Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
The present invention relates to therapeutically active and selective inhibitors of the enzyme DPP-IV of formula I, pharmaceutical compositions comprising the compounds and the use of such compounds for and the manufacture of medicaments for treating diseases that are associated with proteins that are subject to inactivation by DPP-IV, such as type 2 diabetes and obesity
1. A compound of formula I
wherein
A may be attached at either N 1 or at N 2 to the purine system, wherein if A is attached at N 1 then N 2 is NH 2 , and if A is attached at N 2 then N 1 and N 2 are NH, and
n is one or two,
m is one, two, or three,
R 1 is aryl optionally substituted with one or more R 2 independently or heteroaryl optionally substituted with one or more R 2 independently,
R 2 is H, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, —NHCOR 3 , —NHSO 2 R 3 , —SR 3 , —SOR 3 , —SO 2 R 3 , —OCOR 3 , —CO 2 R 4 , —CON(R 4 ) 2 , —CSN(R 4 ) 2 , —NHCON(R 4 ) 2 , —NHCSN(R 4 ) 2 , —NHCONNH 2 , —SO 2 N(R 4 ) 2 , —OR 4 , cyano, nitro, or halogen, wherein each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is optionally substituted with one or more R 3 independently,
R 3 is Halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, aryl, heteroaryl, —OR 11 , —N(R 11 ) 2 , or —SR 11 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl is substituted with one or more R 11 independently,
R 4 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, aryl, aryl-C 1 -C 5 alkyl, heteroaryl, or heteroaryl-C 1 -C 5 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, aryl-C 1 -C 5 alkyl, heteroaryl, and heteroaryl-C 1 -C 5 alkyl is substituted with one or more R 11 independently,
R 5 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 5 alkyl, C 3 -C 7 cycloheteroalkyl, C 3 -C 7 cycloheteroalkyl-C 1 -C 5 alkyl, aryl, heteroaryl aryl-C 1 -C 5 alkyl, heteroaryl-C 1 -C 5 alkyl, —OR 7 , or —[(CH 2 ) o —O] p -alkyl, wherein o and p are 1-3 independently, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-C 1 -C 5 alkyl, cycloheteroalkyl, C 3 -C 7 cycloheteroalkyl-C 1 -C 5 alkyl, aryl, aryl-C 1 -C 5 alkyl, heteroaryl, and heteroaryl-C 1 -C 5 alkyl is optionally substituted with one or more substituents independently selected from R 7 or R 11 independently,
R 6 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, aryl, heteroaryl, aryl-C 1 -C 5 alkyl, heteroaryl-C 1 -C 5 alkyl, or C 3 -C 7 cycloheteroalkyl-C 1 -C 5 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, C 3 -C 7 cycloheteroalkyl-C 1 -C 5 alkyl, aryl, aryl-C 1 -C 5 alkyl, heteroaryl, aryl-C 1 -C 5 alkyl, and heteroaryl-C 1 -C 5 alkyl is optionally substituted with one or more R 11 independently,
R 7 is H, ═O, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, aryl, heteroaryl, —OR 11 , —N(R 11 ) 2 , or —SR 11 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R 11 independently,
R 8 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, aryl, heteroaryl, —OR 11 , —N(R 11 ) 2 , or —SR 11 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R 11 independently,
R 9 and R 10 is independently H, C 1 -C 10 alkyl optionally substituted with one or more R 8 independently, or halogen,
R 11 is H, —CF 3 , —CCl 3 , —OCF 3 , —OMe, cyano, halogen, —OH, —COMe, —CONH 2 , —CONHMe, —CONMe 2 , —NO 2 , C 1 -C 10 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R 12 independently,
R 12 is H, C 1 - 10 alkyl, —CF 3 , —CCl 3 , —OCF 3 , —OMe, cyano, halogen, —OH, —COMe, —CONH 2 , —CONHMe, —CONMe 2 , —NH 2 , or —NO 2
R 9 and R 10 with the carbon atom to which they are attached may form a cyclopropyl ring,
if two R 4 or two R 11 are attached to the same nitrogen, they may be connected with the nitrogen atom to which they are attached to form a 3- to 7-membered ring, or any tautomeric form or any optical isomer or mixture of optical isomers, a racemic mixture, or a salt thereof with a pharmaceutically acceptable acid or base.
2. A compound according to claim 1 , wherein R 1 is aryl optionally substituted with one or more R 2 independently.
3. A compound according to claim 2 , wherein R 1 is phenyl substituted with one or more R 2 independently.
4. A compound according to claim 2 , wherein R 1 is aryl.
5. A compound according to claim 4 , wherein R 1 is phenyl.
6. A compound according claim 1 , wherein R 2 is C 1 -C 7 alkyl, C 2 -C 7 alkynyl, cyano, or halogen, wherein each alkyl and alkynyl is optionally substituted with one or more R 3 independently.
7. A compound according to claim 6 wherein R 2 is C 1 -C 7 alkyl, C 2 -C 7 alkynyl, cyano, or halogen.
8. A compound according to claim 7 wherein R 2 is methyl.
9. A compound according to claim 7 wherein R 2 is cyano or halogen.
10. A compound according to claim 1 , wherein R 3 is C 1 -C 10 alkyl or aryl, wherein each alkyl or aryl is substituted with one or more R 11 independently.
11. A compound according to claim 10 wherein R 3 is C 1 -C 10 alkyl or aryl.
12. A compound according to claim 11 wherein R 3 is methyl or phenyl.
13. A compound according to claim 1 , wherein R 3 is halogen.
14. A compound according to claim 1 , wherein R 4 is H, C 1 -C 10 alkyl or aryl, wherein each alkyl or aryl is substituted with one or more R 11 independently.
15. A compound according to claim 14 wherein R 4 is H, C 1 -C 10 alkyl or aryl.
16. A compound according to claim 15 wherein R 4 is H, methyl or phenyl.
17. A compound according to claim 1 , wherein R 5 is H, C 1 -C 10 alkyl, aryl-C 1 -C 5 alkyl, or heteroaryl-C 1 -C 5 alkyl, wherein each alkyl, aryl-C 1 -C 5 alkyl and heteroaryl-C 1 -C 5 alkyl is optionally substituted with one or more R 7 independently.
18. A compound according to claim 17 , wherein R 5 is H or C 1 -C 10 alkyl optionally substituted with one or more R 7 independently.
19. A compound according to claim 18 , wherein R 5 is H or C 1 -C 10 alkyl.
20. A compound according to claim 19 , wherein R 5 is H.
21. A compound according to claim 19 wherein R 5 is methyl.
22. A compound according to claim 1 , wherein R 6 is C 1 -C 10 alkyl, aryl-C 1 -C 5 alkyl, or heteroaryl-C 1 -C 5 alkyl, wherein each alkyl, aryl-C 1 -C 5 alkyl and heteroaryl-C 1 -C 5 alkyl is optionally substituted with one or more R 11 independently.
23. A compound according to claim 22 , wherein R 6 is C 1 -C 10 alkyl, aryl-C 1 -C 5 alkyl, or heteroaryl-C 1 -C 5 alkyl.
24. A compound according to claim 22 , wherein R 6 is C 1 -C 10 alkyl optionally substituted with one or more R 11 independently.
25. A compound according to claim 24 wherein R 6 is C 1 -C 10 alkyl.
26. A compound according to claim 25 wherein R 6 is methyl.
27. A compound according to claim 1 , wherein R 7 is H, ═O, aryl, heteroaryl, OR 11 , N(R 11 ) 2 , SR 11 , wherein each aryl and heteroaryl is optionally substituted with one or more R 11 independently.
28. A compound according to claim 27 wherein R 7 is H, ═O, C 1 -C 10 alkyl, —OR 11 , —N(R 11 ) 2 , —SR 11 .
29. A compound according to claim 28 wherein R 7 is H, ═O, —OR 11 , or —N(R 11 ) 2 .
30. A compound according to claim 29 , wherein R 7 is H, ═O, or —N(R 11 ) 2 .
31. A compound according to claim 30 , wherein R 7 is ═O or —N(R 11 ) 2 .
32. A compound according to claim 1 , wherein R 8 is aryl or heteroaryl, wherein each aryl and heteroaryl is optionally substituted with one or more R 11 independently.
33. A compound according to claim 32 , wherein R 8 is aryl or heteroaryl.
34. A compound according to claim 33 , wherein R 8 is phenyl.
35. A compound according to claim 1 , wherein R 9 is H, C 1 -C 10 alkyl, or halogen.
36. A compound according claim 35 , wherein R 9 is H.
37. A compound according to claim 1 , wherein R 10 is H, C 1 -C 10 alkyl, or halogen.
38. A compound according claim 37 wherein R 10 is H.
39. A compound according to claim 1 , wherein R 11 is H, —CF 3 , cyano, halogen, —OH, —NO 2 , C 1 -C 10 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R 12 independently.
40. A compound according to claim 39 , wherein R 11 is H, halogen, —OH, C 1 -C 10 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R 12 independently.
41. A compound according to claim 40 , wherein R 11 is H, halogen, —CH 3 , aryl, heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R 12 independently.
42. A compound according to claim 41 , wherein R 11 is H, halogen, —CH 3 , heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, and heteroaryl is optionally substituted with one or more R 12 independently.
43. A compound according to claim 42 , wherein R 11 is H, halogen, or —CH 3 .
44. A compound according to claim 42 , wherein R 11 is heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, wherein each cycloalkyl, cycloheteroalkyl, and heteroaryl is optionally substituted with one or more R 12 independently.
45. A compound according to claim 44 , wherein R 11 is selected from the group consisting of pyridine, cyclopentane, cyclohexane, and pyrrolidine, wherein each cycloalkyl, cycloheteroalkyl, and heteroaryl is optionally substituted with one or more R 12 independently.
46. A compound according to claim 1 , wherein R 12 is H, C 1 -C 10 alkyl, —CF 3 , cyano, halogen, —OH, —COMe, —NH 2 , —NO 2 .
47. A compound according to claim 46 , wherein R 12 is H, —CF 3 , cyano, halogen, —OH, —NH 2 .
48. A compound according to claim 47 , wherein R 12 is —OH or —NH 2 .
49. A compound according to claim 1 , wherein n is two.
50. A compound according to claim 1 , wherein n is one.
51. A compound according to claim 1 , wherein m is two or three.
52. A method for treating type II diabetes, said method comprising administering to a patient in need thereof an effective amount for said treatment of a compound according to claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, a racemic mixture, or any tautomeric form thereof.
53. A pharmaceutical composition for treatment of type 2 diabetes, comprising (i) a compound according to claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, a racemic mixture, or any tautomeric form and (ii) one or more pharmaceutically acceptable carriers or diluents.