Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the P53/MDM2 interaction

Patent metadata

Field	Value
Publication number	US-9556180-B2
Application number	US-201414762051-A
Country	US
Kind code	B2
Filing date	Jan 21, 2014
Priority date	Jan 22, 2013
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The invention relates to compounds of formula (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 MDM2 and/or MDM4, and combinations comprising such compounds.

First claim

What is 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 (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; and
R 4 is (C 2 -C 6 )alkenyl, —(CH 2 ) p —N(CH 3 ) 2 , —(CH 2 ) q -pyridyl, —(CH 2 ) q -pyrimidyl or —(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 (C 1 -C 4 )alkoxy, cyano, —C(O)—NH 2 , —(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 two substituents each independently selected from halo or (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 (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 or o-methyl-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, cyano, —C(O)—NH 2 , —(CH 2 )—NH 2 , —(CH 2 )—NH—C(O)CH 3 and —(CH 2 )—NH—C(O)H, 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 selected from

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

9. A compound of formula (I) according to claim 1 selected from:
2-Benzyl-5-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-methylphenyl)-3-isopropyl-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
(S)-2-Benzyl-5-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-methylphenyl)-3-isopropyl-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
(R)-2-Benzyl-5-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-methylphenyl)-3-isopropyl-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-methylphenyl)-3-isopropyl-2-(3-methylbut-2-en-1-yl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-methylphenyl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
(S)-5-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-methylphenyl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
(R)-5-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-methylphenyl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-methylphenyl)-3-isopropyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(3-Chloro-2-fluorophenyl)-4-(4-chloro-2-methylphenyl)-2-(2-(dimethylamino)ethyl)-3-isopropyl-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
4-(4-Chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
2-Benzyl-4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-3-isopropyl-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(5-Chloro-2-(2-(dimethylamino)ethoxy)phenyl)-4-(4-chloro-2-methylphenyl)-3isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(5-Chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-chlorophenyl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(5-Chloro-1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-chlorophenyl)-3isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(5-Chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-chloro-2-methylphenyl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(5-Chloro-1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-chlorophenyl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(5-Chloro-2-(3-(dimethylamino)ethoxy)phenyl)-4-(4-chlorophenyl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(5-Chloro-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-chlorophenyl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
5-(5-Chloro-1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-chloro-2-methylphenyl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
4-(4-Chlorophenyl)-3-isopropyl-2-(2-methoxyphenyl)-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
4-(4-Chloro-2-methylphenyl)-5-(1-ethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
4-(4-Chlorophenyl)-5-(1-(2-(dimethylamino)ethyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-2-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
3-(4-(4-Chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-3-isopropyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-4-methoxybenzonitrile;
3-(5-(5-Chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-chloro-2-methylphenyl)-3-isopropyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-4-methoxybenzonitrile;
2-(5-(Aminomethyl)-2-methoxyphenyl)-4-(4-chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-3-isopropyl-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidin-6(7H)-one;
N-(3-(4-(4-Chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-3-isopropyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-4-methoxybenzyl)acetamide;
N-(3-(4-(4-Chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-3-isopropyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-4-methoxybenzyl)formamide;
3-(4-(4-Chloro-2-methylphenyl)-5-(5-chloro-2-methylphenyl)-3-isopropyl-6-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)-4-methoxybenzamide;
2-(5-(Aminomethyl)-2-methoxyphenyl)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-

Assignees

• 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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title