Novel multicyclic compounds and the use thereof

Abstract

The present invention is directed to novel multicyclic molecules that mediate enzymatic activity. In particular, the compounds may be effective in the treatment of diseases or disease states related to the activity of PARP, VEGFR2, and MLK3 enzymes, including, for example, neurodegenerative diseases, inflammation, ischemia, and cancer.

1 . A compound of Formula IIIa:  
     
       
         
         
             
             
         
       
     
     wherein: 
 each of A and B is, independently, 
 C(═O), CH(OR 3 ), CH(SR 3 ),  
 CH 2 , CHR 3 , CHR 3 CHR 4 , CR 3 R 4 ,  
 C(═O)NR 3 , SO, or SO 2 ;  
 
 E and F, together with the carbon atoms to which they are attached, form a substituted or unsubstituted C 4  to C 7  cycloalkyl group, wherein said substituted cycloalkyl group has at least one substituent J;  
 R 1 is: 
 hydrogen, lower alkyl, lower alkyl having at least one substituent J, formyl, acetyl, lower alkanoyl, lower alkanoyl having at least one substituent J, lower alkylsulfonyl, or lower arylsulfonyl;  
 
 R 2  is: 
 hydrogen, lower alkyl, lower alkyl having at least one substituent J; formyl; acetyl, lower alkanoyl, lower alkanoyl having at least one substituent J, lower alkylsulfonyl, or arylsulfonyl;  
 
 each of R 3  and R 4  is, independently, hydrogen or lower alkyl;  
 J is independently at each occurrence:  
 J 3 -(J 2 ) n -(J 1 ) m -wherein each of n and m is, independently, 0 or 1;  
 each of J 1 and J 2  is, independently, 
 carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy, sulfonyl, amino, lower alkylamino, lower dialkylamino, amido, lower alkylamido, lower dialkylamido, lower alkyloxycarbonylamino, aryloxycarbonylamino, amidino, guanidino, lower alkoxy, lower aryloxy, aralkoxy, lower alkyl, C 3  to C 7  cycloalkyl, heterocycloalkyl, aryl, heteroaryl, sulfonylamido, alkylsulfonylamido, arylsulfonylamido, an amino acid, or a protected amino acid; and  
 
 J 3  is: 
 hydrogen, halo, hydroxy, thio, cyano, sulfonic acid, NO 2 , carboxyl, lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, phosphonic acid, lower alkyl ester of phosphonic acid, aryl ester of phosphonic acid, aminocarbonyloxy, heteroaryl, or heterocycloalkyl; and  
 
 X 1  and X 2 , together with the atoms to which they are attached, form: 
 a substituted or unsubstituted aryl group wherein said substituted aryl group has at least one substituent J; or  
 a substituted or unsubstituted heteroaryl group wherein said substituted heteroaryl group has at least one substituent J.  
 
 
   
   
       2 . The compound of  claim 1  wherein E and F, together with the carbons they are attached, form a C 5  cycloalkyl group.  
   
   
       3 . The compound of  claim 2  wherein A and B are independently C(═O).  
   
   
       4 . The compound of  claim 3  wherein X 1  and X 2 , together with the atoms to which they are attached, form a substituted or unsubstituted heteroaryl group wherein said substituted heteroaryl group has at least one substituent J.  
   
   
       5 . The compound of  claim 4  wherein the substituted or unsubstituted heteroaryl group is pyridyl or pyrimidyl; wherein said heteroaryl group has at least one substituent J.  
   
   
       6 . The compound of  claim 5  wherein J 1  and J 2  is, independently, carbonyl, amino, carbonyloxy, lower alkylamino, lower dialkylamino or lower alkoxy.  
   
   
       7 . The compound of  claim 6  wherein J 3  is hydrogen, halo, hydroxyl, cyano, NO 2 , lower alkyl, heteroaryl or hetercycloalkyl.  
   
   
       8 . The compound of  claim 4  wherein the substituted or unsubstituted heteroaryl group is pyridine-N-oxide; wherein said heteroaryl group has at least one substituent J.  
   
   
       9 . The compound of  claim 8  wherein J 1  and J 2  is, independently, carbonyl, amino, carbonyloxy, lower alkylamino, lower dialkylamino or lower alkoxy.  
   
   
       10 . The compound of  claim 9  wherein J 3  is hydrogen, halo, hydroxyl, cyano, NO 2 , lower alkyl, heteroaryl or hetercycloalkyl.  
   
   
       11 . The compound of  claim 3  wherein X 1  and X 2 , together with the atoms to which the are attached, form a substituted or unsubstituted aryl group wherein said substituted aryl group has at least one substituent J.  
   
   
       12 . The compound of  claim 11  wherein the substituted or unsubstituted aryl group is phenyl; wherein said phenyl has at least one substituent J.  
   
   
       13 . The compound of  claim 12  wherein J 1  and J 2  is, independently, carbonyl, amino, carbonyloxy, lower alkylamino, lower dialkylamino or lower alkoxy.  
   
   
       14 . The compound of  claim 13  wherein J 3  is hydrogen, halo, hydroxyl, cyano, NO 2 , lower alkyl, heteroaryl or hetercycloalkyl.  
   
   
       15 . A compound of  claim 1:   
     wherein: 
 each of A and B is, independently, C(═O);  
 E and F, together with the carbon atoms to which they are attached, form: 
 a substituted or unsubstituted C 5  cycloalkyl group, wherein said substituted C 5  cycloalkyl group has at least one substituent J;  
 
 R 1  is hydrogen;  
 R 2  is hydrogen, lower alkyl or lower alkyl having at least one substituent J 4 ;  
 J is independently at each occurrence: 
 J 3 -(J 2 ) n -(J 1 ) m - wherein each of n and m is, independently, 0 or 1;  
 
 each of J 1  and J 2  is, independently, 
 carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy, amino, lower alkylamino, lower dialkylamino, amido, lower alkylamido, lower dialkylamido, lower alkoxy, lower alkyl, C 3  to C 7  cycloalkyl, heterocycloalkyl, aryl, or a heteroaryl; and  
 
 J 3  is: 
 hydrogen, halo, hydroxy, cyano, NO 2 , carboxyl, lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, heteroaryl, or heterocycloalkyl; and  
 
 J 4  is independently at each occurrence: 
 J 7 -(J 6 ) n -(J 5 ) m - wherein each of n and m is, independently, 0 or 1;  
 
 each of J 5  and J 6  is, independently, 
 carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy, amino, lower alkylamino, lower dialkylamino, amido, lower alkylamido, lower dialkylamido, lower alkoxy, lower alkyl, C 3  to C 7  cycloalkyl, heterocycloalkyl, aryl, or a heteroaryl; and  
 
 J 7  is: 
 hydrogen, halo, hydroxy, cyano, NO 2 , carboxyl, lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, heteroaryl, or heterocycloalkyl; and  
 
 X 1  and X 2 , together with the atoms to which they are attached, form: 
 a substituted or unsubstituted phenyl group wherein said substituted phenyl group has at least one substituent J; or  
 a substituted or unsubstituted heteroaryl group wherein said substituted heteroaryl group has at least one substituent J and wherein said heteroaryl is pyridine or pyridine-N-oxide.  
 
 
   
   
       16 . The compound of  claim 15  wherein X 1  and X 2 , together with the atoms they are attached, form a phenyl with at least one substituent J.  
   
   
       17 . The compound of  claim 16  wherein J 1  and J 2  is, independently, carbonyl, amino, carbonyloxy, lower alkylamino, lower dialkylamino or lower alkoxy.  
   
   
       18 . The compound of  claim 17  wherein J 3  is hydrogen, halo, hydroxyl, cyano, NO 2 , lower alkyl, heteroaryl or hetercycloalkyl.  
   
   
       19 . The compound of  claim 15  wherein X 1  and X 2  together with the atoms they are attached form a pyridine with at least one substituent J.  
   
   
       20 . The compound of  claim 19  wherein J 1  and J 2  is, independently, carbonyl, amino, carbonyloxy, lower alkylamino, lower dialkylamino or lower alkoxy.  
   
   
       21 . The compound of  claim 20  wherein J 3  is hydrogen, halo, hydroxyl, cyano, NO 2 , lower alkyl, heteroaryl or hetercycloalkyl.  
   
   
       22 . A compound of  claim 1:   
     wherein: 
 each of A and B is, independently, C(═O);  
 E and F, together with the carbon atoms to which they are attached, form: 
 a substituted or unsubstituted C 5  cycloalkyl group;  
 
 R 1  is hydrogen;  
 R 2  is lower alkyl having at least one substituent J 4 ;  
 J is independently at each occurrence: 
 J 3 -(J ) n -(J 1 ) m - wherein each of n and m is, independently, 0 or 1;  
 
 each of J 1  and J 2  is, independently, 
 carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy, amino, lower alkylamino, lower dialkylamino, amido, lower alkylamido, lower dialkylamido, lower alkoxy, lower alkyl, C 3  to C 7  cycloalkyl, heterocycloalkyl, aryl, or a heteroaryl; and  
 
 J 3  is: 
 hydrogen, halo, hydroxy, cyano, NO 2 , carboxyl, lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, heteroaryl, or heterocycloalkyl; and  
 
 J 4  is independently at each occurrence: 
 J 7 -(J 6 ) n -(J 5 ) m - wherein each of n and m is, independently, 0 or 1;  
 
 each of J 5  and J 6  is, independently, 
 carbonyl, lower alkylcarbonyl, arylcarbonyl, carbonyloxy, amino, lower alkylamino, lower dialkylamino, amido, lower alkylamido, lower dialkylamido, lower alkoxy, lower alkyl, C 3  to C 7  cycloalkyl, heterocycloalkyl, aryl, or a heteroaryl; and  
 
 J 7  is: 
 hydrogen, halo, hydroxy, cyano, NO 2 , carboxyl, lower alkyl, aryloxycarbonyl, alkyloxycarbonyl, heteroaryl, or heterocycloalkyl; and  
 
 X 1  and X 2 , together with the atoms to which they are attached, form: 
 a substituted or unsubstituted phenyl group wherein said substituted phenyl group has at least one substituent J; or  
 a substituted or unsubstituted heteroaryl group wherein said substituted heteroaryl group has at least one substituent J and where said heteroaryl is pyridine or pyridine-N-oxide.  
 
 
   
   
       23 . The compound of  claim 22  wherein each of J 5  and J 6  is, independently, amino, lower alkylamino, lower dialkylamino, or heterocycloalkyl.  
   
   
       24 . The compound of  claim 23  where J 7  is hydrogen, lower alkyl, or heterocycloalkyl.  
   
   
       25 . The compound of  claim 24  wherein X 1  and X 2 , together with the atoms to which they are attached, form a phenyl with at least one substituent J.  
   
   
       26 . The compound of  claim 25  wherein J is lower alkoxy.  
   
   
       27 . The compound of  claim 22  wherein J 4  is dimethylamino-, diethylamino, 4-morpholin-4-yl, or 4-methylpiperazin-1-yl.  
   
   
       28 . The compound of  claim 22  wherein J 4  is 4-methylpiperazin-1-yl.  
   
   
       29 . The compound of  claim 28  wherein X 1  and X 2 , together with the atoms to which they are attached, form a phenyl with at least one substituent J.  
   
   
       30 . The compound of  claim 29  where J is lower alkoxy.  
   
   
       31 . A compound of  claim 1  selected from:  
     
       
         
         
             
             
         
       
     
     and pharmacologically acceptable salts thereof.  
   
   
       32 . A compound of  claim 1  selected from:  
     
       
         
         
             
             
         
       
     
     and pharmacologically acceptable salts thereof.  
   
   
       33 . A compound selected from:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and pharmacologically acceptable salts thereof.  
   
   
       34 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       35 . A pharmaceutical composition comprising a compound of  claim 33  and a pharmaceutically acceptable carrier.  
   
   
       36 . A method of inhibiting PARP, VEGFR2, or MLK3 activity comprising contacting said PARP, VEGFR2, or MLK3 with a compound of  claim 1 .  
   
   
       37 . A method for treating or preventing a neurodegenerative disease comprising administering to a mammal a therapeutically effective amount of a compound of  claim 1 .  
   
   
       38 . The method of  claim 37  wherein said neurodegenerative disease is Parkinson's, Huntington's, or Alzheimer's disease.  
   
   
       39 . A method for treating traumatic central nervous system injuries or preventing neuronal degradation associated with traumatic central nervous system injuries comprising administering to a mammal a therapeutically effective amount of a compound of  claim 1 .  
   
   
       40 . A method for treating cerebral ischemia, cardiac ischemia, inflammation, endotoxic shock, or diabetes comprising administering to a mammal a pharmaceutically effective amount of a compound of  claim 1 .  
   
   
       41 . A method for suppressing the formation of blood vessels in a mammal comprising administering to a mammal a pharmaceutically effective amount of a compound of  claim 1 .  
   
   
       42 . A method of treating cellular proliferative disorders comprising administering to a mammal a pharmaceutically effective amount of a compound of  claim 1 .  
   
   
       43 . The method of  claim 42  wherein said cellular proliferative disorders are related to solid tumors, diabetic retinopathy, intraocular neovascular syndromes, macular degeneration, rheumatoid arthritis, psoriasis, or endometriosis.  
   
   
       44 . A method of treating cancer comprising administering to a mammal a pharmaceutically effective amount of a compound of  claim 1.