Substituted isoquinoline and isoquinolinone derivatives

1. A compound of the formula (I)

wherein

R 1 is H;

R 2 is H, halogen or (C 1 -C 6 )alkyl;

R 3 is

H,

halogen,

(C 1 -C 6 )alkyl,

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′,

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, 2, 3 or 4;

m is 3; and

L is S(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 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl,

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

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

wherein in residues 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 6 as (C 6 -C 10 )aryl and (C 5 -C 10 )heterocyclyl are unsubstituted or substituted one or more times by a suitable group independently selected from halogen, OH, NO 2 , N 3 , CN, C(O)—(C 1 -C 6 )alkyl, C(O)—(C 6 -C 10 )aryl, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CONR[(C 1 -C 6 )alkyl] 2 , (C 3 -C 8 )cycloalkyl, (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, NH—SO 2 —(C 6 -C 10 )aryl, NH—SO 2 —(C 5 -C 10 )heterocyclyl, 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], (C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, O—(C 6 -C 10 )aryl, O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, (C 5 -C 10 )heterocyclyl, (C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, and O—(C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl, wherein the (C 6 -C 10 )aryl or (C 5 -C 10 )heterocyclyl in the substituent may be substituted one to three times by a group independently selected from halogen, OH, NO 2 , CN, O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, NH 2 , NH(C 1 -C 6 )alkyl, N[(C 1 -C 6 )alkyl] 2 , SO 2 CH 3 , COOH, C(O)O—(C 1 -C 6 )alkyl, CONH 2 , (C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylene-O—(C 6 -C 10 )aryl, and

O—(C 1 -C 6 )alkylene-(C 6 -C 10 )aryl; or wherein (C 6 -C 10 )aryl is vicinally substituted by a O—(C 1 -C 4 )alkylene-O group whereby a 5-8-membered ring is formed together with the carbon atoms the oxygen atoms are attached to; and wherein aryl or heterocyclyl substituent of (C 6 -C 10 )aryl and (C 5 -C 10 )heterocyclyl substituent groups may not be further substituted by an aryl or heterocyclyl containing group; 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 , wherein R 3 is H, halogen, O—R″ or NHR″.

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

5. The compound according to claim 4 , wherein R 3 is H.

6. The compound according to claim 5 , wherein R 3 is H.

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

8. The compound according to claim 7 , wherein R 8 is H, Cl, F, methyl or ethyl.

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

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

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

12. The compound according to claim 11 , wherein R 4 is H.

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

14. The compound according to claim 13 , wherein R 5 is H, halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl.

15. The compound according to claim 14 , wherein R 5 is H, halogen, methyl, ethyl, or vinyl.

16. The compound according to claim 15 , wherein R 5 is H, halogen, methyl, or ethyl.

17. The compound according to claim 16 , wherein R 5 is H.

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

19. The compound according to claim 18 , wherein R 7 is H, halogen, CN, (C 1 -C 4 )alkyl, O—(C 1 -C 4 )alkyl, or (C 2 -C 4 )alkenyl.

20. The compound according to claim 19 , wherein R 7 is H, fluoro, chloro, bromo, methyl, ethyl, methoxy, phenyl, CN, or vinyl.

21. The compound according to claim 20 , wherein R 7 is H, fluoro, chloro, bromo, methyl or methoxy.

22. The compound according to claim 21 , wherein R 7 is H.

23. The compound according to claim 1 , wherein R 2 is H, halogen, or (C 1 -C 4 )alkyl.

24. The compound according to claim 23 , wherein R 2 is H or (C 1 -C 2 )alkyl.

25. The compound according to claim 24 , wherein R 2 is H, methyl or ethyl.

26. The compound according to claim 1 , wherein n is 1, 2 or 3.

27. The compound according to claim 26 , wherein n is 1 or 2.

28. The compound according to claim 27 , wherein n is 1.

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 p is 0.

42. The compound according to claim 1 , wherein

R 1 is H;

R 3 is H, halogen, 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, 2 or 3,

L is 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.

43. The compound according to claim 1 , wherein

R 1 is H;

R 2 is H or (C 1 -C 4 )alkyl;

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, or (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, or (C 2 -C 6 )alkenyl;

m is 3;

n is 1, 2 or 3;

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

p is 0 or 1.

44. The compound according to claim 1 , wherein

R 1 is H;

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

R 3 is H;

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

R 5 is H, (C 1 -C 4 )alkyl, halogen, or (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, or (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 NH or S.

45. 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 compounds.