Novel syringolin analogues and methods of making and using same

Abstract

The present invention provides, in certain aspects, novel syringolin analogues, In certain embodiments, the compounds of the invention are proteasome inhibitors, In other embodiments, the compounds treat or prevent a cancer such as, but not limited to, leukemia in a subject,

1 - 17 . (canceled) 
     
     
         18 . A method of inhibiting proteasome activity in a cell, the method comprising contacting the cell with an effective amount of at least one compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein:
    represents a single or double bond; 
 X is CH 2  or O; 
 R is C 1 -C 6  alkyl, arylalkyl, or heteroarylalkyl, wherein each of the alkyl, arylakyl or heteroarylalkyl groups is independently optionally substituted with one or more of C 1 -C 6  alkyl, haloalkyl, F, Cl, Br, I, C 1 -C 6  alkoxy, or hydroxy; 
 R′ is C 1 -C 6  alkyl or arylalkyl, wherein each of the alkyl or arylakyl groups is independently optionally substituted with one or more of C 1 -C 6  alkyl, haloalkyl, F, Cl, Br, I, C 1 -C 6  alkoxy, or hydroxy; 
 R′″ is alkylamino or alkenyl, wherein each of the alkylamino and alkenyl groups is independently optionally substituted with one or more of C 1 -C 6  alkyl, C 1 -C 6  alkenyl, and —CO2H; and 
 R iv  is H or OH. 
 
       
     
     
         19 . The method of  claim 18 , wherein   is a single bond. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 18 , wherein X is CH 2 . 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 18 , wherein R is C 1 -C 6  alkyl, aryl(CH 2 )—, or heteroaryl(CH 2 )—, wherein each one of the alkyl, aryl(CH 2 )— or heteroaryl(CH 2 )— groups is independently optionally substituted with one or more of C 1 -C 6  alkyl, haloalkyl, F, Cl, Br, I, C 1 -C 6  alkoxy, or hydroxy. 
     
     
         24 . The method of  claim 18 , wherein R is methyl, isopropyl, isobutyl, benzyl or 3-indolmethyl, wherein each one of the benzyl or 3-indolmethyl groups is independently optionally substituted with one or more of C 1 -C 6  alkyl, haloalkyl, F, Cl, Br, I, C 1 -C 6  alkoxy, or hydroxy. 
     
     
         25 . The method of  claim 24 , wherein the substituted benzyl comprises at least one of 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2,4-difluorobenzyl, 3,5-difluorobenzyl, 2,4-dichlorobenzyl, or 2,4-dimethylbenzyl. 
     
     
         26 . The method of  claim 18 , wherein R′ is isopropyl and R is: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of  claim 18 , wherein R′ is benzyl or substituted benzyl and wherein R is 
       
         
           
           
               
               
           
         
       
     
     
         28 . The method of  claim 18 , wherein R is 
       
         
           
           
               
               
           
         
       
       and R′ is selected from 
       
         
           
           
               
               
           
         
       
     
     
         29 . The method of  claim 18 , wherein R is 
       
         
           
           
               
               
           
         
       
       and R′ is selected from 
       
         
           
           
               
               
           
         
       
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 18 , wherein R′″ is alkylamino where the alkyl is selected from isopropyl, 2-methylbutyl, and 1-hydroxyethyl. 
     
     
         33 . The method of  claim 32 , wherein the alkyl is substituted with —CO 2 H, aminoalkyl, or alkenyl. 
     
     
         34 . The method of  claim 33 , wherein the aminoalkyl is —NHC 12 H 25 . 
     
     
         35 . The method of  claim 33 , wherein the alkenyl is —CH═CH═CH—CH 2 —C 7 H 15 . 
     
     
         36 . The method of  claim 18 , wherein R iv  is H. 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 18 , wherein the compound is Syringolin B Methyl Ester (1): 
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-isobutyl-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-3-methyl-1-oxobutan-2-yl)ureido-3-methylbutanoate (2): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-benzyl-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-3-methyl-1-oxobutan-2-yl)ureido)-3-methylbutanoate (3): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-2,7-dioxo-5-(3-(trifluoromethyl)benzyl)-1,6-diaza cyclododec-3-en-8-yl)amino)-3-methyl-1-oxobutan-2-yl)ureido)-3-methylbutanoate (4): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-(2-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-3-methyl-1-oxobutan-2-yl)ureido)-3-methylbutanoate (5): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-(3-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-3-methyl-1-oxobutan-2-yl)ureido)-3-methylbutanoate (6): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-(3,5-difluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-3-methyl-1-oxobutan-2-yl)ureido)-3-methylbutanoate (7): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-(2-chlorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-3-methyl-1-oxobutan-2-yl)ureido)-3-methylbutanoate (8): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-(2-chlorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-3-methyl-1-oxobutan-2-yl)ureido)-3-methylbutanoate (9): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-(4-chlorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-3-methyl-1-oxobutan-2-yl)ureido)-3-methylbutanoate (10): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 3-methyl-2-(3-((S)-3-methyl-1-(((5S,8S,E)-5-(3-methylbenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-1-oxobutan-2-yl)ureido)butanoate (11): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 3-methyl-2-(3-((S)-3-methyl-1-(((5S,8S,E)-5-(4-methylbenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-1-oxobutan-2-yl)ureido)butanoate (12): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-((1H-indol-3-yl)methyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-3-methyl-1-oxobutan-2-yl)ureido)-3-methylbutanoate (13): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-isopropyl-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl) amino)-1-oxo-3-phenylpropan-2-yl)ureido-3-methylbutanoate (14): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-(((5S,8S,E)-5-benzyl-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-1-oxo-3-phenylpropan-2-yl)ureido)-3-methylbutanoate (15): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-(2-(((5 S, 8 S,E)-5-((1H-indol-3-yl)methyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-2-oxoethyl)ureido-3-methylbutanoate (16): 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-3-(2-chlorophenyl)-1-((5S,8S,E)-5-(2-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino-1-oxopropan-2-yl)ureido)-3-methylbutanoate (17) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-3-(3-chlorophenyl)-1-((5S,8S,E)-5-(2-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-1-oxopropan-2-yl)ureido)-3-methylbutanoate (18) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-((5S,8S,E)-5-(2-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-1-oxo-3-phenylpropan-2-yl)ureido)-3-methylbutanoate (19) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-((5S,8S,E)-5-(2-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-1-oxo-3-m-tolylpropan-2-yl)ureido)-3-methylbutanoate (20) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-((5S,8S,E)-5-(2-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-1-oxo-3-p-tolylpropan-2-yl)ureid0-3-methylbutanoate (21) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-((5S,8S,E)-5-(2-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-3-(2-fluorophenyl)-1-oxopropan-2-yl)ureido)-3-methylbutanoate (22) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-((5S,8S,E)-5-(2-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-3-(3-fluorophenyl)-1-oxopropan-2-yl)ureido)-3-methylbutanoate (23) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-3-(2-chlorophenyl)-1-((5 S,8S,E)-5-(3-fluorobenzyl)-2,7-dioxo 1,6-diazacyclododec-3-en-8-ylamino)-1-oxopropan-2-yl)ureido)-3-ethylbutanoate (24) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-3-(3-chlorophenyl)-1-((5S,8S,E)-5-(3-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-1-oxopropan-2-yl)ureido)-3-methylbutanoate (25) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-(((S)-3-(4-chlorophenyl)-1-((5S,8S,E)-5-(3-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-1-oxopropan-2-yl)ureido)-3-methylbutanoate (26) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-((5S,8S,E)-5-(3-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-1-oxo-3-phenylpropan-2-yl)ureido)-3-methylbutanoate (27) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-((5S,8S,E)-5-(3-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-1-oxo-3-m-tolylpropan-2-yl)ureido)-3-methylbutanoate (28) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-((5S,8S,E)-5-(3-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-1-oxo-3-p-tolylpropan-2-yl)ureido)-3-methylbutanoate (29) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-((5S,8S,E)-5-(3-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-3-(2-fluorophenyl)-1-oxopropan-2-yl)ureido)-3-methylbutanoate (30) 
       
       
         
           
           
               
               
           
         
         (S)-methyl 2-(3-((S)-1-((5S,8S,E)-5-(3-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-3-(3-fluorophenyl)-1-oxopropan-2-yl)ureido)-3-methylbutanoate (31) 
       
       
         
           
           
               
               
           
         
         or 
         (S)-methyl 2-(3-((S)-1-((5S,8S,E)-5-(3-fluorobenzyl)-2,7-dioxo-1,6-diazacyclododec-3-en-8-ylamino)-1-oxo-3-(3-(trifluoromethyl)phenyl)propan-2-yl)ureido)-3-methylbutanoate (32) 
       
       
         
           
           
               
               
           
         
       
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 18 , wherein the at least one compound inhibits the activity of the β2 or β5 subunit of the proteasome. 
     
     
         41 . The method of  claim 18 , wherein the cell is in vitro or in vivo. 
     
     
         42 . The method of  claim 18 , wherein the cell comprises a cancer cell. 
     
     
         43 . The method of  claim 42 , wherein the cancer cell comprise a leukemia cell, non-small cell lung cancer cell, colon cancer cell, CNS cancer cell, melanoma cell, ovarian cancer cell, or breast cancer cell. 
     
     
         44 .- 59 . (canceled)