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

Patent metadata

Field	Value
Publication number	US-9944613-B2
Application number	US-201715827074-A
Country	US
Kind code	B2
Filing date	Nov 30, 2017
Priority date	Aug 11, 2015
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

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.

First claim

What is claimed is:

1. 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 compound 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 compound 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 compound of claim 1 , wherein ring A and ring B, taken together, are selected from the group consisting of:

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 compound of claim 1 , wherein ring A and ring B, taken together, are selected from the group consisting of:

6. The compound 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 compound of claim 5 , wherein R h is selected from the group consisting of hydrogen, methyl,

8. The compound of claim 4 , wherein ring A and ring B taken together are selected from the group consisting of:

9. The compound of claim 8 , wherein R h is selected from the group consisting of hydrogen, methyl,

10. 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 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

Assignees

• Zafgen Inc

Inventors

• Zahler Robert
• Cai Zhenwei
• Wu Zhixing
• Vath James E

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D303/04 Primary

  containing only hydrogen and carbon atoms in addition to the ring oxygen atoms · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D407/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title