Claims for Patent: 8,476,268

Summary for Patent: 8,476,268

Title:	Pyrrolidine-1,2-dicarboxamide derivatives
Abstract:	The present invention relates to a compound of formula (I) ##STR00001## or a salt thereof, wherein the substituents are as defined in the description, to compositions and use of the compounds in the treatment of diseases ameloriated by inhibition of phosphatidylinositol 3-kinase.
Inventor(s):	Fairhurst; Robin Alec (Riehen, CH), Guagnano; Vito (Basel, CH), Imbach-Weese; Patricia (Kaiseraugst, CH), Caravatti; Giorgio (Bottmingen, CH), Furet; Pascal (Thann, FR)
Assignee:	Novartis AG (Basel, CH)
Application Number:	13/488,589
Patent Claims:	1. A compound of formula (IA) ##STR00202## or a salt thereof, wherein R.sup.1 represents one of the following substituents: (1) substituted, C.sub.1-C.sub.7-alkyl, wherein said substituents are independently selected from one to nine of the following moieties: deuterium and fluoro, or one to two of the following moieties: C.sub.3-C.sub.5-cycloalkyl; (2) optionally substituted C.sub.3-C.sub.5-cycloalkyl wherein said substituents are independently selected from one to four of the following moieties: deuterium, methyl, fluoro, cyano and aminocarbonyl; (3) optionally substituted phenyl wherein said substituents are independently selected from one to two of the following moieties: deuterium, halo, cyano, C.sub.1-C.sub.7-alkyl, C.sub.1-C.sub.7-alkylamino, di(C.sub.1-C.sub.7-alkyl)amino, C.sub.1-C.sub.7-alkylaminocarbonyl, di(C.sub.1-C.sub.7-alkyl)aminocarbonyl and C.sub.1-C.sub.7-alkoxy; (4) optionally mono- or di-substituted amine; wherein said substituents are independently selected from the following moieties: deuterium; C.sub.1-C.sub.7-alkyl which is unsubstituted or substituted by one or more substituents selected from deuterium, fluoro, chloro and hydroxy; phenylsulfonyl which is unsubstituted or substituted by one or more groups selected from C.sub.1-C.sub.7-alkyl, C.sub.1-C.sub.7-alkoxy and di(C.sub.1-C.sub.7-alkyl)amino-C.sub.1-C.sub.7-alkoxy); (5) substituted sulfonyl; wherein said substituent is selected from the following moieties: C.sub.1-C.sub.7-alkyl which is unsubstituted or substituted by one or more substituents selected from deuterium and fluoro; and pyrrolidino which is unsubstituted or substituted by one or more substituents selected from deuterium, hydroxy and oxo; (6) fluoro and chloro; and R.sup.3 is selected from: hydrogen; fluoro; chloro; and optionally substituted methyl; wherein said substituents are independently selected from one to three of the following moieties: deuterium, fluoro, chloro and dimethylamino. 2. The compound of claim 1, wherein R.sup.1 represents: (1) cyclopropylmethyl or substituted, branched C.sub.3-C.sub.7-alkyl, wherein said substituents are independently selected from one to nine of the following moieties: deuterium and fluoro; (2) optionally substituted cyclopropyl or cyclobutyl wherein said substituents are independently selected from one to four of the following moieties: methyl, deuterium, fluoro, cyano and aminocarbonyl; (3) optionally substituted phenyl wherein said substituents are independently selected from one to two of the following moieties: deuterium, halo, cyano, C.sub.1-C.sub.7-alkyl, C.sub.1-C.sub.7-alkylamino, di(C.sub.1-C.sub.7-alkyl)amino, C.sub.1-C.sub.7-alkylaminocarbonyl, di(C.sub.1-C.sub.7-alkyl)aminocarbonyl and C.sub.1-C.sub.7-alkoxy; (4) optionally mono- or di-substituted amine; wherein said substituents are independently selected from the following moieties: deuterium; C.sub.1-C.sub.7-alkyl which is unsubstituted or substituted by one or more substituents selected from the group of deuterium, fluoro, chloro and hydroxy; phenylsulfonyl which is unsubstituted or substituted by a group selected from C.sub.1-C.sub.7-alkyl, C.sub.1-C.sub.7-alkoxy and di(C.sub.1-C.sub.7-alkyl)amino-C.sub.1-C.sub.7-alkoxy); (5) substituted sulfonyl wherein said substituent is selected from the following moieties: C.sub.1-C.sub.7-alkyl which is unsubstituted or substituted by deuterium or fluoro; pyrrolidino which is unsubstituted or substituted by a group selected from deuterium, hydroxy and oxo; or (6) fluoro, chloro; and R.sup.3 is selected from hydrogen, methyl, CD.sub.3, CH.sub.2Cl and CH.sub.2F, CH.sub.2N(CH.sub.3).sub.3. 3. A compound, in free form or in pharmaceutically acceptable salt form, selected from, (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-{[5-(2-cyclopropyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide}; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(2-fluoro-phenyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-{[5-(2-cyclobutyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide}; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(1-methyl-cyclopropyl)-pyridin-4-yl]-thiazol-2-yl}-amid- e); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(1-methyl-cyclobutyl)-pyridin-4-yl]-thiazol-2-yl}-amide- ); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-{[5-(2-cyclobutyl-pyridin-4-yl)-thiazol-2-yl]-amide}; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(1-methyl-cyclopropyl)-pyridin-4-yl]-thiazol-2-yl}-amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(1-trifluoromethyl-cyclopropyl)-pyridin-4-yl]-thiazol-2-yl}-amid- e); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}- -amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(1-trifluoromethyl-cyclobutyl)-pyridin-4-yl]-thiazol-2-yl}-amide- ); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(1-trifluoromethyl-cyclopropyl)-pyridin-4-yl]-thiazol-2- -yl}-amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(1-trifluoromethyl-cyclobutyl)-pyridin-4-yl]-thiazol-2-- yl}-amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(1-methyl-cyclobutyl)-pyridin-4-yl]-thiazol-2-yl}-amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(1-cyano-cyclopropyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-amide- ); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(1-cyano-cyclobutyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-amide)- ; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(1-carbamoyl-cyclobutyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-am- ide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(2-dimethylamino-1,1-dimethyl-ethyl)-pyridin-4-yl]-4-methyl-thia- zol-2-yl}-amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-{[5-(2-diethylamino-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide}; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-{[5-(2-diethylamino-pyridin-4-yl)-thiazol-2-yl]-amide}; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-[(5-{2-[1-(4-methoxy-phenyl)-1-methyl-ethyl]-pyridin-4-yl}-4-methyl-thi- azol-2-yl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-[(5-{2-[1-(4-methoxy-phenyl)-1-methyl-ethyl]-pyridin-4-yl}-thiazol-2-yl- )-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-[(5-{2-[1-(4-methoxy-phenyl)-cyclopropyl]-pyridin-4-yl}-4-methyl-thiazo- l-2-yl)-amide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-[(5-{2-[1-(4-methoxy-phenyl)-cyclopropyl]-pyridin-4-yl}-thiazol-2-yl)-a- mide]; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-{[5-(2-{1-[4-(3-dimethylamino-propoxy)-phenyl]-1-methyl-ethyl]-pyridin-- 4-yl)-4-methyl-thiazol-2-yl}-amide} (Example 31); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(1-d.sub.3-methyl-cyclobutyl)-pyridin-4-yl]-thiazol-2-y- l}-amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(1-d.sub.3-methyl-cyclobutyl)-pyridin-4-yl]-thiazol-2-yl}-amide)- ; (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-d.sub.3-methyl-5-[2-(1-methyl-cyclopropyl)-pyridin-4-yl]-thiazol-2-- yl}-amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-d.sub.3-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-- yl]-thiazol-2-yl}-amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-dimethylaminomethyl-5-[2-(1-d.sub.3-methyl-cyclobutyl)-pyridin-4-yl- ]-thiazol-2-yl}-amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-chloro-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thia- zol-2-yl}-amide); and (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-fluoromethyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl- ]-thiazol-2-yl}-amide); (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(2-fluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-4-methyl-thiazol-2-y- l}-amide); and (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({5-[2-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-pyridin-4-yl]-4-methyl-- thiazol-2-yl}-amide. 4. A method of treatment of a proliferative disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 3 in free form or in pharmaceutically acceptable salt form, wherein the proliferative disease is selected from the group consisting of melanoma, colorectal adenoma and cancers of the breast, and pancreas. 5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in free form or in pharmaceutically acceptable salt form and one or more pharmaceutically acceptable carrier.