Claims for Patent: 8,987,457

Summary for Patent: 8,987,457

Title:	Ring-substituted N-pyridinyl amides as kinase inhibitors
Abstract:	The present invention provides a compound of formula (A): ##STR00001## as described herein, and pharmaceutically acceptable salts, enantiomers, rotamers, tautomers, or racemates thereof. Also provided are methods of treating a disease or condition mediated by PIM kinase using the compounds of Formula I, and pharmaceutical compositions comprising such compounds.
Inventor(s):	Burger; Matthew (Albany, CA), Drumm, III; Joseph E. (Walnut Creek, CA), Nishiguchi; Gisele (Albany, CA), Rico; Alice (Castro Valley, CA), Simmons; Robert Lowell (San Francisco, CA), Taft; Benjamin (Oakland, CA), Tanner; Huw (Alameda, CA)
Assignee:	Novartis AG (Basel, CH)
Application Number:	13/897,927
Patent Claims:	1. A compound of Formula (A) ##STR00420## wherein: groups attached to the ring containing Q that are depicted inside the ring are all syn to each other, and all groups attached to that ring that are depicted outside the ring are syn to one another; Q is C; R.sup.q is H; R.sup.1 is selected from C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, and C.sub.4-6 heterocyclyl, each alkyl, cycloalkyl and heterocyclyl is optionally substituted with up to two groups selected from halo, CN, NH.sub.2, hydroxy, oxo, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; R.sup.1c is halo, and R.sup.1d is halo and R.sup.1b is selected from H, halo, OR', R', --(CH.sub.2).sub.1-2OR', and CONR'.sub.2, where each R' is independently H or C.sub.1-4 alkyl; R.sup.2a is --OMe, --SO.sub.2Me, --NHCOOMe, or --O(CH.sub.2).sub.2--X, wherein X is --OMe, COOH, CN or --SO.sub.2Me, or R.sup.2a is 1,2,3-triazolyl or 1-pyridonyl that is optionally substituted with up to two groups selected from halo, C.sub.1-4 alkyl, hydroxy-substituted C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.3-6 cycloalkyl, and C.sub.1-4 alkoxy, or --SO.sub.2Me and R.sup.2b is H; or R.sup.2a and R.sup.2b taken together may form a dialkyl ketal or 5-6 membered cyclic ketal, .dbd.O or .dbd.N--OR'', where R'' is H or C.sub.1-4 alkyl; ring A is selected from pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, each having N positioned as shown in Formula (I); and Ring A is optionally substituted with 1 or 2 groups selected from halo, CN, NH.sub.2, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein R.sup.1d is F. 3. The compound of claim 1, wherein R.sup.1c is F. 4. The compound of claim 1, which is a compound of Formula (I): ##STR00421## wherein: groups attached to the ring containing Q that are depicted inside the ring are all syn to each other, and all groups attached to that ring that are depicted outside the ring are syn to one another; Q is C; R.sup.q is H; R.sup.1 is selected from C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, and C.sub.4-6 heterocyclyl, each alkyl, cycloalkyl and heterocyclyl is optionally substituted with up to two groups selected from halo, CN, NH.sub.2, hydroxy, oxo, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; R.sup.2a is --OMe, --SO.sub.2Me, --NHCOOMe, or --O(CH.sub.2).sub.2--X, wherein X is --OMe, COOH, CN or --SO.sub.2Me, or R.sup.2a is 1-triazolyl (e.g., 1,2,3-triazolyl) or 1-pyridonyl that is optionally substituted with up to two groups selected from halo, C.sub.1-4 alkyl, hydroxy-substituted C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.3-6 cycloalkyl, and C.sub.1-4 alkoxy, or --SO.sub.2Me and R.sup.2b is H; Ring A is selected from pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, each having N positioned as shown in Formula (I); and Ring A is optionally substituted with 1 or 2 groups selected from halo, CN, NH.sub.2, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; or a pharmaceutically acceptable salt thereof. 5. A compound ##STR00422## or a pharmaceutically acceptable salt thereof. 6. The compound of claim 4, which is an optically active compound of Formula IIa or IIb: ##STR00423## wherein Y is H or F, and Z is H or NH.sub.2. 7. A compound selected from the group consisting of: N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)- pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((3R,4S,5S)-3-amino-5-methyl-4-(4-(thiophen-3-yl)-1H-1,2,3-triazol-1- -yl)piperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinami- de, N-(4-((1R,3R,5S,Z)-3-amino-4-(hydroxyimino)-5-methylcyclohexyl)pyridin- -3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,5S)-3-amino-5-methyl-4-oxocyclohexyl)pyridin-3-yl)-6-(2,6-di- fluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,5S,E)-3-amino-4-(methoxyimino)-5-methylcyclohexyl)pyridin-3-- yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,5S,Z)-3-amino-4-(methoxyimino)-5-methylcyclohexyl)pyridin-3-- yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((3R,4S,5S)-3-amino-4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)-5-me- thylpiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinami- de, N-(4-((1R,3R,4S,5S)-3-amino-4-(2-hydroxyethylsulfonyl)-5-methylcyclohe- xyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1S,3S,4S,5R)-3-amino-5-methyl-4-(methylsulfonamido)cyclohexyl)pyri- din-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4R,5 S)-3-amino-5-methyl-4-(methylsulfonamido)cyclohexyl)pyridin-3-yl)-6-(2,6-- difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-((2-methoxyethyl)sulfonyl)-5-methylcyclohexyl)pyridin-3-yl)-- 6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1S,3S,4R,5R)-3-amino-5-methyl-4-(methylsulfonamido)cyclohexyl)pyri- din-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonamido)cyclohexyl)pyri- din-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1S,3S,4R,5R)-3-amino-4-azido-5-methylcyclohexyl)pyridin-3-yl)-6-(2- ,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-azido-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl- )-5-fluoropicolinamide, N-(4-((1R,3R,4R,5 S)-3-amino-5-methyl-4-((R)-methylsulfinyl)cyclohexyl)pyridin-3-yl)-6-(2,6- -difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4R,5 S)-3-amino-5-methyl-4-((S)-methylsulfinyl)cyclohexyl)pyridin-3-yl)-6-(2,6- -difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylthio)cyclohexyl)pyridin-3-y- l)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4R,5S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin- -3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4R,5S)-3-amino-5-methyl-4-(methylthio)cyclohexyl)pyridin-3-y- l)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-((R)-methylsulfinyl)cyclohexyl)pyr- idin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin- -3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, (1R,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)p- yridin-4-yl)-6-methylcyclohexyl dimethylphosphinate, (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)p- yridin-4-yl)-6-methylcyclohexyl dimethylphosphinate, (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)p- yridin-4-yl)-6-methylcyclohexyl methanesulfonate, (1R,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)p- yridin-4-yl)-6-methylcyclohexyl methanesulfonate, N-(4-((6R,8R,10S)-6-amino-10-methyl-1,4-dioxaspiro[4.5]decan-8-yl)pyridin- -3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((6S,8S,10R)-6-amino-10-methyl-1,4-dioxaspiro[4.5]decan-8-yl)pyridin- -3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, 3-((1R,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamid- o)pyridin-4-yl)-6-methylcyclohexyloxy)propanoic acid, 3-((1S,2S,4S,6R)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamid- o)pyridin-4-yl)-6-methylcyclohexyloxy)propanoic acid, N-(4-((1S,3S,4R,5R)-3-amino-5-methyl-4-(1H-1,2,4-triazol-1-yl)cyclohexyl)- pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,4-triazol-1-yl)cyclohexyl)- pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-2-- (2,6-difluorophenyl)thiazole-4-carboxamide, N-(4-((1R,3R,4S,5S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-2-- (2,6-difluorophenyl)pyrimidine-4-carboxamide, 5-amino-N-(4-((3S,4S,5R)-3-amino-4-cyano-5-methylpiperidin-1-yl)pyridin-3- -yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide, N-(4-((1R,3R,4R,5S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-- (2,6-difluoro-4-methylphenyl)-5-fluoropicolinamide, 5-amino-N-(4-((1S,3S,4R,5R)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)- pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide, 5-amino-N-(4-((1R,3R,4S,5 S)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)pyridin-3-yl)-2-(2,6-difl- uorophenyl)thiazole-4-carboxamide, N-(4-((1S,3S,4R,5R)-3-amino-4-cyano-5-methylcyclohexyl)pyridin-3-yl)-6-(2- ,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-4-cyano-5-methylcyclohexyl)pyridin-3-yl)-6-(2- ,6-difluorophenyl)-5-fluoropicolinamide, 5-amino-N-(4-((1R,3R,4R,5S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-- 3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide, 5-amino-N-(4-((1R,3R,4R,5S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-- 3-yl)-2-(2,6-difluorophenyl)pyrimidine-4-carboxamide, 5-amino-N-(4-((1R,3R,4S,5 S)-3-amino-4-ethoxy-5-methylcyclohexyl)pyridin-3-yl)-2-(2,6-difluoropheny- l)thiazole-4-carboxamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyclohex- yl)pyridin-3-yl)-6-(2,6-difluoro-4-methylphenyl)-5-fluoropicolinamide, N-(4-((1S,3S,4R,5R)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyclohex- yl)pyridin-3-yl)-6-(2,6-difluoro-4-meth ylphenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4R,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophen- yl)-5-fluoropicolinamide, N-(4-((1S,3S,4S,5R)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-- (2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyclohex- yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, v, 5-amino-N-(4-((1R,3R,4S,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-2-(2,6-difluorophen- yl)pyrimidine-4-carboxamide, 5-amino-N-(4-((1R,3R,4S,5S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-- 3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difl- uoro-4-methylphenyl)-5-fluoropicolinamide, N-(4-((1S,3S,4R,5R)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)pyridin-- 3-yl)-6-(2,6-difluoro-4-methylphenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)pyridin-- 3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1S,3 S,4R,5R)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,- 6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-ethoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoropheny- l)-5-fluoropicolinamide, N-(4-((1S,3S,4R,5R)-3-amino-4-ethoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(- 2,6-difluoro-4-methylphenyl)-5-fluoropicolinamide, N-(4-((1S,3 S,4R,5R)-3-amino-4-ethoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluor- ophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-4-ethoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(- 2,6-difluoro-4-methylphenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-- (2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-- (2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(4-(1,1-dioxidote- trahydro-2H-thiopyran-4-yl)-2,6-difluorophenyl)-5-fluoropicolinamide, v, N-(4-((1R,3R,4S,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-(- 4-fluorotetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-(- 2-hydroxypropan-2-yl)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-(- 1-hydroxycyclobutyl)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-(- tetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(4-(ethoxymethyl)- -2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-i- sopropoxyphenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-m- eth ylphenyl)-5-fluoropicolinamide, N-(4-((1S,3S,4R,5R)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-- (2,6-difluoro-4-meth ylphenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin-3-yl)-2-(2,6-dif- luorophenyl)pyrimidine-4-carboxamide, N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin-3-yl)-6-(2,6-dif- luoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin- -3-yl)-6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropicolinamide- , 3-amino-N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin-3-yl)-6-(2-fluor- o-5-(isopropylcarbamoyl)phenyl)picolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin-3-yl)-6-(2,6-dif- luoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinamide, 3-amino-N-(4-((1R,3R,4S,5S)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)- pyridin-3-yl)-6-(2-fluoro-5-(isopropylcarbamoyl)phenyl)picolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin-3-yl)-6-(2,6-dif- luoro-4-methoxyphenyl)-5-fluoropicolinamide, N-(4-((1S,3 S,4R,5R)-3-amino-5-methyl-4-(pyridin-2-yloxy)cyclohexyl)pyridin-3-yl)-6-(- 2,6-difluorophenyl)-5-fluoropicolinamide, 3-amino-N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl- )pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, 5-amino-N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl- )pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin- -3-yl)-6-(4-(ethoxymethyl)-2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4R,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-(- 4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyclohex- yl)pyridin-3-yl)-6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phen- yl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin- -3-yl)-6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin-3-yl)-2-(2,6-dif- luorophenyl)thiazole-4-carboxamide, N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin-3-yl)-6-(2,6-dif- luoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(methylsulfonyl)cyclohexyl)pyridin- -3-yl)-6-(2,6-difluoro-4-methylphenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(pyridin-2-yloxy)cyclohexyl)pyridi- n-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4R,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-(- 2-methoxyethoxy)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyclohex- yl)pyridin-3-yl)-6-(4-(ethoxymethyl)-2,6-difluorophenyl)-5-fluoropicolinam- ide, 3-amino-N-(4-((1R,3R,4R,5S)-3-amino-4-methoxy-5-methylcyclohexyl)pyri- din-3-yl)-6-(2-fluoro-5-(isopropylcarbamoyl)phenyl)picolinamide, N-(4-((1R,3R,4R,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-(- 4-fluorotetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinamide, 3-amino-N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)- cyclohexyl)pyridin-3-yl)-6-(2-fluoro-5-(isopropylcarbamoyl)phenyl)picolina- mide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyc- lohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)- phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyclohex- yl)pyridin-3-yl)-6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicoli- namide, N-(4-((3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperid- in-1-yl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide, N-(4-((3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl- )pyridin-3-yl)-6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolina- mide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyc- lohexyl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide, N-(4-((1R,3R,4R,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-2-(2,6-difluorophen- yl)thiazole-4-carboxamide, 5-amino-N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)- cyclohexyl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide, N-(4-((1R,3R,4R,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(4-(ethoxymethyl)- -2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4R,5S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-- (2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-fluoropicolinamid- e, N-(4-((1R,3R,4R,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-(- 1-hydroxycyclobutyl)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyclohexyl)pyridin-3-yl)-- 6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyclohex- yl)pyridin-3-yl)-6-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-- 5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyclohex- yl)pyridin-3-yl)-6-(2,6-difluoro-4-isopropoxyphenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4R,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-i- sopropoxyphenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4R,5 S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoro-4-m- ethoxyphenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(2-(methylsulfonyl)ethoxy)cyclohexyl)pyridin-3-yl)-- 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinamide, 3-amino-N-(4-((1R,3R,4R,5S)-3-amino-4-methoxy-5-methylcyclohexyl)pyridin-- 3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, 3-amino-N-(4-((1R,3R,4S,5S)-3-amino-5-methy-(2-(methylsulfonyl)ethoxy)cyc- lohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, methyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluoro-4-isopropoxyphenyl)-5-fluorop- icolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamate, N-(4-((1S,3S,4R,5R)-3-amino-5-methyl-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)- pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)- pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)pyridin-- 3-yl)-6-(2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl)-5-fluoro- picolinamide, 5-amino-N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyc- lohexyl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide, N-(4-((1S,3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)- pyridin-3-yl)-6-(4-(ethoxymethyl)-2,6-difluorophenyl)-5-fluoropicolinamide- , N-(4-((1R,3R,4S,5S)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)pyridin- -3-yl)-6-(2,6-difluoro-4-(oxetan-3-yl)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)pyridin-- 3-yl)-6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinamide, 3-amino-N-(4-((1R,3R,4S,5S)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)- pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)- pyridin-3-yl)-6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolinam- ide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyclohe- xyl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide, N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)pyridin-3-yl)-6-(- 2,6-difluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)pyridin-3-yl)-6-(- 2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropicolinamide, 3-amino-N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)pyridin-3-yl)-6-(- 2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)- pyridin-3-yl)-6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)- -5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)- pyridin-3-yl)-6-(2,6-difluoro-4-methylphenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)pyridin-- 3-yl)-6-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-fluoropic- olinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-(2-cyanoethoxy)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difl- uoro-4-(1-hydroxycyclobutyl)phenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-(4-cyano-1H-1,2,3-triazol-1-yl)-5-methylcyclohexyl)pyridin-3- -yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-S-methylcyclohexyl)pyr- idin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5 S)-3-amino-5-methyl-4-(4-(prop-1-en-2-yl)-1H-1,2,3-triazol-1-yl)cyclohexy- l)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-- 1-yl)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropico- linamide, 2-((1R,2S,4S,6R)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropi- colinamido)pyridin-4-yl)-6-methylcyclohexyloxy)acetic acid, 2-((1 S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyr- idin-4-yl)-6-methylcyclohexyloxy)acetic acid, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)- pyridin-3-yl)-6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinamide N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)- pyridin-3-yl)-6-(2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-4-yl)phenyl)-- 5-fluoropicolinamide, 3-amino-N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-(1H-1,2,3-triazol-1-yl)cyc- lohexyl)pyridin-3-yl)-6-(2-fluoro-5-(isopropylcarbamoyl)phenyl)picolinamid- e, N-(4-((1R,3R,4S,5 S)-3-amino-4-(2-methoxyacetamido)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6- -difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-3-amino-4-isobutyramido-5-methylcyclohexyl)pyridin-3-- yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, ethyl (1 S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyr- idin-4-yl)-6-methylcyclohexylcarbamate, isopropyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)p- yridin-4-yl)-6-methylcyclohexylcarbamate, N-(4-((1R,3R,4S,5S)-3-amino-5-methyl-4-propionamidocyclohexyl)pyridin-3-y- l)-6-(2,6-difluorophenyl)-5-fluoropicolinamide, methyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)p- yridin-4-yl)-6-methylcyclohexylcarbamate, methyl (1R,2S,4S,6R)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)p- yridin-4-yl)-6-methylcyclohexylcarbamate, N-(4-((1S,3S,4R,5R)-4-acetamido-3-amino-5-methylcyclohexyl)pyridin-3-yl)-- 6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4S,5S)-4-acetamido-3-amino-5-methylcyclohexyl)pyridin-3-yl)-- 6-(2,6-difluorophenyl)-5-fluoropicolinamide, N-(4-((1R,3R,4R,5 S)-4-acetamido-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluoroph- enyl)-5-fluoropicolinamide, methyl (1R,2S,4S,6R)-2-amino-4-(3-(5-amino-2-(2,6-difluorophenyl)thiazole-4-carb- oxamido)pyridin-4-yl)-6-methylcyclohexyl(methyl)carbamate, methyl (1S,2R,4R,6S)-2-amino-4-(3-(5-amino-2-(2,6-difluorophenyl)thiazole-4-carb- oxamido)pyridin-4-yl)-6-methylcyclohexyl(methyl)carbamate, methyl (1R,2S,4S,6R)-2-amino-4-(3-(6-(2,6-difluoro-4-methylphenyl)-5-fluoropicol- inamido)pyridin-4-yl)-6-methylcyclohexyl(methyl)carbamate, methyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluoro-4-methylphenyl)-5-fluoropicol- inamido)pyridin-4-yl)-6-methylcyclohexyl(methyl)carbamate, methyl (3R,4S,5S)-3-amino-1-(3-(6-(2,6-difluoro-4-methylphenyl)-5-fluoropicolina- mido)pyridin-4-yl)-5-methylpiperidin-4-yl(methyl)carbamate, methyl (1R,2S,4S,6R)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)p- yridin-4-yl)-6-methylcyclohexyl(methyl)carbamate, methyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)p- yridin-4-yl)-6-methylcyclohexyl(methyl)carbamate, methyl (3R,4S,5 S)-3-amino-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl- )-5-methylpiperidin-4-yl(methyl)carbamate, methyl ((1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluoro-4-(2-methoxyethoxyl)phenyl)-- 5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl)carbamate, methyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluoro-4-isopropoxyphenyl)-5-fluorop- icolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamate, methyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluoro-4-(1-hydroxycyclobutyl)phenyl- )-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamate, methyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-ylox- y)phenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamate, methyl (1S,2R,4R,6S)-2-amino-4-(3-(3-amino-6-(2,6-difluorophenyl)-5-fluor- opicolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamate, methyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyr- an-4-yl)phenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexylcarba- mate, methyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluoro-4-methylphenyl)-5-fluoropicol- inamido)pyridin-4-yl)-6-methylcyclohexylcarbamate, methyl (1 S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluoro-4-(oxetan-3-yl)phenyl)-5-fluoro- picolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamate, methyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropico- linamido)pyridin-4-yl)-6-methylcyclohexylcarbamate, methyl (1S,2R,4R,6S)-2-amino-4-(3-(3-amino-6-(2-fluoro-5-(isopropylcarbamoyl)phe- nyl)picolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamate, methyl (1 S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluoro-4-(4-fluorotetrahydro-2H-pyran-- 4-yl)phenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamat- e, methyl (1S,2R,4R,6S)-2-amino-4-(3-(6-(4-(ethoxymethyl)-2,6-difluorophen- yl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexylcarbamate, and the pharmaceutically acceptable salts thereof. 8. A pharmaceutical composition comprising a compound of claim 1, admixed with at least one pharmaceutically acceptable excipient. 9. The pharmaceutical composition of claim 8 which further comprises an additional therapeutic agent selected from MEK inhibitors, irinotecan, topotecan, gemcitabine, 5-fluorouracil, cytarabine, daunorubicin, PI3 Kinase inhibitors, mTOR inhibitors, DNA synthesis inhibitors, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, lenalidomide, bortezomib and trastuzumab.

Details for Patent 8,987,457

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2039-02-26
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2039-02-26
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2039-02-26