WO2024067302A1 - 一种酰胺类化合物及其制备Sigma2和5HT2A抑制剂的用途 - Google Patents

一种酰胺类化合物及其制备Sigma2和5HT2A抑制剂的用途 Download PDF

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WO2024067302A1
WO2024067302A1 PCT/CN2023/120114 CN2023120114W WO2024067302A1 WO 2024067302 A1 WO2024067302 A1 WO 2024067302A1 CN 2023120114 W CN2023120114 W CN 2023120114W WO 2024067302 A1 WO2024067302 A1 WO 2024067302A1
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alkylene
ring
cycloalkane
alkoxy
mmol
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邢洪涛
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瀚远医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to the field of pharmaceutical compounds, and in particular to an amide compound and its use as a dual-target inhibitor of Sigma2 and 5HT2A.
  • Schizophrenia is a chronic, disabling disease with positive and negative symptom clusters.
  • Positive and negative symptoms originated in the field of neuroscience and were later adopted by psychiatry to describe schizophrenia using symptom clusters.
  • Positive symptoms reflect an excess or distortion of normal function (e.g., delusions, hallucinations, disorganized behavior), while negative symptoms refer to a reduction or absence of normal behavior related to motivation and interest (e.g., avolition, anhedonia, social withdrawal) or a reduction or absence of expression (e.g., blunted affect, poverty of speech).
  • Negative symptoms are the core symptoms of schizophrenia and account for a large proportion of the morbidity and poor functional outcomes of patients with schizophrenia. Compared with positive symptoms, negative symptoms have a heavier disease burden.
  • Negative symptoms are common and may occur at any stage of the illness. For example, 90% of patients with their first psychotic episode have at least 1 negative symptom, and 35-70% of patients continue to have clinically significant negative symptoms after treatment. Among outpatients with stable schizophrenia receiving conventional antipsychotic medications, 61% have at least 1 moderate or more severe symptom. Of the 5 PANSS negative symptom scale items assessed (blunting of affect, emotional withdrawal, affective communication disorder, social withdrawal, lack of spontaneity and fluency in conversation), social withdrawal (48%), emotional withdrawal (42%), and affective communication disorder (39%) are the most common symptoms, and 19% of patients have all 5 negative symptoms. Studies have shown that negative symptoms persist over time and, in fact, become more prominent as patients age, while positive symptoms become less prominent (National Institute of Mental Health: Research Domain Criteria (RDoC). Positive Valence Systems.).
  • Sigma receptors including Sigma1 and Sigma2 receptors, are regulated by small molecules and are mainly present in endoplasmic reticulum membrane-related sites. They are integral 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 drug haloperidol and the opioid analgesic pentazocine. Sigma receptors are associated with a variety of central nervous system diseases, especially Alzheimer's disease (AD), schizophrenia, and diseases related to motor control such as amyotrophic lateral sclerosis (ALS).
  • AD Alzheimer's disease
  • ALS amyotrophic lateral sclerosis
  • 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 DA and glutamate neurotransmitter pathways.
  • Serotonin or 5-hydroxytryptamine plays an extremely important role in human physiological functions.
  • 5-HT is an important neurotransmitter and neuromodulator, which plays an extremely important role in regulating various behaviors such as sleep, diet, activity, learning and memory, body temperature, blood pressure, and pathological states (such as anxiety, mania, schizophrenia, obesity, drug addiction, migraine and hypertension)
  • pathological states such as anxiety, mania, schizophrenia, obesity, drug addiction, migraine and hypertension
  • 5-HT exerts its effects through its receptors.
  • 5-HT receptors are divided into 7 families (5-HT1 to 5-HT7) and at least 15 different subtypes (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 preference and related functions of different subtypes of receptors are different.
  • 5-HT2A subtype receptors are widely and discretely expressed in the central nervous system, with the highest expression in the cerebral cortex, limbic, hippocampus, hypothalamus and basal ganglia involved in regulating higher cognitive and emotional functions. 5-HT2A receptors are expressed on dopamine, GABA, glutamate and Ach neurons and act as dendritic heteroreceptors (Buhot MC, (1997) Curr Opin Neurobiol, 7, 243-254; Leysen JE, (2004) Curr Drug Targets CNS Neuro Disord, 3, 11-26).
  • 5-HT2A receptors are G-protein coupled receptors, which complete signal transduction by activating guanine nucleotide binding protein (G protein), resulting in an increase or decrease in the level of second messenger molecules such as cyclic adenosine monophosphate (cAMP), inositol phosphates and diacylglycerol.
  • G protein guanine nucleotide binding protein
  • cAMP cyclic adenosine monophosphate
  • inositol phosphates diacylglycerol
  • Abnormal 5-HT transmission is related to the pathogenesis of various psychiatric disorders, such as mental illness (depression, panic attacks, schizophrenia, suicidal tendencies, 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).
  • 5-HT2A receptors are closely related to the pathological state of neuropsychiatric diseases, and 5-HT2A receptors are involved in the molecular mechanism of action of atypical antipsychotics such as clozapine, olanzapine, and risperidone (Gonzalez-Maeso J, et al., (2009) Trends Neurosci, 32: 225-232; Fri dogs M, et al., (2011) Cell, 147: 1011-1023; Kurita M, et al., (2012) Nat Neurosci, 15: 1245-1254).
  • atypical antipsychotics such as clozapine, olanzapine, and risperidone
  • 5-HT2A receptor antagonists are very important for treating negative symptoms of schizophrenia (such as affective disorders, language impairment, etc.) (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, H.Y. (2013) Annu Rev Med 64, 393-406).
  • Drugs used to treat mental illness are divided into two categories. "Typical” antipsychotics or older generation drugs are rarely used in clinical practice due to their side effects on human motor function (extrapyramidal side effects, Parkinson's disease, etc.). Current drugs focus more on “atypical” antipsychotics (Prim Cre Companion J Clin Psychiatry. (2007) 9 (6): 444-54). However, the second generation of antipsychotics all have broad-spectrum receptor activity. These compounds regulate a variety of monoamine receptors such as 5-HT, dopamine, adrenergic, muscarinic or histamine receptors as agonists, competitive antagonists or inverse agonists. This broad-spectrum regulation is likely to be the cause of side effects such as abnormal sedation, abnormal motor function, and type 2 diabetes.
  • Schizophrenia patients with negative symptoms have worse functional outcomes and respond less well to antipsychotics than those with positive symptoms in treatment options.
  • First- and second-generation antipsychotics are mostly ineffective in the sustained treatment of negative symptoms. Therefore, there is a need for the development of new pharmaceutical compounds that can treat central nervous system disorders.
  • the present application discloses a compound of formula I, a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
  • M is selected from O, S or H.
  • R 1 and R 2 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkylene, C 3-7 cycloalkane, C 1-6 alkylene C 3-7 cycloalkane, C 6-10 aryl, or C 1-6 alkylene C 6-10 aryl;
  • n, m are independently selected from integers of 0-4, such as 0, 1, 2, 3 or 4;
  • x and y are independently 0 or 1, and the sum of x and y is 1;
  • R3 is selected from hydrogen, C1-6 alkyl , C1-6 alkoxy, C1-6 alkoxyC1-6 alkylene , C3-7 cycloalkane, C1-6 alkyleneC3-7 cycloalkane, C6-10 aryl, or C1-6 alkyleneC6-10 aryl;
  • R4 is selected from hydrogen, halogen, CN, C1-6 alkyl , C1-6 alkoxy, C1-6 alkoxyC1-6 alkylene, C3-7 cycloalkane, C1-6 alkyleneC3-7 cycloalkane, C6-10 aryl, or C1-6 alkyleneC6-10 aryl;
  • Cy 1 represents a ring substituent, Cy 1 represents only a non-fused monocyclic ring, the monocyclic ring 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, and the heteroatoms in the heteroaromatic ring and the heterocyclic ring are selected from one or more of N, O and S; Cy 1 is further substituted by one or more R 5 ; preferably Cy 1 is a five-membered ring or a six-membered ring, more preferably a benzene ring, cyclohexane, pyridine, thiazole, or Azoles;
  • R 5 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkylene, C 3-7 cycloalkane, C 1-6 alkylene C 3-7 cycloalkane, or C 1-6 alkylene C 6-10 aryl.
  • M is O.
  • R 1 and R 2 are independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane, C 6-10 aryl, or C 1-3 alkylene C 6-10 aryl.
  • n and m are independently selected from integers of 0-2, such as 0, 1 or 2.
  • R 3 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane, C 6-10 aryl, or C 1-3 alkylene C 6-10 aryl.
  • R 4 is selected from hydrogen, halogen, C 1-3 alkyl. In some more specific embodiments of the present invention, R 4 is selected from hydrogen, F, Cl, methyl.
  • the substitution position of R 4 is the para position of the benzene ring.
  • Cy 1 represents a non-fused monocyclic ring, which is a five-membered or six-membered ring, which is an aromatic ring, a heteroaromatic ring, a carbocyclic ring or a heterocyclic ring, wherein the heteroatoms in the heteroaromatic ring and the heterocyclic ring are selected from one or more of N, O and S; Cy 1 is further substituted by one or more R 5 .
  • Cy 1 is a benzene ring or pyridine.
  • R 5 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane, or C 1-3 alkylene C 6-10 aryl.
  • M is O
  • R 1 and R 2 are independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane, C 6-10 aryl, or C 1-3 alkylene C 6-10 aryl;
  • n, m are independently selected from integers of 0-2, such as 0, 1 or 2;
  • x and y are independently 0 or 1, and the sum of x and y is 1;
  • R3 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane, C1-3 alkylene C3-7 cycloalkane, C6-10 aryl, or C1-3 alkylene C6-10 aryl ;
  • R 4 is the para position of the benzene ring, and R 4 is selected from hydrogen, halogen, and C 1-3 alkyl. More preferably, R 4 is selected from hydrogen, F, Cl, and methyl;
  • Cy 1 represents a non-fused monocyclic ring, the monocyclic ring is a five-membered or six-membered ring, the monocyclic ring is an aromatic ring, a heteroaromatic ring, a carbocyclic ring or a heterocyclic ring, the heteroaromatic ring is The heteroatoms in the ring and heterocycle are selected from one or more of N, O, and S; Cy 1 is further substituted by one or more R 5 ; preferably, Cy 1 is a benzene ring, cyclohexane, pyridine, thiazole, or Azole, more preferably a benzene ring or pyridine;
  • R5 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane, C1-3 alkylene C3-7 cycloalkane, or C1-3 alkylene C6-10 aryl.
  • the present application discloses a compound of formula IA, a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
  • R 1 and R 2 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkylene, C 3-7 cycloalkane, C 1-6 alkylene C 3-7 cycloalkane, C 6-10 aryl, or C 1-6 alkylene C 6-10 aryl;
  • n is an integer selected from 0-2, such as 0, 1 or 2;
  • x and y are independently 0 or 1, and the sum of x and y is 1;
  • R3 is selected from hydrogen, C1-6 alkyl, C1-6 alkoxy , C1-6 alkoxyC1-6 alkylene, C3-7 cycloalkane, or C1-6 alkyleneC3-7 cycloalkane;
  • Cy 1 represents a ring substituent, Cy 1 represents only a non-fused monocyclic ring, the monocyclic ring 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, and the heteroatoms in the heteroaromatic ring and the heterocyclic ring are selected from one or more of N, O and S; Cy 1 is further substituted by one or more R 5 ; preferably, Cy 1 is a five-membered ring or a six-membered ring, more preferably a benzene ring, cyclohexane, pyridine, thiazole, or Azole.
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkylene, C 3-7 cycloalkane, C 1-6 alkylene C 3-7 cycloalkane, or C 1-6 alkylene C 6-10 aryl.
  • R 1 and R 2 are independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane, C 6-10 aryl, or C 1-3 alkylene C 6-10 aryl.
  • n is selected from an integer of 0 or 1
  • m and n are not 0 at the same time.
  • R 3 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane.
  • Cy 1 represents a non-fused monocyclic ring, which is a five-membered or six-membered ring, which is an aromatic ring, a heteroaromatic ring, a carbocyclic ring or a heterocyclic ring, wherein the heteroatoms in the heteroaromatic ring and the heterocyclic ring are selected from one or more of N, O and S; Cy 1 is further substituted by one or more R 5 .
  • Cy 1 is a benzene ring or pyridine.
  • R 5 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane hydrocarbon, C 1-3 alkylene C 3-7 cycloalkane, or C 1-3 alkylene C 6-10 aryl.
  • R 5 is a substituent attached to a carbon atom of the ring.
  • R 1 and R 2 are independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane, C 6-10 aryl, or C 1-3 alkylene C 6-10 aryl;
  • n is an integer selected from 0 or 1
  • m and n are not 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, C1-3 alkyl, C1-3 alkoxy, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane, C1-3 alkylene C3-7 cycloalkane;
  • Cy 1 represents a non-fused monocyclic ring, the monocyclic ring is a five-membered or six-membered ring, the monocyclic ring is an aromatic ring, a heteroaromatic ring, a carbocyclic ring or a heterocyclic ring, and the heteroatoms in the heteroaromatic ring and the heterocyclic ring are selected from one or more of N, O, and S; Cy 1 is further substituted by one or more R 5 ; preferably, Cy 1 is a benzene ring, cyclohexane, pyridine, thiazole, or Azole, more preferably a benzene ring or pyridine;
  • R 5 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane, or C 1-3 alkylene C 6-10 aryl; preferably, R 5 is a substituent connected to a carbon atom of the ring.
  • the present application discloses a compound of formula IB, a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkylene, C 3-7 cycloalkane, or C 1-6 alkylene C 3-7 cycloalkane;
  • n is an integer selected from 0 or 1;
  • x and y are independently 0 or 1, and the sum of x and y is 1;
  • R 3 is selected from hydrogen, C 1-6 alkyl, or C 1-6 alkoxy
  • W, Z or V are independently selected from ring atoms of C, N, O or S, the dotted and solid bonds represent double bonds or single bonds, one or more R5 are substituted at any position of the six-membered ring, R5 is selected from hydrogen, C1-6 alkyl, C1-6 alkoxy , C1-6 alkoxyC1-6 alkylene, C3-7 cycloalkane, C1-6 alkyleneC3-7 cycloalkane, or C1-6 alkyleneC6-10 aryl; preferably W, Z or V are independently C or N atoms, and one or more R5 are connected to any ring carbon and/or ring nitrogen atom of the six-membered ring.
  • R 1 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane.
  • n is an integer selected from 0, 1 or 2
  • m and n are not 0 at the same time.
  • R 3 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy.
  • W, Z and V are all C atoms; preferably, the ring containing W, Z and V is a benzene ring.
  • W and Z are C atoms and V is a N atom, or, W and V are C atoms and Z is a N atom, or, V and Z are C atoms and W is a N atom; preferably, the ring containing W, Z and V is pyridine.
  • R 5 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane, or C 1-3 alkylene C 6-10 aryl.
  • R 5 is a substituent attached to a carbon atom of the ring.
  • R 1 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane;
  • n is an integer selected from 0 or 1
  • m and n are not 0 at the same time
  • x and y are independently 0 or 1, and the sum of x and y is 1;
  • R 3 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy
  • W, Z and V are all C atoms, or W and Z are C atoms and V is a N atom, or W and V are C atoms and Z is a N atom, or V and Z are C atoms and W is a N atom;
  • R 5 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane, or C 1-3 alkylene C 6-10 aryl.
  • R 5 is a substituent connected to a carbon atom of the ring.
  • the present invention further protects the following specific compounds, their pharmaceutically acceptable salts, solvates, or stereoisomers:
  • the present invention protects a method for preparing a compound of formula I, characterized in that:
  • Step 1 reacting an amino compound of formula A1 with a compound of formula B1 to obtain a compound of formula I.
  • Step 2 If necessary, the compound of formula I is subjected to functional group modification to convert it into a target product having the structure of formula I, or into a pharmaceutically acceptable salt or precursor compound of the compound.
  • M, R 1 -R 4 , x, y, m, n, and Cy 1 are as defined above, and Z 1 is a leaving group, such as halogen, hydroxyl, and the like.
  • the preparation method is also applicable to the preparation of the compound of formula IA and the compound of formula IB.
  • the compounds of formula I, formula IA, formula IB or pharmaceutically acceptable salts, solvates or stereoisomers of the present invention have Sigma2 receptor inhibitory activity and 5HT2A receptor inhibitory activity, and can be used for the treatment of related diseases mediated by Sigma2 receptor activity, the treatment of related diseases mediated by 5HT2A receptor activity, and the treatment of related diseases mediated by both Sigma2 receptor activity and 5HT2A receptor activity.
  • the inhibitory activity of the compounds of the present invention on 5HT2A is detected by IP-One experiment using Flp-In-CHO-5HT2A stable cell line.
  • the IP-One experiment is based on competitive immunoassay of HTRF (homogeneous time-resolved fluorescence), using anti-IP1 monoclonal antibody labeled with terbium cryptate and IP1 labeled with d2. If the compound shows IC50 ⁇ 1 ⁇ M, the compound tested in the above analysis is considered to have 5HT2A receptor inhibitory activity.
  • Preferred compounds of the present invention have IC50 ⁇ 150nM, more preferred compounds have IC50 ⁇ 100nM, and most preferred compounds have IC50 ⁇ 50nM.
  • the binding rate of the compounds of the present invention to the Sigma2 receptor is determined in a Jurkat cell line expressing human Sigma2 receptor.
  • the compounds of the present invention all have a high binding rate to the Sigma2 receptor.
  • the preferred compounds of the present invention have a binding rate to the Sigma2 receptor greater than 50% at 10 ⁇ M, the more preferred compounds have a binding rate to the Sigma2 receptor greater than 70% at 10 ⁇ M, and the most preferred compounds have a binding rate to the Sigma2 receptor greater than 80% at 10 ⁇ M.
  • the compounds of the present invention also have reduced cardiotoxicity.
  • the present invention provides the use of a compound of formula I, a compound of formula IA, a compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the preparation of a drug for treating diseases mediated by 5HT2A receptor activity.
  • the present invention provides the use of a compound of formula I, a compound of formula IA, a compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the preparation of a drug for treating diseases mediated by Sigma2 receptor activity.
  • the present invention provides the use of a compound of formula I, a compound of formula IA, a compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the preparation of a drug for treating diseases mediated by 5HT2A receptor and Sigma2 receptor activity.
  • the diseases related to the 5HT2A receptor and/or Sigma2 receptor activity-mediated diseases include but are not limited to central nervous system diseases.
  • the central nervous system diseases include, but are not limited to, mental illness, degenerative diseases of the central nervous system, mental disorder symptoms associated with or concurrent with degenerative diseases of the central nervous system, and negative symptoms of mental illness.
  • the mental illnesses include, but are not limited to, depression, anxiety, mania, schizophrenia, schizoaffective disorder, bipolar disorder, insomnia, autism, etc.
  • the central nervous system degenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia, etc.
  • the mental disorder symptoms associated with or concurrent with the degenerative diseases of the central nervous system and the negative symptoms of mental illness include, but are not limited to, affective disorders, decreased language function, hallucinations, loss of interest, emotional dullness, loss of will, lack of pleasure, social withdrawal, etc.
  • the present invention provides a pharmaceutical composition, characterized by comprising a compound of formula I, a compound of formula IA, a compound of formula IB or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the pharmaceutical composition can be used to treat diseases related to 5HT2A receptor and/or Sigma2 receptor activity.
  • diseases related to 5HT2A receptor and/or Sigma2 receptor activity is as described above.
  • the pharmaceutical composition further contains a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carriers are various excipients commonly used or known in the pharmaceutical field, including but not limited to: diluents, binders, antioxidants, pH regulators, preservatives, lubricants, disintegrants, etc.
  • the diluents include, for example, lactose, starch, cellulose derivatives, inorganic calcium salts, sorbitol, etc.
  • the binders include, for example, starch, gelatin, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, etc.
  • the antioxidants include, for example, vitamin E, sodium bisulfite, sodium sulfite, butyrate, etc. Hydroxyanisole, etc.
  • the pH adjuster for example: hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, Tris, acetic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, etc.
  • the preservative for example: methyl parahydroxybenzoate, ethyl parahydroxybenzoate, m-cresol, benzalkonium chloride, etc.
  • the lubricant for example: magnesium stearate, micro powder silica gel, talc, etc.
  • the disintegrant for example: starch, methyl cellulose, xanthan gum, cross-linked sodium carboxymethyl cellulose, etc.
  • the pharmaceutical composition contains the compound of formula I, the compound of formula IA, the compound of formula IB or their pharmaceutically acceptable salts, solvates, or stereoisomers in an amount of 0.1-1000 mg, preferably 1-500 mg, and more preferably 5-100 mg.
  • the mass percentage of the compound of formula I, the compound of formula IA, the compound of formula IB or their pharmaceutically acceptable salts, solvates, or stereoisomers in the pharmaceutical composition is 10%-90%, preferably 20%-80%, and more preferably 30%-70%.
  • the pharmaceutical composition may be in the form of an oral dosage form, such as tablets, capsules, pills, powders, granules, suspensions, syrups, etc.; or in the form of an injectable dosage form, such as an injection, a powder injection, etc., which is administered by intravenous, intraperitoneal, subcutaneous or intramuscular injection. All dosage forms used are well known to those skilled in the art of pharmacy.
  • the routes of administration of the pharmaceutical composition include, but are not limited to: oral; buccal; sublingual; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous; by implanted reservoir or reservoir.
  • the dosage of the compound of formula I, the compound of formula IA, the compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof will depend on the age, health and weight of the recipient, the type of the combined drug, the frequency of treatment, the route of administration, etc.
  • the drug can be administered in a single daily dose, once a day, once every two days, once every three days, once every four days, or the total daily dose is administered in divided doses twice, three times or four times a day.
  • the dose can be administered once or more, and the administration time can be from a single day to several months or longer.
  • the dosage of the compound of formula I, the compound of formula IA, the compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof 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.
  • the pharmaceutical composition can be used in combination with other drugs for treating related diseases mediated by 5HT2A receptor and/or Sigma2 receptor activity.
  • 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.
  • a second therapeutic agent which is another drug for treating diseases mediated by 5HT2A receptor and/or Sigma2 receptor activity.
  • 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, a compound of formula IA, a compound of formula IB or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered to a patient in need.
  • administration routes of the compound of Formula I, the compound of Formula IA, the compound of Formula IB, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof include, but are not limited to: oral; buccal; sublingual; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial; by implanted reservoirs or reservoirs.
  • the method further comprises administering to the patient in need other drugs for treating diseases mediated by 5HT2A receptor and/or Sigma2 receptor activity.
  • drugs for treating diseases mediated by 5HT2A receptor and/or Sigma2 receptor activity include, but are not limited to, drugs for treating mental illness, drugs for treating central nervous system degenerative diseases, etc.
  • the drugs for treating mental illness include but are not limited to: benzodiazepines Class (e.g., methyltriazine, chlordiazepoxide clonazepam, diazepam, sulopenia, flurazepam, midazolam, etc.); barbiturates (e.g. phenobarbital, pentobarbital, etc.); chloral hydrate; buspirone; phenothiazines (e.g. chlorpromazine, thioridazine, fluphenazine, etc.); thioxanthenes (e.g. thiothixene); butyrophenones (e.g.
  • haloperidol haloperidol
  • clozapine risperidone
  • tricyclic antidepressants e.g. imipramine, doxepin, nortriptyline, amitriptyline, etc.
  • heterocyclic antidepressants e.g. amoxapine, maprotiline, trazodone, bupropion, venlafaxine, etc.
  • selective serotonin reuptake inhibitors e.g. fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine, etc.
  • monoamine oxidase inhibitors e.g. phenelzine, moclobemide, etc.
  • ketamine mirtazapine, etc.
  • the drugs for treating degenerative diseases of the central nervous system include, but are not limited to, levodopa, bromocriptine, ergoline, diprofen, amantadine, reserpine, etc.
  • Halogen refers to F, Cl, Br or I.
  • substitution position of the ring means that the substituent group is located at any substitutable position in the ring.
  • the substitution position of the substituent is the ortho, meta or para position of the ring, which refers to the ortho, meta or para position of the ring relative to the main chain connection position.
  • pharmaceutically acceptable salts includes those derived from suitable inorganic acids and bases and organic acids and bases.
  • pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with 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 by using other methods in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, gluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,
  • Prep-HPLC purification under method A conditions: Prep-HPLC purification was performed using method A conditions, which included: column: sunfire 5 ⁇ m 19-150mm or XBridge-1 5 ⁇ m 19-150mm; mobile phase A: water (0.1% TFA), mobile phase B: CAN; gradient Degree: 10-20-9MIN 150VL
  • TFA 2,2,2-trifluoroacetic acid or trifluoroacetic acid
  • THF tetrahydrofuran
  • PEX5 Preparation of 1-(2-(4-fluorophenyl)-2-oxoethyl)piperidine-4-carboxylic acid
  • PEX6 Preparation of 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide
  • 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 DCM (150 mL). The mixture was then stirred at 25 ° C for 16 hours, then diluted with water (150 mL) and extracted with DCM (30 mL ⁇ 3). The combined organic layer was dried over sodium sulfate and evaporated in vacuo to give a residue.
  • PEX8 Preparation of 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one. Hydrochloride
  • PEX11 Preparation of (1-(4-fluorophenethyl)piperidin-4-yl)methylamine. Preparation of the hydrochloride salt
  • PEX12 Preparation of 1-(4-fluorophenethyl)-N-methylpiperidin-4-amine. Hydrochloride
  • 2,2,2-trifluoroacetate was prepared and purified using similar conditions as ER10382 using 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide (100 mg, 0.36 mmol) and 4-(2-bromoacetyl)benzonitrile (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.
  • N-(1-(2-(3-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide.2,2,2 trifluoroacetate was prepared and purified using similar conditions to ER10382 by reacting 2-(6-(methoxymethyl)pyridin-3-yl)-N-methyl-N-(piperidin-4-yl)acetamide (100 mg, 0.36 mmol) and 2-bromo-1-(3-fluorophenyl)ethan-1-one (78.2 mg, 0.36 mmol) to give the desired product N-(1-(2-(3-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-2-(6-(methoxymethyl)pyridin-3-yl)-N-methylacetamide.2,2,2 trifluoroacetate (66.13 mg, 44.30%)
  • N-((1-(2-oxo-2-phenylethyl)piperidin-4-yl)methyl)-2-methoxy-nicotinamide.2,2,2-trifluoroacetate salt was used similarly to ER10388 Conditional preparation and purification, 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) to obtain the desired product (47.5 mg, 24.6%) as a colorless oil.
  • EX12 Preparation of 2-methoxy-N-((1-(2-(4-methoxyphenyl)-2-oxoethyl)piperidin-4-yl)methyl)nicotinamide.2,2,2-trifluoroacetate (ER10383)
  • N-((1-(3-(4-fluorophenyl)-3-oxopropyl)piperidin-4-yl)methyl)-2-(methyloxy)nicotinamide.2,2,2-trifluoroacetate was prepared and purified using similar synthetic conditions as ER10392 using 3-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)propan-1-one hydrochloride (100 mg, 0.332 mmol) and 2-methoxynicotinic acid (61.1 mg, 0.0.400 mmol) to give the desired product (52.5 mg, 39.47%) as a white solid.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)nicotinamide.2,2,2-trifluoroacetate was prepared and purified using similar conditions to the synthesis of ER10392 by using nicotinic acid (54.1 mg, 0.439 mmol, 1.1 eq) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one hydrochloride (100 mg, 0.400 mmol, 1.0 eq) to give the desired product (85.0 mg, 43.1%) as a light yellow oil.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isonicotinamide, 2,2,2-trifluoroacetate was prepared and purified using conditions similar to the synthesis of ER10392 using isonicotinic acid (54.1 mg, 0.439 mmol, 1.1 equiv) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one hydrochloride (100 mg, 0.400 mmol, 1.0 equiv) to afford the desired product (75.0 mg, 38.0%) as a light yellow oil.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-(methoxymethyl)picolinamide was prepared and purified using similar conditions to the synthesis of ER10392 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one hydrochloride (600 mg, 3.59 mmol) and 6-(methoxymethyl)picolinic acid (1.24 g, 4.31 mmol) to give the desired product (26.2 mg, 1.33%).
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-methyl-picolinamide.2,2,2-trifluoroacetate was prepared and purified using conditions similar to the synthesis of ER10392 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol) and 3-methylpicolinic acid (131 mg, 0.959 mmol) to give the desired product (28.7 mg, 7.43%) as a colorless oil.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methylnicotinamide.2,2,2-trifluoroacetate was prepared and purified using conditions similar to the synthesis of ER10392 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-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 body.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methyl-picolinamide.2,2,2-trifluoroacetate was prepared and purified using similar conditions to the synthesis of ER10392 using 2-[4-(aminomethyl)piperidin-1-yl]-1-(4-fluorophenyl)ethanone (200 mg, 0.799 mmol) and 4-methylpicolinic acid (132 mg, 0.959 mmol) to give the desired product (71.4 mg, 18.5%) as a yellow solid.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-5-methyl-nicotinamide.2,2,2-trifluoroacetate was prepared and purified using similar synthetic conditions as ER10392 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-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.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-methoxy-picolinamide.2,2,2-trifluoroacetate was prepared and purified using synthetic conditions similar to ER10392 , using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol) and 3-methoxypicolinic acid (147 mg, 0.959 mmol) gave the desired product (63.8 mg, 16.5%) as a white solid.
  • EX30 N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methoxy-nicotinamide.2,2,2-trifluoroacetate (ER10354)
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methoxy-nicotinamide.2,2,2-trifluoroacetate was prepared and purified using similar synthetic conditions as ER10392 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol) and 4-methoxynicotinic acid (147 mg, 0.959 mol) to give the desired product (110 mg, 27.5%) as a yellow solid.
  • EX31 N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methoxypicolinamide.2,2,2-trifluoroacetate (ER10355)
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methoxypicolinamide.2,2,2-trifluoroacetate was prepared and purified using similar synthetic conditions as ER10392 using 2-[4-(aminomethyl)piperidin-1-yl]-1-(4-fluorophenyl)ethanone (200 mg, 0.799 mmol) and 4-methoxypicolinic acid (147 mg, 0.959 mmol) to give the desired product (57.0 mg, 14.3%) as a yellow solid.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-5-methoxy-nicotinamide.2,2,2-trifluoroacetate was prepared and purified using similar synthetic conditions to ER10392 using 2-[4-(aminomethyl)piperidin-1-yl]-1-(4-fluorophenyl)ethanone (200 mg, 0.799 mmol) and 5-methoxynicotinic acid (147 mg, 0.959 mmol) to give the desired product (173 mg, 43.38%) as a yellow solid.
  • EX33 N-(1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-3-(4-(methoxymethyl)phenyl)-N-methylpropanamide. 2,2,2-trifluoroacetate (ER10295)
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-methoxybenzamide.2,2,2-trifluoroacetate was prepared and purified according to conditions similar to the synthesis of ER10320 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol, 1.0 equiv) and 3-methoxybenzoic acid (122 mg, 0.879 mmol, 1.1 equiv) to give the desired product (15.0 mg, 4.31%) as a light yellow oil.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-4-methoxybenzamide.2,2,2-trifluoroacetate was prepared and purified using synthetic conditions similar to ER10320 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol, 1.0 equiv) and 4-methoxybenzoic acid (134 mg, 0.879 mmol, 1.1 equiv) to give the desired product (45.0 mg, 12.9%) as a light yellow oil.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methoxypicolinamide 2,2,2-trifluoroacetate was prepared and purified according to synthetic conditions similar to ER10320 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol, 1.0 equiv) and 6-methoxypicolinic acid (135 mg, 0.879 mmol, 1.1 equiv) to give the desired product (50.0 mg, 14.4%) as a light yellow solid.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methylpicolinamide 2,2,2-trifluoroacetate was prepared and purified according to similar synthetic conditions as ER10320 using 2-[4-(aminomethyl)piperidin-1-yl]-1-(4-fluorophenyl)ethanone (200 mg, 0.799 mmol, 1.0 equiv) and 6-methylpyridine-2-carboxylic acid (121 mg, 0.879 mmol, 1.1 equiv) to afford the desired product (35.0 mg, 10.4%) as a light yellow oil.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methoxyisonicotinamide.2,2,2-trifluoroacetate was prepared and purified according to the synthetic conditions similar to ER10320 , using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol, 1.0 equiv) and 2-methoxyisonicotinic acid (135 mg, 0.879 mmol, 1.1 equiv) to give the desired product (43.0 mg, 12.4%) as a light yellow oil.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methylisonicotinamide.2,2,2-trifluoroacetate was prepared and purified according to synthetic conditions similar to ER10320 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.697 mmol, 1.0 equiv) and 2-methylisonicotinic acid (115 mg, 0.837 mmol, 1.1 equiv) to give the desired product (99.3 mg, 29.5%) as a light yellow oil.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methoxynicotinamide.2,2,2-trifluoroacetate was prepared and purified according to the synthetic conditions similar to ER10320 , using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol, 1.0 equiv) and 2-methoxynicotinic acid (135 mg, 0.879 mmol, 1.1 equiv) to give the desired product (135 mg, 38.8%) as a light yellow oil.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-2-methylnicotinamide.2,2,2-trifluoroacetate was prepared and purified according to synthetic conditions similar to ER10320 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol, 1.0 equiv) and 2-methylnicotinic acid (121 mg, 0.879 mmol, 1.1 equiv) to give the desired product (40.0 mg, 11.9%) as a light yellow oil.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methoxynicotinamide.2,2,2-trifluoroacetate was prepared and purified following similar synthesis conditions as ER10320 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol, 1.0 equiv) and 6-methoxynicotinic acid (135 mg, 0.879 mmol, 1.1 equiv) to give the desired product (40.0 mg, 11.5%) as a light yellow oil.
  • N-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-6-methylnicotinamide.2,2,2-trifluoroacetate was prepared and purified according to synthetic conditions similar to ER10320 using 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol, 1.0 equiv) and 6-methylnicotinic acid (135 mg, 0.879 mmol, 1.1 equiv) to give the desired product (90.0 mg, 26.7%) as a light yellow oil.
  • the IP-One experiment was selected to complete the detection.
  • the following experiments were completed using the Flp-In-CHO-5HT2A stable cell line.
  • the IP-One experiment is based on HTRF (homogeneous time-resolved fluorescence) competitive immunoassay, using terbium cryptate-labeled anti-IP1 monoclonal antibody and d2-labeled IP1.
  • the IP1 produced by the cells and the d2-labeled IP1 provided by the kit compete for the antigen binding site of the anti-IP1 antibody.
  • Flp-In TM -CHO cell line Chinese hamster ovary cell transformed cell line (Flp-In TM -CHO cell line) (purchased from invitrogen, R75807) was generated by transfecting CHO cells with pFRT//acZeo2 and selecting Zeocin TM resistant clones.
  • Flp-In TM -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 human HTR2A gene (Human HTR2A, GeneBank, NM_000621) to obtain Flp-In-CHO-5HT2A cells.
  • Stably transfected cell lines were cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone) + 1 ⁇ Penicilin-Streptomycin + 800 ⁇ g/ml Hygromycin B (ant-hg-5, Invivogen).
  • the Flp-In-CHO-5HT2A stable cell line was cultured in 384-well plates (7.5K) at 37°C, 5% CO 2 for 20 hours. The compounds were diluted to different concentrations in Ham's F-12K medium, and the culture medium was replaced with fresh medium at 100 ⁇ l/well for overnight culture. After the cells were treated with the compounds for 30 minutes, 5-HT was added and cultured at 37°C for 45 minutes. After that, the lysis detection buffer, IP1-d2 and IP1-Ab were added in sequence and cultured at room temperature for 1 hour before reading the plate on Envision (HTRF module).
  • Human Sigma2 receptor was expressed in Jurkat cells, and the cell membranes were incubated with 25 nM [ 3 H] labeled DTG in modified potassium phosphate buffer (pH 7.6) at 25°C for 60 minutes, and nonspecific binding was determined with 10 ⁇ M haloperidol. The cell membranes were filtered and washed, and [ 3 H]DTG in the filtrate was detected to determine the specific binding of the compound.
  • the same assay method was used to detect the inhibitory activity of the compounds on sigma2 receptors according to the concentration gradient and the corresponding IC50 values were calculated.
  • hERG human Ether-a-go-go Related Gene
  • the hERG-encoded potassium channel 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 special molecular structure, hERG's functional loss or drug inhibition will affect the repolarization process of the cardiac action potential. It can also cause QT interval prolongation and may induce torsades de pointes, leading to arrhythmia.
  • hERG membrane protein, test compound and fixed concentration of radioligand are mixed, so that the test compound and radioligand are competitively bound to hERG membrane protein.
  • the radioligand that is not bound to the membrane protein is filtered out by vacuum, and the filter plate is dried and scintillation fluid is added, and the isotope signal (CPM) is detected on Microbeta.
  • CPM isotope signal
  • the compound, diluted hERG membrane protein and diluted H3-dofetilide ligand (NET1144100UC, PerkinElmer) were added into a 96-well plate (3631, Corning) in sequence. After sealing the plate with a sealing film, the plates were incubated with shaking at room temperature for 1 hour.
  • the incubated hERG membrane protein was transferred to a GF/B plate (600517, PerkinElmer) using a PerkinElmer cell harvester and 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 an oven at 50°C for 30 min to allow the GF/B plate to fully dry.
  • the bottom of the GF/B plate was sealed with a bottom sealing film (6005199, PerkinElmer).
  • This experiment used a manual patch clamp system to evaluate the potential inhibitory effect of video on human hERG channels.
  • the experiment used HEK293 cells stably transfected with hERG gene and dofetilide as a positive control.
  • This experiment uses an automated patch clamp system to evaluate the potential inhibitory effect of video on human hERG channels.
  • the experiment uses a CHO cell line that stably expresses the hERG gene and cisapride as a positive control.
  • the cells in two T175 culture flasks (431082, CORNING) were rinsed 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 detached and transferred to a 10 cm ultra-low binding culture dish (NEST (704001)) using a pipette (BIOFIL (GSP110010)), incubated at 4-10°C for 10 minutes, counted (Invitrogen (Countess II)), and transferred to a Teflon storage tank with orbital shaking (IKA (MS3digital)).
  • NEST 10 cm ultra-low binding culture dish
  • BIOFIL BIOFIL
  • IKA Teflon storage tank with orbital shaking
  • the chip (Nanion (221401, 4xhigh)) was filled with internal and external solutions on a SyncroPatch 384i instrument (Nanion (384i)), cells were added to the chip, and the holding potential was set to -90 mV for 500 ms after sealing the cell.
  • the hERG current was induced by depolarization to +30 mV for 4.8 seconds, and then the Voltage was set to -50 mV for 5.2 seconds, and inactivation was removed to measure inactivation tail current.
  • hERG current was recorded in the presence of test compounds for at least 5 minutes, and the hERG current inhibitory concentration of the compound was determined in two independent experiments.

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Abstract

本发明提供一种酰胺类化合物，其具有Sigma2受体和5HT2A受体抑制活性，可以作为Sigma2和5HT2A双靶标抑制剂，用于治疗Sigma2受体活性介导的相关疾病的治疗，5HT2A受体活性介导的相关疾病的治疗，以及由Sigma2受体活性和5HT2A受体活性共同介导的相关疾病的治疗，例如精神分裂症的阴性症状。

Description

一种酰胺类化合物及其制备Sigma2和5HT2A抑制剂的用途
本申请要求2022年9月28日向中国国家知识产权局提交的专利申请号为202211193932.3，发明名称为“一种酰胺类化合物及其制备Sigma2和5HT2A抑制剂的用途”的在先申请的优先权。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本申请涉及药用化合物领域，具体涉及一种酰胺类化合物，及其作为Sigma2和5HT2A双靶标抑制剂的用途。
背景技术
精神分裂症是一种慢性、致残性疾病，有阳性和阴性症状群。阳性和阴性症状起源于神经科学领域，后来被精神病学采用，在精神分裂症中用症状群来描述。阳性症状反映的是正常功能的过度或扭曲(如妄想、幻觉、紊乱行为)，而阴性症状是指与动机和兴趣相关的正常行为的减少或缺失(例如，意志减退、快感缺乏、社交退缩)或表情的减少或缺失(例如，情感迟钝、言语贫乏)。阴性症状是精神分裂症的核心症状，在精神分裂症患者的发生率和不良功能预后中占很大比例。与阳性症状相比，阴性症状的疾病负担更重。这种明显的疾病负担可归因于有效治疗选择的有限性，因为它们通常对当前可用的抗精神病药物如多巴胺D2受体拮抗剂或部分D2受体激动剂治疗反应不佳(NormanRMG,et al.(2015)Schizophr Res.169:412-417.)。
阴性症状是常见的，在疾病任何阶段都可能出现，例如，在90％首次精神病发作的患者中，至少有1个阴性症状，而35-70％的患者在治疗后仍有临床意义的阴性症状。在临床接受常规抗精神病药物治疗的门诊稳定精神分裂症患者中，61％的患者至少有1个中度或更严重的症状。被纳入评估的5个PANSS阴性症状量表条目中(情感迟钝、情绪退缩、情感交流障碍、社交退缩、交谈缺乏自发性和流畅性)，社交退缩(48％)，情绪退缩(42％)和情感交流障碍(39％)是最常见的症状，19％的患者有全部5个阴性症状。研究表明，阴性症状会随着时间的推移而持续存在，事实上，随着患者年龄的增长会变得更加明显，而阳性症状则会变得不那么突出(National Institute of Mental Health:Research Domain Criteria(RDoC).Positive Valence Systems.)。
到目前为止，FDA还没有批准任何药物用于治疗阴性症状(https://www.nimh.nih.gov/research-priorities/rdoc/constructs/positive-valence-systems.shtml.Accessed March 28,2019.)。矛盾的是，抗精神病药物既能改善也能恶化阴性症状。一方面，通过改善幻觉、妄想和激越，抗精神病药物促进了社交互动。另一方面，通过干扰DA神经传递和大脑奖赏回路动力不足，阴性症状的核心成分被加重并诱发锥体 外系不良反应，这些不良反应通常与原发性阴性症状无法区分。
很少有前瞻性的研究旨在评估治疗对持续性阴性症状的改善，大多数关于阴性症状改善的报告都是基于对急性精神病患者和并发阴性症状患者的短期研究。因此，在大多数报道的研究中，很难确定阴性症状的改善是治疗的真正效果还是其他症状维度改善(例如阳性，抑郁，锥体外系)的继发效果，并且缺乏长期证据(Helfer B,t al.(2016)Am J Psychiatry.2016；173:876-886.)。
考虑到与阴性症状相关的大量未满足的医学需求，在该治疗领域中活跃着对不同受体上具有活性的药物研究，包括NMDA受体，α7烟碱样受体，5-HT2A受体和Sigma-2受体。其中，没有直接多巴胺亲和力的Sigma2受体及5-HT2A受体拮抗剂最受关注(Remington G,et al.(2016)Curr Treat OptionsPsychiatry.3:133-150.)。
Sigma受体，包括Sigma1和Sigma2受体，均受小分子调节，主要存在于内质网膜相关位点，是在中枢神经系统和外周组织中广泛表达的完整膜蛋白(Hellewell,S.B.et al.(1994)Eur.J.Pharmacol.268,9-18)。许多药物与Sigma受体结合，包括抗精神病药物氟哌啶醇和阿片类镇痛药喷他佐辛。Sigma受体与多种中枢神经系统疾病相关，尤其是阿尔兹海默症(AD)、精神分裂症以及与运动控制相关的疾病如肌萎缩侧索硬化症(ALS)等。
对Sigma2受体的拮抗作用也可能调节谷氨酸能通路并影响钙神经元调节(Vilner BJ,Bowen WD.(2020)J PharmacolExpTher.292:900–911)。Sigma2受体参与抵消关键DA和谷氨酸神经递质途径的失调。
血清素或5-羟色胺(5-HT)在人体生理功能中发挥着极为重要的作用。在中枢神经系统中，5-HT是一种重要的神经递质和神经调节剂，它在调控多种行为如睡眠、饮食、活动、学习和记忆、机体体温、血压以及病理状态(如焦虑、躁狂、精神分裂、肥胖、药物成瘾、偏头痛和高血压)方面发挥着极为重要的作用(Alenina N,et al.,(2009)ProcNatl Acad Sci USA,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通过其受体发挥作用，根据结构(氨基酸序列)、生化(信号转导的后受体机制)和药理学差异将5-HT受体分为7个家族(5-HT1～5-HT7)以及至少15个不同亚型(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)。不同亚型受体的分布、配体偏好以及相关功能各不相同。
5-HT2A亚型受体在中枢神经系统呈现广泛而离散的表达，在参与调节高级认知和情感功能的大脑皮质、边缘、海马、下丘脑和基底神经节中表达最高。5-HT2A受体在多巴胺、GABA、谷氨酸和Ach神经元上表达并起着树突状异质受体的作用(Buhot MC,(1997)Curr Opin Neurobiol,7,243-254；Leysen JE,(2004)Curr Drug Targets CNS Neuro Disord,3,11-26)。和大多数5-HT受体一样，5-HT2A受体为G-蛋白偶联受体，它通过激活鸟嘌呤核苷酸结合蛋白(G蛋白)完成信号转导，导致第二信使分子如环腺苷酸(cAMP)、肌醇磷酸酯(inositol phosphates)以及二酰甘油(diacylglycerol)水平升高或降低。这些第二信使分子调节多种胞内酶的功能(如激酶和离子通道)，最终影响细胞兴奋性和细胞功能。
5-HT传递异常与多种精神疾病的发病机制相关，如精神疾病(抑郁、惊恐发作、精神分裂症、自杀倾向等)以及神经系统退行性疾病(阿尔兹海默症、亨廷顿舞蹈症、帕金森病等)(Fioravanti et al.,(1992)Brain Cogn.18,116-124；Sinopoli VM,et al.,(2017)Neurosci Biobehav Rev,80:372-381)。近年来研究发现，5-HT2A受体与神经精神疾病的病理状态密切相关，5-HT2A受体参与了非典型抗精神病药物如氯氮平、奥氮平、利培酮的分子作用机制(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受体拮抗剂对于治疗精神分裂症阴性症状(如情感障碍、语言功能减退等)十分重要(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,H.Y.(2013)Annu Rev Med 64,393-406)。另有研究证实，皮质锥体神经元的5-HT2A受体调节通路对介导致幻剂引发的信号转导和行为反应至关重要(Gonzalez-Maeso J,et al.,(2009)Trends Neurosci,32:225-232)，提示5-HT2A受体在治疗多种神经退行性疾病幻觉症状方面的作用。
用于治疗精神疾病的药物，即抗精神病药物分为两大类。“典型”抗精神病药物或上一代药物由于对人体造成的机动功能副作用(锥体外系副反应、类帕金森病症等)在临床已很少应用，现行药物更多着眼于“非典型”抗精神病药物(Prim Cre Companion J Clin Psychiatry.(2007)9(6):444-54)。但是该第二代抗精神病药物皆有广谱受体活性，这些化合物作为激动剂、竞争性拮抗剂或反向激动剂等方式调节多种单胺能受体如5-HT能、多巴胺能、肾上腺素能、毒蕈碱或组胺能受体，这种广谱调节很有可能是造成镇静异常、运动机能异常、二型糖尿病等副作用的原因。
在治疗阴性症状的治疗方案中，与阳性症状相比，阴性症状的精神分裂症患者的功能结果更差，对抗精神病药物的反应更差。第一代和第二代抗精神病药物在持续治疗阴性症状方面大多无效。因此仍需要开发能够治疗中枢神经系统疾病的新的药用化合物。
发明内容
本申请公开一种如式I结构的化合物、其药学可接受的盐、溶剂化物、或立体异构体，
其中，M选自O、S或H，当M为H时，C＝M表示CH2；优选M为O；
R1、R2独立地选自氢、C1-6烷基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、C6-10芳基、或C1-6亚烷基C6-10芳基；
n、m独立的选自0-4的整数，例如0，1，2，3或4；
x、y独立的为0或1，且x、y之和为1；
R3选自氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、C6- 10芳基、或C1-6亚烷基C6-10芳基；
R4选自氢、卤素、CN、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、C6-10芳基、或C1-6亚烷基C6-10芳基；
Cy1表示环取代基，Cy1仅代表非稠合的单环，所述单环为四元、五元、六元或七元环，所述单环为芳环、杂芳环、碳环或杂环，杂芳环和杂环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代；优选Cy1为五元环或六元环，更优选为苯环、环己烷、吡啶、噻唑、或唑；
R5选自氢、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、或C1-6亚烷基C6-10芳基。
在本发明的一些实施方案中，M为O。
在本发明的一些实施方案中，R1、R2独立地选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、C6-10芳基、或C1-3亚烷基C6-10芳基。
在本发明的一些实施方案中，n、m独立的选自0-2的整数，例如0，1或2。
在本发明的一些实施方案中，R3选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、C6-10芳基、或C1-3亚烷基C6-10芳基。
在本发明的一些实施方案中，R4选自氢、卤素、C1-3烷基。在本发明的一些更具体的实施方案中，R4选自氢、F、Cl、甲基。
在本发明的一些实施方案中，R4的取代位置为苯环的对位。
在本发明的一些实施方案中，Cy1代表非稠合的单环，所述单环为五元或六元环，所述单环为芳环、杂芳环、碳环或杂环，杂芳环和杂环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代。
在本发明的一些实施方案中，Cy1是苯环或吡啶。
在本发明的一些实施方案中，R5选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、或C1-3亚烷基C6-10芳基。
在本发明的一些实施方案中，式I中：M为O；
R1、R2独立地选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、C6-10芳基、或C1-3亚烷基C6-10芳基；
n、m独立的选自0-2的整数，例如0，1或2；
x、y独立的为0或1，且x、y之和为1；
R3选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、C6- 10芳基、或C1-3亚烷基C6-10芳基；
R4的取代位置为苯环的对位，R4选自氢、卤素、C1-3烷基，更优选，R4选自氢、F、Cl、甲基；
Cy1代表非稠合的单环，所述单环为五元或六元环，所述单环为芳环、杂芳环、碳环或杂环，杂芳 环和杂环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代；优选，Cy1是苯环、环己烷、吡啶、噻唑、或唑，更优选是苯环或吡啶；
R5选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、或C1-3亚烷基C6-10芳基。
本申请公开一种如式IA结构的化合物、其药学可接受的盐、溶剂化物、或立体异构体，
其中，R1、R2独立地选自氢、C1-6烷基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、C6-10芳基、或C1-6亚烷基C6-10芳基；
m选自0-4的整数，例如0，1，2，3或4；n选自0-2的整数，例如0，1或2；
x、y独立的为0或1，且x、y之和为1；
R3选自氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、或C1-6亚烷基C3-7环烷烃；
Cy1表示环取代基，Cy1仅代表非稠合的单环，所述单环为四元、五元、六元或七元环，所述单环为芳环、杂芳环、碳环或杂环，杂芳环和杂环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代；优选，Cy1为五元环或六元环，更优选为苯环、环己烷、吡啶、噻唑、或唑。
R5选自氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、或C1-6亚烷基C6-10芳基。
在本发明的一些实施方案中，R1、R2独立地选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、C6-10芳基、或C1-3亚烷基C6-10芳基。
在本发明的一些实施方案中，m选自0、1或2的整数，n选自0或1的整数，且m和n不同时为0。
在本发明的一些实施方案中，R3选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃。
在本发明的一些实施方案中，Cy1代表非稠合的单环，所述单环为五元或六元环，所述单环为芳环、杂芳环、碳环或杂环，杂芳环和杂环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代。
在本发明的一些实施方案中，Cy1是苯环或吡啶。
在本发明的一些实施方案中，R5选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷 烃、C1-3亚烷基C3-7环烷烃、或C1-3亚烷基C6-10芳基。
在本发明的一些实施方案中，R5为一个取代基，与所述环的碳原子连接。
在本发明的一些实施方案中，式IA中，R1、R2独立地选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、C6-10芳基、或C1-3亚烷基C6-10芳基；
m选自0、1或2的整数，n选自0或1的整数，且m和n不同时为0；
x、y独立的为0或1，且x、y之和为1；
R3选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃；
Cy1代表非稠合的单环，所述单环为五元或六元环，所述单环为芳环、杂芳环、碳环或杂环，杂芳环和杂环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代；优选，Cy1是苯环、环己烷、吡啶、噻唑、或唑，更优选为苯环或吡啶；
R5选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、或C1-3亚烷基C6-10芳基；优选，R5为一个取代基，与所述环的碳原子连接。
本申请公开一种如式IB结构的化合物、其药学可接受的盐、溶剂化物、或立体异构体，
其中，R1选自氢、C1-6烷基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、或C1-6亚烷基C3-7环烷烃；
m选自0-4的整数，例如0，1，2，3或4，n选自0或1；
x、y独立的为0或1，且x、y之和为1；
R3选自氢、C1-6烷基、或C1-6烷氧基；
W、Z或V独立地选自C、N、O或S的环原子，虚线与实线键表示双键或单键，一个或多个R5取代在六元环的任意位置，R5选自氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、或C1-6亚烷基C6-10芳基；优选W、Z或V独立地为C或N原子，一个或多个R5连接六元环任意环碳和/或环氮原子。
在本发明的一些实施方案中，R1选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃。
在本发明的一些实施方案中，m选自0、1或2的整数，且m和n不同时为0。
在本发明的一些实施方案中，R3选自氢、C1-3烷基、C1-3烷氧基。
在本发明的一些实施方案中，W、Z和V均为C原子；优选，含W、Z和V的环为苯环。
在本发明的一些实施方案中，W和Z为C原子且V为N原子，或者，W和V为C原子且Z为N原子，或者，V和Z为C原子且W为N原子；优选，含W、Z和V的环为吡啶。
在本发明的一些实施方案中，R5选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、或C1-3亚烷基C6-10芳基。
在本发明的一些实施方案中，R5为一个取代基，与所述环的碳原子连接。
在本发明的一些实施方案中，式IB中，R1选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃；
m选自0、1或2的整数，n选自0或1，且m和n不同时为0；
x、y独立的为0或1，且x、y之和为1；
R3选自氢、C1-3烷基、C1-3烷氧基；
W、Z和V均为C原子，或者，W和Z为C原子且V为N原子，或者，W和V为C原子且Z为N原子，或者，V和Z为C原子且W为N原子；
R5选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、或C1-3亚烷基C6-10芳基，优选，R5为一个取代基，与所述环的碳原子连接。
本发明进一步保护如下具体化合物、其药学可接受的盐、溶剂化物、或立体异构体：



本发明保护一种制备式I化合物的方法，其特征在于：
步骤1、式A1结构的胺基化合物与式B1化合物反应，得到式I化合物，
或，式A2结构的胺基化合物与式B2化合物反应，得到式I化合物；
再或，式C1结构化合物与C2化合物反应，得到式I化合物，
步骤2、如果需要，对式I化合物进行官能团修饰，转化为具有式I结构的目标产物，或者转化为所述化合物的药学可接受的盐，或前体化合物。
其中，M、R1-R4、x、y、m、n、Cy1定义同上，Z1为离去基团，例如卤素、羟基等。
所述制备方法同样适用于式IA化合物和式IB化合物的制备。
本发明的式I化合物、式IA化合物、式IB化合物或其药学上可接受的盐，溶剂化物，或立体异构体具有Sigma2受体抑制活性和5HT2A受体抑制活性，可以用于Sigma2受体活性介导的相关疾病的治疗，5HT2A受体活性介导的相关疾病的治疗，以及由Sigma2受体活性和5HT2A受体活性共同介导的相关疾病的治疗。
本发明化合物对5HT2A的抑制活性是采用Flp-In-CHO-5HT2A稳定细胞系，通过IP-One实验完成检测。IP-One实验基于HTRF(均相时间分辨荧光)的竞争性免疫检测，使用了铽穴状化合物标记的抗IP1单抗和d2标记的IP1。如果化合物表现出IC50≤1μM，认为在以上分析中测试的化合物具有5HT2A受体抑制活性。本发明优选的化合物具有IC50≤150nM，更优选的化合物具有IC50≤100nM，最优选化合物具有IC50≤50nM。
本发明化合物对Sigma2受体的结合率是采用表达人Sigma2受体的Jurkat细胞系中测定的。本发明化合物对Sigma2受体均有较高的结合率。本发明优选的化合物在10μM时对Sigma2受体的结合率大于50％，更优选的化合物在10μM时对Sigma2受体的结合率大于70％，最优选的化合物在10μM时对Sigma2受体的结合率大于80％。
进一步的，本发明化合物还具有降低的心脏毒性。
本发明提供式I化合物、式IA化合物、式IB化合物，或其药学上可接受的盐，溶剂化物，或立体异构体在制备治疗5HT2A受体活性介导的相关疾病的药物中的用途。
本发明提供式I化合物、式IA化合物、式IB化合物，或其药学上可接受的盐，溶剂化物，或立体异构体在制备治疗Sigma2受体活性介导的相关疾病的药物中的用途。
本发明提供式I化合物、式IA化合物、式IB化合物，或其药学上可接受的盐，溶剂化物，或立体异构体在制备治疗5HT2A受体和Sigma2受体活性介导的相关疾病的药物中的用途。
所述5HT2A受体和/或Sigma2受体活性介导的相关疾病包括但不限于中枢神经系统疾病。
所述中枢神经系统疾病包括但不限于：精神疾病，中枢神经系统退行性疾病，中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状。
所述精神疾病包括但不限于：抑郁症、焦虑症、躁狂症、精神分裂症、情感性分裂症、双相精神障碍、失眠、自闭症等。
所述中枢神经系统退行性疾病包括但不限于：阿尔兹海默症、帕金森病、亨廷顿病、路易小体痴呆症等。
所述中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状包括但不限于：情感障碍、语言功能减退、幻觉、兴趣缺失、情感迟钝、意志减退、快感缺乏、社交退缩等。
本发明提供一种药物组合物，其特征在于包括式I化合物、式IA化合物、式IB化合物或其药学上可接受的盐，溶剂化物，或立体异构体。
所述药物组合物可以用于治疗5HT2A受体和/或Sigma2受体活性介导的相关疾病。所述5HT2A受体和/或Sigma2受体活性介导的相关疾病的定义如前文所述。
所述药物组合物进一步含有药学上可接受的载体。
所述药学上可接受的载体是制药领域中常用或已知的各种辅料，包括但不限于：稀释剂、粘合剂、抗氧化剂、pH调节剂、防腐剂、润滑剂、崩解剂等。
所述稀释剂例如：乳糖、淀粉、纤维素衍生物、无机钙盐、山梨醇等。所述粘合剂例如：淀粉、明胶、羧甲基纤维素钠、聚乙烯吡咯烷酮等。所述抗氧化剂例如：维生素E、亚硫酸氢钠、亚硫酸钠、丁 羟基茴香醚等。所述pH调节剂例如：盐酸、氢氧化钠、柠檬酸、酒石酸、Tris、乙酸、磷酸二氢钠、磷酸氢二钠等。所述防腐剂例如：对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、间甲酚、苯扎氯铵等。所述润滑剂例如：硬脂酸镁、微粉硅胶、滑石粉等。所述崩解剂例如：淀粉、甲基纤维素、黄原胶、交联羧甲基纤维素钠等。
所述药物组合物中含有式I化合物、式IA化合物、式IB化合物或其药学上可接受的盐，溶剂化物，或立体异构体的量为0.1-1000mg，优选1-500mg，更优选为5-100mg。
所述药物组合物中式I化合物、式IA化合物、式IB化合物或其药学上可接受的盐，溶剂化物，或立体异构体占药物组合物的质量百分比为10％-90％，优选为20％-80％，更优选为30％-70％。
所述药物组合物的剂型可以是口服剂的形式，例如片剂、胶囊、丸剂、粉剂、颗粒剂、悬浮剂、糖浆剂等；也可以是注射给药的剂型，例如注射液、粉针剂等，通过静脉内、腹膜内、皮下或肌肉内的途径注射给药。所有使用的剂型形式都是药学领域普通技术人员所熟知的。
所述药物组合物的施用途径包括但不限于：口服的；含服的；舌下的；透皮的；肺的；直肠的；肠胃外的，例如，通过注射，包括皮下的、真皮内的、肌内的、静脉内的；通过植入储库或储液器。
式I化合物、式IA化合物、式IB化合物或其药学上可接受的盐，溶剂化物，或立体异构体的施用剂量将取决于接受者的年龄、健康和体重，联用药物的种类，治疗频率，给药途径等。药物可以单一日剂量施用，每天给药一次、每两天给药一次、每三天给药一次、每四天给药一次，或者总日剂量以每天两次、三次或四次的分开剂量施用。剂量可以施用一次或多次，施药时间可以单日至几个月或更长时间。式I化合物、式IA化合物、式IB化合物或其药学上可接受的盐，溶剂化物，或立体异构体的用药量为0.01-100mg/kg/天，优选为0.1-10mg/kg/天，例如为0.5mg/kg/天，1mg/kg/天、2mg/kg/天、5mg/kg/天等等。
所述药物组合物可以和其他的治疗5HT2A受体和/或Sigma2受体活性介导的相关疾病的药物联合应用。
所述药物组合物可以进一步含有第二种治疗剂，所述第二种治疗剂是其他的治疗5HT2A受体和/或Sigma2受体活性介导的相关疾病的药物。
本发明提供一种治疗5HT2A受体和/或Sigma2受体活性介导的相关疾病的方法，其特征在于，对有需要的患者施用治疗有效量的式I化合物、式IA化合物、式IB化合物或其药学上可接受的盐，溶剂化物，或立体异构体。
所述式I化合物、式IA化合物、式IB化合物或其药学上可接受的盐，溶剂化物，或立体异构体的施用途径包括但不限于：口服的；含服的；舌下的；透皮的；肺的；直肠的；肠胃外的，例如，通过注射，包括皮下的、真皮内的、肌内的、静脉内的、动脉内的；通过植入储库或储液器。
所述方法进一步包括，对有需要的患者给予其他的治疗5HT2A受体和/或Sigma2受体活性介导的相关疾病的药物。
其他的治疗5HT2A受体和/或Sigma2受体活性介导的相关疾病的药物包括但不限于：精神疾病治疗药物、中枢神经系统退行性疾病治疗药物等。
所述精神疾病治疗药物包括但不限于：苯二氮类(例如：甲基三唑西泮、氯氮氯硝西泮、地西泮、舒乐安定、氟西泮、咪达唑仑等)；巴比妥类(例如：苯巴比妥、戊巴比妥等)；水合氯醛；丁螺环酮；吩噻嗪类(例如：氯丙嗪、硫利达嗪、氟奋乃静等)；硫杂蒽类(例如：替沃噻吨)；丁酰苯类(例如：氟哌啶醇)；氯氮平；利哌利酮；三环类抗抑郁药(例如：丙咪嗪、多塞平、去甲替林、阿米替林等)；杂环类抗抑郁药(例如：阿莫沙平、马普替林、曲唑酮、安非他酮、文法拉辛等)；选择性5-HT重摄取抑制剂(例如：氟西汀、帕罗西汀、舍曲林、西酞普兰、氟伏沙明等)；单胺氧化酶抑制剂(例如：苯乙肼、吗氯贝胺等)；氯胺酮；米氮平等。
所述中枢神经系统退行性疾病治疗药物包括但不限于：左旋多巴、溴隐亭、硫丙麦角林、丙炔苯丙胺、金刚烷胺、利血平等。
在本发明中：
“卤素”指F、Cl、Br或I。
“彼此独立”表示所述特征彼此独立，不互为关联。
取代基在“所在环任意取代位置”表示，取代基团位于环中任意的可被取代的位置。取代基的取代位置为所述环的邻位、间位或对位，指所述环相对于主链连接位置的邻位、间位或对位。
术语“药学上可接受的盐”包括从适合的无机酸和碱以及有机酸和碱衍生而来的那些盐。药学上可接受的无毒性酸加成盐的实例是氨基与无机酸如盐酸、氢溴酸、磷酸、硫酸和高氯酸等，或者与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸等形成的盐，或者通过使用诸如离子交换等本领域的其他方法形成的盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。
具体实施方式
以下结合实施例对本发明做进一步描述。需要说明的是，实施例不能作为对本发明保护范围的限制，本领域的技术人员理解，任何在本发明基础上所作的改进和变化都在本发明的保护范围之内。
以下实施例所用到的常规试剂均可商购获得，所进行的生物学实验都是本领域中常规的生物学实验，可按照相应实验手册或试剂盒说明书指引进行。
实施例中使用如下术语或简称：
PEX：中间体制备例EX：实施例
Prep-HPLC(在方法A条件下纯化)：Prep-HPLC纯化，其使用方法A条件进行，方法A条件包括：柱:sunfire 5μm 19-150mm或XBridge-1 5μm 19-150mm；流动性A:水(0.1％TFA),流动相B:CAN；梯 度：10-20-9MIN 150VL
ACN：乙腈                    HOBT：1-羟基苯并三唑(1-Hydroxybenzotriazole)
EDCI：1-乙基-3-(3-二甲基氨基丙基)碳二亚氨盐酸盐(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide)
EtOAc和EA：乙酸乙酯        PE：石油醚(petroleum ether)      DIEA：二异丙基乙胺
TEA：三乙基胺              DCM：二氯甲烷                 DMF：N,N-二甲基甲酰胺
TFA：2,2,2-三氟乙酸或三氟乙酸          THF：四氢呋喃。
中间体制备实施例
PEX1：制备3-(4-(甲氧基甲基)苯基)丙酸
步骤1.(E)-3-(4-(甲氧基甲基)苯基)丙烯酸乙酯的制备
向1-溴-4-(甲氧基甲基)苯(2.00g,9.95mmol,1.0当量)在DMF(20mL)中的溶液中加入丙烯酸乙酯(1.99g,19.9mmol,2.0当量)、Pd(OAc)2(223mg,1.00mmol,0.1当量)、PPh3(522mg,1.99mmol,0.2当量)和Et3N(3.02g,29.8mmol,3.0当量)。将混合物在氮气保护下在110℃搅拌过夜并用水(30mL)淬灭。所得混合物用EtOAc(3×60mL)萃取，合并有机层，用盐水(150mL)洗涤，用无水硫酸钠干燥并减压浓缩。残余物在硅胶柱上用乙酸乙酯/石油醚(4/96)进行色谱分离，得到1.1g(产率45％)的(E)-3-[4-(甲氧基甲基)苯基]丙烯酸乙酯，为黄色油状物。LC-MS(ESI,m/z)：221[M+H]+。
步骤2.3-(4-(甲氧基甲基)苯基)丙酸乙酯的制备
向(E)-3-[4-(甲氧基甲基)苯基]丙烯酸乙酯(600mg,2.72mmol,1.0当量)和CoCl2.6H2O(648mg,2.72mmol,1.0当量)的MeOH(12mL)溶液中缓慢加入NaBH4(515mg，13.6mmol，5.0当量)。将混合物在室温搅拌过夜并用水(20mL)淬灭。混合物用EtOAc(3×50mL)萃取。合并有机层，用无水硫酸钠干燥并减压浓缩，得到500mg(产率70％)3-[4-(甲氧基甲基)苯基]丙酸乙酯，为黄色油状物。LC-MS(ESI，m/z)：223[M+H]+。
步骤3.3-(4-(甲氧基甲基)苯基)丙酸的制备。
向3-[4-(甲氧基甲基)苯基]丙酸乙酯(500mg,2.25mmol,1.0当量)的THF(8mL)溶液中加入NaOH(450mg,11.2mmol,5.0当量)的水(2mL)溶液。将混合物在50℃搅拌3小时并用1M盐酸(3mL)淬灭。所得溶液用EtOAc(3×30mL)萃取，合并有机层，用盐水(80mL)洗涤，用无水硫酸钠干燥，过滤并减压浓缩，得到400mg(产率82％)3-[4-(甲氧基甲基)苯基]丙酸，为黄色油状物。LC-MS(ESI,m/z)：195[M+H]+。
PEX2：制备2-(6-(甲氧基甲基)吡啶-3-基)乙酸
步骤1. 5-溴-2-(甲氧基甲基)吡啶的制备
(5-溴吡啶-2-基)甲醇(5.00g,26.6mmol,1.00当量)的DMF(100mL)溶液在N2保护下冷却至0℃，加入NaH(1.60g,39.9mmol,1.5当量)。将混合物搅拌30分钟并加入CH3I(7.55g，53.2mmol，2.0当量)。将所得混合物在室温搅拌1小时。将所得混合物倒入水(300mL)中并用EA(50mL×2)萃取。合并的有机层用水(50mL×3)和盐水(50mL)洗涤，用无水Na2SO4干燥并浓缩，得到呈黄色油状的5-溴-2-(甲氧基甲基)吡啶(5.00g，88.4％)。1H NMR(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]+。
步骤2. 2-(6-(甲氧基甲基)吡啶-3-基)丙二酸二乙酯的制备
5-溴-2-(甲氧基甲基)吡啶(1.00g,4.95mmol,1.00当量)、丙二酸二乙酯(2.35g,14.7mmol,3.00当量)、Pd(dba)2(200mg)、三叔丁基膦(4mL，10％)和K3PO4(2.08g，9.90mmol，2.00当量)的混合物置于甲苯(30mL)中，在N2下加热回流4小时。将其冷却至室温，倒入水(30mL)中并用EA(10mL×3)萃取。合并的有机层用水和盐水洗涤，用无水Na2SO4干燥并浓缩得到粗品，将其通过柱色谱法(PE/EA＝10/1)纯化得到2-(6-(甲氧基甲基)吡啶-3-基)丙二酸二乙酯(600mg，38.8％)，为黄色油状物。LC-MS(ESI,m/z)：282.1[M+H]+。
步骤3. 2-(6-(甲氧基甲基)吡啶-3-基)乙酸的制备：
2-(6-(甲氧基甲基)吡啶-3-基)丙二酸二乙酯(600mg，2.13mmol，1.0当量)的浓盐酸(6mL)溶液加热至100℃持续4小时。所得混合物经减压浓缩，得到呈黄色油状的2-(6-(甲氧基甲基)吡啶-3-基)乙酸.盐酸盐(200mg，33.2％)。LC-MS(ESI,m/z)：182.1[M+H]+。
PEX3：制备2-(甲氧基甲基)烟酸：
步骤1.(3-溴吡啶-2-基)甲醇的制备
将BH3/THF(744mL,0.744mol,1mol/L)溶液加入到3-溴吡啶甲酸(5g,0.025mol)的THF(50mL)溶液中，将混合物在25℃搅拌3小时。混合物用饱和NH4Cl溶液(1L)淬灭并用EA(500mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发，得到产物(3-溴吡啶-2-基)甲醇(2g，40.32％)，为黄色固体。LC-MS(ESI,m/z)：189.6[M+H]+。
步骤2. 3-溴-2-(甲氧基甲基)吡啶的制备
将(3-溴吡啶-2-基)甲醇(2g,0.011mol)在THF(50mL)中的溶液冷却至0℃，加入NaH(510mg,0.021mol,60％在油中)。混合物在25℃搅拌1小时。将混合物冷却至0℃并加入CH3I(3.01g,0.021mol)。将混合物在25℃搅拌6小时。混合物用饱和NH4Cl溶液(30mL)淬灭并用EA(20mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发，得到产物3-溴-2-(甲氧基甲基)吡啶(2.5g，84.91％)，为黄色油状物。LC-MS(ESI,m/z)：203.7[M+H]+。
步骤3. 2-(甲氧基甲基)烟酸甲酯的制备
3-溴-2-(甲氧基甲基)吡啶(2g,0.010mol)、Pd(dppf)Cl2(430mg,0.594mmol)和三乙胺(3.01g,0.030mol)在MeOH(100mL)中的溶液在2MPa的CO下在140℃下搅拌5小时。通过硅藻土垫过滤混合物，用MeOH(3×20mL)洗涤。将合并的滤液浓缩至干，得到产物2-(甲氧基甲基)烟酸甲酯(1g，50.51％)，为黄色油状物。LC-MS(ESI,m/z)：181.7[M+H]+。
步骤4. 2-(甲氧基甲基)烟酸的制备
在0℃混合2-(甲氧基甲基)烟酸甲酯(550mg,3.04mmol)的THF(4mL)溶液、MeOH(4mL)和H2O(1mL)，然后加入LiOH.H2O(255mg,6.07mmol)。将混合物在25℃连续搅拌2小时。将反应混合物用1N HCl酸化至pH＝3并真空蒸发，得到产物2-(甲氧基甲基)烟酸(500mg，17.87％)，为无色油状物。LC-MS(ESI,m/z)：167.6[M+H]+。
PEX4：制备6-(甲氧基甲基)吡啶甲酸
步骤1. 2-溴-6-(甲氧基甲基)吡啶
冷却(6-溴吡啶-2-基)甲醇(2mg,0.011mol)在THF(50mL)中的溶液至0℃，加入NaH(380mg,0.021mol,60％在油中)。混合物在25℃搅拌1小时。将混合物冷却至0℃并加入CH3I(3.01g,0.016mol)。将混合物在25℃搅拌2小时。混合物用饱和NH4Cl溶液(30mL)淬灭并用EA(20mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发，得到黄色油状产物2-溴-6-(甲氧基甲基)吡啶(2g，83.96％)。LC-MS(ESI,m/z)：201.7[M+H]+。
步骤2. 6-(甲氧基甲基)吡啶甲酸甲酯的制备
在高压釜中，在2Mpa的CO下，140℃搅拌2-溴-6-(甲氧基甲基)吡啶(1g,4.90mmol)、Pd(dppf)Cl2(220mg,0.294mmol)和三乙胺(1.49g,14.7mmol)在MeOH(50mL)中的溶液5小时。通过硅藻土垫过滤混合物，再用MeOH(3×20mL)洗涤。将合并的滤液浓缩至干，得到产物6-(甲氧基甲基)吡啶甲酸甲酯(0.66g，48.98％)，为黄色油状物。LC-MS(ESI,m/z)：181.7[M+H]+。
步骤3. 6-(甲氧基甲基)吡啶甲酸的制备
在0℃下，混合6-(甲氧基甲基)吡啶甲酸甲酯(660mg,3.64mmol)的THF(4mL)溶液、MeOH(4mL)和H2O(1mL)，然后加入LiOH.H2O(305.7mg,7.28mmol)。将混合物在25℃连续搅拌2小时。将反应混合物用1N HCl酸化至pH＝3并真空蒸发，得到所需产物6-(甲氧基甲基)吡啶甲酸(600mg，65.83％)，为无色油状物。LC-MS(ESI,m/z)：167.6[M+H]+。
PEX5：制备1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-羧酸
向哌啶-4-羧酸(2.00g，15.5mmol，1.00当量)和K2CO3(3.21g，23.3mmol，1.50当量)与DMF(40mL)的混合物中加入2-溴-1-(4-氟苯基)乙-1-酮(3.20g,14.7mmol,0.95当量)。将所得混合物在室温下搅拌2小时。将所得混合物倒入水(120mL)中并用EA(50mL×3)萃取。合并的有机层用水(50mL×3)和盐水(50mL)洗涤，用无水Na2SO4干燥并浓缩，得到1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-羧酸(1.20g,26.5％)，为黄色油状物。LC-MS(ESI,m/z)：266.1[M+H]+。
PEX6：制备2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-N-(哌啶-4-基)乙酰胺
步骤1. 4-((叔丁氧基羰基)(甲基)氨基)哌啶-1-羧酸苄酯的制备
在0℃，向甲基(哌啶-4-基)氨基甲酸叔丁酯(5.00g,23.0mmol)和TEA(4.70g,46.0mmol)的DCM(150mL)的溶液中逐滴加入氯甲酸苄酯(4.80g,28.0mmol)。然后将混合物在25℃搅拌16小时，然后用水(150mL)稀释并用DCM(30mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发得到残余物。粗产物通过柱色谱法纯化(PE/EA＝100/1-10/1)，得到4-((叔丁氧基羰基)(甲基)氨基)哌啶-1-羧酸苄酯(7.00g，86.1％)，为无色油状物质。LC-MS(ESI,m/z)：248.9[M+H]+。
步骤2. 4-(甲氨基)哌啶-1-甲酸苄酯.盐酸盐的制备
在0℃，向4-((叔丁氧基羰基)(甲基)氨基)哌啶-1-羧酸苄酯(7.00g,20.0mmol)的EA(70mL)溶液中逐滴滴加EA/HCl(70mL,6N)。然后将混合物在25℃搅拌3小时，然后真空蒸发，得到4-(甲氨基)哌啶-1-甲酸苄酯.盐酸盐(5.00g，65.0％)，为白色固体。LC-MS(ESI，m/z)：249.2[M+H]+。
步骤3. 4-(2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰胺基)哌啶-1-羧酸苄酯的制备
2-(6-(甲氧基甲基)吡啶-3-基)乙酸苄酯(1.40g,8.00mmol)、4-(甲氨基)哌啶-1-羧酸苄酯盐酸盐(2.19g,8.00mmol)、HOBt(1.25g，9.00mol)、EDCI(1.77g，9.00mmol)和TEA(2.34g，23.0mmol)在DCM(30mL)中的混合物，在25℃搅拌16小时。将混合物用水(30mL)稀释并用DCM(10mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发得到残余物。粗产物通过柱色谱法纯化(CH2Cl2/MeOH＝100/1-30/1)，得到4-(2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰胺基)哌啶-1-羧酸苄酯(1.80g,28.6％)，为黄色油状物。LC-MS(ESI,m/z)：412.0[M+H]+。
步骤4. 2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-N-(哌啶-4-基)乙酰胺的制备
向4-(2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰胺基)哌啶-1-羧酸苄酯(1.3g，3.20mmol)的甲醇(15ml)溶液中加入Pd/C(340mg)。将混合物在H2气球下在25℃搅拌1小时。通过硅藻土垫过滤悬浮液，并用MeOH(30mL×5)洗涤该垫。将合并的滤液浓缩至干，得到呈黄色固体的2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-N-(哌啶-4-基)乙酰胺(930mg，71.5％)。LC-MS(ESI,m/z)：277.9[M+H]+。
PEX7：制备2-甲氧基-N-(哌啶-4-基甲基)烟酰胺
步骤1. 4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-羧酸苄酯的制备
在0℃，向(哌啶-4-基甲基)氨基甲酸叔丁酯(5.00g,23.0mmol)和TEA(4.70g,46.0mmol)在DCM(150mL)的溶液中滴加氯甲酸苄酯(4.80g,28.0mmol)。然后将混合物在20℃搅拌3小时，用水(50mL)稀释并用DCM(10mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发，得到4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-羧酸苄酯(7.70g，50.0％)，为白色固体。
步骤2. 4-(氨基甲基)哌啶-1-甲酸苄酯.盐酸盐的制备
在0℃，向4-(((叔丁氧基羰基)氨基)甲基)哌啶-1-甲酸苄酯(500mg,1.43mmol)的EtOAc(5mL)溶液中 滴加EtOAc/HCl(5mL,6N)，然后将混合物在25℃搅拌6小时，然后真空蒸发，得到4-(氨基甲基)哌啶-1-甲酸苄酯.盐酸盐(300mg，73.5％)，为黄色固体。LC-MS(ESI，m/z)：249.1[M+H]+。
步骤3. 4-((2-甲氧基烟酰胺)甲基)哌啶-1-羧酸苄酯的制备
将4-(氨基甲基)哌啶-1-羧酸苄酯盐酸盐(300mg，0.934mmol)、2-甲氧基烟酸(157mg，1.03mmol)、HOBt(151mg，1.12mmol)、EDCI(215mg，1.12mmol)和TEA(473mg，4.67mmol)在DCM(10mL)中的混合物在20℃搅拌16小时。将混合物用水(20mL)稀释并用DCM(10mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发得到粗产物。通过Prep-TLC(DCM/MeOH＝10/1)纯化残余物，得到无色油状的4-((2-甲氧基烟酰胺)甲基)哌啶-1-羧酸苄酯(300mg，51.6％)。LC-MS(ESI,m/z)：384.3[M+H]+。
步骤4. 2-甲氧基-N-(哌啶-4-基甲基)烟酰胺的制备
向4-((2-甲氧基烟酰胺)甲基)哌啶-1-羧酸苄酯(300mg，0.781mmol)的MeOH(5mL)溶液中加入Pd/C(100mg)。所得混合物在H2气球下在25℃下搅拌1小时，然后过滤。真空蒸发滤液，得到呈黄色油状的2-甲氧基-N-(哌啶-4-基甲基)烟酰胺(100mg，51.3％)。
PEX8：制备1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.盐酸盐
步骤1.((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)(甲基)氨基甲酸叔丁酯的制备
向甲基(哌啶-4-基甲基)氨基甲酸叔丁酯(2.50g，10.9mmol，1.00当量)和K2CO3(2.26g，16.4mmol，1.50当量)在DMF(50mL)中的溶液加入2-溴-1-(4-氟苯基)乙-1-酮(2.25g,10.4mmol,0.95当量)。将所得混合物在室温下搅拌2小时。将所得混合物倒入水(150mL)中并用EA(50mL×3)萃取。合并的有机层用水(50mL×3)和盐水(50mL)洗涤，经无水Na2SO4干燥并浓缩，得到((1-(2-(4-氟苯基)-2-氧代乙基)哌啶)-4-基)甲基)(甲基)氨基甲酸叔丁酯(4.00g,90.8％)，为黄色油状物。1H 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]+。
步骤2.1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.盐酸盐的制备
在0℃，在((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)(甲基)氨基甲酸叔丁酯(4.00g，11.4mmol，1.00当量)的EtOAc(40mL)溶液中滴加4.0M HCl的EtOAc(20mL)溶液。然后将反应混合物在室温下搅拌2小时并过滤，得到1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.盐酸盐(3.00g,73.7％)，为黄色固体。LC-MS(ESI,m/z)：265.1[M+H]+。
PEX9制备2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮盐酸盐
步骤1.((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)氨基甲酸叔丁酯的制备
向(哌啶-4-基甲基)氨基甲酸叔丁酯(5.00g,23.2mmol,1.00当量)和K2CO3(4.81g,34.8mmol,1.50当量)在DMF(100mL)的混合物中加入2-溴-1-(4-氟苯基)乙-1-酮(4.78g,22.0mmol,0.95当量)。将所得混合物在室温搅拌2小时。将所得混合物倒入水(300mL)中并过滤，得到((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)氨基甲酸叔丁酯(5.00g，55.2％)，为灰白色固体。1H 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]+。
步骤2. 2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮.盐酸盐的制备
在0℃下，向((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)氨基甲酸叔丁酯(5.00g,14.2mmol,1.00当量)的EtOAc(50mL)溶液中滴加4.0M HCl的EtOAc(50mL)溶液。然后将反应混合物在室温下搅拌2小时并过滤得到2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮.盐酸盐(3.00g，59.2％)，为灰白色固体。1H 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]+。
PEX10制备1-(4-氟苯基)-2-(4-(甲基氨基)哌啶-1-基)乙-1-酮.盐酸盐
步骤1.(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)(甲基)氨基甲酸叔丁酯的制备
向甲基(哌啶-4-基)氨基甲酸叔丁酯(1.00g，4.64mmol，1.00当量)和K2CO3(960mg，6.96mmol，1.50当量)的DMF(20mL)混合物中加入2-溴-1-(4-氟苯基)乙-1-酮(957mg，4.41mmol，0.95当量)。将所得混合物在室温搅拌2小时，然后倒入水(60mL)中并用EA(20mL×3)萃取。将合并的有机层用水(30mL×3)和盐水(30mL)洗涤，用无水Na2SO4干燥并浓缩，得到(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)(甲基)氨基甲酸叔丁基酯(1.00g，55.1％)，为黄色油状物。LC-MS(ESI,m/z)：351.2[M+H]+。
步骤2. 1-(4-氟苯基)-2-(4-(甲基氨基)哌啶-1-基)乙-1-酮.盐酸盐的制备
在0℃下，向(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)(甲基)氨基甲酸叔丁酯(1.00g,2.84mmol,1.00当量)的EtOAc(10mL)溶液中滴加4.0M HCl的EtOAc(10mL)溶液。然后将反应混合物在室温下搅拌2小时并过滤，得到1-(4-氟苯基)-2-(4-(甲基氨基)哌啶-1-基)乙-1-酮.盐酸盐(600mg，58.7％)，为黄色固体。LC-MS(ESI,m/z)：251.1[M+H]+。
PEX11：制备(1-(4-氟苯乙基)哌啶-4-基)甲胺.盐酸盐的制备
步骤1. 4-氟苯乙基甲磺酸盐的制备
2-(4-氟苯基)乙-1-醇(200mg,0.630mmol)和TEA(289mg,2.85mmol)的DCM(3mL)溶液冷却到0℃，加入甲磺酰氯(195mg，1.71mmol)。混合物在25℃搅拌3小时。将混合物用水(10mL)稀释并用EA(10mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发，得到所需产物4-氟苯乙基甲磺酸盐(350mg，89.91％)，为无色油状物。
步骤2.((1-(4-氟苯乙基)哌啶-4-基)甲基)氨基甲酸叔丁酯的制备
在0℃下，向4-氟苯乙基甲磺酸盐(176mg,0.825mmol)的DMF(10mL)溶液中加入碳酸钾(143mg,1.031mmol)和(哌啶-4-基甲基)氨基甲酸叔丁酯(150mg,0.687mmol)。混合物在80℃搅拌12小时，然后冷却至0℃。将混合物用水(10mL)稀释并用EA(10mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发，得到产物((1-(4-氟苯乙基)哌啶-4-基)甲基)氨基甲酸叔丁酯(100mg，17.50％)，为白色固体。LC-MS(ESI,m/z)：337.0[M+H]+。
步骤3.(1-(4-氟苯乙基)哌啶-4-基)甲胺.盐酸盐的制备
将((1-(4-氟苯乙基)哌啶-4-基)甲基)氨基甲酸叔丁酯(100mg,0.297mmol)的EA(5mL)溶液冷却至0℃，滴加EA/HCl(5mL，6N)。将反应混合物在25℃搅拌4小时。将混合物真空蒸发，得到粗产物(1-(4-氟苯乙基)哌啶-4-基)甲胺.盐酸盐(90mg，37.18％)，为白色固体，无需进一步纯化直接用于下一步。LC-MS(ESI,m/z)：237.1[M+H]+。
PEX12：1-(4-氟苯乙基)-N-甲基哌啶-4-胺.盐酸盐的制备
步骤1.(1-(4-氟苯乙基)哌啶-4-基)(甲基)氨基甲酸叔丁酯的制备
在0℃，向甲基(哌啶-4-基)氨基甲酸叔丁酯(300mg，1.38mmol)的DMF(10mL)溶液中加入碳酸钾(285mg，2.06mmol)和(哌啶-4-基甲基)氨基甲酸叔丁酯(354mg,1.65mmol)。混合物在80℃搅拌12小时，然后冷却至0℃。将混合物用水(10mL)稀释并用EA(10mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发，得到产物(1-(4-氟苯乙基)哌啶-4-基)(甲基)氨基甲酸叔丁酯(260mg，44.59％)，为白色固体。LC-MS(ESI,m/z)：337.0[M+H]+。
步骤2. 1-(4-氟苯乙基)-N-甲基哌啶-4-胺.盐酸盐的制备
将(1-(4-氟苯乙基)哌啶-4-基)(甲基)氨基甲酸叔丁酯(70mg,0.208mmol)的EA(5mL)溶液冷却至0℃，加入EA/HCl(5毫升，6N)。然后将反应混合物在25℃搅拌4小时。真空蒸发混合物，得到产物1-(4-氟苯乙基)-N-甲基哌啶-4-胺.盐酸盐(180mg，43.48％)，为白色固体。LC-MS(ESI,m/z)：237.1[M+H]+。
PEX13制备3-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)丙-1-酮.盐酸盐的制备
步骤1.((1-(3-(4-氟苯基)-3-氧代丙基)哌啶-4-基)甲基)氨基甲酸叔丁酯的制备
将(哌啶-4-基甲基)氨基甲酸叔丁酯(574mg,2.68mmol)和K2CO3(1.11g,8.04mmol)在DMF(5mL)中的溶液冷却至0℃，向溶液中加入3-氯-1-(4-氟苯基)丙-1-酮(500mg，2.68mmol)。然后将反应混合物在25℃搅拌4小时。将混合物用水(10mL)稀释并用EA(10mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发，得到产物((1-(3-(4-氟苯基)-3-氧代丙基)哌啶-4-基)甲基)氨基甲酸叔丁酯(220mg，82.91％)，为无色油状物。LC-MS(ESI,m/z):365.0[M+H]+.
步骤2. 3-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)丙-1-酮.盐酸盐的制备
((1-(3-(4-氟苯基)-3-氧代丙基)哌啶-4-基)甲基)氨基甲酸叔丁酯(220mg,0.602mmol)的EA(5mL)溶液冷却至20℃，加入EA/HCl(5mL,6N)。然后将反应混合物在25℃搅拌4小时。真空蒸发混合物，得到所需产物3-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)丙-1-酮.盐酸盐(100mg，28.99％)，为白色固体。LC-MS(ESI,m/z)：265.1[M+H]+。
PEX14：制备N-(4-(甲氧基甲基)苄基)-2-(哌啶-4-基)乙酰胺
步骤1. 4-(2-((4-(甲氧基甲基)苄基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯的制备
在1-[4-(甲氧基甲基)苯基]甲胺(200mg,1.32mmol,1.0当量)、[1-(叔丁氧基羰基)哌啶-4-基]乙酸(322mg,1.32mmol,1.0当量)的DMF(5mL)溶液中，加入HATU(754mg，1.98mmol，1.5当量)和DIEA(513mg，3.97mmol，3.0当量)。将反应在室温搅拌2小时并用水(10mL)淬灭。用EA(3×20mL)萃取混合物。合并有机层，用盐水洗涤，用无水硫酸钠干燥并减压浓缩，得到4-(2-((4-(甲氧基甲基)苄 基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(400mg,72.3％)，为无色半固体。LCMS(ESI，m/z)：377[M+H]+。
步骤2.N-(4-(甲氧基甲基)苄基)-2-(哌啶-4-基)乙酰胺的制备
向4-(2-((4-(甲氧基甲基)苄基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(400mg,1.06mmol,1当量)的DCM(5mL)溶液中加入TFA(2毫升)。将反应在室温下搅拌2小时，减压浓缩，得到N-(4-(甲氧基甲基)苄基)-2-(哌啶-4-基)乙酰胺(300mg，92.0％)，为棕色油。LCMS(ESI,m/z):277[M+H]+。
PEX15：(6-(甲氧基甲基)吡啶-3-基)甲胺的制备
步骤1. 6-(甲氧基甲基)烟腈的制备
将5-溴-2-(甲氧基甲基)吡啶(2.00g,9.90mmol,1.00当量)、Zn(CN)2(700mg,5.94mmol,0.6当量)和Pd(PPh3)4(200mg)在DMF(20mL)中的混合物在微波炉中加热5分钟，设定温度为175℃。然后将反应混合物倒入水(60mL)中并用EA(20mL×3)萃取。合并的有机层用水(20mL×3)和盐水(20mL)洗涤，用无水Na2SO4干燥并浓缩得到粗品，将其通过柱色谱法(PE/EA＝10/1)纯化得到6-(甲氧基甲基)烟腈(1.00g,61.6％)，为黄色油状物。LC-MS(ESI,m/z)：149.1[M+H]+。
步骤2.(6-(甲氧基甲基)吡啶-3-基)甲胺的制备
向6-(甲氧基甲基)烟腈(1.00g,6.70mmol,1.00当量)的THF(30mL)的溶液中加入NH3.H2O(10mL)和Ni(2.00g)。将混合物在H2气球下在室温下搅拌4小时。过滤所得混合物，浓缩滤液，得到黄色油状的(6-(甲氧基甲基)吡啶-3-基)甲胺(1.00g，粗品)。LC-MS(ESI,m/z)：153.1[M+H]+。
EX1 N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)苯甲酰胺.2,2,2-三氟乙酸盐(ER10316)的制备
在0℃下，向2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮.盐酸盐(100mg,0.400mmol,1.0当量)和TEA(121mg,1.20mmol,3.0当量)的DCM(3mL)溶液中，加入苯甲酰氯(61.8mg,0.439mmol,1.1当量)。所得混合物在室温下搅拌过夜。所得混合物用水(10mL)稀释并用DCM(5mL)萃取。合并的有机层用无水Na2SO4干燥并减压浓缩。残余物依次通过Prep-TLC(DCM/MeOH＝10/1)，和Prep-HPLC(方法A条件 下)纯化，得到N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)苯甲酰胺.2,2,2-三氟乙酸盐(50.0mg，25.4％)，为淡黄色油状物。1H 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]+。
EX2：2-(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)-N-(4-(甲氧基甲基)苄基)乙酰胺.2,2,2-三氟乙酸盐(ER10296)的制备
向N-{[4-(甲氧基甲基)苯基]甲基}-2-(哌啶-4-基)乙酰胺(150mg,0.543mmol,1.0当量)、2-氯-1-(4-氟苯基)乙酮(93.7mg，0.543mmol，1.0当量)的DMF(3mL)溶液中，添加K2CO3(375mg,2.72mmol,5.0当量)。将反应在60℃搅拌1.5h并通过Prep-HPLC纯化(方法A条件下)，得到2-(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)-N-(4-(甲氧基甲基)苄基)乙酰胺.2,2,2-三氟乙酸盐(27.2mg，9.5％)，为无色油状物。1HNMR(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]+。
EX3：N-(1-(2-(4-氯苯基)-2-氧代乙基)哌啶-4-基)-2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰胺.2,2,2-三氟乙酸盐的制备(ER10382)
在25℃将2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-N-(哌啶-4-基)乙酰胺(100mg，0.36mmol)和碳酸钾(74.7mg，0.54mmol)与DMF(5mL)混合形成混合液，冷却至0℃，加入2-溴-1-(4-氯苯基)乙-1-酮(84.2mg,0.36mmol)。混合物在25℃搅拌1小时。将混合物用水(3×10mL)稀释并用EA(10mL)萃取。水相用EA(2×10mL)萃取。合并的有机层用硫酸钠干燥并真空蒸发得到残余物。残余物用Prep-HPLC纯化(在方法A条件下)，得到所需产物N-(1-(2-(4-氯苯基)-2-氧代乙基)哌啶-4-基)-2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰胺.2,2,2-三氟乙酸盐(58.03mg,29.43％)，为无色油状物。1H 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]+。
EX4：制备N-(1-(2-(4-氰基苯基)-2-氧代乙基)哌啶-4-基)-2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰 胺.2,2,2-三氟乙酸盐(ER10385)
N-(1-(2-(4-氰基苯基)-2-氧代乙基)哌啶-4-基)-2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-乙酰胺.2,2,2-三氟乙酸盐，使用与ER10382类似条件制备且纯化，使用2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-N-(哌啶-4-基)乙酰胺(100mg,0.36mmol)和4-(2-溴乙酰基)苄腈(80.8mg，0.36mmol)得到N-(1-(2-(4-氰基苯基)-2-氧代乙基)哌啶-4-基)-2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰胺.2,2,2-三氟乙酸盐(30.6mg,18.22％)，为黄色固体。1H NMR(400MHz,DMSO_d6)δ9.92(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]+。
EX5：制备N-(1-(2-(3-氟苯基)-2-氧代乙基)哌啶-4-基)-2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰胺.2,2,2三氟乙酸盐(ER10386)
N-(1-(2-(3-氟苯基)-2-氧代乙基)哌啶-4-基)-2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰胺.2,2,2三氟乙酸盐，使用与ER10382类似条件制备和纯化，通过使用2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-N-(哌啶-4-基)乙酰胺(100mg,0.36mmol)和2-溴-1-(3-氟苯基)乙-1-酮(78.2mg,0.36mmol)反应，得到所需产物N-(1-(2-(3-氟苯基)-2-氧代乙基)哌啶-4-基)-2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰胺.2,2,2三氟乙酸盐(66.13mg,44.30％)，为无色油状物。1H 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]+。
EX6：制备N-甲基-2-(6-(甲氧基甲基)吡啶-3-基)-N-(1-(2-氧代-2-(对甲苯基)乙基)哌啶-4-基)-乙酰胺.2,2,2-三氟乙酸盐(ER10377)
N-甲基-N-(1-(2-氧代-2-(对甲苯基)乙基)哌啶-4-基)-2-(6-(甲氧基甲基)吡啶-3-基)-乙酰胺.2,2,2-三氟乙酸盐，使用与ER10382类似条件制备并纯化，通过使用2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-N-(哌啶-4-基)乙酰胺(100mg,0.361mmol)和2-溴-1-(对甲苯基)乙-1-酮(76.9mg，0.361mmol)得到所需产物(24.7mg，13.0％)，为黄色油状物。1H NMR(400MHz,DMSO_d6)δ9.79(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,1.5H),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]+。
EX7：2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-N-(1-(2-氧代-2-苯基乙基)哌啶-4-基)-乙酰胺.2,2,2三氟乙酸盐的制备(ER10378)
2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-N-(1-(2-氧代-2-苯基乙基)哌啶-4-基)-乙酰胺.2,2,2三氟乙酸盐，使用类似于ER10382的条件制备和纯化，使用2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-N-(哌啶-4-基)乙酰胺(100mg,0.361mmol)和2-溴-1-苯基乙-1-酮(76.9mg,0.361mmol)得到所需产物(20.0mg,10.9％)，为无色油状物。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]+。
EX8：制备2-(6-(甲氧基甲基)吡啶-3-基)-N-(1-(2-(4-甲氧基苯基)-2-氧代乙基)哌啶-4-基)-N-甲基乙酰胺.2,2,2-三氟乙酸盐(ER10381)
2-(6-(甲氧基甲基)吡啶-3-基)-N-(1-(2-(4-甲氧基苯基)-2-氧代乙基)哌啶-4-基)-N-甲基乙酰胺.2,2,2-三氟乙酸盐，使用类似于ER10382的条件制备和纯化，通过使用2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-N-(哌啶-4-基)乙酰胺(100mg,0.361mmol)和2-溴-1-(4-甲氧基苯基)乙-1-酮(82.7mg，0.361mmol)得到所需产物(63.1mg，32.3％)，为黄色油状物。1H NMR(400MHz,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]+。
EX9：制备N-((1-(2-(3-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲氧基烟酰胺.2,2,2-三氟乙酸盐(ER10388)
将2-甲氧基-N-(哌啶-4-基甲基)烟酰胺(100mg,0.400mmol)和碳酸钾(83.2mg,0.600mmol)的DMF(5mL)溶液冷却至0℃，加入2-溴-1-(3-氟苯基)乙-1-酮(87.1mg，0.400mmol)。然后将混合物在25℃搅拌1小时。将混合物用水(10mL)稀释并用EA(3×10mL)萃取。合并的有机层用硫酸钠干燥并真空蒸发得到残余物，将其在方法A条件下用Prep-HPLC纯化得到N-((1-(2-(3-氟苯基)-2-氧代乙基)哌啶)-4-基)甲基)-2-甲氧基烟酰胺.2,2,2-三氟乙酸盐(25.0mg，16.0％)，为黄色固体。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]+。
EX10：制备2-甲氧基-N-((1-(2-氧代-2-(对甲苯基)乙基)哌啶-4-基)甲基)烟酰胺.2,2,2-三氟乙酸盐(ER10379)
2-甲氧基-N-((1-(2-氧代-2-(对甲苯基)乙基)哌啶-4-基)甲基)烟酰胺.2,2,2-三氟乙酸盐，使用与ER10388类似的条件制备和纯化，通过使用2-甲氧基-N-(哌啶-4-基甲基)烟酰胺(100mg,0.400mmol)和2-溴-1-(对甲苯基)乙-1-酮(85.5mg,0.400mmol)得到所需产物(27.7mg，13.9％)为无色油状物。1H 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]+。
EX11：制备2-甲氧基-N-((1-(2-氧代-2-苯乙基)哌啶-4-基)甲基)烟酰胺.2,2,2-三氟乙酸盐(ER10380)
N-((1-(2-氧代-2-苯乙基)哌啶-4-基)甲基)-2-甲氧基-烟酰胺.2,2,2-三氟乙酸盐使用与ER10388类似的 条件制备和纯化，通过利用2-甲氧基-N-(哌啶-4-基甲基)烟酰胺(100mg,0.400mmol)和2-溴-1-苯乙-1-酮(79.8mg,0.400mmol)得到所需产物(47.5mg,24.6％)，为无色油状物。1H 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),5.09-5.02(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]+。
EX12：制备2-甲氧基-N-((1-(2-(4-甲氧基苯基)-2-氧代乙基)哌啶-4-基)甲基)烟酰胺.2,2,2-三氟乙酸盐(ER10383)
2-甲氧基-N-((1-(2-(4-甲氧基苯基)-2-氧代乙基)哌啶-4-基)甲基)烟酰胺.2,2,2-三氟乙酸盐使用与ER10388类似的条件制备和纯化，通过使用2-甲氧基-N-(哌啶-4-基甲基)烟酰胺(100mg,0.400mmol)和2-溴-1-(4-甲氧基苯基)乙-1-酮(91.9mg,0.400mmol)得到所需产物(25.0mg,15.1％)，为无色油状物。1H 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,3H),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]+。
EX13：制备N-((1-(2-(4-氯苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲氧基烟酰胺.2,2,2-三氟乙酸盐(ER10384)
2-甲氧基-N-((1-(2-(4-氯苯基)-2-氧代乙基)哌啶-4-基)甲基)烟酰胺.2,2,2-三氟乙酸盐使用与ER10388类似的条件制备和纯化，通过使用2-甲氧基-N-(哌啶-4-基甲基)烟酰胺(100mg,0.400mmol)和2-溴-1-(4-氯苯基)乙-1-酮(93.7mg,0.400mmol)得到所需产物(19.0mg,11.7％)，为无色油状物。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]+。
EX14：制备N-((1-(2-(4-腈苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲氧基烟酰胺.2,2,2-三氟乙酸盐(ER10387)
2-甲氧基-N-((1-(2-(4-腈苯基)-2-氧代乙基)哌啶-4-基)甲基)烟酰胺.2,2,2-三氟乙酸盐使用与ER10388类似的条件制备和纯化，通过使用2-甲氧基-N-(哌啶-4-基甲基)烟酰胺(100mg，0.400mmol)和4-(2-溴乙酰基)苄腈(89.9mg，0.400mmol)得到所需产物(21.2mg，13.3％)，为无色油。1H 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]+。
EX15：制备N-((1-(4-氟苯基乙基)哌啶-4-基)甲基)-2-甲氧基烟酰胺.2,2,2-三氟乙酸盐(ER10389)
(1-(4-氟苯乙基)哌啶-4-基)甲胺盐酸盐(90.0mg，0.330mmol)、2-甲氧基烟酸(60.6mg，0.400mmol)、1-羟基苯并三唑(53.5mg，0.400mmol)，N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(76.0mg，0.400mmol)和三乙胺(100mg，0.990mmol)在DCM(5mL)中的混合物，将混合物在25℃连续搅拌3小时。将混合物用水(10mL)稀释并用EA(10mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发得到残余物，用Prep-HPLC(在方法A条件下)纯化，得到所需产物N-((1-(4-氟苯乙基)哌啶-4-基)甲基)-2-甲氧基烟酰胺.2,2,2-三氟乙酸盐(19.9mg，32.65％)，为无色油状物。1H 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]+。
EX16：制备N-(1-(4-氟苯乙基)哌啶-4-基)-2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰胺.2,2,2-三氟乙酸盐(ER10390)
将含有1-(4-氟苯乙基)-N-甲基哌啶-4-胺盐酸盐(140mg，0.513mmol)、2-(6-(甲氧基甲基)吡啶-3-基)乙酸(112mg，0.616mmol)、1-羟基苯并三唑(83.2mg，0.616mmol)、N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(118.1mg，0.616mmol)和三乙胺(156mg，1.54mmol)的DCM(10mL)混合 液在25℃连续搅拌3小时。将混合物用水(10mL)稀释并用EA(10mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发得到残余物，用prep-HPLC(在方法A条件下)纯化得到所需产物N-(1-(4-氟苯乙基)哌啶-4-基)-2-(6-(甲氧基甲基)吡啶-3-基)-N-甲基乙酰胺.2,2,2-三氟乙酸盐(73mg,35.31％)，为无色油状物。1H NMR(400MHz,DMSO_d6):δ9.73(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]+.
EX17：制备N-(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-2-乙酰胺.2,2,2-三氟乙酸(ER10305)
将1-(4-氟苯基)-2-(4-(甲氨基)哌啶-1-基)乙-1-酮.盐酸盐(600mg,2.40mmol,1.0当量)、2-(6-(甲氧基甲基)吡啶-3-基)乙酸.盐酸盐(217mg，1.20mmol，0.5当量)，HOBT(389mg，2.88mmol，1.2当量)，EDCI(551mg，2.88mmol，1.2当量)和TEA(1.21mg，12.0mmol，5.0当量)的DCM(18mL)混合液在室温下搅拌过夜。将所得混合物用水(20mL)稀释并用DCM(10mL)萃取。合并的有机层用无水Na2SO4干燥并减压浓缩。残余物依次通过Prep-TLC(DCM/MeOH＝10/1)，和Prep-HPLC(在方法A条件下)纯化，得到N-(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)-(6-(甲氧基甲基)吡啶-3-基)-N-甲基-2-乙酰胺.2,2,2-三氟乙酸(50.0mg,33.4％)，为无色油状物。1H 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]+.
EX18：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-(甲氧基甲基)烟酰胺.2,2,2-三氟乙酸盐的制备(ER10392)
2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮盐酸盐(1.03g,3.59mol)、2-(甲氧基甲基)烟酸(500mg,2.99mmol)、1-羟基苯并三唑(485mg,3.59mmol)、N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(688mg,3.59mmol)和三乙胺(908mg,8.97mmol)在DCM(10mL)中的混合物，在25℃连续搅拌3小时。将混合物用水(10mL)稀释并用EA(10mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发得到残 余物，将其在方法A下用prep-HPLC纯化得到产物N-((1-(2-(4-氟苯基)-2-氧代乙基))哌啶-4-基)甲基)-2-(甲氧基甲基)烟酰胺.2,2,2-三氟乙酸盐(39mg,3.26％)。1H 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]+。
EX19：N-((1-(3-(4-氟苯基)-3-氧代丙基)哌啶-4-基)甲基)-2-(甲氧基)烟酰胺.2,2,2-三氟乙酸盐的制备(ER10391)
N-((1-(3-(4-氟苯基)-3-氧代丙基)哌啶-4-基)甲基)-2-(甲氧基)烟酰胺.2,2,2-三氟乙酸盐使用与ER10392类似的合成条件制备和纯化，使用3-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)丙-1-酮盐酸盐(100mg，0.332mmol)和2-甲氧基烟酸(61.1mg，0.0.400mmol)得到所需产物(52.5mg,39.47％)，为白色固体。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]+.
EX20：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-吡啶酰胺.2,2,2-三氟乙酸盐的制备(ER10317)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-吡啶酰胺.2,2,2-三氟乙酸盐的制备和纯化使用类似ER10392合成的条件，使用吡啶甲酸(54.1mg,0.439mmol,1.1当量)和2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮盐酸盐(100mg,0.400mmol,1.0当量)制得所需产物(50.0mg，33.4％)，为白色固体。1H 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]+.
EX21：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)烟酰胺.2,2,2-三氟乙酸盐的制备(ER10318)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)烟酰胺.2,2,2-三氟乙酸盐使用类似ER10392合成的条件进行制备和纯化，通过使用烟酸(54.1mg，0.439mmol，1.1当量)和2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮盐酸盐(100mg，0.400mmol，1.0当量)得到所需产物(85.0mg,43.1％)，为浅黄色油。1H 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]+.
EX22：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)异烟酰胺.2,2,2-三氟乙酸盐的制备(ER10319)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)异烟酰胺.2,2,2-三氟乙酸盐使用类似ER10392合成的条件进行制备和纯化，使用异烟酸(54.1mg,0.439mmol,1.1当量)和2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮盐酸盐(100mg,0.400mmol,1.0当量)所需产物(75.0mg,38.0％)，为淡黄色油状物。1H 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]+。
EX23：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-(甲氧基甲基)烟酰胺.2,2,2-三氟乙酸盐的制备(ER10393)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-(甲氧基甲基)烟酰胺的制备和纯化使用类似ER10392合成的条件，使用6-(甲氧基甲基)烟酸(140mg，0.838mmol)和2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(288.2mg，1.005mmol)作为原料。产物的1H NMR(400MHz,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,1.5H),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]+.
EX24：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-(甲氧基甲基)吡啶酰胺.2,2,2-三氟乙酸盐的制备(ER10394)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-(甲氧基甲基)吡啶酰胺使用与ER10392合成类似的条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮盐酸盐(600mg，3.59mmol)和6-(甲氧基甲基)吡啶甲酸(1.24g，4.31mmol)得到所需产物(26.2mg,1.33％)。1H 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]+.
EX25：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-甲基-吡啶酰胺.2,2,2-三氟乙酸盐的制备(ER10349)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-甲基-吡啶酰胺.2,2,2-三氟乙酸盐使用类似ER10392合成的条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg，0.799mmol)和3-甲基吡啶甲酸(131mg，0.959mmol)得到所需产物(28.7mg,7.43％)，为无色油状物。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]+。
EX26：制备N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-4-甲基烟酰胺.2,2,2-三氟乙酸盐(ER10350)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-4-甲基烟酰胺.2,2,2-三氟乙酸盐使用类似于ER10392合成的条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg,0.799mmol)和4-甲基烟酸(132mg,0.959mmol)得到所需产物(126mg，32.5％)，为黄色固 体。1H 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]+。
EX27：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-4-甲基-吡啶酰胺.2,2,2-三氟乙酸盐的制备(ER10351)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-4-甲基-吡啶酰胺.2,2,2-三氟乙酸盐使用类似ER10392合成的条件制备和纯化，使用2-[4-(氨基甲基)哌啶-1-基]-1-(4-氟苯基)乙酮(200mg，0.799mmol)和4-甲基吡啶甲酸(132mg，0.959mmol)得到所需产物(71.4mg,18.5％)，为黄色固体。1H 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]+。
EX28 N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-5-甲基-烟酰胺.2,2,2-三氟乙酸盐(ER10352)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-5-甲基-烟酰胺.2,2,2-三氟乙酸盐使用与ER10392类似的合成条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg，0.799mmol)和5-甲基烟酸(132mg，0.959mmol)得到所需产物(84.0mg,22.5％)，为白色固体。1H 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]+。
EX29：制备N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-甲氧基-吡啶酰胺.2,2,2-三氟乙酸盐(ER10353)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-甲氧基-吡啶酰胺.2,2,2-三氟乙酸盐使用与ER10392类似的合成条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg， 0.799mmol)和3-甲氧基吡啶甲酸(147mg，0.959mmol)得到所需产物(63.8mg,16.5％)，为白色固体。1H 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]+。
EX30：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-4-甲氧基-烟酰胺.2,2,2-三氟乙酸盐(ER10354)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-4-甲氧基-烟酰胺.2,2,2-三氟乙酸盐使用与ER10392类似的合成条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg，0.799mmol)和4-甲氧基烟酸(147mg，0.959mol)得到所需产物(110mg,27.5％)，为黄色固体。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]+。
EX31：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-4-甲氧基吡啶酰胺.2,2,2-三氟乙酸盐(ER10355)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-4-甲氧基吡啶酰胺.2,2,2-三氟乙酸盐使用与ER10392类似的合成条件制备和纯化，使用2-[4-(氨基甲基)哌啶-1-基]-1-(4-氟苯基)乙酮(200mg，0.799mmol)和4-甲氧基吡啶甲酸(147mg，0.959mmol)得到所需产物(57.0mg,14.3％)为黄色固体。1H 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]+。
EX32：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-5-甲氧基-烟酰胺.2,2,2-三氟乙酸盐的制备(ER10356)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-5-甲氧基-烟酰胺.2,2,2-三氟乙酸盐使用与ER10392类似的合成条件制备和纯化，使用2-[4-(氨基甲基)哌啶-1-基]-1-(4-氟苯基)乙酮(200mg，0.799mmol)和5-甲氧基烟酸(147mg，0.959mmol)得到所需产物(173mg，43.38％)，为黄色固体。1H 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]+。
EX33：N-(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)-3-(4-(甲氧基甲基)苯基)-N-甲基丙酰胺.2,2,2-三氟乙酸盐(ER10295)
N-(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)-3-(4-(甲氧基甲基)苯基)-N-甲基丙酰胺.2,2,2-三氟乙酸盐使用与ER10392类似的合成条件制备和纯化，使用1-(4-氟苯基)-2-[4-(甲基氨基)哌啶-1-基]乙酮(250mg,1.00mmol,1.0当量)和3-[4-(甲氧基甲基)苯基]丙酸(213mg,1.10mmol,1.1当量)得到所需产物(68mg,12％)，为白色半固体。1H-NMR(300MHz,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]+。
EX35：N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲氧基苯甲酰胺.2,2,2-三氟乙酸盐的制备(ER10320)
向2-[4-(氨基甲基)哌啶-1-基]-1-(4-氟苯基)乙酮(200mg，0.799mmol，1.0当量)，2-甲氧基苯甲酸(134mg，0.879mmol，1.1当量)和TEA(243mg,2.40mmol,3.0当量)的DCM(10mL)溶液中滴加50％T3P(763mg,1.20mmol,1.5当量)的EtOAc溶液。将反应混合物在20℃搅拌16小时。将混合物用水(10mL)稀释并用DCM(5mL×3)萃取。合并的有机层用无水硫酸钠干燥并真空蒸发得到粗产物。依次通过Prep-TLC(DCM/MeOH＝10/1)和Prep-HPLC(在方法A条件下)纯化产物，得到N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲氧基苯甲酰胺.2,2,2-三氟乙酸盐(55.0mg,15.8％)，为淡黄色油状物。1H NMR(400MHz,DMSO_d6):δ9.81-9.77(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]+。
EX36 N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-甲氧基苯甲酰胺.2,2,2-三氟乙酸盐的制备(ER10321)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-甲氧基苯甲酰胺.2,2,2-三氟乙酸盐按照类似ER10320合成的条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯)乙-1-酮(200mg,0.799mmol,1.0当量)和3-甲氧基苯甲酸(122mg,0.879mmol,1.1当量)得到所需产物(15.0mg，4.31％)为淡黄色油。1H 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]+.
EX37：制备N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-4-甲氧基苯甲酰胺.2,2,2-三氟乙酸盐(ER10322)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-4-甲氧基苯甲酰胺.2,2,2-三氟乙酸盐使用与ER10320类似的合成条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg,0.799mmol,1.0当量)和4-甲氧基苯甲酸(134mg,0.879mmol,1.1当量)得到所需产物(45.0mg,12.9％)，为淡黄色油状物。1H 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]+.
EX38：制备N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-甲氧基吡啶酰胺2,2,2-三氟乙酸盐(ER10323)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-甲氧基吡啶酰胺2,2,2-三氟乙酸盐按照类似ER10320的合成条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg,0.799mmol,1.0当量)和6-甲氧基吡啶甲酸(135mg,0.879mmol,1.1当量)，得到所需产物(50.0mg,14.4％)，为浅黄色固体。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]+.
EX39：制备N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-甲基吡啶酰胺2,2,2-三氟乙酸盐(ER10324)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-甲基吡啶酰胺2,2,2-三氟乙酸盐按照类似ER10320的合成条件制备和纯化，使用2-[4-(氨基甲基)哌啶-1-基]-1-(4-氟苯基)乙酮(200mg,0.799mmol,1.0当量)和6-甲基吡啶-2-羧酸(121mg,0.879mmol,1.1当量)以提供所需产物(35.0mg,10.4％)为浅黄色油。1H 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]+.
EX40：制备N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲氧基异烟酰胺.2,2,2-三氟乙酸盐(ER10325)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲氧基异烟酰胺.2,2,2-三氟乙酸盐按照类似ER10320的合成条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg,0.799mmol,1.0当量)和2-甲氧基异烟酸(135mg,0.879mmol,1.1当量)反应得到所需的产品(43.0mg,12.4％)，为浅黄色油。1H NMR(400MHz,DMSO_d6):δ9.802(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),7.51-7.47(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]+.
EX41：制备N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲基异烟酰胺.2,2,2-三氟乙酸盐(ER10326)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲基异烟酰胺.2,2,2-三氟乙酸盐按照类似ER10320的合成条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg,0.697mmol,1.0当量)和2-甲基异烟酸(115mg,0.837mmol,1.1当量)以得到所需产物(99.3mg,29.5％)，为浅黄色油状物。1H 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,2H).LC-MS(ESI,m/z):370.0[M+H]+.
EX42：制备N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲氧基烟酰胺.2,2,2-三氟乙酸盐(ER10327)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲氧基烟酰胺.2,2,2-三氟乙酸盐按照类似ER10320的合成条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg,0.799mmol,1.0当量)和2-甲氧基烟酸(135mg,0.879mmol,1.1当量)反应得到所需产物(135mg,38.8％)，为淡黄色油状物。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),5.01(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]+.
EX43：制备N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲基烟酰胺.2,2,2-三氟乙酸盐(ER10328)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-2-甲基烟酰胺.2,2,2-三氟乙酸盐按照类似ER10320的合成条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg,0.799mmol,1.0当量)和2-甲基烟酸(121mg,0.879mmol,1.1当量)得到所需产物(40.0mg,11.9％)，为淡黄色油。1H 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]+。
EX44：制备N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-甲氧基烟酰胺.2,2,2-三氟乙酸盐(ER10329)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-甲氧基烟酰胺.2,2,2-三氟乙酸盐按照类似ER10320合的成条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg,0.799mmol,1.0当量)和6-甲氧基烟酸(135mg,0.879mmol,1.1当量)得到所需产物(40.0mg,11.5％)，为浅黄色油。1H 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]+。
EX45：制备N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-甲基烟酰胺.2,2,2-三氟乙酸盐(ER10330)
N-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-6-甲基烟酰胺.2,2,2-三氟乙酸盐按照类似ER10320的合成条件制备和纯化，使用2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg,0.799mmol,1.0当量)和6-甲基烟酸(135mg,0.879mmol,1.1当量)得到所需产物(90.0mg,26.7％)为浅黄色油。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]+。
EX46：制备1-(2-(4-氟苯基)-2-氧代乙基)-N-((6-(甲氧基甲基)吡啶-3-基)甲基)-哌啶-4-甲酰胺.2,2,2-三氟乙酸盐(ER10306)
将(6-(甲氧基甲基)吡啶-3-基)甲胺(1.00g,6.55mmol,1.0当量)、1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-羧酸(1.23g,4.62mmol,0.7当量)、HOBT(1.07g,7.92mmol,1.2当量)、EDCI(1.52g,7.92mmol,1.2当量)和TEA(2.00g,19.8mmol,3.0当量)在DCM(20mL)溶液的混合物在室温下搅拌过夜。将所得混合物用水(20mL)稀释并用DCM(10mL)萃取。合并的有机层用无水Na2SO4干燥并减压浓缩。将浓缩物依次通过Prep-TLC(DCM/MeOH＝10/1)，和Prep-HPLC(在方法A条件下)纯化，得到1-(2-(4-氟苯基)-2-氧 代乙基)-N-((6-(甲氧基甲基)吡啶-3-基)甲基)-哌啶-4-甲酰胺.2,2,2-三氟乙酸盐(185mg,4.55％)，为无色油状物。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]+.
生物活性测试
1、5-HT2A受体拮抗剂活性筛选试验
为证实本发明化合物对5-HT2A受体的拮抗活性，选择IP-One实验完成检测。以下实验采用Flp-In-CHO-5HT2A稳定细胞系完成。IP-One实验基于HTRF(均相时间分辨荧光)的竞争性免疫检测，使用了铽穴状化合物标记的抗IP1单抗和d2标记的IP1。细胞产生的IP1和试剂盒所提供的标记了d2的IP1竞争抗IP1抗体的抗原结合位点，当铽标记抗IP1抗体与d2标记的IP1结合后，会发生能量共振转移，从而产生信号，随细胞内IP1产生增多，游离的IP1与抗体结合增多，信号逐渐减小。
材料和方法：
依据用户手册，中国地鼠卵巢细胞转化细胞系(Flp-InTM-CHO cell line)(购买于invitrogen，R75807)，通过用pFRT//acZeo2转染CHO细胞并选择ZeocinTM抗性克隆产生Flp-InTM-CHO细胞系。Flp-InTM-CHO细胞系于加有10％FBS(Hyclone)+1×Penicilin-Streptomycin(15140-122,Gibco)的Ham’s F-12K完全培养基(Hyclone)中培养，之后以人HTR2A基因(Human HTR2A,GeneBank,NM_000621)稳定转染得到Flp-In-CHO-5HT2A细胞。稳定转染的细胞系培养于加有10％FBS(Hyclone)+1×Penicilin-Streptomycin+800μg/ml Hygromycin B(ant-hg-5,Invivogen)的Ham’s F-12K完全培养基(Hyclone)中。为验证化合物活性，Flp-In-CHO-5HT2A稳定细胞系在37℃，5％CO2条件下，于384孔板中培养(7.5K)20小时。化合物用Ham’s F-12K培养基稀释成不同浓度，与新鲜培养基一同以100μl/孔更换培养过夜的培养基，细胞用化合物处理30分钟后加入5-HT在37摄氏度下培养45分钟，之后顺序加入裂解检测缓冲液、IP1-d2和IP1-Ab室温培养1小时后在Envision上读板(HTRF模块)。
根据所示结果，Flp-In-CHO-5HT2A稳定细胞系的5HT2A受体活性会被化合物所抑制，提示所述化合物具有5HT2A受体拮抗活性。
2、Sigma2靶点结合性实验
人Sigma2受体在Jurkat细胞中表达，细胞膜在修饰的磷酸钾缓冲液(pH7.6)中，与25nM[3H]标记的DTG在25℃下共同孵育60分钟，以10μM氟哌啶醇确定非特异性结合。细胞膜过滤洗涤，检测滤出液中[3H]DTG来确定化合物的特异性结合。
采用同样的测定方法，按照浓度梯度检测化合物对sigma2受体抑制活性并计算得到相应的IC50值。
3、hERG膜蛋白特异性结合实验
该实验采用稳定表达hERG(human Ether-a-go-go Related Gene)编码钾通道的HEK293细胞系完成实验。在心肌中，hERG编码的钾通道介导一种延迟整流钾电流(IKr)，Ikr抑制是药物导致QT间期延长最重要的机制。hERG因其特殊的分子结构，其功能缺失或药物抑制都会影响心脏动作电位复极过程 并会引起QT间期延长，同时可能诱发尖端扭转性室性心动过速，导致心律失常。
该实验将hERG膜蛋白、检测化合物与固定浓度的放射性配体混合，使检测化合物和放射性配体竞争性地与hERG膜蛋白结合，孵育一定时间达到平衡后，用真空过滤掉没有与膜蛋白结合的放射性配体，烘干过滤板后加入闪烁液，并在Microbeta上检测同位素信号(CPM)。信号越高代表检测化合物与hERG膜蛋白结合能力越弱。
材料和方法：
将化合物、稀释好的hERG膜蛋白以及稀释好的H3-多菲利特配体(NET1144100UC，PerkinElmer)先后加入到96孔板(3631，Corning)内，封板膜封板后，室温摇动孵育1小时，使用PerkinElmer细胞收集器将孵育后的hERG膜蛋白转移至GF/B板(600517，PerkinElmer)上，使用冲洗缓冲液(20mmol/L HEPES(PH 7.4)(Sigma-H3375)；10mmol/L氯化钾(Sigma-P9333)；1mmol/L氯化镁(Sigma-449172)，4℃保存)清洗5次(4℃，每次0.4mL)。随后将GF/B板于50℃烘箱内烘烤30min，使GF/B板充分干燥后，底部封板膜(6005199，PerkinElmer)封闭GF/B板底部，向板子每孔加入50μL闪烁液20(6013621，PerkinElmer)后用顶部封板膜(6005250，PerkinElmer)封板，Microbeta上读板检测放射性信号。
4、hERG膜蛋白特异性结合手动膜片钳实验
该实验采用手动膜片钳系统评估测视频对人hERG通道的潜在抑制作用。实验采用稳定转染hERG基因的HEK293细胞系，以多菲利特为阳性对照品。
材料和方法
取下细胞培养皿(Nunc(150288))盖，置于显微镜(Olympus(IX51/71/73))浴室台上，先在10倍物镜，后在40倍物镜下将电极(AXON(Multiclamp 700B))逐渐接近细胞表面，通过电极夹的侧口轻轻吸住细胞形成一个千兆赫的密封。设置膜电极为-60mV，确保hERG通道关闭，然后保持电势设置为-90mV，持续500毫秒后，+30mV去极化4.8秒引出hERG电流，-50mV 5.2秒去除失活观察失活尾电流，记录电流120秒评估电流稳定性。在测试化合物存在的情况下记录大约5分钟的hERG电流，在剂量反应中，将5个剂量的试验化合物从低浓度到高浓度添加到细胞中进行电流测量。
5、hERG膜蛋白特异性结合自动膜片钳实验
该实验采用自动膜片钳系统评估测视频对人hERG通道的潜在抑制作用。实验采用稳定表达hERG基因的CHO细胞系，以西沙比利为阳性对照品。
材料和方法
将两个T175培养瓶(431082，CORNING)中的细胞室温下用8mL DPBS-2mM EDTA冲洗并转移，加入3mL细胞消化液,轻轻摇晃容器使其覆盖细胞表面，37℃孵育8-10分钟后分离细胞，用移液管(BIOFIL(GSP110010))将细胞转移至10cm超低结合培养皿(NEST(704001))，4-10℃孵育10分钟，计数(Invitrogen(Countess II))后转移至特氟龙储罐中轨道摇晃(IKA(MS3digital))。SyncroPatch384i仪器(Nanion(384i))上用内部和外部溶液填充芯片(Nanion(221401,4xhigh))，在芯片上加入细胞，密封电池后设置保持电势为-90mV，500ms，去极化诱导hERG电流至+30mV，持续4.8秒，再取 电压至-50mV,持续5.2秒，去除失活测量失活尾电流。测试化合物存在下记录hERG电流不少于5分钟，在两个独立实验中检测存在化合物的hERG电流抑制浓度测定。

以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (8)

  1. 一种如式I结构的化合物或其药学可接受的盐或其溶剂化物或其立体异构体，
    其中，M选自O、S或H，当M为H时，C＝M表示CH2；
    R1、R2独立地选自氢、C1-6烷基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、C6-10芳基、或C1-6亚烷基C6-10芳基；
    n、m独立的选自0-4的整数；
    x、y独立的为0或1，且x、y之和为1；
    R3选自氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、C6- 10芳基、或C1-6亚烷基C6-10芳基；
    R4选自氢、卤素、CN、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、C6-10芳基、或C1-6亚烷基C6-10芳基；
    Cy1表示环取代基，Cy1仅代表非稠合的单环，所述单环为四元、五元、六元或七元环，所述单环为芳环、杂芳环、碳环或杂环，杂芳环和杂环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代；
    R5选自氢、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、或C1-6亚烷基C6-10芳基；
    优选，M为O；
    优选，n、m独立的选自0-2的整数；
    优选，R4选自氢、卤素、C1-3烷基；
    优选，R4的取代位置为苯环的对位；和/或，
    优选，式I中：M为O；R1、R2独立地选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、C6-10芳基、或C1-3亚烷基C6-10芳基；n、m独立的选自0-2的整数；x、y独立的为0或1，且x、y之和为1；R3选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、C6-10芳基、或C1-3亚烷基C6-10芳基；R4的取代位置为苯环的对位，R4选自氢、卤素、C1-3烷基，更优选，R4选自氢、F、Cl、甲基；Cy1代表非稠合的单环，所述单环为五元或六元环，所述单环为芳环、杂芳环、碳环或杂环，杂芳环和杂环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被 一个或多个R5取代；优选，Cy1是苯环、环己烷、吡啶、噻唑、或唑，更优选是苯环或吡啶；R5选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、或C1-3亚烷基C6-10芳基。
  2. 如权利要求1所述的化合物或其药学可接受的盐或其溶剂化物或其立体异构体，具有式IA结构，
    其中，R1、R2独立地选自氢、C1-6烷基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、C6-10芳基、或C1-6亚烷基C6-10芳基；
    m选自0-4的整数，n选自0-2的整数；
    x、y独立的为0或1，且x、y之和为1；
    R3选自氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、或C1-6亚烷基C3-7环烷烃；
    Cy1代表非稠合的单环，所述单环为四元、五元、六元或七元环，所述单环为芳环、杂芳环、碳环或杂环，杂芳环和杂环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代；
    R5选自C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、或C1-6亚烷基C6-10芳基；
    优选，m选自0、1或2的整数，n选自0或1的整数，且m和n不同时为0；
    优选，式IA中，R1、R2独立地选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、C6-10芳基、或C1-3亚烷基C6-10芳基；m选自0、1或2的整数，n选自0或1的整数，且m和n不同时为0；x、y独立的为0或1，且x、y之和为1；R3选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃；Cy1代表非稠合的单环，所述单环为五元或六元环，所述单环为芳环、杂芳环、碳环或杂环，杂芳环和杂环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代；优选，Cy1是苯环、环己烷、吡啶、噻唑、或唑，更优选为苯环或吡啶；R5选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、或C1-3亚烷基C6-10芳基；优选，R5为一个取代基，与所述环的碳原子连接。
  3. 如权利要求1或2所述的化合物或其药学可接受的盐或其溶剂化物或其立体异构体，其中Cy1为五元环或六元环，优选为苯环、环己烷、吡啶、噻唑、或唑。
  4. 如权利要求1-3任一项所述的化合物或其药学可接受的盐或其溶剂化物或其立体异构体，具有 式IB结构，
    其中，R1选自氢、C1-6烷基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、或C1-6亚烷基C3-7环烷烃；
    m选自0-4的整数，n选自0或1；
    x、y独立的为0或1，且x、y之和为1；
    R3选自氢、C1-6烷基、或C1-6烷氧基；
    W、Z或V独立地选自C、N、O或S的环原子，虚线与实线键表示双键或单键，一个或多个R5取代在六元环的任意位置，R5选自氢、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-7环烷烃、C1-6亚烷基C3-7环烷烃、或C1-6亚烷基C6-10芳基；优选W、Z或V独立地为C或N原子，一个或多个R5连接六元环任意环碳和/或环氮原子；
    优选，m选自0、1或2的整数，且m和n不同时为0；
    优选，W、Z和V均为C原子；
    优选，W和Z为C原子且V为N原子，或者，W和V为C原子且Z为N原子，或者，V和Z为C原子且W为N原子；
    优选，含W、Z和V的环为苯环或吡啶；
    优选，R5为一个取代基，与所述环的碳原子连接；和/或，
    优选，式IB中，R1选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃；m选自0、1或2的整数，n选自0或1，且m和n不同时为0；x、y独立的为0或1，且x、y之和为1；R3选自氢、C1-3烷基、C1-3烷氧基；W、Z和V均为C原子，或者，W和Z为C原子且V为N原子，或者，W和V为C原子且Z为N原子，或者，V和Z为C原子且W为N原子；R5选自氢、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃、或C1-3亚烷基C6-10芳基，优选，R5为一个取代基，与所述环的碳原子连接。
  5. 如权利要求1-4任一项所述的化合物或其药学可接受的盐或其溶剂化物或其立体异构体，选自如下化合物或其药学可接受的盐或其溶剂化物或其立体异构体：

  6. 一种制备权利要求1-5任一项所述式I化合物或其药学可接受的盐或其溶剂化物或其立体异构体的方法，其特征在于：
    步骤1、式A1结构的胺基化合物与式B1化合物反应，得到式I化合物，
    或，式A2结构的胺基化合物与式B2化合物反应，得到式I化合物；
    再或，式C1结构化合物与C2化合物反应，得到式I化合物，
    步骤2、如果需要，对式I化合物进行官能团修饰，转化为具有式I结构的目标产物，或者转化为所述化合物的药学可接受的盐，或前体化合物；
    其中，Z1为离去基团。
  7. 一种药物组合物，其特征在于，包括权利要求1-5任一项所述的化合物或其药学可接受的盐或其溶剂化物或其立体异构体；
    优选，所述药物组合物进一步含有药学上可接受的载体；
    优选，所述药物组合物，进一步含有其他的治疗5HT2A受体和/或Sigma2受体活性介导的相关疾病的药物；
    优选，所述其他的治疗药物选自精神疾病治疗药物、中枢神经系统退行性疾病治疗药物；优选，所述精神疾病治疗药物选自苯二氮类、巴比妥类、水合氯醛、丁螺环酮、吩噻嗪类、硫杂蒽类、丁酰苯类、氯氮平、利哌利酮、三环类抗抑郁药、杂环类抗抑郁药、选择性5-HT重摄取抑制剂、单胺氧化酶抑制剂、氯胺酮、米氮平；
    优选，所述中枢神经系统退行性疾病治疗药物选自左旋多巴、溴隐亭、硫丙麦角林、丙炔苯丙胺、金刚烷胺、利血平。
  8. 权利要求1-5任一项所述化合物或其药学上可接受的盐或溶剂化物或立体异构体在制备治疗Sigma2受体活性介导的相关疾病、5HT2A受体活性介导的相关疾病、或由Sigma2受体活性和5HT2A 受体活性共同介导的相关疾病的药物中的用途；
    优选，所述5HT2A受体和/或Sigma2受体活性介导的相关疾病为中枢神经系统疾病；
    优选，所述中枢神经系统疾病选自：精神疾病、中枢神经系统退行性疾病、中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状；
    优选，所述精神疾病选自：抑郁症、焦虑症、躁狂症、精神分裂症、情感性分裂症、双相精神障碍、失眠、自闭症；
    优选，所述中枢神经系统退行性疾病选自：阿尔兹海默症、帕金森病、亨廷顿病、路易小体痴呆症；
    优选，所述中枢神经系统退行性疾病相关或并发的精神紊乱症状、精神疾病的阴性症状选自：情感障碍、语言功能减退、幻觉、兴趣缺失、情感迟钝、意志减退、快感缺乏、社交退缩。
PCT/CN2023/120114 2022-09-28 2023-09-20 一种酰胺类化合物及其制备Sigma2和5HT2A抑制剂的用途 WO2024067302A1 (zh)

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