Bicyclic compounds as dual ATX/CA inhibitors

Patent metadata

Field	Value
Publication number	US-10738053-B2
Application number	US-201815933769-A
Country	US
Kind code	B2
Filing date	Mar 23, 2018
Priority date	Sep 24, 2015
Publication date	Aug 11, 2020
Grant date	Aug 11, 2020

Abstract

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

wherein R 1 , R 2 , R 9 , Y, W, m, n, p and q are as defined 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 phenyl, substituted phenyl-C 1-6 -alkyl, substituted phenoxy-C 1-6 -alkyl, substituted phenyl-C 2-6 -alkenyl, substituted phenyl-C 2-6 -alkynyl, substituted pyridinyl, substituted pyridinyl-C 1-6 -alkyl, substituted pyridinyl-C 2-6 -alkenyl, substituted pyridinyl-C 2-6 -alkynyl, substituted thiophenyl, substituted thiophenyl-C 1-6 -alkyl, substituted thiophenyl-C 2-6 -alkenyl or substituted thiophenyl-C 2-6 -alkynyl, wherein substituted phenyl, substituted phenyl-C 1-6 -alkyl, substituted phenoxy-C 1-6 -alkyl, substituted phenyl-C 2-6 -alkenyl, substituted phenyl-C 2-6 -alkynyl, substituted pyridinyl, substituted pyridinyl-C 1-6 -alkyl, substituted pyridinyl-C 2-6 -alkenyl, substituted pyridinyl-C 2-6 -alkynyl, substituted thiophenyl, substituted thiophenyl-C 1-6 -alkyl, substituted thiophenyl-C 2-6 -alkenyl and substituted thiophenyl-C 2-6 -alkynyl are substituted by R 3 , R 4 and R 5 ;
Y is —OC(O)— or —C(O)—;
W is —C(O)—, —S(O) 2 — or —CR 6 R 7 —;
R 2 is substituted phenyl, substituted pyridinyl or substituted thiophenyl, wherein substituted phenyl, substituted pyridinyl and substituted thiophenyl are substituted by R 6 , R 7 and R 8 ;
R 3 is halogen, hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 1-6 -alkoxy, C 3-8 -cycloalkoxy, C 3-8 -cycloalkoxy-C 1-6 -alkyl, C 1-6 -alkylamino, C 1-6 -alkylcarbonylamino, C 3-8 -cycloalkylcarbonylamino, C 1-6 -alkyltetrazolyl, C 1-6 -alkyltetrazolyl-C 1-6 -alkyl or heterocycloalkyl-C 1-6 -alkoxy;
R 4 and R 5 are independently selected from H, halogen, hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 1-6 -alkoxy, C 3-8 -cycloalkoxy, C 3-8 -cycloalkoxy-C 1-6 -alkyl, C 1-6 -alkylcarbonylamino, C 3-8 -cycloalkylcarbonylamino, C 1-6 -alkyltetrazolyl, C 1-6 -alkyltetrazolyl-C 1-6 -alkyl and heterocycloalkyl-C 1-6 -alkoxy;
R 6 is aminosulfonyl;
R 7 and R 8 are independently selected from H, halogen, hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C 3-8 -cycloalkyl-C 1-6 -alkoxy, C 3-8 -cycloalkoxy and C 3-8 -cycloalkoxy-C 1-6 -alkyl;
R 9 is C 1-6 -alkyl, C 1-6 -alkoxy or halogen; and
m, n, p and q are each 1;
or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein
R 1 is substituted phenyl-C 1-6 -alkyl, substituted phenoxy-C 1-6 -alkyl, substituted phenyl-C 2-6 -alkenyl, substituted pyridinyl or substituted pyridinyl-C 1-6 -alkyl, wherein substituted phenyl-C 1-6 -alkyl, substituted phenoxy-C 1-6 -alkyl, substituted phenyl-C 2-6 -alkenyl, substituted pyridinyl and substituted pyridinyl-C 1-6 -alkyl are substituted by R 3 , R 4 and R 5 ;
Y is —OC(O)— or —C(O)—;
W is —C(O)—;
R 2 is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted by R 6 , R 7 and R 8 ;
R 3 is halo-C 1-6 -alkoxy, C 1-6 -alkylcarbonylamino or tetrahydropyranyl-C 1-6 -alkoxy;
R 4 is H, C 1-6 -alkyl or C 3-8 -cycloalkyl;
R 5 is H;
R 6 is aminosulfonyl;
R 7 and R 8 are independently selected from H and halogen;
R 9 is C 1-6 -alkyl, C 1-6 -alkoxy or halogen; and
m, n, p and q are 1;
or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is substituted phenyl-C 1-6 -alkyl, substituted phenoxy-C 1-6 -alkyl, substituted phenyl-C 2-6 -alkenyl, substituted pyridinyl or substituted pyridinyl-C 1-6 -alkyl, wherein substituted phenyl-C 1-6 -alkyl, substituted phenoxy-C 1-6 -alkyl, substituted phenyl-C 2-6 -alkenyl, substituted pyridinyl and substituted pyridinyl-C 1-6 -alkyl are substituted by R 3 , R 4 and R 5 .

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is substituted pyridinyl or substituted pyridinyl-C 1-6 -alkyl, wherein substituted pyridinyl and substituted pyridinyl-C 1-6 -alkyl are substituted by R 3 , R 4 and R 5 .

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

6. A 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 by R 6 , R 7 and R 8 .

7. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is halo-C 1-6 -alkoxy, C 1-6 -alkylcarbonylamino or tetrahydropyranyl-C 1-6 -alkoxy.

8. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is tetrahydropyranyl-C 1-6 -alkoxy.

9. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H, C 1-6 -alkyl or C 3-8 -cycloalkyl.

10. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 3-8 -cycloalkyl.

11. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.

12. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are independently selected from H and halogen.

13. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H or halogen.

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

15. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is halogen or C 1-6 -alkoxy.

16. A compound according to claim 1 , wherein
R 1 is substituted pyridinyl or substituted pyridinyl-C 1-6 -alkyl, wherein substituted pyridinyl and substituted pyridinyl-C 1-6 -alkyl are substituted by R 3 , R 4 and R 5 ;
Y is —C(O)—;
W is —C(O)—;
R 2 is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted by R 6 , R 7 and R 8 ;
R 3 is tetrahydropyranyl-C 1-6 -alkoxy;
R 4 is C 3-8 -cycloalkyl;
R 5 is H;
R 6 is aminosulfonyl;
R 7 is H or halogen;
R 8 is H;
R 9 is halogen or C 1-6 -alkoxy; and
m, n, p and q are 1;
or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 1 , wherein:
R 1 is substituted phenyl-C 1-6 -alkyl, substituted phenoxy-C 1-6 -alkyl, substituted phenyl-C 2-6 -alkenyl, substituted pyridinyl or substituted pyridinyl-C 1-6 -alkyl, wherein substituted phenyl-C 1-6 -alkyl, substituted phenoxy-C 1-6 -alkyl, substituted phenyl-C 2-6 -alkenyl, substituted pyridinyl and substituted pyridinyl-C 1-6 -alkyl are substituted by R 3 , R 4 and R 5 ;
Y is —OC(O)— or —C(O)—;
W is —C(O)—;
R 2 is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted by R 6 , R 7 and R 8 ;
R 3 is halo-C 1-6 -alkoxy, C 1-6 -alkylcarbonylamino or tetrahydropyranyl-C 1-6 -alkoxy;
R 4 is H, C 1-6 -alkyl or C 3-8 -cycloalkyl;
R 5 is H;
R 7 and R 8 are independently selected from H and halogen;
R 9 is C 1-6 -alkyl, C 1-6 -alkoxy or halogen; and
m, n, p and q are 1;
or a pharmaceuticall

Assignees

• Hoffmann La Roche

Inventors

• Hert Jerome
• Hunziker Daniel
• Mattei Patrizio
• Rudolph Markus
• Schmitz Petra
• Ullmer Christoph

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• A61P27/02

  Ophthalmic agents · CPC title