Fused imidazole compounds

Abstract

The present invention provides compounds represented by formula (I), pharmaceutically acceptable salts thereof, N-oxides thereof, solvates thereof or prodrugs thereof (wherein the characters are as defined in the description). The compounds represented by formula (I) have affinity and selectivity for the gamma-aminobutyric acid A receptor subunit alpha 5 (GABA A α5) and act as GABA A α5 negative allosteric modulators (GABA A α5 NAM), so that they are useful in the prevention and/or treatment of diseases which are related to the GABA A α5 such as Alzheimer's disease.

1 . A compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein A represents CR 4  or N; 
         B represents CR 5  or N; 
         D represents CR 6  or N; 
         with the proviso that when A represents N, B must also represent N,
 Cyc 1  represents a (1) 5- to 15-membered mono-, bi- or tri-cyclic aromatic carbocyclic ring which may be partially saturated or (2) 5- to 15-membered mono-, bi- or tri-cyclic aromatic heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially saturated; 
 R 1  represents (1) 3- to 5-membered cycloalkyl wherein one carbon atom may be replaced by oxygen, which may be substituted with one or more groups independently selected from halogen and C1-4 alkyl which may be substituted with halogen or (2) C1-4 alkyl which may be substituted with halogen; 
 R 2  represents hydrogen or C1-4 alkyl; 
 R 3  represents (1) oxo, (2) halogen, (3) cyano, (4) hydroxy, (5) C1-6 alkyl which may be substituted with R 7 , (6) C1-6 alkoxy which may be substituted with R 7 , (7) 3- to 5-membered cycloalkyl wherein one carbon atom may be replaced by oxygen, which may be substituted with R 8 , (8) 5- to 12-membered mono- or bi-cyclic aromatic carbocyclic ring which may be partially or fully saturated and may be substituted with R 8  or (9) 5- to 12-membered mono- or bi-cyclic aromatic heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially or fully saturated and may be substituted with R 8 ; 
 R 4  represents hydrogen or halogen; 
 R 5  represents (1) hydrogen, (2) halogen, (3) hydroxy, (4) cyano, (5) C1-6 alkyl which may be substituted with R 9 , (6) C2-6 alkenyl which may be substituted with R 9 , (7) C1-6 alkoxy which may be substituted with R 9 , (8) C1-6 alkyl-carbonyl which may be substituted with R 9  or (9) 3- to 5-membered cycloalkyl wherein one carbon atom may be replaced by oxygen, which may be substituted with R 9 ; 
 R 6  represents hydrogen, halogen or C1-4 alkyl which may be substituted with halogen;
 R 7  represents (1) halogen, (2) hydroxy, (3) C1-4 alkoxy or (4)3- to 5-membered cycloalkyl wherein one carbon atom may be replaced by oxygen, which may be substituted with one or more groups independently selected from halogen and hydroxy; 
 R 8  represents (1) oxo, (2) halogen, (3) cyano, (4) hydroxy, (5) C1-6 alkyl which may be substituted with one or more groups independently selected from halogen and hydroxy or (6) 3- to 5-membered cycloalkyl which may be substituted with one or more groups independently selected from halogen and hydroxy; 
 R 9  represents halogen or hydroxy; 
 n represents an integer of 0 to 2; and 
 m represents an integer of 0 to 7, wherein when m represents an integer of 2 to 7, each R 3  may be same or different; 
 with the proviso that when A is CH, B is N, D is CH, n is 1, R 1  is cyclopropyl and R 2  is hydrogen, then Cyc 1  is not benzene, pyridine, pyrazole or benzodioxole; 
 with the proviso that (a) the compound represented by formula (I), wherein D is CH, and (1) R 1  is C1-4 alkyl which may be substituted with halogen or (2) n is 0 and R 1  is cycloalkyl, (b) (9-isopropyl-6-methyl-9H-purin-2-yl)-(5-piperazin-1-yl-pyridin-2-yl)-amine, (c) 9-butyl-6-chloro-N-(6-ethoxypyridin-3-yl)-9H-purin-2-amine, (d) 4-[(6-chloro-9-methyl-9H-purin-2-yl)amino]benzonitrile, (e) 6-chloro-9-(oxiran-2-ylmethyl)-N-phenyl-9H-purin-2-amine and (f) 6-chloro-9-(propan-2-yl)-N-(pyridin-4-yl)-9H-purin-2-amine are excluded, 
 or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. 
 
 
       
     
     
         2 . The compound according to  claim 1 , which is a compound represented by formula (I-A): 
       
         
           
           
               
               
           
         
         a compound represented by formula (I-C): 
       
       
         
           
           
               
               
           
         
         or a compound represented by formula (I-E): 
       
       
         
           
           
               
               
           
         
         wherein all the symbols have the same meanings as described in  claim 1 . 
       
     
     
         3 . The compound according to  claim 2 , which is a compound represented by formula (I-A), (I-C) or (I-E), wherein R 6  represents halogen or C1-4 alkyl which may be substituted with halogen. 
     
     
         4 . The compound according to  claim 1 , wherein R 1  represents cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, n-propyl or isopropyl, any of which may be substituted with 1 to 3 halogen. 
     
     
         5 . The compound according to  claim 1 , wherein n represents 0 or 1. 
     
     
         6 . The compound according to  claim 1 , wherein R 2  represents hydrogen. 
     
     
         7 . The compound according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
         wherein E 1 , E 2  and E 4  each independently represent a carbon atom or a nitrogen atom, with the proviso that at least two of E 1 , E 2  and E 4  are carbon atoms; 
         R 3a  represents (1) hydrogen, (2) C1-4 alkyl which may be substituted with 1 to 3 groups selected from halogen, hydroxy and methoxy or (3) —(CH 2 ) p -(3- to 5-membered cycloalkyl), wherein one carbon atom in cycloalkyl may be replaced by oxygen and p represents 0 or 1; 
         R 3b  and R 3c  each independently represent (1) hydrogen, (2) halogen or (3) C1-4 alkyl; 
         R 3d  represents halogen or C1-4 alkyl; 
         md represents an integer of 0 to 2, wherein when md represents 2, each R 3d  may be same or different; 
         monocyclic 1  represents (1) 5- to 7-membered mono-cyclic aromatic carbocyclic ring which may be partially saturated or (2) 5- to 7-membered mono-cyclic aromatic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially saturated; 
         Cyc 2  represents (1) 5- to 6-membered mono-cyclic aromatic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially or fully saturated and may be substituted with 1 to 3 groups selected from oxo, halogen, cyano, hydroxy and C1-4 alkyl which may be substituted with 1 to 3 groups selected from halogen and hydroxy or (2) 8- to 12-membered bicyclic aromatic heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially or fully saturated and may be substituted with 1 to 5 groups selected from oxo, halogen, cyano, hydroxy and C1-4 alkyl which may be substituted with 1 to 3 groups selected from halogen and hydroxyl; 
         R 3-6  represents halogen or C1-4 alkyl which may be substituted with 1 to 3 halogen; 
         m-6 represents 0 to 2; wherein when m-6 represents 2, each R 3-6  may be same or different and 
         the arrow represents a binding position to the N(R 2 ). 
       
     
     
         8 . The compound according to  claim 1 , wherein a compound represented by formula (IV): 
       
         
           
           
               
               
           
         
         wherein A represents CR 4  or N; B represents CR 5  or N; 
         with the proviso that when A represents N, B must also represent N, 
         R 1  represents cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, n-propyl or isopropyl, any of which may be substituted with 1 to 3 halogen; 
         R 4  represents hydrogen or halogen; 
         R 5  represents (1) hydrogen, (2) halogen, (3) hydroxy, (4) cyano, (5) C1-4 alkyl which may be substituted with 1 to 3 groups selected from halogen and hydroxy, (6) C2-4 alkenyl which may be substituted with 1 to 3 groups selected from halogen and hydroxy, (7) C1-4 alkoxy which may be substituted with 1 to 3 groups selected from halogen and hydroxy, (8) C1-4 alkyl-carbonyl which may be substituted with 1 to 3 groups selected from halogen and hydroxy or (9) 3- to 5-membered cycloalkyl wherein one carbon atom may be replaced by oxygen, which may be substituted with 1 to 3 groups selected from halogen and hydroxyl; 
         R 6  represents halogen or methyl which may be substituted with halogen; 
         n represents 0 or 1; 
       
       
         
           
           
               
               
           
         
         wherein E 1 , E 2  and E 4  each independently represent a carbon atom or a nitrogen atom, with the proviso that at least two of E 1 , E 2  and E 4  are carbon atoms; 
         R 3a  represents (1) hydrogen, (2) C1-4 alkyl which may be substituted with 1 to 3 groups selected from halogen, hydroxy and methoxy or (3) —(CH 2  1-(3- to 5-membered cycloalkyl), wherein one carbon atom in cycloalkyl may be replaced by oxygen and p represents 0 or 1; 
         R 3b  and R 3c  each independently represent (1) hydrogen, (2) halogen or (3) C1-4 alkyl; 
         R 3d  represents halogen or C1-4 alkyl; 
         md represents an integer of 0 to 2, wherein when md represents 2, each R 3d  may be same or different; 
         monocyclic 1  represents (1) 5- to 7-membered mono-cyclic aromatic carbocyclic ring which may be partially saturated or (2) 5- to 7-membered mono-cyclic aromatic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially saturated; 
         Cyc 2  represents (1) 5- to 6-membered mono-cyclic aromatic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially or fully saturated and may be substituted with 1 to 3 groups selected from oxo, halogen, cyano, hydroxy and C1-4 alkyl which may be substituted with 1 to 3 groups selected from halogen and hydroxy or (2) 8- to 12-membered bicyclic aromatic heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially or fully saturated and may be substituted with 1 to 5 groups selected from oxo, halogen, cyano, hydroxy and C1-4 alkyl which may be substituted with 1 to 3 groups selected from halogen and hydroxyl; 
         R 3-6  represents halogen or C1-4 alkyl which may be substituted with 1 to 3 halogen; 
         m-6 represents 0 to 2; wherein when m-6 represents 2, each R 3-6  may be same or different; and 
         the arrow represents a binding position to the N(R 2 ). 
       
     
     
         9 . The compound according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
         wherein E 1 , E 2  and E 4  each independently represent a carbon atom or a nitrogen atom, with the proviso that at least two of E 1 , E 2  and E 4  are carbon atoms; 
         R 3a  represents (1) hydrogen, (2) C1-4 alkyl which may be substituted with 1 to 3 groups selected from halogen, hydroxy and methoxy or (3) —(CH 2 ) p -(3- to 5-membered cycloalkyl), wherein one carbon atom in cycloalkyl may be replaced by oxygen and p represents 0 or 1; 
         R 3b  and R 3c  each independently represent (1) hydrogen, (2) halogen or (3) C1-4 alkyl; 
         R 3d  represents halogen or C1-4 alkyl; 
         md represents an integer of 0 to 2, wherein when md represents 2, each R 3d  may be same or different; 
         monocyclic 1  represents (1) 5- to 7-membered mono-cyclic aromatic carbocyclic ring which may be partially saturated or (2) 5- to 7-membered mono-cyclic aromatic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially saturated; and 
         the arrow represents a binding position to the N(R 2 ). 
       
     
     
         10 . The compound according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
         wherein monocyclic 1  represents (1) 5- to 7-membered mono-cyclic aromatic carbocyclic ring which may be partially saturated or (2) 5- to 7-membered mono-cyclic aromatic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially saturated; 
         Cyc 2  represents (1) 5- to 6-membered mono-cyclic aromatic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially or fully saturated and may be substituted with 1 to 3 groups selected from oxo, halogen, cyano, hydroxy and C1-4 alkyl which may be substituted with 1 to 3 groups selected from halogen and hydroxy or (2) 8- to 12-membered bicyclic aromatic heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially or fully saturated and may be substituted with 1 to 5 groups selected from oxo, halogen, cyano, hydroxy and C1-4 alkyl which may be substituted with 1 to 3 groups selected from halogen and hydroxyl; 
         R 3-6  represents halogen or C1-4 alkyl which may be substituted with 1 to 3 halogen; 
         m-6 represents 0 to 2; wherein when m-6 represents 2, each R 3-6  may be same or different; and 
         the arrow represents a binding position to the N(R 2 ). 
       
     
     
         11 . The compound according to  claim 7 , wherein monocyclic 1  represents 6-membered mono-cyclic aromatic ring having 0 to 2 nitrogen atom and Cyc 2  represents nitrogen-containing 5- to 6-membered mono-cyclic aromatic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be substituted with 1 to 3 groups selected from halogen, cyano, hydroxy and C1-4 alkyl which may be substituted with 1 to 3 groups selected from halogen and hydroxy. 
     
     
         12 . The compound according to  claim 7 , wherein monocyclic 1  represents benzene or pyridine. 
     
     
         13 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of
 (1) 4-Cyclopropyl-7-((1-(cyclopropylmethyl)-1H-imidazo[4,5-c]pyridin-6-yl)amino)-2H-benzo[b][1,4]oxazin-3 (4H)-one,   (4) 7-((9-(Cyclopropylmethyl)-9H-purin-2-yl)amino)-4-(2-methoxyethyl)-2H-benzo[b][1,4]oxazin-3 (4H)-one,   (5) 7-((1-((3,3-Difluorocyclobutyl)methyl)-5-fluoro-1H-benzo[d]imidazol-6-yl)amino)-4-methyl-2H-pyrido[3,2-b][1,4]oxazin-3 (4H)-one,   (6) 6-((1-((3,3-Difluorocyclobutyl)methyl)-4-methyl-1H-imidazo[4,5-c]pyridin-6-yl)amino)-3-methylbenzo[d]oxazol-2(3H)-one,   (7) 7-((1-(2-Cyclopropylethyl)-5-fluoro-1H-benzo[d]imidazol-6-yl)amino)-4-methyl-2H-pyrido[3,2-b][1,4]oxazin-3 (4H)-one,   (8) 7-((1-(Cyclopropylmethyl)-5-fluoro-4-methyl-1H-benzo[d]imidazol-6-yl)amino)-4-methyl-2H-pyrido[3,2-b][1,4]oxazin-3 (4H)-one,   (9) 7-((1-(Cyclopropylmethyl)-5-fluoro-4-methyl-1H-benzo[d]imidazol-6-yl)amino)-4-methyl-2H-pyrido[4,3-b][1,4]oxazin-3 (4H)-one,   (10) N-(6-(1H-Imidazol-1-yl)pyridin-3-yl)-1-(cyclopropylmethyl)-5-fluoro-4-methyl-1H-benzo[d]imidazol-6-amine,   (11) 1-(Cyclopropylmethyl)-4,5-difluoro-N-(3-fluoro-4-(1H-imidazol-1-yl)phenyl)-1H-benzo[d]imidazol-6-amine,   (13) 7-((1-(Cyclopropylmethyl)-4-methyl-1H-imidazo[4,5-c]pyridin-6-yl)amino)-4-methyl-2H-benzo[b][1,4]oxazin-3 (4H)-one,   (14) 7-((1-Butyl-4-methyl-1H-imidazo[4,5-c]pyridin-6-yl)amino)-4-methyl-2H-benzo[b][1,4]oxazin-3 (4H)-one,   (15) 7-((1-(Cyclopropylmethyl)-4-methyl-1H-imidazo[4,5-c]pyridin-6-yl)amino)-4-methyl-2H-pyrido[3,2-b][1,4]oxazin-3 (4H)-one,   (16) 6-((1-(Cyclopropylmethyl)-4-methyl-1H-imidazo[4,5-c]pyridin-6-yl)amino)-1-methyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one,   (17) 7-((9-(Cyclopropylmethyl)-6-methyl-9H-purin-2-yl)amino)-4-ethyl-2H-benzo[b][1,4]oxazin-3 (4H)-one,   
     
     
         14 . A gamma-aminobutyric acid A receptor subunit alpha 5 (GABA A  α5) negative allosteric modulator comprising the compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein A represents CR 4  or N; 
         B represents CR 5  or N; 
         D represents CR 6  or N; 
         with the proviso that when A represents N, B must also represent N,
 Cyc 1  represents a (1) 5- to 15-membered mono-, bi- or tri-cyclic aromatic carbocyclic ring which may be partially saturated or (2) 5- to 15-membered mono-, bi- or tri-cyclic aromatic heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially saturated; 
 R 1  represents (1) 3- to 5-membered cycloalkyl wherein one carbon atom may be replaced by oxygen, which may be substituted with one or more groups independently selected from halogen and C1-4 alkyl which may be substituted with halogen or (2) C1-4 alkyl which may be substituted with halogen; 
 R 2  represents hydrogen or C1-4 alkyl; 
 R 3  represents (1) oxo, (2) halogen, (3) cyano, (4) hydroxy, (5) C1-6 alkyl which may be substituted with R 7 , (6) C1-6 alkoxy which may be substituted with R 7 , (7) 3- to 5-membered cycloalkyl wherein one carbon atom may be replaced by oxygen, which may be substituted with R 8 , (8) 5- to 12-membered mono- or bi-cyclic aromatic carbocyclic ring which may be partially or fully saturated and may be substituted with R 8  or (9) 5- to 12-membered mono- or bi-cyclic aromatic heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, which may be partially or fully saturated and may be substituted with R 8 ; 
 
         R 4  represents hydrogen or halogen; 
         R 5  represents (1) hydrogen, (2) halogen, (3) hydroxy, (4) cyano, (5) C1-6 alkyl which may be substituted with R 9 , (6) C2-6 alkenyl which may be substituted with R 9 , (7) C1-6 alkoxy which may be substituted with R 9 , (8) C1-6 alkyl-carbonyl which may be substituted with R 9  or (9) 3- to 5-membered cycloalkyl wherein one carbon atom may be replaced by oxygen, which may be substituted with R 9 ; 
         R 6  represents hydrogen, halogen or C1-4 alkyl which may be substituted with halogen;
 R 7  represents (1) halogen, (2) hydroxy, (3) C1-4 alkoxy or (4)3- to 5-membered cycloalkyl wherein one carbon atom may be replaced by oxygen, which may be substituted with one or more groups independently selected from halogen and hydroxy; 
 R 8  represents (1) oxo, (2) halogen, (3) cyano, (4) hydroxy, (5) C1-6 alkyl which may be substituted with one or more groups independently selected from halogen and hydroxy or (6) 3- to 5-membered cycloalkyl which may be substituted with one or more groups independently selected from halogen and hydroxy; 
 R 9  represents halogen or hydroxy; 
 n represents an integer of 0 to 2; and 
 m represents an integer of 0 to 7, wherein when m represents an integer of 2 to 7, each R 3  may be same or different; 
 with the proviso that when A is CH, B is N, D is CH, n is 1, R 1  is cyclopropyl and R 2  is hydrogen, then Cyc 1  is not benzene, pyridine, pyrazole or benzodioxole, 
 a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, as an active ingredient. 
 
       
     
     
         15 . A pharmaceutical composition comprising the compound according to  claim 1 , a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof as an active ingredient. 
     
     
         16 . The pharmaceutical composition according to  claim 15 , which is a GABA A  α5 negative allosteric modulator. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , which is an agent for the prevention and/or treatment of a disease which is related to the GABA A  α5. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the disease which is related to the GABA A  α5 is acute and/or chronic neurological disorders; cognitive disorders; Alzheimer's disease; memory deficits; mild cognitive impairment (MCI); schizophrenia; positive, negative and/or cognitive symptoms associated with schizophrenia; bipolar disorders; autism; Down syndrome; neurofibromatosis type I; sleep disorders; disorders of circadian rhythms; amyotrophic lateral sclerosis (ALS); dementia caused by AIDS; head trauma; Huntington's disease; Pick's disease; Creutzfeld Jakob disease; psychotic disorders; substance-induced psychotic disorder; anxiety disorders; generalized anxiety disorder; panic disorder; delusional disorder; obsessive/compulsive disorders; acute stress disorder; drug addictions; movement disorders; Parkinson's disease; restless leg syndrome; cognition deficiency disorders; multi-infarct dementia; mood disorders; depression; neuropsychiatric conditions; psychosis; attention-deficit/hyperactivity disorder; neuropathic pain; stroke; multiple sclerosis (MS); acute meningitis; alcoholism; Fetal Alcohol Syndrome; attentional disorders; CNS conditions occurring after stroke; or need for cognition enhancement. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein the disease which is related to the GABA A  α5 is Alzheimer's disease, schizophrenia, Down syndrome or CNS conditions occurring after stroke. 
     
     
         20 . A medicament comprising a combination of the compound according to  claim 1 , a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof with a acetylcholinesterase inhibitor and/or N-methyl-D-aspartate (NMDA) receptor antagonist. 
     
     
         21 . A method of preventing and/or treating a disease which is related to the GABA A  α5 comprising administering an effective amount of the compound according to  claim 1 , a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof to a mammal. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled)