3-Phenoxyazetidin-1-yl-heteroarylpyrrolidine derivatives and their use as medicines

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 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 a 3-phenoxyazetidin-1-yl-heteroarylpyrrolidine derivative of general formula (I) for use as a medicament, a pharmaceutical composition comprising a 3-phenoxyazetidin-1-yl-heteroarylpyrrolidine derivative of general formula (I) and a process for preparing the pharmaceutical composition, as well as a process for producing the compound according to the present invention. [Background technology]

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

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

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

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

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

[0007] (3) Psychotic disorder The psychotic symptoms of schizophrenia are due to excessive presynaptic dopamine activity in the striatum (Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III-the final common pathway. Schizophr Bull. 35, 549-562). The clinical efficacy of existing antipsychotic drugs to treat psychotic symptoms depends on the blockade of D2 receptors. All known antipsychotic drugs effective in treating psychosis are either antagonists or partial agonists of dopamine D2 receptors (Remington G, Kapur S (2010) Antipsychotic dosing: how much but also how often? Schizophr Bull. 36, 900-903). While these antipsychotic drugs can treat the positive (or psychotic) symptoms of schizophrenia, they do not treat other aspects of schizophrenia, such as negative symptoms or cognitive impairment. Based on the co-expression of GPR52 and dopamine D2 receptor, GPR52 agonists should treat psychotic symptoms associated with schizophrenia. In addition, the mechanism of action of GPR52 agonists is unique to known D2 receptor-related antipsychotics, so GPR52 agonists are expected to enhance the antipsychotic efficacy of known neuroleptics. This not only improves antipsychotic efficacy, but can also be used to reduce the dose of antipsychotics, thereby reducing the side effects associated with antipsychotics. While serum prolactin levels are elevated, one of the prominent side effect profiles of known D2R antagonist antipsychotics, GPR52 agonists have been demonstrated to reduce serum prolactin levels, and therefore the combination of GPR52 agonists and D2R antagonist antipsychotics may normalize serum prolactin levels, thereby reducing the side effects associated with D2R antagonist antipsychotics.GPR52 agonists should also treat the psychotic symptoms associated with various psychiatric indications, such as schizoaffective disorder, schizophrenia-type disorder, schizophreniform disorder, treatment-resistant schizophrenia, medication-induced psychosis, bipolar disorder, autism spectrum disorder, and attenuated psychosis syndrome. Furthermore, GPR52 agonists should treat the psychotic and neuropsychiatric symptoms associated with various neurodegenerative indications, such as Parkinson's disease, Alzheimer's disease, frontotemporal dementia, vascular cognitive impairment, and dementia with Lewy bodies. These antipsychotics are also associated with a significant side effect profile, such as weight gain, metabolic syndrome, diabetes, hyperlipidemia, hyperglycemia, insulin resistance, extrapyramidal symptoms, hyperprolactinemia, and tardive dyskinesia. As GPR52 agonists should be functionally similar to D2 antagonists, the GPR52 agonists disclosed herein are useful for the treatment of psychotic disorders.

[0008] (4) Other D1-related disorders Several neurotherapeutic and psychotherapeutic drugs are known to function as D1 agonists, including A-86929, dinapsoline, doxantrin, SKF-81297, SKF-82958, SKF-38393, fenoldopam, 6-Br-APB, and stefoloidin. Because GPR52 agonists should be functionally similar to (and co-localize with) D1 agonists, the GPR52 agonists disclosed herein are useful for treating disorders treatable by D1 agonists, including, but not limited to, addiction (e.g., cocaine addiction), hypertension, restless legs syndrome, Parkinson's disease, and depression. Based on their expression patterns and functional coupling, GPR52 agonists are also useful for treating cognitive deficits associated with schizophrenia, schizophreniform disorders, treatment-resistant schizophrenia-attenuated psychotic syndromes and schizophrenia-type disorders, bipolar disorder, autism spectrum disorder, Alzheimer's disease, Parkinson's disease, frontotemporal dementia (Pick's disease), dementia with Lewy bodies, vascular dementia, post-stroke dementia, and Creutzfeldt-Jakob disease.

[0009] (5) Other D2-related disorders Several neurological disorders, such as obsessive-compulsive disorder and impulse control disorders, involve alterations in dopamine receptor signaling, making GPR52 agonists useful for 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). Additionally, several neurotherapeutic and psychotherapeutic drugs are known to function as D2 antagonists, including atypical antipsychotics (e.g., aripiprazole, clozapine, olanzapine, and ziprasidone), domperidone, eticlopride, falpride, desmethoxyfalpride, L-741, 626, raclopride, hydroxyzine, itopride, 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 for treating disorders treatable by D2 antagonists, including, but not limited to, psychotic disorders, isolation, anxiety, anxiety / tension associated with psychoneurosis, acute mania, agitation, mania in bipolar disorder, dysthymia, nausea, vomiting, gastrointestinal disorders, dyspepsia, and addiction (e.g., cocaine addiction, amphetamine addiction, etc.).

[0010] Therefore, GPR52 agonists are considered to be promising candidates for treating diseases of the central nervous system. Thus, there is a need to develop compounds for the prevention and / or treatment of psychiatric disorders that may have an agonistic effect on GPR52. In particular, there is a need to develop compounds that may have agonistic activity on GPR52 and optimized pharmacological properties that may be useful as agents for the prevention and / or treatment of psychiatric disorders such as schizophrenia. International Patent Application No. WO 2009 / 157196, International Patent Application No. WO 2009 / 107391, International Patent Application No. WO 2011 / 078360, International Patent Application No. WO 2011 / 093352, International Patent Application No. WO 2011 / 145735, International Patent Application No. WO 2012 / 020738, International Patent Application No. WO 2016 / 176571 and International Patent Application Nos. WO 2021 / 090030, WO 2021 / 198149 and WO 2021 / 216705 disclose compounds that modulate GPR52 for treating diseases of the central nervous system and other diseases. Summary of the Invention

[0011] Objective of the invention It has now been found that the compounds of the present invention according to general formula (I), or a pharma- ceutically acceptable salt thereof, are effective agonists of GPR52. In addition to agonist properties for GPR52, the compounds of the present invention offer further advantageous properties that make them viable for human therapy, such as low plasma protein binding, high stability in human hepatocytes, drug metabolism that extends to enzyme metabolism other than CYP, such as hydrolase-mediated pathways, low hERG channel inhibition (or interaction), and / or sufficient water solubility for the compounds to be used as drugs. The compounds of the present invention according to general formula (I) are metabolically stable in human hepatocytes. Thus, it is expected that the compounds of the present invention have favorable in vivo clearance and, as a result, desirable duration of action in humans. As the liver is the main site of metabolism for 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 improved bioavailability and / or longer half-life, which may allow for lower patient doses and / or less frequent administration. Reducing the effective dose and / or reducing the effective frequency of administration of a compound for disease treatment minimizes potential side effects. Thus, improved metabolic stability in human hepatocytes is a favorable property for compounds used as drugs.

[0012] Furthermore, the compounds of the present invention according to general formula (I) exhibit low plasma protein binding and, consequently, a high unbound fraction 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, especially those of general formula (I) having both high / moderate metabolic stability and low plasma protein binding, are feasible for human therapy. Compounds of the invention according to general formula (I), provided that the group R 6 C 1-3 -Alkyl carbonyl moieties exhibit enzyme metabolism other than CYP, particularly via hydrolases, which contributes to overall metabolic diversification and results in a reduced 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 significant pharmacokinetic interactions are those in which a second drug alters the clearance of a first drug. For example, a co-administered drug inhibits the metabolism of a drug, resulting in an increase in the plasma concentration of the first drug, which may result in a clinically relevant increase in therapeutic response or an increase in toxicity. Drug metabolism occurs primarily in the liver and intestine. These organs express a wide variety of drug-metabolizing enzymes and are responsible for the biotransformation of many drugs. Phase I oxidative metabolism occurs primarily by enzymes of the cytochrome P450 (CYP) family present in the hepatic endoplasmic reticulum, but can also be mediated by enzymes other than CYP, such as hydrolases. These functionalization reactions are often followed by conjugation reactions (phase II) 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 non-CYP enzymes 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), respectively, are the main enzymes catalyzing said metabolism. For example, the main enzymes responsible for amide hydrolysis, producing 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 those listed above, including elucidation of the major metabolites.

[0014] In psychiatric clinical practice, combination drug therapy is commonly used to treat patients with psychiatric and physical disorders, to suppress side effects of certain drugs, or to increase drug efficacy. However, such polypharmacy approaches increase the risk of CYP-mediated drug-drug interactions. Therefore, it is desirable to use drugs with a low possibility of drug-drug interactions, especially for elderly patients who are likely to take multiple drugs simultaneously (Spina E, de Leon, J. (2007) Metabolic Drug Interactions with Newer Antipsychotics: A Comparative Review. Basic Clin. Pharmacol. Toxicol. 100, 4-22). Therefore, the group R 6 C 1-3 Further contribution to overall metabolic clearance via pathways dependent on enzymes other than CYP, such as via hydrolases, resulting in more diverse metabolism and reduced risk of drug-drug interactions, as shown by the compounds of the present invention according to general formula (I) with -alkylcarbonyl moiety, is highly desirable. As a result, the compounds of the present invention are viable for human therapy.

[0015] Inhibition of the hERG channel and subsequent delayed cardiac repolarization is associated with an increased risk of torsades de pointes, a specific polymorphic ventricular tachyarrhythmia, as documented by Sanguinetti et al. (1995, Cell, 81 (2): 299-307) and subsequent evidence. To minimize this risk, screening for hERG channel inhibition in in vitro systems using heterologous expression of the hERG channel is common practice and is an important part of late-stage preclinical profiling as recommended by ICH guideline S 7 B (International Conference on Harmonization (2005): ICH Topic S 7 B; The nonclinical Evaluation of the Potential for delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals). Thus, low / moderate hERG channel inhibition or interaction as exhibited by the compounds of the present invention is highly desirable. As a result, the compounds of the present invention are viable for human therapy. The compounds of the present invention according to formula (I) show acceptable water solubility for compounds used as drugs.Improved solubility of compounds leads to improved developability of drug products.Furthermore, as known in the art, poorly soluble compounds may result in poor human exposure.

[0016] Thus, one aspect of the present invention refers to compounds according to general formula (I) or salts thereof, preferably pharma- ceutically acceptable salts thereof, as agonists of GPR52. Another aspect of the present invention refers to the compounds according to general formula (I) or salts thereof, preferably pharma- ceutically acceptable salts thereof, as agonists of GPR52 with high / moderate human hepatocyte stability. Another aspect of the present invention refers to the compounds according to general formula (I) or salts thereof, preferably pharma- ceutically acceptable salts thereof, as agonists of GPR52 with low / moderate human plasma protein binding rate. Another aspect of the present invention is the use of group R agonists as agonists of GPR52 with diversified metabolism, including metabolic pathways dependent on enzymes other than CYP, such as metabolism via hydrolases. 6 C 1-3 -alkylcarbonyl moiety or a salt thereof, preferably a pharma- ceutically acceptable salt thereof. Another aspect of the present invention refers to the compounds according to general formula (I) or salts thereof, preferably pharma- ceutically acceptable salts thereof, as agonists of GPR52 with low / moderate inhibition of the hERG channel.

[0017] Another aspect of the present invention refers to compounds according to general formula (I) or salts thereof, preferably pharma- ceutically acceptable salts thereof, as agonists of GPR52, having sufficient water solubility for the compound to be used as a drug. Another aspect of the present invention refers to compounds according to general formula (I) or salts thereof as agonists of GPR52, having high / moderate human hepatocyte stability and low / moderate human plasma protein binding rate. Another aspect of the present invention refers to compounds according to general formula (I) or salts thereof as agonists of GPR52, having high / moderate human hepatocyte stability, low / moderate human plasma protein binding and diversified metabolism including metabolic pathways dependent on enzymes other than CYP, such as metabolism mediated by hydrolases. Another aspect of the present invention is that it has high / moderate human hepatocyte stability, low / moderate human plasma protein binding, and hydrolase-mediated metabolism (group R 6 C 1-3 -Alkyl carbonyl moiety only for compounds having a diversified metabolism including metabolic pathways dependent on enzymes other than CYP, low / moderate hERG channel inhibition, and, optionally, sufficient water solubility of the compound to be used as a drug, according to general formula (I) or a salt thereof, as an agonist of GPR52.

[0018] In a further aspect, the present invention relates to a pharmaceutical composition containing at least one compound according to general formula (I) or a pharma- ceutically acceptable salt thereof, optionally together with one or more inert adjuvants, diluents and / or carriers. A further aspect of the invention relates to a compound according to general formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to formula (I) or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis and / or treatment of disorders associated with insufficient GPR52 activity. Another aspect of the present invention relates to a process for the preparation of the compounds of the present invention according to general formula (I) or salts thereof, particularly pharma- ceutically acceptable salts. Other objects of the present invention will become apparent to those skilled in the art directly from the above and following description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] In a first aspect, the present invention relates to a compound of general 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 is a group R consisting of H- and F- 1a Selected from; R 2 is a group R consisting of H- and F- 2a Selected from; R 3 is a group R consisting of F-, Cl-, F2HCO-, F3CO-, F2HC- and F3C- 3a Selected from; R 4 is a group R consisting of H- and F- 4a Selected from; R 5 is a group R consisting of H- and F- 5a Selected from; R 6 , H-, C 1-3-Alkylcarbonyl- and C 1-3 -alkylsulfonyl- 6a is selected from Here, the above C 1-3 -Alkylcarbonyl- groups and C 1-3 The -alkylsulfonyl- group is optionally substituted with 1 to 5 (e.g., 2, 3, or 4) substituents independently selected from the group consisting of fluorine and deuterium. Preferably it relates to pharma- ceutically acceptable salts. Unless otherwise stated, the groups, residues and substituents, in particular A, B, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are defined as above and below. If residues, substituents or groups occur several times in a compound, they may have the same or different meanings. Some preferred meanings of groups and substituents of the compounds according to the invention are set out below.

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

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

[0022] A further embodiment of the present invention relates to a compound of general formula (II) [ka] (II) (In the formula, A, B, R 1 , R 2 , R 3 , R 4 , R5 and R 6 are substituents as described in the present invention), and the compounds of general formula (II) are of the groups B, R 4 and R 5 The present invention relates to compounds which are characterized in that they are a single enantiomer according to the meaning of the formula (I) or a plurality of diastereoisomers or a single diastereoisomer.

[0023] The general formula (II) is represented by the general formula (IIB b ) and (IIB c ) [ka] Includes:

[0024] A further embodiment of the present invention relates to a compound 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 are substituents as described in the present invention), and the compounds of general formula (I.II) are of the groups B, R 4 and R 5 The present invention relates to compounds which are characterized in that they are a single enantiomer according to the meaning of the formula (I) or a plurality of diastereoisomers or a single diastereoisomer.

[0025] The general formula (I.II) is the general formula (I.II.B b ) and (I.II.B c ) [ka] Includes:

[0026] General formula (II) (e.g., general formula (IIB b ) or (IIBc )) is group B, R 4 and R 5 The meaning of and, where applicable, R 4 and R 5 It can be understood by those skilled in the art that the present invention includes a single enantiomer or multiple diastereoisomers or a single diastereoisomer due to the configuration of chiral carbon atoms having the general formula (I.II) (e.g., general formula (I.II.B) b ) or (I.II.B c )) also applies. For example, the general formula (IIB b ) is R 4 and R 5 has the same meaning (e.g. R 4 and R 5 are both H-, or R 4 and R 5 are F-), one single enantiomer is included. b ) also applies. For example, the general formula (IIB b ) is R 4 and R 5 has a different meaning (e.g. R 4 is H- and R 5 The same applies to the general formula (I.II.B), which includes multiple diastereoisomers. b ) also applies. For example, the general formula (IIB b ) is R 4 and R 5 has a different meaning (e.g. R 4 is H- and R 5 is F-), and R 4 and R 5 The same applies to compounds of the general formula (I.II.B), which include single diastereoisomers when the chiral carbon atom having the formula b ) also applies.

[0027] A further embodiment of the present invention relates to a compound of the general formula (IIBb ) compounds. A further embodiment of the present invention relates to a compound of the general formula (I.II.B b ) compounds. In a further embodiment of the invention, A is a group consisting of -CH=CH- b is selected from. In a further embodiment of the invention, A is a member of the group A consisting of -S- c is selected from. In a further embodiment of the invention, R 3 is a group R consisting of F-, Cl-, and F2HC- 3b is selected from. In a further embodiment of the invention, R 3 is a group R consisting of F- 3c is selected from. In a further embodiment of the invention, R 6 is C 1-3 -alkylcarbonyl- 6b is selected from Here, the above C 1-3 The -alkylcarbonyl- group may be optionally substituted with one to five (eg, two, three or four) deuterium atoms. In a further embodiment of the invention, R 6 is a group R consisting of acetyl 6c is selected from wherein the acetyl group may be substituted with one, two or three deuterium atoms.

[0028] A x , B x , R 1x , R 2x , R 3x , R 4x , R 5x and R 6x Each of the terms A represents an individual embodiment characterized with respect to the corresponding substituents as described above. Thus, given the above definitions, individual embodiments of the first aspect of the invention are x , B x , R 1x , R 2x , R3x , R 4x , R 5x and R 6x ), where each subscript "x" defines a particular letter ranging from "a" to the last alphabetical letter listed above. With reference to the above definition, all particular embodiments described by the term in brackets with the subscript "x" substituted for it in full are intended to constitute the present invention. Table 1 below shows embodiments E-1 to E-50 of such compounds of general formula (I) or salts thereof, preferably pharma- ceutically acceptable salts, which are considered to be preferred. Embodiments E-8, E-9, E-26, E-27, E-45, and E-46 of Table 1 are more preferred embodiments. All of the embodiments E-1 to E-50 of Table 1 have configurations according to general formula (II) or general formula (I.II), such as general formula (IIB b ), (IIB c ), (I.II.B. b ) or (I.II.B c ) and preferably has the configuration according to general formula (II).

[0029] [Table 1] TIFF2024533565000010.tif242169 Thus, for example, E-2 is a compound of the 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 is a group R consisting of H- and F- 1a Selected from; R 2 is a group R consisting of H- and F- 2a Selected from; R 3is a group R consisting of F-, Cl-, F2HCO-, F3CO-, F2HC- and F3C- 3a Selected from; R 4 is a group R consisting of H- and F- 4a Selected from; R 5 is a group R consisting of H- and F- 5a Selected from; R 6 is C 1-3 -alkylcarbonyl-, 6b is selected from Here, C 1-3 -alkylcarbonyl- groups may be optionally substituted with 1 to 5 deuterium atoms or a salt thereof, preferably a pharma- ceutically acceptable salt.

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

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

[0032] Further preferred are the following compounds or salts thereof or stereoisomers thereof as shown in Table 2 (the numbers refer to the numbers assigned to the compounds in the Experimental Section). Each compound in Table 2 is represented without indicating its stereochemistry, if any. Specific information regarding the stereochemical properties of the compounds in Table 2 can be obtained from the Experimental Section. When the final compounds according to the above Experimental Section are in salt form, they may be converted to neutral compounds by conventional methods.

[0033] [Table 2] TIFF2024533565000015.tif203146

[0034] Further embodiments of the present invention include the compounds of general formula (I), particularly the compounds shown in Table 2, in the form of pharma- ceutically acceptable salts thereof. In a further aspect, the present invention relates to a pharmaceutical composition comprising at least one compound according to general formula (I) or a pharma- ceutically acceptable salt thereof, optionally together with at least one inert auxiliary agent, diluent and / or carrier. In a further embodiment, the present invention relates to a compound of the present invention or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound according to general formula (I) or a pharma- ceutically acceptable salt thereof, for use as a medicament. In a further embodiment, the present invention relates to a compound according to general formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to general formula (I) or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis and / or treatment of a disease or condition that may be affected by activation of GPR52.

[0035] Terms and definitions used In the following, some of the terms used above and below to describe the compounds according to the invention are defined in more detail. Terms not specifically defined herein should be given the meaning that one of ordinary skill in the art would give to such terms, given the present disclosure and its context. However, as used herein, unless otherwise indicated, the following terms have the meanings indicated and the following conventions are observed. The term “C 1-3 "-alkyl", either alone or in combination with another radical, denotes an acyclic, cyclic, saturated, branched or straight-chain hydrocarbon radical having 1, 2 or 3 C atoms. For example, the term C 1-3 -Alkyl includes the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, (CH2)2-CH-.

[0036] Generally, in groups containing two or more subgroups, the last named subgroup is the point of attachment of the radical, e.g., the substituent "C 1-3 -Alkyl-carbonyl-" is a C bonded to a carbonyl group. 1-3 -alkyl groups, the latter of which is C 1-3 -alkyl groups are bonded to the core molecule or group to which the substituent is attached. 1-3 -alkyl-sulfonyl-. For example, "C 1-3 The "-alkylcarbonyl-" group is selected from the group consisting of acetyl (i.e., CHC(O)-), ethanecarbonyl (i.e., CHCHC(O)-), propanecarbonyl (i.e., CH(CH)C(O)-), isopropanecarbonyl (i.e., CHCH(CH)C(O)-), and cyclopropanecarbonyl (i.e., (CH)CHC(O)-), e.g., "C 1-3 The "-alkylsulfonyl-group" is selected from the group consisting of methanesulfonyl (i.e., CHS(O)-), ethanesulfonyl (i.e., CHCHS(O)-), propanesulfonyl (i.e., CH(CH)S(O)-), isopropanesulfonyl (i.e., CHCH(CH)S(O)-), and cyclopropanesulfonyl (i.e., (CH)CHS(O)-).

[0037] As used herein, the term "substituted" means that any one or more hydrogens on the specified atom / group are replaced with one selected from the indicated group, so long as the possible valences of the specified atom are not exceeded and the substitution results in a stable compound. Additionally, 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 specified atom / group. Many of the above defined terms may be used repeatedly in the definition of a formula or a group and may in each case have, independently of one of the above meanings. When a compound of the invention is depicted in the form of a chemical name and as a formula, in the event of any discrepancy the formula shall prevail. dotted line [ka] is used in sub-formulas to indicate the bond or point of attachment that is connected to a core molecule that is the remainder of the molecule, or that is connected to a substituent that is attached as defined.

[0038] Unless otherwise indicated, throughout the specification and the appended claims, a given chemical formula (e.g. all compounds in Table 2) or name is intended to encompass rotamers, 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 with different ratios of the separate enantiomers, mixtures of diastereomers, or any mixture of the aforementioned forms in which said isomers are present, as well as solvates thereof, such as, for example, hydrates. For example, compound #1 in Table 2 will be understood by one of skill in the art to encompass the two enantiomers as a mixture (e.g., a racemic mixture) or as a single enantiomer (e.g., (S) or (R)). Additionally, it will be understood by one of skill in the art that compound #3 (or #14 or #H-2) of Table 2 encompasses the two cis-stereoisomers and the 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 indicated, "pharmaceutically acceptable salts", as defined in more detail below, are also intended to encompass solvates thereof, such as, for example, hydrates.

[0039] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds where the parent compound is modified by making acid or base salts thereof. Pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Such salts include, for example, salts derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Pharmaceutically acceptable salts can also be formed with cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane. The pharma- ceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0040] For example, salts of other acids (eg, trifluoroacetates) that are useful for purifying or isolating the compounds of the invention also form part of this invention. The phrase "pharmacologically acceptable adjuvant, diluent and / or carrier" is used herein to refer to those materials which, within the scope of sound medical judgment, are suitable for use in contact with human tissue without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0041] preparation The compounds according to the invention can be obtained using synthetic methods known in principle.Preferably, the compounds are obtained according to the invention by the following methods, which are described in more detail below. The following schemes generally illustrate, by way of example, how to prepare the compounds of the invention. Omitted substituents may be as defined above, unless otherwise defined within the context of the scheme. The present invention also provides a method for preparing a compound of formula (I). 1 , R 2 , R 3 , R 4 , R 5 and R 6 shall have the meaning as defined for formula (I) in the detailed description of the invention above. Optimum reaction conditions and reaction times may vary depending on the reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions can be readily selected by one skilled in the art. Specific procedures are shown in the experimental section. Reaction progress can usually be monitored by thin layer chromatography (TLC) and, optionally, 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 one of skill in the art will recognize that specific reagents or conditions can be modified as necessary for individual compounds without undue experimentation. Starting materials and intermediates used in the methods described below are either commercially available or readily prepared from commercially available materials by one of skill in the art. [ka] Scheme 1 Scheme 1 shows the synthesis of amines (V) as intermediates in the synthesis of compounds (I). In a first step, a suitably protected (PG is a protecting group, e.g., CO2tBu(BOC), CO2Bn) and suitably activated (sulfonyl ester, substituent R, e.g., methyl, CF3 or tolyl) azetidine (II) is reacted with a phenol (III) using a suitable solvent, such as dimethylacetamide, dimethylformamide, N-methyl-pyrrolidinone, acetonitrile, DMSO, dichloromethane, toluene, and a suitable base, such as cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium hydroxide, N-ethyl-diisopropylamine, pyridine, to produce 3-phenoxyazetidine (IV). This intermediate is deprotected in a second step to give amine (V). Deprotection can be carried out by using a mineral acid such as hydrochloric acid for the BOC-protected intermediate (IV) or by catalytic hydrogenation under hydrogen atmosphere using a catalyst such as palladium on charcoal for the benzyloxycarbonyl-protected intermediate (IV). Other deprotection reactions are described in 'Protective Groups in Organic Synthesis', 3' edition, TW Greene and PGM Wuts, Wiley-Interscience (1999). Depending on the reaction conditions and workup, the amine (V) may be obtained as a salt.

[0043] [ka] Scheme 2 As shown in Scheme 2, amines of formula (V) can be converted to haloesters (VI) (X=halide, R x = alkyl) in an aromatic nucleophilic substitution reaction (step 1) to give the ester compound of formula (VII). Compound (VII) can also be produced using Buchwald-Hartwig type cross-coupling conditions. For example, compound (IV) (X = Cl, Br, I; R x = alkyl) can be reacted with amine (V) in the presence of a suitable catalyst such as palladium (II) acetate, a suitable ligand such as butyl-di-1-adamantyl-phosphine, and a suitable base such as cesium carbonate in a suitable solvent such as toluene to give compounds of general formula (VII).

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

[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, THF / water to generate the corresponding carboxylic acid (IX).

[0046] Peptide coupling reactions known to those skilled in the art (see, for example, M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) can be applied to react amines of formula (X) with carboxylic acids (IX) to give compounds of general formula (I). For example, treatment of amine (X) and carboxylic acid (IX) with coupling agent 2-chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium hexafluorophosphate (CIP), Mukaiyama's reagent, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) in a suitable solvent such as acetonitrile, NMP, DMA or DMF in the presence of a suitable base such as DIPEA or 1-methylimidazole will produce compounds of formula (I).

[0047] Alternatively, treatment of carboxylic acid (IX) with 1-chloro-N,N-2-trimethylpropenylamine, thionyl chloride or oxalyl chloride in a suitable solvent such as DCM, DMF or toluene gives the intermediate acid chloride which is subsequently treated with an amine of formula (X) in the presence of a suitable base such as TEA in a suitable solvent such as DCM, THF or DMF to give the compound of formula (I). Alternatively, amines (X), pre-activated with trimethylaluminum, can be reacted directly with carboxylic esters (VII) in a suitable solvent such as DCM, dichloroethane, THF or toluene to give amides of general formula (I).

[0048] [ka] Scheme 4 Alternatively, compounds of general formula (I) can be synthesized as shown in scheme 4: peptide coupling reactions known to those skilled in the art (see for example M. Bodanszky, 1984, The Practice of Peptide Synthesis, Springer-Verlag) can be applied in a first step to react amines of formula (X) with carboxylic acids (XI) (X=halide, Y=OH) to give haloamides of general formula (XII) (X=halide). For example, treatment of amines (X) and carboxylic acids (XI) (X=halide, Y=OH) with coupling agents 2-chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium hexafluorophosphate (CIP), Mukaiyama's reagent, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) in a suitable solvent such as acetonitrile, NMP, DMA or DMF in the presence of a suitable base such as DIPEA or 1-methyl-imidazole, affords haloamides of general formula (XII) (X=halide). Alternatively, carboxylic 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 give intermediate acid chloride (XI) (Y=Cl), which can then be treated with amine of formula (X) in the presence of a suitable base such as TEA in a suitable solvent such as DCM, THF or DMF to give haloamide of general formula (XII) (X=halide). Alternatively, amine (X) preactivated with trimethylaluminum can be reacted directly with carboxylic acid ester (XI) (X=halide, Y=alkyloxy) in a suitable solvent such as DCM, dichloroethane, THF or toluene to give haloamide of general formula (XII) (X=halide).

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

[0050] Alternatively, haloamides (XII) can be reacted with hydroxyazetidines in an aromatic nucleophilic substitution reaction in the presence of a suitable base such as triethylamine in a suitable solvent such as DMA to give alcohols of general formula (XIII). In a next step, alcohols (XIII) can be converted to compounds of general formula (I) using the "Mitsunobu" method (see, for example, Tet. Lett. 1994, 35, 2819 or Synlett 2005, 18, 2808). Trialkylphosphines or triarylphosphines (such as tributylphosphine or triphenylphosphine) or solid-supported analogs such as polymer-bound triphenylphosphine and an appropriate dialkylazadicarboxylate (e.g., DIAD, DEAD) are added to compounds of general formula (XIII) in the presence of a suitable phenol (III) in a suitable solvent (e.g., THF or toluene) to give compounds of general formula (I).

[0051] Schemes 5 and 6 illustrate the synthesis of amines of general formula (X) as intermediates for the synthesis of compounds of general formula (I). [ka]

[0052] Scheme 5 Mono-fluorinated aminopyrrolidines of general formula (XVII) or general formula (XXI) can be prepared as shown in Scheme 5. Appropriately protected 6-oxa-3-azabicyclo[3.1.0]hexanes (XIV) (PG = protecting group, e.g., CO2tBu or acetyl) are reacted with an azide source such as sodium azide or tetrabutylammonium azide in a suitable solvent such as DMF or DMA to generate racemic trans-substituted azido alcohols (XV). In a second step, alcohols (XV) are 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 generate the corresponding trans-substituted azido fluorides. In the third step, reduction of the azide (XVI) can be achieved by catalytic hydrogenation (e.g., hydrogenation with hydrogen over palladium on charcoal in methanol or ethanol) or by heating the intermediate iminophosphorane with water in THF after addition of triphenylphosphine (Staudinger reaction) to produce the racemic trans-substituted monofluoroaminopyrrolidine (XVII). The corresponding cis-substituted monofluoroaminopyrrolidines (XXI) can be synthesized by a similar sequence (steps 6 and 7) starting from racemic cis-substituted azidoalcohols (XVIII), which can be prepared by inverting the stereochemistry of the hydroxy group of compound (XV) using conventional techniques (e.g., activation of the sulfonyl ester followed by nucleophilic substitution (e.g., R=CH) with potassium acetate and subsequent saponification; see, for example: Tet. Asymm. 2001, 12, 1793-1799).

[0053] Enantioselective epoxide ring opening of 6-oxa-3-azabicyclo[3.1.0]hexanes (XIV) using chiral metal salen complexes and trimethylsilyl azide (J. Am. Chem. Soc. 1995, 117, 5897) provided access to trans-enantiomerically pure precursors of general formula (XV), which could be converted to the chiral fluorinated aminopyrrolidines (XVII) and (XXI), respectively (see, for example, 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]hexanes (XIV) (PG = protecting group, e.g., CO2tBu(BOC) or acetyl) can be desymmetrized in a one- or two-step procedure to generate monoprotected pyrrolidine diols of general formula (XXII). For example, nucleophilic epoxide ring opening with sodium benzyl alcoholate can provide racemic compounds of general formula (XXII) (e.g., PG 1 = benzyl) (see, for example, WO 1999 / 64399, p. 20). Alternatively, epoxide ring opening using a hydroxide source such as sodium hydroxide can provide the intermediate pyrrolidine diol, which may be selectively mono-protected using conventional protecting group strategies (e.g., reaction with a stoichiometric amount of tert-butyldimethylsilyl chloride in the presence of a base such as imidazole in a solvent such as DMF can provide the racemic compound (XXII) (PG 1= tert-butyldimethylsilyl). Alcohols of general formula (XXII) can be converted to ketones of general formula (XXIII). For example, compound (XXII) can be oxidized with Dess-Martin periodinane or by using a combination of oxalyl chloride and DMSO in an inert solvent such as dichloromethane (Swan oxidation, see for example WO 2010 / 111057, p. 28). In a third step, ketones (XXIII) can be 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 give the corresponding difluorides (XXIV) (Deoxo-Fluor, see for example WO 2014 / 075392, p. 72). These intermediates are deprotected in a fourth step to give alcohols (XXVII). Deprotection can be carried out using tetrabutylammonium fluoride for silyl-protected intermediates (XXIV) or catalytic hydrogenation using a catalyst such as palladium on charcoal under a hydrogen atmosphere for benzyl-protected intermediates (XXIV). Additional deprotection reactions are described in 'Protective Groups in Organic Synthesis', 3' edition, TW Greene and PGM Wuts, Wiley-Interscience (1999).

[0055] The hydroxy group of pyrrolidine (XXVII) can be converted in a fifth step to a suitably activated leaving group (e.g., LG = methylsulfonate, trifluoromethylsulfonate, or p-tosylate) by reaction with a suitable sulfonyl acid derivative (e.g., methylsulfonyl chloride, trifluoromethylsulfonyl anhydride, p-tosyl chloride, etc.) in the presence of a base such as triethylamine or pyridine in a solvent such as dichloromethane, THF, etc. to generate the corresponding sulfonyl ester of general formula (XXVIII). In a sixth step, appropriately activated pyrrolidines (XXVIII) can be reacted by nucleophilic substitution with an azide source such as sodium azide or tetrabutylammonium azide in a suitable solvent such as DMF or DMA to generate azidopyrrolidines (XXIX), which can be reduced in a subsequent step by catalytic hydrogenation (e.g., hydrogenation with hydrogen using palladium on charcoal in methanol or ethanol) or by adding triphenylphosphine (Staudinger reaction) followed by heating the intermediate iminophosphorane with water in THF to generate difluoroaminopyrrolidines of the general formula (XXX).

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

[0057] Yet another method for the synthesis of chiral aminopyrrolidines (XXX) may involve chiral inversion of the ketone / hydrate form of general formula (XXVI) via asymmetric enzymatic reactions, for example with transaminases (see, for example, Green Chem. 2019, 21, 75-86). Alternatively, the racemic amine (or its racemic precursor) may be reacted with a suitable optically active compound, for example an acid such as phenylsuccinic acid or dibenzoyltartaric acid, in isopropanol or ethanol / water mixtures. The resulting diastereomeric mixtures can be separated by chromatography and / or fractional crystallization, and one or both diastereoisomers were converted into the corresponding pure enantiomers by techniques known to those skilled in the art. (For example, see the resolution of aminopyrrolidines of general formula (XVII): US Patent Application No. 2015 / 141402, page 48).

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

[0059] In vivo assays and data The numbers in Tables 3 to 7 refer to compounds of the invention (ie, Examples or Intermediates) disclosed in the Experimental section below. A homogeneous time-resolved fluorescence (HTRF) assay for the direct measurement of cAMP HTRF cAMP assays were performed using a commercially available assay kit (cAMP Dynamic 2 Assay Kit; #62AM4PEJ, Cisbio Bioassays, Bedford, MA) according to the manufacturer's instructions. An aliquot of CHO-K1 cells stably expressing recombinant human GPR52 was thawed and diluted with cell buffer (1× PBS (w / o Ca)). 2+ / Mg 2+ )) 4 x 10 per mL 5The cells were resuspended at a density of 10 mM cells. Test compounds were dissolved in DMSO to give 10 mM stock solutions and serially diluted in DMSO using 6-fold dilutions to generate 8-point dose-response curves. These serially diluted samples were then diluted in compound dilution buffer (1× PBS (w / o Ca 2+ / Mg 2+ ), 0.5 mM IBMX, 0.1% BSA) to obtain a 4× stock. The diluted compounds were transferred in duplicate (5 μL per well) to a 384-well assay plate (Optiplate #6007290, PerkinElmer, Waltham, MA). Both a positive control (reference compound) and a negative control (non-stimulating vehicle) were included in column 23 of each assay run. The cell suspension was then dispensed at 15 μL (6000 cells) per well into the 384-well assay plate such that the compounds were diluted to 1×. Column 24 of the plate did not contain cells and was reserved for the cAMP standard curve. After 1 hour of incubation at room temperature, 10 μL of cAMP D2 reagent was added to each well, followed by 10 μL of Cryptate reagent (provided in the Cisbio kit). The plate was then incubated for 1 hour at room temperature before reading. Time-resolved fluorescence measurements were collected on an EnVision® HTRF plate reader (PerkinElmer, Waltham, Mass.). Counts from the plate reader were fitted to a cAMP standard curve included on each plate to determine the amount of cAMP in each test well. Percent control (%) was calculated by setting the positive control to 200% and the negative control to 100%. Dose-response curves were generated from the cAMP data and analyzed using a nonlinear least-squares curve-fitting program to determine the EC 50 The value was obtained. EC 50 The average values ​​are shown in Table 3.

[0060] [Table 3]

[0061] In vitro metabolite profiling In vitro metabolite profiling to assess the involvement of CYP-mediated as well as non-CYP-mediated metabolic pathways, such as hydrolysis, was based on semiquantitative analysis of the formation of representative metabolites in 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 incubation with recombinant CYP enzymes.

[0062] The involvement of hydrolases, such as carboxyl esterases or arylacetamide deacetylases, is 6 Metabolites resulting from amide hydrolysis of the compounds of the present invention of general formula (I) where is an acetyl group, i.e., the deacetylated compounds, are envisaged when they are not produced in the presence of relevant human recombinant drug-metabolizing CYP enzymes, but are produced in human liver microsomes in the absence of NADPH. Hydrolases are highly 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 be produced during incubation of human liver microsomes lacking NADPH.

[0063] Phenotypic assays were performed to identify the CYP enzymes responsible for the metabolic conversion of the compounds. Evaluation of the degradation of the test compounds and the formation of metabolites was performed using Supersomes (human CYPs expressed in baculovirus-infected insect cells) and human liver microsomes, respectively. In particular, the conversion of the compounds by CYP isoenzymes 1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 and 3A5 was examined. Incubations in TRIS buffer (0.1 M, pH 7.6, supplemented with 5 mM magnesium chloride) consisted of 200 pmol / ml of the respective protein of Supersomes or 4 mg / ml of human liver microsome preparation and 10 μM of the test compound. After a short preincubation at 37°C for 15 min, the reaction was started by the addition of NADPH (reduced, 1 mM). An additional incubation with human liver microsomes was performed in the absence of NADPH. After 60 min at 37°C, the incubation was terminated by transferring an aliquot of the sample to acetonitrile. Samples were analyzed for the production of putative metabolites by liquid chromatography-high resolution mass spectrometry.

[0064] An additional measure for the identification of CYP-independent metabolic pathways is the use of the pan-CYP inhibitor proadifen in incubations of test compounds with human hepatocytes. In the presence of proadifen, CYP-related pathways are inhibited and metabolites can be produced primarily via non-CYP pathways. The involvement of non-CYP enzymes in the metabolic conversion of test compounds in the presence or absence of the pan-CYP inhibitor proadifen (50 μM final incubation concentration), hydralazine, was further investigated using primary human hepatocytes in suspension. After recovery from cryopreservation, human hepatocytes were incubated in Dulbecco's modified Eagle's medium supplemented with glucagon 3.5 μg / 500 mL, insulin 2.5 mg / 500 mL, and hydrocortisone 3.75 mg / 500 mL, containing 5% (v / v) human serum. After preincubation for 30 min in the presence or absence of 50 μM proadifen in a cell culture incubator (37 °C, 10% CO2), the final cell density was 1.0 × 10 cells. 6 ~4.0×10 6 Test compound solutions were added to the hepatocyte suspensions to obtain cells / ml (depending on the compound turnover rate observed in primary human hepatocytes), a final test compound concentration of 1 μM, and a final DMSO concentration of 0.05% (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 turnover rate. Samples were quenched with acetonitrile and pelleted by centrifugation. Supernatants were transferred to 96 deep-well plates, evaporated under nitrogen and resuspended before bioanalysis by liquid chromatography-high resolution mass spectrometry to identify putative metabolites. The contribution of hydrolysis was calculated based on the abundance of each deacetylated metabolite of the compounds of the invention relative to all metabolites observed upon incubation with human hepatocytes.

[0065] [Table 4]

[0066] hERG (human delayed rectifier potassium ion channel gene) channel assay The hERG channel inhibition of compounds of the present invention was investigated as follows. cell: HEK (human embryonic kidney) 293 cells were stably transfected with hERG cDNA. Cells determined for use in patch clamp experiments were cultured without antibiotics.

[0067] Pipettes and solutions: Cells were perfused with a bath solution containing NaCl (137), KCl (4.0), MgCl2 (1.0), CaCl2 (1.8), glucose (10), and HEPES (10) (in mM) and adjusted to pH 7.4 with NaOH. Patch pipettes were fabricated from borosilicate glass tubing using a pipette and filled with pipette solution containing K-aspartate (130), MgCl2 (5.0), EGTA (5.0), K2ATP (4.0), and HEPES (10.0) (in mM) and adjusted to pH 7.2 with KOH. Microelectrode resistances were typically in the range of 2 MΩ–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). Recordings of hERG-mediated membrane currents were typically performed at 28°C using the whole-cell configuration of the patch clamp technique. Transfected HEK293 cells were clamped at a holding potential of -60 mV and hERG-mediated inactivation tail currents were evoked using a fixed amplitude pulse pattern (activation / inactivation: 40 mV for 2000 ms; recovery: 120 mV for 2 ms; ramp to 40 mV in 2 ms; inactivation tail current: 40 mV for 50 ms) repeated at 15 s intervals. For the P / n leak subtraction procedure, 4 pulses were recorded during each pulse interval, scaled down by a factor of 0.2. Rs correction was performed below a level that could be safely recorded without ringing. The remaining uncorrected Rs was recorded together with the actual temperature and holding current.

[0069] Compound preparation and application: Concentrations of test articles were applied sequentially to each of the various cells investigated. Steady levels of baseline currents were measured for at least five sweeps before the first test article concentration was applied. Test articles were dissolved in DMSO to obtain stock solutions at 1000x the highest final concentration. This stock was further diluted in DMSO to obtain stock solutions at 1000x the remaining final concentration. Final dilutions in extracellular buffer were freshly prepared from these stocks in 1:1000 dilution steps, respectively, before starting the experiment.

[0070] Data Analysis: Peak current amplitudes were measured 3 ms after the ramp to +40 mV. For baseline and each concentration, peak currents of the last three sweeps before the next concentration was applied were averaged. Residual currents (I / I0) were calculated for each cell as the percentage of the actual mean peak current to the baseline mean peak current. Current inhibition was expressed as (1-I / I0) x 100%. Current inhibition for all cells was reported as the mean ± standard deviation (SD). When possible, IC values ​​were calculated from the mean current inhibition data using least squares fitting based on the Hill equation. 50was estimated.

[0071] [Table 5] Human plasma protein binding assay Equilibrium dialysis (ED) method was used to measure the in vitro 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 cut-off of 5 kDa. Stock solutions of each test compound were prepared at 1 mM in DMSO and serially diluted to a final test concentration of 1 μM. The following dialysates were prepared in plasma (supplemented with NaEDTA as anticoagulant) and aliquots of 200 μL of test compound dialysate in plasma were dispensed into the donor (plasma) chamber. An aliquot of 200 μL of dialysis buffer (100 mM potassium phosphate, pH 7.4) was dispensed into the buffer (acceptor) chamber. To achieve equilibrium, incubation was performed for 2 h at 37°C under rotation. At the end of the dialysis period, aliquots from the donor and acceptor chambers were transferred into reaction tubes, and processed for HPLC-MS / MS analysis with the addition of an internal standard. The concentration of the analyte in the aliquot samples was quantified by HPLC-MS / MS against an external calibration curve. The percent binding was calculated using the following formula: Percent binding = (plasma concentration - buffer concentration / plasma concentration) X 100

[0072] [Table 6]

[0073] Metabolic stability of human hepatocytes The metabolic degradation of test compounds was assayed in human hepatocyte suspensions. Depending on the turnover rate of the test compound, a final cell density of 1.0x10 cells was used.6 4.0x10 cells / mL 6 Human hepatocytes were recovered from cryopreservation so that the cells were concentrated in the culture medium at 100x the concentration of ... After preincubation for 30 min 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). The cell suspension was 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 an internal standard) and pelleted by centrifugation. Supernatants were transferred to 96 deep-well plates and prepared for analysis of parent compound depletion by HPLC-MS / MS. The percentage of test compound remaining was calculated using the peak area ratio (test compound / internal standard) at each incubation time point relative to the peak area ratio at time point 0. Log-transformed data were plotted against incubation time, and the absolute value of the slope obtained by linear regression analysis was used to estimate the in vitro half-life (T1 / 2).

[0074] The in vitro intrinsic clearance (CLint) was calculated from the in vitro T1 / 2 and the following equation was applied: hepatocellular: cells 120 x 10 6 Scaled to whole liver using cells / g liver, human liver per body weight: 25.7 g 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 [cells / g liver] 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 the 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] 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 compounds of the present invention was investigated using a high throughput solubility assay as described below. Test compounds were dissolved in DMSO to a stock solution of 10 mM and further diluted in acetonitrile / water (1:1 v / v), McIlvaine buffer pH 2.2, McIlvaine buffer pH 4.5, and McIlvaine buffer pH 6.8 (McIlvaine buffer is a citrate-phosphate buffer) in a 96-well plate format at 40-fold dilutions. The well plates containing the diluted samples were sealed and shaken upside down for 24 hours at room temperature. Undissolved particles were removed by centrifugal filtration and the resulting sample solutions were analyzed by automated UV absorption on HPLC (default wavelength: 254 nm). If the absorption was too low, alternative wavelengths of 280 nm or 230 nm were used for improved detection. The concentrations of the analytes were quantified by HPLC-UV. Quantification was performed with one-point calibration using samples dissolved in acetonitrile / water as calibration points.

[0077] The solubility of some compounds of the invention was also determined by a solid state solubility assay, as described below. Saturated solutions were prepared in well plates (format dependent on robot) by adding an appropriate amount of selected aqueous medium (usually in the range of 0.25 ml to 1.5 ml) into each well containing a known amount of solid drug substance (usually in the range of 0.5 mg to 5.0 mg). The wells were shaken or stirred for a predefined time (usually in the range of 2 h to 24 h) and then filtered using an appropriate filter membrane (usually a PTFE-filter with 0.45 μm pore size). Filter absorption was avoided by discarding the first few drops of filtrate. The amount of dissolved drug substance was measured by UV spectroscopy. Additionally, the pH of the saturated aqueous solution was measured using a glass-electrode pH meter. In view of their ability to activate GPR52, reduce human protein binding rates potentially representing a moderately low effective dose of the compound for disease treatment, and therefore a potential minimization of side effects, increase human hepatocyte stability, low / moderate inhibition of the hERG channel, more diversified metabolism including hydrolase mediated pathways (if 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 pharma- ceutically acceptable salts are suitable for the therapeutic and / or prophylactic treatment of all diseases or conditions that can be affected by the activation of GPR52, preferably diseases or conditions of the central nervous system disclosed herein.

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

[0079] In a further aspect, the present invention provides a method for the treatment of schizophrenia; positive symptoms associated with schizophrenia, schizoaffective disorder, schizophreniform disorder, schizophreniform disorder, treatment-resistant schizophrenia, attenuated psychotic syndromes, and autism spectrum disorder; augmentation of antipsychotics to treat positive symptoms associated with schizophrenia, schizoaffective disorder, schizophreniform disorder, schizophreniform disorder, treatment-resistant schizophrenia, attenuated psychotic syndromes, and autism spectrum disorder, or to reduce the dosage (and associated side effects) of antipsychotics; Affective disorders, schizophreniform disorders, schizophreniform disorders, treatment-resistant schizophrenia, attenuated psychotic syndromes and negative symptoms associated with autism spectrum disorders;Cognitive disorders associated with schizophrenia (CIAS), schizoaffective disorder, schizophreniform disorders, schizophreniform disorders, treatment-resistant schizophrenia, attenuated psychotic syndromes and autism spectrum disorders;Treatment-resistant schizophrenia;Schizoaffective disorder;Schizophreniform disorders;Schizophreniform (personality) disorders;Medication-induced psychotic disorders;Bipolar disorder I and bipolar disorder II;Attenuated psychotic syndromes Groups; 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 disorders (e.g. D2 receptor agonist-induced impulse control disorders); gambling disorders (e.g. D2 receptor agonist-induced gambling disorder); Tourette's 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to general formula (I) or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis 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; diasthesia; hypothalamic disorders; prolactin-related disorders such as hyperprolactinemia; symptoms associated with frontal lobe hypofunction (e.g. frontal lobe hypofunction associated with drug abuse) and hyperkinesia.

[0080] Preferably, the compounds according to the invention are suitable for the prevention or treatment of schizophrenia; positive symptoms associated with schizophrenia; antipsychotic augmentation for treating positive symptoms associated with schizophrenia or for reducing the dose of antipsychotics and thus reducing the side effects of antipsychotics; negative symptoms associated with schizophrenia; cognitive impairment associated with schizophrenia (CIAS); treatment-resistant schizophrenia; schizoaffective disorder; schizophreniform disorder; schizophreniform disorder; medication-induced psychosis; bipolar disorder type I and bipolar disorder type II; attenuated psychotic syndromes; 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 disorder (e.g. gambling disorder induced by D2 receptor agonists); prolactin-related disorders such as hyperprolactinemia. In a further aspect, the present invention relates to the use of compounds of general formula (I) for preparing a medicament for the treatment and / or prevention of the abovementioned diseases and conditions. In a further aspect, the present invention relates to a method for the treatment and / or prevention of the above mentioned diseases and conditions, said method comprising administering to a human an effective amount of a compound of general formula (I) or a pharma- ceutically acceptable salt thereof.

[0081] The applicable daily dosage range of the compounds of formula (I) is orally usually 0.1 mg to 1000 mg, preferably 1 mg to 500 mg, in each case administered 1 to 4 times a day. Each dosage unit may contain 0.1 mg to 500 mg, preferably 1 mg to 100 mg, for ease of handling. Of course, the actual pharmacologic or therapeutic dose will depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the combination will be administered at a dosage and in a manner that allows delivery of a pharmacologic effective amount based on the patient's unique condition. Suitable formulations for administering the compounds of general formula (I) (including pharma- ceutically acceptable salts thereof) will be apparent to those skilled in the art, and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, liquids, syrups, elixirs, sachets, injections, inhalants, powders, etc. The content of the pharma- ceutical active compound should be in the range of 0.1-95% by mass, preferably 5.0-90% by mass, based on 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, adjuvants, surfactants, binders and / or lubricants. Tablets may also consist of several layers. For this purpose, the compounds of general formula (I) prepared according to the present invention, optionally together with other active substances, can be formulated with one or more conventional inert carriers and / or diluents, for example corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, citric acid, tartaric acid, water, polyvinylpyrrolidone, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose, or fatty substances such as hard fats, or suitable mixtures thereof.

[0083] Combination Therapy The compounds according to the invention are also particularly suitable as combination therapy (i.e., combination, add-on therapy) with currently prescribed antipsychotics to treat positive symptoms associated with schizophrenia as well as cognitive and / or negative symptoms. With respect to the treatment of positive symptoms, combination therapy with antipsychotics may result in not only improved antipsychotic efficacy (e.g., improved treatment of positive symptoms associated with schizophrenia), but also reduced associated side effects, such as weight gain, metabolic syndrome, diabetes, extrapyramidal symptoms, hyperprolactinemia, insulin resistance, hyperlipidemia, hyperglycemia and / or tardive dyskinesia, in combination with reduced doses of antipsychotics. In particular, elevated serum prolactin levels are a prominent side effect profile of antipsychotics, while activators of GPR52 have been demonstrated to reduce serum prolactin levels. Thus, the combination of GPR52 agonists with antipsychotics may normalize serum prolactin levels and thus reduce side effects associated with antipsychotics. Thus, the compounds of general formula (I) according to the invention may be used in combination (e.g. as an adjunct treatment) with other active substances (i.e. combination partners), in particular for the treatment and / or prevention of the diseases and conditions mentioned above (i.e. in the paragraph "Use in Treatment / Method of Use"). Other active substances suitable for such combinations include, for example, BACE inhibitors; amyloid aggregation inhibitors (e.g. ELND-005); directly or indirectly acting neuroprotective and / or disease modifying substances; antioxidants (e.g. vitamin E or ginkgolides); anti-inflammatory substances (e.g. COX inhibitors, NSAIDs additionally or exclusively with amyloid-β lowering properties); HMG-CoA reductase inhibitors (statins); acetylcholinesterase inhibitors (e.g. donepezil, rivastigmine, tacrine, galantamine); NMDA receptor antagonists (e.g. memantine, ketamine, esketamine, NR2b antagonists); AMPA receptor agonists; positive modulators of the AMPA receptor, ampakines. , monoamine receptor reuptake inhibitors, substances that modulate the concentration or release of neurotransmitters; growth hormone secretion inducers (e.g., ibutamoren mesylate and capromorelin); CB-1 receptor antagonists or inverse agonists; antibiotics (e.g., minocycline or rifampicin); 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, metabotropic glutamate receptor 1 positive regulators, metabotropic glutamate receptor 2 positive regulators, metabotropic glutamate receptor 3 positive regulators, metabotropic glutamate receptor 5 positive regulators, The therapeutic agent may be selected from the group consisting of lysine transporter 1 inhibitors, antidepressants (such as citalopram, fluoxetine, paroxetine, sertraline and trazodone); anxiolytics (such as lorazepam and oxazepam); antipsychotics (such as aripiprazole, asenapine, clozapine, iloperidone, haloperidol, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, lurasidone, lumateperone, brexpiprazole and cariprazine); mood stabilizers (such as lithium and valproate) and other substances that modulate receptors or enzymes to increase the efficacy and / or safety of the compounds according to the invention and / or reduce undesirable side effects. The compounds according to the invention may also be used in combination with immunotherapy (such as active immunization with amyloid beta or tau or parts thereof, or passive immunization with humanized anti-amyloid beta or anti-tau antibodies or nanobodies) for the treatment of the above mentioned diseases and conditions;

[0084] The dosage of the partner substance in the above combination is usefully from 1 / 5 of the minimum normally recommended dosage to 1 / 1 of the normally recommended dosage (eg 1 / 4, 1 / 3, or 1 / 2). The use of the compound according to the invention in combination with other active substances can be performed simultaneously or staggered, in particular within a short time period.When administered simultaneously, the two active substances are administered to the patient together; when used staggered, the two active substances are administered to the patient within a time period of 12 hours or less (for example 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), in particular within a time period of 6 hours or less.

[0085] In another aspect, the present invention relates to the use of a compound according to the invention or a pharma- ceutically acceptable salt thereof, in combination with at least one of the abovementioned active substances as combination partners, for preparing a pharmaceutical composition suitable for the treatment and / or prevention of diseases or conditions that can be influenced by agonists of GPR52.Preferably, these are pathologies related to a deficiency in GPR52 activity, in particular one of the diseases or conditions listed above.

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

[0087] Experimental section List of abbreviations [Table 8] TIFF2024533565000029.tif144158

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

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

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

[0091] Method name:C Instrument description: Agilent 1200 with DA and MS detectors Column: XBridge C18, 3.0x30mm, 2.5μm Column supplier:Waters [Table 11]

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

[0093] Method name: E Instrument description: Agilent 1200 with DA and MS detectors Column: Sunfire C18, 3.0x50mm, 2.5μm Column supplier:Waters [Table 13]

[0094] Method name:F Instrument description: Waters Acquity 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, 4.6x250mm, 5μm Column supplier: YMC [Table 15]

[0096] Method name:H Instrument description: Agilent 1260Infinity II SFC with DA detector, back pressure 2175 psi Column: Lux® Cellulose-4, 3x100mm, 3μm Column supplier: Phenomenex [Table 16]

[0097] Method name:I Instrument description: Agilent 1260 SFC with DA and MS detectors, back pressure 2175 psi Column: CHIRAL ART® Cellulose SB, 4.6x250mm, 5μm Column supplier: YMC [Table 17]

[0098] Method name: J Instrument description: Agilent 1260Infinity II SFC with DA detector, back pressure 2175 psi Column: Lux® Cellulose-3, 3x100mm, 3μm Column supplier: Phenomenex [Table 18]

[0099] Method name:K Instrument description: Agilent 1260 Infinity II SFC with DA detector, back pressure 2175 psi Column: CHIRAL ART® Amylose-SA, 3x100mm, 3μm Column supplier: YMC [Table 19]

[0100] Method name:L Instrument description: Agilent 1260Infinity II SFC with DA detector, back pressure 2175 psi Column: Lux® Cellulose-2, 4.6x250mm, 5μm Column supplier: Phenomenex [Table 20]

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

[0102] General notes on the notation of structures: Compounds with stereogenic centers: The structures depicted in the experimental section may not necessarily show all possible stereochemistry of the compounds. The structural representations of the compounds in the experimental section may show stereochemical bonds only in cases where the absolute stereochemistry is known. Structural representations of compounds in the experimental section where the absolute stereochemistry is unknown show planar bonds as well as annotations indicating whether the compound depicted is a racemic mixture, a single stereoisomer, and relative stereochemistry, if applicable. Two examples are shown below.

[0103] Example I: The chemical structure depicted is shown below: [ka] The notation "racemic mixture" (in the figures or experimental description) refers to two stereochemical options, so the compound produced is [ka] It is a mixture of.

[0104] When racemic mixtures of the above depicted structures are isolated, the single stereoisomers may be represented according to their absolute stereochemistry, if known. Alternatively, the single stereoisomers may be represented according to [ka] It is expressed as follows. The annotation "single stereoisomer" and planar bonds indicate that the absolute configuration is unknown. The term "single stereoisomer a" is assigned to the first eluting isomer on chiral HPLC, and "single stereoisomer b" is assigned to the second eluting isomer on chiral HPLC.

[0105] Example II: The chemical structure depicted is represented as follows: [ka] The notation "trans-racemic mixture" (in the figures or experimental description) refers to two stereochemical options, so the compound produced is [ka] It is a mixture of. When a racemic mixture of the structures depicted above is separated, the single stereoisomers [ka] It is expressed as follows. The notation "trans-single stereoisomer" indicates the known relative configuration (trans) and the planar bond indicates the unknown absolute configuration. "Trans-single stereoisomer a" is assigned to the first eluting isomer on chiral HPLC and "trans-single stereoisomer b" is assigned to the second eluting isomer on chiral HPLC. The same 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 assigned by asymmetric synthesis of Examples 8b, 10a, 11b, 13b and 15a starting from optically pure precursors followed by chiral chromatographic comparison of the respective enantiomers between the single enantiomer obtained by the asymmetric synthesis described above and the two single enantiomers obtained by chiral chromatographic separation of the racemate (see Experimental Section). It will be appreciated by those skilled in the art that the absolute configuration of compounds of the present invention may be determined or further determined by X-ray crystallography, for example by single crystal X-ray diffraction of crystalline products or optionally derivatized crystalline intermediates thereof.

[0107] Working Example Preparation of Intermediates and Examples: The following examples and intermediates are intended to illustrate the present invention but not to limit its scope. Intermediate A-1: [ka] A mixture of 3,4-difluoro-phenol (10.0 g, 76.9 mmol) and cesium carbonate (37.6 g, 115.3 mmol) in DMA (558 mL) was stirred at room temperature for 5 min, after which tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (19.3 g, 76.9 mmol) was added. After stirring at 100° C. for 5 h, 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 by MPLC (silica gel, petroleum ether / ethyl acetate 9:1) to give product A-1. ESI-MS: 286 [M+H] + ;HPLC(Rt): 0.72 min (Method A)

[0108] Intermediate A-2: [ka] A mixture of 3,5-difluoro-phenol (1.0 g, 8.0 mmol) and cesium carbonate (5.2 g, 15.9 mmol) in DMA (5 mL) was stirred at room temperature for 10 min, after which tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.0 g, 8.0 mmol) was added. After stirring at 90° C. for 16 h, the mixture was cooled to room temperature and water and ethyl acetate were added. The phases were separated. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 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-trifluoro-phenol (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 min, after which tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (16.1 g, 64.2 mmol) was added. After stirring at 100° C. for 6 h, 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 by MPLC (silica gel, petroleum ether / ethyl acetate 9:1) to give product A-3. ESI-MS: 304 [M+H] + ;HPLC(Rt): 0.75 min (Method A)

[0110] Intermediate A-4: [ka] A mixture of 3-chloro-4-fluoro-phenol (1.5 g, 10.2 mmol) and cesium carbonate (6.7 g, 20.5 mmol) in DMA (10 mL) was stirred at room temperature for 10 min, then tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.6 g, 10.2 mmol) was added. After stirring at 100° C. for 16 h, the mixture was 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 give 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-fluoro-phenol (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 min, after which tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.5 g, 10.1 mmol) was added. After stirring at 90° C. for 16 h, 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 phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 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 min, after which tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (2.5 g, 10.0 mmol) was added. After stirring at 90° C. for 16 h, 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 phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 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-fluoro-phenols (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 min, followed by the addition of tert-butyl-3-methanesulfonyloxy)azetidine-1-carboxylate (0.6 g, 2.2 mmol). After stirring at 90° C. for 16 h, 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 phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give product A-7. ESI-MS: 334 [M+H] + , 278 [M+H-isobutene] + ;HPLC(Rt): 1.05 min (Method D)

[0114] Intermediate B-1: [ka] To a mixture of intermediate A-1 (19.0 g, 66.6 mmol) in diisopropyl ether (200 mL) was added a solution of HCl in 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 give 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) was added a solution of HCl in dioxane (4N, 15.0 mL, 60.0 mmol). After stirring at room temperature for 1 h, the mixture was concentrated under reduced pressure to give product B-2 as the HCl salt. ESI-MS: 186 [M+H] + ;HPLC(Rt): 0.38 min (Method D)

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

[0117] Intermediate B-4: [ka] To the intermediate A-4 (2.3 g, 7.6 mmol) was added a solution of HCl in dioxane (4N, 9.5 mL, 37.9 mmol). After stirring at room temperature for 45 minutes, the mixture was concentrated under reduced pressure to give the 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] To the intermediate A-5 (8.3 g, 27.5 mmol) was added a solution of HCl in dioxane (4N, 34.4 mL, 137.5 mmol). After stirring at room temperature for 1 h, the mixture was concentrated under reduced pressure to give the 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] To the intermediate A-6 (2.6 g, 8.0 mmol) was added a solution of HCl in dioxane (4N, 12.1 mL, 48.2 mmol). After stirring at room temperature for 1 h, the mixture was concentrated under reduced pressure to give the product B-6 as the HCl salt. ESI-MS: 218 [M+H] + ;HPLC(Rt): 0.45 min (Method D)

[0120] Intermediate B-7: [ka] To the intermediate A-7 (625.0 mg, 1.9 mmol) was added a solution of HCl in dioxane (4N, 5.0 mL, 20.0 mmol). After stirring at room temperature for 1 h, the mixture was concentrated under reduced pressure to give the 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] To 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 added acetyl chloride (261.1 μL, 367.2 μmol). After stirring at room temperature for 10 min, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 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) was added hydrochloric acid solution (4N in 1,4-dioxane, 4.47 mL, 17.87 mmol). After stirring at room temperature for 16 h, 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 give intermediate C-1 as the HCl salt as a trans-racemic mixture. ESI-MS: 147 [M+H] + ;HPLC(Rt): 0.13 min (Method B)

[0123] Intermediate C-2.1: [ka] To a mixture of tert.-butyl N-(2-azabicyclo[2.1.1]hexan-4-yl)carbamate (200.0 mg, 1.0 mmol) and DIPEA (0.87 mL, 5.04 mmol) in a mixture of acetonitrile (1.6 mL) and DMF (0.8 mL) was added acetyl chloride (107.59 μL, 1.51 mmol). After stirring the reaction mixture at room temperature for 15 min, saturated aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give 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) was added hydrochloric acid solution (4N in 1,4-dioxane, 0.88 mL, 3.52 mmol) and a few drops of methanol. After stirring at room temperature for 1.5 h, 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 min. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether and dried to give 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 h. The reaction mixture was diluted with water. The precipitate was collected by suction filtration and dried at 50° C. to give 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 h. The reaction mixture was diluted with water. The precipitate was collected by suction filtration and dried at 50° C. to give 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 h. After cooling to room temperature, the reaction mixture was diluted with water. The mixture was extracted with ethyl acetate. The combined organic phase was washed with water and with brine, then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative MPLC (gradient petroleum ether / ethyl acetate 95:5 to 65:35) to give 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 h. After cooling to room temperature, the reaction mixture was diluted with water. The precipitate was filtered off and dried under reduced pressure to give 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 h. After cooling to room temperature, the reaction mixture was diluted with water. The precipitate was filtered off and dried under reduced pressure to give crude intermediate D-5. ESI-MS: 328 [M+H] + ;HPLC(Rt): 1.00 min (Method D)

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

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

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

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

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

[0135] Intermediate F-1.1: [ka] To 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 added TCFH (739.8 mg, 2.6 mmol). The mixture was stirred at room temperature for 15 min. The mixture was concentrated to half its volume and directly purified by preparative HPLC to give 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] To 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 number 2381400-91-3, 420.5 mg, 1.9 mmol) and 1-methylimidazole (304.7 μL, 3.8 mmol) in acetonitrile (5 mL) was added TCFH (584.0 mg, 2.1 mmol). After stirring at room temperature for 3 days, water and aqueous ammonia were added. The mixture was filtered and directly purified by preparative HPLC to give 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) was added hydrochloric acid (4N in 1,4-dioxane, 8.0 mL, 32.0 mmol). After stirring at room temperature for 16 h, the mixture was diluted with diethyl ether. The precipitate was collected by filtration, washed with diethyl ether, and dried to give 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] To a mixture of intermediate (S)-F-1.1 (570.0 mg, 1.6 mmol) in 1,4-dioxane (1.5 mL) was added hydrochloric acid (4N in 1,4-dioxane, 1.6 mL, 6.3 mmol). After stirring at room temperature for 16 h, methanol (3 mL) was added and stirring was continued at room temperature for 2 h. The mixture was concentrated under reduced pressure and the residue was triturated with tert.-butyl methyl ether, collected by filtration and dried to give intermediate (S)-F-1.2. ESI-MS: 263 / 265 [M+H] + ;HPLC(Rt): 0.28 min (Method D)

[0139] Intermediate F-1: [ka] To 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 a solution of acetyl bromide (1.06 mL, 14.34 mmol) in dichloromethane (7 mL) at room temperature. After stirring for 30 min, the reaction mixture was cooled to 0-5 °C. A solution of triethylamine (1.51 mL, 10.75 mmol) in dichloromethane (5 mL) was added dropwise. After stirring for 5 min, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of water / methanol (v / v 5 / 5 mL), then acidified with TFA and purified by preparative HPLC to give 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] To 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 added acetyl chloride (162.2 μL, 2.3 mmol). After stirring at room temperature for 16 h, water was added. The mixture was filtered and directly purified by preparative HPLC to give intermediate (S)-F-1. ESI-MS: 305 / 307 [M+H] + ;HPLC(Rt): 0.44 min (Method D)

[0141] Intermediate F-2: [ka] To 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 added DIPEA (57.5 μL, 334.0 μmol) at room temperature. After stirring at room temperature for 1 h, the reaction mixture was directly purified by preparative HPLC to give 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] To 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 added CIP (299.2 mg, 1.1 mmol). After stirring at room temperature for 16 h, the reaction mixture was diluted with water. The organic phase was separated and directly purified by preparative HPLC to give intermediate G-1 as a racemic mixture. ESI-MS: 512 [M+H] + ;HPLC(Rt): 1.05 min (Method D)

[0143] Intermediate G-2: [ka] To 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 added CIP (249.3 mg, 895.0 μmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with water. The organic phase was separated and directly purified by preparative HPLC to give 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] To 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 added CIP (219.0 mg, 786.0 μmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with water. The organic phase was separated and directly purified by preparative HPLC to give intermediate G-3 as a racemic mixture. ESI-MS: 530 [M+H] + ;HPLC(Rt): 1.11 min (Method D)

[0145] Intermediate G-4: [ka] To 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 added CIP (146.7 mg, 1.4 mmol). After stirring at room temperature for 16 h, 1N aqueous sodium hydroxide was added and the mixture was extracted twice with DCM. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 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] To a mixture of intermediate E-4 (150.0 mg, 479.0 μmol), (S)-tert.-butyl-4-amino-3,3-difluoropyrrolidine-1-carboxylate (CAS number 2381400-91-3, 123.2 mg, 527.0 μmol) and DIPEA (331.3 μL, 1.9 mmol) in acetonitrile (2 mL) was added CIP (146.7 mg, 527.0 μmol). After stirring at room temperature for 16 h, 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 give 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) was added TFA (1.0 mL, 13.0 mmol). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure. To the residue was added a mixture of acetonitrile and water. The mixture was lyophilized to give crude intermediate H-1 as a racemic mixture as a TFA salt. 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) was added TFA (0.8 mL, 10.3 mmol). After stirring at room temperature for 2.5 h, the reaction mixture was concentrated under reduced pressure to give crude intermediate H-2 as a TFA salt as a cis-racemic mixture. 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) was added TFA (0.45 mL, 5.78 mmol). After stirring at room temperature for 1.5 h, 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. The organic phase was separated using a phase separation cartridge and concentrated under reduced pressure. A fraction of this material was purified by HPLC (basic conditions) to give 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-toluenesulfonic acid monohydrate (257.3 mg, 1.4 mmol) in acetonitrile (4 mL) was stirred for 3 h. Water and aqueous ammonia were added, filtered, and purified by preparative HPLC to give 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-toluenesulfonic acid monohydrate (199.4 mg, 1.1 mmol) in acetonitrile (3 mL) was stirred at room temperature for 16 h. Water and aqueous ammonia were added, and the mixture was filtered and purified by preparative HPLC to give 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 for 1 h at 85° C. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give Example 1 as a racemic mixture. ESI-MS: 470 / 472 [M+H] + ;HPLC(Rt): 0.65 min (Method B)

[0153] Example 2 [ka] To 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 added propionyl chloride (13.6 μL, 155.0 μmol). After stirring at room temperature for 30 min, the mixture was made alkaline by the addition of aqueous ammonia and water. The mixture was filtered and directly purified by preparative HPLC to give Example 2 as a racemic mixture. ESI-MS: 468 [M+H] + ;HPLC(Rt): 0.86 min (Method D)

[0154] Example 3 [ka] To 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 added acetyl chloride (44.8 μL, 631.0 μmol) at 0° C. After stirring for 30 min at 0° C., the mixture was made alkaline by the addition of aqueous ammonia and water. The mixture was filtered and directly purified by preparative HPLC to give 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 for 1 h at 85° C. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give 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 for 30 min at 80° C. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give 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 for 1.5 h at 100° C. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give 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 for 30 min at 80° C. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give Example 7 as a racemic mixture. ESI-MS: 502 [M+H] + ;HPLC(Rt): 0.87 min (Method D)

[0159] (Example 8, Example 8a and Example 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 h. 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 directly purified by preparative HPLC to give 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, 10x250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: methanol in 20 mM concentrated aqueous ammonia, 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) to give: Example 8a (single stereoisomer a): Rt=2.72 min (Method G). Enantiomeric purity: 99.1% ee. Example 8b (single stereoisomer b): Rt=3.42 min (Method G). Enantiomeric 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 h. After cooling to room temperature, the reaction mixture was diluted with an acetonitrile / water mixture and aqueous ammonia. The mixture was filtered and directly purified by preparative HPLC to give Example 8b. ESI-MS: 454 [M+H] + ;HPLC(Rt): 0.81 min (Method D) Chiral HPLC: Rt=3.48 min (Method G). Enantiomeric purity: >98% ee.

[0162] Example 9 [ka] To 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 added methanesulfonyl chloride (8.8 μL, 114.0 μmol) at 0° C. After stirring for 2 h at 0° C., 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 aqueous ammonia and purified by preparative HPLC to give Example 9 as a racemic mixture. ESI-MS: 508 [M+H] + ;HPLC(Rt): 0.93 min (Method D)

[0163] (Example 10, Example 10a and Example 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 for 1.5 h at 100° C. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to give 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, 10x250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: methanol in 20 mM concentrated aqueous ammonia, 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) to give: Example 10a (single stereoisomer a): Rt=1.42 min (Method H). Enantiomeric purity: 100.0% ee. Example 10b (single stereoisomer b): Rt=1.62 min (Method H). Enantiomeric 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 h. After cooling to room temperature, the reaction mixture was diluted with an acetonitrile / water mixture and aqueous ammonia. The mixture was filtered and directly purified by preparative HPLC to give Example 10a. ESI-MS: 454 [M+H] + ;HPLC(Rt): 0.83 min (Method D) Chiral HPLC: Rt=1.39 min (Method H). Enantiomeric purity: >98% ee.

[0166] (Example 11, Example 11a and Example 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 h. 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 directly purified by preparative HPLC to give 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, 10x250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: methanol in 20 mM concentrated aqueous ammonia, 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) to give: Example 11a (single stereoisomer a): Rt=3.33 min (Method I). Enantiomeric purity: >98% ee. Example 11b (single stereoisomer b): Rt=4.32 min (Method I). Enantiomeric 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 h. After cooling to room temperature, the reaction mixture was diluted with an acetonitrile / water mixture and aqueous ammonia. The mixture was filtered and directly purified by preparative HPLC to give Example 11b. ESI-MS: 472 [M+H] + ;HPLC(Rt): 0.86 min (Method D) Chiral HPLC: Rt=4.33 min (Method I). Enantiomeric purity: >98% ee.

[0169] Example 12 [ka] To 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 added CIP (46.3 mg, 166.0 μmol). After stirring at room temperature for 2 h, the mixture was diluted with aqueous ammonia and water. The mixture was filtered and then directly purified by preparative HPLC to give Example 12. ESI-MS: 454 [M+H] + ;HPLC(Rt): 0.66 min (Method B)

[0170] (Example 13, Example 13a and Example 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) was added acetyl chloride (18.4 μL, 270.0 μmol). After stirring for 1 h, additional amounts of acetyl chloride (9.0 μL) and DIPEA (30.8 μL) were added and stirring was continued for 30 min. Water was added and the reaction mixture was filtered and directly purified by HPLC to give 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, 10x250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: methanol in 20 mM concentrated aqueous ammonia, 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) to give: Example 13a (single stereoisomer a): Rt=0.86 min (Method J). Enantiomeric purity: >99% ee. Example 13b (single stereoisomer b): Rt=1.07 min (Method J). Enantiomeric purity: 99.2% ee.

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

[0173] (Example 14, Example 14a and Example 14b) [ka] To 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 added CIP (146.7 mg, 527.0 μmol). After stirring at room temperature for 16 h, the mixture was diluted with 1N aqueous sodium hydroxide and extracted twice with DCM. The combined organic phase was washed with water, then dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 14 as a trans-racemic mixture. ESI-MS: 442 [M+H] + ;HPLC(Rt): 0.65 min (Method B)

[0174] Preparative chiral separation: The trans-racemic amide 14 (135.0 mg, 306.0 μmol) was subjected to a 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 in 20 mM concentrated aqueous ammonia, 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) to give: Example 14a (trans-single stereoisomer a): Rt=0.93 min (Method K). Enantiomeric purity: >98% ee. Example 14b (trans-single stereoisomer b): Rt=1.24 min (Method K). Enantiomeric purity: >98% ee.

[0175] (Example 15, Example 15a and Example 15b) [ka] To a mixture of intermediate E-5 (200.0 mg, 575.0 μmol), DIPEA (248.5 μL, 1.4 mmol) and N-acetyl-pyrrolidin-3-ylamine (83.5 mg, 632.0 μmol) in acetonitrile (3 mL) was added CIP (176.1 mg, 632.0 μmol). After stirring at room temperature for 16 h, the mixture was diluted with water and extracted twice with ethyl acetate. The aqueous phase was filtered and purified by preparative HPLC to give 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 a preparative chiral SFC separation (Sepiatec 1 Prep SFC 100, Lux® Cellulose-2, 21.2x250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: ethanol in 20 mM concentrated aqueous ammonia, 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) to give: Example 15a (single stereoisomer a): Rt=3.74 min (Method L). Enantiomeric purity: >98% ee. Example 15b (single stereoisomer b): Rt=4.27 min (Method L). Enantiomeric 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-acetyl-pyrrolidin-3-ylamine hydrochloride (CAS number 1286208-55-6, 1.3 g, 8.0 mmol) in acetonitrile (60 mL) was added CIP (2.2 g, 8.0 mmol). After stirring at room temperature for 45 min, the mixture was filtered and directly purified by preparative HPLC to give Example 15a. ESI-MS: 424 [M+H] + ;HPLC(Rt): 0.99 min (Method C) Chiral HPLC: Rt=3.73 min (Method L). Enantiomeric purity: >98% ee.

[0178] (Example 16, Example 16a and Example 16b) [ka] To a mixture of intermediate E-4 (220.0 mg, 702.0 μmol), DIPEA (303.7 μL, 1.8 mmol) and N-acetyl-pyrrolidin-3-ylamine (102.1 mg, 772.0 μmol) in acetonitrile (3 mL) was added CIP (215.2 mg, 772.0 μmol). After stirring at room temperature for 2 h, the mixture was diluted with water, filtered and directly purified by preparative HPLC to give 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, 21.2x250 mm, 5 μm, mobile phase: eluent A: supercritical CO2, eluent B: ethanol in 20 mM concentrated aqueous ammonia, 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) to give: Example 16a (single stereoisomer a): Rt=1.46 min (Method M). Enantiomeric purity: >98% ee. Example 16b (single stereoisomer b): Rt=1.65 min (Method M). Enantiomeric purity: 96% ee.

Claims

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

2. A is a group consisting of —CH═CH— b 2. The compound of claim 1 selected from:

3. A group consisting of -S- c 2. The compound of claim 1 selected from:

4. B is 【Chemistry 3】 Group B consisting of b 2. The compound of claim 1 selected from:

5. R 3 is F-, Cl-, and F 2 A group R consisting of HC- 3b 2. The compound of claim 1 selected from:

6. R 3 A group R consisting of F- 3c 2. The compound of claim 1 selected from:

7. R 6 is C 1-3 -alkylcarbonyl- 6b is selected from Here, the C 1-3 the alkylcarbonyl group is selected from the group consisting of acetyl, ethanecarbonyl, propanecarbonyl, isopropanecarbonyl, and cyclopropanecarbonyl; Here, the C 1-3 2. The compound of claim 1, wherein the -alkylcarbonyl- group is optionally substituted with one, two or three deuterium atoms. 【Request 8】 【Table 1】 2. The compound of claim 1 selected from the group consisting of:

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 optionally at least one pharmaceutically acceptable adjuvant, diluent and / or carrier.

11. Schizophrenia; positive symptoms associated with schizophrenia, schizoaffective disorder, schizophreniform disorder, schizophreniform disorder, treatment-resistant schizophrenia, attenuated psychotic syndrome and autism spectrum disorder; augmentation of antipsychotics to treat positive symptoms associated with schizophrenia, schizoaffective disorder, schizophreniform disorder, schizophreniform disorder, treatment-resistant schizophrenia, attenuated psychotic syndrome and autism spectrum disorder; negative symptoms associated with schizophrenia, schizoaffective disorder, schizophreniform disorder, schizophreniform disorder, treatment-resistant schizophrenia, attenuated psychotic syndrome and autism spectrum disorder; cognitive impairment associated with schizophrenia (CIAS), schizoaffective disorder, schizophreniform disorder, schizophreniform disorder, treatment-resistant schizophrenia, attenuated psychotic syndrome and autism spectrum disorder; treatment-resistant schizophrenia; schizoaffective disorder; schizophreniform disorder; 11. The pharmaceutical composition of claim 10 for use in the prevention and / or treatment of disorders selected from the group consisting of schizophrenia-type disorders; medication-induced psychosis; bipolar disorder I and bipolar disorder II; attenuated psychotic syndromes; 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 disorders; gambling disorder; Tourette's syndrome; cognitive deficits associated with Alzheimer's disease, Parkinson's disease, vascular dementia, and frontotemporal dementia; depression; attention deficit hyperactivity disorder; major depressive disorder; drug addiction; anxiety; mania in bipolar disorder; acute mania; agitation; anaesthesia; hypothalamic disorders; prolactin-related disorders, hyperprolactinemia; symptoms associated with frontal lobe hypofunction and frontal lobe hypofunction associated with drug abuse; and hyperkinetic symptoms.

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

Images