RU2824581C2 - Substituted tetrahydroisoquinoline derivative as positive allosteric modulator d1 - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: invention relates to chemistry and pharmaceutics, namely, 2-(3,5-dichloro-1-methylindazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methylethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition having activity of a positive allosteric modulator D1, based thereon, method of treating and/or preventing cognitively related and negative symptoms of schizophrenia, mild cognitive impairment (MTI), impulsivity, Parkinson's disease and other movement disorders, dementia with Lewy bodies, Alzheimer's disease, for which the introduction of a positive allosteric modulator D1, and a method of treating Parkinson's disease and other movement disorders, Alzheimer's disease or cognitively related and negative symptoms of schizophrenia, for which the administration of a positive allosteric modulator D1 is indicated, which involve administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in an effective amount.

EFFECT: use of the invention enables effective treatment of diseases for which the introduction of a positive allosteric modulator D1 is indicated.

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Description

The present invention relates to a tetrahydroisoquinoline derivative and its use in therapy. In particular, the present invention relates to a pharmacologically active substituted tetrahydroisoquinoline derivative.

This compound acts as a positive allosteric modulator of D1 and is therefore useful as a pharmaceutical agent for the treatment of diseases in which D1 receptors play a role.

Dopamine, a monoamine, acts on GPCRs (G protein-coupled receptors) of two families and modulates motor function, reward-related mechanisms, cognitive processes, and other physiological functions. In particular, dopamine acts on neurons through D1-like receptors, including dopamine receptors D1 and D5, which are mainly coupled to the G protein G _s , and therefore stimulate the production of cAMP (cyclic adenosine monophosphate) through D2-like receptors, which include receptors D2, D3, and D4, which are coupled to G proteins G _i/q and which suppress the production of cAMP. These receptors are widely expressed in different areas of the brain. In particular, D1 receptors are involved in many physiological functions and behavioral processes. For example, D1 receptors are involved in synaptic plasticity, cognitive function, and goal-directed motor functions, as well as reward-related processes. Because of their role in several physiological/neurological processes, D1 receptors have been implicated in a variety of disorders, including cognitive-related and negative symptoms of schizophrenia, neuroleptic drug-induced cognitive impairment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug overuse disorder, sleep disorders, apathy, traumatic spinal cord injury, or neuropathic pain.

It has been shown that it is difficult to develop orally bioavailable small molecules targeting D1 receptors. D1 agonists developed to date are characterized by the presence of a pyrocatechol moiety and therefore their use in clinical practice is limited to invasive treatment. Ensuring sufficient selectivity has also proven difficult due to the high degree of homology of the ligand binding sites of dopamine receptor subtypes (e.g., dopamine D1 and D5 receptors). In addition, the use of D1 agonists is limited due to possible side effects, including dyskinesia and hypotension.

Therefore, it is necessary to develop new agents that can modulate D1 receptors.

There has been increasing interest in identifying allosteric modulators of GPCRs as tools for understanding the mechanism of receptor action and as potential therapeutic agents. GPCRs represent the largest family of cell surface receptors, and a large number of commercially available drugs directly activate or block signaling pathways mediated by these receptors. However, some GPCRs (e.g., peptide receptors) have proven difficult to design small molecules for or to achieve sufficient selectivity due to the high homology of ligand binding sites across receptor subtypes (e.g., dopamine receptors D1 and D5 or D2 and D3). Accordingly, the focus of much drug discovery has shifted toward identifying small molecules that act at sites distinct from those of the natural orthosteric agonist. Ligands that bind to these sites induce a conformational change in the GPCR and thereby allosterically modulate receptor function. Allosteric ligands have a variety of functions, including the ability to enhance (positive allosteric modulator, PAM) or attenuate (negative allosteric modulator, NAM) the effects of an endogenous ligand by affecting its affinity and/or potency. In addition to subtype selectivity, allosteric modulators may have other potential advantages for drug development, such as having no direct effects or potency of their own; only enhancing the effects of the native mediator at the site and time it is released; reducing the propensity to induce desensitization that occurs with chronic agonist exposure; and reducing the propensity to cause target-related side effects.

The compounds of the present invention enhance the action of D1 agonists or endogenous ligand on D1 receptors by an allosteric mechanism and are therefore positive allosteric modulators of D1 (PAM D1).

Therefore, the compound of the present invention, which is a D1 PAM, is useful for the treatment and/or prevention of diseases and disorders in which D1 receptors play a role. Such diseases include cognitive-related and negative symptoms of schizophrenia, neuroleptic drug-associated cognitive impairment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug or narcotic overuse addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

International patent application WO 2013/051869 A1 discloses certain 3,4-dihydro-1H-isoquinolin-2-yl derivatives that are NK2 antagonists.

International patent application WO 2008/109336 A1 discloses certain tetrahydroisoquinoline compounds that are histamine H3 receptor modulators.

International patent application WO 2014/193781 A1 discloses certain 3,4-dihydroisoquinolin-2(1H)-yl derivatives useful for the treatment of cognitive impairment associated with Parkinson's disease or schizophrenia.

International patent application WO 2016/055479 discloses substituted 3,4-dihydroisoquinolin-2(1H)-yl derivatives and analogues thereof that may be useful for the treatment of diseases in which D1 receptors play a role.

International patent application WO 2019/204418 discloses certain pyrazotetrahydroisoquinoline derivatives that are positive allosteric modulators of D1 and may be useful for the treatment of Parkinson's disease, Alzheimer's disease, schizophrenia and attention deficit hyperactivity disorder (ADHD).

However, there remains a need to develop active positive allosteric D1 modulators that exhibit a combination of favourable pharmacokinetic and pharmacodynamic properties while providing a reduction in side effects commonly associated with treatments involving selective D1 agonists, such as hypotension or dyskinesia.

The present invention relates to 2-(3,5-dichloro-1-methylindazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methylethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone of formula (I),

or a pharmaceutically acceptable salt thereof.

The present invention also relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, intended for use in therapy.

Another object of the present invention is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, intended for use in the treatment of diseases and/or disorders in which D1 receptors play a role.

Another object of the present invention is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, intended for use in the treatment and/or prevention of cognitive-related and negative symptoms of schizophrenia, neuroleptic-associated cognitive impairment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug or narcotic overuse addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

In a preferred embodiment of this object, the present invention relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson's disease and other movement disorders, Alzheimer's disease or cognitive and negative symptoms of schizophrenia.

Therefore, one preferred object of the present invention is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson's disease and other movement disorders.

Another object of the present invention is the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment and/or prevention of diseases and/or disorders in which D1 receptors play a role.

Another object of the present invention is the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment and/or prevention of cognitive-related and negative symptoms of schizophrenia, neuroleptic-associated cognitive impairment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug or narcotic overuse addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

In a preferred embodiment of this aspect, the present invention relates to the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment of Parkinson's disease and other movement disorders, Alzheimer's disease or cognitive and negative symptoms of schizophrenia.

One preferred object of the present invention is the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment of Parkinson's disease and other movement disorders.

The present invention also relates to a method for the treatment and/or prevention of disorders for which administration of a positive allosteric modulator of D1 is indicated, which comprises administering to a patient in need of such treatment a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in an effective amount.

Another object of the present invention is a method for the treatment and/or prevention of cognitive-related and negative symptoms of schizophrenia, neuroleptic-associated cognitive impairment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinson's disease dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug or narcotic overuse addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain, which comprises administering to a patient in need of such treatment a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in an effective amount.

In a preferred embodiment of this aspect, the present invention relates to a method of treating Parkinson's disease and other movement disorders, Alzheimer's disease or cognitive and negative symptoms of schizophrenia, which comprises administering to a patient in need of such treatment a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in an effective amount.

One preferred aspect of the present invention is a method of treating Parkinson's disease and other movement disorders which comprises administering to a patient in need of such treatment a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof in an effective amount.

The present invention includes salts of the compounds of formula (I) above. For use in medicine, salts of the compounds of formula (I) must be pharmaceutically acceptable salts. However, other salts can be used to prepare the compounds useful in the present invention or their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P. H. Stahl & C. G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts, which can be prepared, for example, by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.

It should be understood that each individual atom contained in formula (I) or in the formulae presented hereinafter may in fact be contained in the form of any of its isotopes occurring in nature, with the most abundant isotope(s) being preferred. Thus, for example, each individual hydrogen atom contained in formula (I) or in the formulae presented hereinafter may be contained in the form of ¹ H, ² H (deuterium) or ³ H (tritium) atom, preferably as ¹ H or ² H. Similarly, for example, each individual carbon atom contained in formula (I) or in the formulae presented hereinafter may be contained in the form of ¹² C, ¹³ C or ¹⁴ C atom, preferably as ¹² C.

The present invention includes solvates of the compounds of formula (I) above. Such solvates can be obtained with common organic solvents or with water.

The present invention also includes co-crystals of the compounds of formula (I) above. The technical term "co-crystal" is used to describe the case where neutral molecular components are present in a crystalline compound in a certain stoichiometric ratio. The preparation of pharmaceutical co-crystals allows modification of the crystalline form of the active pharmaceutical ingredient, which in turn can change its physicochemical characteristics without deteriorating its desired biological activity (see the publication Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

The compounds of the present invention may exist in various polymorphic forms. Although not explicitly indicated in the formula above, such forms are within the scope of the present invention.

In a preferred embodiment of the present invention, the compound of formula (I) is isolated in the form of a monohydrate, as further described in the examples.

The present invention also includes prodrug forms of the compounds of formula (I) and their various subclasses and subgroups.

Activity in any of the above therapeutic indications or disorders can, of course, be assessed by conducting appropriate clinical studies using methods known to those skilled in the art for the specific indication and/or by conducting general clinical studies.

For the treatment of diseases, the compound of formula (I) or its pharmaceutically acceptable salts can be used in an effective daily dose and administered in the form of a pharmaceutical composition.

Therefore, the present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as presented above, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers.

To prepare the pharmaceutical composition of the present invention, one or more compounds of formula (I) or pharmaceutically acceptable salts thereof are intimately mixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to skilled practitioners.

Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, such as oral, rectal, parenteral or nasal.

Pharmaceutical compositions containing the compounds of the present invention can be administered, for example, orally, parenterally, i.e. intravenously, intramuscularly or subcutaneously, intrathecally, by inhalation or nasally.

Pharmaceutical compositions suitable for oral administration may be solid or liquid and may, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing gums, etc.

For this purpose, the active ingredient can be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. These pharmaceutical compositions may also optionally contain a binder such as microcrystalline cellulose, tragacanth gum or gelatin, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or coloring agents, or a flavoring such as peppermint extract or methyl salicylate.

The present invention also includes compositions that can release the active substance in a controlled manner. Pharmaceutical compositions that can be used for parenteral administration are in conventional form, such as aqueous or oily solutions or suspensions, usually contained in ampoules, disposable syringes, glass or plastic vials or infusion containers.

In addition to the active ingredient, these solutions or suspensions may also optionally contain a sterile diluent such as water for injection, saline solution, oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents, bactericides such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates or phosphates, and agents for adjusting osmolality such as sodium chloride or dextrose.

These pharmaceutical forms are prepared according to methods that are routinely used by pharmacists.

The amount of the compound for use in the present invention required to prevent or treat a particular pathological condition will vary depending on the compound selected and the condition of the patient being treated. However, the daily dose may typically be in the range of 0.05 to 3000 mg, typically 0.5 to 1000 mg for compositions intended for parenteral administration.

The compound of the present invention or a pharmaceutically acceptable salt thereof may be administered alone (monotherapy) or in combination with L-dopa (combination therapy). When administered alone or in combination with fractions of the doses of L-dopa necessary to alleviate the motor deficit in patients, the compounds of formula (I) of the present invention or a pharmaceutically acceptable salt thereof may be useful for the treatment of dyskinesia associated with the administration of L-dopa. For example, it is believed that when the compound of formula (I) of the present invention is administered with fractions of the doses of L-dopa administered to a patient or is used alone to replace L-dopa, the compound of formula (I) of the present invention will be effective in eliminating the motor deficit and will not cause harmful dyskinesia. It is therefore believed that the compound of the present invention may be useful for the treatment of motor deficits and levodopa-induced dyskinesia (LID).

Therefore, one preferred object of the present invention is also a compound of formula (I), which is useful for the treatment of levodopa-induced dyskinesia (LID).

The compound of formula (I) can be prepared by a procedure comprising the reaction of an intermediate of formula (II) with an intermediate of formula (III).

The intermediate (III) can typically be reacted with an intermediate of formula (II) in the presence of (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or another coupling reagent known to those skilled in the art, in a suitable solvent, such as dimethylformamide, using an excess of a base, such as N,N-diisopropylethylamine.

The intermediate product of formula (III) can be prepared by a procedure involving the reaction of intermediate products of formula (IV),

in which

Z represents halogen or 1-hydroxy-1-methylethyl;

R ^a denotes tert-butyldimethylsilyl; and

R ^c represents hydrogen or tert-butoxycarbonyl.

In a first step, an intermediate of formula (IV) in which Z is bromine and R ^c is hydrogen, hereinafter referred to as intermediate (IVa), can be protected with an appropriate protective group using methods known to those skilled in the art to yield a compound of formula (IV) in which Z is bromine and R ^c is tert-butoxycarbonyl, hereinafter referred to as intermediate (IVb).

In a second step, a metal-halogen exchange reaction can be carried out, for example, in the presence of n-BuLi, in a suitable solvent, for example, tetrahydrofuran, at low temperature, in the presence of dry acetone in a continuous flow, according to the procedure described in the accompanying examples, and obtain the corresponding intermediate product (IV) described above, in which Z is 1-hydroxy-1-methylethyl, hereinafter referred to as intermediate product (IVc).

Then, the tert-butoxycarbonyl (Boc) protecting group (R ^c ) can be first removed by methods known to those skilled in the art or further described in the accompanying examples, and then the trimethylsilyl protecting group formed during the removal of the Boc protecting group and the tert-butyldimethylsilyl group (R ^a ) can be removed to obtain the intermediate product (III).

An intermediate of formula (IVa) can be prepared by a procedure comprising reacting an intermediate of formula (V) in which Y is a halogen, such as bromine, and R ^a is as defined above for the intermediate of formula (IV).

The reaction is usually carried out in the presence of methyl magnesium chloride in a suitable solvent such as tetrahydrofuran, at low temperature.

The intermediate product (V) can be prepared by a 2-step procedure involving the reaction of the intermediate product of formula (VI),

in which Y is as defined above for the intermediate of formula (V), and R ^a is hydrogen or tert-butyldimethylsilyl.

In the first step, the intermediate product (VI), in which R ^a is hydrogen, is reacted with tert-butyldimethylsilyl chloride in the presence of a suitable base, for example 4-dimethylaminopyridine, at room temperature to obtain the intermediate product (VI), in which R ^a is tert-butyldimethylsilyl.

In the second step, the intermediate product (VI), in which R ^a is tert-butyldimethylsilyl, is reacted with N-chlorosuccinimide (NCS) in a suitable solvent, such as THF (tetrahydrofuran), to yield the intermediate product (V).

The intermediate product (VI) in which R ^a is hydrogen can be prepared by a procedure involving the use of an intermediate product of formula (VII) in which Y is as defined above for the intermediate product (V).

The reaction is usually carried out in the presence of a strong base, such as sodium hydroxide, in a suitable solvent, such as a mixture of ethanol and water, at high temperature.

The intermediate product of formula (VII) can be prepared by a procedure involving the reaction of the intermediate product (VIII),

in which Y is as defined above in the present invention for the intermediate product of formula (V).

The reaction is usually carried out in the presence of trimethylsilyl triflate and paraformaldehyde in a suitable solvent such as dichloromethane.

The intermediate product (VIII) can be prepared by a 2-step procedure involving the use of a commercially available intermediate product (IX),

in which Y is as defined above for the intermediate product (V).

The reaction is generally carried out according to the methods described in the accompanying examples or according to methods known to those skilled in the art.

The intermediate product of formula (II) can be prepared by a multi-step procedure involving the reaction of intermediate products of formula (X),

in which

R ¹ represents chlorine, amino group or nitro group; and

R ^b represents hydrogen or tert-butyl.

In the first step, an intermediate of formula (X) in which R ¹ is a nitro group and R ^b is tert-butyl, hereinafter referred to as intermediate (Xa), is reduced to give the corresponding intermediate (X) in which R ¹ is an amino group and R ^b is tert-butyl, hereinafter referred to as intermediate (Xb). The reaction is typically carried out by Pd/C-catalyzed hydrogenation at high pressure in a suitable solvent, such as methanol.

The intermediate (Xb) is converted into the corresponding intermediate (X), in which R ¹ is chlorine and R ^b is hydrogen, hereinafter referred to as intermediate (Xc), by adding concentrated hydrochloric acid and sodium nitrite and then adding hydrochloric acid and copper(II) chloride. The reaction is typically carried out at low temperature.

The intermediate product (II) can then be obtained directly from the intermediate product (Xc) by reaction with N-chlorosuccinimide, carried out according to the methods described in the accompanying examples or according to methods known to those skilled in the art.

The intermediate product of formula (Xa) can be prepared by a procedure involving the use of an intermediate product of formula (XI),

in which R ² denotes hydrogen or methyl.

In the first step, a commercially available intermediate of formula (XI) in which R ² is hydrogen, hereinafter referred to as intermediate (XIa), is reacted with methyl iodide in the presence of a strong base, such as potassium hydroxide, in a suitable solvent, such as dimethylformamide. Then, the resulting intermediate (XI) in which R ² is methyl, hereinafter referred to as intermediate (XIb), is reacted with tert-butyl 2-chloroacetate in the presence of potassium tert-butoxide in a suitable solvent, such as tetrahydrofuran, at low temperature to obtain intermediate (Xa).

If, in using any of the above-described procedures for preparing the compounds of the present invention, a mixture of products is formed, the desired product can be isolated therefrom at a suitable stage using conventional techniques such as preparative HPLC (high performance liquid chromatography) or column chromatography using, for example, silica and/or alumina together with a suitable solvent system.

If, when using the above-described methods for preparing the compounds of the present invention, a mixture of stereoisomers is formed, these isomers can be separated by conventional methods. In particular, when it is necessary to obtain a specific enantiomer of a compound of formula (I), it can be obtained from the corresponding mixture of enantiomers by any conventional method for separating enantiomers. Thus, for example, diastereoisomeric derivatives, for example salts, can be obtained by reacting a mixture of enantiomers of formula (I), for example a racemate, with an appropriate chiral compound, for example a chiral base. The diastereoisomers can then be separated by any conventional methods, for example by crystallization and the desired enantiomer can be isolated, for example by treatment with an acid, in the case where the diastereoisomer is a salt. In another separation method, the racemate of formula (I) can be separated using chiral HPLC. In addition, if desired, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the procedures described above. Alternatively, a specific enantiomer can be obtained by performing an enantiomerically specific enzymatic biological transformation, for example, hydrolysis of an ester using an esterase, followed by purification of only the enantiomerically pure hydrolytic acid from the unreacted ester antipode. If it is desired to obtain a specific geometric isomer of the present invention, chromatography, recrystallization, and other conventional separation techniques can also be used for intermediates or final products. Alternatively, an undesired enantiomer can be racemized in the presence of an acid or base using procedures known to those skilled in the art or using the procedures described in the accompanying examples to obtain the desired enantiomer.

During any of the above synthetic sequences, it may be necessary and/or desirable to protect sensitive or reactive groups contained in any of the molecules involved in the reactions. This can be accomplished by using conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, ^3rd edition, 1999. The protecting groups can be removed at any suitable subsequent step by procedures known in the art.

The compounds of formula (I) proposed in the present invention do not activate the dopamine D1 receptor directly, but enhance the effect of D1 agonists or endogenous ligand on dopamine D1 receptors by an allosteric mechanism and therefore they are positive allosteric modulators of D1 (PAM D1).

Dopamine and other D1 agonists themselves directly activate the dopamine D1 receptor.

The studies are designed to examine the effects of the compounds of the present invention in the absence of dopamine (an "activation study") and in the presence of dopamine (an "enhancement study").

The activation assay measures the stimulation of cyclic adenosine monophosphate (cAMP) production using homogeneous time-resolved fluorescence (HTRF) imaging, with the maximal increase in cAMP produced by increasing concentrations of the endogenous agonist, dopamine, and defined as 100% activation.

According to the study, the compounds of formula (I) proposed in the present invention do not exert significant direct agonist-like effects, since they provide activation that is less than 20% (of the maximum response to dopamine) at a concentration of 10 μM.

In the activity enhancement assay, the ability of compounds to increase the amount of cAMP produced at a low threshold concentration of dopamine is determined. This concentration of dopamine ([EC ₂₀ ]) is used to provide a stimulation equal to 20% of the maximal response (100%) obtained with increasing concentrations of dopamine. To determine this enhancement, compounds are incubated with increasing concentrations of dopamine [EC ₂₀ ] and the enhancement is defined as an increase in cAMP production and the concentration of compound that provides a 50% increase in cAMP concentration is determined.

According to the cAMP assay using OPRV, the compound of formula (I) proposed in the present invention has a pEC ₅₀ value of greater than about 6.5, indicating that it is a positive allosteric modulator of D1.

It is known that inhibition of the GABA _A receptor is directly related to seizures and epilepsy. Therefore, it is necessary to develop compounds that are positive allosteric modulators of D1 and at the same time provide for minimization of such effects.

Therefore, it is preferred that, in the GABA-A receptor inhibition assay described herein, the compound of formula (I) provides a percentage inhibition of the GABA _A receptor of less than or equal to about 20%, ideally less than about 10%, preferably less than about 5%, when the compound of formula (I) is tested at a concentration of 10 μM.

A difficulty that may arise in the development of compounds intended for use in therapy is the ability of certain compounds to induce CYP450 enzymes. Induction of such enzymes may affect the exposure of such compounds or other compounds that may be co-administered to the patient, likely altering their respective safety and efficacy. Therefore, it is necessary to develop compounds that minimize the likelihood of induction.

The ability of the compound of formula (I) according to the present invention to induce CYP450 is investigated by determining the possible increase in CYP450 activities in human hepatocytes treated with the compounds according to the present invention at increasing concentrations.

Preferably, in a CYP3A4 induction study conducted according to the protocols described in the present patent application, the compound of formula (I) according to the present invention has a fold induction value that is at least about 2-fold lower, ideally at least about 3-fold lower, preferably at least about 4-fold lower than that obtained for the positive control compound (rifampicin).

When developing a compound for therapeutic use, it is important to have information about its elimination after it is administered to the body.

Clearance is a parameter that provides such information because it represents the volume of plasma (or blood) completely cleared of the compound of interest per unit time. It is usually expressed as ml/min/kg or l/h. It can then be compared with any physiological blood flow (e.g. hepatic blood flow) to determine whether clearance is low, intermediate or high.

If clearance is low, then depending on the volume of distribution, a low dose requirement and relatively long duration of action can be expected. If clearance is high, then also depending on the volume of distribution, a high dose requirement and relatively short duration of action can be expected.

Clearance is typically estimated according to the protocols described herein using incubation with hepatocytes and calculations by scaling the data, assuming that metabolism is the primary route of elimination. Intrinsic clearance calculated using hepatocytes is expressed as µl/min/10 ⁶ cells.

Preferably, when measured in a clearance assay as described herein, the compound of formula (I) as provided herein has a clearance of less than about 10 μl/min/10 ⁶ cells.

cAMP assay using OFRV

The specific conditions under which the compounds were tested are given below in the present invention.

a. Methods using D1-expressing cell culture

Cells were grown at 37°C in a humidified atmosphere containing 5% CO ₂ . Cells were grown in DMEM-F12+GlutaMAX™-I medium (GIBCO ^® , Invitrogen, Merelbeke, Belgium) containing 10% fetal bovine serum (Bio Whittaker ^® , Lonza, Verviers, Belgium), 400 μg/ml geneticin (GIBCO ^® ), 100 IU/ml penicillin (IU = international units) and 100 IU/ml streptomycin (Pen-Strep solution, Bio Whittaker ^® ). LMtk (Ltk-) mouse fibroblasts expressing the dopamine D1 receptor (BioSignal Inc, Montreal, Canada, now Perkin Elmer) were used and found to bind efficiently and produce robust functional responses (Watts et al, 1995).

b. cAMP study

The study of intracellular cyclic adenosine monophosphate (cAMP) concentration changes was determined using the CisBio FFRP dynamic cAMP assay kit (Codolet, France). The assay utilized a time-resolved homogeneous fluorescence assay and was based on the determination of competition between native cAMP produced by the cells and cAMP labeled with the d2 dye. Label binding was determined using cryptate-labeled cAMP antibodies. The effects of the compound alone (agonism) were determined by performing the assay in the absence of dopamine, whereas the effects of the compound as a positive allosteric modulator (PAM) were determined in the presence of dopamine, at a concentration equal to the EC ₂₀ . Cells (20,000 cells/well) were incubated in 384-well plates at room temperature for 1 h in a final volume of 20 μl in Hanks' Balanced Salt Solution (HBSS) (Lonza, containing calcium, magnesium and 20 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer, pH 7.4) containing isobutylmethylxanthine (Sigma, final concentration: 0.1 mM), test compound at different concentrations (typically 10 ^-9.5 to 10 ^-4.5 M) in the presence and absence of dopamine (final concentration: 1.1 nM). The reaction was then stopped and the cells were lysed by adding d2 detection reagent in lysis buffer (10 μl) and cryptate reagent in lysis buffer (10 μl) according to the manufacturer's instructions. The mixtures were then incubated at room temperature for an additional 60 min and the change in fluorescence emission signals in the RPB was determined according to the manufacturer's instructions using an Envision plate reader (Perkin Elmer, Zaventem, Belgium) under laser excitation. All incubations were performed in duplicate and the results were compared with the concentration-response relationship obtained for dopamine (10 ^-11 to 10 ^-6 M).

p. Analysis of results

The results were analyzed using Excel and PRISM (GraphPad Software) and _pEC50 and _Erel values were obtained using the 4-parameter logistic equation (DeLean et al, 1978), where _Erel is the approximated maximal response to the test compound after subtracting background, expressed as a percentage of the value obtained using dopamine, which is defined as 100%.

The pEC ₅₀ value of a compound is equal to -log ₁₀ of the concentration of the compound that produces a 50% increase in cAMP concentration.

E _rel denotes the relative potency, defined as the maximum increase in activity, expressed as a percentage, provided by the compound compared to the maximum response obtained with increasing concentrations of dopamine (E _rel equal to 1 = maximum response to dopamine).

According to the above study, the compound of formula (I) has a pEC ₅₀ value of approximately 8.1 and an E _rel value of approximately 68%.

Automated voltage-clamp studies using GABA _A receptor-containing cells

CHO-K1 cells stably expressing the α1, α2, and α2 subunits of the human GABA _A receptor were used. Cells were grown with trypsin and maintained in serum-free medium at room temperature. Cells were washed and resuspended in extracellular solution prior to analysis.

Potential clamp studies

Experiments using human GABA _A (α ₁ β ₂ γ ₂ ) channels were performed using an automated voltage-clamp assay (IonFlux™ HT). Compounds were assayed at 3 concentrations (0.1, 1 and 10 μM) using 3 to 4 cells. The external solution for recording GABA _A currents consisted of 137 mM sodium chloride, 4 mM potassium chloride, 1.8 mM calcium chloride, 1 mM magnesium chloride, 10 mM HEPES and 10 mM glucose. The external and internal solutions were titrated with NaOH or KOH and adjusted to a pH of 7.35 or 7.3, respectively. The internal pipetted solution contained 70 mM potassium fluoride, 60 mM potassium chloride, 70 mM sodium chloride, 5 mM HEPES, 5 mM EGTA (ethylene glycol tetraacetic acid), and 4 mM magnesium-ATP (adenosine triphosphate) complex. The final concentration of the solvent, DMSO, used to dilute the compounds was 0.33% in each well. Bicuculline (0.032 to 100 μM) was used as a positive control inhibitor. GABA (15 μM) was used as an agonist. All measurements were performed at a baseline potential of -60 mV.

The sequence of compound addition was as follows: GABA was added at a concentration corresponding to the _EC80 to determine the baseline response. Compound was treated at each concentration for 30 s, then treated with 15 μM GABA in the presence of compound for 2 s. The procedure was repeated using the next higher concentration of compound. The maximum inward current values were determined as a response to the addition of GABA in the presence of compound at one concentration. All results obtained for a compound were normalized to the baseline maximum current value obtained with treatment with 15 μM GABA for 2 s.

According to the above study, the compound of formula (I), at a concentration of 10 μM, provides a percentage inhibition of the GABAA receptor of less than about 0.1%, determined at a concentration of the compound of formula (I) of 10 μM.

Induction study

The following studies are designed to determine the ability of the compound of the present invention to induce the CYP3A4 enzyme.

A. In vitro CYP3A4 induction assay using frozen human hepatocytes

The objective of the study using human hepatocytes was to determine the inducing capacity of the compound of formula (I) by determining CYP3A4 activities after 3 days of treatment of hepatocytes with culture medium only or with culture medium containing NCE (new chemical substance).

For this purpose, frozen human hepatocytes from a single donor were seeded into wells of a 48-well collagen-coated plate at a final seeding density of 0.2 x 10 ⁶ cells/well (final volume in each well was 0.25 ml). The cells were then incubated in seeding medium at 37°C, 95% humidity, 5% CO ₂ to ensure cell adherence. After 4 h, the seeding medium was replaced with 0.25 ml of prewarmed serum-free Williams E medium containing 100 IU/ml penicillin, 100 μg/ml streptomycin, 10 μg/ml insulin, 2 mM L-glutamine, and 0.1 μM hydrocortisone.

The following day, the test compound was added to the cells in the assay medium at a concentration of 1 μM (final DMSO concentration of 0.1%). The positive control inducer, rifampin (10 μM), was incubated simultaneously with the test compound. Negative control wells in which the test compound was replaced with the diluent solvent (0.1% DMSO in the assay medium) were also included in the assay. Each test compound was assayed in triplicate. Cells were treated with the culture medium for 72 h, with the medium being replaced every 24 h.

For determination of catalytic activity, a solution of CYP3A4 marker substrate, midazolam (final concentration 2.5 μM), was prepared in pre-warmed assay medium. After completion of the treatment for 72 h, the medium was replaced with CYP3A4 marker substrate. Hepatocytes were incubated for 30 min. After completion of the incubation, an aliquot was removed and placed in the same volume of methanol containing an internal standard. Samples were centrifuged at 2500 rpm at 4°C for 20 min. An aliquot of the supernatant was diluted with deionized water and 1-hydroxyimidazolam concentrations were determined using typical LC-MS/MS methods.

Hepatocytes were solubilized in 0.1 M sodium hydroxide solution at room temperature and the protein content of each well was determined using the Pierce™ BCA Protein Assay Kit (Thermo Scientific) using bovine serum albumin as a standard.

Analysis of results

The fold induction (increase in CYP activity) was obtained by determining the ratio of the enzymatic activity observed in hepatocytes treated with the compound of formula (I) to that observed in control hepatocytes treated with the diluent. The fold induction for the positive control (rifampicin) was calculated in the same manner. The inducing capacity of the compound of formula (I) was then compared with the inducing capacity of rifampicin by calculating the ratio of the fold induction obtained for rifampicin to the fold induction obtained for the compound of formula (I).

In a CYP3A4 induction study conducted according to the protocols described above in the present invention, the compound of formula (I) according to the present invention, at a concentration of 1 μM, has a fold induction value that is at least about 7 times lower than the value obtained for the compound used as a positive control (rifampicin) at a concentration of 10 μM.

Using the same protocol as described above, the test compound in assay medium was added to the cells at concentrations ranging from 0.03 to 10 μM (final DMSO concentration of 0.1%). The positive control inducer, rifampin, was incubated simultaneously with the test compound at concentrations ranging from approximately 0.1 to 30 μM.

The results of comparison of the highest values of the induction multiplicity obtained in accordance with the protocol described above, i.e. obtained at the maximum possible concentration (3 μM) of the compound of formula (I) proposed in the present invention to ensure dissolution, and at a concentration of the positive control (rifampicin) equal to 10 μM, show that the compound of formula (I) has an inducing capacity approximately 4 times lower than the inducing capacity of the compound used as a positive control (rifampicin).

Azamulin study

Frozen human hepatocytes (mix of 20 donors, BSU lot from Celsis/IVT/Bioreclamation) were thawed according to the supplier's recommendations. Viability (selection with trypan blue dye) was >75%. Pre-incubation (250 μl of hepatocyte suspension at a concentration of 2 × 10 ⁶ hepatocytes/ml) was performed in Williams medium containing 2 mM glutamine and 15 mM HEPES in 48-well plates at +37°C in an incubator (5% CO ₂ ) with gentle shaking (vibrating shaker, Titramax 100, approximately 300 rpm) for 30 min. After pre-incubation, incubation was started by adding 250 μM of culture medium (composition described above) containing UCB compound (1 μM) or midazolam (positive control) with or without azamulin (6 μM, a specific CYP3A4/5 inhibitor) to the hepatocytes. The final concentrations of UCB compound and azamulin in the incubation mixtures were 0.5 μM and 3 μM, respectively. The cell suspensions were quickly rehomogenized by pipetting twice. After incubation for 0, 30, 60, 120, 180 and 240 min, reactions were stopped by transferring 50 μl of the incubated mixtures to appropriate wells of a 96-well plate containing 50 μl of ice-cold acetonitrile supplemented with 1 μM ketoconazole as an internal standard. Before each sampling, incubated cells were rehomogenized by pipetting twice.

When incubated with a suspension of human hepatocytes, the intrinsic clearance (Clint) of the compounds of formula (I) proposed in the present invention at different concentrations is 2.1±0.6 μl/min/10 ⁶ cells.

The following examples illustrate the preparation of compounds of formula (I) proposed in the present invention.

EXAMPLES

Abbreviations/Reusable Reagents

ACN: Acetonitrile

Brine: a saturated aqueous solution of sodium chloride

nBu: n-butyl

tBu: tert-butyl

DCM: dichloromethane

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

EC _20/50 : concentration that provides 20%/50% of the maximum response value

E _rel : relative efficiency

ER ⁺ : electrospray ionization in positive ion mode

Et: ethyl

EtOH: ethanol

Et ₂ O: diethyl ether

EtOAc: ethyl acetate

h: hour(s)

HPLC: High Performance Liquid Chromatography

HRTF: Homogeneous Time-Resolved Fluorescence

LCMS: liquid chromatography mass spectrometry

MeOH: methanol

min: minute(s)

NCS: N-chlorosuccinimide

NMR: Nuclear Magnetic Resonance

iPrOH: isopropanol

CT: room temperature

SLC: supercritical liquid chromatography

TEA: triethylamine

THF: tetrahydrofuran

TLC: thin layer chromatography

cAMP: cyclic adenosine monophosphate.

Names according to IUPAC (International Union of Pure and Applied Chemistry) standards are obtained using Biovia Draw 16.1 software.

Analysis methods

All reactions involving air- or moisture-sensitive reagents are carried out under nitrogen or argon using dried solvents and glassware. Commercially available solvents and reagents are generally used without further purification, including anhydrous solvents when practical (usually Sure-Seal™ from Aldrich Chemical Company or AcroSeal™ from ACROS Organics). Reactions are typically monitored by thin-layer chromatography, HPLC, or mass spectrometry.

Crude substances can be purified by normal phase chromatography, reversed phase chromatography (in acidic or basic medium), chiral separation, or recrystallization.

Before final analysis and biological testing of products, they are usually dried in a vacuum.

All NMR spectra were recorded at 250 MHz, 300 MHz, 400 MHz or 500 MHz.

The compounds are analyzed in solution in DMSO-d ₆ , CDCl ₃ or MeOH-d ₄ at a sensor temperature of 300 K and a concentration of 10 mg/mL. The instrument detects the signal of deuterium contained in DMSO-d ₆ CDCl ₃ or MeOH-d ₄ . Chemical shifts are given in ppm downfield from TMS (tetramethylsilane), which is used as an internal standard.

1. Obtaining an intermediate product of formula (II) - 2-(3,5-dichloro-1-methylindazol-4-yl)acetic acid

1.1. Preparation of intermediate product (XIb) - 1-methyl-5-nitroindazole

In a 50 L three-neck round bottom flask, 5-nitro-1H-indazole (XIa) (3.00 kg, 18.4 mol) and DMF (30.0 L) are placed at 15-30 °C. KOH (2.06 kg, 36.7 mol) is added in one portion to the reactor at 0-5 °C. The mixture is stirred at 0-50 °C for 1 h. Then methyl iodide (2.87 kg, 20.2 mol) is added at 0-5 °C and the mixture is stirred at 15-30 °C for 3 h. The reaction mixture is poured into water (30 L) at 0-10 °C and the mixture is stirred for 10 min, then filtered. The filter cake is washed with water (5 L) and dried. This entire procedure is carried out simultaneously using 4 portions of equal size. The solids obtained from 4 portions were combined to give 1-methyl-5-nitroindazole (XIb) as a brown solid (10.0 kg, 42.3 mol, 75% purity (LC/MS), 57.5% yield), which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (s, 1H), 8.21 (d, J=9.17 Hz, 1H), 8.13 (s, 1H), 7.39 (d, J=9.17 Hz, 1H), 4.08 (s, 3H).

1.2. Preparation of intermediate product (Xa) - tert-butyl 2-(1-methyl-5-nitroindazol-4-yl)acetate

In a 50 L three-neck round-bottomed flask, t-BuOK (4.43 kg, 39.5 mol) and THF (30 L) were placed and the mixture was cooled to -45/-35 °C under nitrogen and stirred. Then 1-methyl-5-nitroindazole (XIb) (3.50 kg, 19.7 mol) was added portionwise at -45/-35 °C. At the same temperature, tert-butyl 2-chloroacetate (3.57 kg, 23.7 mol) was added dropwise and the mixture was stirred for 1 h. The mixture was warmed to 15-30 °C and stirred for 5 h. The reaction was quenched by adding saturated ammonium chloride solution (9 L) and water (2 L) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×5 L). The organic phases were combined, washed with brine (2 L), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by recrystallization from ethyl acetate (5 L). This entire procedure was carried out simultaneously in two equal sized batches. The solids from the two batches were combined and dried together to give tert-butyl 2-(1-methyl-5-nitroindazol-4-yl)acetate as a yellow solid (Xa) (5.30 kg, 17.7 mol, 97.6% pure (LC/MS), 44.9% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.18-8.20 (m, 2H), 7.37 (d, J=9.21 Hz, 1H), 4.27 (s, 2H), 4 .14 (s, 3H), 1.44 (s, 9H).

1.3. Preparation of intermediate product (XЬ) - tert-butyl 2-(5-amino-1-methylindazol-4-yl)acetate

The reactor was charged with tert-butyl 2-(1-methyl-5-nitroindazol-4-yl)acetate (Xa) (7.30 kg, 25.0 mol) and MeOH (76 L). The reactor was purged with argon and Pd/C (50%, 760 g) was added. The reactor was purged with hydrogen three times and the mixture was stirred at 50 °C under hydrogen atmosphere ( ⁵⁰ psi) for 3 h. The reaction mixture was filtered and the solid was washed with MeOH (5 L). The mixture was concentrated to give tert-butyl 2-(5-amino-1-methylindazol-4-yl)acetate (Xb) as a brown oil (6.50 kg, 23.9 mol, 96.2% pure (LC/MS), 95.4% yield), which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (s, 1H), 7.27 (d, J=8.80 Hz, 1H), 6.91 (d, J=8.80 Hz, 1H), 4.60 (s, 2H), 3.93 (s, 3H), 3.68 (s, 2H), 1.38 (s, 9H).

1.4. Preparation of the intermediate product (Xc) - 2-(5-chloro-1-methylindazol-4-yl)acetic acid

In a 50 L three-neck round bottom flask, place tert-Butyl 2-(5-amino-1-methylindazol-4-yl)acetate(Xb) (2.00 kg, 7.65 mol) and concentrated HCl (10.0 L, 12 M) and cool the mixture to -10/-5 °C and stir. At -10/-5 °C, add aqueous solution (5 L) of sodium nitrite (686 g, 9.95 mol) dropwise and stir for 30 min. In a 20 L three-neck round bottom flask, place CuCl (833 g, 8.42 mol) and concentrated HCl (10.0 L, 12 M) and stir the mixture at -10/-5 °C for 30 min, then add to another reactor. The mixture was stirred at -10/-5°C for 1 h, then at 10-30°C for 16 h. The reaction mixture was filtered and the solids were washed with water. This entire procedure was performed simultaneously using 3 equal sized batches. The solids from the 3 batches were combined and dried together to give 2-(5-chloro-1-methylindazol-4-yl)acetic acid (Xc) as a yellow solid (4.00 kg, 16.3 mol, 92% pure (LC/MS), 71.3% yield), which was used in the next step without further purification.

1.5. Preparation of 2-(3,5-dichloro-1-methylindazol-4-yl)acetic acid (II)

In a 50 L three-neck round-bottomed flask were placed 2-(5-chloro-1-methylindazol-4-yl)acetic acid (Xc) (1.30 kg, 5.79 mol) and DMF (6.5 L) at 20 °C. N-chlorosuccinimide (772 g, 5.79 mol) was added portionwise at 20 °C and the mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into water (25 L) and filtered. The crude product was triturated with isopropyl ether:ethyl acetate (3:1) (7.0 L) at 20 °C for 2 h, then filtered and dried. This entire procedure was carried out simultaneously using three equal sized portions. The solids obtained in 3 portions were combined to give 2-(3,5-dichloro-1-methylindazol-4-yl)acetic acid (II) (2.1 kg, 7.9 mol, purity 97.5% (LC/MS), yield 46%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.67 (s, 1H), 7.68 (d, J=9.05 Hz, 1H), 7.53 (d, J=9.05 Hz, 1H), 4.20 (s, 2H), 4.02 (s, 3H).

2. Obtaining a compound of formula (I)

2-(3,5-Dichloro-1-methylindazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methylethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone

2.1. Obtaining the intermediate product (IX).

(2R)-2-Amino-3-(2-bromophenyl)propan-1-ol-ab

(2R)-2-amino-3-(2-bromophenyl)propanoic acid a5 (34.0 kg, 139 mol) and THF (238 L) are placed in a reactor. Sodium borohydride (15.6 kg, 413 mol) is slowly added at 20-30 °C. A solution of iodine (35.3 kg, 139 mol) in dry THF (20.0 L) is slowly added at 0-10 °C and the reaction mixture is stirred at 70 °C for 12 h. The reaction at 0 °C is quenched with methanol (70.0 L) and the mixture is heated at 80 °C for 30 min. The mixture is cooled, concentrated in vacuo and the residue is suspended in NaOH (30.0 L, 2N), then filtered. The filter cake was dried in vacuo to give (2R)-2-amino-3-(2-bromophenyl)propan-1-ol a6 as a white solid (31.0 kg, 135 mol, 96.7% yield), which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J=7.7 Hz, 1H), 7.21-7.29 (m, 2H), 7.07-7.15 (m, 1H), 3.66 (dd, J=10.5, 3.6 Hz, 1H), 3.41 (dd, J=10.5, 7.2 Hz, 1H), 3.18-3.29 (m, 1H), 2.95 (dd, J=13.5, 5.5 Hz, 1H), 2.70 (dd, J=13.5, 8.2 Hz, 1H), 1.51- 1.91 (m, 3H).

2.2. Obtaining an intermediate product of formula (VIII).

(4R)-4-[(2-Bromophenyl)methyl]oxazolidin-2-one - a7

(2R)-2-amino-3-(2-bromophenyl)propan-1-ol a6 (31.0 kg, 135 mol) and dichloromethane (220 L) are placed in a reactor. Triphosgene (13.9 kg, 47.1 mol) is added at room temperature, then N,N-diisopropylethylamine (39.1 kg, 303 mol) is slowly added at 0-10 °C. The reaction mixture is stirred at 0-10 °C for 1 h, then washed twice with water (50.0 L), dried over anhydrous sodium sulfate and filtered to give (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one a7 as a solution in dichloromethane, which is used in the next step without treatment.

2.3. Obtaining the intermediate product (VII).

(10aR)-9-Bromo-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a8

A solution of (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one a7 (135 mol) in dichloromethane (220 L) was placed in the reactor and cooled to 0-5°C. Trimethylsilyl triflate (35.9 kg, 162 mol) and paraformaldehyde (13.3 kg, 148 mol) were added at 0-5°C, then stirred at 15-20°C for 2 h. Water (170 L) was added to the mixture, which was then extracted twice with dichloromethane (50.0 L). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. A mixture of petroleum ether:ethyl acetate (1:1, 45.0 L) was added, and the mixture was stirred at room temperature for 6 h and filtered. The solid was dried to give (10aR)-9-bromo-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a8 as an off-white solid (29.0 kg, 80.2% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.52 (m, 1H), 7.08-7.14 (m, 2H), 4.83 (d, J=17.0 Hz, 1H), 4.62 (t, J=8.4 Hz, 1H), 4.36 (d, J=17.0 Hz, 1H), 4.21 (dd, J=8.6, 4.9 Hz, 1H), 3.91-3.99 (m, 1H), 3.25 (dd, J=16.3, 4.2 Hz, 1H), 2.67 (dd, J=16,l, 11.0 Hz, 1H).

2.4. Obtaining intermediate products (VI)

2.4.1. [(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol a9

Ethanol (120 L) and water (60.0 L) are placed in a reactor. (10aR)-9-bromo-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a8 (29.7 kg, 111 mol) is added at 15-20°C, then sodium hydroxide (13.3 kg, 332 mol) is slowly added. The reaction mixture is stirred at 90°C for 2 h, then cooled to room temperature. Water (300 L) is added to the mixture, which is then centrifuged. The residue obtained after centrifugation was dried in a recirculating gas oven to give [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol a9 as a white solid (23.7 kg, yield 88.3%), which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.47 (m, 1H), 6.95-7.08 (m, 2H), 4.00-4.10 (m, 2H), 3 .85 (dd, J=10.9, 3.7 Hz, 1H), 3.57 (dd, J=10.9, 7.9 Hz, 1H), 3.06 (ddt, J=11.3 , 7.6, 4.1, 4.1 Hz, 1H), 2.79 (dd, J=17.1, 4.4 Hz, 1H), 2.40 (dd, J=17.1, 10 .9 Hz, 1H), 1.93 (br s, 2H).

2.4.2. [(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane a10

[(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol a9 (23.7 kg, 97.8 mol) and dichloromethane (240 L) are placed in a reactor. DMAP (120 g, 0.98 mol) and imidazole (13.3 kg, 196 mol) are added. tert-Butyldimethylsilyl chloride (TBSCl) (17.7 kg, 117 mol) is slowly added at 15-20 °C and the mixture is stirred for 12 h. Ammonium chloride (100 L) is added to the mixture. The organic phase was separated, washed with water (50.0 L), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane a10 as a yellow oil (37.6 kg, 86% purity, 93% yield), which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.45 (m, 1H), 7.01 (d, J=4.6 Hz, 1H), 4.01-4.13 (m, 2H), 3.84 (dd, J=9.9, 3.7 Hz, 1H), 3.64 (dd, J=9.8, 7.2 Hz, 1H), 2.96-3.08 (m, 1H), 2.75 (dd, J=17.0, 4.2 Hz, 1H), 2.44 (dd, J=17.0, 10.8 Hz, 1H), 1.76- 2.20 (m, 2H), 0.89-0.97 (m, 9H), 0.08-0.14 (m, 6H).

2.5. Obtaining the intermediate product (V).

[(3R)-5-Bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane a11

[(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane a10 (3.42 kg, 8.31 mol) and THF (30.0 L) were placed in a reactor. N-chlorosuccinimide (NCS) (1.17 kg, 8.73 mol) was slowly added at room temperature and the mixture was stirred at 25 °C for 30 min. A solution of KOH (1.52 kg, 27.1 mol) in dry methanol (7.00 L) was slowly added at room temperature and the reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with water (10.0 L) and the mixture was extracted with petroleum ether:ethyl acetate (1:2, 5.00 L). The organic layer was separated, washed with brine (10.0 L), dried over anhydrous sodium sulfate, and filtered. This entire procedure was carried out simultaneously in 10 equal-sized batches, and the filtrates from the 10 reactions were combined and concentrated in vacuo to give [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane all as a brown oil (28.0 kg, crude), which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J=2.6 Hz, 1H), 7.58 (dd, J=7.8, 1.2 Hz, 1H), 7.12 -7.25 (m, 2H), 4.03 (dd, J=9.5, 4.0 Hz, 1H), 3.67-3.77 (m, 2H), 3.07 (dd, J =17.0, 6.2 Hz, 1H), 2.68 (dd, J=17.1, 10.9 Hz, 1H), 0.88-0.91 (m, 9H), 0.07 ( d, J=1.5 Hz, 6H).

2.6. Obtaining intermediate products of formula (IV)

2.6.1. [(1S,3R)-5-Bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane (IVa)

[(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane all (3.10 kg, 8.75 mol) and THF (20.0 L) were placed in a reactor. The mixture was cooled to 0 °C and methyl magnesium chloride (3M, 11.6 L) was added. The mixture was stirred at 20 °C for 12 h. The reaction was quenched with saturated ammonium chloride solution. The phases were separated and the aqueous layer was extracted twice with petroleum ether:ethyl acetate (3:1, 5.00 L). The combined organic phases were washed with brine (10.0 L), dried over anhydrous sodium sulfate, and filtered. This entire procedure was carried out simultaneously in nine equal-sized batches, and the filtrates from the nine reactions were combined and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using petroleum ether:ethyl acetate (10:1) to give [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane (IVa) as a brown oil (4.60 kg, 99.7% purity, 15.7% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.41 (dd, J=7.7, 0.9 Hz, 1H), 7.12-7.18 (m, 1H), 7.03- 7.11 (m, 1H), 4.12 (q, J=6.8 Hz, 1H), 3.62 (d, J=5.7 Hz, 2H), 3.07-3.17 (m , 1H), 2.67-2.76 (m, 1H), 2.26 (dd, J=16.9, 10.0 Hz, 1H), 2.12 (br s, 1H), 1.32 (d, J=6.8 Hz, 3H), 0.84-0.93 (m, 9H), 0.07 (d, J=0.9 Hz, 6N).

2.6.2. tert-Butyl (1S,3R)-5-bromo-3-[[tert-butyl (dimethyl) silyl] oxymethyl]-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (IVb)

[(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyldimethylsilane (IVa) (1.85 kg, 4.99 mol) and dichloromethane (13.0 L) were placed in a reactor. N,N-Diisopropylethylamine (1.94 kg, 14.9 mol) and di-tert-butyl dicarbonate (1.14 kg, 5.24 mol) were added at room temperature and the mixture was stirred for 12 h. The reaction mixture was washed twice with saturated ammonium chloride solution (10.0 L) and the organic layer was dried over anhydrous sodium sulfate and filtered. This entire procedure was carried out simultaneously using 2 equal sized portions and the filtrates obtained from the 2 reactions were combined and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using petroleum ether:ethyl acetate (30:1) to give tert-butyl (1S,3R)-5-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (IVb) as a yellow oil (4.00 kg, 99.5% purity, 85.2% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.50 (d, J=7.9 Hz, 1H), 7.22 (br d, J=6.7 Hz, 1H), 7.06- 7.18 (m, 1H), 4.84 (br s, 1H), 4.12 (br s, 1H), 3.46 (br d, J=15.4 Hz, 2H), 2.94 ( br dd, J=15.8, 5.2 Hz, 1H), 2.71 (br t, J=9.5 Hz, 1H), 1.45 (s, 9H), 1.28 (br s, 3H), 0.81 (s, 9H), -0.08 (s, 6H).

2.6.3. tert-Butyl (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(1-hydroxy-1-methylethyl)-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (IVc)

A solution of tert-butyl (1S,3R)-5-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (IVb) (42.5 g, 90.3 mmol) in dry THF (0.5 M solution) and a commercially available solution of n-butyl lithium in hexanes (1.6 M solution) were fed using pumps at rates of 6.0 mL/min (1.0 equiv.) and 2.46 mL/min (1.3 equiv.), respectively, and mixed in a glass microreactor cooled to -40°C. The combined stream was then passed through reaction zone 1 of the microreactor (0.3 mL) and then combined with dry acetone solution (13.5 M) fed by a pump at a rate of 6.0 mL/min (27 equiv). The resulting stream was then passed at -40 °C through reaction zone 2 of the microreactor (0.7 mL). Finally, the combined reactor effluent was collected and the reaction was quenched at RT with saturated aqueous ammonium chloride solution. After all the loaded solutions had been consumed, a bilayer reaction mixture was obtained. The aqueous layer was separated from the organic layer and then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. A yellow oil (46.5 g) was obtained and purified by NLC using a GreenSep Nitro column (10 μm, 5×22.3, eluting with 98% _CO2 /2% EtOH). The solvent was removed in vacuo to give a white solid, tert-butyl (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(1-hydroxy-1-methylethyl)-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate(IVc) (25 g, 56 mmol, 62% yield).

UPLC (ultra-performance liquid chromatography)-MS, alkaline medium, 1 peak at 3.83 min (ER ⁺ ): 350 (M-Boc + H) ⁺ , 332 (M-Boc-H ₂ O + H) ⁺ , purity 100%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.44 (d, J=7.9 Hz, 1H), 7.19 (dt, J=8,l, 5.2 Hz, 1H), 7 .09 (t, J=9.0 Hz, 1H), 4.99 (s, 1H), 4.87 (dq, J=13.4, 6.4 Hz, 1H), 4.11 (s, 1H), 3.96 (t, J=14.9 Hz, 1H), 3.48 (dd, J=9.4, 4.1 Hz, 1H), 2.98 (dd, J=16.5 , 5.0 Hz, 1H), 2.89 (t, J=9.6 Hz, 1H), 1.65 (s, 3H), 1.58 (s, 3H), 1.55 (d, J=2.5 Hz, 9H), 1.34 (dd, J=20.5, 6.6 Hz, 3H), 0.90 (s, 9H) , 0.08 (d, J=7.2 Hz, 3H), -0.00 (s, 3H).

2.7. Preparation of intermediate product (III) - 2-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-5-yl]propan-2-ol chloride

2.7.1. tert-Butyldimethyl-[[(1S,3R)-1-methyl-5-(1-methyl-1-trimethylsilyloxyethyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy]silane -a15

tert-Butyl (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(1-hydroxy-1-methylethyl)-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (IVc) (148 g, 87% purity, 287 mmol) was dissolved in 1000 mL dichloromethane and transferred to a 2 L double-wall reactor. 2,6-lutidine (100 mL, 860 mmol) was added and the jacket temperature was set to -2°C. Trimethylsilyl trifluoromethanesulfonate (154 g, 129 mL, 692 mmol) was added via an addition funnel over 40 min. After 2 h from the start of the addition, the reaction was quenched by adding 650 ml of an aqueous solution of citric acid (1 M) and the temperature of the mixture was adjusted to 20 °C. After 1 h from the start of the quench, the layers were separated. The organic layer was washed twice with 350 ml of an aqueous solution of citric acid (1 M). The organic layer was stirred with 750 ml of an aqueous solution of sodium carbonate (10% w/w) for 10 min, then the layers were separated. The organic layer was dried over anhydrous sodium sulfate. Then the organic layer was filtered and the filtrate was concentrated in vacuo at 40 °C to give a yellow oil (128 g), tert-butyldimethyl-[[(1S,3R)-1-methyl-5-(1-methyl-1-trimethylsilyloxyethyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy]silane a15, which was used in the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.19 (d, J=7.7 Hz, 1H), 7.07 (t, J=7.7 Hz, 1H), 7.00 (d, J =7.6 Hz, 1H), 4.24 (q, J=6.8 Hz, 1H), 3.75 (dd, J=9.7, 4.4 Hz, 1H), 3.60 (dd , J=9.7, 7.0 Hz, 1H), 3.54 (dd, J=16.3, 3.5 Hz, 1H), 3.15 (ddt, J=10.9, 7.4 , 4.0 Hz, 1H), 2.52 (dd, J=16.3, 10.9 Hz, 1H), 1.66 (d, J=14.6 Hz, 6H), 1.52-1.43 (m, 3H), 0.92 (q, J=1.2 Hz, 9H), 0.14 (q, J=1.2 Hz, 2H), 0, 09 (d, J=1.1 Hz, 6H), 0.00 (q, J=1.2, 0.8 Hz, 9H).

2.7.2. 2-[(1S,3R)-3-(Hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-5-yl]propan-2-ol chloride - intermediate product (III)

In a three-necked round-bottomed flask equipped with a mechanical stirrer, tert-butyldimethyl-[[(1S,3R)-1-methyl-5-(1-methyl-1-trimethylsilyloxyethyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy]silane a15 (20.0 g, 47.4 mmol) was dissolved in 220 mL of isopropanol. To this solution was added 42.3 mL of hydrochloric acid in isopropanol (5-6 M, ca. 5 equiv). Forty-five min after the addition of hydrochloric acid, 100 mg of seed crystals of the desired product were added. After keeping at room temperature for 7 h, the reaction mixture was filtered through a sintered glass filter. The filter cake was washed with 40 mL of isopropanol and dried in vacuo at room temperature overnight. 11.1 g of 2-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-5-yl]propan-2-ol chloride (III) are obtained as a pinkish solid. The yield after 2 stages of deprotection is 91%.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.46 (dd, J=7.8, 1.3 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7, 21 (dd, J=7.8, 1.3 Hz, 1H), 4.63 (q, J=6.9 Hz, 1H), 3.97 (dd, J=11.7, 3.8 Hz , 1H), 3.88 (dd, J=17.2, 4.3 Hz, 1H), 3.78 (dd, J=11.8, 6.1 Hz, 1H), 3.66-3, 56 (m, 1H), 3.14 (dd, J=17.2, 11.4 Hz, 1H), 1.73 (d, J=6.8 Hz, 3H), 1.64 (d, J=4.8 Hz, 6H). Signals of protons contained in OH and NH are absent.

2.8. Obtaining a compound of formula (I).

2-(3,5-Dichloro-1-methylindazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methylethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone

In a 100 mL Easymax reactor equipped with a mechanical stirrer, 2-(3,5-dichloro-1-methylindazol-4-yl)acetic acid (II) (4.00 g, 15.4 mmol), 2-[(1S,3R-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-5-yl]propan-2-ol chloride (III) (4.46 g, 16.4 mmol) and 48 mL DMF were placed. The suspension was stirred at 20 °C and then cooled by adjusting the jacket temperature to -2 °C. Once the mixture reached a temperature below 3 °C, N,N-diisopropylethylamine (9.5 mL, 54 mmol) was added. (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (6.4 g, 17 mmol). The mixture was stirred for 1 h 45 min, then the jacket temperature was adjusted to 15°C. Then 16 ml of water was added over several minutes. After 15 min, 30 mg of the solid product was added as seed crystals to initiate crystallization. The jacket temperature was adjusted to 20°C. After 0.5 h, 16 ml of water was added over 17 min. The suspension was stirred at 20°C for 2 h 15 min and then filtered through a sintered glass filter. The filter cake was washed with water (2 x 20 ml) and then dried in vacuo at 50°C overnight to give 6.03 g of 2-(3,5-dichloro-1-methylindazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methylethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (I) (crude material).

Recrystallization of 5.00 g of the crude material is carried out by first suspending it in 50 ml of acetonitrile. The jacket temperature is set at 70°C. After the solid has dissolved and the mixture has reached a temperature of 66°C, 720 μl of water are added. The temperature of the mixture is then lowered to 59°C and 125 mg of the solid product are added as seed crystals. The temperature of the mixture is then lowered to 55°C over 25 min, at which point crystallization occurs. The jacket temperature is then lowered from 58°C to 20°C over 2 h. After 50 min, the suspension is filtered and the filter cake is washed with 7.5 ml of acetonitrile. The filter cake was then dried in vacuo at 45°C overnight and at 50°C for 2 h to give 4.04 g of 2-(3,5-dichloro-1-methylindazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methylethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (I) as an almost white powder (in the form of a hydrate). Yield = 64%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.65 (dd, J=9.0, 2.2 Hz, 1H), 7.52 (dd, J=9.0, 2.1 Hz, 1H), 7.37 (ddd, J=19.6, 7.6, 1.7 Hz, 1H), 7.25-7.03 (m, 2H), 5.30 (q, J=6, 5 Hz, 0.3H), 5.16-4.99 (m, 1.7H), 4.99-4.84 (m, 0.7H), 4.63-4.30 (m, 3. 3H), 4.17-3.93 (m, 4H), 3.28 (dt, J=10.5, 5.1 Hz, 1.3H), 3.10-2.85 (m, 1.7H), 1.56 (dd, J=13.2, 6.9 Hz, 6.7H), 1.24 (d, J=6.5 Hz, 2.3H).

Claims (9)

1. 2-(3,5-Dichloro-1-methylindazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methylethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone of formula (I) or a pharmaceutically acceptable salt thereof 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for use in therapy. 3. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of diseases and/or disorders in which D1 receptors play a role. 4. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of cognitive-related and negative symptoms of schizophrenia, neuroleptic-associated cognitive impairment, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, dementia in Parkinson's disease, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug or narcotic overuse addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain. 5. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson's disease and other movement disorders, Alzheimer's disease or cognitive and negative symptoms of schizophrenia. 6. A pharmaceutical composition having the activity of a positive allosteric modulator of D1, containing an effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. 7. A method for treating and/or preventing cognitive-related and negative symptoms of schizophrenia, mild cognitive impairment (MCI), impulsivity, Parkinson's disease and other movement disorders, dementia with Lewy bodies, Alzheimer's disease, for which administration of a positive allosteric modulator of D1 is indicated, which comprises administering to a patient in need of such treatment a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in an effective amount. 8. A method for treating Parkinson's disease and other movement disorders, Alzheimer's disease or cognitive and negative symptoms of schizophrenia for which administration of a positive allosteric modulator of D1 is indicated, which comprises administering to a patient in need of such treatment a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in an effective amount.