Indenoisoquinolinone analogs and methods of use thereof

Abstract

The present invention relates to Indenoisoquinolinone Analogs, compositions comprising an effective amount of an Indenoisoquinolinone Analog and methods for treating or preventing an inflammatory disease, a reperfusion injury, diabetes mellitus, a diabetic complication, reoxygenation injury resulting from organ transplantation, an ischemic condition, a neurodegenerative disease, renal failure, a vascular disease, a cardiovascular disease, cancer, a complication of prematurity, cardiomyopathy, retinopathy, nephropathy, neuropathy, erectile dysfunction or urinary incontinence, comprising administering to a subject in need thereof an effective amount of an Indenoisoquinolinone Analog.

1 . A compound having the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof 
     wherein
 X is —CH 2 —, —O—, —C(O)—, —NH— or —S—; 
 R 1  is —(CH 2 ) n —N(R 2 )(R 2 ), —O—(CH 2 ) m —N(R 2 )(R 2 ), —(CH 2 ) n —OR 3  or —O—(CH 2 ) m ,—OR 3 ; 
 each R 2  is independently —H, —C 1 -C 6  alkyl, —C 3 -C 8  monocyclic cycloalkyl, —C 1 -C 6  alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C 1 -C 6  alkyl ester of an N-terminal alpha amino acid residue, or a nitrogen-containing 3- to 7-membered monocyclic heterocycle, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6  alkyl, —O—C 1 -C 6  alkyl, —C 3 -C 8  monocyclic, a 3- to 7-membered monocyclic heterocycle, —C 1 -C 6  alkyl-substituted 3- to 7-membered monocyclic heterocycle, or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H, —C 1 -C 5  alkyl, —C 1 -C 5  alkylene-O—C 1 -C 5  alkyl, benzyl, or —C 3 -C 8  monocyclic cycloalkyl, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —N(R a ) 2 , —C 1 -C 5  alkylene-O—C 1 -C 5  alkyl, —NH 2 , a nitrogen-containing 3-to 7-membered monocyclic heterocycle, or an —C 1 -C 6  alkyl-substituted nitrogen-containing 3- to 7-membered monocyclic heterocycle, wherein each occurrence of R a  is independently —H, benzyl, or —C 1 -C 10  alkyl; 
 or N, Z 3  and Z 4  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more of —C 1 -C 5  alkyl, phenyl, -phenyl-substituted C 1 -C 5  alkyl, -hydroxy-substituted C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, -halo-substituted phenyl, -phenylene-O—C 1 -C 5  alkyl, -cyanosubstituted phenyl, —OH, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —C 1 -C 5  alkylene-N(R a ) 2 , —C 1 -C 5  alkylene-C(O)O—C 1 -C 5  alkylene-N(R a ) 2 , —COOH, —C 1 -C 3  alkylene-COOH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 5  alkylene-OP(O)(OH) 2 , —C 1 -C 5  alkylene-OS(O) 2 OH, —C(O)O—C 1 -C 5  alkyl, —OC(O)—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C(O)O—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C(O)NH—C 1 -C 5  alkyl, —C(O)NH 2 , or —CO 2 , wherein each occurrence of R a  is independently —H, benzyl, or —C 1 -C 10  alkyl; 
 or N and both R a  groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle; 
 or N and both R 2  groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle or a nitrogen-containing 7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of —C 1 -C 5  alkyl, —C 3 -C 8  monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, phenyl-substituted C 1 -C 5  alkyl, -hydroxy-substituted C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, -halo-substituted phenyl, -phenylene-O—C 1 -C 5  alkyl, -cyanosubstituted phenyl, —OH, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —C 1 -C 5  alkylene-N(R a ) 2 , —C 1 -C 5  alkylene-C(O)O—C 1 -C 5  alkylene-N(R a ) 2 , —COOH, —C 1 -C 5  alkylene-O—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C 3 -C 8  monocyclic cycloalkyl, —C 1 -C 5  alkylene-COOH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 5  alkylene-OP(O)(OH) 2 , —C 1 -C 5  alkylene-OS(O) 2 OH, —C(O)O—C 1 -C 5  alkyl, —OC(O)—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C(O)O—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C(O)NH—C 1 -C 5  alkyl, —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, —C 1 -C 10  alkyl; 
 or N and both R a  groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle; 
 R 3  is —H, —PO 3 H 2 , —P 2 O 6 H 3 , —P 3 O 9 H 4 , —SO 3 H, —C(O)—C 1 -C 9  alkyl, β-D-glucuronyl, or a C-terminal alpha amino acid residue; 
 n is an integer ranging from 1 to 10; and 
 m is an integer ranging from 2 to 10. 
 
   
   
       2 - 7 . (canceled) 
   
   
       8 . A compound having the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof 
     wherein
 X is —CH 2 —, —O—, —C(O)—, —NH— or —S—; 
 R 1  is —(CH 2 ) n —N(R 2 )(R 2 ), —O—(CF 2 ) m —N(R 2 )(R 2 ), or —O—(CH 2 ) m —OR 3 ; 
 each R 2  is independently —H, —C 1 -C 6  alkyl, —C 3 -C 8  monocyclic cycloalkyl, —C 1 -C 6  alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C 1 -C 6  alkyl ester of an N-terminal alpha amino acid residue, or a nitrogen-containing 3- to 7-membered monocyclic heterocycle, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O)2OH, —C 1 -C 6  alkyl, —O—C 1 -C 6  alkyl, —C 3 -C 8  monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —C 1 -C 6  alkyl-substituted 3- to 7-membered monocyclic heterocycle, or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —C 1 -C 5  alkyl, —C 1 -C 5  alkylene-O—C 1 -C 5  alkyl, benzyl, or —C 3 -C 8  monocyclic cycloalkyl, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —N(R a ) 2 , —C 1 -C 5  alkylene-O—C 1 -C 5  alkyl, —NH 2 , a nitrogen-containing 3-to 7-membered monocyclic heterocycle, or an —C 1 -C 6  alkyl-substituted nitrogen-containing 3- to 7-membered monocyclic heterocycle, wherein each occurrence of R a  is independently —H, benzyl, or —C 1 -C 10  alkyl; 
 or N, Z 3  and Z 4  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more of —C 1 -C 5  alkyl, phenyl, -phenyl-substituted C 1 -C 5  alkyl, -hydroxy-substituted C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, -halo-substituted phenyl, -phenylene-O—C 1 -C 5  alkyl, -cyanosubstituted phenyl, —OH, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —C 1 -C 5  alkylene-N(R a ) 2 , —C 1 -C 5  alkylene-C(O)O—C 1 -C 5  alkylene-N(R a ) 2 , —COON, —C 1 -C 5  alkylene-COOH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 5  alkylene-OP(O)(OH) 2 , —C 1 -C 5  alkylene-OS(O) 2 OH, —C(O)O—C 1 -C 5  alkyl, —OC(O)—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C(O)O—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C(O)NH—C 1 -C 5  alkyl, —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, benzyl, or —C 1 -C 10  alkyl; 
 or N and both R a  groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle; 
 or N and both R 2  groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle or a nitrogen-containing 7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of —C 1 -C 5  alkyl, —C 3 -C 8  monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, phenyl-substituted C 1 -C 5  alkyl, -hydroxy-substituted C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, -halo-substituted phenyl, -phenylene-O—C 1 -C 5  alkyl, -cyanosubstituted phenyl, —OH, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —C 1 -C 5  alkylene-N(R a ) 2 , —C 1 -C 5  alkylene-C(O)O—C 1 -C 5  alkylene-N(R a ) 2 , —COOH, —C 1 -C 5  alkylene-O—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C 3 -C 8  monocyclic cycloalkyl, —C 1 -C 5  alkylene-COOH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 5  alkylene-OP(O)(OH) 2 , —C 1 -C 5  alkylene-OS(O) 2 OH, —C(O)O—C 1 -C 5  alkyl, —OC(O)—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C(O)O—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C(O)NH-C 1 -C 5  alkyl, —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, —C 1 -C 10  alkyl; 
 or N and both R a  groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle; 
 R 3  is —H, —PO 3 H 2 , —P 2 O 6 H 3 , —P 3 O 9 H 4 , —SO 3 H, —C(O)—C 1 -C 9  alkyl, β-D-glucuronyl, or a C-terminal alpha amino acid residue; 
 n is an integer ranging from 1 to 10; and 
 m is an integer ranging from 2 to 10. 
 
   
   
       9 - 14 . (canceled) 
   
   
       15 . A compound having the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof 
     wherein
 R 1  is —(CH 2 ) n —OR 3 ; 
 R 3  is —H, —PO 3 H 2 , —P 2 O 6 H 3 , —P 3 O 9 H 4 , —SO 3 H, —C(O)—C 1 -C 9  alkyl, β-D-glucuronyl, or a C-terminal alpha amino acid residue; and 
 n is an integer ranging from 1 to 3. 
 
   
   
       16 - 17 . (canceled) 
   
   
       18 . A compound having the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof 
     wherein
 X is —CH 2 —, —O—, —C(O)—, —NH— or —S—; 
 R 1  is —(CH 2 ) n —N(R 2 )(R 2 ), —O—(CH 2 ) m —N(R 2 )(R 2 ), —(CH 2 ) n —OR 3  or —O—(CH 2 ) m —OR 3 ; 
 each R 2  is independently —H, —C 1 -C 6  alkyl, —C 3 -C 8  monocyclic cycloalkyl, —C 1 -C 6  alkylene phenyl, phenyl, an N-terminal alpha amino acid residue, an N-terminal alpha amino hydroxymethyl residue, a C 1 -C 6  alkyl ester of an N-terminal alpha amino acid residue, or a nitrogen-containing 3- to 7-membered monocyclic heterocycle, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 6  alkyl, —O—C 1 -C 6  alkyl, —C 3 -C 8  monocyclic cycloalkyl, a 3- to 7-membered monocyclic heterocycle, —C 1 -C 6  alkyl-substituted 3- to 7-membered monocyclic heterocycle, or —N(Z 3 )(Z 4 ), where Z 3  and Z 4  are independently —H, —C 1 -C 5  alkyl, —C 1 -C 5  alkylene-O—C 1 -C 5  alkyl, benzyl, or —C 3 -C 8  monocyclic cycloalkyl, each of which other than hydrogen is independently unsubstituted or substituted with one or more of -halo, —OH, —N(R a ) 2 , —C 1 -C 5  alkylene-O—C 1 -C 5  alkyl, —NH 2 , a nitrogen-containing 3-to 7-membered monocyclic heterocycle, or an —C 1 -C 6  alkyl-substituted nitrogen-containing 3- to 7-membered monocyclic heterocycle, wherein each occurrence of R a  is independently —H, benzyl, or —C 1 -C 10  alkyl; or N, Z 3  and Z 4  are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more of-C1-C5 alkyl, phenyl, -phenyl-substituted C 1 -C 5  alkyl, -hydroxy-substituted C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -C 5  alkyl, -halo-substituted phenyl, -phenylene-O—C 1 -C 5  alkyl, -cyano-substituted phenyl, —OH, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —C 1 -C 5  alkylene-N(R a ) 2 , —C 1 -C 5  alkylene-N(R a ) 2 , —COOH, —C 1 -C 5  alkylene-COOH, —OP(O)(OH) 2 , —OS(O) 2 OH, —C 1 -C 5  alkylene-OP(O)(OH) 2 , —C 1 -C 5  alkylene-OS(O) 2 OH, —C(O)O—C 1 -C 5  alkyl, —OC(O)—C 1 -C 5  alkyl, —C—C 5  alkylene-C(O)O—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C(O)NH—C 1 -C 5  alkyl, —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, benzyl, or —C 1 -C 10  alkyl; 
 or N and both R a  groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle; 
 or N and both R 2  groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle or a nitrogen-containing 7- to 10-membered bicyclic heterocycle, each of which is unsubstituted or substituted with one or more of —C 1 -C 5  alkyl, —C 3 -C 8  monocyclic cycloalkyl, phenyl, a nitrogen-containing 3- to 7-membered monocyclic heterocycle, phenyl-substituted C 1 -C 5  alkyl, -hydroxy-substituted C 1 -C 5  alkyl, -halo, -halo-substituted C 1 -Cs alkyl, -halo-substituted phenyl, -phenylene-O—C 1 -C 5  alkyl, -cyanosubstituted phenyl, —OH, —O—C 1 -C 5  alkyl, —N(R a ) 2 , —C 1 -C 5  alkylene-N(R a ) 2 , —C1-C5 alkylene-C(O)O—C 1 -C 5  alkylene-N(R a ) 2 , —COOH, —C 1 -C 5  alkylene-O—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C 3 -C 8  monocyclic cycloalkyl, —C 1 -C 5  alkylene-COOH, —OP(O)(OH)2, —OS(O)2OH, —C 1 -C 5  alkylene-OP(O)(OH) 2 , —C 1 -C 5  alkylene-OS(O) 2 OH, —C(O)O—C 1 -C 5  alkyl, —OC(O)—C 1 -C 5  alkylene-C(O)O—C 1 -C 5  alkyl, —C 1 -C 5  alkylene-C(O)NH—C 1 -C 5  alkyl, —C(O)NH 2 , or —NO 2 , wherein each occurrence of R a  is independently —H, -benzyl, —C 1 -C 10  alkyl; 
 or N and both R a  groups are taken together to form a nitrogen-containing 3- to 7-membered monocyclic heterocycle; 
 R 3  is —H, —PO 3 H 2 , —P 2 O 6 H 3 , —P 3 O 9 H 4 , —SO 3 H, —C(O)—C 1 -C 9  alkyl, β-D-glucuronyl, or a C-terminal alpha amino acid residue; and 
 n is an integer ranging from 1 to 10; and 
 m is an integer ranging from 2 to 10. 
 
   
   
       19 - 24 . (canceled) 
   
   
       25 . A composition comprising a physiologically acceptable carrier or vehicle and an effective amount of a compound or a pharmaceutically acceptable salt of a compound of  claim 1 ,  claim 8 ,  claim 15  or  claim 18 . 
   
   
       26 - 28 . (canceled) 
   
   
       29 . A method for treating cancer, renal failure, reperfusion injury, inflammatory disease, diabetes mellitus, an ischemic condition, reoxygenation injury resulting from organ transplantation, neurodegenerative disease, vascular disease, diabetic complication, cardiovascular disease, erectile dysfunction, urinary incontinence, a complication of prematurity, cardiomyopathy, retinopathy, nephropathy, neuropathy, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt of a compound of  claim 1 ,  claim 8 ,  claim 15  or  claim 18  to a subject in need thereof. 
   
   
       30 - 108 . (canceled)