Bicyclic compounds as ATX inhibitors

Patent metadata

Field	Value
Publication number	US-10800786-B2
Application number	US-201916380909-A
Country	US
Kind code	B2
Filing date	Apr 10, 2019
Priority date	Sep 24, 2015
Publication date	Oct 13, 2020
Grant date	Oct 13, 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 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 selected from the ring systems B, F, L, M, O, Z, AF, AG, A, AJ, AN, AO, AP, AQ, AR, AS, AT, AU, AV, AW, AX, AY, AZ, BA, BB, BC and BD;

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 H or C 1-6 -alkyl;
R 7 is H, C 1-6 -alkyl, halogen, halo-C 1-6 -alkyl or C 1-6 -alkoxy;
m, n, p and q are independently 1 or 2; and
r is 1, 2 or 3;
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 —R 6 R 7 —;
R 2 is selected from the ring systems B, F, L, M, O, Z, AF, AG, AH, AJ, AN, AO, AP, AQ, AR, AS, AT, AU and AV;

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 H or C 1-6 -alkyl;
R 7 is H, C 1-6 -alkyl, halogen, halo-C 1-6 -alkyl or C 1-6 -alkoxy;
m, n, p and q are independently 1 or 2; and
r is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , wherein
R 1 is substituted phenyl-C 1-6 -alkyl, substituted pyridinyl or substituted pyridinyl-C 1-6 -alkyl, wherein substituted phenyl-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)— or CR 6 R 7 ;
R 2 is selected from the ring systems M, O, Z, AJ, AN, AO, AP, AW, AX, AY, AZ, B, BA, BB, BC and BD;
R 3 is halo-C 1-6 -alkoxy, C 3-8 -cycloalkyl-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, halogen, halo-C 1-6 -alkyl or C 3-8 -cycloalkyl;
R is H or halogen;
R 6 is H or C 1-6 -alkyl;
R 7 is H;
m, n, p and q are 1; and
r is 1;
or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 , wherein
R 1 is substituted phenyl-C 1-6 -alkyl, substituted pyridinyl or substituted pyridinyl-C 1-6 -alkyl, wherein substituted phenyl-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 selected from the ring systems M, O, Z, AJ, AN and AO;
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, halogen, halo-C 1-6 -alkyl or C 3-8 -cycloalkyl;
R 5 is H;
R 6 is C 1-6 -alkyl;
R 7 is H;
m, n, p and q are 1; and
r is 1;
or a pharmaceutically acceptable salt thereof.

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

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

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

8. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the ring systems M, O, Z, AJ, AN, AO, AP, AW, AX, AY, AZ, B, BA, BB, BC and BD.

9. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wher

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• 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

• A61K31/407

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

• C07D519/00

  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

• A61K31/5517

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