An amide compound and use thereof for preparing sigma2 and 5ht2a inhibitors

Abstract

The present application provides an amide compound, which has Sigma2 receptor and 5HT2A receptor inhibitory activity, can be used as a Sigma2 and 5HT2A dual-target inhibitor, and is used for the treatment of a disease related to Sigma2 receptor activity, the treatment of a disease related to 5HT2A receptor activity, and the treatment of a disease related to Sigma2 receptor activity and 5HT2A receptor activity, such as the negative symptoms of schizophrenia.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical compounds, specifically to an amide compound and its use as a dual-target inhibitor of Sigma2 and 5HT2A. Background Technology

[0002] Schizophrenia is a chronic, disabling illness with positive and negative symptom clusters. Originating in neuroscience, the concepts of positive and negative symptoms were later adopted by psychiatry and are used to describe schizophrenia using symptom clusters. Positive symptoms reflect an excess or distortion of normal function (e.g., delusions, hallucinations, disordered behavior), while negative symptoms refer to a reduction or absence of normal behavior related to motivation and interest (e.g., diminished will, anhedonia, social withdrawal) or a reduction or absence of expression (e.g., emotional dullness, poverty of speech). Negative symptoms are the core symptoms of schizophrenia, accounting for a large proportion of the incidence and poor functional prognosis in patients with the disease. The disease burden of negative symptoms is heavier than that of positive symptoms. This significant disease burden can be attributed to the limited availability of effective treatment options, as they often respond poorly to currently available antipsychotic medications such as dopamine D2 receptor antagonists or partial D2 receptor agonists (Norman RMG, et al. (2015) Schizophr Res. 169:412-417.).

[0003] Negative symptoms are common and can occur at any stage of the illness. For example, some patients experience negative symptoms during their first psychotic episode, while others retain clinically significant negative symptoms even after treatment. Of the five items on the PANSS Negative Syndrome Scale included in the assessment (emotional blunting, emotional withdrawal, impaired emotional communication, social withdrawal, and lack of spontaneity and fluency in conversation), social withdrawal, emotional withdrawal, and impaired emotional communication were the most common symptoms. Research indicates that negative symptoms persist over time and in fact become more pronounced with age, while positive symptoms become less prominent (National Institute of Mental Health: Research Domain Criteria (RDoC). Positive Valence Systems.).

[0004] To date, the FDA has not approved any medications for treating negative symptoms (https: / / www.nimh.nih.gov / research-priorities / rdoc / constructs / positive-valence-systems.shtml. Accepted March 28, 2019.). Paradoxically, antipsychotics can both improve and worsen negative symptoms. On the one hand, by improving hallucinations, delusions, and agitation, antipsychotics promote social interaction. On the other hand, by interfering with dopamine (DA) neurotransmission and the brain's reward circuitry, the core components of negative symptoms are exacerbated, and extrapyramidal adverse reactions are induced, which are often indistinguishable from primary negative symptoms.

[0005] Few prospective studies have been conducted to evaluate the improvement of treatment on persistent negative symptoms, and most reports of improvement in negative symptoms are based on short-term studies in patients with acute psychosis and those with concurrent negative symptoms. Therefore, in most reported studies, it is difficult to determine whether the improvement in negative symptoms is a true effect of treatment or a secondary effect of improvements in other symptom dimensions (e.g., positive, depressive, extrapyramidal), and long-term evidence is lacking (Helfer B, et al. (2016) Am J Psychiatry. 2016; 173:876-886.).

[0006] Given the significant unmet medical needs associated with negative symptoms, research on drugs active on various receptors is active in this therapeutic area, including NMDA receptors, α7 nicotinic receptors, 5-HT2A receptors, and Sigma-2 receptors. Among these, Sigma-2 receptor and 5-HT2A receptor antagonists, which lack direct dopamine affinity, have attracted the most attention (Remington G, et al. (2016) Curr Treat Options Psychiatry. 3:133-150.).

[0007] Sigma receptors, including Sigma1 and Sigma2 receptors, are regulated by small molecules and are primarily located at endoplasmic reticulum membrane-associated sites. They are intact membrane proteins widely expressed in the central nervous system and peripheral tissues (Hellewell, S.B. et al. (1994) Eur. J. Pharmacol. 268, 9-18). Many drugs bind to Sigma receptors, including the antipsychotic haloperidol and the opioid analgesic pentazocine. Sigma receptors are associated with a variety of central nervous system diseases, particularly Alzheimer's disease (AD), schizophrenia, and motor control-related diseases such as amyotrophic lateral sclerosis (ALS).

[0008] Antagonism of the Sigma2 receptor may also modulate the glutamatergic pathway and affect calcium neuron regulation (Vilner BJ, Bowen WD. (2020) J Pharmacol Exp Ther. 292: 900–911). The Sigma2 receptor is involved in counteracting dysregulation of key dopamine and glutamate neurotransmitter pathways.

[0009] Serotonin, or serotonin (5-HT), plays a vital role in human physiological functions. In the central nervous system, 5-HT is an important neurotransmitter and neuromodulator, playing a crucial role in regulating various behaviors such as sleep, eating, activity, learning and memory, body temperature, blood pressure, and pathological states (such as anxiety, mania, schizophrenia, obesity, drug addiction, migraine, and hypertension) (Alenina N, et al., (2009) ProcNatl Acad SciUSA, 106, 10332-10337; Filip M, et al., (2005) Pharmacol Rep, 57, 685-700; Greek AR, (2006) Br J Pharmacol, 147, Suppl 1: S145-S152). 5-HT exerts its effects through its receptors, which are classified into seven families (5-HT1 to 5-HT7) and at least 15 distinct subtypes based on structural (amino acid sequence), biochemical (post-receptor mechanism of signal transduction), and pharmacological differences (Barnes NM, et al., (1999) Neuropharmacology, 38, 1083-1152; Hannon J, et al., (2008) Behav Brain Res, 195, 198-213; Hoyer D, et al., (2002) Pharmacol Biochem Behav, 71, 533-554; Pauwels PJ. (2003) Tocris Reviews, No. 25). The distribution, ligand preferences, and related functions of different subtypes vary.

[0010] The 5-HT2A subtype receptor exhibits widespread and discrete expression in the central nervous system, with the highest expression levels in the cerebral cortex, limbic system, hippocampus, hypothalamus, and basal ganglia, which are involved in regulating higher cognitive and emotional functions. The 5-HT2A receptor is expressed on dopamine, GABA, glutamate, and Ach neurons and acts as a dendritic heterogeneous receptor (Buhot MC, (1997) Curr Opin Neurobiol, 7, 243-254; Leysen JE, (2004) Curr Drug Targets CNS Neuro Disord, 3, 11-26). Like most 5-HT receptors, the 5-HT2A receptor is a G-protein-coupled receptor that transduces signals by activating guanine nucleotide-binding proteins (G proteins), leading to increases or decreases in the levels of second messenger molecules such as cyclic adenosine monophosphate (cAMP), inositol phosphates, and diacylglycerol. These second messenger molecules regulate the function of various intracellular enzymes (such as kinases and ion channels), ultimately affecting cellular excitability and cellular function.

[0011] Abnormal 5-HT transmission is associated with the pathogenesis of various mental illnesses, such as mental disorders (depression, panic attacks, schizophrenia, etc.) and neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, etc.) (Fioravanti et al., (1992) Brain Cogn. 18, 116-124; Sinopoli VM, et al., (2017) Neurosci Biobehav Rev, 80: 372-381). Recent studies have found that 5-HT2A receptors are closely related to the pathological state of neuropsychiatric diseases. 5-HT2A receptors are involved in the molecular mechanisms of action of atypical antipsychotic drugs such as clozapine, olanzapine, and risperidone (Gonzalez-Maeso J, et al., (2009) Trends Neurosci, 32:225-232; Fribourg M, et al., (2011) Cell, 147:1011-1023; Kurita M, et al., (2012) Nat Neurosci, 15:1245-1254). 5-HT2A receptor antagonists are important for treating negative symptoms of schizophrenia (such as mood disorders and language impairment) (Blier P, et al., (2005) J Clin Psychiatry 66, Suppl 8, 30-40; Richtand NM, et al., (2008) Prog Brain Res, 172, 141-153; Meltzer, HY (2013) Annu Rev Med 64, 393-406). Other studies have confirmed that the 5-HT2A receptor regulatory pathway in cortical pyramidal neurons is crucial for mediating hallucinogenic signal transduction and behavioral responses (Gonzalez-Maeso J, et al., (2009) Trends Neurosci, 32:225-232), suggesting the role of 5-HT2A receptors in treating hallucinatory symptoms of various neurodegenerative diseases.

[0012] Drugs used to treat mental illnesses, namely antipsychotics, are divided into two main categories. "Typical" antipsychotics or previous-generation drugs are rarely used clinically due to motor function side effects (extrapyramidal side effects, Parkinson's-like symptoms, etc.). Current drugs focus more on "atypical" antipsychotics (Prim Cre Companion J Clin Psychiatry. (2007) 9(6):444-54). However, these second-generation antipsychotics all have broad-spectrum receptor activity. These compounds regulate various monoamine receptors, such as 5-HTergic, dopaminergic, adrenergic, muscarinic, or histaminergic receptors, as agonists, competitive antagonists, or inverse agonists. This broad-spectrum regulation is likely the cause of side effects such as abnormal sedation, motor dysfunction, and type 2 diabetes.

[0013] In treatment regimens for negative symptoms, patients with schizophrenia exhibiting negative symptoms show worse functional outcomes and a poorer response to antipsychotic medications compared to those with positive symptoms. First- and second-generation antipsychotics are largely ineffective in the sustained treatment of negative symptoms. Therefore, the development of new medicinal compounds capable of treating central nervous system disorders remains crucial. Summary of the Invention

[0014] This application discloses a compound with the structure of Formula I, its pharmaceutically acceptable salt, solvate, or stereoisomer.

[0015]

[0016] Wherein, M is selected from O, S or H, and when M is H, C = M represents CH2; preferably M is O;

[0017] R1 and R2 are independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkylene, C 3-7 Cycloalkanes, C 1-6 Alkylene C 3-7 Cycloalkanes, C 6-10 Aryl, or C 1-6 Alkylene C 6-10 Aryl;

[0018] n and m are independent integers selected from 0 to 4, for example, 0, 1, 2, 3 or 4;

[0019] x and y are independently 0 or 1, and the sum of x and y is 1;

[0020] R3 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene, C3-7 Cycloalkanes, C 1-6 Alkylene C 3-7 Cycloalkanes, C 6-10 Aryl, or C 1-6 Alkylene C 6-10 Aryl;

[0021] R4 is selected from hydrogen, halogen, CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene, C 3-7 Cycloalkanes, C 1-6 Alkylene C 3-7 Cycloalkanes, C 6-10 Aryl, or C 1-6 Alkylene C 6-10 Aryl;

[0022] Cy1 represents a cyclic substituent, specifically a non-fused monocyclic ring, which is a four-, five-, six-, or seven-membered ring. The monocyclic ring is an aromatic ring, a heteroaromatic ring, a carbocyclic ring, or a heterocyclic ring, wherein the heteroatom in the heteroaromatic ring or heterocyclic ring is selected from one or more of N, O, and S. Cy1 is further substituted by one or more R5 groups. Preferably, Cy1 is a five- or six-membered ring, more preferably a benzene ring, cyclohexane, pyridine, thiazole, or... Azole.

[0023] R5 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene, C 3-7 Cycloalkanes, C 1-6 Alkylene C 3-7 Cycloalkanes, or C 1-6 Alkylene C 6-10 Aryl.

[0024] In some embodiments of the present invention, M is O.

[0025] In some embodiments of the present invention, R1 and R2 are independently selected from hydrogen and C. 1-3 Alkyl, C 1-3 Alkoxy C 1-3 Alkylene, C 3-7 Cycloalkanes, C 1-3 Alkylene C 3-7 Cycloalkanes, C 6-10 Aryl, or C 1-3 Alkylene C 6-10 Aryl.

[0026] In some embodiments of the present invention, n and m are independently selected from integers of 0-2, such as 0, 1, or 2.

[0027] In some embodiments of the present invention, R3 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkylene, C 3-7 Cycloalkanes, C 1-3 Alkylene C 3-7 Cycloalkanes, C 6-10 Aryl, or C 1-3 Alkylene C 6-10 Aryl.

[0028] In some embodiments of the present invention, R4 is selected from hydrogen, halogens, and C. 1-3 Alkyl group. In some more specific embodiments of the invention, R4 is selected from hydrogen, F, Cl, and methyl.

[0029] In some embodiments of the present invention, R4 is substituted at the para position of the benzene ring.

[0030] In some embodiments of the present invention, Cy1 represents a non-fused monocyclic ring, which is a five- or six-membered ring, and is an aromatic ring, a heteroaromatic ring, a carbocyclic ring, or a heterocyclic ring, wherein the cyclic heteroatom in the heteroaromatic ring and the heterocyclic ring is selected from one or more of N, O, and S; Cy1 is further substituted by one or more R5.

[0031] In some embodiments of the present invention, Cy1 is a benzene ring or pyridine.

[0032] In some embodiments of the present invention, R5 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkylene, C 3-7 Cycloalkanes, C 1-3 Alkylene C 3-7 Cycloalkanes, or C 1-3 Alkylene C 6-10 Aryl.

[0033] This application discloses a compound with the structure of formula IA, its pharmaceutically acceptable salt, solvate, or stereoisomer.

[0034]

[0035] Among them, R1 and R2 are independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkylene, C 3-7 Cycloalkanes, C 1-6 Alkylene C 3-7 Cycloalkanes, C6-10 Aryl, or C 1-6 Alkylene C 6-10 Aryl;

[0036] m is selected from 0 to 4, for example 0, 1, 2, 3 or 4; n is selected from 0 to 2, for example 0, 1 or 2;

[0037] x and y are independently 0 or 1, and the sum of x and y is 1;

[0038] R3 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene, C 3-7 Cycloalkanes, or C 1-6 Alkylene C 3-7 Cycloalkanes;

[0039] Cy1 represents a cyclic substituent, specifically a non-fused monocyclic ring, which is a four-, five-, six-, or seven-membered ring. The monocyclic ring is an aromatic ring, a heteroaromatic ring, a carbocyclic ring, or a heterocyclic ring, wherein the cyclic heteroatom in the heteroaromatic ring or heterocyclic ring is selected from one or more of N, O, and S. Cy1 is further substituted by one or more R5 groups. Preferably, Cy1 is a five- or six-membered ring, more preferably a benzene ring, cyclohexane, pyridine, thiazole, or... Azole.

[0040] R5 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene, C 3-7 Cycloalkanes, C 1-6 Alkylene C 3-7 Cycloalkanes, or C 1-6 Alkylene C 6-10 Aryl.

[0041] In some embodiments of the present invention, R1 and R2 are independently selected from hydrogen and C. 1-3 Alkyl, C 1-3 Alkoxy C 1-3 Alkylene, C 3-7 Cycloalkanes, C 1-3 Alkylene C 3-7 Cycloalkanes, C 6-10 Aryl, or C 1-3 Alkylene C 6-10 Aryl.

[0042] In some embodiments of the present invention, m is selected from an integer of 0, 1 or 2, n is selected from an integer of 0 or 1, and m and n are not both 0.

[0043] In some embodiments of the present invention, R3 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkylene, C 3-7 Cycloalkanes, C 1-3 Alkylene C 3-7 Cycloalkanes.

[0044] In some embodiments of the present invention, Cy1 represents a non-fused monocyclic ring, which is a five- or six-membered ring, and is an aromatic ring, a heteroaromatic ring, a carbocyclic ring, or a heterocyclic ring, wherein the cyclic heteroatom in the heteroaromatic ring and the heterocyclic ring is selected from one or more of N, O, and S; Cy1 is further substituted by one or more R5.

[0045] In some embodiments of the present invention, Cy1 is a benzene ring or pyridine.

[0046] In some embodiments of the present invention, R5 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkylene, C 3-7 Cycloalkanes, C 1-3 Alkylene C 3-7 Cycloalkanes, or C 1-3 Alkylene C 6-10 Aryl.

[0047] In some embodiments of the invention, R5 is a substituent attached to a carbon atom of the ring.

[0048] This application discloses a compound with the structure of formula IB, its pharmaceutically acceptable salt, solvate, or stereoisomer.

[0049]

[0050] R1 is selected from hydrogen and C. 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkylene, C 3-7 Cycloalkanes, or C 1-6 Alkylene C 3-7 Cycloalkanes;

[0051] m is an integer from 0 to 4, for example 0, 1, 2, 3 or 4, and n is selected from 0 or 1;

[0052] x and y are independently 0 or 1, and the sum of x and y is 1;

[0053] R3 is selected from hydrogen, C 1-6 Alkyl, or C 1-6 Alkoxy;

[0054] W, Z, or V are independently selected from the ring atoms of C, N, O, or S. Dashed and solid lines represent double or single bonds. One or more R5 atoms are substituted at any position in the six-membered ring, and R5 is selected from hydrogen, C, and S. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene, C 3-7 Cycloalkanes, C 1-6 Alkylene C 3-7 Cycloalkanes, or C 1-6 Alkylene C 6-10 Aryl group; preferably W, Z or V are independently C or N atoms, and one or more R5 atoms are connected to any cyclic carbon and / or cyclic nitrogen atom of a six-membered ring.

[0055] In some embodiments of the present invention, R1 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy C 1-3 Alkylene, C 3-7 Cycloalkanes, C 1-3 Alkylene C 3-7 Cycloalkanes.

[0056] In some embodiments of the present invention, m is selected from an integer of 0, 1 or 2, and m and n are not both 0.

[0057] In some embodiments of the present invention, R3 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkyl group.

[0058] In some embodiments of the present invention, W, Z and V are all C atoms; preferably, the ring containing W, Z and V is a benzene ring.

[0059] In some embodiments of the present invention, W and Z are C atoms and V is an N atom, or W and V are C atoms and Z is an N atom, or V and Z are C atoms and W is an N atom; preferably, the ring containing W, Z and V is pyridine.

[0060] In some embodiments of the present invention, R5 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkylene, C 3-7 Cycloalkanes, C 1-3 Alkylene C 3-7 Cycloalkanes, or C 1-3 Alkylene C 6-10 Aryl.

[0061] In some embodiments of the invention, R5 is a substituent attached to a carbon atom of the ring.

[0062] This invention further protects the following specific compounds, their pharmaceutically acceptable salts, solvates, or stereoisomers:

[0063]

[0064]

[0065]

[0066]

[0067] This invention protects a method for preparing a compound of formula I, characterized in that:

[0068] Step 1: The amino compound of formula A1 reacts with the compound of formula B1 to obtain the compound of formula I.

[0069]

[0070] Alternatively, an amino compound of formula A2 reacts with a compound of formula B2 to yield a compound of formula I;

[0071] Alternatively, the C1 compound reacts with the C2 compound to yield the compound of formula I.

[0072]

[0073] Step 2, if necessary, functionalize the compound of Formula I to convert it into the target product having the structure of Formula I, or into a pharmaceutically acceptable salt of the compound, or a precursor compound.

[0074] Among them, M, R1-R4, x, y, m, n, and Cy1 are defined as above, and Z1 is a leaving group, such as halogens and hydroxyl groups.

[0075] The preparation method is also applicable to the preparation of compounds of formula IA and formula IB.

[0076] The compounds of formula I, formula IA, formula IB, or their pharmaceutically acceptable salts, solvates, or stereoisomers have Sigma2 receptor inhibitory activity and 5HT2A receptor inhibitory activity, and can be used for the treatment of diseases mediated by Sigma2 receptor activity, diseases mediated by 5HT2A receptor activity, and diseases mediated by both Sigma2 receptor activity and 5HT2A receptor activity.

[0077] The inhibitory activity of the compounds of this invention against 5HT2A was detected using a Flp-In-CHO-5HT2A stable cell line via an IP-One assay. The IP-One assay is a competitive immunoassay based on HTRF (homogeneous time-resolved fluorescence), using a terbium-labeled anti-IP1 monoclonal antibody and d2-labeled IP1. If a compound exhibits an IC50 ≤ 1 μM, it is considered to possess 5HT2A receptor inhibitory activity in the above analysis. Preferred compounds of this invention have an IC50 ≤ 150 nM, more preferred compounds have an IC50 ≤ 100 nM, and most preferred compounds have an IC50 ≤ 50 nM.

[0078] The binding rates of the compounds of this invention to the Sigma2 receptor were determined using the Jurkat cell line expressing the human Sigma2 receptor. All compounds of this invention exhibit high binding rates to the Sigma2 receptor. Preferred compounds of this invention show a binding rate greater than 50% to the Sigma2 receptor at 10 μM, more preferred compounds show a binding rate greater than 70% at 10 μM, and most preferred compounds show a binding rate greater than 80% at 10 μM.

[0079] Furthermore, the compounds of this invention also exhibit reduced cardiotoxicity.

[0080] This invention provides the use of compounds of formula I, formula IA, formula IB, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof in the preparation of medicaments for treating diseases mediated by 5HT2A receptor activity.

[0081] This invention provides the use of compounds of formula I, formula IA, formula IB, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof in the preparation of medicaments for treating diseases mediated by Sigma2 receptor activity.

[0082] This invention provides the use of compounds of formula I, formula IA, formula IB, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof in the preparation of medicaments for treating diseases mediated by 5HT2A receptor and Sigma2 receptor activity.

[0083] Diseases mediated by the activity of the 5HT2A receptor and / or Sigma2 receptor include, but are not limited to, central nervous system diseases.

[0084] The central nervous system diseases mentioned include, but are not limited to: mental illness, central nervous system degenerative diseases, mental disorder symptoms related to or concurrent with central nervous system degenerative diseases, and negative symptoms of mental illness.

[0085] The mental illnesses mentioned include, but are not limited to: depression, anxiety disorder, mania, schizophrenia, affective schizophrenia, bipolar disorder, insomnia, autism, etc.

[0086] The central nervous system degenerative diseases mentioned include, but are not limited to: Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia, etc.

[0087] The mental disorders and negative symptoms of mental illnesses related to or complicated by the central nervous system degenerative diseases include, but are not limited to: affective disorders, language impairment, hallucinations, loss of interest, emotional dullness, diminished will, anhedonia, social withdrawal, etc.

[0088] The present invention provides a pharmaceutical composition characterized in that it comprises a compound of formula I, a compound of formula IA, a compound of formula IB, or a pharmaceutically acceptable salt thereof, a solvate, or a stereoisomer thereof.

[0089] The pharmaceutical composition can be used to treat diseases mediated by 5HT2A receptor and / or Sigma2 receptor activity. The diseases mediated by 5HT2A receptor and / or Sigma2 receptor activity are defined as described above.

[0090] The pharmaceutical composition further contains a pharmaceutically acceptable carrier.

[0091] The pharmaceutically acceptable carriers are various excipients commonly used or known in the pharmaceutical field, including but not limited to: diluents, binders, antioxidants, pH adjusters, preservatives, lubricants, disintegrants, etc.

[0092] Examples of the diluents include lactose, starch, cellulose derivatives, inorganic calcium salts, and sorbitol. Examples of the binders include starch, gelatin, sodium carboxymethyl cellulose, and polyvinylpyrrolidone. Examples of the antioxidants include vitamin E, sodium bisulfite, sodium sulfite, and butylated hydroxyanisole. Examples of the pH adjusters include hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, Tris, acetic acid, sodium dihydrogen phosphate, and disodium hydrogen phosphate. Examples of the preservatives include methylparaben, ethylparaben, m-cresol, and benzalkonium chloride. Examples of the lubricants include magnesium stearate, micronized silica gel, and talc. Examples of the disintegrants include starch, methylcellulose, xanthan gum, and croscarmellose sodium.

[0093] The pharmaceutical composition contains 0.1-1000 mg of a compound of formula I, formula IA, formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, preferably 1-500 mg, and more preferably 5-100 mg.

[0094] The pharmaceutical composition comprises 10%-90% by mass of the compound of formula I, formula IA, formula IB or its pharmaceutically acceptable salt, solvate or stereoisomer, preferably 20%-80%, more preferably 30%-70%.

[0095] The dosage form of the pharmaceutical composition may be an oral dosage form, such as tablets, capsules, pills, powders, granules, suspensions, syrups, etc.; or an injectable dosage form, such as an injection solution, powder for injection, etc., administered via intravenous, intraperitoneal, subcutaneous, or intramuscular routes. All dosage forms used are well known to those skilled in the art of pharmaceutical science.

[0096] The routes of administration of the pharmaceutical composition include, but are not limited to: oral; sublingual; sublingual; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, and intravenous; and by implantation of a reservoir or infusion device.

[0097] The dosage of compounds of formula I, IA, IB, or their pharmaceutically acceptable salts, solvates, or stereoisomers will depend on the recipient's age, health, and weight, the type of concomitant medication, the frequency of treatment, the route of administration, etc. The drug may be administered as a single daily dose, once daily, once every two days, once every three days, once every four days, or the total daily dose may be administered in two, three, or four separate doses per day. Dosage may be administered once or multiple times, and the duration of administration may range from a single day to several months or longer. The dosage of compounds of formula I, IA, IB, or their pharmaceutically acceptable salts, solvates, or stereoisomers is 0.01-100 mg / kg / day, preferably 0.1-10 mg / kg / day, for example, 0.5 mg / kg / day, 1 mg / kg / day, 2 mg / kg / day, 5 mg / kg / day, etc.

[0098] The pharmaceutical composition can be used in combination with other drugs for treating diseases mediated by 5HT2A receptor and / or Sigma2 receptor activity.

[0099] The pharmaceutical composition may further contain a second therapeutic agent, which is another drug for treating diseases mediated by 5HT2A receptor and / or Sigma2 receptor activity.

[0100] The present invention provides a method for treating diseases mediated by 5HT2A receptor and / or Sigma2 receptor activity, characterized in that a therapeutically effective amount of a compound of formula I, formula IA, formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered to a patient in need.

[0101] The routes of administration of the compounds of formula I, formula IA, formula IB, or their pharmaceutically acceptable salts, solvates, or stereoisomers include, but are not limited to: oral; sublingual; sublingual; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, and intraarterial; and by implantation of a reservoir or reservoir.

[0102] The method further includes administering other medications to patients in need of treatment for diseases mediated by 5HT2A receptor and / or Sigma2 receptor activity.

[0103] Other medications for treating diseases mediated by 5HT2A receptor and / or Sigma2 receptor activity include, but are not limited to, medications for treating mental illnesses and medications for treating central nervous system degenerative diseases.

[0104] The medications used to treat mental illnesses include, but are not limited to: benzodiazepines Classes (e.g., methyltriazolidinedione, chlordiazepoxide) Clonazepam, diazepam, lorazepam, flurazepam, midazolam, etc.; barbiturates (e.g., phenobarbital, pentobarbital, etc.); chloral hydrate; buspirone; phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, etc.); thioxanthracene derivatives (e.g., tevothixeol); butyrophenone derivatives (e.g., haloperidol); clozapine; riperidone; tricyclic antidepressants (e.g., imipramine, doxepin, nortriptyline, amitriptyline, etc.); heterocyclic antidepressants (e.g., amoxapine, maprotiline, trazodone, bupropion, venfalacin, etc.); selective serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine, etc.); monoamine oxidase inhibitors (e.g., phenelzine, moclobemide, etc.); ketamine; mirtazapine, etc.

[0105] The drugs mentioned for the treatment of central nervous system degenerative diseases include, but are not limited to: levodopa, bromocriptine, thioprostol, propyne, amantadine, reserpine, etc.

[0106] In this invention:

[0107] "Halogen" refers to F, Cl, Br or I.

[0108] "Independent" means that the features are independent of each other and are not related to each other.

[0109] The phrase "substituent at any substitution position in the ring" indicates that the substituent group is located at any substituted position in the ring. The substitution position of the substituent is the ortho, meta, or para position of the ring relative to the main chain connection position.

[0110] The term "pharmaceutically acceptable salt" includes salts derived from suitable inorganic acids and bases, as well as organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed with amino groups and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by other methods in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate-heptyl, glycerol phosphate, gluconate, hemisulfate, heptanate, hydroiodate, 2-hydroxyethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pyrate, pectinate, persulfate, 3-phenylpropionate, phosphate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Detailed Implementation

[0111] The present invention will be further described below with reference to embodiments. It should be noted that the embodiments are not intended to limit the scope of protection of the present invention, and those skilled in the art will understand that any improvements and variations made based on the present invention are within the scope of protection of the present invention.

[0112] All the common reagents used in the following examples are commercially available, and the biological experiments performed are routine biological experiments in the field, which can be carried out in accordance with the instructions of the corresponding experimental manual or kit.

[0113] The following terms or abbreviations are used in the embodiments:

[0114] PEX: Example of intermediate preparation

[0115] EX: Example

[0116] Prep-HPLC (purification under Method A conditions): Prep-HPLC purification is performed using Method A conditions, which include: column: Sunfire 5μm 19-150mm or XBridge-1 5μm 19-150mm; mobile phase A: water (0.1% TFA); mobile phase B: CAN; gradient: 10-20-9 min 150 VL

[0117] ACN: Acetonitrile

[0118] HOBT: 1-Hydroxybenzotriazole

[0119] EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0120] EtOAc and EA: Ethyl acetate

[0121] PE: Petroleum ether

[0122] DIEA: Diisopropylethylamine

[0123] TEA: Triethylamine

[0124] DCM: Dichloromethane

[0125] DMF: N,N-dimethylformamide

[0126] TFA: 2,2,2-trifluoroacetic acid or trifluoroacetic acid

[0127] THF: Tetrahydrofuran.

[0128] Intermediate preparation examples

[0129] PEX1: Preparation of 3-(4-(methoxymethyl)phenyl)propionic acid

[0130]

[0131] Step 1. Preparation of (E)-3-(4-(methoxymethyl)phenyl)acrylate ethyl ester

[0132]

[0133] To a solution of 1-bromo-4-(methoxymethyl)benzene (2.00 g, 9.95 mmol, 1.0 equivalent) in DMF (20 mL), ethyl acrylate (1.99 g, 19.9 mmol, 2.0 equivalent), Pd(OAc)₂ (223 mg, 1.00 mmol, 0.1 equivalent), PPh₃ (522 mg, 1.99 mmol, 0.2 equivalent), and Et₃N (3.02 g, 29.8 mmol, 3.0 equivalent) were added. The mixture was stirred overnight at 110 °C under nitrogen protection and quenched with water (30 mL). The resulting mixture was extracted with EtOAc (3 × 60 mL), the organic layers were combined, washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography using ethyl acetate / petroleum ether (4 / 96) to give 1.1 g (45% yield) of ethyl (E)-3-[4-(methoxymethyl)phenyl]acrylate as a yellow oil. LC-MS (ESI, m / z): 221 [M+H] + .

[0134] Step 2.3 Preparation of ethyl (4-(methoxymethyl)phenyl)propionate

[0135]

[0136] NaBH4 (515 mg, 13.6 mmol, 5.0 equivalent) was slowly added to a solution of (E)-3-[4-(methoxymethyl)phenyl]acrylate (600 mg, 2.72 mmol, 1.0 equivalent) and CoCl2·6H2O (648 mg, 2.72 mmol, 1.0 equivalent) in MeOH (12 mL). The mixture was stirred overnight at room temperature and quenched with water (20 mL). The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 500 mg (70% yield) of ethyl 3-[4-(methoxymethyl)phenyl]propionate as a yellow oil. LC-MS (ESI, m / z): 223 [M+H] + .

[0137] Step 3.3 Preparation of (4-(methoxymethyl)phenyl)propionic acid.

[0138] A solution of ethyl 3-[4-(methoxymethyl)phenyl]propionate (500 mg, 2.25 mmol, 1.0 equivalent) in THF (8 mL) was added to a solution of NaOH (450 mg, 11.2 mmol, 5.0 equivalent) in water (2 mL). The mixture was stirred at 50 °C for 3 hours and quenched with 1 M hydrochloric acid (3 mL). The resulting solution was extracted with EtOAc (3 × 30 mL), the organic layers were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 400 mg (82% yield) of 3-[4-(methoxymethyl)phenyl]propionic acid as a yellow oil. LC-MS (ESI, m / z): 195 [M+H] + .

[0139] PEX2: Preparation of 2-(6-(methoxymethyl)pyridin-3-yl)acetic acid

[0140]

[0141] Step 1. Preparation of 5-bromo-2-(methoxymethyl)pyridine

[0142]

[0143] A solution of (5-bromopyridin-2-yl)methanol (5.00 g, 26.6 mmol, 1.00 equivalent) in DMF (100 mL) was cooled to 0 °C under N2 protection, and NaH (1.60 g, 39.9 mmol, 1.5 equivalent) was added. The mixture was stirred for 30 min and CH3I (7.55 g, 53.2 mmol, 2.0 equivalent) was added. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water (300 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with water (50 mL × 3) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give 5-bromo-2-(methoxymethyl)pyridine (5.00 g, 88.4%) as a yellow oil. 1 HNMR (400MHz, CDCl3) δ8.64 (d, J=2.0Hz, 1H), 7.84 (dd, J1=2.0Hz, J2=8.0Hz, 1H), 7.35 (d, J=8.0Hz, 1H), 4.56 (s, 2H), 3.50 (s, 3H). LC-MS(ESI,m / z):204.0[M+H] + .

[0144] Step 2.2 Preparation of diethyl 6-(6-(methoxymethyl)pyridin-3-yl)malonate

[0145]

[0146] A mixture of 5-bromo-2-(methoxymethyl)pyridine (1.00 g, 4.95 mmol, 1.00 equivalent), diethyl malonate (2.35 g, 14.7 mmol, 3.00 equivalent), Pd(dba)2 (200 mg), tri-tert-butylphosphine (4 mL, 10%), and K3PO4 (2.08 g, 9.90 mmol, 2.00 equivalent) was placed in toluene (30 mL) and refluxed under N2 for 4 hours. The mixture was cooled to room temperature, poured into water (30 mL), and extracted with EA (10 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude product. This crude product was purified by column chromatography (PE / EA = 10 / 1) to give diethyl 2-(6-(methoxymethyl)pyridin-3-yl)malonate (600 mg, 38.8%) as a yellow oil. LC-MS (ESI, m / z): 282.1 [M+H] + .

[0147] Step 3.2: Preparation of (6-(methoxymethyl)pyridin-3-yl)acetic acid:

[0148] A solution of diethyl 2-(6-(methoxymethyl)pyridin-3-yl)malonate (600 mg, 2.13 mmol, 1.0 equivalent) in concentrated hydrochloric acid (6 mL) was heated to 100 °C for 4 hours. The resulting mixture was concentrated under reduced pressure to give a yellow oily 2-(6-(methoxymethyl)pyridin-3-yl)acetic acid hydrochloride (200 mg, 33.2%). LC-MS (ESI, m / z): 182.1 [M+H] + .

[0149] PEX3: Preparation of 2-(methoxymethyl)nicotinic acid:

[0150]

[0151] Step 1. Preparation of (3-bromopyridin-2-yl)methanol

[0152]

[0153] A BH3 / THF solution (744 mL, 0.744 mol, 1 mol / L) was added to a 50 mL solution of 3-bromopyridinecarboxylic acid (5 g, 0.025 mol) in THF. The mixture was stirred at 25 °C for 3 hours. The mixture was quenched with saturated NH4Cl solution (1 L) and extracted with EA (500 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to give the product (3-bromopyridine-2-yl)methanol (2 g, 40.32%) as a yellow solid. LC-MS (ESI, m / z): 189.6 [M+H] +.

[0154] Step 2. Preparation of 3-bromo-2-(methoxymethyl)pyridine

[0155]

[0156] A solution of (3-bromopyridin-2-yl)methanol (2 g, 0.011 mol) in THF (50 mL) was cooled to 0 °C, and NaH (510 mg, 0.021 mol, 60% in oil) was added. The mixture was stirred at 25 °C for 1 hour. The mixture was then cooled to 0 °C, and CH3I (3.01 g, 0.021 mol) was added. The mixture was stirred at 25 °C for 6 hours. The mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to give the product 3-bromo-2-(methoxymethyl)pyridine (2.5 g, 84.91%) as a yellow oil. LC-MS (ESI, m / z): 203.7 [M+H] + .

[0157] Step 3. Preparation of methyl 2-(methoxymethyl)nicotinic acid

[0158]

[0159] A solution of 3-bromo-2-(methoxymethyl)pyridine (2 g, 0.010 mol), Pd(dppf)Cl2 (430 mg, 0.594 mmol), and triethylamine (3.01 g, 0.030 mol) in MeOH (100 mL) was stirred at 140 °C for 5 hours under CO2 at 2 MPa. The mixture was filtered through a diatomaceous earth filter and washed with MeOH (3 × 20 mL). The combined filtrates were concentrated to dryness to give methyl 2-(methoxymethyl)nicotinic acid (1 g, 50.51%) as a yellow oil. LC-MS (ESI, m / z): 181.7 [M+H] + .

[0160] Step 4. Preparation of 2-(methoxymethyl)nicotinic acid

[0161] A solution of methyl 2-(methoxymethyl)nicotinic acid (550 mg, 3.04 mmol) in THF (4 mL), MeOH (4 mL), and H₂O (1 mL) was mixed at 0 °C, followed by the addition of LiOH·H₂O (255 mg, 6.07 mmol). The mixture was stirred continuously at 25 °C for 2 hours. The reaction mixture was acidified to pH 3 with 1 N HCl and evaporated under vacuum to give 2-(methoxymethyl)nicotinic acid (500 mg, 17.87%) as a colorless oil. LC-MS (ESI, m / z): 167.6 [M+H]+ .

[0162] PEX4: Preparation of 6-(methoxymethyl)pyridinecarboxylic acid

[0163]

[0164] Step 1. 2-Bromo-6-(methoxymethyl)pyridine

[0165]

[0166] A solution of (6-bromopyridin-2-yl)methanol (2 mg, 0.011 mol) in THF (50 mL) was cooled to 0 °C, and NaH (380 mg, 0.021 mol, 60% in oil) was added. The mixture was stirred at 25 °C for 1 hour. The mixture was cooled to 0 °C, and CH3I (3.01 g, 0.016 mol) was added. The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to give a yellow oily product, 2-bromo-6-(methoxymethyl)pyridine (2 g, 83.96%). LC-MS (ESI, m / z): 201.7 [M+H] + .

[0167] Step 2. Preparation of methyl 6-(methoxymethyl)pyridinecarboxylate

[0168]

[0169] In an autoclave, a solution of 2-bromo-6-(methoxymethyl)pyridine (1 g, 4.90 mmol), Pd(dppf)Cl2 (220 mg, 0.294 mmol), and triethylamine (1.49 g, 14.7 mmol) in MeOH (50 mL) was stirred at 140 °C for 5 hours under CO2 at 2 MPa. The mixture was filtered through a diatomaceous earth filter and washed with MeOH (3 × 20 mL). The combined filtrates were concentrated to dryness to give methyl 6-(methoxymethyl)pyridinecarboxylate (0.66 g, 48.98%) as a yellow oil. LC-MS (ESI, m / z): 181.7 [M+H] + .

[0170] Step 3. Preparation of 6-(methoxymethyl)pyridinecarboxylic acid

[0171] At 0 °C, a solution of methyl 6-(methoxymethyl)pyridinecarboxylate (660 mg, 3.64 mmol) in THF (4 mL), MeOH (4 mL), and H₂O (1 mL) was mixed, followed by the addition of LiOH·H₂O (305.7 mg, 7.28 mmol). The mixture was stirred continuously at 25 °C for 2 hours. The reaction mixture was acidified to pH 3 with 1 N HCl and evaporated under vacuum to give the desired product, 6-(methoxymethyl)pyridinecarboxylic acid (600 mg, 65.83%), as a colorless oil. LC-MS (ESI, m / z): 167.6 [M+H] + .

[0172] PEX5: Preparation of 1-(2-(4-fluorophenyl)-2-oxoethyl)piperidine-4-carboxylic acid

[0173]

[0174] 2-Bromo-1-(4-fluorophenyl)ethyl-1-one (3.20 g, 14.7 mmol, 0.95 equivalent) was added to a mixture of piperidine-4-carboxylic acid (2.00 g, 15.5 mmol, 1.00 equivalent) and K₂CO₃ (3.21 g, 23.3 mmol, 1.50 equivalent) with DMF (40 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was poured into water (120 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with water (50 mL × 3) and brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated to give 1-(2-(4-fluorophenyl)-2-oxoethyl)piperidine-4-carboxylic acid (1.20 g, 26.5%) as a yellow oil. LC-MS (ESI, m / z): 266.1 [M+H] + .

[0175] PEX6: Preparation of 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide

[0176]

[0177] Step 1.4 Preparation of benzyl 1-((tert-butoxycarbonyl)(methyl)amino)piperidine-1-carboxylate

[0178]

[0179] At 0 °C, benzyl chloroformate (4.80 g, 28.0 mmol) was added dropwise to a solution of tert-butyl methyl (piperidin-4-yl)carbamate (5.00 g, 23.0 mmol) and TEA (4.70 g, 46.0 mmol) in 150 mL of DCM. The mixture was then stirred at 25 °C for 16 hours, diluted with water (150 mL), and extracted with DCM (30 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to give the residue. The crude product was purified by column chromatography (PE / EA = 100 / 1–10 / 1) to give benzyl 4-((tert-butoxycarbonyl)(methyl)amino)piperidin-1-carboxylic acid ester (7.00 g, 86.1%) as a colorless oil. LC-MS (ESI, m / z): 248.9 [M+H] + .

[0180] Step 2. Preparation of 4-(methylamino)piperidine-1-carboxylic acid benzyl ester hydrochloride.

[0181]

[0182] At 0 °C, EA / HCl (70 mL, 6N) was added dropwise to a solution of 4-((tert-butoxycarbonyl)(methyl)amino)piperidine-1-carboxylic acid benzyl ester (7.00 g, 20.0 mmol) in EA (70 mL). The mixture was then stirred at 25 °C for 3 hours and subsequently evaporated under vacuum to give 4-(methylamino)piperidine-1-carboxylic acid benzyl ester hydrochloride (5.00 g, 65.0%) as a white solid. LC-MS (ESI, m / z): 249.2 [M+H] + .

[0183] Step 3. Preparation of 4-(2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamido)piperidine-1-carboxylic acid benzyl ester

[0184]

[0185] A mixture of 2-(6-(methoxymethyl)pyridin-3-yl)benzyl acetate (1.40 g, 8.00 mmol), 4-(methylamino)piperidin-1-carboxylic acid benzyl ester hydrochloride (2.19 g, 8.00 mmol), HOBt (1.25 g, 9.00 mol), EDCI (1.77 g, 9.00 mmol), and TEA (2.34 g, 23.0 mmol) in DCM (30 mL) was stirred at 25 °C for 16 hours. The mixture was diluted with water (30 mL) and extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to give the residue. The crude product was purified by column chromatography (CH₂Cl₂ / MeOH = 100 / 1-30 / 1) to give 4-(2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamido)piperidin-1-carboxylic acid benzyl ester (1.80 g, 28.6%), as a yellow oil. LC-MS (ESI, m / z): 412.0 [M+H] + .

[0186] Step 4. Preparation of 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide

[0187] Pd / C (340 mg) was added to a methanol (15 mL) solution of 1.3 g (3.20 mmol) of benzyl piperidine-1-carboxylate. The mixture was stirred at 25 °C for 1 hour under an H2 balloon. The suspension was filtered through a diatomaceous earth pad, and the pad was washed with MeOH (30 mL × 5). The combined filtrates were concentrated to dryness to give 930 mg (71.5%) of 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide as a yellow solid.

[0188] LC-MS (ESI, m / z): 277.9 [M+H] + .

[0189] PEX7: Preparation of 2-methoxy-N-(piperidin-4-ylmethyl)nicotinamide

[0190]

[0191] Step 1. Preparation of 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-1-carboxylic acid benzyl ester

[0192]

[0193] At 0 °C, benzyl chloroformate (4.80 g, 28.0 mmol) was added dropwise to a solution of (piperidin-4-ylmethyl)carbamate tert-butyl ester (5.00 g, 23.0 mmol) and TEA (4.70 g, 46.0 mmol) in DCM (150 mL). The mixture was then stirred at 20 °C for 3 hours, diluted with water (50 mL), and extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to give 4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-carboxylic acid benzyl ester (7.70 g, 50.0%) as a white solid.

[0194] Step 2. Preparation of 4-(aminomethyl)piperidine-1-carboxylic acid benzyl ester hydrochloride.

[0195]

[0196] At 0 °C, EtOAc / HCl (5 mL, 6 N) was added dropwise to a solution of 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-1-carboxylate (500 mg, 1.43 mmol) in EtOAc (5 mL). The mixture was then stirred at 25 °C for 6 hours and subsequently evaporated under vacuum to give 4-(aminomethyl)piperidine-1-carboxylate hydrochloride (300 mg, 73.5%) as a yellow solid. LC-MS (ESI, m / z): 249.1 [M+H] + .

[0197] Step 3. Preparation of 4-((2-methoxynicotinamide)methyl)piperidine-1-carboxylic acid benzyl ester

[0198]

[0199] A mixture of 4-(aminomethyl)piperidine-1-carboxylic acid benzyl ester hydrochloride (300 mg, 0.934 mmol), 2-methoxynicotinic acid (157 mg, 1.03 mmol), HOBt (151 mg, 1.12 mmol), EDCI (215 mg, 1.12 mmol), and TEA (473 mg, 4.67 mmol) in DCM (10 mL) was stirred at 20 °C for 16 hours. The mixture was diluted with water (20 mL) and extracted with DCM (10 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to give the crude product. The residue was purified by Prep-TLC (DCM / MeOH = 10 / 1) to give a colorless oil of 4-((2-methoxynicotinamide)methyl)piperidine-1-carboxylic acid benzyl ester (300 mg, 51.6%). LC-MS (ESI, m / z): 384.3 [M+H] + .

[0200] Step 4. Preparation of 2-methoxy-N-(piperidin-4-ylmethyl)nicotinamide

[0201] Pd / C (100 mg) was added to a MeOH (5 mL) solution of 4-((2-methoxynicotinamide)methyl)piperidine-1-carboxylic acid benzyl ester (300 mg, 0.781 mmol). The resulting mixture was stirred at 25 °C for 1 hour under an H2 balloon and then filtered. The filtrate was evaporated under vacuum to give 2-methoxy-N-(piperidine-4-ylmethyl)nicotinamide (100 mg, 51.3%) as a yellow oil.

[0202] PEX8: Preparation of 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethyl-1-one hydrochloride

[0203]

[0204] Step 1. Preparation of ((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)(methyl)carbamate tert-butyl ester

[0205]

[0206] 2-Bromo-1-(4-fluorophenyl)ethyl-1-one (2.25 g, 10.4 mmol, 0.95 equivalent) was added to a solution of methyl (piperidin-4-ylmethyl)carbamate (2.50 g, 10.9 mmol, 1.00 equivalent) and K₂CO₃ (2.26 g, 16.4 mmol, 1.50 equivalent) in DMF (50 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was poured into water (150 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with water (50 mL × 3) and brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated to give ((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin)-4-yl)methyl)(methyl)carbamate tert-butyl ester (4.00 g, 90.8%) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ8.09(brs,2H),7.16-7.12(m,2H), 3.77-3.73(m,2H),3.13-2.98(m,4H),2.87(s,3H),2.16-2.07(m,2H),1.71-1.63(m,3H),1.47(s,9H),1.45-1.37(m,2H). LC-MS(ESI,m / z): 365.1[M+H] + .

[0207] Step 2. Preparation of 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethyl-1-one hydrochloride.

[0208] At 0 °C, a solution of 4.0 M HCl in 20 mL of EtOAc was added dropwise to a solution of ((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)(methyl)carbamate tert-butyl ester (4.00 g, 11.4 mmol, 1.00 equivalent) in 40 mL of EtOAc. The reaction mixture was then stirred at room temperature for 2 hours and filtered to give 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethyl-1-one hydrochloride (3.00 g, 73.7%) as a yellow solid. LC-MS (ESI, m / z): 265.1 [M+H] + .

[0209] PEX9 Preparation of 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one hydrochloride

[0210]

[0211] Step 1. Preparation of tert-butyl ((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)carbamate

[0212]

[0213] To a mixture of tert-butyl (piperidin-4-ylmethyl)carbamate (5.00 g, 23.2 mmol, 1.00 equivalent) and K₂CO₃ (4.81 g, 34.8 mmol, 1.50 equivalent) in DMF (100 mL), 2-bromo-1-(4-fluorophenyl)ethyl-1-one (4.78 g, 22.0 mmol, 0.95 equivalent) was added. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was poured into water (300 mL) and filtered to give tert-butyl ((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)carbamate (5.00 g, 55.2%) as a grayish-white solid. 1 H NMR(400MHz, CDCl3)δ8.09-8.02(m,2H),7.14-7.10(m,2H),4.66(brs,1H), 3.73(s,2H),3.04-3.01(m,2H),2.15-2.05(m,3H),1.70-1.67(m,2H),1.44(s,9H),1.41-1.34(m,4H). LC-MS(ESI,m / z): 351.2[M+H] + .

[0214] Step 2.2 Preparation of 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one hydrochloride

[0215] At 0 °C, a solution of 4.0 M HCl in 50 mL of EtOAc was added dropwise to a solution of tert-butyl (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)carbamate (5.00 g, 14.2 mmol, 1.00 equivalent). The reaction mixture was then stirred at room temperature for 2 hours and filtered to give 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one hydrochloride (3.00 g, 59.2%) as a grayish-white solid. 1 H NMR(400MHz,DMSO_d6)δ10.41-10.26(m,1H), 8.37-8.32(m,3H),8.18-8.06(m,2H),7.49-7.45(m,2H),5.15-5.07(m,2H),3.47-3.07(m,3H),2.89-2.69(m,3H),2.08-1.61(m,5H). LC-MS(ESI,m / z): 251.1[M+H] + .

[0216] PEX10 was used to prepare 1-(4-fluorophenyl)-2-(4-(methylamino)piperidin-1-yl)ethyl-1-one hydrochloride.

[0217]

[0218] Step 1. Preparation of tert-butyl (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)(methyl)carbamate

[0219]

[0220] To a mixture of tert-butyl methyl (piperidin-4-yl)carbamate (1.00 g, 4.64 mmol, 1.00 equivalent) and K₂CO₃ (960 mg, 6.96 mmol, 1.50 equivalent) in DMF (20 mL), 2-bromo-1-(4-fluorophenyl)ethyl-1-one (957 mg, 4.41 mmol, 0.95 equivalent) was added. The resulting mixture was stirred at room temperature for 2 hours, then poured into water (60 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (30 mL × 3) and brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated to give (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)(methyl)carbamate (1.00 g, 55.1%) as a yellow oil. LC-MS (ESI, m / z): 351.2 [M+H] + .

[0221] Step 2. Preparation of 1-(4-fluorophenyl)-2-(4-(methylamino)piperidin-1-yl)ethyl-1-one hydrochloride.

[0222] At 0 °C, a solution of 4.0 M HCl in 10 mL of EtOAc was added dropwise to a solution of 1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)(methyl)carbamate tert-butyl ester (1.00 g, 2.84 mmol, 1.00 equivalent). The reaction mixture was then stirred at room temperature for 2 hours and filtered to give 1-(4-fluorophenyl)-2-(4-(methylamino)piperidin-1-yl)ethyl-1-one hydrochloride (600 mg, 58.7%) as a yellow solid. LC-MS (ESI, m / z): 251.1 [M+H] + .

[0223] PEX11: Preparation of (1-(4-fluorophenylethyl)piperidin-4-yl)methylamine hydrochloride.

[0224]

[0225] Step 1. Preparation of 4-fluorophenylethyl methanesulfonate

[0226]

[0227] A solution of 2-(4-fluorophenyl)ethyl-1-ol (200 mg, 0.630 mmol) and TEA (289 mg, 2.85 mmol) in DCM (3 mL) was cooled to 0 °C, and methanesulfonyl chloride (195 mg, 1.71 mmol) was added. The mixture was stirred at 25 °C for 3 hours. The mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to give the desired product, 4-fluorophenylethyl methanesulfonate (350 mg, 89.91%), as a colorless oil.

[0228] Step 2. Preparation of tert-butyl (1-(4-fluorophenylethyl)piperidin-4-yl)methyl)carbamate

[0229]

[0230] Potassium carbonate (143 mg, 1.031 mmol) and tert-butyl (piperidin-4-ylmethyl)carbamate (150 mg, 0.687 mmol) were added to a DMF (10 mL) solution of 4-fluorophenylethyl methanesulfonate (176 mg, 0.825 mmol) at 0 °C. The mixture was stirred at 80 °C for 12 hours and then cooled to 0 °C. The mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to give the product ((1-(4-fluorophenylethyl)piperidin-4-yl)methyl)carbamate (100 mg, 17.50%) as a white solid. LC-MS (ESI, m / z): 337.0 [M+H] + .

[0231] Step 3. Preparation of (1-(4-fluorophenylethyl)piperidin-4-yl)methylamine hydrochloride

[0232] A solution of tert-butyl (1-(4-fluorophenylethyl)piperidin-4-yl)methyl)carbamate (100 mg, 0.297 mmol) in EA (5 mL) was cooled to 0 °C, and EA / HCl (5 mL, 6 N) was added dropwise. The reaction mixture was stirred at 25 °C for 4 hours. The mixture was then evaporated under vacuum to give crude product (1-(4-fluorophenylethyl)piperidin-4-yl)methylamine hydrochloride (90 mg, 37.18%) as a white solid, which could be used directly for the next step without further purification. LC-MS (ESI, m / z): 237.1 [M+H] + .

[0233] Preparation of PEX12: 1-(4-fluorophenylethyl)-N-methylpiperidine-4-amine hydrochloride

[0234]

[0235] Step 1. Preparation of tert-butyl (1-(4-fluorophenylethyl)piperidin-4-yl)(methyl)carbamate

[0236]

[0237] At 0 °C, potassium carbonate (285 mg, 2.06 mmol) and tert-butyl (piperidin-4-yl)carbamate (354 mg, 1.65 mmol) were added to a DMF (10 mL) solution of methyl (piperidin-4-yl)carbamate (300 mg, 1.38 mmol). The mixture was stirred at 80 °C for 12 hours and then cooled to 0 °C. The mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to give the product (1-(4-fluorophenylethyl)piperidin-4-yl)(methyl)carbamate (260 mg, 44.59%) as a white solid. LC-MS (ESI, m / z): 337.0 [M+H] + .

[0238] Step 2. Preparation of 1-(4-fluorophenylethyl)-N-methylpiperidine-4-amine hydrochloride.

[0239] A solution of (70 mg, 0.208 mmol) tert-butyl (1-(4-fluorophenylethyl)piperidin-4-yl)(methyl)carbamate in EA (5 mL) was cooled to 0 °C, and EA / HCl (5 mL, 6 N) was added. The reaction mixture was then stirred at 25 °C for 4 hours. The mixture was evaporated under vacuum to give the product 1-(4-fluorophenylethyl)-N-methylpiperidin-4-amine hydrochloride (180 mg, 43.48%) as a white solid. LC-MS (ESI, m / z): 237.1 [M+H] + .

[0240] Preparation of 3-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)prop-1-one hydrochloride from PEX13.

[0241]

[0242] Step 1. Preparation of tert-butyl (1-(3-(4-fluorophenyl)-3-oxopropyl)piperidin-4-yl)methyl)carbamate

[0243]

[0244] A solution of tert-butyl (piperidin-4-ylmethyl)carbamate (574 mg, 2.68 mmol) and K₂CO₃ (1.11 g, 8.04 mmol) in DMF (5 mL) was cooled to 0 °C, and 3-chloro-1-(4-fluorophenyl)prop-1-one (500 mg, 2.68 mmol) was added to the solution. The reaction mixture was then stirred at 25 °C for 4 hours. The mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to give the product ((1-(3-(4-fluorophenyl)-3-oxopropyl)piperidin-4-yl)methyl)carbamate (220 mg, 82.91%) as a colorless oil. LC-MS (ESI, m / z): 365.0 [M+H] + .

[0245] Step 2. Preparation of 3-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)prop-1-one hydrochloride.

[0246] A solution of tert-butyl carbamate (220 mg, 0.602 mmol) in EA (5 mL) was cooled to 20 °C, and EA / HCl (5 mL, 6 N) was added. The reaction mixture was then stirred at 25 °C for 4 hours. The mixture was evaporated under vacuum to give the desired product, 3-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)prop-1-one hydrochloride (100 mg, 28.99%), as a white solid. LC-MS (ESI, m / z): 265.1 [M+H] + .

[0247] PEX14: Preparation of N-(4-(methoxymethyl)benzyl)-2-(piperidin-4-yl)acetamide

[0248]

[0249] Step 1. Preparation of tert-butyl 4-(2-((4-(methoxymethyl)benzyl)amino)-2-oxoethyl)piperidine-1-carboxylic acid

[0250]

[0251] In a DMF (5 mL) solution of 1-[4-(methoxymethyl)phenyl]methylamine (200 mg, 1.32 mmol, 1.0 equivalent) and [1-(tert-butoxycarbonyl)piperidin-4-yl]acetic acid (322 mg, 1.32 mmol, 1.0 equivalent), HATU (754 mg, 1.98 mmol, 1.5 equivalent) and DIEA (513 mg, 3.97 mmol, 3.0 equivalent) were added. The reaction was stirred at room temperature for 2 h and quenched with water (10 mL). The mixture was extracted with EA (3 × 20 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-(2-((4-(methoxymethyl)benzyl)amino)-2-oxoethyl)piperidin-1-carboxylic acid tert-butyl ester (400 mg, 72.3%) as a colorless semi-solid. LCMS (ESI, m / z): 377 [M+H] + .

[0252] Step 2. Preparation of N-(4-(methoxymethyl)benzyl)-2-(piperidin-4-yl)acetamide

[0253] TFA (2 mL) was added to a 5 mL solution of 4-(2-((4-(methoxymethyl)benzyl)amino)-2-oxoethyl)piperidin-1-carboxylic acid tert-butyl ester (400 mg, 1.06 mmol, 1 equivalent) in DCM. The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure to give N-(4-(methoxymethyl)benzyl)-2-(piperidin-4-yl)acetamide (300 mg, 92.0%) as a brown oil. LCMS (ESI, m / z): 277 [M+H] + .

[0254] Preparation of PEX15: (6-(methoxymethyl)pyridin-3-yl)methylamine

[0255]

[0256] Step 1. Preparation of 6-(methoxymethyl)nicotinonitrile

[0257]

[0258] A mixture of 5-bromo-2-(methoxymethyl)pyridine (2.00 g, 9.90 mmol, 1.00 equivalent), Zn(CN)₂ (700 mg, 5.94 mmol, 0.6 equivalent), and Pd(PPh₃)₄ (200 mg) in DMF (20 mL) was heated in a microwave oven at 175 °C for 5 minutes. The reaction mixture was then poured into water (60 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3) and brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated to obtain a crude product. This crude product was purified by column chromatography (PE / EA = 10 / 1) to give 6-(methoxymethyl)nicotinonitrile (1.00 g, 61.6%) as a yellow oil. LC-MS (ESI, m / z): 149.1 [M+H] + .

[0259] Step 2. Preparation of (6-(methoxymethyl)pyridin-3-yl)methylamine

[0260] To a solution of 6-(methoxymethyl)nicotinonitrile (1.00 g, 6.70 mmol, 1.00 equivalent) in THF (30 mL), NH3·H2O (10 mL) and Ni (2.00 g) were added. The mixture was stirred at room temperature for 4 hours under an H2 balloon. The resulting mixture was filtered, and the filtrate was concentrated to give a yellow oily (6-(methoxymethyl)pyridin-3-yl)methylamine (1.00 g, crude product). LC-MS (ESI, m / z): 153.1 [M+H] + .

[0261] Preparation of EX1 N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)benzamide 2,2,2-trifluoroacetate (ER10316)

[0262]

[0263] Benzoyl chloride (61.8 mg, 0.439 mmol, 1.1 equivalent) was added to a solution of 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one hydrochloride (100 mg, 0.400 mmol, 1.0 equivalent) and TEA (121 mg, 1.20 mmol, 3.0 equivalent) in DCM (3 mL) at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with DCM (5 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified sequentially by Prep-TLC (DCM / MeOH = 10 / 1) and Prep-HPLC (under Method A conditions) to give N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)benzamide 2,2,2-trifluoroacetate (50.0 mg, 25.4%), as a pale yellow oil. 1 H NMR (400MHz, DMSO_d6): δ10.16-10.13(m,1H),8.74-8.69(m,1H),8.18-8.07(m,2H), 7.91-7.89(m,2H),7.55-7.45(m,5H),5.13-5.06(m,2H),3.57-3.55(m,1.5H),3.34-3.29(m,1H),3. 23-3.20(m,1.5H),3.12-3.04(m,2H),1.91-1.88(m,3H),1.71-1.65(m,2H).LC-MS(ESI,m / z):355.1 [M+H] + .

[0264] EX2: Preparation of 2-(1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-N-(4-(methoxymethyl)benzyl)acetamide 2,2,2-trifluoroacetate (ER10296)

[0265]

[0266] K₂CO₃ (375 mg, 2.72 mmol, 5.0 equivalent) was added to a DMF (3 mL) solution of N-{[4-(methoxymethyl)phenyl]methyl}-2-(piperidin-4-yl)acetamide (150 mg, 0.543 mmol, 1.0 equivalent) and 2-chloro-1-(4-fluorophenyl)ethyl ketone (93.7 mg, 0.543 mmol, 1.0 equivalent). The reaction was stirred at 60 °C for 1.5 h and purified by Prep-HPLC (under Method A) to give 2-(1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-N-(4-(methoxymethyl)benzyl)acetamide-2,2,2-trifluoroacetate (27.2 mg, 9.5%) as a colorless oil. 1 HNMR(300MHz,methanol-d4)δ8.11-8.12(m,2H), 7.26-7.35(m,6H),4.87-4.90(m,2H),4.42(s,2H),4.37(s,2H),3.63-3.66(m,2H),3.35(s,3H) ,3.12-3.17(m,2H),2.28-2.30(m,2H),2.10-2.13(m,1H),1.98-2.03(m,2H),1.66-1.84(m,2H). LCMS(ESI,m / z):413[M+H] + .

[0267] EX3: Preparation of N-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide 2,2,2-trifluoroacetate (ER10382)

[0268]

[0269] 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide (100 mg, 0.36 mmol) and potassium carbonate (74.7 mg, 0.54 mmol) were mixed with DMF (5 mL) at 25 °C, cooled to 0 °C, and 2-bromo-1-(4-chlorophenyl)ethyl-1-one (84.2 mg, 0.36 mmol) was added. The mixture was stirred at 25 °C for 1 hour. The mixture was diluted with water (3 × 10 mL) and extracted with EA (10 mL). The aqueous phase was extracted with EA (2 × 10 mL). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to obtain the residue. The residue was purified by Prep-HPLC (under Method A conditions) to give the desired product N-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide 2,2,2-trifluoroacetate (58.03 mg, 29.43%) as a colorless oil. 1 H NMR(400MHz,DMSO_d6):δ9.89(brs,1H), 8.50-8.49(s,1H),8.11(brs,0.4H),8.00-7.98(m,1.6H),7.91-7.89(m,1H),7.74-7.72(m,2H), 7.60-7.57(m,1H),5.11(brs,0.5H),5.03-5.00(m,1.5H),4.59-4.57(m,2.5H),4.22(brs,0.5H), 3.95(brs,0.5H),3.87(s,1H),2.57-3.54(m,2H),3.21(brs,2H),3.00(s,0.4H),2.94(s,1.6H),2.83(s,0 .2H),2.74(s,0.8H),2.26-2.14(s,2H),1.87-1.83(m,0.7H),1.75-1.71(s,1.3H).LC-MS(ESI,m / z):430.3 [M+H] + .

[0270] EX4: Preparation of N-(1-(2-(4-cyanophenyl)-2-oxoethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide-2,2,2-trifluoroacetate (ER10385)

[0271]

[0272] N-(1-(2-(4-cyanophenyl)-2-oxoethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide.2,2,2-trifluoroacetate was prepared and purified under conditions similar to ER10382, using 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide (100 mg, 0.36 mmol) and 4-(2-bromoacetyl)benzylnitrile (80.8 mg, 0.36 mmol) to give N-(1-(2-(4-cyanophenyl)-2-oxoethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide.2,2,2-trifluoroacetate (30.6 mg, 18.22%) as a yellow solid. 1 H NMR(400MHz,DMSO_d6)δ 9.92(brs,1H),8.45-8.43(m,1H),8.23-8.13(m,4H),7.78-7.71(m,1H),7.11-6.98(m,1H),5. 13-5.03(m,2H),4.56-4.54(m,2H),3.92-3.83(m,1H),3.55(s,2H),3.38(m,3H),3.22(m,2H), 3.02-2.94(m,2H),2.82-2.67(m,1H),2.33-2.13(m,2H),1.84-1.72(m,2H).LC-MS(ESI,m / z):421.1[M+H] + .

[0273] EX5: Preparation of N-(1-(2-(3-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide 2,2,2-trifluoroacetate (ER10386)

[0274]

[0275] N-(1-(2-(3-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide. 2,2,2-trifluoroacetate, used with... ER10382 Under similar conditions, the product N-(1-(2-(3-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide (100 mg, 0.36 mmol) was prepared and purified by reacting 2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide 2,2,2-trifluoroacetate (66.13 mg, 44.30%) with 2-bromo-1-(3-fluorophenyl)ethyl-1-one (78.2 mg, 0.36 mmol), which was a colorless oil. 1 H NMR(400MHz,DMSO_d6)δ10.08(brs,1H),8.53-8.51(m,1H),7.95-7.84(m,3H),7.71-7.48(m,3H), 5.03(s,2H),4.60-4.54(m,2.5H),4.3-4.2(m,0.5H),3.97(s,0.7H),3.88(s,1.3H),3.59-3.57(m,2H) ,3.39(s,3H),3.24-3.22(m,2H),2.96(s,2H),2.78-2.76(m,1H),2.31-2.28(m,2H),1.84-1.72(m,2H). LC-MS (ESI, m / z): 414.0 [M+H] + .

[0276] EX6: Preparation of N-methyl-2-(6-(methoxymethyl)pyridin-3-yl)-N-(1-(2-oxo-2-(p-tolyl)ethyl)piperidin-4-yl)-acetamide.2,2,2-trifluoroacetate (ER10377)

[0277]

[0278] N-Methyl-N-(1-(2-oxo-2-(p-tolyl)ethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)acetamide.2,2,2-trifluoroacetate, used with ER10382 Prepared and purified under similar conditions, the desired product (24.7 mg, 13.0%) was obtained by using 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide (100 mg, 0.361 mmol) and 2-bromo-1-(p-tolyl)ethyl-1-one (76.9 mg, 0.361 mmol), as a yellow oil. 1H NMR(400 MHz,DMSO_d6)δ 9.79(brs,1H),8.46-8.45(m,1H),7.92-7.89(m,2H),7.81-7.79(m,1H),7.52-7.50(m,1H),7.45-7.43(m, 2H),5.09-5.07(m,1H),5.00-4.98(m,2H),4.55(s,3H),3.91(s,0.75H),3.83(s,1.25H),3.59-3.53(m,1.5 H),3.38(s,3H),3.29-3.26(m,2H),2.83(s,1.5H),2.68(s,0.5H),2.23(s ,3H),1.91-1.84(m,2H),1.74-1.71(m,2H).LC-MS(ESI,m / z):410.0[M+H] + .

[0279] EX7: Preparation of 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(1-(2-oxo-2-phenylethyl)piperidin-4-yl)-acetamide 2,2,2-trifluoroacetate (ER10378)

[0280]

[0281] 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(1-(2-oxo-2-phenylethyl)piperidin-4-yl)acetamide 2,2,2-trifluoroacetate was prepared and purified under conditions similar to ER10382, using 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide (100 mg, 0.361 mmol) and 2-bromo-1-phenylethyl-1-one (76.9 mg, 0.361 mmol) to give the desired product (20.0 mg, 10.9%) as a colorless oil. 1H NMR(400MHz,DMSO_d6)δ9.86(brs,1H), 8.47-8.46(m,1H),8.00-8.08(m,2H),7.86-7.76(m,2H),7.67-7.63(m,2H),7.61-7.49(m,1H),5. 13-5.02(m,2H),4.56(s,3H),4.24-4.20(m,1H),3.98(s,0.7H),3.88(s,1.3H),3.62-3.51(m,2H), 3.41(s,3H),3.38-3.26(m,2H),2.83(s,1.3H),2.75(s,0.7H),2.14-1.99(m,2H),1.85-1.72(m,2H).LC-MS(ESI,m / z):396.2[M+H]+.

[0282] EX8: Preparation of 2-(6-(methoxymethyl)pyridin-3-yl)-N-(1-(2-(4-methoxyphenyl)-2-oxoethyl)piperidin-4-yl)-N-methylacetamide 2,2,2-trifluoroacetate (ER10381)

[0283]

[0284] 2-(6-(methoxymethyl)pyridin-3-yl)-N-(1-(2-(4-methoxyphenyl)-2-oxoethyl)piperidin-4-yl)-N-methylacetamide 2,2,2-trifluoroacetate was prepared and purified using conditions similar to ER10382. The desired product (63.1 mg, 32.3%) was obtained by using 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide (100 mg, 0.361 mmol) and 2-bromo-1-(4-methoxyphenyl)ethyl-1-one (82.7 mg, 0.361 mmol) as a yellow oil. 1H NMR(400 MHz, DMSO_d6)δ9.77(brs,1H),8.51-8.50(m,1H),8.33-7.92(m,3H),7.61-7.57(m,1H), 7.17-7.14(m,2H),5.07-4.95(m,2H),4.56(s,3H),4.25-4.35(m,1H),3.98(s,0.6H),3.88(s,3 .4H),3.61-3.53(m,2H),3.40(s,3H),3.36-3.28(m,2H),3.03-2.88(m,2H),2.76-2.72(m,1H), 2.27-2.14(m,2H),1.86-1.59(m,2H).LC-MS(ESI,m / z):426.3[M+H]+.

[0285] EX9: Preparation of N-((1-(2-(3-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methoxynicotinamide 2,2,2-trifluoroacetate (ER10388)

[0286]

[0287] A DMF (5 mL) solution of 2-methoxy-N-(piperidin-4-ylmethyl)nicotinamide (100 mg, 0.400 mmol) and potassium carbonate (83.2 mg, 0.600 mmol) was cooled to 0 °C, and 2-bromo-1-(3-fluorophenyl)ethyl-1-one (87.1 mg, 0.400 mmol) was added. The mixture was then stirred at 25 °C for 1 hour. The mixture was diluted with water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were dried over sodium sulfate and evaporated under vacuum to obtain the residue, which was purified by Prep-HPLC under Method A conditions to give N-((1-(2-(3-fluorophenyl)-2-oxoethyl)piperidin)-4-yl)methyl)-2-methoxynicotinamide 2,2,2-trifluoroacetate (25.0 mg, 16.0%) as a yellow solid. 1H NMR(400MHz,DMSO_d6): δ9.80(brs,1H),8.42–8.40(m,1H),8.39– 8.37(m,1H),8.30–8.27(m,1H),7.96–7.90(m,2H),7.69–7.63(m,2H),7.14–7.11(m,1H),5.08– 5.01(m,2H),3.97(s,3H),3.51–3.55(m,1.6H),3.33–3.30(m,1.1H),3.29–3.27(m,1.6H),3.01– 3.03(m,1.7H),1.93–1.90(m,3H),1.74–1.58(m,2H).LC-MS(ESI,m / z):386.1[M+H] + .

[0288] EX10: Preparation of 2-methoxy-N-((1-(2-oxo-2-(p-tolyl)ethyl)piperidin-4-yl)methyl)nicotinamide 2,2,2-trifluoroacetate (ER10379)

[0289]

[0290] 2-Methoxy-N-((1-(2-oxo-2-(p-tolyl)ethyl)piperidin-4-yl)methyl)nicotinamide 2,2,2-trifluoroacetate was prepared and purified under conditions similar to those of ER10388 by using 2-methoxy-N-(piperidin-4-ylmethyl)nicotinamide (100 mg, 0.400 mmol) and 2-bromo-1-(p-tolyl)ethyl-1-one (85.5 mg, 0.400 mmol) to give the desired product (27.7 mg, 13.9%) as a colorless oil. 1 H NMR(400MHz,DMSO_d6)δ9.77(brs,1H),8.41-8.38(m,1H), 8.31-8.29(m,1H),8.11-8.05(m,1H),7.97-7.88(m,2H),7.44-7.43(m,2H),7.14-7.11(m,1H),5 .05-4.98(m,2H),4.24-4.20(m,1H),4.18-4.17(m,2H),3.97-3.96(m,3H),3.56-3.53(m,1.7H), 3.34-3.32(m,1H),3.25-3.22(m,1.5H),3.07-2.99(m,1.8H),2.42(s,3H),1.92-1.84(m,3H),1.74-1.58(m,2H).LC-MS(ESI,m / z):382.1[M+H]+ .

[0291] EX11: Preparation of 2-methoxy-N-((1-(2-oxo-2-phenylethyl)piperidin-4-yl)methyl)nicotinamide 2,2,2-trifluoroacetate (ER10380)

[0292]

[0293] N-((1-(2-oxo-2-phenylethyl)piperidin-4-yl)methyl)-2-methoxy-nicotinamide.2,2,2-trifluoroacetate was prepared and purified under conditions similar to those of ER10388, yielding the desired product (47.5 mg, 24.6%) as a colorless oil by using 2-methoxy-N-(piperidin-4-ylmethyl)nicotinamide (100 mg, 0.400 mmol) and 2-bromo-1-phenylethyl-1-one (79.8 mg, 0.400 mmol). 1 H NMR(400MHz,DMSO_d6)δ9.82(brs,1H),8.41-8.38(m,1H),8.31-8.29(m,1H), 8.12-8.06(m,1.5H),8.00-7.88(m,1.5H),7.79-7.76(m,1H),7.65-7.61(m,2H),7.14-7.10(m,1H),5.09-5.0 2(m,2H),3.98-3.96(m,3H),3.57-3.54(m,1.6H),3.36-3.33(m,1.1H),3.25-3.22(m,1.6H),3.09-3.01(m,1. 7H),1.93-1.84(m,3H),1.65-1.59(m,2H).LC-MS(ESI,m / z):368.1[M+H] + .

[0294] EX12: Preparation of 2-methoxy-N-((1-(2-(4-methoxyphenyl)-2-oxoethyl)piperidin-4-yl)methyl)nicotinamide 2,2,2-trifluoroacetate (ER10383)

[0295]

[0296] 2-Methoxy-N-((1-(2-(4-methoxyphenyl)-2-oxoethyl)piperidin-4-yl)methyl)nicotinamide 2,2,2-trifluoroacetate was prepared and purified under conditions similar to those described for ER10388, yielding the desired product (25.0 mg, 15.1%) as a colorless oil by using 2-methoxy-N-(piperidin-4-ylmethyl)nicotinamide (100 mg, 0.400 mmol) and 2-bromo-1-(4-methoxyphenyl)ethyl-1-one (91.9 mg, 0.400 mmol). 1 H NMR(400MHz,DMSO_d6)δ9.72(brs,1H),8.38-8.36(m,1H), 8.31-8.29(m,1H),8.11-8.05(m,1.5H),7.98-7.94(m,1.5H),7.16-7.10(m,3H),5.03-4.94(m,2H),3.98(s,3 H),3.88(s,3H),3.70-3.53(m,1.6H),3.44-3.34(m,1H),3.30-3.28(m,1.7H),3.25-3.22(m,1.7H),1.92-1.84 (m,3H),1.65-1.59(m,2H).LC-MS(ESI,m / z):389.1[M+H] + .

[0297] EX13: Preparation of N-((1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methoxynicotinamide 2,2,2-trifluoroacetate (ER10384)

[0298]

[0299] 2-Methoxy-N-((1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)nicotinamide 2,2,2-trifluoroacetate was prepared and purified under conditions similar to those of ER10388, by using 2-methoxy-N-(piperidin-4-ylmethyl)nicotinamide (100 mg, 0.400 mmol) and 2-bromo-1-(4-chlorophenyl)ethyl-1-one (93.7 mg, 0.400 mmol) to give the desired product (19.0 mg, 11.7%) as a colorless oil. 1H NMR(400MHz,DMSO_d6)δ9.82(brs,1H),8.40-8.37(m,1H), 8.31-8.29(m,1H),8.12-8.05(m,1.5H),8.00-7.99(m,1.5H),7.74-7.71(m,2H),7.14-7.11(m,1H),5.08-5. 00(m,2H),3.97-3.96(m,3H),3.56-3.53(m,1.5H),3.31-3.22(m,3H),3.08-2.99(m,1.5H),1.92-1.84(m,3H) ,1.73-1.58(m,2H).LC-MS(ESI,m / z):402.1[M+H] + .

[0300] EX14: Preparation of N-((1-(2-(4-acrylonitrile)-2-oxoethyl)piperidin-4-yl)methyl)-2-methoxynicotinamide 2,2,2-trifluoroacetate (ER10387)

[0301]

[0302] 2-Methoxy-N-((1-(2-(4-acrylonitrile)-2-oxoethyl)piperidin-4-yl)methyl)nicotinamide.2,2,2-trifluoroacetate was prepared and purified under conditions similar to those of ER10388, yielding the desired product (21.2 mg, 13.3%) as a colorless oil by using 2-methoxy-N-(piperidin-4-ylmethyl)nicotinamide (100 mg, 0.400 mmol) and 4-(2-bromoacetyl)benzyl nitrile (89.9 mg, 0.400 mmol). 1 H NMR (400MHz, DMSO_d6): δ9.88(brs,1H),8.38(s,1H),8.31-8.29(m,1H), 8.19-8.09(m,5H),7.14-7.11(m,1H),5.05(s,2H),3.97(s,3H),3.52(s,2H),3.42-3.38(m,2H),3 .33-3.29(m,2H),3.05-3.01(m,2H),1.95-1.83(m,3H),1.61-1.58(m,2H).LC-MS(ESI,m / z):393.2 [M+H] + .

[0303] EX15: Preparation of N-((1-(4-fluorophenylethyl)piperidin-4-yl)methyl)-2-methoxynicotinamide 2,2,2-trifluoroacetate (ER10389)

[0304]

[0305] A mixture of (1-(4-fluorophenylethyl)piperidin-4-yl)methylamine hydrochloride (90.0 mg, 0.330 mmol), 2-methoxynicotinic acid (60.6 mg, 0.400 mmol), 1-hydroxybenzotriazole (53.5 mg, 0.400 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (76.0 mg, 0.400 mmol), and triethylamine (100 mg, 0.990 mmol) in DCM (5 mL) was continuously stirred at 25 °C for 3 hours. The mixture was then diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried with sodium sulfate and vacuum evaporated to obtain the residue, which was purified by Prep-HPLC (under Method A conditions) to give the desired product N-((1-(4-fluorophenylethyl)piperidin-4-yl)methyl)-2-methoxynicotinamide 2,2,2-trifluoroacetate (19.9 mg, 32.65%) as a colorless oil. 1 H NMR (400MHz, DMSO_d6): δ9.41(brs,1H),8.39-8.36(m,1H),8.31-8.28(m,1H), 8.10-8.05(m,1H),7.37-7.30(m,2H),7.21-7.16(m,2H),7.14–7.01(m,1H),3.97–3.95(m,3H),3.61–3.58(m,1 .5H),3.38–3.21(m,4H),3.00–2.90(m,4H),1.93–1.94(m,3H),1.48–1.39(m,2H).LC-MS(ESI,m / z):372.1[M+H] + .

[0306] EX16: Preparation of N-(1-(4-fluorophenylethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide-2,2,2-trifluoroacetate (ER10390)

[0307]

[0308] A mixture of DCM (10 mL) containing 1-(4-fluorophenylethyl)-N-methylpiperidin-4-amine hydrochloride (140 mg, 0.513 mmol), 2-(6-(methoxymethyl)pyridin-3-yl)acetic acid (112 mg, 0.616 mmol), 1-hydroxybenzotriazole (83.2 mg, 0.616 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (118.1 mg, 0.616 mmol), and triethylamine (156 mg, 1.54 mmol) was continuously stirred at 25 °C for 3 hours. The mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried with sodium sulfate and vacuum evaporated to obtain the residue, which was purified by prep-HPLC (under method A conditions) to give the desired product N-(1-(4-fluorophenylethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide 2,2,2-trifluoroacetate (73 mg, 35.31%) as a colorless oil. 1 H NMR(400MHz,DMSO_d6):δ 9.73(brs,1H),8.53-8.52(m,1H),7.97–7.94(m,1H),7.63–7.61(m,1H),7.34-7.31(m,2H),7.19-7. 16(m,2H),4.61(s,2H),4.53–4.50(m,0.65H),4.18(s,0.35H),3.96(s,0.7H),3.88(s,1.3H),3.68– 3.57(m,2H),3.40(s,3H),3.28–3.22(m,2H),3.15–3.10(m,2H),2.92(s,2H),2.71(s,1H),2.08– 1.95(m,2H),1.89-1.59(m,2H).LC-MS(ESI,m / z):372.1[M+H] + .

[0309] EX17: Preparation of N-(1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-2-acetamide.2,2,2-trifluoroacetic acid (ER10305)

[0310]

[0311] A mixture of 1-(4-fluorophenyl)-2-(4-(methylamino)piperidin-1-yl)ethyl-1-one hydrochloride (600 mg, 2.40 mmol, 1.0 equivalent), 2-(6-(methoxymethyl)pyridin-3-yl)acetic acid hydrochloride (217 mg, 1.20 mmol, 0.5 equivalent), HOBT (389 mg, 2.88 mmol, 1.2 equivalent), EDCI (551 mg, 2.88 mmol, 1.2 equivalent), and TEA (1.21 mg, 12.0 mmol, 5.0 equivalent) in DCM (18 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with DCM (10 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified sequentially by Prep-TLC (DCM / MeOH = 10 / 1) and Prep-HPLC (under Method A conditions) to give N-(1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-2-acetamide-2,2,2-trifluoroacetic acid (50.0 mg, 33.4%) as a colorless oil. 1 H NMR (400MHz, DMSO_d6): δ9.89–9.87(m,1H),8.48–8.46 (m,1H),8.18–8.06(m,2H),7.85–7.83(m,1H),7.54–7.47(m,3H),5.11–5.01(m,2H),4.60–4.57(m,2.5H), 4.31–4.25(m,0.5H),3.94–3.85(m,2H),3.58–3.56(m,2H),3.40(s,3H),3.24–3.21(m,2H),3.03–2.95 (m,2H),2.84–2.75(m,1H),2.27–2.12(m,2H),1.86–1.73(m,2H).LC-MS(ESI,m / z):414.1[M+H] + .

[0312] EX18: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-(methoxymethyl)nicotinamide 2,2,2-trifluoroacetate (ER10392)

[0313]

[0314] A mixture of 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one hydrochloride (1.03 g, 3.59 mol), 2-(methoxymethyl)nicotinic acid (500 mg, 2.99 mmol), 1-hydroxybenzotriazole (485 mg, 3.59 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (688 mg, 3.59 mmol), and triethylamine (908 mg, 8.97 mmol) in DCM (10 mL) was continuously stirred at 25 °C for 3 hours. The mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried with sodium sulfate and vacuum evaporated to obtain the residue, which was purified by prep-HPLC under method A to obtain the product N-((1-(2-(4-fluorophenyl)-2-oxoethyl))piperidin-4-yl)methyl)-2-(methoxymethyl)nicotinamide 2,2,2-trifluoroacetate (39 mg, 3.26%). 1 H NMR (400MHz, DMSO_d6): δ9.78(brs,1H),8.60-8.58(m,2H),8.09–8.07(m,1H),7.85– 7.80(m,1H),7.51–7.46(m,3H),5.76–5.01(m,2H),4.64(s,2H),3.57–3.54(m,1.5H),3.26– 3.18(m,5H),3.04–3.00(m,3H),1.92–1.85(m,4H),1.75-1.58(m,1.5H).LC-MS(ESI,m / z):400.1 [M+H] + .

[0315] EX19: Preparation of N-((1-(3-(4-fluorophenyl)-3-oxopropyl)piperidin-4-yl)methyl)-2-(methoxy)nicotinamide 2,2,2-trifluoroacetate (ER10391)

[0316]

[0317] N-((1-(3-(4-fluorophenyl)-3-oxopropyl)piperidin-4-yl)methyl)-2-(methoxy)nicotinamide.2,2,2-trifluoroacetate is used with ER10392 Prepared and purified under similar synthetic conditions, using 3-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)prop-1-one hydrochloride (100 mg, 0.332 mmol) and 2-methoxynicotinic acid (61.1 mg, 0.0400 mmol), the desired product (52.5 mg, 39.47%) was given as a white solid. 1H NMR(400MHz,DMSO_d6):δ9.36–9.23(m,1H),8.39-8.36 (m,1H),8.31–8.29(m,1H),8.11–8.05(m,3H),7.42-7.39(m,2H),7.13-7.10(m,1H),4.07(s,3H),3.60– 3.57(m,4H),3.45–3.37(m,2H),3.33(s,0.5H),3.23–3.20(m,2H),3.04–2.95 (m,1.5H),1.99–1.73(m,3H),1.47-1.38(m,2H).LC-MS(ESI,m / z):400.1[M+H] + .

[0318] EX20: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-pyridineamide 2,2,2-trifluoroacetate (ER10317)

[0319]

[0320] The preparation and purification of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-pyridineamide 2,2,2-trifluoroacetate were performed using similar methods. ER10392 The desired product (50.0 mg, 33.4%) was synthesized using pyridinecarboxylic acid (54.1 mg, 0.439 mmol, 1.1 equivalents) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one hydrochloride (100 mg, 0.400 mmol, 1.0 equivalents) as a white solid. 1 H NMR(400MHz,DMSO_d6):δ9.90–9.70(m,1H),9.00– 8.98(m,1H),8.67–8.66(m,1H),8.17–7.99(m,4H),7.64–7.61(m,1H),7.50–7.46(m,2H),5.09– 5.00(m,2H),3.54–3.52(m,1.5H),3.36–3.25(m,3H),3.04–2.98(m,1.5H),1.90–1.87(m,3H),1.66– 1.60(m,2H).LC-MS(ESI,m / z):356.1[M+H] + .

[0321] EX21: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)nicotinamide 2,2,2-trifluoroacetate (ER10318)

[0322]

[0323] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)nicotinamide.2,2,2-trifluoroacetate is used in a similar manner. ER10392 The synthesis and purification were carried out under the conditions specified in the synthesis, and the desired product (85.0 mg, 43.1%) was obtained as a pale yellow oil by using nicotinic acid (54.1 mg, 0.439 mmol, 1.1 equivalents) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one hydrochloride (100 mg, 0.400 mmol, 1.0 equivalents). 1 H NMR(400MHz,DMSO_d6):δ9.85–9.83(m,1H), 9.05(d,J=1.6Hz,1H),8.84–8.81(m,1H),8.76–8.74(m,1H),8.27–8.24(m,1H),8.16–8.07(m,2H),7.59– 7.56(m,1H),7.51–7.46(m,2H),5.09–5.02(m,2H),3.56–3.53(m,1.5H),3.34–3.24(m,3H),3.06– 3.04(m,1.5H),1.95–1.83(m,3H),1.67–1.58(m,2H).LC-MS(ESI,m / z):356.1[M+H] + .

[0324] EX22: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isonicotinamide 2,2,2-trifluoroacetate (ER10319)

[0325]

[0326] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isonicotinamide.2,2,2-trifluoroacetate is used in a similar manner. ER10392 The product (75.0 mg, 38.0%) was prepared and purified using isonicotinic acid (54.1 mg, 0.439 mmol, 1.1 equivalents) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one hydrochloride (100 mg, 0.400 mmol, 1.0 equivalents).1 H NMR(400MHz,DMSO_d6): δ9.89–9.86(m,1H),8.96– 8.94(m,1H),8.82–8.78(m,2H),8.10–8.07(m,2H),7.85–7.84(m,2H),7.50–7.46(m,2H),5.08– 5.02(m,2H),3.56–3.53(m,1.5H),3.32–3.23(m,3H),3.06–3.03(m,1.5H),1.94–1.83(m,3H),1.66– 1.60(m,2H).LC-MS(ESI,m / z):356.1[M+H] + .

[0327] EX23: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-(methoxymethyl)nicotinamide 2,2,2-trifluoroacetate (ER10393)

[0328]

[0329] The preparation and purification of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-(methoxymethyl)nicotinamide were performed under conditions similar to those of ER10392, using 6-(methoxymethyl)nicotinic acid (140 mg, 0.838 mmol) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (288.2 mg, 1.005 mmol) as starting materials. The product... 1 H NMR (400 MHz, DMSO_d6): δ9.38(s,1H),8.97-8.96(m,1H),8.78–8.76(m,1H),8.24–8.22(m,2H),8.18– 8.14(m,0.5H),8.09–8.06(m,1.5H),7.54–7.46(m,3H),5.08–5.07(m,0.5H),5.01–5.00(m,1.5H), 4.56(s,2H),3.55–3.52(m,1.5H),3.38(s,2.5H),3.34–3.31(m,1H),3.25-3.22(m,1.5 H),3.07-2.99(m,1.5H),1.93–1.84(m,3H),1.73–1.71(m,0.5H),1.65–1.59(m,1.5H). LC-MS(ESI,m / z):400.1[M+H] + .

[0330] EX24: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-(methoxymethyl)pyridineamide.2,2,2-trifluoroacetate (ER10394)

[0331]

[0332] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-(methoxymethyl)pyridineamide is used in conjunction with ER10392 The synthesis was carried out under similar conditions, and the desired product (26.2 mg, 1.33%) was obtained using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one hydrochloride (600 mg, 3.59 mmol) and 6-(methoxymethyl)pyridinecarboxylic acid (1.24 g, 4.31 mmol). 1 H NMR(400MHz,DMSO_d6): δ9.73(brs,1H),8.82-8.79(m,1H),8.17– 8.14(m,0.5H),8.09–8.05(m,1.5H),8.02–7.94(m,2H),7.63–7.61(m,1H),7.51–7.56(m,2H),5.08– 4.99(m,2H),4.58(s,2H),3.53–3.50(m,2H),3.40–3.39(m,3H),3.28-3.20(m,1.5H),3.05– 2.99(m,2H),1.88–1.58(m,2H).LC-MS(ESI,m / z):399.8,400.8[M+H] + .

[0333] EX25: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-methylpyridineamide 2,2,2-trifluoroacetate (ER10349)

[0334]

[0335] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-methylpyridinamide. 2,2,2-trifluoroacetate is used similarly. ER10392 The synthesis conditions were prepared and purified using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol) and 3-methylpyridinecarboxylic acid (131 mg, 0.959 mmol) to give the desired product (28.7 mg, 7.43%) as a colorless oil. 1H NMR(400MHz,DMSO_d6)δ8.79(s,1H),8.77(m,1H),8.46(m,1H),8.18– 8.14(m,2H),8.08–8.06(m,1H),7.72–7.48(m,3H),5.07-5.00(m,2H),3.22–2.99(m,6H),2.54– 2.51(m,3H),2.01–1.88(m,3H),1.65–1.59(m,2H).LC-MS(ESI,m / z):370.1[M+H]+.

[0336] EX26: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methylnicotinamide 2,2,2-trifluoroacetate (ER10350)

[0337]

[0338] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methylnicotinamide.2,2,2-trifluoroacetate is used in a manner similar to... ER10392 The synthesis conditions were prepared and purified using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol) and 4-methylnicotinic acid (132 mg, 0.959 mmol) to give the desired product (126 mg, 32.5%) as a yellow solid. 1 H NMR(400MHz,DMSO_d6)δ9.88(s,1H),8.74–8.68(m,3H),8.63–8.62(m,1H),8.09– 8.07(m,2H),7.57–7.55(m,1H),7.51–7.47(m,2H),5.32–5.02(m,2H),3.57–3.54(m,1.5H),3.23– 3.05(m,4H),2.50–2.29(m,3H),1.92–1.67(m,3H),1.58–1.23(m,2H).LC-MS(ESI,m / z):371.1[M+H] + .

[0339] EX27: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methylpyridineamide 2,2,2-trifluoroacetate (ER10351)

[0340]

[0341] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methylpyridinamide. 2,2,2-trifluoroacetate is used similarly. ER10392 The synthesis conditions were prepared and purified using 2-[4-(aminomethyl)piperidin-1-yl]-1-(4-fluorophenyl)ethyl ketone (200 mg, 0.799 mmol) and 4-methylpyridinecarboxylic acid (132 mg, 0.959 mmol) to give the desired product (71.4 mg, 18.5%) as a yellow solid. 1 H NMR(400MHz,DMSO_d6)δ9.79(s,1H),8.94–8.92(m,1H),8.84-8.42(m,1H), 8.09-7.89(m,3H),7.48-7.30(m,3H),5.08–5.00(m,2H),3.26–3.00(m,6H),2.76 –2.25(m,3H),1.72–1.56(m,3H),1.14-0.85(m,2H).LC-MS(ESI,m / z):370.1[M+H] + .

[0342] EX28 N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-5-methylnicotinamide.2,2,2-trifluoroacetate (ER10352)

[0343]

[0344] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-5-methylnicotinamide.2,2,2-trifluoroacetate is used with ER10392 The product was prepared and purified under similar synthetic conditions using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol) and 5-methylnicotinic acid (132 mg, 0.959 mmol) to give the desired product (84.0 mg, 22.5%) as a white solid. 1 H NMR(400MHz,DMSO_d6)δ9.77(s,1H),8.86–8.78(m,3H),8.30–8.09(m,3H),7.51– 7.47(m,2H),2.08–5.01(m,2H),3.55–3.24(m,6H),2.53–2.38(m,3H),1.94–1.74(m,3H),1.62– 1.59(m,2H).LC-MS(ESI,m / z):370.1[M+H]+.

[0345] EX29: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-methoxy-pyridineamide.2,2,2-trifluoroacetate (ER10353)

[0346]

[0347] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-methoxy-pyridineamide.2,2,2-trifluoroacetate is used with ER10392 The product was prepared and purified under similar synthetic conditions using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol) and 3-methoxypyridinecarboxylic acid (147 mg, 0.959 mmol) to give the desired product (63.8 mg, 16.5%) as a white solid. 1 H NMR(400MHz,DMSO_d6)δ9.79(s,1H),8.49–8.47(m,1H),8.3–8.06(m,3H),7.60– 7.47(m,4H),5.08–5.00(m,3H),4.11–4.00(m,3H),3.82–3.00(m,6H),1.74–1.60(m,3H),1.57– 1.54(m,2H).LC-MS(ESI,m / z):386.1[M+H] + .

[0348] EX30: N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methoxy-nicotinamide.2,2,2-trifluoroacetate (ER10354)

[0349]

[0350] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methoxy-nicotinamide.2,2,2-trifluoroacetate is used with ER10392 The desired product (110 mg, 27.5%) was prepared and purified under similar synthetic conditions using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol) and 4-methoxynicotinic acid (147 mg, 0.959 mol) as a yellow solid. 1H NMR(400MHz,DMSO_d6)δ9.82(s,1H),8.79(s,1H),8.73(s,1H),8.51(s,1H), 8.07(m,2H),7.51–7.47(m,3H),3.53–3.21(m,4.5H),3.04(s,1.5H),1.74–1.58(m,3H),1.24–0.86(m,2H).LC-MS(ESI,m / z):386.1[M+H] + .

[0351] EX31: N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methoxypyridineamide.2,2,2-trifluoroacetate (ER10355)

[0352]

[0353] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methoxypyridineamide.2,2,2-trifluoroacetate is used with ER10392 Prepared and purified under similar synthetic conditions, using 2-[4-(aminomethyl)piperidin-1-yl]-1-(4-fluorophenyl)ethyl ketone (200 mg, 0.799 mmol) and 4-methoxypyridinecarboxylic acid (147 mg, 0.959 mmol), the desired product (57.0 mg, 14.3%) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO_d6)δ9.76(s,1H),8.98–8.95(m,1H),8.49–8.47(m,1H),8.14– 8.06(m,3H),7.55–7.46(m,3H),7.20–7.18(m,1H),5.08–4.92(m,3H),3.915(s,3H),3.27–3.26(m,1.5H), 3.24-3.03(m,2.5H),3.00–2.98(m,1.5H),1.89–1.72(m,3H),1.65–1.56(m,2H).LC-MS(ESI,m / z):386.1 [M+H] + .

[0354] EX32: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-5-methoxy-nicotinamide 2,2,2-trifluoroacetate (ER10356)

[0355]

[0356] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-5-methoxy-nicotinamide.2,2,2-trifluoroacetate is used with ER10392 Prepared and purified under similar synthetic conditions, using 2-[4-(aminomethyl)piperidin-1-yl]-1-(4-fluorophenyl)ethyl ketone (200 mg, 0.799 mmol) and 5-methoxynicotinic acid (147 mg, 0.959 mmol), the desired product (173 mg, 43.38%) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO_d6)δ9.76(s,1H),8.65(s,1H),8.63(s,1H),8.45–8.44(m,1H), 8.06–7.76(m,2H),7.76(s,1H),7.51–7.47(m,2H),5.08-5.07(m,0.5H),5.01–5.00(m,1.5H),3.89(s,3H), 3.55–3.02(m,6H),1.94–1.90(m,3H),1.73–1.59(m,2H).LC-MS(ESI,m / z):386.1[M+H] + .

[0357] EX33: N-(1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-3-(4-(methoxymethyl)phenyl)-N-methylpropionamide.2,2,2-trifluoroacetate (ER10295)

[0358]

[0359] N-(1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-3-(4-(methoxymethyl)phenyl)-N-methylpropionamide. 2,2,2-trifluoroacetate is used with ER10392 Prepared and purified under similar synthetic conditions, using 1-(4-fluorophenyl)-2-[4-(methylamino)piperidin-1-yl]acetone (250 mg, 1.00 mmol, 1.0 equivalent) and 3-[4-(methoxymethyl)phenyl]propionic acid (213 mg, 1.10 mmol, 1.1 equivalent) to give the desired product (68 mg, 12%) as a white semi-solid. 1H-NMR (300 MHz, CD3OD) δ8.11(s,2H),7.30-7.36(m,2H),7.10-7.27(m,4H),4.87-4.94(m,2H),4.55-4.70(m,1H), 4.39-4.41(m,2H),3.47-4.05(m,3H),3.34-3.35(m,3H),3.04-3.08(m,1H),2.63-2.99(m,7H),2.10-2.23(m,2H),1.61-1.96(m ,2H).LC-MS(ESI,m / z):427[M+H] + .

[0360] EX35: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methoxybenzamide 2,2,2-trifluoroacetate (ER10320)

[0361]

[0362] A solution of 50% T3P (763 mg, 1.20 mmol, 1.5 equivalents) in EtOAc was added dropwise to a solution of 2-[4-(aminomethyl)piperidin-1-yl]-1-(4-fluorophenyl)ethyl ketone (200 mg, 0.799 mmol, 1.0 equivalent), 2-methoxybenzoic acid (134 mg, 0.879 mmol, 1.1 equivalent), and TEA (243 mg, 2.40 mmol, 3.0 equivalent) in DCM (10 mL). The reaction mixture was stirred at 20 °C for 16 hours. The mixture was diluted with water (10 mL) and extracted with DCM (5 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under vacuum to give the crude product. The product was purified sequentially by Prep-TLC (DCM / MeOH = 10 / 1) and Prep-HPLC (under Method A conditions) to give N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methoxybenzamide 2,2,2-trifluoroacetate (55.0 mg, 15.8%), a pale yellow oil. 1H NMR (400MHz, DMSO_d6): δ 9.81-9.77(s,1H),8.31-8.28(m,1H),8.16–8.06(m,2H),7.71-7.69(m,1H),7.51-7.45(m,3H), 7.15-7.13(m,1H),7.05-7.01(m,1H),5.07-5.00(m,2H),3.88-3.86(m,3H),3.56-3.53(m,2H),3.42-3.17(m,2H),3.08-2.99( m,2H),1.92-1.84(m,3H),1.64-1.58(m,2H).LC-MS(ESI,m / z):385.0[M+H] + .

[0363] Preparation of EX36 N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-methoxybenzamide 2,2,2-trifluoroacetate (ER10321)

[0364]

[0365] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-methoxybenzamide.2,2,2-trifluoroacetate is disposed in a similar manner. ER10320 The synthesis conditions were prepared and purified using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol, 1.0 equivalent) and 3-methoxybenzoic acid (122 mg, 0.879 mmol, 1.1 equivalent) to give the desired product (15.0 mg, 4.31%) as a pale yellow oil. 1 H NMR(400MHz,DMSO_d6)δ9.78-9.75(s,1H), 8.59-8.56(m,1H),8.17-8.06(m,2H),7.51-7.37(m,5H),7.12-7.09(m,1H),5.09-5.00(m,2H),3.81-3.78(s ,3H),3.55-3.52(m,1.5H),3.31(s,1H),3.23-3.20(m,1.5H),3.08-2.99(m,1.5H),1.92-1.82(m,3H),1.65-1 .55(m,2H).LC-MS(ESI,m / z):385.1[M+H] + .

[0366] EX37: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methoxybenzamide.2,2,2-trifluoroacetate (ER10322)

[0367]

[0368] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methoxybenzamide.2,2,2-trifluoroacetate is used with ER10320 The desired product (45.0 mg, 12.9%) was prepared and purified under similar synthetic conditions using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol, 1.0 equivalent) and 4-methoxybenzoic acid (134 mg, 0.879 mmol, 1.1 equivalent) as a pale yellow oil. 1 H NMR(400MHz,CD3OD)δ8.14-8.10(m,2H), 7.84-7.82(m,2H),7.37-7.32(m,2H),7.02-7.00(m,2H),4.93-4.90(m,2H),3.87(s,3H),3.72-3.69(s, 1.5H),3.39-3.32(m,1.5H),3.14(s,1H),2.10-2.06(m,3H),1.74(m,2H).LC-MS(ESI,m / z):385.0[M+H] + .

[0369] EX38: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methoxypyridineamide 2,2,2-trifluoroacetate (ER10323)

[0370]

[0371] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methoxypyridineamide 2,2,2-trifluoroacetate according to similar ER10320 The product was prepared and purified under the specified synthetic conditions using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol, 1.0 equivalent) and 6-methoxypyridinecarboxylic acid (135 mg, 0.879 mmol, 1.1 equivalent) to give the desired product (50.0 mg, 14.4%), which was a pale yellow solid. 1H NMR(400MHz,DMSO_d6)9.73(s,1H),8.74-8.71(m,1H), 8.16-8.06(m,2H),7.89-7.86(m 1H),7.64-7.62(m,1H),7.51-7.46(m,1H),7.04-7.02(m,1H),5.08-4.99(m ,2H),3.99(m,1H),3.54-3.47(m,2H),3.36-3.26(m,2H),3.07-2.98(m,2H), 1.90-1.81(m,3H),1.67-1.61(m,2H).LC-MS(ESI,m / z):386.1[M+H] + .

[0372] EX39: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methylpyridineamide 2,2,2-trifluoroacetate (ER10324)

[0373]

[0374] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methylpyridinamide 2,2,2-trifluoroacetate according to similar ER10320 The synthesis conditions were prepared and purified using 2-[4-(aminomethyl)piperidin-1-yl]-1-(4-fluorophenyl)ethyl ketone (200 mg, 0.799 mmol, 1.0 equivalent) and 6-methylpyridine-2-carboxylic acid (121 mg, 0.879 mmol, 1.1 equivalent) to provide the desired product (35.0 mg, 10.4%) as a pale yellow oil. 1 H NMR(400MHz,DMSO_d6):δ9.73–9.71(m,1H), 8.82-8.79(m,1H),8.15(s,0.5H),8.09–8.06(m,1.5H),7.90–7.84(m,2H),7.50–7.46(m,3H),5.08– 5.07(m,0.5H),5.01–4.99(m,1.5H),3.64–3.51(m,2H),3.45–3.40(m,2H),3.05–2.97(m,2H),2. 57(s,0.3H),2.46–2.44(m,2.7H),2.08–1.89(m,3H),1.86–1.62(m,2H).LC-MS(ESI,m / z):370.1 [M+H] + .

[0375] EX40: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methoxyisonicotinamide 2,2,2-trifluoroacetate (ER10325)

[0376]

[0377] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methoxyisonicotinamide.2,2,2-trifluoroacetate is disposed in a similar manner. ER10320 The product was prepared and purified under the following synthetic conditions, using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol, 1.0 equivalent) and 2-methoxyisonicotinic acid (135 mg, 0.879 mmol, 1.1 equivalent) to give the desired product (43.0 mg, 12.4%) as a pale yellow oil. 1 H NMR(400MHz,DMSO_d6):δ 9.802(s,1H),8.83-8.80(s,1H),8.31-8.30(m,1H),8.18–8.14(m,0.5H),8.10–8.06(m,1.5H),7.51-7.4 7(m,2H),7.37–7.36(m,1H),7.21–7.19(m,1H),5.08–5.07(m,0.45H),5.02–5.01(m,1.55H),3.90(s,3H), 3.55–3.52(m,1.7H),3.31(s,1H),3.23–3.20(m,1.6H),3.10-3.00(m,1. 71H),1.92–1.82(m,3H),1.64–1.56(m,2H).LC-MS(ESI,m / z):386.1[M+H] + .

[0378] EX41: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methylisonicotinamide 2,2,2-trifluoroacetate (ER10326)

[0379]

[0380] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methylisonicotinamide.2,2,2-trifluoroacetate is disposed in a similar manner. ER10320 The product was prepared and purified under the following synthetic conditions using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.697 mmol, 1.0 equivalent) and 2-methylisonicotinic acid (115 mg, 0.837 mmol, 1.1 equivalent) to give the desired product (99.3 mg, 29.5%), which is a pale yellow oil. 1 H NMR(400MHz,DMSO_d6)δ9.82(s,1H),8.94(s,1H), 8.68(s,1H),8.18-8.06(m,2H),7.78(s,1H),7.70(s,1H),7.51-7.46(m,2H),5.08-5.01(m,2H),3.55- 3.52(m,1.5H),3.33-3.22(m,3H),3.07-3.00(m,1.5H),2.60(s,1H),1.93-1.83(m,3H),1.65-1.59(m,2 H).LC-MS(ESI,m / z):370.0[M+H] + .

[0381] EX42: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methoxynicotinamide 2,2,2-trifluoroacetate (ER10327)

[0382]

[0383] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methoxynicotinamide.2,2,2-trifluoroacetate is disposed in a similar manner. ER10320 The product was prepared and purified under the following synthetic conditions. It was obtained by reacting 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol, 1.0 equivalent) and 2-methoxynicotinic acid (135 mg, 0.879 mmol, 1.1 equivalent) to give the desired product (135 mg, 38.8%), which was a pale yellow oil. 1H NMR(400MHz,DMSO_d6): δ9.84(s,1H),8.39-8.38(m,1H), 8.32-8.30(m,1H),8.11(m,0.35H),8.10–8.07(m,2.65H),7.51-7.47(m,2H),7.14–7.11(m,1H),5.0 1(m,2H),3.98-3.96(m,3H),3.56–3.53(m,1.7H),3.33(s,1H),3.24(m,1.6H),3.05-3.03(m,1.7H), 1.92–1.89(m,3H),1.65–1.56(m,2H).LC-MS(ESI,m / z):386.1[M+H] + .

[0384] EX43: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methylnicotinamide 2,2,2-trifluoroacetate (ER10328)

[0385]

[0386] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methylnicotinamide.2,2,2-trifluoroacetate is disposed in a similar manner. ER10320 The product was prepared and purified under the specified synthetic conditions using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol, 1.0 equivalent) and 2-methylnicotinic acid (121 mg, 0.879 mmol, 1.1 equivalent) to obtain the desired product (40.0 mg, 11.9%), which was a pale yellow oil. 1 H NMR (400MHz, DMSO_d6): δ9.86-9.85(m,1H),8.65-8.58(m,2H), 8.16-8.07(m,2H),7.92-7.90(m,1H),7.52–7.42(m,3H),5.08-5.02(m,2H),3.57–3.54(m,1.5H),3.32-3. 20(m,3H),3.07-3.05(m,1.5H),2.58(s,3H),1.96-1.85(m,3H),1.66–1.60(m,2H).LC-MS(ESI,m / z):370.1 [M+H] + .

[0387] EX44: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methoxynicotinamide 2,2,2-trifluoroacetate (ER10329)

[0388]

[0389] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methoxynicotinamide.2,2,2-trifluoroacetate is disposed in a similar manner. ER10320 The product was prepared and purified under the following synthetic conditions using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol, 1.0 equivalent) and 6-methoxynicotinic acid (135 mg, 0.879 mmol, 1.1 equivalent) to give the desired product (40.0 mg, 11.5%) as a pale yellow oil. 1 H NMR(400MHz,DMSO_d6): δ9.752(s,1H),8.69-8.68(m,1H), 8.60-8.57(m,1H),8.15-8.06(m,3H),7.51–7.46(m,2H),6.92-6.90(m,1H),5.08–5.00(m,2H),3.91( s,3H),3.55-3.52(m,2H),3.31–3.20(m,2H),3.07-2.99(m,2H),1.92–1.83(m,3H),1.65–1.59(m,2H). LC-MS(ESI,m / z):386.0[M+H] + .

[0390] EX45: Preparation of N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methylnicotinamide 2,2,2-trifluoroacetate (ER10330)

[0391]

[0392] N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methylnicotinamide.2,2,2-trifluoroacetate is disposed in a similar manner. ER10320 The product was prepared and purified under the synthetic conditions using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethyl-1-one (200 mg, 0.799 mmol, 1.0 equivalent) and 6-methylnicotinic acid (135 mg, 0.879 mmol, 1.1 equivalent) to give the desired product (90.0 mg, 26.7%) as a pale yellow oil. 1H NMR (400MHz, DMSO_d6): δ9.82-9.82(m,1H),8.97-8.96(m,1H), 8.80-8.77(m,1H),8.25-8.22(m,1H),8.09-8.07(m,2H),7.51-7.46(m,3H),5.09–5.01(m,2H),3.56-3. 53(m,1.5H),3.32–3.22(m,3H),3.05-3.03(m,1.5H),2.58(s,3H),1.94-1.83(m,3H),1.66–1.60(m,2H). LC-MS (ESI, m / z): 370.1[M+H]+.

[0393] EX46: Preparation of 1-(2-(4-fluorophenyl)-2-oxoethyl)-N-((6-(methoxymethyl)pyridin-3-yl)methyl)piperidin-4-carboxamide 2,2,2-trifluoroacetate (ER10306)

[0394]

[0395] A mixture of (6-(methoxymethyl)pyridin-3-yl)methylamine (1.00 g, 6.55 mmol, 1.0 equivalent), 1-(2-(4-fluorophenyl)-2-oxoethyl)piperidine-4-carboxylic acid (1.23 g, 4.62 mmol, 0.7 equivalent), HOBT (1.07 g, 7.92 mmol, 1.2 equivalent), EDCI (1.52 g, 7.92 mmol, 1.2 equivalent), and TEA (2.00 g, 19.8 mmol, 3.0 equivalent) in a DCM (20 mL) solution was stirred overnight at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with DCM (10 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The concentrate was purified sequentially by Prep-TLC (DCM / MeOH = 10 / 1) and Prep-HPLC (under Method A conditions) to give 1-(2-(4-fluorophenyl)-2-oxoethyl)-N-((6-(methoxymethyl)pyridin-3-yl)methyl)piperidin-4-carboxamide 2,2,2-trifluoroacetate (185 mg, 4.55%) as a colorless oil. 1H NMR (400MHz, DMSO_d6): δ9.98– 9.94(m,1H),8.63–8.60(m,1H),8.50(s,1H),8.14–8.06(m,2H),7.84–7.82(m,1H),7.52– 7.47(m,3H),5.03(s,2H),4.55(s,2H),4.35–4.34(m,2H),3.58–3.55(m,1.5H),3.37–3.35(m,4H),3.09– 3.06(m,1.5H),2.62–2.58(m,1H),2.00–1.98(m,4H).LC-MS(ESI,m / z):400.1[M+H] + .

[0396] Bioactivity test

[0397] 1. Screening test for 5-HT2A receptor antagonist activity

[0398] To confirm the antagonistic activity of the compounds of this invention against the 5-HT2A receptor, the IP-One assay was performed. The following experiments were conducted using the Flp-In-CHO-5HT2A stable cell line. The IP-One assay is based on competitive immunoassay using HTRF (homogeneous time-resolved fluorescence), employing terbium-labeled anti-IP1 monoclonal antibody and d2-labeled IP1. Cell-produced IP1 and the d2-labeled IP1 provided by the kit compete for the antigen-binding site of the anti-IP1 antibody. When the terbium-labeled anti-IP1 antibody binds to the d2-labeled IP1, energy resonance transfer occurs, generating a signal. As intracellular IP1 production increases, more free IP1 binds to the antibody, and the signal gradually decreases.

[0399] Materials and methods:

[0400] According to the user manual, the Chinese hamster ovary cell-transformed cell line (Flp-In) TM -CHO cell line (purchased from Invitrogen, R75807), CHO cells were transfected with pFRT / / acZeo2 and selected for Zeocin. TM resistant clones produce Flp-In TM -CHO cell line. Flp-In TMThe -CHO cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone) + 1×Penicilin-Streptomycin (15140-122, Gibco), and then stably transfected with the human HTR2A gene (Human HTR2A, GeneBank, NM_000621) to obtain Flp-In-CHO-5HT2A cells. The stably transfected cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone) + 1×Penicilin-Streptomycin + 800 μg / ml Hygromycin B (ant-hg-5, Invivogen). To verify the compound activity, Flp-In-CHO-5HT2A stable cell lines were cultured in 384-well plates (7.5K) at 37°C and 5% CO2 for 20 hours. The compound was diluted to different concentrations with Ham's F-12K medium, and 100 μl / well was added along with fresh medium to replace the overnight culture medium. After treating the cells with the compound for 30 minutes, 5-HT was added and the cells were cultured at 37°C for 45 minutes. Then, lysis detection buffer, IP1-d2, and IP1-Ab were added sequentially, and the cells were incubated at room temperature for 1 hour before being read on an Envision plate (HTRF module).

[0401] According to the results shown, the 5HT2A receptor activity of the Flp-In-CHO-5HT2A stable cell line was inhibited by the compound, suggesting that the compound has 5HT2A receptor antagonistic activity.

[0402] 2. Sigma2 target binding assay

[0403] Human Sigma2 receptor was expressed in Jurkat cells, and the cell membrane was in modified potassium phosphate buffer (pH 7.6) with 25 nM [ 3 [H]-labeled DTG was co-incubated at 25°C for 60 minutes, and nonspecific binding was determined using 10 μM haloperidol. Cells were washed by membrane filtration, and the presence of [H] in the filtrate was detected. 3 H]DTG is used to determine the specific binding of compounds.

[0404] 3. hERG membrane protein specific binding assay

[0405] This experiment was conducted using the HEK293 cell line, which stably expresses hERG (human Ether-a-go-go Related Gene) encoding a potassium channel. In the myocardium, the potassium channel encoded by hERG mediates a delayed rectifier potassium current (IKr), and IKr inhibition is the most important mechanism by which drugs cause QT interval prolongation. Due to its unique molecular structure, the loss of hERG function or drug inhibition can affect the cardiac action potential repolarization process and cause QT interval prolongation, and may also induce torsades de pointes ventricular tachycardia, leading to arrhythmias.

[0406] In this experiment, the hERG membrane protein, the detection compound, and a fixed concentration of radioligands were mixed, allowing the detection compound and radioligands to competitively bind to the hERG membrane protein. After incubation for a certain period to reach equilibrium, the radioligands that did not bind to the membrane protein were filtered out using vacuum filtration. The filter plate was dried, scintillation solution was added, and the isotope signal (CPM) was detected on a Microbeta. A higher signal indicates a weaker binding affinity between the detection compound and the hERG membrane protein.

[0407] Materials and methods:

[0408] The compound, diluted hERG membrane protein, and diluted H3-dofeliate ligand (NET1144100UC, PerkinElmer) were added sequentially to a 96-well plate (3631, Corning). After sealing with a sealing membrane, the plate was incubated at room temperature with shaking for 1 hour. The incubated hERG membrane protein was then transferred to a GF / B plate (600517, PerkinElmer) using a PerkinElmer cell collector. The plate was washed 5 times (4°C, 0.4 mL each time) with washing buffer (20 mmol / L HEPES (pH 7.4) (Sigma-H3375); 10 mmol / L potassium chloride (Sigma-P9333); 1 mmol / L magnesium chloride (Sigma-449172), stored at 4°C). The GF / B plate was then baked in a 50°C oven for 30 minutes to ensure it was fully dried. The bottom of the GF / B plate was then sealed with a bottom sealing film (6005199, PerkinElmer). 50 μL of scintillation solution 20 (6013621, PerkinElmer) was added to each well of the plate, and then the plate was sealed with a top sealing film (6005250, PerkinElmer). The plate was then read on a Microbeta to detect the radioactive signal.

[0409] 4. hERG membrane protein-specific binding manual patch-clamp experiment

[0410] This experiment used a manual patch-clamp system to assess the potential inhibitory effect of the test on human hERG channels. HEK293 cell lines stably transfected with the hERG gene were used, with dofetilide as a positive control.

[0411] Materials and methods

[0412] Remove the cap from the cell culture dish (Nunc(150288)) and place it on the bathroom stage of the microscope (Olympus(IX51 / 71 / 73)). Using a 10x objective lens, followed by a 40x objective lens, gradually bring the electrode (AXON(Multiclamp 700B)) closer to the cell surface, gently aspirating the cells through the side opening of the electrode clamp to form a gigahertz seal. Set the membrane electrode to -60mV, ensuring the hERG channel is closed. Then, maintain the potential at -90mV for 500ms, followed by a +30mV depolarization for 4.8 seconds to extract the hERG current. Deactivate the cell at -50mV for 5.2 seconds to observe the inactivation tail current, recording the current for 120 seconds to assess current stability. Record the hERG current for approximately 5 minutes in the presence of the test compound. In the dose-response test, add five doses of the test compound from low to high concentrations to the cells for current measurement.

[0413] 5. Automated patch-clamp assay for specific binding of hERG membrane proteins

[0414] This experiment used an automated patch-clamp system to assess the potential inhibitory effect of cytokines on human hERG channels. The experiment employed a CHO cell line stably expressing the hERG gene, with cisapride as a positive control.

[0415] Materials and methods

[0416] Cells from two T175 culture flasks (431082, CORNING) were washed with 8 mL of DPBS-2 mM EDTA at room temperature and transferred. 3 mL of cell digestion solution was added, and the container was gently shaken to cover the cell surface. After incubation at 37°C for 8-10 minutes, the cells were separated. The cells were then transferred to a 10 cm ultra-low binding culture dish (NEST (704001)) using a pipette (BIOFIL (GSP110010)). The cells were incubated at 4-10°C for 10 minutes, counted (Invitrogen (Countess II)), and then transferred to a Teflon container and shaken (IKA (MS3 digital)). On a SyncroPatch 384i instrument (Nanion(384i)), the chip (Nanion(221401,4xhigh)) was filled with internal and external solutions. Cells were added to the chip, the battery was sealed, and the potential was set to -90mV for 500ms. Depolarization was then used to induce hERG current to +30mV for 4.8 seconds, followed by a voltage reduction to -50mV for 5.2 seconds. The inactivation tail current was then measured. The hERG current was recorded for at least 5 minutes in the presence of the test compound. The hERG current inhibition concentration of the compound was determined in two independent experiments.

[0417]

[0418]

[0419] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, It has an IA-type structure. in, R1 and R2 are independently selected from hydrogen and C. 1-6 alkyl; x and y are independently 0 or 1, and the sum of x and y is 1; R3 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy; Cy1 represents a non-fused monocyclic ring, which is a five- or six-membered ring, and is an aromatic ring or a heteroaromatic ring, wherein the cyclic heteroatom in the heteroaromatic ring is selected from one or more of N, O, and S; Cy1 is further substituted by one or more R5; R5 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene; m is an integer selected from 0, 1, or 2, and n is an integer selected from 0 or 1, and m and n are not both 0.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Cy1 is a benzene ring, pyridine, thiazole, or oxazole.

3. A compound with a structure of formula I or a pharmaceutically acceptable salt thereof, It has an IB structure. in, R1 is selected from hydrogen, C 1-6 alkyl; m is an integer selected from 0, 1 or 2, n is selected from 0 or 1, and m and n are not both 0 at the same time; x and y are independently 0 or 1, and the sum of x and y is 1; R3 is selected from hydrogen, C 1-6 Alkyl, or C 1-6 Alkoxy; W, Z, or V are independently selected from C or N ring atoms; dashed and solid lines represent double bonds; one or more R5 atoms are substituted at any position in the six-membered ring; R5 is selected from hydrogen, C, and N. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, characterized in that, W, Z, and V are all C atoms.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, characterized in that, W and Z are C atoms and V is an N atom, or W and V are C atoms and Z is an N atom, or V and Z are C atoms and W is an N atom.

6. The compound of claim 3 or a pharmaceutically acceptable salt thereof, characterized in that, The ring containing W, Z, and V is a benzene ring or pyridine.

7. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 3-6, characterized in that, R5 is a substituent attached to a carbon atom of the ring.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds or pharmaceutically acceptable salts thereof: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ,or .

9. A method for preparing a compound of formula I according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof, characterized in that: The reaction of an amino compound of formula A1 with a compound of formula B1 yields a compound of formula I. Alternatively, an amino compound of formula A2 reacts with a compound of formula B2 to yield a compound of formula I; Alternatively, the C1 compound reacts with the C2 compound to yield the compound of formula I. ； Z1 is a leaving group.

10. A pharmaceutical composition, characterized in that, Includes the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition of claim 10, characterized in that, The pharmaceutical composition further contains a pharmaceutically acceptable carrier.

12. Use of the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases mediated by 5HT2A receptor activity.

13. 、 、 、 、 、 、 Use of its pharmaceutically acceptable salts in the preparation of medicaments for treating diseases mediated by Sigma2 receptor activity, or diseases mediated by both Sigma2 receptor activity and 5HT2A receptor activity.

14. The use as described in claim 12, characterized in that, The diseases mediated by the 5HT2A receptor activity are central nervous system diseases.

15. The use as described in claim 13, characterized in that, The diseases mediated by Sigma2 receptor activity, or those mediated by both Sigma2 receptor activity and 5HT2A receptor activity, are central nervous system diseases.

16. The use as described in claim 14 or 15, characterized in that, The central nervous system diseases mentioned are selected from: mental illnesses, central nervous system degenerative diseases, mental disorder symptoms related to or concurrent with central nervous system degenerative diseases, and negative symptoms of mental illnesses.

17. The use as described in claim 16, characterized in that, The mental illnesses mentioned are selected from: depression, anxiety disorder, mania, schizophrenia, affective schizophrenia, bipolar disorder, insomnia, and autism.

18. The use as described in claim 16, characterized in that, The central nervous system degenerative diseases mentioned are selected from: Alzheimer's disease, Parkinson's disease, Huntington's disease, and Lewy body dementia.

19. The use as described in claim 16, characterized in that, The mental disorder symptoms related to or complicated by central nervous system degenerative diseases, and negative symptoms of mental illnesses, are selected from: affective disorders, language impairment, hallucinations, loss of interest, emotional dullness, diminished will, anhedonia, and social withdrawal.

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