alkoxyC 1-4 alkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, trifluoromethyl, aryl, and heteroaryl, wherein alkyl, heterocycloalkyl, aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 9 is chosen from hydrogen, halo, hydroxyl, C 1-4 alkyl, cyano, trifluoromethyl, —C(O)CH 3 , amido, and aryl;
R 10 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo, trifluoromethyl and CN;
m is an integer chosen from 1, 2 and 3;
n is an integer chosen from 0, 1, 2, and 3;
p and q are each independently an integer chosen from 1 and 2.
25 . A compound of claim 24 , wherein R 1 is chosen from phenyl, pyridine, pyrimidine, pyrazine, pyridinone, pyrrolopyridine, and pyrrolopyrimidine, any of which may be optionally substituted with one or more R 3 substituents.
26 . A compound according to claim 24 , chosen from:
N-(1-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide; N-(1-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide; N-(1-(3-(6-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide; N-(1-(3-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide; N-(1-(3-(2-cyanopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide; N-(1-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide, N-(1-(3-(2-(methylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide, (S)-N-(1-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidin-3-yl)acrylamide, (S)-N-(1-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidin-3-yl)cyanamide, and (S)-N-(1-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperidin-3-yl)acrylamide.
27 . A compound of claim 24 , wherein p is 1 and q is 1.
28 . A compound according to claim 27 , chosen from:
N-(1-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide; N-(1-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide; N-(1-(3-(6-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide; N-(1-(3-(2-methylpyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide; N-(1-(3-(2-cyanopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide; N-(1-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide, and N-(1-(3-(2-(methylamino)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)azetidin-3-yl)acrylamide, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
29 . A compound of claim 24 , wherein p is 2 and q is 1.
30 . A compound according to claim 29 , chosen from:
(S)-N-(1-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidin-3-yl)acrylamide and (S)-N-(1-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidin-3-yl)cyanamide, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
31 . A compound of claim 24 , wherein p is 2 and q is 2.
32 . A compound according to claim 31 , wherein the compound is (S)-N-(1-(3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)piperidin-3-yl)acrylamide, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
33 . A compound of claim 1 , wherein the compound has formula (IX):
or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
R 1 is chosen from mono- and bicyclic aryl and heteroaryl, wherein R 1 may be optionally substituted with one or more R 3 substituents;
R 2 is chosen from heterocycloalkyl, aryl, heteroaryl, each of which is substituted with one R 4 substituent, and any of which may be further optionally substituted with one or more R 8 substituents, or alternatively R 2 is R 12 R 13 ;
R 3 is independently chosen from hydrogen, hydroxyl, cyano, C 1-6 alkyl, hydroxyC 1-4 alkyl, C 1-6 alkoxyalkyl, arylC 1-6 alkyl, arylC 1-6 alkoxy, heteroarylC 1-6 alkyl, heteroarylC 1-6 alkoxy, aryloxyC 1-6 alkyl, heteroaryloxyC 1-6 alkyl, cyclopropylC 1-4 alkyl, cyclopropylC 1-4 alkoxy, cyclopropoxyC 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkylarylamino, C 1-4 alkylheteroarylamino, di(C 1-4 alkyl)amino, —C(O)NR 6 R 6′ , C 1-4 alkanoyl, —C(O)aryl, —C(O)heteroaryl, —C(O)NHaryl, —C(O)NHheteroaryl, trifluoromethyl, and halo, wherein aryl and heteroaryl may be optionally substituted with R 9 ;
R 4 is chosen from NR 5 R 6 , —(CH 2 ) n CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) n CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) n CR 7 ═CR 9 CN;
R 5 is chosen from cyano, —C(O)CF 3 , —C(O)CH═CH 2 , —C(O)CR 7 ═CH 2 , —C(O)CH═CHR 7 , —C(O)CR 7 ═CHR 7 , —C(O)CH═CR 7 R 7′ , —C(O)CH═CHCH 2 R 8 , —C(O)CH═CHC(O)CH 2 R 8 , —COC(CN)═CHR 6 , —C(O)(C(O)NH 2 )═CHR 6 , C(O)alkynylR 7 , —S(O) 2 CH═CH 2 , —(CH 2 ) m CR 7 ═CR 9 C(O)CH 3 , —(CH 2 ) m CR 7 ═CR 9 C(O)NR 7 R 7′ , and —(CH 2 ) m CR 7 ═CR 9 CN;
R 6 and R 6′ are each independently chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, and phenylC 1-4 alkyl;
R 7 and R 7′ are each independently chosen from hydrogen, cyano, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxyalkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, (NR 6 R 6′ )C 1-4 alkyl, aryl, and heteroaryl, wherein aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 8 is chosen from hydrogen, halo, cyano, C 1-4 alkyl, arylC 1-4 alkyl, heteroarylC 1-4 alkyl, C 3-7 cycloalkyl, hydroxyC 1-6 alkyl, heterocycloalkylC 1-4 alkyl, C 3-7 heterocycloalkyl, hydroxyl, C 1-4 alkoxy, C 3-7 cycloalkoxy, C 3-7 cycloalkoxyalkyl, heteroaryloxy, aryloxy, (NR 6 R 6′ )alkyl, arylalkoxy, C 1-4 alkoxyC 1-4 alkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, trifluoromethyl, aryl, and heteroaryl, wherein alkyl, heterocycloalkyl, aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 9 is chosen from hydrogen, halo, hydroxyl, C 1-4 alkyl, cyano, trifluoromethyl, alkanoyl, amido, and aryl;
R 10 is chosen from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo, trifluoromethyl, and cyano;
R 11 is chosen from hydrogen, C 1-4 alkyl, C 3-7 cycloalkylalkyl, heterocycloalkylalkyl, arylC 1-4 alkyl, and heteroarylC 1-4 alkyl, wherein aryl and heteroaryl may be optionally substituted with one or more R 9 ;
R 12 is a nitrogen-containing C 3-7 heterocycloalkyl, wherein said nitrogen is further substituted by R 5 ;
R 13 is chosen from hydrogen, C 1-4 alkyl, and C 3-7 cycloalkylalkyl;
X is N or CR 11 ;
m is an integer chosen from 1, 2 and 3;
n is an integer chosen from 0, 1, 2, and 3;
p and q are each independently an integer chosen from 1, 2, and 3.
34 . A compound of claim 33 , wherein R 1 is chosen from phenyl, pyridine, pyrimidine, pyrazine, pyridinone, pyrrolopyridine, and pyrrolopyrimidine, any of which may be optionally substituted with one or more R 3 substituents.
35 . A compound of claim 33 , wherein p is 1 and q is 1.
36 . A compound of claim 33 , wherein p is 2 and q is 1.
37 . A compound of claim 33 , wherein p is 2 and q is 2.
38 . A compound of claim 33 , wherein p is 3 and q is 1.
39 . A compound according to claim 33 , chosen from the compounds in Table 3 having a an N-linked nitrogen-containing C 3-7 heterocycloalkyl at R 2 , wherein said nitrogen is further substituted by R 5 .
40 . A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
41 . A method of inhibiting ITK activity in a biological sample comprising contacting the biological sample with a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof.
42 . A method of treating an ITK-mediated disorder in a subject in need thereof, comprising the step of administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof.
43 . The method according to claim 42 , wherein the subject is a human.
44 . The method according to claim 42 , wherein the subject is a companion animal, exotic animal or farm animal.
45 . The method according to claim 42 , wherein the ITK-mediated disorder is selected from cancer, autoimmune disorders, chronic inflammatory disorders, auto-inflammatory disorders, pain, inflammatory disorders, and allergic disorders.
46 . The method according to claim 42 , wherein the ITK-mediated disorder is selected from asthma, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, contact hypersensitivity and inflammatory bowel disease.
47 . The method according to claim 42 , wherein the ITK-mediated disorder is selected from T-cell lymphoma and lymphoblastic T-cell leukemia.
48 . The method according to claim 42 , wherein the ITK-mediated disorder is selected from a solid tumor, colorectal cancer and a hematological tumor.
49 . The method according to claim 42 , wherein the ITK-mediated disorder is HIV.
50 . A method of treating an ITK-mediated disorder in a subject in need thereof, comprising the sequential or co-administration of a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another therapeutic agent.
51 . The method according to claim 50 , wherein the therapeutic agent is selected from taxanes, inhibitors of bcr-abl, inhibitors of EGFR, DNA damaging agents, and antimetabolites.
52 . The method according to claim 50 , wherein the therapeutic agent is selected from Paclitaxel, Gleevec, dasatinib, nilotinib, Tarceva, Iressa, cisplatin, oxaliplatin, carboplatin, anthracyclines, AraC and 5-FU.
53 . The method according to claim 59 , wherein the therapeutic agent is selected from camptothecin, doxorubicin, idarubicin, Cisplatin, taxol, taxotere, vincristine, tarceva, a MEK inhibitor, U0126, an ERK inhibitor, a cell cycle checkpoint inhibitor, vorinostat, Gleevec, dasatinib, and nilotinib.
54 . The method according to claim 50 , wherein the therapeutic agent is an immune checkpoint inhibitor.
55 . The method according to claim 54 , wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab and ipilumimab.
56 . The method according to claim 50 , wherein the therapeutic agent is an immunotherapeutic agent.
57 . The method according to claim 56 , wherein the immunotherapeutic agent is selected from aPD1, aPDL1 and CTLA4.Join the waitlist — get patent alerts
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