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 - 20 . (canceled) 
     
     
         21 . A method of treating a disorder mediated, at least in part, by KSP in a mammalian patient comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a composition comprising
 (i) a therapeutically effective amount of a compound of 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; and 
 (ii) a pharmaceutically acceptable carrier. 
 
     
     
         22 . The method of  claim 21 , wherein the disorder is a cellular proliferative disease. 
     
     
         23 . The method of  claim 22 , 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 . A method for inhibiting KSP kinesin in a mammalian patient, wherein said method comprises administering to the patient an effective inhibitory amount of a compound of 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 Q 1, 2, or 3; 
 n is 0, 1, 2 or 3; and 
 p is 0 or 1. 
 
     
     
         28 . A method for inhibiting the activity of KSP kinesin which method comprises contacting said kinesin with an effective inhibitory amount of a compound of 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. 
 
     
     
         29 . A method for inhibiting the activity of KSP kinesin in a cell which method comprises contacting said cell with an effective inhibitory amount of a compound of 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.