Substituted pyridines and pyridazines with angiogenesis inhibiting activity

Abstract

Methods of treating a mammal having a condition characterized by abnormal angiogenesis or hyperpermiability processes using substituted pyridazines having angiogenesis inhibiting activity and the generalized structural formula wherein the ring containing A, B, D, E, and L is phenyl or a nitrogen-containing heterocycle; groups X and Y may be any of a variety of defined linking units; R 1 and R 2 may be defined independent substituents or together may be a ring-defining bridge; ring J may be an aryl, pyridyl, or cycloalkyl group; and G groups may be any of a variety of defined substituents.

1 . A method of treating a mammal having a condition characterized by abnormal angiogenesis or hyperpermiability processes, comprising administering to said mammal a therapeutically effective amount of a compound having the generalized structural formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  
 together form a bridge containing two T 2  moieties and one T 3  moiety, said bridge, taken together with the ring to which it is attached, forming a bicyclic of structure 
 
       
       
         
           
           
               
               
           
         
         
           wherein
 each T 2  independently represents CH, or CG 1 ; and 
 T 3  represents CR 4 G 1  or C(R 4 ) 2 ; 
 
         
         and wherein
 G 1  is a substituent independently selected from the group consisting of 
 —N(R 6 ) 2 ; 
 —NR 3 COR 6 ; 
 halogen; 
 alkyl; 
 cycloalkyl; 
 lower alkenyl; 
 lower cycloalkenyl; 
 halogen-substituted alkyl; 
 amino-substituted alkyl; 
 N-lower alkylamino-substituted alkyl; 
 N,N-di-lower alkylamino-substituted alkyl; 
 N-lower alkanoylamino-substituted alkyl; 
 hydroxy-substituted alkyl; 
 cyano-substituted alkyl; 
 carboxy-substituted alkyl; 
 lower alkoxycarbonyl-substituted alkyl; 
 phenyl lower alkoxycarbonyl-substituted alkyl; 
 halogen-substituted alkylamino; 
 amino-substituted alkylamino; 
 N-lower alkylamino-substituted alkylamino; 
 N,N-di-lower alkylamino-substituted alkylamino; 
 N-lower alkanoylamino-substituted alkylamino; 
 hydroxy-substituted alkylamino; 
 cyano-substituted alkylamino; 
 carboxy-substituted alkylamino; 
 lower alkoxycarbonyl-substituted alkylamino; 
 phenyl-lower alkoxycarbonyl-substituted alkylamino; 
 —OR 6 ; 
 —SR 6 ; 
 —S(O)R 6 ; 
 —S(O) 2 R 6 ; 
 halogenated lower alkoxy; 
 halogenated lower alkylthio; 
 halogenated lower alkylsulfonyl; 
 —OCOR 6 ; 
 —COR 6 ; 
 —CO 2 R 6 ; 
 —CON(R 6 ) 2 ; 
 —CH 2 OR 3 ; 
 —NO 2 ; 
 —CN; 
 amidino; 
 guanidino; 
 sulfo; 
 —B(OH)2; 
 optionally substituted aryl; 
 optionally substituted heteroaryl; 
 optionally substituted saturated heterocyclyl; 
 optionally substituted saturated heterocyclylalkyl; 
 optionally substituted partially unsaturated heterocyclyl; 
 optionally substituted partially unsaturated heterocyclylalkyl; 
 —OCO 2 R 3 ; 
 optionally substituted heteroarylalkyl; 
 optionally substituted heteroaryloxy; 
 —S(O) p (optionally substituted heteroaryl); 
 optionally substituted heteroarylalkyloxy; 
 —S(O) p (optionally substituted heteroarylalkyl); 
 —CHO; 
 —OCON(R 6 ) 2 ; 
 —NR 3 CO 2 R 6 ; 
 —NR 3 CON(R 6 ) 2    
 
         R 3  is H or lower alkyl; 
         R 6  is independently selected from the group consisting of 
         H; 
         alkyl; 
         cycloalkyl; 
         optionally substituted aryl; and 
         optionally substituted aryl lower alkyl; 
         lower alkyl-N(R 3 ) 2 ; and 
         lower alkyl-OH; 
         R 4  is H, halogen, or lower alkyl; 
         p is 0, 1, or 2; 
         X is selected from the group consisting of O, S, and NR 3 ; 
         Y is selected from the group consisting of 
         lower alkylene; 
         —CH 2 —O—; 
         —CH 2 —S—; 
         —CH 2 —NH—; 
         —O—; 
         —S—; 
         —NH—; 
         —(CR 4   2 ) n —S(O) p -(5-membered heteroaryl)-(CR 4   2 ) s —; 
         —(CR 4   2 ) n —C(G 2 )(R 4 )—(CR 4   2 ) s —; 
         wherein
 n and s are each independently 0 or an integer of 1-2; and
 G 2  is selected from the group consisting of —CN, —CO 2 R 3 , —CON(R 6 ) 2 , and —CH 2 N(R 6 ) 2 ; 
 
 
         —O—CH 2 —; 
         —S(O)—; 
         —S(O) 2 —; 
         —SCH 2 —; 
         —S(O)CH 2 —; 
         —S(O) 2 CH 2 —; 
         —CH 2 S(O)—; and 
         —CH 2 S(O) 2    
         Z is N; 
         q is 0, 1, or 2; 
         G 3  is a monovalent or bivalent moiety selected from the group consisting of: 
         lower alkyl; 
         —NR 3 COR 6 ; 
         carboxy-substituted alkyl; 
         lower alkoxycarbonyl-substituted alkyl; 
         —OR 6 ; 
         —SR 6 ; 
         —S(O)R 6 ; 
         —S(O) 2 R 6 ; 
         —OCOR 6 ; 
         —COR 6 ; 
         —CO 2 R 6 ; 
         —CH 2 OR 3 ; 
         —CON(R 6 ) 2 ; 
         —S(O) 2 N(R 6 ) 2 ; 
         —NO 2 ; 
         —CN; 
         optionally substituted aryl; 
         optionally substituted heteroaryl; 
         optionally substituted saturated heterocyclyl; 
         optionally substituted partially unsaturated heterocyclyl; 
         optionally substituted heteroarylalkyl; 
         optionally substituted heteroaryloxy; 
         —S(O) p (optionally substituted heteroaryl); 
         optionally substituted heteroarylalkyloxy; 
         —S(O) p (optionally substituted heteroarylalkyl); 
         —OCON(R 6 ) 2 ; 
         —NR 3 CO 2 R 6 ; 
         —NR 3 CON(R 6 ) 2 ; and
 bivalent bridge of structure T 2 =T 2 −T 3    
 wherein
 each T 2  independently represents N, CH, or CG 3′ ; and 
 T 3  represents S, O, CR 4 G 3′ , C(R 4 ) 2 , or NR 3 ; wherein
 G 3′  represents any of the above-defined moieties G 3  which are monovalent; and 
 
 the terminal T 2  is bound to L, and T 3  is bound to D, forming a 5-membered fused ring; 
 
 
         A and D independently represent N or CH; 
         B and E independently represent N or CH; 
         L represents N or CH; and 
       
       with the provisos that
 a) the total number of N atoms in the ring containing A, B, D, E, and L is 0, 1, 2, or 3; and 
 b) when L represents CH and q=0 or any G 3  is a monovalent substituent, at least one of A and D is an N atom; and 
 c) when L represents CH and a G 3  is a bivalent bridge of structure T 2 =T 2 −T 3 , then A, B, D, and E are also CH; 
 J is a ring selected from the group consisting of 
 aryl; 
 pyridyl; and 
 cycloalkyl; 
 q′ represents the number of substituents G 4  on ring J and is 0, 1, 2, 3, 4, or 5, and 
 G 4  is a monovalent or bivalent moiety selected from the group consisting of 
 —N(R 6 ) 2 ; 
 —NR 3 COR 6 ; 
 halogen; 
 alkyl; 
 cycloalkyl; 
 lower alkenyl; 
 lower cycloalkenyl; 
 halogen-substituted alkyl; 
 amino-substituted alkyl; 
 N-lower alkylamino-substituted alkyl; 
 N,N-di-lower alkylamino-substituted alkyl; 
 N-lower alkanoylamino-substituted alkyl; 
 hydroxy-substituted alkyl; 
 cyano-substituted alkyl; 
 carboxy-substituted alkyl; 
 lower alkoxycarbonyl-substituted alkyl; 
 phenyl lower alkoxycarbonyl-substituted alkyl; 
 halogen-substituted alkylamino; 
 amino-substituted alkylamino; 
 N-lower alkylamino-substituted alkylamino; 
 N,N-di-lower alkylamino-substituted alkylamino; 
 N-lower alkanoylamino-substituted alkylamino; 
 hydroxy-substituted alkylamino; 
 cyano-substituted alkylamino; 
 carboxy-substituted alkylamino; 
 lower alkoxycarbonyl-substituted alkylamino; 
 phenyl-lower alkoxycarbonyl-substituted alkylamino; 
 —OR 6 ; 
 —SR 6 ; 
 —S(O)R 6 ; 
 —S(O) 2 R 6 ; 
 halogenated lower alkoxy; 
 halogenated lower alkylthio; 
 halogenated lower alkylsulfonyl; 
 —OCOR 6 ; 
 —COR 6 ; 
 —CO 2 R 6 ; 
 —CON(R 6 ) 2 ; 
 —CH 2 OR 3 ; 
 —NO 2 ; 
 —CN; 
 amidino; 
 guanidino; 
 sulfo; 
 —B(OH)2; 
 optionally substituted aryl; 
 optionally substituted heteroaryl; 
 optionally substituted saturated heterocyclyl; 
 optionally substituted partially unsaturated heterocyclyl; 
 —OCO 2 R 3 ; 
 optionally substituted heteroarylalkyl; 
 optionally substituted heteroaryloxy; 
 —S(O) p (optionally substituted heteroaryl); 
 optionally substituted heteroarylalkyloxy; 
 —S(O) p (optionally substituted heteroarylalkyl); 
 —CHO; 
 —OCON(R 6 ) 2 ; 
 —NR 3 CO 2 R 6 ; 
 —NR 3 CON(R 6 ) 2 ; and
 fused ring-forming bivalent bridges attached to and connecting adjacent positions of ring J, said bridges having the structures: 
 
 
       
         
           
           
               
               
           
         
         
           
             wherein
 each T 2  independently represents N, CH, or CG 4′ ; 
 T 3  represents S, O, CR 4 G 4′ , C(R 4 ) 2 , or NR 3 ; wherein 
  G4′ represents any of the above-defined moieties G 4  which are monovalent; and 
 binding to ring J is achieved via terminal atoms T 2  and T 3 ; 
 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein
 each T 2  independently represents N, CH, or CG 4′ ; wherein 
  G4′ represents any of the above-defined moieties G 4  which are monovalent; and 
 with the proviso that a maximum of two bridge atoms T 2  may be N; and binding to ring J is achieved via terminal atoms T 2 ; and 
 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein
 each T 4 , T 5 , and T 6  independently represents O, S, CR 4 G 4′ , C(R 4 ) 2 , or NR 3 ; wherein 
  G4′ represents any of the above-defined moieties G 4  which are monovalent; and 
 binding to ring J is achieved via terminal atoms T 4  or T 5 ; 
 with the provisos that: 
 
             i) when one T 4  is O, S, or NR 3 , the other T 4  is CR 4 G 4′  or C(R 4 ) 2 ;
 ii) a bridge comprising T 5  and T 6  atoms may contain a maximum of two heteroatoms O, S, or N; and 
 iii) in a bridge comprising T 5  and T 6  atoms, when one T 5  group and one T 6  group are O atoms, or two T 6  groups are O atoms, said O atoms are separated by at least one carbon atom; 
 
           
         
         when G 4  is an alkyl group located on ring J adjacent to the linkage —(CR 4   2 ) p —, and X is NR 3  wherein R 3  is an alkyl substituent, then G 4  and the alkyl substituent R 3  on X may be joined to form a bridge of structure —(CH 2 ) p′ — wherein p′ is 2, 3, or 4, with the proviso that the sum of p and p′ is 2, 3, or 4, resulting in formation of a nitrogen-containing ring of 5, 6, or 7 members; 
         and with the further provisos that:
 in G 1 , G 2 , G 3 , and G 4 , when two groups R 3  or R 6  are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR 3  to form a N-containing heterocycle of 5-7 ring atoms; 
 when an aryl, heteroaryl, or heterocyclyl ring is optionally substituted, that ring may bear up to 5 substituents which are independently selected from the group consisting of amino, mono-loweralkyl-substituted amino, di-loweralkyl-substituted amino, lower alkanoylamino, halogen, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyloxy, —CO 2 R 3 , —CHO, —CH 2 OR 3 , —OCO 2 R 3 , —CON(R 6 ) 2 , —OCON(R 6 ) 2 , —NR 3 CON(R 6 ) 2 , nitro, amidino, guanidino, mercapto, sulfo, and cyano; and 
 when any alkyl group is attached to O, S, or N, and bears a hydroxyl substituent, then said hydroxyl substituent is separated by at least two carbon atoms from the O, S, or N to which the alkyl group is attached 
 
         or a pharmaceutically acceptable salt or prodrug thereof 
       
       which is effective to treat said condition. 
     
     
         2 . The method of  claim 1 , wherein said condition is tumor growth; retinopathy, including diabetic retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, and age-related macular degeneration; rheumatoid arthritis; psoriasis; or a bullous disorder associated with subepidermal blister formation, including bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis. 
     
     
         3 . The method of  claim 1 , wherein
 R 1  and R 2  
 together form a bridge containing two T 2  moieties and one T 3  moiety, said bridge, taken together with the ring to which it is attached, forming a bicyclic of structure 
   
       
         
           
           
               
               
           
         
         
           wherein
 each T 2  independently represents CH, or CG 1 ; and 
 T 3  represents CH 2 . 
 
         
       
     
     
         4 . A method of treating a mammal having a condition characterized by abnormal angiogenesis or hyperpermiability processes, comprising administering to said mammal a therapeutically effective amount of a compound having the generalized structural formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2 : 
       
       i) independently represent H or lower alkyl;
 ii) together form a bridge of structure 
 
       
         
           
           
               
               
           
         
         
           wherein binding is achieved via the terminal carbon atoms; 
         
         iii) together form a bridge of structure 
       
       
         
           
           
               
               
           
         
         
           wherein binding is achieved via the terminal carbon atoms; 
           or 
         
         v) together form a bridge containing two T 2  moieties and one T 3  moiety, said bridge, taken together with the ring to which it is attached, forming a bicyclic of structure 
       
       
         
           
           
               
               
           
         
         wherein
 each T 2  independently represents CH, or CG 1 ; and 
 T 3  represents CR 4 G 1 , or C(R 4 ) 2 ; 
 
         and wherein 
         m is 0 or an integer 1-4; and
 G 1  is a substituent independently selected from the group consisting of 
 —N(R 6 ) 2 ; 
 —NR 3 COR 6 ; 
 halogen; 
 alkyl; 
 cycloalkyl; 
 lower alkenyl; 
 lower cycloalkenyl; 
 halogen-substituted alkyl; 
 amino-substituted alkyl; 
 N-lower alkylamino-substituted alkyl; 
 N,N-di-lower alkylamino-substituted alkyl; 
 N-lower alkanoylamino-substituted alkyl; 
 hydroxy-substituted alkyl; 
 cyano-substituted alkyl; 
 carboxy-substituted alkyl; 
 lower alkoxycarbonyl-substituted alkyl; 
 phenyl lower alkoxycarbonyl-substituted alkyl; 
 halogen-substituted alkylamino; 
 amino-substituted alkylamino; 
 N-lower alkylamino-substituted alkylamino; 
 N,N-di-lower alkylamino-substituted alkylamino; 
 N-lower alkanoylamino-substituted alkylamino; 
 hydroxy-substituted alkylamino; 
 cyano-substituted alkylamino; 
 carboxy-substituted alkylamino; 
 lower alkoxycarbonyl-substituted alkylamino; 
 phenyl-lower alkoxycarbonyl-substituted alkylamino; 
 —OR 6 ; 
 —SR 6 ; 
 —S(O)R 6 ; 
 —S(O) 2 R 6 ; 
 halogenated lower alkoxy; 
 halogenated lower alkylthio; 
 halogenated lower alkylsulfonyl; 
 —OCOR 6 ; 
 —COR 6 ; 
 —CO 2 R 6 ; 
 —CON(R 6 ) 2 ; 
 —CH 2 OR 3 ; 
 —NO 2 ; 
 —CN; 
 amidino; 
 guanidino; 
 sulfo; 
 —B(OH)2; 
 optionally substituted aryl; 
 optionally substituted heteroaryl; 
 optionally substituted saturated heterocyclyl; 
 optionally substituted saturated heterocyclylalkyl; 
 optionally substituted partially unsaturated heterocyclyl; 
 optionally substituted partially unsaturated heterocyclylalkyl; 
 —OCO 2 R 3 ; 
 optionally substituted heteroarylalkyl; 
 optionally substituted heteroaryloxy; 
 —S(O) p (optionally substituted heteroaryl); 
 optionally substituted heteroarylalkyloxy; 
 —S(O) p (optionally substituted heteroarylalkyl); 
 —CHO; 
 —OCON(R 6 ) 2 ; 
 —NR 3 CO 2 R 6 ; 
 —NR 3 CON(R 6 ) 2    
 
         R 3  is H or lower alkyl; 
         R 6  is independently selected from the group consisting of 
         H; 
         alkyl; 
         cycloalkyl; 
         optionally substituted aryl; and 
         optionally substituted aryl lower alkyl; 
         lower alkyl-N(R 3 ) 2 ; and 
         lower alkyl-OH; 
         R 4  is H, halogen, or lower alkyl; 
         p is 0, 1, or 2; 
         X is selected from the group consisting of O, S, and NR 3 ; 
         Y is selected from the group consisting of 
         lower alkylene; 
         —CH 2 —O—; 
         —CH 2 —S—; 
         —CH 2 —NH—; 
         —O—; 
         —S—; 
         —NH—; 
         —(CR 4   2 ) n —S(O) p -(5-membered heteroaryl)-(CR 4   2 ) s —; 
         —(CR 4   2 ) n —C(G 2 )(R 4 )—(CR 4   2 ) s —;
 wherein
 n and s are each independently 0 or an integer of 1-2; and
 G 2  is selected from the group consisting of —CN, —CO 2 R 3 , —CON(R 6 ) 2 , and —CH 2 N(R 6 ) 2 ; 
 
 
 
         —O—CH 2 —; 
         —S(O)—; 
         —S(O) 2 —; 
         —SCH 2 —; 
         —S(O)CH 2 —; 
         —S(O) 2 CH 2 —; 
         —CH 2 S(O)—; and 
         —CH 2 S(O) 2    
         —Z is N; 
         q is 1 or 2; 
         G 3  is a monovalent or bivalent moiety selected from the group consisting of 
         lower alkyl; 
         —NR 3 COR 6 ; 
         carboxy-substituted alkyl; 
         lower alkoxycarbonyl-substituted alkyl; 
         —OR 6 ; 
         —SR 6 ; 
         —S(O)R 6 ; 
         —S(O) 2 R 6 ; 
         —OCOR 6 ; 
         —COR 6 ; 
         —CO 2 R 6 ; 
         —CH 2 OR 3 ; 
         —CON(R 6 ) 2 ; 
         —S(O) 2 N(R 6 ) 2 ; 
         —NO 2 ; 
         —CN; 
         optionally substituted aryl; 
         optionally substituted heteroaryl; 
         optionally substituted saturated heterocyclyl; 
         optionally substituted partially unsaturated heterocyclyl; 
         optionally substituted heteroarylalkyl; 
         optionally substituted heteroaryloxy; 
         —S(O) p (optionally substituted heteroaryl); 
         optionally substituted heteroarylalkyloxy; 
         —S(O) p (optionally substituted heteroarylalkyl); 
         —OCON(R 6 ) 2 ; 
         —NR 3 CO 2 R 6 ; 
         —NR 3 CON(R 6 ) 2 ; and
 bivalent bridge of structure T 2 =T 2 −T 3 :
 wherein 
 each T 2  independently represents N, CH, or CG 3′ ; and 
 T 3  represents S, O, CR 4 G 3′ , C(R 4 ) 2 , or NR 3 ; wherein 
 G 3′  represents any of the above-defined moieties G3 which are monovalent; and 
 the terminal T 2  is bound to L, and T 3  is bound to D, forming a 5-membered fused ring; 
 
 
         A and D are CH; 
         B and E are CH; 
         L is CH;
 with the proviso that the resulting phenyl ring bears as a G 3  substituent said bivalent bridge of structure T 2 =T 2 −T 3 ; 
 
         J is a ring selected from the group consisting of 
         aryl; 
         pyridyl; and 
         cycloalkyl; 
         q′ represents the number of substituents G 4  on ring J and is 0, 1, 2, 3, 4, or 5, and 
         G 4  is a monovalent or bivalent moiety selected from the group consisting of 
         —N(R 6 ) 2    
         —NR 3 COR 6 ; 
         halogen; 
         alkyl; 
         cycloalkyl; 
         lower alkenyl; 
         lower cycloalkenyl; 
         halogen-substituted alkyl; 
         amino-substituted alkyl; 
         N-lower alkylamino-substituted alkyl; 
         N,N-di-lower alkylamino-substituted alkyl; 
         N-lower alkanoylamino-substituted alkyl; 
         hydroxy-substituted alkyl; 
         cyano-substituted alkyl; 
         carboxy-substituted alkyl; 
         lower alkoxycarbonyl-substituted alkyl; 
         phenyl lower alkoxycarbonyl-substituted alkyl; 
         halogen-substituted alkylamino; 
         amino-substituted alkylamino; 
         N-lower alkylamino-substituted alkylamino; 
         N,N-di-lower alkylamino-substituted alkylamino; 
         N-lower alkanoylamino-substituted alkylamino; 
         hydroxy-substituted alkylamino; 
         cyano-substituted alkylamino; 
         carboxy-substituted alkylamino; 
         lower alkoxycarbonyl-substituted alkylamino; 
         phenyl-lower alkoxycarbonyl-substituted alkylamino; 
         —OR 6 ; 
         —SR 6 ; 
         —S(O)R 6 ; 
         —S(O) 2 R 6 ; 
         halogenated lower alkoxy; 
         halogenated lower alkylthio; 
         halogenated lower alkylsulfonyl; 
         —OCOR 6 ; 
         —COR 6 ; 
         —CO 2 R 6 ; 
         —CON(R 6 ) 2 ; 
         —CH 2 OR 3 ; 
         —NO 2 ; 
         —CN; 
         amidino; 
         guanidino; 
         sulfo; 
         —B(OH)2; 
         optionally substituted aryl; 
         optionally substituted heteroaryl; 
         optionally substituted saturated heterocyclyl; 
         optionally substituted partially unsaturated heterocyclyl; 
         —OCO 2 R 3 ; 
         optionally substituted heteroarylalkyl; 
         optionally substituted heteroaryloxy; 
         —S(O) p (optionally substituted heteroaryl); 
         optionally substituted heteroarylalkyloxy; 
         —S(O) p (optionally substituted heteroarylalkyl); 
         —CHO; 
         —OCON(R 6 ) 2 ; 
         —NR 3 CO 2 R 6 ; 
         —NR 3 CON(R 6 ) 2 ; and
 fused ring-forming bivalent bridges attached to and connecting adjacent positions of ring J, said bridges having the structures: 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein
 each T 2  independently represents N, CH, or CG 4′ ; 
 T 3  represents S, O, CR 4 G 4′ , C(R 4 ) 2 , or NR 3 ; wherein 
  G 4′  represents any of the above-defined moieties G 4  which are monovalent; and 
 binding to ring J is achieved via terminal atoms T 2  and T 3 ; 
 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein
 each T 2  independently represents N, CH, or CG 4′ ; wherein 
  G4′ represents any of the above-defined moieties G 4  which are monovalent; and 
 with the proviso that a maximum of two bridge atoms T 2  may be N; and binding to ring J is achieved via terminal atoms T 2 ; and 
 
           
         
       
       
         
           
           
               
               
           
         
         
           
             wherein
 each T 4 , T 5 , and T 6  independently represents O, S, CR 4 G 4′ , C(R 4 ) 2 , or NR 3 ; wherein 
  G4′ represents any of the above-identified moieties G4 which are monovalent; and 
 binding to ring J is achieved via terminal atoms T 4  or T 5 ; with the provisos that: 
 
             i) when one T 4  is O, S, or NR 3 , the other T 4  is CR 4 G 4′  or C(R 4 ) 2 ;
 ii) a bridge comprising T 5  and T 6  atoms may contain a maximum of two heteroatoms O, S, or N; and 
 iii) in a bridge comprising T 5  and T 6  atoms, when one T 5  group and one T 6  group are O atoms, or two T 6  groups are O atoms, said O atoms are separated by at least one carbon atom; 
 
           
         
         when G 4  is an alkyl group located on ring J adjacent to the linkage —(CR 4   2 ) p —, and X is NR 3  wherein R 3  is an alkyl substituent, then G 4  and the alkyl substituent R 3  on X may be joined to form a bridge of structure —(CH 2 ) p′ — wherein p′ is 2, 3, or 4, with the proviso that the sum of p and p′ is 2, 3, or 4, resulting in formation of a nitrogen-containing ring of 5, 6, or 7 members; 
         and with the further provisos that:
 in G 1 , G 2 , G 3 , and G 4 , when two groups R 3  or R 6  are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR 3  to form a N-containing heterocycle of 5-7 ring atoms; 
 when an aryl, heteroaryl, or heterocyclyl ring is optionally substituted, that ring may bear up to 5 substituents which are independently selected from the group consisting of amino, mono-loweralkyl-substituted amino, di-loweralkyl-substituted amino, lower alkanoylamino, halogeno, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyloxy, —CO 2 R 3 , —CHO, —CH 2 OR 3 , —OCO 2 R 3 , —CON(R 6 ) 2 , —OCON(R 6 ) 2 , —NR 3 CON(R 6 ) 2 , nitro, amidino, guanidino, mercapto, sulfo, and cyano; and 
 when any alkyl group is attached to O, S, or N, and bears a hydroxyl substituent, then said hydroxyl substituent is separated by at least two carbon atoms from the O, S, or N to which the alkyl group is attached, 
 
         or a pharmaceutically acceptable salt or prodrug thereof 
       
       which is effective to treat said condition. 
     
     
         5 . The method of  claim 4 , wherein said condition is tumor growth; retinopathy, including diabetic retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, and age-related macular degeneration; rheumatoid arthritis; psoriasis; or a bullous disorder associated with subepidermal blister formation, including bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis. 
     
     
         6 . A method of  claim 4 , wherein in the ring comprising A, B, D, E, and L and a bivalent bridge of structure T 2 =T 2 −T 3 , the terminal T 2  represents N and the T 3  unit of said bridge represents S, O, CR 4   2 , or NR 3 . 
     
     
         7 . A method of treating a mammal having a condition characterized by abnormal angiogenesis or hyperpermiability processes, comprising administering to said mammal a therapeutically effective amount of a compound selected from the group consisting of:
 N-(1,3-benzothiazol-6-yl)-N-[4-(1,3-benzothiazol-6-ylamino)-1-phthalazinyl]amine;   N-(1H-benzimidazol-6-yl)-N-{4-[(4-chlorophenyl)amino]-1-phthalazinyl}amine;   N-(1H-1,2,3-benzotriazol-5-yl)-N-{4-[(4-chlorophenyl)amino]-1-phthalazinyl}amine;   N-(1,3-benzothiazol-6-yl)-4-(5-bromo-2,3-dihydro-1H-indol-1-yl)-1-phthalazinamine;   N-(1,3-benzothiazol-6-yl)-N-{4-[(2,2-difluoro-1,3-benzodioxol-5-yl)amino]-1-phthalazinyl}amine;   N-(1,3-benzothiazol-6-yl)-N-(4-{[4-(1-piperidinyl)phenyl]amino}-1-phthalazinyl)amine;   N-(1,3-benzothiazol-6-yl)-N-[4-({4-[ethyl(isopropyl)amino]phenyl}amino)-1-phthalazinyl]amine;   N-(1,3-benzothiazol-6-yl)-N-{4-[(3-bromophenyl)amino]-1-phthalazinyl}amine;   N-(1,3-benzothiazol-6-yl)-N-{4-[(4-isopropylphenyl)amino]-1-phthalazinyl}amine;   N-(1,3-benzothiazol-6-yl)-N-{4-[(3-methoxyphenyl)amino]-1-phthalazinyl}amine;   N-(1,3-benzothiazol-6-yl)-N-{4-[(3-fluoro-4-methylphenyl)amino]-1-phthalazinyl}amine; and   N-(1,3-benzothiazol-6-yl)-N-{4-[(4-chlorophenyl)amino]-1-phthalazinyl}amine;   which is effective to treat said condition.   
     
     
         8 . The method of  claim 7 , wherein said condition is tumor growth; retinopathy, including diabetic retinopathy, ischemic retinal-vein occlusion, retinopathy of prematurity, and age-related macular degeneration; rheumatoid arthritis; psoriasis; or a bullous disorder associated with subepidermal blister formation, including bullous pemphigoid, erythema multiforme, and dermatitis herpetiformis.