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

Patent metadata

Field	Value
Publication number	US-9624247-B2
Application number	US-201414892623-A
Country	US
Kind code	B2
Filing date	May 27, 2014
Priority date	May 28, 2013
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; (1) a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

The invention claimed is:

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

wherein
A is selected from

B is

C is

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

or
R 3 is

 and R 4 is selected from H; (C 1 -C 4 )alkyl optionally substituted by —OH or —O—(C 1 -C 4 )alkyl; and cyclopropyl;
R 5 is H;
R 6 is selected from methyl, methoxy, —NH 2 and —NH—C(O)—(C 1 -C 4 )alkyl
R 7 is 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 1 is selected from methyl and difluoromethyl.

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

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

5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 4 is methyl or —CH 2 CH 2 OCH 3 .

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

and
R 4 is H.

7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 , which is selected from:
Example 1: 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 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-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 4: 6-(4-chlorophenyl)-3-cyclopropyl-5-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 5: -(4-chlorophenyl)-3-cyclopropyl-5-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 6: 6-(4-chlorophenyl)-3-cyclopropyl-5-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one
Example 7: (R)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3-(difluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 8: 6-(4-chlorophenyl)-3-cyclopropyl-5-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 9: (R)-6-(4-chlorophenyl)-3-cyclopropyl-5-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 10: 6-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-methoxypyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 11: (R)-6-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-methoxypyridin-3-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 12: 6-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-methoxypyridin-3-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 13: (R)-6-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-methoxypyridin-3-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 14: (R)-6-(4-chlorophenyl)-3-cyclopropyl-5-(8-methoxy-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 15: (R)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-(2-methoxyethyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 16: 6-(4-chlorophenyl)-3-cyclopropyl-5-(3-(fluoromethyl)-8-methyl -[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 17: (R)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3-(fluoromethyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 18: 6-(4-chlorophenyl)-3-cyclopropyl-5-(3-(fluoromethyl)-8-methyl -[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-(2-methoxyethyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 19: (R)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1_((R)-3,3,3-trifluoro-2-hydroxypropyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 20: (R)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-((S)-3,3,3-trifluoro-2-hydroxypropyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 21: 6-(4-chlorophenyl)-3-cyclopropyl-5-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-6-yl)-1-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 22: 6-(4-chlorophenyl)-3-cyclopropyl-5-(3-(difluoromethyl)-8-methoxy-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 23: 6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 24: (R)-6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 25: 6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one;
Example 26: 6-(4-chlorophenyl)-3-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one; and
Example 28: 5-(8-amino-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-6-(4-chlorophenyl)-3-cyclopropyl-1-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-4(1H)-one.

8. 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.

9. A combination comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more therapeutically active agents.

10. A method of modulating BET protein activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. A method of claim 10 , wherein said subject having a cancer.

Assignees

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

Inventors

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

Classifications

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title

• A61P35/00

  Antineoplastic agents · CPC title