Dihydroisoquinolinyl derivatives

Abstract

The present invention relates to tetrahydroisoquinolinyl derivatives of formula (I) [Formula 1] JPEG2023554033000030.jpg4651 It is a positive allosteric modulator of D1 and is therefore useful as a pharmaceutical agent for the treatment of diseases in which the D1 receptor is involved.

Description

[Technical Field]

[0001] The present invention relates to dihydroisoquinolinyl derivatives and their use in therapy. In particular, the present invention relates to pharmacologically active fused dihydroisoquinolinyl derivatives and analogs thereof. More particularly, the present invention relates to substituted 3,4-dihydro-1H-isoquinolin-2-yl derivatives and analogs thereof.

[0002] The compounds according to the present invention are D1 positive allosteric modulators and are therefore useful as pharmaceuticals for the treatment of diseases in which the D1 receptor is involved. [Background technology]

[0003] The monoamine dopamine acts through two families of GPCRs to regulate motor function, reward mechanisms, cognitive processes, and other physiological functions. Specifically, dopamine acts on neurons primarily through D1-like receptors, including dopamine D1 and D5, which are receptors that couple to Gs G proteins and thereby stimulate cAMP production, and D2-like receptors, including D2, D3, and D4, which are receptors that couple to Gi / q G proteins and attenuate cAMP production. These receptors are widely expressed in different brain regions. In particular, D1 receptors are involved in numerous physiological and behavioral processes. D1 receptors are involved in, for example, synaptic plasticity, cognitive function, and goal-directed motor function, as well as reward processes. Due to their involvement in physiological / neurological processes, D1 receptors have been implicated in a variety of disorders, including cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

[0004] It is well known that developing orally bioavailable small molecules targeting the D1 receptor is difficult. D1 agonists developed to date generally feature a catechol moiety, limiting their clinical use to invasive treatments. Achieving sufficient selectivity has also been challenging due to the high degree of homology in the ligand-binding sites between dopamine receptor subtypes (e.g., dopamine D1 and D5). Furthermore, D1 agonists are associated with potentially limiting side effects, including, but not limited to, dyskinesia and hypotension.

[0005] Therefore, there is a need for the design of new drugs that can modulate the D1 receptor.

[0006] There is considerable interest in identifying allosteric modulators of GPCRs, both as tools for understanding receptor mechanisms and as potential therapeutic agents. GPCRs represent the largest family of cell surface receptors, and numerous marketed drugs directly activate or block signaling pathways mediated by these receptors. However, for some GPCRs (e.g., peptide receptors), developing small molecules or achieving sufficient selectivity has proven difficult due to the high degree of homology in the ligand-binding sites between subtypes (e.g., dopamine D1 and D5 or D2 and D3). Therefore, much drug research has shifted to identifying small molecules that target sites distinct from orthosteric natural agonists. Ligands that bind to these sites induce conformational changes in GPCRs, thereby allosterically modulating receptor function. Allosteric ligands possess a diverse range of activities, including the ability to enhance (positive allosteric modulators, PAMs) or attenuate (negative allosteric modulators, NAMs) the effects of endogenous ligands by affecting affinity and / or efficacy. As well as subtype selectivity, allosteric modulators may exhibit other potential advantages from a drug discovery perspective, such as a lack of direct effects or inherent efficacy, only enhancing the effect of the natural transmitter if and when released, a reduced tendency to induce desensitization resulting from constant exposure to agonists, and a reduced tendency to induce target-related side effects. Summary of the Invention

[0007] The compounds according to the invention potentiate the effects of D1 agonists or endogenous ligands on the D1 receptor via an allosteric mechanism and are therefore D1 positive allosteric modulators (D1 PAMs).

[0008] The compounds according to the invention, which are D1 PAMs, are useful in the treatment and / or prevention of diseases and disorders in which the D1 receptor is involved, including cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

[0009] International Patent Application WO2017 / 178377 discloses certain substituted 3,4-dihydroisoquinol-2(1H)-yl derivatives and analogues thereof useful as D1 positive allosteric modulators.

[0010] International patent application WO2019 / 204418 discloses certain pyrazo-tetrahydroisoquinoline derivatives that are D1 positive allosteric modulators and may be useful in the treatment of Parkinson's disease, Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder (ADHD).

[0011] However, there remains a need to develop potent D1 positive allosteric modulators that combine favorable pharmacokinetic and pharmacodynamic properties while reducing side effects traditionally associated with treatments involving selective D1 agonists, such as hypotension or dyskinesia.

[0012] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] However, R a and R b are independently hydrogen or C 1-6 Represents alkyl.

[0013] As used herein, "C 1-6The term "alkyl" refers to an aliphatic hydrocarbon group which may be straight or branched and may contain 1 to 6 carbon atoms in the chain. Suitable alkyl groups which may be present in the compounds used in the present invention include straight and branched C 1-4 Exemplary C alkyl groups include: 1-6 Alkyl groups include methyl, ethyl, propyl and butyl.

[0014] Formula (I) and the formulae depicted below are intended to represent all individual stereoisomers and all possible mixtures thereof unless otherwise stated or indicated.

[0015] Stereoisomers of the compounds of formula (I) include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotamers, atropisomers, and conformational isomers of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures thereof (e.g., racemates and diastereomeric pairs).

[0016] The compounds of formula (I) contain asymmetric carbon atoms. The carbon-carbon bonds of the compounds of formula (I) are represented herein by solid lines ( [ka] ), solid wedge ( [ka] ) or dotted wedge ( [ka] ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.) are included. The use of a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of Formula (I) may contain two or more asymmetric carbon atoms. In these compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.

[0017] Some compounds of formula (I) may exist in tautomeric forms. Such forms, although not explicitly depicted in the formula above, are intended to be included within the scope of the present invention. Examples of tautomers include keto (CHC=O) <-> enol (CH=CHOH) tautomers or amide (NHC=O) <-> hydroxyimine (N=COH) tautomers. Formula (I) and the formulae depicted below are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise stated or indicated.

[0018] It is to be understood that the atoms of formula (I) or individual atoms present in the formulae shown below may in fact be present in any of their naturally occurring isotopic forms, with the most abundant isotopes being preferred. Thus, for example, an individual hydrogen atom present in formula (I) or the formulae shown below may be: 1 H, 2 H (deuterium) or 3 H (tritium) atoms, preferably 1 H. Similarly, for example, individual carbon atoms present in formula (I) or the formulae shown below may be present as: 12 C. 13 C or 14 C atoms, preferably 12 It may exist as C.

[0019] Specific embodiments of the compounds of formula (I) according to the present invention are described below.

[0020] In one aspect according to the present invention, R a represents hydrogen. In another embodiment according to the present invention, R a is C 1-6 In certain aspects according to this embodiment, R a represents methyl.

[0021] In one aspect according to the present invention, R b represents hydrogen. In another embodiment according to the present invention, R b is C 1-6 In certain aspects according to this embodiment, R b represents methyl.

[0022] Thus, in certain aspects, the present invention relates to compounds of formula (I) as set out in the accompanying examples.

[0023] Illustratively, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, 2-(3,5-dichloro-1H-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, and 2-(3,5-Dichloro-1H-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone The present invention relates to a compound of formula (I) selected from the group consisting of:

[0024] The present invention also provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in therapy.

[0025] In another aspect, the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for use in the treatment of diseases and / or disorders in which the D1 receptor is involved.

[0026] In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for use in the treatment and / or prophylaxis of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

[0027] In a particular embodiment of this aspect, the invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in the treatment of cognitive and negative symptoms in Parkinson's disease and other movement disorders, Alzheimer's disease, or schizophrenia.

[0028] Thus, in one particular aspect, the present invention provides 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.

[0029] In a further aspect, the present invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment and / or prevention of diseases and / or disorders in which the D1 receptor is involved.

[0030] In another further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above for the manufacture of a medicament useful for the treatment and / or prophylaxis of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

[0031] In a particular embodiment of this aspect, the invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment of cognitive and negative symptoms in Parkinson's disease and other movement disorders, Alzheimer's disease, or schizophrenia.

[0032] In one particular aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in the treatment of Parkinson's disease and other movement disorders.

[0033] The present invention also provides a method for the treatment and / or prevention of disorders for which administration of a D1 positive allosteric modulator is indicated, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0034] In another aspect, the present invention provides a method for the treatment and / or prophylaxis of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0035] In a particular embodiment of this aspect, the invention provides a method for the treatment of cognitive and negative symptoms in Parkinson's disease and other movement disorders, Alzheimer's disease, or schizophrenia, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0036] In one particular aspect, the present invention provides a method for the treatment of Parkinson's disease and other movement disorders, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0037] Activity in any of the above therapeutic indications or disorders can, of course, be determined by conducting appropriate clinical trials for the particular indication and / or in a manner known to those skilled in the art in clinical trial design in general.

[0038] When used in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. However, other salts may also be useful in the preparation of compounds of formula (I) 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 compounds of formula (I) include acid addition salts, which may be formed, for example, by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.

[0039] The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed using common organic solvents or water.

[0040] The present invention also includes within its scope co-crystals of compounds of formula (I) above. The term "co-crystal" is used to describe a situation in which neutral molecular components exist in a crystalline compound in a defined stoichiometric ratio. The preparation of pharmaceutical co-crystals allows modifications to be made to the crystalline form of a pharmaceutically active ingredient, thereby altering its physicochemical properties without impairing its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0041] Compounds according to the present invention may exist in different polymorphic forms, and although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the invention.

[0042] The present invention also includes within its scope prodrug forms of the compounds of formula (I) and the various sub-scopes and sub-groups of the same.

[0043] To treat a disease, the compounds of formula (I) or their pharmaceutically acceptable salts are used in effective daily dosages and may be administered in the form of a pharmaceutical composition.

[0044] Therefore, another embodiment of the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[0045] To prepare pharmaceutical compositions according to the invention, one or more of the compounds of formula (I) or pharmaceutically acceptable salts thereof are intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to those skilled in the art.

[0046] Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, for example oral, rectal, parenteral, or intranasal.

[0047] Pharmaceutical compositions containing compounds according to the invention can, for example, be administered orally, parenterally, ie, intravenously, intramuscularly or subcutaneously, intrathecally, by inhalation or intranasally.

[0048] Pharmaceutical compositions suitable for oral administration may be solid or liquid and may be in the form of, for example, tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing gum, or the like.

[0049] For this purpose, the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier, such as starch or lactose. Optionally, these pharmaceutical compositions may also contain a binder such as microcrystalline cellulose, tragacanth gum or gelatin, a disintegrating agent 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 a coloring agent or a flavoring agent such as peppermint or methyl salicylate.

[0050] The present invention also contemplates compositions that can release the active substance in a controlled manner. Pharmaceutical compositions that can be used for parenteral administration are in conventional forms such as aqueous or oily solutions or suspensions, which are generally contained in ampoules, disposable syringes, glass or plastic vials or infusion containers.

[0051] In addition to the active ingredient, these solutions or suspensions may optionally contain a sterile diluent such as water for injection, saline solution, oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents, antibacterial agents 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 osmotic pressure such as sodium chloride or dextrose.

[0052] These pharmaceutical forms are prepared using methods routinely used by pharmacists.

[0053] The amount of active ingredient in the pharmaceutical composition can fall within a wide range of concentrations and depends on various factors such as the patient's sex, age, weight and condition, as well as the method of administration. Thus, the amount of the compound of formula (I) in a composition for oral administration can be at least 0.5% by weight and up to 80% by weight based on the total weight of the composition.

[0054] It has also been found in accordance with the present invention that the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered alone or in combination with other pharmaceutically active ingredients.

[0055] In compositions for parenteral administration, the amount of compound of formula (I) present is at least 0.5% by weight and can be up to 33% by weight, based on the total weight of the composition. For preferred parenteral compositions, dosage units range from 0.5 mg to 3000 mg of compound of formula (I).

[0056] The daily dose can fall within a wide range of dosage units of the compound of formula (I), generally ranging from 0.5 to 3000 mg, although it will be understood that the specific dose can be adapted to a particular case according to the individual requirements at the physician's discretion.

[0057] It will be apparent to those skilled in the art that there are a variety of synthetic routes that can lead to compounds according to the invention. The following methods are intended to illustrate some of these synthetic routes, but should in no way be construed as a limitation on how compounds according to the invention should be prepared.

[0058] Compounds of formula (I) may be prepared by a process comprising reacting an intermediate of formula (II) with an intermediate of formula (III). [ka] R a and R b is as defined herein above.

[0059] Intermediate (III) may conveniently be reacted with an intermediate of formula (II) in a suitable solvent, such as acetonitrile, with an excess of a base, such as triethylamine, in the presence of chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) or another coupling agent known to those skilled in the art.

[0060] Intermediate (III) may be prepared by a process comprising reaction of an intermediate of formula (IV). [ka] R a is as defined herein above.

[0061] The reaction is suitably carried out in a suitable solvent, for example a mixture of ethanol and water, in the presence of a strong base, for example sodium hydroxide, at elevated temperature.

[0062] The intermediate of formula (IV) may be prepared by a process involving intermediate (V). [ka] Z represents a halogen.

[0063] The reaction is suitably carried out in a suitable solvent, such as a 1,4-dioxane / water mixture, in the presence of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate or 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, in the presence of a base, such as potassium carbonate, and a suitable catalyst, tetrakis(triphenylphosphine)palladium, at elevated temperature.

[0064] The intermediate of formula (V) may be prepared by a multi-step process from the intermediate of formula (VI). [ka] R c represents tert-butyl-dimethylsilyl, and Z is as defined above for intermediate (V). (i) The amino group of the intermediate of formula (VI) is first protected according to conventional methods known to those skilled in the art or according to the methods described in the accompanying examples. (ii) then removing both protecting groups (R c and the protecting group on the amino group) is removed by addition of an acid, such as HCl, in a suitable solvent, such as 2-propanol. (iii) the resulting intermediate of formula (VI), where Z is as defined above and R c represents hydrogen) with 1,1'-carbonyldiimidazole in the presence of a suitable base such as N,N-diisopropylethylamine in a suitable solvent such as dichloromethane to give intermediate (V).

[0065] Alternatively, compounds of formula (I) may be prepared by a multi-step process comprising the reaction of an intermediate of formula (II) as defined above with an intermediate of formula (VI) as defined above.

[0066] The first step is a coupling reaction with an excess of a base, such as N,N-diisopropylethylamine, in the presence of (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or another coupling agent known to those skilled in the art, in a suitable solvent, such as dimethylformamide.

[0067] The second step comprises another coupling reaction of the intermediate obtained in the first step with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in the presence of a suitable base, such as potassium carbonate, in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium(0), in a suitable solvent, such as a dioxane / water mixture.

[0068] In a third step, the tert-butyl-dimethylsilyl protecting group is removed by reaction with cesium fluoride in a suitable solvent such as dimethylformamide to give compounds of formula (I).

[0069] The intermediate of formula (VI) can be an intermediate of formula (VII) c may be prepared by a process comprising the reaction of: [ka]

[0070] The reaction is suitably carried out in a suitable solvent such as tetrahydrofuran in the presence of methylmagnesium chloride at low temperature.

[0071] The intermediate of formula (VII) may be prepared by a two-step process involving reaction of an intermediate of formula (VIII). [ka] Z is as defined above for the intermediate of formula (V), and R d represents hydrogen or tert-butyl-dimethylsilyl.

[0072] In the first step, intermediate (VIII) (wherein R d represents hydrogen) with tert-butyldimethylsilyl chloride in the presence of a suitable base, for example 4-dimethylamino-pyridine, at room temperature to give intermediate (VI) (wherein R d represents tert-butyl-dimethylsilyl).

[0073] In the second step, intermediate (VIII) (wherein R d represents tert-butyl-dimethylsilyl) is reacted with N-chlorosuccinimide (NCS) in a suitable solvent such as THF to give intermediate (VII).

[0074] Intermediate (VIII) (wherein R d represents hydrogen) may be prepared by a process which involves an intermediate of formula (IX) where Z is as defined above for intermediate (V). [ka]

[0075] The reaction is suitably carried out in a suitable solvent, for example a mixture of ethanol and water, in the presence of a strong base, for example sodium hydroxide, at elevated temperature.

[0076] Intermediates of formula (IX) may be prepared by a process comprising reaction of intermediate (X). [ka] Z is as defined herein above for the intermediate of formula (V).

[0077] The reaction is suitably carried out in the presence of trimethylsilyl triflate and paraformaldehyde in a suitable solvent such as dichloromethane.

[0078] Intermediate (X) may be prepared by a two-step process involving the commercially available intermediate (XI). [ka] Z is as defined above for intermediate (V).

[0079] The reaction is suitably carried out according to the methods described in the accompanying examples or according to methods known to those skilled in the art.

[0080] The intermediate of formula (II) may be prepared by a process comprising reacting an intermediate of formula (XII). [ka] R b is as defined above for compounds of formula (I).

[0081] The reaction is suitably carried out in a suitable solvent, such as dimethylformamide, in the presence of N-chlorosuccinimide.

[0082] The intermediate of formula (XII) may be prepared according to the methods described in International Patent Applications WO2016 / 055479 and WO2017 / 178377.

[0083] When a mixture of products is obtained from any of the above-described processes for the preparation of compounds or intermediates according to the invention, the desired product may be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC or normal phase column chromatography utilizing, for example, silica and / or alumina in combination with a suitable solvent system.

[0084] If the above-described methods for preparing the compounds according to the present invention result in a mixture of stereoisomers, these isomers may be separated by conventional techniques. In particular, if it is desired to obtain a specific enantiomer of a compound of formula (I) or intermediate (II) or (III), this may be produced from the corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g., salts, may be produced by reacting a mixture of enantiomers of formula (I), e.g., the racemate, with a suitable chiral compound, e.g., a chiral base. The diastereomers may then be separated by any suitable means, e.g., by crystallization, and the desired enantiomer may be recovered, e.g., by treatment with an acid if the diastereomer is a salt. In another resolution method, the racemate of formula (I) may be separated using chiral HPLC or chiral SFC.

[0085] Furthermore, if desired, a specific enantiomer may be obtained by using an appropriate chiral intermediate in one of the methods described above. Alternatively, a specific enantiomer may be obtained by enantiospecific enzymatic biotransformation, e.g., ester hydrolysis using an esterase, followed by purification of the enantiomerically pure hydrolyzed acid alone from the unreacted ester antipode. Chromatography, recrystallization, and other conventional separation procedures may be used with intermediates or final products if it is desired to obtain a specific geometric isomer of the present invention. Alternatively, the undesired enantiomer may be racemized to the desired enantiomer in the presence of acid or base according to methods known to those skilled in the art or as described in the accompanying examples.

[0086] During any of the above synthetic sequences it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by protecting sensitive or reactive groups on any of the molecules concerned, as is well known in the art, as 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, 1993. rd This may be achieved by conventional protecting groups, such as those described in the "Protein-Based Chemistry of Organic Synthesis" series, edition, 1999. The protecting groups may be removed at any convenient subsequent stage using methods known in the art.

[0087] The compounds of formula (I) according to the present invention do not directly activate the dopamine D1 receptor, but potentiate the effect of D1 agonists or endogenous ligands on the D1 receptor, dopamine, via an allosteric mechanism and are therefore D1 positive allosteric modulators (D1 PAMs).

[0088] Dopamine and other D1 agonists themselves directly activate the dopamine D1 receptor.

[0089] The assays are designed to measure the effects of compounds according to the invention in the absence of dopamine (the "activation assay") and in the presence of dopamine (the "potentiation assay").

[0090] The activation assay measures stimulation of cyclic adenosine monophosphate (cAMP) production in a homogeneous time-resolved fluorescence (HTRF) assay, with 100% activation defined as the maximal increase in cAMP with increasing concentrations of the endogenous agonist, dopamine.

[0091] In tests, compounds of formula (I) according to the invention lack a significant direct agonist-like effect, since when present at a concentration of 10 μM, the extent of activation is less than 20% (relative to the maximum dopamine response).

[0092] The potentiation assay measures the ability of a compound to increase the level of cAMP produced by a low-threshold concentration of dopamine. The concentration of dopamine used (EC20) is designed to produce a 20% stimulation compared to the maximal response (100%) seen with increasing concentrations of dopamine. To measure this potentiation, increasing concentrations of a compound with the EC20 of dopamine are incubated, and potentiation is measured as an increase in cAMP production. The concentration of compound that produces 50% potentiation of cAMP levels is determined.

[0093] When tested in the cAMP HTRF assay, the compounds of formula (I) according to the present invention exhibit pEC50 values ​​greater than about 7.5, preferably greater than about 8.0, indicating that they are D1 positive allosteric modulators.

[0094] GABA A Receptor inhibition is known to be closely related to seizures and epilepsy, therefore it is desirable to develop compounds that are D1 positive allosteric modulators while at the same time minimizing such effects.

[0095] Thus, when tested in the GABA-A receptor inhibition assay described herein, the compounds of formula (I) inhibited less than about 5% of the GABA A receptor activity when measured at a concentration of 10 μM of the compound of formula (I). A It is desirable to show the percentage of receptor inhibition.

[0096] cAMP HTRF assay The conditions for testing the compounds of the present invention are specifically described below.

[0097] a. Method D1 Cell Culture Cells were cultured at 37°C in a humidified atmosphere of 5% CO. Cells were grown in DMEM-F12 + GlutaMAX™-I medium (GIBCO®, Invitrogen, Merelbeke, Belgium) containing 10% fetal bovine serum (BioWhittaker®, Lonza, Verviers, Belgium), 400 μg / mL Geneticin (GIBCO®), 100 IU / mL penicillin, and 100 IU / mL streptomycin (Pen-Strep solution, BioWhittaker®). LMtk (Ltk-) mouse fibroblasts expressing dopamine D1 receptors (BioSignal Inc, Montreal, Canada, now Perkin Elmer) were used because they have been shown to efficiently bind and confer robust functional responses (Watts et al., 1995).

[0098] b. cAMP assay Measurement of changes in intracellular cyclic adenosine monophosphate (cAMP) was determined using the HTRF cAMP kinetic assay kit from CisBio (Codres, France). Using homogeneous time-resolved fluorescence technology, the assay is based on the competition between natural cAMP produced by the cells and cAMP labeled with the dye d2. Tracer binding is determined by an anti-cAMP antibody labeled with cryptate. The effect of the compound alone (agonism) was determined by performing the assay in the absence of dopamine, while the effect of the compound as a positive allosteric modulator (PAM) was determined by measuring the EC 20 Cells (20,000 cells per well) were incubated with isobutylmethylxanthine (Sigma, final 0.1 mM), various concentrations of test compound (typically 10%), and 100% ATP in the presence or absence of dopamine (final 1.1 nM). -9.5 M~10 -4.5The cells are incubated in a 384-well plate for 1 hour at room temperature in a final volume of 20 μL of HBSS (Lonza, containing calcium, magnesium, and HEPES buffer 20 mM, pH 7.4) containing 10 mM ATP. The reaction is then terminated and the cells are 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. This is then incubated for a further 60 minutes at room temperature, and the change in the HTRF fluorescence emission ratio is determined using an Envision plate reader with laser excitation (Perkin Elmer, Zaventem, Belgium) according to the manufacturer's instructions. All incubations were performed in duplicate, and the results were compared to a concentration-effect curve for dopamine (10 μL). -11 M~10 -6 M).

[0099] c. Data analysis Data were analyzed using Excel and PRISM (GraphPad Software) and pEC was calculated using a four-parameter logistic equation (DeLean et al., 1978). 50 and Erel was obtained, where Erel is the matched maximal response of the test compound minus the basal value, expressed as a percentage of that obtained with dopamine, which was defined as 100%.

[0100] pEC of the compound 50 is the −log10 of the concentration of compound that produces 50% of the enhancement of cAMP levels.

[0101] Erel was measured as the relative efficacy, defined as the % maximal enhancement produced by a compound compared to the maximal response produced by increasing concentrations of dopamine (Erel of 1 = maximal dopamine response). When tested in the above assay, the compounds of formula (II) according to the examples show the following pEC50 and Erel values: [Table 1]

[0102] GABA A Automated patch clamp studies on receptor cells Human GABA A CHO-K1 cells stably expressing the receptor α1, β2, and γ2 subunits were used. Cells were harvested using trypsin and maintained in serum-free medium at room temperature. Cells were washed and resuspended in extracellular solution before testing.

[0103] Patch clamp testing Human GABA A Experiments on α1β2γ2 channels were performed using an automated patch clamp assay (IonFlux™ HT). Compounds were tested at three concentrations (0.1, 1, and 10 μM) in triplicate cells. A The external solution for recording 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. Both the external and internal solutions were titrated with NaOH or KOH to obtain a pH of 7.35 or 7.3, respectively. The internal pipette solution contained 70 mM potassium fluoride, 60 mM potassium chloride, 70 mM sodium chloride, 5 mM HEPES, 5 mM EGTA, and 4 mM magnesium ATP. The final concentration of vehicle used to dilute compounds was 0.33% DMSO in each well. Bicuculline (0.032–100 μM) was used as a positive control inhibitor. GABA (15 μM) was used as an agonist. All recordings were obtained from a holding potential of -60 mV.

[0104] The order of compound addition was as follows: EC 80A single addition of 15 μM GABA was used to establish a baseline response. Each compound concentration was applied for 30 seconds, followed by a 2-second addition of 15 μM GABA in the presence of compound. The procedure was repeated with the next increasing concentration of compound. The peak inward current in response to the addition of GABA in the presence of a single compound concentration was measured. All compound data were normalized to the baseline peak current induced by the 2-second addition of 15 μM GABA.

[0105] When tested in the above assay at a concentration of 10 μM, the compounds of formula (I) according to the examples inhibited the activity of GABA A The following inhibition rates are shown: [Table 2]

[0106] The following examples illustrate the preparation of compounds of formula (I) according to the invention.

[0107] example The following examples illustrate the preparation of compounds of formula (I) according to the invention.

[0108] Abbreviations / Repeated Reagents ACN: acetonitrile Brine: saturated aqueous sodium chloride solution nBu: n-butyl tBu: tert-butyl COMU:(1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide EC 20 / 50 : Concentration that produces 20% / 50% of the maximum response Erel: Relative Effectiveness ESI: Electrospray positive ionization Et: Ethyl EtOH: ethanol Et2O: Diethyl ether EtOAc: ethyl acetate h: time HBTU: [Benzotriazol-1-yloxy(dimethylamino)methylene]-dimethyl-ammonium HPLC: High-pressure liquid chromatography HTRF: Homogeneous time-resolved fluorescence LCMS: Liquid Chromatography Mass Spectrometry MeOH: Methanol min.:minutes NCS: N-chlorosuccinimide NMR: nuclear magnetic resonance iPrOH: Isopropanol rt: room temperature SFC: Supercritical Fluid Chromatography TEA: Triethylamine THF: tetrahydrofuran TLC: Thin Layer Chromatography cAMP: cyclic adenosine monophosphate IUPAC names were determined using Biovia Draw 20.1.

[0109] Analysis method All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen or argon atmosphere using dry solvents and glassware. Commercially available solvents and reagents were generally used without further purification, including anhydrous solvents where appropriate (generally Sure-Seal™ products from Aldrich Chemical Company or AcroSeal™ from ACROS Organics). In general, reactions were followed by thin-layer chromatography, HPLC, or mass spectrometry.

[0110] Mass spectrometry measurements in LCMS mode are performed using different methods and instruments as follows: -Basic LCMS method 1: A QDA Waters simple quadrupole mass spectrometer is used for LCMS analysis. The spectrometer is equipped with a UPLC Acquity Classic equipped with an ESI source and a diode array detector (210-400 nm). Data are acquired as full MS scans from m / z 70-800 in positive / negative mode using basic elution. Reversed-phase separation is performed on a Waters Acquity UPLC BEH C18 1.7 μm (2.1 × 50 mm) column at 45 °C for basic elution. Gradient elution is performed using HO / ACN / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent A) and ACN / HO / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent B). Injection volume: 1 μL. Total flow rate on MS. [Table 3]

[0111] -Basic LCMS method 2: A QDA Waters simple quadrupole mass spectrometer was used for LCMS analysis. The spectrometer was equipped with a UPLC Acquity Classic equipped with an ESI source and a diode array detector (210-400 nm). Data were acquired as full MS scans from m / z 70 to 800 in positive / negative mode using basic elution. Reversed-phase separation was performed on a Waters Acquity UPLC BEH C18 1.7 μm (2.1 × 50 mm) column at 45 °C for basic elution. Gradient elution was performed using HO / ACN / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent A) and ACN / HO / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent B). Injection volume: 1 μL. Total flow rate on MS. [Table 4]

[0112] -Acidic LCMS method 1: A QDA Waters simple quadrupole mass spectrometer is used for LCMS analysis. The spectrometer is equipped with a UPLC Acquity with an ESI source and a diode array detector (200-400 nm). Data are acquired as full MS scans from m / z 70 to 800 in positive / negative mode using acidic elution. Reversed-phase separation is performed on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 × 50 mm) column at 45 °C for acidic elution. Gradient elution is performed using HO / ACN / TFA (95 / 5 / 0.05%) (solvent A) and ACN (solvent B). [Table 5]

[0113] Some reaction mixtures could be processed using Isolute® separator phase cartridges (Biotage), acidic columns or capture and release SPE (solid phase extraction) cartridges. Crude materials could be purified by normal phase chromatography, preparative TLC, (acidic or basic) reverse phase chromatography, chiral separation, tritylation or recrystallization.

[0114] Normal phase chromatography was performed using a silica gel column (100:200 mesh silica gel or a cartridge for a normal phase column chromatography system, such as Biotage® Isolera™ Four or Teledyne Isco CombiNormal phase column®).

[0115] Preparative reverse phase chromatography is performed as follows. -Basic LCMS prep: LCMS purification was performed using an SQD Waters single quadrupole mass spectrometer (basic mode, LCMS prep). The spectrometer was equipped with a Waters 2525 binary pump coupled to an ESI source, a 2767 sample manager, and a diode array detector (210-400 nm). Data were acquired in full MS scans from m / z 100-850 in positive and negative modes using basic elution.

[0116] LC parameters: Reverse-phase separation is performed on a Waters XBridge OBD MS C18 column (5 μm, 30 × 50 mm) at room temperature. Gradient elution is performed using solvent A1 (H2O + NH4HCO3 10 mM + 50 μl / L NH4OH) and solvent B1 (100% ACN) (pH approx. 8.5). HPLC flow rate: 35 mL / min - 45 mL / min, injection volume: 990 μL. The split ratio is set to + / - 1 / 6000 for MS. [Table 6]

[0117] Products were generally dried under vacuum before final analysis and biological testing.

[0118] NMR spectra were recorded on a Windows 7 Professional workstation running Topspin 3.2 software and a 5 mm double-resonance broadband probe (PABBI). 1 H / 19 F-BB Z-GRD Z82021 / 0075 or 1mm triple resonance probe (PATXI 1 H / D- 13 C / 15 The NMR spectra were recorded on a BRUKER AVANCE III 400 MHz-Ultrashield NMR spectrometer equipped with a 1000 MHz NMR spectrometer (N Z-GRD Z868301 / 004).

[0119] Chemical shifts are referenced to signals from residual protons of the deuterated solvent (DMSO-d6, MeOH-d4, or CDCl3). Chemical shifts are given in parts per million (ppm), and coupling constants (J) are given in Hertz (Hz). Spin multiplicities are given as broad (br), singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m).

[0120] All final products were analyzed by LCMS in both basic and acidic modes as follows: -Basic LCMS method 3: A QDA Waters simple quadrupole mass spectrometer was used for LCMS analysis. The spectrometer was equipped with a UPLC Acquity Classic equipped with an ESI source and a diode array detector (210-400 nm). Data were acquired as full MS scans from m / z 70 to 800 in positive / negative mode using basic elution. Reversed-phase separation was performed on a Waters Acquity UPLC BEH C18 1.7 μm (2.1 × 100 mm) column at 45 °C for basic elution. Gradient elution was performed using HO / ACN / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent A) and ACN / HO / ammonium formate (95 / 5 / 63 mg / L) + 100 μL / L NH4OH (solvent B). Injection volume: 1 μL. Total flow rate on MS. [Table 7]

[0121] -Acidic LCMS method 2: A QDA Waters simple quadrupole mass spectrometer is used for LCMS analysis. The spectrometer is equipped with a UPLC Acquity Hclass with an ESI source and a diode array detector (210-400 nm). Data are acquired as full MS scans from m / z 70 to 800 in positive / negative mode using acidic elution. Reversed-phase separation is performed on a Waters Acquity UPLC HSS T3 1.8 μm (2.1 × 100 mm) column at 45 °C for acidic elution. Gradient elution is performed using HO / ACN / TFA (95 / 5 / 0.05%) (solvent A) and ACN (solvent B). [Table 8]

[0122] 1. Preparation of Intermediate IIa - 2-(3,5-Dichloro-1H-indazol-4-yl)acetic Acid [ka] To a solution of 2-(5-chloro-1H-indazol-4-yl)acetic acid Xa (CAS: 1904662-08-3, WO2016055479, 2.1 g, 10 mmol) in DMF (10 mL) was added NCS (1.5 g, 11 mmol) portionwise at room temperature, and the mixture was stirred overnight. The reaction mixture was quenched by adding 100 mL of water dropwise. After stirring for 1 hour, the product precipitated. The solid was filtered and washed twice with the mother liquor and twice with water (50 mL). The solid was then dried overnight under vacuum at 45 °C to give 2-(3,5-dichloro-1H-indazol-4-yl)acetic acid IIa (2.0 g, 93% purity, 77% yield), which was used in the next step without further purification. Acidic LCMS method 1 (ES + ):245 / 247 / 249(M+H) + 1 H NMR (400 MHz, DMSO-d6): δ 13.52 (s, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 4.21 (s, 2H).

[0123] 2. Preparation of Intermediate IIb 2-(3,5-Dichloro-1-methyl-indazol-4-yl)acetic acid [ka] 2-(5-Chloro-1-methyl-indazol-4-yl)acetic acid Xb (CAS: 2139360-05-5, WO2017178377, 1.3 kg, 5.79 mol) and DMF (6.50 L) are charged into a 50 L three-necked round-bottom flask at 20 °C. N-chlorosuccinimide (772 g, 5.79 mol) is added portionwise at 20 °C, and the mixture is stirred at 20 °C for 2 hours. The reaction mixture is poured into water (25 L) and filtered. The crude product is triturated with isopropyl ether:ethyl acetate (3:1) (7.0 L) at 20 °C for 2 hours, then filtered and dried. This overall procedure is carried out in parallel on three batches of the same size. The solids obtained from the three batches are combined to give 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid IIb (2.1 kg, 7.90 mol, 97.5% purity, 45.5% yield). 1 H NMR (400 MHz, CDCl3) δ 12.67 (s, 1 H), 7.68 (d, J = 9.05 Hz, 1 H), 7.53 (d, J = 9.05 Hz, 1 H), 4.20 (s, 2 H), 4.02 (s, 3 H).

[0124] 3. Preparation of intermediate (VI) [(1S,3R)-5-Bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane [ka] 3.1. Preparation of intermediate a6 (2R)-2-amino-3-(2-bromophenyl)propan-1-ol (2R)2-Amino-3-(2-bromophenyl)propanoic acid a5 (34.0 kg, 139 mol) and THF (238 L) are charged to a reactor. Sodium borohydride (15.6 kg, 413 mol) is added slowly at 20-30°C. A solution of iodine (35.3 kg, 139 mol) in dry THF (20.0 L) is added slowly at 0-10°C, and the reaction mixture is stirred at 70°C for 12 h. The reaction is quenched with methanol (70.0 L) at 0°C and heated to 80°C for 30 min. The mixture is cooled and concentrated under vacuum. The residue is suspended in NaOH (30.0 L, 2N) and then filtered. The filter cake is dried under vacuum 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 is used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) 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).

[0125] 3.2. Preparation of intermediate a7 (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one (2R)-2-amino-3-(2-bromophenyl)propan-1-ol a6 (31.0 kg, 135 mol) and dichloromethane (220 L) are charged to a reactor. Triphosgene (13.9 kg, 47.1 mol) is added at room temperature, followed by the slow addition of N,N-diisopropylethylamine (39.1 kg, 303 mol) at 0-10°C. The reaction mixture is stirred at 0-10°C for 1 hour, 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 directly in the next step.

[0126] 3.3. Preparation of intermediate a8 (10aR)-9-Bromo-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one A solution of (4R)-4-[(2-bromophenyl)methyl]oxazolidin-2-one a7 (135 mol) in dichloromethane (220 L) was charged to a 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, followed by stirring at 15-20°C for 2 hours. 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 under vacuum. A mixture of petroleum ether:ethyl acetate (1:1, 45.0 L) was added, and the mixture was stirred at room temperature for 6 hours and filtered. The solid is 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). 1H NMR (400 MHz, CDCl3) 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 = 16.1, 11.0 Hz, 1H).

[0127] 3.4. Preparation of intermediate a9 [(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol Ethanol (120 L) and water (60.0 L) were mixed in a reactor. (10aR)-9-bromo-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a8 (29.7 kg, 111 mol) was added, followed by the slow addition of sodium hydroxide (13.3 kg, 332 mol) at 15-20 °C. The reaction mixture was stirred at 90 °C for 2 hours and then cooled to room temperature. Water (300 L) was added to the mixture, which was then centrifuged. The centrifuge cake was dried in a circulating oven to obtain [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol a9 as a white solid (23.7 kg, 88.3% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) 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).

[0128] 3.5. Preparation of intermediate a10 [(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane [(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol a9 (23.7 kg, 97.8 mol) and dichloromethane (240 L) were charged to a reactor. DMAP (120 g, 0.98 mol) and imidazole (13.3 kg, 196 mol) were added. tert-Butyldimethylsilyl chloride (TBSCl) (17.7 kg, 117 mol) was added slowly at 15-20 °C, and the mixture was stirred for 12 h. Ammonium chloride (100 L) was added to the mixture. The organic phase is 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-butyl-dimethyl-silane a10 as a yellow oil (37.6 kg, 86% purity, 93% yield), which is used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.45 (m, 1H), 7.01 (d, J = 4.6 Hz, 2H), 4.01 - 4.13 (m, 1H), 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).

[0129] 3.6. Preparation of intermediate a11 [(3R)-5-Bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane [(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane a10 (3.42 kg, 8.31 mol) and THF (30.0 L) are charged to a reactor. N-Chlorosuccinimide (NCS) (1.17 kg, 8.73 mol) is added slowly at room temperature, and the mixture is stirred at 25°C for 30 minutes. A solution of KOH (1.52 kg, 27.1 mol) in dry methanol (7.00 L) is added slowly at room temperature, and the reaction is stirred at 25°C for 1 hour. The reaction is quenched with water (10.0 L) and extracted with petroleum ether:ethyl acetate (1:2, 5.00 L). The organic layer is separated, washed with brine (10.0 L), dried over anhydrous sodium sulfate, and filtered. This overall procedure was carried out in parallel on 10 batches of equal size, and the 10 reaction filtrates were combined and concentrated under vacuum to give [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane a11 as a brown oil (28.0 kg, crude), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) 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).

[0130] 3.7. Preparation of intermediate (VI) [(1S,3R)-5-Bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane [(3R)-5-Bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane a11 (3.10 kg, 8.75 mol) and THF (20.0 L) are charged to a reactor. The mixture is cooled to 0 °C, and methylmagnesium chloride (3 M, 11.6 L) is added. The mixture is stirred at 20 °C for 12 hours. The reaction is quenched with a saturated solution of ammonium chloride. The phases are separated, and the aqueous layer is extracted twice with petroleum ether:ethyl acetate (3:1, 5.00 L). The combined organic phases are washed with brine (10.0 L), dried over anhydrous sodium sulfate, and filtered. This overall procedure is carried out in parallel on nine batches of the same size, and the nine reaction filtrates are combined and concentrated under vacuum. 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-butyl-dimethyl-silane (VI) as a brown oil (4.60 kg, purity 99.7%, yield 15.7%). 1H NMR (400 MHz, DMSO-d6) 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, 6H).

[0131] 2. Preparation of the compounds of Examples 1 and 2 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethenone, and 2-(3,5-Dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethenone [ka] 2.1. Synthesis of intermediate a12 compound 1-[(1S,3R)-5-Bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone To a solution of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane (VI) (500 mg, 1.35 mmol) and 2-(3,5-dichloro-1-methyl-indazol-4-yl)acetic acid (IIb) (385 mg, 1.48 mmol) in DMF (10 mL) was added HBTU (0.61 g, 1.62 mmol) followed by DIPEA (0.68 mL, 4.05 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then taken up in DCM (50 mL) and washed four times with saturated aqueous sodium bicarbonate (4 × 10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue is purified by normal phase column chromatography (elution: EtOAc / heptane) to give 1-[(1S,3R)-5-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone a12 (590 mg, 71% yield) as a white solid. Basic LCMS Method 2 (ES + ):610 / 612 / 614(M+H) +

[0132] 2.2 Synthesis of intermediate a13-a 1-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone To a solution of 1-[(1S,3R)-5-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone a12 (0.295 mg, 0.48 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.15 g, 0.74 mmol) in dioxane / HO (7 mL / 0.7 mL), potassium carbonate (200 mg, 1.45 mmol) was added, followed by tetrakis(triphenylphosphine)palladium(0) (56 mg, 0.048 mmol). The reaction mixture was then heated at 115° C. for 2 hours. The reaction mixture was taken up in DCM (50 mL) and washed four times with saturated aqueous sodium bicarbonate (4 × 10 mL). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase column chromatography (elution: EtOAc / heptane) to give 1-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone a13-a (0.14 g, 49%) as a white solid, which still contained impurities but was used directly in the next step.

[0133] Basic LCMS Method 2 (ES + ):612 / 614 / 616(M+H) + Using the same procedure as above with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate, 1-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone a13-b is obtained as a white solid (17% yield). Basic LCMS Method 2 (ES+ ):598 / 600 / 602(M+H) +

[0134] 2.3. Synthesis of the Compound of Example 1 2-(3,5-Dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone To a solution of 1-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-2-(3,5-dichloro-1-methyl-indazol-4-yl)ethanone a13-a (140 mg, 0.230 mmol) in DMF (3 mL) cooled to 0 °C, cesium fluoride (180 mg, 1.19 mmol) is added. The reaction mixture is heated at 50 °C overnight. The reaction mixture is then taken up in EtOAc (20 mL) and washed three times with saturated aqueous sodium bicarbonate (3 × 10 mL). The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude residue is purified by LCMS purification (basic LCMS prep) to give 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone 1 (30.0 g, 25% yield) as a white solid. Basic LCMS Method 3 (ES + ):498 / 500 / 502(M+H) + , 100% purity Acidic LCMS method 2 (ES + ):498 / 500 / 502(M+H) + , 100% purity 1H NMR (400 MHz, CDCl3) δ7.61 (d, J = 9.3 Hz, 1H), 7.52 (d, J = 3.3 Hz, 1H), 7.41 (dd, J= 9.0, 4.2 Hz, 1H), 7.31 - 7.19 (m, 3H), 7.14 (dd, J = 5.7, 3.1 Hz, 1H), 5.32 -5.17 (m, 1H), 4.63 - 4.44 (m, 3H), 4.02 - 3.94 (m, 6H), 3.55 - 3.38 (m, 2H), 3.23 - 3.09 (m, 2H), 1.72 (d, J = 6.7 Hz, 2H), 1.42 (d, J = 6.5 Hz, 1H).

[0135] 2.4. Synthesis of the compound in Example 2 2-(3,5-Dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone Starting from intermediate a13-b, the same procedure as above is used to obtain 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone 2 (49% yield) as a white solid. Basic LCMS Method 3 (ES + ):484 / 486 / 488(M+H) + , 100% purity Acidic LCMS method 2 (ES + ):484 / 486 / 488(M+H) + , 100% purity 1H NMR (400 MHz, CDCl3) δ7.69 (s, 1H), 7.63 (s, 1H), 7.40 (dd, J = 12.2, 8.9 Hz, 1H), 7.33 - 7.23 (m, 3H), 7.23 - 7.11 (m, 1H), 5.32 - 5.17 (m, 1H), 4.56 (t, J = 5.7 Hz, 2H), 4.50 (s, 1H), 3.96 (s, 3H), 3.61 - 3.44 (m, 2H), 3.18 - 3.01 (m, 2H), 1.72 (d, J = 6.7 Hz, 2H), 1.41 (d, J = 6.5 Hz, 1H).

[0136] 3. Preparation of Compounds of Examples 3 and 4 2-(3,5-dichloro-1H-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethenone, and 2-(3,5-Dichloro-1H-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone [ka] 3.1. Preparation of intermediate a14 tert-Butyl (1S,3R)-5-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate [(1S,3R)-5-Bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane (VI) (1.85 kg, 4.99 mol) and dichloromethane (13.0 L) are charged to a reactor. N,N-Diisopropylethylamine (1.94 kg, 14.9 mol) and di-tert-butyl dicarbonate (1.14 kg, 5.24 mol) are added at room temperature, and the mixture is stirred for 12 hours. The reaction mixture is washed twice with saturated ammonium chloride solution (10.0 L), and the organic layer is dried over anhydrous sodium sulfate and filtered. This entire procedure is carried out in parallel on two batches of the same size. The two reaction filtrates are combined and concentrated under vacuum. The crude mixture is purified by silica gel chromatography using petroleum ether: EtOAc (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 a14 as a yellow oil (4.00 kg, 99% purity, 85% yield). 1 H NMR (400 MHz, DMSO-d6) 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, 9 H), 1.28 (br s, 3H), 0.81 (s, 9H), -0.08 (s, 6H).

[0137] 3.2. Preparation of intermediate a15 [(1S,3R)-5-Bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol hydrochloride To a solution of tert-butyl (1S,3R)-5-bromo-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate a14 (51.0 g, 108 mmol) in 2-propanol (200 mL) was added hydrochloric acid (200 mL, 4 M in dioxane) dropwise at 0 °C, and the resulting mixture was allowed to warm to room temperature overnight. The reaction mixture was evaporated in vacuo, and the resulting solid was dried in vacuo for 2 hours to give [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol hydrochloride a15 (31.8 g, 99% crude yield), which was used in the next step without further purification. LCMS Method 1 (ES) + ):256 / 258(M+H) +

[0138] 3.3. Preparation of intermediate a16 (5S,10aR)-9-Bromo-5-methyl-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one To a solution of [(1S,3R)-5-bromo-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol hydrochloride a15 (31.8 g, 108 mmol) in DCM (400 mL) was added 1,1'-carbonyldiimidazole (35.0 g, 2156 mmol) at room temperature. The reaction mixture was cooled to 0 °C and stirred for 15 minutes. N,N-Diisopropylethylamine (90 mL, 541.8 mmol) was added dropwise. The mixture was allowed to stir at room temperature overnight. The reaction mixture was then diluted with DCM (200 mL). The resulting organic layer was washed twice with 500 mL of HCl 1M and 500 mL of water, then dried over MgSO4, filtered, and the solvent removed under vacuum to give (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a16 (31.8 g, quantitative crude yield), which was used in the next step without further purification. Acidic LCMS method 1 (ES + ):282 / 284(M+H) + 1 H NMR (DMSO-d6): δ 7.55 (dd, J = 7.9, 1.2 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 4.86 (q, J = 6.8 Hz, 1H), 4.55 (t, J = 7.9 Hz, 1H), 4.25 - 4.11 (m, 2H), 3.13 (dd, J = 16.7, 4.5 Hz, 1H), 2.61 (dd, J = 16.7, 10.2 Hz, 1H), 1.43 (d, J = 6.8 Hz, 3H).

[0139] 3.4. Preparation of intermediate a17-a (5S,10aR)-5-Methyl-9-(1H-pyrazol-4-yl)-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one To a mixture of (5S,10aR)-9-bromo-5-methyl-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a16 (200 mg, 0.71 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (1.5 equiv., 322 mg, 1.06 mmol) in 1,4-dioxane (7 mL) and water (0.7 mL) at room temperature, potassium carbonate (294 mg, 2.13 mmol) and tetrakis(triphenylphosphine)palladium(0) (83.0 mg, 0.070 mmol) were added sequentially, and the reaction mixture was heated at 100° C. for 18 h. The reaction mixture was cooled to room temperature, and EtOAc and a saturated solution of NaHCO were added. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were then dried over MgSO4, filtered, and concentrated to dryness to give a yellow oil, which was purified by reverse-phase flash chromatography on a Biotage Isolera Four under basic conditions (a C18 SNAP 60 g gel column with a gradient of 5% to 70% ACN in water / NH4OH over 12 CV). The purest fractions were directly lyophilized to give (5S,10aR)-5-methyl-9-(1H-pyrazol-4-yl)-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a17-a (84.0 mg, 44% yield) as a white solid. Basic LCMS Method 1 (ES + ):270(M+H) + 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 2H), 7.29 - 7.19 (m, 3H), 4.86 (q, J = 6.7 Hz, 1H), 4.49 (t, J = 8.2 Hz, 1H), 4.17 (dd, J = 8.6, 5.0 Hz, 1H), 4.09 - 3.97 (m, 1H), 2.98 (dd, J= 16.3, 4.5 Hz, 1H), 2.85 (dd, J = 16.4, 10.7 Hz, 1H), 1.46 (d, J= 6.8 Hz, 3H).

[0140] Using the same procedure as above with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, (5S,10aR)-5-methyl-9-(1-methylpyrazol-4-yl)-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a17-b (63% yield) was obtained as a white solid. Basic LCMS Method 1 (ES + ):284(M+H) + 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 0.9 Hz, 1H), 7.77 (s, 0.4H), 7.71 (s, 0.6H), 7.61 (d, J = 0.8 Hz, 1H), 7.30 - 7.19 (m, 2H), 4.86 (q, J = 6.7 Hz, 1H), 4.49 (t, J = 8.2 Hz, 1H), 4.16 (dd, J = 8.6, 4.9 Hz, 1H), 4.09 - 3.97 (m, 1H), 3.88 (s, 3H), 2.99 (dd, J = 16.3, 4.4 Hz, 1H), 2.81 (dd, J = 16.3, 10.8 Hz, 1H), 1.45 (d, J = 6.8 Hz, 3H).

[0141] 3.5. Preparation of Intermediate IIIa [(1S,3R)-1-Methyl-5-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol To a solution of (5S,10aR)-5-methyl-9-(1H-pyrazol-4-yl)-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a17-a (84.0 mg, 0.31 mmol) in ethanol (0.4 mL) at room temperature, sodium hydroxide (50% w / w aqueous solution, 0.08 mL, 1.51 mmol) was added, and the reaction mixture was stirred at 70 °C for 3 h 30 min. EtOAc and a saturated solution of NaCl were then added to the resulting mixture, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were then dried over MgSO 4 , filtered, and concentrated to dryness to give a yellow solid and a yellow oil, which was purified by reverse-phase flash chromatography Biotage Isolera Four under basic conditions (C18 SNAP 30 g gel column with a gradient of 5% to 95% ACN in water / NH 4 OH over 12 CV). The purest fractions are directly lyophilized to give [(1S,3R)-1-methyl-5-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol III-a (40 mg, 0.14 mmol, 47% yield) as a white solid. Basic LCMS Method 1 (ES + ):244(M+H) + , 87% purity.

[0142] Using the same procedure as above, starting from (5S,10aR)-5-methyl-9-(1-methylpyrazol-4-yl)-1,5,10,10a-tetrahydrooxazolo[3,4-b]isoquinolin-3-one a17-b, the crude mixture was purified by reverse-phase preparative HPLC on a Waters XBridge OBD MS C18 column (5 μm, 30 × 50 mm) using a gradient elution with solvent A (95% HO - 5% ACN + 50 mM NH4HCO3 + 200 μL / L NH4OH) and solvent B (100% ACN) 95 / 5 to 5 / 95 (pH 8.5) to give [(1S,3R)-1-methyl-5-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol III-b (65% yield) as a colorless oil. Basic LCMS Method 1 (ES + ):258(M+H)+ , 99% purity. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 0.9 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.17 - 7.06 (m, 2H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 4.61 (t, J = 5.4 Hz, 1H), 4.16 (q, J = 6.8 Hz, 1H), 3.87 (s, 3H), 3.41 (m, 1H), 3.09 - 2.92 (m, 1H), 2.75 - 2.59 (m, 1H), 2.43 - 2.26 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H).

[0143] 3.6. Preparation of the Compound of Example 3 2-(3,5-Dichloro-1H-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone To a solution of 2-(3,5-dichloro-1H-indazol-4-yl)acetic acid IIa (35.0 mg, 0.130 mmol) in acetonitrile (0.5 mL) at 0 °C, triethylamine (0.047 mL, 0.33 mmol), [(1S,3R)-1-methyl-5-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol a18-a (40.0 mg, 0.140 mmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH, 44.0 mg, 0.150 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 4 h. Then, a saturated solution of EtOAc and NH4Cl was added to the resulting mixture, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were then dried over MgSO, filtered, and concentrated to dryness to give a yellow solid, which was purified by reverse-phase preparative HPLC on a Waters XBridge OBD MS C18 column (5 μm, 30 × 50 mm) using a gradient elution with solvent A (95% HO - 5% ACN + 50 mM NHHCO + 200 μL / L NHOH) and solvent B (100% ACN) (pH ∼8.5) from 25% to 45% to give 2-(3,5-dichloro-1H-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone 3 (3.60 mg, 6% yield) as a white solid. Basic LCMS Method 3 (ES + ):470 / 472 / 474(M+H) + , 99% purity. Acidic LCMS method 2 (ES + ):470 / 472 / 474(M+H) + , 100% purity. 1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 7.89 (bs, 3H), 7.48 (d, J = 8.9 Hz, 1H), 7.39 (s, 1H), 7.33 - 7.19 (m, 2H), 7.16 - 7.10 (m, 1H), 5.40 - 5.32 (m, 0.3H), 5.08 (q, J = 6.5 Hz, 0.7H), 4.93 (dd, J = 6.2, 4.0 Hz, 0.7H), 4.72 - 4.32 (m, 3.3H), 3.52 - 3.30 (m, 1H), 3.10 - 2.75 (m, 2H), 1.57 (d, J = 6.6 Hz, 0.9H), 1.35 - 1.21 (m, 2.1H).

[0144] 3.7. Preparation of the Compound of Example 4 2-(3,5-Dichloro-1H-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone The same procedure as above is used starting from [(1S,3R)-1-methyl-5-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol a18-b. The resulting crude mixture was purified by reverse-phase preparative HPLC on a Waters XBridge OBD MS C18 column (5 μm, 30 × 50 mm) using a gradient elution with solvent A (95% HO - 5% ACN + 50 mM NHHCO + 200 μL / L NHOH) and solvent B (100% ACN) 75 / 25 to 50 / 50 (pH ∼8.5) to give 2-(3,5-dichloro-1H-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone 4 (16.4 mg, 25% yield) as a white solid. Basic LCMS Method 3 (ES + ):484 / 486 / 488(M+H) + , 98% purity. Acidic LCMS Method 2 (ES) + ):484 / 486 / 488(M+H) + Purity 99%. 1 H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 7.93 (m, 1H), 7.68 (s, 1H), 7.54 - 7.43 (m, 2H), 7.34 - 7.04 (m, 3H), 5.35 (m, 0.3H), 5.08 (q, J = 6.3 Hz, 0.7H), 4.94 (t, J = 5.3 Hz, 0.7H), 4.70 - 4.26 (m, 3.3H), 3.90 (d, J = 5.7 Hz, 3H), 3.60 - 3.39 (m, 1H), 3.18 (dd, J = 15.8, 4.6 Hz, 1H), 3.01 (dd, J = 15.8, 5.3 Hz, 0.3H), 2.84 (q, J = 9.4, 8.9 Hz, 0.7H), 1.57 (d, J = 6.5 Hz, 0.9H), 1.29 (d, J = 6.4 Hz, 2.1H).

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof 【Chemistry 1】 However, R ａ and R ｂ are independently hydrogen or C １－６ Represents alkyl.

2. R ａ 2. The compound of formula (I) according to claim 1, wherein is hydrogen.

3. R ａ is C １－６ 2. The compound of formula (I) according to claim 1, wherein the compound is alkyl.

4. R ｂ 2. The compound of formula (I) according to claim 1, wherein is hydrogen.

5. R ｂ is C １－６ 2. The compound of formula (I) according to claim 1, wherein the compound is alkyl.

6. The compound of claim 1 selected from the group consisting of: 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, 2-(3,5-dichloro-1H-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, and 2-(3,5-Dichloro-1H-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methylpyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for use in therapy.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 for use in the treatment and / or prevention of diseases and / or disorders in which the D1 receptor is involved.

9. 9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 for use in the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

10. 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 for use in the treatment of cognitive and negative symptoms in Parkinson's disease and other movement disorders, Alzheimer's disease, or schizophrenia.

11. Use of a compound of formula (I) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment and / or prevention of diseases and / or disorders in which the D1 receptor is involved.

12. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for the manufacture of a medicament useful for the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain.

13. A pharmaceutical composition for use in the treatment and / or prevention of a disorder for which administration of a D1 positive allosteric modulator is indicated, comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

14. 10. A pharmaceutical composition for use in the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, apathy, traumatic spinal cord injury or neuropathic pain, comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, used together with a pharmaceutically acceptable carrier.

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