Octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors

Patent metadata

Field	Value
Publication number	US-10913745-B2
Application number	US-201815975528-A
Country	US
Kind code	B2
Filing date	May 9, 2018
Priority date	Mar 12, 2013
Publication date	Feb 9, 2021
Grant date	Feb 9, 2021

Abstract

The invention provides novel compounds having the general formula (I)

wherein R 1 , Y, A, W, R 2 , m, n, p and q are as described herein, compositions including the compounds and methods of using the compounds.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
R 1 is substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted naphthyl, substituted naphthylalkyl, substituted naphthyloxyalkyl, substituted naphthylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl, or substituted benzofuran-2-yl,
wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted naphthyl, substituted naphthylalkyl, substituted naphthyloxyalkyl, substituted naphthylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted indolyl, substituted quinolyl, substituted isoquinolyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl, and substituted benzofuran-2-yl are substituted with R 7 , R 8 and R 9 ;

R 2 is substituted phenyl, substituted pyridinyl, substituted pyrrolyl, oxodihydropyridinyl, or substituted thiophenyl, wherein substituted phenyl, substituted pyridinyl, substituted pyrrolyl, and substituted thiophenyl are substituted with R 10 , R 11 and R 12 ;
Y is —OC(O)—, —NR 5 C(O)—, —C(O)—, —S(O) 2 —,

A is —N—;
W is —O—, —S—, —NR 6 —, —C(O)—, —S(O) 2 —, or —CR 3 R 4 —;
R 3 and R 4 are independently selected from H, halogen, alkyl and cycloalkyl;
R 5 and R 6 are independently selected from H, alkyl and cycloalkyl;
R 7 , R 8 and R 9 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, 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,
wherein at least one of R 7 , R 8 and R 9 is not H;

R 10 is substituted aminosulfonyl, alkoxycarbonyl, alkylcarbonylamino, alkylsulfonylamino, substituted amino, carboxy, cyano, hydroxyl, or tetrazolyl,
wherein substituted amino is substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;

R 11 and R 12 are independently selected from H, alkyl, cycloalkyl, alkoxy, halogen and haloalkyl; and
m, n, p and q are independently selected from 1 or 2;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl, or substituted isoquinolyl, wherein substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl and substituted isoquinolyl are substituted with R 7 , R 8 , and R 9 .

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenylalkyl substituted with R 7 , R 8 , and R 9 .

4. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1 is 3,5-dichlorobenzyl, 4-trifluoromethoxybenzyl, or 4-trifluoromethoxyphenylethyl.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with R 10 , R 11 , and R 12 .

6. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl substituted with R 10 , R 11 , and R 12 .

7. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 4-aminosulfonylphenyl, 3-fluoro-4-aminosulfonylphenyl, 3-aminosulfonylpyridin-6-yl, or 2-aminosulfonylpyridin-5-yl.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is —OC(O)— or —C(O)—.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is —C(O)— or —S(O) 2 —.

10. The compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein W is —C(O)—.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 , R 8 and R 9 are independently selected from H, alkoxy, haloalkoxy, halogen, alkylsulfonyl, and phenyl substituted with one halogen, and wherein at least one of R 7 , R 8 , and R 9 is not H.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is alkoxy, haloalkoxy, halogen, or phenyl substituted with one halogen.

13. The compound according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 7 is haloalkoxy or halogen.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H, halogen, or alkylsulfonyl.

15. The compound according to claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H or halogen.

16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is H.

17. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is aminosulfonyl.

18. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 are independently selected from H, alkyl, and halogen.

19. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 are independently selected from H and halogen.

20. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein m and n are 1.

21. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein m, n, p, and q are 1.

22. The compound according to cla

Assignees

• Hoffmann La Roche

Inventors

• Hert Jerome
• Hunziker Daniel
• Mattei Patrizio
• Mauser Harald
• Tang Guozhi
• Wang Lisha

Classifications

• A61P37/06

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title