Pyrazoline derivatives and their use as selective androgen receptor modulators

Patent metadata

Field	Value
Publication number	US-9051326-B2
Application number	US-201214234599-A
Country	US
Kind code	B2
Filing date	Jul 25, 2012
Priority date	Jul 27, 2011
Publication date	Jun 9, 2015
Grant date	Jun 9, 2015

Abstract

The invention relates to a compound of formula (I) in free form or in pharmaceutically acceptable salt form (I), in which the substituents are as defined in the specification; to compounds of formula (I) for use as androgen receptor modulators. 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) in free form or in pharmaceutically acceptable salt form,

wherein
R 1 is C 1 -C 3 alkyl;
R 2 is halogen;
R 3 is cyano;
R 4 is selected from amino, halogen, hydroxy, C 1 -C 3 alkyl, halogen-C 1 -C 3 alkyl, hydroxy-C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, halogen-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy-C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl-C 1 -C 3 alkoxy, C 3 -C 6 cycloalkoxy; or R 4 is selected from a (═O), (═S) or (═N(R 8 )) group;
R 5 is selected from hydrogen, amino, halogen, hydroxy, C 1 -C 3 alkyl, halogen-C 1 -C 3 alkyl, hydroxy-C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, halogen-C 1 -C 3 alkoxy, C 3 -C 6 cycloalkoxy; or
R 5 is selected from a (═O), (═S) or (═N(R′ 8 )) group;
R 6 is selected from hydrogen, amino, halogen, hydroxy, C 1 -C 3 alkyl, halogen-C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, halogen-C 1 -C 3 alkoxy, C 3 -C 6 cycloalkoxy;
R 7 is selected from hydrogen, halogen, halogen-C 1 -C 3 alkyl;
or R 6 and R 7 together with the carbon to which they are attached form a —C(═O)— or —C(═S)— group;
R 8 and R′ 8 are independently selected from hydrogen, hydroxy;
provided R 5 , R 6 , and R 7 are not all hydrogen.

2. A compound of formula (Ia) according to claim 1 in free from or in pharmaceutically acceptable salt form

wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1 , wherein R 5 is not hydrogen.

3. A compound of formula (Ib) according to claim 1 in free from or in pharmaceutically acceptable salt form

wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1 , wherein R 5 is not hydrogen.

4. A compound of formula (Ic) according to claim 1 in free from or in pharmaceutically acceptable salt form

wherein R 1 , R 2 , R 3 , R 4 and R 6 are as defined in claim 1 , wherein R 6 is not hydrogen.

5. A compound of formula (Id) according to claim 1 in free form or in pharmaceutically acceptable salt form

wherein R 1 , R 2 , R 3 , R 4 and R 6 are as defined in claim 1 , wherein R 6 is not hydrogen.

6. A compound according to claim 1 in free form or in pharmaceutically acceptable salt form,
wherein
R 1 is methyl; R 2 is chloro; R 3 is cyano.

7. A compound according to claim 1 in free form or in pharmaceutically acceptable salt form, wherein R 4 is selected from hydroxy, C 1 -C 3 alkoxy.

8. A compound according to claim 1 in free from or in pharmaceutically acceptable salt form, wherein R 5 if present is selected from halogen, hydroxy.

9. A compound according to claim 1 in free form or in pharmaceutically acceptable salt form, wherein R 6 if present is selected from halogen, hydroxy.

10. A compound according to claim 1 in free form or in pharmaceutically acceptable salt form, wherein R 7 if present is hydrogen.

11. A compound according to claim 1 in free form or in pharmaceutically acceptable salt form, which is selected from
2-chloro-4-(4-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(3,4-dihydroxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(3-ethoxy-4-hydroxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(4-hydroxy-3-isopropoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(5-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(3-methoxy-5-oxo-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(3,5-dihydroxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(5-hydroxy-3-methoxy-5-(trifluoromethyl)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(4-fluoro-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(5-fluoro-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(5,5-difluoro-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(3-(2-fluoroethoxy)-4-hydroxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(3-(cyclopropylmethoxy)-4-hydroxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(5-iodo-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(3,4-dimethoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(4-hydroxy-3-(2-methoxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(4-fluoro-3-(2-methoxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-(4-fluoro-3-(2-fluoroethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile and
2-chloro-4-(5,5-difluoro-3-(2-methoxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile.

12. A compound according to claim 11 in free form or in pharmaceutically acceptable salt form which is selected from
2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-((3S,3aS,4R)-4-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-((3S,3aS,4S)-3-ethoxy-4-hydroxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-((3S,3aS,4R)-3-ethoxy-4-hydroxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-((3S,3aR,4R)-4-fluoro-3-methoxy-3a,4, 5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-((3S,3aR,4S)-4-fluoro-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-((3S,3aS)-5,5-difluoro-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-((3S,3aS,5S)-5-iodo-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-((3S,3aS,4S)-3,4-dimethoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-((3S,3aS,4S)-4-hydroxy-3-(2-methoxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-((3S,3aR,4R)-4-fluoro-3-(2-methoxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile;
2-chloro-4-((3S,3aR,4R)-4-fluoro-3-(2-fluoroethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile; and
2-chloro-4-((3S,3aS)-5,5-difluoro-3-(2-methoxyethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-3-methylbenzonitrile.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 in free form or in pharmaceutically acceptable salt form and one or more pharmaceutically acceptable carriers.

14. A combination comprising a therapeutically effective amount of a compound according to

Assignees

• Bock Mark Gary
• Lagu Bharat
• Pandit Chetan
• Sasmal Sanjita
• Ullrich Thomas
• Novartis Ag

Inventors

• Bock Mark Gary
• Lagu Bharat
• Pandit Chetan
• Sasmal Sanjita
• Ullrich Thomas

Classifications

• A61P5/26

  Androgens · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title