Bicyclic compounds as ATX inhibitors

Patent metadata

Field	Value
Publication number	US-10787459-B2
Application number	US-201916380863-A
Country	US
Kind code	B2
Filing date	Apr 10, 2019
Priority date	Sep 24, 2015
Publication date	Sep 29, 2020
Grant date	Sep 29, 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 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 or 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;
R 9 is halogen, 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-C 1-6 -alkyl or substituted pyridinyl, wherein substituted phenyl-C 1-6 -alkyl 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 O, AJ, AN and AO;
R 3 is halo-C 1-6 -alkoxy or tetrahydropyranyl-C 1-6 -alkoxy;
R 4 is H or C 3-8 -cycloalkyl;
R 5 is H;
R 6 is C 1-6 -alkyl;
R 9 is halogen, C 1-6 -alkyl or C 1-6 -alkoxy; 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 or substituted pyridinyl, wherein substituted phenyl-C 1-6 -alkyl 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 Y is —C(O)—.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the ring systems O, AJ, AN and AO.

6. A compound according claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the ring systems AJ and AO.

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

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

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

10. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is C 1-6 -alkyl.

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

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

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

14. A compound according to claim 1 , wherein
R 1 is substituted phenyl-C 1-6 -alkyl or substituted pyridinyl, wherein substituted phenyl-C 1-6 -alkyl 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 selected from the ring systems AJ and AO;
R 3 is halo-C 1-6 -alkoxy or tetrahydropyranyl-C 1-6 -alkoxy;
R 4 is H or C 3-8 -cycloalkyl;
R 5 is H;
R 6 is C 1-6 -alkyl;
R 7 is H;
R 9 is C 1-6 -alkoxy; and
m, n, p and q are 1;
or a pharmaceutically acceptable salt thereof.

15. A compound selected from the group consisting of:
trans-5-(1H-benzotriazole-5-carbonyl)-3a-fluoro-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
trans-5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
trans-1-[5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one;
trans-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-(1H-benzotriazol-5-yl)methanone;
trans-5-(1H-benzotriazole-5-carbonyl)-3a-methyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
trans-5-[3a-methoxy-2-[3-[4-(trifluoromethoxy)phenyl]propanoyl]-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]-3-methyl-1H-benzimidazol-2-one;
trans-5-[5-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carbonyl]-3-methyl-1H-benzimidazol-2-one;
trans-[3a-methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone;
trans-1-[3a-methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one;
trans-1-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one;
trans-[5-(3-hydroxy-5,7-dihydro-4H-[1,2]oxazolo[5,4-c]pyridine-6-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone; and
trans-[3a-methoxy-5-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridin-4-yl]methanone;
or a pharmaceutically acceptable salt thereof.

16. A compound of claim 15 , selected from the group consisting of:
trans-1-[5-(1H-benzotriazole-5-carbonyl)-3a-methoxy-3,4,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluorometh

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• 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

• A61P27/02

  Ophthalmic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/407

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