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

Patent metadata

Field	Value
Publication number	US-11098048-B2
Application number	US-202016827136-A
Country	US
Kind code	B2
Filing date	Mar 23, 2020
Priority date	Mar 26, 2014
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

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.

First claim

The invention claimed is:

1. A Compound of formula (I)

or a pharmaceutically acceptable salt thereof, 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—, or —C())—NR 10 —;
R 2 is the ring systems B, H, M, O, Z, AJ, AN, AO, AQ, AT, or AV:

R 3 is heterocycloalkoxy substituted with R 11 , R 12 , and R 13 ;
R 4 and R 5 are independently selected from H and cycloalkyl;
m and n are both 1;
p and q are both 2;
R 8 is H, alkyl, haloalkyl, or cycloalkyl;
R 9 is H, alkyl, halogen, haloalkyl, and 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 4 is cycloalkyl.

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

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

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

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

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

9. 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 ;
A is —N—;
W is —C(O)—;
R 2 is the ring system M or AJ;
R 3 is heterocycloalkylalkoxy substituted with R 11 , R 12 and R 13 ;
R 4 is cycloalkyl;
R 5 is H;
m and n are both 1;
p and q are both 2;
R 9 is H; and
R 11 , R 12 and R 13 are H.

10. A compound, wherein the compound is:
((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]azepine-2(1H)-yl)-3-(1H-1,2,3-triazol-4-yl)propan-1-one;
5-((3aR,8aS)-6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepin-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,8aS)-6-(3-cyclopropyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoyl)octahydropyrrolo[3,4-c]azepin-2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-5-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;
(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; or
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;
or a pharmaceutically acceptable salts thereof.

11. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

12. A pharmaceutical composition comprising a compound of claim 10 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

13. A method for the treatment of a condition, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the condition is an ocular condition.

14. The method of claim 13 , wherein the ocular condition is proliferative retinopathy, non-proliferative diabetic retinopathy, dry age-related macular degeneration, wet age-related macular degeneration, macular edema, central arterial occlusion, central venous occlusion, traumatic injury, or glaucoma.

15. A method for the treatment of a condition, comprising administering an effective amount of a compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the condition is an ocular condition.

16. The method of claim 15 , wherein the ocular condition is proliferative retinopathy, non-proliferative diabetic retinopathy, dry age-related macular degeneration, wet age-related macular degeneration, macular edema, central arterial occlusion, central venous occlusion, traumatic injury, or glaucoma.

17. A process to prepare a compound of claim 1 , or a pharmaceutically acceptable salt thereof, the process 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)—:

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

• A61P1/16

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

• A61K31/407

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

• A61K31/55

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

• A61P3/00

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