EA041402B1 - PYRASOTETRAHYDROISOQUINOLINE DERIVATIVES AS POSITIVE MODULATORS OF THE DOPAMINE D1 RECEPTOR - Google Patents

Description

The invention provides certain (phenyl)-(pyrazole)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one compounds, pharmaceutical compositions thereof, and methods for their use in the treatment of disease

Parkinson's disease, Alzheimer's disease, schizophrenia and attention deficit hyperactivity disorder (ADHD).

Many currently used drugs act directly or indirectly through dopamine receptors. These include dopamine agonists and the dopamine precursor LDOPA in Parkinson's disease, dopamine releasing agents in attention deficit disorder and narcolepsy, and dopamine reuptake inhibitors in depression. The D1 receptor plays an important role in motor activity and satisfaction, as well as a special role in maintaining the higher cognitive functions of working memory, attention and executive functions (Arnsten AF, Cereb. Cortex (2013) 123, 2269-2281). Attempts to develop D1 agonists for clinical use have so far been unsuccessful, which has given impetus to the search for alternative approaches to increase the activity of the D1 receptor.

One such approach is to identify an allosteric potentiator, also known as a positive allosteric modulator or PAM, of the dopamine D1 receptor. (Svensson K, et al., J. Pharmacol. Exp. Ther. (2017) 360:117-128). Allosteric modulators are agents that either potentiate (positive allosteric modulator, or PAM) or inhibit (negative allosteric modulator, or NAM) the action of a natural ligand by binding to a site that is different from the orthosteric binding site on the receptor (allosteric binding site). By increasing the affinity of dopamine for the D1 receptor, the D1 potentiator can enhance the response to endogenous dopamine by increasing D1 tone when and where dopamine is released. This mode of activity is different from a D1 agonist, which activates all D1 receptors it has access to while it is present. In animal models of cognition and motor activity, D1 agonists show bell-shaped dose-dependence, which is likely due to overstimulation at higher doses. Some D1 agonists also show rapid development of tolerance due to persistent activation of the D1 receptor. On the contrary, since the D1 potentiator will be dependent on endogenous tone and subject to normal feedback control, it may be much less prone to over-stimulation. Given the involvement of dopamine and D1 receptor signaling in these central nervous system functions, a D1 potentiator that can increase D1 receptor activity may provide an alternative and/or improved agent for the treatment of certain dopamine-related diseases.

Parkinson's disease is a chronic progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the brain. Parkinson's disease presents with resting tremor along with other motor symptoms (eg, bradykinesia and postural instability) and non-motor symptoms (eg, cognitive impairment, sleep disturbance, and depression). Current treatments for Parkinson's disease include the administration of non-selective dopamine precursors such as levodopa and dopamine receptor agonists. Therapy with direct-acting dopamine receptor agonists may also be associated with impulse control disorders, psychoses, and cognitive decline due to their relatively greater affinity for D2 receptors. Schizophrenia is a debilitating disease with complex pathological mechanisms. A component of schizophrenia are cognitive impairments that may be associated with a lack of activation of the D1 receptor or downregulation of the D1 receptor. It has been hypothesized that D1 activation, selective over D2 modulation, may be effective in the treatment of cognitive impairment associated with schizophrenia. Alzheimer's disease is a chronic progressive neurodegenerative disease characterized by the loss of neurons and synapses in the cerebral cortex and some subcortical regions. Disease progression includes cognitive impairment, which is thought to be due in part to decreased D1 receptor activation; thus, activation of D1 may provide a therapeutic effect in the treatment of cognitive impairment associated with Alzheimer's disease. ADHD is a neurodevelopmental disorder characterized by difficulty concentrating, being overly active, or having difficulty managing one's behavior in an age-appropriate manner. It is hypothesized that D1 activation may provide a therapeutic effect in the treatment of ADHD. Thus, there remains a significant unmet need for the safe and effective treatment of cognitive or other neurological disorders associated with schizophrenia, Parkinson's disease, Alzheimer's disease and/or ADHD, such as alternative and/or improved allosteric modulators positive for the D1 dopamine receptor (D1 DAM). ).

WO 2014/193781 lists certain 3,4-dihydroisoquinolin-2(1H)-yl compounds as D1 PAM for the treatment of cognitive impairment associated with Parkinson's disease, Alzheimer's disease, schizophrenia, depression or ADHD.

The present invention provides some novel compounds that are dopamine 1 (D1) receptor selective PAMs and exhibit an advantageous combination of pharmacological properties such as enhancement of human D1 receptor signaling in response to dopamine, high oral availability in vivo, and in vivo efficacy in locomotor activation of animals that

- 1 041402 accustomed to the environment. As such, the compounds of the present invention are believed to be useful in the treatment of Parkinson's disease, Alzheimer's disease, schizophrenia and/or ADHD. The compounds of the present invention may provide an alternative treatment for such disorders.

The present invention provides a compound of formula I

Where

R ¹ is -H, -CH ₃ , -CH ₂ CH ₃ -CH ₂ CH ₂ OH, or

R ² is -F or -Cl and

R ³ represents -H, -F or -Cl;

or a pharmaceutically acceptable salt thereof.

Compounds of formula I, or pharmaceutically acceptable salts thereof, are particularly useful in the methods of treatment of the invention, but certain configurations are preferred. The following paragraphs describe such preferred configurations. Although the invention, as embodied in formula I, embraces all individual enantiomers and diastereomers, as well as mixtures of diastereomers and mixtures of enantiomers of these compounds, including racemic mixtures, compounds with absolute configuration as defined below are preferred. It should be understood that these preferences apply to the methods of treatment, and to the new compounds according to the invention, and their pharmaceutically acceptable salts.

A specific compound of formula I is a compound of formula Ia

Where

R ¹ is -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH,

or

or a pharmaceutically acceptable salt thereof.

A specific compound of formula I is a compound of formula Ib

or a pharmaceutically acceptable salt thereof, which in its free base form may also be referred to as 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl -1 H-pyrazol-4-yl)-3,4- 2 041402 dihydroisoquinolin-2(1 H)-yl)ethan-1-one.

In addition, the present invention provides a pharmaceutical composition containing a compound of formula I, Ia and/or Ib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or auxiliary agent.

The following specific implementation options are compounds and/or salts of formula I, Ia and/or Ib.

The present invention provides a compound which is 2-(2,6dichlorophenyl)-1-((1S,3R)-5-(1-ethyl-1H-pyrazol-4-yl)-3-(hydroxymethyl)-1- methyl-3,4dihydroisoquinolin-2(1H)-yl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 1-((1S,3R)-5-(1cyclopropyl-1H-pyrazol-4-yl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinoline-2( 1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 2-(2,6dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-(oxetan-3-yl)-1H -pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 1-((1S,3R)-5-(1-(2(1-oxidaneyl)ethyl)-1H-pyrazol-4-yl)-3-(hydroxymethyl)-1- methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2(2,6-dichlorophenyl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 2-(2-chloro-6fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-(oxetan-3-yl) -1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 2-(2-chlorophenyl)-1((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl) -3,4-dihydroisoquinolin-2(1H)-yl)ethan1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 2-(2,6dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3, 4-dihydroisoquinolin-2(1H)yl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 2-(2-chloro-6fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl )-3,4-dihydroisoquinolin-2(1 H)yl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 2-(2,6difluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-( 1 H-pyrazol-4-yl)-3 ,4-dihydroisoquinolin-2(1H)yl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 2-(2-chloro-5fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl )-3,4-dihydroisoquinolin-2(1 H)yl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 2-(2-chloro-4fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl )-3,4-dihydroisoquinolin-2(1 H)yl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 2-(2-fluorophenyl)-1((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3, 4-dihydroisoquinolin-2(1H)-yl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 2-(2,3difluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-( 1 H-pyrazol-4-yl)-3 ,4-dihydroisoquinolin-2(1H)yl)ethan-1-one or a pharmaceutically acceptable salt thereof.

The present invention provides a compound which is 2-(2,5difluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-( 1 H-pyrazol-4-yl)-3 ,4-dihydroisoquinolin-2(1H)yl)ethan-1-one or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a compound and/or salt of one of the specific implementation options from the above list, as well as a pharmaceutically acceptable carrier, diluent or auxiliary agent.

The compounds of the present invention are selective dopamine 1 receptor (D1) PAMs with minimal activity at the dopamine 2 receptor (D2). The compounds of the present invention may further provide their therapeutic benefits while avoiding the risks of drug-drug interactions. As such, the compounds of the present invention are considered useful in the treatment of conditions in which reduced D1 activity plays a role and D2 activation is undesirable, such as Parkinson's disease and schizophrenia, including the alleviation of certain associated symptoms such as motor symptoms and cognitive impairment associated with Parkinson's disease. and cognitive impairment, and negative symptoms associated with schizophrenia, such as, for example, mild cognitive impairment or dementia. It is also believed that the compounds of the present invention are useful for improving the motor symptoms of Parkinson's disease as monotherapy or in combination with other treatments. The compounds of the present invention are also believed to be useful in the treatment of certain symptoms of Alzheimer's disease such as cognitive impairment, eg mild cognitive impairment. In addition, the compounds of the present invention are believed to be useful in the treatment of certain symptoms of ADHD.

In addition, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in therapy. In addition, the present invention provides a compound of formula Ia, or a pharmaceutically acceptable salt thereof, for use in therapy. In addition, the present invention provides a compound of formula Ib, or a pharmaceutically acceptable salt thereof, for use in therapy.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I, Ia or Ib and one or more pharmaceutically acceptable carriers, diluents or adjuvants. In addition, this aspect of the invention provides a pharmaceutical composition for the treatment of Parkinson's disease, for example, cognitive impairment associated with Parkinson's disease, containing a compound of formula I, Ia or Ib and one or more pharmaceutically acceptable excipients, carriers or auxiliary agents. In another embodiment of this aspect of the invention, there is provided a pharmaceutical composition for alleviating a movement disorder associated with Parkinson's disease, comprising a compound of Formula I, Ia or Ib and one or more pharmaceutically acceptable excipients, carriers or adjuvants.

In another embodiment of this aspect of the invention, there is provided a pharmaceutical composition for the treatment of Alzheimer's disease, e.g., for alleviating cognitive impairment associated with Alzheimer's disease, comprising a compound of Formula I, Ia or Ib and one or more pharmaceutically acceptable excipients, carriers or adjuvants.

In another embodiment of this aspect of the invention, there is provided a pharmaceutical composition for the treatment of schizophrenia, e.g., for alleviating cognitive impairment associated with schizophrenia, comprising a compound of Formula I, Ia or Ib and one or more pharmaceutically acceptable excipients, carriers or adjuvants.

In another embodiment, the present invention provides a pharmaceutical composition for the treatment of ADHD comprising a compound of Formula I, Ia or Ib and one or more pharmaceutically acceptable excipients, carriers or adjuvants.

In addition, the present invention provides a method of treating Parkinson's disease, for example, cognitive impairment associated with Parkinson's disease, or, for example, alleviating motor impairment associated with Parkinson's disease, comprising administering to a patient in need thereof, an effective amount of a compound of formula I, Ia or Ib .

In addition, the present invention provides a method of treating Alzheimer's disease, for example, cognitive impairment associated with Alzheimer's disease, comprising administering to a patient in need thereof an effective amount of a compound of formula I, Ia or Ib.

In addition, the present invention provides a method for treating schizophrenia, eg cognitive impairment associated with schizophrenia, comprising administering to a patient in need thereof an effective amount of a compound of formula I, Ia or Ib.

In addition, the present invention provides a method of treating ADHD comprising administering to a patient in need thereof an effective amount of a compound of formula I, Ia or Ib.

In one embodiment of this aspect, the present invention provides a compound of formula I, Ia or Ib for use in the treatment of Parkinson's disease. In one specific embodiment, the invention provides a compound of formula I, Ia or Ib for use in the treatment of cognitive impairment associated with Parkinson's disease. In another specific embodiment, the invention provides a compound of formula I, Ia or Ib for use in alleviating a motor disorder associated with Parkinson's disease.

In addition, the present invention provides a compound of formula I, Ia or Ib for use in the treatment of schizophrenia, for example in the treatment of cognitive impairment associated with schizophrenia.

In addition, the present invention provides a compound of formula I, Ia or Ib for use in the treatment of ADHD.

In addition, the present invention provides a compound of formula I, Ia or Ib for use in the treatment of Alzheimer's disease, for example in the treatment of cognitive impairment associated with Alzheimer's disease.

In yet another aspect, the present invention provides the use of a compound of formula I, Ia or Ib in the manufacture of a medicament for the treatment of Parkinson's disease, for example, for the treatment of cognitive impairment associated with Parkinson's disease or the mitigation of motor impairment associated with Parkinson's disease.

In addition, the present invention provides the use of a compound of formula I, Ia or Ib in the manufacture of a medicament for the treatment of schizophrenia, for example for the treatment of cognitive impairment associated with schizophrenia.

In addition, the present invention provides the use of a compound of formula I, Ia or Ib in

- 4 041402 the manufacture of a drug for the treatment of Alzheimer's disease, for example, for the treatment of cognitive impairment associated with Alzheimer's disease.

In addition, the present invention provides the use of a compound of formula I, Ia or Ib in the manufacture of a medicament for the treatment of ADHD.

Although the compounds used in the methods of the present invention can be administered directly without the use of any formulation, the compounds are generally administered in the form of pharmaceutical compositions containing a compound of formula I, Ia or Ib as the active ingredient and at least at least one pharmaceutically acceptable carrier, diluent and/or auxiliary agent. These compositions can be administered by various routes, including oral, sublingual, intranasal, subcutaneous, intravenous and intramuscular. These pharmaceutical compositions and methods for their preparation are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy (University of the Sciences in Philadelphia, ed., 21st ^ed ., Lippincott Williams & Wilkins Co., 2005).

The compositions are preferably prepared in unit dosage form, where each dosage contains from about 0.5 to about 800 mg of the active ingredient. The term unit dosage form refers to physically discrete forms suitable for administration as unit dosages to a human subject and other mammals, where each unit form contains a predetermined amount of active substance that is calculated to provide the desired therapeutic effect, together with at least one suitable pharmaceutically acceptable carrier, diluent and/or auxiliary agent. It should be understood that the amount of compound actually administered will be determined by the clinician, taking into account relevant circumstances including the condition being treated, the mode of administration chosen, the compound or compounds actually administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms. It is contemplated that the compound of the invention, as for example in the pharmaceutical composition of the invention, will be used in the treatment of Alzheimer's disease, Parkinson's disease and/or schizophrenia, such as in the treatment of mild cognitive impairment associated with these diseases when administered on a long-term basis.

As used herein, the term patient refers to a mammal, such as a human, in need of treatment for a disorder or disease. The human is the preferred patient.

As used herein, the terms treatment or mitigation are intended to refer to all processes in which there may be a slowing, interruption, halt, control or halt in the progression of an existing disorder and/or a reduction in its symptoms, but does not necessarily indicate complete elimination of all symptoms.

As used herein, the term effective amount of a compound of formula I, Ia, or Ib refers to an amount, ie dosage, that is effective to enhance a dopamine-mediated response in a patient. A preferred effective amount can be defined as an amount that can promote wakefulness or anxiety in a patient compared to a patient without treatment. In determining an effective amount or dose of a compound of Formula I, Ia, or Ib, a number of factors are taken into account, including, but not limited to, the compound to be administered and its specific composition; patient size, age and general health; the extent of the lesion or the severity of the disorder; individual patient response; administration mode; and other relevant circumstances.

Pharmaceutically acceptable salts or pharmaceutically acceptable salt refers to a relatively non-toxic inorganic and organic salt or salts of the compounds according to the present invention. Those skilled in the art will appreciate that the compounds of this invention may form salts. The compounds of this invention contain basic heterocycles and, accordingly, react with any of a variety of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Such pharmaceutically acceptable acid addition salts and general procedures for their preparation are known in the art. See, for example, P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2008); S.M. Berge, et al., Pharmaceutical Salts, Journal of Pharmaceutical Sciences, Vol 66, no. 1, January 1977.

The abbreviations used in this document have the following definitions:

ABT stands for 1-aminobenzotriazole.

AMPA means a-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid.

Bn means benzyl

Saline means saturated NaCl.

BSA stands for bovine serum albumin cAMP stands for cyclic adenosine monophosphate.

CHO stands for Chinese Hamster Ovary.

DCM stands for dichloromethane.

- 5 041402

DMEM stands for Dulbecco's Modified Eagle's Medium

DMSO stands for dimethyl sulfoxide (perdeuterated [d6] if used for

NMR).

EC _x means the concentration of the test compound that gives x% of the maximum observed effect.

EtOAc is ethyl acetate.

EtOH means ethanol or ethyl alcohol.

FBS stands for fetal bovine serum.

HEPES stands for 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid.

HTRF stands for Homogeneous Time Resolved Fluorescence.

h means hour or hours.

IBMX means 3,7-dihydro-1-methyl-3-(2-methylpropyl)-1H-purine-2,6-dione.

LCMS stands for liquid chromatography - mass spectrometry.

LMA stands for locomotor activity.

MeOH means methanol or methyl alcohol.

min means minutes.

MOM stands for methoxymethyl.

MS stands for mass spectroscopy or mass spectrum.

PCR stands for polymerase chain reaction.

PG means protecting group

RAF stands for Relative Activity Factor.

SEM stands for standard error of the mean;

SEM, N means the standard error of the mean followed by the number of data points.

STIM stands for Stimulation Buffer (as defined herein).

THF stands for tetrahydrofuran.

TBDMS means tert-butyldimethylsilyl.

TBDPS means tert-butyldiphenylsilyl.

general chemistry

The compounds of the present invention may be prepared by general methods known and recognized in the art, or by the methods described herein. Suitable reaction conditions for the various steps of these reactions are known in the art, and appropriate substitutions of solvents and co-reagents are well known in the art. It will also be understood by those skilled in the art that synthetic intermediates can be isolated and/or purified by various known techniques, as needed or desired, and that various intermediates can often be used directly in subsequent synthetic steps with little or no purification. In addition, those skilled in the art will appreciate that in some cases the order in which fragments are introduced is not critical.

Scheme 1

Scheme 1 shows the preparation of compound 8. One skilled in the art will appreciate that commercially available and suitably 2-substituted phenylalanine 1 (e.g., X=Br, Cl, I) dissolved in a polar protic solvent can be esterified with an appropriate strong acid to give esterified salt 2. Subsequent acylation by washing the salt with aqueous base to give the free base, dissolution in an aprotic solvent and addition of the appropriate acid chloride can be done to give 3. Cyclization of the 2-substituted N-acylated phenylalanine methyl ester 3 by treatment with paraformaldehyde in an appropriate strong acid and stirring to give tetrahydroisoquinoline 4 is well known in the art. Demethylation and decarboxylation can be carried out by treatment with aqueous acid and stirring under reflux to give 5 as the corresponding amine salt. One skilled in the art will appreciate that the N-protected tetrahydroisoquinoline 6 may be

- 6 041402 is formed by dissolving the amine salt 5 in a suitable polar aprotic solvent, adding a base and a suitable anhydride or alkyl chloroformate to give tert-butyl carbamate 6. Subsequent reduction to a methanol derivative 7 can be carried out using a set of reducing agents such as metal hydride, borohydride salt or diborane in a polar aprotic solvent. The O-protected tetrahydroisoquinoline 8 can be obtained by first treating the N-protected tetrahydroisoquinoline 7 with an appropriate strong acid and concentrating in vacuo. The amine salt can then be dissolved in a suitable aprotic solvent, treated with a base and a suitable protecting group (PG) (e.g. PG=OSi, OBn, OMOM, etc.) to give 8. For example, protecting a primary alcohol with an acid-stable silyl group such as TBDMS or TBDPS is well known in the art.

Scheme 2

Scheme 2 shows the synthesis of type I' compounds. Formation of the imine from tetrahydroisoquinoline 8 can be carried out under various oxidizing conditions known to the skilled artisan, in particular halogenation of the secondary amine and subsequent elimination with a suitable strong base to give dihydroisoquinoline 9. A stereoselective Grignard reaction can be used by treating imine 9 with an appropriate alkylmagnesium halide to give transtetrahydroisoquinoline 10. The relative configuration of tetrahydroisoquinoline 10 can be determined using an appropriate NMR spectroscopic experiment, in particular 1D-NOESY. Subsequent N-acylation can be carried out using amide condensation methods well known in the art, for example benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate in the presence of a weak non-nucleophilic base to give compound 11. , Cl, I, etc.) can be carried out under transition metal catalysis, for example using Pd, Pt, Ni or Cu, with a suitable aryl or heteroaryl boronic acid or ester, as is well known in the art. For example, condensation of Suzuki 11 with an appropriately substituted N-methylpyrrazolboronate can be done to give 12. The skilled artisan will appreciate that deprotection of protected alcohol 12 where PG=OSi, OBn, OMOM, etc., can be done at various conditions. For example, a silyl protecting group can be removed with tetrabutylammonium fluoride to give type I' chiral compounds.

Scheme 3

Scheme 3 shows an alternative synthesis of type I' compounds in which, at elevated temperatures, cyclization of the 2-substituted N-acylated phenylalanine methyl ester 3 by treatment with paraformaldehyde in a suitable strong acid can give a mixture of tetrahydroisoquinoline methyl ester 4 and carboxylic acid 13, as will be apparent to one skilled in the art. this field of technology. A mixture of methyl ester 4 and carboxylic acid 13 can be treated with an appropriate aqueous acid to completely hydrolyze the ester to give the carboxylic acid amine salt.

- 7 041402 voic acid 14. Subsequent reduction to the methanol derivative 15 can be carried out using a set of reducing agents such as a metal hydride, borohydride salt or diborane in a polar aprotic solvent. The O-protected dihydroisoquinoline 16 can be prepared by treating with a suitable base and adding an appropriate protecting group as described previously in Scheme 1 and as is customary in the art, followed by halogenation of the secondary amine followed by elimination with a suitable strong base and stirring with oxalic acid with obtaining the dihydroisoquinoline oxalate salt 16. Stereoselective methylation can be accomplished by first treating the imoxalate salt 16 with an aqueous base and extracting with a suitable organic solvent to give the free base. The Grignard reaction can then be used by treatment with an appropriate alkylmagnesium halide followed by stirring with concentrated sulfuric acid to give transtetrahydroisoquinoline hemisulfate 17. The relative configuration of tetrahydroisoquinoline 17 can be determined using an appropriate NMR spectroscopic experiment, in particular 1D-NOESY. One skilled in the art will appreciate that trans-tetrahydroisoquinoline hemisulfate 17 can be converted to the free base by adding a suitable aqueous base and then extracting with a suitable organic solvent. N-acylation of said free base can be carried out using amide coupling techniques well known in the art, e.g., 1-propanephosphonic anhydride in the presence of a mild non-nucleophilic base, to give compound 11. Aryl condensation using an appropriately substituted compound 11 (e.g., X = Br, Cl, I, etc.) can be carried out under transition metal catalysis, for example using Pd, Pt, Ni or Cu, with a suitable aryl or heteroaryl boronic acid or ester, as is well known in the art. For example, condensation of Suzuki 11 with an appropriately substituted N-methylpyrrazolboronate can be performed to give 12. The skilled artisan will appreciate that deprotection of the protected alcohol 12 is similar to that described in Scheme 2 to give Type I' compounds.

In the following illustrative preparations and examples, the solvents are typically removed under reduced pressure (evaporated). In some procedures, the reported yields are representative of the crude yields of products isolated by evaporation or filtration and used directly without further purification.

Preparation 1. Methyl 2-bromo-D-phenylalaninate hydrochloride

HCI

Dissolve 2-bromo-D-phenylalanine (22.4 g, 91.8 mmol) in MeOH (459 ml). Add acetyl chloride (65.3 mL, 917.7 mmol) at room temperature and stir for 36 h. Concentrate under reduced pressure to give the title compound (27.2 g, >99% yield).

MS: m/z 258/260 [M-Cl, ⁷⁹ Br/ ⁸¹ Br].

Alternatively, add acetyl chloride (562.79 g, 7.17 mol) to MeOH (10.00 L) at 0°C. The mixture is heated to 17.5° C. and stirred for 30 minutes. Add 2-bromo-D-phenylalanine (500.00 g, 2.05 mol) and heat to reflux for 4 hours. The mixture was cooled to 20° C. and the solvent removed under reduced pressure to give the title compound (589 g, 96% yield) as an off-white solid.

MS: m/z 258/260 [M-Cl, ⁷⁹ Br/ ⁸¹ Br].

Preparation 2 Methyl 2-bromo-N-(methoxycarbonyl)-D-phenylalaninate.

Br O

Dissolve methyl 2-bromo-D-phenylalaninate hydrochloride (27.2 g, 92.3 mmol) in dichloromethane (923 ml) and water (185 ml). Add sodium bicarbonate (31.0 g, 369.4 mmol) and methyl chloroformate (7.86 ml, 101.6 mmol) at room temperature and stir for 2.5 h. Dilute with water and extract with dichloromethane. The dichloromethane extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. Purify the residue by silica gel chromatography eluting with EtOAc:hexanes (10-75% gradient) to give the title compound (29.1 g, 99%).

MS: m/z 316/318 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Alternatively, add water (2.94 L) and sodium hydrogen carbonate (648.25 g, 7.64 mol) to methyl 2-bromo-D-phenylalaninate hydrochloride (580 g, 1.91 mol) in dichloromethane (9, 86 l) at 10°C. After 5 minutes, methyl chloroformate (198.5 g, 2.10 mol) is added and the mixture is stirred at 20° C. for 3 hours. Water (2.5 L) is added and the layers are separated. The aqueous layer is extracted with dichloromethane, the combined organic extracts are dried over sodium sulfate and concentrated under reduced pressure with

- 8 041402 to obtain the title compound (556 g, 91% yield).

MS (m/z): 315/317 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Preparation 3. Dimethyl (3R)-5-bromo-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylate

Stir a mixture of methyl 2-bromo-N-(methoxycarbonyl)-D-phenylalaninate (29.1 g, 92.1 mmol) and paraformaldehyde (9.13 g, 101.3 mmol) in glacial acetic acid (115 mL, 2 .0 mol) and concentrated sulfuric acid (38.4 ml, 719.9 mmol) at room temperature for 7 hours. Partition between water and EtOAc. Separate the layers and extract the aqueous layer with EtOAc. Combine the EtOAc extracts and dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with EtOAc:hexanes (5-40% gradient) to give the title compound (27.6 g, 91%).

MS: m/z 328/330 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Getting 3a.

Dimethyl (3R)-5-bromo-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylate (3a) and (3R)-5-6pom-2methoxycarbonyl-3,4-dihydro-1H-isoquinoline-3 -carboxylic acid (3b)

Add methyl 2-bromo-N-(methoxycarbonyl)-D-phenylalaninate (572 g, 1.81 mol) and paraformal dehyde (205.9 g, 2.17 mol) to acetic acid (4.3 L) at 10° WITH. After 10 minutes, concentrated sulfuric acid (2.63 kg, 26.83 mol) was added slowly and stirred at 35°C for 12 hours. The reaction mixture was cooled to 15°C and water (7.5 L) and EtOAc (6 l). Separate the layers and re-extract the aqueous fraction with EtOAc (2.5 L). Dry the combined organic extracts over sodium sulfate, filter and concentrate under reduced pressure to give a mixture of the title compounds with acetic acid (640 g, >97% yield).

MS (m/z): 3a: 328/330 [M+H, ⁷⁹ Br/ ⁸¹ Br], 3b: 314/316 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Preparation 4. Methyl (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride

6g about 0eC

HCI

Dissolve dimethyl (3R)-5-bromo-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylate (27.6 g, 84.0 mmol) in 5N. HCl (330.6 ml, 1.7 mol) and heated to reflux for three days. Evaporated under reduced pressure to give a white solid. The solid is washed with diethyl ether and dried in vacuo at 40° C. overnight to give (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1:1) (20.8 g, 71.1 mmol). Add acetyl chloride (50.6 ml, 711.0 mmol) to a mixture of (3R)-5-bromo-l,2,3,4-tetrahydroisoquinoline-3carboxylic acid hydrochloride (1:1) at 0°C (20.8 g , 71.1 mmol) in MeOH (474 ml). Warm to room temperature and stir 36 hours. Concentrate under reduced pressure and dry to give the title compound (21.9 g, 85% yield).

MS: m/z 270/272 [M-Cl, ⁷⁹ Br/ ⁸¹ Br].

Preparation 5 (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride

Vg O

AUXIN

HCl

Add water (1.3 L) and 36.5% hydrochloric acid (9.1 kg, 90.8 mol) to a mixture of dimethyl (3R)-5-6pom3,4-dihydro-1 H-isoquinoline-2,3- dicarboxylate and (3R)-5-bromo-2-methoxycarbonyl-3,4-dihydro-1H-isoquinoline-3-carboxylic acid (520 g, 1.27 mol) and the mixture was stirred at 95°C for 12 hours. The mixture is cooled to 10°C and stirred for another 15 minutes. The mixture is filtered and the solid is dried in vacuo at 40° C. to give the title compound (332 g, 89% yield).

MS (m/z): 256/258 [M-Cl, ⁷⁹ Br/ ⁸¹ Br].

Preparation 6 2-tert-Butyl-3-methyl-(3R)-5-bromo-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylate

- 9 041402

Dissolve methyl (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (21.0 g, 68.5 mmol) in 1,4-dioxane (685 ml). Add a saturated solution of sodium bicarbonate (685 ml, 17.5 mol) and di-t-butyl dicarbonate (29.9 g, 137.0 mmol) at room temperature and stir the biphasic mixture for 90 minutes. Extract with EtOAc. The organic layer is dried over sodium sulfate, filtered and evaporated under reduced pressure. Purify the residue by silica gel chromatography eluting with EtOAc:hexanes (5-50% gradient) to give the title compound (19.5 g, 77%). MS (m/z): 270/272 [M- ^t Boc+H, ⁷⁹ Br/ ⁸¹ Br].

Preparation 7 [(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol

Add lithium aluminum hydride (2 L, 2.00 mol, 1M in THF) to (3R)-5-6pom-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid hydrochloride (325.4 g, 1.11 mol) in THF (4.88 l) at -35°C. Heat to 25°C for 60 min with stirring. After 3 h, cool the mixture to -5°C, add water (76 ml), add 15% aqueous sodium hydroxide (76 ml) and then additional water (228 ml). The mixture is heated to 25° C., anhydrous magnesium sulfate (750 g) is added with stirring. Filter the mixture and concentrate under reduced pressure to give a solid residue. Dichloromethane (690 ml) was added to the solid and stirred for 30 minutes before filtering to give a solid. Dry the solid in vacuo at 35° C. to give the title compound (148.9 g, 59% yield). MS (m/z): 242/244 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Preparation 8. tert-Butyl(3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

Add methanol (10.1 ml, 248.5 mmol) and lithium borohydride (99.4 ml, 198.8 mmol, 2M in THF) to a solution of 2-tert-butyl-3-methyl-(3R)-5-bromo -3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid (18.4 g, 49.7 mmol) in THF (497 ml) at room temperature on a water bath. Stirred for 40 min and quenched with water. Extract with ethyl acetate. Dry the ethyl acetate extracts over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by chromatography on silica gel eluting with ethyl acetate:hexanes (5-80% gradient). Dry under high vacuum overnight to give the title compound as a white solid (19.1 g, >99% yield).

MS (m/z): 286/288 [M-'Bu+H, ⁷⁹ Br/ ⁸¹ Br].

Preparation 9 [(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxytert-butyldimethylsilane.

Add trifluoroacetic acid (75.5 mL, 998.3 mmol) to a solution of tert-butyl(3R)-5-bromo-3(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (15.5 g , 45.3 mmol) in dichloromethane (226 ml) at room temperature. Stirred for 30 minutes and concentrated under reduced pressure. Dry in vacuo to give [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2trifluoroacetic acid as a wet solid. Dissolve [(3R)-5-6pom-1,2,3,4tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid in dichloromethane (753 ml). 1H-imidazole (51.3 g, 753 mmol), K,K-dimethyl-4-pyridinamine (460 mg, 3.77 mmol) and tert-butyldimethylchlorosilane (13.6 g, 90.4 mmol) are added. Stir at room temperature overnight. Add saturated ammonium chloride solution and extract with dichloromethane. The dichloromethane extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. Combine with crude product from essentially the same reaction cycle with tert-butyl(3R)-5-bromo-3(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (6.6 g, 19.4 mmol ). Purify the residue by silica gel chromatography eluting with ethyl acetate:hexanes (5-40% gradient) to give the title compound (14.3 g, 89%). MS (m/z): 356/358 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Alternative synthesis of [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxytert-butyldimethylsilane

Add tert-butyldimethylchlorosilane (193.7 g, 1.3 mol) to a mixture of [(3R)-5-6pom-1,2,3,4tetrahydroisoquinolin-3-yl]methanol (148.9 g, 0.6 mol) , 1H-imidazole (202.9 g, 2.92 mol), 4-dimethylaminopyridine (720 mg, 5.8 mmol) and K,K-dimethylformamide (1.04 L) in dichloromethane (2.61 L) at 20°C and mix in an appropriate vessel. After 3 hours, the mixture is cooled to 10° C. and saturated aqueous ammonium chloride solution (1.3 L) is added. The aqueous solution was extracted with dichloromethane and the combined organic extracts were washed with brine (2x2 L), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue is taken up in methyl tert-butyl ether (1.5 L) and washed with brine (2x1 L). The organic phase is diluted with toluene (5 L) and

- 10 041402 concentrated under reduced pressure, obtaining the residue. Toluene (2.6 L) was added to the residue and concentrated under reduced pressure to give the title compound (210 g, yield

81%).

MS (m/z). 356/358 [M+H, ⁷⁹ Br/ ⁸¹ Br].

^Preparation 10

Dissolve [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane (4.2 g, 11.8 mmol) in diethyl ether (118 ml). N-chlorosuccinimide (2.36 g, 17.7 mmol) is added. Stir 30 minutes at room temperature and concentrate under reduced pressure. The residue was dissolved in potassium hydroxide (42.0 ml, 30.3 mmol, 5% in MeOH) and stirred for 30 minutes at room temperature. Pour into water and extract with dichloromethane. The dichloromethane extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. Purify the residue by silica gel chromatography eluting with ethyl acetate:hexanes (5-100% gradient) to give the title compound (3.40 g, 82%). MS (m/z): 354/356 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Alternative synthesis of [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane.

Add N-chlorosuccinimide (106.7 g, 790 mmol) to a solution of [(3R)-5-6pom-3,4dihydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane. (220 g, 520 mmol) in tetrahydrofuran (3.85 L) at 20° C. in a suitable vessel and stirred. After 30 minutes, the mixture is concentrated under reduced pressure and the residues are dissolved in 5% w/w. potassium hydroxide in methanol (2.2 l, 1.7 mol) and stirred at 20°C. After 30 minutes, add the mixture to water (3 L) and extract three times with dichloromethane (3x1 L). Dry the combined organic extracts over anhydrous magnesium sulfate and concentrate under reduced pressure to give the title compound (210 g, >99% yield). MS (m/z): 354/356 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Preparation 11 [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane

V. o- ^s '^ώ/

Dissolve [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane (3.4 g, 9.6 mmol) in diethyl ether (160 ml). Cool to -78°C in a dry ice-acetone bath. A 3M solution of methylmagnesium chloride in THF (26.9 ml, 80.6 mmol) was added dropwise. Slowly warm the reaction mixture to room temperature and stir overnight. Quench slowly with saturated ammonium chloride solution. Extract with dichloromethane and dry over sodium sulfate, filter and evaporate under reduced pressure. The crude product of essentially the same reaction is combined with 1.7 mmol of [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane. The combined residues were purified by silica gel chromatography eluting with ethyl acetate:hexanes (565% gradient) to give the title compound (3.78 g, >99% yield).

MS (m/z): 370/372 [M+H, ⁷⁹ Br ⁸¹ Br].

The relative configuration of the compound [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin3-yl]methoxytert-butyldimethylsilane is determined by NMR spectroscopy using one-dimensional NEO experiments (1D-NOESY). Selective excitation of the methyl group at 1.30 ppm leads to NOE for Ha at 3.11 ppm. This NOE enhancement is only consistent with a configuration in which methyl and Na are on the same side of the ring (the trans isomer), because in the cis isomer the methyl protons are too far away from Na to show NOE. Since the absolute chemical position for position 3 is known to be R, the absolute chemical position for position 1 is assumed to be S.

Br °, —y-Na ^Hc Hb Me

Alternative synthesis of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane

- 11 041402

Add a 3M solution of methylmagnesium chloride in THF (0.66 L, 1.99 mol) to a solution of [(3R)-5-6pom-3,4dihydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane (93.5 g, 0.2 mol) in diethyl ether (2.8 l) at -65°C in an appropriate vessel. Heat the reaction mixture to 20°C for 2 h and stir. After 16 hours, cool the mixture to 0°C and quench the reaction with saturated aqueous ammonium chloride (2.5 L), extract with ethyl acetate (2.5 L) and filter the mixture. The combined organic extracts were washed with brine (1 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crude title compound as an oil. Combine the oil with crude products from essentially the same reactions of [(3R)-5-bromo-3,4-dihydroisoquinolin3-yl]methoxy-tert-butyldimethylsilane and purify the combined crude products by chromatography on silica gel eluting with ethyl acetate in hexanes (gradient 5-65% ethyl acetate) to give the title compound (151 g, 97% yield, combined from 2 experimental steps). MS (m/z): 370/372 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Preparation 12 -(2,6-dichlorophenyl)ethanone

Add benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (7.9 g, 15.3 mmol) to the mixture of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl ]methoxy-tert-butyldimethylsilane (3.78 g, 10.2 mmol) and 2,6-dichlorophenylacetic acid (2.3 g, 11.2 mmol) in dimethylformamide (51.0 ml). Triethylamine (2.1 ml, 15.3 mmol) is added and stirred at room temperature for 3 hours. Dilute with water and extract with dichloromethane. The dichloromethane extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. Purify the residue by silica gel chromatography eluting with ethyl acetate:hexanes (0-50% gradient) to give the title compound (4.7 g, 55% yield).

MS: m/z 556/558 [M+H, ³⁵ Cl/ ³⁷ Cl)].

The following compounds were prepared essentially by the method described in Preparation 12.

Cooking No. Name Structure Physical Data 13 1-((1 S,3R)-5-bromo-3-(((τpetbutyldimethylsilyl)oxi)methyl)1-methyl-3,4-dihydroisoquinoline- 2(1Н)-yl)-2-(2-chloro-6- fluorophenyl)ethan-1-one ι.Λτ Br O' ^Sk cr MS (m/z): 540 (M+H)

- 12 041402

14 1-((1 S, _3R )-5-6poM-3-((( T - difluorophenyl)ethan-1-one Вг ό Ζ—/ o=( '—O A j MS (m/z): 524 (M+H) 15 1-((1 S,3R)-5-6poM-3-(((Tp etbutyldimethylsilyl)oxy)methyl)1-methyl-3,4-dihydroisoquinoline- 2( 1H)-yl)-2-(2-chloro-5 fluorophenyl)ethan-1-one Vg & and Y- V o - ) \u003d o to MS (m/z): 540 (M+H) 16 1-((1 S,3R)-5-6poM-3-(((Tp etbutyldimethylsilyl)oxy)methyl)1-methyl-3,4-dihydroisoquinoline- 2(1Н)-yl)-2-(2-chloro-4fluorophenyl)ethan-1-one Vg & । o' ^Si ι /A g XXX MS (m/z): 540 (M+H) 17 1-((1 S,3R)-5-6poM-3-((( _T peTbutyldimethylsilyl)oxy)methyl)1-methyl-3,4-dihydroisoquinolin2(1H)-yl)-2-(2-fluorophenyl)ethane - 1-he ά MS (m/z): 506 (M+H) 18 1-((1 S,3R)-5-6poM-3-((( _T - difluorophenyl)ethan-1-one Вг ό 1 Ag F MS (m/z): 524 (M+H) 19 1-((1 S,3R)-5-6poM-3-(((Tp etbutyldimethylsilyl)oxy)methyl)1-methyl-3,4-dihydroisoquinoline- 2(1Н)-yl)-2-(2, 5- difluorophenyl)ethan-1-one Vg th I o' ^Si 1 ^r MS (m/z): 524 (M+H) 20 l-((lS,3R)-5-6poM-3-((( _T peTbutyldimethylsilyl)oxy)methyl)1-methyl-3,4-dihydroisoquinolin2(1H)-yl)-2-(2-chlorophenyl)ethane -1 he Вг ό oA J ^Ύ w MS (m/z): 522 (M+H)

Preparation 21 1-((1S,3R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1-methyl-1Hpyrazol-4-yl)-3,4-dihydroisoquinoline -2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one

Dissolve 1-((1S,3R)-5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2 ,6-dichlorophenyl)ethan-1-one (200 mg; 0.4 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl1,3,2-dioxa-2-yl)pyrazole (149 mg; 0.7 mmol) in 1,4-dioxane (3.6 ml). Add 0.2 M aqueous sodium carbonate solution (1.8 ml, 0/4 mmol) and sparge with nitrogen for 10 minutes. Bis(triphenylphosphine)palladium(II) chloride (50 mg, 72 µmol) is added. Heat to 90°C for 2 hours. Cool to ambient temperature, dilute with water, extract with EtOAc, dry over sodium sulfate, filter, concentrate and purify by silica gel chromatography eluting with a gradient of 5 to 50% EtOAc in hexanes to give the title in title compound (195 mg, 97% yield) MS: m/z 558/560 [M+H, ³⁵ Cl/ ³⁷ Cl].

The following compounds were prepared essentially by the method of Preparation 21 using 2( 1 H)-yl)2-(2,6-dichlorophenyl)ethan-1-one and a suitably substituted pyrazoloboronic acid or boronic ester derivative.

- 13 041402

Cooking No. Name Structure Physical Data 22 1-((1S,3R)-3-(((TpeTbutyldimethylsilyl)oxy)methyl)-5-(1-ethyl-1Hpyrazol-4-yl)-1-methyl3,4-dihydroisoquinoline- 2(1H)-yl)-2-(2,6dichlorophenyl)ethan-1-one G~ . N-N I K γ X MS (m/z): 572/574 [M+H, ³⁵ C1/ ³⁷ C1] 23 1-((1 S,3R)-3-(((Tperbutyldimethylsilyl)oxy)methyl)-5-(1cyclopropyl-1Hpyrazol-4-yl)-1-methyl3,4-dihydroisoquinoline- 2(1H)-yl)-2-(2,6dichlorophenyl)ethan-1-one N-N^I K γ X Cl MS (m/z): 584/586 [M+H, ³⁵ C1/ ³⁷ C1] 24 1-((1 S,3R)-3-(((TpeTbutyldimethylsilyl)oxy)methyl)-1-methyl-5-(1- (oxetan-3-and l)-1Hpyrazol-4-yl)-3,4dihydroisoquinolin2(1H)-yl)-2-(2-chloro-6fluorophenyl)ethan-1-one £ , NN 1 V oA ¹ °C!” MS (m/z): 584/586 [M+H, ³⁵ C1/ ³⁷ C1] 25 1-((1 S,3R)-5-(l-(2-((rpeTbutyldimethylsilyl)oxy)ethyl)-1 H-pyrazol-4-yl)3-(((tert-butyldimethylsilyl)oxy)methyl)-1 - methyl-3,4dihydroisoquinoline- 2(1Н)-yl)-2-(2chlorophenyl)ethan-1-one y ^si A NN I 1 MS (m/z): 668/670 [M+H, ³⁵ C1/ ³⁷ C1] 26 1-((1 S,3R)-3-(((TpeTbutyldimethylsilyl)oxy)methyl)-1-methyl-5-(1methyl-1H-pyrazol-4-yl)3,4-dihydroisoquinolin- 2(1Н)-yl)-2-(2chlorophenyl)ethan-1-one / , N-N I . γ Ji >x> Cl MS (m/z): 524/526 [M+H, ³⁵ C1/ ³⁷ C1]

Preparation 27 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-pyrazole

Dissolve 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 g, 5.2 mmol) in dimethylformamide (20 ml), add cesium carbonate (3.358 g; 10.3 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.356 g, 5.7 mmol). Heat to 60°C for 3 hours. Dilute with water and extract twice with dichloromethane, dry over sodium sulfate, filter, concentrate and purify by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to give the title compound (1 .2 g, 67% yield.

MS (m/z): 353 [M+H].

Preparation 28 Benzyl (1S,3R)-5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3,4dihydroisoquinoline-2( 1 H)-carboxylate

Dissolve [(1 S,3R)-5-6pom-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane (2.1 g, 5.7 mmol) in acetonitrile ( 28.5 ml). Potassium carbonate (2.362 g, 17.089 mmol) and benzyl chloroformate (1 mL, 6.8 mmol) are added. Stir overnight, dilute with saturated aqueous ammonium chloride and extract twice with dichloromethane, dry over sodium sulfate, filter, concentrate and purify by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to give the title compound (3 g, >99% yield.

MS: 504/506 [M+H, ⁷⁹ Br/ ⁸¹ Br)].

Preparation 29 Benzyl (1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1-(oxetan3-yl)-1H-pyrazol-4-yl)-3 ,4-dihydroisoquinoline-2( 1 H)-carboxyαt

- 14 041402

Dissolve benzyl (1S,3R)-5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3,4dihydroisoquinoline-2(1H)-carboxylate (500 mg; 1 mmol) and 1- (oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole (297 mg; 1.2 mmol) in 1,4-dioxane (9.9 ml). Add 0.2 M aqueous sodium carbonate solution (5.0 ml, 1 mmol) and sparge with nitrogen for 10 minutes. Bis(triphenylphosphine)palladium(II) chloride (139 mg, 198 µmol) is added. Heat to 80°C for 2 hours. Cool to ambient temperature, dilute with water, extract with EtOAc, dry over sodium sulfate, filter, concentrate and purify by silica gel chromatography eluting with a gradient of 5 to 50% EtOAc in hexanes to give the title in the title compound (180 mg, 33% yield).

MS: m/z 548 [M+H].

Preparation 30 (1S,3R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1-(oxetan-3-yl)1 H-pyrazol-4-yl)-1 ,2,3,4-tetrahydroisoquinoline

Add benzyl (1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1-(oxetan-3-yl)H-pyrazol-4-yl)-3.4 -dihydroisoquinoline-2(III)-carboxylate (180 mg 0.3 mmol) and palladium on carbon (17.5 mg, 16.4 μmol) in ethanol (6.5 ml). Stir under balloon hydrogen for 4 hours. Filter through celite, wash with EtOAc, evaporate to give the crude title compound (140 mg, >99% yield). MS: m/z 414 [M+H].

Preparation 31 1-((1S,3R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-methyl-5-( 1-(oxetan-3 yl)-1 H-pyrazol-4-yl )-3,4-dihydroisoquinolin-2( 1 H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one

Dissolve (1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1-(oxetan-3-yl)-1Hpyrazol-4-yl)-1,2,3 ,4-tetrahydroisoquinoline (136.5 mg, 0.3 mmol) and 2,6-dichlorophenylacetic acid (74.4 mg, 0.3 mmol) in dichloromethane (3.3 ml). Add O-(7-azabenzotriazol-1-yl)-N,N,N',N'tetramethyluronium hexafluorophosphate (188.2 mg, 0.5 mmol) and N,N'-diisopropylethylamine (86.32 µl, 0. 5 mmol). The resulting mixture was stirred for 2 hours. Dilute with water, extract twice with dichloromethane, dry over sodium sulfate, filter, concentrate in vacuo and purify by silica gel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes to give the title compound (166 mg, yield 84%). MS: m/z 600/602 [M+H, ³⁵ Cl/ ³⁷ Cl].

Example 1 2-(2,6-Dichlorophenyl)-1-((1 S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4yl)-3, 4-dihydroisoquinolin-2(1 H)-yl)ethan-1-one

Add tetrabutylammonium fluoride (1M in THF, 0.4 ml) to a solution of l-[(1S,3R)-3-[(tert-butyl(dimethyl)silyl)oxymethyl]-1-methyl-5-(1-methylpyrazole-4- yl)-3,4-dihydro-1 H-isoquinolin-2-yl]-2(2,6-dichlorophenyl)ethanone (195 mg, 0.3 mmol) in THF (3.5 ml) at room temperature. Stir 4 hours. Quench with saturated aqueous ammonium chloride, extract three times with EtOAc, dry over sodium sulfate, filter, concentrate and purify by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes to give the title compound as a white foam. (141 mg, 91% yield).

MS: m/z 444/446 [M+H, ³⁵ Cl/ ³⁷ Cl].

The following compounds were obtained essentially using the method described in example 1.

- 15 041402

Example No. Name Structure Physical Data 2 2-(2,6-dichlorophenyl)-1 - ((lS,ЗR)-5-(l-ethyl-lH- pyrazol-4-yl)-3(hydroxymethyl)-1-methyl3,4-dihydroisoquinolin2( 1Н)-yl)ethan-1-one oz 45 ^Ί o \u003d (\u003e - o MS (m/z): 458/460 [M+H, ³⁵ C1/ ³⁷ C1] 3 1-((1 S,3R)-5-(lcyclopropyl-1 H-pyrazol4-yl)-3 -(hydroxymethyl)-1 methyl-3,4- dihydroisoquinolin-2(1H)yl)-2-(2,6d ichlorophenyl)ethan-1-one Ν-Ν 0+ MS (m/z): 470/472 [M+H, ³⁵ C1/ ³⁷ C1] 4 2-(2,6-dichlorophenyl)-1 ((lS,3R)-3(hydroxymethyl)-1-methyl5-(1-(oxetan-3-yl)-1Hpyrazol-4-yl)-3,4dihydroisoquinoline-2 (1Н)yl)ethan-1-one £3 N-N TONE Λ-φ a co MS (m/z): 486/488 [M+H, ³⁵ C1/ ³⁷ C1] 5 l-((lS,3R)-5-(l-(2-(ll- oxidaneyl)ethyl)-1Hpyrazol-4-yl)-3(hydroxymethyl)-1-methyl3,4-d ihydroisoquinolin2(1H)-yl)-2-(2chlorophenyl)ethan-1-one He S N-N γ he OO OO MS (m/z): 440/442 [M+H, ³⁵ C1/ ³⁷ C1] 6 2-(2-chloro-6-fluorophenyl)-1 ((lS,3R)-3(hydroxymethyl)-1-methyl5-(1-(oxetan-3-yl)-1Hpyrazol-4-yl)-3,4dihydroisoquinoline -2(1Н)yl)ethan-1-one N-N OH ^00 MS (m/z): 470/472 [M+H, ³⁵ C1/ ³⁷ C1] 7 2-(2-chlorophenyl)-1 -((1 S,3R)3 -(hydroxymethyl)-1 methyl- 5 -(1-methyl-1Hpyrazol-4-yl)-3,4- dihydroisoquinolin-2(1Н)yl)ethan-1-one n-v' V he Fpe MS (m/z): 410/412 [M+H, ³⁵ C1/ ³⁷ C1]

Preparation 32 (R)-5-bromo-3-(((tert-Butyldiphenylsilyl)oxy)methyl)-3,4-dihydroisoquinoline, oxalate salt

Add (1H)-imidazole (30.7 g, 0.4 mol) to a solution of (3R)-(5-bromo-1,2,3,4-tetrahydroisoquinolin3-yl)methanol (69.0 g, 0.3 mol) in dichloromethane (459.0 g, 5.4 mol) at room temperature and stirred for 20 minutes. tert-Butylchlorodiphenylsilane (100.4 g, 0.4 mol) is added dropwise. Stir at room temperature for 12 hours. Cool to 0°C.

Triethylamine (100.2 g, 1.0 mol) is added at 0° C. and stirred for 20 minutes. Add N-chlorosuccinimide (60 g, 0.45 mol) in portions keeping the temperature <5°C and stir at 0°C for 12 h. Add 15% ammonium chloride aqueous solution keeping the temperature <5°C and stir at for 2 h at 0°C. Extract the organic layer and wash twice with water. Concentrate under reduced pressure and add EtOAc. Add oxalic acid (30.8 g, 0.3 mol) and stir 10 h at 40°C. The mixture is filtered and the collected solid is washed with water. Dry the solids at 45°C for 16 hours to give the title intermediate (131.9 g, 74.6% yield).

MS (m/z): 478.0/480 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Preparation 33 (1 S,3R)-5-Bromo-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methyl-1,2,3,4tetrahydroisoquinoline, hemisulfate

- 16 041402

Add a mixture of potassium carbonate (9.7 g, 70.3 mmol) in water (200 ml) to a solution of (R)-5-bromo-3-(((tert-butyldiphenylsilyl)oxy)methyl)-3,4-dihydroisoquinoline ( 20 g, 35.2 mmol) in dichloromethane (280 g, 3.3 mol). Stir at 25° C. for 2 hours. Extract the organic layer and wash with water. Concentrate under reduced pressure and add dry THF (repeat). Add dry THF (360 g, 5.0 mol) and cool to -75°C. Trimethylsilyl chloride (6 g, 55.0 mmol) was added and stirred for 30 minutes. Portions add 1M solution of methyllithium in THF (77 g, 90.6 mol), maintaining the temperature <-70°C. Stirred for 6 hours at -75°C. Slowly add a saturated solution of ammonium chloride, maintaining the temperature <0°C. Warm to room temperature, add water and EtOAc and stir for 2 h. The organic layer is extracted and washed with water and saturated aqueous NaCl. Concentrate under reduced pressure and add EtOAc (145 g, 1.65 mol). Add concentrated sulfuric acid (1.4 g, 14.3 mmol) in portions and stir at 50° C. for 4 hours. Cool to 20° C. and stir for 16 hours. The mixture is filtered and the cake is washed with EtOAc. Dry the solids at 45°C for 16 hours. Dissolve the solids in THF (63 g, 0.9 mol) and heat to 50°C. Stir for one hour and slowly add EtOAc (108 g), maintaining the temperature at 45-50°C. Stirred for 1 h and cooled to 20°C. Stir for 6 h, then filter and collect the solids. The filter cake was washed with EtOAc and the solids were dried at 45° C. to give the title intermediate (9.9 g, 57% yield).

MS (m/z): 494/496 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Preparation 34 [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldiphenylsilane

Stir a solution of (1S,3R)-5-bromo-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methyl-1,2,3,4tetrahydroisoquinoline, hemisulfate (91.0 g, 167.4 mmol) in dichloromethane (700 ml) and a solution of sodium carbonate (145.5 g, 1373.0 mmol) in water (700 ml) was added and stirred at ambient temperature for 15 minutes. The layers are separated and the aqueous layer is extracted with dichloromethane (250 ml). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated to give the title compound as a yellow-orange oil (86.5 g, 95% yield, sufficient purity for further use).

MS: m/z 494/496 [M+H, ⁷⁹ Br/ ⁸¹ Br].

Preparation 35 1-[(1S,3R)-5-Bromo-3-[[t-butyl(diphenyl)silyl]oxymethyl]-1-methyl-3,4dihydro-1H-isoquinolin-2-yl]-2- (2,6-dichlorophenyl)ethanone

Dissolve [(1 S,3R)-5-6pom-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldiphenylsilane (86.5 g, 159.1 mmol) in acetonitrile (750 ml ) and add trimethylamine (50 ml, 359 mmol) and 2-(2,6-dichlorophenyl)acetic acid (38.4 g, 187.0 mmol) and stir the mixture for 5 minutes. The mixture is cooled to 5 - 10°C. In a separate container, dilute 50% solution of 1-propanephosphonic anhydride in EtOAc (103 ml, 173.0 mmol) with acetonitrile (85 ml) and add dropwise to the reaction mixture over 15 min, maintaining the internal temperature below 10°C. Stir between 510° C. for 1 hour and warm to ambient temperature. The mixture was filtered and the resulting precipitate was washed with acetonitrile (2 x 150 ml) and dried in vacuo at 45° C. overnight to give the title intermediate (100.5 g, 93% yield).

MS: m/z 680/682/684 [M+H, ³⁵ Cl/ ³⁷ Cl/ ⁷⁹ Br/ ⁸¹ Br)].

- 17 041402

Preparation 36.

l-[(1S,3R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro1 H-isoquinoline-2 -yl]-2-(2,6-dichlorophenyl)ethanone

Add 1-[(1S,3R)-5-bromo-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1-methyl-3,4-dihydro-1Hisoquinolin-2-yl]-2-(2 ,6-dichlorophenyl)ethanone (60.3 g, 83.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrazole (20.7 g, 99.5 mmol), sodium carbonate (26.4 g, 249 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.2 g, 1.7 mmol) into a 2 L three-necked flask, seal and purge the reaction system with a vacuum/nitrogen cycle three times. 1,4-dioxane (550 ml) and water (300 ml) are added, degassed followed by a vacuum/nitrogen cycle three times, and the resulting mixture is heated to 80° C. for 75 minutes. Add 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrazole (5.0 g, 24.0 mmol) and bis(triphenylphosphine)palladium(II) dichloride (580 mg, 0.8 mmol). Seal and purge with a vacuum/nitrogen cycle three times and heat to 80°C for another 75 minutes. Cool to room temperature, dilute with EtOAc (500 ml), separate layers and pass the organic layer through a pad of silica gel to give the crude title compound as an orange oil (99.67 g of sufficient purity for further use).

MS: m/z 682/684 [M+H, ³⁵ a/ ³⁷ Cl].

Alternative method for Example 1 3,4-dihydroisoquinolin-2( 1 H)-yl)ethan- 1-one

Dissolve 1-[(1 S,3R)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-1-methyl-5-(1-methylpyrazol-4-yl)3,4-dihydro-1H-isoquinoline -2-yl]-2-(2,6-dichlorophenyl)ethanone (99.67 g, 103.6 mmol) in 2-methyltetrahydrofuran (1 L) and placed under nitrogen in a 2 L flask. Add 1M solution of tetrabutylammonium fluoride in THF (155 ml, 155 mmol) over 2 min and stir at room temperature for 4 h. Dilute with water (500 ml) and separate the organic layer. Dry over magnesium sulfate, filter and concentrate in vacuo to give a pale orange oil. The resulting residue was purified by silica gel chromatography eluting with heptane (2 L), heptane/EtOAc (1:1, 4 L) and EtOAc (6 L) to give the title compound as a white foam (33 g). Purify again by silica gel chromatography eluting with a gradient of 0 to 50% MTBE in dichloromethane to give the title compound as a white foam (28.6 g, 61% yield).

MS: m/z 444/446 [M+H, ³⁵ a/ ³⁷ Cl].

Preparation 37 1-((1 S,3R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1H-pyrazol-4yl)-3,4-dihydroisoquinoline-2( 1 H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one

Dissolve 1-((1S,3R)-5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2 ,6-dichlorophenyl)ethan-1-one (2.0 g; 3.6 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole ( 1.74 g; 9.0 mmol) in 1,2-dimethoxyethane (36 ml). Add 0.2 M aqueous potassium carbonate solution (17.9 ml, 0.4 mmol) and sparge with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium (414.0 mg, 359.0 µmol) is added. Heat to 100°C and stir for 18 hours. Cool to room temperature, dilute with water, extract with EtOAc, dry over sodium sulfate, filter, concentrate in vacuo and purify by silica gel chromatography eluting with a gradient of 2 to 80% EtOAc in hexanes, to give the title compound (750 mg, 38% yield).

MS: m/z 544/546 [M+H, ³⁵ a/ ³⁷ Cl].

Example 8 2-(2,6-Dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4dihydroisoquinoline-2( 1 H)-yl)ethan- 1-one

Add a 1M solution of tetrabutylammonium fluoride in THF (1.5 ml, 1.5 mmol) to a solution of 1-18 041402 ((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5 -(III-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one (750 mg, 1.4 mmol) in THF (13.8 ml) at room temperature. The resulting mixture was stirred for 3 hours. Quenched with saturated aqueous ammonium chloride, extracted three times with EtOAc, dried over sodium sulfate, filtered, concentrated in vacuo and purify the resulting residue by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes to give the title compound as a white foam (560 mg, 83% yield).

MS: m/z 430/432 [M+H, ³⁵ Cl/ ³⁷ Cl].

Alternative synthesis of example 8.

Preparation 38 1-((1S,3R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1-(tetrahydro2H-pyran-2-yl)-1H-pyrazol- 4-yl)-3,4-dihydroisoquinolin-2(1Н)-yl)-2-(2,6-dichlorophenyl)ethan-1-one

Dissolve 1-((1S,3R)-5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2 ,6-dichlorophenyl)ethan-1-one (4.2 g; 7.5 mmol) and (1-tetrahydropyran-2-ylpyrazol-4yl)boronic acid (2.2 g; 11.3 mmol) in 1.4 -dioxane (63 ml). Sodium carbonate (1.6 g, 15.1 mmol), (1,H-bis(diphenylphosphino)ferrocene)palladium (II) chloride (307 mg, 0.4 mmol) and water (21 ml) are added. Nitrogen is sparged for 5 min. Heat to 90° C. for 19 hours. Cool to room temperature, dilute with water, extract with EtOAc, dry over sodium sulfate, filter, concentrate in vacuo and purify by silica gel chromatography eluting with 3:7 EtOAc/heptane to give title compound (2.98 g, 63% yield). MS: m/z 628/630 [M+H, ³⁵ Cl/ ³⁷ Cl].

2-(2,6-Dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1Н-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1Н )-yl)ethan-1-one

Add 10-camphorsulfonic acid (3.2 g, 13.4 mmol) portionwise over 10 min to a solution of 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl- 5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one (3.8 g, 6.1 mmol) in MeOH (38.2 ml) at room temperature. Stirred for 17 hours. Remove the solvent in vacuo, distribute the resulting residue between EtOAc (50 ml) and water (50 ml), separate the layers and extract the aqueous layer twice with EtOAc. Dry the combined organic extracts over MgSO ₄ , filter, concentrate in vacuo and purify by silica gel chromatography eluting with a gradient of 20 to 100% EtOAc in hexanes to give the title compound as a white foam (1.72 g, 66% yield). .

MS: m/z 430/432 [M+H, ³⁵ Cl/ ³⁷ Cl].

Example 9 2-(2-Chloro-6-fluorophenyl)-1-((1 S,3R)-3-(hydroxymethyl)-1-methyl-5-(1 H-pyrazol-4-yl)-3, 4dihydroisoquinolin-2(1 H)-yl)ethan-1-one

Heat a mixture of potassium carbonate (92 mg, 0.7 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-pyrazole (160.0 mg, 0.4 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (11.6 mg, 20 µmol), 1-[(1S,3R)-5 -bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-(2-chloro-6-fluorophenyl)ethanone ( 240.0 mg, 0.4 mmol), THF (1.5 ml) and water (1.0 ml) in a microwave at 100°C for 1 hour. Cool to room temperature, dilute with water, extract with EtOAc and concentrate in vacuo to give a crude brown residue. The residue was dissolved in methanol (6 ml) and a 1.25 M aqueous solution of HCl in methanol (2.8 ml, 3.5 mmol) was added. Heat the resulting solution to 50° C. for 8 hours. Cool to room temperature and pour onto an SCX column, eluting first with methanol and eluting the desired product with 2N HCl. ammonia in methanol. Concentrate the ammonia fractions in methanol and purify by reverse phase chromatography to give the title compound (40 mg, 24% yield).

MS (m/z): 414/414 [M+H, ³⁵ Cl/ ³⁷ Cl]

The following compounds were obtained essentially using the method described in example 9.

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Example No. Name Structure Physical Data 10 2-(2,6-difluorophenyl)-1 ((18,3K)-3-(hydroxymethyl)1-methyl-5-(1H-pyrazol-4yl)-3,4-dihydroisoquinolin2(1H)-yl) ethane-1-one N-N V OH MS (m/z): 398/400 [M+H] eleven 2-(2-chloro-5-fluorophenyl)-1 ((18,3K)-3-(hydroxymethyl)1-methyl-5-(1H-pyrazol-4yl)-3,4-dihydroisoquinoline2(1H)- yl) ethane-1-one n N-N V he MS (m/z): 414/416 [M+H] 12 2-(2-chloro-4-fluorophenyl)-1((18,3K)-3-(hydroxymethyl)1-methyl-5-(1H-pyrazol-4yl)-3,4-dihydroisoquinoline2(1H)- yl) ethane-1-one Η N-N V he A MS (m/z): 414/416 [M+H] 13 2-(2-fluorophenyl)-1-((18,3K)3 -(hydroxymethyl)-1 -methyl5-(1H-pyrazol-4-yl)-3,4dihydroisoquinolin-2( 1H)yl)ethan-1- He Η N-N Does he have s?«, MS (m/z): 380 [M+H] 14 2-(2,3-difluorophenyl)-1 ((18,3K)-3-(hydroxymethyl)1-methyl-5-(1H-pyrazol-4yl)-3,4-dihydroisoquinolin2(1H)-yl) ethane-1-one Η N-N ψ OH F MS (m/z): 398 [M+H] 15 2-(2,5-difluorophenyl)-1 ((18,3K)-3-(hydroxymethyl)1-methyl-5-(1H-pyrazol-4yl)-3,4-dihydroisoquinolin2(1H)-yl) ethane-1-one Η N-N Y he MS (m/z): 398 [M+H]

Obtaining example 1A. 2-(2,6-Dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3 hydrochloride monohydrate, 4-dihydroisoquinolin-2( 1 H)-yl)ethan-1-one

Compound of Example 1. (2-(2,6-Dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1Hpyrazol-4-yl)-3, 4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, 412 mg, 0.9 mmol) was dissolved in acetone (5 ml) at 60° C./1000 rpm. 1M HCl solution in EtOAc (1 ml) was added dropwise. Upon addition, a white solid precipitated, resulting in a thick white slurry. The resulting white solid was isolated by filtration on Whatman paper and dried in a stream of air for 30 minutes to give the title compound (400 mg isolated, 86.5% yield) as a crystalline solid.

Obtaining example 1B. Hydrobromide 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline- 2(1Н)-yl)ethan-1-one

Compound of Example 1 (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1Hpyrazol-4-yl)-3, 4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, 432.6 g, 563 mmol) was dissolved in acetone (6 L) at 55°C. Once the internal temperature reaches 50° C., 48% HBr aqueous solution (70 ml, 619 mmol) is added. After 2 minutes a precipitate formed and the mixture was stirred for 10 minutes and cooled to room temperature. The resulting precipitate was collected by filtration through a sintered glass filter, washed with acetone (~1.5 L) and dried under suction on the filter to give the title compound (271.2 g, 91% yield) as a light peach crystalline solid.

Getting example 1C. Hydrobromide monohydrate 2-(2,6-dichlorophenyl)-1-((1S,3R)-3(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4- dihydroisoquinolin-2(1H)-yl)ethan-1-one

The compound of example 1 (2.6 g, 5.8 mmol) is dissolved in acetone (20 ml) at 60° C./1000 rpm. A mixture of 48% aqueous HBr diluted 1:9 in acetone (8 ml) was added at a rate of 500 μl/min. After the addition of 1 ml, a white precipitate begins to form. After adding the acid, a thick white slurry forms and the mixture is cooled to room temperature. The white solid was collected by filtration on Whatman paper and dried in a stream of air for 90 min to give the title compound (2.9 g, 91% yield) as a crystalline solid.

The present invention provides crystalline 2-(2,6

- 20 041402 dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H )-yl)ethan-1-one. One embodiment of the invention is crystalline 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1Hpyrazol-4-yl) hydrobromide monohydrate )-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, characterized by an X-ray powder diffraction pattern using CuKa radiation having a diffraction peak at a 2-theta diffraction angle of 17.4, in combination with one or more peaks selected from the group consisting of 27.0, 18.3 and 21.7; with a diffraction angle tolerance of 0.2°. The present invention provides a pharmaceutical composition containing 2-(2,6-dichlorophenyl)-1-((1S, 3R)-3-(hydroxymethyl)-1-methyl-5(1-methyl-1H-pyrazol-4-yl )-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one; and a pharmaceutically acceptable carrier, diluent or auxiliary agent. The present invention also relates to a pharmaceutical composition containing crystalline 2-(2,6-dichlorophenyl)-1((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazole) hydrobromide monohydrate -4-yl)-3,4-dihydroisoquinolin-2(1 H)-yl)ethan1-one; and a pharmaceutically acceptable carrier, diluent or auxiliary agent.

Obtaining a 1D example. Hydroiodide 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline -2(1H)-yl)ethan-1-one

The compound of example 1 (166 mg, 0.37 mmol) is dissolved in acetone (3 ml) at room temperature/1000 rpm. Add an aqueous solution of 57% HI (60 μl). The mixture was stirred for 1 hour and a white solid precipitated out of solution, forming a thick suspension of a white solid in a brown supernatant. The white solid was collected by filtration on Whatman paper and dried in a stream of air for 10 min to give the title compound (158 mg, 74% yield) as a crystalline solid.

Getting example 1E. Hydroiodide monohydrate 2-(2,6-dichlorophenyl)-1-((1S,3R)-3(hydroxemethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4 -dihydroisoquinolin-2(1 H)-yl)ethan-1-one

Compound of Example 1 (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1Hpyrazol-4-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)ethan-1-one, 209.6 mg, 0.47 mmol) was dissolved in acetone (3 ml) at room temperature/1000 rpm. Add an aqueous solution of 57% HI (80 μl). The mixture was stirred for 30 minutes and a white solid precipitated out of solution, forming a thick suspension of white solid in the brown supernatant. The white solid was collected by filtration on Whatman paper and dried in a stream of air for 10 min to give the title compound (262 mg, 94% yield) as a crystalline solid.

X-ray powder diffraction of crystalline forms

RPD diffraction patterns of crystalline substances were recorded on a Bruker D4 Endeavor X-ray powder diffractometer equipped with a CuKa radiation source, λ = 1.54060 A) and a Vantec sensor operating at 35 kV and 50 mA. The sample was scanned from 4 to 40° 2θ with a step of 0.008° 2θ and a scan rate of 0.5 s/step, and with a divergence of 1.0 mm, a fixed anti-scatter slit of 6.6 mm and a detector slit of 11.3 mm. The dry powder is packed in a quartz cuvette and a smooth surface is obtained using a glass slide. The diffraction patterns of the crystalline form were taken at ambient temperature and relative humidity. Crystal peak positions are determined in MDI-Jade after full sample shearing based on NIST 675 internal standard with peaks at 8.853 and 26.774 29°. It is well known in the art of crystallography that for any given crystal form, the relative intensities of the diffraction peaks can vary due to preferred orientation due to factors such as crystal morphology and structure. If the influence of the preferred orientation is present, the peak intensities change, but the characteristic peak positions of the polymorph remain unchanged. See, for example, USP #23, NF #18, pp. 1843-1844, 1995. Additionally, it is also well known in the art of crystallography that, for any given crystal shape, peak angular positions may vary slightly. For example, peak positions shift due to a change in temperature or humidity at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In this case, the peak position variability of ± 0.2 2θ takes into account these potential changes without interfering with the unambiguous identification of the specified crystalline form. Crystal form confirmation is made based on any unique combination of distinctive peaks.

RPD example 1A.

The resulting sample of crystalline Example 1A (2-(2,6dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl) hydrochloride monohydrate) -3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one) was characterized by an RPD diagram using CuKa radiation as having the diffraction peaks (2-theta values) described in Table 1. 1 below, and in particular having peaks at 8.6 in combination with one or more peaks selected from the group consisting of 15.3, 17.5 and 28.3; with a tolerance for diffraction angles of 0.2°.

- 21 041402

Table 1 X-ray powder diffraction peaks of crystalline example 1A

Peak Angle (°2-theta) +/- 0.2° Relative intensity (% of most intense peak) 1 8.6 100.0% 2 9.3 40.2% 3 14.6 50.3% 4 15.3 69.3% 5 17.5 68.9% 6 19.1 23.3% 7 22.5 36.1% 8 23.9 34.1% 9 25.4 22.9% 10 28.3 57.3%

RPD example 1B.

The resulting sample of crystalline Example 1B (2-(2,6-dichlorophenyl)-1-((1S, 3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazole-4-hydrobromide) yl)-3,4-dihydroisoquinolin-2( 1 H)-yl)ethan-1 it) was characterized by an RPD diagram using CuKa radiation as having the diffraction peaks (2-theta values) described in Table 1. 2 below, and in particular having peaks at 15.5 in combination with one or more peaks selected from the group consisting of 24.9, 11.9 and 21.5; with a tolerance for diffraction angles of 0.2°.

Table 2. X-ray powder diffraction peaks of crystalline example 1B

Peak Angle (°2-theta) +/- 0.2° Relative intensity (% of most intense peak) 1 11.9 69.3% 2 12.7 55.7% 3 15.5 100.0% 4 16.8 50.3% 5 17.9 47.7% 6 19.1 38.4% 7 19.6 46.6% 8 21.5 65.8% 9 24.9 92.1% 10 27.7 31.2%

RPD example 1C.

A sample of crystalline Example 1C (2-(2,6dichlorophenyl)-1-hydrobromide monohydrate)-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazole-4- yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one) was characterized by an RPD diffraction pattern using CuKa radiation as having the diffraction peaks (2-theta values) described in Table 1. 3 below, and in particular having peaks at 17.4 in combination with one or more peaks selected from the group consisting of 27.0, 18.3 and 21.7; with a tolerance for diffraction angles of 0.2°.

Table 3 X-ray powder diffraction peaks of crystalline Example 1C

Peak Angle (°2-theta) +/- 0.2° Relative intensity (% of most intense peak) 1 8.4 26.9% 2 I,5 23.6% 3 14.1 19.5% 4 16.8 30.8% 5 17.4 100.0% 6 18.3 52.1% 7 19.7 37.2% 8 21.7 39.7% 9 23.1 37.8% 10 27.0 65.5%

RPD example 1D.

The resulting sample of crystalline Example 1D (2-(2,6-dichlorophenyl)-1-((1S,3R)3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl hydroiodide) )-3,4-dihydroisoquinolin-2( 1 I)-yl)ethan-1-one) was characterized by the RPD diffraction pattern using CuKa radiation as having the diffraction peaks (2-theta values) described in Table 1. 4 below, and in particular having peaks at 15.3 in combination with one or more peaks selected from the group consisting of 21.5, 11.7 and 24.5; with a tolerance for the angles of the di- 22 041402 fraction of 0.2°.

Table 4 X-ray powder diffraction peaks of crystalline example 1D

Peak Angle (°2-theta) +/- 0.2° Relative intensity (% of most intense peak) 1 11.7 45.2% 2 15.3 100.0% 3 17.9 18.3% 4 19.1 21.1% 5 19.6 22.6% 6 20.2 32.0% 7 21.3 37.2% 8 21.5 46.1% 9 21.9 39.7% 10 24.5 40.3%

RPD example 1E.

Sample obtained from crystalline example 1E (2-(2,6-dichlorophenyl) hydroiodide monohydrate 1 -((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazole-4 -yl)-3,4-dihydroisoquinolin-2( 1H)yl)ethan-1-one) was characterized by the RPD diffraction pattern using CuKa radiation as having the diffraction peaks (2-theta values) described in Table 1. 5 below, and in particular having peaks at 17.2 in combination with one or more peaks selected from the group consisting of 21.5, 19.6 and 28.1; with a tolerance for diffraction angles of 0.2°.

Table 5 X-ray powder diffraction peaks of crystalline example 1E

Peak Angle (°2-theta) +/- 0.2° Relative intensity (% of most intense peak) 1 I,4 16.5% 2 14.5 8.9% 3 16.7 25.7% 4 17.2 100.0% 5 17.8 11.3% 6 18.2 20.7% 7 19.6 33.7% 8 21.5 36.2% 9 25.1 20.5% 10 28.1 31.7%

Study of human PAM receptor D1

PAM activity of the compounds of the present invention can be measured essentially as described in Svensson et al., An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-in Mices without Casusing Stereotypy or Tachyphylaxis. J Pharmacol. Exp. Ther. (2017) 360:117-128.

More specifically, HEK293 cells that stably express the human D1 receptor (accession number NM_000794) are generated by gene transduction using the pBABE-bleo retroviral vector and selected using Zeocin™ (InvivoGen). At about 80% confluency, cells were harvested using TrypLE™ Express (Gibco), suspended in FBS plus 8% DMSO, and stored in liquid nitrogen. On the day of the study, the cells are thawed and resuspended in STIM buffer (Hanks' balanced salt solution supplemented with 0.1% BSA, 20 mM HEPES, 500 μM IBMX and 100 μM ascorbic acid).

The test compound is serially diluted (1:2) with DMSO in assay plates (ProxiPlate384 Plus, PerkinElmer) using acoustic dosing (Labcyte) to give 20 concentrations to obtain complete response curves. The test compound (80 nl) is added to 5 µl of STIM buffer containing 2000 cells and 5 µl of dopamine solution at 2-fold concentration in STIM buffer, which causes an EC ₂₀ level response (24 nM in the original solution or 12 nM in the final solution) and a final concentration of DMSO in the well of 0.8%. The plates are incubated at room temperature for the entire reaction time of 60 minutes.

cAMP production is quantified using HTRF® detection (Cisbio) according to the manufacturer's instructions. Typically, lysis buffer containing anti-cAMP cryptate (5 µl) and D2-conjugate (from the HTRF® kit) (5 µl) is added to the wells, the plates are incubated for an additional 60-90 min, and time-resolved fluorescence is read using the plate. -EnVision™ reader (PerkinElmer). Fluorescence data are converted to cAMP concentrations using a standard cAMP curve and analysis using a 4-23 041402 parametric non-linear logistic equation (Genedata Screener, version 13.0.5-standard).

For concentration-response curves in potentiator mode, the results are expressed as the percentage of the window between the response at a concentration of dopamine EC20 alone (normalized to 0%) and the maximum response to dopamine (determined by the response to 5 μM dopamine, final concentration, normalized as 100%).

Absolute EC50 values are calculated from the maximum and minimum responses of the reference agonist (dopamine). The % Potentiation (% Upper) is determined from the fitted top of the concentration response curve. The absolute values of EC ₅₀ and % Upper are shown in the following table. 6:

Table 6

Example No. Abs EC50 (nM) (SEM, N) % Upper (SEM, N) 1 16.4 (3.18, n=10) 91.4 (3.65, n=10) 2 172 (29.5, n=3) 91.2 (6.46, n=3) 3 287 (38.1, n=3) 88.1 (2.52, n=3) 4 28.5 (5.45, n=3) 78.8 (4.86, n=3) 5 18.3 (2.62, n=3) 79.1 (4.34, n=3) 6 42.2 (3.70, n=3) 80.4 (3.40, n=3) 7 81.2 (11.6, n=3) 82.4 (2.83, n=3) 8 13.4 (3.93, n=3) 75.9 (3.16, n=3) 9 28.0 (6.81, n=3) 81.5 (3.16, n=3) 10 127 (24.8, n=3) 78.1 (4.68, n=3) AND 112 (13.8, n=3) 79.8 (3.10, n=3) 12 540 (41.6, n=3) 77.1 (2.50, n=3) 13 484 (14.9, n=2) 89.8 (2.42, n=2) 14 677 (23.9, n=2) 72.6 (3.38, n=2) 15 836 (46.4, n=2) 75.5 (0.226, n=2)

The absolute values of EC ₅₀ presented for examples 1-15 in table. 6 illustrate the enhancement of human D1 receptor signaling in response to dopamine and illustrate the activity of the compounds of claim 1 as a positive allosteric modulator of the human D1 receptor for dopamine.

Creation of Knockin Mice with Human D1 Receptor A transgenic mouse in which the mouse dopamine 1 (D1) receptor is replaced by its human counterpart can be generated by standard methods (see generally Svensson et al., J. Pharmacol. Exp. Ther. (2017) 360:117-128). For example, mouse genomic fragments are subcloned from the bacterial artificial chromosome library RP23 and recloned into the PGK-neo targeting vector. The mouse open reading frame is replaced by the human D1 receptor open reading frame in exon 2. The peo selection marker before exon 2 is flanked by frt sites for subsequent deletion. Flanking of exon 2 with 1oxP selection sites makes it possible to obtain D1 knockout mice by crossing with mice expressing the ce nuclease gene.

The B6-3 C57BL/6 N embryonic stem cell line is grown on a mitotically inactivated mouse embryonic fibroblast feeder layer in high glucose DMEM with 20% FBS and 2 x 10 ⁶ units/L leukemia inhibitory factor. Ten million embryonic stem cells plus 30 micrograms of linearized vector DNA were electroporated and subjected to G418 selection (200 μg/ml). Clones are isolated and analyzed by Southern blotting.

A clone containing an insert of the expected size is inserted into blastocysts and the resulting mice are genotyped by PCR. The male chimera is crossed with a female containing the flp nuclease gene to eliminate the selection marker. Progeny containing the human D1 receptor without a selection marker are identified by PCR. Male heterozygotes are mated with female C57BL/6 mice. Male and female offspring containing the human D1 receptor are mated and homozygotes are identified by PCR. It was found that the behavior and reproduction of homozygotes is normal and the colony is preserved in a homozygous state for subsequent generations.

Basal (accustomed) motor activity

It can be demonstrated that the in vivo efficacy of the present compounds works through the D1 receptor using mouse locomotor activity. Motor activity is measured using an automated mouse tracking system. Mice were monitored for locomotor activity in 45 x 25 x 20 cm clear plastic shoe cages, with 1 cm wood shavings for absorbent bedding, and covered with a ventilated filtered plastic cage cover. The cells were placed in a rectangular frame containing an array of 12 photocell beams in an 8x4 configuration (Kinder Scientific, Poway, CA) positioned 2.5 cm from the floor of the cage to detect body movement (movement) and register with a computer.

- 24 041402

Male mice with knockin of the human D1 receptor are placed in the chambers and allowed to habituate to the chambers for 60 minutes. During the acclimatization period, the mice, as expected, show a decrease in mobility over time. It has been found that after administration of the compound of the invention, the degree of locomotor activity of the animals increases in a dose dependent manner.

Mice are randomly assigned to treatment groups. In the dose-response study, each mouse was individually placed in one of the exercise boxes for 60 minutes. habituation period. Mice are then dosed orally with test compound in 20% hydroxypropyl betacyclodextrin vehicle and using a volume dose of 10 ml/kg. After dosing, mice are placed back into the LMA boxes and total movements are recorded over a 10 minute interval for each mouse during the 60 minute measurement period. Statistical analysis was performed using one-way ANOVA followed by post hoc analysis using Dunnett's test. The compounds of examples 1 and 8 were tested as described above and found to increase basal motion in a dose dependent manner (Tables 7 and 8).

Table 7

Example 1 (dose, mg/kg, PO) Basal locomotor activity (Total number of movements during 60 minutes) Mean values (SEM, %SE), N=8/rpynna ο,θ (Solvent - 20% hydroxypropyl-betacyclodextrin) 541 (98.18%) 1.0 410(113.28%) h, o 490 (67.14%) 6.0 1517* (324.21%) 10 2426*** (596, 25%) thirty 3568**** (387, 11%) Statistical analysis is performed on total displacement data after Log 10 transformation. One-way analysis of variance AN0VA: *p<0.05, ***p<0.001, ****p<0.0001, (Dunnett's multiple comparison test: comparison with control solvent on converted log 10 data)

Table 8

Example 8 (dose, mg/kg, PO) Basal locomotor activity (Total number of movements during 60 minutes) Mean values (SEM, %SE), N=8/rpynna 0.0 Solvent - 20% hydroxypropyl-betacyclodextrin) 614 (105.17%) 3.0 335 (59.18%) 10 753 (159.21%) 20 3629* (690, 19%) thirty 3746** (463, 12%) 60 4080*** (664, 16%) Statistical analysis is performed on total displacement data after Log 10 transformation. One-way ANOVA: *p<0.05, **p<0.01, ***p<0.001, (Dunnett's multiple comparison test: comparison with solvent control on the data transformed by loglO)

The data of basal motor activity for examples 1 and 8 are given in table. 7 and 8 show that the compounds of the present invention, and in particular examples 1 and 8, are effective in activating locomotor movement in animals that have become accustomed to the environment. This activity is believed to be the result of central activation of D1 receptors via allosteric potentiation (see, for example, Svensson et al., J. Pharmacol. Exp. Ther. (2017) 360:117-128). The data presented in Tables 7 and 8 for Examples 1 and 8 illustrate the pharmacologically beneficial in vivo efficacy of the compounds of the present invention in enhancing endogenous dopamine-mediated responses. The data presented in Tables 7 and 8 for Examples 1 and 8 further illustrate the pharmacologically beneficial oral bioavailability of Examples 1 and 8 and compounds of Formula I.

Plasma and brain levels:

Example 1 was orally administered to male mice at a dose of 1 mg/kg to 30 mg/kg during feeding, and plasma and brain concentrations were determined 1.5 hours post-dose. The unbound fraction of a compound is determined in vitro as previously described (Zamek-Gliszczynski MJ, Ruterbories KJ, Ajamie RT, Wickremsinhe ER, Pothuri L, Rao MV, Basavanakatti VN, Pinjari J, Ramanathan VK, Chaudhary AK (2011) Validation of 96-well equilibrium dialysis with non-radiolabeled drug for definitive measurement of

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Claims (17)

protein binding and application to clinical development of highly-bound drugs. J Pharm Sci 100: 2498-2507). The ratio (Kpuu) of unbound brain concentration (Cu, brain) to unbound plasma concentration (Cu, plasma) was determined as previously described (Raub TJ, Wishart GN, Kulanthaivel P, Staton BA, Ajamie RT, Sawada GA, Gelbert LM, Shannon HE, Sanchez-Martinez C, De Dios A (2015) 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 Xenograft.Drug Metab Dispos.43:1360- 71). The data below for Example 1 are averages from 3 animals at each dose. Conc. refers to concentration. Dose mg/kg Time Conc, plasma nM Conc, in the brain nM fu, plasma fu brain Cu, plasma nM Xi, brain nM Kree 1 1.5 6.74 BQL 0.027 0.025 0.182 BQL N/A 3 1.5 86.6 60 0.027 0.025 2.34 1.5 1.06 6 1.5 173 129 0.027 0.025 4.67 3.22 0.65 10 1.5 120 57.6 0.027 0.025 3.23 1.44 0.44 thirty 1.5 1660 794 0.027 0.025 44.9 19.9 0.65 BQL is below the quantitative limit of 1 ng/mg tissue. Example 8 was orally administered to male mice at a dose of 3 to 60 mg/kg during feeding and the concentration in plasma and brain was determined 1 hour after dosing. The unbound fraction of the compound was determined in vitro as described previously (Zamek-Gliszczynski MJ, et al, Validation of 96-well equilibrium dialysis with non-radiolabeled drug for definitive measurement of protein binding and application to clinical development of highly-bound drugs., J Pharm Sci (2011) 100: 2498-2507). The ratio (Kpuu) of unbound brain concentration (Cu, brain) to unbound plasma concentration (Cu, plasma) was determined as previously described (Raub TJ, et al., 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 Xenograft Drug Metab Dispos (2015) 43:1360-71). The data presented below for example 8 are the average of 3 animals at each dose. Dose mg/kg Time h Conc, plasma nM Conc, in the brain nM fu, plasma fu brain Cu, plasma nM Xi, brain nM Kree 3 1.5 87.4 66.3 0.031 0.01 2.71 0.66 0.24 10 1.5 901 267 0.031 0.01 27.9 2.67 0.10 20 1.5 2442 721 0.031 0.01 75.7 7.21 0.10 thirty 1.5 10321 2391 0.031 0.01 320 23.9 0.07 60 1.5 20077 5000 0.031 0.01 622 50 0.08 Compounds of the present invention, eg Example 1, show an advantageous combination of pharmacological properties such as potency, high in vivo oral availability, in vivo efficacy and a favorable toxicity profile in preclinical studies. For example, Example 1 demonstrates an increase in human D1 receptor signaling in response to dopamine (16.4 ± 3.18 nM (n = 10)) and significant in vivo efficacy at oral doses of 6, 10, and 30 mg/kg po at locomotor activation mice with human D1 receptor knockin, which are accustomed to the environment, also demonstrate favorable oral bioavailability of this compound. In addition, the compound of Example 1 was generally well tolerated when administered in vivo to healthy rats for four days and showed a favorable lack of toxicity in this in vivo experiment. Thus, Example 1 demonstrates an advantageous combination of favorable pharmacological properties supporting possible use as an orally administered therapeutic agent for enhancing the dopamine D1 receptor and treating Parkinson's disease, schizophrenia, ADHD and/or Alzheimer's disease. CLAIM 1. Compound formula where /\ O R ¹ is -H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ OH, or R ² is -F or -Cl and R ³ represents -H, -F or -Cl; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1 of the formula - 26 041402 Where R ¹ is -H, -CH ₃ , -CH ₂ CH ₃ , -CH2CH2OH, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, selected from the group consisting of 2-(2,6-dichlorophenyl)-1-((1S,3R)-5-(1-ethyl-1H-pyrazol-4-yl)-3-(hydroxymethyl)-1-methyl-3,4dihydroisoquinoline-2 (1 H)-yl)ethan-1-one; 1-((1S,3R)-5-(1-cyclopropyl-1 H-pyrazol-4-yl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin2(1H)-yl)-2- (2,6-dichlorophenyl)ethan-1-one; 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl) 3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one; 1-((1S,3R)-5-(1-(2-(11-oxidaneyl)ethyl)-1 H-pyrazol-4-yl)-3 -(hydroxymethyl)-1-methyl-3,4-dihydroisoquinoline -2(1H)-yl)-2-(2-chlorophenyl)ethan-1-one; 2-(2-chloro-6-fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-(oxetan-3-yl)-1H-pyrazol-4yl) -3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one; 2-(2-chlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-III-pyrazol-4-yl)-3,4-dihydroisoquinoline-2 (1H)-yl)ethan-1-one; 2-(2,6-dichlorophenyl)-1 -((1 S,3R)-3-(hydroxymethyl)-1 -methyl-5 -(1 H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2 (1H)-yl)ethan-1-one; 2-(2-chloro-6-fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2 (1H)-yl)ethan-1-one; 2-(2,6-difluorophenyl)- 1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-( 1 H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2( 1H)-yl)ethan-1-one; 2-(2-chloro-5-fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2 (1H)-yl)ethan-1-one; 2-(2-chloro-4-fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2 (1H)-yl)ethan-1-one; 2-(2-fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1Н)- yl) ethane-1-one; 2-(2,3-difluorophenyl)- 1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-( 1 H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2( 1Н)-yl)ethan-1-one and 2-(2,5-difluorophenyl)- 1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-( 1 H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2( 1H)-yl)ethan-1-one; or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 4, which is 6. The compound, which is 2-(2,6-dichlorophenyl)-1-((1S,3R)-3(hydroxymethyl)-1-methyl-5-(1-methyl-1 H-pyrazole-4-) hydrobromide monohydrate yl)-3,4-dihydroisoquinolin-2(1 H)-yl)ethan-1-one. 7. The compound according to claim 6, characterized in that it is a crystalline hydrobromide monohydrate 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1 -methyl-1H-pyrazol-4-yl)-3,4dihydroisoquinolin-2(1H)-yl)ethan-1-one. 8. The compound according to claim 7, characterized in that it is a crystalline hydrobromide monohydrate 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1 -methyl-1H-pyrazol-4-yl)-3,4dihydroisoquinolin-2(1H)-yl)ethan-1-one, characterized by an X-ray powder diffraction pattern using CuKa radiation, having a diffraction peak at a diffraction angle of 2θ equal to - 27 041402 nom 17.4, in combination with one or more peaks selected from the group consisting of 27.0, 18.3 and 21.7; with a diffraction angle tolerance of 0.2°. 9. A pharmaceutical composition containing a compound according to any of pi. 1-8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or auxiliary agent. 10. Pharmaceutical composition according to claim 9, containing ^NNZ or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or auxiliary agent. 11. Pharmaceutical composition according to claim 10, containing ^NNZ and a pharmaceutically acceptable carrier, diluent or auxiliary agent. 12. Pharmaceutical composition according to claim 9, containing 2-(2,6dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-) hydrobromide monohydrate pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one; and a pharmaceutically acceptable carrier, diluent or auxiliary agent. 13. The use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the treatment of Parkinson's disease. 14. The use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the treatment of Alzheimer's disease. 15. 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 the treatment of Parkinson's disease or Alzheimer's disease. 16. A method of treating Parkinson's disease, comprising administering to a patient in need thereof an effective amount of a compound that is 2-(2,6-dichlorophenyl)-1-((1 S,3R)3-(hydroxymethyl)-1 - methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one or a pharmaceutically acceptable salt thereof. 17. A method of treating Alzheimer's disease, comprising administering to a patient in need thereof an effective amount of a compound that is 2-(2,6-dichlorophenyl)-1-((1 S,3R)3-(hydroxymethyl)-1 - methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one or a pharmaceutically acceptable salt thereof. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2