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

Patent metadata

Field	Value
Publication number	US-10654857-B2
Application number	US-201816226363-A
Country	US
Kind code	B2
Filing date	Dec 19, 2018
Priority date	Mar 26, 2014
Publication date	May 19, 2020
Grant date	May 19, 2020

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 substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with R 3 , R 4 and R 5 ;
A is —N—;
W is —C(O)—, —C(O)O—, —S(O) 2 —, —C(O)—NR 10 — or —CR 6 R 7 —;
R 2 is selected from the ring systems B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, X, Z, AA, AB, AC, AD, AE, AF, AG, AH, AI, AJ, AK, AL, AM, AN, AO, AP, AQ, AR, AS, AT, AU and AV;

R 3 is substituted heterocycloalkoxy, substituted heterocycloalkylalkoxy, substituted heterocycloalkylamino or substituted heterocycloalkylalkylamino, wherein substituted heterocycloalkoxy, substituted heterocycloalkylalkoxy, substituted heterocycloalkylamino and substituted heterocycloalkylalkylamino are substituted with R 11 , R 12 and R 13 ;
R 4 and R 5 are independently selected from H, amino, alkylamino, dialkylamino, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, halogen and cyano;
m, n, p and q are each 1;
R 6 and R 7 are independently H or alkyl;
R 8 is H, alkyl, haloalkyl, or cycloalkyl;
R 9 is H, alkyl, halogen, haloalkyl, or alkoxy;
R 10 is H or alkyl; and
R 11 , R 12 ; and R 13 are independently selected from H, alkyl, alkoxy, cycloalkyl, cycloalkoxy, halogen, haloalkyl, and cyano;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is pyridinyl substituted with R 3 , R 4 and R 5 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is substituted heterocycloalkoxy, substituted heterocycloalkylalkoxy or substituted heterocycloalkylamino, wherein substituted heterocycloalkoxy, substituted heterocycloalkylalkoxy and substituted heterocycloalkylamino are substituted with R 11 , R 12 and R 13 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is substituted heterocycloalkoxy or substituted heterocycloalkylalkoxy, wherein substituted heterocycloalkoxy and substituted heterocycloalkylalkoxy are substituted with R 11 , R 12 and R 13 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is heterocycloalkylalkoxy substituted with R 11 , R 12 and R 13 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is dialkylamino, haloalkyl, cycloalkyl or halogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is cycloalkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 , R 12 and R 13 are H.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is —C(O)—, —C(O)O—, —C(O)—NR 10 — or —CR 6 R 7 —.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is —C(O)—.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is the ring system B, M, O, Z, AJ, AK, or AL.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is the ring system M or AJ.

14. The compound of claim 1 , wherein the compound is:
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-yloxy)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)pyridin-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-((3 aR,6aR)-5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-3-fluorobenzenesulfonamide;
4-((3aS,6aS)-5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)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)(5-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyri din-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;
((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-((3 aR,6aR)-5-(3-cyclopropyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-3-fluorobenzenesulfonamide;
((3aS,6aS)-5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)

Assignees

• Hoffmann La Roche

Inventors

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

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

• A61P3/00

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

• A61P1/16

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/55

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