IP Library › Granted Patent US 10,150,783

Granted Patent B2

US 10,150,783 · App. 15/609,876 · Granted Dec 11, 2018

Heterocyclic ITK inhibitors for treating inflammation and cancer

Inventors: Eric Jon Jacobsen (Chesterfield, MO); James Robert Blinn (O'Fallon, MO); John Robert Springer (Wentzville, MO); Susan L. Hockerman (Kirkwood, MO)

Assignee: ACLARIS THERAPEUTICS, INC.

C07D519/00 A61K45/06 C07D471/04

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Quick Facts

Patent No.: US 10,150,783
App. No.: 15/609,876
Granted: Dec 11, 2018
Kind: B2

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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 (256)

1. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, of Formula (I):

wherein:

R 1 is chosen from monocyclic heteroaryl, wherein R 1 is optionally substituted with one or more R 3 substituents;

R 2 is chosen from aryl and heteroaryl, each of which is substituted with one R 4 substituent, and any of which is further optionally substituted with one or more R 8 substituents;

each R 3 is independently chosen from hydrogen, hydroxyl, methoxy, 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 are optionally substituted with R 9 ;

R 4 is chosen from NR 5 R 6 , —(CH 2 ) n CR′═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)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 are 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 are 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 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 are optionally substituted with one or more R 9 ;

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 is further optionally substituted with one or more R 8 substituents.

3. A compound of claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 1 is chosen from pyridinyl, pyrimidinyl, pyrazinyl, and pyridinonyl, any of which is optionally substituted with one or more R 3 substituents.

4. A compound according to claim 1 , 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.

5. A compound according to claim 4 , 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.

6. A compound according to claim 4 , 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.

7. A compound according to claim 1 , wherein each R 3 is independently chosen from hydrogen, halo, C 1-6 alkyl, methoxy, cyano, and C 1-4 alkylamino.

8. A compound according to claim 1 , 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-(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-(6-methoxy-4-methylpyridin-2-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,

(E)-2-cyano-3-(3-(3-(6-fluoropyridin-3-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,

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,

(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-(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-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,

(E)-2-cyano-N-(3-(3-(2-methoxypyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-methylpent-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,

(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,

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

9. A compound of claim 1 , wherein the compound has formula (III):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

R 1 is chosen from monocyclic heteroaryl, wherein R 1 is optionally substituted with one or more R 3 substituents;

R 3 is independently chosen from hydrogen, hydroxyl, cyano, C 1-6 alkyl, methoxy, 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 are 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)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 are 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;

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: