Pyrazolopyrimidines for treating CNS disorders

Abstract

Substituted pyrazolopyrimidine derivatives of formula (I) wherein Y 1 , Y 2 , Y 3 , Y 4 represent N or C—, whereby at least two of the groups Y 1 to Y 4 represent a carbon atom, R 1 represents chloro or bromo, R 2 to R7 represent e.g. hydrogen, methyl or ethyl; and R 10 and R 11 independently represent e.g. hydrogen or C 1 -C 6 alkyl, are potent mGluR5 modulators and are useful for the prevention of acute and chronic neurological disorders.

1 . A method for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission or a method for modulating mGluR5 receptors to achieve therapeutic benefit, in a subject in need thereof comprising administering a therapeutically effective amount of a compound selected from those of formula (I): 
       
         
           
           
               
               
           
         
         wherein, 
         Y 1  represents N or C—, 
         Y 2  represents N or C—, 
         Y 3  represents N or C—, and 
         Y 4  represents N or C—, 
         wherein at least two of the groups Y 1  to Y 4  represent a carbon atom; 
         R 1  represents chloro or bromo; 
         R 2  and R 3  each independently represent hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or trifluoromethyl; or 
         R 2  and R 3  both together with the carbon atom of the ring represent a carbonyl group; 
         R 4  and R 5  each independently represent hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or trifluoromethyl; or 
         R 4  and R 5  both together with the carbon atom of the ring represent a carbonyl group; 
         R 6  and R 7  independently represent hydrogen, C 1-6 -alkyl, C 3-7 cycloalkyl or trifluoromethyl; or 
         R 6  and R 7  both together with the carbon atom of the ring represent a carbonyl group; 
         R 2  or R 3  together with R 6  and R 7  may also form a bivalent radical selected from the group CH 2 —CH 2  and CH 2 —O; 
         R 10  and R 11  independently represent hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, aryl, C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-7 -cycloalkyloxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, heterocyclyloxy, C 1-6 alkylamino, di-C 1-6 alkylamino, C 3-7 -cycloalkylamino, di-C 3-7 -cycloalkylamino, C 1-6 alkyl-C 3-7 -cycloalkylamino, C 2-6 alkenylamino, C 2-6 alkynylamino, di-C 2-6 alkenylamino, di-C 2-6 alkynylamino, C 1-6 alkyl-C 2-6 -alkenylamino, C 1-6 alkyl-C 2-6 -alkynylamino, C 2-6 alkenyl-C 3-7 -cycloalkylamino, C 2-6 alkynyl-C 3-7 -cycloalkylamino, C 2-6 alkenyl-C 2-6 -alkynylamino, arylamino, diarylamino, aryl-C 1-6 alkylamino, aryl-C 2-6 alkenylamino, aryl-C 2-6 alkynylamino, aryl-C 3-7 -cycloalkylamino, heteroarylamino, diheteroarylamino, heteroaryl-C 1-6 alkylamino, heteroaryl-C 2-6 alkenylamino, heteroaryl-C 2-6 alkynylamino, heteroaryl-C 3-7 -cycloalkylamino, heteroarylarylamino, heterocyclylamino, diheterocyclylamino, heterocyclyl-C 1-6 alkylamino, heterocyclyl-C 2-6 alkenylamino, heterocyclyl-C 2-6 alkynylamino, heterocyclyl-C 3-7 -cycloalkylamino, heterocyclylarylamino, heterocyclylhetero-arylamino, acyl, acyloxy, acylamino, C 1-6 alkoxycarbonyl, C 3-7 -cycloalkoxy-carbonyl, C 2-6 alkenyloxycarbonyl, C 2-6 alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, aminocarbonyl, C 1-6 alkylamino-carbonyl, di-C 1-6 alkylaminocarbonyl, C 3-7 -cycloalkylaminocarbonyl, di-C 3-7 -cycloalkylaminocarbonyl, C 1-6 alkyl-C 3-7 -cycloalkylaminocarbonyl, C 2-6 alkenyl-aminocarbonyl, C 2-6 alkynylaminocarbonyl, di-C 2-6 alkenylaminocarbonyl, di-C 2-6 alkynylaminocarbonyl, C 1-6 alkyl-C 2-6 -alkenyl aminocarbonyl, C 1-6 alkyl-C 2-6 -alkynyl-aminocarbonyl, C 2-6 alkenyl-C 3-7 -cycloalkylaminocarbonyl, C 2-6 alkynyl-C 3-7 -cycloalkylaminocarbonyl, C 2-6 alkenyl-C 2-6 -alkynylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aryl-C 1-6 alkylaminocarbonyl, aryl-C 2-6 alkenylaminocarbonyl, aryl-C 2-6 alkynylaminocarbonyl, aryl-C 3-7 -cycloalkylaminocarbonyl heteroarylaminocarbonyl, diheteroarylaminocarbonyl, heteroaryl-C 1-6 alkylaminocarbonyl, heteroaryl-C 2-6 alkenylaminocarbonyl, heteroaryl-C 2-6 alkynylaminocarbonyl, heteroaryl-C 3-7 -cycloalkylaminocarbonyl, heteroarylarylaminocarbonyl, heterocyclylaminocarbonyl, diheterocyclylamino-carbonyl, heterocyclyl-C 1-6 alkylaminocarbonyl, heterocyclyl-C 2-6 alkenylamino-carbonyl, heterocyclyl-C 2-6 alkynylaminocarbonyl, heterocyclyl-C 3-7 -cycloalkyl-aminocarbonyl, heterocyclylarylaminocarbonyl, heterocyclylheteroarylamino-carbonyl, C 1-6 alkylsulfinyl, C 3-7 -cycloalkylsulfinyl, C 2-6 alkenylsulfinyl, C 2-6 alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclylsulfinyl, C 1-6 alkylsulfonyl, C 3-7 -cycloalkylsulfonyl, C 2-6 alkenylsulfonyl, C 2-6 alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclylsulfonyl, C 1-6 alkylsulfonylamino, or arylsulfonylamino; 
         or R 10  and R 11  together with the two carbon atoms carrying them represent a heteroaryl having 5 or 6 ring members or a heterocyclyl group having 5 or 6 ring members, which can be substituted by one of the following groups: halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C 1-6 alkoxy; 
       
       and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. 
     
     
         2 . The method of  claim 1 , wherein the condition associated with abnormal glutamate transmission, or wherein modulation of mGluR5 receptors results in therapeutic benefit is selected from: Alzheimer's disease, Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), systemic lupus erythematosus, systemic clerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson's disease, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injuries, head or brain or spinal cord trauma, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear insult, inner ear insult in tinnitus, tinnitus, sound- or drug-induced inner ear insult, sound- or drug-induced tinnitus, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, torticollis spasmodicus, blepharospasm, focal and generalized dystonia, nystagmus, hereditary cerebellar ataxias, corticobasal degeneration, tremor, essential tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, fragile-X syndrome, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, diabetic neuropathic pain (DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux-related asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or delirium; inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS; neoplasia, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal carcinoma, rhabdomyosarcoma, brain tumour, tumour of a nerve tissue, glioma, malignant glioma, astroglioma, neuroglioma, neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial neoplasm, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, and other tumours. 
     
     
         3 . The method of  claim 1 , wherein the condition associated with abnormal glutamate transmission, or wherein modulation of mGluR5 receptors results in therapeutic benefit is selected from: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, Huntington's chorea, epilepsy, Alzheimer's disease, positive and negative symptoms of schizophrenia, cognitive impairment, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), migraine, irritable bowel syndrome (IBS), cognitive enhancement and neuroprotection. 
     
     
         4 . The method of  claim 1 , wherein the condition associated with abnormal glutamate transmission, or wherein modulation of mGluR5 receptors results in therapeutic benefit is selected from: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, migraine, irritable bowel syndrome (IBS), functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Huntington's chorea and epilepsy. 
     
     
         5 . The method of  claim 1 , wherein the condition associated with abnormal glutamate transmission, or wherein modulation of mGluR5 receptors results in therapeutic benefit is selected from: Alzheimer's disease, positive and/or negative symptoms of schizophrenia, cognitive impairment, cognitive enhancement and neuroprotection. 
     
     
         6 . The method of  claim 1 , wherein the condition associated with abnormal glutamate transmission, or wherein modulation of mGluR5 receptors results in therapeutic benefit, is a binge eating disorder. 
     
     
         7 . The method of  claim 1 , wherein R 10  and R 11  independently represent hydrogen, halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, cyclohexyl, phenyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrazolyl, benzofuryl, benzothienyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl or isoquinolinyl. 
     
     
         8 . The method of  claim 1 , wherein R 10  and R 11  independently represent hydrogen, halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, cyclohexyl, phenyl, thienyl, pyrrolyl, furanyl, pyrazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl or morpholino. 
     
     
         9 . The method of  claim 1 , wherein one of R 2  and R 3  represents methyl, ethyl or trifluoromethyl and the remaining of R 2  and R 3  represents hydrogen. 
     
     
         10 . The method of  claim 1 , wherein R 2 , R 3 , R 4  and R 5  independently represent hydrogen, methyl, ethyl or trifluoromethyl; and
 R 6  and R 7  independently represent hydrogen or methyl.   
     
     
         11 . The method of  claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 6  and R 7  independently represent hydrogen, methyl or ethyl. 
     
     
         12 . The method of  claim 1 , wherein R 2  and R 3  independently represent hydrogen, methyl or ethyl. 
     
     
         13 . The method of  claim 1 , wherein R 2  represents methyl or ethyl and R 3  represents hydrogen and which has at least one chiral carbon atom. 
     
     
         14 . The method of  claim 1 , wherein R 2  represents methyl or ethyl and R 3 , R 4 , R 5 , R 6  and R 7  represent hydrogen and which has at least one chiral carbon atom in the R-configuration. 
     
     
         15 . The method of  claim 1 , wherein R 2  represents methyl or ethyl and R 3 , R 4 , R 5 , R 6  and R 7  represent hydrogen and which has at least one chiral carbon atom in the S-configuration. 
     
     
         16 . The method of  claim 1 , wherein Y 1 , Y 2 , Y 3  and Y 4  all represent a carbon atom. 
     
     
         17 . The method of  claim 1 , wherein R 1  represents chloro. 
     
     
         18 . The method of  claim 1 , wherein R 1  represents bromo. 
     
     
         19 . The method of  claim 1 , wherein R 4 , R 5 , R 6  and R 7  represent hydrogen. 
     
     
         20 . The method of  claim 1 , wherein three of the groups Y 1 , Y 2 , Y 3  and Y 4  represent a carbon atom and one of the groups Y 1 , Y 2 , Y 3  and Y 4  represents N. 
     
     
         21 . The method of  claim 1 , wherein R 10  represents hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, phenyl, thienyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, or morpholinyl and R 11  represents hydrogen. 
     
     
         22 . The method of  claim 1 , wherein the compound of formula (I) is selected from:
 (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-hydroxy-7-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,3-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,3-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-hydroxy-7-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dimethoxy-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dimethoxy-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dimethoxy-3,3-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dimethoxy-3,3-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-methyl-5,8-dihydro-6H-[1,7]naphthyridin-7-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-methyl-5,8-dihydro-6H-[1,7]naphthyridin-7-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-3,4-dihydro-1H-[2,6]naphthyridin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-3,4-dihydro-1H-[2,6]naphthyridin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-methyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-methyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-fluoro-1-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-fluoro-1-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-fluoro-1-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-fluoro-1-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-fluoro-1-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-fluoro-1-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-fluoro-1-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-fluoro-1-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-fluoro-1-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-fluoro-1-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-fluoro-1-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-fluoro-1-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-fluoro-1-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-fluoro-1-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-fluoro-1-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-fluoro-1-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2yl)-(3-ethyl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2yl)-((R)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2yl)-((S)-3-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (7-Bromo-3,4-dihydro-1H-isoquinolin-2-yl)-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (7-Bromo-3,4-dihydro-1H-isoquinolin-2-yl)-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-fluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromopyrazolo[1,5-a]pyrimidin-2yl)-(1-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)methanone,   (6-Bromopyrazolo[1,5-a]pyrimidin-2yl)-(1-isopropyl-3,4-dihydro-1H-isoquinolin-2-yl)methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-isopropyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (7-Bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (7-Bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-cyclohexyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-cyclohexyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-propyl-3,4-dihydro-1H-isoquinolin-2yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-((S)1-methyl-3,4-dihydro-1H-isoquinolin-2yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-((R)1-methyl-3,4-dihydro-1H-isoquinolin-2yl)-methanone,   (5-Bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-(6-chloro-pyrazolo[1,5-a]pyrimidin-2yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-5-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (5-Bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-pyridin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2yl)-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,6-dimethoxy-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5,8-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-methyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone,   (3-Bromo-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-6-pyridin-3-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (3-Bromo-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-pyridin-3-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   2-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl-)1,2,3,4-tetrahydro-isoquinoline-7-carbonitrile,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-pyridin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-pyrimidin-5-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-6-pyrimidin-5-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-pyrimidin-5-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-pyrimidin-3-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (3-Bromo-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,5-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,7-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,7-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,5-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (7-Chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (5-Chloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   N-[2-(6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-acetamide,   N-[2-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-acetamide,   N-[2-(6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl]-acetamide,   N-[2-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl]-acetamide,   N-[2-(6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl]-acetamide,   2-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid dimethylamide,   2-(6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid dimethylamide,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-methyl-2,3,5,8-tetrahydro-6H-1,4-dioxa-7-aza-phenanthren-7-yl)-methanone,   2-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1,2,3,4-tetrahydro-isoquinoline-5-carbonitrile,   2-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1,2,3,4-tetrahydro-isoquinoline-7-carbonitrile,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-pyridin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-pyridin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-6-pyridin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-6-pyridin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-methyl-8,9-dihydro-6H-[1,3]dioxolo[4,5-f]isoquinolin-7-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-pyridin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-pyridin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-3,4-dihydro-1H-isoquinolin-2-yl)-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-pyridin-2-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-6-pyridin-2-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-6-pyridin-2-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-pyridin-2-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (5-Bromo-3,4-dihydro-1H-isoquinolin-2-yl)-(6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (5-Bromo-3,4-dihydro-1H-isoquinolin-2-yl)-(6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-pyridin-2-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(2,4-dimethoxy-pyrimidin-5-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(2,4-dimethoxy-pyrimidin-5-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(2,6-dimethoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(2,6-dimethoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(6-fluoro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(6-fluoro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(2-methoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(2-methoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(6-methoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(6-methoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(2-methoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(2-methoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(2-fluoro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(2-fluoro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(6-fluoro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(6-fluoro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(2,6-dimethoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(2,6-dimethoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(2,4-dimethoxy-pyrimidin-5-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(2,4-dimethoxy-pyrimidin-5-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[7-(6-methoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[7-(2-methoxy-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[7-(2,4-dimethoxy-pyrimidin-5-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[7-(2,4-dimethoxy-pyrimidin-5-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[7-(2-fluoro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[7-(2-fluoro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(2-fluoro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(2-fluoro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-furan-2-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-furan-2-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-furan-2-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-furan-2-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-8-(5-methyl-furan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(5-methyl-furan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(5-methyl-furan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(5-methyl-furan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-furan-3-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-furan-3-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-furan-3-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-furan-3-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[8-(3,5-dimethyl-isoxazol-4-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[7-(3,5-dimethyl-isoxazol-4-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(3,5-dimethyl-isoxazol-4-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(3,5-dimethyl-isoxazol-4-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-8-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-8-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-8-(2H-tetrazol-5-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(2H-tetrazol-5-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(2H-tetrazol-5-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(2H-tetrazol-5-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-3,4-dihydro-1H-[2,6]naphthyridin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-8-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-nitro-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-methanone,   2-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonitrile,   2-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid methyl ester,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2,6-dimethyl-8,9-dihydro-6H-3-oxa-1,7-diaza-cyclopenta[a]naphthalen-7-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-1,4-dihydro-2H-[3,7]phenanthrolin-3-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(2,6-dimethyl-8,9-dihydro-6H-thiazolo[4,5-f]isoquinolin-7-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-methanesulfonyl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-methanesulfonyl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methanesulfonyl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-methanesulfonyl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4,7-dimethyl-1,4,7,8,9,10-hexahydro-2H-[3,7]phenanthrolin-3-yl)-methanone,   1-[2-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl]-ethanone,   2-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid methyl ester,   2-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-7-carboxylic acid methyl ester,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(morpholine-4-carbonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(morpholine-4-carbonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(morpholine-4-carbonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-methyl-8,9-dihydro-6H-furo[3,2-f]isoquinolin-7-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dimethyl-3,6,8,9-tetrahydro-pyrrolo[3,2-f]isoquinolin-7-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-methyl-5,8-dihydro-6H-furo[3,2-g]isoquinolin-7-yl)-methanone,   7-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-2,6-dimethyl-1,2,6,7,8,9-hexahydro-pyrrolo[3,4-f]isoquinolin-3-one,   7-(6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-2,6-dimethyl-2,3,6,7,8,9-hexahydro-pyrrolo[3,4-f]isoquinolin-1-one,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-diethylamino-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-diethylamino-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-diethylamino-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-diethylamino-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-difluoro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dichloro-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dibromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6,7-dibromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-8-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-8-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-6-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-6-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-morpholin-4-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-piperidin-1-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-piperidin-1-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone,   (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-pyrrolidin-1-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone and   (6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-pyrrolidin-1-yl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone.