Glycinamide derivatives as raf-kinase inhbitors

Abstract

The present invention relates to glycinamide derivatives of formula I, A-D-B  (I), wherein A, D, and B are as herein defined, as well as the use of the compounds of formula I as inhibitors of raf-kinase, the use of the compounds of formula I for the manufacture of a pharmaceutical composition, and a method of treatment comprising administering said pharmaceutical composition to a patient.

1 . A method for the treatment and/or prophylaxis of disorders in a patient caused, mediated and/or propagated by kinases, said method comprising administering to said patient one or more compounds according to formula I
   A-D-B  (I)   
     wherein
 D is a bivalent glycine amide moiety, or a derivative thereof, 
 A is an unsubstituted or substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L′) α ; 
 L is a 5, 6 or 7 membered cyclic structure containing 0-4 members selected from nitrogen, oxygen and sulfur bound directly to D; 
 L′ comprises an optionally substituted cyclic moiety having at least 5 members and containing 0-4 members selected from nitrogen, oxygen and sulfur, wherein L′ is optionally substituted by at least one substituent selected from —SO β R x  and —C(NR y )R z ; 
 M is a bond or a bridging group having at least one atom; 
 α is an integer of from 1-4; 
 B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms, comprising at least one 5-, 6-, or 7-membered cyclic structure, bound directly to D and containing 0-4 members selected from nitrogen, oxygen and sulfur; 
 where when B is substituted, L is substituted or L′ is additionally substituted, the substituents are selected from halogen, up to per-halo, and Wγ; 
 R y  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo; 
 R z  is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; 
 R x  is R z  or NR a R b ; 
 R a  and R b  are
 a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or 
  —OSi(R f ) 3  where R f  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or 
 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or 
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;
 γ is 0-3; 
 
 W is, in each case, independently selected from —CN, —CO 2 R, —C(O)NR 5 R 5 , —C(O)—R 5 , —NO 2 , —OR 5 , —SR 5 , —SO 2 R 5 , —SO 3 H, —NR 5 R 5 , —NR 5 C(O)OR 5 , —NR 5 C(O)R 5 , -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the groups consisting of —CN, —CO 2 R, —C(O)NR 5 R 5 , —C(O)—R 5 , —NO 2 , —OR 5 , —SR 5 , —SO 2 R 5 , —SO 3 H, —NR 5 R 5 , —NR 5 C(O)OR 5 , —NR 5 C(O)R 5  and halogen up to per-halo;
 R 5  is, in each case, independently H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen; 
 Q is —O—, —S—, —N(R 5 )—, —(CH 2 ) β , —C(O)—, —CH(OH)—, —(CH 2 ) β O—, —(CH 2 ) β S—, —(CH 2 ) β N(R 5 )—, —O(CH 2 ) β , —CHHal-, —CHal 2 -, —S—(CH 2 )— or —N(R 5 )(CH 2 ) β —; 
 β is 1-3; 
 Hal is halogen; 
 Ar is 5- or 6-member aromatic structure containing 0-2 members selected from nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z δ1 ; 
 δ1 is 0 to 3; and 
 Z is, in each case, independently selected from —CN, —CO 2 R 5 , —C(O)NR 5 R 5 , —C(O)—R 5 , —NO 2 , —OR 5 , —SR 5 , —SO 2 R 5 , —SO 3 H, —NR 5 R 5 , —NR 5 C(O)OR 5 , —NR 5 C(O)R 5 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from —CN, —CO 2 R 5 , —C(O)NR 5 R 5 , —C(O)—R 5 , —NO 2 , —OR 5 , —SR 5 , —SO 2 R 5 , —SO 3 H, —NR 5 R 5 , —NR 5 C(O)OR 5 , and —NR 5 C(O)R 5 ; or 
 
 a physiologically acceptable derivative, salts or solvate thereof. 
 
   
   
       2 . A method according to  claim 1 , wherein
 each M, independently from one another, represents a bond or is a bridging group selected from (CR 5 R 5 ) h , and (CHR 5 ) h -Q-(CHR 5 ) i ,   Q is O, S, N—R 5 , (CHal 2 ) j , (O—CHR 5 ) j , (CHR 5 —O) j , CR 5 ═CR 5 , (O—CHR 5 CHR 5 ) j , (CHR 5 CHR 5 —O) j , C═O, C═S, C═NR 5 , CH(OR 5 ), C(OR 5 )(OR 5 ), C(═O)O, OC(═O), OC(═O)O, (C═O)N(R 5 )C(═O), OC(═O)N(R 5 ), N(R 5 )C(═O)O, CH═N—NR 5 , S═O, SO 2 , SO 2 NR 5 , or NR 5 SO 2 ,   h, i are independently from each other 0, 1, 2, 3, 4, 5, or 6, and   j is 1, 2, 3, 4, 5 or 6.   
   
   
       3 . A method according to  claim 1 , selected from the compounds of formula II, 
     
       
         
         
             
             
         
       
     
     wherein
 Ar 1 , Ar 2  are each, independently from one another, selected from aromatic hydrocarbons containing 6 to 14 carbon atoms and ethylenical unsaturated or aromatic heterocyclic residues containing 3 to 10 carbon atoms and one or two hetero atoms, independently selected from N, O and S, 
 R 8 , R 9  and R 10  are independently selected from H, A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH 2 Hal, CH(Hal) 2 , C(Hal) 3 , NO 2 , (CH 2 ) n CN, (CH 2 ) n NR 11 R 12 , (CH 2 ) n OR 11 , (CH 2 ) n O(CH 2 ) k NR 11 R 12 , (CH 2 ) n COOR 12 , (CH 2 ) n CONR 11 R 12 , (CH 2 ) n NR 11 COR 13 , (CH 2 ) n NR 11 CONR 11 R 12 , (CH 2 ) n NR 11 SO 2 A, (CH 2 ) n SO 2 NR 11 R 12 , (CH 2 ) n S(O) u R 13 , (CH 2 ) n OC(O)R 13 , (CH 2 ) n COR 13 , (CH 2 ) n SR 11 , CH═N—OA, CH 2 CH═N—OA, (CH 2 ) n NHOA, (CH 2 ) n CH═N—R 11 , (CH 2 ) n OC(O)NR 11 R 12 , (CH 2 ) n NR 11 COOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 OR 13 , (CH 2 ) n N(R 11 )CH 2 CH 2 OCF 3 , (CH 2 ) n N(R 11 )C(R 13 )HCOOR 12 , C(R 13 )HCOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 N(R 12 )CH 2 COOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 NR 11 R 12 , CH═CHCOOR 11 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 OR 13 , (CH 2 ) n N(COOR 11 )COOR 12 , (CH 2 ) n N(CONH 2 )COOR 11 , (CH 2 ) n N(CONH 2 )CONH 2 , (CH 2 ) n N(CH 2 COOR 11 )COOR 12 , (CH 2 ) n N(CH 2 CONH 2 )COOR 11 , (CH 2 ) n N(CH 2 CONH 2 )CONH 2 , (CH 2 ) n CHR 13 COR 11 , (CH 2 ) n CHR 13 COOR 11 , (CH 2 ) n CHR 13 CH 2 OR 14 , (CH 2 ) n OCN and (CH 2 ) n NCO, 
 R 11 , R 12  are independently selected from H, A, (CH 2 ) m Ar 3  and (CH 2 ) m Het, or, 
 in NR 11 R 12 , R 11  and R 12  form, together with the N-Atom they are bound to, a 5-, 6- or 7-membered heterocycle which optionally contains 1 or 2 additional hetero atoms, selected from N, O an S, 
 R 13 , R 14  are independently selected from H, Hal, A, (CH 2 ) m Ar 4  and (CH 2 ) m Het, 
 A is selected from alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, alkoxy and alkoxyalkyl, 
 Ar 3 , Ar 4  are independently from one another aromatic hydrocarbon residues comprising 5 to 12 which are optionally substituted by one or more substituents, selected from A, Hal, NO 2 , CN, OR 15 , NR 15 R 16 , COOR 15 , CONR 15 R 16 , NR 15 COR 16 , NR 15 CONR 15 R 16 , NR 16 SO 2 A, COR 15 , SO 2 R 15 R 16 , S(O) u A and OOCR 15 , 
 Het is a saturated, unsaturated or aromatic heterocyclic residue which is optionally substituted by one or more substituents, selected from A, Hal, NO 2 , CN, OR 15 , NR 15 R 16 , COOR 15 , CONR 15 R 16 , NR 15 COR 16 , NR 15 CONR 15 R 16 , NR 16 SO 2 A, COR 15 , SO 2 R 15 R 16 , S(O) u A and OOCR 15 , 
 R 15 , R 16  are independently selected from H, A, and (CH 2 ) m Ar 5 , 
 Ar 5  is a 5- or 6-membered aromatic hydrocarbon which is optionally substituted by one or more substituents selected from methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN, OH, NH 2  and CF 3 , 
 k, n, m are independently of one another 0, 1, 2, 3, 4, or 5; 
 X represents a bond or is (CR 11 R 12 ) h , or (CHR 11 ) h -Q-(CHR 12 ) i , 
 Q is selected from O, S, N—R 15 , (CHal 2 ) j , (O—CHR 18 ) j , (CHR 18 —O) j , CR 18 ═CR 19 , (O—CHR 18 CHR 19 ) j , CHR 18 CHR 19 —O) j , C═O, C═S, C═NR 15 , CH(OR 15 ), C(OR 17 )(OR 20 ), C(═O)O, OC(═O), OC(═O)O, C(═)N(R 15 ), N(R 15 )C(═O), OC(═O)N(R 15 ), N(R 15 )C(═O)O, CH═N—O, CH═N—NR 15 , OC(O)NR 15 , NR 15 C(O)O, S═O, SO 2 , SO 2 NR 15  and NR 15 SO 2 , 
 h, i are independently from each other 0, 1, 2, 3, 4, 5 or 6, 
 j is 1, 2, 3, 4, 5 or 6, 
 Y is selected from O, S, NR 21 , C(R 22 )—NO 2 , C(R 22 )—CN and C(CN) 2 , 
 R 21  is H, Hal, A, (CH 2 ) m Ar 4  and (CH 2 ) m Het, 
 R 22  is H, A, (CH 2 ) m Ar 3  and (CH 2 ) m Het, 
 p, r are independently from one another 0, 1, 2, 3, 4 or 5, 
 q is 0, 1, 2, 3 or 4, 
 u is 0, 1, 2 or 3, and 
 Hal is independently selected from F, Cl, Br and I; 
 
     and the salts and solvates thereof. 
   
   
       4 . A method according to  claim 1 , wherein said compound is selected from the compounds of formulas IIa, IIb, IIc, IId, IIe, IIf, IIg and IIh, 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein 
       R 8 , R 9  
 and R 10  are independently selected from H, A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH 2 Hal, CH(Hal) 2 , C(Hal) 3 , NO 2 , (CH 2 ) n CN, (CH 2 ) n NR 11 R 12 , (CH 2 ) n OR 11 , (CH 2 ) n O(CH 2 ) k NR 11 R 12 , (CH 2 ) n COOR 12 , (CH 2 ) n CONR 11 R 12 , (CH 2 ) 2 NR 11 COR 13 , (CH 2 ) n NR 11 CONR 11 R 12 , (CH 2 ) n NR 11 SO 2 A, (CH 2 ) n SO 2 NR 11 R 12 , (CH 2 ) n S(O) u R 13 , (CH 2 ) n OC(O)R 13 , (CH 2 ) n COR 13 , (CH 2 ) n SR 11 , CH═N—OA, CH 2 CH═N—OA, (CH 2 ) n NHOA, (CH 2 ) n CH═N—R 11 , (CH 2 ) n OC(O)NR 11 R 12 , (CH 2 ) n NR 11 COOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 OR 13 , (CH 2 ) n N(R 11 )CH 2 CH 2 OCF 3 , (CH 2 ) n N(R 11 )C(R 13 )HCOOR 12 , C(R 13 )HCOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 N(R 12 )CH 2 COOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 NR 11 R 12 , CH═CHCOOR 11 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 OR 13 , (CH 2 ) n N(COOR 11 )COOR 12 , (CH 2 ) n N(CONH 2 )COOR 11 , (CH 2 ) n N(CONH 2 )CONH 2 , (CH 2 ) n N(CH 2 COOR 11 )COOR 12 , (CH 2 ) n N(CH 2 CONH 2 )COOR 11 , (CH 2 ) n N(CH 2 CONH 2 )CONH 2 , (CH 2 ) n CHR 13 COR 11 , (CH 2 ) n CHR 13 COOR 11 , (CH 2 ) n CHR 13 CH 2 OR 14 , (CH 2 ) n OCN and (CH 2 ) n NCO, 
 
       R 11 , R 12  are independently selected from H, A, (CH 2 ) m Ar 3  and (CH 2 ) m Het, or, in NR 11 R 12 , R 11  and R 12  form, together with the N-Atom they are bound to, a 5-, 6- or 7-membered heterocycle which optionally contains 1 or 2 additional hetero atoms, selected from N, O an S, 
       R 13 , R 14  are independently selected from H, Hal, A, (CH 2 ) m Ar 4  and (CH 2 ) m Het, 
       A is selected from alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl alkoxy and alkoxyalkyl, 
       Ar 3 , Ar 4  are independently from one another aromatic hydrocarbon residues comprising 5 to 12 carbon atoms which are optionally substituted by one or more substituents, selected from A, Hal, NO 2 , CN, OR 15 , NR 15 R 16 , COOR 15 , CONR 15 R 16 , NR 15 COR 16 , NR 15 CONR 15 R 16 , NR 16 SO 2 A, COR 15 , SO 2 R 15 R 16 , S(O) u A and OOCR 15 , 
       Het is a saturated, unsaturated or aromatic heterocyclic residue which is optionally substituted by one or more substituents, selected from A, Hal, NO 2 , CN, OR 15 , NR 15 R 16 , COOR 15 , CONR 15 R 16 , NR 15 COR 16 , NR 15 CONR 16 , NR 6 SO 2 A, COR 15 , SO 2 R 15 R 16 , S(O) u A and OOCR 15 , 
       R 15 , R 16  are independently selected from H, A, and (CH 2 ) m Ar 5 , 
       Ar 5  is a 5- or 6-membered aromatic hydrocarbon which is optionally substituted by one or more substituents selected from methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN, OH, NH 2  and CF 3 , 
       n, m are independently of one another 0, 1, 2, 3, 4, or 5; 
       p is 0, 1, 2, 3, 4 or 5, 
       q is 0, 1, 2, 3 or 4, 
       u is 0, 1, 2 or 3, 
       Y is selected from O, S, NR 21 , C(R 22 )—NO 2 , C(R 22 )—CN and C(CN) 2 , 
       R 21  is H, Hal, A, (CH 2 ) m Ar 4  and (CH 2 ) m Het 
       R 22  is H, A, (CH 2 ) m Ar 3  and (CH 2 ) m Het, 
     
     and the salts and solvates thereof. 
   
   
       5 . A method according to  claim 1 , wherein said compound is selected from 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       6 . (canceled) 
   
   
       7 . (canceled) 
   
   
       8 . A method according to  claim 1 , wherein said kinases are raf-kinases. 
   
   
       9 . (canceled) 
   
   
       10 . (canceled) 
   
   
       11 . (canceled) 
   
   
       12 . (canceled) 
   
   
       13 . (canceled) 
   
   
       14 . (canceled) 
   
   
       15 . (canceled) 
   
   
       16 . A method according to  claim 1 , wherein said disorders are selected from hyperproliferative and nonhyperproliferative disorders. 
   
   
       17 . A method according to  claim 1 , wherein said disorder is cancer. 
   
   
       18 . A method according to  claim 1 , wherein said disorder is noncancerous. 
   
   
       19 . A method according to  claim 1  wherein said noncancerous disorder is selected from infection, psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immunodeficiency diseases. 
   
   
       20 . A method according to  claim 1 , wherein said disorders are selected from brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynaecological cancer, thyroid cancer, lymphoma, chronic leukemia and acute leukemia. 
   
   
       21 . A method according to  claim 1 , wherein said disorders are selected from arthritis, restenosis, fibrotic disorders, mesangial cell proliferative disorders, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection, glomerulopathies, metabolic disorders, inflammation and neurodegenerative diseases. 
   
   
       22 . (canceled) 
   
   
       23 . A method according to  claim 8 , wherein said raf-kinase is selected from A-Raf, B-Raf and c-Raf-11. 
   
   
       24 . (canceled) 
   
   
       25 . (canceled) 
   
   
       26 . (canceled) 
   
   
       27 . A method according to  claim 1 , wherein said disorder is cancerous cell growth mediated by raf-kinase. 
   
   
       28 . (canceled) 
   
   
       29 . A compound of formula III, 
     
       
         
         
             
             
         
       
     
     wherein
 L 1  is Cl, Br, I, OH, a reactive esterified OH-group or a diazonium moiety, 
 R 8  is selected from H, A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH 2 Hal, CH(Hal) 2 , C(Hal) 3 , NO 2 , (CH 2 ) n CN, (CH 2 ) n NR 11 R 12 , (CH 2 ) n OR 11 , (CH 2 ) n O(CH 2 ) k NR 11 R 12 , (CH 2 ) n COOR 12 , (CH 2 ) n CONR 11 R 12 , (CH 2 ) n NR 11 COR 13 , (CH 2 ) n NR 11 CONR 11 R 12 , (CH 2 ) n NR 11 SO 2 A, (CH 2 ) n SO 2 NR 11 R 12 , (CH 2 ) n S(O) n R 13 , (CH 2 ) n OC(O)R 13 , (CH 2 ) n COR 13 , (CH 2 ) n SR 11 , CH═N—OA, CH 2 CH═N—OA, (CH 2 ) n NHOA, (CH 2 ) n CH═N—R 11 , (CH 2 ) n OC(O)NR 11 R 12 , (CH 2 ) n NR 11 COOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 OR 13 , (CH 2 ) n N(R 11 )CH 2 CH 2 OCF 3 , (CH 2 ) n N(R 11 )C(R 13 )HCOOR 12 , C(R 13 )HCOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 N(R 12 )CH 2 COOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 NR 11 R 12 , CH═CHCOOR 11 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 OR 13 , (CH 2 ) n N(COOR 11 )COOR 12 , (CH 2 ) n N(CONH 2 )COOR 11 , (CH 2 ) n N(CONH 2 )CONH 2 , (CH 2 ) n N(CH 2 COOR 11 )COOR 12 , (CH 2 ) n N(CH 2 CONH 2 )COOR 11 , (CH 2 ) n N(CH 2 CONH 2 )CONH 2 , (CH 2 ) n CHR 13 COR 11 , (CH 2 ) n CHR 13 COOR 11 , (CH 2 ) n CHR 13 CH 2 OR 14 , (CH 2 ) n OCN and (CH 2 ) n NCO, 
 p is 0, 1, 2, 3, 4 or 5, 
 Ar 1  is selected from aromatic hydrocarbons containing 6 to 14 carbon atoms and ethylenical unsaturated or aromatic heterocyclic residues containing 3 to 10 carbon atoms and one or two hetero atoms, independently selected from N, O and S, 
 Y is selected from O, S, NR 21 , C(R 22 )—NO 2 , C(R 22 )—CN and C(CN) 2 , 
 R 11 , R 12  are independently selected from H, A, (CH 2 ) m Ar 3  and (CH 2 ) m Het, or, in NR 11 R 12 , R 11  and R 12  form, together with the N-Atom they are bound to, a 5-, 6- or 7-membered heterocycle which optionally contains 1 or 2 additional hetero atoms, selected from N, O an S, 
 n, m are independently of one another 0, 1, 2, 3, 4, or 5, 
 A is selected from alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, alkoxy and alkoxyalkyl, 
 R 13 , R 14  are independently selected from H, Hal, A, (CH 2 ) m Ar 4  and (CH 2 ) m Het, 
 Ar 3 , Ar 4  are independently from one another aromatic hydrocarbon residues comprising 5 to 12 carbon atoms which are optionally substituted by one or more substituents, selected from A, Hal, NO 2 , CN, OR 15 , NR 15 R 16 COOR 15 , CONR 15 R 16 , NR 15 COR 16 , NR 15 CONR 15 R 16 , NR 16 SO 2 A, COR 15 , SO 2 R 15 R 16 , S(O) u A and OOCR 15 , 
 Het is a saturated, unsaturated or aromatic heterocyclic residue which is optionally substituted by one or more substituents, selected from A, Hal, NO 2 , CN, OR 15 , NR 15 R 16 , COOR 15 , CONR 15 R 16 , NR 15 COR 16 , NR 15 CONR 15 R 16 , NR 16 SO 2 A, COR 15 , SO 2 R 15 R 16 , S(O) u A and OOCR 15 , 
 R 15 , R 16  are independently selected from H, A, and (CH 2 ) m AR 5 , 
 Ar 5  is a 5- or 6-membered aromatic hydrocarbon which is optionally substituted by one or more substituents selected from methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN, OH, NH 2  and CF 3 . 
 u is 0, 1, 2 or 3, 
 R 21  is H, Hal, A, (CH 2 ) m Ar 4  and (CH 2 ) m Het, 
 R 22  is H, A, (CH 2 ) m Ar 3  and (CH 2 ) m Het. 
 
   
   
       30 . A compound of formula IV, 
     
       
         
         
             
             
         
       
     
     wherein
 L 2 , L 3  are independently from one another H or a metal ion, 
 R 9  and R 10  are independent from one another selected from H, A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH 2 Hal, CH(Hal) 2 , C(Hal) 3 , NO 2 , (CH 2 ) n CN, (CH 2 ) n NR 11 R 12 , (CH 2 ) n OR 11 , (CH 2 ) n O(CH 2 ) k NR 11 R 12 , (CH 2 ) n COOR 12 , (CH 2 ) n CONR 11 R 12 , (CH 2 ) n NR 11 COR 13 , (CH 2 ) n NR 11 CONR 11 R 12 , (CH 2 ) n NR 11 SO 2 A, (CH 2 ) n SO 2 NR 11 R 12 , (CH 2 ) n S(O) u R 13 , (CH 2 ) n OC(O)R 13 , (CH 2 ) n COR 13 , (CH 2 ) n SR 11 , CH═N—OA, CH 2 CH═N—OA, (CH 1 ) n NHOA, (CH 2 ) n CH═N—R 11 , (CH 2 ) n OC(O)NR 11 R 12 , (CH 2 ) n NR 11 COOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 OR 13 , (CH 2 ) n N(R 11 )CH 2 CH 2 OCF 3 , (CH 2 ) n N(R 11 )C(R 13 )HCOOR 12 , C(R 13 )HCOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 N(R 12 )CH 2 COOR 12 , (CH 2 ) n N(R 11 )CH 2 CH 2 NR 11 R 12 , CH═CHCOOR 11 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 OR 13 , (CH 2 ) n N(COOR 11 )COOR 12 , (CH 2 ) n N(CONH 2 )COOR 11 , (CH 2 ) n N(CONH 2 )CONH 2 , (CH 2 ) n N(CH 2 COOR 11 )COOR 12 , (CH 2 ) n N(CH 2 CONH 2 )COOR 11 , (CH 2 ) n N(CH 2 CONH 2 )CONH 2 , (CH 2 ) n CHR 13 COR 11 , (CH 2 ) n CHR 13 COOR 11 , (CH 2 ) n CHR 13 CH 2 OR 14 , (CH 2 ) n OCN and (CH 2 ) n NCO, 
 A is selected from alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, alkoxy and alkoxyalkyl, 
 R 11 , R 12  are independently selected from H, A, (CH 2 ) m Ar 3  and (CH 2 ) m Het, or, in NR 11 R 12 , R 11  and R 12  form, together with the N-Atom they are bound to, a 5-, 6- or 7-membered heterocycle which optionally contains 1 or 2 additional hetero atoms, selected from N, O an S, 
 k, n, m are independently of one another 0, 1, 2, 3, 4, or 5, 
 R 13 , R 14  are independently selected from H, Hal, A, (CH 2 ) m Ar 4  and (CH 2 ) m Het, 
 Ar 3 , Ar 4  are independently from one another aromatic hydrocarbon residues comprising 5 to 12 carbon atoms which are optionally substituted by one or more substituents, selected from A, Hal, NO 2 , CN, OR 15 , NR 15 R 16 , COOR 15 , CONR 15 R 16 , NR 15 COR 16 , NR 15 CONR 15 R 16 , NR 16 SO 2 A, COR 15 , SO 2 R 15 R 16 , S(O) u A and OOCR 15 , 
 q is 0, 1, 2, 3, or 4, 
 X represents a bond or is (CR 11 R 12 ) h , or (CHR 11 ) h -Q-(CHR 12 ) i , 
 Ar 2  is selected from aromatic hydrocarbons containing 6 to 14 carbon atoms and ethylenical unsaturated or aromatic heterocyclic residues containing 3 to 10 carbon atoms and one or two hetero atoms, independently selected from N, O and S, 
 Het is a saturated, unsaturated or aromatic heterocyclic residue which is optionally substituted by one or more substituents, selected from A, Hal, NO 2 —CN, OR 15 , NR 15 R 16 , COOR 15 , CONR 15 R 16 , NR 15 COR 16 , NR 15 CONR 15 R 16 , NR 16 SO 2 A, COR 15 , SO 2 R 15 R 16 , S(O) u A and OOCR 15 , 
 R 15 , R 16  are independently selected from H, A, and (CH 2 ) m Ar 5 , 
 Ar 5  is a 5- or 6-membered aromatic hydrocarbon which is optionally substituted by one or more substituents selected from methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN, OH, NH 2  and CF 3 , 
 u is 0, 1, 2 or 3, 
 h, i are independently from each other 0, 1, 2, 3, 4, 5 or 6, and 
 r is 0, 1, 2, 3, 4 or 5. 
 
   
   
       31 . A method according to  claim 3 , wherein
 Ar 1  is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl,   p is 1, 2 or 3,   R 8  is selected from the group consisting of alkyl comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH 2 Hal, CH(Hal) 2 , perhaloalkyl comprising 1 to 4 carbon atoms, NO 2 , (CH 2 ) n CN, (CH 2 ) n NR 11 R 12 , (CH 2 ) n COR 13 , (CH 2 ) n COOR 11 , (CH 2 ) n CONR 11 R 12 , (CH 2 ) n SO 2 NR 11 R 12  and (CH 2 ) n S(O) u R 13  wherein   n is 0 or 1,   u is 0 or 2,   q is 0 or 1, and   X is O, S, NR 15 , CHOR 11 , CH 2 , CH 2 CH 2 , OCH 2 , CH 2 O, OCH 2 CH 2 , or CH 2 CH 2 O.   
   
   
       32 . A method according to  claim 31 , wherein A 2  is phenyl or pyridinyl. 
   
   
       33 . A method according to  claim 31 , wherein X is O or S. 
   
   
       34 . A method according to  claim 31 , wherein Y is O or S. 
   
   
       35 . A method according to  claim 31 , wherein A 1  is phenyl or oxazolyl. 
   
   
       36 . A method according to  claim 31 , wherein A 2  is pyridinyl. 
   
   
       37 . A method according to  claim 31 , wherein X is O. 
   
   
       38 . A method according to  claim 31 , wherein Y is O. 
   
   
       39 . A method according to  claim 31 , wherein Ar 1  is phenyl, pyridinyl or isoxazolyl. 
   
   
       40 . A method according to  claim 39 , wherein A 1  is phenyl. 
   
   
       41 . A method according to  claim 3 , wherein A is alkyl having 1 to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having 3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, or C u H 2u+1 —O—(CH 2 ) v  wherein u is 1 to 6 and v is 1 to 6. 
   
   
       42 . A method according to  claim 4 , wherein A is alkyl having 1 to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having 3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, or C u H 2u+1 —O—(CH 2 ) v  wherein u is 1 to 6 and v is 1 to 6. 
   
   
       43 . A method according to  claim 39 , wherein A is alkyl having 1 to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having 3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, or C u H 2u+1 —O—(CH 2 ) v  wherein u is 1 to 6 and v is 1 to 6. 
   
   
       44 . A compound according to  claim 35 , wherein A is alkyl having 1 to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having 3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, or C u H 2u+1 —O—(CH 2 ) v  wherein u is 1 to 6 and v is 1 to 6. 
   
   
       45 . A compound according to  claim 40 , wherein A is alkyl having 1 to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl, sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having 3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, or C u H 2u+1 —O—(CH 2 ) v  wherein u is 1 to 6 and v is 1 to 6. 
   
   
       46 . A compound according to  claim 39 , wherein A 2  is pyridinyl and X is O. 
   
   
       47 . A compound according to  claim 35 , wherein A 2  is pyridinyl and X is O. 
   
   
       48 . A compound according to  claim 40 , wherein A 2  is pyridinyl and X is O. 
   
   
       49 . A compound according to  claim 43 , wherein A 2  is pyridinyl and X is O. 
   
   
       50 . A compound according to  claim 44 , wherein A 2  is pyridinyl and X is O. 
   
   
       51 . A compound according to  claim 45 , wherein A 2  is pyridinyl and X is O.