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.

1 . A method of treating Prader-Willi syndrome in a patient in need thereof, comprising administering to the patient an effective amount of a compound represented by: 
       
         
           
           
               
               
           
         
       
       wherein:
 n is 0; 
 m is 1; 
 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 
 R 1  and R 2 , together with the carbon or carbons to which they are attached, form a 3-6 membered saturated carbocyclic ring B, wherein 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, C 1-3 alkyl, and —C 1-6 alkylene-NR i R j , wherein C 1-3 alkyl or C 1-6 alkylene-NR i R j  may optionally be substituted by one or more fluorine atoms; 
 Ring A may be optionally substituted by a substituent selected from the group consisting of halogen, hydroxyl, and C 1-3 alkyl, wherein C 1-3 alkyl 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 h  is independently selected for each occurrence from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 alkenyl, and C 3-6 alkynyl, wherein C 1-6 alkyl, C 3-6 alkenyl, and C 3-6 alkynyl 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, and R i R j N—; 
 R i  and R j  are selected independently for each occurrence from the group consisting of hydrogen and C 1-6 alkyl, 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 if said 4-9 membered 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 optionally be substituted by one or more substituents selected from the group consisting of fluorine, hydroxyl, and cyano; 
 R a  and R b  are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-4 alkyl; 
 and pharmaceutically acceptable salts and/or stereoisomers thereof. 
 
     
     
         2 . The method of  claim 1 , wherein R 1  and R 2 , together with the carbon or carbons to which they are attached, form a 4-membered saturated heterocyclic ring B having one NR h . 
     
     
         3 . The method of  claim 1 , wherein R 1  and R 2 , together with the carbon or carbons to which they are attached, form a 4 membered saturated heterocyclic ring B having one S(O) 2 . 
     
     
         4 . The method of  claim 1 , wherein ring A and ring B, taken together, 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 each independently selected from the group consisting of hydrogen, halogen, and —C 1-6 alkylene-NR i R j , wherein R i  and R j  taken together with the nitrogen to which they are attached form a 4-9 membered heterocyclic ring wherein if said heterocyclic ring contains a —NH moiety that nitrogen may be optionally substituted by a substituent C 1-6 alkyl optionally 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, and C 1-6 alkyl, wherein C 1-6 alkyl 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, and cyano. 
 
     
     
         5 . The method of  claim 1 , wherein ring A and ring B, taken together, are selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 5 , wherein R h  is selected from the group consisting of hydrogen and C 1-3 alkyl optionally substituted by one or more fluorine atoms. 
     
     
         7 . The method of  claim 5 , wherein R h  is selected from the group consisting of hydrogen, methyl, 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 4 , wherein ring A and ring B taken together are selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 8 , wherein R h  is selected from the group consisting of hydrogen, methyl, 
       
         
           
           
               
               
           
         
       
     
     
         10 . A method of treating Prader-Willi syndrome in a patient in need thereof, comprising administering to the patient an effective amount of a compound represented by: 
       
         
           
           
               
               
           
         
       
       wherein:
 n is 0; 
 m is 1; 
 R 1  and R 2 , together with the carbon or carbons to which they are attached, form a 4 membered saturated heterocyclic ring B, wherein ring A and B, taken together, are represented by: 
 
       
         
           
           
               
               
           
         
         R h  is independently selected for each occurrence from the group consisting of hydrogen and C 1-6 alkyl, wherein C 1-6 alkyl 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, and cyano; 
         and pharmaceutically acceptable salts and/or stereoisomers thereof. 
       
     
     
         11 . A method of treating Prader-Willi syndrome in a patient in need thereof, comprising administering to the patient an effective amount of 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 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 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-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 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 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 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 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 6-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate;   and a pharmaceutically acceptable salt or stereoisomer thereof.   
     
     
         12 . A method of treating Prader-Willi syndrome in a patient in need thereof, comprising administering to the patient an effective amount of the compound (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 or pharmaceutically acceptable salts thereof. 
     
     
         13 .- 14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the patient is obese. 
     
     
         16 . The method of  claim 1 , wherein the patient is overweight.