Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease

Patent metadata

Field	Value
Publication number	US-9714249-B2
Application number	US-201414892628-A
Country	US
Kind code	B2
Filing date	May 27, 2014
Priority date	May 28, 2013
Publication date	Jul 25, 2017
Grant date	Jul 25, 2017

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the pyrazolo-pyrrolidin-4-one derivatives, and their use as BET inhibitors for the treatment of conditions or diseases such as cancer. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

What is claimed is:

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

wherein
A is

B is

C is selected from:

R 1 is selected from methyl and chloro;
R 2 is selected from chloro and fluoro;
R 3 is selected from methyl and cyclopropyl; and R 4 is selected from H; (C 1 -C 4 )alkyl optionally substituted by —OH or —O—(C 1 -C 4 )alkyl; cyclopropyl;

and

R 5 is H;
R 6 is —O—(C 1 -C 4 )alkyl;
R 7 is selected from H and methoxy;
and * indicates the point of attachment to the remainder of the molecule.

2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 2 is chloro.

3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 3 is selected from methyl and cyclopropyl.

4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 4 is selected from methyl, ethyl, isopropyl, —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , cyclopropyl,
and

or R 4 is H.

5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 , selected from:
Example 1: 6-(4-chlorophenyl)-3-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 2: (R)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 3: 6-(4-chlorophenyl)-3-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-hydroxyethyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 4: 6-(4-chlorophenyl)-3-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methoxyethyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 6: 5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3 -yl)-6-(4-chlorophenyl)-3-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one;
Example 9: 6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one;
Example 10: 6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1,3-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 11: 6-(4-chlorophenyl)-1-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 12: 6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-isopropyl-3-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 13: 6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-methoxy-phenyl)-3-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 23: 6-(4-chlorophenyl)-3-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 24: (R)-6-(4-chlorophenyl)-3-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 27: (R)-6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one; and
Example 28: (R)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-3-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(2H)-one.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

Assignees

• Blank Jutta
• Cotesta Simona
• Guagnano Vito
• Rueeger Heinrich
• Novartis Ag

Inventors

• Blank Jutta
• Cotesta Simona
• Guagnano Vito
• Rueeger Heinrich

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

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