IP Library › Granted Patent US 8,278,294
Granted Patent B2
US 8,278,294 · App. 12/487,403 · Granted Oct 2, 2012

Substituted isoquinoline and isoquinolinone derivatives as inhibitors of Rho-kinase

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Quick Facts
Patent No.
US 8,278,294
App. No.
12/487,403
Granted
Oct 2, 2012
Kind
B2
Abstract

The invention relates to 6-substituted isoquinoline and isochinolone 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 (231)

1. A compound of the formula (I)

wherein

R 1 is OH;

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

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′,

(C 1 -C 6 )alkylene-R′;

R 5 is

H,

halogen,

CN,

NO 2 ,

(C 1 -C 6 )alkyl,

(C 2 -C 6 )alkenyl,

R′,

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

(C 2 -C 6 )alkenylene-(C 6 -C 10 )aryl,

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

CH(OH)—(C 1 -C 6 )alkyl,

NH 2 ,

NH—R′,

NH—SO 2 H,

NH—SO 2 —(C 1 -C 6 )alkyl,

NH—SO 2 —R′,

NH—C(O)—(C 1 -C 6 )alkyl,

NH—C(O)—R′,

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

C(O)OH, or

C(O)O—(C 1 -C 6 )alkyl;

R 6 is

(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)(C 1 -C 6 )alkyl,

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

C(O)—(C 5 -C 10 )heterocyclyl,

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,

NO 2 ,

(C 1 -C 6 )alkyl,

O—(C 1 -C 6 )alkyl,

(C 2 -C 6 )alkenyl,

R′,

(C 2 -C 6 )alkenylene-(C 6 -C 10 )aryl,

(C 1 -C 6 )alkylene-R′,

CH(OH)—(C 1 -C 6 )alkyl,

NH 2 ,

NH—R′,

NH—SO 2 H,

NH—SO 2 —(C 1 -C 6 )alkyl,

NH—SO 2 —R′,

SO 2 —NH 2 ,

SO 2 —NHR′,

NH—C(O)—(C 1 -C 6 )alkyl,

NH—C(O)—R′,

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 1, 2, 3, 4 or 5;

L is O or O—(C 1 -C 6 )alkylene;

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 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 , 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 3 to R 8 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 1 -C 6 )aryl, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON[(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 )heterocyclylin 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 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 , wherein

R 6 is

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.

3. The compound according to claim 2 , wherein

R 6 is

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

C(O)(C 3 -C 6 )cycloalkyl;

C(O)—(C 5 -C 6 )heterocyclyl wherein the heterocyclyl is unsubstituted;

C(O)(C 1 -C 4 )alkylene-(C 5 -C 10 )heterocyclyl wherein the heterocyclyl is unsubstituted; or

C(O)(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl wherein the aryl is unsubstituted or substituted one or more times by halogen;

and wherein

a (C 1 -C 6 )alkyl residue is unsubstituted or substituted one to three times by a group independently selected from halogen, OH, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ,

a (C 1 -C 4 )alkylene residue is unsubstituted or substituted once by amino or N(CH 3 ) 2 and a (C 3 -C 6 )cycloalkyl residue is unsubstituted or substituted once by NH 2 .

4. A compound of the formula (I)

wherein

R 1 is OH;

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

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, (C 6 -C 10 )aryl, NH—(C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl, (C 5 -C 10 )heterocyclyl or (C 1 -C 6 )alkylene-(C 5 -C 10 )heterocyclyl;

R 6 is (C 1 -C 6 )alkylene-C(O)N[(C 1 -C 4 )alkyl] 2 , C(O)(C 1 -C 6 )alkyl, C(O)(C 3 -C 8 )cycloalkyl, 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 or R′;

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

m is 2, 3 or 4

n is 1, 2 or 3, and

L is O, O-methylene or O-ethylene

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 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 , 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 3 to R 8 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 1 -C 6 )aryl, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON[(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 10 )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 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.

5. A compound of the formula (I)

wherein;

R 1 is OH;

R 2 is (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, (C 2 -C 4 )alkenyl, (C 6 -C 10 )aryl, (C 1 -C 6 )alkylene-(C 6 -C 10 )aryl or (C 5 -C 10 )heterocyclyl;

R 6 is 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 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 or R′;

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

m is 2, 3 or 4

n is 1, 2 or 3; and

L is O

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 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 , 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 3 to R 8 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 1 -C 6 )aryl, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON[(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 substituent of (C 6 -C 10 )aryl and (C 5 -C 10 )heterocyclyl substituent groups may not be further substituted by am aryl or heterocyclyl containing group;

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

6. A compound of the formula (I)

wherein;

R 1 —OH;

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

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, (C 6 -C 10 )aryl, (C 1 -C 2 )alkyl-(C 6 -C 10 )aryl or (C 5 -C 6 )heteroaryl;

R 6 is 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, phenyl, cyclopropyl, (C 5 -C 6 )heteroaryl;

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

m is 3;

n is 1; and

L is O

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

7. A compound selected from the group consisting of:

and a stereoisomeric form, a tautomeric form and a pharmaceutically acceptable salt thereof.

Assignments (2)
CHANGE OF NAME Recorded Jun 20, 2012
From: SANOFI-AVENTIS
To: SANOFI
Reel/Frame 028413/0927 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 20, 2009
From: PLETTENBURG, OLIVER; HOFMEISTER, ARMIN; LOHN, MATTHIAS; BRENDEL, JOACHIM
To: SANOFI-AVENTIS
Reel/Frame 023551/0691 →