Cyclized derivatives as eg-5 inhibitors

Abstract

The present invention relates to new substituted imidazole compounds have the following Formula (I) and to the pharmaceutically acceptable salts, esters, or prodrugs thereof, to compositions of the compounds together with pharmaceutically acceptable carriers, and to uses of the compounds:

1 . A compound or a pharmaceutically acceptable salt thereof having the Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of alkyl and substituted alkyl; 
         R 2  is selected from the group consisting of hydrogen, alkyl, and substituted alkyl; 
         L is selected from the group consisting of
 a) —O—; 
 b) —OCH 2 —, —CH 2 O—, —C(O)NR 7 —; 
 c) —CH 2 OCH 2 —, —CH 2 NR 7 CH 2 —, —CH 2 CH 2 O—, —C(O)NR 7 CH 2 —, and —CH 2 CH 2 NR 7 —; 
 
         R 3  and R 4  are independently selected from the group consisting of halo, alkyl, and substituted alkyl; 
         R 5  and R 6  are independently selected from the group consisting of cyano, alkyl, substituted alkyl, alkoxy, substituted alkoxy, halo, and hydroxy; 
         R 7  is selected from the group consisting of hydrogen, alkyl, and —SO 2 alkyl; 
         m is 0, 1, 2, or 3; 
         n is 0, 1, 2, or 3; and 
         p is 0 or 1. 
       
     
     
         2 . A compound of  claim 1  wherein R 1  and R 2  are alkyl. 
     
     
         3 . A compound of  claim 1  wherein R 1  is alkyl and R 2  is hydrogen. 
     
     
         4 . A compound of  claim 3  wherein R 1  is selected from the group consisting of isopropyl, t-butyl, and propyl. 
     
     
         5 . (canceled) 
     
     
         6 . A compound of  claim 5  wherein R 4  is alkyl substituted with 1 to 5 substituents selected from the group consisting of amino, substituted amino, halo, alkoxy, substituted alkoxy, and hydroxy. 
     
     
         7 . A compound of  claim 1  wherein R 4  is selected from the group consisting of halo, —CH 2 NH 2 , —(CH 2 ) 2 NH 2 , —(CH 2 ) 3 NH 2 , and —CH 2 OH. 
     
     
         8 . A compound of  claim 1  wherein m is 0. 
     
     
         9 . A compound of  claim 1  wherein R 6  is halo. 
     
     
         10 . A compound of  claim 1  wherein R 6  and the phenyl ring to which it is attached is selected from the group consisting of phenyl, 3-bromophenyl, 3-chlorophenyl, 4-cyanophenyl, 2,5-difluorophenyl, 3-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, and 3-trifluoromethylphenyl. 
     
     
         11 . A compound of  claim 1 , wherein L and the atoms to which it is joined form a ring selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . (canceled) 
     
     
         13 . A compound of  claim 1  having Formula (Ib)-(Id) or a pharmaceutically acceptable salt, ester, or prodrug thereof: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound of  claim 1  having Formula (Ie)-(Ii) or a pharmaceutically acceptable salt, ester, or prodrug thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 - 16 . (canceled) 
     
     
         17 . A compound that is
 (5R)-5-(2-aminoethyl)-3-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,3-oxazolidin-2-one;   (5S)-5-(2-aminoethyl)-3-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,3-oxazolidin-2-one;   5-(aminomethyl)-3-{(1R)-1-[1-benzyl-4-(3-chlorophenyl)-1H-imidazol-2-yl]-2-methylpropyl}-1,3-oxazolidin-2-one;   (5S)-5-(aminomethyl)-3-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,3-oxazinan-2-one;   (5R)-5-(aminomethyl)-3-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,3-oxazinan-2-one;   (6S)-6-(aminomethyl)-4-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2, dimethylpropyl]morpholin-3-one;   (6R)-6-(aminomethyl)-4-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]morpholin-3-one;   (6R)-6-(aminomethyl)-4-{(1R)-1-[1-benzyl-4-(3-chlorophenyl)-1H-imidazol-2-yl]-2-methylpropyl}morpholin-3-one;   (6S)-6-(aminomethyl)-4-{(1R)-1-[1-benzyl-4-(3-chlorophenyl)-1H-imidazol-2-yl]-2-methylpropyl}morpholin-3-one;   (6R)-6-(2-aminoethyl)-4-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]morpholin-3-one;   (6S)-6-(2-aminoethyl)-4-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]morpholin-3-one;   (6S)-6-(2-aminoethyl)-4-{(1R)-1-[1-benzyl-4-(3-chlorophenyl)-1H-imidazol-2-yl]-2-methylpropyl}morpholin-3-one;   (6R)-6-(2-aminoethyl)-4-{(1R)-1-[1-benzyl-4-(3-chlorophenyl)-1H-imidazol-2-yl]-2-methylpropyl}morpholin-3-one;   (2S,6R)-6-(aminomethyl)-4-{(1R)-1-[1-benzyl-4-(3-fluorophenyl)-1H-imidazol-2-yl]-2,2-dimethylpropyl}-2-methylmorpholin-3-one;   (2R,6R)-6-(aminomethyl)-4-{(1R)-1-[1-benzyl-4-(3-fluorophenyl)-1H-imidazol-2-yl]-2,2-dimethylpropyl}-2-methylmorpholin-3-one;   (5R)-5-(aminomethyl)-1-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]piperazine-2,3-dione;   (5S)-5-(aminomethyl)-1-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]piperazine-2,3-dione;   (5R)-5-(aminomethyl)-1-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-4-methylpiperazine-2,3-dione;   (2S)-4-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-2-(hydroxymethyl)-1,4-diazepan-5-one;   (2R)-2-(aminomethyl)-4-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4-diazepan-5-one;   (2R)-2-(aminomethyl)-4-[(1R)-1-(1-benzyl-4-phenyl-1′-1-imidazol-2-yl)-2,2-dimethylpropyl]-1-(methylsulfonyl)-1,4-diazepan-5-one;   (2S)-2-(aminomethyl)-4-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4-oxazepan-5-one;   (2R)-2-(aminomethyl)-4-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4-oxazepan-5-one;   (6S)-6-(aminomethyl)-4-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4-oxazepan-3-one;   (6R)-6-(aminomethyl)-4-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4-oxazepan-3-one;   (6R)-6-(aminomethyl)-4-{(1R)-1-[1-(3,5-difluorobenzyl)-4-(3-fluorophenyl)-1H-imidazol-2-yl]-2,2-dimethylpropyl}-1,4-oxazepan-3-one;   (6R)-6-(aminomethyl)-4-{(1R)-1-[1-benzyl-4-(3-fluorophenyl)-1H-imidazol-2-yl]-2,2-dimethylpropyl}-1,4-oxazepan-3-one;   (6S)-6-(aminomethyl)-4-{(1R)-1-[1-(3-fluorobenzyl)-4-(3-fluorophenyl)-1H-imidazol-2-yl]-2,2-dimethylpropyl}-1,4-oxazepan-3-one;   (6S)-6-(aminomethyl)-4-{(1R)-1-[1-(3-fluorobenzyl)-4-(3-fluorophenyl)-1H-imidazol-2-yl]-2,2-dimethylpropyl}-1,4-oxazepan-3-one;   (6S)-6-(aminomethyl)-1-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-1,4-diazepane-2,3-dione;   (6R)-1-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-6-fluoro-1,4-diazepan-2-one; or   (6S)-1-[(1R)-1-(1-benzyl-4-phenyl-1H-imidazol-2-yl)-2,2-dimethylpropyl]-6-fluoro-1,4-diazepan-2-one;   or a pharmaceutically acceptable salt thereof.   
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         19 . The composition of  claim 18  further comprising at least one additional agent for the treatment of cancer. 
     
     
         20 . The composition of  claim 19 , wherein the additional agent for the treatment of cancer is selected from the group consisting of irinotecan, topotecan, gemcitabine, imatinib, trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, and trastuzumab. 
     
     
         21 . A method of treating a cellular proliferative disease in a mammalian patient comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of  claim 1 . 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 21 , wherein the cellular proliferative disease is cancer. 
     
     
         24 . The method of  claim 23 , wherein the cancer is selected from the group consisting of lung and bronchus; prostate; breast; pancreas; colon and rectum; thyroid; stomach; liver and intrahepatic bile duct; kidney and renal pelvis; urinary bladder; uterine corpus; uterine cervix; ovary; multiple myeloma; esophagus; acute myelogenous leukemia; chronic myelognous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; melanoma; and villous colon adenoma. 
     
     
         25 . The method of  claim 23 , further comprising administering to the mammalian patient one additional agent for the treatment of cancer. 
     
     
         26 . The method of  claim 24 , wherein the additional agent for the treatment of cancer is selected from the group consisting of irinotecan, topotecan, gemcitabine, imatinib, trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, and trastuzumab. 
     
     
         27 .- 29 . (canceled)