Difluoromethyl-phenyl triazoles

Abstract

The present invention relates to difluoromethyl-phenyl triazoles of general formula (1) which are modulators of GABAA receptors containing the α5 subunit, useful in treating central nervous system diseases and other diseases. In addition, the invention relates to processes for preparing pharmaceutical compositions as well as processes for manufacture the compounds according to the invention.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group R 1a  consisting of
 heteroaryl,
 wherein the heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-5 -alkyl-, C 1-5 -alkyl-O—, C 1-5 -alkyl-C(O)—, C 1-5 -alkyl-O—C(O)—, H(O)C—, HOOC—, C 3-6 -cycloalkyl-, (R 3 ) 2 N—, (R 3 ) 2 N—C 1-5 -alkyl-, (R 3 ) 3 N + —C 1-5 -alkyl-, (R 3 ) 2 N—C(O)—, NC—, HO—, oxo, C 1-5 -alkyl-S(O)—, C 1-5 -alkyl-S(O) 2 —, halogen and imidazolyl, and
 wherein the above mentioned C 1-5 -alkyl-, C 1-5 -alkyl-O—, C 1-5 -alkyl-C(O)—, C 1-5 -alkyl-O—C(O)—, C 3-6 -cycloalkyl-, (R 3 ) 2 N—, (R 3 ) 2 N—C 1-5 -alkyl-, (R 3 ) 3 N + —C 1-5 -alkyl-, (R 3 ) 2 N—C(O)—, C 1-5 -alkyl-S(O)—, C 1-5 -alkyl-S(O) 2 — and imidazolyl groups are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, halogen, NC—, and HO—, and 
 
 wherein the heteroaryl group is a mono- or bicyclic-ring system containing one to three heteroatoms selected from N, O or S(O) r , wherein r=0, 1 or 2, consisting of 5 to 10 ring atoms wherein at least one of the heteroatoms is part of an aromatic ring; 
 
 
 R 2  is selected from the group R 2  consisting of
 H—, halogen and C 1-3 -alkyl-,
 wherein the above mentioned C 1-3 -alkyl-groups may optionally be substituted with 1 to 7 substituents independently from each other selected from the group consisting of halogen, NC—, and HO—; 
 
 
 R 3  is selected from the group R 3  consisting of
 H— and C 1-3 -alkyl-,
 wherein the above mentioned C 1-3 -alkyl-groups may optionally be substituted with 1 to 7 substituents independently from each other selected from the group consisting of halogen, NC—, and HO—; 
 
 
 
       or a salt thereof. 
     
     
         2 . A compound according to  claim 1 , wherein
 R 1  is selected from the group R 1b  consisting of
 an aromatic monocyclic ring consisting of 5 or 6 ring atoms containing one to three heteroatoms selected from N and O,
 wherein the above mentioned aromatic monocyclic ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-5 -alkyl-, C 1-5 -alkyl-O—, C 1-5 -alkyl-C(O)—, C 1-5 -alkyl-O—C(O)—, H(O)C—, HOOC—, C 3-6 -cycloalkyl-, (R 3 ) 2 N—, (R 3 ) 2 N—C 1-5 -alkyl-, (R 3 ) 2 N—C(O)—, NC—, HO—, oxo, C 1-5 -alkyl-S(O)—, C 1-5 -alkyl-S(O) 2 —, halogen and imidazolyl, and
 wherein the above mentioned C 1-5 -alkyl-, C 1-5 -alkyl-O—, C 1-5 -alkyl-C(O)—, C 1-5 -alkyl-O—C(O)—, C 3-6 -cycloalkyl-, (R 3 ) 2 N—, (R 3 ) 2 N—C 1-5 -alkyl-, (R 3 ) 2 N—C(O)—, C 1-5 -alkyl-S(O)—, C 1-5 -alkyl-S(O) 2 — and imidazolyl groups are optionally substituted with 1 to 5 substituents independently selected from the group consisting of oxo, halogen, NC—, and HO—; 
 
 
   
       or a salt thereof. 
     
     
         3 . A compound according to  claim 1 , wherein
 R 1  is selected from the group R 1c  consisting of
 an aromatic monocyclic ring system containing one to three heteroatoms selected from N, O consisting of 5 to 6 ring atoms,
 wherein the aromatic monocyclic ring system is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-5 -alkyl-, C 1-5 -alkyl-O—, C 3-6 -cycloalkyl-, (R 3 ) 2 N—C(O)—, NC— and halogen, and
 wherein the above mentioned C 1-5 -alkyl-, C 1-5 -alkyl-O—, C 3-6 -cycloalkyl- and (R 3 ) 2 N—C(O)-groups are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen and NC—; 
 
 
   
       or a salt thereof. 
     
     
         4 . A compound according to  claim 1 , wherein
 R 1  is selected from the group R 1d  consisting of   
       
         
           
           
               
               
           
         
         
           wherein the above aromatic monocyclic ring system is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-5 -alkyl-, C 1-5 -alkyl-O—, C 3-6 -cycloalkyl-, (R 3 ) 2 N—C(O)—, NC— and halogen, and
 wherein the above mentioned C 1-5 -alkyl-, C 1-5 -alkyl-O—, C 3-6 -cycloalkyl- and (R 3 ) 2 N—C(O)-groups are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen and NC—; 
 
         
       
       or a salt thereof. 
     
     
         5 . A compound according to any one or more of the  claims 1  to  4 , wherein
 R 2  is selected from the group R 2  consisting of
 C 1-3 -alkyl-,
 wherein the above mentioned C 1-3 -alkyl-group may optionally be substituted with 1 to 7 substituents independently from each other selected from the group consisting of halogen, NC—, and HO—; 
 
 
 
       or a salt thereof. 
     
     
         6 . A compound according to any one or more of the  claims 1  to  5 , wherein
 R 3  is selected from the group R 3  consisting of
 H— and H 3 C—; 
 
 
       or a salt thereof. 
     
     
         7 . A compound selected from the group consisting of 
       
         
           
                 
               
                     
                 
                   Structure 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         8 . A pharmaceutically acceptable salt of the compound of  claim 7 . 
     
     
         9 . A compound according to any one or more of  claims 1  to  7 , or a pharmaceutically acceptable salt thereof for use as a medicament. 
     
     
         10 . A pharmaceutical composition comprising at least one compound according to one or more of the  claims 1  to  7 , or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers. 
     
     
         11 . A method of treating or preventing a disease or condition in a subject comprising administering to the subject a compound according to one or more of  claims 1  to  7 , or a pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from the group consisting of acute neurological disorders, chronic neurological disorders, cognitive disorders, Alzheimer's disease, memory deficits, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, bipolar disorders, autism, Down syndrome, neurofibromatosis type I, post operative cognitive decline, sleep disorders, disorders of circadian rhythms, amyotrophic lateral sclerosis, dementia caused by AIDS, 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, major depressive disorder, neuropsychiatric conditions, psychosis, attention-deficit hyperactivity disorder, neuropathic pain, stroke, attentional disorders, eating disorders, anorexia, anorexia nervosa, cachexia, weight loss, muscle atrophy, pain conditions, chronic pain, nociceptive pain, post-operative pain, osteoarthritis pain, rheumatoid arthritis pain, musculoskeletal pain, burn pain, ocular pain, pain due to inflammation, pain due to bone fracture, hyperalgesia, neuropathic pain, herpes-related pain, HIV-related neuropathic pain, traumatic nerve injury, recovery after traumatic brain injury, post-stroke pain, post-ischemia pain, fibromyalgia, chronic headache, migraine, tension-type headache, diabetic neuropathic pain, phantom limb pain, visceral pain, and cutaneous pain. 
     
     
         12 . A method of treating or preventing a disease or condition in a subject comprising administering to the subject a compound according to one or more of  claims 1  to  7 , or a pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from the group consisting of cognitive disorders, post operative cognitive decline, Alzheimer's disease, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, cognitive deficits associated with Down syndrome, cognitive deficits associated with autism, cognitive deficits associated with neurofibromatosis type I, and cognitive deficits after stroke.