BICYCLIC COMPOUNDS AS AUTOTAXIN (ATX) AND LYSOPHOSPHATIDIC ACID (LPA) PRODUCTION INHIBITORS

• US 20170008900A1
• Filed: 09/21/2016
• Published: 01/12/2017
• Est. Priority Date: 03/26/2014
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Di Giorgio, Patrick, Hert, Jerome, Hunziker, Daniel, Kuehne, Holger, Mattei, Patrizio, Rudolph, Markus
• Granted Patent: US 9,802,944 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 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

Abstract

Compounds of formula (I)

wherein R¹, R², A, W, m, n, p and q are as described herein, compositions including the compounds and methods of using the compounds as autotaxin inhibitors.

Claims

1. A Compound of formula (I)

2. The compound of claim 1, wherein R¹ is pyridinyl substituted with R³, R⁴ and R⁵.

3. The compound of claim 1, wherein R³ is substituted heterocycloalkoxy, substituted heterocycloalkylalkoxy or substituted heterocycloalkylamino, wherein substituted heterocycloalkoxy, substituted heterocycloalkylalkoxy and substituted heterocycloalkylamino are substituted with R¹¹, R¹² and R¹³.

4. The compound of claim 1, wherein R³ is substituted heterocycloalkoxy or substituted heterocycloalkylalkoxy, wherein substituted heterocycloalkoxy and substituted heterocycloalkylalkoxy are substituted with R¹¹, R¹² and R¹³.

5. The compound of claim 1, wherein R³ is heterocycloalkylalkoxy substituted with R¹¹, R¹² and R¹³.

6. The compound of claim 1, wherein R⁴ is dialkylamino, haloalkyl, cycloalkyl or halogen.

7. The compound of claim 1, wherein R⁴ is cycloalkyl.

8. The compound of claim 1, wherein R⁵ is H.

9. The compound of claim 1, wherein R¹¹, R¹² and R¹³ are H.

10. The compound of claim 1, wherein A is —

N—

.

11. The compound of claim 1, wherein W is —

C(O)—

, —

C(O)O—

, —

C(O)—

NR¹⁰—

or —

CR⁶R⁷—

.

12. The compound of claim 1, wherein W is —

C(O)—

.

13. The compound of claim 1, wherein R² is selected from the ring systems B, M, O, Z, AJ, AK, or AL.

14. The compound of claim 1, wherein R² is the ring system M or AJ.

15. The compound of claim 1, wherein m and n are 1 and p and q are 2.

16. The compound of claim 1, wherein

R¹ is pyridinyl substituted with R³, R⁴ and R⁵;

A is —

N—

;

W is —

C(O)—

;

R² is the ring system M or AJ;

R³ is heterocycloalkylalkoxy substituted with R¹¹, R¹² and R¹³;

R⁴ is cycloalkyl;

R⁵ is H;

m and n are 1;

p and q are 2;

R⁹ is H;

R¹¹, R¹² and R¹³ are H;

or pharmaceutically acceptable salts.

17. The compound of claim 1, selected from

5-((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridine-2-sulfonamide;

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

4-((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;

4-((3aR,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;

((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;

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

((3aR,6aR)-5-(1H-benzo[d][1,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-cyclopropyl-4-(tetrahydrofuran-3-yloxy)phenyl)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-ylamino)pyridin-3-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-(tetrahydrofuran-3-yloxy)pyridin-3-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-3-yloxy)pyridin-3-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-yloxy)pyridin-3-yl)methanone;

((3aS,6aS)-5-(1H-benzo[d][1,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-(oxetan-3-yloxy)-5-(trifluoromethyl)pyri din-3-yl)methanone;

((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)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;

4-((3aR,6aR)-5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-2-fluorobenzenesulfonamide;

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

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

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

((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;

1-((3aS,6aS)-5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(1H-1,2,3-triazol-5-yl)propan-1-one;

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

1-((3aR,8aS)-6-(3-cyclopropyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)-3-(1H-1,2,3-triazol-4-yl)propan-1-one;

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

4-((3aS,6aS)-5-(3-cyclopropyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;

4-((3aR,6aR)-5-(3-cyclopropyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-3-fluorobenzenesulfonamide;

5-((3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepine-2-carbonyl)-1H-benzo[d]imidazol-2(3H)-one;

6-((3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepine-2-carbonyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

5-(3-((3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)-3-oxopropyl)oxazol-2(3H)-one;

5-(3-((3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)-3-oxopropyl)thiazol-2(3H)-one;

1-((3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)-3-(3-hydroxyisoxazol-5-yl)propan-1-one;

((3aS,6aS)-5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)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-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-ylamino)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-(5-cyclopropyl-6-(tetrahydro-2H-pyran-3-yloxy)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;

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

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

((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-3-yl)methoxy)pyridin-4-yl)methanone;

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

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

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

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

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

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

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

6-(((3aS,6aS)-5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)benzo[d]oxazol-2(3H)-one;

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

((3aR,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;

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

((3aR,8aS)-6-(3-cyclopropyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoyl)octahydropyrrolo[3,4-d]azepin-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)(3-cyclopropyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)methanone;

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

6-((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzo[d]oxazol-2(3H)-one;

6-((3aS,6aS)-5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzo[d]oxazol-2(3H)-one;

6-((3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepine-2-carbonyl)benzo[d]oxazol-2(3H)-one;

6-(((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)benzo[d]oxazol-2(3H)-one;

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

((3aR,6aR)-5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone;

1-((3aR,6aR)-5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)piperidine-4-sulfonamide;

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

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

(3aR,8aS)-N-((1H-1,2,3-triazol-4-yl)methyl)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepine-2(1H)-carboxamide;

(3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)-N-((3-hydroxyisoxazol-5-yl)methyl)octahydropyrrolo[3,4-d]azepine-2(1H)-carboxamide;

1H-triazol-4-ylmethyl (3aS,8aR)-6-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]-1,3,3a,4,5,7,8,8a-octahydropyrrolo[3,4-d]azepine-2-carboxylate;

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

((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)(2-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-4-yl)methanone;

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

and pharmaceutically acceptable salts thereof.

18. The compound of claim 1, selected from

5-((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridine-2-sulfonamide;

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

4-((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;

4-((3aR,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;

((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;

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

((3aR,6aR)-5-(1H-benzo[d][1,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-cyclopropyl-4-(tetrahydrofuran-3-yloxy)phenyl)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-ylamino)pyridin-3-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-(tetrahydrofuran-3-yloxy)pyridin-3-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-3-yloxy)pyridin-3-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-yloxy)pyridin-3-yl)methanone;

((3aS,6aS)-5-(1H-benzo[d][1,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-(oxetan-3-yloxy)-5-(trifluoromethyl)pyri din-3-yl)methanone;

((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)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;

and pharmaceutically acceptable salts thereof.

19. The compound of claim 1, selected from

5-((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridine-2-sulfonamide;

((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;

((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)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;

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

4-((3aR,6aR)-5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)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;

5-((3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepine-2-carbonyl)-1H-benzo[d]imidazol-2(3H)-one;

6-((3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepine-2-carbonyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

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

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

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

6-((3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepine-2-carbonyl)benzo[d]oxazol-2(3H)-one;

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

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

and pharmaceutically acceptable salts thereof.

20. The compound of claim 1, selected from

5-((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridine-2-sulfonamide;

((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;

((3aS,6aS)-5-(5-cyclopropyl-6-(tetrahydro-2H-pyran-4-yloxy)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;

and pharmaceutically acceptable salts thereof.

21. A process to prepare a compound of claim 1 comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein A is —

N— and

W is —

C(O)—

;

22. A pharmaceutical composition comprising a compound of claim 1 and a therapeutically inert carrier.

23. A method for the treatment or prophylaxis a renal condition selected from the group consisting of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection, which method comprises administering an effective amount of a compound of claim 1.