Imidazopyrrolidine derivatives and their use in the treatment of disease

Patent metadata

Field	Value
Publication number	US-9890166-B2
Application number	US-201414892616-A
Country	US
Kind code	B2
Filing date	May 26, 2014
Priority date	May 27, 2013
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; 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 selected from

C is

R 1 is selected from H, halo and methyl;
R 2 is selected from halo, cyano, methyl, —CF 3 and —O(C 1 -C 4 alkyl);
R 3 is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and methoxyethyl;
R 4 is selected from:
methyl, cyclopropyl, cyclobutyl, cyclopentyl,

wherein
R 8 is independently selected from OCH 3 , OH and OCF 3 ;
R 9 is selected from H and halo;
R 10 is selected from H, O(C 1 -C 4 )alkyl, and OH;
each R 11 is independently selected from H, and CH 3 ;
R 5 is H;
R 6 is selected from methyl and methoxy; and
R 7 is selected from methyl, —CH 2 F and —CHF 2 ;
and wherein * 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 A is selected from:

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

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

5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 , which is selected from:
Example 3: 6-(4-chlorophenyI)-5-(3,7-dimethyl-3H-benzo[d][1,2,3]triazol-5-yl)-3-isopropyl-2-methyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one;
Example 6: 6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(6-methoxypyridin-3-yl)-3-methyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one;
Example 7: (R)-6-(4-chlorophenyI)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(6-methoxypyridin-3-yl)-3-methyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one;
Example 36: 6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-3-propyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one;
Example 37: 5-(4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-6-oxo-1-propyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)nicotinonitrile;
Example 38: 6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-ethyl-2-(6-methoxypyridin-3-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one;
Example 39: (R)-6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-ethyl-2-(6-methoxypyridin-3-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one;
Example 40: 6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-ethyl-2-(2-methoxypyridin-3-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one;
Example 41: (R)-6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-ethyl-2-(2-methoxypyridin-3-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one;
Example 42: 6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-ethyl-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one;
Example 44: 6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-2-(2-methoxypyridin-3-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one;
Example 45: (R)-6-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-isopropyl-2-(2-methoxypyridin-3-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one;
Example 46: 6-(4-chlorophenyl)-2-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-one; and
Example 47: R- 6-(4-chlorophenyl)-2-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3H)-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.

7. 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.

8. 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.

9. A method of claim 8 , wherein said subject having a cancer.

10. A compound, or a pharmaceutically acceptable salt thereof, which is

11. A compound, or a pharmaceutically acceptable salt thereof, which is

12. A compound, or a pharmaceutically acceptable salt thereof, which is

13. A compound, or a pharmaceutically acceptable salt thereof, which is

Assignees

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

Inventors

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

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/513

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

• A61K31/4192

  1,2,3-Triazoles · CPC title