Treating diabetes with dipeptidyl peptidase-IV inhibitors
View Patent ↗The present invention is directed to novel substituted dihydropyrrolopyrazoles of structural Formula I which are inhibitors of the dipeptidyl peptidase-N enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase IV enzyme is involved.
1. A compound of structural Formula I:
or a pharmaceutically acceptable salt thereof; wherein
R 1 , R 2 and R 4 are independently selected from the group consisting of C 1-6 alkyl, halogen and hydrogen;
R 3 is hydrogen or halogen or, taken together with R 5 , form a C 5-7 cycloalkyl or 5-7 membered heterocycle wherein the cycloalkyl or heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of —OH, C 1-6 alkyl, halogen and C 1-6 alkoxy;
R 5 is hydrogen, halogen, heterocycle, C 3-7 cycloalkyl or, taken together with the carbon R 5 is attached, form a C 3-7 cycloalkyl or 4-7 membered heterocycle wherein the cycloalkyl or heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of —OH, C 1-6 alkyl, halogen and C 1-6 alkoxy or, taken together with R 3 , form a C 5-7 cycloalkyl or 5-7 membered heterocycle wherein the cycloalkyl or heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of —OH, C 1-6 alkyl, halogen and C 1-6 alkoxy or, taken together with R 6 , form an aryl, cyclopropyl C 5-7 cycloalkyl or 5-7 membered heterocycle wherein the aryl, cycloalkyl or heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of —OH, C 1-6 alkyl, halogen and C 1-6 alkoxy;
R 6 is hydrogen, heterocycle, C 3-7 cycloalkyl or, together with the carbon R 6 is attached, form a C 3-7 cycloalkyl or 4-7 membered heterocycle wherein the cycloalkyl or heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of —OH, C 1-6 alkyl, halogen and C 1-6 alkoxy or taken together with R 5 form an aryl, cyclopropyl C 5-7 cycloalkyl or 5-7 membered heterocycle wherein the aryl, cycloalkyl or heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of —OH, C 1-6 alkyl, halogen and C 1-6 alkoxy;
R 7 is selected from the group consisting of hydrogen C 1-6 alkyl, C 1-6 alkylOH and C 1-6 alkoxy; wherein R 5 , R 6 , and R 7 cannot be simultaneously hydrogen; and
R 8 is selected from the group consisting of hydrogen, C 1-6 alkyl, SO 2 C 1-6 alkyl, and SO 2 C 3-6 cycloalkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 are fluorine.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 are fluorine.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is taken together with R 5 to form a cyclohexyl or tetrahydropyran, wherein the cyclohexyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, halogen and C 1-6 alkoxy.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the R 8 is selected from the group consisting of hydrogen, SO 2 CH 3 , and SO 2 cyclopropyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is taken with the carbon it is attached to and forms a C 3-7 cycloalkyl, wherein the C 3-7 cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of —OH and flourine.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is heterocycle, wherein the heterocycle is furan.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is taken with R 5 and forms a cyclopropyl, C 5-7 cycloalkyl or phenyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is taken with the carbon it is attached to and forms a heterocycle.
10. The compound claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is taken with R 5 and forms a heterocycle.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is taken with the carbon it is attached to and forms a heterocycle, wherein the heterocycle is imidazolidine-2,4-dione.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.
13. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is taken together with R 7 to form a 5-7 membered heterocycle wherein the heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, halogen and C 1-6 alkoxy.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having structural Formula Ia or Ib having the indicated stereochemical configuration at the two stereogenic carbon atoms marked with an *:
wherein W is
16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, having structural Formula Ia having the indicated absolute stereochemical configuration at the two stereogenic carbon atoms marked with an *:
wherein W is
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having structural formulae Ic or Id having the indicated stereochemical configuration at the three stereogenic carbon atoms marked with an *:
18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, having structural Formula Id having the indicated absolute stereochemical configuration at the three stereogenic carbon atoms marked with an *:
19. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition which comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
21. A method of treating a condition selected from the group consisting of insulin resistance, hyperglycemia, and Type 2 diabetes comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.