HETEROCYCLIC ITK INHIBITORS FOR TREATING INFLAMMATION AND CANCER
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.
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.