GPR52 modulator compounds

Abstract

FIELD: pharmaceutical composition.SUBSTANCE: invention relates to a compound of formula (1a) or (1b) or a pharmaceutically acceptable salt thereof. In a compound of formula (1a) or (1b), R1 and R2 independently represent H or C1-3 alkyl optionally substituted with OH; R3 represents -P(O)OR6OR7 or -COR5; R4 represents halogen or C1-3 alkyl optionally substituted with 1-6 fluorine atoms; R5 represents C1-6 alkyl optionally substituted with 1-6 fluorine atoms; R6 and R7 independently represent H or С1-6 alkyl optionally substituted with 1-6 fluorine atoms; and R8, R9 and R10 independently represent H, halogen or C1-3 alkyl optionally substituted with 1–3 fluorine atoms. Also proposed are the use of a compound of formula (1a) or (1b), a pharmaceutical composition containing it, and the use of said composition. The compound of formula (1a) or (1b) is a prodrug of a GPR52 modulator and may be useful in the treatment of mental disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorder; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma- or stressor-related disorders; disruptive disorders, drive disorders, or conduct disorders; sleep-wake schedule disorders; substance use disorders; addictive disorders; conduct disorders; hypofrontality; abnormalities of the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways; decreased striatal activity; cortical dysfunction; neurocognitive dysfunction, or conditions or symptoms associated therewith.EFFECT: useful in the treatment of above-mentioned mental disorders.15 cl, 1 dwg, 7 tbl, 12 ex

Description

[0001] This application relates to new compounds and their use as prodrugs of G protein-coupled receptor 52 (GPR52) modulators. The compounds described herein may be useful for the treatment or prevention of diseases in which GPR52 receptors are involved or in which modulation of GPR52 receptors may be beneficial. The application also relates to pharmaceutical compositions comprising these compounds and to the preparation and use of these compounds and compositions for the prevention or treatment of diseases in which GPR52 receptors are involved or in which modulation of GPR52 receptors may be beneficial.

[0002] Background of the invention

[0003] G protein-coupled receptor 52 (GPR52) is a constitutively active G-coupled orphan receptor that is highly expressed in the striatum and cerebral cortex. In the striatum, GPR52 is expressed exclusively on dopamine D2 medium spiny neurons, and in the cerebral cortex, it is found on cortical pyramidal neurons expressing dopamine D1 receptors (Komatsu et al., 2014, PLoS One 9:e90134). Based on its localization and functional connectivity, GPR52 is proposed to play a role in the modulation of frontostriatal and limbic dopamine and therefore may be useful for the treatment of neuropsychiatric disorders. GPR52 agonists are considered to be particularly relevant for the treatment of schizophrenia, where they are thought to indirectly improve cognitive function and negative symptoms by enhancing D1 signaling, but alleviate positive symptoms by inhibiting D2-mediated signaling in the striatum.

[0004] GPR52 agonists can be used to treat psychiatric disorders associated with dysfunction of the mesolimbic and mesocortical pathways. Examples include the treatment of positive, negative, and cognitive symptoms of schizophrenia, depression, attention deficit hyperactivity disorder, anxiety disorders (generalized anxiety disorder, obsessive-compulsive disorder, panic disorder), bipolar disorder, addiction / impulse control disorders, and autism spectrum disorders. Neuropsychiatric symptoms (e.g., psychosis, anhedonia, agitation, etc.) of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.) can also be treated with GPR52 agonists. GPR52 expression in the pituitary and hypothalamus suggests the utility of GPR52 modulators in pituitary and hypothalamic diseases, and there is preclinical data (Xiong et al., 2016, WO 2016 / 176571), suggesting that GPR52 agonists may be useful in the treatment of hyperprolactinemia.

[0005] It is desirable to modify the physicochemical properties of GPR52 modulators.

[0006] INVENTION

[0007] The present invention relates to compounds that are prodrugs of G protein-coupled receptor 52 (GPR52) modulators.

[0008] Accordingly, the invention provides a compound of formula (1a) or (1b):

[0009]

[0010] or its salt, where;

[0011] R 1 and R 2 independently represent H or C 1-3 alkyl optionally substituted with OH or from 1 to 6 fluorine atoms; or R 1 and R 2 joined to form a 4, 5, 6, or 7-membered ring which is optionally substituted with OH or 1-6 fluorine atoms;

[0012] R 3is a functional group that can be cleaved in vivo to yield a compound where R 3 represents H;

[0013] R 4 is H, CN, halogen, or C 1-3 alkyl optionally substituted with OH or 1-6 fluorine atoms;

[0014] R 8 , R 9 and R 10 independently represent H, CN, halogen or C 1-3 alkyl optionally substituted with 1-6 fluorine atoms.

[0015] The compounds of the present invention can be used as prodrugs of GPR52 modulators. The compounds of the present invention can be used as prodrugs of GPR52 agonists. The compounds of the present invention can be used in the preparation of medicaments. The compounds or medicaments can be used to treat, prevent, ameliorate, control, or reduce the risk of diseases or disorders in which GPR52 receptors are involved. The compounds or medicaments can be used to treat, prevent, ameliorate, control, or reduce the risk of diseases or disorders in which modulation of GPR52 receptors may be beneficial. The compounds of the present invention can be useful in the treatment of mental disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders;Hyperkinetic movement disorders; Catatonia; Mood disorders; Depressive disorders; Anxiety disorders; Obsessive-compulsive disorder (OCD); Autism spectrum disorders; Depressive disorders; Hypothalamic disorders; Pituitary disorders; Prolactin-related disorders; Trauma- or stressor-related disorders; Disruptive, drive, or conduct disorders; Sleep-wake schedule disorders; Substance use disorders; Addictive disorders; Conduct disorders; Hypofrontality; Abnormalities of the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways; Striatal underactivity; Cortical dysfunction; Neurocognitive dysfunction, or conditions or symptoms related thereto.

[0016] The compounds of the present invention can be useful in the treatment of schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorders, autism spectrum disorders, psychosis, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, pituitary adenoma, prolactinoma, craniopharyngioma, Cushing's disease, diabetes insipidus, non-functioning tumors, obesity, post-traumatic stress disorder (PTSD), akathisia and related movements, athetosis, ataxia, ballism, hemiballismus, chorea, choreoathetosis, dyskinesia, tardive dyskinesia, neuroleptic-induced dyskinesia, myoclonus, mirror movement disorder,Paroxysmal kinesigenic dyskinesia, restless legs syndrome, seizures, stereotypic movement disorder, stereotypy, tic disorder, tremor, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or drug-induced psychotic disorder, delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance- or drug-induced bipolar disorder and related disorders, bipolar disorder and related disorder due to another medical condition, separation anxiety disorder, selective mutism, specific phobia,Social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, anxiety disorders due to another medical condition, delirium, major neurocognitive disorder, minor neurocognitive disorder, amnesia, dementia, dyspraxia, stereotypic movement disorder, post-stroke effect, dentatorubropallidolewisian atrophy, decreased emotional expression, evolution, alogia, and asociality.

[0017] DETAILED DESCRIPTION OF THE INVENTION

[0018] The invention relates to new compounds. The new compounds of the invention are prodrugs of GPR52 modulators. The invention also relates to the use of the new compounds as prodrugs of GPR52 receptor modulators. The invention also relates to the use of the new compounds as prodrugs of GPR52 receptor agonists. The invention also relates to the use of the new compounds in the production of medicaments for use as GPR52 modulators. The compounds of the present invention are prodrugs of GPR52 agonists. The compounds or medicaments can be used to treat, prevent, mitigate, control or reduce the risk of diseases or disorders in which GPR52 receptors are involved. The compounds or medicaments can be used to treat, prevent, mitigate, control or reduce the risk of diseases or disorders in which modulation of GPR52 receptors may be beneficial.

[0019] The invention also relates to compounds, compositions and drugs that may be useful in the treatment of mental disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorder; depressive disorders; prolactin-related disorders; trauma- or stressor-related disorders; disruptive disorders, drive disorders or conduct disorders; sleep-wake patterns disorders; disorders associated with the use of psychoactive substances; addictive disorders; conduct disorders; hypofrontality;abnormalities of the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways; decreased striatal activity; cortical dysfunction; neurocognitive dysfunction, or conditions or symptoms associated therewith.

[0020] The invention relates to a compound of formula (1a) or (1b):

[0021]

[0022] or its salts, where;

[0023] R 1 and R 2 independently represent H or C 1-3 alkyl optionally substituted with OH or 1-6 fluorine atoms; or R 1 and R 2 combined to form a 4, 5, 6, or 7-membered ring that is optionally substituted with OH or 1-6 fluorine atoms;

[0024] R 3 is a functional group that can be cleaved in vivo to yield a compound where R 3 represents H;

[0025] R 4 is H, CN, halogen, or C 1-3alkyl optionally substituted with OH or 1-6 fluorine atoms;

[0026] R 8 , R 9 and R 10 independently represent H, CN, halogen or C 1-3 alkyl optionally substituted with 1-6 fluorine atoms.

[0027] The invention relates to a compound of formula (1a) or (1b):

[0028]

[0029] or its salts, where;

[0030] R 1 and R 2 independently represent H or C 1-3 alkyl optionally substituted with OH or 1-6 fluorine atoms; or R 1 and R 2 combined to form a 4, 5, 6, or 7-membered ring that is optionally substituted with OH or 1-6 fluorine atoms;

[0031] R 3 represents -P(O)OR 6 OR 7 or -COR 5 ;

[0032] R 4 is H, CN, halogen, or C 1-3 alkyl optionally substituted with OH or 1-6 fluorine atoms;

[0033] R 5is optionally substituted C 1-6 alkyl, optionally substituted 3-6-membered heterocyclyl or optionally substituted C 3-6 cycloalkyl;

[0034] R 6 and R 7 independently represent H, optionally substituted with C 1-6 alkyl, optionally substituted 3-6-membered heterocyclyl or optionally substituted C 3-6 cycloalkyl; or R 6 and R 7 combined to form an optionally substituted 5- or 6-membered ring;

[0035] R 8 , R 9 and R 10 independently represent H, CN, halogen, or C 1-3 alkyl optionally substituted with 1-6 fluorine atoms.

[0036] In the compounds in this document, R 1 and R 2 can independently represent H or C 1-3 alkyl, optionally substituted by OH or 1-6 fluorine atoms R 1 and R 2may be combined to form a 4, 5, 6, or 7-membered ring, which is optionally substituted with OH or 1-6 fluorine atoms R 1 and R 2 can both represent H.R. 1 and R 2 can both be methyl. R 1 may represent methyl, and R 2 may represent N.

[0037] R 1 can be H or C 1-3 alkyl, optionally substituted by OH or 1-6 fluorine atoms R 1 may represent H.R. 1 can represent C 1-3 alkyl, optionally substituted by OH or 1-6 fluorine atoms R 1 can represent C 1-3 alkyl. R 1 may represent methyl. R 1 may represent ethyl. R 1 may be n-propyl. R 1 may be isopropyl. R 1 may represent CH2CH2OH. R 1 can be combined with R 2to form a 4, 5, 6, or 7-membered ring, which is optionally substituted with OH or 1-6 fluorine atoms R 1 can be combined with R 2 to form a 4, 5, 6, or 7-membered carbocyclic ring, which is optionally substituted with OH or 1-6 fluorine atoms. R 1 can be combined with R 2 with the formation of a 4, 5, 6, or 7-membered carbocyclic ring. R 1 can be combined with R 2 with the formation of an azetidine ring R 1 can be combined with R 2 with the formation of a pyrrolidine ring R 1 can be combined with R 2 with the formation of a piperidine ring. R 1 can be combined with R 2 with the formation of an azepane ring.

[0038] R 2 can be H or C 1-3 alkyl, optionally substituted by OH or 1-6 fluorine atoms R 2 may represent H.R. 2 can represent C 1-3alkyl, optionally substituted by OH or 1-6 fluorine atoms R 2 can represent C 1-3 alkyl. R 2 may represent methyl. R 2 may represent ethyl. R 2 may be n-propyl. R 2 may be isopropyl. R 2 may represent CH2CH2OH. R 2 can be combined with R 1 to form a 4, 5, 6, or 7-membered ring, which is optionally substituted with OH or 1-6 fluorine atoms R 2 can be combined with R 1 to form a 4, 5, 6, or 7-membered carbocyclic ring, which is optionally substituted with OH or 1-6 fluorine atoms R 2 can be combined with R 1 with the formation of a 4, 5, 6, or 7-membered carbocyclic ring. R 2 can be combined with R 1 with the formation of an azetidine ring R 2 can be combined with R 1 with the formation of a pyrrolidine ring R 2can be combined with R 1 with the formation of a piperidine ring. R 2 can be combined with R 1 with the formation of an azepane ring.

[0039] R 3 is a prodrug fragment that can be cleaved in vivo. R 3 may represent a functional group that can be cleaved in vivo to form a compound where R 3 represents H. Examples of such functional groups include those that form carbonates, carbamates, esters, phosphates, and phosphonooxymethyl esters with the O atom to which they are attached. Examples of specific groups that may be suitable can be found in Rautio, J. et al. Nat. Rev. Drug Discov. 17, 559–587 (2018).

[0040] R 3 may represent -P(O)OR 6 OR 7 or -COR 5 . R 3 may be -PO3H2 or -COR 5 . R 3 may be -РО3Н2, or its salt. R 3may represent -РО3Н2. R 3 may represent -COR 5 . R 3 may represent -COME. R 3 may represent -COEt. R 3 may be a salt -РО3Н2. R 3 may be -PO3HX, -PO3X, or -PO3X2, where X is a suitable counterion. X may be any suitable counterion, including, but not limited to, Na, K, Li, Mg, and Ca ions.

[0041] R 4 may be H, CN, halogen, or C 1-3 alkyl, optionally substituted by OH or 1-6 fluorine atoms R 4 may represent H.R. 4 may represent CN. R 4 may be a halogen. R 4 may represent Cl. R 4 may represent F.R 4 may represent Br. R 4 can represent C 1-3 alkyl, optionally substituted by OH or 1-6 fluorine atoms R 4can represent C 1-3 alkyl. R 4 may represent methyl. R 4 may represent ethyl. R 4 may be n-propyl. R 4 may be isopropyl. R 4 may represent CH2OH. R 4 may represent CF3. R 4 may represent CHF2.

[0042] R 5 may be optionally substituted C 1-6 alkyl, optionally substituted 3-6-membered heterocyclyl or optionally substituted C 3-6 cycloalkyl. R 5 can represent C 1-6 alkyl optionally substituted with 1-6 fluorine atoms R 5 may represent methyl. R 5 may represent ethyl.

[0043] R 6 and R 7 may independently represent H, optionally substituted with C 1-6 alkyl, optionally substituted 3-6-membered heterocyclyl or optionally substituted C 3-6cycloalkyl; or R 6 and R 7 may be combined to form an optionally substituted 5- or 6-membered ring. R 6 and R 7 together may represent any such functional group that is suitable for use in phosphate prodrugs. Groups such as those described in Top. Curr. Chem. 2015; 360; 115-160, for example, may be suitable. R 6 and R 7 can independently represent H or C 1-6 alkyl optionally substituted with 1-6 fluorine atoms R 6 and R 7 can both represent N.

[0044] R 6 may be H, optionally substituted with C 1-6 alkyl, optionally substituted 3-6-membered heterocyclyl or optionally substituted C 3-6 cycloalkyl; or R 6 can be combined with R 7 to form an optionally substituted 5- or 6-membered ring R 6 can represent C 1-6alkyl optionally substituted with 1-6 fluorine atoms R 6 may represent methyl. R 6 may represent ethyl. R 6 may represent N.

[0045] R 7 may be H, optionally substituted with C 1-6 alkyl, optionally substituted 3-6-membered heterocyclyl or optionally substituted C 3-6 cycloalkyl; or R 7 can be combined with R 6 to form an optionally substituted 5- or 6-membered ring R 7 can represent C 1-6 alkyl optionally substituted with 1-6 fluorine atoms R 7 may represent methyl. R 7 may represent ethyl. R 7 may represent N.

[0046] R 8 , R 9 and R 10 may independently represent H, CN, halogen, or C 1-3 alkyl optionally substituted with 1-6 fluorine atoms R 8 , R 9 and R 10can be independently selected from H, F, CHF2 and CF3.

[0047] R 8 may be H, CN, halogen, or C 1-3 alkyl optionally substituted with 1-6 fluorine atoms R 8 can be H, F, CHF2, or CF3. R 8 may represent H.R. 8 may represent F.R 8 may represent CHF2. R 8 may represent CF3.

[0048] R 9 may be H, CN, halogen, or C 1-3 alkyl optionally substituted with 1-6 fluorine atoms R 9 can be H, F, CHF2, or CF3. R 9 may represent H.R. 9 may represent F.R 9 may represent CHF2. R 9 may represent CF3.

[0049] R 10 may be H, CN, halogen, or C 1-3 alkyl optionally substituted with 1-6 fluorine atoms R 10 can be H, F, CHF2, or CF3. R10 may represent H.R. 10 may represent F.R 10 may represent CHF2. R 10 may represent CF3.

[0050] Group:

[0051]

[0052] may represent:

[0053]

[0054] The compound may be a compound of formula (2a), (2b), (2c) or (2d):

[0055]

[0056] or its salt, where R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 have the meanings defined above.

[0057] The compound may be a compound of formula (3):

[0058]

[0059] or its salt, where R 3 has the meaning defined above.

[0060] The compound may be a compound of formula (4a) or (4b):

[0061]

[0062] or its salt, where R 5 , R 6 and R 7 have the meanings defined above.

[0063] Upon administration, the prodrug compounds described herein are metabolized to a compound that is particularly active as a GPR52 modulator. Metabolism may involve cleavage of the R-containing group. 3 In particular, the metabolized compound may be active as a GPR52 agonist.

[0064] The said metabolism of the compounds of formula (1a) and (1b) described above may include conversion into compounds of formula (1ai) and (1bi), respectively.

[0065]

[0066] The compounds of formulas (1ai) and (1bi) are particularly active as GPR52 modulators, in particular as GPR52 agonists.

[0067] The compounds may be prodrugs of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide.

[0068] The compounds may be prodrugs of:

[0069]

[0070] The connection can be selected from a group consisting of:

[0071] (4-carbamyl-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)methyl acetate;

[0072] (4-carbamoyl-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl) dihydrogen phosphate;

[0073] or its salts.

[0074] The connection can be selected from a group consisting of:

[0075]

[0076] or its salts.

[0077] The compounds may be prodrugs of:

[0078] 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide;

[0079] 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide;

[0080] 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide;

[0081] 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-N,3-dimethyl-1H-pyrazole-4-carboxamide; or

[0082] 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide.

[0083] The compounds may be prodrugs of:

[0084]

[0085] The connection can be selected from a group consisting of:

[0086]

[0087] or its salts.

[0088] The connection can be selected from a group consisting of:

[0089] (1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-((2-hydroxyethyl)carbamoyl)-3-methyl-1H-pyrazol-5-yl)methylacetate;

[0090] (4-carbamoyl-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1H-pyrazol-5-yl)methylacetate;

[0091] (1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-4-((2-hydroxyethyl)carbamoyl)-3-methyl-1H-pyrazol-5-yl)methylacetate;

[0092] (1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-4-(methylcarbamoyl)-1H-pyrazol-5-yl)methylacetate;

[0093] (4-carbamoyl-1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)methylacetate;

[0094] (1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-((2-hydroxyethyl)carbamoyl)-3-methyl-1H-pyrazol-5-yl)methyldihydrogenphosphate;

[0095] (4-carbamoyl-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1H-pyrazol-5-yl)methyldihydrogenphosphate;

[0096] (1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-4-((2-hydroxyethyl)carbamoyl)-3-methyl-1H-pyrazol-5-yl)methyldihydrogen phosphate;

[0097] (1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-4-(methylcarbamoyl)-1H-pyrazol-5-yl)methyldihydrogen phosphate;

[0098] (4-carbamoyl-1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)methyldihydrogen phosphate;

[0099] or its salts.

[0100] Additional embodiments of the invention include the use of a compound of formula (1a), (1b), (2a), (2b), (2c), (2d),

[0101] (3), (4a), (4b) or a salt thereof or a pharmaceutical composition comprising a compound of formula (1a), (1b), (2a), (2b), (2c), (2d),

[0102] (3), (4a), (4b) or a salt thereof, in the treatment or prevention of diseases in which GPR52 receptors are involved or in which modulation of GPR52 receptors may be beneficial. The compounds of the present invention can be used as prodrugs of GPR52 modulators. The compounds of the present invention can be used as prodrugs of GPR52 agonists.

[0103] The compounds of the present invention can be used for the treatment of mental disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorder; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma- or stressor-related disorders; disruptive disorders, drive disorders, or behavioral disorders; sleep-wake patterns disorders; substance use disorders; addictive disorders; behavioral disorders; hypofrontality;abnormalities of the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways; decreased striatal activity; cortical dysfunction; neurocognitive dysfunction, or conditions or symptoms associated therewith.

[0104] The compounds of the present invention can be used for the treatment of schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorders, autism spectrum disorder, psychosis, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, pituitary adenoma, prolactinoma, craniopharyngioma, Cushing's disease, diabetes insipidus, non-functioning tumors, obesity, post-traumatic stress disorder (PTSD), akathisia and related movements, athetosis, ataxia, ballismus, hemiballismus, chorea, choreoathetosis, dyskinesia, tardive dyskinesia, neuroleptic-induced dyskinesia, myoclonus, mirror movement disorder,Paroxysmal kinesigenic dyskinesia, restless legs syndrome, seizures, stereotypic movement disorder, stereotypy, tic disorder, tremor, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or drug-induced psychotic disorder, delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance- or drug-induced bipolar disorder and related disorders, bipolar disorder and related disorder due to another medical condition, separation anxiety disorder, selective mutism, specific phobia,Social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, anxiety disorders due to another medical condition, delirium, major neurocognitive disorder, minor neurocognitive disorder, amnesia, dementia, dyspraxia, stereotypic movement disorder, post-stroke effect, dentatorubropallidolewisian atrophy, decreased emotional expression, evolution, alogia, and asociality.

[0105] The compounds of the present invention can be used for the treatment of schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorders, autism spectrum disorder, psychosis, neurocognitive disorder, delirium, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, obesity, and post-traumatic stress disorder (PTSD). The compounds of the present invention can be used for the treatment of schizophrenia.

[0106] DEFINITIONS

[0107] The following definitions apply in this application unless otherwise stated.

[0108] The term "GPR52 modulator" as used herein refers to any compound that binds to and modulates the function of the GPR52 receptor. The term "modulator" should be interpreted to include modulation by modalities, including, but not limited to, agonists, partial agonists, and inverse agonists.

[0109] The term "prodrug" as used herein refers to a compound that is metabolically or chemically activated in vivo to form an active parent drug molecule that itself exerts a therapeutic pharmacological effect. The prodrugs described herein can be converted by one or more metabolic processes in vivo to produce a compound that is active as a GPR52 modulator. The prodrugs described herein can be converted by one or more metabolic processes in vivo to produce a compound that is active as a GPR52 agonist. Unmetabolized prodrug compounds themselves may or may not have GPR52 activity. The use of prodrugs is well precedented, and indeed, many marketed drugs are prodrugs (Rautio, J. et al. Nat. Rev. Drug Discov. 17, 559-587 (2018)).

[0110] The term "treatment" with respect to the use of any of the compounds described herein, including compounds of formula (1a), (1b), (2a), (2b), (2c), (2d), (3), (4a), (4b), is used to describe any form of intervention in which the compound is administered to a subject suffering from, at risk of, or potentially at risk of the disease or disorder in question. Thus, the term "treatment" encompasses both preventive (prophylactic) treatment and treatment in which measurable or detectable symptoms of the disease or disorder are manifested.

[0111] The term "effective therapeutic amount" (e.g., in relation to methods of treating a disease or condition) refers to the amount of a compound that is effective in producing the desired therapeutic effect. For example, if the condition is pain, then an effective therapeutic amount is the amount sufficient to provide the desired level of pain relief. The desired level of pain relief may be, for example, complete elimination of pain or a reduction in its severity.

[0112] Terms such as "alkyl" and "halogen" are used in their generally accepted senses (e.g., as defined in the IUPAC Gold Book) unless otherwise noted. "Optionally substituted" with respect to any group means that the group may optionally be substituted by one or more substituents, which may be the same or different.

[0113] To the extent that any of the compounds described have chiral centers, the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers. The invention described herein applies to all crystalline forms, solvates, and hydrates of any of the disclosed compounds, however prepared. To the extent that any of the compounds disclosed herein have acidic or basic centers, such as carboxylates or amino groups, all salt forms of said compounds are included herein. For pharmaceutical use, a salt should be considered a pharmaceutically acceptable salt.

[0114] Salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts can be formed by conventional methods, for example, by reacting the free acid or free base form of the compound with one or more equivalents of the appropriate acid or base, optionally in a solvent or medium in which the salt is insoluble, followed by removal of said solvent or medium using standard methods (e.g., in vacuum, freeze-drying, or filtration). Salts can also be prepared by replacing the counterion of the compound in salt form with another counterion, for example, using a suitable ion-exchange resin.

[0115] Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, as well as salts derived from metals such as sodium, magnesium, potassium, and calcium.

[0116] Examples of the acid addition salts include acid addition salts formed with acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acid (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+) camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic, fumaric, galactaric, gentisic, glucoheptone, gluconic (e.g., D-gluconic), glucuronic (e.g., D-glucuronic), glutamic (e.g., L-glutamic), α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydroiodic, isethionic, lactic (e.g., (+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g.,(-)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-aminosalicylic, sebacic, stearic, succinic, sulfuric, tannic, tartaric (e.g. (+)-L-tartaric), thiocyanic, undecylenic and valerianic acids.

[0117] Also included are any solvates of the compounds and their salts. Preferred solvates are those formed by incorporating molecules of a non-toxic pharmaceutically acceptable solvent (hereinafter referred to as a solvating solvent) into the solid-state structure (e.g., crystal structure) of the compounds of the invention. Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds of the invention with a solvent or solvent mixture containing the solvating solvent.

[0118] Whether a solvate has been formed in a particular case can be determined by subjecting crystals of the compound to analysis using well-known and standard methods such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0119] Solvates can be stoichiometric or nonstoichiometric solvates. Specific solvates can be hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates. For a more detailed discussion of solvates and methods for their preparation and characterization, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc. of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0120] The term "pharmaceutical composition" in the context of the present invention means a composition comprising an active agent and further comprising one or more pharmaceutically acceptable carriers. The composition may further include ingredients selected, for example, from diluents, adjuvants, excipients, carriers, preservatives, fillers, disintegrants, wetting agents, emulsifying agents, suspending agents, sweeteners, flavoring agents, aromatizing agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the administration route and the dosage form.The compositions may take the form of, for example, tablets, dragees, powders, elixirs, syrups, liquid dosage forms including suspensions, sprays, inhalation dosage forms, tablets, lozenges, emulsions, solutions, wafers, granules, capsules and suppositories, as well as liquid dosage forms for injection, including liposomal preparations.

[0121] The compounds of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope 1 H, 2 H (D) and 3 H (T). Similarly, references to carbon and oxygen include in their volume, respectively. 12 WITH, 13 With and 14 With and 16 O and 18O. Similarly, a reference to a specific functional group also includes isotopic variations within its scope unless the context otherwise indicates. For example, a reference to an alkyl group, such as an ethyl group, or an alkoxy group, such as a methoxy group, also encompasses variations in which one or more hydrogen atoms in the group are in the form of a deuterium or tritium isotope, such as in an ethyl group in which all five hydrogen atoms are in the isotopic form of deuterium (a perdeuteroethyl group), or in a methoxy group in which all three hydrogen atoms are in the isotopic form of deuterium (a trideuteromethoxy group). Isotopes may be radioactive or non-radioactive.

[0122] Therapeutic doses may vary depending on the patient's needs, the severity of the condition being treated, and the compound being used. Determining the appropriate dose for a specific situation is within the competence of a specialist in the field. Typically, treatment begins with lower doses, less than the optimal dose of the compound. The dosage is then increased in small increments until the optimal effect for the given circumstances is achieved. For convenience, the total daily dose can be divided and taken in portions throughout the day, if desired.

[0123] The effective dose of a compound will, of course, vary depending on the severity of the condition being treated, as well as the specific compound and route of administration. Selecting appropriate dosages is within the capabilities of a skilled artisan without undue burden.In general, the daily dose range may be from about 10 μg to about 30 mg per kg body weight of humans and non-human animals, preferably from about 50 μg to about 30 mg per kg body weight of humans and non-human animals, such as from about 50 μg to about 10 mg per kg body weight of humans and non-human animals, such as from about 100 μg to about 30 mg per kg body weight of humans and non-human animals, such as from about 100 μg to about 10 mg per kg body weight of humans and non-human animals, and most preferably from about 100 μg to about 1 mg per kg body weight of humans and non-human animals.

[0124] PHARMACEUTICAL COMPOSITIONS

[0125] Although the active compound can be administered alone, it is preferably presented as a pharmaceutical composition (e.g., a preparation).

[0126] Accordingly, in some embodiments of the invention, there is provided a pharmaceutical composition comprising at least one compound of formula (1a), (1b), (2a), (2b), (2c), (2d), (3), (4a), (4b), as defined above, together with at least one pharmaceutically acceptable excipient.

[0127] The composition may be a tablet composition. The composition may be a capsule composition.

[0128] The pharmaceutically acceptable excipient(s) can be selected, for example, from carriers (e.g., a solid, liquid, or semi-solid carrier), adjuvants, diluents (e.g., solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flowability agents, coating agents, release rate regulators (e.g., release-slowing or retarding polymers or waxes), binders, disintegrants, buffering agents, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffering agents, tonicity adjusting agents, thickeners, flavoring agents, sweeteners, pigments, plasticizers, flavoring agents, stabilizers, or any other excipients commonly used in pharmaceutical compositions.

[0129] The term "pharmaceutically acceptable" as used herein means compounds, materials, compositions, and / or dosage forms that, within the limits of sound medical judgment, are suitable for use in contact with the tissues of a subject (e.g., a human) without undue toxicity, irritation, allergic reaction, or other problems or complications commensurate with a reasonable benefit / risk ratio. Each excipient must also be "acceptable" in terms of compatibility with the other ingredients of the composition.

[0130] Pharmaceutical compositions containing compounds of formulas (1a), (1b), (2a), (2b), (2c), (2d), (3), (4a), (4b) can be prepared according to known methods, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intravaginal or transdermal administration.

[0131] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, troches, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0132] Tablet compositions may contain a unit dose of the active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, for example; lactose, sucrose, sorbitol or mannitol; and / or a sugar-free diluent such as sodium carbonate, calcium phosphate, calcium carbonate or cellulose or a derivative thereof, for example microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose and starches such as corn starch. Tablets may also contain standard ingredients such as binders and granulating agents such as polyvinylpyrrolidone, disintegrating agents (e.g., swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffering agents (e.g., phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures.Such excipients are well known and there is no need to discuss them in more detail here.

[0133] Tablets may be designed to release the drug either upon contact with gastric fluids (immediate-release tablets) or in a controlled manner (controlled-release tablets) over an extended period of time or upon contact with a specific area of ​​the gastrointestinal tract.

[0134] Pharmaceutical compositions typically comprise from about 1% (w / w) to about 95%, preferably % (w / w) of the active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (e.g., as defined above), or a combination of such excipients. Preferably, the compositions comprise from about 20% (w / w) to about 90% (w / w) of the active ingredient and from 80% (w / w) to 10% of a pharmaceutically acceptable excipient or a combination of excipients. The pharmaceutical compositions comprise from about 1% to about 95%, preferably from about 20% to about 90% of the active ingredient. The pharmaceutical compositions of the present invention may be, for example, in unit dose form, such as ampoules, vials, suppositories, pre-filled syringes, dragees, powders, tablets or capsules.

[0135] Tablets and capsules may contain, for example, 0-20% disintegrant, 0-5% lubricants, 0-5% flow agents and / or 0-99% (w / w) fillers and / or bulking agents (depending on the dose of the drug). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Sustained-release tablets typically additionally contain 0-99% (w / w) release-controlling (e.g., delaying) polymers (depending on the dose). The film coating of a tablet or capsule typically contains 0-10% (w / w) polymers, 0-3% (w / w) pigments and / or 0-2% (w / w) plasticizers.

[0136] Compositions for parenteral administration typically contain 0-20% (w / w) buffers, 0-50% (w / w) cosolvents, and / or 0-99% (w / w) water for injection (WFI) (depending on the dose and if a lyophilisate is used). Compositions for intramuscular depots may also contain 0-99% (w / w) oil.

[0137] Pharmaceutical compositions may be provided to the patient in "patient packs" containing the complete course of treatment in a single package, typically a blister pack.

[0138] The compounds of formulae (1a), (1b), (2a), (2b), (2c), (2d), (3), (4a), (4b) are typically presented as a unit dosage form and, as such, will typically contain a sufficient amount of the compound to provide the desired level of biological activity. For example, the composition may contain from 1 ng to 2 g of the active substance, such as from 1 ng to 2 mg of the active substance. Within these ranges, particular subranges of the compound are from 0.1 mg to 2 g of the active substance (typically from 10 mg to 1 g, such as from 50 mg to 500 mg) or from 1 μg to 20 mg (such as from 1 μg to 10 mg, such as from 0.1 mg to 2 mg of the active substance).

[0139] In compositions for oral administration, the unit dosage form may contain from 1 mg to 2 g, typically from 10 mg to 1 g, such as from 50 mg to 1 g, such as from 100 mg to 1 g of the active compound.

[0140] The active compound is administered to a patient in need thereof (e.g., a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount). The exact amounts of the compound administered can be determined by the attending physician in accordance with standard procedures.

[0141] EXAMPLES

[0142] The invention will now be illustrated, but not limited, by reference to the following examples shown in Table 1.

[0143]

[0144]

[0145] Preparation of compounds according to the invention

[0146] Compounds of formulas (1a), (1b), (2a), (2b), (2c), (2d), (3), (4a), (4b) can be obtained according to synthetic methods known to those skilled in the art. The invention also provides a method for preparing a compound defined in formulas (1a), (1b) and (2) above. Commercial reagents were used without further purification.

[0147] Abbreviations

[0148] AcOH=acetic acid

[0149] Water=water

[0150] DCM=dichloromethane

[0151] DIPEA=N,N-diisopropylethylamine

[0152] DMAP=4-dimethylaminopyridine

[0153] DMF=N,N-dimethylformamide

[0154] DMSO=dimethyl sulfoxide

[0155] Dppf=1,1'-ferrocenediyl-bis(diphenylphosphine)

[0156] EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0157] ES=electrospray

[0158] EtOAc=ethyl acetate

[0159] EtOH=ethanol

[0160] h=hour (hours)

[0161] HATU=N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide

[0162] l=liter

[0163] LC=liquid chromatography

[0164] LCMS=liquid chromatography mass spectrometry

[0165] MeCN=acetonitrile

[0166] MeOH=methanol

[0167] min=minute(minutes)

[0168] MS=mass spectrometry

[0169] NMR=nuclear magnetic resonance

[0170] Pet.-ether=petroleum ether

[0171] Room temperature = room temperature

[0172] TEA=trifluoroacetic acid

[0173] THE=tetrahydrofuran

[0174] UV=Ultraviolet radiation.

[0175] LCMS Methods

[0176] LCMS experiments were performed under electrospray conditions with the following conditions (Solvents: A1=0.1% TFA in H2O:MeCN (95:5); A2=5 mM ammonium acetate in H2O; A3=2.5 L H2O+2.5 mL 28% ammonia in H2O solution; A4=0.1% HCO2H in H2O:MeCN (95:5); A5=10 mM NH4HCO3 in H2O; A6=0.2% 28% ammonia in H2O; A7=0.1% TFA in H2O; A8=50 mM ammonium acetate pH 7.4; A9=10 mM ammonium acetate in H2O; A10=0.1% formic acid in H2O; B1=0.1% TFA in MeCN; B2=MeCN; B3=2.5 L MeCN+135 mL H2O+2.5 mL 28% ammonia in H2O solution; B4=0.1% formic acid in MeCN. LCMS data are presented as: ion mass, electrospray mode (positive or negative), retention time; Ion mass, electrospray mode (positive or negative), retention time, approximate purity.

[0177] Method 1. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Atlantis dC18 5 micron, 4.6×50 mm; Gradient [time (min) / solvent B2 in A1 (%)]: 0.0 / 5, 2.5 / 95, 4.0 / 95, 4.5 / 5, 6.0 / 5; Injection volume 1 μL; UV detection 210-400 nM; Column temperature 25°C; 1.5 mL / min.

[0178] Method 2. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Zorbax XDB C18, 5 micron; Gradient [time (min) / solvent B2 in A4 (%)]: 0.00 / 5, 2.50 / 95, 4.00 / 95, 4.50 / 5, 6.00 / 5; Injection volume 1 μL; UV detection 210-400 nm; Column temperature 25 ° C; Flow rate 1.5 mL / min.

[0179] Method 3. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Waters XBridgeC8 3.5 micron, 4.6×50 mm; Gradient [time (min) / solvent B1 in Al (%)]: 0.0 / 5, 2.5 / 95, 4.0 / 95, 4.5 / 5, 6.0 / 5; Injection volume 1 μL; UV detection 210-400 nM; Column temperature 25°C; 1.5 mL / min.

[0180] Method 4. Instruments: Agilent Technologies 1260 LC with Chemstation software, diode array detector, Agilent 6120 Quadrupole MS with APCI and ES source; Column: Phenomenex Gemini-NX C18, 3 micron, 2×30 mm; Gradient [time (min) / solvent B3 in A3 (%)]: 0.00 / 5, 2.00 / 95, 2.50 / 95, 2.60 / 5, 3.00 / 5; Injection volume 0.5 μL; UV detection 190-400 nm; Column temperature 40°C; Flow rate 1.5 mL / min.

[0181] Method 5. Instruments: Agilent Technologies 1260 LC with Chemstation software, diode array detector, Agilent 6120 Quadrupole MS with APCI and ES source; Column: Phenomenex Gemini-NX C18, 3 micron, 2×30 mm; Gradient [time (min) / solvent VZ in A3 (%)]: 0.00 / 2, 0.10 / 2, 8.40 / 95, 10.0 / 95, 10.1 / 2, 12.0 / 2; Injection volume 0.5 μL; UV detection 190-400 nm; Column temperature 40°C; Flow rate 1.5 mL / min.

[0182] Method 6. Instruments: Waters Acquity H-Class UPLC MS system with MassLynx software, Photo Diode Array Detector (PDA), QDa mass detector with electrospray source; Column: Phenomenex Luna PFP, 5 micron, 2.1×50 mm; Gradient [time (min) / solvent B4 in A10 (%)]: 0.0 / 5, 0.1 / 5, 8.5 / 95, 8.8 / 100, 9.6 / 100, 9.8 / 5, 10.0 / 5; Injection volume 1 μL; UV detection 200-400 nm; Column temperature 40°C; Flow rate 0.5 mL / min.

[0183] Method 7. Instruments: Agilent Technologies 1290 Infinity II Series LC, 6125 Quadrupole MSD SL; Column: Waters XBridgeC8 3.5 micron, 4.6×50 mm; Gradient [time (min) / solvent B2 in A5 (%)]: 0.0 / 10, 4.0 / 95, 5.0 / 95, 5.5 / 10, 7.0 / 10.; Injection volume 1 μL; UV detection 210-400 nM; Column temperature 25°C; 1.2 mL / min.

[0184] GCMS Methods

[0185] GCMS data is provided in the format: Ion mass, electrospray mode (positive or negative), retention time.

[0186] Method 1. Instrument: Agilent GCMS 7890 B; Column: HP-5ms UI (30 m × 250 μm × 0.25 μm); Inlet temperature: 250°C; split ratio: 75:1; oven temperature: 50°C, retention time 3 min; linear change 1:40°C / min to 300°C, retention time 2 min; Detector temperature: 310°C; Column flow: 2 mL / min; Air flow: 300 mL / min; H2 flow: 40 mL / min; Makeup flow (He): 25 mL / min; Source temperature: 230°C.

[0187] Method 2. Instrument: Agilent GCMS 7890 B; Column: HP-5ms UI (30 m × 250 μm × 0.25 μm); Inlet temperature: 250°C; split ratio: 75:1; oven temperature: 120°C, retention time 1 min; linear change 1:40°C / min to 300°C, retention time 4 min; Detector temperature: 310°C; Column flow: 2 mL / min; Air flow: 300 mL / min; H2 flow: 40 mL / min; Makeup flow (He): 25 mL / min; Source temperature: 230°C.

[0188] OBTAINING INTERMEDIATE COMPOUNDS

[0189] Scheme 1

[0190]

[0191] Preparation of the intermediate compound 1-2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine

[0192]

[0193] PdCl2(dppf).DCM (284 mg, 0.38 mmol) was added to a degassed solution of (2-fluoropyridin-4-yl)boronic acid (1.3 g, 7.77 mmol), potassium carbonate (3.2 g, 22.3 mmol), and 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (1.3 g, 9.30 mmol) in 1,4-dioxane (20 mL) / water (5 mL), and the resulting reaction mixture was heated at 90 °C for 1 h. The reaction mixture was partitioned between water (70 mL) and EtOAc (100 mL). The organic layer was separated, washed with saturated brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-30% EtOAc in petroleum ether to give 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine as a brown oil (1.8 g, 86%).

[0194] LCMS (Method 2): m / z 274.0 (M+H) + (ES+), at 2.54 min.

[0195] 1 H NMR: (400 MHz, DMSO-d6) δ: 8.17 (d, J=4.4 Hz, 1H), 7.61 (s, 3H), 7.29 (d, J=1.2 Hz, 1H), 7.16 (s, 1H), 4.17 (d, J=3.6 Hz, 2H).

[0196] Preparation of the intermediate compound 2-4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine

[0197]

[0198] Hydrazine hydrate (0.17 mL, 3.52 mmol) was added to a stirred solution of 2-fluoro-4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (intermediate 1, 300 mg, 1.17 mmol) in EtOH (10 mL), and the resulting reaction mixture was heated at 60 °C for 16 h. The solvent was removed in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo to give 4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine as a brown oil (350 mg, 100%).

[0199] LCMS (Method 2): m / z 286.2 (M+H) + (ES+), at 1.37 min.

[0200] 1 H NMR: (400 MHz, DMSO-d6) 5: 7.88 (d, J=5.2 Hz, 1H), 7.53-7.44 (m, 3H), 7.36 (s, 1H), 6.57 (s, 1H), 6.45-6.44 (m, 1H), 4.07 (s, 2H), 3.95 (s, 2H).

[0201] Preparation of the intermediate compound 3-ethyl-2-methyl-4-oxo-4,5-dihydrofuran-3-carboxylate

[0202]

[0203] Sodium ethoxide (7.84 g, 115 mmol) was added to a suspension of ethyl 3-oxobutanoate (10 g, 76.8 mmol) in toluene (50 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. MeCN (20 mL) and 2-chloroacetyl chloride (6.15 mL, 38.4 mmol) were added, and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified with 6 N aqueous H2SO4 (60 mL), the organic layer was removed, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with saturated brine (100 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-10% EtOAc in petroleum ether to give ethyl 2-methyl-4-oxo-4,5-dihydrofuran-3-carboxylate as a yellow liquid (2.8 g, 21%).

[0204] LCMS (Method 3): m / z 171.0 (M+H) + (ES+), at 1.94 min.

[0205] 1H NMR: (400 MHz, DMSO-d6) δ: 4.78 (s, 2H), 4.17 (q, J=3.6 Hz, 2H), 2.50 (s, 3H), 1.22 (t, J=9.6 Hz, 3H).

[0206] Preparation of the intermediate compound 4-ethyl-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylate

[0207]

[0208] 4-(3-Fluoro-5-(trifluoromethyl)benzyl)-2-hydrazinylpyridine (intermediate 2, 4.69 g, 16.5 mmol) was added to a stirred solution of ethyl 2-methyl-4-oxo-4,5-dihydrofuran-3-carboxylate (intermediate 3, 2.8 g, 16.5 mmol) in ethanol (50 mL) at room temperature, followed by the addition of a catalytic amount of acetic acid (0.094 mL, 1.65 mmol), and the resulting reaction mixture was heated at 80 °C for 16 h. Upon cooling, the precipitated solid was filtered off, washed with EtOH (2×10 mL), and dried in vacuo to give ethyl 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylate as a white solid (1.95 g, 27%).

[0209] LCMS (Method 2): m / z 438.0 (M+H) + (ES+), at 2.80 min.

[0210] 1H NMR: (400 MHz, DMSO-d6) δ: 8.48 (d, J=7.2 Hz, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 7.61-7.59 (m, 2H), 7.43 (d, J=6.4 Hz, 1H), 5.27 (t, J=9.2 Hz, 1H), 5.01 (d, J=8.8 Hz, 2H), 4.29-4.27 (m, 4H), 2.42 (s, 3H), 1.32 (t, J=9.6 Hz, 3H).

[0211] Preparation of the intermediate compound 5-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid

[0212]

[0213] Lithium hydroxide monohydrate (1.07 g, 44.5 mmol) was added to a stirred solution of ethyl 1-(4-(3-fluoro-5-

[0214] (trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylate (intermediate 4, 1.95 g, 4.45 mmol) in THF (10 mL), MeOH (10 mL), and water (5 mL) and the resulting reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo. The resulting residue was dissolved in water (30 mL) and acidified with 2 N HCl to pH ~2, and the aqueous layer was extracted with EtOAc (4×50 mL). The combined organic layers were separated, washed with brine (30 mL), dried (Na2SO4), and the solvent was removed in vacuo to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid as a white solid (1.81 g, 99%).

[0215] LCMS (Method 1): m / z 410.0 (M+H) + (ES+), at 2.49 min

[0216] 1H NMR: (400 MHz, DMSO-d6) δ: 8.46 (d, J=6.8 Hz, 1H), 7.84 (s, 1H), 7.66-7.55 (m, 3H), 7.41 (d, J=6.8 Hz, 1H), 5.01 (s, 2H), 4.24 (s, 2H), 2.44 (s, 3H). No exchangeable protons are observed.

[0217] Preparation of intermediate compound 6 - 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide

[0218]

[0219] DIPEA (3.06 mL, 17.68 mmol) was added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid (intermediate 5, 1.81 g, 4.42 mmol) and ammonium chloride (0.354 g, 6.63 mmol) in DMF (50 mL), then HATU (3.36 g, 8.84 mmol) was added and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography, eluting with 0-85% EtOAc in petroleum ether. The compound was dissolved in MeOH (35 mL) and heated to reflux. The resulting clear solution was allowed to cool to room temperature and kept undisturbed for 48 hours.The recrystallized solid was filtered, washed with MeOH (2×10 mL), and dried under vacuum to afford 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide as a white crystalline solid (0.52 g). The recrystallization process was repeated from the remaining stock solution to yield an additional 0.208 g of material. Overall yield 0.728 g, 40%.

[0220] LCMS (Method 2): m / z 409.0 (M+H) + (ES+), at 2.08 min

[0221] 1 H NMR: (400 MHz, DMSO-d6) δ: 8.44 (d, J=6.8 Hz, 1H), 7.80 (s, 1H), 7.66-7.55 (m, 4H), 7.42-7.37 (m, 2H), 5.63 (t, J=8.4 Hz, 1H), 4.91 (d, J=8.4 Hz, 2H), 4.23 (s, 2H), 2.36 (s, 3H).

[0222] Preparation of intermediate compound 7 - 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide

[0223]

[0224] HATU (0.11 g, 0.293 mmol) was added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid (intermediate 5, 0.06 g, 0.15 mmol) and 2-aminoethan-1-ol (0.012 g, 0.22 mmol) in DMF (3 mL) at 0 °C, followed by the addition of DIPEA (0.038 mg, 0.29 mmol), and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was separated and washed with brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-50% EtOAc in petroleum ether to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide as a white solid (18 mg, 27%).

[0225] LCMS (Method 7): m / z 453.0 (M+H) + (ES+), at 2.08 min, 95%.

[0226] 1 H NMR: (400 MHz, DMSO-d6) δ: 8.44 (d, J=5.2 Hz, 1H), 8.08 (t, J=5.6 Hz, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.62-7.58 (m, 2H), 7.39 (d, J=1.2 Hz, 1H), 5.62 (t, J=6.4 Hz, 1H), 4.89 (d, J=6.4 Hz, 2H), 4.74 (t, J=5.6 Hz, 1H), 4.24 (s, 2H), 3.53-3.52 (m, 2H), 3.34-3.30 (m, 2H), 2.34 (s, 3H).

[0227] Preparation of the intermediate compound 8-2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-hydrazinylpyridine

[0228]

[0229] Step 1. A pinch of iodine was added to a stirred solution of activated zinc (35 g, 583 mmol) in DMF (300 mL), and the solution was heated at 50°C for 5 min, followed by the addition of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (32 g, 124 mmol) in DMF (50 mL). The reaction mixture was heated at 50°C for 1 h and then allowed to cool to room temperature. The residual zinc was allowed to settle and the supernatant pale green DMF layer was transferred via cannula to a degassed suspension of 2-bromo-4-chloropyridine (16 g, 83.3 mmol) and RuPhos (2.3 g, 4.99 mmol) in DMF (50 mL), followed by the addition of tris(dibenzylideneacetone)dipalladium(0) (3.8 g, 4.16 mmol). The reaction mixture was heated at 70 °C for 16 h, then filtered through Celite and washed with EtOAc (600 mL). The filtrate was washed with saturated brine (3 x 300 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo.The residue was purified by gradient flash column chromatography eluting with 0-5% EtOAc in petroleum ether to give 4-chloro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine as a yellow semi-solid (8 g, 33%).

[0230] LCMS (Method 2): m / z 290.1 ​​(ES+), at 2.65 min.

[0231] 1 H NMR: (400 MHz, DMSO-d6) δ: 8.49 (d, J=5.2 Hz, 1H), 7.83-7.79 (m, 1H), 7.61-7.41 (m, 4H), 4.23 (s, 2H).

[0232] Step 2. Hydrazine hydrate (20 g, 415 mmol) was added to a stirred solution of 4-chloro-2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridine (8 g, 27.68 mmol) in IPA (100 mL) in a sealed tube, and the reaction mixture was heated at 110 °C for 72 h. The solvent was removed in vacuo, and the residue was partitioned between water (200 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine (200 mL), dried (Na2SO4), and the solvent was removed in vacuo to give 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-hydrazinylpyridine as a yellow gum (5 g, 63%).

[0233] LCMS (Method 2): m / z 286.1 (ES+), at 1.19 min.

[0234] 1 H NMR: (400 MHz, DMSO-d6) δ: 7.95 (d, J=6.0 Hz, 1H), 7.56-7.21 (m, 4H), 6.59 (d, J=1.6 Hz, 1H), 6.51-6.49 (m, 1H), 4.15 (s, 2H), 3.99 (s, 2H).

[0235] Preparation of intermediate 9-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid

[0236]

[0237] Step 1. 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-hydrazinylpyridine (intermediate 8, 600 mg, 2.10 mmol) was added to a stirred solution of ethyl 2-methyl-4-oxo-4,5-dihydrofuran-3-carboxylate (intermediate 3, 430 mg, 2.52 mmol) in ethanol (20 mL) at room temperature, followed by the addition of a catalytic amount of acetic acid (0.120 mL, 2.10 mmol), and the resulting reaction mixture was heated at 80 °C for 16 h. Upon cooling, the precipitated solid was filtered off, washed with EtOH (2×10 mL), and dried in vacuo to give ethyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylate.

[0238] Step 2. LiOH (11.07 mg, 0.462 mmol), water (0.5 mL), and MeOH (0.5 mL) were added to a solution of ethyl 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylate (60 mg, 0.15 mmol) in 1,4-dioxane (20 mL) at room temperature, and the resulting reaction mixture was stirred at room temperature for 16 h.

[0239] After completion of step 2, the title compound (230 mg, 26%) was isolated as a pale yellow solid by removing the solvent in vacuo, acidifying with 1.5 N HCl (5 mL) to pH ~6, and partitioning between water (10 mL) and EtOAc (15 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo.

[0240] LCMS (Method 2): m / z 410.0 (ES+), at 2.03 min.

[0241] 1H NMR: (400 MHz, DMSO-d6) δ: 8.65 (d, J=7.2 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J=12.4 Hz, 2H), 4.81 (s, 2H), 4.32 (s, 2H), 3.57 (s, 1H), 2.41 (s, 3H). 1 exchangeable proton is not observed.

[0242] Preparation of intermediate compound 10 - 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide

[0243]

[0244] DIPEA (3.06 mL, 17.68 mmol) was added to a stirred solution of 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid (intermediate 9, 1.81 g, 4.42 mmol) and ammonium chloride (0.354 g, 6.63 mmol) in DMF (50 mL), then HATU (3.36 g, 8.84 mmol) was added and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography, eluting with 0-85% EtOAc in petroleum ether. The compound was dissolved in MeOH (35 mL) and heated to reflux. The resulting clear solution was allowed to cool to room temperature and kept undisturbed for 48 hours.The recrystallized solid was filtered, washed with MeOH (2×10 mL), and dried in vacuo to give 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide.

[0245] LCMS (Method 3): m / z 409.0 (M+H) + (ES+), at 1.77 min, 96%.

[0246] 1 H NMR: (400 MHz, DMSO-d6) δ: 8.64 (dd, J=5.4, 1.6 Hz, 1H), 7.74 (s, 1H), 7.63-7.61 (m, 2H), 7.55-7.53 (m, 2H), 7.45 (s, 1H), 7.39 (s, 1H), 5.89 (t, J=3.6 Hz, 1H), 4.65 (d, J=5.2 Hz, 2H), 4.31 (s, 2H), 2.37 (s, 3H).

[0247] Preparation of intermediate compound 11 - 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide

[0248]

[0249] DIPEA (3.06 mL, 17.68 mmol) was added to a stirred solution of 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid (intermediate 9, 1.81 g, 4.42 mmol) and ethanolamine (0.354 g, 6.63 mmol) in DMF (50 mL), then HATU (3.36 g, 8.84 mmol) was added and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography, eluting with 0-85% EtOAc in petroleum ether. The compound was dissolved in MeOH (35 mL) and heated to reflux. The resulting clear solution was allowed to cool to room temperature and kept undisturbed for 48 hours.The recrystallized solid was filtered, washed with MeOH (2×10 mL), and dried in vacuo to give 1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide.

[0250] LCMS (Method 3): m / z 453.0 (M+H)+ (ES+), at 1.99 min, 99%.

[0251] 1 H NMR: (400 MHz, DMSO-d6) δ: 8.63 (d, J=5.6 Hz, 1H), 7.94 (t, J=5.2 Hz, 1H), 7.74 (s, 1H), 7.64-7.63 (m, 2H), 7.55-7.53 (m, 2H), 5.87 (t, J=4.4 Hz, 1H), 4.75 (t, J=4.4 Hz, 1H), 4.63 (d, J=5.2 Hz, 2H), 4.31 (s, 2H), 3.52 (kv, J=5, 6 Hz, 2H), 3.37-3.33 (m, 2H), 2.35 (s, 3H).

[0252] Preparation of intermediate compound 12 - 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-N,3-dimethyl-1H-pyrazole-4-carboxamide

[0253]

[0254] DIPEA (3.06 mL, 17.68 mmol) was added to a stirred solution of 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid (intermediate 5, 1.81 g, 4.42 mmol) and methylamine (0.354 g, 6.63 mmol) in DMF (50 mL), then HATU (3.36 g, 8.84 mmol) was added and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography, eluting with 0-85% EtOAc in petroleum ether. The compound was dissolved in MeOH (35 mL) and heated to reflux. The resulting clear solution was allowed to cool to room temperature and kept undisturbed for 48 hours.The recrystallized solid was filtered, washed with MeOH (2×10 mL), and dried in vacuo to give 1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-N,3-dimethyl-1H-pyrazole-4-carboxamide.

[0255] LCMS (Method 3): m / z 422.9 (M+H) + (ES+), at 2.29 min, 99%.

[0256] 1 H NMR: (400 MHz, DMSO-d6) δ: 8.44 (d, J=4.8 Hz, 1H), 7.97 (d, J=4.8 Hz, 1H), 7.81 (s, 1H), 7.67-7.56 (m, 3H), 7.38 (d, J=5.2 Hz, 1H), 5.58 (t, J=6.4 Hz, 1H), 4.87 (d, J=6.4 Hz, 2H), 4.24 (s, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.34 (s, 3H).

[0257] Preparation of intermediate compound 13 - 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene

[0258]

[0259] Step 1. LiAlH4 (1.0 M in THF, 7.0 mL, 7.0 mmol) was added to a stirred solution of dimethyl 5-fluoroisophthalate (3 g, 14.1 mmol) in THF (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was neutralized with 1.5 N HCl (50 mL) to pH ~7, and the reaction mixture was partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo to give methyl 3-fluoro-5-(hydroxymethyl)benzoate as a colorless liquid (1.12 g, 43%).

[0260] GCMS (Method 1): m / z 184.0 (ES+), at 7.34 min.

[0261] 1 H NMR: (400 MHz, DMSO-d6) δ: 7.79 (s, 1H), 7.55 (d, J=12.8 Hz, 1H), 7.43 (d, J=12.8 Hz, 1H), 5.49 (t, J=7.6 Hz, 1H), 4.58 (d, J=7.6 Hz, 2H), 3.87 (d, J=2.4 Hz, 3H).

[0262] Step 2. Dess-Martin periodinane (2.3 g, 5.54 mmol) was added to a solution of methyl 3-fluoro-5-(hydroxymethyl)benzoate (510 mg, 2.77 mmol) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by gradient flash column chromatography, eluting with 0-30% EtOAc in hexane to give methyl 3-fluoro-5-formylbenzoate as a white solid (410 mg, 81%).

[0263] GCMS (Method 1): m / z 182.0 (ES+), at 6.76 min.

[0264] 1 H NMR: (400 MHz, DMSO-d6) δ: 10.08 (d, J=2.4 Hz, 1H), 8.33 (d, J=1.6 Hz, 1H), 8.05-8.04 (m, 2H), 3.92 (s, 3H).

[0265] Step 3. DAST (0.44 mL, 3.37 mmol) was added to a solution of methyl 3-fluoro-5-formylbenzoate (410 mg, 2.25 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was neutralized with 10% NaHCO3 (20 mL) to pH ~7, and the reaction mixture was partitioned between water (100 mL) and DCM (50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-30% EtOAc in hexane to give methyl 3-(difluoromethyl)-5-fluorobenzoate as a colorless liquid (400 mg, 87%).

[0266] GCMS (Method 2): m / z 204.0 (ES+), at 2.36 min.

[0267] 1 H NMR: (400 MHz, DMS0-d6) δ: 7.99 (s, 1H), 7.89 (d, J=11.2 Hz, 1H), 7.80 (d, J=11.2 Hz, 1H), 7.35-6.98 (m, 1H), 3.91 (s, 3H).

[0268] Step 4. LiAlH4 (2.0 M in THF, 0.45 mL, 0.90 mmol) was added to a solution of methyl 3-(difluoromethyl)-5-fluorobenzoate (390 mg, 1.81 mmol) in THF (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with 1.5 N HCl (50 mL) to pH ~7 and then partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo to give (3-(difluoromethyl)-5-fluorophenyl)methanol as a colorless liquid (230 mg, 72%).

[0269] GCMS (Method 2): m / z 176.0 (ES+), at 6.36 min.

[0270] 1 H NMR: (400 MHz, DMSO-d6) δ: 7.39 (s, 1H), 7.32-7.29 (m, 3H), 5.46 (d, J=6.4 Hz, 1H), 4.57 (t, J=6.4 Hz, 2H).

[0271] Step 5. Thionyl chloride (3 mL, 43.2 mmol) was added to a solution of (3-(difluoromethyl)-5-fluorophenyl)methanol (170 mg, 0.96 mmol) in chloroform (10 mL) at room temperature, and the reaction mixture was heated at 65°C for 12 h. The reaction mixture was neutralized with 10% NaHCO3 (20 mL) to pH ~7, then partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo to give 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene as a colorless liquid (170 mg, crude). The crude product was used in the next step without further purification.

[0272] GCMS (Method 2): m / z 193.9 (ES+), at 2.25 min.

[0273] Preparation of intermediate compound 14 - 4-(3-(difluoromethyl)-5-fluorobenzyl)-2-hydrazinylpyridine

[0274]

[0275] Step 1. PdCl2(dppf) DCM (84 mg, 0.103 mmol) was added to a degassed solution of (2-fluoropyridin-4-yl)boronic acid (145 mg, 1.03 mmol), potassium carbonate (426 mg, 3.09 mmol), and 1-(chloromethyl)-3-(difluoromethyl)-5-fluorobenzene (intermediate 13, 200 mg, 1.03 mmol) in 1,4-dioxane (8 mL) / water (2 mL), and the resulting reaction mixture was heated at 110 °C for 16 h. The reaction mixture was partitioned between water (70 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-30% EtOAc in petroleum ether to give 2-fluoro-4-(3-fluoro-5-(difluoromethyl)benzyl)pyridine.

[0276] Step 2. Hydrazine hydrate (0.5 mL, 9.77 mmol) was added to a stirred solution of 2-fluoro-4-(3-fluoro-5-(difluoromethyl)benzyl)pyridine in IPA (10 mL), and the resulting reaction mixture was heated at 100°C for 48 h.

[0277] After completion of Step 2, the title compound (110 mg, crude) was isolated as a yellow gum by partitioning between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were washed with saturated brine (10 mL), dried (Na2SO4), and the solvent was removed in vacuo. The crude product was used in the next step without further purification.

[0278] LCMS (Method 3): m / z 267.9 (ES+), at 3.00 min.

[0279] Preparation of the intermediate compound 15-1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid

[0280]

[0281] Step 1. 4-(3-(difluoromethyl)-5-fluorobenzyl)-2-hydrazinylpyridine (intermediate 14, 1.0 g, 3.74 mmol) was added to a stirred solution of ethyl 2-methyl-4-oxo-4,5-dihydrofuran-3-carboxylate (intermediate 3, 0.638 g, 3.74 mmol) in ethanol (30 mL) at room temperature, followed by the addition of a catalytic amount of acetic acid (0.021 mL, 0.374 mmol), and the resulting reaction mixture was heated at 80 °C for 16 h. Upon cooling, the precipitated solid was filtered off, washed with EtOH (2×10 mL), and dried in vacuo to give ethyl 1-(4-(3-fluoro-5-(difluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylate.

[0282] Step 2. Lithium hydroxide monohydrate (0.756 g, 31.6 mmol) was added to a stirred solution of ethyl 1-(4-(3-fluoro-5-(difluoromethyl)benzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylate (1.95 g, 4.45 mmol) in THF (20 mL), MeOH (20 mL), and water (5 mL), and the resulting reaction mixture was stirred at room temperature for 16 h.

[0283] After completion of step 2, the title compound was isolated as a white solid by removing the solvent in vacuo, dissolving in water (50 mL), and acidifying with 2N HCl to pH ~2. The aqueous layer was extracted with EtOAc (4×50 mL). The combined organic layers were washed with saturated brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo.

[0284] LCMS (Method 2): m / z 392.0 (ES+), at 2.48 min.

[0285] 1H NMR: (300 MHz, DMSO-d6) δ: 8.40 (d, J=5.1 Hz, 1H), 7.74 (s, 1H), 7.45-7.41 (m, 2H), 7.32-7.30 (m, 2H), 7.03 (t, J=55.5 Hz, 1H), 4.92 (d, J=8.1 Hz, 2H), 4.18 (s, 2H), 2.38 (s, 3H). 2 exchangeable protons are not observed.

[0286] Preparation of intermediate compound 16 - 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide

[0287]

[0288] DIPEA (3.06 mL, 17.68 mmol) was added to a stirred solution of 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxylic acid (intermediate 15, 1.81 g, 4.42 mmol) and ammonium chloride (0.354 g, 6.63 mmol) in DMF (50 mL), then HATU (3.36 g, 8.84 mmol) was added and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by gradient flash column chromatography, eluting with 0-85% EtOAc in petroleum ether. The compound was dissolved in MeOH (35 mL) and heated to reflux. The resulting clear solution was allowed to cool to room temperature and kept undisturbed for 48 hours.The recrystallized solid was filtered, washed with MeOH (2×10 mL), and dried in vacuo to give 1-(4-(3-(difluoromethyl)-5-fluorobenzyl)pyridin-2-yl)-5-(hydroxymethyl)-3-methyl-1H-pyrazole-4-carboxamide.

[0289] LCMS (Method 2): m / z 391.0 (M+H)+ (ES+), at 1.88 min, 97%.

[0290] 1 H NMR: (400 MHz, DMSO-d6) δ: 8.44 (d, J=5.2 Hz, 1H), 7.78 (s, 1H), 7.53-7.50 (m, 1H), 7.46-7.43 (m, 3H), 7.37-7.31 (m, 2H), 7.03 (t, J=55.2 Hz, 1H), 5.64 (t, J=6.4 Hz, 1H), 4.91 (d, J=6.4 Hz, 2H), 4.20 (s, 2H), 2.37 (s, 3H).

[0291] GETTING EXAMPLES

[0292] Preparation of Example 1 - (4-carbamyl-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)methyl acetate

[0293] Scheme 2

[0294]

[0295] 1-[4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-pyridyl]-5-(hydroxymethyl)-3-methyl-pyrazole-4-carboxamide (intermediate 6, 100 mg, 0.24 mmol), acetic acid (0.03 ml, 0.49 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (93.89 mg, 0.49 mmol), and DMAP (59.84 mg, 0.49 mmol) were added to THF (10 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (40 ml) and water (40 ml). The organic layer was dried (MgSO4), and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (normal phase, [5.9 x 2.0 cm (10 g)], Biotage® SNAP KP-Sil - 50 µm irregular silica gel, 45 mL / min, [gradient 0%-100% ethyl acetate in isohexane], 0-100 psi).inch, [the residue was taken up in a small volume of DCM]) to give 2-(4-carbamoyl-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)methyl dihydrogen phosphate as a colorless solid (79 mg, 72%).

[0296] [4-carbamoyl-2-[4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-pyridyl]-5-methyl-pyrazol-3-yl]methyl acetate (53 mg, 0.1200 mmol) was dissolved in a minimal amount of near-boiling ethyl acetate. The solution was allowed to cool to room temperature and left overnight. The solvent was evaporated - the solid residue appeared crystalline. Drying in a vacuum oven for 3 h at 40 °C gave 2-(4-carbamoyl-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)methyl dihydrogen phosphate as a colorless crystalline solid (41 mg, 77%).

[0297] LCMS (Method 5): m / z 451.2. (M+H) + (ES+), at 4.11 min

[0298] 1H NMR: (400 MHz, CDCl3) d: 8.30 (d, J=6.8 Hz, 1H), 7.64 (s, 1H), 7.04-6.97 (m, 4H), 7.21-7.16 (m, 2H), 5.75 (s, 2H), 4.04 (s, 2H), 2.44 (s, 3H), 1.90 (s, 3H)

[0299] Preparation of Example 2 - (4-carbamoyl-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl) dihydrogen phosphate

[0300] Scheme 3

[0301]

[0302] Step 1-5-(bromomethyl)-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazole-4-carboxamide

[0303] 1-[4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-pyridyl]-5-(hydroxymethyl)-3-methyl-pyrazole-4-carboxamide (intermediate 6, 2500 mg, 6.12 mmol) was added to DCM (20 mL). Phosphorus tribromide (1.74 mL, 18.37 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (40 mL) and water (40 mL). The organic layer was dried (MgSO4) and the solvent was evaporated in vacuo. The residue was triturated with ether:isohexane (1:1, 25 mL) and the solid was filtered off, the solid was washed twice with ether:isohexane (1:1, 2×25 mL) to give 5-(bromomethyl)-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazole-4-carboxamide as a colorless solid (2200 mg, 76%).

[0304] LCMS (Method 4): m / z 471.2 ( 79 Br), 473.2 ( 81 Br) (M+H) + (ES+), at 1.66 min.

[0305] 1H NMR: (400 MHz, DMSO-d6) d: 8.40-8.32 (m, 1H), 7.82 (s, 1H), 7.56-7.27 (m, 6H), 5.30 (s, 2H), 4.15 (s, 2H), 2.34 (s, 3H).

[0306] Step 2 - dibenzyl((4-carbamoyl-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)methyl)phosphate

[0307] 5-(bromomethyl)-1-[4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-pyridyl]-3-methyl-pyrazole-4-carboxamide (2100 mg, 4.46 mmol), dibenzyl hydrogen phosphate (1487.88 mg, 5.35 mmol), and potassium carbonate (1231.79 mg, 8.91 mmol) were added to MeCN (10 mL). The reaction mixture was heated at 80°C for 2 h. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organics were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (normal phase, [5.9 x 2.0 cm (10 g)], Biotage® SNAP KP-Sil - 50 µm irregular silica gel, 50 mL / min, [gradient 0% to 5% MeOH in DCM], 0-100 psi / 7 bar, [residue loaded into a small volume of DCM]) to afford dibenzyl ((4-carbamoyl-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)methyl)phosphate as a colorless solid (2700 mg, 87%).

[0308] LCMS (Method 4): m / z 669.2 (M+H) + (ES+), at 1.81 min.

[0309] 1H NMR: (400 MHz, DMSO-d6) d: 8.22 (d, J=6.8 Hz, 1H), 7.53 (s, 1H), 7.24-7.10 (m, 12H), 6.96-6.93 (m, 1H), 6.88-6.86 (m, 1H), 5.74 (d, J=7.9 Hz, 2H), 4.79 (s, 4H), 4.05 (s, 2H), 2.41 (s, 3H). 2 exchangeable protons are not observed.

[0310] Step 3 - Example 2 (4-carbamoyl-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl) dihydrogen phosphate

[0311] Dibenzyl[4-carbamoyl-2-[4-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-2-pyridyl]-5-methyl-pyrazol-3-yl]methyl phosphate (2700.00 mg, 4.04 mmol) was dissolved in IPA (200 mL) and water (10 mL). Ammonium formate (2546.66 mg, 40.38 mmol) was added to the solution, and the solution was purged with nitrogen. Palladium on activated carbon (49.46 mg, 0.40 mmol) was added to the reaction mixture under a nitrogen atmosphere, and the mixture was heated at 75 °C for 2 h. The palladium catalyst was filtered off using a Biotage Isolute Celite 545 cartridge (2.5 g / 25 mL). The solvent in the initial solutions was evaporated in vacuum.The residue was purified by reversed-phase chiral chromatography using the following method: Instruments: Gilson Semi-preparative HPLC System - 321 Pump / 171 Diode Array Detector / GX-271 Liquid Handler; Column: Phenomenex Luna PFP 5 micron 30×100 mm; 12.5 min gradient, solvent A is acetonitrile, solvent B is 0.1% aqueous trifluoroacetic acid, gradient 30% A to 60% A over 12.5 min to give (4-carbamoyl-1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazol-5-yl) dihydrogen phosphate as a colorless solid (310 mg, 16%).

[0312] LCMS (Method 6): m / z 489.0 (M+H) + (ES+), at 2.64 min

[0313] 1 H NMR: (400 MHz, DMSO-d6) δ: 8.40 (d, J=6.8 Hz, 1H), 7.76 (s, 2H), 7.66-7.55 (m, 3H), 7.46 (s, 1H), 7.33 (s, 1H), 5.52 (d, J=7.9 Hz, 2H), 4.23 (s, 2H), 2.34 (s, 3H). No exchangeable protons are observed.

[0314] Other examples obtained using the above methods are detailed in Table 2. The skilled person can modify the methods if necessary, for example, by using protecting groups where necessary.

[0315]

[0316]

[0317]

[0318]

[0319] BIOLOGICAL ACTIVITY

[0320] Functional analysis of cAMP agonist GPR52

[0321] HEKf suspension cells were infected for 24 hours with 0.1% (v / v) human GPR52 expressing BacMam virus, a modified baculovirus designed to express mammalian genes. Following BacMam infection, cells were pelleted by centrifugation (335 g, 5 min), resuspended in cell freezing medium (Sigma), and frozen at -150°C until needed. On the day of the experiment, 25 nL of GPR52 compound dilutions prepared in DMSO were applied to proxy plates (PerkinElmer) using a LabCyte ECHO acoustic pipette. Frozen cells were thawed and resuspended in assay stimulation buffer (Cisbio) containing 0.5 mM 3-isobutyl-1-methylxanthine (IBMX, Sigma) to a density of 2000 cells per well. 10 µl of cells were added to assay plates using a Multidrop reagent combination dispenser (ThermoFisher) before centrifugation (1 min).Cells were incubated with the compounds at 37°C for 30 minutes before adding cAMP detection reagents (HiRange cAMP kit, Cisbio), which were prepared according to the manufacturer's instructions. Plates were shaken for 1 hour at room temperature before being read on a PHERAstar FS plate reader (BMG Labtech) using standard HTRF settings. HTRF coefficients were obtained by dividing the acceptor emission (665 nm) by the donor emission (620 nm) and multiplying by 10000. Data were normalized to DMSO (0%) and the maximal responses of 3-(2-(3-chloro-5-fluorobenzyl)benzo[b]thiophen-7-yl)-N-(2-methoxyethyl)benzamide (compound 7t in J. Med. Chem., 2014, 57, 5226) (100%) and fitted to a 4-parameter logistic fit to obtain pEC. 50 agonists and maximal responses, which are presented in Table 3 below. In addition, pharmacokinetic data for intermediate compound 6 are presented in the applicant's earlier application PCT / GB2021 / 050638 (see Example 39).

[0322]

[0323] Caffeine-induced locomotor activity in intermediate compound b rats

[0324] Caffeine, a non-selective adenosine receptor antagonist, is a psychostimulant that increases locomotor activity in rodents primarily through blockade of A receptors. 2А (Br. J. Pharmacol., 2000, 129, 1465). These receptors are densely expressed on the terminals of GABAergic striopallidal neurons of the indirect pathway of the basal ganglia, in which dopamine D2 receptors are coexpressed (J. Comp. Neurol., 1998, 401, 163; J. Comp. Neurol., 2001, 431, 331). Tonic activation of A receptors 2А reduces the affinity of D2 receptors to dopamine, and antagonism to A receptors 2Аfacilitates dopaminergic signaling (Curr. Pharm. Des., 2008, 14, 1468). A number of antipsychotic drugs have been shown to block caffeine-induced hyperlocomotion (Pharmacol. Biochem. Behav., 1994, 47, 89; Naunyn-Schmiedeberg's Arch. Pharmacol., 2016, 389, 11).

[0325] Male Sprague-Dawley rats (200-250 g) were housed in groups with a 12-hour light / dark cycle (lights on at 07:00) at an ambient temperature of 21 ± 2°C and with a standard pelleted diet and water ad libitum. Testing was performed during the light phase. On the day of the experiment, animals were habituated to the cages for determination of locomotor activity for 60 min. Rats were then orally administered the vehicle or intermediate 6 (0.1, 0.3, 1, and 3 mg / kg) and returned to the appropriate cage for determination of locomotor activity. Intermediate 6 was prepared in a vehicle of 10% DMAC, 10% solutol (Kolliphor HS15), and 80% water (v / v / v). Sixty minutes later, the animals were administered vehicle (saline) or caffeine (15 mg / kg) subcutaneously. Locomotor activity was assessed for 2 hours after caffeine administration.Data represent back-transformed means adjusted for differences between treatment groups in activity within 30 minutes prior to treatment with the test compound or vehicle (n=10-12). Analysis was performed using a general linear model with treatment, cohort, and treatment as factors. SEM was calculated from the residuals of the statistical model. Intermediate 6 was compared with caffeine using the Williams test.

[0326] As shown in Fig. 1, treatment with intermediate compound 6 caused a dose-dependent decrease in the caffeine-induced hyperlocomotor response, reaching statistical significance at doses of 1 and 3 mg / kg.

[0327] Pharmacokinetic profile of example 2

[0328] The systemic exposure of Example 2 and Intermediate 6 was evaluated in male Sprague-Dawley rats and male Beagle dogs following oral (oral, PO) administration of Example 2. Plasma concentration-time data (mean ± standard deviation) are detailed in Tables 4 and 5. Plasma concentrations of Example 2 were below the limit of quantification (1 ng / mL) at all time points in both rats and dogs, demonstrating no detectable oral bioavailability. Conversely, the mean maximum plasma concentrations (Cmax) of Intermediate 6 were 240 ng / mL and 1079 ng / mL in rats and dogs, respectively, demonstrating the conversion of Example 2 to Intermediate 6 and its in vivo bioavailability.

[0329] Methods:

[0330] Three male Sprague-Dawley rats (weighing 269-270 g) and three male Beagle dogs (weighing 7-10 kg) were orally administered a single dose of Example 2 using the dose and vehicle indicated in Table #. After dosing, blood samples were collected at several time points (pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours in both species, and additional samples at 32 hours and 48 hours in dog) by sequentially drawing blood from the jugular vein (rat) or cephalic vein (dog) and centrifuged to separate the plasma for quantitative bioanalysis of Example 2 and intermediate 6 by LC-MS / MS.

[0331]

[0332]

[0333] Solubility Example 2

[0334] This experiment was designed to evaluate the thermodynamic solubility of Example 2 in different biologically relevant media (fasting artificial intestinal juice (FaSSIF) pH 6.5, FaSSIF pH 6.5, and enzyme-free artificial gastric juice (SGF) pH 1.2).

[0335] A 10 mM stock solution of Example 2 in dimethyl sulfoxide (DMSO) was prepared. From the 10 mM stock solution, a 1 mM intermediate solution of Example 2 in DMSO was obtained. A 1 μM working solution of Example 2 was obtained by diluting the intermediate solution with a mobile phase solution (methanol: 2 mM ammonium acetate containing a suitable internal standard, carbamazepine). The working solution was serially diluted with the mobile phase solution to 8 linearity points to obtain standard solutions for constructing a calibration curve. The area of ​​each standard solution was analyzed by LCMS / MS. Normalized area values ​​were plotted against concentration to obtain a calibration equation.

[0336] Example 2 (1 mg) was added to 1 ml of each desired biorelevant medium (SGF without enzyme, pH 1.2, zero FaSSIF, pH 6.5, and FaSSIF pH 6.5) to achieve a theoretical concentration equivalent to 1 mg / ml.

[0337] The resulting solutions were then incubated on a RotoSpin shaker at 50 rpm for 4 hours at room temperature (25°C). After the incubation period, the contents were filtered through a 0.45 μm PVDF syringe filter (hydrophilic), and the filtrate was collected for LCMS / MS quantification. The filtrate was diluted with the mobile phase, and the area under the curve (AUC) of the diluted sample was then determined by LCMS / MS. Based on the AUC of the test sample, the corresponding concentration was calculated using a 6-8-point linear / calibration curve.

[0338] The solubility of Example 2 in various biorelevant media is shown in Table 6.

[0339]

[0340] Pharmacokinetic profile of intermediate compound 6

[0341] The pharmacokinetic profiles of intermediate 6 were evaluated in male Sprague-Dawley rats via intravenous (IV) delivery. The pharmacokinetic data (mean ± standard deviation) for intermediate 6 are detailed in Table 7.

[0342] Methods:

[0343] For pharmacokinetic analysis, three male Sprague-Dawley rats weighing 200 to 230 g were administered a single dose of intermediate 6 intravenously using the indicated dose, dose volume, and vehicle shown in Table 7. After dosing, blood samples were collected at multiple time points (pre-dose, 2 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, and 24 hours for intravenous administration) by sequentially collecting blood from the tail vein and centrifuged to separate plasma for LCMS / MS analysis. WinNonlin v8.2 statistical software (Pharsight Corporation, California, USA) was used to determine the pharmacokinetic parameters using non-compartmental analysis.

[0344] Brain penetration of intermediate compound 6

[0345] Plasma and brain exposure were assessed to evaluate the brain penetration of intermediate compound 6 after intravenous administration. The ratio of free concentrations in brain tissue to plasma (K p, uu ) was calculated as detailed in Table 7 after experimental determination of binding in rat plasma and brain homogenate. Methods:

[0346] To assess brain penetration, male Sprague-Dawley rats (n=3) were administered a single 1 mg / kg dose (formulated as 10% DMAC + 10% Solutol HS15 + 80% saline) intravenously. Ten minutes after dosing, the animals were sacrificed, and the brains were removed, homogenized with 2 volumes (w / v) of 50 mM sodium phosphate buffer (pH 7.4), and analyzed by LC-MS / MS. Blood samples were collected at the same time point via tail vein aspiration, centrifuged, and plasma was analyzed by LC-MS / MS.

[0347] To calculate the ratio of free concentrations in brain tissue and plasma (Kp, uu ), binding of test compound in rat plasma and brain homogenate was accomplished using rapid equilibrium dialysis (RED). Test compound prepared in DMSO (final 1 μM, 0.2% DMSO) was added to (i) undiluted plasma from male Sprague Dawley rats and (ii) rat brain tissue homogenized with 2 volumes (w / v) sodium phosphate buffer (pH 7.4) and dialyzed against phosphate buffer for 5 h at 37°C. After incubation, the contents of each plasma / brain and buffer reservoir were removed and mixed with equal volumes of control dialysis buffer or plasma / brain to maintain matrix similarity for the assay. The proteins were then precipitated by adding acetonitrile containing the analytical internal standard (which allowed the ratio of the test compound to the internal standard to be determined), centrifuged, and the supernatant removed for LC-MS / MS analysis. The unbound fraction (F u) in plasma and brain was calculated using the following formula and then used to adjust total plasma and brain concentrations to obtain K p, uu :

[0348] Bound fraction = (Total plasma or brain ratio) - (Total buffer ratio) / Total plasma or brain ratio

[0349] Unrelated Faction (F u , brain or plasma) = 1 - Bound fraction

[0350] For dilution correction in brain binding assay:

[0351] Undiluted F u ,brain = (1 / dilution factor) / ((1 / F u diluted)) - 1) + (1 / dilution factor)

[0352] Where the dilution factor = 4

[0353]

[0354] Brief description of figures

[0355] Fig. 1: The effect of acute treatment with intermediate compound 6 (0.1, 0.3, 1, and 3 mg / kg, p.o.) on caffeine-induced hyperlocomotor activity. Significant differences compared with caffeine are represented as *p<0.05, **p<0.01, ***p<0.001.

Claims

1. A compound of formula (1a) or (1b): or a pharmaceutically acceptable salt thereof, where: R 1 and R 2 independently represent H or C1-3 alkyl optionally substituted with OH; R 3 represents -P(O)OR 6 OR 7 or -COR 5 ; R 4 is a halogen or C 1-3 alkyl optionally substituted with 1-6 fluorine atoms; R 5 represents C 1-6 alkyl optionally substituted with 1-6 fluorine atoms; R 6 and R 7 independently represent H or C1-6alkyl, optionally substituted with 1-6 fluorine atoms; And R 8 , R 9 and R 10 independently represent H, halogen, or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms.

2. The compound according to item 1, where R 1 and R 2 both represent N.

3. The compound according to item 1 or 2, where R 4 represents C 1-3 alkyl.

4. The connection according to any one of paragraphs 1-3, where R 4 is methyl.

5. The connection according to any one of paragraphs 1-4, where R 8 , R 9 and R 10 independently selected from H, F, CHF2, and CF3.

6. A compound according to any one of paragraphs 1-5, where the group: represents:

7. A compound according to claim 1 or 2, which is a compound of formula (3): or a pharmaceutically acceptable salt thereof.

8. A connection according to any one of paragraphs 1-7, where R 3 is -PO3H2, or a pharmaceutically acceptable salt thereof.

9. The connection according to any one of paragraphs 1-7, where R 3 represents -COME.

10. The compound according to claim 1, which is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition having agonistic activity with respect to the G protein-coupled receptor 52 (GPR52), comprising an effective therapeutic amount of a compound as defined in any one of claims 1 to 10 and a pharmaceutically acceptable excipient.

12. The use of a compound according to any one of claims 1 to 10 in the treatment of a disease or disorder in which a G protein-coupled receptor 52 (GPR52) is involved, wherein the disease or disorder is selected from mental disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorder; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma- or stressor-related disorders; disruptive disorders, drive disorders or conduct disorders; sleep-wake pattern disorders;substance use disorders; addictive disorders; conduct disorders; hypofrontality; abnormalities of the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways; decreased striatal activity; cortical dysfunction; neurocognitive dysfunction, or conditions or symptoms related thereto.

13. Use of a composition according to claim 11 in the treatment of a disease or disorder involving a G protein-coupled receptor 52 (GPR52), wherein the disease or disorder is selected from mental disorders; neuropsychiatric disorders; neurodegenerative disorders; psychotic disorders; cognitive disorders; neurocognitive disorders; extrapyramidal disorders; movement disorders; motor disorders; hyperkinetic movement disorders; catatonia; mood disorders; depressive disorders; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorder; depressive disorders; hypothalamic disorders; pituitary disorders; prolactin-related disorders; trauma- or stressor-related disorders; disruptive disorders, drive disorders or behavioral disorders; sleep-wake patterns disorders; disorders associated with the use of psychoactive substances;addictive disorders; conduct disorders; hypofrontality; abnormalities of the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways; decreased striatal activity; cortical dysfunction; neurocognitive dysfunction, or conditions or symptoms associated therewith.

14. The use according to claim 12 or 13, wherein the disorder or symptom is selected from positive symptoms of schizophrenia, negative symptoms of schizophrenia, cognitive symptoms of schizophrenia, schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorders, autism spectrum disorders, psychosis, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, pituitary adenoma, prolactinoma, craniopharyngioma, Cushing's disease, diabetes insipidus, non-functioning tumors, obesity, post-traumatic stress disorder disorders (PTSD), akathisia and related movements, athetosis, ataxia, ballismus, hemiballismus, chorea, choreoathetosis, dyskinesia, tardive dyskinesia, dyskinesia,neuroleptic-induced, myoclonus, mirror movement disorder, paroxysmal kinesigenic dyskinesia, restless legs syndrome, seizures, stereotypic movement disorder, stereotypy, tic disorder, tremor, Wilson's disease, schizotypal personality disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance- or drug-induced psychotic disorder, delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal motor behavior, catatonia, major depressive disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, bipolar disorder and related disorders due to psychoactive substance or drug use, bipolar disorder and related disorders due to another medical condition, anxiety disorder,separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, agoraphobia, generalized anxiety disorder, substance- or medication-induced anxiety disorder, anxiety disorders due to another medical condition, delirium, major neurocognitive disorder, minor neurocognitive disorder, amnesia, dementia, dyspraxia, stereotypic movement disorder, post-stroke effect, dentatorubropallidolewisian atrophy, decreased emotional expression, evolution, alogia, and asociality.

15. The use according to claim 12 or 13, wherein the disorder or symptom is selected from positive symptoms of schizophrenia, negative symptoms of schizophrenia, cognitive symptoms of schizophrenia, schizophrenia, depression, attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, bipolar disorder, addiction / impulse control disorders, autism spectrum disorders, psychosis, neurocognitive disorder, delirium, anhedonia, agitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Tourette's syndrome, hyperprolactinemia, obesity and post-traumatic stress disorder (PTSD).

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