4,5-dihydropyrazole derivatives, pharmaceutical compositions containing them, and their use in therapy

Patent metadata

Field	Value
Publication number	US-9550754-B2
Application number	US-201514849470-A
Country	US
Kind code	B2
Filing date	Sep 9, 2015
Priority date	Sep 11, 2014
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

The present invention relates to 4,5-dihydropyrazole derivatives of the formula (I)

and physiologically tolerated salts thereof which are GlyT1 inhibitors. The invention further relates to pharmaceutical compositions comprising such 4,5-dihydropyrazole derivatives, and the use of such 4,5-dihydropyrazole derivatives for therapeutic purposes.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl or optionally substituted pyrrolidinyl;
R 2 is optionally substituted C 6 -C 12 -aryl, optionally substituted M 3 -M 12 -heterocyclyl, optionally substituted C 3 -C 12 -cycloalkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 12 -alkyl, (optionally substituted M 3 -M 12 -heterocyclyl)-C 1 -C 12 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 12 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 12 -alkoxy-C 1 -C 12 -alkyl, (optionally substituted M 3 -M 12 -heterocyclyl)-C 1 -C 12 -alkoxy-C 1 -C 12 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 12 -alkoxy-C 1 -C 12 -alkyl, C 1 -C 12 -alkoxy-C 1 -C 12 -alkyl or halogenated C 1 -C 12 -alkyl;
R 3a is optionally substituted C 6 -C 12 -aryl, optionally substituted M 3 -M 12 -heterocyclyl, optionally substituted C 3 -C 12 -cycloalkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 12 -alkyl, (optionally substituted M 3 -M 12 -heterocyclyl)-C 1 -C 12 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 12 -alkyl, (optionally substituted C 6 -C 12 -aryl)-C 1 -C 12 -alkoxy-C 1 -C 12 -alkyl, (optionally substituted M 3 -M 12 -heterocyclyl)-C 1 -C 12 -alkoxy-C 1 -C 12 -alkyl, (optionally substituted C 3 -C 12 -cycloalkyl)-C 1 -C 12 -alkoxy-C 1 -C 12 -alkyl, C 1 -C 12 -alkoxy or halogenated C 1 -C 12 -alkyl;
R 3b is hydrogen or C 1 -C 6 -alkyl; and
R 4a and R 4b are independently hydrogen or C 1 -C 4 -alkyl;
or a physiologically tolerated salt thereof.

2. The compound of claim 1 , wherein R 1 is optionally substituted imidazolyl.

3. The compound of claim 1 , wherein R 1 is optionally substituted pyrazolyl.

4. The compound of claim 1 , wherein R 1 is optionally substituted triazolyl.

5. The compound of claim 1 , wherein R 1 is optionally substituted imidazole-4-yl, optionally substituted pyrazol-4-yl or optionally substituted 1,2,3-triazol-4-yl.

6. The compound of claim 1 , wherein R 1 is imidazolyl, pyrazolyl, triazolyl, or pyrrolidinyl each of which are optionally substituted with C 1 -C 4 -alkyl at the nitrogen ring atom at position 1.

7. The compound of claim 1 , wherein each of R 4a and R 4b is hydrogen.

8. The compound of claim 1 , wherein R 3b is hydrogen.

9. The compound of claim 1 , wherein at least one of R 2 and R 3a is optionally substituted C 6 -C 12 -aryl or optionally substituted M 3 -M 12 -heterocyclyl.

10. The compound of claim 1 ; wherein R 3a is C 6 -C 12 -aryl optionally substituted with 1-3 substituents independently selected from cyano, halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and halogenated C 1 -C 4 -alkoxy.

11. The compound of claim 1 , wherein R 3a is M 4 -M 6 -heterocyclyl optionally substituted with 1-3 substituents independently selected from cyano, halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and halogenated C 1 -C 4 -alkoxy.

12. The compound of claim 1 , wherein R 3a is phenyl optionally substituted with 1-3 substituents independently selected from cyano, halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and halogenated C 1 -C 4 -alkoxy.

13. The compound of claim 1 , wherein R 2 is C 6 -C 12 -aryl optionally substituted with 1-3 substituents independently selected from cyano, halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and halogenated C 1 -C 4 -alkoxy.

14. The compound of claim 1 , wherein R 2 is M 4 -M 6 -heterocyclyl optionally substituted with 1-3 substituents independently selected from cyano, halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and halogenated C 1 -C 4 -alkoxy.

15. The compound of claim 1 , wherein R 2 is phenyl optionally substituted with 1-3 substituents independently selected from cyano, halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and halogenated C 1 -C 4 -alkoxy.

16. The compound of claim 1 , wherein R 2 is pyridyl optionally substituted with 1-3 substituents independently selected from cyano, halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and halogenated C 1 -C 4 -alkoxy.

17. The compound of claim 1 , wherein
R 1 is optionally substituted imidazolyl, optionally substituted pyrazolyl or optionally substituted triazolyl;
R 2 is optionally substituted C 6 -C 12 -aryl, optionally substituted M 3 -M 12 -heterocyclyl or C 1 -C 12 -alkyl;
R 3a is optionally substituted C 6 -C 12 -aryl; and
each of R 3b , R 4a and R 4b is hydrogen.

18. The compound of claim 1 which is
4-({4-(4-fluorophenyl)-3-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-pyrazol-1-yl}-sulfonyl)-1-methyl-1H-1,2,3-triazole;
3-(4-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole;
4-{[4-(4-fluorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl]sulfonyl}-1-methyl-1H-1,2,3-triazole;
4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-phenyl-4,5-dihydro-1H-pyrazole;
3-(3-chlorophenyl)-4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4,5-dihydro-1H-pyrazole;
4-{[3-(3-chlorophenyl)-4-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]sulfonyl}-1-methyl-1H-1,2,3-triazole;
4-{[3-(3-chlorophenyl)-4-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]sulfonyl}-1-methyl-1H-pyrazole;
4-(4-fluorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-pyrazole;
4-{[4-(4-fluorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl]sulfonyl}-1-methyl-1H-pyrazole;
4-({4-(4-fluorophenyl)-3-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-pyrazol-1-yl}sulfonyl)-1-methyl-1H-pyrazole;
4-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]sulfonyl}-1-methyl-1H-pyrazole;
4-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]sulfonyl}-1-methyl-1H-1,2,3-triazole;
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-3-[3-(trifluoromethoxy)phenyl]-4,5-dihydro-1H-pyrazole;
1-methyl-4-({4-phenyl-3-[3-(trifluoromethoxy)phenyl]-4,5-dihydro-1H-pyrazol-1-yl}sulfonyl)-1H-pyrazole;
1-methyl-4-({4-phenyl-3-[3-(trifluoromethoxy)phenyl]-4,5-dihydro-1H-pyrazol-1-yl}sulfonyl)-1H-1,2,3-triazole;
(4R)-3-(4-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole;
(4S)-3-(4-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole;
1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-(2-methylpropyl)-4-phenyl-4,5-dihydro-1H-pyrazole;
2-{1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazol-3-yl}pyridine;
2-{1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazol-3-yl}pyridine;
2-{1-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazol-3-yl}pyridine;
2-{1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazol-3-yl}-4-(trifluoromethyl)pyridine;
2-{1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl}-4-(trifluoromethyl)pyridine;
2-{1-[(1-methyl-1,2,3-triazol-4-yl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazol-3-yl}-4-(trifluoromethyl)pyridine;
4-(4-chlorophenyl)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-phenyl-4,5-dihydro-1H-pyrazole;
3-{1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-3-phenyl-4,5-dihydro-1H-pyrazol-4-yl}benzonitrile;
4-{[4-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl]sulfonyl}-1-methyl-1H-pyrazole;
4-{[4-(4-chl

Assignees

• Abbvie Deutschland
• Abbvie Inc

Inventors

• Amberg Wilhelm
• Brewer Jason
• Hutchins Charles
• Lange Udo
• Lao Yanbin
• Li Huan-Qiu
• Pohlki Frauke
• Vasudevan Anil
• Wang Ying
• Zhao Hongyu

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title