Substituted purinone compounds

Patent metadata

Field	Value
Publication number	US-9403827-B2
Application number	US-201414762037-A
Country	US
Kind code	B2
Filing date	Jan 21, 2014
Priority date	Jan 22, 2013
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The invention relates to compounds of formula (I): (I) as described herein, pharmaceutical preparations comprising such compounds, uses and methods of use for such compounds in the treatment of a disorder or a disease mediated by the activity of as MDM2 and/or MDM4, and combinations comprising such compounds.

First claim

The invention claimed is:

1. A compound of formula (I), or a salt thereof,

wherein
R 1 is
(a) a phenyl substituted with one to five substituents each independently selected from halo, (C 1 -C 4 )alkyl and —O—(CH 2 ) n —N(CH 3 ) 2 , wherein n is 1 or 2; or
(b) a 6-oxo-1,6-dihydropyridin-3-yl having Formula (Ia) or a 2-oxo-1,2-dihydropyridin-3-yl having Formula (Ib),

 wherein R 1a is H, halo or (C 1 -C 4 )alkyl, and R 1b is H, (C 1 -C 4 )alkyl, —(CH 2 ) m —N(CH 3 ) 2 , or —(CH 2 ) m —OR 1c , where R 1c is H or (C 1 -C 4 )alkyl, and m is 1 or 2;

R 2 is a phenyl substituted with one substituent in the para position selected from chloro, fluoro, trifluoromethyl, methyl and cyano and optionally one additional substituent selected from halo and (C 1 -C 4 )alkyl-, optionally substituted with (C 1 -C 4 )alkoxy;
R 3 is selected from isopropyl, cyclopropyl, isobutyl, cyclobutyl and cyclopentyl;
R 4 is halo, —(CH 2 ) q -pyridyl, —(CH 2 ) q -pyrimidyl, —(CH 2 ) q -phenyl, where said pyridyl, said pyrimidyl, and said phenyl moieties are optionally substituted with one, two or three substituents each independently selected from halo, (C 1 -C 4 )alkoxy, cyano, —NH 2 , (C 1 -C 4 )alkyl-NH—, ((C 1 -C 4 )alkyl) 2 -N—, —(CH 2 )—OH, —C(O)—NH 2 , —C(O)—NH—(C 1 -C 4 )alkyl, —C(O)—N((C 1 -C 4 )alkyl) 2 , —C(O)—NH—(CH 2 ) p —OH, —(CH 2 )—NH 2 , —(CH 2 )—NH—C(O)CH 3 and —(CH 2 )—NH—C(O)H;
p is 1 or 2, and q is 0 or 1.

2. A compound of formula (I), or a salt thereof, according to claim 1 wherein R 1 is a phenyl substituted with one or two substituents each independently selected from halo and (C 1 -C 4 )alkyl.

3. A compound of formula (I), or a salt thereof, according to claim 1 wherein R 1 is a 6-oxo-1,6-dihydropyridin-3-yl having Formula (Ia) or a 2-oxo-1,2-dihydropyridin-3-yl having Formula (Ib),

wherein R 1a is halo and R 1b is H or (C 1 -C 4 )alkyl.

4. A compound of formula (I), or a salt thereof, according to claim 1 wherein R 2 is selected from p-chlorophenyl, p-cyanophenyl, o-methyl-p-chlorophenyl, p-fluoro-m-chlorophenyl and m-fluoro-p-chlorophenyl.

5. A compound of formula (I), or a salt thereof, according to claim 1 wherein R 3 is isopropyl.

6. A compound of formula (I), or a salt thereof, according to claim 1 wherein R 4 is selected from —(CH 2 ) q -pyridyl, —(CH 2 ) q -pyrimidyl and —(CH 2 ) q -phenyl, where said pyridyl, said pyrimidyl, and said phenyl moieties are optionally substituted with one or two substituents each independently selected from (C 1 -C 4 )alkoxy, ((C 1 -C 4 )alkyl) 2 -N—, —C(O)—NH—(C 1 -C 4 )alkyl and —C(O)—N((C 1 -C 4 )alkyl) 2 where q is 0 or 1.

7. A compound of formula (I), or a salt thereof, according to claim 1 wherein R 4 is selected from

where * indicates the point of attachment to the remainder of the molecule.

8. A compound of formula (I), or a salt thereof, according to claim 1 wherein R 4 is

where * indicates the point of attachment to the remainder of the molecule.

9. A compound of formula (I) according to claim 1 selected from:
1-(3-Chloro-2-fluorophenyl)-6-(4-chlorophenyl)-7-isopropyl-8-(2-methoxyphenyl)-6,7-dihydro-1H-purin-2(3H)-one;
1-(3-Chloro-2-fluorophenyl)-6-(4-chloro-2-methylphenyl)-7-isopropyl-8-(2-methoxyphenyl)-6,7-dihydro-1H-purin-2(3H)-one;
6-(4-Chloro-2-methylphenyl)-1-(5-chloro-2-methylphenyl)-7-isopropyl-8-(2-methoxyphenyl)-6,7-dihydro-1H-purin-2(3H)-one;
6-(4-Chloro-2-methylphenyl)-1-(5-chloro-2-methylphenyl)-7-isopropyl-8-(4-methoxypyridin-3-yl)-6,7-dihydro-1H-purin-2(3H)-one;
8-Bromo-1-(3-chloro-2-fluorophenyl)-6-(4-chlorophenyl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one;
1-(3-Chloro-2-fluorophenyl)-6-(4-chlorophenyl)-7-isopropyl-8-(4-methoxypyridin-3-yl)-6,7-dihydro-1H-purin-2(3H)-one;
6-(4-Chloro-2-methylphenyl)-1-(5-chloro-2-methylphenyl)-8-(5-fluoro-2-methoxyphenyl)-7-isopropyl-6, 7-dihydro-1H-purin-2(3H)-one;
3-(6-(4-Chloro-2-methylphenyl)-1-(5-chloro-2-methylphenyl)-7-isopropyl-2-oxo-2, 3,6,7-tetrahydro-1H-purin-8-yl)-N-(2-hydroxyethyl)-4-methoxybenzamide;
3-(6-(4-Chloro-2-methylphenyl)-1-(5-chloro-2-methylphenyl)-7-isopropyl-2-oxo-2, 3,6,7-tetrahydro-1H-purin-8-yl)-4-methoxy-N-methylbenzamide;
3-(6-(4-Chloro-2-methylphenyl)-1-(5-chloro-2-methylphenyl)-7-isopropyl-2-oxo-2, 3,6,7-tetrahydro-1H-purin-8-yl)-4-methoxy-N,N-dimethylbenzamide;
6-(4-Chloro-2-methylphenyl)-1-(5-chloro-2-methylphenyl)-8-(5-(hydroxymethyl)-2-methoxyphenyl)-7-isopropyl-6, 7-dihydro-1H-purin-2(3H)-one;
3-(6-(4-Chloro-2-methylphenyl)-1-(5-chloro-2-methylphenyl)-7-isopropyl-2-oxo-2, 3,6,7-tetrahydro-1H-purin-8-yl)-4-methoxybenzonitrile;
4-(1-(5-Chloro-2-methylphenyl)-7-isopropyl-8-(2-methoxyphenyl)-2-oxo-2,3,6,7-tetrahydro-1H-purin-6-yl)benzonitrile; and
4-(1-(3-Chloro-2-fluorophenyl)-7-isopropyl-8-(2-methoxyphenyl)-2-oxo-2,3, 6,7-tetrahydro-1H-purin-6-yl)benzonitrile;
6-(4-Chloro-3-fluorophenyl)-1-(3-chloro-4-fluorophenyl)-8-(2,4-dimethoxypyrimidin-5-yl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one;
1-(5-Chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chloro-2-methylphenyl)-8-(2,4-dimethoxypyrimidin-5-yl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one;
1-(5-Chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chloro-3-fluorophenyl)-8-(2,4-dimethoxypyrimidin-5-yl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one;
1-(5-Chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-8-(2,4-dimethoxypyrimidin-5-yl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one;
1-(5-Chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chloro-3-fluorophenyl)-8-(2,4-dimethoxypyrimidin-5-yl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one;
1-(5-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chloro-3-fluorophenyl)-8-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one;
8-(2-Amino-4-methoxypyrimidin-5-yl)-1-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one;
1-(5-Chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-8-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one;
6-(4-Chloro-3-fluorophenyl)-1-(3-chloro-4-fluorophenyl)-8-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one;
1-(5-Chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chloro-3-fluorophenyl)-8-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one; and
1-(5-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chloro-3-fluorophenyl)-8-(2,4-dimethoxypyrimidin-5-yl)-7-isopropyl-6,7-dihydro-1H-purin-2(3H)-one;

or a salt thereof.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or salt thereof according to claim 1 , and one or more pharmaceutically acceptable carriers.

Assignees

• Furet Pascal
• Guagnano Vito
• Holzer Philipp
• Kallen Joerg
• Mah Robert
• Masuya Keiichi
• Schlapbach Achim
• Vaupel Andrea
• Novartis Ag

Inventors

• Furet Pascal
• Guagnano Vito
• Holzer Philipp
• Kallen Joerg
• Mah Robert
• Masuya Keiichi
• Schlapbach Achim
• Vaupel Andrea

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/522

  having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir · CPC title

• C07D473/28 Primary

  Oxygen atom · CPC title