Novel anthranilamide pyridinureas as vascular endothelial growth factor (vegf) receptor kinase inhibitors

Abstract

The invention relates to novel anthranilamide pyridinureas as VEGF receptor kinase inhibitors, their production and use as pharmaceutical agents for preventing or treating diseases that are triggered by persistent angiogenesis.

1 - 46 . (canceled) 
     
     
         47 . A method for treating or preventing a disease associated with persistent angiogenesis or a disease associated with excessive lymphangiogenesis;
 for treating or preventing a tumor- or metastases-growth; psoriasis; Karposi's sarcoma; restenosis; stent-induced restenosis; Crohn's disease; Hodgkin's disease; leukemia; arthritis; rheumatoid arthritis, hemangioma, angiofibroma; endometriosis; an eye disease; diabetic retinopathy, neovascular glaucoma; corneal transplants; a renal disease; glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndrome, a transplant rejections; glomerulopathy; a fibrotic disease; cirrhosis of the liver; a mesangial cell proliferative disease; arteriosclerosis; injuries to the nerve tissue, or for inhibiting the reocclusion of vessels after balloon catheter treatment; in vascular prosthetics or after a mechanical device is used to keep a vessel open, or for supporting scar-free healing; senile keratosis; contact dermatitis; or asthma;   for inhibiting VEGF receptor kinase 3 of lymphangiogenesis;   for the prevention or treatment of a disease for which an inhibition of angiogenesis and/or lymphangiogenesis and/or the VEGF receptor kinases is beneficial;   comprising administering to a subject in need thereof an effective amount of a compound of formula I   
       
         
           
           
               
               
           
         
       
       wherein:
 X is CH or N; 
 W is hydrogen or fluorine; 
 A, E and Q, independently of one another, are CH or N, wherein only a maximum of two nitrogen atoms are contained in the ring; 
 R 1  is aryl or heteroaryl, which are optionally substituted in one or more places in the same way or differently with halogen, hydroxy, C 1 -C 12 -alkyl, C 2 -C 6 -alkenyl, C 1 -C 12 -alkoxy, halo-C 1 -C 6 -alkyl, ═O, —SO 2 R 6 , —OR 5 , —SOR 4 , —COR 6 , —CO 2 R 6  or —NR 7 R 8 , wherein C 1 -C 12 -alkyl is optionally substituted with —OR 5  or —NR 7 R 8 , with the proviso that when R 2  and R 3  are both —CH 3 , R 1  is not any one of the following: 
 
       
         
           
           
               
               
           
         
         R 2  and R 3 , independently of one another, are C 1 -C 12  alkyl optionally substituted with —OR 5 ; 
         R 4  is C 1 -C 12 -alkyl, C 3 -C 8 -cycloalkyl, aryl or heteroaryl; 
         R 5  is hydrogen, C 1 -C 12 -alkyl, C 3 -C 8 -cycloalkyl or halo-C 1 -C 6 -alkyl; 
         R 6  is hydrogen, C 1 -C 12 -alkyl, C 3 -C 8 -cycloalkyl, halo-C 1 -C 6 -alkyl, aryl, or —NR 7 R 8 ; and 
         R 7  and R 8 , independently of one another, are hydrogen, —SO 2 R 6 , —COR 6 , aryl, C 3 -C 8 -cycloalkyl, C 1 -C 12 -alkyl, halo-C 1 -C 12 -alkyl, or C 1 -C 12 -alkoxy, wherein C 1 -C 12 -alkyl is optionally substituted with —OR 5  or —N( CH   3 ) 2 , or 
         R 7  and R 8  provide a 3-8 membered cycloalkyl ring, which optionally contains one or more further heteroatoms, and is optionally substituted in one or more places in the same way or differently with halogen, cyano, C 1 -C 12 -alkyl, C 1 -C 12 -alkoxy, halo-C 1 1 -C 6 -alkyl, ═O, —OR 5 , COR 6 , —SR 4 , —SOR 4  or —SO 2 R 6 ; 
       
       or an isomer, diastereoisomer, enantiomer, tautomer or salt thereof. 
     
     
         48 . A method according to  claim 47 , which is for treating or preventing a disease associated with persistent angiogenesis or a disease associated with excessive lymphangiogenesis. 
     
     
         49 . A method according to  claim 47 , which is for treating or preventing a tumor- or metastases-growth; psoriasis; Karposi's sarcoma; restenosis; stent-induced restenosis; Crohn's disease; Hodgkin's disease; leukemia; arthritis; rheumatoid arthritis, hemangioma, angiofibroma; endometriosis; an eye disease; diabetic retinopathy, neovascular glaucoma; corneal transplants; a renal disease; glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndrome, a transplant rejections; glomerulopathy; a fibrotic disease; cirrhosis of the liver; a mesangial cell proliferative disease; arteriosclerosis; injuries to the nerve tissue, or for inhibiting the reocclusion of vessels after balloon catheter treatment; in vascular prosthetics or after a mechanical device is used to keep a vessel open, or for supporting scar-free healing; senile keratosis; contact dermatitis; or asthma. 
     
     
         50 . A method according to  claim 47 , which is for inhibiting VEGF receptor kinase 3 of lymphangiogenesis. 
     
     
         51 . A method according to  claim 47 , which is for the prevention or treatment of a disease for which an inhibition of angiogenesis and/or lymphangiogenesis and/or the VEGF receptor kinases is beneficial. 
     
     
         52 . A method according to  claim 51 , which is for inhibiting the tyrosine kinase VEGFR-1 or VEGFR-2. 
     
     
         53 . A method according to  claim 47 , wherein the compound of formula I is
 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide   2-{[2-(3,3-diethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide   2-({2-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-2H-indazol-6-yl)-benzamide   2-({2-[3-(2-methoxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-2H-indazol-6-yl)-benzamide   2-{[2-(3-ethyl-3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(4-fluoro-2-methyl-2H-indazol-6-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(7-methoxy-isoquinolin-3-yl)-benzamide   6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-methyl-2H-indazole-3-carboxylic acid methyl ester   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-benzotriazol-5-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-7-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-3a,7a-dihydro-1H-indazol-4-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro-2-methyl-2H-indazol-4-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-2-methyl-2H-indazol-7-yl)-benzamide   6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-1-methyl-1H-indazole-3-carboxylic acid methyl ester   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-hydroxymethyl-l-methyl-1H-indazol-6-yl)-benzamide   N-(3,6-difluoro-quinolin-2-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-sulfamoyl-phenyl)-benzamide   N-(2,3-dimethyl-2H-indazol-6-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxymethyl-2-methyl-2H-indazol-6-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxymethyl-1-methyl-1H-indazol-6-yl)-benzamide   6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-1-methyl-1H-indazole-3-carboxylic acid methylamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-l-methyl-1H-indazol-5-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro-l-methyl-1H-indazol-4-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-quinolin-3-yl-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-fluoro-6-methoxy-quinolin-2-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methyl-3H-benzoimidazol-5-yl)-benzamide   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-1H-benzoimidazol-5-yl)-benzamide   2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methanesulfonyl-phenyl)-benzamide or   2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide   
       or an isomer, diastereoisomer, enantiomer, tautomer or salt thereof. 
     
     
         54 . A method according to  claim 47 , wherein the compound of formula I is 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CH; 
 W is hydrogen or fluorine; 
 A, E and Q, are CH; 
 R 1  is 2-methyl-2H-indazol-6-yl; 
 R 2  and R 3 , independently of one another, are C 1 -C 12  alkyl optionally substituted with —OR 5 ; and 
 
       or an isomer, diastereoisomer, enantiomer, tautomer or salt thereof. 
     
     
         55 . A method according to  claim 47 , wherein the compound of formula I is
 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide   2-{[2-(3,3-diethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide   2-({2-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-2H-indazol-6-yl)-benzamide   2-({2-[3-(2-methoxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-2H-indazol-6-yl)-benzamide   2-{[2-(3-ethyl-3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide   
       or
 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide 
 
       or an isomer, diastereoisomer, enantiomer, tautomer or salt thereof. 
     
     
         56 . A method according to  claim 47 , wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered. 
     
     
         57 . A method according to  claim 53 , wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered. 
     
     
         58 . A method according to  claim 47 , wherein in the compound of formula I
 X is CH;   W is hydrogen or fluorine;   A, E and Q, are CH;   R 1  is 2-methyl-2H-indazol-6-yl;   R 2  and R 3 , independently of one another, are C 1 -C 12  alkyl optionally substituted with —OR 5 .   
     
     
         59 . A method according to  claim 47 , wherein in the compound of formula I
 W is fluorine.   
     
     
         60 . A method according to  claim 47 , wherein in the compound of formula I
 W is hydrogen.   
     
     
         61 . A method according to  claim 47 , wherein in the compound of formula I
 R 2  and R 3  independently of one another, are C 1 -C 12  alkyl optionally substituted with —OR 5 .   
     
     
         62 . A method according to  claim 47 , wherein in the compound of formula I
 R 2  and R 3  are both —CH 3 .   
     
     
         63 . A method according to  claim 47 , wherein in the compound of formula I
 R 5  is —CH 3  or hydrogen.   
     
     
         64 . A method according to  claim 47 , wherein in the compound of formula I
 R 2  and R 3  independently of one another are unsubstituted C 1 -C 2  alkyl.