Kinase Inhibitors

A pharmaceutical formulation comprising a compound of Formula I:

• wherein:
• R1 is hydrogen, C1-C4 alkyl, or tolyl;
• W is 1-(4-methylsulfonylbenzoyl)-piperidin-4-yl-, [1-(2,6-dichlorobenzoyl)-piperidin-4-yloxy]naphthyl-, [1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-(C1-C2 alkoxy)-naphthyl-, [1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-phenyl-, (1-Y-piperidin-4-yloxy)-phenyl-, [1-(2,6-dichlorobenzoyl)-piperazin-4-yl]-methyl-phenyl-, (1-Y-piperazin-4-yl)-methyl-phenyl-, (1-Y-piperazin-4-yl)-phenyl-, or 4-[1-(pyridin-4-ylmethyl)-piperazin-4-ylcarbonyl]-phenyl- wherein phenyl is optionally substituted with one to two substituents from the group consisting of halo, methyl, and trifluoromethyl;
• Y is —C(O)—R2, C1-C3 alkylsulfonyl, or cyclopropylsulfonyl;
• and
• R2 is C1-C6 alkyl, C1-C6 alkoxy-(C1-C6 alkyl), amino, benzyloxy, indolyl, tetrahydrofuryl, piperidinyl, trichloromethyl, cyclopentylmethyl;
• C3-C5 cycloalkyl optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl, C1-C4 alkyl, and halo, pyridinyl optionally substituted with 1-2 substituents independently selected from the group consisting of C1-C4 alkoxy and halo, thienyl optionally substituted with 1-2 halo or C1-C4 alkyl substituents, pyrrolyl optionally substituted with 1-2 C1-C4 alkyl substituents, imidazolyl, pyrazolyl optionally substituted with 1-3 C1-C4 alkyl substituents, or phenyl substituted with 1-2 substituents independently selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, 2-(dimethylamino)ethoxy, and morpholin-4-ylmethyl;
• or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

A method of inhibiting p-38 kinase in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I:

• wherein:
• R1 is hydrogen, C1-C4 alkyl, or tolyl;
• W is 1-(4-methylsulfonylbenzoyl)-piperidin-4-yl-, [1-(2,6-dichlorobenzoyl)-piperidin-4-yloxy]naphthyl-, [1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-(C1-C2 alkoxy)-naphthyl-, [1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-phenyl-, (1-Y-piperidin-4-yloxy)-phenyl-, [1-(2,6-dichlorobenzoyl)-piperazin-4-yl]-methyl-phenyl-, (1-Y-piperazin-4-yl)-methyl-phenyl-, (1-Y-piperazin-4-yl)-phenyl-, or 4-[1-(pyridin-4-ylmethyl)-piperazin-4-ylcarbonyl]-phenyl- wherein phenyl is optionally substituted with one to two substituents from the group consisting of halo, methyl, and trifluoromethyl;
• Y is —C(O)—R2, C1-C3 alkylsulfonyl, or cyclopropylsulfonyl;
• and
• R2 is C1-C6 alkyl, C1-C6 alkoxy-(C1-C6 alkyl), amino, benzyloxy, indolyl, tetrahydrofuryl, piperidinyl, trichloromethyl, cyclopentylmethyl;
• C3-C5 cycloalkyl optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl, C1-C4 alkyl, and halo, pyridinyl optionally substituted with 1-2 substituents independently selected from the group consisting of C1-C4 alkoxy and halo, thienyl optionally substituted with 1-2 halo or C1-C4 alkyl substituents, pyrrolyl optionally substituted with 1-2 C1-C4 alkyl substituents, imidazolyl, pyrazolyl optionally substituted with 1-3 C1-C4 alkyl substituents, or phenyl substituted with 1-2 substituents independently selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, 2-(dimethylamino)ethoxy, and morpholin-4-ylmethyl;
• or a pharmaceutically acceptable salt thereof.

A method of treating conditions resulting from excessive cytokine production in a mammal comprising administering to a mammal in need of such treatment a cytokine-suppressing amount of a compound of Formula I:

• wherein:
• R1 is hydrogen, C1-C4 alkyl, or tolyl;
• W is 1-(4-methylsulfonylbenzoyl)-piperidin-4-yl-, [1-(2,6-dichlorobenzoyl)-piperidin-4-yloxy]naphthyl-, [1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-(C1-C2 alkoxy)-naphthyl-, [1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-phenyl-, (1-Y-piperidin-4-yloxy)-phenyl-, [1-(2,6-dichlorobenzoyl)-piperazin-4-yl]-methyl-phenyl-, (1-Y-piperazin-4-yl)-methyl-phenyl-, (1-Y-piperazin-4-yl)-phenyl-, or 4-[1-(pyridin-4-ylmethyl)-piperazin-4-ylcarbonyl]-phenyl- wherein phenyl is optionally substituted with one to two substituents from the group consisting of halo, methyl, and trifluoromethyl;
• Y is —C(O)—R2, C1-C3 alkylsulfonyl, or cyclopropylsulfonyl;
• and
• R2 is C1-C6 alkyl, C1-C6 alkoxy-(C1-C6 alkyl), amino, benzyloxy, indolyl, tetrahydrofuryl, piperidinyl, trichloromethyl, cyclopentylmethyl;
• C3-C5 cycloalkyl optionally substituted with 1-3 substituents independently selected from the group consisting of phenyl, C1-C4 alkyl, and halo, pyridinyl optionally substituted with 1-2 substituents independently selected from the group consisting of C1-C4 alkoxy and halo, thienyl optionally substituted with 1-2 halo or C1-C4 alkyl substituents, pyrrolyl optionally substituted with 1-2 C1-C4 alkyl substituents, imidazolyl, pyrazolyl optionally substituted with 1-3 C1-C4 alkyl substituents, or phenyl substituted with 1-2 substituents independently selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy, C1-C4 alkoxy, 2-(dimethylamino)ethoxy, and morpholin-4-ylmethyl;
• or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.