I NOLINE DERIVATIVES AS DOPAMINE D1 RECEPTOR POSITIVE MODULATORS The invention provides certain pharmaceutical compositions and methods for their use in the treatment of and Attention deficit hyperactivity disorder Many currently used drugs work directly or indirectly through dopamine These include dopamine agonists and the dopamine precursor for dopamine releasers for attention deficit disorder and and dopamine reuptake inhibitors for The Dl receptor has an important role in motor activity and and a special role in maintaining higher cognitive functions for working and executive functions Cortex Attempts to develop Dl agonists for clinical use have so far not been giving impetus to the search for alternative approaches to augmenting Dl receptor One such approach is to identify an allosteric also known as a positive allosteric modulator or of the dopamine Dl et J Allosteric modulators are agents that either potentiate Allosteric or or inhibit Allosteric or the effect of the natural ligand by binding to a site that is distinct from the orthosteric binding site on the receptor allosteric binding By increasing the affinity of dopamine for the Dl a Dl potentiator may amplify the response to endogenous increasing Dl tone when and where dopamine is This mode of activity is in contrast to a Dl which will activate all Dl receptors to which it has access for as long as it is In animal models of cognition and locomotor Dl agonists show which are probably due to overstimulation at higher Some Dl agonists also show rapid development of tolerance due to constant activation of the Dl In because a Dl potentiator would be dependent on endogenous tone and subject to normal feedback it may have a much lower propensity for Given the involvement of dopamine and Dl receptor signaling in these central nervous system a Dl potentiator which can augment Dl receptor activity may provide an alternative improved agent for the treatment of certain dopamine related disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the disease manifests in resting tremor along with other motor symptoms bradykinesia and postural and symptoms cognitive sleep and Current therapies for the treatment of disease include administration of dopamine precursors such as and dopamine receptor Direct acting dopamine receptor agonist therapies may also be associated with impulse control and worsening of due to their relatively greater affinity for D2 Schizophrenia is a debilitating disease with complex pathological A component of Schizophrenia is cognitive which may be associated with a deficiency in Dl receptor activation or Dl receptor down It has been hypothesized that Dl selective over D2 may be effective in the treatment of cognitive impairment associated with disease is a neurodegenerative disorder characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical Disease progression includes cognitive which is hypothesized to be due at least in part to reduced Dl receptor such that Dl activation may provide therapeutic benefit in the treatment of cognitive impairment associated with ADHD is a neurodevelopmental disorder characterized by difficulties with focused excessive or difficulty in controlling behavior as appropriate for the It is hypothesized that Dl activation may provide therapeutic benefit in the treatment of there remains a significant unmet need for safe and effective treatment of cognitive or other neurological impairments associated with disease such as alternative improved dopamine Dl receptor positive allosteric modulators WO recites certain compounds as Dl PAMs for the treatment of cognitive impairment associated with depression or The present invention provides certain novel compounds that are selective PAMs of the dopamine 1 receptor and demonstrate an advantageous combination of pharmacological such as potentiation of human Dl receptor signaling in response to high oral in vivo and in vivo efficacy in locomotor activation of animals that are habituated to the As compounds of the present invention are believed to be useful in the treatment of The compounds of the present invention may provide an alternative treatment for such The present invention provides a compound of formula R3 is or or a pharmaceutically acceptable salt The compounds of formula or pharmaceutically acceptable salts thereof are particularly useful in the treatment methods of the but certain configurations are The following paragraphs describe such preferred Although the present invention as embodied in formula I contemplates all individual enantiomers and as well as mixtures of diastereomers and mixtures of enantiomers of said including compounds with the absolute configuration as set forth below are It is understood that these preferences are applicable to the treatment methods and to the new compounds of the and the pharmaceutically acceptable salts A particular compound of formula I is a compound of formula or a pharmaceutically acceptable salt A particular compound of formula I is a compound of formula or a pharmaceutically acceptable salt which in the free base form can also be named as the present invention provides a pharmaceutical composition comprising a compound of formula or a pharmaceutically acceptable salt and a pharmaceutically acceptable diluent or The following particular embodiments are compounds salts of formula The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is 3 or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt The present invention provides a compound which is or a pharmaceutically acceptable salt the present invention provides a compound salt of one of the particular embodiments of the preceding list immediately and a pharmaceutically acceptable diluent or Compounds of the present invention are selective PAMs of the dopamine 1 receptor with minimal activity at the dopamine 2 The compounds of present invention may further provide their therapeutic benefits while avoiding risks of As compounds of the present invention are believed to be useful for the treatment of conditions in which reduced Dl activity plays a and D2 activation is such as disease and including relief of certain associated symptoms such as motor symptoms and cognitive impairment associated with disease and cognitive impairment and negative symptoms associated with as for example mild cognitive impairment or Compounds of the present invention are also believed to be useful in improving motor symptoms in disease as a monotherapy or in combination with other Compounds of the present invention are also believed to be useful in treating certain symptoms of disease such as cognitive as for example mild cognitive compounds of the present invention are believed to be useful in treating certain symptoms of the present invention provides a compound of formula or a pharmaceutically acceptable salt for use in the present invention provides a compound of formula or a pharmaceutically acceptable salt for use in the present invention provides a compound of formula or a pharmaceutically acceptable salt for use in In another aspect the present invention provides a pharmaceutical composition comprising the compound of formula la or and one or more pharmaceutically acceptable or this of the invention provides a pharmaceutical composition for treating as for cognitive impairment associated with comprising the compound of formula la or and one or more pharmaceutically acceptable or In another embodiment of this aspect of the there is provided a pharmaceutical composition for mitigating motor impairment associated with comprising a compound of formula la or and one or more pharmaceutically acceptable or In another embodiment of this aspect of the there is provided a pharmaceutical composition for treating as for example mitigating cognitive impairment associated with comprising a compound of formula la or and one or more pharmaceutically acceptable or Another embodiment of this aspect of the invention provides a pharmaceutical composition for treating as for example mitigating cognitive impairment associated with comprising the compound of formula la or and one or more pharmaceutically acceptable or Another embodiment of present invention provides a pharmaceutical composition for treating comprising the compound of formula la or and one or more pharmaceutically acceptable or the present invention provides a method of treating as for cognitive impairment associated with or for mitigating motor impairment associated with comprising administering to a patient in need thereof an effective amount of a compound of formula la or the present invention provides a method of treating as for cognitive impairment associated with comprising administering to a patient in need thereof an effective amount of a compound of formula la or the present invention provides a method of treating as for cognitive impairment associated with comprising administering to a patient in need thereof an effective amount of a compound of formula la or the present invention provides a method of treating comprising administering to a patient in need thereof an effective amount of a compound of formula la or In one embodiment of this the present invention provides a compound of formula la or for use in the treatment of In one particular embodiment the invention provides a compound of formula la or for use in the treatment of cognitive impairment associated with In another particular embodiment the invention provides a compound of formula la or for use in mitigating motor impairment associated with the present invention provides a compound of formula la or for use in the treatment of as for example in the treatment of cognitive impairment associated with the present invention provides a compound of formula la or for use in the treatment of the present invention provides a compound of formula la or for use in the treatment of as for example in the treatment of cognitive impairment associated with In yet another the present invention provides the use of a compound of formula la or in the manufacture of a medicament for the treatment of as for example the treatment of cognitive impairment associated with or the mitigation of motor impairment associated with the present invention provides the use of a compound of formula la or in the manufacture of a medicament for the treatment of as for example the treatment of cognitive impairment associated with the present invention provides the use of a compound of formula la or in the manufacture of a medicament for the treatment of as for example the treatment of cognitive impairment associated with the present invention provides the use of a compound of formula la or in the manufacture of a medicament for the treatment of While it is possible to administer compounds employed in the methods of this invention directly without any the compounds are usually administered in the form of pharmaceutical compositions comprising the compound of formula la or as an active and at least one pharmaceutically acceptable diluent These compositions can be administered by a variety of routes including and Such pharmaceutical compositions and processes for preparing them are well known in the The Science and Practice of Pharmacy of the Sciences in 2lst Lippincott Williams Wilkins The compositions are preferably formulated in a unit dosage each dosage containing from about to about 800 mg of the active The term dosage refers to physically discrete units suitable as unitary dosages for human subjects and other each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic in association with at least one suitable pharmaceutically acceptable diluent It will be understood that the amount of the compound actually administered will be determined by a in the light of the relevant including the condition to be the chosen route of the actual compound the and response of the individual and the severity of the It is contemplated that the compound of the as for example in a pharmaceutical composition of the will be used to treat disease as for example the treatment of mild cognitive impairment associated with these by chronic As used the refers to a as for example a in need of treatment for a disorder or A human is a preferred As used the are intended to refer to all processes wherein there may be a or stopping of the progression of an existing disorder a reduction in symptoms but does not necessarily indicate a total elimination of all As used the of a compound of formula la or lb refers to an that is a which is effective in potenitiating a dopamine mediated response in a A can be determined as an amount that can promote a wakeful or alert state in the patient as compared to the patient when In determining an effective amount or dose of a compound of formula la or a number of factors are but not limited to the compound to be administered and its particular the patients and general the degree of involvement or the severity of the the response of the individual the mode of and other relevant acceptable pharmaceutically acceptable refers to the relatively inorganic and organic salt or salts of the compound of the present It will be understood by the skilled artisan that compounds of the present invention are capable of forming The compounds of the present invention contain basic and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition Such pharmaceutically acceptable acid addition salts and common methodology for preparing them are well known in the et HANDBOOK OF PHARMACEUTICAL SELECTION AND et Journal of Pharmaceutical Sciences Vol January Abbreviations used herein are defined as means means means benzyl means saturated means bovine serum means cyclic adenosine means Chinese hamster means means Minimum means dimethyl sulfoxide if for means the concentration of a test compound that produces the of the maximum effect means ethyl means ethanol or ethyl means Fetal Bovine means droxy 1 ethanesulfonic means homogeneous means hour or means means liquid chromatography mass means Locomotor means methanol or methyl means meams means mass spectroscopy or mass means polymerase chain means protecting group means relative activity means standard error of the means standard error of the mean followed by the number of data means Stimulation Buffer defined means means means General Chemistry The compounds of the present invention can be prepared by general methods known and appreciated in the art or by processes described Suitable reaction conditions for the steps of these schemes are well known in the art and appropriate substitutions of solvents and are within the skill of the it will be appreciated by those skilled in the art that synthetic intermediates may be isolated purified by various well known techniques as needed or and that it will be possible to use various intermediates directly in subsequent synthetic steps with little or no the skilled artisan will appreciate that in some the order in which moieties are introduced is not Scheme 1 Scheme 1 depicts the preparation of compound One skilled in the art will recognize the commercially available and appropriately phenylalanine 1 X dissolved in a polar protic solvent may be esterified with a suitably strong acid to obtain the esterified salt 2 Subsequent acylation by washing the salt with aqueous base to obtain the free dissolving in an aprotic and adding the appropriate acid chloride may be accomplished to obtain 3 Cyclization of the phenylalanine methyl ester 3 by treatment with paraformaldehyde in an appropriate strong acid and stirring to obtain the tetrahydroisoquinoline 4 is well known in the Dem ethylation and decarboxylation may be achieved by treatment with aqueous acid and stirring under to obtain 5 as the corresponding amine One skilled in the art will recognize that protected tetrahydroisoquinoline 6 may be formed by dissolving amine salt 5 in the appropriate polar aprotic adding base and the suitable anhydride or alkyl chloroformate to obtain tertbutyl carbamate Subsequent reduction to the methanol derivative 7 may be effected using an array of reducing such as with a metal borohydride or diborane in a polar aprotic tetrahydroisoquinoline 8 may be achieved by first treating the tetrahydroisoquinoline 7 with the appropriate strong acid and concentrating under the amine salt may be dissolved in the appropriate aprotic treated with base and a suitable protecting group PG OMOM to provide For protecting the primary alcohol with an acid stable silyl group such as TBDMS or is well known in the Scheme 2 depicts the synthesis of the compounds of type Imine formation from the tetrahydroisoquinoline 8 may be accomplished under various oxidative conditions recognizable to the skilled specifically halogenation of the secondary amine and subsequent elimination with a suitably strong base to provide dihydroisoquinoline A stereoselective Grignard reaction may be used by treating the imine 9 with a suitable alkylmagnesium halide to obtain the trans tetrahydroisoquinoline 10 Relative configuration of the tetrahydroisoquinoline 10 may be determined with the appropriate NMR spectroscopic specifically Subsequent may be achieved with amide coupling techniques well known in the oxytripyrrolidinophosphonium hexafluorophosphate in the presence of a mild nucleophilic base to prepare compound 11 Aryl coupling using the appropriately substituted compound 11 X may be effected under transition metal such as using or with an appropriate aryl or heteroaryl boronic acid or as is well known in the For 11 with an appropriately substituted methylpyrrazoleboronate may be accomplished to obtain 12 The skilled artisan will recognize that the deprotection of the protected alcohol 12 wherein PG OMOM may be executed under a variety of For a silyl protecting group may be removed with tetrabutylammonium fluoride to obtain the chiral compounds of type Scheme 3 Scheme 3 depicts an alternative synthesis of the compounds of type at elevated cyclization of the phenylalanine methyl ester 3 by treatment with paraformaldehyde in an appropriate strong acid may produce a mixture of tetrahydroisoquinoline methyl ester 4 and carboxylic acid 13 as is evident to one adept in the The mixture of methyl ester 4 and carboxylic acid 13 may be subjected to the appropriate aqueous acid for complete ester hydrolysis to afford the carboxylic acid amine salt Subsequent reduction to the methanol derivative 15 may be effected using an array of reducing such as with a metal borohydride or diborane in a polar aprotic dihydroisoquinoline 16 may be achieved by treatment with a suitable base and addition of the appropriate protecting previously described in Scheme 1 and as is common in the followed by halogenationtion of the secondary subsequent elimination with a suitably strong base and stirring with oxalic acid to provide dihydroisoquinoline oxalate salt 16 A stereoselective methylation may be effected by first treating the imine oxalate salt 16 with aqueous base and extracting with a suitable organic solvent to afford the free A Grignard reaction may then be employed by treatment with the appropriate alkylmagnesium halide followed by stirring with concentrated sulfuric acid to obtain the trans tetrahydroisoquinoline 17 Relative configuration of the tetrahydroisoquinoline 17 may be determined with the appropriate NMR spectroscopic specifically One skilled in the art will recognize that the trans tetrahydroisoquinoline hemisulfate 17 may be converted to the free base by addition of a suitable aqueous base and subsequent extraction with the appropriate organic acylation of said free base may be achieved with amide coupling techniques well known in the anhydride in the presence of a mild base to prepare compound 11 Aryl coupling using the appropriately substituted compound 11 X may be effected under transition metal such as using or with an appropriate aryl or heteroaryl boronic acid or as is well known in the For 11 with an appropriately substituted methylpyrrazoleboronate may be accomplished to obtain 12 The skilled artisan will recognize that the deprotection of the protected alcohol 12 similar to those described in Scheme to provide compounds of type In the following illustrative preparations and solvents are generally removed under reduced pressure In some procedures indicated yields are representative crude yields for products which are isolated by evaporation or filtration and used directly without further Preparation 1 Methyl Dissolve in MeOH Add acetyl chloride at room temperature and stir for 36 Concentrate under reduced pressure to give the title compound add acetyl chloride to MeOH at 0 Heat the mixture to and stir for 30 Add and heat to reflux for 4 Cool the mixture to 20 and remove the solvent under reduced pressure to give the title compound as an Preparation 2 Methyl Dissolve methyl hydrochloride in dichloromethane and water Add sodium bicarbonate and methyl chloroformate at room temperature and stir for Dilute with water and extract with Dry the dichloromethane extracts over sodium and concentrate under reduced Purify the residue by silica gel chromatography eluting with hexanes to give the title compound add water and sodium hydrogen carbonate to methyl hydrochloride in dichloromethane at 10 After 5 min add methyl chloroformate and stir the mixture at 20 for 3 Add water and separate the Extract the aqueous fraction with dry the combined organic extracts over sodium sulfate and concentrate under reduced pressure to give the title compound MS Preparation 3 Dimethyl 3 carboxyl Stir a mixture of methyl lg and paraformaldehyde in glacial acetic acid and concentrated sulfuric acid at room temperature for 7 Partition between water and Separate the layers and extract the aqueous layer with Combine the EtOAc extracts and dry over sodium and concentrate under reduced Purify the residue by silica gel chromatography eluting with hexanes to give the title compound Preparation 3a Dimethyl and acid 3a 3b Add methyl and paraformaldehyde to acetic acid at 10 After 10 slowly add concentrated sulfuric acid and stir at 35 for 12 Cool the reaction mixture to 15 and add water and EtOAc Separate the layers and extract the aqueous fraction with EtOAc Dry the combined organic extracts over sodium filter and concentrate under reduced pressure to give a mixture of the title compounds with acetic acid MS Preparation 4 Methyl Dissolve dimethyl in 5 N HC1 and heat to reflux for three Concentrate under reduced pressure to give a white Wash the solid with diethyl ether and dry under vacuum at 40 overnight to give acid hydrochloride Add acetyl chloride to a 0 mixture of acid hydrochloride in MeOH Warm to room temperature and stir for 36 Concentrate under reduced pressure and dry to give the title compound Preparation 5 acid Add water and hydrochloric acid to a mixture of dimethyl l and l acid and stir the mixture at 95 for 12 Cool the mixture to 10 and stir for an additional 15 Filter the mixture and dry the solid under vacuum at 40 to give the title compound MS Preparation 6 ethyl 3 carboxyl Dissolve methyl hydrochloride in Add saturated sodium bicarbonate solution and carbonate at room temperature and stir the biphasic mixture for 90 Extract with Dry the EtOAc over sodium and concentrate under reduced Purify the residue by silica gel chromatography eluting with hexanes to give the title compound MS Preparation 7 Add lithium aluminium hydride 1M in to acid hydrochloride in THF at Warm to 25 over 60 min with After 3 cool the mixture to add water add aqueous sodium hydroxide followed by additional water Heat the mixture to 25 add anhydrous magnesium sulfate with Filter the mixture and concentrate under reduced pressure to give a Add dichloromethane to the solid and slurry for 30 min before filtration to give a Dry the solid under vacuum at 35 to give the title compound MS Preparation 8 ethyl l noli Add methanol and lithium borohydride 2M in to a solution of 2 in THF at room temperature on a water Stir 40 min and quench the reaction with Extract with ethyl Dry the ethyl acetate extracts over sodium and concentrate under reduced Purify the residue by silica gel chromatography eluting with ethyl hexanes Dry under high vacuum overnight to give the title compound as a white solid MS Preparation 9 Add trifluoroacetic acid to solution of in dichloromethane at room Stir 30 min and concentrate under reduced Dry under vacuum to give acid as a wet Dissolve acid in dichloromethane Add 753 and Stir at room temperature Add saturated ammonium chloride solution and extract with Dry the dichloromethane extracts over sodium and concentrate under reduced Combine with the crude product from a substantially same reaction run with of Purify the residue by silica gel chromatography eluting with ethyl hexanes to give the title compound MS Alternative synthesis of Add to a mixture of and in dichlormethane at 20 and stir in an appropriate After 3 cool the mixture to 10 and add saturated aqueous ammonium chloride solution Extract the aqueous with dichloromethane and wash the combined organic extracts with brine x dry over anhydrous sodium sulfate and concentrate under reduced pressure to give a Dissolve the residue in methyl ether and wash with brine x 1 Dilute the organic phase with toluene and concentrate under reduced pressure to give a Add toluene to the residue and concentrate under reduced pressure to give the title compound MS Preparation 10 Dissolve dimethyl in diethyl ether Add Stir 30 min at room temperature and concentrate under reduced Dissolve the residue in potassium hydroxide in and stir for 30 min at room Pour into water and extract with Dry the dichloromethane extracts over sodium and concentrate under reduced Purify the residue by silica gel chromatography eluting with ethyl hexanes to give the title compound MS Alternative synthesis of Add 790 to a solution of 520 in tetrahydrofuran at 20 in an appropriate vessel and After 30 minutes concentrate the mixture under reduced pressure and dissolve the residues in potassium hydroxide in methanol and stir at 20 After 30 add the mixture to water and extract three times with dichlorom ethane x1 Dry the combined organic extracts over anhydrous magnesium sulfate and concentrate under reduced pressure to give the title compound MS Preparation 11 silane Dissolve silane in diethyl ether Cool to on a dry ice acetone Add a 3M solution of methylmagnesium chloride in THF Warm the reaction mixture slowly to room temperature and stir Quench with saturated ammonium chloride solution Extract with dichloromethane and dry over sodium and concentrate under reduced Combine with the crude product from a substantially same reaction run with mmol of Purify the combined residues by silica gel chromatography eluting with ethyl hexanes to give the title compound MS The relative configuration of compound is determined by NMR spectroscopy using NOE experiments Selective excitation of the methyl group at ppm gives rise to a NOE for Ha at This NOE enhancement is only consistent with a configuration in which the methyl and Ha are on the same side of the ring because in the cis isomer the methyl protons are too far away from Ha to show an Since the absolute chemistry for position 3 is known to be then the absolute chemistry at position 1 is deduced to be Alternative synthesis of Add a 3M solution of methylmagnesium chloride in THF to a solution of in diethyl ether at in an appropriate Then heat the reaction mixture to 20 over 2 hours and After 16 cool the mixture to 0 and quench the reaction with saturated aqueous ammonium chloride solution and extract with ethyl acetate and filter the Wash the combined organic extracts with brine dry over anhydrous magnesium sulfate and concentrate under reduced pressure to give the crude title compound as an Combine the oil with crude products from substantially same reactions of and purify the pooled crude products by silica gel chromatography eluting with ethyl acetate in hexanes ethyl to give the title compound combined from 2 experimental MS Preparation 12 Add hexafluorophosphate to a mixture of and acid in dimethylformamide Add triethylamine and stir at room temperature 3 Dilute with water and extract with Dry the dichloromethane extracts over sodium filter and concentrate under reduced Purify the residue by silica gel chromatography eluting with ethyl hexanes to give the title compound The following compounds are prepared essentially by the method of Preparation Preparation 21 Dissolve and in dioxane Add a aqueous solution of sodium carbonate and bubble nitrogen for 10 Add chloride 72 Heat to 90 for 2 Cool to ambient dilute with extract with dry over sodium concentrate and purify by silica gel chromatography eluting with a gradient from to EtOAc in hexanes to provide the title compound The following compounds are prepared essentially by the method of Preparation 21 using and the appropriately substituted boronic acid or boronic ester Preparation 27 pyrazole Dissolve dimethylformamide add cesium carbonate and Heat to to 60 for 3 Dilute with and extract with dichloromethane dry over sodium concentrate and purify by silica gel chromatography eluting with a gradient from to EtOAc in hexanes to get the title compound 353 Preparation 28 Benzyl Dissolve in acetonitrile Add potassium carbonate and benzyl chloroformate Stir dilute with saturated aqeous ammonium and extract with dichloromethane dry over sodium concentrate and purify by silica gel chromatography eluting with a gradient from to EtOAc in hexanes to get the title compound Preparation 29 Benzyl Dissolve benzyl 1 and in dioxane Add a aqueous solution of sodium carbonate 1 and bubble nitrogen for 10 Add chloride 198 Heat to 80 for 2 Cool to ambient dilute with extract with dry over sodium concentrate and purify by silica gel chromatography eluting with a gradient from to EtOAc in hexanes to get the title compound 548 Preparation 30 Add benzyl mg and palladium on carbon to ethanol Stir under a hydrogen balloon for 4 Filter through wash with evaporate to get the crude title compound 414 Preparation 31 Dissolve and dichlorophenylacetic acid in dichloromethane Add hexafluorophosphate and ethylamine Stir the resulting mixture for 2 Dilute with extract twice with dry over soldium concentrate in vacuo and purify by silica gel chromatography eluting with a gradient from to EtOAc in hexanes to get the title compound Example 1 Add tetrabutylammonium fluoride in to a solution of in THF at Stir for 4 Quench with saturated aqueous ammonium extract with EtOAc three dry over sodium concentrate and purify by silica gel chromatography eluting with a gradient from to EtOAc in hexanes to get the title compound as a white foam The following compounds are prepared essentially by the method of Example Preparation 32 oxalate salt Add to a solution of in dichloromethane at room temperature and stir for 20 Add Stir at room temperature for 12 Cool to 0 Add triethylamine at 0 and stir for 20 Add maintaining temperature 5 and stir at 0 for 12 Add aqueous ammonium chloride maintaining temperature 5 and stir for 2 hr at 0 Extract the organic layer and wash with water Concentrate under reduced pressure and add Add oxalic acid and stir for 10 hr at 40 Filter the mixture and wash the solids with Dry the solids at 45 for 16 hr to give the title intermediate MS Preparation 33 Add a potassium carbonate in water mixture to a solution of oxalate salt in dichloromethane Stir at 25 for 2 Extract the organic layer and wash with Concentrate under reduced pressure and add dry THF Add dry THF and cool to Add trimethyl silyl chloride and stir for 30 Add a 1M solution of methyllithium in THF maintaining temperature Stir for 6 hr at Add saturated ammonium chloride solution maintaining temperature 0 Warm to add water and and stir for 2 Extract the organic layer and wash with water and saturated aqueous Concentrate under reduced pressure and add EtOAc Add concentrated sulfuric acid and stir at 50 for 4 Cool to 20 and stir for 16 Filter the mixture and wash the filtercake with Dry the solids at 45 for 16 Dissolve solids in THF and heat to 50 Stir for one hr and add EtOAc maintaining temperature between 50 Stir for 1 hr and cool to 20 Stir for 6 hr then filter and collect the Wash the filtercake with EtOAc and dry the solids at 45 to give the title intermediate MS Preparation 34 Stir a solution of in dichloromethane and add a solution of sodium carbonate in water and stir at ambient temperature for 15 Separate the layers and extract the aqueous with dichloromethane Combine the organic dry over magnesium filter and evaporate to afford the title compound as a oil of sufficient purity for additional Preparation 35 Dissolve in acetonitrile and add trimethylamine 359 and acid and stir the mixture for 5 Cool the mixture at 5 and 10 In a separate dilute a solution of anhydride in EtOAc with acetonitrile and add dropwise to the reaction mixture over 15 maintaining the internal temperature below 10 Stir between for 1 and warm to ambient Filter the mixture and wash the resulting filtercake with acetonitrile x 150 and dry under vacuum at 45 overnight to afford the title intermediate Preparation 36 Add sodium carbonate 249 dichloride to a 2L and seal and purge the reaction system with cycle three Add and water and degas with further cycling three and heat the resulting mixture to 80 for 75 Add and dichloride Seal and purge with cycle three and heat to 80 for another 75 Cool to dilute with EtOAc separate and pass the organic layer through a plug of silica gel to afford the crude title compound as an orange oil g of sufficient purity for additional Alternative Procedure for Example 1 Dissolve in and placed under a nitrogen atmosphere in a 2 L Add a 1M solution of tetrabutylammonium fluoride in THF 155 over 2 and stir at RT for 4 Dilute with water and separate the organic Dry over magnesium and concentrate in vacuo to afford a pale orange Purify the resulting residue by silica gel eluting with heptane and EtOAc to afford the title compound as a white foam Purify again by silica gel chromatography eluting with a gradient from to MTBE in dichloromethane to afford the title compound as a white foam Preparation 37 Dissolve and in dimethoxyethane Add a aqueous solution of potassium carbonate and bubble nitrogen for 10 Add Heat to 100 for 18 Cool to dilute with extract with dry over sodium concentrate in vacuo and purify by silica gel chromatography eluting with a gradient from to EtOAc in hexanes to provide the title compound mg Example 8 dihydroi 1 1 Add a 1M solution of tetrabutylammonium fluoride in THF to a solution of in THF at Stir the resulting mixture for 3 Quench with saturated aqueous ammonium extract three times with dry over sodium concentrate in vacuo and purify the resulting residue by silica gel chromatography eluting with a gradient from to EtOAc in hexanes to get the title compound as a white foam Alternative Synthesis of Example Preparation 38 Dissolve and acid in Add sodium carbonate chloride and water Bubble nitrogen for 5 Heat to 90 for 19 Cool to dilute with extract with dry over sodium concentrate in vacuo and purify by silica gel chromatography eluting with EtO to get the title compound dihydroi 1 1 Add over 10 min acid to a solution of in MeOH at Stir for 17 Remove solvent under partition the resulting residue between EtOAc and water separate the and extract the aqueous layer twice with Dry the combined organic extracts over concentrate in vacuo and purify by silica gel chromatography eluting with a gradient from to EtOAc in hexanes to get the title compound as a white foam Example 9 1 Heat a mixture of potassium carbonate palladium dichloride 20 THF and water in a microwave reactor at 100 for 1 Cool to dilute with extract with and concentrate in vacuo to obtain a crude brown Dissolve the residue in methanol and add aqueous HC1 solution in methanol Heat the resulting solution to 50 for 8 Cool to and pour over an SCX column first eluting with methanol and eluting the desired product with 2N ammonia in Concentrate the methanolic ammonia fractions and purify by chromatography to give the title compound MS The following compounds are prepared essentially by the method of Example Preparation of Example 1 A hydrochloride monohydrate The compound of Example 1 412 is dissolved in acetone at A 1M solution of HC1 in EtOAc is added A white solid precipitates after resulting in a thick white The resulting white solid is isolated by filtration on Whatman paper and dried under air stream for 30 min to yield the title compound mg as a crystalline Preparation of Example IB hydrobromide The compound of Example 1 563 is dissolved in acetone at 55 Once internal temperature reaches at 50 a aqueous solution of HBr 619 is After 2 mins a precipitate and the mixture is stirred forlO min and cooled to The resulting precipitate is collected by filtration over a sintered glass washed with acetone and dried by vacuum suction on the to give the title compound as a light crystalline Preparation of Example 1C hydrobromide monohydrate The compound of Example 1 is dissolved in acetone at A mixture of aqueous HBr diluted 1 in acetone is added at 500 A white solid starts to precipitate after addition of 1 After the acid a thick white slurry resultsand the mixture is cooled to The white solid is collected by filtration on Whatman paper and dried under air stream for 90 min to obtain the title compound as a crystalline The present invention provides crystalline hydrobromide An embodiment of the invention is crystalline hydrobromide monohydrate characterized by an X ray powder diffraction pattern using CuKa radiation having a diffraction peak at diffraction angle of in combination with one or more of the peaks selected from the group consisting of and with a tolerance for the diffraction angles of The present invention further provides a pharmaceutical composition comprising hydrobromide and a pharmaceutically acceptable diluent or The present invention further provides a pharmaceutical composition comprising crystalline hydrobromide and a pharmaceutically acceptable diluent or Preparation of Example ID hydroiodide The compound of Example 1 is dissolved in acetone at An aqueous solution of HI is The mixture is stirred for 1 and a white solid precipitates out of forming a thick slurry of white solid in brown The white solid is collected by filtration on Whatman paper and dried under air stream for 10 min to obtain the title compound as a crystalline Preparation of Example IE hydroiodide monohydrate The compound of Example is dissolved in acetone at An aqueous solution of HI is The mixture is stirred for 30 and a white solid precipitates out of forming a thick slurry of white solid in brown The white solid is collected by filtration on Whatman paper and dried under air stream for 10 min to obtain the title compound as a crystalline Powder Diffraction of Crystalline Forms The XRD patterns of crystalline solids are obtained on a Bruker D4 Endeavor powder equipped with a CuKa source l and a Vantec operating at 35 kV and 50 The sample is scanned between 4 and in with a step size of in 20 and a scan rate of and with mm fixed and mm detector The dry powder is packed on a quartz sample holder and a smooth surface is obtained using a glass The crystal form diffraction patterns are collected at ambient temperature and relative Crystal peak positions are determined in after whole pattern shifting based on an internal NIST 675 standard with peaks at and It is well known in the crystallography art for any given crystal the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and Where the effects of preferred orientation are peak intensities are but the characteristic peak positions of the polymorph are The United States Pharmacopeia National Formulary pages it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary For peak positions can shift due to a variation in the temperature at which a sample is sample or the presence or absence of an internal In the present a peak position variability of is presumed to take into account these potential variations without hindering the unequivocal identification of the indicated crystal Confirmation of a crystal form may be made based on any unique combination of distinguishing XRD of Example 1 A A prepared sample of crystalline Example 1A hydrochloride is characterized by an XRD pattern using CuKa radiation as having diffraction peaks as described in Table 1 and in particular having peaks at in combination with one or more of the peaks selected from the group consisting of and with a tolerance for the diffraction angles of Table powder diffraction peaks of the crystalline Example 1A XRD of Example IB A prepared sample of the crystalline Example 1B 3 is characterized by an XRD pattern using CuKa radiation as having diffraction peaks as described in Table 2 and in particular having peaks at in combination with one or more of the peaks selected from the group consisting of and with a tolerance for the diffraction angles of Table powder diffraction peaks of the crystalline Example 1B XRD of Example 1C A prepared sample of the crystalline Example 1C 3 hydrobromide is characterized by an XRD pattern using CuKa radiation as having diffraction peaks as described in Table 3 and in particular having peaks at in combination with one or more of the peaks selected from the group consisting of and with a tolerance for the diffraction angles of Table powder diffraction peaks of the crystalline Example 1C XRD of Example ID A prepared sample of the crystalline Example 1D 3 is characterized by an XRD pattern using CuKa radiation as having diffraction peaks as described in Table 4 and in particular having peaks at in combination with one or more of the peaks selected from the group consisting of and with a tolerance for the diffraction angles of Table powder diffraction peaks of the crystalline Example 1D XRD of Example IE A prepared sample of the crystalline Example 1E 3 hydroiodide is characterized by an XRD pattern using CuKa radiation as having diffraction peaks as described in Table 5 and in particular having peaks at in combination with one or more of the peaks selected from the group consisting of and with a tolerance for the diffraction angles of Table powder diffraction peaks of the crystalline Example 1E Human D1 Receptor PAM Assay The PAM activity of the compounds of the present invention may be measured essentially as described in Svensson et al An Allosteric Potentiator of the Dopamine Dl Receptor Increases Locomotor Activity in Human Dl Mices without Casusing Stereotypy or More HEK293 cells that stably express the human Dl receptor number NM are generated by gene transduction using the retroviral vector and selected with At approximately the cells are harvested using Express suspended in FBS plus and stored in liquid On the day of the cells are thawed and resuspended in STIM buffer Balanced Salt Solution supplemented with 20 mM 500 mM IB and 100 pM ascorbic Test compound is serially diluted with DMSO into assay plates using acoustic dispensing to provide 20 concentrations for full response Test compound is added to 5 pL STIM buffer containing 2000 and 5 pL of a 2X concentration dopamine solution in STIM buffer that will generate an EC20 level response nM in stock or 12 nM and a final DMSO concentration in the well of Plates are incubated at room temperature for a total reaction time of 60 cAMP production is quantified using detection according to the lysis buffer containing cryptate and is added to the plates are incubated for an additional and the fluorescence is detected using an plate reader Fluorescence data is converted to cAMP concentrations using a cAMP standard curve and analyzing using a logistic equation version For potentiator mode results are expressed as percent of the window between a response at EC20 concentration of dopamine alone to and the maximum response to dopamine by response to 5 mM final normalized as Absolute EC50 values are calculated based on the maximum and minimum responses of the control agonist The Potentiation is determined from the fitted top of the concentration response The absolute EC50 and Top are showed in the following Table Table 6 The absolute EC50 values provided for Examples 1 15 in Table 6 illustrate the potentiation of human Dl receptor signaling in response to and illustrate the activity of the compounds of Claim 1 as a positive allosteric modulator of the human dopamine Dl Generation of Human Dl Receptor Mouse A transgenic mouse in which the murine dopamine 1 receptor is replaced by its human counterpart may be generated by standard techniques generally Svensson el al For mouse genomic fragments are subcloned from the RP23 bacterial artificial chromosome library and recloned into a neo targeting The mouse open reading frame is replaced with the human Dl receptor open reading frame in exon A neo selection marker upstream of exon 2 is flanked by fit sites for later The flanking of exon 2 by loxP selection sites allows for the option to generate Dl mice by crossing with mice expressing the ere nuclease The N embryonic stem cell line is grown on a mitotically inactivated feeder layer of mouse embryonic fibroblasts in DMEM with FBS and 2x1 leukemia inhibitory Ten million embryonic stem cells plus 30 micrograms of linearized vector DNA are electroporated and subjected to G418 selection Clones are isolated and analyzed by Southern A clone containing the expected size insert is inserted into blastocysts and the resulting mice are genotyped by A male chimera is crossed with a female containing the flp nuclease gene to eliminate the selection Progeny containing the human Dl receptor without the selection marker are identified by A male heterozygote is mated with female Male and female progeny containing the human Dl receptor are mated and homozygotes are identified by Behavior and reproduction of the homozygotes is found to be and the colony is maintained in the homozygote state for succeeding Basal Locomotor Activity The in vivo efficacy of the present compounds may be demonstrated to act through the Dl receptor using mouse locomotor Locomotor activity is measured using an automated system to track movement in Monitoring of mouse locomotor activity behaviors take place in transparent plastic shoebox cages having dimensions of 45 x 25 x 20 with a 1 cm depth of wood chips for absorbent and covered with a ventilated filtered plastic cage Cages were placed in a rectangular frame containing a grid of 12 photocell beams in an 8 x 4 configuration that is positioned centimeters from the floor of the cage for the detection of body movements and recorded by Male human Dl receptor mice are placed in chambers and allowed to habituate to the chambers for 60 During the habituation the mice show decreasing locomotion over as Following administration of a compound of the animal movement is found to increase in a The mice are randomly assigned to treatment In the dose response each mouse is placed individually into one of the locomotor activity boxes for a 60 habituation The mice are then dosed orally using test compound in a vehicle and using a 10 dose After the mice are placed back into the LMA boxes and the total number of ambulations is recorded per 10 min interval for each mouse over a 60 min measurement Statistical analysis is carried out using ANOVA followed by analysis using Comparison The compounds of Example 1 and 8 are assayed essentially as described above and are found to increase basal movement in a dose dependent manner 7 and Table 7 Table 8 The Basal Locomotor Activity data for Example 1 and 8 shown in Table 7 and 8 illustrate that compounds of the and Example 1 and 8 in are effective in locomotor activation of animals that are habituated to the This activity is believed to be the result of central activation of Dl receptors via allosteric potentiation See Svensson et The data provided in Tables 7 and 8 for Examples 1 and 8 illustrate the pharmacologically advantageous in vivo efficacy of the compounds of the invention for the potentiation of endogenous dopamine mediated The data provided in Table 7 and 8 for Examples 1 and further illustrate the pharmacologically advantageous oral bioavailabilitiy of Examples 1 and 8 and the compounds of formula Plasma and Brain Example 1 is orally dosed to male mouse from 1 to 30 in fed and the plasma and brain concentration are determined hr The fraction unbound of the compound is determined in vitro as described previously Ruterbories Ajamie Wickremsinhe Pothuri Rao Basavanakatti Pinjari Ramanathan Chaudhary AK Validation of equilibrium dialysis with el ed drug for definitive measurement of protein binding and application to clinical development of J Pharm Sci The ratio of unbound brain concentration unbound plasma concertation is determined as described previously Wishart Kulanthaivel Staton Ajamie Sawada Gelbert Shannon Sanchez De Dios A Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Drug Metab 43 The data presented below for Example 1 are averages from 3 animals at each refers to Plasma Dose Time Brain plasma brain plasma brain Kpuu hr nM nM nM nM 1 1 5 BQL 0 025 BQL NA 3 5 60 0 025 6 1 5 173 129 0 025 10 1 5 120 0 025 30 5 1660 794 0 025 below the quantitative limit 1 Example 8 was orally dosed to male mouse from 3 to 60 in fed and the plasma and brain concentration was determined 1 hr The fraction unbound of the compound was determined in vitro as described previously el al Validation of equilibrium dialysis with drug for definitive measurement of protein binding and application to clinical development of The ratio of unbound brain concentration unbound plasma concertation was determined as described previously et Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Drug The data presented below for Example 8 are averages from 3 animals at each Plasma Dose Time Brain plasma brain plasma brain Kpuu hr nM nM nM nM 3 10 901 267 20 2442 721 30 10321 2391 320 60 20077 5000 622 50 Compounds of the for instance Example show an advantageous combination of pharmacological such as potentiation of human Dl receptor signaling in response to high oral in vivo in vivo efficacy in locomotor activation of animals that are habituated to the and a favorable toxicity profile in preclinical For instance Example 1 demonstrates potentiation of human Dl receptor signaling in response to dopamine nM and significant in vivo efficacy when orally administered at and 30 in locomotor activation of human Dl receptor mice that are habituated to the also illustrating the favorable oral bioavailability of this Example 1 is generally well tolerated when administered in vivo to normal rats over a broad dose and shows an advantageous lack of toxicity in this in vivo Example 1 demonstrates an advantageous combination of favorable pharmacological properties supporting possible use as an orally administered therapeutic agent for dopamine Dl receptor and treatment for insufficientOCRQuality

We claim:

1. A compound of the formula:

R3 is -H, -F or -Cl;

or a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 1 of the formula:

wherein:

or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 selected from the group consisting of:

2-(2,6-dichlorophenyl)-l-((lS,3R)-5-(l-ethyl-lH-pyrazol-4-yl)-3-(hydroxymethyl)-l- methyl-3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one;

1-((lS,3R)-5-(l-cyclopropyl-lH-pyrazol-4-yl)-3-(hydroxymethyl)-l-methyl-3,4- dihydroisoquinolin-2(lH)-yl)-2-(2,6-dichlorophenyl)ethan-l-one;

2-(2,6-dichlorophenyl)-l-((lS,3R)-3-(hydroxymethyl)-l-methyl-5-(l-(oxetan-3-yl)- 1 H-pyrazol -4-yl)-3 ,4-dihydroi soquinolin-2( 1 H)-yl)ethan- 1 -one;

1-((lS,3R)-5-(l-(2-(ll-oxidaneyl)ethyl)-lH-pyrazol-4-yl)-3-(hydroxymethyl)-l- methyl-3,4-dihydroisoquinolin-2(lH)-yl)-2-(2-chlorophenyl)ethan-l-one;

2-(2-chloro-6-fluorophenyl)-l-((lS,3R)-3-(hydroxymethyl)-l-methyl-5-(l-(oxetan-3- yl)-lH-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one;

2-(2-chlorophenyl)- l-((lS,3R)-3-(hydroxymethyl)-l-methyl-5-(l -methyl- lH-pyrazol- 4-yl)-3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one;

2-(2,6-dichlorophenyl)-l-((lS,3R)-3-(hydroxymethyl)-l-methyl-5-(lH-pyrazol-4-yl)- 3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one;

2-(2-chloro-6-fluorophenyl)-l-((lS,3R)-3-(hydroxymethyl)-l-methyl-5-(lH-pyrazol- 4-yl)-3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one;

2-(2,6-difluorophenyl)-l-((lS,3R)-3-(hydroxymethyl)-l-methyl-5-(lH-pyrazol-4-yl)- 3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one;

2-(2-chloro-5-fluorophenyl)-l-((lS,3R)-3-(hydroxymethyl)-l-methyl-5-(lH-pyrazol- 4-yl)-3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one;

2-(2-chloro-4-fluorophenyl)-l-((lS,3R)-3-(hydroxymethyl)-l-methyl-5-(lH-pyrazol- 4-yl)-3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one;

2-(2-fluorophenyl)-l-((l S,3R)-3-(hydroxymethyl)-l-methyl-5-(lH-pyrazol-4-yl)-3,4- dihydroisoquinolin-2(lH)-yl)ethan-l-one;

2-(2,3-difluorophenyl)-l-((lS,3R)-3-(hydroxymethyl)-l-methyl-5-(lH-pyrazol-4-yl)- 3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one; and

2-(2,5-difluorophenyl)-l-((lS,3R)-3-(hydroxymethyl)-l-methyl-5-(lH-pyrazol-4-yl)- 3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one;

or a pharmaceutically acceptable salt thereof.

4. The compound of Claim 1 which is:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 which is:

6. A compound which is 2-(2,6-dichlorophenyl)-l-((lS,3R)-3-(hydroxymethyl)-l- methyl-5-(l -methyl- lH-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(lH)-yl)ethan-l -one hydrobromide monohydrate.

7. A compound of Claim 6 which is crystalline 2-(2,6-dichlorophenyl)-l-((lS,3R)-3- (hydroxymethyl)-l-methyl-5-(l -methyl- lH-pyrazol-4-yl)-3,4-dihydroisoquinolin- 2(lH)-yl)ethan-l-one hydrobromide monohydrate.

8. A compound of Claim 7 which is crystalline 2-(2,6-dichlorophenyl)-l-((lS,3R)-3- (hydroxymethyl)-l-methyl-5-(l -methyl- lH-pyrazol-4-yl)-3,4-dihydroisoquinolin- 2(lH)-yl)ethan-l-one hydrobromide monohydrate characterized by an X-ray powder diffraction pattern using CuKa radiation having a diffraction peak at diffraction angle 2-theta of 17.4 in combination with one or more of the peaks selected from the group consisting of 27.0, 18.3, and 21.7; with a tolerance for the diffraction angles of 0.2 degrees.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

10 A pharmaceutical composition of Claim 9 comprising:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

11 A pharmaceutical composition of Claim 10 comprising:

and a pharmaceutically acceptable carrier, diluent or excipient.

12. A pharmaceutical composition of Claim 9 comprising 2-(2,6-dichlorophenyl)-l- ((1 S,3R)-3-(hydroxymethyl)-l-methyl-5-(l -methyl- lH-pyrazol-4-yl)-3, 4- dihydroisoquinolin-2(lH)-yl)ethan-l-one hydrobromide monohydrate, and a pharmaceutically acceptable carrier, diluent or excipient.

13. A compound according to any one of claims 1 to 8, or pharmaceutically acceptable salt thereof, for use in therapy.

14. A compound according to any one of claims 1 to 8, or pharmaceutically acceptable salt thereof, for the treatment of Parkinson’s disease.

15. A compound according to any one of claims 1 to 8, or pharmaceutically acceptable salt thereof, for the treatment of Alzheimer’s disease.

16. The use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating Parkinson’s disease or Alzheimer’s disease.

17. A method of treating Parkinson’s disease comprising administering to a patient in need thereof an effective amount of a compound which is 2-(2,6-dichlorophenyl)-l-

((1 S,3R)-3-(hydroxymethyl)-l-methyl-5-(l -methyl- lH-pyrazol-4-yl)-3, 4- dihydroisoquinolin-2(lH)-yl)ethan-l-one, or a pharmaceutically acceptable salt thereof.

18. A method of treating Alzheimer’s disease comprising administering to a patient in need thereof an effective amount of a compound which is 2-(2,6-dichlorophenyl)-l- ((1 S,3R)-3-(hydroxymethyl)-l-methyl-5-(l -methyl- lH-pyrazol-4-yl)-3, 4- dihydroisoquinolin-2(lH)-yl)ethan-l-one, or a pharmaceutically acceptable salt thereof.