Novel 1-substituted indazole derivative

Abstract

A medicament for treating diseases associated with cholinergic properties in the central nervous system (CNS) and/or peripheral nervous system (PNS), diseases associated with smooth muscle contraction, endocrine disorders, neurodegenerative disorders and the like, which comprises a compound of Formula (I): wherein A is CR 1E or a nitrogen atom, X—Y—Z is N—CO—NR 3A R 3B and the like, R 1A to R 1E are each independently a hydrogen atom and the like, R 2A to R 2D are each independently a hydrogen atom and the like, R 3A and R 3B are each independently an optionally-substituted C 3-10 cycloalkyl and the like, and n is 1 or 2 or a pharmaceutically acceptable salt thereof, which exhibits potent modulatory-effects on the activity of α7 nicotinic acetylcholine receptor (α7 nAChR).

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 A is CR 1E  or a nitrogen atom, 
 X—Y—Z is N—CO—NR 3A R 3B , N—CO—R 4 , CR 2E —CO—NR 3A R 3B , CR 2E —NR 5 —COR 4  or CR 2E —NR 5 —CONR 3A R 3B , 
 R 1A  is a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, a C 3-6  cycloalkyl, —NR 6 R 7 , —CONR 6 R 7  and —NR 6 COR 7 ; a C 3-10  cycloalkyl or a 4- to 10-membered saturated heterocycle (wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 6 R 7 ); a C 1-6  alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, —NR 6 R 7 , —CONR 6 R 7  and —NR 6 COR 7 ; a hydrogen atom; a halogen; —NR 6 R 7 ; a cyano group; —CONR 6 R 7 ; —NR 6 COR 7 ; or —SO 2 R 6 , provided that both R 6  and R 7  are not a hydrogen atom, 
 R 1B  to R 1E  are each independently a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, a C 3-6  cycloalkyl, —NR 6′ R 7′ , —CONR 6′ R 7′  and —NR 6′ COR 7′ ; a C 3-10  cycloalkyl or a 4- to 10-membered saturated heterocycle (wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy, —NR 6′ R 7′ , —CONR 6′ R 7′  and —NR 6′ COR 7′ ); a C 1-6  alkoxy or a C 3-10  cycloalkoxy (wherein the alkoxy and the cycloalkoxy may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, —CONR 6′ R 7′  and —NR 6′ COR 7′ ); a hydrogen atom; a hydroxy group; a halogen; an aryl or a heteroaryl (wherein the aryl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C 1-6  alkyl optionally substituted with 1 to 5 fluorine atoms, a C 1-6  alkoxy, —NR 6′ R 7′ , —CONR 6′ R 7′  and —NR 6′ COR 7′ ); —NR 6′ R 7′ ; a cyano group; —CONR 6′ R 7′ ; —NR 6′ COR 7′ ; or —SO 2 R 6′ , provided that both R 6′  and R 7′  are not a hydrogen atom, 
 R 2A  to R 2E  are each independently a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C 1-6  alkoxy and —NR 8 R 9 ; a hydrogen atom; a halogen; a hydroxy group; or a C 1-6  alkoxy optionally substituted with 1 to 5 fluorine atoms, or when two of R 2A  to R 2E  are a C 1-6  alkyl, they may be taken together to form a 4- to 10-membered saturated carbocyclic ring (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 8 R 9 ), 
 R 3A , R 3B  and R 4  are each independently a C 1-10  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of phenyl, a monocyclic heteroaryl, a 4- to 10-membered saturated heterocycle, a C 3-10  cycloalkyl, a fluorine atom, a hydroxy group, a C 1-6  alkoxy optionally substituted with 1 to 5 fluorine atoms, and —NR 10 R 11 ; a C 3-10  cycloalkyl; a 4- to 10-membered saturated heterocycle; phenyl; a monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle, the phenyl and the monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of an aryl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6  alkoxy and —NR 10 R 11 ), a halogen, a hydroxy group, a C 1-6  alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6  alkoxy and —NR 10 R 11 ), a C 1-6  alkoxy (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a C 3-6  cycloalkyl, a C 3-6  cycloalkyl-C 1-6  alkyl, a C 1-6  alkoxy and a fluorine atom), a C 1-6  alkylcarbonyl and —NR 10 R 11 , provided that (1) R 3A  and R 3B  may be taken together to form a 4- to 10-membered saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 10 R 11 ), (2) only one of R 3A  and R 3B  can be a hydrogen atom, and (3) R 4  is not a hydrogen atom, 
 R 5  to R 11 , R 6′  and R 7′  are the same or different (each symbol is also the same or different when each symbol exists plurally) and are a hydrogen atom or a C 1-6  alkyl optionally substituted with 1 to 5 fluorine atoms, provided that in each combination of R 6 -R 7 , R 6′ -R 7′ , R 8 -R 9 , and R 10 -R 11 , (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 6 R 7 ), and 
 n is 1 or 2. 
 
     
     
         2 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR 3A R 3B , N—CO—R 4  or CR 2E —NR 5 —COR 4 . 
     
     
         3 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein n is 1. 
     
     
         4 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein either R 3A  or R 3B  is a hydrogen atom. 
     
     
         5 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein R 2A  to R 2E  are each independently a C 1-6  alkyl optionally substituted with 1 to 5 fluorine atoms; a C 1-6  alkoxy; a hydrogen atom; or a fluorine atom. 
     
     
         6 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein R 3A , R 3B  and R 4  are each independently a C 1-10  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a 4- to 10-membered saturated heterocycle, a C 3-10  cycloalkyl, a fluorine atom, a hydroxy group, a C 1-6  alkoxy optionally substituted with 1 to 5 fluorine atoms and —NR 10 R 11 ; a C 3-10  cycloalkyl; a 4- to 10-membered saturated heterocycle; a nitrogen-containing monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle and the nitrogen-containing monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6  alkoxy and —NR 10 R 11 ), a C 1-6  alkoxy optionally substituted with a C 3-6  cycloalkyl or 1 to 5 fluorine atoms and —NR 10 R 11 , provided that (1) R 3A  and R 3B  may be taken together to form a 4- to 10-membered nitrogen-containing saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 10 R 11 ), (2) only one of R 3A  and R 3B  can be a hydrogen atom, and (3) R 4  is not a hydrogen atom. 
     
     
         7 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein R 1A  to R 1E  are each independently a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 3-6  cycloalkyl, a hydroxy group and a C 1-6  alkoxy; a C 3-8  cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl and a C 1-6  alkoxy; a C 1-6  alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group and a C 1-6  alkoxy; a hydrogen atom; a halogen; or a 4- to 10-membered saturated heterocycle optionally substituted with a C 1-6  alkyl. 
     
     
         8 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR 3A R 3B  or CR 2E —NR 5 —COR 4 . 
     
     
         9 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein A is CR 1E . 
     
     
         10 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein R 3A , R 3B  and R 4  are each independently a C 1-10  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6  alkoxy optionally substituted with 1 to 5 fluorine atoms; a C 3-10  cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6  alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6  alkoxy) and a C 1-6  alkoxy optionally substituted with 1 to 5 fluorine atoms, provided that (1) only one of R 3A  and R 3B  can be a hydrogen atom, and (2) R 4  is not a hydrogen atom. 
     
     
         11 . The compound of  claim 7  or a pharmaceutically acceptable salt thereof wherein R 1A  to R 1E  are each independently a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6  alkoxy; a C 3-8  cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6  alkyl and a C 1-6  alkoxy; a C 1-6  alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6  alkoxy; a hydrogen atom; or a halogen. 
     
     
         12 . The compound of  claim 8  or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR 3A R 3B . 
     
     
         13 . The compound of  claim 1  selected from the following compounds or a pharmaceutically acceptable salt thereof:
 N-(cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexyl)-4,4-difluorocyclohexanecarboxamide, 
 1-(4,4-difluorocyclohexyl)-3-(cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexyl)urea, and 
 cis-N-(4,4-difluorocyclohexyl)-4-(5-ethyl-1H-indazol-1-yl)cyclohexanecarboxamide. 
 
     
     
         14 . (canceled) 
     
     
         15 . A compound of Formula (I′): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 A is CR 1E ; 
 X—Y—Z is N—CO—NR 3A R 3B ; 
 R 1A  to R 1E  are each independently a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6  alkoxy; a C 3-8  cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6  alkyl and a C 1-6  alkoxy; a C 1-6  alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6  alkoxy; a hydrogen atom; or a halogen; 
 R 2A  to R 2E  are each independently a C 1-6  alkyl optionally substituted with 1 to 5 fluorine atoms; a C 1-6  alkoxy; a hydrogen atom; or a fluorine atom; 
 R 3A  and R 3B  are each independently a C 1-10  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6  alkoxy optionally substituted with 1 to 5 fluorine atoms; a C 3-10  cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6  alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6  alkoxy) and a C 1-6  alkoxy optionally substituted with 1 to 5 fluorine atoms, provided that either R 3A  or R 3B  is a hydrogen atom; and 
 n is 1. 
 
     
     
         16 . A pharmaceutical composition comprising the compound of either  claim 1  or  15  or a pharmaceutically acceptable salt thereof. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . A method for treating or preventing a nervous system disease, psychiatric disease or inflammatory disease which comprises administering a therapeutically effective amount of the compound of either  claim 1  or  15  or a pharmaceutically acceptable salt thereof to a patient in need thereof. 
     
     
         20 . A combination drug comprising the compound of either  claim 1  or  15  or a pharmaceutically acceptable salt thereof, and at least one drug selected from drugs classified as atypical antipsychotic drugs. 
     
     
         21 . A method for treating a disease due to an abnormality of the intracellular signaling mediated by acetylcholine which comprises administering a therapeutically effective amount of the compound of either  claim 1  or  15  or a pharmaceutically acceptable salt thereof to a patient in need thereof. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . A method for treating or preventing a nervous system disease, psychiatric disease or inflammatory disease which comprises administering a therapeutically effective amount of the compound of Formula (I″): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 A is CR 1E , 
 X—Y—Z is N—CO—NR 3A R 3B  or N—CO—R 4 , 
 R 1A  is a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, a C 3-6  cycloalkyl, —NR 6 R 7 , —CONR 6 R 7  and —NR 6 COR 7 ; a C 3-10  cycloalkyl or a 4- to 10-membered saturated heterocycle, wherein the cycloalkyl and the saturated heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 6 R 7 ; a C 1-6  alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, —NR 6 R 7 , —CONR 6 R 7  and —NR 6 COR 7 ; a hydrogen atom; a halogen; —NR 6 R 7 ; a cyano group; —CONR 6 R 7 ; —NR 6 COR 7 ; or —SO 2 R 6 , provided that both R 6  and R 7  are not a hydrogen atom, 
 R 1B  to R 1E  are each independently a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, a C 3-6  cycloalkyl, —NR 6′ R 7′ , —CONR 6′ R 7′  and —NR 6′ COR 7′ ; a C 3-10  cycloalkyl or a 4- to 10-membered saturated heterocycle, wherein the cycloalkyl and the saturated heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy, —NR 6′ R 7′ , —CONR 6′ R 7′  and —NR 6′ COR 7′ ; a C 1-6  alkoxy or a C 3-10  cycloalkoxy, wherein the alkoxy and the cycloalkoxy are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, —CONR 6′ R 7′  and —NR 6′ COR 7′ ; a hydrogen atom; a hydroxy group; a halogen; an aryl or a heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C 1-6  alkyl optionally substituted with 1 to 5 fluorine atoms, a C 1-6  alkoxy, —NR 6′ R 7′ , —CONR 6′ R 7′  and —NR 6′ COR 7′ ; —NR 6′ R 7′ ; a cyano group; —CONR 6′ R 7′ ; —NR 6′ COR 7′ ; or —SO 2 R 6′ , provided that both R 6′  and R 7′  are not a hydrogen atom, 
 R 2A  to R 2D  are each independently a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C 1-6  alkoxy and —NR 8 R 9 ; a hydrogen atom; a halogen; a hydroxy group; or a C 1-6  alkoxy optionally substituted with 1 to 5 fluorine atoms, or when two of R 2A  to R 2D  are a C 1-6  alkyl, they may be taken together to form a 4- to 10-membered saturated carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 8 R 9 , 
 R 3A , R 3B  and R 4  are each independently a C 1-10  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of phenyl, a monocyclic heteroaryl, a 4- to 10-membered saturated heterocycle, a C 3-10  cycloalkyl, a fluorine atom, a hydroxy group, a C 1-6  alkoxy optionally substituted with 1 to 5 fluorine atoms, and —NR 10 R 11 ; a C 3-10  cycloalkyl; a 4- to 10-membered saturated heterocycle; phenyl; a monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle, the phenyl and the monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of an aryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6  alkoxy and —NR 10 R 11 , a halogen, a hydroxy group, a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6  alkoxy and —NR 10 R 11 , a C 1-6  alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a C 3-6  cycloalkyl, a C 3-6  cycloalkyl-C 1-6  alkyl, a C 1-6  alkoxy and a fluorine atom, a C 1-6  alkylcarbonyl, and —NR 10 R 11 , provided that (1) R 3A  and R 3B  may be taken together to form a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 10 R 11 , (2) only one of R 3A  and R 3B  can be a hydrogen atom, and (3) R 4  is not a hydrogen atom, 
 R 6  to R 11 , R 6′  and R 7′  are the same or different and are a hydrogen atom or a C 1-6  alkyl optionally substituted with 1 to 5 fluorine atoms, provided that in each combination of R 6 -R 7 , R 6′ -R 7′ , R 8 -R 9 , and R 10 -R 11 , (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 6 R 7 , and 
 n is 1. 
 
     
     
         25 . The method of  claim 24  wherein the nervous system disease, the psychiatric disease or the inflammatory disease is dementia, schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit disorder or cerebral angiopathy. 
     
     
         26 . A method for treating a disease due to an abnormality of the intracellular signaling mediated by acetylcholine which comprises administering a therapeutically effective amount of the compound of Formula (I″): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein
 A is CR 1E , 
 X—Y—Z is N—CO—NR 3A R 3B  or N—CO—R 4 , 
 R 1A  is a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, a C 3-6  cycloalkyl, —NR 6 R 7 , —CONR 6 R 7  and —NR 6 COR 7 ; a C 3-10  cycloalkyl or a 4- to 10-membered saturated heterocycle, wherein the cycloalkyl and the saturated heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 6 R 7 ; a C 1-6  alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, —NR 6 R 7 , —CONR 6 R 7  and —NR 6 COR 7 ; a hydrogen atom; a halogen; —NR 6 R 7 ; a cyano group; —CONR 6 R 7 ; —NR 6 COR 7 ; or —SO 2 R 6 , provided that both R 6  and R 7  are not a hydrogen atom, 
 R 1B  to R 1E  are each independently a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, a C 3-6  cycloalkyl, —NR 6′ R 7′ , —CONR 6′ R 7′  and —NR 6′ COR 7′ ; a C 3-10  cycloalkyl or a 4- to 10-membered saturated heterocycle, wherein the cycloalkyl and the saturated heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy, —NR 6′ R 7′ , —CONR 6′ R 7′  and —NR 6′ COR 7′ ; a C 1-6  alkoxy or a C 3-10  cycloalkoxy, wherein the alkoxy and the cycloalkoxy are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkoxy, —CONR 6′ R 7′  and —NR 6′ COR 7′ ; a hydrogen atom; a hydroxy group; a halogen; an aryl or a heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C 1-6  alkyl optionally substituted with 1 to 5 fluorine atoms, a C 1-6  alkoxy, —NR 6′ R 7′ , —CONR 6′ R 7′  and —NR 6′ COR 7′ ; —NR 6′ R 7′ ; a cyano group; —CONR 6′ R 7′ ; —NR 6′ COR 7′ ; or —SO 2 R 6′ , provided that both R 6′  and R 7′  are not a hydrogen atom, 
 R 2A  to R 2D  are each independently a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C 1-6  alkoxy and —NR 8 R 9 ; a hydrogen atom; a halogen; a hydroxy group; or a C 1-6  alkoxy optionally substituted with 1 to 5 fluorine atoms, or when two of R 2A  to R 2D  are a C 1-6  alkyl, they may be taken together to form a 4- to 10-membered saturated carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 8 R 9 , 
 R 3A , R 3B  and R 4  are each independently a C 1-10  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of phenyl, a monocyclic heteroaryl, a 4- to 10-membered saturated heterocycle, a C 3-10  cycloalkyl, a fluorine atom, a hydroxy group, a C 1-6  alkoxy optionally substituted with 1 to 5 fluorine atoms, and —NR 10 R 11 ; a C 3-10  cycloalkyl; a 4- to 10-membered saturated heterocycle; phenyl; a monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle, the phenyl and the monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of an aryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6  alkoxy and —NR 10 R 11 , a halogen, a hydroxy group, a C 1-6  alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6  alkoxy and —NR 10 R 11 , a C 1-6  alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a C 3-6  cycloalkyl, a C 3-6  cycloalkyl-C 1-6  alkyl, a C 1-6  alkoxy and a fluorine atom, a C 1-6  alkylcarbonyl, and —NR 10 R 11 , provided that (1) R 3A  and R 3B  may be taken together to form a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 10 R 11 , (2) only one of R 3A  and R 3B  can be a hydrogen atom, and (3) R 4  is not a hydrogen atom, 
 R 6  to R 11 , R 6′  and R 7′  are the same or different and are a hydrogen atom or a C 1-6  alkyl optionally substituted with 1 to 5 fluorine atoms, provided that in each combination of R 6 -R 7 , R 6′ -R 7′ , R 8 -R 9 , and R 10 -R 11 , (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6  alkyl, a C 1-6  alkoxy and —NR 6 R 7 , and 
 n is 1. 
 
     
     
         27 . The method of  claim 19  wherein the nervous system disease, the psychiatric disease or the inflammatory disease is dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder or cerebral angiopathy.