Pyrazolopyridine derivative having GLP-1 receptor agonist effect
The present invention provides a compound having the basic structure shown by Formula (I) in which the indole ring and the pyrazolopyridine structure is bound through a substituent, a salt thereof or a solvate of either the compound or a salt of the compound, as well as a preventative agent or a therapeutic agent for non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity containing such compound, salt or solvate as an active ingredient.
1. A compound represented by Formula (I):
wherein, X is —N═ or —CR a ═; R a is selected from a hydrogen atom, a halogen atom, and C 1-6 alkyl;
Y is selected from —C(═O)—, —CHR—, and —S(═O) 2 —; R is a hydrogen atom or C 1-6 alkyl;
Q 1 is C 6-10 aryl or 5 to 10 membered heteroaryl, wherein C 6-10 aryl and 5 to 10 membered heteroaryl are optionally substituted with one to five substituents independently selected from a halogen atom, C 1-6 alkyl (wherein C 1-6 alkyl is optionally substituted with one or more halogen atoms), and C 1-6 alkoxy;
Q 2 is 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein 3 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl are optionally substituted with one to three substituents independently selected from a halogen atom, C 1-6 alkyl (wherein C 1-6 alkyl is optionally substituted with one or more halogen atoms), C 1-6 alkoxy, and —NR Qa R Qb , and two C 1-6 alkyl groups together with a carbon atom to which they are attached may form C 3-8 carbocyclic ring; and R Qa and R Qb are independently selected from a hydrogen atom, C 1-6 alkyl, and (C 1-6 alkyl)carbonyl;
R 1 , R 2 and R 3 are each independently selected from a hydrogen atom and C 1-6 alkyl (wherein, C 1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom, C 1-6 alkoxy, and hydroxy);
R 4 , R 5 and R 6 are independently selected from a hydrogen atom, a halogen atom, and C 1-6 alkyl;
R 7 and R 8 are independently a hydrogen atom or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom and C 3-15 cycloalkyl, or R 7 and R 8 together with a carbon atom to which they are attached may form C 3-15 cycloalkane ring, wherein C 3-15 cycloalkane ring formed by R 7 and R 8 together is optionally substituted with one to three C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom, hydroxy, —NR 7a R 7b , C 1-6 alkoxy, and 3 to 12 membered heterocyclyl, and R 7a and R 7b are independently selected from a hydrogen atom, C 1-6 alkyl, and (C 1-6 alkyl)carbonyl;
n1 is an integer of 0 to 3; n2 is an integer of 0 to 5;
R 9 is selected from the group consisting of
—CO 2 R 9f , and —C(═O)—NR 9g R 9h ;
R 9a , R 9b , R 9c , R 9d , and R 9g are each independently selected from a hydrogen atom, C 1-6 alkyl (wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom and C 1-6 alkoxy), and (C 1-6 alkyl)carbonyl; R 9e is a hydrogen atom, or C 1-6 alkyl that is optionally substituted with one or more halogen atoms; R 9f is a hydrogen atom or C 1-6 alkyl; R 9h is a hydrogen atom, C 1-6 alkyl, (C 1-6 alkyl)carbonyl, cyano, or —S(═O) n3 —R 9i ; n3 is an integer of 0 to 2; and R 9i is C 1-6 alkyl;
Z 1 is selected from the group consisting of
wherein R za is selected from a hydrogen atom, C 1-6 alkyl, and (C 1-6 alkyl)carbonyl; R zb and R zc are independently a hydrogen atom or C 1-6 alkyl; n4 is an integer of 1 to 3; n5 and n6 are independently an integer of 0 to 10 (* represents a binding position with a pyrazolopyridine structure, and ** represents a binding position with Z 2 );
Z 2 is selected from the group consisting of C 1-6 alkyl, C 3-15 cycloalkyl, 3 to 12 membered heterocyclyl, C 6-10 aryl and 5 to 10 membered heteroaryl, wherein C 3-15 cycloalkyl, 3 to 12 membered heterocyclyl, C 6-10 aryl, and 5 to 10 membered heteroaryl are optionally substituted with one to five substituents independently selected from Group A:
Group A: a) oxo,
b) a halogen atom,
c) cyano,
d) —NR zd R ze ; wherein R zd and R ze are independently selected from a hydrogen atom, C 1-6 alkyl and (C 1-6 alkyl)carbonyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, a halogen atom and C 1-6 alkoxy,
e) —C(═O)—NR zf R zg ; wherein R zf and R zg are independently selected from a hydrogen atom, C 1-6 alkyl and (C 1-6 alkyl)carbonyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, a halogen atom and C 1-6 alkoxy,
f) —S(═O) n7 —R zh ; wherein n7 is an integer of 0 to 2; and R zh is a hydrogen atom or C 1-6 alkyl,
g) C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more substituent independently selected from a halogen atom, hydroxy, —NR zi R zj , C 1-6 alkoxy, and 3 to 12 membered heterocyclyl, wherein R zi and R zj are independently a hydrogen atom or C 1-6 alkyl, and wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from hydroxy, C 1-6 alkyl and 3 to 12 membered heterocyclyl,
h) C 1-6 alkoxy; wherein C 1-6 alkoxy is optionally substituted with one or more substituent independently selected from hydroxy, a halogen atom, and C 1-6 alkoxy,
i) 3 to 12 membered heterocyclyl; wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from C 1-6 alkyl and (C 1-6 alkyl)carbonyl,
j) C 6-10 aryl; wherein C 6-10 aryl is optionally substituted with one or more (C 1-6 alkyl)carbonyl, and
k) 5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl is optionally substituted with one or more substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, —NR zk R zl , and 3 to 12 membered heterocyclyl, wherein R zk and R zl are independently selected from a hydrogen atom, C 1-6 alkyl and (C 1-6 alkyl)carbonyl, and wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from C 1-6 alkyl and (C 1-6 alkyl)carbonyl;
or a salt thereof.
2. The compound according to claim 1 , or a salt thereof, wherein Q 1 is phenyl or pyridyl, and phenyl or pyridyl is substituted with one to four substituents independently selected from a halogen atom and C 1-6 alkyl.
3. The compound according to claim 2 , or a salt thereof, wherein R 7 and R 8 are both a hydrogen atom; R 7 and R 8 are both C 1-6 alkyl; R 7 is a hydrogen atom and R 8 is C 1-6 alkyl; or R 7 and R 8 together with a carbon atom to which they are attached form C 3-8 cycloalkane ring, wherein C 3-8 cycloalkyl formed is optionally substituted with one to two C 1-6 alkyl, and C 1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, C 1-6 alkoxy, and 3 to 12 membered heterocyclyl.
4. The compound according to claim 3 or a salt thereof, wherein Z 2 is selected from C 1-6 alkyl, C 3-15 cycloalkyl, 3 to 12 membered heterocyclyl, C 6-10 aryl, and 5 to 10 membered heteroaryl, wherein C 3-15 cycloalkyl, 3 to 12 membered heterocyclyl, C 6-10 aryl, and 5 to 10 membered heteroaryl are optionally substituted with one to four substituents independently selected from Group B:
Group B: a) oxo,
b) a halogen atom,
c) —NR zd1 R ze1 ; wherein R zd1 and R ze1 are independently selected from a hydrogen atom, C 1-6 alkyl and (C 1-6 alkyl)carbonyl, and C 1-6 alkyl is optionally substituted with one or more C 1-6 alkoxy,
d) —S(═O) n7 —R zh1 ; wherein n7 is an integer of 0 to 2, R zh1 is C 1-6 alkyl,
e) C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom, hydroxy, —NR zi R zj , C 1-6 alkoxy, and 3 to 12 membered heterocyclyl, wherein R zi and R zj are independently a hydrogen atom or C 1-6 alkyl, and wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from hydroxy, C 1-6 alkyl and 3 to 12 membered heterocyclyl,
f) C 1-6 alkoxy; wherein C 1-6 alkoxy is optionally substituted with one or more hydroxy,
g) 3 to 12 membered heterocyclyl; wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more (C 1-6 alkyl)carbonyl,
h) 5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl is optionally substituted with one or more substituents independently selected from C 1-6 alkyl, and —NR zk1 R zl1 ; and R zk1 and R zl1 are independently selected from a hydrogen atom and C 1-6 alkyl.
5. The compound according to claim 4 , or a salt thereof, wherein Y is —C(═O)—.
6. The compound according to claim 5 , or a salt thereof, wherein R 1 is a hydrogen atom.
7. The compound according to claim 6 , or a salt thereof, wherein n1 and n2 are both 0.
8. The compound according to claim 7 , or a salt thereof, wherein R 9 is the Formula
9. The compound according to claim 8 , or a salt thereof, wherein X is —N═, —CH═, or —CF═.
10. The compound according to claim 9 , or a salt thereof, wherein Z 1 is the Formula:
wherein * represents a binding position with a pyrazolopyridine structure, and ** represents a binding position with Z 2 .
11. A pharmaceutical composition comprising the compound according to claim 10 , or a salt thereof, as an active ingredient.
12. A method for treating non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity comprising administering an effective amount of the compound according to claim 1 , or a salt thereof, as an active ingredient to a patient in need of such treatment.
13. The compound according to claim 1 , or a salt thereof, represented by the formula:
14. The compound according to claim 13 , or a salt thereof, of the formula:
15. The hemicalcium salt hydrate of the compound according to claim 14 .
16. A pharmaceutical composition comprising the compound according to claim 14 or, a salt thereof, or of claim 15 as an active ingredient.
17. A method for treating non-insulin-dependent diabetes mellitus (Type 2 diabetes) or obesity in a patient in need thereof, comprising administering an effective amount of a compound according to claim 14 or a salt thereof, or of claim 15 .
18. A compound selected from:
or a mixture thereof, or a salt thereof.
19. A compound of the formula:
or a salt thereof.
20. A compound of the formula:
21. A hemicalcium salt hydrate compound of:
22. A pharmaceutical composition comprising the compound according to claim 18 .
23. A pharmaceutical composition comprising the compound according to claim 18 and a pharmaceutically acceptable additive.
24. A method for treating non-insulin-dependent diabetes mellitus (Type 2 diabetes) in a patient in need thereof, comprising administering an effective amount of the compound according to claim 18 .
25. A method for treating obesity in a patient in need thereof, comprising administering an effective amount of the compound according to claim 18 .
26. A method for treating hyperglycemia in a patient in need thereof, comprising administering an effective amount of the compound according to claim 18 .
27. A pharmaceutical composition comprising the compound according to claim 19 .
28. A pharmaceutical composition comprising the compound according to claim 19 and a pharmaceutically acceptable additive.
29. A method for treating non-insulin-dependent diabetes mellitus (Type 2 diabetes) in a patient in need thereof, comprising administering an effective amount of the compound according to claim 19 .
30. A method for treating obesity in a patient in need thereof, comprising administering an effective amount of the compound according to claim 19 .
31. A method for treating hyperglycemia in a patient in need thereof, comprising administering an effective amount of the compound according to claim 19 .
32. A pharmaceutical composition comprising the compound according to claim 20 .
33. A pharmaceutical composition comprising the compound according to claim 20 and a pharmaceutically acceptable additive.
34. A method for treating non-insulin-dependent diabetes mellitus (Type 2 diabetes) in a patient in need thereof, comprising administering an effective amount of the compound according to claim 20 .
35. A method for treating obesity in a patient in need thereof, comprising administering an effective amount of the compound according to claim 20 .
36. A method for treating hyperglycemia in a patient in need thereof, comprising administering an effective amount of the compound according to claim 20 .
37. A pharmaceutical composition comprising the compound according to claim 21 .
38. A pharmaceutical composition comprising the compound according to claim 21 and a pharmaceutically acceptable additive.
39. A method for treating non-insulin-dependent diabetes mellitus (Type 2 diabetes) in a patient in need thereof, comprising administering an effective amount of the compound according to claim 21 .
40. A method for treating obesity in a patient in need thereof, comprising administering an effective amount of the compound according to claim 21 .
41. A method for treating hyperglycemia in a patient in need thereof, comprising administering an effective amount of the compound according to claim 21 .