Kinase inhibitors and methods of their use

Abstract

New compounds, compositions and methods of inhibition of Provirus Integration of Maloney Kinase (PIM kinase) activity associated with tumorigenesis in a human or animal subject are provided. In certain embodiments, the compounds and compositions are effective to inhibit the activity of at least one PIM kinase. The new compounds and compositions may be used either alone or in combination with at least one additional agent for the treatment of a serine/threonine kinase- or receptor tyrosine kinase-mediated disorder, such as cancer.

1 . A compound of Formula II, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         Y is cyclohexyl, substituted with one to three substituents; 
         R 1  is hydrogen, —NH 2 , or halo; 
         R 12  independently at each occurrence is selected from the hydrogen, and halo; and 
         R 5  is selected from cyclohexyl, phenyl, and pyridyl, wherein said cycloalkyl, said phenyl, and said pyridyl are each independently substituted with up to three substituents selected from halo, hydroxyl, C 1-4  alkyl, or OC 1-4  alkyl. 
       
     
     
         2 . A compound of  claim 1  wherein Y is substituted with one to three substituents selected from hydroxyl, amino, C 1-4  alkyl, and C 1-4  halo alkyl. 
     
     
         3 . A compound of  claim 2  wherein Y is substituted with one to three substituents selected from methyl, hydroxyl, amino, and CF 3 . 
     
     
         4 . A compound of  claim 2  wherein R 1  is hydrogen, amino, or fluoro. 
     
     
         5 . A compound of  claim 2  wherein R 5  is pyridyl or phenyl. 
     
     
         6 . A compound of  claim 5  wherein R 5  is phenyl substituted with up to three substituents selected from halo, hydroxyl, C 1-4  alkoxy, and C 1-4  alkyl. 
     
     
         7 . A compound of  claim 5  wherein Y is substituted with one to three substituents selected from methyl, hydroxyl, amino, and CF 3 ; R 1  is hydrogen; and R 5  is phenyl substituted with up to three substituents selected from fluoro, hydroxyl, methyl, ethyl, methoxy, and propoxy. 
     
     
         8 . A compound of  claim 7  wherein R 5  is 2,6-difluorophenyl. 
     
     
         9 . A compound of  claim 1 , selected from the group consisting of
 N-(4-((3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide;   3-amino-N-(4-((1R,3R,4S,5S)-3-amino-4-hydroxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)picolinamide;   N-(4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide;   3-amino-N-(4-((1R,3S)-3-aminocyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide; and   N-(4-((3 S)-3-aminocyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.   
     
     
         10 . A method for treating a condition by modulation of Provirus Integration of Maloney Kinase (PIM Kinase) activity comprising administering to a patient in need of such treatment an effective amount of a compound of  claim 1 . 
     
     
         11 . A method of  claim 10  wherein the condition is a cancer selected from carcinoma of the lungs, pancreas, thyroid, ovarian, bladder, breast, prostate, or colon, melanoma, myeloid leukemia, multiple myeloma and erythro leukemia, villous colon adenoma, and osteosarcoma. 
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 1  or  claim 9 . 
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 1  or  claim 9 , wherein said pharmaceutical composition comprises an additional agent for the treatment of cancer. 
     
     
         14 . The pharmaceutical composition of  claim 13  wherein the additional agent is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide,  vinca  alkaloids, imatinib (Gleevec), anthracyclines, rituximab, and trastuzumab. 
     
     
         15 . A compound of Formula II selected from Table I or Table II. 
     
     
         16 . A compound of Formula II, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         Y is piperidinyl substituted with methyl, hydroxyl, and amino; 
         R 1  is hydrogen, NH 2 , or fluoro; 
         R 12  independently at each occurrence is selected from the group consisting of hydrogen, and halo; and 
         R 5  is pyridyl, fluoro pyridyl, cyclohexyl, or phenyl, wherein said phenyl is substituted with up to three substituents selected from fluoro, hydroxyl, and methyl. 
       
     
     
         17 . A compound of  claim 16  wherein Y is 3-amino-4-hydroxy-5-methylpiperidin-1-yl. 
     
     
         18 . A compound of  claim 16  or  17  wherein R 1  is hydrogen. 
     
     
         19 . A compound of  claim 18  wherein R 5  is difluoro phenyl. 
     
     
         20 . A compound of  claim 16  or  claim 17  wherein R 5  is 2,6-difluoro phenyl. 
     
     
         21 . A compound of  claim 16  selected from the group consisting of
 N-(4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide; 
 3-amino-N-(4-((3R,4R,5 S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide; and 
 N-(4-((3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluoro-3-methylphenyl)-5-fluoropicolinamide. 
 
     
     
         22 . A pharmaceutical composition comprising a compound of  claim 16  or  claim 21 , wherein said pharmaceutical composition comprises at least one additional agent for the treatment of cancer. 
     
     
         23 . The pharmaceutical composition of  claim 22  wherein the additional agent is selected from the group consisting of irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide,  vinca  alkaloids, imatinib (Gleevec), anthracyclines, rituximab, and trastuzumab. 
     
     
         24 . A method for treating a condition by modulation of Provirus Integration of Maloney Kinase (PIM Kinase) activity comprising administering to a patient in need of such treatment an effective amount of a compound of  claim 16  or  claim 21 . 
     
     
         25 . A method of  claim 24  wherein the condition is a cancer selected from carcinoma of the lungs, pancreas, thyroid, ovarian, bladder, breast, prostate, or colon, melanoma, myeloid leukemia, multiple myeloma and erythro leukemia, villous colon adenoma, and osteosarcoma. 
     
     
         26 . A compound of Formula II selected from Table I or Table II.