Fumagillol spirocyclic compounds and fused bicyclic compounds and methods of making and using same

Abstract

Disclosed herein, in part, are fumagillol compounds and methods of use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making fumagillol compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.

What is claimed is: 
     
         1 . A compound represented by Formula I or Formula Ia: 
       
         
           
           
               
               
           
         
       
       wherein:
    is a single or double bond; 
 Y is a bond or NR a ; 
 X is N or CR N ; wherein X is N when Y is a bond and X is CR N  when Y is NR a ; 
 n is 0 or 1; 
 m is 1 or 2; 
 Ring A may be optionally substituted by one or two substituents each independently selected from the group consisting of halogen, hydroxyl, C 1-3 alkyl and C 1-3 alkoxy, wherein C 1-3 alkyl and C 1-3 alkoxy may optionally be substituted by one or more fluorine atoms or a substituent selected from the group consisting of cyano, hydroxyl, and N(R a R b ); 
 R 1  and R 2 , together with the carbon or carbons to which they are attached, form a 4-6 membered saturated heterocyclic ring B having one or two heteroatoms selected from the group consisting of O, S(O) w  (wherein w is 0, 1 or 2) and NR h  or form a 3-6 membered saturated carbocyclic ring B; wherein the heterocyclic or carbocyclic ring B may optionally be substituted on a free carbon by one or two substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-3 alkyl, C 1-3 alkoxy, —C(O)—NR i R j , —C(O)—N(R a )—C 1-6 alkylene-NR i R j , —C 1-6 alkylene-NR i R j , —C 1-6 alkylene-O—C(O)—NR i R j , and —O—C(O)—NR i R j ; wherein C 1-3 alkyl, C 1-3 alkoxy, —C(O)—NR i R j , —C(O)—N(R a )—C 1-6 alkylene-NR i R j , —C 1-6 alkylene-NR i R j , —C 1-6 alkylene-O—C(O)—NR i R j , and —O—C(O)—NR i R j  may optionally be substituted by one or more fluorine atoms or a group selected from cyano, hydroxyl, or N(R a R b ); 
 R i  and R j  are selected independently for each occurrence from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, heterocyclyl and heterocyclylcarbonyl; wherein C 1-6 alkyl, C 2-6 alkenyl and C 3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from the group consisting of fluorine, hydroxyl, cyano, R a R b N—, R a R b N-carbonyl- and C 1-3 alkoxy; and wherein heterocyclyl and heterocyclylcarbonyl may be optionally substituted by one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halo-C 1-6 -alkyl, hydroxyl-C 1-6 -alkyl, R a R b N—C 1-6 alkyl- and C 1-6 -alkoxy-C 1-6 -alkyl; and wherein if said heterocyclyl or heterocyclylcarbonyl contains a —NH moiety that nitrogen may optionally be substituted by one or more groups independently selected from the group consisting of C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 — and C 1-6 -alkylcarbonyl; 
 or R i  and R j  taken together with the nitrogen to which they are attached form a 4-9 membered heterocyclic ring, which may have an additional heteroatom selected from the group consisting of N, O, and S(O) w  (wherein w is 0, 1 or 2); wherein the heterocyclic ring may be optionally substituted on carbon by one, two, or more substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, C 1-6 alkyl, C 1-6 alkoxy, R a R b N—, R a R b N—SO 2 — and R a R b N-carbonyl-; wherein said C 1-6 alkyl and C 1-6 alkoxy may optionally be substituted the group consisting of fluorine, hydroxyl, and cyano; and wherein if said heterocyclic ring contains a —NH moiety that nitrogen may be optionally substituted by a substituent selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 —, C 1-6 alkylcarbonyl-, C 1-6 alkoxycarbonyl-, R i R j N-carbonyl- and R i R j N—SO 2 —; wherein C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 —, C 1-6 alkylcarbonyl-, and C 1-6 alkoxycarbonyl- may optionally be substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, and cyano; 
 R h  is independently selected for each occurrence from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 —, C 1-6 alkylcarbonyl-, C 1-6 alkoxycarbonyl-, R i R j N-carbonyl- and R i R j N—SO 2 —; wherein C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkyl-S(O) 2 —, C 1-6 alkylcarbonyl-, and C 1-6 alkoxycarbonyl- may optionally be substituted by one or more substituents selected from R P ; 
 R P  is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkoxy, R i R j N—, R i R j N-carbonyl-, R i R j N—SO 2 —, and R i R j N-carbonyl-N(R a )—; 
 R N  is selected from the group consisting of hydrogen, halogen, hydroxyl, and C 1-6 alkyl; and 
 R a  and R b  are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-4 alkyl; wherein C 1-4 alkyl may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; 
 and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein X is N and Y is a bond. 
     
     
         3 . The compound of  claim 1 , wherein X is CR N  and Y is NR a . 
     
     
         4 . The compound of  claim 1  or  3 , wherein X is CH and Y is NH. 
     
     
         5 . The compound of any one of  claims 1 - 4 , wherein R 1  and R 2 , together with the carbon or carbons to which they are attached, form a 4, 5, or 6-membered saturated heterocyclic ring B having one oxygen. 
     
     
         6 . The compound of any one of  claims 1 - 4 , wherein R 1  and R 2 , together with the carbon or carbons to which they are attached, form a 4, 5, or 6-membered saturated heterocyclic ring B having one NR g . 
     
     
         7 . The compound of any one of  claims 1 - 4 , wherein R 1  and R 2 , together with the carbon or carbons to which they are attached, form a 4, 5, or 6-membered saturated heterocyclic ring B having one S(O) 2 . 
     
     
         8 . The compound of any one of  claims 1 - 4 , wherein R 1  and R 2 , together with the carbon or carbons to which they are attached, form a 4, 5, or 6-membered saturated carbocyclic ring B. 
     
     
         9 . The compound of any one of  claims 1 - 8 , wherein the compound is represented by Formula I. 
     
     
         10 . The compound of  claim 9 , wherein n is 0 and m is 1. 
     
     
         11 . The compound of  claim 9 , wherein n is 1 and m is 1. 
     
     
         12 . The compound of  claim 9 , wherein n is 1 and m is 2. 
     
     
         13 . The compound of any one of  claims 1 - 8 , wherein the compound is represented by Formula Ia. 
     
     
         14 . The compound of  claim 13 , wherein m is 1. 
     
     
         15 . The compound of  claim 1 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of any one of  claims 1 - 15 , wherein A and B are selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 X 11  is selected from the group consisting of C(R 11 R 22 ), NR h , O, and S(O) 2 ; and 
 R 11  and R 22  are independently selected from the group consisting of hydrogen, halogen, —C(O)—NR i R j , —C(O)—N(R a )—C 1-6 alkylene-NR i R j , —C 1-6 alkylene-NR i R j , —C 1-6 alkylene-O—C(O)—NR i R j , and —O—C(O)—NR i R j . 
 
     
     
         17 . The compound of any one of  claims 1 - 16 , wherein A and B are selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 17 , wherein R h  is selected from the group consisting of hydrogen, C 1-3 alkyl optionally substituted by one or more fluorine atoms, —C(O)—O—C 1-3 alkyl, —C(O)—NR i R j , —C(O)—C 1-3 alkyl, and —C 1-3 alkylene-C(O)—NR i R j . 
     
     
         19 . The compound of  claim 18 , wherein R i  and R j  are independently selected from the group consisting of hydrogen and C 1-3 alkyl; or R i  and R j  taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, which may have an additional heteroatom selected from the group consisting of NH, O, and S(O) w  (wherein w is 0, 1 or 2). 
     
     
         20 . The compound of any one of  claim 17 - 19 , wherein R h  is selected from the group consisting of hydrogen, methyl, 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 17 , wherein R 11  and R 22  are hydrogen. 
     
     
         22 . The compound of  claim 17 , wherein R 11  and R 22  are fluorine atoms. 
     
     
         23 . The compound of  claim 17 , wherein one of R 11  or R 22  is hydrogen and the other is selected from the group consisting of —C(O)—NR i R j , —C(O)—NH—CH 2 —CH 2 —NR i R j , —C(O)—NMe-CH 2 —CH 2 —NR i R j , —CH 2 —NR i R j , —CH 2 —O—C(O)—NR i R j , and —O—C(O)—NR i R j . 
     
     
         24 . The compound of  claim 23 , wherein R i  and R j  are independently selected from the group consisting of hydrogen and C 1-3 alkyl, or R i  and R j  taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, which may have an additional heteroatom selected from the group consisting of N and O; wherein the heterocyclic ring may be optionally substituted on carbon by one, two, or more fluorine atoms; and wherein if said heterocyclic ring contains a —NH moiety that nitrogen may be optionally substituted by C 1-3 alkyl; wherein C 1-3 alkyl may optionally be substituted by one or more fluorine atoms. 
     
     
         25 . The compound of  claim 23  or  24 , wherein one of R 11  or R 22  is hydrogen and the other is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         26 . A compound selected from the group consisting of: (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 3-oxa-9-azaspiro[5.5]undecane-9-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 2-oxa-6-azaspiro[3.3]heptane-6-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 7-oxa-2-azaspiro[3.5]nonane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 2-oxa-6-azaspiro[3.4]octane-6-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 2-oxa-7-azaspiro[3.5]nonane-7-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-oxa-2-azaspiro[3.4]octane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (7-methyl-7-azaspiro[3.5]nonan-2-yl)carbamate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 7-methyl-2,7-diazaspiro[3.5]nonane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 7-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (2-methyl-2-azaspiro[3.3]heptan-6-yl)carbamate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (6-methyl-6-azaspiro[3.4]octan-2-yl)carbamate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3 aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5 (3H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 9-(2,2-difluoroethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 2-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octane-6-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 8-(2,2-difluoroethyl)-2,8-diazaspiro[4.5]decane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-(2,2-difluoroethyl)-2,6-diazaspiro[3.4]octane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3 aR,6aS)-5-(2,2-difluoroethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 2-thia-6-azaspiro[3.3]heptane-6-carboxylate 2,2-dioxide; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 8-methyl-2,8-diazaspiro[4.5]decane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 8-oxa-2-azaspiro[4.5]decane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 9-methyl-3,9-diazaspiro[5.5]undecane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 8-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 9-methyl-8-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-(methylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-(dimethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-(3,3-difluoroazetidine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-(diethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-((2-morpholinoethyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-(methyl(2-morpholinoethyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6S)-6-((3,3-difluoroazetidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6S)-6-(morpholinomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6S)-6-((diethylamino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; 2-((3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl) 5-methyl (3aR,6aS)-tetrahydropyrrolo[3,4-c]pyrrole-2,5 (1H,3H)-dicarboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3aR,6aS)-5-(dimethylcarbamoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3aR,6aS)-5-(ethylcarbamoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3 aR,6aS)-5-(methylcarbamoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3aR,6aS)-5-isobutyrylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3aR,6aS)-5-propionylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3aR,6aS)-5-(2-(diethylamino)-2-oxoethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3aR,6aS)-5-(2-morpholino-2-oxoethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-(((methylcarbamoyl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-(((dimethylcarbamoyl)oxy)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-(morpholinomethyl)-2-azaspiro[3.3]heptane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3aR,6aS)-5-(2,2-difluoropropyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl 6-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3 aR,6aS)-5-(morpholinomethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-(ethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-(pyrrolidine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3aR,5S,6aS)-5-((dimethylcarbamoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (1R,5S,6R)-6-(azetidine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3 aR,6aS)-5-((diethylamino)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate; (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (3aR,6aS)-5(((methylcarbamoyl)oxy)methyl)hexahydrocyclopenta[c] pyrrole-2(1H)-carboxylate; and a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         27 . A pharmaceutically acceptable composition comprising a compound of any one of  claims 1 - 26  and a pharmaceutically acceptable excipient. 
     
     
         28 . The composition of  claim 27 , wherein the composition is formulated as a unit dose. 
     
     
         29 . The composition of  claim 27 , wherein the composition is formulated for subcutaneous administration. 
     
     
         30 . The composition of  claim 27 , wherein the composition is formulated for intravenous administration. 
     
     
         31 . A method of treating and/or controlling obesity, comprising administering to a patient in need thereof an effective amount of a compound of any one of  claims 1 - 26 . 
     
     
         32 . A method of inducing weight loss in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of  claims 1 - 26 . 
     
     
         33 . A method of substantially preventing weight gain in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of  claims 1 - 26 . 
     
     
         34 . The method of any one of  claims 31 - 33 , wherein the patient is a human. 
     
     
         35 . The method of any one of  claims 31 - 33 , wherein the patient is a cat or dog. 
     
     
         36 . The method of any one of  claims 31 - 33 , wherein the patient has a body mass index greater than or equal to about 30 kg/m 2  before the administration. 
     
     
         37 . The method of any one of  claims 31 - 36 , wherein administering comprises subcutaneous administration. 
     
     
         38 . The method of any one of  claims 31 - 36 , wherein administering comprises intravenous administration. 
     
     
         39 . The method of any one of  claims 31 - 36 , wherein administering comprises once, twice, or thrice weekly administration. 
     
     
         40 . The method of any one of  claims 31 - 39 , comprising administering said compound in an amount sufficient to establish inhibition of intracellular MetAP2 effective to increase thioredoxin production in the patient and to induce multi organ stimulation of anti-obesity processes in the subject. 
     
     
         41 . The method of  claim 40 , comprising administering said compound in an amount insufficient to reduce angiogenesis in the patient.