IP Library › Granted Patent US 8,772,492
Granted Patent B2
US 8,772,492 · App. 12/487,409 · Granted Jul 8, 2014

Substituted isoquinoline and isoquinolinone derivatives

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Quick Facts
Patent No.
US 8,772,492
App. No.
12/487,409
Granted
Jul 8, 2014
Kind
B2
Abstract

The invention relates to 6-substituted isoquinoline and isoquinoline derivatives of the formula (I) useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, and compositions containing such compounds.

Claims (350)

1. A compound of the formula (I)

wherein

R 1 is H, OH or NH 2

R 2 is

(C 6 -C 10 )aryl,

(C 7 -C 8 )alkyl,

(C 2 -C 6 )alkenyl,

(C 2 -C 6 )alkynyl,

(C 1 -C 6 )alkylene-C(O)NH 2 ,

(C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-C(O)N[(C 1 -C 6 )alkyl] 2 ,

(C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl,

C(O)O—(C 1 -C 6 )alkyl,

C(O)(C 1 -C 6 )alkyl,

C(O)NH—(C 1 -C 6 )alkyl,

C(O)NHR′,

C(O)—NH(C 2 -C 6 )alkenyl,

C(O)—NH(C 2 -C 6 )alkynyl,

C(O)—NH(C 1 -C 6 )alkylene-R′,

C(O)N[(C 1 -C 6 )alkyl] 2 or

R 2 is (C 1 -C 6 )alkyl, provided that in said alkyl residue at least one hydrogen is substituted by OH, OCH 3 , COOH, COOCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 or CON(CH 3 ) 2 ; or

R 2 is a (C 1 -C 4 )alkylene bound to the cyclic amine, in which the (C 1 -C 4 ) alkylene forms a second bond to a different carbon atom of the cyclic amine ring and forms, together with carbon atoms of cyclic amine, a second, 4-8 membered ring;

R 3 is

H,

halogen,

(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-R′,

OH,

O—R″,

NH 2 ,

NHR″,

NR″R″ or

NH—C(O)—R″,

R 4 is

H,

halogen,

hydroxy,

CN,

(C 1 -C 6 )alkyl;

R 5 is

H,

halogen,

CN,

NO 2 ,

(C 1 -C 6 )alkyl,

(C 2 -C 6 )alkenyl,

CH(OH)—(C 1 -C 6 )alkyl,

NH 2 ,

NH—SO 2 H,

NH—SO 2 —(C 1 -C 6 )alkyl,

NH—C(O)—(C 1 -C 6 )alkyl,

C(O)N[(C 1 -C 6 )alkyl] 2 ,

C(O)OH, or

C(O)O—(C 1 -C 6 )alkyl;

R 6 is

H,

R′,

(C 1 -C 8 )alkyl,

(C 1 -C 6 )alkylene-R′,

(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-O—R′,

(C 1 -C 6 )alkylene-CH[R′] 2 ,

(C 1 -C 6 )alkylene-C(O)—R′,

(C 1 -C 6 )alkylene-C(O)NH 2 ,

(C 1 -C 6 )alkylene-C(O)NH—R′,

(C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-C(O)N[(C 1 -C 6 )alkyl] 2 ,

(C 1 -C 6 )alkylene-C(O)N[R′] 2 ;

(C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl,

C(O)O—(C 1 -C 6 )alkyl,

C(O)OR′,

C(O)(C 1 -C 6 )alkyl,

C(O)R′,

C(O)NH—(C 1 -C 6 )alkyl,

C(O)NHR′,

C(O)N[(C 1 -C 6 )alkyl]R′

C(O)N[(C 1 -C 6 )alkyl] 2 ,

C(O)—(C 1 -C 6 )alkylene-R′, or

C(O)O(C 1 -C 6 )alkylene-R′;

R 7 is

H,

halogen,

CN,

NO 2 ,

(C 1 -C 6 )alkyl,

O—(C 1 -C 6 )alkyl,

(C 2 -C 6 )alkenyl,

CH(OH)—(C 1 -C 6 )alkyl,

NH 2 ,

NH—SO 2 H,

NH—SO 2 —(C 1 -C 6 )alkyl,

SO 2 —NH 2 ,

NH—C(O)—(C 1 -C 6 )alkyl,

C(O)N[(C 1 -C 6 )alkyl] 2 ,

C(O)OH, or

C(O)O—(C 1 -C 6 )alkyl;

R 8 is H, halogen or (C 1 -C 6 )alkyl;

n is 1;

m is 3;

L is O—(CH 2 )p, S(CH 2 )p, S(O)(CH 2 )p, S(O)(CH 2 )p, SO 2 (CH 2 )p, NH(CH 2 )p, N(C 1 -C 6 )alkyl-(CH 2 )p, N(C 3 -C 6 )cycloalkyl-(CH 2 )p, N[CO(C 1 -C 6 )alkyl]-(CH 2 )p or N[(C 1 -C 3 )alkylene-R′]-(CH 2 )p;

p is 0, 1, 2, 3, or 4;

R′ is

(C 3 -C 8 )cycloalkyl,

(C 5 -C 10 )heterocyclyl,

(C 6 -C 10 )aryl;

R″ is

(C 3 -C 8 )cycloalkyl,

(C 5 -C 10 )heterocyclyl,

(C 6 -C 10 )aryl,

(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-R′,

(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-O—R′, or

(C 1 -C 6 )alkylene-NR x R y ; and

R x and R y are independently of each other

(C 1 -C 6 )alkyl,

(C 5 -C 10 )heterocyclyl,

(C 6 -C 10 )aryl,

(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl,

(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl,

(C 1 -C 4 )alkylene-NH(C 1 -C 6 )alkyl,

(C 1 -C 4 )alkylene-N[(C 1 -C 6 )alkyl] 2 ,

(C 1 -C 4 )alkylene-N[(C 6 -C 10 )aryl] 2 , or

(C 1 -C 4 )alkylene-N[(C 5 -C 10 )heterocyclyl] 2 ;

wherein in residues R 2 , R 4 , R 5 , R 6 , R 7 and R 8 as alkyl, alkylene or cycloalkyl can optionally be substituted one or more times by OH, OCH 3 , COOH, COOCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 or CON(CH 3 ) 2 ;

wherein in residues R 2 to R 8 as alkyl or alkylene can optionally be substituted one or more times by halogen;

wherein in residues R 2 , R 3 , R 6 as (C 6 -C 10 )aryl and (C 5 -C 10 )heterocyclyl are unsubstituted or substituted one or more times by suitable groups independently selected from halogen, OH, NO 2 , N 3 , CN, C(O)—(C 1 -C 6 )alkyl, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON[(C 1 -C 6 )alkyl] 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-OH, (C 1 -C 6 )alkylene-NH 2 , (C 1 -C 6 )alkylene-NH(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-N[(C 1 -C 6 )alkyl] 2 , (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, O—(C 1 -C 6 )alkyl, O—C(O)—(C 1 -C 6 )alkyl, PO 3 H 2 , SO 3 H, SO 2 —NH 2 , SO 2 NH(C 1 -C 6 )alkyl, SO 2 N[(C 1 -C 6 )alkyl] 2 , S—(C 1 -C 6 )alkyl; SO—(C 1 -C 6 )alkyl, SO 2 —(C 1 -C 6 )alkyl, SO 2 —N═CH—N[(C 1 -C 6 )alkyl] 2 , C(NH)(NH 2 ), NH 2 , NH—(C 1 -C 6 )alkyl, N[(C 1 -C 6 )alkyl] 2 , NH—C(O)—(C 1 -C 6 )alkyl, NH—C(O)O—(C 1 -C 6 )alkyl, NH—SO 2 —(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl-C(O)—(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl-C(O)O—(C 1 -C 6 )alkyl, N(C 1 -C 6 )alkyl-C(O)—NH—(C 1 -C 6 )alkyl]; or

stereoisomeric form thereof and/or tautomeric form thereof and/or pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , having the formula (II)

3. The compound according to claim 1 , having the formula (III)

4. The compound according to claim 1 , having the formula (III′)

5. The compound according to claim 1 wherein R 1 is NH 2 .

6. The compound according to claim 1 , wherein R 3 is H, halogen, (C 1 -C 4 )alkylene-R′, O—R″ or NHR″.

7. The compound according to claim 6 , wherein R 3 is H or NHR″.

8. The compound according to claim 7 , wherein R 3 is H; NH—(C 5 -C 6 )heterocyclyl, or NH-phenyl.

9. The compound according to claim 8 , wherein R 3 is H.

10. The compound according to claim 1 , wherein R 8 is H, halogen or (C 1 -C 4 )alkyl.

11. The compound according to claim 10 , wherein R 8 is H, Cl, F, methyl or ethyl.

12. The compound according to claim 11 , wherein R 8 is H.

13. The compound according to claim 1 , wherein R 4 is H, halogen or (C 1 -C 6 )alkyl.

14. The compound according to claim 13 , wherein R 4 is H, halogen or (C 1 -C 4 )alkyl.

15. The compound according to claim 14 , wherein R 4 is H.

16. The compound according to claim 1 , wherein R 5 is H, halogen, CN, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl.

17. The compound according to claim 16 , wherein R 5 is H, halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl.

18. The compound according to claim 17 , wherein R 5 is H, halogen, methyl, ethyl, vinyl.

19. The compound according to claim 18 , wherein R 5 is H, halogen, methyl, or ethyl.

20. The compound according to claim 19 , wherein R 5 is H.

21. The compound according to claim 1 , wherein R 7 is H, halogen, CN, (C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl.

22. The compound according to claim 21 , wherein R 7 is H, halogen, CN, (C 1 -C 4 )alkyl, O—(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl.

23. The compound according to claim 22 , wherein R 7 is H, fluoro, chloro, bromo, methyl, ethyl, methoxy, CN, or vinyl.

24. The compound according to claim 23 , wherein R 7 is H, fluoro, chloro, bromo, methyl or methoxy.

25. The compound according to claim 24 , wherein R 7 is H.

26. The compound according to claim 1 , wherein R 2 is (C 6 -C 10 )aryl, (C 7 -C 8 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkylene-C(O)NH 2 , (C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-C(O)N[(C 1 -C 6 )alkyl] 2 , (C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl, C(O)NH—(C 1 -C 6 )alkyl, C(O)NHR′, C(O)—NH(C 2 -C 6 )alkenyl, C(O)—NH(C 2 -C 6 )alkynyl, C(O)—NH(C 1 -C 6 )alkylene-R′, C(O)N[(C 1 -C 6 )alkyl] 2 , or

R 2 is (C 1 -C 6 )alkyl, provided that in said alkyl residue at least one hydrogen is substituted by OH, OCH 3 , COOH, COOCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 or CON(CH 3 ) 2 ; or

R 2 is a (C 1 -C 4 )alkylene bound to the cyclic amine, in which the (C 1 -C 4 ) alkylene forms a second bond to a different carbon atom of the cyclic amine ring and forms, together with carbon atoms of cyclic amine, a second, 4-8 membered ring.

27. The compound according to claim 26 , wherein R 2 is

(C 6 -C 10 )aryl,

(C 2 -C 6 )alkenyl,

(C 1 -C 6 )alkylene-C(O)NH 2 ,

(C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

C(O)NH—(C 1 -C 6 )alkyl,

C(O)NHR′,

C(O)—NH(C 2 -C 6 )alkenyl,

C(O)—NH(C 2 -C 6 )alkynyl, or

C(O)—NH(C 1 -C 6 )alkylene-R′, or

R 2 is (C 1 -C 3 )alkyl, provided that in said alkyl residue at least one hydrogen is substituted by OH, OCH 3 , COOH, COOCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 or CON(CH 3 ) 2 ; or

R 2 is a (C 1 -C 4 )alkylene bound to the cyclic amine, in which the (C 1 -C 4 ) alkylene forms a second bond to a different carbon atom of the cyclic amine ring and forms, together with carbon atoms of cyclic amine, a second, 4-8 membered ring.

28. The compound according to claim 27 , wherein R 2 is

(C 6 -C 10 )aryl,

(C 2 -C 6 )alkenyl,

(C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

C(O)NH—(C 1 -C 6 )alkyl,

C(O)NHR′,

C(O)—NH(C 2 -C 6 )alkynyl, or

C(O)—NH(C 1 -C 6 )alkylene-R′, or

R 2 is a (C 1 -C 2 )alkylene bound to the cyclic amine, in which the (C 1 -C 4 ) alkylene forms a second bond to a different carbon atom of the cyclic amine ring and forms, together with carbon atoms of cyclic amine, a second, 4-8 membered ring.

29. The compound according to claim 1 , wherein

R 6 is

H,

(C 1 -C 6 )alkyl,

R′,

(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl,

(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl,

(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl,

(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl,

(C 1 -C 4 )alkylene-C(O)—(C 5 -C 10 )heterocyclyl,

(C 1 -C 4 )alkylene-C(O)—(C 6 -C 10 )aryl,

(C 1 -C 6 )alkylene-C(O)N[(C 1 -C 6 )alkyl] 2 ,

(C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl,

C(O)O—(C 1 -C 6 )alkyl,

C(O)(C 1 -C 6 )alkyl,

C(O)R′,

C(O)NH—(C 1 -C 6 )alkyl,

C(O)N[(C 1 -C 6 )alkyl] 2 , or

C(O)(C 1 -C 6 )alkylene-R′.

30. The compound according to claim 29 , wherein R 6 is

H,

(C 1 -C 6 )alkyl,

(C 5 -C 10 )heterocyclyl,

(C 3 -C 8 )cycloalkyl,

(C 6 -C 10 )aryl,

(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl,

(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl,

(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl,

(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-C(O)N[(C 1 -C 6 )alkyl] 2 ,

(C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl,

C(O)O—(C 1 -C 6 )alkyl,

C(O)(C 1 -C 6 )alkyl,

C(O)(C 5 -C 10 )heterocyclyl,

C(O)(C 3 -C 8 )cycloalkyl

C(O)NH—(C 1 -C 6 )alkyl,

C(O)N[(C 1 -C 6 )alkyl] 2 ,

C(O)(C 1 -C 6 )alkylene-(C 3 -C 8 )cycloalkyl,

C(O)(C 1 -C 6 )alkylene-C 5 -C 10 )heterocyclyl, or

C(O)(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl.

31. The compound according to claim 30 , wherein

R 6 is

H,

(C 1 -C 6 )alkyl,

(C 3 -C 8 )cycloalkyl,

(C 5 -C 10 )heterocyclyl,

(C 6 -C 10 )aryl,

(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl,

(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl,

(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl,

(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

(C 1 -C 6 )alkylene-C(O)N[(C 1 -C 6 )alkyl] 2 ,

C(O)O—(C 1 -C 6 )alkyl,

C(O)(C 1 -C 6 )alkyl,

C(O)(C 3 -C 8 )cycloalkyl,

C(O)—(C 5 -C 10 )heterocyclyl,

C(O)NH—(C 1 -C 6 )alkyl,

C(O)N[(C 1 -C 6 )alkyl] 2 ,

C(O)(C 1 -C 6 )alkylene-(C 3 -C 8 )cycloalkyl,

C(O)(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, or

C(O)(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl.

32. The compound according to claim 31 , wherein

R 6 is

H,

(C 1 -C 6 )alkyl,

(C 3 -C 8 )cycloalkyl,

(C 6 -C 10 )aryl,

(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl,

(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl,

(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl,

(C 1 -C 4 )alkylene-O—(C 1 -C 4 )alkyl,

C(O)(C 1 -C 6 )alkyl,

C(O)(C 3 -C 8 )cycloalkyl,

C(O)—(C 5 -C 10 )heterocyclyl,

C(O)(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl, or

C(O)(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl.

33. The compound according to claim 32 , wherein

R 6 is

H;

(C 1 -C 6 )alkyl;

(C 3 -C 8 )cycloalkyl;

(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl;

(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl wherein heterocyclyl is unsubstituted or substituted one or more times by (C 1 -C 4 )alkyl;

(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl wherein aryl is unsubstituted or substituted one or more times by halogen, (C 1 -C 4 )alkyl, O—(C 1 -C 4 )alkyl, SO 2 —(C 1 -C 4 )alkyl or SO 2- N[(C 1 -C 6 )alkyl] 2 .

34. The compound according to claim 33 , wherein R 6 is H, (C 1 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl.

35. The compound according to claim 34 , wherein R 6 is H, unsubstituted (C 1 -C 6 )alkyl or unsubstituted (C 3 -C 8 )cycloalkyl.

36. The compound according to claim 35 , wherein R 6 is H.

37. The compound according to claim 1 , wherein m is 3 and L is attached to the 3-position or to the 4-position of the piperidine ring.

38. The compound according to claim 1 , wherein m is 3 and L is attached to the 4-position of the piperidine ring.

39. The compound according to claim 1 , wherein L is S(CH 2 )p, S(O)(CH 2 )p or SO 2 (CH 2 )p.

40. The compound according to claim 1 , wherein L is NH(CH 2 )p or N(C 1 -C 6 )alkyl-(CH 2 )p.

41. The compound according to claim 1 , wherein L is O—(CH 2 )p.

42. The compound according to claim 1 , wherein p is 0.

43. The compound according to claim 1 , wherein

R 1 is H or OH;

R 2 is (C 6 -C 10 )aryl, (C 7 -C 8 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkylene-C(O)NH 2 , (C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-C(O)N[(C 1 -C 6 )alkyl] 2 , (C 1 -C 6 )alkylene-C(O)O—(C 1 -C 6 )alkyl, C(O)NH—(C 1 -C 6 )alkyl, C(O)NHR′, C(O)—NH(C 2 -C 6 )alkenyl, C(O)—NH(C 2 -C 6 )alkynyl, C(O)—NH(C 1 -C 6 )alkylene-R′, C(O)N[(C 1 -C 6 )alkyl] 2 , or

R 2 is (C 1 -C 6 )alkyl, provided that in said alkyl residue at least one hydrogen is substituted by OH, OCH 3 , COOH, COOCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 or CON(CH 3 ) 2 ; or

R 2 is a (C 1 -C 4 )alkylene bound to the cyclic amine, in which the (C 1 -C 4 ) alkylene forms a second bond to a different carbon atom of the cyclic amine ring and forms, together with carbon atoms of cyclic amine, a second, 4-8 membered ring;

R 3 is H, halogen, (C 1 -C 4 )alkylene-R′, O—R″ or NHR″;

R 4 is H, halogen or (C 1 -C 6 )alkyl;

R 5 is H, (C 1 -C 6 )alkyl, halogen, CN, (C 2 -C 6 )alkenyl;

R 6 is H, R′, (C 1 -C 8 )alkyl, (C 1 -C 6 )alkylene-R′, (C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-O—R′, (C 1 -C 6 )alkylene-CH[R′] 2 , (C 1 -C 6 )alkylene-C(O)NH 2 , (C 1 -C 6 )alkylene-C(O)NH—R′, (C 1 -C 6 )alkylene-C(O)N[(C 1 -C 4 )alkyl] 2 , (C 1 -C 6 )alkylene-C(O)N[R′] 2 ; C(O)O—(C 1 -C 6 )alkyl, C(O)(C 1 -C 6 )alkyl, C(O)(C 3 -C 8 )cycloalkyl, C(O)NH—(C 1 -C 6 )alkyl, C(O)N[(C 1 -C 6 )alkyl] 2 , C(O)(C 1 -C 6 )alkylene-(C 3 -C 8 )cycloalkyl, C(O)(C 1 -C 6 )alkylene-C 5 -C 10 )heterocyclyl, or C(O)(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl; R 7 is H, halogen, CN, (C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl;

m is 3

n is 1,

L is O—(CH 2 )p, S(CH 2 )p, NH(CH 2 )p or N(C 1 -C 6 )alkyl-(CH 2 )p, and

p is 0, 1 or 2.

44. The compound according to claim 1 , wherein

R 1 is H or OH;

R 2 is (C 6 -C 10 )aryl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkylene-C(O)NH 2 , C(O)—NH(C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl, C(O)NH—(C 1 -C 6 )alkyl, C(O)NHR′ or C(O)—NH(C 1 -C 6 )alkylene-R′, or

R 2 is (C 1 -C 3 )alkyl, provided that in said alkyl residue at least one hydrogen is substituted by OH, OCH 3 , COOH, COOCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH 3 or CON(CH 3 ) 2 ; or

R 2 is a (C 1 -C 4 )alkylene bound to the cyclic amine, in which the (C 1 -C 4 ) alkylene forms a second bond to a different carbon atom of the cyclic amine ring and forms, together with carbon atoms of cyclic amine, a second, 4-8 membered ring;

R 3 is H, halogen or NHR″;

R 4 is H, halogen or (C 1 -C 4 )alkyl;

R 5 is H, (C 1 -C 6 )alkyl, halogen, (C 2 -C 4 )alkenyl;

R 6 is H, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkyl, (C 1 -C 3 )alkylene-R′, C(O)O—(C 1 -C 6 )alkyl, C(O)(C 1 -C 6 )alkyl, C(O)(C 3 -C 8 )cycloalkyl, C(O)—(C 5 -C 10 )heterocyclyl, C(O)NH—(C 1 -C 6 )alkyl, C(O)N[(C 1 -C 6 )alkyl] 2 , C(O)(C 1 -C 6 )alkylene-(C 3 -C 8 )cycloalkyl, C(O)(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, or C(O)(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl;

R 7 is H, halogen, CN, (C 1 -C 6 )alkyl, O—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl;

m is 3

n is 1;

L is O—(CH 2 )p, S(CH 2 )p or NH(CH 2 )p, and

p is 0 or 1.

45. The compound according to claim 1 , wherein

R 1 is H or OH;

R 2 is

(C 6 -C 10 )aryl,

(C 2 -C 6 )alkenyl,

(C 1 -C 6 )alkylene-C(O)NH—(C 1 -C 6 )alkyl,

C(O)NH—(C 1 -C 6 )alkyl,

C(O)NHR′,

C(O)—NH(C 2 -C 6 )alkynyl or

C(O)—NH(C 1 -C 6 )alkylene-R′, or

R 2 is a (C 1 -C 2 )alkylene bound to the cyclic amine, in which the (C 1 -C 4 ) alkylene forms a second bond to a different carbon atom of the cyclic amine ring and forms, together with carbon atoms of cyclic amine, a second, 4-8 membered ring;

R 3 is H, NH—(C 5 -C 6 )heteroaryl or NH-phenyl;

R 4 is H, halogen or (C 1 -C 4 )alkyl;

R 5 is H, (C 1 -C 4 )alkyl, halogen, (C 2 -C 4 )alkenyl;

R 6 is H, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkyl, (C 1 -C 3 )alkylene-R′; C(O)(C 1 -C 6 )alkyl,

C(O)(C 3 -C 8 )cycloalkyl, C(O)—(C 5 -C 10 )heterocyclyl, C(O)(C 1 -C 3 )alkylene-(C 5 -C 10 )heterocyclyl or C(O)(C 1 -C 3 )alkylene-(C 6 -C 10 )aryl;

R 7 is H, halogen, CN, (C 1 -C 4 )alkyl, O—(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl;

R 8 is H, halogen or (C 1 -C 4 )alkyl;

m is 3;

n is 1; and

L is O, NH or S.

46. A compound selected from the group consisting of

(2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester,

(2R,4R)-4-(Isoquinolin-6-yloxy)-2-o-tolylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester,

(2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid o-tolylamide,

(2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid isobutyl-amide,

(2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid 3-methoxy-benzylamide (11),

(2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid 2-chloro-benzylamide (12),

(2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid phenethyl-amide,

(2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (3-methoxy-propyl)-amide,

(2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (2-hydroxy-ethyl)-amide,

(2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (furan-2-ylmethyl)-amide,

(2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (furan-2-ylmethyl)-amide,

(2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (3-methoxy-propyl)-amide,

(2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid (pyridin-2-ylmethyl)-amide,

(2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid prop-2-ynylamide,

(2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid phenethyl-amide,

(2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid 2-chloro-benzylamide,

(2S,4S)-4-(Isoquinolin-6-yloxy)-piperidine-2-carboxylic acid isobutyl-amide,

6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-isoquinoline, and

6-(1-benzyl-4-phenyl-piperidin-4-yloxy)-7-chloro-isoquinolin-1-one, or

stereoisomeric form thereof and/or tautomeric form thereof and/or pharmaceutically acceptable salt thereof.

47. A compound selected from the group consisting of

6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-2H-isoquinolin-1-one,

6-(8-Aza-bicyclo[3.2.1]oct-3-yloxy)-7-chloro-2H-isoquinolin-1-one,

6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-2H-isoquinolin-1-one,

7-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-2H-isoquinolin-1-one,

7-Methyl-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-2H-isoquinolin-1-one, and

N6-(4-Amino-4-phenyl-cyclohexyl)-isoquinoline-1,6-diamine, or

stereoisomeric form thereof and/or tautomeric form thereof and/or pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound according to claim 1 and/or a pharmacologically acceptable salt thereof, and physiologically tolerated excipient or carriers, and optionally one or more additives and/or one or more other active ingredients.

Assignments (2)
CHANGE OF NAME Recorded Jun 20, 2012
From: SANOFI-AVENTIS
To: SANOFI
Reel/Frame 028413/0927 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 9, 2010
From: PLETTENBURG, OLIVER; LORENZ, KATRIN; GOERLITZER, JOCHEN; LOHN, MATTHIAS
To: SANOFI-AVENTIS
Reel/Frame 023917/0634 →