Bicyclic compounds as dual ATX/CA inhibitors

Patent metadata

Field	Value
Publication number	US-10889588-B2
Application number	US-202016889322-A
Country	US
Kind code	B2
Filing date	Jun 1, 2020
Priority date	Sep 24, 2015
Publication date	Jan 12, 2021
Grant date	Jan 12, 2021

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 method, wherein the method is for the treatment of an ocular condition in a mammal, the method comprising administering to the mammal a compound, wherein the compound is of formula (I):

or a pharmaceutically acceptable salt thereof, 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.

2. The method of 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.

3. The method of 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 .

4. The method of 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 .

5. The method of claim 1 , wherein Y is —C(O)—.

6. The method of claim 1 , wherein R 2 is substituted phenyl or substituted pyridinyl, wherein the substituted phenyl or substituted pyridinyl are substituted by R 6 , R 7 and R 8 .

7. The method of claim 1 , wherein R 3 is halo-C 1-6 -alkoxy, C 1-6 -alkylcarbonylamino or tetrahydropyranyl-C 1-6 -alkoxy.

8. The method of claim 1 , wherein R 3 is tetrahydropyranyl-C 1-6 -alkoxy.

9. The method of claim 1 , wherein R 4 is H, C 1-6 -alkyl or C 3-8 -cycloalkyl.

10. The method of claim 1 , wherein R 4 is C 3-8 -cycloalkyl.

11. The method of claim 1 , wherein R 5 is H.

12. The method of claim 1 , wherein R 7 and R 8 are independently selected from H and halogen.

13. The method of claim 1 , wherein R 7 is H or halogen.

14. The method of claim 1 , wherein R 8 is H.

15. The method of claim 1 , wherein R 9 is halogen or C 1-6 -alkoxy.

16. The method of 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.

17. The method of 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.

18. The method of 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 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.

19. The method of claim 1 , wherein the compound

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