Condensed [1,4] diazepine compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors

Patent metadata

Field	Value
Publication number	US-10669285-B2
Application number	US-201615272085-A
Country	US
Kind code	B2
Filing date	Sep 21, 2016
Priority date	Mar 26, 2014
Publication date	Jun 2, 2020
Grant date	Jun 2, 2020

Abstract

Compounds of formula (I)

wherein R 1 , R 2 , A 1 and A 2 are as described herein, compositions including the compounds and methods of using the compounds as autotaxin inhibitors.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, or substituted phenylalkenyl, wherein substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, and substituted phenylalkenyl are substituted with R 3 , R 4 and R 5 ;
A 1 is —N— or —CR 7 —;
A 2 is —N— or —CR 8 — and at least one of A 1 and A 2 is —N—;
R 2 is selected from the ring systems A, B, C, D, E, F, G, H, I, K and L

R 3 , R 4 and R 5 are independently selected from H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, heterocycloalkylalkoxy, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfanyl, haloalkylsulfinyl, cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, alkylcarbonylamino, substituted aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy and haloalkoxy;
R 6 is H, alkyl, haloalkyl or cycloalkyl; and
R 7 and R 8 are independently selected from H, alkyl, haloalkyl and cycloalkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein
R 1 is substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, or substituted phenylalkenyl, wherein substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, and substituted phenylalkenyl are substituted with R 3 , R 4 and R 5 ;
A 1 is —N— or —CR 7 —;
A 2 is —N— or —CR 8 — and at least one of A 1 and A 2 is —N—;
R 2 is selected from the ring systems A, B, C, D, E, F, G, H, I, K and L;
R 3 , R 4 and R 5 are independently selected from H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl, cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, alkylcarbonylamino, substituted aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy and haloalkoxy;
R 6 is H, alkyl, haloalkyl or cycloalkyl; and
R 7 and R 8 are independently selected from H, alkyl, haloalkyl and cycloalkyl;
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is substituted phenylalkyl, substituted phenoxyalkyl or substituted phenylalkoxy, wherein substituted phenylalkyl, substituted phenoxyalkyl and substituted phenylalkoxy are substituted with R 3 , R 4 and R 5 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is substituted phenoxyalkyl or substituted phenylalkoxy, wherein substituted phenoxyalkyl and substituted phenylalkoxy are substituted with R 3 , R 4 and R 5 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenylalkoxy substituted with R 3 , R 4 and R 5 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the ring systems A and E.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is the ring system A.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is —N— and A 2 is —N— or —CR 8 —.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 5 are independently selected from H, alkyl, cycloalkyl, heterocycloalkylalkoxy, haloalkoxy, halogen, cyano and alkylcarbonylamino.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 and R 5 are independently selected from H, alkyl, cycloalkyl, haloalkoxy, halogen, cyano and alkylcarbonylamino.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is heterocycloalkylalkoxy, haloalkoxy or cyano.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is haloalkoxy or cyano.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H, alkyl, cycloalkyl or halogen.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H, alkyl or halogen.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H.

18. The compound of claim 1 , wherein
R 1 is substituted phenylalkoxy substituted with R 3 , R 4 and R 5 ;
A 1 is —N—;
A 2 is —N— or —CR 8 —;
R 2 is the ring system A;
R 3 is haloalkoxy or cyano;
R 4 is H or halogen;
R 5 is H; and
R 8 is H;
or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , selected from
Benzyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate;
Benzyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate;
[3-Fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate;
2-Fluoro-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;
[4-(Trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate;
4-Cyanobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;
4-Cyano-3-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-car

Assignees

• Hoffmann La Roche

Inventors

• Hunziker Daniel
• Hert Jerome
• Kuehne Holger
• Mattei Patrizio
• Rudolph Markus

Classifications

• 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 Primary

  Ortho-condensed systems · CPC title

• A61K31/5517

  condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam · CPC title

• A61P13/00

  Drugs for disorders of the urinary system · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title