NEW OCTAHYDRO-PYRROLO[3,4-c]-PYRROLE DERIVATIVES AND ANALOGS THEREOF AS AUTOTAXIN INHIBITORS

• US 20150376194A1
• Filed: 09/10/2015
• Published: 12/31/2015
• Est. Priority Date: 03/12/2013
• Status: Abandoned Application

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Hert, Jerome, Hunziker, Daniel, Mattei, Patrizio, Mauser, Harald, Tang, Guozhi, Wang, Lisha
• Application Number:
  US14/850,497
• Publication Number:
  US 20150376194A1
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

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

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

Claims

1. A Compound of formula (I)

2. The compound according to claim 1, wherein R¹ is substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl, or substituted isoquinolyl, wherein substituted phenyl, substituted phenylalkyl, substituted phenylalkenyl, substituted naphthyl, substituted indolyl, substituted quinolyl and substituted isoquinolyl are substituted with R⁷, R⁸ and R⁹.

3. The compound according to claim 1, wherein R¹ is phenylalkyl substituted with R⁷, R⁸ and R⁹.

4. The compound according to claim 1, wherein R¹ is 3,5-dichlorobenzyl, 4-trifluoromethoxybenzyl or 4-trifluoromethoxyphenylethyl.

5. The compound according to claim 1, wherein R² is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with R¹⁰, R¹¹ and R¹².

6. The compound according to claim 1, wherein R² is phenyl substituted phenyl with R¹⁰, R¹¹ and R¹².

7. The compound according to claim 1, wherein R² is 4-aminosulfonylphenyl, 3-fluoro-4-aminosulfonylphenyl, 3-aminosulfonylpyridin-6-yl or 2-aminosulfonylpyridin-5-yl.

8. The compound according to claim 1, wherein Y is —

OC(O)—

or —

C(O)—

.

9. The compound according to claim 1, wherein A is —

N—

.

10. The compound according to claim 1, wherein W is —

C(O)—

or —

S(O)₂—

.

11. The compound according to claim 1, wherein W is —

C(O)—

.

12. The compound according to claim 1, wherein R⁷, R⁸ and R⁹ are independently selected from H, alkoxy, haloalkoxy, halogen, alkylsulfonyl and phenyl substituted with one halogen, and wherein at least one of R⁷, R⁸ and R⁹ is not H.

13. The compound according to claim 1, wherein R⁷ is alkoxy, haloalkoxy, halogen or phenyl substituted with one halogen.

14. The compound according to claim 1, wherein R⁷ is haloalkoxy or halogen.

15. The compound according to claim 1, wherein R⁸ is H, halogen or alkylsulfonyl.

16. The compound according to claim 1, wherein R⁸ is H or halogen.

17. The compound according to claim 1, wherein R⁹ is H.

18. The compound according to claim 1, wherein R¹⁰ is aminosulfonyl.

19. The compound according to claim 1, wherein R¹¹ and R¹² are independently selected from H, alkyl and halogen.

20. The compound according to claim 1, wherein R¹¹ and R¹² are independently selected from H and halogen.

21. The compound according to claim 1, wherein m and n are 1.

22. The compound according to claim 1, wherein m, n, p and q are 1.

23. The compound according to claim 1 of formula (Ia).

24. The compound according to claim 1, selected from

(3aR,6aS)-3,5-dichlorobenzyl 5-(4-(N-methylsulfamoyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aR,6aS)-3,5-dichlorobenzyl 5-(5-hydroxypicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aR,6aS)-3,5-dichlorobenzyl 5-(4-hydroxybenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5 (6H)-carboxylate;

(3aR,6aS)-3,5-dichlorobenzyl 5-(5-sulfamoylthiophene-2-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aR,6aS)-3,5-dichlorobenzyl 5-(4-aminobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aR,6aS)-3,5-dichlorobenzyl 5-(5-aminopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aR,6aS)-3,5-dichlorobenzyl 5-(4-cyanobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aR,6aS)-3,5-dichlorobenzyl 5-(4-(methoxycarbonyl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

4-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4-d]azepine-2-carbonyl}-benzenesulfonamide;

(3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aS,6aS)-5-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aS,6aS)-5-(1-methyl-4-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aS,6aS)-5-(1-methyl-5-sulfamoyl-1H-pyrrole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aS,6aS)-5-(5-hydroxy-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aS,6aS)-5-(4-hydroxy-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aR,6aS)-3,5-dichlorobenzyl 5-(4-acetamidobenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aR,6aS)-3,5-dichlorobenzyl 5-(5-acetamidopicolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylphenylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aR,6aS)-3,5-dichlorobenzyl 5-(4-(1H-tetrazol-5-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

4-((3aR,6aS)-5-((3,5-dichlorobenzyloxy)carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzoic acid;

(3aR,6aS)-3,5-dichlorobenzyl 5-(5-(methylsulfonamido)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;

(3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-fluoro-4-trifluoromethoxy-benzyl ester;

(3aR,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

4-{(3 aR,6aR)-5-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;

4-{(3 aR,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;

4-[(3aR,6aS)-5-(4-isopropoxy-naphthalene-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;

4-{(3 aR,6aS)-5-[1-(2,2,2-trifluoro-ethoxy)-isoquinoline-3-carbonyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;

4-[(3 aR,6aS)-5-(1-Methyl-5-trifluoromethoxy-1H-indole-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;

4-[(3 aR,6aS)-5-(4-Isopropoxy-quinoline-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;

4-[(3 aS,6aR)-5-(4′

-chloro-biphenyl-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzenesulfonamide;

4-{(3 aS,6aR)-5-[3-(2-fluoro-4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;

4-{(3 aS,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;

4-((3aR,6aR)-5-(3-(2-fluoro-4-(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;

(+)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5 (6H)-carboxylate;

(−

)-trans-3,5-dichlorobenzyl 2-(4-sulfamoylbenzoyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate;

(3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

5-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-pyridine-2-sulfonic acid amide;

5-((3aS,6aS)-5-(4-ethoxyquinoline-2-carbonyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridine-2-sulfonamide;

(3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;

(3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;

(3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzylester;

(3aS,6aS)-5-(2-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;

(3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;

and pharmaceutically acceptable salts thereof.

25. A compound according to claim 1, selected from

(3aR,6aS)-3,5-dichlorobenzyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

(3aS,6aS)-5-(3-fluoro-4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aS,6aS)-5-(6-sulfamoyl-pyridine-3-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aS,6aS)-5-(4-sulfamoyl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

4-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl}-benzenesulfonamide;

(3aS,6aS)-5-(5-sulfamoyl-pyridine-2-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2-dimethyl-propionylamino)-benzyl ester;

and pharmaceutically acceptable salts thereof.

26. A process to prepare a compound according to claim 1 comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein R¹, R², A, W, m, n, p and q are as defined above, Y is —

OC(O)—

.

28. A pharmaceutical composition comprising a compound according to claim 1 and a therapeutically inert carrier.

32. 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 according to claim 1.

27. (canceled)

29-31. -31. (canceled)

33-34. -34. (canceled)