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US 8,710,077 B2Granted
Cycloalkylamine substituted isoquinoline and isoquinolinone derivatives
AssigneeSanofi
InventorsOliver Plettenburg, Katrin Lorenz, Jochen Goerlitzer, Matthias Löhn, Sandrine Biscarrat, Fréderic Jeannot, Olivier Duclos
Life of this patent
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Abstract
The invention relates to 6-substituted isoquinoline and isoquinolinone 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.
Claims47
A compound of the formula (I)
- wherein
- R1 is H, OH or NH2;
- R2 is
- (C3-C8)cycloalkyl,
- (C6-C10)aryl,
- (C7-C8)alkyl,
- (C1-C6)alkylene-(C6-C10)aryl,
- (C2-C6)alkenyl,
- (C2-C6)alkynyl,
- (C1-C6)alkylene-C(O)NH2,
- (C1-C6)alkylene-C(O)NH—(C1-C6)alkyl,
- (C1-C6)alkylene-C(O)N[(C1-C6)alkyl]2,
- (C1-C6)alkylene-C(O)O—(C1-C6)alkyl,
- C(O)O—(C1-C6)alkyl,
- C(O)(C1-C6)alkyl,
- C(O)—NH—(C2-C6)alkenyl,
- C(O)—NH—(C2-C6)alkynyl,
- C(O)NH—(C1-C6)alkyl or
- C(O)N[(C1-C6)alkyl]2;
- or
- R2 is (C1-C6)alkyl, provided that in said alkyl residue at least one hydrogen is substituted by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2;
- R3 is
- H,
- halogen,
- (C1-C6)alkyl,
- OH,
- O—R″,
- NH2,
- NHR″,
- NR″R″ or
- NH—C(O)—R″,
- R4 is
- H,
- halogen,
- hydroxy,
- CN,
- (C1-C6)alkyl,
- R5 is
- H,
- halogen,
- CN,
- NO2,
- (C1-C6)alkyl,
- (C2-C6)alkenyl,
- CH(OH)—(C1-C6)alkyl,
- NH2,
- NH—SO2H,
- NH—SO2—(C1-C6)alkyl,
- NH—C(O)—(C1-C6)alkyl,
- C(O)N[(C1-C6)alkyl]2,
- C(O)OH, or
- C(O)O—(C1-C6)alkyl;
- R6 and R6′ are independently of each other
- H,
- (C1-C8)alkyl,
- (C1-C6)alkylene-O—(C1-C6)alkyl,
- (C1-C6)alkylene-C(O)NH2,
- (C1-C6)alkylene-C(O)NH—(C1-C6)alkyl,
- (C1-C6)alkylene-C(O)N[(C1-C6)alkyl]2,
- (C1-C6)alkylene-C(O)O—(C1-C6)alkyl,
- C(O)O—(C1-C6)alkyl,
- C(O)(C1-C6)alkyl,
- C(O)NH—(C1-C6)alkyl,
- C(O)N[(C1-C6)alkyl]2,
- or
- R6 and R6′, together with the N-atom to which they are attached, form a (C5-C10) heterocyclyl group;
- R7 is
- H,
- halogen,
- CN,
- NO2,
- (C1-C6)alkyl,
- O—(C1-C6)alkyl,
- (C2-C6)alkenyl,
- CH(OH)—(C1-C6)alkyl,
- NH2,
- NH—SO2H,
- NH—SO2—(C1-C6)alkyl,
- SO2—NH2,
- NH—C(O)—(C1-C6)alkyl,
- C(O)N[(C1-C6)alkyl]2,
- C(O)OH, or
- C(O)O—(C1-C6)alkyl;
- R8 is H, halogen or (C1-C6)alkyl;
- n is 1;
- m is 3;
- r is 0, 1 or 2 and
- L is O—(CH2)p;
- p 0, 1, 2, 3 or 4;
- R′ is
- (C3-C8)cycloalkyl,
- (C5-C10)heterocyclyl,
- (C6-C10)aryl;
- and
- R″ is
- (C1-C6)alkyl,
- (C1-C6)alkylene-O—(C1-C6)alkyl,
- or
- (C1-C6)alkylene-NRxRy;
- and
- Rx and Ry are independently of each other
- (C1-C6)alkyl,
- (C1-C4)alkylene-NH(C1-C6)alkyl or
- (C1-C4)alkylene-N[(C1-C6)alkyl]2,
- wherein in residues R2, R4, R5, R6, R6′, R7 and R8 as alkyl, alkylene or cycloalkyl can optionally be substituted one or more times by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2;
- wherein in residues R2 to R8 as alkyl or alkylene can optionally be substituted one or more times by halogen;
- wherein in residue R2 as (C6-C10)aryl are unsubstituted or substituted one or more times by a group independently selected from halogen, OH, NO2, N3, CN, C(O)—(C1-C6)alkyl, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C1-C6)alkyl, (C1-C6)alkylene-OH, (C1-C6)alkylene-NH2, (C1-C6)alkylene-NH(C1-C6)alkyl, (C1-C6)alkylene-N[(C1-C6)alkyl]2, (C2-C6)alkenyl, (C2-C6)alkynyl, O—(C1-C6)alkyl, O—C(O)—(C1-C6)alkyl, PO3H2, SO3H, SO2—NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2, S—(C1-C6)alkyl;
- SO—(C1-C6)alkyl, SO2—(C1-C6)alkyl, SO2—N═CH—N[(C1-C6)alkyl]2, C(NH)(NH2), NH2, NH—(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH—C(O)—(C1-C6)alkyl, NH—C(O)O—(C1-C6)alkyl, NH—SO2—(C1-C6)alkyl, N(C1-C6)alkyl-C(O)—(C1-C6)alkyl, N(C1-C6)alkyl-C(O)O—(C1-C6)alkyl, N(C1-C6)alkyl-C(O)—NH—(C1-C6)alkyl], or
- stereoisomeric form thereof and/or tautomeric form thereof and/or pharmaceutically acceptable salt thereof.
106 more elements
A compound selected from the group consisting of
- 6-(4-Allyl-4-amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one,
- 6-(4-Allyl-4-amino-cyclohexyloxy)-2H-isoquinolin-1-one,
- 6-(4-amino-4-benzyl-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one,
- 6-(4-Amino-4-phenyl-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one,
- 6-(4-Aminomethyl-4-phenyl-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one,
- 6-[4-Aminomethyl-4-(4-chloro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[4-Aminomethyl-4-(3-chloro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[4-Aminomethyl-4-(3-methyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[4-Aminomethyl-4-(3,4-dimethoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[4-Aminomethyl-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[4-Aminomethyl-4-(4-methoxy-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[4-Aminomethyl-4-(4-methyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[4-Aminomethyl-4-(3,4-chloro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, and
- C—[4-(7-Chloro-isoquinolin-6-yloxy)-1-phenyl-cyclohexyl]-methylamine), and
- stereoisomeric form thereof and/or tautomeric form thereof and/or pharmaceutically acceptable salt thereof.
12 more elements
A compound selected from the group consisting of
- 6-(4-Allyl-4-amino-cyclohexyloxy)-4,7-dimethyl-2H-isoquinolin-1-one,
- 6-(cis-4-Allyl-4-amino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one,
- 6-(cis-4-Amino-4-cyclopropyl-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one,
- 6-(trans-4-amino-4-cyclopropyl-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one,
- 6-(trans-4-amino-4-cyclopropyl-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one,
- 6-(cis-1-amino-bicyclohexyl-4-yloxy)-7-chloro-2H-isoquinolin-1-one,
- 6-(trans-1-amino-bicyclohexyl-4-yloxy)-7-chloro-2H-isoquinolin-1-one,
- 6-[cis-4-amino-4-(3-methoxy-propyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[trans-4-amino-4-(3-methoxy-propyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-(trans-4-Benzylamino-4-cyclopropyl-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one,
- 7-chloro-6-(trans-4-cyclopropyl-4-isopropylamino-cyclohexyloxy)-2H-isoquinolin-1-one,
- 7-chloro-6-(4-cyclopropyl-4-ethylamino-cyclohexyloxy)-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(3-hydroxy-propyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[trans-4-amino-4-(3-hydroxy-propyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[4-amino-4-(2,3-dihydroxy-propyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-(cis-4-Amino-4-phenyl-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one,
- 6-(trans-4-Amino-4-phenyl-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(4-trifluoromethyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(3,5-dimethyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(3,5-dimethyl-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-difluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(2,6-difluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(2,6-difluoro-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(4-fluoro-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(2,4-difluoro-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(2-fluoro-phenyl)-cyclohexyloxy]-7-methyl-2H-isoquinolin-1-one,
- 6-[cis-4-Amino-4-(3,5-dimethyl-phenyl)-cyclohexyloxy]-7-chloro-2H-isoquinolin-1-one, and
- stereoisomeric form thereof and/or tautomeric form thereof and/or pharmaceutically acceptable salt thereof.
27 more elements
Dependencies are inferred from the claim text.