Pyrazolopyridine derivative having GLP-1 receptor agonist effect

Abstract

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.

The invention claimed is: 
     
       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 .