Benzodiazepine vitronectin receptor antagonist pharmaceuticals

Abstract

The present invention describes novel compounds of the formula: (Q) d —L n —C h , useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient. The present invention also provides novel compounds useful for monitoring therapeutic angiogenesis treatment and destruction of new angiogenic vasculature. The pharmaceuticals are comprised of a targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety. The imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.

What is claimed is described below:  
     
         1 . A compound, comprising: a targeting moiety and a chelator, wherein the targeting moiety is bound to the chelator, is a benzodiazepine nonpeptide, and binds to a receptor that is upregulated during angiogenesis and the compound has 0-1 linking groups between the targeting moiety and chelator.  
     
     
         2 . A compound according to  claim 1 , wherein the targeting moiety comprises a benzodiazepine and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α v β 3 , α v β 5 , α 5 β 1 , α 4 β 1 , α 1 β 1 , and α 2 β 2  and the linking group is present between the targeting moiety and chelator.  
     
     
         3 . A compound according to  claim 2 , wherein the receptor is the integrin α v β 3  and the compound is of the formula: 
       (Q) d —L n —C h or(Q) d —L n —(C h ) d′   wherein, Q is a compound of Formula (I):                           wherein: 
 one of R or R 1  is selected from a bond to L n  or (CH 2 ) 1-4  or an NH bond to L n  and the other of R or R 1  is selected from C 1-4  alkyl, benzyl or phenethyl;  
 R 2  is selected from benzimidazole or imidazole;  
 R 3  is selected from H, C 1-4  alkyl or benzyl;  
 R 4  is selected from H, C 1-4  alkyl or benzyl;  
 d is selected from 1, 2 and 3;  
 L n  is a linking group having the formula: 
 (CR 6 R 7 ) g —(W) h —(CR 6a R 7a ) g′ —(Z) k —(W) h′ —(CR 8 R 9 ) g″ —(W) h″ —(CR 8a R 9a ) g′″ —(W) h′″ —(CR 8b R 9b ) g″″   
  provided that g+h+g′+k+h′+g″+h″+g′″ is other than 0;  
 W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , (OCH 2 CH 2 ) s , (CH 2 CH 2 O) s′ , (OCH 2 CH 2 CH 2 ) s″ , (CH 2 CH 2 CH 2 O) t , and (aa) t′ ;  
 aa is independently at each occurrence an amino acid;  
 Z is selected from the group: aryl substituted with 0-3 R 10 , C 3-10  cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 10 ;  
 R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 8b , R 9 , R 9a  and R 9b  are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, PO 3 H, C 1 -C 5  alkyl substituted with 0-3 R 10 , aryl substituted with 0-3 R 10 , benzyl substituted with 0-3 R 10 , and C 1 -C 5  alkoxy substituted with 0-3 R 10 , NHC(═O)R 11 , C(═O) NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to C h ;  
 R 10  is independently selected at each occurrence from the group: a bond to C h , COOR 11 , OH, NHR 11 , C(═O)NHR 11 , NH(C═O)R 11 , SO 3 H, PO 3 H, ═O, R 11 , aryl substituted with 0-3 R 11 , C 1-5  alkyl substituted with 0-1 R 12 , C 1-5  alkoxy substituted with 0-1 R 12 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 11 ;  
 R 11  is independently selected at each occurrence from the group: H, C 1 -C 10  alkyl substituted with 0-1 R 12 , aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 12 , C 3-10  cycloalkyl substituted with 0-1 R 12 , polyalkylene glycol substituted with 0-1 R 12 , carbohydrate substituted with 0-1 R 12 , cyclodextrin substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , polycarboxyalkyl substituted with 0-1 R 12 , polyazaalkyl substituted with 0-1 R 12 , peptide substituted with 0-1 R 12 , wherein the peptide is comprised of 2-10 amino acids, and a bond to C h ;  
 R 12  is a bond to C h ;  
 k is selected from 0, 1, and 2;  
 h is selected from 0, 1, and 2;  
 h′ is selected from 0, 1, 2, 3, 4, and 5;  
 h″ is selected from 0, 1, 2, 3, 4, and 5;  
 h′″ is selected from 0, 1, 2, 3, 4, and 5;  
 g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 g″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 g′″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 g″″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; 
 s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 
 s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 C h  is a metal bonding unit having a formula selected from the group:  
                     
  A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8  are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), O, OH, PR 13 , PR 13 R 14 , P(O)R 15 R 16 , CO 2 H and a bond to L n ;  
 E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C 1 -C 10  alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10  cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10  alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10  aryl-C 1-10  alkyl substituted with 0-3 R 17 , C 1-10  alkyl-C 6-10  aryl-substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;  
 R 13  and R 14  are each independently selected from the group: a bond to L n , hydrogen, C 1 -C 10  alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 1-10  cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10  alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10  aryl-C 1-10  alkyl substituted with 0-3 R 17 , C 1-10  alkyl-C 6-10  aryl-substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 , and an electron, provided that when one of R 13  or R 14  is an electron, then the other is also an electron;  
 alternatively, R 13  and R 14  combine to form ═C(R 20 ) (R 21 );  
 R 15  and R 16  are each independently selected from the group: a bond to L n , —OH, C 1 -C 10  alkyl substituted with 0-3 R 17 , C 1 -C 10  alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10  cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10  alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10  aryl-C 1-10  alkyl substituted with 0-3 R 17 , C 1-10  alkyl-C 6-10  aryl-substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;  
 R 17  is independently selected at each occurrence from the group: a bond to L n , ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 18 , —C(═O)R 18 , —C(═O)N(R 18 ) 2 , —CHO, —CH 2 OR 18 , —OC(═O)R 18 , —OC(═O)OR 18a , —OR 18 , —OC(═O)N(R 18 ) 2 , —NR 19 C(═O)R 18 , —NR 19 C(═O)OR 18a , —NR 19 C(═O)N(R 18 ) 2 , —NR 19 SO 2 N(R 18 ) 2 , —NR 19 SO 2 R 18a , —SO 3 H, —SO 2 R 18a , —SR 18 , —S(═O)R 18a , —SO 2 N(R 18 ) 2 , —N(R 18 ) 2 , —NHC(═S)NHR 18 , ═NOR 18 , NO 2 , —C(═O)NHOR 18 , —C(═O)NHNR 18 R 18a , —OCH 2 CO 2 H, 2-(1-morpholino)ethoxy, C 1 -C 5  alkyl, C 2 -C 4  alkenyl, C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkylmethyl, C 2 -C 6  alkoxyalkyl, aryl substituted with 0-2 R 18 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;  
 R 18 , R 18a , and R 19  are independently selected at each occurrence from the group: a bond to L n , H, C 1 -C 6  alkyl, phenyl, benzyl, C 1 -C 6  alkoxy, halide, nitro, cyano, and trifluoromethyl;  
 Pg is a thiol protecting group;  
 R 20  and R 21  are independently selected from the group: H, C 1 -C 10  alkyl, —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , C 2 -C 10  1-alkene substituted with 0-3 R 23 , C 2 -C 10  1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 23 , and unsaturated C 3-10  carbocycle substituted with 0-3 R 23 ;  
 alternatively, R 20  and R 21 , taken together with the divalent carbon radical to which they are attached form:  
                     
  R 22  and R 23  are independently selected from the group: H, R 24 , C 1 -C 10  alkyl substituted with 0-3 R 24 , C 2 -C 10  alkenyl substituted with 0-3 R 24 , C 2 -C 10  alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 24 , and C 3-10  carbocycle substituted with 0-3 R 24 ;  
 alternatively, R 22 , R 23  taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;  
 a and b indicate the positions of optional double bonds and n is 0 or 1;  
 R 24  is independently selected at each occurrence from the group: ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , —N(R 25 ) 3   + , —CH 2 OR 25 , —OC(═O)R 25 , —OC(═O)OR 25a , —OR 25 , —OC(═O)N(R 25 ) 2 , —NR 26 C(═O)R 25 , —NR 26 C(═O)OR 25a , —NR 26 C(═O)N(R 25 ) 2 , —NR 26 SO 2 N(R 25 ) 2 , —NR 26 SO 2 R 25a , —SO 3 H, —SO 2 R 25a , —SR 25 , —S (═O)R 25a , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , ═NOR 25 , —C(═O)NHOR 25 , —OCH 2 CO 2 H, and 2-(1-morpholino)ethoxy; and,  
 R 25 , R 25a , and R 26  are each independently selected at each occurrence from the group: hydrogen and C 1 -C 6  alkyl;  
 and a pharmaceutically acceptable salt thereof.  
   
     
     
         4 . A compound according to  claim 3 , wherein: 
 d is selected from 1, 2, 3, 4, and 5;    Z is selected from the group: aryl substituted with 0-1 R 10 , C 3-10  cycloalkyl substituted with 0-1 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 10 ;    A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8  are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), OH, and a bond to L n ;    E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C 1 -C 10  alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10  cycloalkyl substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;    R 13 , and R 14  are each independently selected from the group: a bond to L n , hydrogen, C 1 -C 10  alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 , and an electron, provided that when one of R 13  or R 14  is an electron, then the other is also an electron;    alternatively, R 13  and R 14  combine to form ═C(R 20 ) (R 21 );    R 17  is independently selected at each occurrence from the group: a bond to L n , ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 18 , —C(═O)R 18 , —C(═O)N(R 18 ) 2 , —CH 2 OR 18 , —OC(═O) 18 , —OC(═O)OR 18a , —OR 18 , —OC(═O)N(R 18 ) 2 , —NR 19 C(═O)R 18 , —NR 19 C(═O)OR 18a , —NR 19 C(═O)N(R 18 ) 2 , —NR 19 SO 2 N(R 18 ) 2 , —NR 19 SO 2 R 18a , —SO 3 H, —SO 2 R 18a , —S(═O)R 18a , —SO 2 N(R 18 ) 2 , —N(R 18 ) 2 , —NHC(═S)NHR 18 , ═NOR 18 , —C(═O)NHNR 18 R 18a , —OCH 2 CO 2 H, and 2-(1-morpholino)ethoxy;    R 18 , R 18a , and R 19  are independently selected at each occurrence from the group: a bond to L n , H, and C 1 -C 6  alkyl;    R 20  and R 21  are independently selected from the group: H, C 1 -C 5  alkyl, —CO 2 R 25 , C 2 -C 5  1-alkene substituted with 0-3 R 23 , C 2 -C 5  1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 23 ;    alternatively, R 20  and R 21 , taken together with the divalent carbon radical to which they are attached form:                          R 22  and R 23  are independently selected from the group: H, and R 24 ; 
 alternatively, R 22 , R 23  taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;  
 R 24  is independently selected at each occurrence from the group: —CO 2 R 25 , —C(═O)N(R 25 ) 2 , —CH 2 OR 25 , —OC(═O)R 25 , —OR 25 , —SO 3 H, —N(R 25 ) 2 , and —OCH 2 CO 2 H; and,  
 R 25  is independently selected at each occurrence from the group: H and C 1 -C 3  alkyl.  
   
     
     
         5 . A compound according to  claim 4 , wherein: 
 Q is a peptide selected from the group:                           K is an L-amino acid independently selected at each occurrence from the group: arginine, citrulline, N-methylarginine, lysine, homolysine, 2-aminoethylcysteine, d-N-2-imidazolinylornithine, d-N-benzylcarbamoylornithine, and b-2-benzimidazolylacetyl-1,2-diaminopropionic acid; 
 L is glycine;  
 M is L-aspartic acid;  
 M′ is D-aspartic acid;  
 R 1  is L-valine, D-valine or L-lysine optionally substituted on the e amino group with a bond to L n ;  
 R 2  is L-phenylalanine, D-phenylalanine, D-1-naphthylalanine, 2-aminothiazole-4-acetic acid or tyrosine, the tyrosine optionally substituted on the hydroxy group with a bond to L n ;  
 R 3  is D-valine;  
 R 4  is D-tyrosine substituted on the hydroxy group with a bond to L n ;  
 provided that one of R 1  and R 2  in each Q is substituted with a bond to L n , and further provided that when R 2  is 2-aminothiazole-4-acetic acid, K is N-methylarginine;  
 provided that at least one Q is a benzodiazepine;  
 d is 1, 2, or 3;  
 A 1  is selected from the group: OH, and a bond to L n ;  
 A 2 , A 4 , and A 6  are each N;  
 A 3 , A 5 , and A 8  are each OH;  
 A 7  is a bond to L n  or NH-bond to L n ;  
 E is a C 2  alkyl substituted with 0-1 R 17 ;  
 R 17  is ═O;  
 alternatively, C h  is  
                     
  A 1  is selected from the group: OH, and a bond to L n ;  
 A 2 , A 3  and A 4  are each N;  
 A 5 , A 6  and A 8  are each OH;  
 A 7  is a bond to L n ;  
 E is a C 2  alkyl substituted with 0-1 R 17 ;  
 R 17  is ═O;  
 alternatively, C h  is  
                     
  A 1  is NH 2  or N═C(R 20 ) (R 21 );  
 E is a bond;  
 A 2  is NHR 13 ;  
 R 13  is a heterocycle substituted with R 17 , the heterocycle being selected from pyridine and pyrimidine;  
 R 17  is selected from a bond to L n , C(═O)NHR 18  and C(═O)R 18 ;  
 R 18  is a bond to L n ;  
 R 24  is selected from the group: —CO 2 R 25 , —OR 25 , —SO 3 H, and —N(R 25 ) 2 ; and,  
 R 25  is independently selected at each occurrence from the group: hydrogen and methyl.  
   
     
     
         6 . A compound according to  claim 3 , wherein the compound is selected from the group: 
 (S,S,S)-4-(N-(3-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-4-(4-carboxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl) cyclodecyl)acetylamino)butanoyl amino)butanoic acid;    (S)-2-(2,5-diaza-5-(6((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)hexyl)-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-4-oxobicyclo [5.4.0]undeca-1(7),8,10-trien-3-yl) acetic acid;    (S)-2-(2,5-diaza-9-(N-(6-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)hexyl)-N-(benzimidazol-2-ylmethyl)carbamoyl)-5-methyl-4-oxobicyclo [5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid;    (S,S)-2-(2-aza-2-((5-(N-(1,3-bis(N-(6-(aminohexyl-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid)(2-(2,5-diaza-9-(N-(benzimidazol-2-ylmethyl)propyl)carbamoyl)(2-pyridyl))amino)vinyl) benzenesulfonic acid;    (S,S,S)-4-(N-(3-(3,6-diaza-5-(carboxymethyl)-10-(N-(imidazol-2-ylmethyl)-N-benzylcarbamoyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)propyl) carbamoyl)-4-(4-carboxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl) cyclododecyl)acetylamino)butanoylamino) butanoic acid;    (S,S)-3-(N-(3-(3,6-diaza-5-(carboxymethyl)-10-(N-(imidazol-2-ylmethyl)-N-benzylcarbamoyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)propyl) carbamoyl)-3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl) cyclododecyl)acetylamino)propanoic acid;    (S,S,S,S,S,S,S,S)-4-(N-1,3-bis(N-3-carboxy-1-(N-(3-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-4,4-dihydroxypentyl) carbamoyl)propyl)carbamoyl)-4-(5,5-dihydroxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclodecyl)acetylamino) butanoic acid;    (S,S,S,S,S,S,S,S,S,S)-2-(4-(N-(1,3-bis(N-(3-(N-(3-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-5-((methoxycarbonyl)methyl)-4-oxobicyclo [5.4.0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-1-(methoxycarbonyl)propyl)carbamoyl)propyl)carbamoyl)propyl)carbamoyl)-4-(2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl) cyclodecyl)acetylamino)-4-carboxybutanoylamino)-4-carboxybutanoylamino)butanoylamino)-4-(N-(3-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl)-N-methyl carbamoyl)-5-((methoxycarbonyl)methyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)butanoic acid;    (S)-2-(2,5-diaza-5-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino) propoxy)ethoxy)ethoxy)propyl)-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid;    (S,S,S,S,S)-4-(N-(1,3-bis(N-(3-(2-(2-(3-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)propoxy)ethoxy)ethoxy)propyl)carbamoyl) propyl)carbamoyl)-4-(5,5-dihydroxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxy methyl)cyclododecyl)acetylamino) hexanoylamino)butanoic acid;    (S,S,S)-2-(2,5-diaza-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-4-oxo-5-(6-(4-(N-((R,S,S,S)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl)-2-(4-(N-((R,S,S,S)-2,3,4,5,6-pentahydroxy hexyl)carbamoyl)-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclodecyl) acetylamino)butanoylamino)butanoylamino)hexyl)bicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid;    (S,S,S,S)-2-(4-(N-(1-(N-(1-(N-(6-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)hexyl)carbamoyl)-3-(N-cyclo{Lys-Arg(Mtr)-Gly-Asp(OtBu)-D-Phe}[gamma-LysNH]carbamoyl)propyl)carbamoyl)-3-carboxypropyl) carbamoyl)-4-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl) cyclododecyl)acetylamino)butanoic acid; and    or a pharmaceutically acceptable salt form thereof.    
     
     
         7 . A kit comprising a compound of  claim 3 , or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier.  
     
     
         8 . A kit according to claim, wherein the kit further comprises one or more ancillary ligands and a reducing agent.  
     
     
         9 . A kit according to  claim 8 , wherein the ancillary ligands are tricine and TPPTS.  
     
     
         10 . A kit according to  claim 9 , wherein the reducing agent is tin(II).  
     
     
         11 . A diagnostic or therapeutic metallopharmaceutical composition, comprising: a metal, a chelator capable of chelating the metal and a targeting moiety, wherein the targeting moiety is bound to the chelator, is a benzodiazepine nonpeptide and binds to a receptor that is upregulated during angiogenesis and the compound has 0-1 linking groups between the targeting moiety and chelator.  
     
     
         12 . A composition according to  claim 11 , wherein the metallopharmaceutical is a diagnostic radiopharmaceutical, the metal is a radioisotope selected from the group:  99m Tc,  95 Tc,  111 In,  62 Cu,  64 Cu,  67 Ga, and  68 Ga, the targeting moiety comprises a benzodiazepine and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α v β 3 , α v β 5 , α 5 β 1 , α 4 β 1 , α 1 β 1 , and α 2 β 2  and the linking group is present between the targeting moiety and chelator.  
     
     
         13 . A composition according to  claim 12 , wherein the targeting moiety is a benzodiazepine and the receptor is α v β 3 .  
     
     
         14 . A composition according to  claim 12 , wherein the radioisotope is  99m Tc or  95 Tc, the radiopharmaceutical further comprises a first ancillary ligand and a second ancillary ligand capable of stabilizing the radiopharmaceutical.  
     
     
         15 . A composition according to  claim 14 , wherein the radioisotope is  99m Tc.  
     
     
         16 . A composition according to  claim 15 , wherein the radiopharmaceutical is selected from the group: 
   99m Tc ((S)-2-(2,5-diaza-5-(6((6-(diazenido) (3-pyridyl))carbonylamino)hexyl)-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-4-oxobicyclo [5.4.0]undeca-1(7),8,10-trien-3-yl) acetic acid)(tricine)(TPPTS) and    99mTc ( (S)-2-(2,5-diaza-9-(N-(6-((6-(diazenido)(3-pyridyl))carbonylamino)hexyl)-N-(benzimidazol-2-ylmethyl)carbamoyl)-5-methyl-4-oxobicyclo [5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid)(tricine)(TPPTS);    
     
     
         17 . A composition according to  claim 13 , wherein the radioisotope is  111 In.  
     
     
         18 . A composition according to  claim 17 , wherein the radiopharmaceutical is selected from the group: 
   111 In complex of 6-(N-(3-(3-aza-10-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo [5.4.0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-3-(2-((2-((carboxymethyl) (2-((carboxymethyl)methylamino)ethyl)amino) ethyl)(2-((carboxymethyl)ethylamino)ethyl)amino)-acetylamino)-4-oxooctane-1,8-dicarboxylic acid;      111 In complex of (S,S,S)-4-(N-(3-(3,6-diaza-5-(carboxymethyl)-10-(N-(imidazol-2-ylmethyl)-N-benzylcarbamoyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)propyl) carbamoyl)-4-(4-carboxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl) cyclododecyl)acetylamino)butanoylamino) butanoic acid; and      111 In complex of (S,S)-3-(N-(3-(3,6-diaza-5-(carboxymethyl)-10-(N-(imidazol-2-ylmethyl)-N-benzylcarbamoyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)propyl) carbamoyl)-3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl) cyclododecyl)acetylamino)propanoic acid.    
     
     
         19 . A composition according to  claim 11 , wherein the metallopharmaceutical is a therapeutic radiopharmaceutical, the metal is a radioisotope selected from the group:  186 Re,  188 Re,  153 Sm,  166 Ho,  177 Lu,  149 Pm,  90 y,  212 Bi,  103 Pd,  109 Pd,  159 Gd,  140 La,  198 Au,  199 Au, 169Yb,  175 Yb,  165 Dy,  166 Dy,  67 Cu,  105 Rh,  111 Ag, and  192 Ir, the targeting moiety is a benzodiazepine nonpeptide and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α v β 3 , α v β 5 , α 5 β 1 , α 4 β 1 , α 1 β 1 , and α 2 β 2  and the linking group is present between the targeting moiety and chelator.  
     
     
         20 . A composition according to  claim 19 , the targeting moiety is an benzodiazepine and the receptor is α v β 3 .  
     
     
         21 . A composition according to  claim 20 , wherein the radioisotope is  153 Sm.  
     
     
         22 . A composition according to  claim 20 , wherein the radioisotope is  177 Lu.  
     
     
         23 . A composition according to  claim 20 , the radioisotope is  90 Y.  
     
     
         24 . A composition according to  claim 11 , wherein the metallopharmaceutical is a MRI contrast agent, the metal is a paramagnetic metal ion selected from the group: Gd(III), Dy(III), Fe(III), and Mn(II), the targeting moiety is a benzodiazepine nonpeptide and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α v β 3 , α v β 5 , α 5 β 1 , α 4 β 1 , α 1 β 1 , and α 2 β 2  and the linking group is present between the targeting moiety and chelator.  
     
     
         25 . A composition according to  claim 24 , wherein the targeting moiety is an indazole and the receptor is α v β 3 .  
     
     
         26 . A composition according to  claim 25 , wherein the metal ion is Gd(III).  
     
     
         27 . A composition according to  claim 11 , wherein the metallopharmaceutical is a X-ray contrast agent, the metal is selected from the group: Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag, and Ir, the targeting moiety is a benzodiazepine nonpeptide, the receptor is α v β 3 , and the linking group is present between the targeting moiety and chelator.  
     
     
         28 . A method of treating rheumatoid arthritis in a patient comprising: administering a therapeutic radiopharmaceutical of  claim 11  capable of localizing in new angiogenic vasculature to a patient by injection or infusion.  
     
     
         29 . A method of treating cancer in a patient comprising: administering to a patient in need thereof a therapeutic radiopharmaceutical of  claim 11  by injection or infusion.  
     
     
         30 . A method of imaging formation of new blood vessels in a patient comprising: (1) administering a diagnostic radiopharmaceutical, a MRI contrast agent, or a X-ray contrast agent of of  claim 11  to a patient by injection or infusion; (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.  
     
     
         31 . A method of imaging cancer in a patient comprising: 
 (1) administering a diagnostic radiopharmaceutical of  claim 11  to a patient by injection or infusion; (2) imaging the patient using planar or SPECT gamma scintigraphy, or positron emission tomography.    
     
     
         32 . A method of imaging cancer in a patient comprising: 
 (1) administering a MRI contrast agent of  claim 24;  and    (2) imaging the patient using magnetic resonance imaging.    
     
     
         33 . A method of imaging cancer in a patient comprising: 
 (1) administering a X-ray contrast agent of  claim 27;  and    (2) imaging the patient using X-ray computed tomography.    
     
     
         34 . A compound, comprising: a targeting moiety and a surfactant, wherein the targeting moiety is bound to the surfactant, is a benzodiazepine nonpeptide, and binds to a receptor that is upregulated during angiogenesis and the compound has 0-1 linking groups between the targeting moiety and surfactant.  
     
     
         35 . A compound according to  claim 34 , wherein the targeting moiety comprises an benzodiazepine and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-l/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α v β 3 , α v β 5 , α 5 β 1 , α 4 β 1 , α 1 β 1 , and α 2 β 2  and the linking group is present between the targeting moiety and surfactant.  
     
     
         36 . A compound according to  claim 35 , wherein the receptor is the integrin α v β 3  and the compound is of the formula: 
       (Q) d —L n —S f   wherein, Q is a compound of Formula (I):                          wherein: 
 one of R or R 1  is selected from a bond to L n  or (CH 2 ) 1-4  or an NH bond to L n  and the other of R or R 1  is selected from C 1-4  alkyl, benzyl or phenethyl;  
 R 2  is selected from benzimidazole or imidazole;  
 R 3  is selected from H, C 1-4  alkyl or benzyl;  
 R 4  is selected from H, C 1-4  alkyl or benzyl;  
 d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 S f  is a surfactant which is a lipid or a compound of the formula:  
                     
  A 9  is selected from the group: OH and OR 27 ;  
 A 10  is OR 27 ;  
 R 27  is C(═O)C 1-20  alkyl;  
 E 1  is C 1-10  alkylene substituted with 1-3 R 28 ;  
 R 28  is independently selected at each occurrence from the group: R 30 , —PO3H-R 30 ,═O, —CO 2 R 29 , —C(═O)R 29 , —C(═O)N(R 29 ) 2 , —CH 2 OR 29 , —OR 29 , —N(R 29 ) 2 , C 1 -C 5  alkyl, and C 2 -C 4  alkenyl;  
 R 29  is independently selected at each occurrence from the group: R 30 , H, C 1 -C 6  alkyl, phenyl, benzyl, and trifluoromethyl;  
 R 30  is a bond to L n ;  
 L n  is a linking group having the formula: 
 (CR 6 R 7 ) g —(W) h —(CR 6a R 7a ) g′ —(Z) k —(W) h′ —(CR 8 R 9 ) g″ —(W) h″ —(CR 8a R 9a ) g′″   
  W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , (OCH 2 CH 2 ) 20-200 , (CH 2 CH 2 O) 20-200 , (OCH 2 CH 2 CH 2 ) 20-200 , (CH 2 CH 2 CH 2 O) 20-200 , and (aa) t′ ;  
 aa is independently at each occurrence an amino acid;  
 Z is selected from the group: aryl substituted with 0-3 R 10 , C 3-10  cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 10 ;  
 R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9  and R 9a  are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, PO 3 H, C 1 -C 5  alkyl substituted with 0-3 R 10 , aryl substituted with 0-3 R 10 , benzyl substituted with 0-3 R 10 , and C 1 -C 5  alkoxy substituted with 0-3 R 10 , NHC(═O)R 11 , C(═O)NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to S f ;  
 R 10  is independently selected at each occurrence from the group: a bond to S f , COOR 11 , OH, NHR 11 , SO 3 H, PO 3 H, aryl substituted with 0-3 R 11 , C 1-5  alkyl substituted with 0-1 R 12 , C 1-5  alkoxy substituted with 0-1 R 12 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 11 ;  
 R 11  is independently selected at each occurrence from the group: H, aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 12 , C 3-10  cycloalkyl substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , and a bond to S f ;  
 R 12  is a bond to S f ;  
 k is selected from 0, 1, and 2;  
 h is selected from 0, 1, and 2;  
 h′ is selected from 0, 1, 2, 3, 4, and 5;  
 h″ is selected from 0, 1, 2, 3, 4, and 5;  
 g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 g″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 g′″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;  
 and a pharmaceutically acceptable salt thereof.  
   
     
     
         37 . A compound according to  claim 36 , wherein the compound is of the formula: 
       Q—L n —S f   wherein, Q is a compound of Formula (I):                           wherein: 
 one of R or R 1  is selected from a bond to L n  or (CH 2 ) 1-4  or an NH bond to L n  and the other of R or R 1  is selected from C 1-4  alkyl, benzyl or phenethyl;  
 R 2  is selected from benzimidazole or imidazole;  
 R 3  is selected from H, C 1-4  alkyl or benzyl;  
 R 4  is selected from H, C 1-4  alkyl or benzyl;  
 S f  is a surfactant which is a lipid or a compound of the formula:  
                     
  A 9  is OR 27 ;  
 A 10  is OR 27 ;  
 R 27  is C(═O)C 1-15  alkyl;  
 E 1  is C 1-4  alkylene substituted with 1-3 R 28 ;  
 R 28  is independently selected at each occurrence from the group: R 30 , —PO 3 H-R 30 , ═O, —CO 2 R 29 , —C(═O)R 29 , —CH 2 OR 29 , —OR 29 , and C 1 -C 5  alkyl;  
 R 29  is independently selected at each occurrence from the group: R 30 , H, C 1 -C 6  alkyl, phenyl, and benzyl;  
 R 30  is a bond to L n ;  
 L n  is a linking group having the formula: 
 (CR 6 R 7 ) g —(W) h —(CR 6a R 7a ) g′ —(Z) k —(W) h′ —(CR 8 R 9 ) g″ —(W) h″ —(CR 8a R 9a ) g′″   
  W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , (OCH 2 CH 2 ) 20-200 , (CH 2 CH 2 O) 20-200 , (OCH 2 CH 2 CH 2 ) 20-200 , (CH 2 CH 2 CH 2 O) 20-200 , and (aa) t′ ;  
 aa is independently at each occurrence an amino acid;  
 Z is selected from the group: aryl substituted with 0-3 R 10 , C 3-10  cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 10 ;  
 R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9  and R 9a  are independently selected at each occurrence from the group: H, ═O, C 1 -C 5  alkyl substituted with 0-3 R 10 , and C 1 -C 5  alkoxy substituted with 0-3 R 10 , and a bond to S f ;  
 R 10  is independently selected at each occurrence from the group: a bond to S f , COOR 11 , OH, NHR 11 , C 1-5  alkyl substituted with 0-1 R 12 , and C 1-5  alkoxy substituted with 0-1 R 12 ;  
 R 11  is independently selected at each occurrence from the group: H, aryl substituted with 0-1 R 12 , C 3-10  cycloalkyl substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , and a bond to S f ;  
 R 12  is a bond to S f ;  
 k is selected from 0, 1, and 2;  
 h is selected from 0, 1, and 2;  
 h′ is selected from 0, 1, 2, 3, 4, and 5;  
 h″ is selected from 0, 1, 2, 3, 4, and 5;  
 g is selected from 0, 1, 2, 3, 4, and 5;  
 g′ is selected from 0, 1, 2, 3, 4, and 5;  
 g″ is selected from 0, 1, 2, 3, 4, and 5;  
 g′″ is selected from 0, 1, 2, 3, 4, and 5;  
 s is selected from 0, 1, 2, 3, 4, and 5;  
 s′ is selected from 0, 1, 2, 3, 4, and 5;  
 s″ is selected from 0, 1, 2, 3, 4, and 5;  
 t is selected from 0, 1, 2, 3, 4, and 5;  
 t′ is selected from 0, 1, 2, 3, 4, and 5;  
 and a pharmaceutically acceptable salt thereof.  
   
     
     
         38 . A compound according to  claim 37 , wherein the compound selected from the group: 
 Sodium 1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine-(S)-2-(2,5-diaza-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-5-(6-aminohexyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid-dodecoanoate conjugate;    DPPE-PEG 3400 -[(S)-2-(2,5-diaza-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-5-(6-aminohexyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid]-dodecoanoate conjugate; and    [(S)-2-(2-aza-(2-((5-(N-(1,3-bis-N-(6-(aminohexyl-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid)(2-(2,5-diaza-9-(N-(benzimidazol-2-ylmethyl) carbamoyl) propyl) carbamoyl]-w-amino-PEG 3400 -dodecanoate-DPPE conjugate.    
     
     
         39 . An ultrasound contrast agent composition, comprising: 
 (a) a compound of  claim 35 , comprising: a benzodiazepine that binds to the integrin α v β 3 , a surfactant and a linking group between the benzodiazepine and the surfactant;    (b) a parenterally acceptable carrier; and,    (c) an echogenic gas.    
     
     
         40 . An ultrasound contrast agent composition of  claim 39 , further comprising: 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, and N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine.  
     
     
         41 . An ultrasound contrast agent composition of  claim 40 , wherein the echogenic gas is a C 2-5  perfluorocarbon.  
     
     
         42 . A method of imaging cancer in a patient comprising: 
 (1) administering, by injection or infusion, a ultrasound contrast agent composition of  claim 35  to a patient; and    (2) imaging the patient using sonography.    
     
     
         43 . A method of imaging formation of new blood vessels in a patient comprising: (1) administering, by injection or infusion, a ultrasound contrast agent composition of of  claim 36  to a patient; (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.  
     
     
         44 . A therapeutic radiopharmaceutical composition, comprising: 
 (a) a therapeutic radiopharmaceutical of  claim 11;  and,    (b) a parenterally acceptable carrier.    
     
     
         45 . A diagnostic radiopharmaceutical composition, comprising: 
 (a) a diagnostic radiopharmaceutical, a MRI contrast agent, or a X-ray contrast agent of  claim 11;  and,    (b) a parenterally acceptable carrier.