The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are ERK2 inhibitors. The invention also provides a method of inhibiting ERK2 in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of Formula (I). The invention also provides a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one compound of Formula (I).
1. A compound of formula I
or a pharmaceutically acceptable salt thereof, wherein
R 1 is
1) —C 1-4 alkyl, unsubstituted or substituted with R 1′ , wherein R 1′ is independently selected from halogen and OC 1-4 alkyl,
2) 6-membered unsaturated heterocycle having 1 N atom, wherein the heterocycle is unsubstituted or substituted on any ring atom with C 1-4 alkyl,
3) 6-membered unsaturated carbocycle unsubstituted or substituted on any ring atom with C 1-4 alkyl, or,
4) —C(O)C 1-4 alkyl;
R 2 is
hydrogen or halogen;
—X—Z is
1) —C 1-4 alkylene-Z, wherein the alkylene is unsubstituted or substituted with OH, ═CH 2 , —C 1-4 alkyl, —C 1-4 alkylene OH, or —OC 1-4 alkyl,
2)
3) —C 1-4 alkenylene-Z,
4) —NR 3 C 1-4 alkylene-Z,
5) —OC 1-4 alkylene-Z,
6) —CH 2 NR 3 C 1-4 alkylene-Z,
7) —CH 2 C(O)C 1-4 alkylene-Z, or
8) —CH 2 OC 1-4 alkylene-Z;
Z—Y is
O—Y, C 1-4 alkylene-Y, NR 3 —Y or
NH—Y is
NH—CH(C 6 H 3 R 4 R 5 )C 1-4 alkylene-, where C 1-4 alkylene is unsubstituted or independently mono- or di-substituted with R 6 ;
R 3 is independently
hydrogen or C 1-4 alkyl;
R 4 is
hydrogen or halogen;
R 5 is
hydrogen or —OC 1-4 alkyl; and
R 6 is
OH or C 1-4 alkyl wherein alkyl is unsubstituted or substituted with OH.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is
1) —C 1-4 alkyl, unsubstituted or substituted with R 1′ , wherein R 1′ is independently selected from F and OC 1-4 alkyl, or
2) 6-membered unsaturated heterocycle having 1 N atom, wherein the heterocycle is unsubstituted or substituted on any ring atom with C 1-4 alkyl,
R 2 is
hydrogen;
—X—Z is
1) —C 1-4 alkylene-Z, wherein the alkylene is unsubstituted or substituted with OH, ═CH 2 , —CH 3 , —CH 2 OH, or —OC 1-4 alkyl,
2)
3) —C 1-4 alkenylene-Z,
4) —NR 3 C 1-4 alkylene-Z,
5) —OC 1-4 alkylene-Z,
6) —CH 2 NR 3 C 1-4 alkylene-Z,
7) —CH 2 C(O)C 1-4 alkylene-Z, or
8) —CH 2 OC 1-4 alkylene-Z;
Z—Y is
O—Y, C 1-4 alkylene-Y, NR 3 —Y or
NH—Y is
NH—CH(C 6 H 3 R 4 R 5 )C 1-4 alkylene-, where C 1-4 alkylene is unsubstituted or independently mono- or di-substituted with R 6 ;
R 3 is independently
hydrogen or C 1-4 alkyl;
R 4 is
hydrogen or F;
R 5 is
hydrogen or —OC 1-4 alkyl; and
R 6 is
OH or C 1-4 alkyl wherein alkyl is unsubstituted or substituted with OH.
3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is
—CH 2 CH 3 , —CHF 2 , —CH 3 , —(CH 2 ) 3 OCH 3 , —(CH 2 ) 2 OCH 3 , or
R 2 is
hydrogen;
Z is
O, CH 2 , N(CH 3 ),
and
NH—Y— is
NH—CH(C 6 H 5 )CH 2 —, NH—CH(C 6 H 5 )CH(OH), NH—CH(C 6 H 5 )C(OH)(CH 3 )—,
NH—CH(C 6 H 5 )C(CH 3 ) 2 —, NH—CH(C 6 H 5 )CH(CH(OH)(CH 3 )), or
NH—CH(C 6 H 3 (F)(OCH 3 ))CH 2 —.
4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of
(9S,13S)-1-ethyl-13-hydroxy-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,13R)-1-ethyl-13-hydroxy-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9R,10R)-1-ethyl-10-(hydroxymethyl)-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,10S)-1-ethyl-10-(hydroxymethyl)-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S)-1-ethyl-10,10-dimethyl-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9R)-1-ethyl-10,10-dimethyl-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S)-1-ethyl-13-hydroxy-13-methyl-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,12aS,13aR)-1-ethyl-9-phenyl-1,6,9,10,12,12a,13,13a-octahydro-5,14-(azeno)cyclopropa[1]pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,12aR,13aS)-1-ethyl-9-phenyl-1,6,9,10,12,12a,13,13a-octahydro-5,14-(azeno)cyclopropa[1]pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S)-1-(difluoromethyl)-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,13Z)-1-(difluoromethyl)-9-phenyl-1,6,9,10-tetrahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S)-1-methyl-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6,12]oxatriazacyclotetradecin-7(8H)-one,
(9S)-1-ethyl-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
1,14-dimethyl-9-phenyl-1,6,9,10,11,12,13,14-octahydro-5,15-(azeno)pyrazolo[4,3-f][1,3,9]triazacyclotetradecin-7(8H)-one,
(9S,10S)-10-hydroxy-1-methyl-9-phenyl-1,6,8,9,10,11,12,13-octahydro-7H-5,15-(azeno)pyrazolo[3,4-c][1,7,9]oxadiazacyclotetradecin-7-one,
(9S,10R)-10-hydroxy-1-methyl-9-phenyl-1,6,8,9,10,11,12,13-octahydro-7H-5,15-(azeno)pyrazolo[3,4-c][1,7,9]oxadiazacyclotetradecin-7-one,
1-ethyl-9-phenyl-1,6,9,10,11,12,13,14-octahydro-5,15-(azeno)pyrazolo[4,3-f][1,3,9]triazacyclotetradecin-7(8H)-one,
(9S,10S)-1-ethyl-10-hydroxy-9-phenyl-1,6,8,9,10,11,12,13-octahydro-7H-5,15-(azeno)pyrazolo[3,4-c][1,7,9]oxadiazacyclotetradecin-7-one,
(9S,10R)-1-ethyl-10-hydroxy-9-phenyl-1,6,8,9,10,11,12,13-octahydro-7H-5,15-(azeno)pyrazolo[3,4-c][1,7,9]oxadiazacyclotetradecin-7-one,
(9S)-1,11-dimethyl-9-phenyl-1,6,9,10,11,12,13,14-octahydro-5,15-(azeno)pyrazolo[3,4-k][1,3,6]triazacyclotetradecin-7(8H)-one,
(9S,10R)-1-ethyl-10-hydroxy-10-methyl-9-phenyl-1,6,8,9,10,11,12,13-octahydro-7H-5,15-(azeno)pyrazolo[3,4-c][1,7,9]oxadiazacyclotetradecin-7-one,
13-hydroxy-1-methyl-9-phenyl-1,6,9,10,11,12,13,14-octahydro-5,15-(azeno)pyrazolo[4,3-f][1,3]diazacyclotetradecin-7(8H)-one,
(9S)-1-ethyl-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6,12]oxatriazacyclotetradecin-7(8H)-one,
(9S,10S)-1-ethyl-10-hydroxy-10-methyl-9-phenyl-1,6,8,9,10,11,12,13-octahydro-7H-5,15-(azeno)pyrazolo[3,4-c][1,7,9]oxadiazacyclotetradecin-7-one,
1-methyl-9-phenyl-1,6,9,10,11,12-hexahydro-5,15-(azeno)pyrazolo[4,3-k][1,6,8]oxadiazacyclotetradecin-7(8H,14H)-one,
1-ethyl-9-phenyl-1,6,8,9,10,11,12,13-octahydro-7H-5,15-(azeno)pyrazolo[3,4-c][1,7,9]oxadiazacyclotetradecin-7-one,
1,13-dimethyl-9-phenyl-1,6,9,10,11,12,13,14-octahydro-5,15-(azeno)pyrazolo[3,4-k][1,3,8]triazacyclotetradecin-7(8H)-one,
(9S)-1-methyl-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9R)-1-methyl-9-phenyl-1,6,9,10,11,12,13,14-octahydro-5,15-(azeno)pyrazolo[4,3-f][1,3,9]triazacyclotetradecin-7(8H)-one,
(9S)-1-methyl-9-phenyl-1,6,9,10,12,13-hexahydro-5,15-(azeno)pyrazolo[4,3-i][1,12,4,6]dioxadiazacyclotetradecin-7(8H)-one,
1-(3-methoxypropyl)-9-phenyl-1,6,9,10-tetrahydro-5,16-(azeno)-14,11-(metheno)pyrazolo[4,3-l][1,2,3,7,9]pentaazacyclopentadecin-7(8H,15H)-one,
(9R)-1-methyl-9-phenyl-1,6,8,9,10,11,12,13-octahydro-7H-5,15-(azeno)pyrazolo[3,4-c][1,7,9]oxadiazacyclotetradecin-7-one,
1-methyl-9-phenyl-1,6,9,10,11,12,13,14-octahydro-5,15-(azeno)pyrazolo[4,3-f][1,3]diazacyclotetradecin-7(8H)-one,
1-(2-methoxyethyl)-9-phenyl-1,6,9,10-tetrahydro-5,16-(azeno)-14,11-(metheno)pyrazolo[4,3-l][1,2,3,7,9]pentaazacyclopentadecin-7(8H,15H)-one,
1-(2-methylpyri din-4-yl)-9-phenyl-1,6,9,10-tetrahydro-5,16-(azeno)-14,11-(metheno)pyrazolo[4,3-l][1,2,3,7,9]pentaazacyclopentadecin-7(8H,15H)-one,
1-(2-methylpyri din-4-yl)-9-phenyl-1,6,9,10-tetrahydro-5,16-(azeno)-14,11-(metheno)pyrazolo[4,3-l][1,2,3,7,9]pentaazacyclopentadecin-7(8H,15H)-one,
1,18-dimethyl-9-phenyl-1,6,9,10-tetrahydro-5,16-(azeno)-14,11-(metheno)pyrazolo[4,3-l][1,2,3,7,9]pentaazacyclopentadecin-7(8H,15H)-one,
1-methyl-9-phenyl-1,6,9,10,11,12,13,14-octahydro-5,15-(azeno)pyrazolo[3,4-k][1,3, 8]triazacyclotetradecin-7(8H)-one,
(9R)-1-methyl-9-phenyl-1,6,9,10-tetrahydro-5,16-(azeno)-14,11-(metheno)pyrazolo[4,3-l][1,2,3,7,9]pentaazacyclopentadecin-7(8H,15H)-one,
1-methyl-9-phenyl-1,6,9,10-tetrahydro-5,16-(azeno)-14,11-(metheno)pyrazolo[4,3-l][1,2,3,7,9]pentaazacyclopentadecin-7(8H,15H)-one,
(9S, 13Z)-1-Ethyl-10,10-dimethyl-9-phenyl-1,6,9,10-tetrahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9R, 13Z)-1-Ethyl-10,10-dimethyl-9-phenyl-1,6,9,10-tetrahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S)-1-ethyl-9-phenyl-1,6,9,10-tetrahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecine-7,13(8H,14H)-dione,
(9R,13R)-1-Ethyl-13-methoxy-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,10S)-1-ethyl-10-[(1R)-1-hydroxyethyl]-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacycl otetradecin-7(8H)-one,
(9S,10S)-1-ethyl-10-[(1S)-1-hydroxyethyl]-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9R,10R)-1-ethyl-10-[(1R)-1-hydroxyethyl]-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9R,10R)-1-ethyl-10-[(1S)-1-hydroxyethyl]-9-phenyl-1, 6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,13R)-9-(3-chlorophenyl)-1-ethyl-13-hydroxy-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,13S)-9-(3-chlorophenyl)-1-ethyl-13-hydroxy-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,13S)-1-ethyl-9-(3-fluorophenyl)-13-hydroxy-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,13R)-1-ethyl-9-(3-fluorophenyl)-13-hydroxy-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,13S)-1-ethyl-9-(3-fluoro-4-methoxyphenyl)-13-hydroxy-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S,13R)-1-ethyl-9-(3-fluoro-4-methoxyphenyl)-13-hydroxy-1,6,9, 10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S)-1-ethyl-13-(hydroxymethyl)-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S)-1-ethyl-13-methylidene-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one,
(9S)-1-ethyl-13-(hydroxymethyl)-9-phenyl-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one, and
(9S,13R)-1-ethyl-9-(3-fluorophenyl)-13-hydroxy-1,6,9,10,13,14-hexahydro-12H-5,15-(azeno)pyrazolo[4,3-i][1,4,6]oxadiazacyclotetradecin-7(8H)-one.
5. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
6. A method for treating non-small cell lung cancer, pancreatic cancer, colorectal cancer, kidney cancer, hepatocellular carcinoma, and melanoma comprising administering to a patient in need there of a composition of claim 5 .