Methylene Urea Derivatives

Abstract

The present invention relates to methylene urea derivatives of formula (I), 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 compound of formula I
   A-D-B  (I)
   wherein   D is a bivalent methylene urea moiety, or a derivative thereof,   A is a unsubstituted or substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L′) α , where L is a 5, 6 or 7 membered cyclic structure, selected from the group consisting of aryl, heteroaryl, arylene and heteroarylene, bound directly to D, L′ comprises an optionally substituted cyclic moiety having at least 5 members, preferably selected from the group consisting of aryl, heteroaryl, aralkyl, cycloalkyl and heterocyclyl, M is a bond or a bridging group haying at least one atom, α is an integer of from 1-4; and each cyclic structure of L and L′ contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L′ is substituted by at least one substituent selected from the group consisting of —SO β R x , —C(O)R, and —C(NR y )R z      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, a 5- or 6-membered cyclic structure, bound directly to D containing 0-4 members of the croup consisting of nitrogen, oxygen and sulfur, wherein said cyclic structure directly bound to D is selected from the group consisting of aryl, heteroaryl and heterocyclyl, 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 N a R b , where R a  and R 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;
 where B is substituted, L is substituted or L′ is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wγ, where γ is 0-3; wherein each W is independently selected from the group consisting of —CN, —CO 2 R, —C(O)NR 5 R 5 , —C(O)—R 5 , —NO 2 , —OR 5 , —SR 5 , —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, —C(O)NR 5 R 5 , —C(O)—R 5 , —NO 2 , —OR 5 , —SR 5 , —NR 5 R 5 , —NR 5 C(O)OR 5 , —NR 5 C(O)R 5  and halogen up to per-halo; with each R 5  independently selected from 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, wherein is —O—, —S—, —N(R 5 )—, —(CH 2 ) β , —C(O)—, —CH(OH)—, —(CH 2 ) β —, —(CH 2 ) β S—, —(CH 2 ) β N(R 5 )—, —O(CH 2 ) β —CHHal-, —CHal 2 -, —S—(CH 2 ).— and —N(R 5 )(CH 2 ) β — where β=1-3, and Hal is halogen; and 
 Ar is 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zδ1 wherein δ1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO 2 R 5 , —C(O)NR 5 R 5 , —C(O)—R 5 , —NO 2 , —OR 5 , —SR, —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 the group consisting of —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 pharmaceutically acceptable derivatives, salts and solvates thereof. 
 
   
     
     
         2 . The compound according to  claim 1 , wherein each M independently from one another represents a bond OR is a bridging group, selected from the group consisting of (CR 5 R 5 ) h , or (CHR 5 ) n -Q-(CHR 5 ) i , wherein
 Q is selected from a group consisting of O, S, N—R 5 , (CHal 2 ), (O—CHR 5 ) j , (CHR 5 —O) j , CR 5 ═CR 5 , (O—CHR 5 CHR 5 ) j , (CHR 5 CHR 5 —O), C═O, C═S, C═NR, CH(OR 5 ), C(OR 5 )(OR 5 ), C(═O)O, OC(═O), OC(═O)O, C═)N(R 5 )C(═O), OC(═O)N(R 5 ), N(R 5 )C(═O)O, CH═N—NR 5 , OC(O)NR 5 , NR 5 C(O)O, S═O, SO 2 , SO 2 NR 5  and NR 5 SO 2 , wherein   R 5  is in each case independently selected from the meanings given above, hydrogen, halogen, alkyl, aryl, aralkyl,   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 . The compound according to  claim 1 , selected from the compounds of formula II, 
       
         
           
           
               
               
           
         
         wherein 
         Ar 1 , Ar 2  are selected independently from one another 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 6 , R 7  are independently selected from the meanings given for R 8 , R 9  and R 10 , or
 R 6  and R 7  together form a carbocyclic residue comprising 3 to 7 carbon atoms or a heterocyclic residue comprising 1, 2 or 3 hetero atoms, selected from the group consisting of O, N and S, and 2 to 6 carbon atoms, said carbocyclic or heterocyclic residue being unsubstituted or comprising 1, 2 or 3 substituents, selected from the meanings given for R 8 , R 9  and R 10 , 
 
         E, G, M, Q and U are selected, independently from one another, from carbon atoms and nitrogen atoms, with the proviso that one or more of E, G, M, Q and U are carbon atoms and that X is bonded to a carbon atom, 
         R 8 , R 9  and R 10  are independently selected from the group consisting of 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 O(CH 2 ) k NR 11 R 12 , (CH 2 ) n NR(CH 2 ) k NR 11 R 12 , (CH 2 ) n O(CH 2 ) k OR 11 , (CH 2 ) n NR 11 (CH 2 ) k OR 12 , (CH 2 ) n COOR 13 , (CH 2 ) n COR 13 , (CH 2 ) n CONR 11 R 12 , (CH 2 ) n NR 11 COR 13 , (CH 2 ) n NR 8 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 )NHOA, (CH 2 ) n CH═N—R 11 , (CH 2 ) n OC(O)NR 11 R 12 , (CH 2 )NR 11 COOR 13 , (CH 2 )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 8 , (CH 2 ) n N(R 11 ), C(R 13 )HCOR 8 , (CH 2 ) n N(R 11 )CH 2 CH 2 N(R 12 )CH 2 COOR 8 , (CH 2 ) n N(R 8 )CH 2 CH 2 NR 12 R 8 , CH═CHCOOR 13 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 OR 13 , (CH 2 ) n N(COOR 13 )COOR 14 , (CH 2 ) n N(CONH 2 )COOR 13 , (CH 2 ) n N(CONH 2 )CONH 2 , (CH 2 ) n N(CH 2 COOR 13 )COOR 14 , (CH 2 ) n N(CH 2 CONH 2 )COOR 13 , (CH 2 ) n N(CH 2 CONH 2 )CONH 2 , (CH 2 ) n CHR 13 COR 14 , (CH 2 ) n CHR 13 COOR 14 , (CH 2 ) n CHR 13 CH 2 OR 14 , (CH 2 ) n OCN and (CH 2 ) n NCO, wherein 
         R 11 , R 12  are independently selected from the group consisting of 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 pound to, a 5-, 6- or 7-membered heterocyclus which optionally contains 1 or 2 additional hetero atoms, selected from N, O and S. 
         R 13 , R 14  are independently selected from the group consisting of H, Hal, A, (CH 2 ) m Ar 4  and (CH 2 ) m Het,
 A is selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, alkoxy, alkoxyalkyl and saturated heterocyclyl, 
 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 the group consisting of 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 the group consisting of 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 the group consisting of H, A, and (CH 2 ) m Ar 6 , wherein 
 Ar 6  is a 5- or 6-membered aromatic hydrocarbon which is optionally substituted by one or more substituents selected from the group consisting of methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN, OH, NH 2  and CF 3 , 
 k, n and 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 , wherein 
 O is selected from the group consisting of 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 15 )(OR 20 ), C(═O)O, OC(═O), OC(═O)O, C(═)(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 , R 15 C(O)O, S═O, SO 2 , SO 2 NR 15  and NR 15 SO 2 , wherein 
 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, 
 
         Y selected from O, S, NR 21 , C(R 22 )—NO 2 , C(R 22 )—CN and C(CN) 2 , wherein
 R 21  is independently selected from the meanings given for R 13 R 14 , and 
 R 22  is independently selected from the meanings given for R 11 , R 12 , 
 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 the group consisting of F, Cl, Br and I; 
 and pharmaceutically acceptable derivatives, salts and solvates thereof. 
 
       
     
     
         4 . The compound according to  claim 1 , selected from the compounds of formula IIc, IId, IIe, IIf, IIg, IIh, IIi, IIj, IIk, IIl, IIm, IIn, IIo, IIp, IIq, IIr, IIs, IIt, IIu, IIv, IIw and IIx, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 6 , R 7 , R 8 , p, Ar 1 , Y, X, R 9  and q is 0, 1, 2, 3 or 4, R 10  selected from the group consisting of H, A, cycloalkyl comprising 3 to 7 carbon atom 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 O(CH 2 ) k NR 11 R 12 , (CH 2 ) n NR 11 (CH 2 ) k NR 11 R 12 , (CH 2 ) n O(CH 2 ) k OR 11 , (CH 2 ) n NR 11 (CH 2 ) k OR 12 , (CH 2 ) n COOR 13 , (CH 2 ) n COR 13 , (CH 2 ) n CONR 11 R 12 , (CH 2 ) n NR 11 COR 13 , (CH 2 ) n NR 8 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 OR(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 13 , (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 8 , (CH 2 ) n N(R 11 ), C(R 13 )HCOR 8 , (CH 2 ) n N(R 11 )CH 2 CH 2 N(R 12 )CH 2 COOR 8 , (CH 2 ) n N(R 8 )CH 2 CH 2 NR 12 R 8 , CH═CHCOOR 13 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 NR 11 R 12 , CH═CHCH 2 OR 13 , (CH 2 ) n N(COOR 13 )COOR 14 , (CH 2 ) n N(CONH 2 )COOR 13 , (CH 2 ) n N(CONH 2 )CONH 2 , (CH 2 ) n N(CH 2 COOR 13 )COOR 14 , (CH 2 ) n N(CH 2 CONH 2 )COOR 13 , (CH 2 ) n N(CH 2 CONH 2 )CONH 2 , (CH 2 ) n CHR 13 COR 14 , (CH 2 ) n CHR 13 COOR 14 , (CH 2 ) n CHR 13 CH 2 OR 14 , (CH 2 ) n OCN and (CH 2 ) n NCO, 
         and pharmaceutically acceptable derivatives, salts and solvates thereof. 
       
     
     
         5 . The compound according to  claim 1 , selected from the compounds (1) to (224) of table 1, the compounds (225) to (449) of table 2 and/or the compounds (450) to (672) of table 3, and pharmaceutically acceptable derivatives, salts and solvates thereof. 
     
     
         6 . The compound according to  claim 1 , selected from the compounds (673) to (758), the compounds (759) to (825) and/or the compounds (826) to (874), and pharmaceutically acceptable derivatives, salts and solvates thereof. 
     
     
         7 . A medicament comprising the compound according to  claim 1 . 
     
     
         8 . The compound according to  claim 1  as a kinase inhibitor. 
     
     
         9 . The compound according to  claim 8 , wherein the kinases are selected from raf-kinases. 
     
     
         10 . A pharmaceutical composition, comprising the compound according to  claim 1 . 
     
     
         11 . The pharmaceutical composition according to  claim 10 , wherein it contains one or more additional compounds, selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, carriers and pharmaceutical active ingredients. 
     
     
         12 . A process for manufacture of a pharmaceutical composition, wherein one or more compounds according to  claim 1  and one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients, are processed by mechanical means into a pharmaceutical composition that is suitable as a dosage form for application and/or administration to a patient. 
     
     
         13 . Use of a compound according to  claim 1  as a pharmaceutical. 
     
     
         14 . Use of a compound according to  claim 1  in the treatment and/or prophylaxis of disorders. 
     
     
         15 . Use of a compound according to  claim 1  for producing a pharmaceutical composition for the treatment and/or prophylaxis of disorders. 
     
     
         16 . Use according to  claim 14 , wherein the disorders are caused, mediated and/or propagated by raf-kinases. 
     
     
         17 . Use according to  claim 14 , wherein the disorders are selected from the group consisting of hyperproliferative and nonhyperproliferative disorders. 
     
     
         18 . Use according to  claim 14 , wherein the disorder is cancer. 
     
     
         19 . Use according to  claim 14 , wherein the disorder is noncancerous. 
     
     
         20 . Use according to  claim 14 , wherein the disorders are selected from the group consisting of psoriasis, arthritis, inflammation, endometriosis, scarring,  Helicobacter pylori  infection, Influenza A, begnin prostatic hyperplasia, immunological diseases, autoimmune diseases and immunodeficiency diseases. 
     
     
         21 . Use according to  claim 14 , wherein the disorders are selected from the group consisting of melanoma, 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, ovarian cancer, ovary cancer, uterine cancer, prostate cancer, thyroid cancer, lymphoma, chronic leukaemia and acute leukaemia. 
     
     
         22 . Use according to  claim 14 , wherein the disorders are selected from the group consisting of arthritis, restenosis; fibrotic disorders; mesangial cell proliferative disorders, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection, glomerulopathies, metabolic disorders, inflammation, solid tumors, rheumatic arthritis, diabetic retinopathy, and neurodegenerative diseases. 
     
     
         23 . Use according to  claim 14 , wherein the disorders are selected from the group consisting of rheumatoid arthritis, inflammation, autoimmune disease, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, fibrosis, atherosclerosis, restenosis, vascular disease, cardiovascular disease, inflammation, renal disease and angiogenesis disorders. 
     
     
         24 . Use of a compound according to  claim 1  as a raf-kinase inhibitor. 
     
     
         25 . Use according to  claim 24 , wherein the raf-kinase is selected from the group consisting of A-Raf, B-Raf and c-Raf1. 
     
     
         26 . A method for the treatment and/or prophylaxis of disorders, wherein one or more compounds according to  claim 1  is administered to a patient in need of such a treatment. 
     
     
         27 . A method for the treatment and/or prophylaxis of disorders, comprising administering to a patient in need thereof the pharmaceutical composition according to  claim 10 . 
     
     
         28 . A method for the treatment and/or prophylaxis of disorders comprising administering to a patient in need thereof the pharmaceutical composition according to  claim 10 , wherein the disorders are caused, mediated and/or propagated by raf-kinases. 
     
     
         29 . A method according to  claim 28 , wherein the disorder is cancerous cell growth mediated by raf-kinase. 
     
     
         30 . A method for producing compounds of formula II, wherein
 a) a compound of formula III   
       
         
           
           
               
               
           
         
         wherein 
         FG is a functional group, selected from
   —N═C═Y
 
   and 
   —NH—(C═Y)-LG,
 
 
         wherein Y is as defined as in  claim 3  and LG is a leaving group, 
         is reacted 
         b) with a compound of IV, 
       
       
         
           
           
               
               
           
         
         wherein 
         L 2 , L 3  are independently from one another H or a metal ion, and R 6 , R 7 , E, G, M, Q, U, R 9 , q, X, Ar 2 , R 10  and r are as defined in  claim 3 , 
         and optionally 
         c) isolating and/or treating the compound of formula II obtained by said reaction with an acid, to obtain the sat thereof. 
       
     
     
         31 . Compound of formula III, 
       
         
           
           
               
               
           
         
         wherein 
         FG is a functional group, selected from
   —N═C═Y
 
   and 
   —NH—(C═Y)-LG,
 
 
         wherein Y is as defined as in  claim 3  and LG is a leaving group. 
       
     
     
         32 . Compound of formula IV, 
       
         
           
           
               
               
           
         
         wherein 
         L 2 , L 3  are independently from one another H or a metal ion, and R 6 , R 7 , E, G, M, Q, U, R 9 , q, X, Ar 2 , R 10  and r are as defined in  claim 3 .