Inhibitors of protein kinases
View Patent ↗The present invention is directed to 2-cycloalkylamino-4-arylamino-benzamide compounds of formula I pharmaceutically acceptable salts thereof which are inhibitors of syk and/or JAK kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition syk and/or JAK kinase activity, and methods to prevent or treat a number of conditions mediated at least in part by syk and/or JAK kinase activity, such as cardiovascular disease, inflammatory disease, autoimmune disease and cell proliferative disorder.
1. A compound having the formula I:
or a pharmaceutically acceptable salt thereof, wherein:
D 1 is C 3-8 cycloalkyl, optionally substituted with from 1 to 4 substituents independently selected from the group consisting of: C 1-8 alkyl, amino, hydroxy, C 1-8 alkylcarbonyl, aminocarbonyl, C 1-8 alkoxycarbonylamino, arylC 1-8 alkoxycarbonylamino, phenyl and heterocyclylC 1-8 alkylene; wherein the cycloalkyl does not have more than one double bond;
R 1 is selected from the group consisting of H, C 1-8 alkyl, amino, aminocarbonyl, hydroxyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, oxo, cyano, C 1-8 alkoxycarbonyl, C 3-8 cycloalkyl, aryl and heterocyclyl; and each heterocyclyl is optionally substituted with from 1 to 4 substituents selected from the group consisting of: C 1-8 alkyl, halo, oxo, amino, C 1-8 alkoxy, C 1-8 alkylcarbonyl, arylC 1-8 alkoxycarbonyl, aminocarbonyl, arylC 1-8 alkylenecarbonyl and C 1-8 alkylsulfonyl
Y 1 is aryl; optionally substituted with from 1 to 3 substituents, R 4a , independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxyC 1-8 alkyl, aminocarbonyl-, hydroxyl, oxo, halogen, hydroxy, C 1-8 alkoxy and C 1-8 alkylsulfonyl;
R 2 is selected from the group consisting of heterocyclyl and heteroaryl, each of which is substituted with at least one group, R 3 , selected from the group consisting of aminoC 1-8 alkyl-, C 1-8 alkoxyC 1-8 alkyl-, oxo-, C 1-8 alkylcarbonyl, C 3-8 cycloalkylcarbonyl, heterocyclylcarbonyl, C 1-8 alkylcarbonylamino, C 3-8 cycloalkylcarbonylamino, heterocyclylcarbonylamino, aminosulfonyl, C 1-8 alkylsulfonyl, C 3-8 cycloalkylsulfonyl and heterocyclylsulfonyl;
and wherein R 2 is further optionally substituted with from 1 to 2 substituents, R 4c , independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, halo, aminocarbonyl, oxo, hydroxyl, aminoC 1-8 alkylene, C 1-8 alkoxyC 1-8 alkylene, C 1-8 alkylcarbonyl, C 3-8 cycloalkylcarbonyl, heterocyclylcarbonyl, C 1-8 alkylcarbonylamino, C 3-8 cycloalkylcarbonylamino, heterocyclylcarbonylamino, C 1-8 alkylsulfonyl, C 3-8 cycloalkylsulfonyl, heterocyclylsulfonyl, C 3-8 cycloalkyl, C 1-8 alkylcycloalkylene, and heteroaryl.
2. The compound of claim 1 , wherein: Y 1 is phenyl.
3. The compound of claim 1 , wherein: R 2 is heterocyclyl.
4. The compound of claim 1 , wherein the moiety —Y 1 —R 2 is selected from the group consisting of:
Y 2 is CH or C;
R 4a is selected from the group consisting of H and C 1-8 alkyl;
each R 4c is independently selected from the group consisting of H, C 1-8 alkyl, C 1-8 alkoxyC 1-8 alkyl, aminocarbonyl-, hydroxyl, oxo, C 1-8 alkoxy and halo;
each R 4b is independently selected from the group consisting of H, C 1-8 alkyl, amino, C 1-8 alkoxy and heterocyclyl;
the subscript p is 0, 1, or 2; and
the wavy line indicates the point of attachment to the rest of the molecule.
5. The compound of claim 4 , wherein —Y 1 —R 2 is selected from the group consisting of:
Y 2 is C;
each R 4a is selected from the group consisting of H and halo;
each R 4c is independently selected from the group consisting of H and C 1-8 alkyl;
each R 4b is independently selected from the group consisting of H and C 1-8 alkyl;
the subscript p is 0, 1, or 2; and
the wavy line indicates the point of attachment to the rest of the molecule.
6. The compound of claim 4 , wherein the moiety —Y 1 —R 2 is selected from the group consisting of:
and the wavy line indicates the point of attachment to the rest of the molecule.
7. The compound of claim 6 , having the formula Id:
or a pharmaceutically acceptable tautomer, salt, or stereoisomer thereof.
8. The compound of claim 6 , having the formula Id1:
or a pharmaceutically acceptable tautomer, salt, or stereoisomer thereof.
9. The compound of claim 6 , having the formula:
or a pharmaceutically acceptable tautomer, salt, or stereoisomer thereof.
10. The compound of claim 1 , wherein: D 1 is cyclopropyl.
11. The compound of claim 1 , wherein: D 1 is cyclobutyl.
12. The compound of claim 1 , wherein: D 1 is cyclopentyl.
13. The compound of claim 1 , wherein: D 1 is cyclohexyl.
14. The compound of claim 1 , wherein the moiety —Y 1 —R 2 is selected from the group consisting of:
Y 2 is C;
each R 4a is selected from the group consisting of H and C 1-8 alkyl;
each R 4c is independently selected from the group consisting of H, C 1-8 alkyl, C 1-8 alkoxyC 1-8 alkyl, aminocarbonyl-, hydroxyl, oxo, C 1-8 alkoxy and halo;
each R 4b is independently selected from the group consisting of H, C 1-8 alkyl, amino, C 1-8 alkoxy and heterocyclyl; and
the subscript p is 0, 1, or 2; and the wavy line indicates the point of attachment to the rest of the molecule.
15. A compound having the formula:
or a pharmaceutically acceptable tautomer, salt, or stereoisomer thereof.
16. A compound having the formula:
a pharmaceutically acceptable tautomer, salt, or stereoisomer thereof.
17. A compound having the formula:
or a pharmaceutically acceptable tautomer, salt, or stereoisomer thereof.
18. A composition comprising a compound of any one of the preceding claims, in combination with a pharmaceutically acceptable carrier or diluent.
19. A kit comprising a composition of claim 18 , packaging and instructions for use.