Triazole compounds as ksp inhibitors

Abstract

The present invention provides triazole compounds of Formula I: as further described herein. The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, and 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 compound of Formula I.

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from C 1-6  straight chain alkyl, C 3-6  branched alkyl, and —C 3-6  cyclo alkyl; 
 R 2  is selected from H, and C 1-6  straight chain alkyl; 
 R 3  represents —(CH 2 ) 0-3  substituted or unsubstituted pyrrolidinyl; 
 R 4  is selected from —C(O)—CH 2 OH, —C(O)-tetrahydrofuranyl, —C(O)—CH(CH 3 )—OH, —C(O)-unsubstituted morpholinyl, and —C(O)-morpholinyl substituted with up to three alkyl groups; 
 R 5  is selected from substituted or unsubstituted benzyl, wherein the substituents are selected from Cl, F, Br, and I; and 
 R 6  is selected from phenyl substituted with up to three halogen atoms. 
 
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . A compound of  claim 1 , wherein:
 R 1  is selected from C 3-6  branched alkyl;   R 2  represents H;   R 3  represents —(CH 2 ) 1-3 -substituted pyrrolidinyl;   R 4  is selected from —C(O)-tetrahydrofuranyl, —C(O)—CH(CH 3 )—OH, —C(O)-morpholinyl substituted with up to three alkyl groups;   R 5  represents benzyl, or benzyl substituted with up to two fluoro atoms; and   R 6  is selected from phenyl substituted with up to two halogen atoms.   
     
     
         5 . A compound of  claim 1 , wherein:
 R 1  represents t-butyl;   R 3  represents —(CH 2 )-fluoro-pyrrolidinyl;   R 4  is selected from —C(O)-tetrahydrofuranyl, —C(O)—CH(CH 3 )—OH, —C(O)-2,6-dimethyl morpholinyl;   R 5  represents benzyl, or benzyl substituted with one fluoro atom; and   R 6  is selected from phenyl substituted with up to two fluoro atoms.   
     
     
         6 . A compound of  claim 4 , wherein:
 R 3  represents —CH 2-3 -fluoro-pyrrolidinyl; and   R 4  represents —C(O)-2-tetrahydrofuranyl, —C(O)—CH(CH 3 )—OH, or —C(O)-2,6-dimethyl morpholinyl.   
     
     
         7 . A compound of  claim 6 , wherein:
 R 3  represents   
       
         
           
           
               
               
           
         
         R 4  is selected from —C(O)—CH(CH 3 )—OH, and 
       
       
         
           
           
               
               
           
         
       
     
     
         8 . (canceled) 
     
     
         9 . A compound according to  claim 1 , wherein R 4  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound of  claim 1 , selected from:
 N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3R,4R)-4-fluoropyrrolidin-3-yl)methyl)-2,6-dimethylmorpholine-4-carboxamide;   N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3R,4R)-4-fluoropyrrolidin-3-yl)methyl)-2,6-dimethylmorpholine-4-carboxamide;   (S)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3R,4R)-4-fluoropyrrolidin-3-yl)methyl)tetrahydrofuran-2-carboxamide;   (S)—N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3R,4R)-4-fluoropyrrolidin-3-yl)methyl)tetrahydrofuran-2-carboxamide;   (S)—N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3R,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide; and   (S)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3R,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide;
 and the pharmaceutically acceptable salts of any of these compounds. 
   
     
     
         11 . (canceled) 
     
     
         12 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein,
 R 1  is selected from C 1-6  straight chain alkyl, C 3-6  branched alkyl, and —C 3-6  cyclo alkyl; 
 R 3  represents —(CH 2 ) 0-3 -substituted or unsubstituted pyrrolidinyl or C 3-5  alkyl substituted with up to three groups selected from amino and halo; 
 R 4  is selected from —C(O)—CH 2 OH, —C(O)-tetrahydrofuranyl, —C(O)—CH(CH 3 )—OH, —C(O)-unsubstituted morpholinyl, and —C(O)-morpholinyl substituted with up to three alkyl groups; 
 R 5  is selected from substituted or unsubstituted benzyl, wherein the substituents are selected from Cl, F, Br, and I; and 
 
         R 6  is selected from phenyl substituted with up to three halogen atoms. 
       
     
     
         13 . The compound of  claim 12 , wherein:
 R 1  is selected from C 3-6  branched alkyl, and C 3-6  cyclo alkyl;   R 3  represents —(CH 2 ) 0-3 -substituted pyrrolidinyl or —CH 2 —CH 2 —CH(NH 2 )—CH 2 F;   R 4  is selected from —C(O)—CH 2 OH, —C(O)-tetrahydrofuranyl, —C(O)—CH(CH 3 )—OH, —C(O)-unsubstituted morpholinyl, and —C(O)-morpholinyl substituted with up to three alkyl groups;   R 5  is selected from substituted or unsubstituted benzyl, wherein the substituents are selected from Cl, F, Br, and I; and   R 6  is selected from phenyl substituted with up to three halogen atoms.   
     
     
         14 - 19 . (canceled) 
     
     
         20 . The compound of  claim 12 , wherein R 4  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         21 . (canceled) 
     
     
         22 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         23 . The composition of  claim 22  further comprising at least one additional agent for the treatment of cancer. 
     
     
         24 . The composition of  claim 23 , 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. 
     
     
         25 . 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 compound of  claim 1 ;
 wherein the disorder is a 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.   
     
     
         26 - 28 . (canceled) 
     
     
         30 . A method for inhibiting KSP in a mammalian patient, wherein said method comprises administering to the patient an effective KSP-inhibiting amount of a compound of  claim 1 . 
     
     
         31 . A method to make a fluorinated pyrrolidine, which comprises reacting a trans-3,4-disubstituted protected pyrrolidine of Formula V 
       
         
           
           
               
               
           
         
         with a fluorination reagent to provide a compound of Formula VI: 
       
       
         
           
           
               
               
           
         
          and oxidizing the compound of Formula VI to an aldehyde of Formula VII: 
       
       
         
           
           
               
               
           
         
         wherein PG represents a protecting group, and R is selected from H and an optionally substituted alkyl or aryl group. 
       
     
     
         32 . The method of  claim 31 , which further comprises reductive amination of the compound of Formula VII with a compound of Formula Ia: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from C 1-6  alkoxy-C 1-4 -alkyl, C 1-6  straight chain alkyl, C 3-6  branched alkyl, and —C 3-6  cyclo alkyl; 
         R 2  is selected from H, and C 1-6  straight chain alkyl; 
         R 5  is selected from substituted or unsubstituted benzyl, wherein the substituents are selected from Cl, F, Br, and I; and 
         R 6  is selected from phenyl substituted with up to three halogen atoms;
 to provide a compound of Formula Ib: 
 
       
       
         
           
           
               
               
           
         
       
     
     
         33 - 34 . (canceled)