Aminocarbonyl compounds and their use as sigma2 and 5ht2a dual target inhibitors

Abstract

The present application provides a kind of carbamic acid compound, it has Sigma2 receptor and 5HT2A receptor inhibitory activity, can be used as Sigma2 and 5HT2A dual-target inhibitor, for the treatment of Sigma2 receptor activity mediated related disease treatment, 5HT2A receptor activity mediated related disease treatment and the treatment of related disease by Sigma2 receptor activity and 5HT2A receptor activity jointly mediated, for example the treatment of negative symptoms of schizophrenia.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical compounds, specifically to an aminocarbamate 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 into drugs active on various receptors is active in this therapeutic area, including NMDA receptors, α7 nicotinic receptors, 5-HT2A receptors, and Sigma2 receptors. Among these, Sigma2 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 mainly 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). Antagonism of Sigma2 receptors may also modulate glutamatergic pathways and affect calcium neuron regulation (Vilner BJ, Bowen WD. (2020) J Pharmacol Exp Ther. 292: 900–911). Sigma2 receptors are involved in counteracting dysregulation of key dopamine (DA) and glutamate neurotransmitter pathways.

[0008] 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 JPharmacol, 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.

[0009] 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.

[0010] 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.

[0011] 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.

[0012] 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

[0013] This application discloses a compound with the structure of Formula I or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0014]

[0015] R1 is 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;

[0016] n and m are independent integers selected from 0 to 4, for example, 0, 1, 2, 3 or 4;

[0017] R2 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, C 6-10 Aryl, or C 1-6 Alkylene C 6-10 Aryl;

[0018] R3 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;

[0019] Cy1 represents a cyclic substituent. Cy1 represents only a non-fused monocyclic ring, which is a four-membered, five-membered, six-membered, or seven-membered ring. The monocyclic ring is an aromatic ring, a heteroaromatic ring, a carbocyclic ring, or a heterocyclic ring. 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 R4.

[0020] R4 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, or C 1-6 Alkylene C 3-7 Cycloalkanes.

[0021] 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 or C 1-3 Alkylene C 3-7 Cycloalkanes.

[0022] In some embodiments of the present invention, R2 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkoxy C 1-3 Alkylene.

[0023] In some embodiments of the present invention, R3 is selected from hydrogen, halogen, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkoxy C 1-3 Alkylene. In one embodiment of the invention, R3 is selected from F.

[0024] In some embodiments of the present invention, the R3 substitution position is located at the para position of the benzene ring.

[0025] In some embodiments of the present invention, Cy1 is 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 or heterocyclic ring is selected from one or more of N, O, and S; Cy1 is further substituted by one or more R4.

[0026] In some embodiments of the present invention, Cy1 is a benzene ring or a pyridine ring, and Cy1 is further substituted with one or more R4s.

[0027] In some embodiments of the present invention, R4 is selected from hydrogen, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 alkylene, or C 1-3 Alkylene C 3-7 Cycloalkanes.

[0028] In some embodiments of the present invention, R4 is a substituent located at the para position of the Cy1 ring.

[0029] In some embodiments of the invention, n is selected from an integer from 1 to 3, such as 1, 2 or 3.

[0030] In some embodiments of the invention, m is selected from an integer between 0 and 2, such as 0, 1, or 2.

[0031] This invention discloses a compound having the structure of formula IA, its pharmaceutically acceptable salt, solvate, or stereoisomer.

[0032]

[0033] R1 is 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;

[0034] m is an independent integer selected from 0 to 4, for example, 0, 1, 2, 3 or 4;

[0035] R2 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;

[0036] Cy1 represents a cyclic substituent. Cy1 represents only a non-fused monocyclic ring, which is a four-membered, five-membered, six-membered, or seven-membered ring. The monocyclic ring is an aromatic ring, a heteroaromatic ring, a carbocyclic ring, or a heterocyclic ring. 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 R4.

[0037] R4 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, or C 1-6 Alkylene C 3-7 Cycloalkanes.

[0038] 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 or C 1-3 Alkylene C 3-7 Cycloalkanes.

[0039] In some embodiments of the present invention, R2 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkoxy C 1-3 Alkylene.

[0040] In some embodiments of the present invention, Cy1 is 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 or heterocyclic ring is selected from one or more of N, O, and S; Cy1 is further substituted by one or more R4.

[0041] In some embodiments of the present invention, Cy1 is a benzene ring or a pyridine ring, and Cy1 is further substituted with one or more R4s.

[0042] In some embodiments of the present invention, R4 is selected from hydrogen, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 alkylene, or C 1-3 Alkylene C 3-7 Cycloalkanes.

[0043] In some embodiments of the present invention, R4 is a substituent located at the para position of the Cy1 ring.

[0044] In some embodiments of the invention, m is selected from an integer between 0 and 2, such as 0, 1, or 2.

[0045] This invention discloses a compound having the formula IB, its pharmaceutically acceptable salt, solvate, or stereoisomer.

[0046]

[0047] 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;

[0048] m is selected from an integer between 0 and 4, such as 0, 1, 2, 3 or 4, preferably m is 0, 1 or 2;

[0049] R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 alkoxy, or C 3-7 Cycloalkanes;

[0050] Each Independently represented double bonds or single bonds;

[0051] W and Z are independently selected from one of C, N, O, or S; preferably, W and Z are independently selected from C or N.

[0052] One or more R4 atoms are attached to any carbon and / or nitrogen atom of a six-membered ring, wherein R4 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene, C 1-6 Alkylene C 3-7 Cycloalkanes.

[0053] Further preferred, in the compound of formula IB,

[0054] R1 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy C 1-3 Alkylene, C 3-7 Cycloalkanes or C 1-3 Alkylene C 3-7 Cycloalkanes;

[0055] m is 0, 1, or 2;

[0056] R2 is selected from hydrogen, C 1-3 alkyl;

[0057] Each Independent double bonds;

[0058] Both W and Z are C, or W is C and Z is N, or W is N and Z is C;

[0059] One or more R4 atoms are attached to any six-membered ring carbon and / or cyclic nitrogen atoms, wherein R4 is selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 alkylene, or C 1-3 Alkylene C 3-7 Cycloalkanes. In some embodiments of the invention, R4 is a substituent located at the para position of the six-membered ring.

[0060] This invention further protects the following specific compounds, their pharmaceutically acceptable salts, solvates, or stereoisomers:

[0061]

[0062] This invention protects a method for preparing a compound of formula I, characterized in that:

[0063] Step 1: The amino compound of formula IIA reacts with the compound of formula IIB to synthesize the compound of formula I.

[0064]

[0065] Alternatively, compounds of formula IIA and IIB' react with trifluoroacetic acid to yield compound I;

[0066]

[0067] Alternatively, the compound of formula IIA' reacts with the compound of formula IIB” to obtain the compound of formula I;

[0068] Step 2: If necessary, the compound of Formula I may be functionalized according to the target product 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.

[0069] R1, R2, R3, m, n, and Cy1 are defined as above, and X is a leaving group, such as halogen or hydroxyl group.

[0070] The preparation method is also applicable to the preparation of compounds of formula IA and formula IB.

[0071] 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.

[0072] 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 ≤ 500 nM, more preferred compounds have an IC50 ≤ 200 nM, and most preferred compounds have an IC50 ≤ 100 nM.

[0073] 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 85% at 10 μM.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] Diseases mediated by the activity of the 5HT2A receptor and / or Sigma2 receptor include, but are not limited to, central nervous system diseases.

[0078] 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.

[0079] The mental illnesses mentioned include, but are not limited to: depression, anxiety disorder, mania, schizophrenia, affective schizophrenia, bipolar disorder, insomnia, autism, etc.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] The pharmaceutical composition further contains a pharmaceutically acceptable carrier.

[0085] 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.

[0086] 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 and ethylparaben. Examples of the lubricants include magnesium stearate, micronized silica gel, and talc. Examples of the disintegrants include starch, methylcellulose, xanthan gum, and croscarmellose sodium.

[0087] 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.

[0088] 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%.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] The pharmaceutical composition can be used in combination with other drugs for treating diseases mediated by 5HT2A receptor and / or Sigma2 receptor activity.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] The method further includes administering other medications to patients in need of treatment for diseases mediated by 5HT2A receptor and / or Sigma2 receptor activity.

[0097] 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.

[0098] The medications used to treat mental illnesses include, but are not limited to: benzodiazepines Classes (e.g., methyltriazolidinedione, chlordiazepoxide) Drugs containing: 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.

[0099] 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.

[0100] In this invention:

[0101] "Halogen" refers to F, Cl, Br or I.

[0102] "Independent" means that the features are independent of each other and are not related to each other.

[0103] 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.

[0104] 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

[0105] 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.

[0106] 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.

[0107] The following terms or abbreviations are used in the embodiments:

[0108] PEX: Example of intermediate preparation

[0109] EX: Example

[0110] 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: ACN; gradient: 10-20-9 MIN 150VL

[0111] ACN: Acetonitrile

[0112] HOBT: 1-Hydroxybenzotriazole

[0113] EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0114] EtOAc and EA: Ethyl acetate

[0115] PE: Petroleum ether

[0116] DIEA: Diisopropylethylamine

[0117] TEA: Triethylamine

[0118] DCM: Dichloromethane

[0119] DMF: N,N-dimethylformamide

[0120] HMDSK: Potassium bis(trimethylsilyl)amide

[0121] TFA: 2,2,2-trifluoroacetic acid or trifluoroacetic acid

[0122] THF: Tetrahydrofuran

[0123] Preparation of PEX1: N-(4-(methoxymethyl)benzyl)-2-(piperidin-4-yloxy)acetamide

[0124]

[0125] Step 1: Preparation of tert-butyl 4-(2-((4-(methoxymethyl)benzyl)amino)-2-oxoethoxy)piperidine-1-carboxylic acid

[0126]

[0127] A solution of {[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}acetic acid (500 mg, 1.93 mmol, 1.0 equiv), 1-[4-(methoxymethyl)phenyl]methylamine (320 mg, 2.12 mmol, 1.1 equiv), HOBT (953 mg, 2.51 mmol, 1.3 equiv), EDCI (480 mg, 2.51 mmol, 1.3 equiv), and DIEA (748 mg, 5.78 mmol, 3.0 equiv) in DCM (10 mL) was stirred overnight at room temperature and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was separated by EtOAc / PE (1 / 1) chromatography on a silica gel column to obtain tert-butyl 4-(2-((4-(methoxymethyl)benzyl)amino)-2-oxoethoxy)piperidine-1-carboxylic acid (300 mg, 39.6%), as a brown oil. LC-MS (ESI, m / z): 393 [M+H] + .

[0128] Step 2: Preparation of N-(4-(methoxymethyl)benzyl)-2-(piperidin-4-yloxy)acetamide

[0129] A solution of tert-butyl 4-(2-((4-(methoxymethyl)benzyl)amino)-2-oxoethoxy)piperidine-1-carboxylic acid (300 mg, 0.764 mmol, 1.0 equiv) and TFA (1 mL) in DCM (6 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give N-(4-(methoxymethyl)benzyl)-2-(piperidine-4-yloxy)acetamide (180 mg crude), a colorless oil that could be used directly in the next step without further purification. LC-MS (ESI, m / z): 293 [M+H] + .

[0130] Preparation of PEX2: Piperidin-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)(methyl)carbamate

[0131]

[0132] Step 1: Preparation of 1-(6-methoxypyridin-3-yl)-N-methylmethylamine

[0133]

[0134] A methanol solution of 40% methylamine (2.52 g, 21.9 mmol) was added to a methanol solution of 20 mL containing 2.00 g of 6-methoxynicotinaldehyde (2.00 g, 14.6 mmol). The resulting solution was stirred at 65 °C for 2 hours, followed by the addition of sodium borohydride (1.10 g, 29.2 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 4 hours. The mixture was diluted with 50 mL of saturated NH4Cl solution and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under vacuum to give crude 1-(6-methoxypyridin-3-yl)-N-methylmethylamine (1.00 g, 40.41%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ8.06–8.05(m,1H),7.58– 7.54(m,1H),6.72–6.70(m,1H),3.91(s,3H),3.66(s,2H),2.43(s,3H),1.63(s,1H).

[0135] Step 2: Preparation of 4-nitrophenyl ((6-methoxypyridin-3-yl)methyl)(methyl)carbamate

[0136]

[0137] Under nitrogen protection and at 0°C, a solution of (6-methoxypyridin-3-yl)methyl(methyl)carbamate (360 mg, 2.37 mmol) and a solution of DIEA (611 mg, 4.73 mmol) in THF (8 mL) were added dropwise. The reaction mixture was then stirred at 20°C for 1 hour. The mixture was diluted with water (30 mL) and extracted with EA (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under vacuum to give a crude product, which was purified by rapid chromatography (PE / EtOAc = 10 / 1) to give 4-nitrophenyl((6-methoxypyridin-3-yl)methyl(methyl)carbamate (520 mg, 63.2%) as a pale yellow solid. LC-MS (ESI, m / z): 318.1 [M+H] + .

[0138] Step 3: Preparation of 4-(((((6-methoxypyridin-3-yl)methyl)(methyl)carbamoyl)oxy)methyl)piperidine-1-carboxylic acid benzyl ester

[0139]

[0140] Under nitrogen protection at 0°C, 1M HMDSK (2.96 mL, 2.96 mmol) was added dropwise to a solution of 4-nitrobenzene chloroformate (470 mg, 1.48 mmol) and 1-(benzyloxy)-O-[4-(hydroxymethyl)piperidin-1-yl]methyl ketone (371 mg, 1.48 mmol) in 10 mL of THF. The reaction mixture was then stirred at 20°C for 1 hour. The mixture was diluted with 20 mL of saturated NH4Cl solution and extracted with EA (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under vacuum to give the crude product. The residue was purified by prep-TLC (DCM / MeOH = 15 / 1) to give the product 4-(((((6-methoxypyridin-3-yl)methyl)(methyl)carbamoyl)oxy)methyl)piperidin-1-carboxylic acid benzyl ester (290 mg, 42.6%) as a yellow oil. LC-MS (ESI, m / z): 428.2 [M+H] + .

[0141] Step 4: Preparation of piperidine-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)(methyl)carbamate

[0142]

[0143] A mixture of 3 mL of THF solution containing {1-[(E)-[(benzyloxy)methylene]oxo]piperidin-4-yl}methyl N-[(6-methoxypyridin-3-yl)methyl]-N-methylcarbamate (300 mg, 0.700 mmol) and Pd / C (60.0 mg, 10%) was stirred at 20 °C for 3 hours under hydrogen atmosphere. The mixture was filtered, and the filtrate was evaporated under vacuum to give crude piperidin-4-ylmethyl((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (170 mg, 75.9%) as a yellow oil. LC-MS (ESI, m / z): 294.2 [M+H] + .

[0144] Preparation of PEX3: Piperidin-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)carbamate

[0145]

[0146] The preparation method of piperidine-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)carbamate is similar to that of piperidine-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)(methyl)carbamate, using (6-methoxypyridin-3-yl)methylamino as the raw material.

[0147] Preparation of PEX4 1-(4-fluorophenyl)-2-(4-(hydroxymethyl)piperidin-1-yl)ethyl-1-one

[0148]

[0149] A mixture of 2-chloro-1-(4-fluorophenyl)ethyl ketone (500 mg, 2.90 mmol, 1.0 equiv), piperidin-4-ylmethanol (434 mg, 3.77 mmol, 1.3 equiv), KI (96.2 mg, 0.579 mmol, 0.2 equiv), and K₂CO₃ (1.20 g, 8.69 mmol, 3.0 equiv) in DMF (10 mL) was stirred at 60 °C for 2 h, followed by quenching with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was separated by chromatographic analysis on a silica gel column using EtOAc / PE (3 / 2) to give 1-(4-fluorophenyl)-2-(4-(hydroxymethyl)piperidin-1-yl)ethyl-1-one (400 mg, 55%) as a brown oil. LC-MS (ESI, m / z): 252 [M+H] + .

[0150] EX1: Preparation of 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)oxy)-N-(4-(methoxymethyl)benzyl)acetamide·2,2,2-trifluoroacetate (ER10300)

[0151]

[0152] A solution of N-(4-(methoxymethyl)benzyl)-2-(piperidin-4-yloxy)acetamide (200 mg, 0.68 mmol, 1.0 equiv), 2-chloro-1-(4-fluorophenyl)ethyl ketone (118 mg, 0.684 mmol, 1.0 equiv), K₂CO₃ (283 mg, 2.05 mmol, 3.0 equiv), and KI (22.7 mg, 0.137 mmol, 0.2 equiv) in DMF (8 mL) was stirred at 60 °C for 2 h and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was separated by chromatography on a silica gel column using CH2Cl2 / MeOH (96:4) to obtain a crude residue, which was purified by prep-HPLC (under method A conditions) to obtain 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)oxy)-N-(4-(methoxymethyl)benzyl)acetamide·2,2,2-trifluoroacetate (24.5 mg, 8.3%) as a colorless oil. 1 H NMR (300MHz, CD3OD) δ8.08-8.13(m,2H),7.36-7.37(m,2H),7.30-7.35(m,4H),4.85-4. 91(m,2H),4.42-4.45(m,4H),4.10(s,2H),3.72-3.88(m,2H),3.46-3.54(m,2H) ,3.32(s,3H),3.07-3.30(m,1H),1.98-2.41(m,4H).LC-MS(ESI,m / z):429[M+H] + .

[0153] EX2: Preparation of (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl-((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (ER10344)

[0154]

[0155] Under nitrogen protection at 0°C, K₂CO₃ (120 mg, 0.869 mmol) and 2-bromo-1-(4-fluorophenyl)ethyl ketone (126 mg, 0.580 mmol) were added to a DMF (1 mL) solution of piperidin-4-ylmethyl((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (170 mg, 0.580 mmol). The mixture was then stirred at 20°C for 1 hour, diluted with water (20 mL), and extracted with EA (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under vacuum to give the crude product. The residue was purified by Prep-TLC (DCM / MeOH = 15 / 1) to give (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (150 mg, 47.1%) as a yellow oil. 1 H NMR(400 MHz, DMSO_d6)δ9.80(brs,1H),8.13–8.06(m,3H),7.60–7.46(m,3H),6.84–6.82(m,1H),5.01 –5.00(m,2H),5.00–4.37(m,2H),4.00–3.95(m,2H),3.83(s,3H),3.52–2.82(m,4H),2 .67–2.51(m,3H),1.99–1.72(m,3H),1.65–1.24(m,2H).LC-MS(ESI,m / z):430.2[M+H] + .

[0156] EX3: Preparation of (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (ER10345)

[0157]

[0158] Under nitrogen protection at 0°C, K₂CO₃ (87.6 mg, 0.634 mmol) and 2-bromo-1-(4-fluorophenyl)ethyl ketone (91.7 mg, 0.422 mmol) were added to a DMF (10 mL) solution of piperidin-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)carbamate (118 mg, 0.422 mmol). The mixture was stirred at 20°C for 1 hour, diluted with water (30 mL), and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under vacuum to give the crude product. The residue was purified by prpe-TLC (DCM / MeOH = 15 / 1) to give (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl ((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (70.0 mg, 31.2%) as a yellow oil. 1 H NMR(400MHz,DMSO_d6)δ9.83(brs,1H),8.09 –8.05(s,3H),7.51–7.49(m,1H),7.47(m,1H),7.27(m,2H),6.81–6.79(m,1H),5.03–5.00(s, 2H),4.14(m,2H),3.90(m,2H),3.83(m,3H),3.55(m,1.5H),3.45(m,1H),3.29(m,1H),3.04(m, 1.5H),1.78–1.58(m,3H),1.24(m,2H).LC-MS(ESI,m / z):416.2[M+H] + .

[0159] EX4: Preparation of (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl(4-(methoxymethyl)benzyl)carbamate·2,2,2-trifluoroacetate (ER10299)

[0160]

[0161] At 0 °C, 4-nitrobenzyl chloride (230 mg, 1.14 mmol, 1.1 equiv) was added to a solution of 1-(4-fluorophenyl)-2-(4-(hydroxymethyl)piperidin-1-yl)ethyl-1-one (260 mg, 1.04 mmol, 1.0 equiv) and Et3N (419 mg, 4.14 mmol, 4.0 equiv) in 10 mL of DCM. The mixture was stirred at room temperature for 1 hour. 1-[4-(methoxymethyl)phenyl]methylamine (234 mg, 1.55 mmol, 1.5 equiv) was added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was separated by chromatography on a silica gel column using CH2Cl2 / MeOH (96 / 4) to obtain a crude residue, which was then purified by prep-HPLC (under Method A conditions) to obtain (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl(4-(methoxymethyl)benzyl)carbamic acid·2,2,2-trifluoroacetate (26.0 mg, 5.8%), as a colorless oil. 1 H NMR(300MHz,CD3OD)δ8.08-8.13(m,2H),7.3 6-7.36(m,6H),4.86-4.91(m,2H),4.28-4.43(m,4H),4.03(s,2H),3.67-3.70(m,2H),3.31-3 .35(m,4H),3.09-3.30(m,2H),2.02-2.06(m,2H),1.68-1.77(m,2H).LC-MS(ESI,m / z):429[M+ H] + .

[0162] EX5: Preparation of 2,2,2-trifluoroacetate of (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl(methyl)(pyridin-2-yl)carbamate (ER10348)

[0163]

[0164] Under nitrogen protection and at 0°C, a solution of N-methylpyridin-2-amine (700 mg, 6.47 mmol) and pyridine (1.02 g, 12.9 mmol) in THF (20 mL) was added dropwise to a solution of bis(trichloromethyl) carbonate (960 mg, 3.24 mmol) in THF (4 mL). The reaction mixture was then stirred at 20°C for 1 hour, diluted with water (20 mL), and extracted with EA (3 × 6 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under vacuum to give a crude intermediate, which was used directly in the next step without further purification.

[0165] Under nitrogen protection and at 0°C, a THF solution (10 mL) of the crude intermediate (625 mg, crude) was added dropwise to a THF solution (10 mL) of 1-(4-fluorophenyl)-2-(4-(hydroxymethyl)piperidin-1-yl)ethyl-1-one (921 mg, 3.67 mmol) and TEA (1.11 g, 11.0 mmol). The reaction mixture was then stirred at 50°C for 16 hours, cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3 × 6 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under vacuum to give the crude product. The residue 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)piperidin-4-yl)methyl(methyl)(pyridin-2-yl)carbamate·2,2,2-trifluoroacetate (38.1 mg, 1.18%) as a pale yellow solid. 1 H NMR(400MHz,DMSO_d6)δ9.82(brs,1H),8.42–8.41(m, 1H),8.07(m,2H),7.71(m,1H),7.47(m,1H),7.20–7.17(m,2H),6.99(m,1H),5.02–5.01(m,2H), 4.13–4.16(m,2H),3.53(m,1.5H),3.36(m,3H),3.17(m,1H),3.05(m,1. 5H),1.89–1.80(m,3H),1.73–1.64(m,2H).LC-MS(ESI,m / z):386.1[M+H] + .

[0166] Bioactivity test

[0167] 1. Screening test for 5-HT2A receptor antagonist activity

[0168] 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.

[0169] Materials and methods:

[0170] 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 TM The -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).

[0171] 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.

[0172] 2. Sigma2 target binding assay

[0173] 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. 3H]DTG is used to determine the specific binding of compounds.

[0174] ER10299 49 101％ ER10344 110 104％ ER10345 97 91％ ER10348 126 95％ ER10300 240 95％

[0175] 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 is selected from hydrogen, C 1-6 alkyl; R2 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 R4; R4 is selected from hydrogen, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene; m is an integer between 0 and 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R1 is selected from hydrogen, C 1-3 alkyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R2 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkyl group.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Cy1 is a benzene ring or a pyridine ring.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R4 is selected from hydrogen, halogens, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkylene.

6. 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 selected from integers between 0 and 2; R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy; Each Independent double bonds; W and Z are independently selected from C or N; One or more R4 atoms are attached to any carbon atom of a six-membered ring, and R4 is selected from hydrogen, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkylene.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from hydrogen, C 1-3 alkyl; m is 0, 1, or 2; R2 is selected from hydrogen, C 1-3 alkyl; Both W and Z are C, or W is C and Z is N, or W is N and Z is C; One or more R4 atoms are attached to any carbon atom of a six-membered ring, and R4 is selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkylene.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: ,or 。 9. Compounds Or its pharmaceutically acceptable salt.

10. A method for preparing the compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, the method comprising: The reaction of an amino compound of formula IIA with a compound of formula IIB yields a compound of formula I. ； Alternatively, the compound of formula IIA' reacts with the compound of formula IIB'' to give the compound of formula I. ； Where X is a leaving group.

11. A pharmaceutical composition comprising the compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 11, further comprising a pharmaceutically acceptable carrier.

13. Use of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases mediated by Sigma2 receptor activity, diseases mediated by 5HT2A receptor activity, or diseases mediated by both Sigma2 receptor activity and 5HT2A receptor activity.

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

15. The use as described in claim 14, 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.

16. The use as described in claim 15, characterized in that, The mental illnesses mentioned are selected from: depression, anxiety disorder, mania, schizophrenia, affective schizophrenia, bipolar disorder, insomnia, and autism.

17. The use as described in claim 15, 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.

18. The use as described in claim 15, 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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