5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a sulfoximine group

Patent metadata

Field	Value
Publication number	US-9650340-B2
Application number	US-201314443279-A
Country	US
Kind code	B2
Filing date	Nov 12, 2013
Priority date	Nov 15, 2012
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

The present invention relates to 5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing a sulfoximine group of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I).

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is a C 1 -C 6 -alkyl- or C 3 -C 5 -cycloalkyl group,
wherein said group is optionally substituted with one substituent selected from the group consisting of hydroxy, C 1 -C 3 -alkoxy-, —NH 2 , alkylamino-, dialkylamino-, cyclic amines, and —OP(O)(OH) 2 ;

R 2 is a group selected from

R 3 is a hydrogen atom, fluoro atom, chloro atom, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or fluoro-C 1 -C 3 -alkyl group;
R 4 is a hydrogen atom, fluoro atom or bromo atom;
R 5 is a group selected from a hydrogen atom, cyano, —C(O)R 9 , —C(O)OR 9 , —C(O)NR 10 R 11 , —P(O)(OR 12 ) 2 , —CH 2 OP(OR 12 ) 2 and C 1 -C 3 -alkyl-,
wherein said C 1 -C 3 -alkyl group is optionally substituted with one substituent selected from —NH 2 , alkylamino-, dialkylamino-, and cyclic amines;

R 6 and R 7 are, independently from each other, a group selected from a hydrogen atom, fluoro atom and chloro atom;
R 8 is a group selected from
a) a C 1 -C 3 -alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen and halo-C 1 -C 3 -alkyl-; and
b) a phenyl-C 1 -C 3 -alkyl- group, the phenyl group of which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, cyano, C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, C 1 -C 3 -fluoroalkoxy-, and C 1 -C 3 -alkoxy-;

R 9 is a group selected from C 1 -C 3 -alkyl-, halo-C 1 -C 3 -alkyl-, and a benzyl group, the phenyl group of which is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of halogen, C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, —NH 2 , alkylamino-, and dialkylamino-;
R 10 and R 11 are, independently from each other, a group selected from a hydrogen atom, C 1 -C 3 -alkyl-, and benzyl,
or
R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a cyclic amine; and
R 12 is a group selected from a hydrogen atom and C 1 -C 2 -alkyl,
or an enantiomer, diastereomer, or salt thereof.

2. The compound of formula (I) according to claim 1 , wherein
R 1 is a C 1 -C 6 -alkyl group,
wherein said group is optionally substituted with one substituent selected from the group consisting of hydroxy, C 1 -C 3 -alkoxy, —NH 2 , alkylamino-, dialkylamino-, and cyclic amines;

R 2 is a group selected from

R 3 is a hydrogen atom, fluoro atom, chloro atom, methyl, methoxy, difluoromethyl or trifluoromethyl group;
R 4 is a hydrogen atom or bromo atom;
R 5 is a group selected from a hydrogen atom, cyano, —C(O)R 9 , —C(O)OR 9 , and —C(O)NR 10 R 11 ;
R 6 and R 7 are, independently from each other, a group selected from a hydrogen atom, fluoro atom and chloro atom;
R 8 is a C 1 -C 3 -alkyl group;
R 9 is a C 1 -C 3 -alkyl group, a benzyl group, or trifluoromethyl; and
R 10 and R 11 are, independently from each other, a group selected from a hydrogen atom and C 1 -C 2 -alkyl-,
or an enantiomer, diastereomer, or salt thereof.

3. The compound of formula (I) according to claim 1 , wherein
R 1 is a C 1 -C 3 -alkyl group,
wherein said group is optionally substituted with one substituent selected from the group consisting of hydroxyl and —NH 2 ;

R 2 is a group

R 3 is a hydrogen atom, fluoro atom, chloro atom, methyl, methoxy, difluoromethyl or trifluoromethyl group;
R 4 is a hydrogen atom or bromo atom;
R 5 is a group selected from a hydrogen atom, cyano, —C(O)R 9 , —C(O)OR 9 , and —C(O)NR 10 R 11 ;
R 6 is a fluoro atom;
R 7 is a hydrogen atom;
R 8 is a methyl or ethyl group;
R 9 is a methyl, ethyl or trifluoromethyl group; and
R 10 and R 11 are, independently from each other, a group selected from a hydrogen atom and C 1 -C 2 -alkyl-,
or an enantiomer, diastereomer, or salt thereof.

4. The compound of formula (I) according to claim 1 , wherein
R 1 is a methyl, ethyl, 2-hydroxyethyl or 2-aminoethyl group;
R 2 is a 4-fluoro-2-methoxyphenyl or 4-fluoro-2-ethoxyphenyl group;
R 3 is a hydrogen atom, fluoro atom, chloro atom, methyl, methoxy, difluoromethyl or trifluoromethyl group;
R 4 is a hydrogen atom or bromo atom; and
R 5 is a hydrogen atom or a group selected from cyano, —C(O)CH 3 , —C(O)CF 3 , —C(O)OC 2 H, and —C(O)N(H)C 2 H 5 ,
or an enantiomer, diastereomer, or salt thereof.

5. The compound according to claim 1 , which is
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine;
(+)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine;
(−)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine;
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-methyl-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine;
(rac)-5-Bromo-N-[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]-6-methyl-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-amine;
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-methoxy-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine;
(rac)-N-{6-Chloro-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-amine;
(rac)-2-{S-[(2-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}pyridin-4-yl)methyl]sulfonimidoyl}ethanol;
(rac)-N-(4-{[S-(2-Aminoethyl)sulfonimidoyl]methyl}pyridin-2-yl)-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-amine;
{[(2-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}pyridin-4-yl)methyl](methyl)oxido-λ 6 -sulfanylidene}cyanamide;
(rac)-Ethyl{[(2-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}pyridin-4-yl)methyl](methyl)oxido-λ 6 -sulfanylidene}carbamate;
(rac)-1-Ethyl-3-{[(2-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl) pyridin-2-yl]amino}pyridin-4-yl)methyl](methyl)oxido-λ 6 -sulfanylidene}urea;
(rac)-N-{[(2-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}pyridin-4-yl)methyl](methyl)oxido-λ 6 -sulfanylidene}acetamide;
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine hydrochloride; enantiomer 2;
(rac)-Ethyl{[(2-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl) pyridin-2-yl]amino}-6-methoxypyridin-4-yl)methyl](methyl)oxido-λ 6 -sulfanylidene}carbamate;
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine hydrochloride; enantiomer 1;
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-fluoro-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine;
(rac)-2,2,2-Trifluoro-N-{[(2-fluoro-6-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl]amino}pyridin-4-yl)methyl](methyl)oxido-λ 6 -sulfanylidene}acetamide;
(+)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-fluoro-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine;
(−5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{6-fluoro-4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine;
(rac)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]-6-(trifluoromethyl)pyridin-2-yl}pyridin-2-amine;
(+)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methyls

Assignees

• Bayer Pharma AG

Inventors

• Lücking Ulrich
• Böhnke Niels
• Scholz Arne
• Lienau Philip
• Siemeister Gerhard
• Bömer Ulf
• Kosemund Dirk
• Bohlmann Rolf
• Zorn Ludwig

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title