Substituted 3-phenoxyazetidin-1-yl-pyrazines with GPR52 agonist activity

Abstract

The present invention relates to substituted 3-phenoxyazetidin-1-yl-pyrazines of general formula (I), which are agonists of GPR52 and are useful in the treatment of central nervous system disorders and other diseases. The present invention also relates to 3-phenoxyazetidin-1-yl-pyrazines of general formula (I) for use as medicines, pharmaceutical compositions containing 3-phenoxyazetidin-1-yl-pyrazines of general formula (I), methods for preparing pharmaceutical compositions, and methods for preparing compounds according to the invention.

Description

[Technical field]

[0001] The present invention relates to substituted 3-phenoxyazetidin-1-yl-pyrazines of general formula (I) that are agonists of GPR52, useful for the treatment of central nervous system disorders and other disorders.The present invention also relates to 3-phenoxyazetidin-1-yl-pyrazines of general formula (I) for use as medicines, pharmaceutical compositions containing 3-phenoxyazetidin-1-yl-pyrazines of general formula (I) and methods for preparing pharmaceutical compositions, as well as methods for preparing compounds according to the invention. [Background technology]

[0002] Human GPR52 is a G protein-coupled receptor (GPCR). The highest expression levels in the human central nervous system (CNS) are found in the striatum (WO2016 / 176571). Lower, but significant, expression levels are found in many other structures of the CNS, including the cortex. GPR52 colocalizes almost exclusively with D2 receptors in the human and rodent striatum and almost exclusively with D1 receptors in the human and rodent cortex (WO2016 / 176571). D1 receptors are generally Gs-coupled, stimulating the production of the second messenger cAMP and the activity of PKA, whereas D2 receptors are generally Gi-coupled, negatively regulating the production of cAMP and decreasing the activity of PKA. Because GPR52 colocalizes with D1 receptors in the cortex and both GPR52 and D1 receptors are Gs-coupled, GPR52 agonists should be functionally similar to D1 agonists and therefore affect cortical function and frontal lobe hypofunction. Several compounds are known to function as D1 agonists in the cortex, improving cortical function and reversing frontal lobe hypofunction.

[0003] The efficacy of existing antipsychotic drugs has been reported to be mediated by D2 antagonist activity on medium spiny neurons (MSNs) in the striatum. However, D2 antagonists produce side effects such as motor symptoms and hyperprolactinemia. Because GPR52 almost exclusively colocalizes with D2 receptors in the striatum, and GPR52 is Gs-coupled and D2 is Gi-coupled, GPR52 agonists should be functionally similar to D2 antagonists and therefore exhibit antipsychotic efficacy. In addition, many of the side effects associated with D2 antagonists are mediated by D2 receptors, so GPR52 agonists may avoid the side effects associated with existing D2 antagonists. Based on expression patterns, colocalization, intracellular signaling, and functional properties, GPR52 is suggested to be a key regulator of brain function with therapeutic relevance for several neurological and psychiatric disorders, including those mentioned below.

[0004] (1) Frontal lobe dysfunction Reduced blood flow in the prefrontal cortex (frontal hypofunction) is a symptom of several neurological conditions, including the cognitive and negative symptoms associated with schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and frontal hypofunction associated with substance abuse. Dopaminergic transmission in the prefrontal cortex is primarily mediated by D1 receptors, and D1 dysfunction is associated with cognitive impairment and negative symptoms in schizophrenia (Goldman-Rakic ​​PS, Castner SA, Svensson TH, Siever LJ, Williams GV (2004) Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology 174, 3-16). Therefore, improving prefrontal cortex function with GPR52 agonists is useful for treating symptoms associated with frontal hypofunction.

[0005] (2) Movement disorder The striatum is involved in the control of movement. Pathologies of the striatum are associated with a number of movement disorders, including hyperkinetic disorders (also known as hyperkinesia), characterized by excessive, abnormal involuntary movements. Examples of hyperkinetic disorders include tremor, dystonia, chorea, ballismus, athetosis, Tourette's syndrome, Huntington's disease, myoclonus and startle syndrome, stereotypies, and akathisia.

[0006] In the striatum, GPR52 is expressed almost exclusively on striatal indirect pathway neurons. Hyperkinesia is associated with dysfunction of inhibitory D2-expressing neurons in this pathway. This dysfunction results in an inability to inhibit movements, resulting in tics, chorea, vocalization, tremor, and other hyperkinesia symptoms. For example, the early hyperkinesia symptoms of Huntington's disease are the result of selective damage to the indirect pathway, including D2 (Albin RL, Reiner A, Anderson KD, Penney JB, Young AB. (1990) Striatal and nigral neuron subpopulations in rigid Huntington's disease: implications for the functional anatomy of chorea and rigidity-akinesia. Ann Neurol. 27, 357-365). Furthermore, D2 receptor binding in the striatum is associated with the severity of Tourette syndrome (Wolf SS, Jones DW, Enable MB, Gorey JG, Lee KS, Hyde TM, Coppola R, Weinberger DR (1996) Tourette syndrome: prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding. Science 273, 1225- 1227).

[0007] Stimulating GPR52 with an agonist activates the indirect pathway in the striatum, providing more inhibitory control over movement and reversing hyperkinetic symptoms, and thus the GPR52 agonists disclosed herein are useful for treating such conditions.

[0008] (3) Psychotic disorder The psychotic symptoms of schizophrenia are due to excessive presynaptic dopamine activity in the striatum (Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III-the final common pathway. Schizophr Bull. 35, 549-562). The clinical effectiveness of existing antipsychotic drugs to treat psychotic symptoms depends on the blockade of D2 receptors. All known antipsychotic drugs that are effective in treating psychosis are either antagonists or partial agonists of dopamine D2 receptors (Remington G, Kapur S (2010) Antipsychotic dosing: how much but also how often? Schizophr Bull. 36, 900-903). While these antipsychotic drugs can treat the positive (or psychotic) symptoms of schizophrenia, they do not treat other aspects of schizophrenia, such as negative symptoms or cognitive impairment. Based on the co-expression of GPR52 and dopamine D2 receptor, GPR52 agonists should treat the psychotic symptoms associated with schizophrenia. In addition, the mechanism of action of GPR52 agonists is unique to known D2 receptor-related antipsychotics, so GPR52 agonists are expected to enhance the antipsychotic efficacy of known neuroleptics. This not only improves antipsychotic efficacy, but can also be used to reduce the dose of antipsychotics, thereby reducing the side effects associated with antipsychotics. While serum prolactin levels are elevated, one of the prominent side effect profiles of known D2R antagonist antipsychotics, GPR52 agonists have been demonstrated to reduce serum prolactin levels, and therefore the combination of GPR52 agonists and D2R antagonist antipsychotics may normalize serum prolactin levels, thereby reducing the side effects associated with D2R antagonist antipsychotics.GPR52 agonists should also treat psychotic symptoms associated with various psychiatric indications, such as schizoaffective disorder, schizophreniform disorder, schizophreniform disorder, treatment-resistant schizophrenia, medication-induced psychosis, bipolar disorder, autism spectrum disorder, and attenuated psychosis syndrome. In addition, GPR52 agonists should treat psychotic and neuropsychiatric symptoms associated with various neurodegenerative indications, such as Parkinson's disease, Alzheimer's disease, frontotemporal dementia, vascular cognitive impairment, and dementia with Lewy bodies. These antipsychotics are also associated with a significant side effect profile, such as weight gain, metabolic syndrome, diabetes, hyperlipidemia, hyperglycemia, insulin resistance, extrapyramidal symptoms, hyperprolactinemia, and tardive dyskinesia. As GPR52 agonists should be functionally similar to D2 antagonists, the GPR52 agonists disclosed herein are useful for the treatment of psychotic disorders.

[0009] (4) Other D1-related disorders Some neurotherapeutic and psychotherapeutic drugs are known to function as D1 agonists, including A-86929, dinapsoline, doxantrin, SKF-81297, SKF-82958, SKF-38393, fenoldopam, 6-Br-APB, and stefoloidin. Because GPR52 agonists should be functionally similar to (and co-localize with) D1 agonists, the GPR52 agonists disclosed herein are useful for treating disorders treatable by D1 agonists, including, but not limited to, addiction (e.g., cocaine addiction), hypertension, restless legs syndrome, Parkinson's disease, and depression. Based on their expression patterns and functional coupling, GPR52 agonists may also be useful in treating cognitive deficits associated with schizophrenia, schizoaffective disorder, schizophreniform and schizophreniform disorders, treatment-resistant schizophrenia, attenuated psychotic syndromes and autism spectrum disorders, bipolar disorder, Alzheimer's disease, Parkinson's disease, frontotemporal dementia (Pick's disease), dementia with Lewy bodies, vascular dementia, post-stroke dementia, and Creutzfeldt-Jakob disease.

[0010] (5) Other D2-related disorders Several neurotherapeutic and psychotherapeutic drugs are known to function as D2 antagonists, including atypical antipsychotics (e.g., aripiprazole, clozapine, olanzapine, and ziprasidone), domperidone, eticlopride, falpride, desmethoxyfalpride, L-741, 626, raclopride, hydroxyzine, itopride, SV 293, typical antipsychotics, yohimbine, amisulpride, and UH-232. Because GPR52 agonists should be functionally similar to D2 antagonists, the GPR52 agonists disclosed herein are useful for treating disorders treatable by D2 antagonists, including, but not limited to, psychotic disorders, estrangement, anxiety, anxiety / tension associated with psychoneurosis, acute mania, agitation, mania in bipolar disorder, dysthymia, nausea, vomiting, gastrointestinal disorders, dyspepsia, and addiction (e.g., cocaine addiction, amphetamine addiction, etc.). Therefore, GPR52 agonists are considered to be promising candidates for ameliorating diseases of the central nervous system. Compounds that modulate GPR52 have been previously disclosed in WO2009 / 157196; WO2009 / 107391, WO2011 / 078360, WO2011 / 093352, WO2011 / 145735, WO2012 / 020738, and WO2016 / 176571. Summary of the Invention

[0011] Objective of the invention It has now been found that the compounds of the present invention according to general formula (I) are potent agonists of GPR52. The compounds of the present invention are also particularly useful as pharmaceuticals since, in addition to other properties such as agonistic properties for GPR52 and low to moderate inhibition of the hERG channel, they are metabolized in an aldehyde oxidase-mediated metabolism, which contributes to overall metabolic diversification and subsequently results in a reduced risk of pharmacokinetic drug-drug interactions via cytochrome P450 enzymes.

[0012] The term "drug-drug interaction" refers to the effect of one drug on another, typically occurring when a drug affects the function or expression of metabolic enzymes or transporters. The most significant pharmacokinetic interactions are those in which a second drug alters the clearance of a first drug. For example, when a co-administered drug inhibits the metabolism of a drug, the plasma concentration of the first drug increases, which can result in a clinically relevant increase in therapeutic response or increased toxicity. Drug metabolism occurs primarily in the liver and intestine. These organs express a wide variety of drug-metabolizing enzymes and are responsible for the biotransformation of many drugs. Phase I oxidative metabolism occurs primarily by enzymes of the cytochrome P450 (CYP) family present in the hepatic endoplasmic reticulum, but can also be mediated by enzymes other than CYP, such as aldehyde oxidase. These functionalization reactions are often followed by conjugation reactions (phase II) to enhance the excretion of xenobiotics.

[0013] Cytochrome P450 (CYP) enzymes are considered the major enzyme family capable of catalyzing the oxidative biotransformation (phase I metabolism) of most drugs and other lipophilic xenobiotics (Zanger UM, Schwab M. (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. Apr; 138(1): 103-41), whereas aldehyde oxidase-mediated metabolism remains rare in marketed drugs to date (Scerny, MA. (2016) Prevalence of Non-Cytochrome P450-Mediated Metabolism in Food and Drug Administration-Approved Oral and Intravenous Drugs: 2006-2015. Drug Metab. Dispos. 44(8), 1246-1252). Therefore, expanding the metabolism of drugs to metabolic pathways other than CYPs, for example metabolism via aldehyde oxidase, would be advantageous to reduce the risk of adverse drug-drug interactions with much more common drugs that interact with CYPs.

[0014] In psychiatric clinical practice, combination drug therapy is commonly used to treat patients with psychiatric and physical disorders, to suppress side effects of certain drugs, or to increase drug efficacy. However, such polypharmacy approaches increase the risk of CYP-mediated drug-drug interactions. Therefore, it is desirable to use drugs with a low potential for drug interactions, especially for elderly patients who are likely to take multiple drugs simultaneously (Spina E, de Leon, J. (2007) Metabolic Drug Interactions with Newer Antipsychotics: A Comparative Review. Basic Clin. Pharmacol. Toxicol. 100, 4-22). Therefore, it is highly desirable to have a more diverse metabolism involving additional oxidative metabolic pathways that are non-CYP dependent, i.e., via aldehyde oxidase, which would subsequently result in a reduced risk of drug-drug interactions. In addition to their agonistic properties towards GPR52, the compounds of the present invention are metabolized by oxidative biotransformation via aldehyde oxidase as an important part of their overall oxidative metabolism, making them more viable for human therapy.

[0015] Inhibition of the hERG channel and subsequent delayed cardiac repolarization is associated with an increased risk of torsades de pointes, a specific polymorphic ventricular tachyarrhythmia, as documented by Sanguinetti et al. (1995, Cell, 81 (2): 299-307) and subsequent evidence. To minimize this risk, screening for hERG channel inhibition in in vitro systems using heterologous expression of the hERG channel is common practice and is an important part of late-stage preclinical profiling as recommended by ICH guideline S 7 B (International Conference on Harmonization (2005): ICH Topic S 7 B; The nonclinical Evaluation of the Potential for delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals). Thus, low hERG channel inhibition or interaction, as exhibited by the compounds of the present invention, is highly desirable. As a result, the compounds of the present invention are more viable for human therapy. Thus, one aspect of the present invention refers to compounds according to formula (I) or salts thereof as agonists of GPR52. Thus, one aspect of the present invention refers to compounds according to formula (I) or pharma- ceutically acceptable salts thereof, as agonists of GPR52.

[0016] Another aspect of the present invention refers to the compounds according to formula (I) or pharma- ceutically acceptable salts thereof as agonists of GPR52, which renders metabolism more diversified, including metabolic pathways dependent on enzymes other than CYP, and subsequently reduces the risk of drug-drug interactions mediated by CYP.

[0017] Another aspect of the present invention refers to the compounds according to formula (I), or pharma- ceutically acceptable salts thereof, as agonists of GPR52, which provide low to moderate inhibition of the hERG channel, thereby diversifying metabolism, including metabolic pathways dependent on enzymes other than CYP, and subsequently reducing the risk of CYP-mediated drug-drug interactions. In a further aspect, the present invention relates to a pharmaceutical composition comprising at least one compound according to formula (I) or a pharma- ceutically acceptable salt thereof, optionally together with one or more inert carriers and / or diluents.

[0018] A further aspect of the invention relates to a compound according to formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to formula (I) or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis and / or treatment of disorders associated with insufficient GPR52 activity.

[0019] Another aspect of the present invention relates to methods for preparing the compounds of the present invention. A further aspect of the invention relates to a compound according to formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to formula (I) or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis and / or treatment of diseases or conditions which may be affected by activation of GPR52, such as, for example, schizophrenia; positive symptoms associated with schizophrenia, schizoaffective disorder, schizophreniform and schizophreniform disorders, treatment-resistant schizophrenia, attenuated psychotic syndromes and autism spectrum disorders; augmented treatment of positive symptoms associated with schizophrenia; augmentation of antipsychotics to improve treatment of positive symptoms associated with schizophrenia or to reduce the dosage of antipsychotics and thereby reduce the side effects of antipsychotics; negative symptoms associated with schizophrenia, schizoaffective disorder, schizophreniform and schizophreniform disorders, treatment-resistant schizophrenia, attenuated psychotic syndromes and autism spectrum disorders; schizophrenia (CIAS), schizoaffective disorder, schizophreniform and schizophreniform disorders, treatment-resistant schizophrenia, attenuated psychotic syndromes and autism spectrum disorders; Affective disorders, schizophreniform and schizophreniform disorders, treatment-resistant schizophrenia, attenuated psychotic syndromes and cognitive disorders associated with autism spectrum disorders;treatment-resistant schizophrenia;schizoaffective disorder;schizophreniform disorders;schizophreniform disorders;medication-induced psychotic disorders;bipolar disorder;attenuated psychotic syndromes and neuropsychiatric symptoms associated with Alzheimer's disease, Parkinson's disease, vascular dementia and frontotemporal dementia;autism spectrum disorder (ASD);D2 receptor agonists and treatment of impulse control disorders induced by sedatives such as methamphetamine; gambling disorder induced by D2 receptor agonists, Tourette's syndrome; cognitive deficits associated with Alzheimer's disease, Parkinson's disease, vascular dementia, and frontotemporal dementia; depression; attention deficit hyperactivity disorder; major depressive disorder; drug addiction; anxiety; mania in bipolar disorder; acute mania; agitation; estrangement; and symptoms associated with frontal lobe hypofunction (e.g., frontal lobe hypofunction associated with substance abuse) and / or hyperactivity.

[0020] Other objects of the present invention will become apparent to those skilled in the art directly from the above and following description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] In a first aspect, the present invention provides a compound of general formula (I) or a salt thereof [ka] (In the formula, A is,

[0022] [ka] Group A consisting of a Selected from; R 1 is the group R consisting of H- and F- 1a Selected from; R 2 is the group R consisting of H- and F- 2a Selected from; R 3 is the group R consisting of halogen, F2HCO-, F3CO-, F2HC- and F3C- 3a Selected from; R 4 H- and C- 1-3 -alkyl- 4a is selected from Here, the above C 1-3 The -alkyl- group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine. Regarding. Unless otherwise stated, groups, residues and substituents, in particular A, R 1 , R 2 , R 3 and R 4 are defined as above and below. If residues, substituents or groups occur several times in a compound, they may have the same or different meanings. Some preferred meanings of groups and substituents of the compounds according to the invention are set out below.

[0023] In a further embodiment of the invention, A is [ka] Group A consisting of b is selected from.

[0024] In a further embodiment of the invention, R 3 is a group R consisting of F-, Cl- and F2HC- 3b is selected from. In a further embodiment of the invention, R 3 is a group R consisting of F- 3c is selected from.

[0025] In a further embodiment of the invention, R 4 , H-, C 1-2 The group R consists of -alkyl- and F3C- 4b is selected from. In a further embodiment of the invention, R 4 is C 1-2 -alkyl- 4c is selected from.

[0026] A x , R 1x , R 2x , R 3x and R 4x Each of the terms A represents an individual embodiment characterized with respect to the corresponding substituents as described above. Thus, given the above definitions, individual embodiments of the first aspect of the invention are x , R 1x , R 2x , R 3x and R 4x ), where for each subscript x, a particular letter is defined ranging from "a" to the last alphabetical such letter. With reference to the above definition, all particular embodiments described by the term in brackets with the subscript x substituted for it are intended to constitute the present invention.

[0027] The following Table 1 shows embodiments E-1 to E-18 of the present invention which are considered to be preferred. The embodiment E-18 shown in the last row of Table 1 is the most preferred embodiment. [Table 1]

[0028] Thus, for example, E-2 is a compound of formula (I) or a salt thereof (In the formula, A is, [ka] Group A consisting of a Selected from; R 1 is the group R consisting of H- and F- 1a Selected from; R 2 is the group R consisting of H- and F- 2a Selected from; R 3 is the group R consisting of halogen, F2HCO-, F3CO-, F2HC- and F3C- 3a Selected from; R 4 , H-, C 1-2 The group R consists of -alkyl- and F3C- 4b (selected from Includes:

[0029] Thus, for example, E-10 is a compound of formula (I) or a salt thereof (In the formula, A is, [ka] Group A consisting of b Selected from; R 1 is the group R consisting of H- and F- 1a Selected from; R 2 is the group R consisting of H- and F- 2a Selected from; R 3 is the group R consisting of halogen, F2HCO-, F3CO-, F2HC- and F3C- 3a Selected from; R 4 H- and C- 1-3 -alkyl- 4a is selected from Here, the above C1-3 The -alkyl- group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine. Includes:

[0030] Thus, for example, E-18 is a compound of formula (I) or a salt thereof (In the formula, A is, [ka] Group A consisting of b Selected from; R 1 is the group R consisting of H- and F- 1a Selected from; R 2 is the group R consisting of H- and F- 2a Selected from; R 3 is a group R consisting of F- 3c Selected from; R 4 is C 1-2 -alkyl- 4c (selected from Includes:

[0031] More preferred are the following compounds shown in Table 2: [Table 2] TIFF0007617134000009.tif249149 TIFF0007617134000010.tif248150 TIFF0007617134000011.tif248152 TIFF0007617134000012.tif249151 TIFF0007617134000013.tif190151

[0032] Further embodiments of the present invention include the compounds set forth in Table 2 in the form of pharma- ceutically acceptable salts thereof. In a further aspect, the present invention relates to a compound of the present invention, or a pharma- ceutically acceptable salt thereof, for use as a medicament. In the following, some of the terms used above and below to describe the compounds according to the invention are defined in more detail. Terms not specifically defined herein should be given the meaning that one of ordinary skill in the art would give to such terms, given this disclosure and its context. However, as used herein, unless otherwise indicated, the following terms have the meanings indicated and the following conventions are observed.

[0033] In the groups, radicals or moieties defined below, the number of carbon atoms is often specified before the group, e.g., C 1-6 -alkyl means an alkyl group or alkyl radical having 1 to 6 carbon atoms. Generally, in groups containing two or more subgroups, the last named subgroup is the point of attachment of the radical, e.g., the substituent "aryl-C 1-3 -Alkyl-" is C 1-3 an aryl group attached to an -alkyl- group, the latter of which is C 1-3 -Alkyl groups refer to groups that are attached to a core molecule or group. In general, the site of attachment of a given residue to another group is intended to be variable, i.e., unless otherwise specified, any available atom in the residue having a hydrogen to be replaced may be the point of attachment to the attached group. When a compound of the invention is depicted in the form of a chemical name and as a formula, in the event of any discrepancy the formula shall prevail. A dashed line ------- is used in a subformula to indicate a bond or point of attachment that is connected to a core molecule that is the remainder of the molecule, or to a substituent that is attached as defined. The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0034] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. Pharmaceutically acceptable salts include, but are not limited to, for example, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Such salts include, for example, salts derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0035] Pharmaceutically acceptable salts can also be formed with cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane.

[0036] The pharma- ceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. For example, salts of other acids (eg, trifluoroacetates) that are useful in purifying or isolating the compounds of the invention also form part of this invention.

[0037] As used herein, the term "substituted" means that any one or more hydrogens on the specified atom / group are replaced with one selected from the indicated group, so long as the possible valences of the specified atom are not exceeded and the substitution results in a stable compound. The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The term “C 1-n "-alkyl" (where n is an integer from 2 to n), either alone or in combination with another radical, denotes an acyclic, saturated, branched or straight-chain hydrocarbon radical having 1 to n C atoms. For example, the term "C 1-5 "-alkyl" encompasses the radicals HC-, HC-CH2-, HC-CH2-CH2-, HC-CH(CH3)-, HC-CH2-CH2-CH2-, HC-CH2-CH(CH3)-, HC-CH(CH3)-CH2-, HC-C(CH3)2-, HC-CH2-CH2-CH2-CH2-, HC-CH2-CH2-CH(CH3)-, HC-CH2-CH(CH3)-CH2-, HC-CH2-CH(CH3)-CH2-, HC-CH(CH3)-CH2-CH2-CH2-, HC-CH2-C(CH3)2-, HC-C(CH3)2-CH2-, HC-CH(CH3)-CH(CH3)-CH2-CH2-, and HC-CH2-CH(CH2CH3)-. Many of the above defined terms may be used repeatedly in the definition of a formula or a group and may in each case have, independently of one of the above meanings.

[0038] The compounds according to the invention can be obtained using synthetic methods known in principle.Preferably, the compounds are obtained according to the invention by the following methods, which are described in more detail below. preparation The following schemes are intended to generally illustrate, by way of example, how to prepare the compounds of the invention. Omitted substituents may be as defined above, unless otherwise defined within the context of the scheme. General synthesis method The present invention also provides a method for preparing a compound of formula (I). 1 , R 2 , R 3 , R 4 and ring A has the meaning as defined for formula (I) in the detailed description of the invention above. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions can be readily selected by those skilled in the art. Specific procedures are shown in the synthetic examples section. In general, reaction progress can be monitored by thin layer chromatography (TLC) and, if desired, liquid chromatography-mass spectrometry (LC-MS), and intermediates and products can be purified by chromatography and / or recrystallization.

[0039] The following examples are illustrative, and one of skill in the art will recognize that specific reagents or conditions can be modified as necessary for individual compounds without undue experimentation. The starting materials and intermediates used in the methods described below are either commercially available or readily prepared from commercially available materials by one of ordinary skill in the art.

[0040] [ka] Scheme 1 shows the synthesis of amines (V) as intermediates in the synthesis of compounds (I). In a first step, a suitably protected (PG is a protecting group, e.g., CO2tBu, CO2Bn) and suitably activated (sulfonyl ester substituent R, e.g., methyl, CF3 or tolyl) azetidine (II) is reacted with a phenol (III) using a suitable solvent, such as dimethylacetamide, dimethylformamide, N-methyl-pyrrolidinone, acetonitrile, DMSO, dichloromethane, toluene, and a suitable base, such as cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium hydroxide, N-ethyl-diisopropylamine, pyridine, to produce 3-phenoxyazetidine (IV). This intermediate is deprotected in a second step to give amine (V). Deprotection can be carried out, for example, with a mineral acid such as hydrochloric acid for the BOC-protected intermediate (IV) or by catalytic hydrogenation under hydrogen atmosphere using a catalyst such as palladium on charcoal for the benzyloxycarbonyl-protected intermediate (IV). Other deprotection reactions are described in 'Protective Groups in Organic Synthesis', 3' edition, TW Greene and PGM Wuts, Wiley-Interscience (1999). Depending on the reaction conditions and workup, the amine (V) may be obtained as a salt.

[0041] [ka] As shown in Scheme 2, amines of formula (V) can be reacted with haloesters (VI) (X=halide, R x= alkyl) in an aromatic nucleophilic substitution reaction (step 1) to give the ester compound of formula (VII). Compound (VII) can also be produced using Buchwald-Hartwig type cross-coupling conditions. For example, compound (IV) (X = Cl, Br, I, R x = alkyl) can be reacted with amine (V) in the presence of a suitable catalyst such as palladium (II) acetate, a suitable ligand such as butyl-di-1-adamantyl-phosphine, and a suitable base such as cesium carbonate in a suitable solvent such as toluene to give compounds of general formula (VII).

[0042] Alternatively, the haloester (VI) can be reacted with hydroxyazetidine in an aromatic nucleophilic substitution reaction in the presence of a suitable base such as triethylamine in a suitable solvent such as DMA to give the alcohol of general formula (VIII). In a next step, the alcohol (VIII) can be converted to a phenyl ether compound of formula (VII) using the "Mitsunobu" method (see, for example, Tet. Lett. 1994, 35, 2819 or Synlett 2005, 18, 2808): a trialkylphosphine or triarylphosphine (such as, for example, tributylphosphine or triphenylphosphine) or a solid-supported analog such as polymer-bound triphenylphosphine and a suitable dialkylazadicarboxylate (such as, for example, DIAD, DEAD) is added to the compound of general formula (VIII) in the presence of a suitable phenol (III) in a suitable solvent (such as, for example, THF or toluene) to give the aryl ether of general formula (VII).

[0043] [ka] The preparation of compounds of general formula (I) is shown in Scheme 3. In the first step, the carboxylic acid ester (VII) can be hydrolyzed and acidified with a suitable hydroxide base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc.) in a solvent / water mixture such as acetone / water, 1,4-dioxane / water, THF / water to generate the corresponding carboxylic acid (IX).

[0044] Peptide coupling reactions known to those skilled in the art (see, for example, M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) can be applied to react amines of formula (X) with carboxylic acids (IX) to give compounds of general formula (I). For example, treatment of amine (X) and carboxylic acid (IX) with coupling agents 2-chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium hexafluorophosphate (CIP), Mukaiyama's reagent, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) in a suitable solvent such as acetonitrile, NMP, DMA or DMF in the presence of a suitable base such as DIPEA or 1-methylimidazole will produce compounds of formula (I).

[0045] Alternatively, treatment of carboxylic acid (IX) with 1-chloro-N,N-2-trimethylpropenylamine, thionyl chloride or oxalyl chloride in a suitable solvent such as DCM, DMF or toluene gives the intermediate acid chloride which is subsequently treated with an amine of formula (X) in the presence of a suitable base such as TEA in a suitable solvent such as, for example, DCM, THF or DMF to give the compound of formula (I).

[0046] Alternatively, amines (X), pre-activated with trimethylaluminum, can be reacted directly with carboxylic esters (VII) in a suitable solvent such as DCM, dichloroethane, THF or toluene to give amides of general formula (I).

[0047] [ka] Alternatively, compounds of general formula (I) can be synthesized as shown in scheme 4: peptide coupling reactions known to those skilled in the art (see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) can be applied in a first step to react amines of formula (X) with carboxylic acids (XI) (X=halide, Y=OH) to give haloamides of general formula (XII) (X=halide). For example, treatment of amines (X) and carboxylic acids (XI) (X=halide, Y=OH) with coupling agents 2-chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium hexafluorophosphate (CIP), Mukaiyama's reagent, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) in a suitable solvent such as acetonitrile, NMP, DMA or DMF in the presence of a suitable base such as DIPEA or 1-methyl-imidazole, affords haloamides of general formula (XII) (X=halide). Alternatively, carboxylic acids (XI) (X=halide, Y=OH) can be treated with 1-chloro-N,N-2-trimethylpropenylamine, thionyl chloride or oxalyl chloride in a suitable solvent such as DCM, DMF or toluene to give intermediate acid chlorides (XI) (Y=Cl), which are subsequently treated with amines of formula (X) in the presence of a suitable base such as TEA in a suitable solvent such as DCM, THF or DMF to give haloamides of general formula (XII) (X=halide). Alternatively, amines (X) preactivated with trimethylaluminum can be reacted directly with carboxylic esters (XI) (X=halide, Y=alkyloxy) in a suitable solvent such as DCM, dichloroethane, THF or toluene to give haloamides of general formula (XII) (X=halide).

[0048] In the second step, the amine of formula (V) is reacted with haloamide (XII) (X=halide) in an aromatic nucleophilic substitution reaction in the presence of a suitable base such as potassium tert-butoxide, NaH, potassium carbonate, pyridine, triethylamine or N-ethyl-diisopropylamine in a suitable solvent such as 2-propanol, dioxane, THF, NMP, DMA, DMF or toluene / water mixture to give compounds of general formula (I). Alternatively, Buchwald-Hartwig type cross-coupling conditions may be used to generate the final compound (I). For example, compound (XII) (X=Cl, Br, I) can be reacted with amine (V) in the presence of a suitable catalyst such as palladium(II) acetate, a suitable ligand such as butyl-di-1-adamantyl-phosphine and a suitable base such as cesium carbonate in a suitable solvent such as toluene to give compounds of general formula (I).

[0049] Alternatively, the haloamide (XII) may be reacted with hydroxyazetidine in an aromatic nucleophilic substitution reaction in the presence of a suitable base such as triethylamine in a suitable solvent such as DMA to give the alcohol of general formula (XIII). In a next step, the alcohol (XIII) may be converted to a compound of general formula (I) using the "Mitsunobu" method (see, for example, Tet. Lett. 1994, 35, 2819 or Synlett 2005, 18, 2808): a trialkylphosphine or triarylphosphine (such as tributylphosphine or triphenylphosphine) or a solid-supported analog such as polymer-bound triphenylphosphine and a suitable dialkylazadicarboxylate (such as DIAD, DEAD) are added to the compound of general formula (XIII) in the presence of a suitable phenol (III) in a suitable solvent (such as THF or toluene) to produce the compound of general formula (I).

[0050] Biological Examples A homogeneous time-resolved fluorescence (HTRF) assay for the direct measurement of cAMP HTRF cAMP assays were performed using a commercially available assay kit (cAMP Dynamic 2 Assay Kit; #62AM4PEJ, Cisbio Bioassays, Bedford, MA) according to the manufacturer's instructions. An aliquot of CHO-K1 cells stably expressing recombinant human GPR52 was thawed and diluted with cell buffer (1× PBS (w / o Ca)). 2+ / Mg 2+ )) at a density of 4 x 105 cells per mL. Test compounds were dissolved in DMSO to a stock solution of 10 mM and serially diluted in DMSO using 6-fold dilutions to generate 8-point dose-response curves. These serially diluted samples were then diluted in compound dilution buffer (1x PBS (w / o Ca 2+ / Mg 2+ ), 0.5 mM IBMX, 0.1% BSA) to obtain a 4× stock. The diluted compounds were transferred in duplicate (5 μL per well) to a 384-well assay plate (Optiplate #6007290, PerkinElmer, Waltham, MA). Both a positive control (reference compound) and a negative control (non-stimulating vehicle) are included in column 23 of each assay run. The cell suspension was then dispensed at 15 μL (6000 cells) per well into the 384-well assay plate such that the compounds were diluted to 1×. Column 24 of the plate did not contain cells and was reserved for the cAMP standard curve. After 1 hour of incubation at room temperature, 10 μL of cAMP D2 reagent was added to each well, followed by 10 μL of Cryptate reagent (provided in the Cisbio kit). The plate was then incubated at room temperature for 1 hour before reading. Time-resolved fluorescence measurements were collected on an EnVision® HTRF plate reader (PerkinElmer, Waltham, Mass.). Counts from the plate reader were fitted to a cAMP standard curve included on each plate to determine the amount of cAMP in each test well. Percent control (%) was calculated by setting the positive control to 200% and the negative control to 100%. Dose-response curves were generated from the cAMP data and analyzed using a nonlinear least-squares curve-fitting program to determine the EC 50 The value was obtained. EC50 The average values ​​are shown in Table 3.

[0051] [Table 3]

[0052] In vitro metabolite profiling In vitro metabolite profiling to assess the involvement of aldehyde oxidase in addition to CYP-mediated metabolic pathways was based on semiquantitative analysis of the formation of oxygenated metabolites in primary human hepatocytes and their reduction in the presence of the specific aldehyde oxidase inhibitor hydralazine. If the respective hydralazine-inhibitable metabolites were also formed in incubations with human liver cytosol in the absence of any cofactors, then it was highly likely that aldehyde oxidase was involved in the metabolism of the respective compound.

[0053] Primary human hepatocytes in suspension were used to investigate the involvement of aldehyde oxidase in the metabolic conversion of test compounds in the presence or absence of the specific aldehyde oxidase inhibitor hydralazine. After recovery from cryopreservation, human hepatocytes were incubated in Dulbecco's modified Eagle's medium containing 5% human serum and supplemented with glucagon 3.5 μg / 500 ml, insulin 2.5 mg / 500 ml, and hydrocortisone 3.75 mg / 500 ml.

[0054] After preincubation for 30 min in the presence or absence of 50 μM hydralazine in a cell culture incubator (37 °C, 10% CO2), the final cell density was 1.0 × 10 cells. 6 ~4.0×10 6 Test compound solutions are added to the hepatocyte suspension to give cells / ml (depending on the compound turnover rate observed in primary human hepatocytes), a final test compound concentration of 1 μM, and a final DMSO concentration of 0.05%. Cells are incubated (incubator, horizontal shaker) for 6 h and samples are removed from the incubator after 0, 0.5, 1, 2, 4 or 6 h depending on turnover rate. Samples are quenched with acetonitrile and pelleted by centrifugation. Supernatants are transferred to 96 deep-well plates, evaporated under nitrogen and resuspended before bioanalysis by liquid chromatography-high resolution mass spectrometry to identify putative metabolites.

[0055] Pooled human liver cytosol fractions are used to confirm the involvement of aldehyde oxidase in the metabolic transformation of test compounds at 37°C. Incubations, performed in a final incubation volume of 60 μl per time point, consist of phosphate buffer (100 mM, pH 7.4), magnesium chloride (5 mM) and human liver cytosol (5 mg / ml). After a short preincubation period at 37°C, the reaction is started by adding the test compound to a final concentration of 10 μM. After 0 and 60 min, the incubation is terminated by transferring aliquots to organic solvent, followed by centrifugation (10000 g, 5 min). The resulting supernatant is used for bioanalysis by liquid chromatography-high resolution mass spectrometry to identify putative metabolites.

[0056] [Table 4] TIFF0007617134000020.tif54170

[0057] hERG (human delayed rectifier potassium ion channel gene) channel assay Compounds of the invention can be examined for hERG channel inhibition as follows.

[0058] cell: HEK (human embryonic kidney) 293 cells are stably transfected with hERG cDNA. Cells determined to be used for patch clamp experiments are cultured without antibiotics.

[0059] Pipettes and solutions: The cells are perfused with a bath solution containing NaCl (137), KCl (4.0), MgCl2 (1.0), CaCl2 (1.8), glucose (10), and HEPES (10) (in mM in parentheses), pH 7.4 with NaOH. Patch pipettes are made from borosilicate glass tubing using a pipette and filled with pipette solution containing K-aspartate (130), MgCl2 (5.0), EGTA (5.0), K2ATP (4.0), and HEPES (10.0) (in mM in parentheses), pH 7.2 with KOH. The resistance of the microelectrode is typically in the range of 2-5 MΩ.

[0060] Stimulation and recording: Membrane currents are recorded using an EPC-10 patch clamp amplifier (HEKA Electronics, Lambrecht, FRG) and PatchMaster software (HEKA). Recordings of hERG-mediated membrane currents are typically performed at 28° C. using the whole-cell configuration of the patch clamp technique. Transfected HEK293 cells are clamped at a holding potential of −60 mV and hERG-mediated inactivation tail currents are evoked using a fixed amplitude pulse pattern (activation / inactivation: 2000 ms at 40 mV; recovery: 2 ms at 120 mV; ramp to 40 mV in 2 ms; inactivation tail current: 50 ms at 40 mV), repeated at 15 s intervals. For the P / n leak subtraction procedure, 4 pulses are recorded during each pulse interval, scaled down by a factor of 0.2. Rs correction is performed below a level that can be safely recorded without ringing. The remaining uncorrected Rs is recorded together with the actual temperature and holding current.

[0061] Compound preparation and application: Concentrations of the test article are applied sequentially to each of the various cells investigated. Before applying the first test article concentration, the steady level of the baseline current is measured for at least five sweeps. Dissolve the test article in DMSO to obtain a stock solution 1000 times the highest final concentration. Further dilute this stock in DMSO to obtain a stock solution 1000 times the remaining final concentration. Prepare the final dilutions in extracellular buffer fresh from these stocks, each in 1:1000 dilution steps, before starting the experiment.

[0062] Data Analysis: Peak current amplitudes are measured 3 ms after the ramp to +40 mV. For each concentration and baseline, peak currents of the last three sweeps before the next concentration is applied are averaged. Residual currents (I / I0) are calculated for each cell as the percentage of the actual mean peak current to the baseline mean peak current. Current inhibition is expressed as (1-I / I0) x 100%. Current inhibition for all cells is reported as the mean ± standard deviation (SD). When possible, IC50s are estimated from the mean current inhibition data using least squares fitting based on the Hill equation. In view of the ability of the compounds of general formula (I) according to the invention to activate GPR52, to inhibit the hERG channel to a low / moderate extent and to render the metabolism more diverse with a subsequent reduced risk of CYP-mediated drug-drug interactions, the compounds of general formula (I) according to the invention, or their physiologically acceptable salts, are suitable for the therapeutic and / or prophylactic treatment of all diseases or conditions that may be affected by the activation of GPR52.

[0063] The compounds according to the invention, including the physiologically acceptable salts thereof, are therefore particularly suitable for the prevention or treatment of diseases, in particular schizophrenia; positive symptoms associated with schizophrenia; enhanced treatment of positive symptoms associated with schizophrenia; augmentation of antipsychotics to improve the treatment of positive symptoms associated with schizophrenia or to reduce the dosage of antipsychotics and thereby reduce the side effects of antipsychotics; negative symptoms associated with schizophrenia; cognitive impairment associated with schizophrenia (CIAS); treatment-resistant schizophrenia; schizoaffective disorder; schizophreniform disorder; schizophreniform disorder; medication-induced psychosis; bipolar disorder; Alzheimer's disease, Parkinson's disease, vascular It is suitable for the treatment of attenuated psychotic syndromes and neuropsychiatric symptoms associated with dementia and frontotemporal dementia; autism spectrum disorder (ASD); impulse control disorders induced by D2 receptor agonists; gambling disorder induced by D2 receptor agonists; Tourette's syndrome; cognitive deficits associated with Alzheimer's disease, Parkinson's disease, vascular dementia and frontotemporal dementia; depression; attention deficit hyperactivity disorder; major depressive disorder; drug addiction; anxiety; mania in bipolar disorder; acute mania; agitation; estrangement; and symptoms associated with frontal lobe hypofunction (e.g. frontal lobe hypofunction associated with drug abuse) and / or hyperkinetic symptoms.

[0064] The compounds according to the invention are also particularly suitable as combination drugs with neuroleptics currently prescribed to treat the positive symptoms associated with schizophrenia, which may result in not only improved antipsychotic efficacy but also, in combination with reduced doses of neuroleptics, reduced associated side effects such as weight gain, metabolic syndrome, diabetes, extrapyramidal symptoms, hyperprolactinemia, insulin resistance, hyperlipidemia, hyperglycemia and tardive dyskinesia. In particular, elevated serum prolactin levels are a prominent side effect profile of neuroleptics, whereas activators of GPR52 have been demonstrated to reduce serum prolactin levels, and thus the combination of a GPR52 agonist with a neuroleptic may normalize serum prolactin levels and thus reduce the side effects associated with neuroleptics.

[0065] Preferably, the compounds according to the invention are suitable for the prevention or treatment of schizophrenia; positive symptoms associated with schizophrenia; enhanced treatment of positive symptoms associated with schizophrenia; augmentation of antipsychotics to improve the treatment of positive symptoms associated with schizophrenia or to reduce the dosage of antipsychotics and thereby reduce the side effects of antipsychotics; negative symptoms associated with schizophrenia; cognitive impairment associated with schizophrenia (CIAS); treatment-resistant schizophrenia; schizoaffective disorder; schizophreniform disorder; schizophreniform disorder; medication-induced psychotic disorders; bipolar disorder; attenuated psychotic syndromes and neuropsychiatric symptoms associated with Alzheimer's disease, Parkinson's disease, vascular dementia and frontotemporal dementia; autism spectrum disorder (ASD); impulse control disorders induced by D2 receptor agonists; and gambling disorder induced by D2 receptor agonists. In a further aspect, the present invention relates to a method for the treatment or prevention of the above mentioned diseases and conditions, said method comprising administering to a human an effective amount of a compound of general formula (I) or a pharma- ceutically acceptable salt thereof.

[0066] The applicable daily dosage range of the compounds of formula (I) is orally usually 0.1-1000 mg, preferably 1-500 mg, administered in each case 1-4 times per day. Each dosage unit may contain 0.1-500 mg, preferably 1-100 mg, for ease of handling. Of course, the actual pharmacologic or therapeutic dose will depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the combination will be administered at a dosage and in a manner that allows for the delivery of a pharmacologic effective amount based on the patient's unique condition. Suitable formulations for administering the compounds of formula I (including pharma- ceutically acceptable salts thereof) will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, liquids, syrups, elixirs, sachets, injections, inhalants, powders, etc. The content of the pharma- ceutical active compound should be in the range of 0.1-95% by weight, preferably 5.0-90% by weight, based on the total composition.

[0067] Suitable tablets can be obtained, for example, by mixing one or more compounds according to formula I with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. Tablets may also consist of several layers. For this purpose, the compounds of formula I prepared according to the present invention, optionally together with other active substances, can be formulated with one or more conventional inert carriers and / or diluents, for example, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, citric acid, tartaric acid, water, polyvinylpyrrolidone, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose, or fatty substances such as hard fats, or suitable mixtures thereof.

[0068] The compounds according to the invention can also be used in combination with other active substances, in particular for the treatment and / or prevention of the above-mentioned diseases and conditions. Other active substances suitable for such combinations include, for example, BACE inhibitors; amyloid aggregation inhibitors (e.g. ELND-005); directly or indirectly acting neuroprotectants and / or disease modifiers; antioxidants (e.g. vitamin E or ginkgolides); anti-inflammatory substances (e.g. Cox inhibitors, NSAIDs with additionally or exclusively amyloid-β lowering properties); HMG-CoA reductase inhibitors (statins); acetylcholinesterase inhibitors (e.g. donepezil, rivastigmine, tacrine, galantamine); NMDA receptor antagonists (e.g. memantine, ketamine, esketamine, NR2b antagonists); AMPA receptor agonists; positive regulators of the AMPA receptor, ampakines (AMPAkins, etc.). e), monoamine receptor reuptake inhibitors, substances that modulate the concentration or release of neurotransmitters; growth hormone secretion inducers (e.g., ibutamoren mesylate and capromorelin); CB-1 receptor antagonists or inverse agonists; antibiotics (e.g., minocycline or rifampicin); PDE2, PDE4, PDE5, PDE9, PDE10 inhibitors, GABAA receptor agonists or positive regulators, GABAA receptor inverse agonists, GABAA receptor antagonists, nicotinic receptor agonists or partial agonists or positive regulators, α4β2 nicotinic receptor agonists or partial agonists or positive regulators, α7 nicotinic receptor agonists or partial agonists or positive regulators;histamine H3 antagonists, 5HT-4 agonists or partial agonists, 5HT-6 antagonists, α2-adrenergic receptor antagonists, calcium antagonists, muscarinic receptor M1 agonists or partial agonists or positive regulators, muscarinic receptor M2 antagonists, muscarinic receptor M4 antagonists, metabotropic glutamate receptor 1 positive regulators, metabotropic glutamate receptor 2 positive regulators, metabotropic glutamate receptor 3 positive regulators, metabotropic glutamate receptor 5 positive regulators, glycine transporter 1 inhibitors, antidepressants (e.g., citalopram, fluoxetine, paroxetine, sertraline and trazodone; anxiolytics (e.g., lorazepam and oxazepam); antipsychotics (e.g., aripiprazole, asenapine, clozapine, iloperidone, haloperidol, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, lurasidone, lumateperone, brexpiprazole and cariprazine); mood stabilizers (e.g., lithium and valproate), and other substances that modulate receptors or enzymes to increase the efficacy and / or safety of the compounds according to the invention and / or reduce undesirable side effects. The compounds according to the invention can also be used in combination with immunotherapy (e.g., active immunization with amyloid beta or tau or portions thereof, or passive immunization with humanized anti-amyloid beta or anti-tau antibodies or nanobodies) for the treatment of the above diseases and conditions.

[0069] The dosage of the partner substance in the above combination is useful in a range from 1 / 5 of the minimum normally recommended dosage to 1 / 1 of the normally recommended dosage. Therefore, in another aspect, the present invention relates to the use of a compound according to the invention or a pharma- ceutically acceptable salt thereof, in combination with at least one of the abovementioned active substances as combination partners, for preparing a pharmaceutical composition suitable for the treatment or prevention of diseases or conditions that can be influenced by agonists of GPR52, preferably pathologies related to a deficiency in GPR52 activity, in particular one of the diseases or conditions listed above.

[0070] The use of the compounds according to the invention in combination with other active substances can be performed simultaneously or staggered, in particular within a short time period.When administered simultaneously, the two active substances are administered to the patient together; when used staggered, the two active substances are administered to the patient within a time period of not more than 12 hours, in particular not more than 6 hours.

[0071] Consequently, in another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the invention or a pharma- ceutically acceptable salt thereof and at least one of the above-mentioned active substances as combination partner substances, optionally together with one or more inert carriers and / or diluents.

[0072] The compounds according to the invention may both be present together in one formulation (e.g. a tablet or capsule) or alternatively may be present separately in two identical or different formulations (e.g. a so-called kit of parts). EXAMPLES

[0073] Experimental section List of abbreviations [Table 5]

[0074] HPLC-Method: Preparation of mobile phase: The mobile phase "H2O 0.1% TFA" is prepared by adding 1 ml of a commercially available TFA solution to 999 ml of water. The mobile phase "H2O 0.1% NH3" is prepared by adding 4 ml of a commercially available concentrated ammonium hydroxide solution (25% by weight) to 996 ml of water.

[0075] Method name:A Instrument description: Waters Acquity with DA and MS detectors Column: XBridge, BEH C18, 2.1 x 30 mm, 2.5 μm Column supplier: Waters [Table 6] Method name: B Instrument description: Waters Acquity with DA and MS detectors Column: XBridge, BEH C18, 2.1 x 30 mm, 2.5 μm Column supplier: Waters [Table 7]

[0076] Method name:C Instrument description: Waters Acquity with DA and MS detectors Column: BEH C18, 1.7 μm, 2.1 × 50 mm Column supplier: Waters [Table 8]

[0077] Method name:D Instrument description: Waters Acquity with DA and MS detectors Column: Sunfire, C18, 3.0 x 30 mm, 2.5 μm Column supplier: Waters [Table 9]

[0078] Method name: E Instrument description: Waters Acquity with DA and MS detectors Column: CSH C18, 1.7 μm, 2.1 × 50 mm Column supplier: Waters [Table 10]

[0079] Method name:F Instrument description: ThermoFinnigan HPLC Surveyor DAD, MSQ single quadrupole Column: Synergi Hydro RP100A, 2.5 μm, 3 × 50 mm Column supplier: Phenomenex [Table 11]

[0080] Method name:G Instrument description: Waters Acquity with DA and MS detectors Column: Atlantis T3 3.0 μm, 4.6 × 50 mm Column supplier: Waters [Table 12]

[0081] Working Example The following examples are intended to illustrate the invention but not to limit its scope.

[0082] Preparation of intermediates Intermediate A-1: [ka] A mixture of 3,4-difluoro-phenol (10.0 g, 76.9 mmol) and cesium carbonate (37.6 g, 115.3 mmol) in DMA (558 mL) is stirred at room temperature for 5 min, then tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (19.3 g, 76.9 mmol) is added. After stirring at 100° C. for 5 h, the mixture is cooled to room temperature and concentrated under reduced pressure. Water and ethyl acetate are added. The phases are separated. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by MPLC (silica gel, petroleum ether / ethyl acetate 9:1) to give product A-1. ESI-MS: 286 [M+H] + ;HPLC(Rt): 0.72 min (Method A)

[0083] Intermediate A-2: [ka] A mixture of 3,5-difluoro-phenol (1.0 g, 8.0 mmol) and cesium carbonate (5.2 g, 15.9 mmol) in DMA (5 mL) is stirred at room temperature for 10 min, then tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.0 g, 8.0 mmol) is added. After stirring at 90° C. for 16 h, the mixture is cooled to room temperature and water and ethyl acetate are added. The phases are separated. The combined organic phase is washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is purified by preparative HPLC to give product A-2. ESI-MS: 286 [M+H] + ;HPLC(Rt): 1.02 min (Method D)

[0084] Intermediate A-3: [ka] A mixture of 3,4,5-trifluoro-phenol (10.0 g, 64.2 mmol) and cesium carbonate (31.4 g, 96.2 mmol) in DMA (465 mL) is stirred at room temperature for 10 min, after which tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (16.1 g, 64.2 mmol) is added. After stirring at 100° C. for 6 h, the mixture is cooled to room temperature and concentrated under reduced pressure. Water and ethyl acetate are added. The phases are separated. The aqueous phase is extracted three times with ethyl acetate. The combined organic phase is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by MPLC (silica gel, petroleum ether / ethyl acetate 9:1) to give product A-3. ESI-MS: 304 [M+H] + ;HPLC(Rt): 0.75 min (Method A)

[0085] Intermediate A-4: [ka] A mixture of 3-chloro-4,5-difluoro-phenol (1.8 g, 10.1 mmol) and cesium carbonate (4.9 g, 15.1 mmol) in DMA (15 mL) is stirred at room temperature for 10 min, then tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.5 g, 10.1 mmol) is added. After stirring at 90° C. for 16 h, the mixture is cooled to room temperature and water and ethyl acetate are added. The phases are separated and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative HPLC to give product A-4. ESI-MS: 320 / 322 [M+H] + ;HPLC(Rt): 0.79 min (Method A)

[0086] Intermediate A-5: [ka] A mixture of 3-chloro-4-fluoro-phenol (1.5 g, 10.2 mmol) and cesium carbonate (6.7 g, 20.5 mmol) in DMA (10 mL) is stirred at room temperature for 10 min, then tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.6 g, 10.2 mmol) is added. After stirring at 100° C. for 16 h, the mixture is cooled to room temperature. Water and DCM are added. The phases are separated. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative HPLC to give product A-5. ESI-MS: 302 / 304 [M+H] + ;HPLC(Rt): 0.78 min (Method A)

[0087] Intermediate A-6: [ka] A mixture of 3-chloro-5-fluoro-phenol (4.8 g, 33.0 mmol) and cesium carbonate (21.5 g, 66.1 mmol) in DMF (20 mL) is stirred at room temperature for 10 min, then tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.5 g, 10.1 mmol) is added. After stirring at 90° C. for 16 h, the mixture is cooled to room temperature and water and ethyl acetate are added. The phases are separated and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative HPLC to give product A-6. ESI-MS: 302 / 304 [M+H] + ;HPLC(Rt): 0.77 min (Method A)

[0088] Intermediate A-7: [ka] A mixture of 3-fluoro-5-(trifluoromethyl)-phenol (0.7 g, 4.0 mmol), cesium carbonate (2.6 g, 8.0 mmol) and tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (1.0 g, 4.0 mmol) in DMF (30 mL) is stirred at 90° C. for 16 h. The mixture is then cooled to room temperature and diluted with ethyl acetate. The organic phase is washed successively with saturated aqueous NaHCO3, brine and saturated aqueous NH4Cl, and concentrated under reduced pressure to give product A-7. ESI-MS: 336 [M+H] + , 280 [M+H-isobutene] + ;HPLC(Rt): 1.44 min (Method J)

[0089] Intermediate A-8: [ka] A mixture of 3-fluoro-5-(difluoromethyl)-phenol (2.5 g, 10.0 mmol) and cesium carbonate (6.5 g, 20.0 mmol) in DMA (10 mL) is stirred at room temperature for 10 min, followed by the addition of tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.5 g, 10.0 mmol). After stirring at 90° C. for 16 h, the mixture is cooled to room temperature and water and ethyl acetate are added. The phases are separated. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative HPLC to give product A-8. ESI-MS: 318 [M+H] + , 262 [M+H-isobutene] + ;HPLC(Rt): 1.03 min (Method D)

[0090] Intermediate B-1: [ka] To a mixture of intermediate A-1 (19.0 g, 66.6 mmol) in diisopropyl ether (200 mL) is added a solution of HCl in dioxane (4N, 83.3 mL, 333.0 mmol). After stirring at room temperature for 16 h, the mixture is concentrated under reduced pressure. The precipitate is washed with diethyl ether and dried to give product B-1 as the HCl salt. ESI-MS: 186 [M+H] + ;HPLC(Rt): 0.38 min (Method A)

[0091] Intermediate B-2: [ka] To intermediate A-2 (1.85 g, 6.49 mmol) is added a solution of HCl in dioxane (4N, 15.0 mL, 60.0 mmol). After stirring at room temperature for 1 h, the mixture is concentrated under reduced pressure to give product B-2 as the HCl salt. ESI-MS: 186 [M+H] + ;HPLC(Rt): 0.38 min (Method D)

[0092] Intermediate B-3: [ka] To intermediate A-3 (3.24 g, 10.68 mmol) is added a solution of HCl in dioxane (4N, 25.0 mL, 100.0 mmol). After stirring at room temperature for 1 h, the mixture is concentrated under reduced pressure to give product B-3 as the HCl salt. ESI-MS: 204 [M+H] + ;HPLC(Rt): 0.45 min (Method A)

[0093] Intermediate B-4: [ka] To intermediate A-4 (2.6 g, 8.2 mmol) is added a solution of HCl in dioxane (4N, 20.5 mL, 82.0 mmol). After stirring at room temperature for 1 h, the mixture is concentrated under reduced pressure to give product B-4 as the HCl salt. ESI-MS: 220 / 222 [M+H] + ;HPLC(Rt): 0.48 min (Method A)

[0094] Intermediate B-5: [ka] To intermediate A-5 (2.3 g, 7.6 mmol) is added a solution of HCl in dioxane (4N, 9.5 mL, 37.9 mmol). After stirring at room temperature for 45 minutes, the mixture is concentrated under reduced pressure to give the product B-5 as the HCl salt. ESI-MS: 202 / 204 [M+H] + ;HPLC(Rt): 0.51 min (Method B)

[0095] Intermediate B-6: [ka] To intermediate A-6 (8.3 g, 27.5 mmol) is added a solution of HCl in dioxane (4N, 34.4 mL, 137.5 mmol). After stirring at room temperature for 1 h, the mixture is concentrated under reduced pressure to give the product B-4 as the HCl salt. ESI-MS: 202 / 204 [M+H] + ;HPLC(Rt): 0.52 min (Method A)

[0096] Intermediate B-7: [ka] To a mixture of intermediate A-7 (1.3 g, 3.9 mmol) in 1,4-dioxane (20 mL) is added HCl in dioxane (4N, 6.8 mL, 27.1 mmol). After stirring at room temperature for 16 h, the mixture is concentrated under reduced pressure. The residue is washed with diethyl ether to give product B-7 as the HCl salt. ESI-MS: 236 [M+H] + ;HPLC(Rt): 0.63 min (Method K)

[0097] Intermediate B-8: [ka] To intermediate A-8 (2.6 g, 8.0 mmol) is added a solution of HCl in dioxane (4N, 12.1 mL, 48.2 mmol). After stirring at room temperature for 1 h, the mixture is concentrated under reduced pressure to give the product B-8 as the HCl salt. ESI-MS: 218 [M+H] + ;HPLC(Rt): 0.45 min (Method D)

[0098] Intermediate C-1.1: [ka] To a mixture of 5-amino-3-chloropyridazine (1.3 g, 10.0 mmol), bis(triphenylphosphine)palladium(II) chloride (1.4 g, 2.0 mmol) and lithium chloride (0.68 g, 16.00 mmol) in DMF (40 mL) is added tributyl(vinyl)tin (5.07 g, 16.00 mmol) under argon atmosphere. After stirring at 115 °C for 5 h, the reaction mixture is cooled to room temperature, acidified with TFA and diluted with methanol / acetonitrile (1:1). 3 g of thiol polymer is added to remove heavy metal content. The mixture is filtered, the polymer beads are washed with methanol / acetonitrile (1:1) and the combined filtrate is concentrated under reduced pressure to remove methanol and acetonitrile. The remaining solution containing the crude product is purified by preparative HPLC to give intermediate C-1.1 as the HCl salt. ESI-MS: 122 [M+H] + ;HPLC(Rt): 1.58 min (Method G)

[0099] Intermediate C-1: [ka] Intermediate C-1.1 (HCl salt, 500.0 mg, 3.2 mmol) is hydrogenated in methanol (20 mL) over palladium on charcoal (10%, 50 mg) at room temperature for 3 h (3 bar hydrogen atmosphere). The reaction mixture is filtered and the catalyst is washed with water (20 mL). The combined filtrates are acidified with hydrochloric acid (4 N) and concentrated under reduced pressure to give intermediate C-1 as the HCl salt. ESI-MS: 124 [M+H] + ;HPLC(Rt): 1.53 min (Method G)

[0100] Intermediate D-1: [ka] A mixture of methyl 3-fluoropyrazine-2-carboxylate (100.0 mg, 641.0 μmol), intermediate B-7 (208.8 mg, 769.0 μmol) and triethylamine (0.27 mL, 1.9 mmol) in DMA (8 mL) is stirred at room temperature for 1 day. The reaction mixture is diluted with acetonitrile / methanol (1:1 v / v) and purified by preparative HPLC to give intermediate D-1. ESI-MS: 372 [M+H] + ;HPLC(Rt): 0.72 min (Method B)

[0101] Intermediate D-2: [ka] A mixture of methyl 3-chloropyrazine-2-carboxylate (1.5 g, 8.7 mmol), intermediate B-3 (HCl salt, 2.5 g, 10.4 mmol) and TEA (2.93 mL, 20.86 mmol) in DMF (9.2 mL) is stirred at room temperature for 1 h. The reaction mixture is diluted with water. The precipitate is collected by suction filtration and dried at 50 °C to give intermediate D-2. ESI-MS: 340 [M+H] + ;HPLC(Rt): 0.63 min (Method A)

[0102] Intermediate D-3: [ka] A mixture of methyl 3-chloropyrazine-2-carboxylate (1.0 g, 5.8 mmol), intermediate B-1 (HCl salt, 1.5 g, 7.0 mmol) and TEA (1.95 mL, 13.91 mmol) in DMA (10 mL) is stirred at room temperature for 1 h. The reaction mixture is diluted with water. The precipitate is collected by suction filtration and dried at 50 °C to give intermediate D-3. ESI-MS: 322 [M+H] + ;HPLC(Rt): 0.60 min (Method A)

[0103] Intermediate D-4: [ka] A mixture of methyl 3-chloropyrazine-2-carboxylate (673.9 mg, 3.9 mmol), intermediate B-4 (1.0 g, 3.9 mmol) and triethylamine (1.6 mL, 11.7 mmol) in DMA (10 mL) is stirred at room temperature for 2 h. The reaction mixture is diluted with water. The precipitate is collected by suction filtration and dried to give intermediate D-4. ESI-MS: 356 / 358 [M+H] + ;HPLC(Rt): 0.68 min (Method A)

[0104] Intermediate E-1: [ka] To a mixture of intermediate D-1 (210.0 mg, 566.0 μmol) in acetone (2 mL) is added aqueous lithium hydroxide (67.7 mg, 2.8 mmol in 2 mL water). The mixture is stirred at room temperature for 4 h. Aqueous hydrochloric acid (1N) is added dropwise until a neutral pH is reached, and the mixture is subsequently extracted with ethyl acetate and dichloromethane. The combined organic phase is separated from the residual water content by passing through a phase separation cartridge and concentrated under reduced pressure to give intermediate E-1. ESI-MS: 358 [M+H] + ;HPLC(Rt): 0.88 min (Method D)

[0105] Intermediate E-2: [ka] To a mixture of intermediate D-2 (4.15 g, 12.23 mmol) in acetone (40 mL) is added aqueous lithium hydroxide (585.9 mg, 24.5 mmol in 40 mL water). The reaction mixture is stirred for 2 h, then diluted with water and acidified to pH 4 with hydrochloric acid (4 N). The precipitate is collected by suction filtration and dried at 50 °C to give intermediate E-2. ESI-MS: 326 [M+H] + ;HPLC(Rt): 0.31 min (Method A)

[0106] Intermediate E-3: [ka] To a mixture of intermediate D-3 (1.6 g, 4.9 mmol) in acetone (15 mL) is added aqueous lithium hydroxide (230.0 mg, 9.8 mmol in 15 mL water). The reaction mixture is stirred at room temperature for 1.5 h, then diluted with water and acidified to pH 4 with hydrochloric acid (4 N). The precipitate is collected by suction filtration and dried at 50 °C to give intermediate E-3. ESI-MS: 308 [M+H] + ;HPLC(Rt): 0.27 min (Method A)

[0107] Intermediate E-4: [ka] To a mixture of intermediate D-4 (1.3 g, 3.6 mmol) in a mixture of THF (5 mL), methanol (2.5 mL) and water (2.5 mL) is added sodium hydroxide (435.2 mg, 10.9 mmol). The mixture is stirred at room temperature for 18 h and then at 50° C. to complete the saponification. After concentration under reduced pressure, water and DCM are added and the phases are separated. The aqueous phase is acidified with hydrochloric acid and the resulting precipitate is collected and dried to give intermediate E-4. ESI-MS: 342 / 344 [M+H] + ;HPLC(Rt): 0.32 min (Method A)

[0108] Intermediate F-1: [ka] To a mixture of 3-chloropyrazine-2-carboxylic acid (100.0 mg, 631.0 μmol), 4-aminopyridazine (60.0 mg, 631.0 μmol) and triethylamine (0.44 mL, 3.15 mmol) in DCM (2 mL) is added T3P (50% solution in DMF, 0.41 mL, 694.0 μmol). The mixture is stirred at room temperature for 30 min and directly purified by preparative HPLC to give intermediate F-1. ESI-MS: 236 / 238 [M+H] + ;HPLC(Rt): 0.11 min (Method A)

[0109] Intermediate F-2: [ka] To a mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 4-amino-6-methylpyridazine (HCl salt, 45.9 mg, 315.0 μmol) and triethylamine (0.13 mL, 946.0 μmol) in THF (1 mL) is added T3P (50% solution in ethyl acetate, 0.21 mL, 347.0 μmol). The mixture is stirred at room temperature for 2 h and directly purified by preparative HPLC to give intermediate F-2. ESI-MS: 250 / 252 [M+H] + ;HPLC(Rt): 0.32 min (Method D)

[0110] Example 1 [ka] A mixture of intermediate E-1 (90.0 mg, 252.0 μmol), HATU (105.4 mg, 277.0 μmol) and DIPEA (131.0 μL, 756.0 μmol) in DMF (3 mL) is stirred at room temperature for 5 minutes. 4-Aminopyridazine (HCl salt, 49.7 mg, 378.0 μmol) is added and the mixture is stirred for 1 day, and then directly purified by preparative HPLC to give Example 1. ESI-MS: 435 [M+H] + ;HPLC(Rt): 0.63 min (Method B)

[0111] Example 2 [ka] A mixture of intermediate F-1 (60.0 mg, 255.0 μmol), intermediate B-6 (60.6 mg, 255.0 μmol) and triethylamine (106.2 μL, 764.0 μmol) in 2-propanol (2 mL) is stirred at 125° C. for 3 h. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in DCM and washed with an aqueous solution of citric acid (10%). After phase separation on a separatory cartridge, the organic phase is concentrated under reduced pressure to give the crude product. The crude product is purified by preparative HPLC to give Example 2. ESI-MS: 401 / 403 [M+H] + ;HPLC(Rt): 4.28 min (Method F)

[0112] Example 3 [ka] A mixture of intermediate F-1 (60.0 mg, 255.0 μmol), intermediate B-2 (56.4 mg, 255.0 μmol) and triethylamine (106.2 μL, 764.0 μmol) in 2-propanol (2 mL) is stirred at 125° C. for 3 h. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in DCM and washed with an aqueous solution of citric acid (10%). After phase separation on a separatory cartridge, the organic phase is concentrated under reduced pressure to give the crude product. The crude product is purified by preparative HPLC to give Example 3. ESI-MS: 385 [M+H] + ;HPLC(Rt): 3.99 min (Method F)

[0113] Example 4 [ka] A mixture of intermediate E-2 (1.5 g, 3.0 mmol), HATU (1.2 g, 3.1 mmol) and DIPEA (1.0 mL, 6.0 mmol) in DMA (8 mL) is stirred at room temperature for 5 min. 4-Aminopyridazine (285.1 mg, 300.0 μmol) is added and the mixture is stirred for 1 day, then directly purified by preparative HPLC to give Example 4. ESI-MS: 403 [M+H] + ;HPLC(Rt): 0.60 min (Method A)

[0114] Example 5 [ka] A mixture of intermediate E-3 (46.1 mg, 150.0 μmol), HATU (59.9 mg, 158.0 μmol) and DIPEA (51.6 μL, 300.0 μmol) in DMA (2 mL) is stirred at room temperature for 5 min. 4-Aminopyridazine (HCl salt, 23.7 mg, 180.0 μmol) is added and the mixture is stirred for 1.5 h, then directly purified by preparative HPLC to give Example 5. ESI-MS: 385 [M+H] + ;HPLC(Rt): 0.56 min (Method A)

[0115] Example 6 [ka] A mixture of intermediate F-1 (30.0 mg, 127.0 μmol), intermediate B-8 (32.3 mg, 127.0 μmol) and potassium carbonate (44.0 mg, 318.0 μmol) in toluene (2 mL) and water (1 mL) is stirred at 100° C. for 1 day. After cooling to room temperature, the reaction mixture is dissolved in DCM. The organic phase is separated on a separation cartridge and purified by preparative HPLC to give Example 6. ESI-MS: 417 [M+H] + ;HPLC(Rt): 0.55 min (Method B)

[0116] Example 7 [ka] To a mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol) and T3P (50% in ethyl acetate, 0.21 mL, 347.0 μmol) in DMF (1.5 mL), TEA (0.13 mL, 946.0 μmol) and 4-aminopyrazine (30.0 mg, 315.0 μmol) are added. After stirring at room temperature for 5 days, intermediate B-5 (88.8 mg, 347.0 μmol) is added and the reaction mixture is stirred at 100° C. for 4 hours. After cooling to room temperature, the reaction mixture is directly purified by preparative HPLC to give Example 7. ESI-MS: 401 / 403 [M+H] + ;HPLC(Rt): 0.59 min (Method B)

[0117] Example 8 [ka] To a mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol) and T3P (50% in ethyl acetate, 0.21 mL, 347.0 μmol) in THF (2.5 mL) is added TEA (0.13 mL, 946.0 μmol) and 4-aminopyridazine (30.0 mg, 315.0 μmol). After stirring at room temperature for 1 day, the mixture is filtered and concentrated under reduced pressure. The residue is dissolved in DMF (1.5 mL) and intermediate B-4 (88.8 mg, 347.0 μmol) and TEA (88.6 μL, 631.0 μmol) are added. The reaction mixture is stirred at room temperature for 3 h. After cooling to room temperature, the reaction mixture is filtered and directly purified by preparative HPLC to give Example 8. ESI-MS: 417 / 419 [M+H] + ;HPLC(Rt): 0.62 min (Method B)

[0118] Example 9 [ka] A mixture of intermediate E-1 (100.0 mg, 280.0 μmol), HATU (117.1 mg, 308.0 μmol) and DIPEA (145.3 μL, 840.0 μmol) in DMF (3 mL) is stirred at room temperature for 5 min. 6-Methylpyridazin-4-amine (HCl salt, 61.1 mg, 420.0 μmol) is added and the mixture is stirred for 1 day, then directly purified by preparative HPLC to give Example 9. ESI-MS: 449 [M+H] + ;HPLC(Rt): 0.66 min (Method B)

[0119] Example 10 [ka] To a mixture of intermediate F-2 (50.0 mg, 65% purity, 130.0 μmol), intermediate B-6 (31.0 mg, 130.0 μmol) and potassium carbonate (45.0 mg, 325.0 μmol) in toluene (2 mL) is added water (1 mL). The reaction mixture is stirred at 100° C. for 16 hours. After cooling to room temperature, the formed precipitate is filtered off, washed with water and dried at 50° C. to give Example 10. ESI-MS: 415 / 417 [M+H] + ;HPLC(Rt): 0.64 min (Method B)

[0120] Example 11 [ka] To a mixture of intermediate F-2 (30.0 mg, 120.0 μmol), intermediate B-8 (30.5 mg, 120.0 μmol) and potassium carbonate (41.5 mg, 300.0 μmol) in toluene (2 mL) is added water (1 mL). The reaction mixture is stirred at 100° C. for 16 h. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure. The residue is dissolved in DCM. The organic phase is separated on a separation cartridge and concentrated under reduced pressure. The residue is purified by preparative HPLC to give Example 11. ESI-MS: 431 [M+H] + ;HPLC(Rt): 0.59 min (Method B)

[0121] Example 12 [ka] A mixture of intermediate E-3 (60.0 mg, 195.0 μmol), HATU (78.0 mg, 205.0 μmol) and DIPEA (67.2 μL, 391.0 μmol) in DMA (1 mL) is stirred at room temperature for 10 min. 4-Amino-6-methyl-pyridazine (21.3 mg, 195.0 μmol) is added and the mixture is stirred for 16 h, then directly purified by preparative HPLC to give Example 12. ESI-MS: 399 [M+H] + ;HPLC(Rt): 0.49 min (Method A)

[0122] (Example 13) [ka] To a mixture of intermediate F-2 (170.0 mg, 647.0 μmol), intermediate B-2 (143.4 mg, 647.0 μmol) and potassium carbonate (223.5 mg, 1.6 mmol) in toluene (10 mL) is added water (5 mL). The reaction mixture is stirred at 100° C. for 16 hours. After cooling to room temperature, the formed precipitate is filtered off, washed with water and dried at 50° C. to give Example 13. ESI-MS: 399 [M+H] + ;HPLC(Rt): 0.58 min (Method B)

[0123] Example 14 [ka] A mixture of intermediate F-2 (65.0 mg, 260.0 μmol), intermediate B-4 (80.0 mg, 312.0 μmol) and TEA (73.1 μL, 521.0 μmol) in DMA (1.5 mL) is stirred at 100° C. for 1.5 h. After cooling to room temperature, the reaction mixture is filtered and directly purified by preparative HPLC to give Example 14. ESI-MS: 433 / 435 [M+H] + ;HPLC(Rt): 0.65 min (Method B)

[0124] Example 15 [ka] To a mixture of intermediate F-2 (78.0 mg, 312.0 μmol), intermediate B-3 (74.9 mg, 312.0 μmol) and potassium carbonate (108.0 mg, 781.0 μmol) in toluene (5 mL) is added water (2.5 mL). The reaction mixture is stirred at 100° C. for 3 h. After cooling to room temperature, the formed precipitate is filtered off, washed with water and dried at 50° C. to give Example 15. ESI-MS: 417 [M+H] +;HPLC(Rt): 0.61 min (Method B)

[0125] Example 16 [ka] To a mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol) and T3P (50% in ethyl acetate, 0.21 mL, 347.0 μmol) in THF (2.5 mL), add TEA (0.13 mL, 946.0 μmol) and 4-amino-6-methylpyridazine (HCl salt, 88.8 mg, 347.0 μmol). Add DMF (2 mL). After stirring at room temperature for 5 days, add intermediate B-5 (88.8 mg, 347.0 μmol). Stir the reaction mixture at 100° C. for 4 h. After cooling to room temperature, filter the reaction mixture and directly purify by preparative HPLC to give Example 16. ESI-MS: 417 / 419 [M+H] + ;HPLC(Rt): 0.62 min (Method B)

[0126] (Example 17) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), HATU (79.9 mg, 210.0 μmol) and DIPEA (103.2 μL, 600.0 μmol) in NMP (2 mL) is stirred at room temperature for 5 min. Intermediate C-1 (HCl salt, 41.2 mg, 240.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-7 (51.6 mg, 190.0 μmol) and additional DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 80° C. for 45 min, then cooled to room temperature and directly purified by preparative HPLC to give Example 17. ESI-MS: 463 [M+H] + ;HPLC(Rt): 0.70 min (Method B)

[0127] (Example 18) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), HATU (79.9 mg, 210.0 μmol) and DIPEA (103.2 μL, 600.0 μmol) in NMP (2 mL) is stirred at room temperature for 5 min. Intermediate C-1 (HCl salt, 41.2 mg, 240.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-6 (45.2 mg, 190.0 μmol) and additional DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 80° C. for 45 min, then cooled to room temperature and directly purified by preparative HPLC to give Example 18. ESI-MS: 429 / 431 [M+H] + ;HPLC(Rt): 0.68 min (Method B)

[0128] (Example 19) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), HATU (79.9 mg, 210.0 μmol) and DIPEA (103.2 μL, 600.0 μmol) in NMP (2 mL) is stirred at room temperature for 5 min. Intermediate C-1 (HCl salt, 41.2 mg, 240.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-5 (45.2 mg, 190.0 μmol) and additional DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 80° C. for 45 min, then cooled to room temperature and directly purified by preparative HPLC to give Example 19. ESI-MS: 429 / 431 [M+H] + ;HPLC(Rt): 0.66 min (Method B)

[0129] (Example 20) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), HATU (79.9 mg, 210.0 μmol) and DIPEA (103.2 μL, 600.0 μmol) in NMP (2 mL) is stirred at room temperature for 5 min. Intermediate C-1 (HCl salt, 41.2 mg, 240.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-3 (47.9 mg, 190.0 μmol) and additional DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 80° C. for 45 min, then cooled to room temperature and directly purified by preparative HPLC to give Example 20. ESI-MS: 431 [M+H] + ;HPLC(Rt): 0.65 min (Method B)

[0130] Example 21 [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), HATU (79.9 mg, 210.0 μmol) and DIPEA (103.2 μL, 600.0 μmol) in NMP (2 mL) is stirred at room temperature for 5 min. Intermediate C-1 (HCl salt, 41.2 mg, 240.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-5 (42.1 mg, 190.0 μmol) and additional DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 80 °C for 45 min, then cooled to room temperature and poured into water. The precipitate is collected, then dissolved in DCM and washed with saturated aqueous NaHCO3 and brine. The organic phase is mixed with charcoal and filtered through a phase separation cartridge before being concentrated under reduced pressure to give the crude product. The crude product is purified by preparative HPLC to give Example 21. ESI-MS: 413 [M+H] + ;HPLC(Rt): 0.61 min (Method B)

[0131] Example 22 [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), HATU (79.9 mg, 210.0 μmol) and DIPEA (103.2 μL, 600.0 μmol) in NMP (2 mL) is stirred at room temperature for 5 min. Intermediate C-1 (HCl salt, 41.2 mg, 240.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-8 (48.2 mg, 190.0 μmol) and additional DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 80° C. for 45 min, then cooled to room temperature and directly purified by preparative HPLC to give Example 22. ESI-MS: 445 [M+H] + ;HPLC(Rt): 0.63 min (Method B)

[0132] Example 23 [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), HATU (79.9 mg, 210.0 μmol) and DIPEA (103.2 μL, 600.0 μmol) in NMP (2 mL) is stirred at room temperature for 5 min. Intermediate C-1 (HCl salt, 41.2 mg, 240.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-4 (48.7 mg, 190.0 μmol) and additional DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 80° C. for 45 min, then cooled to room temperature and directly purified by preparative HPLC to give Example 23. ESI-MS: 447 / 449 [M+H] + ;HPLC(Rt): 0.69 min (Method B)

[0133] (Example 24) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), HATU (79.9 mg, 210.0 μmol) and DIPEA (103.2 μL, 600.0 μmol) in NMP (2 mL) is stirred at room temperature for 5 min. Intermediate C-1 (HCl salt, 41.2 mg, 240.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-2 (42.1 mg, 190.0 μmol) and DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 80° C. for 45 min, then cooled to room temperature and directly purified by preparative HPLC to give Example 24. ESI-MS: 413 [M+H] + ;HPLC(Rt): 0.63 min (Method B)

[0134] (Example 25) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), 1-methylimidazole (40.3 μL, 500.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (70.1 mg, 250.0 μmol) in NMP (1 mL) is stirred at room temperature for 10 min. 4-Amino-6-methylpyrimidine (22.9 mg, 210.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-5 (45.2 mg, 190.0 μmol) and DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 3.5 h and then cooled to room temperature. Stirring is continued at room temperature for 20 h and the mixture is directly purified by preparative HPLC to give Example 25. ESI-MS: 415 / 417 [M+H] + ;HPLC(Rt): 0.72 min (Method B)

[0135] (Example 26) [ka] A mixture of intermediate E-2 (100.0 mg, 307.0 μmol), 1-methylimidazole (97.7 μL, 1230.0 μmol), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (103.5 mg, 369.0 μmol) and 4-amino-6-methylpyrimidine (36.9 mg, 338.0 μmol) in acetonitrile (2 mL) is stirred at room temperature for 1 day. The reaction mixture is diluted with acetonitrile / methanol (v / v 1:1) and directly purified by preparative HPLC to give Example 26. ESI-MS: 417 [M+H] + ;HPLC(Rt): 0.71 min (Method B)

[0136] Example 27 [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), 1-methylimidazole (40.3 μL, 500.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (70.1 mg, 250.0 μmol) in NMP (1 mL) is stirred at room temperature for 10 min. 4-Amino-6-methylpyrimidine (22.9 mg, 210.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-8 (48.2 mg, 190.0 μmol) and DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 3.5 h and then cooled to room temperature. Stirring is continued at room temperature for 20 h and the mixture is directly purified by preparative HPLC to give Example 27. ESI-MS: 431 [M+H] + ;HPLC(Rt): 0.69 min (Method B)

[0137] (Example 28) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), 1-methylimidazole (40.3 μL, 500.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (70.1 mg, 250.0 μmol) in NMP (1 mL) is stirred at room temperature for 10 min. 4-Amino-6-methylpyrimidine (22.9 mg, 210.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-2 (42.1 mg, 190.0 μmol) and DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 3.5 h and then cooled to room temperature. Stirring is continued at room temperature for 20 h and the mixture is directly purified by preparative HPLC to give Example 28. ESI-MS: 399 [M+H] + ;HPLC(Rt): 0.70 min (Method B)

[0138] (Example 29) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 minutes. 4-Amino-6-methylpyrimidine (36.1 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 75 minutes. Intermediate B-1 (73.4 mg, 331.0 μmol) and DIPEA (300.0 μL, 1744.0 μmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 1 hour, then cooled to room temperature and poured into water. The precipitate is collected by filtration, washed with water and dried at 40° C. for 2 days to give Example 29. ESI-MS: 399 [M+H] + ;HPLC(Rt): 0.68 min (Method B)

[0139] (Example 30) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), 1-methylimidazole (40.3 μL, 500.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (70.1 mg, 250.0 μmol) in NMP (1 mL) is stirred at room temperature for 10 min. 4-Amino-6-methylpyrimidine (22.9 mg, 210.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-6 (45.2 mg, 190.0 μmol) and DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 3.5 h and then cooled to room temperature. Stirring is continued at room temperature for 20 h and the mixture is directly purified by preparative HPLC to give Example 30. ESI-MS: 415 / 417 [M+H] + ;HPLC(Rt): 0.75 min (Method B)

[0140] (Example 31) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), 1-methylimidazole (40.3 μL, 500.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (70.1 mg, 250.0 μmol) in NMP (1 mL) is stirred at room temperature for 10 min. 4-Amino-6-methylpyrimidine (22.9 mg, 210.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-7 (51.6 mg, 190.0 μmol) and DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 4 h, then cooled to room temperature and directly purified by preparative HPLC to give Example 31. ESI-MS: 449 [M+H] + ;HPLC(Rt): 0.77 min (Method B)

[0141] Example 32 [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (31.7 mg, 200.0 μmol), 1-methylimidazole (40.3 μL, 500.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (70.1 mg, 250.0 μmol) in NMP (1 mL) is stirred at room temperature for 10 min. 4-Amino-6-methylpyrimidine (22.9 mg, 210.0 μmol) is added and the mixture is stirred at room temperature for 18 h. Intermediate B-4 (48.7 mg, 190.0 μmol) and DIPEA (100.0 μL, 581.0 μmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 3.5 h and then cooled to room temperature. Stirring is continued at room temperature for 20 h and the mixture is directly purified by preparative HPLC to give Example 32. ESI-MS: 433 / 435 [M+H] + ;HPLC(Rt): 0.75 min (Method B)

[0142] (Example 33) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 4-Amino-6-ethylpyrimidine (40.8 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-2 (73.4 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and directly purified by preparative HPLC to give Example 33. ESI-MS: 413 [M+H] + ;HPLC(Rt): 0.75 min (Method B)

[0143] (Example 34) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 4-Amino-6-ethylpyrimidine (40.8 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-7 (90.0 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and directly purified by preparative HPLC to give Example 34. ESI-MS: 463 [M+H] + ;HPLC(Rt): 0.82 min (Method B)

[0144] Example 35 [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 4-Amino-6-ethylpyrimidine (40.8 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-6 (78.8 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and directly purified by preparative HPLC to give Example 35. ESI-MS: 429 / 431 [M+H] +;HPLC(Rt): 0.81 min (Method B)

[0145] (Example 36) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 4-Amino-6-ethylpyrimidine (40.8 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-3 (79.4 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and directly purified by preparative HPLC to give Example 36. ESI-MS: 431 [M+H] + ;HPLC(Rt): 0.77 min (Method B)

[0146] (Example 37) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 4-Amino-6-ethylpyrimidine (40.8 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-1 (73.4 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and directly purified by preparative HPLC to give Example 37. ESI-MS: 413 [M+H] + ;HPLC(Rt): 0.74 min (Method B)

[0147] (Example 38) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 4-Amino-6-ethylpyrimidine (40.8 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-4 (84.8 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and directly purified by preparative HPLC to give Example 38. ESI-MS: 447 / 449 [M+H] + ;HPLC(Rt): 0.81 min (Method B)

[0148] (Example 39) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 4-Amino-6-ethylpyrimidine (40.8 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-8 (84.0 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and directly purified by preparative HPLC to give Example 39. ESI-MS: 445 [M+H] + ;HPLC(Rt): 0.75 min (Method B)

[0149] (Example 40) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 4-Amino-6-ethylpyrimidine (40.8 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-5 (78.8 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and directly purified by preparative HPLC to give Example 40. ESI-MS: 429 / 431 [M+H] + ;HPLC(Rt): 0.78 min (Method B)

[0150] (Example 41) [ka] A mixture of intermediate E-4 (50.0 mg, 146.0 μmol), 1-methylimidazole (46.5 μL, 585.0 μmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (49.3 mg, 176.0 μmol) and 4-aminopyrimidine (15.3 mg, 161.0 μmol) in DMA (2 mL) is stirred at room temperature for 3 h. After addition of water, the resulting precipitate is collected by filtration. The precipitate is dissolved in DCM and passed through a phase separation cartridge to remove residual water. The organic phase is concentrated under reduced pressure, dissolved in acetonitrile and lyophilized to give the crude product. The crude product is slurried in a mixture of acetonitrile / methanol (1 / 1 v / v) and DMF, then filtered. The organic phase is purified by preparative HPLC to give Example 41. ESI-MS: 419 / 421 [M+H] + ;HPLC(Rt): 0.73 min (Method B)

[0151] (Example 42) [ka] A mixture of intermediate E-2 (50.0 mg, 154.0 μmol), 1-methylimidazole (48.8 μL, 615.0 μmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (51.8 mg, 184.0 μmol) and 4-aminopyrimidine (16.1 mg, 169.0 μmol) in DMA (2 mL) is stirred at room temperature for 3 h. After addition of water, the precipitate formed is collected by filtration. The precipitate is dissolved in DCM and passed through a phase separation cartridge to remove residual water. The organic phase is concentrated under reduced pressure, dissolved in acetonitrile and lyophilized to give the crude product. The crude product is purified by MPLC (silica gel, gradient DCM / methanol 100→95 / 5 v / v). The fractions containing the product are collected and concentrated under reduced pressure. Repurification by preparative HPLC gives Example 42. ESI-MS: 403 [M+H] +;HPLC(Rt): 0.89 min (Method D)

[0152] (Example 43) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 4-Aminopyrimidine (31.5 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-1 (73.4 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and directly purified by preparative HPLC to give Example 43. ESI-MS: 385 [M+H] + ;HPLC(Rt): 0.65 min (Method B)

[0153] (Example 44) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 4-Aminopyrimidine (31.5 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-5 (78.8 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and directly purified by preparative HPLC to give Example 44. ESI-MS: 401 / 403 [M+H] + ;HPLC(Rt): 0.69 min (Method B)

[0154] (Example 45) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 5-Trifluoromethyl-4-aminopyrimidine (54.0 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-5 (78.8 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and directly purified by preparative HPLC to give Example 45. ESI-MS: 469 / 471 [M+H] + ;HPLC(Rt): 0.84 min (Method B)

[0155] (Example 46) [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (50.0 mg, 315.0 μmol), 1-methylimidazole (63.5 μL, 788.0 μmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (110.6 mg, 394.0 μmol) in NMP (0.7 mL) is stirred at room temperature for 5 min. 5-Trifluoromethyl-4-aminopyrimidine (54.0 mg, 331.0 μmol) is added and the mixture is stirred at room temperature for 4 h. Intermediate B-1 (73.4 mg, 331.0 μmol) and DIPEA (0.3 mL, 1.7 mmol) are added to the reaction mixture. The mixture is stirred at 100° C. for 18 h and then cooled to room temperature. The reaction mixture is diluted with acetonitrile and purified twice by preparative HPLC to give Example 46. ESI-MS: 453 [M+H] + ;HPLC(Rt): 0.79 min (Method B)

Claims

1. A compound of formula (I) or a salt thereof. 【Chemistry 1】 (In the formula, A is, 【Chemistry 2】 Group A consisting of a Selected from: R 1 is a group R consisting of H- and F- 1a Selected from: R 2 is a group R consisting of H- and F- 2a Selected from: R 3 is a halogen, F 2 HCO-, F 3 CO-, F 2 HC- and F 3 A group R consisting of C- 3a Selected from: R 4 is H- and C 1-3 -alkyl- 4a is selected from Here, the C 1-3 The -alkyl- group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine.

2. A, 【Chemistry 3】 Group A consisting of b 2. The compound of claim 1, or a salt thereof, selected from:

3. R 3 is F-, Cl- and F 2 The group R consists of HC- 3b 3. The compound according to claim 1 or 2, or a salt thereof, selected from:

4. R 3 is a group R consisting of F- 3c 3. The compound according to claim 1 or 2, or a salt thereof, selected from:

5. R 4 But H-, C 1-2 -Alkyl- and F 3 A group R consisting of C- 4b The compound according to any one of claims 1 to 4, or a salt thereof, selected from the group consisting of

6. R 4 But, C 1-2 -alkyl- 4c The compound according to any one of claims 1 to 4, or a salt thereof, selected from the group consisting of 【Request 7】 【Table 1】 A compound selected from the group consisting of:

8. A pharma- ceutically acceptable salt of the compound of claim 7.

9. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 7 or a pharma- ceutically acceptable salt thereof, optionally including one or more pharma- ceutically acceptable carriers.

10. Schizophrenia; Positive symptoms associated with schizophrenia, schizoaffective disorder, schizophreniform and schizophreniform disorders, treatment-resistant schizophrenia, attenuated psychotic syndromes and autism spectrum disorder; Enhancement treatment of positive symptoms associated with schizophrenia, antipsychotic augmentation; Negative symptoms associated with schizophrenia, schizoaffective disorder, schizophreniform and schizophreniform disorders, treatment-resistant schizophrenia, attenuated psychotic syndromes and autism spectrum disorder; Cognitive impairment associated with schizophrenia (CIAS), schizoaffective disorder, schizophreniform and schizophreniform disorders, treatment-resistant schizophrenia, attenuated psychotic syndromes and autism spectrum disorder; Treatment-resistant schizophrenia; Schizoaffective disorder; Schizophreniform disorders; Schizophreniform disorders; Medication-induced psychotic disorder The pharmaceutical composition of claim 9 for use in the prevention or treatment of: bipolar disorder; Alzheimer's disease; Parkinson's disease; attenuated psychotic syndromes and neuropsychiatric symptoms associated with vascular dementia and frontotemporal dementia; autism spectrum disorder (ASD); impulse control disorders induced by D2 receptor agonists; gambling disorder induced by D2 receptor agonists, Tourette's syndrome; cognitive deficits associated with Alzheimer's disease, Parkinson's disease, vascular dementia and frontotemporal dementia; depression; attention deficit hyperactivity disorder; major depressive disorder; drug addiction; anxiety; mania in bipolar disorder; acute mania; agitation; isolation; and symptoms associated with frontal lobe hypofunction (e.g. frontal lobe hypofunction associated with drug abuse) and / or hyperkinetic symptoms.

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