3-Phenoxyazetidine-1-yl-heteroarylpyrrolidine derivatives and their use as pharmaceuticals

Abstract

The present invention relates to (3)-phenoxyazetidin-(1)-yl-heteroarylpyrrolidine derivatives 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-heteroarylpyrrolidine derivatives of general formula (I) for use as medicines, pharmaceutical compositions comprising at least one compound of general formula (I) and methods for preparing pharmaceutical compositions, as well as methods for preparing the compounds according to the invention.

Description

[Technical Field]

[0001] The present invention relates to a 3-phenoxyazetidine-1-yl-heteroarylpyrrolidine derivative of general formula (I), which is a GPR52 agonist and is useful for the treatment of central nervous system diseases and other diseases. Furthermore, the present invention relates to a 3-phenoxyazetidine-1-yl-heteroarylpyrrolidine derivative of general formula (I) for use as a pharmaceutical, a pharmaceutical composition containing the 3-phenoxyazetidine-1-yl-heteroarylpyrrolidine derivative of general formula (I), a method for preparing the pharmaceutical composition, and a method for producing the compound according to the present invention. [Background technology]

[0002] Human GPR52 is a G protein-coupled receptor (GPCR). Its highest expression level in the human central nervous system (CNS) is found in the striatum (WO2016 / 176571). Lower but significant expression levels are found in many other CNS structures, including the cortex. GPR52 co-localizes almost exclusively with the D2 receptor in the human and rodent striatum, and almost exclusively with the D1 receptor 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. In contrast, D2 receptors are generally Gi-coupled, negatively regulating cAMP production and reducing PKA activity. GPR52 co-localizes with D1 receptors in the cortex, and since both GPR52 and D1 receptors are Gs-coupled, GPR52 agonists are functionally similar to D1 agonists and therefore should affect cortical and frontal lobe function decline. Several compounds are known to function as D1 agonists in the cortex, improving cortical function and restoring frontal lobe function decline.

[0003] The efficacy of existing antipsychotic drugs has been reported to be mediated by D2 antagonist activity against medium spiny neurons (MSNs) in the striatum. However, D2 antagonists cause side effects such as motor symptoms and hyperprolactinemia. GPR52 co-localizes almost exclusively with D2 receptors in the striatum, and since GPR52 is Gs-coupled and D2 is Gi-coupled, GPR52 agonists are functionally similar to D2 antagonists and should therefore exhibit antipsychotic efficacy. Furthermore, since many of the side effects associated with D2 antagonists are mediated by D2 receptors, GPR52 agonists may avoid the side effects associated with existing D2 antagonists. Based on its expression pattern, co-localization, intracellular signaling, and functional characteristics, GPR52 is suggested to be an important regulator of brain function related to the treatment of several neurological and psychiatric disorders, including those described below.

[0004] (1) Frontal lobe dysfunction Reduced blood flow in the prefrontal cortex (frontal lobe dysfunction) is a symptom of several neurological conditions, including cognitive and negative symptoms associated with schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and frontal lobe dysfunction 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 using GPR52 agonists is useful in treating symptoms associated with frontal lobe dysfunction.

[0005] (2) Movement impairment The striatum is involved in the control of movement. Pathophysiology of the striatum is associated with many movement disorders, including hyperkinetic disorders (known as hyperkinesia), which are characterized by excessive abnormal involuntary movements. Examples of hyperkinetic disorders include tremor, dystonia, chorea, ballism, athetosis, Tourette syndrome, Huntington's disease, myoclonus and startle syndrome, stereotypic disorders, and akathisia.

[0006] In the striatum, GPR52 is expressed almost exclusively on indirect pathway neurons in the striatum. Hyperkinesia is associated with dysfunction of inhibitory D2-expressing neurons in this pathway. This dysfunction prevents the suppression of movement, resulting in tics, chorea, phonation, tremors, and other hyperkinesia symptoms. For example, the early hyperkinesia symptoms of Huntington's disease are a 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). Stimulating GPR52 with an agonist activates the indirect pathway in the striatum, leading to more inhibitory control of movement and reversal of hyperactivity symptoms. Therefore, the GPR52 agonists disclosed herein are useful for treating such symptoms.

[0007] (3) Psychotic disorders The psychotic symptoms of schizophrenia are attributed 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 antipsychotics for treating psychotic symptoms depends on D2 receptor blockade. All known antipsychotics effective in treating psychosis are either dopamine D2 receptor antagonists or partial agonists (Remington G, Kapur S (2010) Antipsychotic dosing: how much but also how often? Schizophr Bull. 36, 900-903). While these antipsychotics can treat the positive (or psychotic) symptoms of schizophrenia, they do not treat other aspects of the disease, such as negative symptoms or cognitive impairment. Based on the co-expression of GPR52 and dopamine D2 receptors, GPR52 agonists should treat psychotic symptoms associated with schizophrenia. Furthermore, because the mechanism of action of GPR52 agonists is specific to known D2 receptor-associated antipsychotics, GPR52 agonists are expected to enhance the antipsychotic efficacy of known neuroleptics. This could not only improve antipsychotic efficacy but also allow for a reduction in antipsychotic dosage, thereby reducing the side effects associated with antipsychotics. While elevated serum prolactin levels are one of the prominent side effect profiles of known D2R antagonist antipsychotics, GPR52 agonists have been shown to lower serum prolactin levels; 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.Furthermore, GPR52 agonists are expected to treat psychotic symptoms associated with a variety of psychiatric signs, including schizoaffective disorder, schizotypal disorder, schizotypal-like disorder, treatment-resistant schizophrenia, drug-induced mental disorders, bipolar disorder, autism spectrum disorder, and debilitating psychosis syndrome. In addition, GPR52 agonists are expected to treat psychotic and neuropsychiatric symptoms associated with a variety of neurodegenerative signs, including Parkinson's disease, Alzheimer's disease, frontotemporal dementia, vascular cognitive impairment, and Lewy body dementia. These antipsychotics also come with a significant side effect profile, including weight gain, metabolic syndrome, diabetes, hyperlipidemia, hyperglycemia, insulin resistance, extrapyramidal symptoms, hyperprolactinemia, and tardive dyskinesia. Since GPR52 agonists should be functionally similar to D2 antagonists, the GPR52 agonists disclosed herein are useful for the treatment of psychotic disorders.

[0008] (4) Other D1-related disorders Several neurological and psychotropic drugs are known to function as D1 agonists, including A-86929, dinapsolin, doxanthrine, SKF-81297, SKF-82958, SKF-38393, phenoldopam, 6-Br-APB, and stephoroidin. Since GPR52 agonists should be functionally similar to (and co-localize with) D1 agonists, the GPR52 agonists disclosed herein are useful in treating disorders treatable by D1 agonists, including, but not limited to, addiction (e.g., cocaine addiction), hypertension, restless limb syndrome, Parkinson's disease, and depression. Furthermore, based on their expression patterns and functional coupling, GPR52 agonists are useful in treating cognitive deficits associated with schizophrenia, schizophrenia-like disorders, treatment-resistant schizophrenia-degenerative psychosis syndrome and schizophrenic disorders, bipolar disorder, autism spectrum disorder, Alzheimer's disease, Parkinson's disease, frontotemporal dementia (Pick's disease), Lewy body dementia, vascular dementia, post-stroke dementia, and Creutzfeldt-Jakob disease.

[0009] (5) Other D2-related disorders Since some neurological disorders, such as obsessive-compulsive disorder and impulse control disorder, involve alterations in dopamine receptor signaling, GPR52 agonists are useful in treating these symptoms (Lopez AM, Weintraub D, Claassen DO (2017) Impulse control disorders and related complications of Parkinson's Disease Therapy. Semin Neurol. 37, 186-192) (Koo MS, Kim EJ, Roh D, Kim CH (2014) Role of dopamine in the pathophysiology and treatment of obsessive-compulsive disorder. Exp. Rev. Neurotherap. 10, 275-290). Furthermore, it is known that several neurological and psychotropic drugs function as D2 antagonists. Such drugs include atypical antipsychotics (e.g., aripiprazole, clozapine, olanzapine, and ziprasidone), domperidone, eticlopride, falprid, desmethoxyfalprid, L-741, 626, lacloprid, hydroxyzine, itopride, SV293, typical antipsychotics, yohimbine, amisulpride, and UH-232. Since GPR52 agonists should be functionally similar to D2 antagonists, the GPR52 agonists disclosed herein are useful in treating disorders treatable by D2 antagonists, including, but not limited to, psychotic disorders, separation, anxiety, anxiety / tension associated with neuropsychiatric disorders, acute mania, agitation, mania in bipolar disorder, dysthymia, nausea, vomiting, gastrointestinal disorders, indigestion, and addictions (e.g., cocaine addiction, amphetamine addiction, etc.).

[0010] Therefore, GPR52 agonists are considered promising candidates for treating central nervous system disorders. Thus, there is a need to develop compounds that may have agonist activity against GPR52 for the prevention and / or treatment of mental disorders. In particular, there is a need to develop compounds that possess optimized drug properties that could be useful as agonists for GPR52 and as agents for the prevention and / or treatment of mental disorders such as schizophrenia. International Patent Applications 2009 / 157196, 2009 / 107391, 2011 / 078360, 2011 / 093352, 2011 / 145735, 2012 / 020738, 2016 / 176571, and 2021 / 090030, 2021 / 198149, and 2021 / 216705 disclose compounds that modulate GPR52 for the treatment of central nervous system disorders and other diseases. [Overview of the project]

[0011] Objective of the present invention We have now found that the compound of the present invention according to general formula (I), or a pharmaceutically acceptable salt thereof, is an effective agonist of GPR52. In addition to their agonist properties against GPR52, the compounds of the present invention offer further effective properties that are feasible for human therapeutics, such as low plasma protein binding rates, high stability within human hepatocytes, drug metabolism involving non-CYP enzymatic metabolism such as hydrolytic enzyme pathways, low hERG channel inhibition (or interaction), and / or sufficient water solubility of compounds used as drugs. The compounds of the present invention according to general formula (I) are metabolically stable in human hepatocytes. Therefore, the compounds of the present invention are expected to have favorable in vivo clearance and, as a result, a desired duration of action in humans. Since the liver is the primary site for metabolizing many drugs, hepatocytes represent a model system for studying in vitro drug metabolism. Improved stability in human hepatocytes is associated with several pharmacokinetic advantages, including a longer half-life that can enable improved bioavailability and / or reduced patient dosage and / or reduced administration frequency. Reducing the effective dose and / or effective frequency of administration of compounds for disease treatment minimizes potential side effects. Thus, improved metabolic stability in human hepatocytes is a desirable characteristic of compounds used as drugs.

[0012] Furthermore, the compounds of the present invention according to general formula (I) exhibit low plasma protein binding rates, resulting in a high fraction unbound in plasma, which represents further potential advantages such as a sufficiently low effective dose of the compound for disease treatment, and consequently, minimization of side effects. Consequently, the compounds of the present invention, particularly those of general formula (I) possessing both high / moderate metabolic stability and low plasma protein binding rates, are viable for human treatment. The compound of the present invention according to general formula (I), provided that group R 6 C 1-3 Alkylcarbonyl moieties exhibit enzymatic metabolism other than CYP enzymes, particularly through hydrolytic enzymes, which contributes to the diversification of the overall metabolism and results in a reduction of the risk of pharmacokinetic drug-drug interactions mediated by cytochrome P450 enzymes.

[0013] Drug-drug interactions refer 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 serious pharmacokinetic interactions involve a second drug altering the clearance of a first drug. For example, a co-administered drug may inhibit the metabolism of a first drug, leading to increased plasma concentrations of the first drug, which can result in a clinically relevant increase in therapeutic response or increased toxicity. Drug metabolism primarily takes place in the liver and intestines. These organs express a wide variety of drug-metabolizing enzymes and are responsible for the biotransformation of many drugs. Phase I oxidative metabolism is mainly mediated by enzymes of the cytochrome P450 (CYP) family found in the hepatic endoplasmic reticulum, but can also be mediated by enzymes other than CYP, such as hydrolases. Following these functionalization reactions, conjugation reactions (Phase II) often occur to enhance the excretion of xenobiotics. 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, while drug metabolism via pathways mediated by enzymes other than CYP is less prominent. If CYP-independent pathways are involved in the oxidation, hydrolysis, or conjugation of drugs, aldehyde oxidases, esterases / hydrolases, and uridine diphosphate glucuronosyltransferases (UGTs) are the main enzymes that catalyze these metabolic processes, respectively. For example, the main enzymes responsible for amide hydrolysis, which produce N-deacylation of drugs, are serine hydrolases such as arylacetamide deacetylases. Liver microsomes provide an excellent in vitro tool for identifying metabolic pathways other than the CYP pathway mentioned above, including elucidating the main metabolites.

[0014] In psychiatric clinical practice, combination drug therapy is commonly used to treat patients with co-occurring mental or physical illnesses, to suppress the side effects of specific drugs, or to enhance drug efficacy. However, such polypharmacy approaches increase the risk of drug-drug interactions mediated by CYP enzymes. Therefore, especially in elderly patients who are likely to take multiple drugs simultaneously, it is desirable to use drugs with a low probability of drug-drug interactions (Spina E, de Leon, J. (2007) Metabolic Drug Interactions with Newer Antipsychotics: A Comparative Review. Basic Clin. Pharmacol. Toxicol. 100, 4-22). Therefore, group R 6 C 1-3 -Further contributions to overall metabolic clearance via enzyme-dependent pathways other than CYP, such as hydrolytic enzymes, are highly desirable, as exemplified by the compounds of the present invention with the alkylcarbonyl moiety of general formula (I), resulting in greater metabolic diversification and a reduced risk of drug-drug interactions. Consequently, the compounds of the present invention are viable for human therapeutic use.

[0015] Inhibition of hERG channels and subsequent delayed cardiac repolarization are 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, in vitro screening for hERG channel inhibition using heterologous expression of hERG channels is a common practice and an important part of late preclinical profiling, as recommended in 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). Therefore, low / moderate hERG channel inhibition or interaction, as demonstrated by the compounds of the present invention, is highly desirable. Consequently, the compounds of the present invention are viable for human therapeutic use. The compounds of the present invention according to formula (I) exhibit the acceptable water solubility of compounds used as drugs. Improving the solubility of compounds leads to improved development possibilities for drug products. Furthermore, as is well known in this art, poorly soluble compounds may result in insufficient human exposure.

[0016] Accordingly, one aspect of the present invention refers to a compound according to general formula (I) or a salt thereof as an agonist of GPR52, preferably a pharmaceutically acceptable salt thereof. Another aspect of the present invention refers to a compound according to general formula (I) or a salt thereof, preferably a pharmaceutically acceptable salt thereof, as an agonist of GPR52 having high / moderate human hepatocyte stability. Another aspect of the present invention refers to a compound according to general formula (I) or a salt thereof, preferably a pharmaceutically acceptable salt thereof, as an agonist of GPR52 having a low / moderate human plasma protein binding rate. Another aspect of the present invention relates to a group R as an agonist of GPR52 having diversified metabolism including metabolic pathways dependent on enzymes other than CYP, such as hydrolytic enzyme-mediated metabolism. 6 C 1-3 - This refers to a compound with a general formula (I) that is an alkylcarbonyl moiety, or a salt thereof, preferably a pharmaceutically acceptable salt thereof. Another aspect of the present invention refers to a compound according to general formula (I) or a salt thereof, preferably a pharmaceutically acceptable salt thereof, as a GPR52 agonist that inhibits hERG channels to a low / moderate degree.

[0017] Another aspect of the present invention refers to a compound according to general formula (I) or a salt thereof, preferably a pharmaceutically acceptable salt thereof, as an agonist of GPR52, which has sufficient water solubility for compounds used as drugs. Another aspect of the present invention refers to a compound according to general formula (I) or a salt thereof as an agonist of GPR52 having high / moderate human hepatocyte stability and low / moderate human plasma protein binding. Another aspect of the present invention refers to a compound according to general formula (I) or a salt thereof as an agonist of GPR52 having high / moderate human hepatocyte stability, low / moderate human plasma protein binding rate, and diversified metabolism including metabolic pathways dependent on enzymes other than CYP, such as hydrolytic enzyme-mediated metabolism. Another aspect of the present invention relates to high / moderate human hepatocyte stability, low / moderate human plasma protein binding rate, and metabolism via hydrolytic enzymes (group R). 6 C 1-3 This refers to compounds according to general formula (I) or salts thereof that act as agonists of GPR52, including diversified metabolic pathways that depend on enzymes other than CYP (such as the alkylcarbonyl moiety), low / moderate hERG channel inhibition, and optionally, compounds that have sufficient water solubility for use as drugs.

[0018] In a further embodiment, the present invention relates to a pharmaceutical composition comprising at least one compound according to general formula (I) or a pharmaceutically acceptable salt thereof, together with one or more inert auxiliaries, diluents and / or carriers. A further aspect of the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of disorders associated with insufficient GPR52 activity, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. Another aspect of the present invention relates to a process for preparing a compound of the present invention of general formula (I) or a salt thereof, particularly a pharmaceutically acceptable salt. Other objects of the present invention will be apparent to those skilled in the art directly from the foregoing and following descriptions.

BRIEF DESCRIPTION OF THE INVENTION

[0019] In a first aspect, the present invention provides a compound of general formula (I) or a salt thereof

CHEMICAL FORMULA

CHEMICAL FORMULA

[0020] In a further embodiment of the present invention, B is [ka] Group B consisting of b Selected from.

[0021] In a further embodiment of the present invention, B is [ka] Group B consisting of c Selected from.

[0022] Further embodiments of the present invention include compounds of general formula (II). [ka] (II) (In the formula, A, B, R 1 , R 2 , R 3 , R 4 , R5 and R 6 (wherein is a substituent as described in the present invention), and the compounds of general formula (II) are from group B, R 4 and R 5 This invention relates to a compound characterized by being a single enantiomer, multiple diastereoisomers, or a single diastereoisomer, in the sense of a single enantiomer.

[0023] General formula (II) is General formula (IIB) b ) and (IIB c ) [ka] It includes.

[0024] Further embodiments of the present invention include compounds of general formula (I.II). [ka] (I.II) (In the formula, A, B, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 (wherein is a substituent as described in the present invention), and compounds of general formula (I.II) belong to groups B and R. 4 and R 5 This invention relates to a compound characterized by being a single enantiomer, multiple diastereoisomers, or a single diastereoisomer, in the sense of a single enantiomer.

[0025] General formula (I.II) is General formula (I.II.B b ) and (I.II.B c ) [ka] It includes.

[0026] General formula (II) (for example, general formula (IIB) b ) or (IIBc )) are Group B, R 4 and R 5 The meaning of R 4 and R 5 It can be understood by those skilled in the art that the arrangement of chiral carbon atoms having a single enantiomer or multiple diastereoisomers or a single diastereoisomer can be included. The same applies to general formula (I.II) (for example, general formula (I.II.B b ) or (I.II.B c This also applies to )). For example, the general formula (IIB b ) is R 4 and R 5 The same meaning (for example, R 4 and R 5 Both are H-, or R 4 and R 5 The case where all of the elements are F- contains one type of single enantiomer. The same applies to the general formula (I.II.B b This also applies to ). For example, the general formula (IIB b ) is R 4 and R 5 Different meanings (for example, R 4 is H-, and R 5 If it has F-, it includes multiple types of diastereoisomers. The same applies to the general formula (I.II.B b This also applies to ). For example, the general formula (IIB b ) is R 4 and R 5 Different meanings (for example, R 4 is H-, and R 5 (is F-), and R 4 and R 5 A single diastereoisomer is included when the chiral carbon atoms having the specified configuration (i.e., (S) or (R)) are included. The same applies to general formula (I.II.B b This also applies to ).

[0027] Further embodiments of the present invention include the general formula (IIBb relates to the compound of (). A further embodiment of the present invention is a compound of the general formula (I.II.B b relates to the compound of (). In a further embodiment of the present invention, A is selected from the group A consisting of -CH=CH- b selected from. In a further embodiment of the present invention, A is selected from the group A consisting of -S- c selected from. In a further embodiment of the present invention, R 3 is selected from the group R consisting of F-, Cl-, and F2HC- 3b selected from. In a further embodiment of the present invention, R 3 is selected from the group R consisting of F- 3c selected from. In a further embodiment of the present invention, R 6 is selected from the group R consisting of C 1-3 -alkylcarbonyl-, 6b selected from, where the C 1-3 -alkylcarbonyl- group may be substituted with 1 to 5 (e.g., 2, 3, or 4) deuteriums. In a further embodiment of the present invention, R 6 is selected from the group R consisting of acetyl 6c selected from, where the acetyl- group may be substituted with 1, 2, or 3 deuteriums.

[0028] A x 、B x 、R 1x 、R 2x 、R 3x 、R 4x 、R 5x and R 6x each represent individual embodiments characterized by the corresponding substituents as described above. Thus, when the above definitions are given, the individual embodiments of the first aspect of the present invention are the terms (A x 、B x 、R 1x 、R 2x 、R3x , R 4x , R 5x and R 6x The invention is fully characterized by the above definitions, where each subscript "x" is defined as an individual character ranging from "a" to the last letter in alphabetical order. All individual embodiments described by the parenthetical terms, with reference to the above definitions and with complete substitution of the subscript "x", constitute the present invention. Table 1 below shows embodiments E-1 to E-50 or salts thereof of compounds of general formula (I) that are considered preferred, preferably pharmaceutically acceptable salts. Embodiments E-8, E-9, E-26, E-27, E-45, and E-46 in Table 1 are more preferred embodiments. All embodiments E-1 to E-50 in Table 1 are configurations of general formula (II) or general formula (I.II), for example, general formula (IIB b ), (IIB c ), (I.II.B b ) or (I.II.B c The arrangement may be as follows, preferably as follows:

[0029] [Table 1] TIFF0007883575000010.tif242169 Therefore, for example, E-2 is a compound of general formula (I) (In the formula, A is a group consisting of -CH=CH- and -S-. a Selected from; B is [ka] Group B consisting of a Selected from; R 1 This is the group R consisting of H- and F- 1a Selected from; R 2 This is the group R consisting of H- and F- 2a Selected from; R 3The group R consists of F-, Cl-, F2HCO-, F3CO-, F2HC-, and F3C-. 3a Selected from; R 4 This is the group R consisting of H- and F- 4a Selected from; R 5 This is the group R consisting of H- and F- 5a Selected from; R 6 C 1-3 -alkylcarbonyl-, group R 6b Selected from, Here, C 1-3 (The alkylcarbonyl group may be substituted with 1 to 5 deuterium atoms.) or a salt thereof, preferably a pharmaceutically acceptable salt.

[0030] Therefore, for example, E-26 is a compound of general formula (I). (In the formula, A is a group consisting of -CH=CH-. b Selected from; B is [ka] Group B consisting of b Selected from; R 1 This is the group R consisting of H- and F- 1a Selected from; R 2 This is the group R consisting of H- and F- 2a Selected from; R 3 This is the group R consisting of F- 3c Selected from; R 4 This is the group R consisting of H- and F- 4a Selected from; R 5 This is the group R consisting of H- and F- 5a Selected from; R 6 C 1-3 -alkylcarbonyl-, group R 6b Selected from, Here, C 1-3 (The alkylcarbonyl group may be substituted with 1 to 5 deuterium atoms.) or a salt thereof, preferably a pharmaceutically acceptable salt.

[0031] Therefore, for example, E-45 is a compound of general formula (I). (In the formula, A is a group consisting of -S- c Selected from; B is [ka] Group B consisting of b Selected from; R 1 This is the group R consisting of H- and F- 1a Selected from; R 2 This is the group R consisting of H- and F- 2a Selected from; R 3 This is the group R consisting of F- 3c Selected from; R 4 This is the group R consisting of H- and F- 4a Selected from; R 5 This is the group R consisting of H- and F- 5a Selected from; R 6 C 1-3 -alkylcarbonyl- group R 6b Selected from, Here, C 1-3 (The alkylcarbonyl group may be substituted with 1 to 5 deuterium atoms.) or a salt thereof, preferably a pharmaceutically acceptable salt.

[0032] Even more preferable are the following compounds shown in Table 2, their salts, or their stereoisomers (the numbers refer to the numbers assigned to the compounds in the Experiment section). Each compound in Table 2 is represented without indicating its stereochemistry, if present. Specific information considering the stereochemical properties of the compounds in Table 2 can be obtained from the Experiment section. If the final compound obtained from the Experiment section is in salt form, it may be converted to a neutral compound by conventional methods.

[0033] [Table 2] TIFF0007883575000015.tif203146

[0034] Further embodiments of the present invention include compounds of general formula (I), in particular pharmaceutically acceptable forms of their salts, as shown in Table 2. In a further embodiment, the present invention relates to a pharmaceutical composition comprising at least one compound according to general formula (I) or a pharmaceutically acceptable salt thereof, which may together comprise at least one inert auxiliaries, diluents and / or carriers. In further embodiments, the present invention relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a pharmaceutical, or at least one compound according to general formula (I) or a pharmaceutically acceptable salt thereof. In further embodiments, the present invention relates to a compound according to general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to general formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of diseases or conditions that may be affected by the activation of GPR52.

[0035] Terms and definitions used Hereinafter, several terms used above and below to describe the compounds according to the present invention will be defined in more detail. Terms not specifically defined herein should be given the meaning that a person skilled in the art would give to such terms, considering this disclosure and its context. However, as used herein, unless otherwise specified, the following terms have the meanings shown and the following conventions shall be observed. The term “C 1-3 "-alkyl" refers to an acyclic, cyclic, saturated, branched, or linear hydrocarbon radical having one, two, or three carbon atoms, either alone or in combination with another radical. For example, the term C 1-3 -Alkyl radicals include H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, and (CH2)2-CH-.

[0036] Generally, in groups containing two or more subgroups, the last named subgroup is the radical attachment site, for example, the substituent "C 1-3 "-alkyl-carbonyl-" indicates that the carbonyl group is bonded to the carbonyl group. 1-3 - an alkyl group, and the latter C 1-3 -This means that the alkyl group is bonded to the core molecule or base to which the substituent is attached. The same applies to the substituent "C 1-3 This also applies to "-alkyl-sulfonyl-". For example, "C 1-3 The "-alkylcarbonyl-" group is selected from the group consisting of acetyl (i.e., CH3C(O)-), ethanecarbonyl (i.e., CH3CH2C(O)-), propanecarbonyl (i.e., CH3(CH2)2C(O)-), isopropanecarbonyl (i.e., CH3CH(CH3)C(O)-), and cyclopropanecarbonyl (i.e., (CH2)2CHC(O)-), for example, "C 1-3 The "-alkylsulfonyl- group" is selected from the group consisting of methanesulfonyl (i.e., CH3S(O)2-), ethanesulfonyl (i.e., CH3CH2S(O)2-), propanesulfonyl (i.e., CH3(CH2)2S(O)2-), isopropanesulfonyl (i.e., CH3CH(CH3)S(O)2-), and cyclopropanesulfonyl (i.e., (CH2)2CHS(O)2-).

[0037] As used herein, the term “substituted” means that any one or more hydrogen atoms on a given atom / group are replaced by those selected from the indicated group, provided that the number of valencies of the given atom is not exceeded and the substitution results in a stable compound. Furthermore, as used herein, the term “substituted with 1 to 5 substituents” means that 1, 2, 3, 4, or 5 substituents may be present on the given atom / group. Many of the terms defined above may be used repeatedly in the definitions of formulas or bases, and in each case, one of the above meanings may be independent of the others. If the compounds of the present invention are expressed in both chemical name form and formula form, the formula shall prevail in the event of any inconsistency. dotted line [ka] The sub-formula is used to indicate a bond or attachment point connected to the core molecule, which is the rest of the molecule, or a bond or attachment point connected to a substituent that is bonded as defined.

[0038] Unless otherwise specified, throughout the specification and the attached claims, a given chemical formula (e.g., all compounds in Table 2) or name shall encompass rotational isomers, tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., diastereomers, enantiomers, E / Z, trans / cis isomers, etc., according to general formula (II) or (I.II)) and their racemates, as well as mixtures of different enantiomers in varying proportions, mixtures of diastereomers, or any mixture of the aforementioned forms in which the isomers exist, and their solvates, such as hydrates. For example, it can be understood by those skilled in the art that compound 1 in Table 2 encompasses two enantiomers, either as a mixture (e.g., a racemic mixture) or as a single enantiomer (e.g., (S) or (R)). Furthermore, it will be understood by those skilled in the art that compound 3 (or 14 or H-2) in Table 2 encompasses two cis-stereoisomers and two trans-stereoisomers, either as a mixture of two or four stereoisomers (e.g., a cis-racemic mixture and / or a trans-racemic mixture) or as a single stereoisomer. Unless otherwise specified, the term "pharmaceutically acceptable salt," as defined in more detail below, also includes its solvates, such as hydrates.

[0039] As used herein, “pharmaceutically acceptable salt” refers to a derivative of a compound of the disclosure in which the parent compound is modified to produce an acid salt or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of such salts include 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-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Furthermore, pharmaceutically acceptable salts can be produced from cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in free acid or free base form with a sufficient amount of a suitable base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0040] For example, salts of other acids (e.g., trifluoroacetates) that are useful for purifying or isolating the compounds of the present invention also constitute part of the present invention. The term "pharmaceutically acceptable adjuvants, diluents and / or carriers" is used herein to mean materials that, within the bounds of sound medical judgment, are suitable for use in contact with human tissue without causing excessive toxicity, irritation, allergic reactions or other problems or complications, and that have a reasonable benefit-risk ratio.

[0041] preparation The compounds according to the present invention can, in principle, be obtained using known synthesis methods. Preferably, the compounds are obtained by the method described below according to the present invention, which will be explained in more detail below. The following scheme illustrates, in general terms, a method for producing the compounds of the present invention. Substituents that are omitted may be as defined above unless otherwise defined in the context of the scheme. The present invention also provides a method for producing the compound of formula (I). Unless otherwise specified, A, B, and R in the following formulas 1 , R 2 , R 3 , R 4 , R 5 and R 6 This has the meaning defined for formula (I) in the detailed description of the invention described above. The optimal reaction conditions and reaction time may vary depending on the reactants used. Unless otherwise specified, the solvent, temperature, pressure, and other reaction conditions can be easily selected by those skilled in the art. Specific procedures are described in the Experimental section. Typically, the progress of the reaction can be monitored by thin-layer chromatography (TLC), and optionally by liquid chromatography-mass spectrometry (LC-MS), and intermediates and products can be purified by chromatography and / or recrystallization.

[0042] The following examples are illustrative, and as those skilled in the art will recognize, specific reagents or conditions may be modified as needed for individual compounds without excessive experimentation. The starting materials and intermediates used in the methods described below are commercially available or readily prepared by those skilled in the art from commercially available materials. [ka] Scheme 1 Scheme 1 shows the synthesis of amine (V) as an intermediate in the synthesis of compound (I). In the first step, a properly protected (PG is a protecting group, e.g., CO2tBu(BOC), CO2Bn) and properly activated (sulfonyl ester, substituent R, e.g., methyl, CF3, or tolyl) azetidine (II) is reacted with phenol (III) using a suitable solvent such as dimethylacetamide, dimethylformamide, N-methylpyrrolidinone, acetonitrile, DMSO, dichloromethane, or toluene, and a suitable base such as cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium hydroxide, N-ethyl-diisopropylamine, or pyridine to produce 3-phenoxyazetidine (IV). This intermediate is deprotected in the second step to obtain amine (V). Deprotection can be carried out by using a mineral acid, such as hydrochloric acid, on the BOC-protected intermediate (IV), or by catalytic hydrogenation of the benzyloxycarbonyl-protected intermediate (IV) using a catalyst such as palladium carbon under a hydrogen atmosphere. Other deprotection reactions are described in 'Protective Groups in Organic Synthesis', 3rd edition, TW Greene and PGM Wuts, Wiley-Interscience (1999). Depending on the reaction conditions and workup, amine (V) may be obtained as a salt.

[0043] [ka] Scheme 2 As shown in Scheme 2, the amine of formula (V) is converted into a haloester (VI) (X = halide, R) in a suitable solvent such as dioxane, THF, DMA, or DMF, in the presence of a suitable base such as potassium tert-butoxide or NaH. x By reacting with an alkyl group (X=Cl, Br, I;R) in an aromatic nucleophilic substitution reaction (Step 1), the ester compound of formula (VII) is obtained. Alternatively, compound (VII) can be produced using Buchwald-Hartwig type cross-coupling conditions. For example, compound (IV) (X=Cl, Br, I;R) x Compounds of general formula (VII) can be obtained by reacting an amine (V) with an alkyl group (=alkyl) in a suitable solvent such as toluene, in the presence of a suitable catalyst such as palladium(II) acetate, a suitable ligand such as butyl-di-1-adamantylphosphine, and a suitable base such as cesium carbonate.

[0044] Alternatively, the haloester (VI) can be reacted with hydroxyazetidine via aromatic nucleophilic substitution in a suitable solvent such as DMA and in the presence of a suitable base such as triethylamine to obtain the alcohol of general formula (VIII). In the next step, the alcohol (VIII) can be converted to the phenyl ether compound of formula (VII) using the "Mitsunobu" method (see, e.g., Tet. Lett. 1994, 35, 2819 or Synlett 2005, 18, 2808). In a suitable solvent (e.g., THF or toluene) and in the presence of a suitable phenol (III), a solid-supported analog such as a trialkylphosphine or triarylphosphine (e.g., tributylphosphine or triphenylphosphine) or polymer-linked triphenylphosphine, and a suitable dialkylazadicarboxylate (e.g., DIAD, DEAD) are added to the compound of general formula (VIII) to produce the aryl ether of general formula (VII).

[0045] [ka] Scheme 3 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, or THF / water to produce the corresponding carboxylic acid (IX).

[0046] By applying peptide coupling reactions known to those skilled in the art (see, for example, M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag), the amine of formula (X) can be reacted with a carboxylic acid (IX) to obtain the compound of general formula (I). For example, when an amine (X) and a carboxylic acid (IX) are treated in a suitable solvent such as acetonitrile, NMP, DMA, or DMF, in the presence of a suitable base such as DIPEA or 1-methylimidazole, with a coupling agent such as 2-chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium hexafluorophosphate (CIP), Mukaiyama reagent, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (HATU), the compound of formula (I) is produced.

[0047] Alternatively, carboxylic acid (IX) may 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 obtain an intermediate acid chloride, which is then treated with the amine of formula (X) in a suitable solvent such as DCM, THF, or DMF in the presence of a suitable base such as TEA to obtain the compound of formula (I). Alternatively, an amine (X) pre-activated with trimethylaluminum can be directly reacted with a carboxylic acid ester (VII) in a suitable solvent such as DCM, dichloroethane, THF, or toluene to obtain an amide of general formula (I).

[0048] [ka] Scheme 4 Alternatively, compounds of general formula (I) can be synthesized as shown in Scheme 4: by applying a peptide coupling reaction known to those skilled in the art (see, for example, M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) to the first step, the amine of formula (X) can be reacted with a carboxylic acid (XI) (X = halide, Y = OH) to obtain a haloamide of general formula (XII) (X = halide). For example, when an amine (X) and a carboxylic acid (XI) (X = halide, Y = OH) are treated with a coupling agent such as 2-chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium hexafluorophosphate (CIP), Mukaiyama 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, a haloamide of general formula (XII) is produced. Alternatively, a carboxylic acid (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 obtain an intermediate acid chloride (XI) (Y=Cl), which is then treated with an amine of formula (X) in a suitable solvent such as DCM, THF, or DMF, in the presence of a suitable base such as TEA, to obtain a haloamide (X=halide) of general formula (XII). Alternatively, a amine (X) pre-activated with trimethylaluminum can be directly reacted with a carboxylic acid ester (XI) (X=halide, Y=alkyloxy) in a suitable solvent such as DCM, dichloroethane, THF, or toluene to obtain a haloamide (X=halide) of general formula (XII).

[0049] In the second step, the amine of formula (V) is reacted with a haloamide (XII) (X=halide) by aromatic nucleophilic substitution in a suitable solvent such as 2-propanol, dioxane, THF, NMP, DMA, DMF, or a toluene / water mixture, in the presence of a suitable base such as potassium tert-butoxide, NaH, potassium carbonate, pyridine, triethylamine, or N-ethyl-diisopropylamine, to obtain the compound of general formula (I). Alternatively, the final compound (I) may be produced using Buchwald-Hartwig type cross-coupling conditions. For example, compound (XII) (X=Cl, Br, I) can be reacted with amine (V) in a suitable solvent such as toluene, in the presence of a suitable catalyst such as palladium(II) acetate, a suitable ligand such as butyl-di-1-adamantylphosphine, and a suitable base such as cesium carbonate to obtain the compound of general formula (I).

[0050] Alternatively, in a suitable solvent such as DMA and in the presence of a suitable base such as triethylamine, the haloamide (XII) can be reacted with hydroxyazetidine by aromatic nucleophilic substitution to obtain the alcohol of general formula (XIII). In the next step, the alcohol (XIII) can be converted to the compound of general formula (I) using the "Mitsunobu" method (see, e.g., Tet. Lett. 1994, 35, 2819 or Synlett 2005, 18, 2808). In a suitable solvent (e.g., THF or toluene) and in the presence of a suitable phenol (III), a solid-supported analog such as a trialkylphosphine or triarylphosphine (e.g., tributylphosphine or triphenylphosphine) or polymer-linked triphenylphosphine, and a suitable dialkylazadicarboxylate (e.g., DIAD, DEAD) are added to the compound of general formula (XIII) to produce the compound of general formula (I).

[0051] Schemes 5 and 6 describe the synthesis of an amine of general formula (X) as an intermediate for the synthesis of a compound of general formula (I). [ka]

[0052] Scheme 5 Monofluorinated aminopyrrolidines of general formula (XVII) or general formula (XXI) can be prepared as shown in Scheme 5. A well-protected 6-oxa-3-azabicyclo[3.1.0]hexane(XIV) (PG = protecting group, e.g., CO2tBu or acetyl) is reacted with an azide source such as sodium azide or tetrabutylammonium azide in a suitable solvent such as DMF or DMA to produce a racemic trans-substituted azide alcohol (XV). In the second step, alcohol (XV) is fluorinated with a fluorinating agent such as (diethylamino)sulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) in a solvent such as dichloromethane to produce the corresponding trans-substituted azide fluoride. In the third step, the reduction of azide (XVI) can be carried out by catalytic hydrogenation (for example, hydrogenation using palladium carbon in methanol or ethanol) or by heating the intermediate iminophosphorane with water in THF after adding triphenylphosphine (Staudinger reaction) to produce a racemic trans-substituted monofluoroaminopyrrolidine (XVII). The corresponding cis-substituted monofluoroaminopyrrolidine (XXI) can be synthesized by a similar sequence (steps 6 and 7) starting from a racemic cis-substituted azido alcohol (XVIII), which can be prepared by inverting the stereochemistry of the hydroxyl group of compound (XV) using the prior art (e.g., nucleophilic substitution with potassium acetate after activation of a sulfonyl ester (e.g., R=CH3), followed by saponification; e.g., see Tet. Asymm. 2001, 12, 1793-1799).

[0053] Enantioselective epoxide ring-opening of 6-oxa-3-azabicyclo[3.1.0]hexane(XIV) using chiral metal salen complexes and trimethylsilyl azide (J. Am. Chem. Soc. 1995, 117, 5897) provides access to a trans-enantiomer of general formula (XV) with high purity, which can be converted to chiral fluorinated aminopyrrolidines (XVII) and (XXI), respectively (see, e.g., Synlett 2019, 30, 1228-1230).

[0054] [ka] Scheme 6 Difluorinated aminopyrrolidines of general formula (XXX) can be prepared as shown in Scheme 6. 6-Oxa-3-azabicyclo[3.1.0]hexane(XIV) (PG = protecting group, e.g., CO2tBu(BOC) or acetyl) can be desymmetrized in a one-step or two-step procedure to produce monoprotected pyrrolidinediols of general formula (XXII). For example, nucleophilic epoxide ring-opening using sodium benzyl alkoxide is a one-step process to produce racemic compounds of general formula (XXII) (e.g., PG 1 (See, for example, International Patent Application No. 1999 / 64399, page 20) can be produced. Alternatively, epoxide ring-opening using a hydroxide source such as sodium hydroxide can produce the intermediate pyrrolidinediol, which may be selectively mono-protected using conventional protecting group strategies (for example, a reaction using stoichiometric amounts of tert-butyldimethylsilyl chloride in the presence of a base such as imidazole in a solvent such as DMF can produce a racemic compound (XXII) (PG 1=tert-butyldimethylsilyl) can be produced. The alcohol of general formula (XXII) can be converted to the ketone of general formula (XXIII). For example, compound (XXII) can be oxidized using Dess-Martin periodinane, or by using a combination of oxalyl chloride and DMSO (Swahn oxidation, see, e.g., International Patent Application No. 2010 / 111057, p. 28) in an inert solvent such as dichloromethane. In the third step, the ketone (XXIII) is reacted with a deoxygenating-fluorinating agent such as (diethylamino)sulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride in a solvent such as dichloromethane to obtain the corresponding difluoride (XXIV) (Deoxo-Fluor, see, e.g., International Patent Application No. 2014 / 075392, p. 72). These intermediates are deprotected in the fourth step to obtain alcohol (XXVII). Deprotection can be carried out by using tetrabutylammonium fluoride on the silyl-protected intermediate (XXIV), or by catalytic hydrogenation of the benzyl-protected intermediate (XXIV) using a catalyst such as palladium carbon under a hydrogen atmosphere. Additional deprotection reactions are described in 'Protective Groups in Organic Synthesis', 3rd edition, TW Greene and PGM Wuts, Wiley-Interscience (1999).

[0055] In the fifth step, the hydroxyl group of pyrrolidine (XXVII) can be converted to a properly activated leaving group (e.g., LG = methylsulfonate, trifluoromethylsulfonate, or p-tosylate) by a reaction using a suitable sulfonylic acid derivative (e.g., methylsulfonyl chloride, trifluoromethylsulfonylic anhydride, p-tosylate, etc.) in a solvent such as dichloromethane or THF, in the presence of a base such as triethylamine or pyridine, thereby producing the corresponding sulfonyl ester of general formula (XXVIII). In the sixth step, appropriately activated pyrrolidine (XXVIII) can be reacted by nucleophilic substitution in a suitable solvent such as DMF or DMA with an azide source such as sodium azide or tetrabutylammonium azide to produce azidopyrrolidine (XXIX), which can then be reduced in a subsequent step by catalytic hydrogenation (e.g., hydrogenation using palladium carbon in methanol or ethanol) or by heating the intermediate iminophosphorane with water in THF after adding triphenylphosphine (Staudinger reaction) to produce difluoroaminopyrrolidine of general formula (XXX).

[0056] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors. For example, a suitable optically pure precursor can be obtained from tartaric acid, which can be converted to a chiral mono-protected pyrrolidinediol of general formula (XXII) (see, e.g., Tet. Asymm. 2001, 12, 1793-1799 or Org. Process Res. Dev. 2019, 23, 1970-1978), and following the aforementioned reaction sequence, may produce chiral fluorinated aminopyrrolidines of general formula (XXX) or (XVII). Another method for synthesizing chiral aminopyrrolidine (XXX) may involve the asymmetric reduction of the ketone hydrate of general formula (XXVI) by iridium-catalyzed asymmetric hydrogenation using N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine as a ligand and sodium formate as a reducing agent (see, e.g., J. Org. Chem. 2016, 81, 4359-4363), which may produce the optically active alcohol of general formula (XXVII). The ketone hydrate precursor (XXVI) can be obtained by oxidation of the alcohol (XXV) using potassium peroxymonosulfate (e.g., Oxone®) in the presence of 2-iodoxybenzene sulfate (see, for example, J. Am. Chem. Soc. 2009, 131, 251), using Dess Martin periodinane in dichloromethane (see, for example, J. Org. Chem. 2010, 75, 929-932), or using sodium hypochlorite together with TEMPO(2,2,6,6-tetramethylpiperidine-1-yl)oxyl as a catalyst (see, for example, Org. Process Res. Dev. 2015, 19, 270-283). The chiral alcohol (XXVII) may be converted to the corresponding chiral amine (XXX) in a similar sequence to the reaction steps described in Scheme 6.

[0057] Further alternative methods for synthesizing chiral aminopyrrolidines (XXX) may involve, for example, the chiral conversion of the ketone / hydrate form of general formula (XXVI) via asymmetric enzymatic reactions using transaminases (see, e.g., Green Chem. 2019, 21, 75-86). Alternatively, a racemic amine (or its racemic precursor) may be reacted with a suitable optically active compound, such as an acid like phenylsuccinic acid or dibenzoyl tartaric acid, in isopropanol or an ethanol / water mixture. The resulting diastereomer mixture can be separated by chromatography and / or fractional crystallization, and one or both diastereoisomers can be converted to the corresponding pure enantiomers by methods known to those skilled in the art. (For example, separation of aminopyrrolidine of general formula (XVII): see U.S. Patent Application No. 2015 / 141402, page 48).

[0058] The chiral compounds of the present invention of general formula (I) (and their chiral precursors) can be obtained in a form of high enantiomer purity by chromatography, usually supercritical fluid chromatography (SFC), using a resin supported on which a mobile phase having an asymmetric stationary phase and consisting of, for example, supercritical CO2 containing 15% to 35% methanol (%v / v) and a 20 mM concentrated aqueous ammonia solution is used. Concentration of the eluent produces a mixture of high concentrations. The mixture of stereoisomers can be separated by prior art known to those skilled in the art [see, for example, "Stereochemistry of Organic Compounds" by EL Eliel (Wiley, New York, 1994)].

[0059] Live assays and data The numbers in Tables 3 to 7 refer to the compounds of the present invention (i.e., examples or intermediates) disclosed in the following experimental section. Homogeneous time-resolved fluorescence (HTRF) assay for direct measurement of cAMP An HTRF cAMP assay was performed using a commercially available assay kit (cAMP Dynamic 2 Assay Kit; #62AM4PEJ, Cisbio Bioassays, Bedford, MA) according to the manufacturer's instructions. Aliquots of CHO-K1 cells stably expressing recombinant human GPR52 were thawed and refrigerated in cell buffer (1× PBS (w / o Ca). 2+ / Mg 2+ )) 4 × 10 per mL 5The cells were resuspended at a specific density. The test compound was dissolved in DMSO to prepare a 10 mM stock solution, which was then serially diluted with DMSO using a 6-fold dilution to create an 8-point dose-response curve. Subsequently, these serially diluted samples were mixed in compound dilution buffer (1×PBS (w / o Ca)). 2+ / Mg 2+ 4× stock was obtained by diluting 1:50 with 0.5 mM IBMX (containing 0.1% BSA). The diluted compound was transferred in double decans to a 384-well assay plate (Optiplate #6007290, PerkinElmer, Waltham, MA) (5 μL per well). Both the positive control (reference compound) and the negative control (non-irritating medium) were included in column 23 for each assay run. Subsequently, the cell suspension was dispensed into the 384-well assay plate at 15 μL per well (6000 cells) so that the compound was diluted to 1×. Column 24 of the plate was left empty and reserved for the cAMP standard curve. After incubation at room temperature for 1 hour, 10 μL of cAMP D2 reagent and then 10 μL of cryptotate reagent (provided in the Cisbio kit) were added to each well. The plate was then incubated at room temperature for 1 hour before reading. Time-resolved fluorescence measurements were collected using an EnVision® HTRF plate reader (PerkinElmer, Waltham, MA). The cAMP levels in each test well were measured by fitting the counts from the plate reader to a standard cAMP curve included in each plate. The control percentage (%) was calculated with a positive control set to 200% and a negative control set to 100%. Dose-response curves were created from the cAMP data and analyzed using a nonlinear least squares curve-fitting program to determine the EC (Emission Control Value). 50 Value obtained. EC 50 The average values ​​are shown in Table 3.

[0060] [Table 3]

[0061] In vitro metabolite profiling In vitro metabolite profiling to evaluate the involvement of metabolic pathways mediated by enzymes other than CYP, such as hydrolysis, in addition to CYP-mediated pathways, is based on semi-quantitative analysis of typical metabolite formation in incubations using liver microsomes (with and without beta-nicotinamide adenine dinucleotide phosphate, i.e., NADPH), primary human hepatocytes (with and without the pan-CYP inhibitor proadifen), and recombinant CYP enzymes.

[0062] The involvement of hydrolytic enzymes, such as carboxysylesterase or arylacetamide deacetylase, is R 6 This scenario assumes that metabolites resulting from the amide hydrolysis of the compounds of the present invention having general formula (I), where is an acetyl group, i.e., the deacetylated compounds, do not occur in the presence of the relevant human recombinant drug-metabolizing CYP enzymes but do occur in human liver microsomes in the absence of NADPH. Hydrolases are very abundant in liver microsomes. However, in contrast to CYP-related metabolic processes, the catalytic activity of hydrolases is independent of NADPH. Thus, deacetylated metabolites can occur during the incubation of human liver microsomes lacking NADPH.

[0063] Phenotypic assays were performed to identify the CYP enzymes responsible for the metabolic transformation of the compounds. Metabolism reduction of the test compounds and metabolite formation were evaluated using Supersomes (human CYP expressed in baculovirus-infected insect cells) and human liver microsomes, respectively. In particular, the transformation of compounds by CYP isoenzymes 1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5 were tested. The incubation material in TRIS buffer (supplemented with 0.1M, pH 7.6, 5mM magnesium chloride) consisted of 200 pmol / ml of each Supersome protein or 4 mg / ml of human liver microsome preparation and 10 μM of the test compound. After a short preliminary incubation of 15 minutes at 37°C, the reaction was initiated by adding reduced NADPH (1 mM). An additional incubation using human liver microsomes was performed in the absence of NADPH. After 60 minutes at 37°C, the incubation was terminated by transferring aliquots of the sample to acetonitrile. The sample was analyzed by liquid chromatography-high-resolution mass spectrometry to determine the generation of putative metabolites.

[0064] An additional measurement for identifying CYP-independent metabolic pathways is the use of the pan-CYP inhibitor proadifen in incubation products of test compounds using human hepatocytes. In the presence of proadifen, CYP-related pathways are inhibited, and metabolites can be produced primarily via non-CYP pathways. Using primary human hepatocytes in suspension, the involvement of enzymes other than CYP in the metabolic conversion of test compounds in the presence or absence of hydralazine, a pan-CYP inhibitor (50 μM final incubation concentration). After recovering human hepatocytes from cryopreservation, they were incubated in Dulbecco's modified Eagle medium supplemented with 3.5 μg / 500 mL of glucagon, 2.5 mg / 500 mL of insulin, and 3.75 mg / 500 mL of hydrocortisone, containing 5% (v / v) human serum. After pre-incubation for 30 minutes in a cell culture incubator (37°C, 10% CO2) in or without 50 μM proadifen, the final cell density was 1.0 × 10⁶ cells. 6 ~4.0×10 6 The test compound solution was added to the hepatocyte suspension at a concentration of cells / ml (which varies depending on the metabolic turnover rate of the compound observed in primary human hepatocytes), with a final test compound concentration of 1 μm and a final DMSO concentration of 0.05% (v / v). Cells were incubated for 6 hours (incubator, horizontal shaker), and samples were removed from the incubator after 0, 0.5, 1, 2, 4, or 6 hours, depending on the turnover rate. Samples were quenched with acetonitrile and pelletized by centrifugation. The supernatant was transferred to a 96-deep-well plate, evaporated under nitrogen, and resuspended before bioanalysis by liquid chromatography-high-resolution mass spectrometry to identify putative metabolites. The contribution rate of hydrolysis was calculated based on the abundance of each deacetylated metabolite of the compound of the present invention relative to all metabolites observed in incubation using human liver cells.

[0065] [Table 4]

[0066] hERG (Human Delayed Rectification Potassium Ion Channel Gene) Channel Assay The inhibition of hERG channels by the compounds of the present invention was investigated as follows. cell: HEK (human fetal kidney) 293 cells were stably transfected with hERG cDNA. Cells selected for use in patch-clamp experiments were cultured without antibiotics.

[0067] Pipettes and solutions: Cells were placed in a bath containing NaCl (137), KCl (4.0), MgCl2 (1.0), CaCl2 (1.8), glucose (10), and HEPES (10) (values ​​in parentheses are mM), with pH 7.4 adjusted with NaOH. Patch pipettes were prepared from borosilicate glass tubes using a pipette and filled with a pipette solution containing aspartate K (130), MgCl2 (5.0), EGTA (5.0), K2ATP (4.0), and HEPES (10.0) (values ​​in parentheses are mM), with pH 7.2 adjusted with KOH. The resistance of the microelectrode was typically in the range of 2 MΩ to 5 MΩ.

[0068] Stimulation and recording: Membrane currents were recorded using an EPC-10 patch-clamp amplifier (HEKA Electronics, Lambrecht, FRG) and PatchMaster software (HEKA). Recording of membrane currents via hERG was typically performed at 28°C using a whole-cell configuration of the patch-clamp technique. Transfected HEK293 cells were clamped at a holding potential of -60mV, and an inactivation tail current was induced via hERG using a fixed-amplitude pulse pattern (activation / inactivation: 40mV for 2000ms; recovery: 120mV for 2ms; gradient to 40mV for 2ms; inactivation tail current: 40mV for 50ms), repeated at 15-second intervals. Four pulses, reduced to 0.2x, were recorded between each pulse interval for P / n leak subtraction. Rs correction was performed at a level below which recording could be safely performed without ringing. The remaining uncorrected Rs were recorded along with the actual temperature and holding current.

[0069] Preparation and application of compounds: The test substance concentration was applied sequentially to each of the various cell types being investigated. Before applying the first test substance concentration, the steady-state level of the baseline current was measured during at least five sweeps. The test substance was dissolved in DMSO to obtain a stock solution 1000 times the highest final concentration. This stock was further diluted with DMSO to obtain another stock solution 1000 times the remaining final concentration. Before starting the experiment, fresh final dilutions in extracellular buffer were prepared from each of these stocks using a 1:1000 dilution step.

[0070] Data analysis: The amplitude of the peak current was measured 3 ms after a slope to +40 mV. For baseline and each concentration, the peak currents of the last three sweeps before applying the next concentration were averaged. The residual current (I / I0) was calculated for each cell as the ratio of the actual mean peak current to the baseline mean peak current. Current inhibition was expressed as (1-I / I0) × 100%. Current inhibition for all cells was reported as mean ± standard deviation (SD). Where possible, IC was calculated from the mean current inhibition data using the least squares method based on Hill's formula. 50This was estimated.

[0071] [Table 5] Human plasma protein binding assay Equilibrium dialysis (ED) was used to measure the fractional binding of test compounds to plasma proteins. Dianorm Teflon dialysis cells (0.2 μm) were used. Each dialysis cell consisted of a donor chamber and an acceptor chamber, separated by an ultrathin semipermeable membrane with a molecular weight cutoff of 5 kDa. Stock solutions of each test compound were prepared to 1 mM in DMSO and sequentially diluted to a final test concentration of 1 μM. The following dialysate was prepared in plasma (supplemented with NaEDTA as an anticoagulant), and 200 μL of the test compound dialysate was dispensed as an aliquot into the donor (plasma) chamber. 200 μL of dialysate buffer (100 mM potassium phosphate, pH 7.4) was dispensed as an aliquot into the buffer (acceptor) chamber. Incubation was performed at 37°C for 2 hours under rotation to achieve equilibrium. At the end of the dialysis period, the aliquots obtained from the donor chamber and acceptor chamber were transferred to reaction tubes, and internal standard solutions were added for HPLC-MS / MS analysis. The concentrations of analytes in the aliquot samples were quantified by HPLC-MS / MS against an external calibration curve. The percentage join was calculated using the following formula: Percentage binding = (Plasma concentration - Buffer concentration / Plasma concentration) x 100

[0072] [Table 6]

[0073] Metabolic stability of human liver cells The metabolic reduction of the test compound in human hepatocyte suspension was assayed. Depending on the turnover rate of the test compound, the final cell density was 1.0 x 10⁶ cells.6 cells / mL or 4.0 x 10 cells 6 Human hepatocytes were recovered from cryopreservation to a cell / mL ratio, and then diluted in Dulbecco's modified Eagle medium (supplemented with 3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, 3.75 mg hydrocortisone / 500 mL, and 5% human serum). After pre-incubation for 30 minutes in a cell culture incubator (37°C, 10% CO2), the test compound solution was added to the hepatocyte suspension so that the final test compound concentration was 1 μm and the final DMSO concentration was 0.05% (v / v). Cell suspensions were incubated at 37°C (cell culture incubator, horizontal shaker), and samples were removed from the incubator after 0, 0.5, 1, 2, 4, and 6 hours. Samples were quenched with acetonitrile (containing internal standard solution) and pelletized by centrifugation. The supernatant was transferred to a 96-deep-well plate and prepared for analysis of the reduction of the parent compound by HPLC-MS / MS. The percentage of residual test compound was calculated using the peak area ratio (test compound / internal standard) at each incubation time point relative to the peak area ratio at time 0. The logarithmically transformed data was plotted against incubation time, and the in vitro half-life (T1 / 2) was estimated using the absolute value of the slope obtained by linear regression analysis.

[0074] In vitro intrinsic clearance (CLint) is calculated from in vitro T1 / 2, and the following equation is applied to hepatocytes: 120x10 cells 6 The study scaled to the whole liver using liver cells / g, human liver per body weight: 25.7g liver / kg, and in vitro incubation parameters. CL_INTRINSIC_IN VIVO[mL / min / kg]=(CL_INTRINSIC[μL / min / cell 10 6 cells] x hepatocellular [cells 10 6 [Number of liver cells / g] x Liver factor [g / kg body weight]) / 1000 Considering a mean hepatic blood flow (QH) of 20.7 mL / min / kg, in vivo hepatic blood clearance (CL) was predicted according to a well-stirred liver model: CL[mL / min / kg]=CL_INTRINSIC_IN VIVO[mL / min / kg]x hepatic blood flow [mL / min / kg] / (CL_INTRINSIC_IN VIVO[mL / min / kg]+hepatic blood flow [mL / min / kg])

[0075] The results were expressed as a percentage of hepatic blood flow: QH[%]=CL[mL / min / kg] / hepatic blood flow [mL / min / kg]) [Table 7]

[0076] Solubility evaluation The solubility of the compound of the present invention was investigated using a high-throughput solubility assay, as described below. The test compound was dissolved in DMSO to prepare a 10 mM stock solution, which was then further diluted 40-fold in a 96-well plate format with acetonitrile / water (1:1 v / v) solution, McIlbain buffer solution pH 2.2, McIlbain buffer solution pH 4.5, and McIlbain buffer solution pH 6.8 (McIlbain buffer is citrate-phosphate buffer). The well plates containing the diluted samples were sealed and shaken upside down at room temperature for 24 hours. Undissolved particles were removed by centrifugal filtration, and the resulting sample solution was analyzed by automated UV absorption using HPLC (default wavelength: 254 nm). If the absorption was too low, alternative wavelengths of 280 nm or 230 nm were used to improve detection. The concentration of the analyte was quantified by HPLC-UV. A single-point calibration was performed using a sample dissolved in acetonitrile / water as the calibration point.

[0077] The solubility of some compounds of the present invention was also measured by solid-state solubility assays, as described below. A saturated solution was prepared by adding an appropriate amount of selected aqueous medium (typically in the range of 0.25 ml to 1.5 ml) to each well containing a known amount of solid drug substance (typically in the range of 0.5 mg to 5.0 mg) in a well plate (format dependent on the robot). After shaking or stirring the wells for a predetermined time (typically in the range of 2 to 24 hours), the solution was filtered using a suitable filter membrane (typically a PTFE filter with a pore size of 0.45 μm). Filter absorption was avoided by discarding the first few drops of filtrate. The amount of dissolved drug substance was measured by UV spectroscopy. Furthermore, the pH of the saturated aqueous solution was measured using a glass electrode pH meter. Given their ability to activate GPR52, reduce human protein binding rates which may result in moderately low effective doses of compounds for disease treatment, potentially minimizing side effects, enhance human hepatocyte stability, moderately inhibit hERG channels, diversify metabolism including hydrolytic enzyme-mediated pathways (where applicable), and subsequently reduce the risk of CYP-mediated drug-drug interactions, the compounds of general formula (I) according to the present invention or their pharmaceutically acceptable salts are suitable for all diseases or conditions that may be affected by GPR52 activation, preferably for the treatment and / or prophylactic treatment of central nervous system diseases or conditions disclosed herein.

[0078] Use / Method of Use in Treatment Accordingly, the compounds according to the present invention, or compositions comprising at least one of the compounds according to the present invention, including their pharmacoacceptable salts, are particularly suitable for use in the prevention and / or treatment of diseases that may be affected by GPR52 activation, such as psychiatric disorders, psychotic disorders, cognitive impairment, major depressive disorder, anxiety disorders, obsessive-compulsive disorder (OCD), impulse-control disorders, substance-related disorders, and motor symptoms and motor disorders.

[0079] In a further embodiment, the present invention relates to schizophrenia; positive symptoms associated with schizophrenia, schizoaffective disorder, schizophrenia-like disorder, schizophrenia-type disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome and autism spectrum disorder; augmentation of antipsychotics to treat or reduce the dosage (and side effects) of antipsychotics; schizophrenia, schizophrenia-like disorder, schizophrenia-type disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome and autism spectrum disorder; schizophrenia, schizophrenia-like disorder, schizophrenia-type disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome and autism spectrum disorder; Negative symptoms associated with affective disorders, schizoaffective disorder, schizotypal disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome, and autism spectrum disorder; cognitive impairment associated with schizophrenia (CIAS), schizoaffective disorder, schizoaffective disorder, schizotypal disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome, and autism spectrum disorder; treatment-resistant schizophrenia; schizoaffective disorder; schizoaffective disorder; schizotypal disorder; schizotypal (personality) disorder; drug-induced mental disorders; bipolar disorder type I and bipolar disorder type II; debilitating psychosis syndrome Group; neuropsychiatric symptoms associated with Alzheimer's disease, Parkinson's disease, vascular dementia, and frontotemporal dementia; autism spectrum disorder (ASD); obsessive-compulsive disorder (OCD); impulse control disorder (e.g., impulse control disorder induced by D2 receptor agonists); gambling disorder (e.g., gambling disorder induced by D2 receptor agonists); Tourette syndrome; cognitive deficits associated with Alzheimer's disease, Parkinson's disease, vascular dementia, and frontotemporal dementia; depression; attention deficit hyperactivity disorder (ADHD); The present invention relates to a compound according to general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound according to general formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of a disease or condition selected from the group consisting of major depressive disorder (MDD); drug addiction; anxiety; mania in bipolar disorder; acute mania; agitation; separation; hypothalamic disorders; prolactin-related disorders such as hyperprolactinemia; symptoms associated with frontal lobe dysfunction (e.g., frontal lobe dysfunction associated with drug abuse); and hyperkinetic symptoms.

[0080] Preferably, the compounds according to the present invention are suitable for the prevention or treatment of schizophrenia; positive symptoms associated with schizophrenia; augmentation of antipsychotics to treat 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; schizophrenia-like disorder; schizophrenia-type disorder; drug-induced mental disorders; bipolar disorder type I and bipolar disorder type II; debilitating psychosis syndrome; neuropsychiatric symptoms associated with Alzheimer's disease, Parkinson's disease, vascular dementia, and frontotemporal dementia; autism spectrum disorder (ASD); impulse control disorders (e.g., impulse control disorders induced by D2 receptor agonists); gambling disorders (e.g., gambling disorders induced by D2 receptor agonists); and prolactin-related disorders such as hyperprolactinemia. In a further embodiment, the present invention relates to the use of compounds of general formula (I) for preparing pharmaceuticals for the treatment and / or prevention of the above-mentioned diseases and conditions. In a further embodiment of the present invention, the present invention relates to a method for treating and / or preventing the above-mentioned diseases and conditions, the method comprising administering an effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof to a human.

[0081] The applicable daily dose range for the compound of general formula (I) is typically 0.1 mg to 1000 mg, preferably 1 mg to 500 mg, administered orally, one to four times a day in each case. Each dose unit may contain 0.1 mg to 500 mg, preferably 1 mg to 100 mg, for ease of handling. Of course, the actual pharmacokinetic or therapeutic dose is determined by factors known to those skilled in the art, such as the patient's age and weight, the route of administration, and the severity of the disease. In all cases, the combination of dose and method is administered in a manner that delivers a pharmacokinetic dose based on the patient's specific condition. Suitable formulations for administering compounds of general formula (I) (including pharmaceutically acceptable salts thereof) are obvious to those skilled in the art, and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, liquids, syrups, elixirs, sachets, injections, inhalants, and powders. The content of the pharmaceutically active compound should be in the range of 0.1 to 95% by mass, preferably 5.0 to 90% by mass, of the total composition.

[0082] 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, auxiliaries, surfactants, binders, and / or lubricants. The tablets may also consist of multiple layers. For this purpose, the compounds of general formula (I) prepared by the present invention may optionally be formulated together with other active substances, one or more conventional inert carriers and / or diluents, such as corn starch, lactose, glucose, crystalline cellulose, magnesium stearate, citric acid, tartaric acid, water, polyvinylpyrrolidone, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose, or fatty substances such as hard fat, or suitable mixtures thereof.

[0083] Combination therapy Furthermore, the compounds according to the present invention are particularly suitable as adjunctive therapy (i.e., combination, supplemental therapy) with currently prescribed antipsychotics to treat not only the positive symptoms associated with schizophrenia, but also cognitive and / or negative symptoms. With regard to the treatment of positive symptoms, adjunctive therapy with antipsychotics may result in not only improved antipsychotic efficacy (e.g., improved treatment of positive symptoms associated with schizophrenia), but also a reduction in associated side effects, such as weight gain, metabolic syndrome, diabetes, extrapyramidal symptoms, hyperprolactinemia, insulin resistance, hyperlipidemia, hyperglycemia, and / or tardive dyskinesia, when combined with a reduction in the dosage of the antipsychotic. In particular, elevated serum prolactin levels are a prominent side effect profile of antipsychotics, while GPR52 activators have been shown to lower serum prolactin levels. Therefore, the combination of a GPR52 agonist and an antipsychotic may reduce the side effects associated with antipsychotics by normalizing serum prolactin levels. Therefore, compounds of general formula (I) according to the present invention may be used in combination with other active substances (i.e., combination partners) (e.g., as additional treatment) for the treatment and / or prevention of the diseases and conditions described above (i.e., paragraph "Use / Method of Use in Therapy"). Other active substances suitable for such combinations include, for example, BACE inhibitors; amyloid aggregation inhibitors (e.g., ELND-005); neuroprotective and / or disease-modifying substances acting directly or indirectly; antioxidants (e.g., vitamin E or ginkgolides); anti-inflammatory substances (e.g., COX inhibitors, NSAIDs having additional or exclusive amyloid-β-reducing 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, ampaquine. Monoamine receptor reuptake inhibitors; substances that regulate the concentration or release of neurotransmitters; growth hormone secretion inducers (e.g., ibutamorene mesylate and capromolel); CB-1 receptor antagonists or inverse agonists; antibiotics (e.g., minocycline or rifampicin); PDE1, 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;Somatostatin receptor 4 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 agonists or partial agonists or positive regulators, muscarinic receptor M4 antagonists, positive regulators of metabotropic glutamate receptor 1, positive regulators of metabotropic glutamate receptor 2, positive regulators of metabotropic glutamate receptor 3, positive regulators of metabotropic glutamate receptor 5, The compounds may be selected from the group consisting of lysine 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 caliprazine); 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 present invention and / or reduce undesirable side effects. The compounds according to the present invention may also be used in combination with immunotherapy (e.g., active immunization with amyloid-beta or tau or a portion thereof, or passive immunization with humanized anti-amyloid-beta antibodies or anti-tau antibodies or nanobodies) for the treatment of the above-mentioned diseases and conditions.

[0084] For the above combinations of partner substances, a dosage of 1 / 5 to 1 / 2 of the minimum dose usually recommended is useful (e.g., 1 / 4, 1 / 3, or 1 / 2). The compounds according to the present invention, when used in combination with other active substances, may be used simultaneously or with a time stagger, and in particular, within a short time period. When administered simultaneously, the two active substances are administered to the patient together; when used with a time stagger, the two active substances are administered to the patient within 12 hours or less (e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 8 hours, 9 hours, 10 hours, or 11 hours), and in particular within 6 hours or less.

[0085] In another aspect, the present invention relates to the use of a compound according to the present invention or a pharmaceutically acceptable salt thereof, in combination with at least one of the above-mentioned active substances, as a combination partner substance for preparing a pharmaceutical composition suitable for the treatment and / or prevention of diseases or conditions that may be affected by GPR52 agonists. Preferably, these are conditions relating to GPR52 activity deficiency, and in particular, one of the diseases or conditions listed above.

[0086] In another aspect of the present invention, the present invention relates to a pharmaceutical composition comprising at least one of the active substances as a compound of general formula (I) according to the present invention or a pharmaceutically acceptable salt thereof, and a partner substance of a combination thereof, and which may together comprise at least one inactivating agent, diluent, and / or carrier. The compound of general formula (I) and at least one of the above-mentioned active substances according to the present invention may both be present together in one formulation (e.g., a tablet or a capsule), or they may be present separately in two identical or different formulations (e.g., a so-called kit of parts). [Examples]

[0087] Experiment section List of abbreviations [Table 8] TIFF0007883575000029.tif144158

[0088] HPLC-Method: Preparation of mobile phase: The mobile phase "H2O 0.1% TFA" was prepared by adding 1 ml of commercially available TFA solution to 999 ml of water. The mobile phase "H2O 0.1% NH3" was prepared by adding 4 ml of commercially available concentrated ammonium hydroxide solution (25% by mass) to 996 ml of water.

[0089] Method name: A Equipment description: Waters Acquity equipped with DA and MS detectors Column: XBridge, BEH C18, 2.1×30 mm, 2.5 μm Column supplier: Waters [Table 9]

[0090] Method name: B Equipment description: Waters Acquity equipped with DA and MS detectors Column: XBridge, BEH C18, 2.1×30 mm, 2.5 μm Column supplier: Waters [Table 10]

[0091] Method name: C Equipment description: Agilent 1200 equipped with DA and MS detectors Column: XBridge C18, 3.0x30 mm, 2.5 μm Column supplier: Waters [Table 11]

[0092] Method name: D Equipment description: Waters Acquity equipped with DA and MS detectors Column: Sunfire, C18, 3.0×30 mm, 2.5 μm Column supplier: Waters [Table 12]

[0093] Method name: E Instrument Description: Agilent 1200 equipped with DA and MS detectors. Column: Sunfire C18, 3.0 x 50 mm, 2.5 μm Column supplier: Waters [Table 13]

[0094] Method name:F Instrument Description: Waters Acquity equipped with DA and MS detectors Column: XBridge BEH C18, 2.1x30mm, 1.7μm Column supplier: Waters [Table 14]

[0095] Method name:G Instrument Description: Agilent 1260 SFC with DA and MS detectors, back pressure 2175 psi Column: CHIRAL ART® Cellulose SB, 4.6 x 250 mm, 5 μm Column supplier: YMC [Table 15]

[0096] Method name:H Instrument Description: Agilent 1260 Infinity II SFC with DA detector, back pressure 2175 psi Column: Lux(registered trademark) Cellulose-4, 3x100mm, 3μm Column supplier: Phenomenex

Table 16

[0097] Method name: I Description of the instrument: Agilent 1260 SFC equipped with detectors for DA and MS, back pressure 2175 psi Column: CHIRAL ART (registered trademark) cellulose SB, 4.6 x 250 mm, 5 μm Column supplier: YMC

Table 17

[0098] Method name: J Description of the instrument: Agilent 12,60 Infinity II SFC equipped with a DA detector, back pressure 2175 psi Column: Lux (registered trademark) Cellulose-3, 3 x 100 mm, 3 μm Column supplier: Phenomenex

Table 18

[0099] Method name: K Description of the instrument: Agilent 12,60 Infinity II SFC equipped with a DA detector, back pressure 2175 psi Column: CHIRAL ART (registered trademark) Amylose-SA, 3 x 100 mm, 3 μm Column supplier: YMC

Table 19

[0100] [[ID=((57))]]Method name: L Description of the instrument: Agilent 12,60 Infinity II SFC equipped with a DA detector, back pressure 2175 psi Column: Lux(registered trademark) Cellulose-2, 4.6 x 250 mm, 5 μm Column supplier: Phenomenex [Table 20]

[0101] Method name: M Instrument Description: Agilent 1260 Infinity II SFC with DA detector, back pressure 2175 psi Column: Lux(registered trademark) Cellulose-2, 3x100mm, 3μm Column supplier: Phenomenex [Table 21]

[0102] General notes on structural notation: Compounds containing a stereogenic center: The structures shown in the experimental section may not necessarily represent all possible stereochemical configurations of the compound. The structural representation of compounds in the experimental section may only show stereochemical bonds in cases where absolute stereochemistry is known. In the section describing experiments where absolute stereochemistry is unknown, the structural representation of compounds should include, in addition to planar bonding, notes indicating whether the described compound is a racemic mixture, a single stereoisomer, and, where applicable, relative stereochemistry. Two examples are shown below.

[0103] Example I: The chemical structure shown is represented as follows: [ka] Note: "Racemic mixture" (in the diagram or experimental description) refers to two stereochemical options; therefore, the compound produced is: [ka] It is a mixture of [the two elements].

[0104] When a racemic mixture of the structures described above is separated, the single stereoisomer is represented according to its absolute stereochemistry, if known. Alternatively, the single stereoisomer is [ka] It is expressed as follows. Note: The terms "single stereoisomer" and "planar bond" indicate that the absolute configuration is unknown. The term "single stereoisomer a" is assigned to the first eluted isomer in chiral HPLC, and "single stereoisomer b" is assigned to the second eluted isomer in chiral HPLC.

[0105] Example II: The chemical structure shown is represented as follows: [ka] Note: "Trans-racemic mixture" (in the diagram or experimental description) refers to two stereochemical options; therefore, the compound produced is: [ka] It is a mixture of [the two elements]. When a racemic mixture of the structures described above is separated, the single stereoisomer is [ka] It is expressed as follows. Note: "Trans-single stereoisomer" indicates a known relative configuration (trans), while planar bonding indicates an unknown absolute configuration. "Trans-single stereoisomer a" is assigned to the first eluted isomer in chiral HPLC, and "Trans-single stereoisomer b" is assigned to the second eluted isomer in chiral HPLC. A similar principle applies to the terms “cis-racemic mixture,” “cis-single stereoisomer a,” and “cis-single stereoisomer b.”

[0106] The absolute configurations of Examples 8a, 8b, 10a, 10b, 11a, 11b, 13a, 13b, 15a, and 15b were determined by the asymmetric synthesis of Examples 8b, 10a, 11b, 13b, and 15a, starting from optically pure precursors, followed by a comparison of the chiral chromatography of each of the multiple enantiomers between the single enantiomer obtained by the above asymmetric synthesis and the two single enantiomers obtained by the chiral chromatography separation of its racemic mixture (see Experiments section). Those skilled in the art will understand that the absolute configuration of the compounds of the present invention can be measured, or further determined, by X-ray crystallography, for example, by single-crystal X-ray diffraction of their crystalline products or, optionally, their derivatized crystalline intermediates.

[0107] Examples Preparation of intermediates and examples: The following examples and intermediates are for illustrative purposes only and do not limit the scope of the present invention. Intermediate A-1: [ka] A mixture of 3,4-difluorophenol (10.0 g, 76.9 mmol) and cesium carbonate (37.6 g, 115.3 mmol) in DMA (558 mL) was stirred at room temperature for 5 minutes, and then tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (19.3 g, 76.9 mmol) was added. After stirring at 100 °C for 5 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. Water and ethyl acetate were added. The phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified with MPLC (silica gel, petroleum ether / ethyl acetate 9:1) to obtain product A-1. ESI-MS:286[M+H] + ;HPLC(Rt): 0.72 min (Method A)

[0108] Intermediate A-2: [ka] A mixture of 3,5-difluorophenol (1.0 g, 8.0 mmol) and cesium carbonate (5.2 g, 15.9 mmol) in DMA (5 mL) was stirred at room temperature for 10 minutes, after which tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.0 g, 8.0 mmol) was added. After stirring at 90°C for 16 hours, the mixture was cooled to room temperature, and water and ethyl acetate were added. The phases were separated. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain product A-2. ESI-MS:286[M+H] + ;HPLC(Rt): 1.02 min (Method D)

[0109] Intermediate A-3: [ka] A mixture of 3,4,5-trifluorophenol (10.0 g, 64.2 mmol) and cesium carbonate (31.4 g, 96.2 mmol) in DMA (465 mL) was stirred at room temperature for 10 minutes, after which tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (16.1 g, 64.2 mmol) was added. After stirring at 100 °C for 6 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. Water and ethyl acetate were added. The phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified with MPLC (silica gel, petroleum ether / ethyl acetate 9:1) to obtain product A-3. ESI-MS:304[M+H] + ;HPLC(Rt): 0.75 min (Method A)

[0110] Intermediate A-4: [ka] A mixture of 3-chloro-4-fluorophenol (1.5 g, 10.2 mmol) and cesium carbonate (6.7 g, 20.5 mmol) in DMA (10 mL) was stirred at room temperature for 10 minutes, after which tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.6 g, 10.2 mmol) was added. The mixture was stirred at 100 °C for 16 hours, and then cooled to room temperature. Water and DCM were added. The phases were separated. The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain product A-4. ESI-MS:302 / 304[M+H] + ;HPLC(Rt): 0.78 min (Method A)

[0111] Intermediate A-5: [ka] A mixture of 3-chloro-5-fluorophenol (4.8 g, 33.0 mmol) and cesium carbonate (21.5 g, 66.1 mmol) in DMF (20 mL) was stirred at room temperature for 10 minutes, after which tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.5 g, 10.1 mmol) was added. After stirring at 90°C for 16 hours, the mixture was cooled to room temperature, and water and ethyl acetate were added. The phases were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain product A-5. ESI-MS:302 / 304[M+H] + ;HPLC(Rt): 0.77 min (Method A)

[0112] Intermediate A-6: [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) was stirred at room temperature for 10 minutes, after which tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.5 g, 10.0 mmol) was added. After stirring at 90°C for 16 hours, the mixture was cooled to room temperature, and water and ethyl acetate were added. The phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain product A-6. ESI-MS:318[M+H] + , 262[M+H-isobutene] + ;HPLC(Rt): 1.03 min (Method D)

[0113] Intermediate A-7: [ka] A mixture of 3-(difluoromethoxy)-5-fluorophenols (0.4 g, 2.2 mmol) and cesium carbonate (1.4 g, 4.4 mmol) in DMA (2.5 mL) was stirred at room temperature for 10 minutes, and then tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (0.6 g, 2.2 mmol) was added. After stirring at 90°C for 16 hours, the mixture was cooled to room temperature, and water and ethyl acetate were added. The phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain product A-7. ESI-MS:334[M+H] + , 278[M+H-isobutene] + ;HPLC(Rt): 1.05 min (Method D)

[0114] Intermediate B-1: [ka] A mixture of intermediate A-1 (19.0 g, 66.6 mmol) in diisopropyl ether (200 mL) was mixed with a HCl solution of dioxane (4N, 83.3 mL, 333.0 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The precipitate was washed with diethyl ether and dried to obtain product B-1 as the HCl salt. ESI-MS:186[M+H] + ;HPLC(Rt): 0.38 min (Method A)

[0115] Intermediate B-2: [ka] To intermediate A-2 (1.85 g, 6.49 mmol), a solution of dioxane in HCl (4N, 15.0 mL, 60.0 mmol) was added. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to obtain product B-2 as the HCl salt. ESI-MS:186[M+H] + ;HPLC(Rt): 0.38 min (Method D)

[0116] Intermediate B-3: [ka] Intermediate A-3 (3.24 g, 10.68 mmol) was mixed with a HCl solution of dioxane (4N, 25.0 mL, 100.0 mmol). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to obtain product B-3 as the HCl salt. ESI-MS:204[M+H] + ;HPLC(Rt): 0.45 min (Method A)

[0117] Intermediate B-4: [ka] Intermediate A-4 (2.3 g, 7.6 mmol) was mixed with a HCl solution of dioxane (4N, 9.5 mL, 37.9 mmol). After stirring at room temperature for 45 minutes, the mixture was concentrated under reduced pressure to obtain product B-4 as the HCl salt. ESI-MS:202 / 204[M+H] + ;HPLC(Rt): 0.51 min (Method B)

[0118] Intermediate B-5: [ka] Intermediate A-5 (8.3 g, 27.5 mmol) was mixed with a HCl solution of dioxane (4N, 34.4 mL, 137.5 mmol). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to obtain product B-5 as the HCl salt. ESI-MS:202 / 204[M+H] + ;HPLC(Rt): 0.52 min (Method A)

[0119] Intermediate B-6: [ka] Intermediate A-6 (2.6 g, 8.0 mmol) was mixed with a HCl solution of dioxane (4N, 12.1 mL, 48.2 mmol). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to obtain product B-6 as the HCl salt. ESI-MS:218[M+H] + ;HPLC(Rt): 0.45 min (Method D)

[0120] Intermediate B-7: [ka] Intermediate A-7 (625.0 mg, 1.9 mmol) was mixed with a HCl solution of dioxane (4N, 5.0 mL, 20.0 mmol). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to obtain product B-7 as the HCl salt. ESI-MS:234[M+H] + ;HPLC(Rt): 0.45 min (Method D)

[0121] Intermediate C-1.1: [ka] A mixture of trans-(3-tert-butyloxycarbonyl-amino)-4-fluoropyrrolidine (500.0 mg, 244.8 μmol) and DIPEA (2.12 mL, 12.24 mmol) in acetonitrile (2 mL) was mixed with acetyl chloride (261.1 μL, 367.2 μmol). After stirring at room temperature for 10 minutes, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain intermediate C-1.1 as a trans-racemic mixture. ESI-MS:247[M+H] + ;HPLC(Rt): 0.44 min (Method B)

[0122] Intermediate C-1: [ka] To a mixture of intermediate C-1.1 (550.0 mg, 223.3 μmol, trans-racemic mixture) in 1,4-dioxane (2.2 mL), hydrochloric acid solution (4N in 1,4-dioxane, 4.47 mL, 17.87 mmol) was added. After stirring at room temperature for 16 hours, the reaction mixture was diluted with diethyl ether. The precipitate was collected by filtration, washed with diethyl ether, dissolved in an acetonitrile / water mixture, and lyophilized to obtain intermediate C-1 as an HCl salt in a trans-racemic mixture. ESI-MS:147[M+H] + ;HPLC(Rt): 0.13 min (Method B)

[0123] Intermediate C-2.1: [ka] A mixture of tert.-butyl N-(2-azabicyclo[2.1.1]hexane-4-yl)carbamate (200.0 mg, 1.0 mmol) and DIPEA (0.87 mL, 5.04 mmol) was added to a mixture of acetonitrile (1.6 mL) and DMF (0.8 mL), to which acetyl chloride (107.59 μL, 1.51 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, then saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain intermediate C-2.1. ESI-MS:241[M+H] + ;HPLC(Rt): 0.54 min (Method D)

[0124] Intermediate C-2: [ka] To intermediate C-2.1 (211.4 mg, 880.0 μmol), hydrochloric acid solution (4N in 1,4-dioxane, 0.88 mL, 3.52 mmol) and a few drops of methanol were added. After stirring at room temperature for 1.5 hours, an additional 0.45 mL of hydrochloric acid solution (4N in 1,4-dioxane, 0.45 mL, 1.80 mmol) was added, and stirring was continued for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was pulverized with diethyl ether and dried to obtain intermediate C-2 as the HCl salt. ESI-MS:141[M+H] + ;HPLC(Rt): 0.12 min (Method D)

[0125] Intermediate D-1: [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) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water. The precipitate was collected by suction filtration and dried at 50°C to obtain intermediate D-1. ESI-MS:340[M+H] + ;HPLC(Rt): 0.63 min (Method A)

[0126] Intermediate D-2: [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) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water. The precipitate was collected by suction filtration and dried at 50°C to obtain intermediate D-2. ESI-MS:322[M+H] + ;HPLC(Rt): 0.60 min (Method A)

[0127] Intermediate D-3: [ka] A mixture of methyl 4-bromo-1,2,5-thiadiazole-3-carboxylate (300.0 mg, 1.3 mmol), intermediate B-3 (HCl salt, 322.3 mg, 1.3 mmol), cesium carbonate (525.9 mg, 1.6 mmol), and sodium iodide (302.4 mg, 2.0 mmol) in DMF (8 mL) was stirred at 80°C for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with water. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative MPLC (gradient petroleum ether / ethyl acetate 95:5~65:35) to obtain intermediate D-3. ESI-MS:346[M+H] + ;HPLC(Rt): 1.11 min (Method C)

[0128] Intermediate D-4: [ka] A mixture of methyl 4-bromo-1,2,5-thiadiazole-3-carboxylate (2.0 g, 9.0 mmol), intermediate B-1 (HCl salt, 2.0 g, 9.0 mmol), cesium carbonate (3.5 g, 10.8 mmol), and sodium iodide (2.0 g, 13.5 mmol) in DMF (45 mL) was stirred at 80°C for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with water. The precipitate was filtered off and dried under reduced pressure to obtain crude intermediate D-4. ESI-MS:328[M+H] + ;HPLC(Rt): 1.01 min (Method D)

[0129] Intermediate D-5: [ka] A mixture of methyl 4-bromo-1,2,5-thiadiazole-3-carboxylate (2.0 g, 9.0 mmol), intermediate B-2 (HCl salt, 2.0 g, 9.0 mmol), cesium carbonate (3.5 g, 10.8 mmol), and sodium iodide (2.0 g, 13.5 mmol) in DMF (45 mL) was stirred at 80°C for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with water. The precipitate was filtered off and dried under reduced pressure to obtain crude intermediate D-5. ESI-MS:328[M+H] + ;HPLC(Rt): 1.00 min (Method D)

[0130] Intermediate E-1: [ka] A mixture of intermediate D-1 (4.15 g, 12.23 mmol) in acetone (40 mL) was mixed with an aqueous lithium hydroxide solution (585.9 mg, 24.5 mmol in 40 mL of water). The reaction mixture was stirred for 2 hours, then diluted with water and acidified to pH 4 with hydrochloric acid (4N). The precipitate was collected by suction filtration and dried at 50°C to obtain intermediate E-1. ESI-MS:326[M+H] + ;HPLC(Rt): 0.31 min (Method A)

[0131] Intermediate E-2: [ka] A mixture of intermediate D-2 (1.6 g, 4.9 mmol) in acetone (15 mL) was mixed with an aqueous lithium hydroxide solution (230.0 mg, 9.8 mmol in 15 mL of water). The reaction mixture was stirred at room temperature for 1.5 hours, then diluted with water and acidified to pH 4 with hydrochloric acid (4N). The precipitate was collected by suction filtration and dried at 50°C to obtain intermediate E-2. ESI-MS:308[M+H] + ;HPLC(Rt): 0.27 min (Method A)

[0132] Intermediate E-3: [ka] A mixture of intermediate D-3 (438.0 mg, 1.3 mmol) in THF (10 mL) was mixed with a 5 mL aqueous solution of lithium hydroxide (135.0 mg, 5.6 mmol). The mixture was stirred at room temperature for 2 hours, then acidified with 4 N hydrochloric acid. The mixture was extracted with ethyl acetate, the organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude intermediate E-3. ESI-MS:332[M+H] + ;HPLC(Rt): 1.03 min (Method E)

[0133] Intermediate E-4: [ka] Lithium hydroxide (858.9 mg, 35.9 mmol) was added to a mixture of intermediate D-4 (2.2 g, 6.7 mmol) in THF (60 mL) and water (35 mL). The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure to remove THF. The water-soluble residue was acidified with 4N hydrochloric acid. A precipitate formed, which was collected by filtration and dried under reduced pressure at 40°C to obtain crude intermediate E-4. ESI-MS:314[M+H] + ;HPLC(Rt): 0.85 min (Method D)

[0134] Intermediate E-5: [ka] Lithium hydroxide (858.9 mg, 35.9 mmol) was added to a mixture of intermediate D-5 (2.3 g, 6.9 mmol) in THF (60 mL) and water (35 mL). The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure to remove THF. The water-soluble residue was acidified with 4N hydrochloric acid. A precipitate formed, which was collected by filtration and dried under reduced pressure at 40°C to obtain crude intermediate E-5. ESI-MS:314[M+H] + ;HPLC(Rt): 0.84 min (Method D)

[0135] Intermediate F-1.1: [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (380.0 mg, 2.4 mmol), tert-butyl-4-amino-3,3-difluoropyrrolidine-1-carboxylate (532.7 mg, 2.4 mmol), and 1-methylimidazole (386.0 μL, 4.8 mmol) in acetonitrile (3 mL) was mixed with TCFH (739.8 mg, 2.6 mmol). The mixture was stirred at room temperature for 15 minutes. The mixture was concentrated to half its volume and purified directly by preparative HPLC to obtain intermediate F-1.1 as a racemic mixture. ESI-MS:307 / 309[M+H-tert-butyl] + ;HPLC(Rt): 0.81 min (Method D)

[0136] Intermediate (S)-F-1.1: [ka] A mixture of 3-chloropyrazine-2-carboxylic acid (300.0 mg, 1.9 mmol), (S)-tert-butyl-4-amino-3,3-difluoropyrrolidine-1-carboxylate (CAS No. 2381400-91-3, 420.5 mg, 1.9 mmol), and 1-methylimidazole (304.7 μL, 3.8 mmol) in acetonitrile (5 mL) was mixed with TCFH (584.0 mg, 2.1 mmol). After stirring at room temperature for 3 days, water and aqueous ammonia solution were added. The mixture was filtered and purified directly by preparative HPLC to obtain the intermediate (S)-F-1.1. ESI-MS:307 / 309[M+H-tert-butyl] + ;HPLC(Rt): 0.80 min (Method D)

[0137] Intermediate F-1.2: [ka] To a mixture of intermediate F-1.1 (736.0 mg, 2.0 mmol) in 1,4-dioxane (2.9 mL), hydrochloric acid (4N in 1,4-dioxane, 8.0 mL, 32.0 mmol) was added. After stirring at room temperature for 16 hours, the mixture was diluted with diethyl ether. The precipitate was collected by filtration, washed with diethyl ether, and dried to obtain intermediate F-1.2 as a racemic mixture. ESI-MS:263 / 265[M+H] + ;HPLC(Rt): 0.28 min (Method D)

[0138] Intermediate (S)-F-1.2: [ka] A mixture of intermediate (S)-F-1.1 (570.0 mg, 1.6 mmol) in 1,4-dioxane (1.5 mL) was mixed with hydrochloric acid (4N in 1,4-dioxane, 1.6 mL, 6.3 mmol). After stirring at room temperature for 16 hours, methanol (3 mL) was added and stirring was continued at room temperature for 2 hours. The mixture was concentrated under reduced pressure, the residue was ground with tert-butyl methyl ether, collected by filtration, and dried to obtain intermediate (S)-F-1.2. ESI-MS:263 / 265[M+H] + ;HPLC(Rt): 0.28 min (Method D)

[0139] Intermediate F-1: [ka] A mixture of intermediate F-1.1 (1.3 g, 3.6 mmol) and methanol (287.3 μL, 7.2 mmol) in dichloromethane (30 mL) was added dropwise with acetyl bromide solution (1.06 mL, 14.34 mmol) of dichloromethane (7 mL) at room temperature. After stirring for 30 minutes, the reaction mixture was cooled to 0-5°C. Dichloromethane solution (5 mL) of triethylamine (1.51 mL, 10.75 mmol) was added dropwise. After stirring for 5 minutes, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a water / methanol (v / v 5 / 5 mL) mixture, acidified with TFA, and purified by preparative HPLC to obtain intermediate F-1 as a racemic mixture. ESI-MS:305 / 307[M+H] + ;HPLC(Rt): 0.43 min (Method D)

[0140] Intermediate (S)-F-1 [ka] A mixture of intermediate (S)-F-1.2 (455.0 mg, 1.5 mmol) and triethylamine (640.7 μL, 4.6 mmol) in acetonitrile (4 mL) was mixed with acetyl chloride (162.2 μL, 2.3 mmol). After stirring at room temperature for 16 hours, water was added. The mixture was filtered and purified directly by preparative HPLC to obtain intermediate (S)-F-1. ESI-MS:305 / 307[M+H] + ;HPLC(Rt): 0.44 min (Method D)

[0141] Intermediate F-2: [ka] A mixture of intermediate F-1.2 (50.0 mg, 167.0 μmol), D4-acetic acid (10.5 μL, 184.0 μmol), and HATU (66.7 mg, 176.0 μmol) in DMF (2 mL) was mixed with DIPEA (57.5 μL, 334.0 μmol) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was purified directly by preparative HPLC to obtain intermediate F-2 as a racemic mixture. ESI-MS:308 / 310[M+H] + ;HPLC(Rt): 0.28 min (Method B)

[0142] Intermediate G-1: [ka] A mixture of intermediate E-2 (300.0 mg, 976.0 μmol), tert-butyl-4-amino-3,3-difluoropyrrolidine-1-carboxylate (227.8 mg, 1.0 mmol), and DIPEA (663.9 μL, 3.9 mmol) in acetonitrile (5 mL) was mixed with CIP (299.2 mg, 1.1 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted with water. The organic phase was separated and purified directly by preparative HPLC to obtain intermediate G-1 as a racemic mixture. ESI-MS:512[M+H] + ;HPLC(Rt): 1.05 min (Method D)

[0143] Intermediate G-2: [ka] A mixture of intermediate E-2 (250.0 mg, 814.0 μmol), cis-tert-butyl-4-amino-3-fluoropyrrolidine-1-carboxylate (174.5 mg, 854.0 μmol), and DIPEA (553.3 μL, 3.3 mmol) in acetonitrile (4 mL) was mixed with CIP (249.3 mg, 895.0 μmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water. The organic phase was separated and purified directly by preparative HPLC to obtain intermediate G-2 as a cis-racemic mixture. ESI-MS:494[M+H] + ;HPLC(Rt): 1.01 min (Method D)

[0144] Intermediate G-3: [ka] A mixture of intermediate E-1 (250.0 mg, 715.0 μmol), tert-butyl-4-amino-3,3-difluoropyrrolidine-1-carboxylate (166.8 mg, 751.0 μmol), and DIPEA (486.1 μL, 2.9 mmol) in acetonitrile (4 mL) was mixed with CIP (219.0 mg, 786.0 μmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water. The organic phase was separated and purified directly by preparative HPLC to obtain intermediate G-3 as a racemic mixture. ESI-MS:530[M+H] + ;HPLC(Rt): 1.11 min (Method D)

[0145] Intermediate G-4: [ka] A mixture of intermediate E-4 (150.0 mg, 479.0 μmol), tert.-butyl-4-amino-3,3-difluoropyrrolidine-1-carboxylate (117.1 mg, 527.0 μmol), and DIPEA (248.5 μL, 1.4 mmol) in acetonitrile (5 mL) was mixed with CIP (146.7 mg, 1.4 mmol). After stirring at room temperature for 16 hours, 1N sodium hydroxide aqueous solution was added, and the mixture was extracted twice with DCM. The combined organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain intermediate G-4 as a racemic mixture. ESI-MS:518[M+H] + ;HPLC(Rt): 0.88 min (Method B)

[0146] Intermediate (S)-G-4: [ka] A mixture of intermediate E-4 (150.0 mg, 479.0 μmol), (S)-tert.-butyl-4-amino-3,3-difluoropyrrolidine-1-carboxylate (CAS No. 2381400-91-3, 123.2 mg, 527.0 μmol), and DIPEA (331.3 μL, 1.9 mmol) in acetonitrile (2 mL) was mixed with CIP (146.7 mg, 527.0 μmol). After stirring at room temperature for 16 hours, water was added and the mixture was extracted with DCM. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the chiral intermediate (S)-G-4. ESI-MS:518[M+H] + ;HPLC(Rt): 1.14 min (Method D)

[0147] Intermediate H-1: [ka] To a mixture of intermediate G-1 (358.0 mg, 700.0 μmol) in dichloromethane (4 mL), TFA (1.0 mL, 13.0 mmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. A mixture of acetonitrile and water was added to the residue. The mixture was freeze-dried to obtain crude intermediate H-1 as a TFA salt in a racemic mixture. ESI-MS:412[M+H] + ;HPLC(Rt): 0.57 min (Method D)

[0148] Intermediate H-2: [ka] To a mixture of intermediate G-2 (283.0 mg, 573.0 μmol, cis-racemic mixture) in dichloromethane (3.5 mL), TFA (0.8 mL, 10.3 mmol) was added. After stirring at room temperature for 2.5 hours, the reaction mixture was concentrated under reduced pressure to obtain crude intermediate H-2 as a cis-racemic mixture with a TFA salt. ESI-MS:394[M+H] + ;HPLC(Rt): 0.54 min (Method D)

[0149] Intermediate H-3: [ka] To a mixture of intermediate G-3 (161.0 mg, 304.0 μmol) in dichloromethane (4 mL), TFA (0.45 mL, 5.78 mmol) was added. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of dichloromethane / methanol (9:1 v / v) and washed with saturated aqueous NaHCO3 solution. The organic phase was separated using a phase separation cartridge and concentrated under reduced pressure. The fraction of this material was purified by HPLC (basic conditions) to obtain intermediate H-3 as a racemic mixture. ESI-MS:430[M+H] + ;HPLC(Rt): 0.59 min (Method B)

[0150] Intermediate H-4: [ka] A mixture of intermediate G-4 (200.0 mg, 386.0 μmol) and p-toluenesulfate monohydrate (257.3 mg, 1.4 mmol) in acetonitrile (4 mL) was stirred for 3 hours. Water and aqueous ammonia solution were added, the mixture was filtered, and purified by preparative HPLC to obtain intermediate H-4 as a racemic mixture. ESI-MS:418[M+H] + ;HPLC(Rt): 0.64 min (Method D)

[0151] Intermediate (S)-H-4: [ka] A mixture of intermediate (S)-G-4 (155.0 mg, 300.0 μmol) and p-toluenesulfuric acid monohydrate (199.4 mg, 1.1 mmol) in acetonitrile (3 mL) was stirred at room temperature for 16 hours. Water and aqueous ammonia solution were added, the mixture was filtered, and purified by preparative HPLC to obtain intermediate (S)-H-4. ESI-MS:418[M+H] +;HPLC(Rt): 0.64 min (Method D)

[0152] (Example 1) [ka] A mixture of intermediate F-1 (50.0 mg, 164.0 μmol), intermediate B-4 (46.9 mg, 197.0 μmol), and triethylamine (49.8 mg, 492.0 μmol) in DMA (2 mL) was stirred at 85°C for 1 hour. After cooling to room temperature, the reaction mixture was purified directly by preparative HPLC to obtain Example 1 as a racemic mixture. ESI-MS:470 / 472[M+H] + ;HPLC(Rt): 0.65 min (Method B)

[0153] (Example 2) [ka] A mixture of intermediate H-1 (crude TFA salt, 100.0 mg, 129.0 μmol) and DIPEA (56.0 μL, 324.0 μmol) in acetonitrile (1 mL) was mixed with propionyl chloride (13.6 μL, 155.0 μmol). After stirring at room temperature for 30 minutes, the mixture was made alkaline by adding aqueous ammonia and water. The mixture was filtered and purified directly by preparative HPLC to obtain Example 2 as a racemic mixture. ESI-MS:468[M+H] + ;HPLC(Rt): 0.86 min (Method D)

[0154] (Example 3) [ka] A mixture of intermediate H-2 (crude TFA salt, 548.0 mg, 573.0 μmol, cis-racemic mixture) and DIPEA (0.4 mL, 2.3 mmol) in acetonitrile (3 mL) was mixed with acetyl chloride (44.8 μL, 631.0 μmol) at 0°C. After stirring at 0°C for 30 minutes, the mixture was made alkaline by adding aqueous ammonia and water. The mixture was filtered and purified directly by preparative HPLC to obtain Example 3 as a cis-racemic mixture. ESI-MS:436[M+H] + ;HPLC(Rt): 0.75 min (Method D)

[0155] (Example 4) [ka] A mixture of intermediate F-1 (50.0 mg, 164.0 μmol), intermediate B-1 (46.9 mg, 197.0 μmol), and triethylamine (49.8 mg, 492.0 μmol) in DMA (2 mL) was stirred at 85°C for 1 hour. After cooling to room temperature, the reaction mixture was purified directly by preparative HPLC to obtain Example 4 as a racemic mixture. ESI-MS:457[M+H] + ;HPLC(Rt): 0.80 min (Method D)

[0156] (Example 5) [ka] A mixture of intermediate F-1 (23.0 mg, 75.0 μmol), intermediate B-5 (19.8 mg, 83.0 μmol), and triethylamine (21.2 μL, 151.0 μmol) in DMA (0.5 mL) was stirred at 80°C for 30 minutes. After cooling to room temperature, the reaction mixture was purified directly by preparative HPLC to obtain Example 5 as a racemic mixture. ESI-MS:470 / 472[M+H] + ;HPLC(Rt): 0.91 min (Method D)

[0157] (Example 6) [ka] A mixture of intermediate F-1 (85.0 mg, 179.0 μmol), intermediate B-6 (58.4 mg, 214.0 μmol), and triethylamine (50.1 μL, 357.0 μmol) in DMA (1.5 mL) was stirred at 100 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was purified directly by preparative HPLC to obtain Example 6 as a racemic mixture. ESI-MS:486[M+H] + ;HPLC(Rt): 0.63 min (Method B)

[0158] (Example 7) [ka] A mixture of intermediate F-1 (23.0 mg, 75.0 μmol), intermediate B-7 (22.4 mg, 83.0 μmol), and triethylamine (21.2 μL, 151.0 μmol) in DMA (0.5 mL) was stirred at 80°C for 30 minutes. After cooling to room temperature, the reaction mixture was purified directly by preparative HPLC to obtain Example 7 as a racemic mixture. ESI-MS:502[M+H] + ;HPLC(Rt): 0.87 min (Method D)

[0159] (Examples 8, 8a, and 8b) [ka] A mixture of intermediate F-1 (80.0 mg, 263.0 μmol), intermediate B-1 (69.8 mg, 315.0 μmol), and triethylamine (73.7 μL, 525.0 μmol) in DMA (1.5 mL) was stirred at 100 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was extracted three times with ethyl acetate. The combined organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified directly by preparative HPLC to obtain Example 8 as a racemic mixture. ESI-MS:454[M+H] + ;HPLC(Rt): 0.58 min (Method B)

[0160] Preparative Chiral Separation: Racemic amide 8 (90.0 mg, 199.0 μmol) was subjected to preparative chiral SFC separation (Sepiatec basic, Chiral pak ART® Cellulose-SB, 10 x 250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: methanol-containing 20 mM concentrated ammonia water, gradient A:B 75:25, flow rate 10 mL / min, temperature 40°C, wavelength 220 nm, system back pressure 150 bar, sample concentration 25 mg / mL, injection volume 200 μL), and the following was obtained: Example 8a (single stereoisomer a): Rt = 2.72 mins (Method G). Enantiomer purity: 99.1% ee. Example 8b (single stereoisomer b): Rt = 3.42 mins (Method G). Enantiomer purity: 96.8% ee.

[0161] Synthesis of Example 8b from chiral intermediate (S)-F-1 A mixture of intermediate (S)-F-1 (70.0 mg, 230.0 μmol), intermediate B-1 (61.1 mg, 276.0 μmol), and triethylamine (80.6 μL, 574.0 μmol) in DMA (0.5 mL) was stirred at 100 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with an acetonitrile / water mixture and an aqueous ammonia solution. The mixture was filtered and purified directly by preparative HPLC to obtain Example 8b. ESI-MS:454[M+H] + ;HPLC(Rt): 0.81 min (Method D) Chiral HPLC: Rt = 3.48 mins (Method G). Enantiomer purity: >98% ee.

[0162] (Example 9) [ka] A mixture of intermediate H-3 (crude TFA salt, 100.0 mg, 114.0 μmol) and triethylamine (96.8 μL, 685.0 μmol) in THF (2 mL) was mixed with methanesulfonyl chloride (8.8 μL, 114.0 μmol) at 0°C. After stirring at 0°C for 2 hours, water was added, and the reaction mixture was extracted with dichloromethane. The organic phase was separated and concentrated under reduced pressure. The residue was dissolved in a mixture of acetonitrile / water / concentrated ammonia aqueous solution and purified by preparative HPLC to obtain Example 9 as a racemic mixture. ESI-MS:508[M+H] + ;HPLC(Rt): 0.93 min (Method D)

[0163] (Examples 10, 10a, and 10b) [ka] A mixture of intermediate F-1 (100.0 mg, 210.0 μmol), intermediate B-2 (60.1 mg, 252.0 μmol), and triethylamine (59.0 μL, 420.0 μmol) in DMA (1.5 mL) was stirred at 100 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was purified directly by preparative HPLC to obtain Example 10 as a racemic mixture. ESI-MS:454[M+H] + ;HPLC(Rt): 0.63 min (Method B)

[0164] Preparative Chiral Separation: Racemic amide 10 (30.0 mg, 66.0 μmol) was subjected to preparative chiral SFC separation (Sepiatec basic, Lux® Cellulose-4, 10 x 250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: 20 ​​mM concentrated ammonia water containing methanol, gradient A:B 80:20, flow rate 10 mL / min, temperature 40°C, wavelength 220 nm, system back pressure 150 bar, sample concentration 10 mg / mL, injection volume 100 μL), and the following results were obtained: Example 10a (single stereoisomer a): Rt = 1.42 mins (Method H). Enantiomer purity: 100.0% ee. Example 10b (single stereoisomer b): Rt = 1.62 mins (Method H). Enantiomer purity: 96.0% ee.

[0165] Synthesis of Example 10a from Chiral Intermediate (S)-F-1 A mixture of intermediate (S)-F-1 (70.0 mg, 230.0 μmol), intermediate B-2 (61.1 mg, 276.0 μmol), and triethylamine (80.6 μL, 574.0 μmol) in DMA (0.5 mL) was stirred at 100 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with an acetonitrile / water mixture and an aqueous ammonia solution. The mixture was filtered and purified directly by preparative HPLC to obtain Example 10a. ESI-MS:454[M+H] + ;HPLC(Rt): 0.83 min (Method D) Chiral HPLC: Rt = 1.39 mins (Method H). Enantiomer purity: >98%ee.

[0166] (Examples 11, 11a, and 11b) [ka] A mixture of intermediate F-1 (85.0 mg, 179.0 μmol), intermediate B-3 (55.2 mg, 214.0 μmol), and triethylamine (50.1 μL, 357.0 μmol) in DMA (1.5 mL) was stirred at 100 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was extracted three times with ethyl acetate. The combined organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified directly by preparative HPLC to obtain Example 11 as a racemic mixture. ESI-MS:472[M+H] + ;HPLC(Rt): 0.65 min (Method B)

[0167] Preparative Chiral Separation: Racemic amide 11 (207.0 mg, 439.0 μmol) was subjected to preparative chiral SFC separation (Sepiatec basic, Chiral pak ART® Cellulose-SB, 10 x 250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: methanol-containing 20 mM concentrated ammonia water, gradient A:B 80:20, flow rate 10 mL / min, temperature 40°C, wavelength 220 nm, system back pressure 150 bar, sample concentration 25 mg / mL, injection volume 100 μL), and the following results were obtained: Example 11a (single stereoisomer a): Rt = 3.33 mins (Method I). Enantiomer purity: >98%ee. Example 11b (single stereoisomer b): Rt = 4.32 mins (Method I). Enantiomer purity: nd.

[0168] Synthesis of Example 11b from chiral intermediate (S)-F-1 A mixture of intermediate (S)-F-1 (70.0 mg, 230.0 μmol), intermediate B-3 (66.1 mg, 276.0 μmol), and triethylamine (80.6 μL, 574.0 μmol) in DMA (0.5 mL) was stirred at 100 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with an acetonitrile / water mixture and an aqueous ammonia solution. The mixture was filtered and purified directly by preparative HPLC to obtain Example 11b. ESI-MS:472[M+H] + ;HPLC(Rt): 0.86 min (Method D) Chiral HPLC: Rt = 4.33 mins (Method I). Enantiomer purity: >98% ee.

[0169] (Example 12) [ka] A mixture of intermediate E-3 (50.0 mg, 151.0 μmol), DIPEA (104.4 μL, 604.0 μmol), and intermediate C-2 (HCl salt, 30.9 mg, 166.0 μmol) in acetonitrile (0.7 mL) was mixed with CIP (46.3 mg, 166.0 μmol). After stirring at room temperature for 2 hours, the mixture was diluted with aqueous ammonia and water. After filtering the mixture, it was purified directly by preparative HPLC to obtain Example 12. ESI-MS:454[M+H] + ;HPLC(Rt): 0.66 min (Method B)

[0170] (Examples 13, 13a, and 13b) [ka] To a mixture of intermediate H-4 (75.0 mg, 180.0 μmol) and DIPEA (123.1 μL, 719.0 μmol) in acetonitrile (2 mL), acetyl chloride (18.4 μL, 270.0 μmol) was added. After stirring for 1 hour, additional amounts of acetyl chloride (9.0 μL) and DIPEA (30.8 μL) were added, and stirring was continued for 30 minutes. Water was added, the reaction mixture was filtered, and the product was purified directly by HPLC to obtain product 13 as a racemic mixture. ESI-MS:460[M+H] + ;HPLC(Rt): 0.90 min (Method D)

[0171] Preparative Chiral Separation: Racemic amide 13 (60.0 mg, 131.0 μmol) was subjected to preparative chiral SFC separation (Sepiatec basic, Lux® Cellulose-3, 10 x 250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: 20 ​​mM concentrated ammonia water containing methanol, gradient A:B 85:15, flow rate 10 mL / min, temperature 40°C, wavelength 220 nm, system back pressure 150 bar, sample concentration 11 mg / mL, injection volume 200 μL), and the following results were obtained: Example 13a (single stereoisomer a): Rt = 0.86 min (Method J). Enantiomer purity: >99%ee. Example 13b (single stereoisomer b): Rt = 1.07 min (Method J). Enantiomer purity: 99.2% ee.

[0172] Synthesis of Example 13b from chiral intermediate (S)-H-4 To a mixture of the intermediate (S)-H-4 (30.0 mg, 68.0 μmol) and DIPEA (46.8 μL, 273.0 μmol) in acetonitrile (0.75 mL), acetyl chloride (7.0 μL, 102.0 μmol) was added. After stirring at room temperature for 2.5 hours, water was added, and the reaction mixture was filtered and purified directly by HPLC to obtain Example 13b. ESI-MS:460[M+H] + ;HPLC(Rt): 0.90 min (Method D) Chiral HPLC: Rt = 1.10 min (Method J). Enantiomer purity: >98%ee.

[0173] (Examples 14, 14a, and 14b) [ka] A mixture of intermediate E-4 (150.0 mg, 479.0 μmol), DIPEA (248.5 μL, 1.4 mmol), and intermediate C-1 (HCl salt, 96.2 mg, 527.0 μmol, trans-racemic mixture) in acetonitrile (5 mL) was mixed with CIP (146.7 mg, 527.0 μmol). After stirring at room temperature for 16 hours, the mixture was diluted with 1 N sodium hydroxide aqueous solution and extracted twice with DCM. The combined organic phases were washed with water, dried, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Example 14 as a trans-racemic mixture. ESI-MS:442[M+H] + ;HPLC(Rt): 0.65 min (Method B)

[0174] Preparative Chiral Separation: Trans-racemic amide 14 (135.0 mg, 306.0 μmol) was subjected to preparative chiral SFC separation (Sepiatec 2 Prep SFC 100, CHIRAL ART® Amylose-SA, 20x250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: methanol-containing 20 mM concentrated ammonia water, gradient A:B 75:25, flow rate 40 mL / min, temperature 40°C, wavelength 220 nm, system back pressure 150 bar, sample concentration 23 mg / mL, injection volume 100 μL), and the following results were obtained: Example 14a (trans-single stereoisomer a): Rt = 0.93 min (Method K). Enantiomer purity: >98%ee. Example 14b (trans-single stereoisomer b): Rt = 1.24 min (Method K). Enantiomer purity: >98%ee.

[0175] (Examples 15, 15a, and 15b) [ka] A mixture of intermediate E-5 (200.0 mg, 575.0 μmol), DIPEA (248.5 μL, 1.4 mmol), and N-acetyl-pyrrolidine-3-ylamine (83.5 mg, 632.0 μmol) in acetonitrile (3 mL) was mixed with CIP (176.1 mg, 632.0 μmol). After stirring at room temperature for 16 hours, the mixture was diluted with water and extracted twice with ethyl acetate. The aqueous phase was filtered and purified by preparative HPLC to obtain Example 15 as a racemic mixture. ESI-MS:424[M+H] + ;HPLC(Rt): 0.84 min (Method D)

[0176] Preparative Chiral Separation: Racemic amide 15 (128.6 mg, 304.0 μmol) was subjected to preparative chiral SFC separation (Sepiatec 1 Prep SFC 100, Lux® Cellulose-2, 21.2 x 250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: 20 ​​mM concentrated ammonia water containing ethanol, gradient A:B 70:30, flow rate 60 mL / min, temperature 40 °C, wavelength 220 nm, system back pressure 150 bar, sample concentration 20 mg / mL, injection volume 200 μL), and the following results were obtained: Example 15a (single stereoisomer a): Rt = 3.74 mins (Method L). Enantiomer purity: >98%ee. Example 15b (single stereoisomer b): Rt = 4.27 mins (Method L). Enantiomer purity: 96.8% ee.

[0177] Synthesis of Example 15a from Chiral Starting Materials To a mixture of intermediate E-5 (2.5 g, 8.0 mmol), DIPEA (248.5 μL, 1.4 mmol), and (R)-1-acetylpyrrolidine-3-ylamine hydrochloride (CAS No. 1286208-55-6, 1.3 g, 8.0 mmol) in acetonitrile (60 mL), CIP (2.2 g, 8.0 mmol) was added. After stirring at room temperature for 45 minutes, the mixture was filtered and purified directly by preparative HPLC to obtain Example 15a. ESI-MS:424[M+H] + ;HPLC(Rt): 0.99 min (Method C) Chiral HPLC: Rt = 3.73 mins (Method L). Enantiomer purity: >98%ee.

[0178] (Examples 16, 16a, and 16b) [ka] A mixture of intermediate E-4 (220.0 mg, 702.0 μmol), DIPEA (303.7 μL, 1.8 mmol), and N-acetyl-pyrrolidine-3-ylamine (102.1 mg, 772.0 μmol) in acetonitrile (3 mL) was mixed with CIP (215.2 mg, 772.0 μmol). After stirring at room temperature for 2 hours, the mixture was diluted with water, filtered, and purified directly by preparative HPLC to obtain Example 16 as a racemic mixture. ESI-MS:424[M+H] + ;HPLC(Rt): 0.83 min (Method D)

[0179] Preparative Chiral Separation: Racemic amide 16 (128.6 mg, 304.0 μmol) was subjected to preparative chiral SFC separation (Sepiatec 2 Prep SFC 100, Lux® Cellulose-2, 21.2 x 250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: 20 ​​mM concentrated ammonia water containing ethanol, gradient A:B 65:35, flow rate 60 mL / min, temperature 40 °C, wavelength 220 nm, system back pressure 150 bar, sample concentration 20 mg / mL, injection volume 250 μL), and the following results were obtained: Example 16a (single stereoisomer a): Rt = 1.46 min (Method M). Enantiomer purity: >98%ee. Example 16b (single stereoisomer b): Rt = 1.65 min (Method M). Enantiomer purity: 96%ee. Another aspect of the present invention may be as follows: [1] A compound of formula (I) or a salt thereof. [ka] (I) (In the formula, A is a group consisting of -CH=CH- and -S-. a Selected from; B is [ka] Group B consisting of a Selected from; R 1 This is the group R consisting of H- and F- 1a Selected from; R 2 This is the group R consisting of H- and F- 2a Selected from; R 3 F-, Cl-, F 2 HCO-, F 3 CO-, F 2 HC- and F 3 Group R consisting of C- 3a Selected from; R 4 This is the group R consisting of H- and F- 4a Selected from; R 5 This is the group R consisting of H- and F- 5a Selected from; R 6 H-, C 1-3 -alkylcarbonyl- and C 1-3 - A group consisting of alkylsulfonyls R 6a Selected from; Here, C 1-3 The alkylcarbonyl group is selected from the group consisting of acetyl, ethanecarbonyl, propanecarbonyl, isopropanecarbonyl, and cyclopropanecarbonyl. Here, C 1-3 The alkylsulfonyl group is selected from the group consisting of methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, and cyclopropanesulfonyl. Here, C 1-3 -alkylcarbonyl- group and C 1-3 The alkylsulfonyl group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and deuterium. [2] Group A consisting of -CH=CH- b A compound selected from the above [1]. [3] Group A consisting of -S- c A compound selected from the above [1]. [4] B

change

[10] A pharmaceutical composition comprising at least one compound described in any one of the above items [1] to [8], or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable auxiliary agent, diluent and / or carrier.

[11] A compound described in any one of the above items [1] to [8] or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in

[10] , for use as a pharmaceutical.

[12] Schizophrenia; Positive symptoms associated with schizophrenia, schizoaffective disorder, schizophrenia-like disorder, schizophrenia-type disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome and autism spectrum disorder; Enhancement of antipsychotics for the treatment of positive symptoms associated with schizophrenia, schizoaffective disorder, schizophrenia-like disorder, schizophrenia-type disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome and autism spectrum disorder; Schizophrenia, schizoaffective disorder , schizophrenia-like disorder, schizophrenia-type disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome, and negative symptoms associated with autism spectrum disorder; schizophrenia (CIAS), schizoaffective disorder, schizophrenia-like disorder, schizophrenia-type disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome, and cognitive impairment associated with autism spectrum disorder; treatment-resistant schizophrenia; schizoaffective disorder; schizophrenia-like disorder; schizophrenia-type disorder; drug-induced mental disorders; A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as described in item

[10] above, for use in the prevention and / or treatment of a disorder selected from the group consisting of bipolar disorder I and bipolar disorder II; debilitating psychosis; neuropsychiatric symptoms associated with Alzheimer's disease, Parkinson's disease, vascular dementia and frontotemporal dementia; autism spectrum disorder (ASD); obsessive-compulsive disorder (OCD); impulse control disorder; gambling disorder; Tourette 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; separation; hypothalamic disorder; prolactin-related disorders, hyperprolactinemia; symptoms associated with frontal lobe dysfunction and frontal lobe dysfunction associated with drug abuse; and hyperkinetic symptoms.

[13] The compound for use described in

[12] or a pharmaceutically acceptable salt thereof, characterized in that the compound is administered in addition to treatment with at least one antipsychotic drug.

Claims

1. A compound of formula (I) or a salt thereof. 【Chemistry 1】 (I) (In the formula, A is a group consisting of -CH=CH- and -S-. a Selected from; B is, 【Chemistry 2】 Group B consisting of a Selected from; R 1 This is the group R consisting of H- and F-. 1a Selected from; R 2 This is the group R consisting of H- and F-. 2a Selected from; R 3 is selected from the group R consisting of F−, Cl−, F 2 HCO−, F 3 CO−, F 2 HC− and F 3 C−; 3a is selected from; R 4 This is the group R consisting of H- and F-. 4a Selected from; R 5 This is the group R consisting of H- and F-. 5a Selected from; R 6 H-, C 1-3 -Alkylcarbonyl- and C 1-3 - Group R consisting of alkylsulfonyl 6a Selected from; Here, C 1-3 The alkylcarbonyl group is selected from the group consisting of acetyl, ethanecarbonyl, propanecarbonyl, isopropanecarbonyl, and cyclopropanecarbonyl. Here, C 1-3 The alkylsulfonyl group is selected from the group consisting of methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, and cyclopropanesulfonyl. Here, C 1-3 -Alkylcarbonyl- group and C 1-3 The alkylsulfonyl group may be substituted with one to five substituents independently selected from the group consisting of fluorine and deuterium.

2. Group A consisting of -CH=CH- b A compound according to claim 1, selected from the following.

3. A is a group consisting of -S- c A compound according to claim 1, selected from the following.

4. B 【Transformation 3】 Group B consisting of b A compound according to claim 1, selected from the following.

5. R 3 F-, Cl-, and F 2 Group R consisting of HC- 3b A compound according to claim 1, selected from the following.

6. R 3 The group R consists of F- 3c A compound according to claim 1, selected from the following.

7. R 6 C 1-3 Group R consisting of -alkylcarbonyl- 6b Selected from, Here, C 1-3 The alkylcarbonyl group is selected from the group consisting of acetyl, ethanecarbonyl, propanecarbonyl, isopropanecarbonyl, and cyclopropanecarbonyl. Here, C 1-3 The compound according to claim 1, wherein the alkylcarbonyl group may be substituted with one, two, or three deuterium atoms. 【Request Item 8】 【Table 1】 A compound according to claim 1, selected from the group consisting of the following.

9. A pharmaceutically acceptable salt of the compound according to any one of claims 1 to 8.

10. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and which may also comprise at least one pharmaceutically acceptable auxiliaries, diluents and / or carriers.

11. Schizophrenia; Positive symptoms associated with schizophrenia, schizoaffective disorder, schizophrenia-like disorder, schizophrenia-type disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome, and autism spectrum disorder; Enhancement of antipsychotics to treat positive symptoms associated with schizophrenia, schizoaffective disorder, schizophrenia-like disorder, schizophrenia-type disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome, and autism spectrum disorder; Negative symptoms associated with schizophrenia, schizoaffective disorder, schizophrenia-like disorder, schizophrenia-type disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome, and autism spectrum disorder; Cognitive impairment associated with schizophrenia (CIAS), schizoaffective disorder, schizophrenia-like disorder, schizophrenia-type disorder, treatment-resistant schizophrenia, debilitating psychosis syndrome, and autism spectrum disorder; Treatment-resistant schizophrenia; Schizoaffective disorder; Schizophrenia-like disorder; The pharmaceutical composition according to claim 10 for use in the prevention and / or treatment of disorders selected from the group consisting of: pharmacopsychiatric disorders; drug-induced mental disorders; bipolar disorder I and bipolar disorder II; debilitating psychosis; neuropsychiatric symptoms associated with Alzheimer's disease, Parkinson's disease, vascular dementia, and frontotemporal dementia; autism spectrum disorder (ASD); obsessive-compulsive disorder (OCD); impulse control disorder; gambling disorder; Tourette 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; separation; hypothalamic disorders; prolactin-related disorders, hyperprolactinemia; symptoms associated with frontal lobe dysfunction and frontal lobe dysfunction associated with drug abuse; and hyperkinetic symptoms.

12. The pharmaceutical composition according to claim 11, characterized in that it is used in addition to treatment with at least one antipsychotic drug.

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