Bicyclic compounds as dual ATX/CA inhibitors

Patent metadata

Field	Value
Publication number	US-10647719-B2
Application number	US-201815933701-A
Country	US
Kind code	B2
Filing date	Mar 23, 2018
Priority date	Sep 24, 2015
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

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

wherein R 1 , R 2 , 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 quinolinyl, substituted quinolinyl-C 1-6 -alkyl, substituted quinolinyl-C 1-6 -alkenyl, substituted quinolinyl-C 1-6 -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 quinolinyl, substituted quinolinyl-C 1-6 -alkyl, substituted quinolinyl-C 1-6 -alkenyl, substituted quinolinyl-C 1-6 -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, heterocycloalkyl-C 1-6 -alkoxy or C 1-6 -alkylpiperidinyl-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; and
m, n, p and q are independently selected from 1 and 2;
or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , 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; and
m, n, p and q are independently selected from 1 and 2;
or a pharmaceutically acceptable salt thereof.

3. 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 quinolinyl-C 1-6 -alkyl, 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 quinolinyl-C 1-6 -alkyl, 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, C 1-6 -alkyltetrazolyl-C 1-6 -alkyl, C 1-6 -alkylpiperidinyl-C 1-6 -alkoxy or tetrahydropyranyl-C 1-6 -alkoxy;
R 4 is H, cyano, halogen, C 1-6 -alkyl, halo-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;
m and q are 1; and
n and p are independently selected from 1 and 2;
or a pharmaceutically acceptable salt thereof.

4. 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, C 1-6 -alkyltetrazolyl-C 1-6 -alkyl or tetrahydropyranyl-C 1-6 -alkoxy;
R 4 is H, cyano, halogen, C 1-6 -alkyl, halo-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;
m and q are 1; and
n and p are independently selected from 1 and 2;
or a

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · 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