Bicyclic compounds as autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors

Patent metadata

Field	Value
Publication number	US-9802944-B2
Application number	US-201615272114-A
Country	US
Kind code	B2
Filing date	Sep 21, 2016
Priority date	Mar 26, 2014
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

Compounds of formula (I)

wherein R 1 , R 2 , A, W, m, n, p and q are as described herein, compositions including the compounds and methods of using the compounds as autotaxin inhibitors.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is pyridinyl substituted with R 3 , R 4 , and R 5 ;
A is —N—;
W is —C(O)—;
R 2 is:

R 3 is tetrahydropyranylmethoxy;
R 4 is cycloalkyl;
R 5 is H;
m, n, p and q are independently selected from 1 and 2; and
R 9 is H, alkyl, halogen, haloalkyl or alkoxy;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein m, n, p and q are 1; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein m and n are 1 and p and q are 2; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein m and n are 2 and p and q are 1; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein R 2 is:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein R 2 is:

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein R 2 is:

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein R 2 is:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein R 2 is:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein R 2 is:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein R 2 is:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein R 4 is cyclopropyl; or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is selected from:

5-((3aR,6aR)-5-(2-cyclopropyl-6- ((tetrahydro-2H-pyran-4-yl)methoxy)iso- nicotinoyl)octahydropyrrolo[3,4-c]pyrrole- 2-carbonyl)pyridine-2-sulfonamide;

4-((3aR,6aR)-5-(2-cyclopropyl-6-((tetra- hydro-2H-pyran-4-yl)methoxy)iso- nicotinoyl)octahydropyrrolo[3,4-c]pyrrole- 2-carbonyl)-2-fluorobenzenesulfonamide;

2-chloro-4-((3aR,6aR)-5-(2-cyclopropyl-6- ((tetrahydro-2H-pyran-4-yl)methoxy)iso- nicotinoyl)octahydropyrrolo[3,4-c]pyrrole- 2-carbonyl)benzenesulfonamide;

4-((3aR,6aR)-5-(2-cyclopropyl-6-((tetra- hydro-2H-pyran-4-yl)methoxy)iso- nicotinoyl)octahydropyrrolo[3,4-c]pyrrole- 2-carbonyl)-3-fluorobenzenesulfonamide;

((3aR,8aS)-2-(1H-benzo[d][1,2,3]triazole-5- carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)(2-cyclopropyl-6-((tetrahydro-2H- pyran-4-yl)methoxy)pyridin-4- yl)methanone;

4-((3aS,6aS)-5-(2-cyclopropyl-6-((tetra- hydro-2H-pyran-4-yl)methoxy)iso- nicotinoyl)octahydropyrrolo[3,4-c]pyrrole- 2-carbonyl)benzenesulfonamide;

4-((3aR,8aS)-6-(2-cyclopropyl-6-((tetra- hydro-2H-pyran-4-yl)methoxy)iso- nicotinoyl)decahydropyrrolo[3,4-d]azepine- 2-carbonyl)benzenesulfonamide;

((3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro- 2H-pyran-4-yl)methoxy)isonicotinoyl)- octahydropyrrolo[3,4-d]azepin-2(1H)- yl)(4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazol-5-yl)methanone;

((3aS,6aS)-5-(1H-benzo[d][1,2,3]triazole-5- carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(5-cyclopropyl-6-((tetrahydro-2H- pyran-4-yl)methoxy)pyridin-3- yl)methanone;

((3aS,6aS)-5-(5-cyclopropyl-6-((tetrahydro- 2H-pyran-4-yl)methoxy)nicotinoyl)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)((R)-4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazol-5-yl)methanone;

((3aS,6aS)-5-(1H-benzo[d][1,2,3]triazole-5- carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-cyclopropyl-6-((tetrahydro-2H- pyran-4-yl)methoxy)pyridin-4- yl)methanone;

Assignees

• Hoffmann La Roche

Inventors

• Di Giorgio Patrick
• Hert Jerome
• Hunziker Daniel
• Kuehne Holger
• Mattei Patrizio
• Rudolph Markus

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · 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

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title