WO2024067304A1 - Compound with inhibitory activity against sigma2 and 5ht2a and use - Google Patents

Compound with inhibitory activity against sigma2 and 5ht2a and use Download PDF

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WO2024067304A1
WO2024067304A1 PCT/CN2023/120119 CN2023120119W WO2024067304A1 WO 2024067304 A1 WO2024067304 A1 WO 2024067304A1 CN 2023120119 W CN2023120119 W CN 2023120119W WO 2024067304 A1 WO2024067304 A1 WO 2024067304A1
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ring
alkylene
cycloalkane
alkoxy
hydrogen
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PCT/CN2023/120119
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French (fr)
Chinese (zh)
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邢洪涛
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瀚远医药有限公司
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Priority claimed from CN202211194326.3A external-priority patent/CN117820202A/en
Priority claimed from CN202211305570.2A external-priority patent/CN117964547A/en
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Publication of WO2024067304A1 publication Critical patent/WO2024067304A1/en

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application relates to the field of pharmaceutical compounds, and in particular to a urea or aminocarbamate 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 increased or decreased levels 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 associated with the pathogenesis of many psychiatric disorders, such as depression, panic attacks, schizophrenia, suicide 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 antipsychotic drugs 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 antipsychotic drugs 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, HY (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,
  • X is selected from N or O, wherein, when X is O, R 1 is absent;
  • 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;
  • R3 is independently selected from hydrogen, halogen, OH, 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, OH, 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 heteroatom in the heterocyclic ring or heteroaromatic ring is selected from one or more of N, O and S; Cy 1 is further substituted by one or more R 5 ;
  • R 5 is independently selected from hydrogen, halogen , OH, CN, 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 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.
  • Cy1 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; Cy1 is further substituted by one or more R5 .
  • Cy 1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, imidazole.
  • 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 located at the para position 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, m are independently selected from integers of 0-2, such as 0, 1 or 2;
  • 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 selected from hydrogen, halogen, C 1-3 alkyl, preferably, R 4 is selected from hydrogen, F, Cl, methyl; preferably, the substitution position of R 4 is the para position of the benzene ring;
  • Cy1 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; Cy1 is further substituted by one or more R5 ; preferably, Cy1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, imidazole;
  • 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 located at the para position of the ring.
  • the present application discloses a compound of formula II, 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, m are independently selected from integers of 0-4, such as 0, 1, 2, 3 or 4;
  • R3 is independently selected from hydrogen, halogen, OH, 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, OH, 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 heteroatom in the heterocyclic ring or heteroaromatic ring is selected from one or more of N, O and S; Cy 1 is further substituted by one or more R 5 ;
  • R 5 is independently selected from hydrogen, halogen , OH, CN, 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 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.
  • Cy1 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; Cy1 is further substituted by one or more R5 .
  • Cy 1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, imidazole.
  • 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 located at the para position 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- C 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;
  • 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 selected from hydrogen, halogen, C 1-3 alkyl, preferably, R 4 is selected from hydrogen, F, Cl, methyl; preferably, the substitution position of R 4 is the para position of the benzene ring;
  • Cy1 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; Cy1 is further substituted by one or more R5 ; preferably, Cy1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, imidazole;
  • 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 located at the para position of the ring.
  • the present invention discloses a compound having a structure of Formula IIA, and 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 1-6 alkylene C 6-10 aryl;
  • n and n are independently selected from integers of 0-4, such as 0, 1, 2, 3 or 4;
  • R3 is selected from hydrogen, halogen, OH, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkylene;
  • Cy 1 is selected from cyclohexane, benzene ring, pyridine ring, thiazole ring, imidazole ring, oxazole ring substituted with one or more R 5 ;
  • R 5 is independently selected from hydrogen, halogen , OH, CN, 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.
  • n and n are independently selected from integers of 0-4, such as 0, 1, 2, 3 or 4, and m and n are preferably 0, 1 or 2.
  • R 3 is selected from hydrogen, fluorine, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxyC 1-3 alkylene.
  • R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkyl, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane.
  • R 5 is a substituent located at the para position of the ring.
  • R 1 and R 2 are independently selected from hydrogen, C 1-3 alkyl, C 3-7 cycloalkane; m is 0 or 1; n is 1; R 3 is selected from hydrogen, fluorine, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene; Cy 1 is a benzene ring or pyridine; R 5 is hydrogen, or is located at The para position of the ring is C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxy-C 1-3 alkyl.
  • the present application also discloses a compound of formula III or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
  • R 2 is 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;
  • 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 or 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 ;
  • R5 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkylene , C3-7 cycloalkane , or C1-6 alkyleneC3-7 cycloalkane.
  • R2 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane or C1-3 alkylene C3-7 cycloalkane.
  • R 3 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 alkoxyC 1-3 alkylene.
  • R 4 is selected from hydrogen, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxyC 1-3 alkylene. In one embodiment of the present invention, R 4 is selected from F.
  • the R 4 substitution position is located at the para position of the benzene ring.
  • Cy 1 is 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 or 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 a pyridine ring, and Cy 1 is further substituted by one or more R 5 .
  • R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy , C 1-3 alkoxy C 1-3 alkylene, or C 1-3 alkylene C 3-7 cycloalkane.
  • R 5 is a substituent, and the substitution position is located at the para position of the Cy 1 ring.
  • n is selected from an integer of 1-3, such as 1, 2 or 3.
  • m is selected from an integer of 0-2, such as 0, 1 or 2.
  • R 2 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkylene , C 3-7 cycloalkane or C 1-3 alkylene C 3-7 cycloalkane;
  • n is an integer selected from 1-3, such as 1, 2 or 3;
  • m is an integer selected from 0-2, such as 0, 1 or 2;
  • R3 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy or C1-3 alkoxyC1-3 alkylene;
  • R 4 is selected from hydrogen, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxy C 1-3 alkylene, preferably, R 4 is selected from F; preferably, the substitution position of R 4 is located at the para position of the benzene ring;
  • Cy 1 is 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 or 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 or a pyridine ring;
  • R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, or C 1-3 alkylene C 3-7 cycloalkane.
  • R 5 is a substituent, and the substitution position is located at the para position of the Cy 1 ring.
  • the present invention discloses a compound having a structure of formula IIIA, and a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • R 2 is 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 independently selected from an integer of 0-4, such as 0, 1, 2, 3 or 4;
  • 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 or 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 ;
  • R5 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkylene , C3-7 cycloalkane , or C1-6 alkyleneC3-7 cycloalkane.
  • R2 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane or C1-3 alkylene C3-7 cycloalkane.
  • R 3 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 alkoxyC 1-3 alkylene.
  • Cy 1 is 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 or 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 a pyridine ring, and Cy 1 is further substituted by one or more R 5 .
  • R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, or C 1-3 3 Alkylene C 3-7 cycloalkane.
  • R 5 is a substituent, and the substitution position is located at the para position of the Cy 1 ring.
  • m is selected from an integer of 0-2, such as 0, 1 or 2.
  • R 2 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane or C 1-3 alkylene C 3-7 cycloalkane;
  • n is an integer selected from 0-2, such as 0, 1 or 2;
  • R3 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy or C1-3 alkoxyC1-3 alkylene;
  • Cy 1 is 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 or 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 or a pyridine ring;
  • R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, or C 1-3 alkylene C 3-7 cycloalkane.
  • R 5 is a substituent, and the substitution position is located at the para position of the Cy 1 ring.
  • the present invention discloses a compound having a structure of formula IIIB, and a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • R 2 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 0-4, such as 0, 1, 2, 3 or 4, preferably m is 0, 1 or 2;
  • R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or C 3-7 cycloalkane
  • W, Z 1 are independently selected from C, N, O or S; preferably W, Z 1 are independently selected from C or N;
  • R 5 are connected to any ring carbon and/or ring nitrogen atom of the six-membered ring, and R 5 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkylene, C 1-6 alkylene C 3-7 cycloalkane.
  • R2 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane or C1-3 alkylene C3-7 cycloalkane;
  • n 0, 1 or 2;
  • R 3 is selected from hydrogen, C 1-3 alkyl
  • W and Z1 are both C, or W is C and Z1 is N, or W is N and Z1 is C;
  • R 5 are connected to any ring carbon and/or ring nitrogen atom of the six-membered ring, and R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy Oxy C 1-3 alkylene, or C 1-3 alkylene C 3-7 cycloalkane.
  • R 5 is a substituent, and the substitution position is located at the para position of the six-membered 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, when X is N, reacting an amino compound of formula A structure and a compound of formula B with a carbonylation reagent to synthesize a compound of formula I,
  • Step 2 If necessary, the compound of formula I is functionally modified according to the needs of the target product to convert it into the target product having the structure of formula I, or into a pharmaceutically acceptable salt or precursor compound of the compound.
  • the carbonylation reagent is selected from triphosgene, 1,1'-carbonyldiimidazole (CDI), etc.; R 1 -R 4 , m, n, Cy 1 are as defined above; and Z is a leaving group, such as halogen, hydroxyl, etc.
  • the preparation method is also applicable to the preparation of compounds of formula II, IIA, III, IIIA or IIIB.
  • the compounds of formula I, formula II, formula IIA, formula III, formula IIIA or formula IIIB of the present invention or their pharmaceutically acceptable salts, solvates, or stereoisomers have Sigma2 receptor inhibitory activity and 5HT2A receptor inhibitory activity, and can be used for the treatment of diseases mediated by Sigma2 receptor activity, the treatment of diseases mediated by 5HT2A receptor activity, and the treatment of diseases mediated by Sigma2 receptor activity and 5HT2A receptor activity. Treatment of co-mediated related diseases.
  • 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 ⁇ 500nM, more preferred compounds have IC50 ⁇ 200nM, and most preferred compounds have IC50 ⁇ 100nM.
  • 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 cardiac toxicity.
  • the preferred compounds of the present invention have a hERG binding rate of less than 90% at 10 ⁇ M, the more preferred compounds have a hERG binding rate of less than 80% at 10 ⁇ M, and the most preferred compounds have a hERG binding rate of less than 70% at 10 ⁇ M.
  • the present invention provides the use of a compound of Formula I, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB 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, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB 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, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB 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, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB 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 carrier is various excipients commonly used or known in the pharmaceutical field, including but not limited to: diluents, binders, antioxidants, pH regulators, preservatives, lubricants, disintegrants, etc.
  • Examples of the diluent include lactose, starch, cellulose derivatives, inorganic calcium salts, sorbitol, etc.
  • Examples of the binder include starch, gelatin, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, etc.
  • Examples of the antioxidant include vitamin E, sodium bisulfite, sodium sulfite, butylated hydroxyanisole, etc.
  • Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, Tris, acetic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, etc.
  • Examples of the preservative include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, metacresol, benzalkonium chloride, etc.
  • Examples of the lubricant include magnesium stearate, micropowder silica gel, talc, etc.
  • Examples of the disintegrant include starch, methyl cellulose, xanthan gum, cross-linked sodium carboxymethyl cellulose, etc.
  • the pharmaceutical composition contains a compound of Formula I, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof 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, formula II, formula IIA, formula III, formula IIIA or formula IIIB or its pharmaceutically acceptable salt, solvate, or stereoisomer 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 a compound of formula I, formula II, formula IIA, formula III, formula IIIA or formula IIIB or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof will depend on the age, health and weight of the recipient, the type of 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 a compound of formula I, a compound of formula IA 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 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered to a patient in need.
  • administration routes of the compound of Formula I, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB or a pharmaceutically acceptable salt, solvate, or stereoisomer 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 implantation of a reservoir or reservoir.
  • 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 related to 5HT2A receptor and/or Sigma2 receptor activity include but are not limited to: Therapeutic drugs, drugs for the treatment of degenerative diseases of the central nervous system, 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.
  • Oxazole Equivalent to oxazole, in English it is called oxazole.
  • C 1-6 alkyl includes 1-6 carbon chain atoms, including straight chain and branched chain alkanes, which may be further substituted by common groups such as OH, halogen, NO 2 , etc.
  • C 3-7 cycloalkanes include cycloalkanes containing 3-7 ring carbon atoms, cycloalkanes containing a total of 3-7 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, propylcyclopropyl, propylcyclobutyl, etc.
  • C 1-6 alkylene includes alkylene groups containing 1 to 6 carbon atoms, and the group plays a bridging role.
  • C1-6 alkoxy equivalent to C1-6 alkyl-O-group, i.e. an alkyloxy group containing 1 to 6 carbon atoms.
  • C 6-10 aryl includes aromatic groups containing 6 to 10 carbon atoms and containing only ring carbon atoms, and carbocyclic aromatic groups containing a total of 6 to 10 carbon atoms.
  • 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 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.
  • Prep-HPLC purification under Method A conditions: Prep-HPLC purification was performed using Method A conditions, which included: column: sunfire 5 ⁇ m 19-150 mm or XBridge-1 5 ⁇ m 19-150 mm; mobile phase A: water (0.1% TFA), mobile phase B: ACN; gradient: 10-20-9 MIN 150 VL
  • PE petroleum ether
  • TFA 2,2,2.Trifluoroacetic acid or trifluoroacetic acid
  • HMDSK Potassium bis(trimethylsilyl)amide
  • Red-Al Sodium bis(2-methoxyethoxy)aluminium hydride or sodium dihydrogen bis(2-methoxyethoxy)aluminium hydride
  • CDI 1,1'-Carbonyldiimidazole
  • (6-(Ethoxymethyl)pyridin-3-yl)methanamine was prepared and purified by a method similar to that for (6-(methoxymethyl)pyridin-3-yl)methanamine, using 6-(ethoxymethyl)nicotinonitrile (400 mg, 2.47 mmol, 1.00 equiv) as starting material to give (6-(ethoxymethyl)pyridin-3-yl)methanamine (400 mg, crude) as a yellow oil, LC-MS (ESI, m/z): 167.1 [M+H] + .
  • 6-(Ethoxymethyl)pyridin-3-amine was prepared and purified by a method similar to that for 6-(methoxymethyl)pyridin-3-amine, using 5-bromo-2-(ethoxymethyl)pyridine as starting material to give the desired compound 6-(ethoxymethyl)pyridin-3-amine (1.20 g, 30.4%) as a yellow oil, LC-MS (ESI, m/z): 153.1 [M+H] + .
  • the preparation method of (2-methyloxazol-5-yl)methylamine is similar to that of (2-methyl-1H-oxazol-4-yl)methylamine, using 2-methyl-1,3-oxazole-5-carboxylic acid as the raw material.
  • the preparation method of (2-methylthiazol-4-yl)methylamine is similar to that of (2-methylthiazol-5-yl)methylamine, using 2-methylthiazole-4-carboxaldehyde as the raw material.
  • Step 4 Preparation of tert-butyl ((5-(methoxymethyl)thiazol-2-yl)methyl)carbamate
  • Step 1 Preparation of tert-butyl 4-((3-(4-methoxybenzyl)-1-methylureido)methyl)piperidine-1-carboxylate
  • Step 1 Preparation of tert-butyl 4-[(cyclopropylamino)methyl]piperidine-1-carboxylate
  • Step 2 Preparation of 1-cyclopropyl-3-(4-(methoxymethyl)benzyl)-1-(piperidin-4-ylmethyl)urea-trifluoroacetic acid
  • 3-Benzyl-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid, starting from tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate (955 mg, 4.18 mmol, 0.8 equiv) and benzylamine (560 mg, 5.23 mmol, 1.0 equiv) to give the desired 3-benzyl-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid (500 mg, 30% yield over 2 steps) as a yellow oil, LC-MS (ESI, m/z): 262 [M+H] + .
  • 3-Benzyl-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10298 starting from 3-benzyl-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid (500 mg, 1.91 mmol, 1.0 equiv) and 2-chloro-1-(4-fluorophenyl)ethanone (396 mg, 2.30 mmol, 1.2 equiv) to give the desired product (21.8 mg, 2% yield) as a white solid.
  • Trifluoroacetic acid (18 mg, 3% yield) as a light brown oil, 1 H-NMR (300MHz, Chloroform-d) ⁇ 8.07-8.12 (m, 1H), 7.94 (s, 1H), 7.02-7.24 (m, 2H), 4.39-4.71 (m, 2H), 3.42-3.79 (m, 5H), 2.90-3.31 (m, 9H), 1.78-2.12 (m, 7H), 1.32-1.50 (m, 2H), 1.11-1.25 (m, 6H), 0.85-1.11 (m, 2H).
  • Trifluoroacetic acid (13 mg, 2%) was a light yellow oil, 1 H-NMR (300 MHz, Chloroform-d) ⁇ 7.92 (s, 2H), 7.15-7.20 (m, 2H), 4.53-4.60 (m, 2H), 3.30-3.82 (m, 6H), 3.00-3.30 (m, 5H), 2.92 (s, 3H), 1.70-2.12 (m, 6H), 1.30-1.52 (m, 6H), 1.09-1.23 (m, 4H), 0.72-1.08 (m, 1H).
  • LC-MS (ESI, m/z): 448 [M+H] + .
  • Step 1 Preparation of tert-butyl 4-(2-((4-(methoxymethyl)benzyl)amino)-2-oxoethoxy)piperidine-1-carboxylate
  • PEX32 Preparation of piperidin-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)(methyl)carbamate
  • Step 3 Preparation of benzyl 4-(((((6-methoxypyridin-3-yl)methyl)(methyl)carbamoyl)oxy)methyl)piperidine-1-carboxylate
  • PEX33 Preparation of piperidin-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)carbamate
  • the preparation method of piperidin-4-ylmethyl((6-methoxypyridin-3-yl)methyl)carbamate is similar to the preparation method of piperidin-4-ylmethyl((6-methoxypyridin-3-yl)methyl)(methyl)carbamate, using (6-methoxypyridin-3-yl)methylamino as the starting material.
  • 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.
  • the 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.
  • the 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).
  • Flp-In-CHO-5HT2A cells were obtained by transfection. 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). To verify the activity of the compound, the Flp-In-CHO-5HT2A stable cell line was cultured in a 384-well plate (7.5K) at 37°C and 5% CO 2 for 20 hours. The compound was diluted to different concentrations with Ham's F-12K medium, and the culture medium that was cultured overnight was replaced with fresh medium at 100 ⁇ l/well.
  • 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 experiment was conducted using a HEK293 cell line that stably expresses hERG (human Ether-a-go-go Related Gene)-encoded potassium channels.
  • hERG human Ether-a-go-go Related Gene
  • the potassium channels encoded by hERG mediate a delayed rectifier potassium current (IKr), and Ikr inhibition is the most important mechanism for drug-induced QT interval prolongation. Due to its special molecular structure, hERG's functional loss or drug inhibition will affect the cardiac action potential repolarization process and cause QT interval prolongation, and may also induce torsades de pointes, leading to arrhythmias.
  • 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 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 DPBS-2 mM EDTA at room temperature and transferred. 3 mL of cell digestion solution was added, and the container was gently shaken to cover the cell surface. After incubation at 37°C for 8-10 minutes, the cells were separated 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 tank with orbital shaking (IKA (MS3digital)).
  • NEST 10 cm ultra-low binding culture dish
  • BIOFIL BIOFIL
  • IKA Teflon tank with orbital shaking
  • the chip was filled with internal and external solutions on the SyncroPatch 384i instrument (Nanion (384i)) (Nanion (221401, 4xhigh)), and cells were added to the chip. After sealing the cell, the holding potential was set to -90 mV for 500 ms, and the hERG current was induced by depolarization to +30 mV for 4.8 seconds, and then the voltage was taken to -50 mV for 5.2 seconds, and the inactivation tail current was measured by removing inactivation. hERG currents were recorded in the presence of test compounds for at least 5 min and the inhibitory concentration of hERG currents in the presence of the compounds was determined in two independent experiments.
  • Nion (384i) Nion (221401, 4xhigh

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Abstract

The present invention provides a compound with inhibitory activity against Sigma2 and 5HT2A. The compound can be used as a dual-target inhibitor of Sigma2 and 5HT2A for the treatment of a related disease mediated by Sigma2 receptor activity, the treatment of a related disease mediated by 5HT2A receptor activity, and the treatment of a related disease mediated jointly by Sigma2 receptor activity and 5HT2A receptor activity, such as negative symptoms of schizophrenia.

Description

一种具有Sigma2和5HT2A抑制活性的化合物及用途A compound with Sigma2 and 5HT2A inhibitory activity and its use
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202211194326.3，发明名称为“一种胺基甲酸类化合物及其作为Sigma2和5HT2A双靶标抑制剂的用途”和2022年10月24日向中国国家知识产权局提交的专利申请号为202211305570.2，发明名称为“一种脲类化合物及其作为Sigma2和5HT2A双靶标抑制剂的用途”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。This application claims priority to the prior application with patent application number 202211194326.3 filed with the State Intellectual Property Office of China on September 28, 2022, and the invention title "A kind of amino formic acid compound and its use as a dual-target inhibitor of Sigma2 and 5HT2A" and patent application number 202211305570.2 filed with the State Intellectual Property Office of China on October 24, 2022, and the invention title "A kind of urea compound and its use as a dual-target inhibitor of Sigma2 and 5HT2A". The entire text of the prior application is incorporated into this application by reference.
技术领域Technical Field
本申请涉及药用化合物领域，具体涉及一种脲类或胺基甲酸类化合物，及其作为Sigma2和5HT2A双靶标抑制剂的用途。The present application relates to the field of pharmaceutical compounds, and in particular to a urea or aminocarbamate compound, and its use as a dual-target inhibitor of Sigma2 and 5HT2A.
背景技术Background technique
精神***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***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***症的核心症状，在精神***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.)。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. This significant disease burden can be attributed to the limited effective treatment options, as they generally respond poorly to currently available antipsychotic drugs such as dopamine D2 receptor antagonists or partial D2 receptor agonists (Norman RMG, 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***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.)。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.).
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。So far, the FDA has not approved any drug for the treatment of negative symptoms (https://www.nimh.nih.gov/research-priorities/rdoc/constructs/positive-valence-systems.shtml. Accessed March 28, 2019.). Paradoxically, antipsychotics can both improve and worsen negative symptoms. On the one hand, by improving hallucinations, delusions, and agitation, antipsychotics promote social interaction. On the other hand, by disrupting DA neurotransmission and under-motorization of the brain reward circuitry, core components of negative symptoms are exacerbated and induce extrapyramidal adverse effects that are often indistinguishable from primary negative symptoms.
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.)。Few prospective studies have been designed to evaluate the effects of treatment on persistent negative symptoms, and most reports of negative symptom improvement are based on short-term studies of patients with acute psychosis and those with concurrent negative symptoms. Therefore, in most reported studies, it is difficult to determine whether the improvement in negative symptoms is a true effect of treatment or a secondary effect of improvements in other symptom dimensions (e.g., positive, depressive, extrapyramidal), and long-term evidence is lacking (Helfer B, 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Sigma2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.)。Considering the large unmet medical needs associated with negative symptoms, active research on drugs with activity on different receptors is active in this therapeutic field, including NMDA receptors, α7 nicotinic receptors, 5-HT2A receptors and Sigma2 receptors. Among them, Sigma2 receptors and 5-HT2A receptor antagonists without direct dopamine affinity are the most concerned (Remington G, et al. (2016) Curr Treat Options Psychiatry. 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***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***疾病相关，尤其是阿尔兹海默症(AD)、精神***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。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). Antagonism of Sigma2 receptors may also modulate glutamatergic pathways and affect calcium neuron regulation (Vilner BJ, Bowen WD. (2020) J Pharmacol Exp Ther. 292: 900–911). Sigma2 receptors are involved in counteracting dysregulation of key DA and glutamate neurotransmitter pathways.
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***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***、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。Serotonin or 5-hydroxytryptamine (5-HT) plays an extremely important role in human physiological functions. In the central nervous system, 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) (Alenina N, et al., (2009) Proc Natl 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 exerts its effects through its receptors. Based on the differences in structure (amino acid sequence), biochemistry (post-receptor mechanism of signal transduction) and pharmacology, 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亚型受体在中枢神经***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-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). Like most 5-HT receptors, 5-HT2A receptors are G-protein coupled receptors, which complete signal transduction by activating guanine nucleotide binding protein (G protein), resulting in increased or decreased levels of second messenger molecules such as cyclic adenosine monophosphate (cAMP), inositol phosphates and diacylglycerol. These second messenger molecules regulate the functions of various intracellular enzymes (such as kinases and ion channels), ultimately affecting cell excitability and cellular function.
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***症、*** 倾向等)以及神经***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***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。Abnormal 5-HT transmission is associated with the pathogenesis of many psychiatric disorders, such as depression, panic attacks, schizophrenia, suicide 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 antipsychotic drugs such as clozapine, olanzapine, and risperidone (Gonzalez-Maeso J, et al., (2009) Trends Neurosci, 32: 225-232; Fribourg M, et al., (2011) Cell, 147: 1011-1023; Kurita M, et al., (2012) Nat Neurosci, 15: 1245-1254). 5-HT2A receptor antagonists are 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, HY (2013) Annu Rev Med 64, 393-406). Other studies have confirmed that the 5-HT2A receptor regulatory pathway of cortical pyramidal neurons is crucial for mediating signal transduction and behavioral responses induced by hallucinogens (Gonzalez-Maeso J, et al., (2009) Trends Neurosci, 32: 225-232), suggesting that 5-HT2A receptors play a role in treating hallucination symptoms in a variety of neurodegenerative diseases.
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。Drugs used to treat mental illness, namely antipsychotics, 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.
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***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***疾病的新的药用化合物。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.
发明内容Summary of the invention
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，
The present application discloses a compound of formula I, a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
其中，in,
X选自N或O，其中，当X为O时，R1不存在；X is selected from N or O, wherein, when X is O, R 1 is absent;
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；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独立的选自0-4的整数，例如0，1，2，3或4；n, m are independently selected from integers of 0-4, such as 0, 1, 2, 3 or 4;
R3独立地选自氢、卤素、OH、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； R3 is independently selected from hydrogen, halogen, OH, 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选自氢、卤素、OH、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； R4 is selected from hydrogen, halogen, OH, 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;
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，杂环或杂芳环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代；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 heteroatom in the heterocyclic ring or heteroaromatic ring is selected from one or more of N, O and S; Cy 1 is further substituted by one or more R 5 ;
R5独立地选自氢、卤素、OH、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、或C1-6亚烷基C6-10芳基。R 5 is independently selected from hydrogen, halogen , OH, CN, 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 .
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。In some embodiments of the present invention, 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.
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。In some embodiments of the present invention, n and m are independently selected from integers of 0-2, such as 0, 1 or 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。In some embodiments of the present invention, 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.
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。In some embodiments of the present invention, 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.
在本发明的一些实施方案中，R4的取代位置为苯环的对位。In some embodiments of the present invention, the substitution position of R 4 is the para position of the benzene ring.
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。In some embodiments of the present invention, Cy1 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; Cy1 is further substituted by one or more R5 .
在本发明的一些实施方案中，Cy1是苯环、吡啶、环己烷、噻唑、噁唑、咪唑。In some embodiments of the present invention, Cy 1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, imidazole.
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。In some embodiments of the present invention, 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.
在本发明的一些实施方案中，R5为一个取代基，位于所述环的对位。In some embodiments of the present invention, R 5 is a substituent located at the para position of the ring.
在本发明的一些实施方案中，式I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；In some embodiments of the present invention, in Formula I, 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独立的选自0-2的整数，例如0，1或2；n, m are independently selected from integers of 0-2, such as 0, 1 or 2;
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； 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;
R4选自氢、卤素、C1-3烷基，优选，R4选自氢、F、Cl、甲基；优选，R4的取代位置为苯环的对位；R 4 is selected from hydrogen, halogen, C 1-3 alkyl, preferably, R 4 is selected from hydrogen, F, Cl, methyl; preferably, the substitution position of R 4 is the para position of the benzene ring;
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、吡啶、环己烷、噻唑、噁唑、咪唑；Cy1 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; Cy1 is further substituted by one or more R5 ; preferably, Cy1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, imidazole;
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，位于所述环的对位。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 located at the para position of the ring.
本申请公开一种如式II结构的化合物、其药学可接受的盐、溶剂化物、或立体异构体，
The present application discloses a compound of formula II, a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
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；wherein 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独立的选自0-4的整数，例如0，1，2，3或4；n, m are independently selected from integers of 0-4, such as 0, 1, 2, 3 or 4;
R3独立地选自氢、卤素、OH、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； R3 is independently selected from hydrogen, halogen, OH, 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选自氢、卤素、OH、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； R4 is selected from hydrogen, halogen, OH, 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;
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，杂环或杂芳环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代；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 heteroatom in the heterocyclic ring or heteroaromatic ring is selected from one or more of N, O and S; Cy 1 is further substituted by one or more R 5 ;
R5独立地选自氢、卤素、OH、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、或C1-6亚烷基C6-10芳基。R 5 is independently selected from hydrogen, halogen , OH, CN, 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 .
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。In some embodiments of the present invention, 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.
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。In some embodiments of the present invention, n and m are independently selected from integers of 0-2, such as 0, 1 or 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。In some embodiments of the present invention, 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.
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。In some embodiments of the present invention, 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.
在本发明的一些实施方案中，R4的取代位置为苯环的对位。In some embodiments of the present invention, the substitution position of R 4 is the para position of the benzene ring.
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。In some embodiments of the present invention, Cy1 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; Cy1 is further substituted by one or more R5 .
在本发明的一些实施方案中，Cy1是苯环、吡啶、环己烷、噻唑、噁唑、咪唑。In some embodiments of the present invention, Cy 1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, imidazole.
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。In some embodiments of the present invention, 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.
在本发明的一些实施方案中，R5为一个取代基，位于所述环的对位。In some embodiments of the present invention, R 5 is a substituent located at the para position of the ring.
在本发明的一些实施方案中，式II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；In some embodiments of the present invention, in Formula II, R 1 and R 2 are independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 3- C 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独立的选自0-2的整数，例如0，1或2；n, m are independently selected from integers of 0-2, such as 0, 1 or 2;
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； 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;
R4选自氢、卤素、C1-3烷基，优选，R4选自氢、F、Cl、甲基；优选，R4的取代位置为苯环的对位；R 4 is selected from hydrogen, halogen, C 1-3 alkyl, preferably, R 4 is selected from hydrogen, F, Cl, methyl; preferably, the substitution position of R 4 is the para position of the benzene ring;
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、吡啶、环己烷、噻唑、噁唑、咪唑；Cy1 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; Cy1 is further substituted by one or more R5 ; preferably, Cy1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, imidazole;
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，位于所述环的对位。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 located at the para position of the ring.
本发明公开一种具有式IIA结构的化合物、其药学可接受的盐、溶剂化物、或立体异构体，
The present invention discloses a compound having a structure of Formula IIA, and a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
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、C1-6亚烷基C6-10芳基；Wherein, 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 1-6 alkylene C 6-10 aryl;
m、n独立的选自0-4的整数，例如0，1，2，3或4；m and n are independently selected from integers of 0-4, such as 0, 1, 2, 3 or 4;
R3选自氢、卤素、OH、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基； R3 is selected from hydrogen, halogen, OH, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkylene;
Cy1选自被一个或多个R5取代的环己烷、苯环、吡啶环、噻唑环、咪唑环、噁唑环；Cy 1 is selected from cyclohexane, benzene ring, pyridine ring, thiazole ring, imidazole ring, oxazole ring substituted with one or more R 5 ;
R5独立地选自氢、卤素、OH、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、或C1-6亚烷基C6-10芳基。R 5 is independently selected from hydrogen, halogen , OH, CN, 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 .
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。In some embodiments of the present invention, 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.
在本发明的一些实施方案中，m、n独立的选自0-4的整数，例如0，1，2，3或4，m、n优选为0、1或2。In some embodiments of the present invention, m and n are independently selected from integers of 0-4, such as 0, 1, 2, 3 or 4, and m and n are preferably 0, 1 or 2.
在本发明的一些实施方案中，R3选自氢、氟、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基。In some embodiments of the present invention, R 3 is selected from hydrogen, fluorine, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxyC 1-3 alkylene.
在本发明的一些实施方案中，R5选自氢、卤素、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃。In some embodiments of the present invention, R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkyl, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane.
在本发明的一些实施方案中，R5为一个取代基，位于所述环的对位。In some embodiments of the present invention, R 5 is a substituent located at the para position of the ring.
在本发明的一些实施方案中，式IIA中，R1、R2独立地选自氢、C1-3烷基、C3-7环烷烃；m为0或1；n为1；R3选自氢、氟、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基；Cy1为苯环或吡啶；R5为氢，或位于 所述环对位的C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3烷基。In some embodiments of the present invention, in Formula IIA, R 1 and R 2 are independently selected from hydrogen, C 1-3 alkyl, C 3-7 cycloalkane; m is 0 or 1; n is 1; R 3 is selected from hydrogen, fluorine, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene; Cy 1 is a benzene ring or pyridine; R 5 is hydrogen, or is located at The para position of the ring is C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxy-C 1-3 alkyl.
本申请还公开一种如式III结构的化合物或其药学可接受的盐、溶剂化物、或立体异构体，
The present application also discloses a compound of formula III or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
其中，R2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；wherein R 2 is 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独立的选自0-4的整数，例如0，1，2，3或4；n, m are independently selected from integers of 0-4, such as 0, 1, 2, 3 or 4;
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； 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； 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;
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，杂芳环或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；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 or 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 ;
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、或C1-6亚烷基C3-7环烷烃。 R5 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkylene , C3-7 cycloalkane , or C1-6 alkyleneC3-7 cycloalkane.
在本发明的一些实施方案中，R2选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃或C1-3亚烷基C3-7环烷烃。In some embodiments of the present invention, R2 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane or C1-3 alkylene C3-7 cycloalkane.
在本发明的一些实施方案中，R3选自氢、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基。In some embodiments of the present invention, R 3 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 alkoxyC 1-3 alkylene.
在本发明的一些实施方案中，R4选自氢、卤素、CN、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基。在本发明的一个实施方式中，R4选自F。In some embodiments of the present invention, R 4 is selected from hydrogen, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxyC 1-3 alkylene. In one embodiment of the present invention, R 4 is selected from F.
在本发明的一些实施方案中，R4取代位置位于苯环的对位。In some embodiments of the present invention, the R 4 substitution position is located at the para position of the benzene ring.
在本发明的一些实施方案中，Cy1是非稠合的单环，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，杂芳环或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。In some embodiments of the present invention, Cy 1 is 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 or 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 .
在本发明的一些实施方案中，Cy1是苯环或吡啶环，Cy1进一步被一个或多个R5取代。In some embodiments of the present invention, Cy 1 is a benzene ring or a pyridine ring, and Cy 1 is further substituted by one or more R 5 .
在本发明的一些实施方案中，R5选自氢、卤素、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、或C1- 3亚烷基C3-7环烷烃。In some embodiments of the present invention, R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy , C 1-3 alkoxy C 1-3 alkylene, or C 1-3 alkylene C 3-7 cycloalkane.
在本发明的一些实施方案中，R5为一个取代基，取代位置位于Cy1环的对位。In some embodiments of the present invention, R 5 is a substituent, and the substitution position is located at the para position of the Cy 1 ring.
在本发明的一些实施方案中，n选自1-3的整数，例如1，2或3。In some embodiments of the present invention, n is selected from an integer of 1-3, such as 1, 2 or 3.
在本发明的一些实施方案中，m选自0-2的整数，例如0，1或2。 In some embodiments of the present invention, m is selected from an integer of 0-2, such as 0, 1 or 2.
在本发明的一些实施方案中，式III中，R2选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃或C1- 3亚烷基C3-7环烷烃；In some embodiments of the present invention, in Formula III, R 2 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkylene , C 3-7 cycloalkane or C 1-3 alkylene C 3-7 cycloalkane;
n选自1-3的整数，例如1，2或3；m选自0-2的整数，例如0，1或2；n is an integer selected from 1-3, such as 1, 2 or 3; m is an integer selected from 0-2, such as 0, 1 or 2;
R3选自氢、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基； R3 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy or C1-3 alkoxyC1-3 alkylene;
R4选自氢、卤素、CN、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基，优选，R4选自F；优选，R4取代位置位于苯环的对位；R 4 is selected from hydrogen, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxy C 1-3 alkylene, preferably, R 4 is selected from F; preferably, the substitution position of R 4 is located at the para position of the benzene ring;
Cy1是非稠合的单环，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，杂芳环或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是苯环或吡啶环；Cy 1 is 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 or 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 or a pyridine ring;
R5选自氢、卤素、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、或C1-3亚烷基C3-7环烷烃，优选，R5为一个取代基，取代位置位于Cy1环的对位。R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, or C 1-3 alkylene C 3-7 cycloalkane. Preferably, R 5 is a substituent, and the substitution position is located at the para position of the Cy 1 ring.
本发明公开一种具有式IIIA结构的化合物、其药学可接受的盐、溶剂化物、或立体异构体，
The present invention discloses a compound having a structure of formula IIIA, and a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
其中，R2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；wherein R 2 is 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;
m独立的选自0-4的整数，例如0，1，2，3或4；m is independently selected from an integer of 0-4, such as 0, 1, 2, 3 or 4;
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； 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;
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，杂芳环或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；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 or 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 ;
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、或C1-6亚烷基C3-7环烷烃。 R5 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkylene , C3-7 cycloalkane , or C1-6 alkyleneC3-7 cycloalkane.
在本发明的一些实施方案中，R2选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃或C1-3亚烷基C3-7环烷烃。In some embodiments of the present invention, R2 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane or C1-3 alkylene C3-7 cycloalkane.
在本发明的一些实施方案中，R3选自氢、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基。In some embodiments of the present invention, R 3 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 alkoxyC 1-3 alkylene.
在本发明的一些实施方案中，Cy1是非稠合的单环，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，杂芳环或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。In some embodiments of the present invention, Cy 1 is 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 or 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 .
在本发明的一些实施方案中，Cy1是苯环或吡啶环，Cy1进一步被一个或多个R5取代。In some embodiments of the present invention, Cy 1 is a benzene ring or a pyridine ring, and Cy 1 is further substituted by one or more R 5 .
在本发明的一些实施方案中，R5选自氢、卤素、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、或C1- 3亚烷基C3-7环烷烃。In some embodiments of the present invention, R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, or C 1-3 3 Alkylene C 3-7 cycloalkane.
在本发明的一些实施方案中，R5为一个取代基，取代位置位于Cy1环的对位。In some embodiments of the present invention, R 5 is a substituent, and the substitution position is located at the para position of the Cy 1 ring.
在本发明的一些实施方案中，m选自0-2的整数，例如0，1或2。In some embodiments of the present invention, m is selected from an integer of 0-2, such as 0, 1 or 2.
在本发明的一些实施方案中，式IIIA中，R2选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃或C1-3亚烷基C3-7环烷烃；In some embodiments of the present invention, in Formula IIIA, R 2 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane or C 1-3 alkylene C 3-7 cycloalkane;
m选自0-2的整数，例如0，1或2；m is an integer selected from 0-2, such as 0, 1 or 2;
R3选自氢、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基； R3 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy or C1-3 alkoxyC1-3 alkylene;
Cy1是非稠合的单环，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，杂芳环或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是苯环或吡啶环；Cy 1 is 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 or 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 or a pyridine ring;
R5选自氢、卤素、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、或C1-3亚烷基C3-7环烷烃，优选，R5为一个取代基，取代位置位于Cy1环的对位。R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, or C 1-3 alkylene C 3-7 cycloalkane. Preferably, R 5 is a substituent, and the substitution position is located at the para position of the Cy 1 ring.
本发明公开一种具有式IIIB结构的化合物、其药学可接受的盐、溶剂化物、或立体异构体，
The present invention discloses a compound having a structure of formula IIIB, and a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
其中，R2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；wherein R 2 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;
m选自0-4的整数，例如0，1，2，3或4，优选m为0，1或2；m is an integer selected from 0-4, such as 0, 1, 2, 3 or 4, preferably m is 0, 1 or 2;
R3选自氢、C1-6烷基、C1-6烷氧基、或C3-7环烷烃；R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or C 3-7 cycloalkane;
每个独立的表示双键或单键；Each Independent ones represent double or single bonds;
W、Z1独立的选自C、N、O或S中的一个；优选W、Z1独立的选自C或N；W, Z 1 are independently selected from C, N, O or S; preferably W, Z 1 are independently selected from C or N;
一个或多个R5连接六元环任意环碳和/或环氮原子上，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、C1-6亚烷基C3-7环烷烃。One or more R 5 are connected to any ring carbon and/or ring nitrogen atom of the six-membered ring, and R 5 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkylene, C 1-6 alkylene C 3-7 cycloalkane.
进一步优选，式IIIB化合物中，Further preferably, in the compound of formula IIIB,
R2选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃或C1-3亚烷基C3-7环烷烃； R2 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane or C1-3 alkylene C3-7 cycloalkane;
m为0、1或2；m is 0, 1 or 2;
R3选自氢、C1-3烷基；R 3 is selected from hydrogen, C 1-3 alkyl;
每个独立的表示双键；Each Independent ones represent double bonds;
W和Z1均为C，或，W为C且Z1为N，或，W为N且Z1为C；W and Z1 are both C, or W is C and Z1 is N, or W is N and Z1 is C;
一个或多个R5连接六元环任意环碳和/或环氮原子，R5选自氢、卤素、C1-3烷基、C1-3烷氧基、C1-3烷 氧基C1-3亚烷基、或C1-3亚烷基C3-7环烷烃。在本发明的一些实施方案中，R5为一个取代基，取代位置位于六元环的对位。One or more R 5 are connected to any ring carbon and/or ring nitrogen atom of the six-membered ring, and R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy Oxy C 1-3 alkylene, or C 1-3 alkylene C 3-7 cycloalkane. In some embodiments of the present invention, R 5 is a substituent, and the substitution position is located at the para position of the six-membered ring.
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：


The present invention further protects the following specific compounds, their pharmaceutically acceptable salts, solvates, or stereoisomers:


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、当X为N时，将式A结构的胺基化合物、式B化合物与羰基化试剂反应，合成得到式I化合物，
The present invention protects a method for preparing a compound of formula I, characterized in that: step 1, when X is N, reacting an amino compound of formula A structure and a compound of formula B with a carbonylation reagent to synthesize a compound of formula I,
或，当X为N时，式A’化合物与式B’化合物反应，得到式I化合物；
Or, when X is N, the compound of formula A' reacts with the compound of formula B' to obtain a compound of formula I;
或、当X为O时，将式C结构的胺基化合物与式D化合物反应，合成得到式I化合物，
Or, when X is O, the amino compound of formula C is reacted with the compound of formula D to synthesize the compound of formula I,
或，当X为O时，式C化合物、式D’化合物与三氟乙酸反应，得到式I化合物；
Or, when X is O, the compound of formula C and the compound of formula D' are reacted with trifluoroacetic acid to obtain a compound of formula I;
或，当X为O时，式E化合物与式F化合物反应，得到式I化合物；Or, when X is O, the compound of formula E reacts with the compound of formula F to obtain a compound of formula I;
步骤2、如果需要，再根据目标产物的需要，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。Step 2: If necessary, the compound of formula I is functionally modified according to the needs of the target product to convert it into the target product having the structure of formula I, or into a pharmaceutically acceptable salt or precursor compound of the compound.
其中，羰基化试剂选自三光气、1,1’-羰基二咪唑(CDI)等；R1-R4、m、n、Cy1定义同上；Z为离去基团，例如卤素、羟基等。Wherein, the carbonylation reagent is selected from triphosgene, 1,1'-carbonyldiimidazole (CDI), etc.; R 1 -R 4 , m, n, Cy 1 are as defined above; and Z is a leaving group, such as halogen, hydroxyl, etc.
所述制备方法同样适用于式II、IIA、III、IIIA或IIIB化合物的制备。The preparation method is also applicable to the preparation of compounds of formula II, IIA, III, IIIA or IIIB.
本发明的式I、式II、式IIA、式III、式IIIA或式IIIB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。The compounds of formula I, formula II, formula IIA, formula III, formula IIIA or formula IIIB of the present invention or their pharmaceutically acceptable salts, solvates, or stereoisomers have Sigma2 receptor inhibitory activity and 5HT2A receptor inhibitory activity, and can be used for the treatment of diseases mediated by Sigma2 receptor activity, the treatment of diseases mediated by 5HT2A receptor activity, and the treatment of diseases mediated by Sigma2 receptor activity and 5HT2A receptor activity. Treatment of co-mediated related diseases.
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≤500nM，更优选的化合物具有IC50≤200nM，最优选化合物具有IC50≤100nM。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≤1μM, the compound tested in the above analysis is considered to have 5HT2A receptor inhibitory activity. Preferred compounds of the present invention have IC50≤500nM, more preferred compounds have IC50≤200nM, and most preferred compounds have IC50≤100nM.
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％。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 μM, the more preferred compounds have a binding rate to the Sigma2 receptor greater than 70% at 10 μM, and the most preferred compounds have a binding rate to the Sigma2 receptor greater than 80% at 10 μM.
进一步的，本发明化合物还具有降低的心脏毒性。本发明优选的化合物在10μM时对hERG的结合率小于90％，更优选的化合物在10μM时对hERG的结合率小于80％，最优选的化合物在10μM时对hERG的结合率小于70％。Furthermore, the compounds of the present invention also have reduced cardiac toxicity. The preferred compounds of the present invention have a hERG binding rate of less than 90% at 10 μM, the more preferred compounds have a hERG binding rate of less than 80% at 10 μM, and the most preferred compounds have a hERG binding rate of less than 70% at 10 μM.
本发明提供式I、式II、式IIA、式III、式IIIA或式IIIB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。The present invention provides the use of a compound of Formula I, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the preparation of a drug for treating diseases mediated by 5HT2A receptor activity.
本发明提供式I、式II、式IIA、式III、式IIIA或式IIIB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。The present invention provides the use of a compound of Formula I, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the preparation of a drug for treating diseases mediated by Sigma2 receptor activity.
本发明提供式I、式II、式IIA、式III、式IIIA或式IIIB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。The present invention provides the use of a compound of Formula I, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB 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.
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***疾病。The diseases related to the 5HT2A receptor and/or Sigma2 receptor activity-mediated diseases include but are not limited to central nervous system diseases.
所述中枢神经***疾病包括但不限于：精神疾病、中枢神经***退行性疾病、中枢神经***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。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.
所述精神疾病包括但不限于：抑郁症、焦虑症、躁狂症、精神***症、情感性***症、双相精神障碍、失眠、自闭症等。The mental illnesses include, but are not limited to, depression, anxiety, mania, schizophrenia, schizoaffective disorder, bipolar disorder, insomnia, autism, etc.
所述中枢神经***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。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.
所述中枢神经***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。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.
本发明提供一种药物组合物，其特征在于包括式I、式II、式IIA、式III、式IIIA或式IIIB化合物或其药学上可接受的盐，溶剂化物，或立体异构体。The present invention provides a pharmaceutical composition, characterized by comprising a compound of Formula I, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
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。The pharmaceutical composition can be used to treat diseases related to 5HT2A receptor and/or Sigma2 receptor activity. The definition of diseases related to 5HT2A receptor and/or Sigma2 receptor activity is as described above.
所述药物组合物进一步含有药学上可接受的载体。The pharmaceutical composition further contains a pharmaceutically acceptable carrier.
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。 The pharmaceutically acceptable carrier is various excipients commonly used or known in the pharmaceutical field, including but not limited to: diluents, binders, antioxidants, pH regulators, preservatives, lubricants, disintegrants, etc.
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。Examples of the diluent include lactose, starch, cellulose derivatives, inorganic calcium salts, sorbitol, etc. Examples of the binder include starch, gelatin, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, etc. Examples of the antioxidant include vitamin E, sodium bisulfite, sodium sulfite, butylated hydroxyanisole, etc. Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, Tris, acetic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, etc. Examples of the preservative include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, metacresol, benzalkonium chloride, etc. Examples of the lubricant include magnesium stearate, micropowder silica gel, talc, etc. Examples of the disintegrant include starch, methyl cellulose, xanthan gum, cross-linked sodium carboxymethyl cellulose, etc.
所述药物组合物中含有式I、式II、式IIA、式III、式IIIA或式IIIB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。The pharmaceutical composition contains a compound of Formula I, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in an amount of 0.1-1000 mg, preferably 1-500 mg, and more preferably 5-100 mg.
所述药物组合物中式I、式II、式IIA、式III、式IIIA或式IIIB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％。The mass percentage of the compound of formula I, formula II, formula IIA, formula III, formula IIIA or formula IIIB or its pharmaceutically acceptable salt, solvate, or stereoisomer in the pharmaceutical composition is 10%-90%, preferably 20%-80%, and more preferably 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。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.
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。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.
式I、式II、式IIA、式III、式IIIA或式IIIB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。The dosage of a compound of formula I, formula II, formula IIA, formula III, formula IIIA or formula IIIB or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof will depend on the age, health and weight of the recipient, the type of 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 a compound of formula I, a compound of formula IA 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.
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。The pharmaceutical composition can be used in combination with other drugs for treating related diseases mediated by 5HT2A receptor and/or Sigma2 receptor activity.
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。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.
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化合物或其药学上可接受的盐，溶剂化物，或立体异构体。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 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered to a patient in need.
所述式I、式II、式IIA、式III、式IIIA或式IIIB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。The administration routes of the compound of Formula I, Formula II, Formula IIA, Formula III, Formula IIIA or Formula IIIB or a pharmaceutically acceptable salt, solvate, or stereoisomer 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 implantation of a reservoir or reservoir.
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。The method further comprises administering to the patient in need other drugs for treating diseases mediated by 5HT2A receptor and/or Sigma2 receptor activity.
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***退行性疾病治疗药物等。Other drugs for treating diseases related to 5HT2A receptor and/or Sigma2 receptor activity include but are not limited to: Therapeutic drugs, drugs for the treatment of degenerative diseases of the central nervous system, etc.
所述精神疾病治疗药物包括但不限于：苯二氮类(例如：甲基***西泮、氯氮氯硝西泮、***、舒乐安定、氟西泮、咪达***等)；巴比妥类(例如：***、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)；***；米氮平等。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); 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.
所述中枢神经***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***、金刚烷胺、利血平等。The drugs for treating degenerative diseases of the central nervous system include, but are not limited to, levodopa, bromocriptine, ergoline, diprofen, amantadine, reserpine, etc.
在本发明中：In the present invention:
“卤素”指F、Cl、Br或I。"Halogen" refers to F, Cl, Br or I.
恶唑：等同于噁唑，英文为oxazole。Oxazole: Equivalent to oxazole, in English it is called oxazole.
C1-6烷基：包括含1-6个碳链原子，包括直链和支链烷烃，所述烷烃进一步可被常见基团取代，如OH、卤素、NO2等。C 1-6 alkyl: includes 1-6 carbon chain atoms, including straight chain and branched chain alkanes, which may be further substituted by common groups such as OH, halogen, NO 2 , etc.
C3-7环烷烃：包括含3-7个环碳原子的环烷烃，共含3-7个碳原子的环烷烃，包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、甲基环丙基、甲基环丁基、甲基环戊基、甲基环己基、乙基环丙基、乙基环丁基、乙基环戊基、丙基环丙基、丙基环丁基等。C 3-7 cycloalkanes: include cycloalkanes containing 3-7 ring carbon atoms, cycloalkanes containing a total of 3-7 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, propylcyclopropyl, propylcyclobutyl, etc.
C1-6亚烷基：包括含有1-6个碳原子的亚烷基，所述基团起到桥联作用。C 1-6 alkylene: includes alkylene groups containing 1 to 6 carbon atoms, and the group plays a bridging role.
C1-6烷氧基：等同于C1-6烷基-O-基团，即含有1-6碳原子烷基氧基。 C1-6 alkoxy: equivalent to C1-6 alkyl-O-group, i.e. an alkyloxy group containing 1 to 6 carbon atoms.
C6-10芳基：包括含有6-10个碳原子且仅含环碳原子的芳香基团，和共含6-10个碳原子的碳环芳香基团。C 6-10 aryl: includes aromatic groups containing 6 to 10 carbon atoms and containing only ring carbon atoms, and carbocyclic aromatic groups containing a total of 6 to 10 carbon atoms.
“彼此独立”表示所述特征彼此独立，不互为关联。“Independent of each other” means that the features are independent of each other and are not related to each other.
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。Substituents in "any 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.
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。The term "pharmaceutically acceptable salts" includes those derived from suitable inorganic acids and bases and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed 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.
具体实施方式Detailed ways
实施例中使用如下术语或简称：The following terms or abbreviations are used in the examples:
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；流动相A:水(0.1％TFA)，流动相B:ACN；梯度：10-20-9 MIN 150VL Prep-HPLC (purification under Method A conditions): Prep-HPLC purification was performed using Method A conditions, which included: column: sunfire 5 μm 19-150 mm or XBridge-1 5 μm 19-150 mm; mobile phase A: water (0.1% TFA), mobile phase B: ACN; gradient: 10-20-9 MIN 150 VL
PEX：中间体制备例           EX：实施例PEX: Intermediate Preparation Example EX: Example
ACN：乙腈        EtOAc/EA：乙酸乙酯        TEA：三乙基胺ACN: acetonitrile        EtOAc/EA: ethyl acetate        TEA: triethylamine
DIEA：二异丙基乙胺    DCM：二氯甲烷        DMF：N,N-二甲基甲酰胺DIEA: diisopropylethylamine    DCM: dichloromethane        DMF: N,N-dimethylformamide
THF：四氢呋喃         DMSO：二甲亚砜       AcOH：乙酸THF: Tetrahydrofuran         DMSO: Dimethyl sulfoxide       AcOH: Acetic acid
PE：石油醚(petroleum ether)           TFA：2,2,2.三氟乙酸或三氟乙酸PE: petroleum ether TFA: 2,2,2.Trifluoroacetic acid or trifluoroacetic acid
HOBT：1-羟基苯并***(1-Hydroxybenzotriazole)HOBT: 1-Hydroxybenzotriazole
EDCI：1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide)EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
HMDSK：双三甲基硅基胺基钾(Potassium bis(trimethylsilyl)amide)HMDSK: Potassium bis(trimethylsilyl)amide
STAB：三乙酰氧基硼氢化钠(Sodium triacetoxyborohydride)STAB: Sodium triacetoxyborohydride
Red-Al：双(2-甲氧基乙氧基)氢化铝钠或二氢双(2-甲氧乙氧基)铝酸钠(Sodium bis(2-methoxyethoxy)aluminium hydride)Red-Al: Sodium bis(2-methoxyethoxy)aluminium hydride or sodium dihydrogen bis(2-methoxyethoxy)aluminium hydride
CDI：1,1’-羰基二咪唑(1,1'-Carbonyldiimidazole)CDI: 1,1'-Carbonyldiimidazole
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。The present invention is further described below in conjunction with the examples. It should be noted that the examples cannot be used as a limitation on the protection scope of the present invention, and those skilled in the art understand that any improvements and changes made on the basis of the present invention are within the protection scope of the present invention.
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。The conventional reagents used in the following examples are all commercially available, and the biological experiments performed are all conventional biological experiments in the art and can be performed according to the instructions in the corresponding experimental manual or kit instructions.
实施例1Example 1
PEX1制备(6-(甲氧基甲基)吡啶-3-基)甲胺
Preparation of (6-(methoxymethyl)pyridin-3-yl)methylamine by PEX1
Step 1. 6-(甲氧基甲基)烟腈的制备
Step 1. Preparation of 6-(methoxymethyl)nicotinonitrile
将5-溴-2-(甲氧基甲基)吡啶(2.00g，9.90mmol，1.00equiv)、Zn(CN)2(700mg，5.94mmol，0.6equiv)和Pd(PPh3)4(200mg)在DMF(20mL)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，经无水Na2SO4干燥并浓缩得到粗品，将其通过柱色谱法纯化(PE/EA＝10/1)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]+.A mixture of 5-bromo-2-(methoxymethyl)pyridine (2.00 g, 9.90 mmol, 1.00 equiv), Zn(CN) 2 (700 mg, 5.94 mmol, 0.6 equiv) and Pd(PPh 3 ) 4 (200 mg) in DMF (20 mL) was heated in a microwave oven for 5 minutes, with the temperature set at 175° C. The reaction mixture was then poured into water (60 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with water (20 mL×3) and brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated to give a crude product, which was purified by column chromatography (PE/EA=10/1) to give 6-(methoxymethyl)nicotinonitrile (1.00 g, 61.6%) as a yellow oil, LC-MS (ESI, m/z): 149.1 [M+H] + .
Step 2. (6-(甲氧基甲基)吡啶-3-基)甲胺的制备Step 2. Preparation of (6-(methoxymethyl)pyridin-3-yl)methylamine
向6-(甲氧基甲基)烟腈(1.00g，6.70mmol，1.00equiv)在THF(30mL)中的溶液中加入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。所得混合物过滤，浓缩滤液，得到(6-(甲氧基甲基)吡啶-3-基)甲胺(1.00g，粗品)，黄色油状物，LC-MS(ESI,m/z):153.1[M+H]+.To a solution of 6-(methoxymethyl)nicotinonitrile (1.00 g, 6.70 mmol, 1.00 equiv) in THF (30 mL) was added NH 3 .H 2 O (10 mL) and Ni (2.00 g). The mixture was stirred under a H 2 balloon at room temperature for 4 hours. The resulting mixture was filtered and the filtrate was concentrated to give (6-(methoxymethyl)pyridin-3-yl)methanamine (1.00 g, crude) as a yellow oil, LC-MS (ESI, m/z): 153.1 [M+H] + .
PEX2制备(6-(乙氧基甲基)吡啶-3-基)甲胺
Preparation of (6-(ethoxymethyl)pyridin-3-yl)methylamine with PEX2
(6-(乙氧基甲基)吡啶-3-基)甲胺通过类似于制备(6-(甲氧基甲基)吡啶-3-基)甲胺的方法制备和纯化，以6-(乙氧基甲基)烟腈(400mg，2.47mmol，1.00equiv)为原料，得到(6-(乙氧基甲基)吡啶-3-基)甲胺(400mg，粗品)，为黄色油状物，LC-MS(ESI,m/z):167.1[M+H]+.(6-(Ethoxymethyl)pyridin-3-yl)methanamine was prepared and purified by a method similar to that for (6-(methoxymethyl)pyridin-3-yl)methanamine, using 6-(ethoxymethyl)nicotinonitrile (400 mg, 2.47 mmol, 1.00 equiv) as starting material to give (6-(ethoxymethyl)pyridin-3-yl)methanamine (400 mg, crude) as a yellow oil, LC-MS (ESI, m/z): 167.1 [M+H] + .
PEX3制备6-(甲氧基甲基)吡啶-3-胺
Preparation of 6-(methoxymethyl)pyridin-3-amine by PEX3
Step 1. 5-溴-2-(甲氧基甲基)吡啶的制备
Step 1. Preparation of 5-bromo-2-(methoxymethyl)pyridine
在N2下，冷却(5-溴吡啶-2-基)甲醇(5.00g，26.6mmol，1.00equiv)在DMF(100mL)中的溶液至0℃，加入NaH(1.60g，39.9mmol，1.5equiv)，将混合物搅拌30分钟并加入CH3I(7.55g，53.2mmol，2.0equiv)。所得混合物在室温下搅拌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]+.Under N2 , a solution of (5-bromopyridin-2-yl)methanol (5.00 g, 26.6 mmol, 1.00 equiv) in DMF (100 mL) was cooled to 0 °C, NaH (1.60 g, 39.9 mmol, 1.5 equiv) was added, the mixture was stirred for 30 min and CH3I (7.55 g, 53.2 mmol, 2.0 equiv) was added. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water (300 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with water (50 mL×3) and brine (50 mL), dried over anhydrous Na 2 SO 4 and concentrated to give 5-bromo-2-(methoxymethyl)pyridine (5.00 g, 88.4%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.64 (d, J=2.0 Hz, 1H), 7.84 (dd, J 1 =2.0 Hz, J 2 =8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 4.56 (s, 2H), 3.50 (s, 3H). LC-MS (ESI, m/z): 204.0 [M+H] + .
Step 2. N-(6-(甲氧基甲基)吡啶-3-基)-1,1-二苯基甲亚胺的制备
Step 2. Preparation of N-(6-(methoxymethyl)pyridin-3-yl)-1,1-diphenylmethanimine
在N2下，将5-溴-2-(甲氧基甲基)吡啶(2.00g，9.90mmol，1.00equiv)、二苯基甲亚胺(3.59g，19.8mmol，2.00equiv)、Pd(dba)2(200mg)、BINAP(400mg)、Cs2CO3(16.1g，49.5mmol，5.00equiv)和甲苯(40mL)的混合物加热回流4小时。将其冷却至室温，倒入水(40mL)中并用EA(20mL×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。通过柱色谱法(PE/EA＝5/1)纯化得到黄色油状N-(6-(甲氧基甲基)吡啶-3-基)-1,1-二苯基甲亚胺(2.50g,74.8％)LC-MS(ESI,m/z):303.2[M+H]+. A mixture of 5-bromo-2-(methoxymethyl)pyridine (2.00 g, 9.90 mmol, 1.00 equiv), diphenylmethanimine (3.59 g, 19.8 mmol, 2.00 equiv), Pd(dba) 2 (200 mg), BINAP (400 mg), Cs 2 CO 3 (16.1 g, 49.5 mmol, 5.00 equiv) and toluene (40 mL) was heated to reflux for 4 h under N 2. It was cooled to room temperature, poured into water (40 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with water and brine, dried over anhydrous Na 2 SO 4 and concentrated to give a crude product. Purification by column chromatography (PE/EA=5/1) gave yellow oily N-(6-(methoxymethyl)pyridin-3-yl)-1,1-diphenylmethanimine (2.50 g, 74.8%). LC-MS (ESI, m/z): 303.2 [M+H] + .
Step 3. 6-(甲氧基甲基)吡啶-3-胺的制备Step 3. Preparation of 6-(methoxymethyl)pyridin-3-amine
向N-(6-(甲氧基甲基)吡啶-3-基)-1,1-二苯基甲亚胺(2.50g，8.28mmol，1.0equiv)的THF(50mL)溶液中加入浓HCl(25mL)并在室温下搅拌1小时。将所得混合物浓缩，将残余物用水(20mL)稀释并用EA(5mL×3)萃取。用饱和NaHCO3溶液调节水层的pH＝8，用EA(10mL×3)萃取。合并有机层，用无水Na2SO4干燥并减压浓缩，得到6-(甲氧基甲基)吡啶-3-胺(700mg，61.4％)，为黄色油状物，LC-MS(ESI,m/z):139.1[M+H]+.Concentrated HCl (25 mL) was added to a solution of N-(6-(methoxymethyl)pyridin-3-yl)-1,1-diphenylmethanimine (2.50 g, 8.28 mmol, 1.0 equiv) in THF (50 mL) and stirred at room temperature for 1 hour. The resulting mixture was concentrated, and the residue was diluted with water (20 mL) and extracted with EA (5 mL×3). The pH of the aqueous layer was adjusted to 8 with saturated NaHCO 3 solution and extracted with EA (10 mL×3). The organic layers were combined, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give 6-(methoxymethyl)pyridin-3-amine (700 mg, 61.4%) as a yellow oil, LC-MS (ESI, m/z): 139.1 [M+H] + .
PEX4制备6-(乙氧基甲基)吡啶-3-胺
Preparation of 6-(ethoxymethyl)pyridin-3-amine by PEX4
6-(乙氧基甲基)吡啶-3-胺通过类似于制备6-(甲氧基甲基)吡啶-3-胺的方法制备和纯化，以5-溴-2-(乙氧基甲基)吡啶为原料，得到所需化合物6-(乙氧基甲基)吡啶-3-胺(1.20g，30.4％)，为黄色油状物，LC-MS(ESI,m/z):153.1[M+H]+。6-(Ethoxymethyl)pyridin-3-amine was prepared and purified by a method similar to that for 6-(methoxymethyl)pyridin-3-amine, using 5-bromo-2-(ethoxymethyl)pyridine as starting material to give the desired compound 6-(ethoxymethyl)pyridin-3-amine (1.20 g, 30.4%) as a yellow oil, LC-MS (ESI, m/z): 153.1 [M+H] + .
PEX5制备(2-甲基-恶唑-4-基)甲胺的制备
Preparation of (2-methyl-oxazol-4-yl)methylamine by PEX5
Step 1. N-甲氧基-N,2-二甲基恶唑-4-甲酰胺的合成
Step 1. Synthesis of N-methoxy-N,2-dimethyloxazole-4-carboxamide
将2-甲基恶唑-4-羧酸(4.00g，32.0mmol)、N,O-二甲基羟胺盐酸盐(4.61g，47.0mmol)、HOBt(5.11g，38.0mmol)、EDCI(7.25g，38.0mmol)、TEA(15.9g，160mmol)和DMF(80mL)的混合物在20℃搅拌3小时，将混合物用水(200mL)稀释并用DCM(50mL×10)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。粗品经硅胶层析(DCM/MeOH＝200/1～50/1洗脱)得到黄色油状N-甲氧基-N,2-二甲基恶唑-4-甲酰胺(4.00g，64.2％)。LC-MS(ESI,m/z):170.7[M+H]+.A mixture of 2-methyloxazole-4-carboxylic acid (4.00 g, 32.0 mmol), N,O-dimethylhydroxylamine hydrochloride (4.61 g, 47.0 mmol), HOBt (5.11 g, 38.0 mmol), EDCI (7.25 g, 38.0 mmol), TEA (15.9 g, 160 mmol) and DMF (80 mL) was stirred at 20°C for 3 hours, and the mixture was diluted with water (200 mL) and extracted with DCM (50 mL×10). The combined organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give a crude product. The crude product was chromatographed on silica gel (eluted with DCM/MeOH=200/1 to 50/1) to give yellow oily N-methoxy-N,2-dimethyloxazole-4-carboxamide (4.00 g, 64.2%). LC-MS (ESI, m/z): 170.7 [M+H] + .
Step 2. 2-甲基恶唑-4-甲醛的合成
Step 2. Synthesis of 2-methyloxazole-4-carboxaldehyde
在N2下，将N-甲氧基-N,2-二甲基恶唑-4-甲酰胺(4.00g，24.0mol)在THF(50mL)中的溶液冷却至-70℃，加入二异丁基氢化铝溶液(31.3mL，47.0mmol，1.5M)，混合物在-70℃搅拌2小时。用饱和NH4Cl水溶液(5mL)淬灭反应混合物，然后升温至25℃搅拌1小时。悬浮液通过硅藻土垫过滤，滤饼用THF(20mL×3)洗涤。将合并的滤液浓缩得到粗品。粗品用DCM(50mL)稀释并用水(20mL×3)洗涤。合并的有机层用硫酸钠干燥并真空蒸发，得到呈黄色固体的2-甲基恶唑-4-甲醛(3.00g，31.49％)。LC-MS(ESI,m/z):111.7[M+H]+.Under N2 , a solution of N-methoxy-N,2-dimethyloxazole-4-carboxamide (4.00 g, 24.0 mol) in THF (50 mL) was cooled to -70 ° C, diisobutylaluminum hydride solution (31.3 mL, 47.0 mmol, 1.5 M) was added, and the mixture was stirred at -70 ° C for 2 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (5 mL), then warmed to 25 ° C and stirred for 1 hour. The suspension was filtered through a celite pad, and the filter cake was washed with THF (20 mL × 3). The combined filtrate was concentrated to give a crude product. The crude product was diluted with DCM (50 mL) and washed with water (20 mL × 3). The combined organic layer was dried over sodium sulfate and evaporated in vacuo to give 2-methyloxazole-4-carboxaldehyde (3.00 g, 31.49%) as a yellow solid. LC-MS (ESI, m / z): 111.7 [M + H] + .
Step 3. 2-甲基恶唑-4-甲醛肟的合成
Step 3. Synthesis of 2-methyloxazole-4-carbaldehyde oxime
将2-甲基恶唑-4-甲醛(3.00g，27.0mmol)和盐酸羟胺(3.75g，54.0mmol)在EtOH(150mL)中的溶液冷却至0℃，加入无水乙酸钠(8.86g，108mmol)。然后将混合物在25℃搅拌3小时。真空蒸发混合物得到残余物。将残余物用水(50mL)稀释并用DCM(50mL×3)萃取。合并的有机层用硫酸钠干燥并真空蒸发，得到2-甲基恶唑-4-甲醛肟(2.09g，53.7％)，为淡黄色固体，LC-MS(ESI,m/z):126.7[M+H]+.Step 4.(2-甲基-恶唑-4-基)甲胺的合成A solution of 2-methyloxazole-4-carboxaldehyde (3.00 g, 27.0 mmol) and hydroxylamine hydrochloride (3.75 g, 54.0 mmol) in EtOH (150 mL) was cooled to 0 ° C, and anhydrous sodium acetate (8.86 g, 108 mmol) was added. The mixture was then stirred at 25 ° C for 3 hours. The mixture was evaporated in vacuo to give a residue. The residue was diluted with water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give 2-methyloxazole-4-carboxaldehyde oxime (2.09 g, 53.7%) as a light yellow solid, LC-MS (ESI, m/z): 126.7 [M+H] + .Step 4. Synthesis of (2-methyl-oxazol-4-yl)methylamine
向2-甲基恶唑-4-甲醛肟(2.09g，16.0mmol)的THF(40mL)溶液中加入Raney Ni(2.09g)。混合物在H2气球下，在25℃搅拌3小时。通过硅藻土垫过滤悬浮液并用THF(30mL×3)洗涤该垫。将合并的滤液浓缩至干，得到呈黄色固体的粗制(2-甲基-恶唑-4-基)甲胺(2.80g，93.7％)，LC-MS(ESI,m/z):113.1[M+H]+.。 Raney Ni (2.09 g) was added to a solution of 2-methyloxazole-4-carbaldehyde oxime (2.09 g, 16.0 mmol) in THF (40 mL). The mixture was stirred at 25 ° C for 3 hours under a H 2 balloon. The suspension was filtered through a celite pad and the pad was washed with THF (30 mL × 3). The combined filtrate was concentrated to dryness to give crude (2-methyl-oxazol-4-yl)methylamine (2.80 g, 93.7%) as a yellow solid, LC-MS (ESI, m / z): 113.1 [M + H] + .
PEX6(2-甲基恶唑-5-基)甲胺的制备。
Preparation of PEX6 (2-methyloxazol-5-yl)methanamine.
(2-甲基恶唑-5-基)甲胺的制备方法与(2-甲基-1H-恶唑-4-基)甲胺的制备方法相似，以2-甲基-1,3-恶唑-5-羧酸作为原料。The preparation method of (2-methyloxazol-5-yl)methylamine is similar to that of (2-methyl-1H-oxazol-4-yl)methylamine, using 2-methyl-1,3-oxazole-5-carboxylic acid as the raw material.
PEX7(2-甲基噻唑-5-基)甲胺的制备
Preparation of PEX7 (2-methylthiazol-5-yl)methylamine
Step 1. (E)-2-甲基噻唑-5-甲醛肟的制备
Step 1. Preparation of (E)-2-methylthiazole-5-carbaldehyde oxime
在0℃，向2-甲基噻唑-5-甲醛(5.00g，39.4mmol)在EtOH(150mL)中的溶液中加入盐酸羟胺(5.46g，78.7mmol)和NaOAc(13.0g，157mmol)。将混合物在25℃搅拌3小时，然后倒入水(100mL)中并用DCM(50mL×3)萃取。合并的有机层用无水Na2SO4干燥并浓缩，得到(E)-2-甲基噻唑-5-甲醛肟(5.50g，87.02％)，为白色固体，其无需进一步纯化直接用于下一步。Hydroxylamine hydrochloride (5.46 g, 78.7 mmol) and NaOAc (13.0 g, 157 mmol) were added to a solution of 2-methylthiazole-5-carbaldehyde (5.00 g, 39.4 mmol) in EtOH (150 mL) at 0°C. The mixture was stirred at 25°C for 3 hours, then poured into water (100 mL) and extracted with DCM (50 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated to give (E)-2-methylthiazole-5-carbaldehyde oxime (5.50 g, 87.02%) as a white solid, which was used directly in the next step without further purification.
Step 2. (2-甲基噻唑-5-基)甲胺的制备Step 2. Preparation of (2-methylthiazol-5-yl)methylamine
向(E)-2-甲基噻唑-5-甲醛肟(5.00g，35.0mmol)在THF(100mL)中的溶液中加入Ni(5.00g)。在40℃，H2气球下将混合物搅拌16小时。然后过滤混合物，浓缩滤液，得到(2-甲基噻唑-5-基)甲胺(1.83g，23.01％)，为黄色油状物，无需进一步纯化直接用于下一步。To a solution of (E)-2-methylthiazole-5-carbaldehyde oxime (5.00 g, 35.0 mmol) in THF (100 mL) was added Ni (5.00 g). The mixture was stirred at 40° C. under a balloon of H 2 for 16 hours. The mixture was then filtered and the filtrate was concentrated to give (2-methylthiazol-5-yl)methanamine (1.83 g, 23.01%) as a yellow oil which was used in the next step without further purification.
PEX8(2-甲基噻唑-4-基)甲胺的制备
Preparation of PEX8 (2-methylthiazol-4-yl)methylamine
(2-甲基噻唑-4-基)甲胺的制备方法与(2-甲基噻唑-5-基)甲胺的制备方法相似，以2-甲基噻唑-4-甲醛为原料。The preparation method of (2-methylthiazol-4-yl)methylamine is similar to that of (2-methylthiazol-5-yl)methylamine, using 2-methylthiazole-4-carboxaldehyde as the raw material.
PEX9(5-(甲氧基甲基)噻唑-2-基)甲胺的制备
Preparation of PEX9 (5-(methoxymethyl)thiazol-2-yl)methylamine
Step 1:2-溴-5-(甲氧基甲基)噻唑的制备
Step 1: Preparation of 2-bromo-5-(methoxymethyl)thiazole
在氮气氛下，向(2-溴噻唑-5-基)甲醇(6.0g,30.9mmol,1.0equiv)在DCM(60mL)中的溶液中加入CH3I(5.27g,37.1mmol,1.2equiv)和Ag2O(10.7g,46.4mmol,1.5equiv)。将所得混合物在40℃搅拌2天并用水(400mL)淬灭。所得混合物用二氯甲烷(200mLx3)萃取。合并的有机层用盐水(400mL)洗涤并用无水硫酸钠干燥。残余物通过硅胶柱色谱法用甲醇/二氯甲烷(4/96)纯化，得到棕色油状2-溴-5-(甲氧基甲基)噻唑(4.5g，70％)。LC-MS(ESI,m/z):208[M+H]+. To a solution of (2-bromothiazol-5-yl)methanol (6.0 g, 30.9 mmol, 1.0 equiv) in DCM (60 mL) was added CH 3 I (5.27 g, 37.1 mmol, 1.2 equiv) and Ag 2 O (10.7 g, 46.4 mmol, 1.5 equiv) under nitrogen atmosphere. The resulting mixture was stirred at 40° C. for 2 days and quenched with water (400 mL). The resulting mixture was extracted with dichloromethane (200 mL×3). The combined organic layers were washed with brine (400 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography with methanol/dichloromethane (4/96) to give 2-bromo-5-(methoxymethyl)thiazole (4.5 g, 70%) as a brown oil. LC-MS (ESI, m/z): 208 [M+H] + .
Step 2:5-(甲氧基甲基)噻唑-2-甲醛的制备
Step 2: Preparation of 5-(methoxymethyl)thiazole-2-carboxaldehyde
在-78℃和氮气氛下，向2-溴-5-(甲氧基甲基)噻唑(4.5g，21.6mmol，1.0equiv)的THF(50mL)溶液中滴加n-BuLi(10mL，25.0mmol，1.1equiv)，搅拌30分钟。然后加入DMF(3.64g，49.7mmol，2.3equiv)。将所得溶液在-78℃搅拌20分钟，用饱和NH4Cl溶液(100mL)淬灭。所得混合物用EtOAc(3×100mL)萃取。合并的有机层用盐水(200mL)洗涤并用无水硫酸钠干燥。过滤后，将滤液减压浓缩。残余物通过硅胶柱色谱法用石油醚/乙酸乙酯(84/16)纯化，得到5-(甲氧基甲基)噻唑-2-甲醛(2g，59％)，为无色油状物，LC-MS(ESI,m/z):158[M+H]+.To a solution of 2-bromo-5-(methoxymethyl)thiazole (4.5 g, 21.6 mmol, 1.0 equiv) in THF (50 mL) was added n-BuLi (10 mL, 25.0 mmol, 1.1 equiv) dropwise at -78°C under nitrogen atmosphere and stirred for 30 minutes. DMF (3.64 g, 49.7 mmol, 2.3 equiv) was then added. The resulting solution was stirred at -78°C for 20 minutes and quenched with saturated NH 4 Cl solution (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (84/16) to give 5-(methoxymethyl)thiazole-2-carbaldehyde (2 g, 59%) as a colorless oil, LC-MS (ESI, m/z): 158 [M+H] + .
Step 3:N-(4-甲氧基苄基)-1-(5-(甲氧基甲基)噻唑-2-基)甲胺的制备
Step 3: Preparation of N-(4-methoxybenzyl)-1-(5-(methoxymethyl)thiazol-2-yl)methanamine
在室温下，将5-(甲氧基甲基)噻唑-2-甲醛(2.0g，12.7mmol，1.0equiv)、(4-甲氧基苯基)甲胺(2.09g，15.3mmol，1.2equiv)、STAB(8.09g，38.2mmol，3.0equiv)和DCE(30mL)的溶液搅拌过夜，用水(200mL)淬灭并用DCM(3×100mL)萃取。合并的有机层用盐水(200mL)洗涤并用无水硫酸钠干燥。过滤后，将滤液减压浓缩。残余物通过硅胶柱色谱法用甲醇/二氯甲烷(2/98)纯化，得到N-(4-甲氧基苄基)-1-(5-(甲氧基甲基)噻唑-2-基)甲胺(1.8g,57％)，为一种无色油，LC-MS(ESI,m/z):279[M+H]+。A solution of 5-(methoxymethyl)thiazole-2-carbaldehyde (2.0 g, 12.7 mmol, 1.0 equiv), (4-methoxyphenyl)methanamine (2.09 g, 15.3 mmol, 1.2 equiv), STAB (8.09 g, 38.2 mmol, 3.0 equiv) and DCE (30 mL) was stirred overnight at room temperature, quenched with water (200 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with methanol/dichloromethane (2/98) to give N-(4-methoxybenzyl)-1-(5-(methoxymethyl)thiazol-2-yl)methanamine (1.8 g, 57%) as a colorless oil, LC-MS (ESI, m/z): 279 [M+H] + .
Step 4:((5-(甲氧基甲基)噻唑-2-基)甲基)氨基甲酸叔丁酯的制备
Step 4: Preparation of tert-butyl ((5-(methoxymethyl)thiazol-2-yl)methyl)carbamate
在80℃下，将N-(4-甲氧基苄基)-1-(5-(甲氧基甲基)噻唑-2-基)甲胺(1.6g，5.75mmol，1.0equiv)在TFA(20mL)的溶液搅拌6小时。将所得混合物减压浓缩，得到1-[5-(甲氧基甲基)-1,3-噻唑-2-基]甲胺(700mg粗品)，其为棕色油状物，包括若干不可分离的副产物。A solution of N-(4-methoxybenzyl)-1-(5-(methoxymethyl)thiazol-2-yl)methanamine (1.6 g, 5.75 mmol, 1.0 equiv) in TFA (20 mL) was stirred for 6 hours at 80° C. The resulting mixture was concentrated under reduced pressure to give 1-[5-(methoxymethyl)-1,3-thiazol-2-yl]methanamine (700 mg crude) as a brown oil including several inseparable by-products.
将上述混合物(700mg，4.42mmol，1.0equiv)、Boc2O(1.44g，6.64mmol，1.5equiv)、Et3N(895mg，8.85mmol，2.0equiv)和DCM(10mL)的溶液在室温下搅拌4小时，然后用水(200mL)淬灭并用DCM(3×100mL)萃取。合并的有机层用盐水(200mL)洗涤并用无水硫酸钠干燥。过滤后，将滤液减压浓缩。将残余物通过硅胶柱色谱法用石油醚/乙酸乙酯(90/10)纯化，得到无色油状的((5-(甲氧基甲基)噻唑-2-基)甲基)氨基甲酸叔丁酯(500mg粗品)，LC-MS(ESI,m/z):259[M+H]+。A solution of the above mixture (700 mg, 4.42 mmol, 1.0 equiv), Boc 2 O (1.44 g, 6.64 mmol, 1.5 equiv), Et 3 N (895 mg, 8.85 mmol, 2.0 equiv) and DCM (10 mL) was stirred at room temperature for 4 hours, then quenched with water (200 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether/ethyl acetate (90/10) to give tert-butyl ((5-(methoxymethyl)thiazol-2-yl)methyl)carbamate (500 mg crude) as a colorless oil, LC-MS (ESI, m/z): 259 [M+H] + .
Step 5:(5-(甲氧基甲基)噻唑-2-基)甲胺的制备Step 5: Preparation of (5-(methoxymethyl)thiazol-2-yl)methylamine
将((5-(甲氧基甲基)噻唑-2-基)甲基)氨基甲酸叔丁酯(500mg，1.94mmol，1.0equiv)、HCl(1.0N)和二恶烷(5mL)的溶液在室温下搅拌2小时。减压浓缩所得混合物，得到(5-(甲氧基甲基)噻唑-2-基)甲胺.氯化氢(400mg粗品)，为棕色油状物，LC-MS(ESI,m/z):159[M+H]+.。A solution of tert-butyl ((5-(methoxymethyl)thiazol-2-yl)methyl)carbamate (500 mg, 1.94 mmol, 1.0 equiv), HCl (1.0 N) and dioxane (5 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give (5-(methoxymethyl)thiazol-2-yl)methanamine.hydrochloride (400 mg crude) as a brown oil, LC-MS (ESI, m/z): 159 [M+H] + .
PEX10 1-((3-氟哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苄基)-1-甲基脲的制备
Preparation of PEX10 1-((3-fluoropiperidin-4-yl)methyl)-3-(4-(methoxymethyl)benzyl)-1-methylurea
Step 1. 3-氟-4-(甲基氨基甲酰基)哌啶-1-羧酸叔丁酯的制备
Step 1. Preparation of tert-butyl 3-fluoro-4-(methylcarbamoyl)piperidine-1-carboxylate
向1-(叔丁氧基羰基)-3-氟哌啶-4-羧酸(860mg，3.48mmol，1.0equiv)在DCM(15mL)中的溶液中加入吡啶(0.7mL，8.7mmol，2.5equiv)。在氮气氛下，将混合物在0℃搅拌并加入SOCl2(0.3mL，4.17mmol，1.2equiv)。然后加入甲胺(1.08g，34.8mmol，10equiv)并将混合物在室温搅拌过夜。将反应用水(10mL)淬灭并用EtOAc(3×15mL)萃取。合并的有机层用盐水(20mL)洗涤，用无水硫酸钠干燥。过滤后，将滤液减压浓缩，得到550mg(粗品)3-氟-4-(甲基氨基甲酰基)哌啶-1-羧酸叔丁酯，为橙色油状物，LC-MS(ESI,m/z):261[M+H]+.。To a solution of 1-(tert-butoxycarbonyl)-3-fluoropiperidine-4-carboxylic acid (860 mg, 3.48 mmol, 1.0 equiv) in DCM (15 mL) was added pyridine (0.7 mL, 8.7 mmol, 2.5 equiv). Under nitrogen atmosphere, the mixture was stirred at 0 °C and SOCl2 (0.3 mL, 4.17 mmol, 1.2 equiv) was added. Methylamine (1.08 g, 34.8 mmol, 10 equiv) was then added and the mixture was stirred at room temperature overnight. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 550 mg (crude) of tert-butyl 3-fluoro-4-(methylcarbamoyl)piperidine-1-carboxylate as an orange oil. LC-MS (ESI, m/z): 261 [M+H] + .
Step 2. 3-氟-4-((甲基氨基)甲基)哌啶-1-羧酸叔丁酯的制备
Step 2. Preparation of tert-butyl 3-fluoro-4-((methylamino)methyl)piperidine-1-carboxylate
在0℃和氮气气氛下，向3-氟-4-(甲基氨基甲酰基)哌啶-1-羧酸叔丁酯(550mg，2.1mmol，1.0equiv)在THF(8mL)中的溶液中加入Red-Al(1.95mL，6.34mmol，3.0equiv，65％的甲苯溶液)。将混合物在室温搅拌6小时并用水(8mL)淬灭，用EtOAc(3×10mL)萃取。合并的有机层用盐水(15mL)洗涤，并用无水硫酸钠干燥。过滤后，将滤液减压浓缩，得到500mg橙色油状的(粗品)3-氟-4-((甲基氨基)甲基)哌啶-1-羧酸叔丁酯，LC-MS(ESI,m/z):247[M+H]+.。To a solution of tert-butyl 3-fluoro-4-(methylcarbamoyl)piperidine-1-carboxylate (550 mg, 2.1 mmol, 1.0 equiv) in THF (8 mL) was added Red-Al (1.95 mL, 6.34 mmol, 3.0 equiv, 65% in toluene) at 0°C under nitrogen atmosphere. The mixture was stirred at room temperature for 6 hours and quenched with water (8 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 500 mg of (crude) tert-butyl 3-fluoro-4-((methylamino)methyl)piperidine-1-carboxylate as an orange oil, LC-MS (ESI, m/z): 247 [M+H] + .
Step 3. 3-氟-4-((3-(4-(甲氧基甲基)苄基)-1-甲基脲基)甲基)哌啶-1-羧酸叔丁酯的制备
Step 3. Preparation of tert-butyl 3-fluoro-4-((3-(4-(methoxymethyl)benzyl)-1-methylureido)methyl)piperidine-1-carboxylate
向1-[4-(甲氧基甲基)苯基]甲胺(400mg，2.64mmol，1.3equiv)的DMSO(5mL)溶液中加入CDI(428mg，2.64mmol，1.3equvi)。将混合物在室温搅拌30分钟并加入3-氟-4-((甲基氨基)甲基)哌啶-1-羧酸叔丁酯(500mg，2.03mmol，1.0equiv)。将混合物在室温搅拌过夜，用水(5mL)淬灭，用EtOAc(3×10mL)萃取。合并有机层，用无水硫酸钠干燥，过滤并减压浓缩。将残余物在硅胶柱上用EtOAc/PE(1/1)进行色谱分离，得到300mg(产率28％)3-氟-4-((3-(4-(甲氧基甲基)苄基)-1-甲基脲基)甲基)哌啶-1-羧酸叔丁酯，为橙色油状物，LC-MS(ESI,m/z):424[M+H]+。To a solution of 1-[4-(methoxymethyl)phenyl]methanamine (400 mg, 2.64 mmol, 1.3 equiv) in DMSO (5 mL) was added CDI (428 mg, 2.64 mmol, 1.3 equiv). The mixture was stirred at room temperature for 30 minutes and tert-butyl 3-fluoro-4-((methylamino)methyl)piperidine-1-carboxylate (500 mg, 2.03 mmol, 1.0 equiv) was added. The mixture was stirred at room temperature overnight, quenched with water (5 mL), extracted with EtOAc (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EtOAc/PE (1/1) to afford 300 mg (yield 28%) of tert-butyl 3-fluoro-4-((3-(4-(methoxymethyl)benzyl)-1-methylureido)methyl)piperidine-1-carboxylate as an orange oil, LC-MS (ESI, m/z): 424 [M+H] + .
Step 4. 1-((3-氟哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苄基)-1-甲基脲的制备方法Step 4. Preparation method of 1-((3-fluoropiperidin-4-yl)methyl)-3-(4-(methoxymethyl)benzyl)-1-methylurea
3-氟-4-((3-(4-(甲氧基甲基)苄基)-1-甲基脲基)甲基)哌啶-1-羧酸叔丁酯溶液(300mg，0.71mmol，1.0equiv)在DCM(5mL)中加入TFA(1mL)。将混合物在室温下搅拌1小时并减压浓缩以提供145mg(粗 品)1-((3-氟哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苄基)-1-甲基脲为棕色油状物。LC-MS(ESI,m/z):324[M+H]+.A solution of tert-butyl 3-fluoro-4-((3-(4-(methoxymethyl)benzyl)-1-methylureido)methyl)piperidine-1-carboxylate (300 mg, 0.71 mmol, 1.0 equiv) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to provide 145 mg (crude The product) 1-((3-fluoropiperidin-4-yl)methyl)-3-(4-(methoxymethyl)benzyl)-1-methylurea was a brown oil. LC-MS (ESI, m/z): 324 [M+H] + .
PEX11 3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的制备
PEX11 Preparation of 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.Trifluoroacetic acid
Step 1:4-((3-(4-甲氧基苄基)-1-甲基脲基)甲基)哌啶-1-羧酸叔丁酯的制备
Step 1: Preparation of tert-butyl 4-((3-(4-methoxybenzyl)-1-methylureido)methyl)piperidine-1-carboxylate
将4-((甲基氨基)甲基)哌啶-1-羧酸叔丁酯(600mg，2.63mmol，0.5equiv)、三光气(780mg，2.63mmol，0.5equiv)和DCM(10mL)装入40mL小瓶中。在0℃，滴加N,N-二异丙基乙胺(2.72g，21.0mmol，4.0equiv)。在0℃搅拌30分钟反应后，加入(4-甲氧基苯基)甲胺(721mg，5.26mmol，1.0equiv)，在室温搅拌2小时。所得溶液用水(10mL)淬灭。所得混合物用二氯甲烷(3×20mL)萃取，合并有机层，用盐水(2×10mL)洗涤，经无水硫酸钠干燥，过滤并减压浓缩。残余物在硅胶柱上用乙酸乙酯/石油醚(1/1)进行色谱分离，得到740mg(产率24％)4-((3-(4-甲氧基苄基)-1-甲基脲基)甲基)哌啶-1-羧酸叔丁酯，为黄色固体，LC-MS(ESI,m/z):392[M+H]+。Tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate (600 mg, 2.63 mmol, 0.5 equiv), triphosgene (780 mg, 2.63 mmol, 0.5 equiv) and DCM (10 mL) were placed in a 40 mL vial. At 0°C, N,N-diisopropylethylamine (2.72 g, 21.0 mmol, 4.0 equiv) was added dropwise. After stirring the reaction at 0°C for 30 minutes, (4-methoxyphenyl)methanamine (721 mg, 5.26 mmol, 1.0 equiv) was added and stirred at room temperature for 2 hours. The resulting solution was quenched with water (10 mL). The resulting mixture was extracted with dichloromethane (3×20 mL), and the organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to give 740 mg (yield 24%) of tert-butyl 4-((3-(4-methoxybenzyl)-1-methylureido)methyl)piperidine-1-carboxylate as a yellow solid, LC-MS (ESI, m/z): 392 [M+H] + .
Step 2:3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的制备Step 2: Preparation of 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea-trifluoroacetic acid
在40mL小瓶中装入4-((3-(4-甲氧基苄基)-1-甲基脲基)甲基)哌啶-1-羧酸叔丁酯(740mg，1.28mmol，1.0equiv)和DCM(10mL)。在0℃滴加三氟乙酸(3mL)。将反应溶液在室温下搅拌2小时，然后减压浓缩，得到粗品3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸，为黄色油状物.LC-MS(ESI,m/z):292[M+H]+.。A 40 mL vial was charged with tert-butyl 4-((3-(4-methoxybenzyl)-1-methylureido)methyl)piperidine-1-carboxylate (740 mg, 1.28 mmol, 1.0 equiv) and DCM (10 mL). Trifluoroacetic acid (3 mL) was added dropwise at 0°C. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give the crude product 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid as a yellow oil. LC-MS (ESI, m/z): 292 [M+H] + .
PEX12制备1-环丙基-3-(4-(甲氧基甲基)苄基)-1-(哌啶-4-基甲基)脲.三氟乙酸
PEX12 Preparation of 1-cyclopropyl-3-(4-(methoxymethyl)benzyl)-1-(piperidin-4-ylmethyl)urea.Trifluoroacetic acid
Step 1:制备4-[(环丙基氨基)甲基]哌啶-1-羧酸叔丁酯
Step 1: Preparation of tert-butyl 4-[(cyclopropylamino)methyl]piperidine-1-carboxylate
向4-甲酰基哌啶-1-甲酸叔丁酯(1.00g，4.69mmol，1.0equiv)和氨基环丙烷(0.32g，5.63mmol，1.2equiv)在DCM(20mL)中的溶液中加入AcOH(0.56g，9.38mmol，2.0equiv)，将混合物在室温搅拌3小时。加入STAB(2.48g，11.7mmol，2.5equiv)。混合物在室温下搅拌过夜。所得溶液用NaHCO3(15mL)淬灭。所得溶液用二氯甲烷(20mL)、乙酸乙酯(20mL×3)萃取，然后合并有机层，用盐水(50mL)洗涤，经无水硫酸钠干燥并减压浓缩。将残余物在硅胶柱上用甲醇/二氯甲烷(1/9)进行色谱分离，得到黄色油状的4-[(环丙基氨基)甲基]哌啶-1-羧酸叔丁酯(1.2g，95％产率).LC-MS(ESI,m/z):255[M+H]+。 To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (1.00 g, 4.69 mmol, 1.0 equiv) and aminocyclopropane (0.32 g, 5.63 mmol, 1.2 equiv) in DCM (20 mL) was added AcOH (0.56 g, 9.38 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 3 hours. STAB (2.48 g, 11.7 mmol, 2.5 equiv) was added. The mixture was stirred at room temperature overnight. The resulting solution was quenched with NaHCO 3 (15 mL). The resulting solution was extracted with dichloromethane (20 mL), ethyl acetate (20 mL×3), and the organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with methanol/dichloromethane (1/9) to give tert-butyl 4-[(cyclopropylamino)methyl]piperidine-1-carboxylate (1.2 g, 95% yield) as a yellow oil. LC-MS (ESI, m/z): 255 [M+H] + .
Step 2:1-环丙基-3-(4-(甲氧基甲基)苄基)-1-(哌啶-4-基甲基)脲.三氟乙酸的制备Step 2: Preparation of 1-cyclopropyl-3-(4-(methoxymethyl)benzyl)-1-(piperidin-4-ylmethyl)urea-trifluoroacetic acid
1-环丙基-3-(4-(甲氧基甲基)苄基)-1-(哌啶-4-基甲基)脲.三氟乙酸在类似于3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的条件下制备和纯化，以4-[(环丙基氨基)甲基]哌啶-1-羧酸叔丁酯(500mg，1.97mmol，1.0equiv)和(4-(甲氧基甲基)苯基)甲胺(892mg，5.90mmol，3.0equiv)为原料，得到所需产物(2步分离产率为38％)，为淡黄色油状物，LC-MS(ESI,m/z):332[M+H]+.1-Cyclopropyl-3-(4-(methoxymethyl)benzyl)-1-(piperidin-4-ylmethyl)urea.Trifluoroacetic acid was prepared and purified under similar conditions to 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.Trifluoroacetic acid, starting from tert-butyl 4-[(cyclopropylamino)methyl]piperidine-1-carboxylate (500 mg, 1.97 mmol, 1.0 equiv) and (4-(methoxymethyl)phenyl)methanamine (892 mg, 5.90 mmol, 3.0 equiv) to give the desired product (38% isolated yield over 2 steps) as a light yellow oil, LC-MS (ESI, m/z): 332 [M+H] + .
PEX13制备3-苄基-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸
PEX13 Preparation of 3-Benzyl-1-methyl-1-(piperidin-4-ylmethyl)urea. Trifluoroacetic acid
在类似于3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的条件下制备和纯化3-苄基-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸，以4-((甲基氨基)甲基)哌啶-1-羧酸叔丁酯(955mg，4.18mmol，0.8equiv)和苯甲胺(560mg，5.23mmol，1.0equiv)为原料，得到所需的3-苄基-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸(500mg，2步收率为30％)，为黄色油状物，LC-MS(ESI,m/z):262[M+H]+.3-Benzyl-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid, starting from tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate (955 mg, 4.18 mmol, 0.8 equiv) and benzylamine (560 mg, 5.23 mmol, 1.0 equiv) to give the desired 3-benzyl-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid (500 mg, 30% yield over 2 steps) as a yellow oil, LC-MS (ESI, m/z): 262 [M+H] + .
PEX14 3-((5-(甲氧基甲基)吡啶-2-基)甲基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的制备
PEX14 Preparation of 3-((5-(methoxymethyl)pyridin-2-yl)methyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.Trifluoroacetic acid
在类似于3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的条件下制备和纯化，以4-((甲基氨基)甲基)哌啶-1-羧酸叔丁酯(360mg，1.58mmol，1.2equiv)和(5-(甲氧基甲基)吡啶-2-基)甲胺(200mg，1.31mmol，1.0equiv)为原料，得到粗的所需产物(112mg，2步的产率约24％)，为棕色油。LC-MS(ESI,m/z):307[M+H]+.Prepared and purified under conditions similar to 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid, starting from tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate (360 mg, 1.58 mmol, 1.2 equiv) and (5-(methoxymethyl)pyridin-2-yl)methanamine (200 mg, 1.31 mmol, 1.0 equiv) to give the crude desired product (112 mg, 2-step yield about 24%) as a brown oil. LC-MS (ESI, m/z): 307 [M+H] + .
PEX15 1-((6-(甲氧基甲基)吡啶-3-基)甲基)-3-(哌啶-4-基甲基)脲.三氟乙酸的制备
PEX15 1-((6-(methoxymethyl)pyridin-3-yl)methyl)-3-(piperidin-4-ylmethyl)urea. Preparation of trifluoroacetic acid
1-((6-(甲氧基甲基)吡啶-3-基)甲基)-3-(哌啶-4-基甲基)脲.三氟乙酸在类似于3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的条件下制备和纯化，以4-(氨基甲基)哌啶-1-羧酸叔丁酯(845mg，3.94mmol，1.5equiv)和1-[6-(甲氧基甲基)吡啶-3-基]甲胺(400mg，2.63mmol，1.0equiv)为原料，得到粗的所需产物(150mg，2步产率28％)，为棕色固体。LCMS(ESI,m/z):293[M+H]+.1-((6-(methoxymethyl)pyridin-3-yl)methyl)-3-(piperidin-4-ylmethyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid starting from tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (845 mg, 3.94 mmol, 1.5 equiv) and 1-[6-(methoxymethyl)pyridin-3-yl]methanamine (400 mg, 2.63 mmol, 1.0 equiv) to give the crude desired product (150 mg, 28% yield over 2 steps) as a brown solid. LCMS (ESI, m/z): 293 [M+H] + .
PEX16 1-(4-(甲氧基甲基)苄基)-1,3-二甲基-3-(哌啶-4-基甲基)脲.三氟乙酸的制备
PEX16 1-(4-(methoxymethyl)benzyl)-1,3-dimethyl-3-(piperidin-4-ylmethyl)urea. Preparation of trifluoroacetic acid
1-(4-(甲氧基甲基)苄基)-1,3-二甲基-3-(哌啶-4-基甲基)脲.三氟乙酸以类似于3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的条件下制备和纯化，以4-((甲基氨基)甲基)哌啶-1-羧酸叔丁酯(332mg,1.45mmol,1.2equiv)和1-(4-(甲氧基甲基)苯基)-N-甲基甲胺(200mg，1.21mmol，1.0equiv)为原料，得到浅黄色半固体粗产物(200mg，38％，经过两步)，LC-MS(ESI,m/z):320[M+H]+.。 1-(4-(Methoxymethyl)benzyl)-1,3-dimethyl-3-(piperidin-4-ylmethyl)urea.trifluoroacetic acid was prepared and purified under conditions similar to 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid, starting from tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate (332 mg, 1.45 mmol, 1.2 equiv) and 1-(4-(methoxymethyl)phenyl)-N-methylmethanamine (200 mg, 1.21 mmol, 1.0 equiv) to give a pale yellow semisolid crude product (200 mg, 38% over two steps), LC-MS (ESI, m/z): 320 [M+H] + .
PEX17 3-(5-(甲氧基甲基)吡啶-2-基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸
PEX17 3-(5-(Methoxymethyl)pyridin-2-yl)-1-methyl-1-(piperidin-4-ylmethyl)urea.Trifluoroacetic acid
3-(5-(甲氧基甲基)吡啶-2-基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸在类似于3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的条件下制备和纯化，以5-(甲氧基甲基)吡啶-2-胺(980mg，7.09mmol，1.0equiv)和4-[(甲基氨基)甲基]哌啶-1-羧酸叔丁酯(6.48g，28.4mmol，4.0equiv)为原料，得到粗的所需产物(230mg，10％,经过2个步骤)，为深黄色油状物，LC-MS(ESI,m/z):293[M+H]+.。3-(5-(Methoxymethyl)pyridin-2-yl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid, starting from 5-(methoxymethyl)pyridin-2-amine (980 mg, 7.09 mmol, 1.0 equiv) and tert-butyl 4-[(methylamino)methyl]piperidine-1-carboxylate (6.48 g, 28.4 mmol, 4.0 equiv) to give the crude desired product (230 mg, 10% over 2 steps) as a dark yellow oil, LC-MS (ESI, m/z): 293 [M+H] + .
PEX18制备1-((6-(甲氧基甲基)吡啶-3-基)甲基)-1-甲基-3-(哌啶-4-基甲基)脲.三氟乙酸的制备
Preparation of 1-((6-(methoxymethyl)pyridin-3-yl)methyl)-1-methyl-3-(piperidin-4-ylmethyl)urea by PEX18. Preparation of trifluoroacetic acid
1-((6-(甲氧基甲基)吡啶-3-基)甲基)-1-甲基-3-(哌啶-4-基甲基)脲.三氟乙酸在类似于3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的条件下制备和纯化，以1-(6-(甲氧基甲基)吡啶-3-基)-N-甲基甲胺(210mg，1.26mmol，1.0equiv)和4-(氨基甲基)哌啶-1-甲酸叔丁酯(812mg，3.79mmol，3.0equiv)为原料，得到粗的所需产物(315mg，2步65％产率)，为棕色油状物，LCMS(ESI,m/z):307[M+H]+.。1-((6-(Methoxymethyl)pyridin-3-yl)methyl)-1-methyl-3-(piperidin-4-ylmethyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid starting from 1-(6-(methoxymethyl)pyridin-3-yl)-N-methylmethanamine (210 mg, 1.26 mmol, 1.0 equiv) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (812 mg, 3.79 mmol, 3.0 equiv) to give the crude desired product (315 mg, 65% yield for 2 steps) as a brown oil, LCMS (ESI, m/z): 307 [M+H] + .
PEX19 3-((6-(甲氧基甲基)吡啶-3-基)甲基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的制备
PEX19 Preparation of 3-((6-(methoxymethyl)pyridin-3-yl)methyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.Trifluoroacetic acid
3-((6-(甲氧基甲基)吡啶-3-基)甲基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸在类似于3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸的条件下制备和纯化，以1-[6-(甲氧基甲基)吡啶-3-基]甲胺(200mg，1.31mmol，1.0equiv)和4-[(甲基氨基)甲基]哌啶-1-羧酸叔丁酯(450mg，1.97mmol，1.5equiv)为原料，得到粗的所需产物(150mg，24％产率，2步)，为棕色固体，LCMS(ESI,m/z):307[M+H]+.。3-((6-(Methoxymethyl)pyridin-3-yl)methyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid starting from 1-[6-(methoxymethyl)pyridin-3-yl]methanamine (200 mg, 1.31 mmol, 1.0 equiv) and tert-butyl 4-[(methylamino)methyl]piperidine-1-carboxylate (450 mg, 1.97 mmol, 1.5 equiv) to give the crude desired product (150 mg, 24% yield, 2 steps) as a brown solid, LCMS (ESI, m/z): 307 [M+H] + .
PEX20制备1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙烷-1-酮盐酸盐
Preparation of 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one hydrochloride with PEX20
Step 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
Step 1. Preparation of tert-butyl ((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)(methyl)carbamate
向甲基(哌啶-4-基甲基)氨基甲酸叔丁酯(2.50g，10.9mmol，1.00equiv)和K2CO3(2.26g，16.4mmol，1.50equiv)在DMF(50mL)中的溶液加入2-溴-1-(4-氟苯基)乙-1-酮(2.25g,10.4mmol,0.95equiv)。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，得到叔丁基((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]+.。To a solution of tert-butyl methyl(piperidin-4-ylmethyl)carbamate (2.50 g, 10.9 mmol, 1.00 equiv) and K 2 CO 3 (2.26 g, 16.4 mmol, 1.50 equiv) in DMF (50 mL) was added 2-bromo-1-(4-fluorophenyl)ethan-1-one (2.25 g, 10.4 mmol, 0.95 equiv). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was poured into water (150 mL) and extracted with EA (50 mL*3). The combined organic layers were washed with water (50 mL*3) and brine (50 mL), dried over anhydrous Na 2 SO 4 and concentrated to give tert-butyl((1-(2-(4-fluorophenyl)ethyl)carbamate)-1-one; tert-butyl)-2-oxoethyl)piperidin-4-yl)methyl)(methyl)carbamate (4.00 g, 90.8%) was obtained as a yellow oil, 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (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] + .
Step 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Step 2. Preparation of 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one hydrochloride
在0℃下，向((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，1.00equiv)在EtOAc(40mL)中的溶液滴加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.氯化氢(3.00g,73.7％)，为黄色固体,LC-MS(ESI,m/z):265.1[M+H]+.。To a solution of tert-butyl ((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)(methyl)carbamate (4.00 g, 11.4 mmol, 1.00 equiv) in EtOAc (40 mL) was added dropwise 4.0 M HCl in EtOAc (20 mL) at 0°C. The reaction mixture was then stirred at room temperature for 2 hours and filtered to give 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one. Hydrogen chloride (3.00 g, 73.7%) as a yellow solid, LC-MS (ESI, m/z): 265.1 [M+H] + .
PEX21制备2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮.盐酸盐
PEX21 Preparation of 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one. hydrochloride
Step 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
Step 1. Preparation of tert-butyl ((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)carbamate
向(哌啶-4-基甲基)氨基甲酸叔丁酯(5.00g，23.2mmol，1.00equiv)和K2CO3(4.81g，34.8mmol，1.50equiv)在DMF(100mL)中的混合物中加入2-溴-1-(4-氟苯基)乙-1-酮(4.78g，22.0mmol，0.95equiv)。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]+.To a mixture of tert-butyl (piperidin-4-ylmethyl)carbamate (5.00 g, 23.2 mmol, 1.00 equiv) and K 2 CO 3 (4.81 g, 34.8 mmol, 1.50 equiv) in DMF (100 mL) was added 2-bromo-1-(4-fluorophenyl)ethan-1-one (4.78 g, 22.0 mmol, 0.95 equiv). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was poured into water (300 mL) and filtered to give tert-butyl ((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)carbamate (5.00 g, 55.2%)) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.09-8.02 (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] + .
Step 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Step 2. Preparation of 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one hydrochloride
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，1.00equiv)的EtOAc(50mL)溶液中加入滴加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.氯化氢(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]+.。To a solution of tert-butyl ((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)carbamate (5.00 g, 14.2 mmol, 1.00 equiv) in EtOAc (50 mL) at 0 °C was added dropwise 4.0 M HCl in EtOAc (50 mL). The reaction mixture was then stirred at room temperature for 2 hours and filtered to give 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one. Hydrogen chloride (3.00 g, 59.2%) was an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.41-10.26 (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] + .
PEX22 1-(4-氟苯基)-2-(4-(甲基氨基)哌啶-1-基)乙-1-酮.氯化氢的制备
PEX22 Preparation of 1-(4-fluorophenyl)-2-(4-(methylamino)piperidin-1-yl)ethan-1-one. Hydrogen chloride
Step 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
Step 1. Preparation of tert-butyl (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)(methyl)carbamate
向甲基(哌啶-4-基)氨基甲酸叔丁酯(1.00g，4.64mmol，1.00equiv)和K2CO3(960mg，6.96mmol，1.50equiv)在DMF(20mL)中的混合物中加入2-溴-1-(4-氟苯基)乙-1-酮(957mg，4.41mmol，0.95equiv)。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)氨基甲酸叔丁酯(1.00g，55.1％)，为黄色油状物，LC-MS(ESI,m/z):351.2[M+H]+.。To a mixture of tert-butyl methyl(piperidin-4-yl)carbamate (1.00 g, 4.64 mmol, 1.00 equiv) and K2CO3 ( 960 mg, 6.96 mmol, 1.50 equiv) in DMF (20 mL) was added 2-bromo-1-(4-fluorophenyl)ethan-1-one (957 mg, 4.41 mmol, 0.95 equiv). The resulting mixture was stirred at room temperature for 2 h, then poured into water (60 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with water (30 mL x 3) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated to give tert - butyl (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)(methyl)carbamate (1.00 g, 55.1%) as a yellow oil, LC-MS (ESI, m/z): 351.2 [M+H] + .
Step 2. 1-(4-氟苯基)-2-(4-(甲基氨基)哌啶-1-基)乙-1-酮.氯化氢的制备Step 2. Preparation of 1-(4-fluorophenyl)-2-(4-(methylamino)piperidin-1-yl)ethan-1-one.hydrogen chloride
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，1.00equiv)在EtOAc(10mL)的溶液中加入滴加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.氯化氢(600mg,58.7％)为黄色固体，LC-MS(ESI,m/z):251.1[M+H]+.。To a solution of tert-butyl (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)(methyl)carbamate (1.00 g, 2.84 mmol, 1.00 equiv) in EtOAc (10 mL) was added dropwise 4.0 M HCl in EtOAc (10 mL) at 0° C. The reaction mixture was then stirred at room temperature for 2 hours and filtered to give 1-(4-fluorophenyl)-2-(4-(methylamino)piperidin-1-yl)ethan-1-one. Hydrogen chloride (600 mg, 58.7%) was obtained as a yellow solid, LC-MS (ESI, m/z): 251.1 [M+H] + .
EX1制备3-({3-氟-1-[2-(4-氟苯基)-2-氧代乙基]哌啶-4-基}甲基)-1-{[4-(甲氧基甲基)苯基]甲基}-3-甲基脲.三氟乙酸(ER10298)
EX1 Preparation of 3-({3-fluoro-1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}methyl)-1-{[4-(methoxymethyl)phenyl]methyl}-3-methylurea.Trifluoroacetic acid (ER10298)
向1-[(3-氟哌啶-4-基)甲基]-3-{[4-(甲氧基甲基)苯基]甲基}-1-甲基脲(145mg，0.448mmol，1equiv)在DMF(3mL，38.765mmol，86.46equiv)溶液中加入2-氯-1-(4-氟苯基)乙酮(77.38mg，0.448mmol，1equiv)和K2CO3(123.93mg，0.896mmol，2equiv)。将混合物在55℃搅拌2h并用水(5mL)淬灭，用乙酸乙酯(3×10mL)萃取。合并的有机层用盐水(3×8mL)洗涤，经无水硫酸钠干燥。过滤后，将滤液减压浓缩。在方法A条件下，通过pre-HPLC纯化残余物，以得到3-({3-氟-1-[2-(4-氟苯基)-2-氧代乙基]哌啶-4-基}甲基)-1-{[4-(甲氧基甲基)苯基]甲基}-3-甲基脲.三氟乙酸(48.9mg，产率23％)，为灰白色半固体。1H NMR(300MHz,CD3OD)δ8.08-8.14(m,2H),7.25-7.36(m,6H),4.90-5.08(m,3H),4.36-4.42(m 4H),3.82-4.18(m,2H),3.42-3.77(m,2H),3.31-3.41(m,5H),2.94-3.00(m,3H),1.83-2.45(m,3H).LC-MS(ESI,m/z):460[M+H]+.To a solution of 1-[(3-fluoropiperidin-4-yl)methyl]-3-{[4-(methoxymethyl)phenyl]methyl}-1-methylurea (145 mg, 0.448 mmol, 1 equiv) in DMF (3 mL, 38.765 mmol, 86.46 equiv) was added 2-chloro-1-(4-fluorophenyl)ethanone (77.38 mg, 0.448 mmol, 1 equiv) and K 2 CO 3 (123.93 mg, 0.896 mmol, 2 equiv). The mixture was stirred at 55° C. for 2 h and quenched with water (5 mL), extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×8 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by pre-HPLC under Method A conditions to give 3-({3-fluoro-1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}methyl)-1-{[4-(methoxymethyl)phenyl]methyl}-3-methylurea.trifluoroacetic acid (48.9 mg, 23% yield) as an off-white semisolid. 1 H NMR (300 MHz, CD 3 OD) δ8.08-8.14 (m, 2H), 7.25-7.36 (m, 6H), 4.90-5.08 (m, 3H), 4.36-4.42 (m 4H), 3.82-4.18 (m, 2H), 3.42-3.77 (m, 2H), 3.31-3.41 (m, 5H), 2.94-3.00 (m, 3H), 1.83-2.45 (m, 3H). LC-MS (ESI, m/z): 460 [M+H] + .
EX2制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(4-甲氧基苄基)-1-甲基脲.三氟乙酸(ER10279)
EX2 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-methoxybenzyl)-1-methylurea trifluoroacetic acid (ER10279)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(4-甲氧基苄基)-1-甲基脲.三氟乙酸在类似于ER10298的制备条件下得到，以3-(4-甲氧基苄基)-1-甲基-1-(哌啶-4-基甲基)脲(300mg，1.03mmol， 1.0equiv)和2-氯-1-(4-氟苯基)乙-1-酮(213mg，1.24mmol，1.2equiv)为原料，得到所需产物(17/8mg,3.0％收率)，为白色固体，1H NMR(300MHz,methanol-d4)δ8.08-8.12(m,2H),7.30-7.36(m,2H),7.21(d,J＝8.7Hz,2H),6.84(d,J＝8.7Hz,2H),4.28(s,2H),3.76(s,3H),3.64-3.68(m,2H),3.38(br,1H),3.32(br,1H),3.28(br,2H),3.04-3.12(m,2H),2.95(s,3H),1.90-2.02(m,3H),1.60-1.70(m,2H).LC-MS(ESI,m/z):428[M+H]+.。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-methoxybenzyl)-1-methylurea.Trifluoroacetic acid was obtained under similar preparation conditions to ER10298 with 3-(4-methoxybenzyl)-1-methyl-1-(piperidin-4-ylmethyl)urea (300 mg, 1.03 mmol, 1.0equiv) and 2-chloro-1-(4-fluorophenyl)ethan-1-one (213mg, 1.24mmol, 1.2equiv) were used as starting materials to obtain the desired product (17/8mg, 3.0% yield) as a white solid. 1 H NMR (300MHz, methanol-d 4 )δ8.08-8.12(m,2H),7.30-7.36(m,2H),7.21(d,J＝8.7Hz,2H),6.84(d,J＝8.7Hz,2H),4.28(s,2H),3.76(s,3H),3.64-3.68(m,2H),3.38(br,1H),3.32(br,1H),3.28(br,2H),3.04-3.12(m,2H),2.95(s,3H),1.90-2.02(m,3H),1.60-1.70(m,2H).LC-MS(ESI,m/z):428[M+H] + .。
EX3制备1-环丙基-1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苄基)脲.三氟乙酸(ER10278)
EX3 Preparation of 1-cyclopropyl-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-(methoxymethyl)benzyl)urea.Trifluoroacetic acid (ER10278)
1-环丙基-1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苄基)脲.三氟乙酸在类似于ER10298的条件下制备和纯化，以1-环丙基-3-(4-(甲氧基甲基)苄基)-1-(哌啶-4-基甲基)脲(200mg，0.60mmol，1.0equiv)和2-氯-1-(4-氟苯基)乙酮(125mg，0.72mmol，1.2equiv)为原料，得到所需产物(56mg，16％产率)，为白色固体，1H-NMR(300MHz,DMSO-d6)δ9.70(s,1H),8.06-8.17(m,2H),7.45-7.52(m,2H),7.23-7.27(m,3H),6.86-6.93(m,1H),4.99-5.05(m,2H),4.06-4.37(m,5H),3.49-3.53(m,2H),2.96-3.26(m,7H),1.55-2.26(m,5H),0.85(s,2H),0.65(s,2H).LC-MS(ESI,m/z):468[M+H]+.。1-Cyclopropyl-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-(methoxymethyl)benzyl)urea.Trifluoroacetic acid was prepared and purified under conditions similar to ER10298 starting from 1-cyclopropyl-3-(4-(methoxymethyl)benzyl)-1-(piperidin-4-ylmethyl)urea (200 mg, 0.60 mmol, 1.0 equiv) and 2-chloro-1-(4-fluorophenyl)ethanone (125 mg, 0.72 mmol, 1.2 equiv) to give the desired product (56 mg, 16% yield) as a white solid, 1 H-NMR (300 MHz, DMSO-d 6 )δ9.70(s,1H),8.06-8.17(m,2H),7.45-7.52(m,2H),7.23-7.27(m,3H),6.86-6.93(m,1H),4.99-5.05(m,2H),4.06-4.37(m,5H),3.49-3.53(m,2H),2.96-3.26(m,7H),1.55-2.26(m,5H),0.85(s,2H),0.65(s,2H).LC-MS(ESI,m/z):468[M+H] + .。
EX4制备3-苄基-1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸(ER10277)
EX4 Preparation of 3-benzyl-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.Trifluoroacetic acid (ER10277)
3-苄基-1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸在类似于ER10298的条件下制备和纯化，以3-苄基-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸(500mg，1.91mmol，1.0equiv)和2-氯-1-(4-氟苯基)乙酮(396mg，2.30mmol，1.2equiv)为原料，得到所需产物(21.8mg,2％产率)，为白色固体。1H NMR(300MHz,methanol-d4)δ8.08-8.12(m,2H),7.18-7.36(m,7H),4.90-4.94(m,2H),4.36(s,2H),3.65-3.69(m,2H),3.38(br,1H),3.29(br,1H),3.04-3.13(m,2H),2.97(s,3H),1.92-2.03(m,3H),1.57-1.70(m,2H).LC-MS(ESI,m/z):398[M+H]+.3-Benzyl-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10298 starting from 3-benzyl-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid (500 mg, 1.91 mmol, 1.0 equiv) and 2-chloro-1-(4-fluorophenyl)ethanone (396 mg, 2.30 mmol, 1.2 equiv) to give the desired product (21.8 mg, 2% yield) as a white solid. 1 H NMR (300 MHz, methanol-d 4 )δ8.08-8.12 (m, 2H), 7.18-7.36 (m, 7H), 4.90-4.94 (m, 2H), 4.36 (s, 2H), 3.65-3.69 (m, 2H), 3.38 (br, 1H), 3.29 (br, 1H), 3.04-3.13 (m, 2H), 2.97 (s, 3H), 1.92-2.03 (m, 3H), 1.57-1.70 (m, 2H). LC-MS (ESI, m/z): 398 [M+H] + .
EX5 1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((5-(甲氧基甲基)吡啶-2-基)甲基)-1-甲基脲.三氟乙酸(ER10273)
EX5 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((5-(methoxymethyl)pyridin-2-yl)methyl)-1-methylurea.trifluoroacetic acid (ER10273)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((5-(甲氧基甲基)吡啶-2-基)甲基)-1-甲基脲.三氟乙酸在与ER10298类似的条件下制备和纯化，以3-((5-(甲氧基甲基)吡啶-2-基)甲基)-1-甲基-1-(哌啶-4-基甲基)脲.三氟乙酸(112mg，0.366mmol，1.0equiv)和2-氯-1-(4-氟苯基)乙-1-酮(75.7mg，0.439mmol，1.2equiv)为原料，得到所需产物(15.2mg，7％产率)，为灰白色固体，1H NMR(300MHz,methanol-d4)δ8.61(s,1H),8.27(d,J＝6.9Hz,1H),8.08-8.13(m,2H),7.79(d,J＝9.3Hz,1H),7.33(t,J＝8.7Hz,2H), 4.91(s,2H),4.60(s,4H),3.65-3.69(m,2H),3.46(s,3H),3.38(br,2H),3.03-3.19(m,5H),1.93-2.08(m,3H),1.60-1.69(m,2H).LC-MS(ESI,m/z):443[M+H]+.。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((5-(methoxymethyl)pyridin-2-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10298 starting from 3-((5-(methoxymethyl)pyridin-2-yl)methyl)-1-methyl-1-(piperidin-4-ylmethyl)urea.trifluoroacetic acid (112 mg, 0.366 mmol, 1.0 equiv) and 2-chloro-1-(4-fluorophenyl)ethan-1-one (75.7 mg, 0.439 mmol, 1.2 equiv) to give the desired product (15.2 mg, 7% yield) as an off-white solid, 1 H NMR (300 MHz, methanol-d 4 )δ8.61(s,1H),8.27(d,J＝6.9Hz,1H),8.08-8.13(m,2H),7.79(d,J＝9.3Hz,1H),7.33(t,J＝8.7Hz,2H), 4.91(s, 2H),4.60(s, 4H),3.65-3.69(m, 2H),3.46(s, 3H),3.38(br, 2H),3.03-3.19(m, 5H),1.93-2.08(m, 3H),1.60-1.69(m, 2H).LC-MS(ESI,m/z):443[M+H] + .
EX6制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((6-(甲氧基甲基)吡啶-3-基)甲基)脲.三氟乙酸(ER10272)
EX6 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((6-(methoxymethyl)pyridin-3-yl)methyl)urea.Trifluoroacetic acid (ER10272)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((6-(甲氧基甲基)吡啶-3-基)甲基)脲.三氟乙酸在类似于ER10298的条件下制备和纯化，以1-((6-(甲氧基甲基)吡啶-3-基)甲基)-3-(哌啶-4-基甲基)脲.三氟乙酸(150mg，0.490mmol，1.00equiv))和2-氯-1-(4-氟苯基)乙酮(84.5mg，0.490mmol，1.0equiv)为原料，得到所需产物(25.0mg，9.0％)，为灰白色半固体。1HNMR(300MHz,methanol-d4)δ8.54(s,1H),8.08-8.17(m,3H),7.72-7.75(m,1H),7.30-7.36(m,2H),4.90(s,2H),4.69(s,2H),4.43(s,2H),3.65-3.69(m,2H),3.51(s,3H),3.11-3.13(m,4H),1.98-2.02(m,2H),1.55-1.81(m,3H).LCMS(ESI,m/z):429[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((6-(methoxymethyl)pyridin-3-yl)methyl)urea.trifluoroacetic acid was prepared and purified under conditions similar to ER10298 starting from 1-((6-(methoxymethyl)pyridin-3-yl)methyl)-3-(piperidin-4-ylmethyl)urea.trifluoroacetic acid (150 mg, 0.490 mmol, 1.00 equiv)) and 2-chloro-1-(4-fluorophenyl)ethanone (84.5 mg, 0.490 mmol, 1.0 equiv) to give the desired product (25.0 mg, 9.0%) as an off-white semi-solid. 1 HNMR (300MHz,methanol-d4)δ8.54(s,1H),8.08-8.17(m,3H),7.72-7.75(m,1H),7.30-7.36(m,2H),4.90(s,2H),4.69(s,2H),4.43(s,2H),3.65-3.69(m,2H),3.51(s,3H),3.11-3.13(m,4H),1.98-2.02(m,2H),1.55-1.81(m,3H).LCMS(ESI,m/z):429[M+H] + .
EX7制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苄基)-1,3-二甲基脲.三氟乙酸(ER10271)
EX7 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-(methoxymethyl)benzyl)-1,3-dimethylurea.trifluoroacetic acid (ER10271)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苄基)-1,3-二甲基脲.三氟乙酸在与ER10298类似的条件下制备和纯化，以1-(4-(甲氧基甲基)苄基)-1,3-二甲基-3-(哌啶-4-基甲基)脲(182mg，0.570mmol，1.0equiv)和2-氯-1-(4-氟苯基)乙酮(118mg，0.684mmol，1.2equiv)为原料，得到所需产物(22.8mg，7.0％)，为灰白色固体，1H NMR(300MHz,methanol-d4)δ8.08-8.13(m,2H),7.26-7.36(m,6H),4.40-4.44(m,4H),3.63-3.67(m,2H),3.36(s,4H),3.21-3.24(m,3H),3.04-3.12(m,2H),2.94(s,3H),2.79(s,3H),1.89-2.00(m,3H),1.50-1.620(m,2H).LC-MS(ESI,m/z):456[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-(methoxymethyl)benzyl)-1,3-dimethylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10298 starting from 1-(4-(methoxymethyl)benzyl)-1,3-dimethyl-3-(piperidin-4-ylmethyl)urea (182 mg, 0.570 mmol, 1.0 equiv) and 2-chloro-1-(4-fluorophenyl)ethanone (118 mg, 0.684 mmol, 1.2 equiv) to give the desired product (22.8 mg, 7.0%) as an off-white solid. 1 H NMR (300 MHz, methanol-d 4 )δ8.08-8.13 (m, 2H), 7.26-7.36 (m, 6H), 4.40-4.44 (m, 4H), 3.63-3.67 (m, 2H), 3.36 (s, 4H), 3.21-3.24 (m, 3H), 3.04-3.12 (m, 2H), 2.94 (s, 3H), 2.79 (s, 3H), 1.89-2.00 (m, 3H), 1.50-1.620 (m, 2H). LC-MS (ESI, m/z): 456 [M+H] + .
EX8制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(5-(甲氧基甲基)吡啶-2-基)-1-甲基脲.三氟乙酸(ER10270)
EX8 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(5-(methoxymethyl)pyridin-2-yl)-1-methylurea.Trifluoroacetic acid (ER10270)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(5-(甲氧基甲基)吡啶-2-基)-1-甲基脲.三氟乙酸在与ER10298类似的条件下制备和纯化，以3-(5-(甲氧基甲基)吡啶-2-基)-1-甲基-1-(哌啶-4-基甲基)脲(230mg，0.79mmol，1.0equiv)和2-氯-1-(4-氟苯基)乙酮(163mg，0.94mmol，1.2equiv)为原料，得到所需产物(42mg，9.0％)，为白色半固体，1H-NMR(400MHz,CD3OD)δ8.20-8.24(m,2H),8.11-8.12(m,2H),7.68-7.70(m,1H),7.30-7.34(m,2H),4.91-5.10(m,2H),4.51(s,2H),3.62-3.78(m,2H),3.42-3.50(m,5H),3.01-3.26(m,5H),2.14(s,1H),2.00-2.04(m,2H),1.69-1.78(m,2H).LC-MS(ESI,m/z): 429[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(5-(methoxymethyl)pyridin-2-yl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10298 starting from 3-(5-(methoxymethyl)pyridin-2-yl)-1-methyl-1-(piperidin-4-ylmethyl)urea (230 mg, 0.79 mmol, 1.0 equiv) and 2-chloro-1-(4-fluorophenyl)ethanone (163 mg, 0.94 mmol, 1.2 equiv) to give the desired product (42 mg, 9.0%) as a white semi-solid, 1 H-NMR (400 MHz, CD 3 OD) δ8.20-8.24 (m, 2H), 8.11-8.12 (m, 2H), 7.68-7.70 (m, 1H), 7.30-7.34 (m, 2H), 4.91-5.10 (m, 2H), 4.51 (s, 2H), 3.62-3.78 (m, 2H), 3.42-3.50 (m, 5H), 3.01-3.26 (m, 5H), 2.14 (s, 1H), 2.00-2.04 (m, 2H), 1.69-1.78 (m, 2H). LC-MS (ESI, m/z): 429[M+H] + .
EX9制备3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-((6-(甲氧基甲基)吡啶-3-基)甲基)-1-甲基脲.三氟乙酸(ER10269)
EX9 Preparation of 3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-((6-(methoxymethyl)pyridin-3-yl)methyl)-1-methylurea.Trifluoroacetic acid (ER10269)
3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-((6-(甲氧基甲基)吡啶-3-基)甲基)-1-甲基脲.三氟乙酸在与ER10298类似的条件下制备和纯化，以1-((6-(甲氧基甲基)吡啶-3-基)甲基)-1-甲基-3-(哌啶-4-基甲基)脲(200mg，0.653mmol，1.0equiv)和2-氯-1-(4-氟苯基)乙酮(113mg，0.653mmol，1.0equiv)为原料，得到所需产物(15.2mg，4.18％)，为灰白色固体，1HNMR(300MHz,methanol-d4)δ8.53(s,1H),8.08-8.18(m,3H),7.77-7.80(m,1H),7.30-7.36(m,2H),4.94(s,2H),4.73(s,2H),4.64(s,2H),3.66-3.70(m,2H),3.52(s,3H),3.06-3.18(m,4H),2.97(s,3H),1.60-2.03(m,5H).LCMS(ESI,m/z):443[M+H]+。3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-((6-(methoxymethyl)pyridin-3-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions as ER10298 starting from 1-((6-(methoxymethyl)pyridin-3-yl)methyl)-1-methyl-3-(piperidin-4-ylmethyl)urea (200 mg, 0.653 mmol, 1.0 equiv) and 2-chloro-1-(4-fluorophenyl)ethanone (113 mg, 0.653 mmol, 1.0 equiv) to give the desired product (15.2 mg, 4.18%) as an off-white solid, 1 H NMR (300 MHz, methanol-d4) δ 8.53 (s, 1H), 8.08-8.18 (m, 3H), 7.77-7.80 (m, 1H), 7.30-7.36 (m, 2H), 4.94 (s, 2H), 4.73 (s, 2H), 4.64 (s, 2H), 3.66-3.70 (m, 2H), 3.52 (s, 3H), 3.06-3.18 (m, 4H), 2.97 (s, 3H), 1.60-2.03 (m, 5H). LCMS (ESI, m/z): 443 [M+H] + .
EX10制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((6-(甲氧基甲基)吡啶-3-基)甲基)-1-甲基脲.三氟乙酸(ER10268)
EX10 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((6-(methoxymethyl)pyridin-3-yl)methyl)-1-methylurea.Trifluoroacetic acid (ER10268)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((6-(甲氧基甲基)吡啶-3-基)甲基)-1-甲基脲.三氟乙酸在与ER10298类似的条件下制备和纯化，以3-((6-(甲氧基甲基)吡啶-3-基)甲基)-1-甲基-1-(哌啶-4-基甲基)脲(150mg，0.490mmol，1.0equiv)和2-氯-1-(4-氟苯基)乙酮(84.5mg，0.490mmol，1.0equiv)为原料，得到所需产物(18.1mg，6.64％)，为灰白色固体，1HNMR(300MHz,methanol-d4)δ8.56(s,1H),8.20-8.23(m,1H),8.08-8.13(m,2H),7.75-7.78(m,1H),7.30-7.36(m,2H),4.91(s,2H),4.72(s,2H),4.46(s,2H),3.65-3.69(m,2H),3.52(s,3H),3.32-3.38(m,2H),3.06-3.13(m,2H),2.98(s,3H),1.91-2.03(m,3H),1.57-1.69(m,2H).LCMS(ESI,m/z):443[M+H]+.。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((6-(methoxymethyl)pyridin-3-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions as ER10298 starting from 3-((6-(methoxymethyl)pyridin-3-yl)methyl)-1-methyl-1-(piperidin-4-ylmethyl)urea (150 mg, 0.490 mmol, 1.0 equiv) and 2-chloro-1-(4-fluorophenyl)ethanone (84.5 mg, 0.490 mmol, 1.0 equiv) to give the desired product (18.1 mg, 6.64%) as an off-white solid, 1 HNMR (300 MHz, methanol-d4) δ8.56 (s, 1H), 8.20-8.23 (m, 1H), 8.08-8.13 (m, 2H), 7.75-7.78 (m, 1H), 7.30-7.36 (m, 2H), 4.91 (s, 2H), 4.72 (s, 2H), 4.46 (s, 2H), 3.65-3.69 (m, 2H), 3.52 (s, 3H), 3.32-3.38 (m, 2H), 3.06-3.13 (m, 2H), 2.98 (s, 3H), 1.91-2.03 (m, 3H), 1.57-1.69 (m, 2H). LCMS (ESI, m/z): 443 [M+H] + .
EX11制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(6-(甲氧基甲基)吡啶-3-基)-1-甲基脲.三氟乙酸(ER10301)
EX11 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(6-(methoxymethyl)pyridin-3-yl)-1-methylurea.Trifluoroacetic acid (ER10301)
在氮气和0℃下，向三光气(752mg，2.53mmol，0.5equiv)的DCM(10mL)溶液中加入6-(甲氧基甲基)吡啶-3-胺(700mg，5.07mmol，1.0equiv)和TEA(1.28g，12.7mmol，2.5equiv)的DCM(10mL)溶液。将所得混合物在室温下搅拌2小时。然后在0℃，加入1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.氯化氢(1.34g，5.07mmol，1.0equiv)和TEA(1.28g，12.7mmol，2.5equiv)的DCM(10mL)溶液。将所得混合物在室温搅拌过夜，用水(30mL)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。然后依次通过prep-TLC(DCM/MeOH＝10/1)和方法A条件下的prep- HPLC纯化残余物，得到1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(6-(甲氧基甲基)吡啶-3-基)-1-甲基脲.三氟乙酸(30.0mg,1.04％)，为淡黄色油状物。1H NMR(400MHz,DMSO_d6):δ9.82–9.80(m,1H),8.74–8.71(m,2H),8.16–8.07(m,3H),7.51–7.44(m,3H),5.07–5.01(m,2H),4.49(s,2H),3.56–3.53(m,1.5H),3.39-3.26(m,6H),3.07-2.98(m,4.5H),1.95–1.75(m,3H),1.63–1.57(m,2H).LC-MS(ESI,m/z):429.1[M+H]+。To a solution of triphosgene (752 mg, 2.53 mmol, 0.5 equiv) in DCM (10 mL) was added a solution of 6-(methoxymethyl)pyridin-3-amine (700 mg, 5.07 mmol, 1.0 equiv) and TEA (1.28 g, 12.7 mmol, 2.5 equiv) in DCM (10 mL) under nitrogen at 0°C. The resulting mixture was stirred at room temperature for 2 hours. Then, a solution of 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one.hydrogen chloride (1.34 g, 5.07 mmol, 1.0 equiv) and TEA (1.28 g, 12.7 mmol, 2.5 equiv) in DCM (10 mL) was added at 0°C. The resulting mixture was stirred at room temperature overnight, diluted with water (30 mL) and extracted with DCM (10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Then, the mixture was analyzed by prep-TLC (DCM/MeOH=10/1) and prep-TLC under the conditions of method A. The residue was purified by HPLC to give 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(6-(methoxymethyl)pyridin-3-yl)-1-methylurea trifluoroacetic acid (30.0 mg, 1.04%) as a light yellow oil. 1 H NMR (400 MHz, DMSO_d 6 ): δ 9.82–9.80 (m, 1H), 8.74–8.71 (m, 2H), 8.16–8.07 (m, 3H), 7.51–7.44 (m, 3H), 5.07–5.01 (m, 2H), 4.49 (s, 2H), 3.56–3.53 (m, 1.5H), 3.39-3.26 (m, 6H), 3.07-2.98 (m, 4.5H), 1.95–1.75 (m, 3H), 1.63–1.57 (m, 2H). LC-MS (ESI, m/z): 429.1 [M+H] + .
EX12制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(6-甲氧基吡啶-3-基)-1-甲基脲.三氟乙酸(ER10302)
EX12 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(6-methoxypyridin-3-yl)-1-methylurea.Trifluoroacetic acid (ER10302)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(6-甲氧基吡啶-3-基)-1-甲基脲.三氟乙酸在类似ER10301的条件下制备和纯化，以6-甲氧基吡啶-3-胺(103mg,0.832mmol,1.1equiv)和1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.氯化氢(200mg，0.757mmol，1.0equiv)为原料，得到所需产物(20.0mg，6.05％)，为淡黄色油状物。1H NMR(400MHz,DMSO_d6):δ9.78–9.76(m,1H),8.28(s,1H),8.20–8.19(m,1H),8.17–8.07(m,2H),7.78–7.75(m,1H),7.51–7.46(m,2H),6.76–6.72(m,1H),5.06–5.01(m,2H),3.80(s,3H),3.56–3.53(m,1.5H),3.36-3.17(m,3H),3.04-2.97(m,4.5H),1.92–1.75(m,3H),1.62–1.56(m,2H).LC-MS(ESI,m/z):415.1[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(6-methoxypyridin-3-yl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from 6-methoxypyridin-3-amine (103 mg, 0.832 mmol, 1.1 equiv) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one.hydrogen chloride (200 mg, 0.757 mmol, 1.0 equiv) to give the desired product (20.0 mg, 6.05%) as a light yellow oil. 1 H NMR (400 MHz, DMSO_d 6 ): δ9.78–9.76 (m, 1H), 8.28 (s, 1H), 8.20–8.19 (m, 1H), 8.17–8.07 (m, 2H), 7.78–7.75 (m, 1H), 7.51–7.46 (m, 2H), 6.76–6.72 (m, 1H), 5.06–5.01 (m, 2H), 3.80 (s, 3H), 3.56–3.53 (m, 1.5H), 3.36-3.17 (m, 3H), 3.04-2.97 (m, 4.5H), 1.92–1.75 (m, 3H), 1.62–1.56 (m, 2H). LC-MS (ESI, m/z): 415.1 [M+H] + .
EX13制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苯基)-1-甲基脲.三氟乙酸(ER10274)
EX13 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-(methoxymethyl)phenyl)-1-methylurea.trifluoroacetic acid (ER10274)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苯基)-1-甲基脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以4-(甲氧基甲基)苯胺(104mg，0.76mmol，1.0equiv)和1-(4-氟苯基)-2-{4-[(甲基氨基)甲基]哌啶-1-基}乙酮(200mg，0.76mmol，1.0equiv)为原料，得到所需产物(57.3mg，产率9％)，为白色固体，1H NMR(300MHz,CD3OD)δ8.09-8.22(m,2H),7.23-7.64(m,6H),4.89-4.96(m,2H),4.39(s,2H),3.66-3.70(m,2H),3.29-3.58(m,5H),2.90-3.24(m,5H),1.86-2.27(m,3H),1.63-1.87(m,2H).LC-MS(ESI,m/z):428[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-(methoxymethyl)phenyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from 4-(methoxymethyl)aniline (104 mg, 0.76 mmol, 1.0 equiv) and 1-(4-fluorophenyl)-2-{4-[(methylamino)methyl]piperidin-1-yl}ethanone (200 mg, 0.76 mmol, 1.0 equiv) to give the desired product (57.3 mg, 9% yield) as a white solid, 1 H NMR (300 MHz, CD 3 OD) δ8.09-8.22 (m, 2H), 7.23-7.64 (m, 6H), 4.89-4.96 (m, 2H), 4.39 (s, 2H), 3.66-3.70 (m, 2H), 3.29-3.58 (m, 5H), 2.90-3.24 (m, 5H), 1.86-2.27 (m, 3H), 1.63-1.87 (m, 2H). LC-MS (ESI, m/z): 428 [M+H] + .
EX14制备3-((6-(乙氧基甲基)吡啶-3-基)甲基)-1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸(ER10311)
EX14 Preparation of 3-((6-(ethoxymethyl)pyridin-3-yl)methyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.trifluoroacetic acid (ER10311)
3-((6-(乙氧基甲基)吡啶-3-基)甲基)-1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙 酸在与ER10301类似的条件下制备和纯化，以(6-(乙氧基甲基)吡啶-3-基)甲胺(400mg，2.41mmol，1.1equiv)和1-(4-氟苯基)-2-(4-((甲氨基)甲基)哌啶-1-基)乙-1-酮.氯化氢(658mg，2.19mmol，1.0equiv)得到所需产物(90.0mg，9.02％)，为淡黄色油状物，1H NMR(400MHz,DMSO_d6):δ9.86–9.82(m,1H),8.51(s,1H),8.16–8.07(m,2H),7.92–7.90(m,1H),7.57–7.47(m,3H),7.05–7.02(m,1H),5.01(s,2H),4.58(s,2H),4.29(d,J＝5.2Hz,2H),3.59–3.52(m,3H),3.28-3.26(m,1.5H),3.17–3.16(m,1.5H),3.04–2.99(m,1.5H),2.87(s,3H),1.86–1.72(m,3H),1.58–1.51(m,2H),1.20–1.67(m,3H).LC-MS(ESI,m/z):457.1[M+H]+。3-((6-(ethoxymethyl)pyridin-3-yl)methyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.Trifluoroethyl The acid was prepared and purified under similar conditions to ER10301 with (6-(ethoxymethyl)pyridin-3-yl)methanamine (400 mg, 2.41 mmol, 1.1 equiv) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one.hydrochloric acid (658 mg, 2.19 mmol, 1.0 equiv) to give the desired product (90.0 mg, 9.02%) as a light yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ):δ9.86–9.82(m,1H),8.51(s,1H),8.16–8.07(m,2H),7.92–7.90(m,1H),7.57–7.47(m,3H),7.05–7.02(m,1H),5.01(s,2H),4.58(s,2H),4.29(d,J＝5.2Hz,2H),3.59–3.52 (m, 3H), 3.28-3.26 (m, 1.5H), 3.17–3.16 (m, 1.5H), 3.04–2.99 (m, 1.5H), 2.87 (s, 3H), 1.86–1.72 (m, 3H), 1.58–1.51 (m, 2H), 1.20–1.67 (m, 3H). LC-MS (ESI, m/z): 457.1 [M+H] + .
EX15制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-((2-甲基恶唑-4-基)甲基)脲.2,2,2.三氟乙酸(ER10371)
EX15 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((2-methyloxazol-4-yl)methyl)urea. 2,2,2.Trifluoroacetic acid (ER10371)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-((2-甲基恶唑-4-基)甲基)脲.2,2,2.三氟乙酸在与ER10301类似的条件下制备和纯化，以1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.盐酸盐(1.01g，3.37mmol)和(2-甲基恶唑-4-基)甲胺(500mg，3.37mmol)为原料，得到所需产物(20.0mg，0.35％)，为无色油状物，1H NMR(400MHz,DMSO_d6)δ9.71(brs,1H),8.14-8.06(m,2H),7.64-7.65(m,1H),7.51-7.46(m,2H),6.67(m,1H),5.03-4.99(m,2H),4.06-4.0(m,2H),3.53-3.50(m,1.5H),3.25-3.24(m,1H),3.15-3.13(m,1.5H),3.01-2.98(m,2H),2.83-2.82(m,3H),2.36-2.35(m,3H),1.79-1.71(m,3H),1.56-1.49(m,2H).LC-MS(ESI,m/z):403.3[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((2-methyloxazol-4-yl)methyl)urea.2,2,2.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one.hydrochloride (1.01 g, 3.37 mmol) and (2-methyloxazol-4-yl)methanamine (500 mg, 3.37 mmol) to give the desired product (20.0 mg, 0.35%) as a colorless oil, 1 H NMR (400 MHz, DMSO-d 6 )δ9.71(brs,1H),8.14-8.06(m,2H),7.64-7.65(m,1H),7.51-7.46(m,2H),6.67(m,1H),5.03-4.99(m,2H),4.06-4.0(m,2H),3.53-3.50(m,1.5H),3.25-3.24(m,1H),3.15-3.13(m,1.5H),3.01-2.98(m,2H),2.83-2.82(m,3H),2.36-2.35(m,3H),1.79-1.71(m,3H),1.56-1.49(m,2H).LC-MS(ESI,m/z):403.3[M+H] + .
EX16制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((6-甲氧基吡啶-3-基)甲基)-1-甲基脲.三氟乙酸(ER10312)
EX16 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((6-methoxypyridin-3-yl)methyl)-1-methylurea.Trifluoroacetic acid (ER10312)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((6-甲氧基吡啶-3-基)甲基)-1-甲基脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以(6-甲氧基吡啶-3-基)甲胺(57.5mg，0.416mmol，1.1equiv)和1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.氯化氢(100mg，0.378mmol，1.0equiv)为原料，得到所需产物(30.0mg，13.9％)，为淡黄色油状物，1H NMR(400MHz,DMSO_d6):δ9.78–9.76(m,1H),8.16–8.04(m,3H),7.63–7.59(m,1H),7.51–7.46(m,2H),6.88–6.85(m,1H),6.78–6.74(m,1H),5.04–5.00(m,2H),4.17–4.16(m,2H),3.82(s,3H),3.54–3.51(m,1.5H),3.27-3.25(m,1.5H),3.16–3.14(m,1.5H),3.04–2.96(m,1.5H),2.84(s,3H),1.85–1.71(m,3H),1.57–1.48(m,2H).LC-MS(ESI,m/z):429.1[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((6-methoxypyridin-3-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from (6-methoxypyridin-3-yl)methanamine (57.5 mg, 0.416 mmol, 1.1 equiv) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one.hydrogen chloride (100 mg, 0.378 mmol, 1.0 equiv) to give the desired product (30.0 mg, 13.9%) as a light yellow oil, 1 H NMR (400 MHz, DMSO-d 6 ):δ9.78–9.76(m,1H),8.16–8.04(m,3H),7.63–7.59(m,1H),7.51–7.46(m,2H),6.88–6.85(m,1H),6.78–6.74(m,1H),5.04–5.00(m,2H),4.17–4.16(m,2H),3.82(s,3H) ,3.54–3.51(m,1.5H),3.27-3.25(m,1.5H),3.16–3.14(m,1.5H),3.04–2.96(m,1.5H),2.84(s,3H),1.85–1.71(m,3H),1.57–1.48(m,2H).LC-MS(ESI,m/z):429.1[M+H] + .
EX17制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(4-甲氧基苄基)-1-甲基脲.三氟乙酸(ER10313)
EX17 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-methoxybenzyl)-1-methylurea.trifluoroacetic acid (ER10313)
1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-3-(4-甲氧基苄基)-1-甲基脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以(4-甲氧基苯基)甲胺(57.1mg，0.416mmol，1.1equiv)和1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.氯化氢(100mg，0.378mmol，1.0equiv)为原料，得到所需产物(25.0mg，14.7％)，为白色固体，1H NMR(400MHz,DMSO_d6):δ9.78–9.76(m,1H),8.16–8.06(m,2H),7.51–7.47(m,2H),7.19–7.16(m,2H),6.87–6.79(m,3H),5.04–5.00(m,2H),4.18–4.16(m,2H),3.72(s,3H),3.54–3.51(m,1.5H),3.28-3.26(m,1.5H),3.17–3.15(m,1.5H),3.05–2.96(m,1.5H),2.84(s,3H),1.85–1.71(m,3H),1.57–1.48(m,2H).LC-MS(ESI,m/z):428.1[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-methoxybenzyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from (4-methoxyphenyl)methanamine (57.1 mg, 0.416 mmol, 1.1 equiv) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one.hydrogen chloride (100 mg, 0.378 mmol, 1.0 equiv) to give the desired product (25.0 mg, 14.7%) as a white solid, 1 H NMR (400 MHz, DMSO-d 6 ):δ9.78–9.76(m,1H),8.16–8.06(m,2H),7.51–7.47(m,2H),7.19–7.16(m,2H),6.87–6.79(m,3H),5.04–5.00(m,2H),4.18–4.16(m,2H),3.72(s,3H),3.54–3.51(m,1.5H),3.28-3.26(m,1.5H),3.17–3.15(m,1.5H),3.05–2.96(m,1.5H),2.84(s,3H),1.85–1.71(m,3H),1.57–1.48(m,2H).LC-MS(ESI,m/z):428.1[M+H] + .
EX18制备3-(5-(乙氧基甲基)吡啶-2-基)-1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸(ER10303)
EX18 Preparation of 3-(5-(ethoxymethyl)pyridin-2-yl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.Trifluoroacetic acid (ER10303)
3-(5-(乙氧基甲基)吡啶-2-基)-1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以5-(乙氧基甲基)吡啶-2-胺(1.20g，7.90mmol，1.0equiv)和1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.氯化氢(2.09g，7.90mmol，1.0equiv)为原料，得到所需产物(25.0mg，0.716％)，为淡黄色固体，1H NMR(400MHz,DMSO_d6):δ9.84–9.82(m,1H),9.37–9.31(m,1H),8.22–8.07(m,3H),7.86–7.79(m,2H),7.51–7.46(m,2H),5.24–5.16(m,2H),4.44(s,2H),3.56–3.47(m,3H),3.41–3.32(m,3H),3.30–3.05(m,5H),1.96–1.76(m,3H),1.72–1.54(m,2H),1.19–1.08(m,3H).LC-MS(ESI,m/z):443.1[M+H]+。3-(5-(Ethoxymethyl)pyridin-2-yl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under conditions similar to ER10301 starting from 5-(ethoxymethyl)pyridin-2-amine (1.20 g, 7.90 mmol, 1.0 equiv) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one.hydrogen chloride (2.09 g, 7.90 mmol, 1.0 equiv) to give the desired product (25.0 mg, 0.716%) as a light yellow solid, 1 H NMR (400 MHz, DMSO-d 6 ):δ9.84–9.82(m,1H),9.37–9.31(m,1H),8.22–8.07(m,3H),7.86–7.79(m,2H),7.51–7.46(m,2H),5.24–5.16(m,2H),4.44(s,2H),3.56–3.47(m,3H),3.41–3.32(m,3H),3.30–3.05(m,5H),1.96–1.76(m,3H),1.72–1.54(m,2H),1.19–1.08(m,3H).LC-MS(ESI,m/z):443.1[M+H] + .
EX19制备3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-1-苯基脲.三氟乙酸(ER10314)
EX19 Preparation of 3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-1-phenylurea.Trifluoroacetic acid (ER10314)
3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-1-苯基脲.三氟乙酸在类似于ER10301的条件下制备和纯化。以2-(4-(氨甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮.氯化氢(100mg，0.400mmol，1.0equiv)和N-甲基苯胺(47.1mg，0.439mmol，1.1equiv)为原料，得到所需的产品(45.0mg，29.4％)，为浅黄色油状物，1H NMR(400MHz,DMSO_d6):δ9.99–9.97(m,1H),8.17-8.07(m,2H),7.51–7.46(m,2H),7.41–7.37(m,2H),7.29–7.21(m,3H),6.19–6.18(m,1H),5.07–5.04(m,2H),3.55–3.52(m,2H),3.29–3.27(m,1H),3.16(s,3H),3.07-2.94(m,4H),1.82–1.73(m,3H),1.57–1.51(m,2H).LC-MS(ESI,m/z):384.1[M+H]+。3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-1-phenylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 . Starting from 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one.hydrogen chloride (100 mg, 0.400 mmol, 1.0 equiv) and N-methylaniline (47.1 mg, 0.439 mmol, 1.1 equiv) the desired product (45.0 mg, 29.4%) was obtained as a light yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ):δ9.99–9.97(m,1H),8.17-8.07(m,2H),7.51–7.46(m,2H),7.41–7.37(m,2H),7.29–7.21(m,3H),6.19–6.18(m,1H),5.07–5.04(m,2H),3.55–3.52(m,2H),3.29–3.27(m,1H),3.16(s,3H),3.07-2.94(m,4H),1.82–1.73(m,3H),1.57–1.51(m,2H).LC-MS(ESI,m/z):384.1[M+H] + .
EX20制备3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-1-(吡啶-2-基)脲.三氟乙酸(ER10315)
EX20 Preparation of 3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-1-(pyridin-2-yl)urea.Trifluoroacetic acid (ER10315)
3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-1-(吡啶-2-基)脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以N-甲基吡啶-2-胺(47.5mg，0.439mmol，1.1equiv)和2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮.氯化氢(100mg，0.400mmol，1.0equiv)为原料，得到所需产物(45.0mg，29.4％)，为淡黄色油状物。1H NMR(400MHz,DMSO_d6):δ9.85–9.83(m,1H),9.55–9.53(m,1H),8.35–8.34(m,1H),8.15–8.07(m,2H),7.85–7.81(m,1H),7.51–7.46(m,2H),7.31–7.29(m,1H),7.10–7.07(m,1H),5.07–5.01(m,2H),3.55–3.52(m,1.5H),3.32–3.25(m,4H),3.19–3.17(m,2H),3.05–3.00(m,1.5H),1.90–1.80(m,3H),1.64–1.58(m,2H).LC-MS(ESI,m/z):385.1[M+H]+.3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-1-(pyridin-2-yl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from N-methylpyridin-2-amine (47.5 mg, 0.439 mmol, 1.1 equiv) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one.hydrogen chloride (100 mg, 0.400 mmol, 1.0 equiv) to give the desired product (45.0 mg, 29.4%) as a light yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ):δ9.85–9.83(m,1H),9.55–9.53(m,1H),8.35–8.34(m,1H),8.15–8.07(m,2H),7.85–7.81(m,1H),7.51–7.46(m,2H),7.31–7.29(m,1H),7.10–7.07(m,1H),5.07– 5.01 (m, 2H), 3.55–3.52 (m, 1.5H), 3.32–3.25 (m, 4H), 3.19–3.17 (m, 2H), 3.05–3.00 (m, 1.5H), 1.90–1.80 (m, 3H), 1.64–1.58 (m, 2H). LC-MS (ESI, m/z): 385.1 [M+H] + .
EX21制备3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-(6-甲氧基吡啶-2-基)-1-甲基脲.三氟乙酸(ER10331)
EX21 Preparation of 3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-(6-methoxypyridin-2-yl)-1-methylurea.Trifluoroacetic acid (ER10331)
3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-(6-甲氧基吡啶-2-基)-1-甲基脲.三氟乙酸在与ER10301类似的条件下制备和纯化，以6-甲氧基-N-甲基吡啶-2-胺(121mg，0.879mmol，1.0equiv)和2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg，0.799mmol，1.0equiv)为原料，得到所需产物(50.0mg，13.6％)，为淡黄色油状物，1H NMR(400MHz,DMSO_d6):δ9.73(s,1H),9.02–8.99(m,1H),8.16-8.06(m,2H),7.75-7.71(m,1H),751.10–7.47(m,2H),6.85–6.81(m,1H),6.53–6.51(m,1H),5.06-5.00(m,2H),3.86–3.85(m,3H),3.54–3.51(m,1.5H),3.30-3.17(m,5.5H),3.07-2.99(m,2H),1.92–1.81(m,3H),1.61–1.53(m,2H).LC-MS(ESI,m/z):415.1[M+H]+.。3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-(6-methoxypyridin-2-yl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from 6-methoxy-N-methylpyridin-2-amine (121 mg, 0.879 mmol, 1.0 equiv) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.799 mmol, 1.0 equiv) to give the desired product (50.0 mg, 13.6%) as a light yellow oil, 1 H NMR (400 MHz, DMSO-d 6 ):δ9.73(s,1H),9.02–8.99(m,1H),8.16-8.06(m,2H),7.75-7.71(m,1H),751.10–7.47(m,2H),6.85–6.81(m,1H),6.53–6.51(m,1H),5.06-5.00(m,2H),3.86–3.85(m,3H),3.54–3.51(m,1.5H),3.30-3.17(m,5.5H),3.07-2.99(m,2H),1.92–1.81(m,3H),1.61–1.53(m,2H).LC-MS(ESI,m/z):415.1[M+H] + .
EX22制备3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-1-(6-甲基吡啶-2-基)脲.三氟乙酸(ER10332)
EX22 Preparation of 3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-1-(6-methylpyridin-2-yl)urea.Trifluoroacetic acid (ER10332)
3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-1-(6-甲基吡啶-2-基)脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以N,6-二甲基吡啶-2-胺(42.6mg，0.349mmol，1.0equiv)和2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮.盐酸盐(100mg，0.399mol，1.0equiv)为原料，得到所需产物(33.0mg，18.5％)，为淡黄色油状物，1H NMR(400MHz,DMSO_d6):δ9.97-9.94(m,1H),9.76–9.74(m,1H),8.17-8.06(m,2H),7.75-7.71(m,1H),7.51–7.47(m,2H),7.06–6.97(m,1H),6.96–6.94(m,1H),5.07-5.00(m,2H),3.55–3.52(m,1.5H),3.29–3.19(m,4H),3.09-3.06(m,1.5H),3.03-3.00(m,2H),2.46-2.40(m, 2H),236–2.34(m,1H)1.92–1.72(m,3H),1.65–1.56(m,2H).LC-MS(ESI,m/z):399.2[M+H]+。3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-1-(6-methylpyridin-2-yl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from N,6-dimethylpyridin-2-amine (42.6 mg, 0.349 mmol, 1.0 equiv) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one.hydrochloride (100 mg, 0.399 mol, 1.0 equiv) to give the desired product (33.0 mg, 18.5%) as a light yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ):δ9.97-9.94(m,1H),9.76–9.74(m,1H),8.17-8.06(m,2H),7.75-7.71(m,1H),7.51–7.47(m,2H),7.06–6.97(m,1H),6.96–6.94(m,1H),5.07-5.00(m,2H),3.55–3.52(m,1.5H),3.29–3.19(m,4H),3.09-3.06(m,1.5H),3.03-3.00(m,2H),2.46-2.40(m, 2H), 236–2.34 (m, 1H) 1.92–1.72 (m, 3H), 1.65–1.56 (m, 2H). LC-MS (ESI, m/z): 399.2 [M+H] + .
EX23制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-(吡啶-3-基甲基)脲.三氟乙酸(ER10333)
EX23 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-(pyridin-3-ylmethyl)urea.Trifluoroacetic acid (ER10333)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-(吡啶-3-基甲基)脲.三氟乙酸在与ER10301相似条件下制备和纯化，以吡啶-3-基甲胺(45.0mg，0.416mmol)和1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮(100mg，0.378mmol)为原料，得到所需产物(65mg，33.6％)，为淡黄色油状物。1H NMR(400MHz,DMSO_d6)δ9.82-9.80(brs,1H),8.72(m,2H),8.24-8.22(m,1H),8.14-8.07(m,2H),7.85-7.82(m,1H),7.51-7.47(m,2H),7.14-7.11(m,1H),5.01(s,1H),4.37-4.36(m,2H),3.54-3.51(m,1.5H),3.27-3.15(m,4H),3.03(s,1H),1.85-1.71(m,3H),1.57-1.50(m,2H).LC-MS(ESI,m/z):399.2[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-(pyridin-3-ylmethyl)urea.trifluoroacetic acid was prepared and purified under similar conditions as ER10301 starting from pyridin-3-ylmethanamine (45.0 mg, 0.416 mmol) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one (100 mg, 0.378 mmol) to give the desired product (65 mg, 33.6%) as a light yellow oil. 1 H NMR (400 MHz, DMSO_d 6 ) δ 9.82-9.80 (brs, 1H), 8.72 (m, 2H), 8.24-8.22 (m, 1H), 8.14-8.07 (m, 2H), 7.85-7.82 (m, 1H), 7.51-7.47 (m, 2H), 7.14-7.11 (m, 1H), 5.01 (s, 1H), 4.37-4.36 (m, 2H), 3.54-3.51 (m, 1.5H), 3.27-3.15 (m, 4H), 3.03 (s, 1H), 1.85-1.71 (m, 3H), 1.57-1.50 (m, 2H). LC-MS (ESI, m/z): 399.2 [M+H]+.
EX24制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-(吡啶-2-基甲基)脲.三氟乙酸(ER10334)
EX24 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-(pyridin-2-ylmethyl)urea.Trifluoroacetic acid (ER10334)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-(吡啶-2-基甲基)脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮(100mg，0.332mmol)和吡啶-2-基甲胺(71.9mg，0.665mmol)为原料，得到所需产物(31.5mg，18.5％)，为黄色油状物，1H NMR(400MHz,DMSO_d6)δ9.72(s,1H),8.59-8.57(m,1H),8.10-7.98(m,2H),7.48-7.46(m,4H),7.06(m,1H),5.01-5.00(m,2H),4.41-4.39(m,2H),3.54-3.17(m,6H),2.91(s,3H),1.82-1.643(m,3H),1.51-1.24(m,2H).LC-MS(ESI,m/z):399.1[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-(pyridin-2-ylmethyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one (100 mg, 0.332 mmol) and pyridin-2-ylmethanamine (71.9 mg, 0.665 mmol) to give the desired product (31.5 mg, 18.5%) as a yellow oil, 1 H NMR (400 MHz, DMSO_d 6 )δ9.72(s,1H),8.59-8.57(m,1H),8.10-7.98(m,2H),7.48-7.46(m,4H),7.06(m,1H),5.01-5.00(m,2H),4.41-4.39(m,2H),3.54-3.17(m,6H),2.91(s,3H),1.82-1.643(m,3H),1.51-1.24(m,2H).LC-MS(ESI,m/z):399.1[M+H] + .
EX25 1制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-(噻唑-2-基甲基)脲.三氟乙酸(ER10335)
EX25 1 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-(thiazol-2-ylmethyl)urea.Trifluoroacetic acid (ER10335)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-(噻唑-2-基甲基)脲.三氟乙酸在类似于ER10301的条件下制备和纯化，利用1,3-噻唑-2-基甲胺二盐酸盐(229mg，1.22mmol)得到所需的黄色油状产物(60.0mg，9.45％)，1H NMR(400MHz,DMSO_d6)δ9.75(s,1H),8.14-8.07(m,2H),7.71-7.57(m,1H),7.49-7.29(m,4H),5.05-5.00(m,2H),4.51-4.49(m,2H),3.20-3.03(m,6H),2.99(s,3H),1.79-1.58(m,3H),1.53-1.24(m,2H).LC-MS(ESI,m/z):405.0[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-(thiazol-2-ylmethyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 using 1,3-thiazol-2-ylmethylamine dihydrochloride (229 mg, 1.22 mmol) to give the desired product as a yellow oil (60.0 mg, 9.45%), 1 H NMR (400 MHz, DMSO-d 6 )δ9.75(s,1H),8.14-8.07(m,2H),7.71-7.57(m,1H),7.49-7.29(m,4H),5.05-5.00(m,2H),4.51-4.49(m,2H),3.20-3.03(m,6H),2.99(s,3H),1.79-1.58(m,3H),1.53-1.24(m,2H).LC-MS(ESI,m/z):405.0[M+H] + .
EX26制备3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-((6-甲氧基吡啶-3-基)甲基)-1-甲基脲.三氟 乙酸(ER10336)
EX26 Preparation of 3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-((6-methoxypyridin-3-yl)methyl)-1-methylurea.Trifluoro Acetic acid (ER10336)
3-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-((6-甲氧基吡啶-3-基)甲基)-1-甲基脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以1-(6-甲氧基吡啶-3-基)-N-甲基甲胺(100mg,0.657mmol)为原料，得到所需产物(150mg，42.1％)，为黄色油状物，1H NMR(400MHz,DMSO_d6)δ9.70(s,1H),8.15-8.03(m,3H),7.57-7.47(m,3H),6.81-6.79(m,1H),6.56-6.54(m,1H),5.05-4.99(m,2H),4.35(s,1H),3.94-3.91(m,3H),3.27-3.25(m,2H),3.10-2.98(m,4H),1.85-1.72(m,5H).LC-MS(ESI,m/z):429.2[M+H]+。3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-((6-methoxypyridin-3-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301, starting from 1-(6-methoxypyridin-3-yl)-N-methylmethanamine (100 mg, 0.657 mmol) to give the desired product (150 mg, 42.1%) as a yellow oil, 1 H NMR (400 MHz, DMSO-d 6 )δ9.70(s,1H),8.15-8.03(m,3H),7.57-7.47(m,3H),6.81-6.79(m,1H),6.56-6.54(m,1H),5.05-4.99(m,2H),4.35(s,1H),3.94-3.91(m,3H),3.27-3.25(m,2H),3.10-2.98(m,4H),1.85-1.72(m,5H).LC-MS(ESI,m/z):429.2[M+H] + .
EX27制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-((6-甲基吡啶-2-基)甲基)脲.三氟乙酸(ER10337)
EX27 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((6-methylpyridin-2-yl)methyl)urea.Trifluoroacetic acid (ER10337)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-((6-甲基吡啶-2-基)甲基)脲.三氟乙酸在与ER10301类似的条件下制备和纯化，以1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮(500mg，1.53mmol)和(6-甲基吡啶-2-基)甲胺(187mg，1.53mmol)为原料，得到所需产物(35.0mg，4.34％)，为黄色油状物，1H NMR(400MHz,DMSO_d6)δ9.80(s,1H),8.13-8.07(m,3H),7.51-7.42(m,4H),7.17(s,1H),5.00(s,2H),4.41(s,2H),3.54-3.16(m,6H),2.91(s,3H),2.60(s,3H),1.77-1.56(m,3H),1.50-1.24(m,2H).LC-MS(ESI,m/z):413.2[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((6-methylpyridin-2-yl)methyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one (500 mg, 1.53 mmol) and (6-methylpyridin-2-yl)methanamine (187 mg, 1.53 mmol) to give the desired product (35.0 mg, 4.34%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ9.80(s,1H),8.13-8.07(m,3H),7.51-7.42(m,4H),7.17(s,1H),5.00(s,2H),4.41(s,2H),3.54-3.16(m,6H),2.91(s,3H),2.60(s,3H),1.77-1.56(m,3H),1.50-1.24(m,2H).LC-MS(ESI,m/z):413.2[M+H] + .
EX28制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-((5-甲基噻唑-2-基)甲基)脲.三氟乙酸(ER10338)
EX28 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((5-methylthiazol-2-yl)methyl)urea.Trifluoroacetic acid (ER10338)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-((5-甲基噻唑-2-基)甲基)脲.三氟乙酸在与ER10301类似的条件下制备和纯化，以N-({1-[2-(4-氟苯基)-2-氧乙基]哌啶-4-基}甲基)-N-甲基氨基甲酰氯(400mg，1.22mmol)和(5-甲基-1,3-噻唑-2-基)甲胺(157mg，1.22mmol)为原料，得到所需产物(90.0mg，13.8％)，为黄色油状物，1H NMR(400MHz,DMSO_d6)δ9.73(s,1H),8.01-8.06(m,2H),7.51-7.49(m,2H),7.47-7.32(m,4H),5.03-5.00(m,2H),4.41-4.39(m,2H),3.17-2.87(m,9H),2.38-2.33(m,3H),1.81-1.78(m,3H),1.55-1.52(m,2H).LC-MS(ESI,m/z):419.1[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((5-methylthiazol-2-yl)methyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from N-({1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}methyl)-N-methylcarbamoyl chloride (400 mg, 1.22 mmol) and (5-methyl-1,3-thiazol-2-yl)methanamine (157 mg, 1.22 mmol) to give the desired product (90.0 mg, 13.8%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ9.73(s,1H),8.01-8.06(m,2H),7.51-7.49(m,2H),7.47-7.32(m,4H),5.03-5.00(m,2H),4.41-4.39(m,2H),3.17-2.87(m,9H),2.38-2.33(m,3H),1.81-1.78(m,3H),1.55-1.52(m,2H).LC-MS(ESI,m/z):419.1[M+H] + .
EX29制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((2-甲氧基吡啶-3-基)甲基)-1-甲基脲.三氟乙酸(ER10339)
EX29 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((2-methoxypyridin-3-yl)methyl)-1-methylurea.Trifluoroacetic acid (ER10339)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((2-甲氧基吡啶-3-基)甲基)-1-甲基脲.三氟乙酸在类似于ER10301条件下制备和纯化，以(2-甲氧基吡啶-3-基)甲胺(50.0mg，0.362mmol)和1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮(109mg，0.362mmol)为原料，得到所需的产品(27.0mg，13.8％)，为黄色油状物，1H NMR(400MHz,DMSO_d6)δ9.77(s,1H),8.16-8.074(m,2H),8.04-8.02(m,1H),7.51-7.47(m,3H),6.98-6.94(m,1H),6.81-6.78(m,1H),5.04-5.00(m,2H),4.18-4.17(m,2H),3.90-3.89(m,3H),3.55-3.52(m,1.5H),3.29-3.27(m,1.5H),3.19-3.17(m,1.5H),3.03-3.00(m,1.5H),2.97-2.91(m,3H),1.87-1.73(m,3H),1.58-1.48(m,2H).LC-MS(ESI,m/z):429.1[M+H]+ 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((2-methoxypyridin-3-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 , starting from (2-methoxypyridin-3-yl)methanamine (50.0 mg, 0.362 mmol) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one (109 mg, 0.362 mmol) to give the desired product (27.0 mg, 13.8%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ9.77(s,1H),8.16-8.074(m,2H),8.04-8.02(m,1H),7.51-7.47(m,3H),6.98-6.94(m,1H),6.81-6.78(m,1H),5.04-5.00(m,2H),4.18-4.17(m,2H),3.90-3.89(m,3H),3 .55-3.52 (m, 1.5H), 3.29-3.27 (m, 1.5H), 3.19-3.17 (m, 1.5H), 3.03-3.00 (m, 1.5H), 2.97-2.91 (m, 3H), 1.87-1.73 (m, 3H), 1.58-1.48 (m, 2H). LC-MS (ESI, m/z): 429.1 [M+H] +
EX30制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((6-甲氧基吡啶-2-基)甲基)-1-甲基脲.三氟乙酸(ER10340)
EX30 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((6-methoxypyridin-2-yl)methyl)-1-methylurea.Trifluoroacetic acid (ER10340)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((6-甲氧基吡啶-2-基)甲基)-1-甲基脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮(200mg，0.665mmol)和(6-甲氧基吡啶-2-基)甲胺(184mg，1.33mmol)为原料，得到所需产物(40.0mg，11.1％)，为黄色油状物，1H NMR(400MHz,DMSO_d6)δ9.77(s,1H),8.13-8.07(m,2H),7.64-7.47(m,3H),6.83-6.82(m,2H),6.66-6.63(m,3H),5.33-5.01(m,2H),4.26-4.24(m,2H),3.84(s,3H),3.20-3.15(m,3H),3.05-2.92(m,6H),1.79-1.49(m,3H),1.24-1.07(m,2H).LC-MS(ESI,m/z):429.1[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((6-methoxypyridin-2-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one (200 mg, 0.665 mmol) and (6-methoxypyridin-2-yl)methanamine (184 mg, 1.33 mmol) to give the desired product (40.0 mg, 11.1%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ9.77(s,1H),8.13-8.07(m,2H),7.64-7.47(m,3H),6.83-6.82(m,2H),6.66-6.63(m,3H),5.33-5.01(m,2H),4.26-4.24(m,2H),3.84(s,3H),3.20-3.15(m,3H),3.05-2.92(m,6H),1.79-1.49(m,3H),1.24-1.07(m,2H).LC-MS(ESI,m/z):429.1[M+H] + .
EX31制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-((4-甲基噻唑-2-基)甲基)脲.三氟乙酸(ER10341)
EX31 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((4-methylthiazol-2-yl)methyl)urea.Trifluoroacetic acid (ER10341)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基-3-((4-甲基噻唑-2-基)甲基)脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以1-(4-氟苯基)-2-{4-[(甲基氨基)甲基]哌啶-1-基}乙酮.盐酸盐(0.55g，1.77mmol)和(4-甲基-1,3-噻唑-2-基)甲胺(196mg，1.53mmol)为原料，得到所需产物(50.0mg，6.14％)，为淡黄色油状物，1H NMR(400MHz,DMSO_d6)δ9.77(brs,1H),8.14–8.07(m,2H),7.48–7.47(m,2H),7.27–7.26(m,1H),7.24–7.09(m,1H),5.05–5.00(m,3H),4.45–4.43(m,2H),3.52–3.29(m,3H),3.18–3.03(m,3H),2.97(s,3H),2.31(s,3H),1.78–1.65(m,3H),1.59–1.49(m,2H).LC-MS(ESI,m/z):419.0[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((4-methylthiazol-2-yl)methyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301, starting from 1-(4-fluorophenyl)-2-{4-[(methylamino)methyl]piperidin-1-yl}ethanone.hydrochloride (0.55 g, 1.77 mmol) and (4-methyl-1,3-thiazol-2-yl)methanamine (196 mg, 1.53 mmol) to give the desired product (50.0 mg, 6.14%) as a light yellow oil, 1 H NMR (400 MHz, DMSO-d 6 )δ9.77(brs,1H),8.14–8.07(m,2H),7.48–7.47(m,2H),7.27–7.26(m,1H),7.24–7.09(m,1H),5.05–5.00(m,3H),4.45–4.43(m,2H),3.52–3.29(m,3H),3.18–3.03(m,3H),2.97(s,3H),2.31(s,3H),1.78–1.65(m,3H),1.59–1.49(m,2H).LC-MS(ESI,m/z):419.0[M+H] + .
EX32制备1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((6-甲基吡啶-3-基)甲基)脲.三氟乙酸(ER10342)
EX32 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((6-methylpyridin-3-yl)methyl)urea.Trifluoroacetic acid (ER10342)
1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((6-甲基吡啶-3-基)甲基)脲.三氟乙酸在与ER10301类似的条件下制备和纯化，以(6-甲基吡啶-3-基)甲胺(50.0mg，0.409mmol)和1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮(123mg，0.409mmol)为原料，得到所需产物为浅黄色油状物，1H NMR(400MHz,DMSO_d6)δ9.79(brs,1H),8.53(s,1H),8.10-8.06(m,2H),8.01(s,1H),7.60-7.59(m,1H),7.51-7.47(m,2H),7.05-7.02(m,1H),5.00(s,2H),4.30-4.28(m,2H),3.53-3.50(m,1.5H),3.27-3.24(m,1.5H),3.16-3.14(m,1.5H),3.03-2.99(m,1.5H),2.86(s,3H),2.59-2.50(m,3H),1.79-1.76(m,3H),1.53-1.49(m,2H).LC-MS(ESI,m/z):413.1[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((6-methylpyridin-3-yl)methyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301, starting from (6-methylpyridin-3-yl)methanamine (50.0 mg, 0.409 mmol) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one (123 mg, 0.409 mmol) to give the desired product as a light yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ9.79(brs,1H),8.53(s,1H),8.10-8.06(m,2H),8.01(s,1H),7.60-7.59(m,1H),7.51-7.47(m,2H),7.05-7.02(m,1H),5.00(s,2H),4.30-4.28(m,2H),3.53-3.50(m,1. 5H), 3.27-3.24 (m, 1.5H), 3.16-3.14 (m, 1.5H), 3.03-2.99 (m, 1.5H), 2.86 (s, 3H), 2.59-2.50 (m, 3H), 1.79-1.76 (m, 3H), 1.53-1.49 (m, 2H). LC-MS (ESI, m/z): 413.1 [M+H] + .
EX33制备1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-3-((5-甲氧基吡啶-2-基)甲基)-1-甲基脲.三氟乙酸(ER10343)
EX33 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((5-methoxypyridin-2-yl)methyl)-1-methylurea.Trifluoroacetic acid (ER10343)
1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-3-((5-甲氧基吡啶-2-基)甲基)-1-甲基脲.三氟乙酸在与ER10301类似的条件下制备和纯化，以N-({1-[2-(4-氟苯基)-2-氧乙基]哌啶-4-基}甲基)-N-甲基氨基甲酰氯(500mg,1.53mmol)和(5-甲氧基吡啶-2-基)甲胺(211mg，1.53mmol)为原料，得到所需产物(30.0mg，3.61％)，为淡黄色油状物，1H NMR(400MHz,DMSO_d6)δ9.76(brs,1H),8.25(s,1H),8.12–8.07(m,2H),7.49–7.33(m,3H),7.29(s,1H),6.97(s,1H),5.00(s,2H),4.31–4.29(m,2H),3.84–3.82(m,3H),3.51–3.16(m,6H),2.97(s,3H),1.78–1.57(m,3H),1.51–1.23(m,2H).LC-MS(ESI,m/z):429.2[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((5-methoxypyridin-2-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301, starting from N-({1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}methyl)-N-methylcarbamoyl chloride (500 mg, 1.53 mmol) and (5-methoxypyridin-2-yl)methanamine (211 mg, 1.53 mmol) to give the desired product (30.0 mg, 3.61%) as a light yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ9.76(brs,1H),8.25(s,1H),8.12–8.07(m,2H),7.49–7.33(m,3H),7.29(s,1H),6.97(s,1H),5.00(s,2H),4.31–4.29(m,2H),3.84–3.82(m,3H),3.51–3.16(m,6H),2.97(s,3H),1.78–1.57(m,3H),1.51–1.23(m,2H).LC-MS(ESI,m/z):429.2[M+H] + .
EX34制备1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((2-甲基吡啶-3-基)甲基)脲.三氟乙酸(ER10346)
EX34 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((2-methylpyridin-3-yl)methyl)urea.Trifluoroacetic acid (ER10346)
1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((2-甲基吡啶-3-基)甲基)脲.三氟乙酸在与ER10301类似的条件下制备和纯化，以(2-甲基吡啶-3-基)甲胺(50.0mg，0.409mmol)和1-(4-氟苯基)-2-{4-[(甲基氨基)甲基]哌啶-1-基}乙酮.盐酸盐(123mg，0.409mmol)得到所需产物(35.0mg，16.2％)，为黄色油状物，1H NMR(400MHz,DMSO_d6)δ9.92(brs,1H),8.60–8.59(s,1H),8.13–8.09(m,3H),7.72–7.68(m,1H),7.51–7.46(m,2H),7.09–7.06(m,1H),5.01(s,2H),4.31–4.30(m,2H),3.54–3.51(m,1.5H),3.27–3.16(m,3H),3.01(m,1.5H),2.67(m,3H),2.51(m,3H),1.80–1.76(m,3H),1.53–1.51(m,2H).LC-MS(ESI,m/z):413.1[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((2-methylpyridin-3-yl)methyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 with (2-methylpyridin-3-yl)methanamine (50.0 mg, 0.409 mmol) and 1-(4-fluorophenyl)-2-{4-[(methylamino)methyl]piperidin-1-yl}ethanone.hydrochloride (123 mg, 0.409 mmol) to give the desired product (35.0 mg, 16.2%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ9.92(brs,1H),8.60–8.59(s,1H),8.13–8.09(m,3H),7.72–7.68(m,1H),7.51–7.46(m,2H),7.09–7.06(m,1H),5.01(s,2H),4.31–4.30(m,2H),3.54–3.51(m,1.5H),3.27–3.16(m,3H),3.01(m,1.5H),2.67(m,3H),2.51(m,3H),1.80–1.76(m,3H),1.53–1.51(m,2H).LC-MS(ESI,m/z):413.1[M+H] + .
EX35制备1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((5-甲基吡啶-2-基)甲基)脲.三氟乙酸 (ER10347)
EX35 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((5-methylpyridin-2-yl)methyl)urea.Trifluoroacetic acid (ER10347)
1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((5-甲基吡啶-2-基)甲基)脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以1-(4-氟苯基)-2-{4-[(甲基氨基)甲基]哌啶-1-基}乙酮盐酸盐(200mg，0.665mmol)和(5-甲基吡啶)-2-基)甲胺(162mg，1.33mmol)为原料，得到所需产物(22.0mg，6.28％)，为黄色油状物，1H NMR(400MHz,DMSO_d6)δ9.78(brs,1H),8.57(s,1H),8.08(m,3H),7.59(m,1H),7.49(m,2H),7.17(m,1H),5.01(s,2H),4.43(s,2H),3.51(m,3H),3.15(m,3H),2.90(m,3H),2.40(m,3H),1.77(m,3H),1.49(m,2H).LC-MS(ESI,m/z):413.1[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((5-methylpyridin-2-yl)methyl)urea.trifluoroacetic acid was prepared and purified under conditions similar to ER10301 starting from 1-(4-fluorophenyl)-2-{4-[(methylamino)methyl]piperidin-1-yl}ethanone hydrochloride (200 mg, 0.665 mmol) and (5-methylpyridin-2-yl)methanamine (162 mg, 1.33 mmol) to give the desired product (22.0 mg, 6.28%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ9.78(brs,1H),8.57(s,1H),8.08(m,3H),7.59(m,1H),7.49(m,2H),7.17(m,1H),5.01(s,2H),4.43(s,2H),3.51(m,3H),3.15(m,3H),2.90(m,3H),2.40(m,3H),1.77(m,3H),1.49(m,2H).LC-MS(ESI,m/z):413.1[M+H] + .
EX36制备1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((2-甲基噻唑-5-基)甲基)脲.三氟乙酸(ER10368)
EX36 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((2-methylthiazol-5-yl)methyl)urea.Trifluoroacetic acid (ER10368)
1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((2-甲基噻唑-5-基)甲基)脲.三氟乙酸在与ER10301相似的条件下通过制备和纯化，以1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.盐酸盐(1.03g，1.95mol)和(2-甲基噻唑-5-基)甲胺(500mg，3.90mmol)为原料，得到所需产物(40mg，2.41％)，为浅黄色固体，1H NMR(400MHz,DMSO_d6)δ9.81(brs,1H),8.14-8.06(m,2H),7.50-7.46(m,2H),7.44(s,1H),7.00-6.98(m,1H),5.06-5.00(m,2H),3.54-3.51(m,1.5H),3.29-3.25(m,1.5H),3.16-3.14(m,1.5H),3.02-2.99(m,1.5H),2.81(s,3H),2.58-2.57(m,3H),1.95-1.75(m,3H),1.63-1.48(m,2H).LC-MS(ESI,m/z):419.0[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((2-methylthiazol-5-yl)methyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one.hydrochloride (1.03 g, 1.95 mol) and (2-methylthiazol-5-yl)methanamine (500 mg, 3.90 mmol) to give the desired product (40 mg, 2.41%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ9.81(brs,1H),8.14-8.06(m,2H),7.50-7.46(m,2H),7.44(s,1H),7.00-6.98(m,1H),5.06-5.00(m,2H),3.54-3.51(m,1.5H),3.29-3.25(m,1.5H),3.16-3.14(m,1.5H),3.02-2.99(m,1.5H),2.81(s,3H),2.58-2.57(m,3H),1.95-1.75(m,3H),1.63-1.48(m,2H).LC-MS(ESI,m/z):419.0[M+H] + .
EX37制备1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((2-甲基恶唑-5-基)甲基)脲.三氟乙酸(ER10369)
EX37 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((2-methyloxazol-5-yl)methyl)urea.Trifluoroacetic acid (ER10369)
1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((2-甲基恶唑-5-基)甲基)脲.三氟乙酸在与ER10301相似的条件下通过制备和纯化，以1-(4-氟苯基)-2-{4-[(甲基氨基)甲基]哌啶-1-基}乙酮(1.88g，6.24mmol)和(2-甲基-1,3-恶唑-5-基)甲胺(700mg，6.24mmol)为原料，得到所需产物(30.0mg，1.20％)，为无色油状物，1H NMR(400MHz,DMSO_d6)δ9.77(brs,1H),8.16-8.12(m,0.5H),8.10-8.06(m,1.5H),7.50-7.46(m,2H),6.83-6.81(m,1H),6.75-6.74(m,1H),5.04-5.03(m,0.5H),5.01-4.99(m,1.5H),4.22-4.21(m,2H),3.54-3.51(m,1.5H),3.28-3.24(m,1.5H),3.16-3.14(m,1.5H),3.04-2.96(m,1.5H),2.83-2.82(m,3H),2.36-2.34(m,3H),1.84-1.71(m,3H),1.57-1.48(m,2H).LC-MS(ESI,m/z):403.2[M+H]+. 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((2-methyloxazol-5-yl)methyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from 1-(4-fluorophenyl)-2-{4-[(methylamino)methyl]piperidin-1-yl}ethanone (1.88 g, 6.24 mmol) and (2-methyl-1,3-oxazol-5-yl)methanamine (700 mg, 6.24 mmol) to give the desired product (30.0 mg, 1.20%) as a colorless oil, 1 H NMR (400 MHz, DMSO-d 6 )δ9.77(brs,1H),8.16-8.12(m,0.5H),8.10-8.06(m,1.5H),7.50-7.46(m,2H),6.83-6.81(m,1H),6.75-6.74(m,1H),5.04-5.03(m,0.5H),5.01-4.99(m,1.5H),4.22-4.21(m,2H),3.54- 3.51 (m, 1.5H), 3.28-3.24 (m, 1.5H), 3.16-3.14 (m, 1.5H), 3.04-2.96 (m, 1.5H), 2.83-2.82 (m, 3H), 2.36-2.34 (m, 3H), 1.84-1.71 (m, 3H), 1.57-1.48 (m, 2H). LC-MS (ESI, m/z): 403.2 [M+H] + .
EX38制备1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((2-甲基噻唑-4-基)甲基)脲.三氟乙酸(ER10370)
EX38 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((2-methylthiazol-4-yl)methyl)urea.Trifluoroacetic acid (ER10370)
1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基-3-((2-甲基噻唑-4-基)甲基)脲.三氟乙酸在与ER10301相似的条件下通过制备和纯化，以1-(4-氟苯基)-2-{4-[(甲基氨基)甲基]哌啶-1-基}乙酮(2.20g，7.32mmol)和(2-甲基噻唑-4-基)甲胺为原料，得到所需产物(42.0mg，1.64％)，为无色油状物，1H NMR(400MHz,DMSO_d6):δ9.81(brs,1H),8.14-8.07(m,2H),7.48-7.46(m,2H),7.07-7.05(m,1H),6.85(s,1H),6.66-6.64(m,1H),5.04-5.00(m,2H),4.28-4.27(m,2H),3.55-3.52(m,1.5H),3.27-3.28(m,1.5H),3.17-3.16(m,1.5H),3.06-2.97(m,1.5H),2.87(m,3H),2.62-2.61(m,3H),1.97-1.73(m,3H),1.64-1.49(m,2H).LC-MS(ESI,m/z):419.0[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methyl-3-((2-methylthiazol-4-yl)methyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from 1-(4-fluorophenyl)-2-{4-[(methylamino)methyl]piperidin-1-yl}ethanone (2.20 g, 7.32 mmol) and (2-methylthiazol-4-yl)methanamine to give the desired product (42.0 mg, 1.64%) as a colorless oil. 1 H NMR (400 MHz, DMSO-d 6 ):δ9.81(brs,1H),8.14-8.07(m,2H),7.48-7.46(m,2H),7.07-7.05(m,1H),6.85(s,1H),6.66-6.64(m,1H),5.04-5.00(m,2H),4.28-4.27(m,2H),3.55-3.52(m,1.5H ), 3.27-3.28 (m, 1.5H), 3.17-3.16 (m, 1.5H), 3.06-2.97 (m, 1.5H), 2.87 (m, 3H), 2.62-2.61 (m, 3H), 1.97-1.73 (m, 3H), 1.64-1.49 (m, 2H). LC-MS (ESI, m/z): 419.0 [M+H] + .
EX39制备1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苄基)-1-甲基脲.三氟乙酸(ER10256)
EX39 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-(methoxymethyl)benzyl)-1-methylurea.trifluoroacetic acid (ER10256)
1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苄基)-1-甲基脲.三氟乙酸在与ER10301类似的条件下制备和纯化，以(4-(甲氧基甲基)苯基)甲胺(128mg，0.85mmol)和1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1基)乙-1-酮(280mg，1.06mmol)为原料，得到所需产物(50mg，9％)，为白色固体，1H NMR(400MHz,CD3OD)δ8.12-8.09(m,2H),7.35-7.28(m,6H),4.90-4.87(m,2H),4.42(S,2H),4.35(S,2H),3.67(d,J＝16Hz,2H),3.38-3.34(m,2H),3.35(S,3H),3.30-3.20(m,2H),2.97(S,3H),2.02-2.92(m,4H),1.65-1.62(m,1H).LC-MS(ESI,m/z):442.3[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-(methoxymethyl)benzyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from (4-(methoxymethyl)phenyl)methanamine (128 mg, 0.85 mmol) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one (280 mg, 1.06 mmol) to give the desired product (50 mg, 9%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ8.12-8.09 (m, 2H), 7.35-7.28 (m, 6H), 4.90-4.87 (m, 2H), 4.42 (S, 2H), 4.35 (S, 2H), 3.67 (d, J=16 Hz, 2H), 3.38-3.34 (m, 2H), 3.35 (S, 3H), 3.30-3.20 (m, 2H), 2.97 (S, 3H), 2.02-2.92 (m, 4H), 1.65-1.62 (m, 1H). LC-MS (ESI, m/z): 442.3 [M+H] + .
EX40制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苄基)脲.三氟乙酸(ER10257)
EX40 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-(methoxymethyl)benzyl)urea.Trifluoroacetic acid (ER10257)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(4-(甲氧基甲基)苄基)脲.三氟乙酸在与ER10301类似的条件下制备和纯化，以(4-(甲氧基甲基)苯基)甲胺(97mg，0.64mmol，0.8eq)和2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(200mg，0.80mmol，1.0eq)为原料，得到所需产物(40mg，13％)，为黄色固体，1H NMR(400MHz,CD3OD)δ8.18-8.10(m,2H),7.35-7.28(m,6H),4.92-4.87(m,2H),4.43(S,2H),4.32(S,2H),3.67(d,J＝16Hz,2H),3.35-3.31(m,4H),3.15-3.08(m,3H),,2.01-1.91(m,2H),1.82-1.80(m,1H),1.69-1.50(m,2H).LC-MS(ESI,m/z):428.3[M+H]+。 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(4-(methoxymethyl)benzyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from (4-(methoxymethyl)phenyl)methanamine (97 mg, 0.64 mmol, 0.8 eq) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (200 mg, 0.80 mmol, 1.0 eq) to give the desired product (40 mg, 13%) as a yellow solid. 1 H NMR (400 MHz, CD 3 OD) δ8.18-8.10 (m, 2H), 7.35-7.28 (m, 6H), 4.92-4.87 (m, 2H), 4.43 (s, 2H), 4.32 (s, 2H), 3.67 (d, J=16 Hz, 2H), 3.35-3.31 (m, 4H), 3.15-3.08 (m, 3H), , 2.01-1.91 (m, 2H), 1.82-1.80 (m, 1H), 1.69-1.50 (m, 2H). LC-MS (ESI, m/z): 428.3 [M+H] + .
EX41制备3-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-(4-(甲氧基甲基)苄基)-1-甲基脲.三氟乙酸(ER10258)
EX41 Preparation of 3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-(4-(methoxymethyl)benzyl)-1-methylurea.trifluoroacetic acid (ER10258)
3-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-(4-(甲氧基甲基)苄基)-1-甲基脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以1-(4-(甲氧基甲基)苯基)-N-甲基甲胺(100mg,0.61mmol,0.8eq)和2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(300mg,1.13mmol,1.0eq)得到所需产物(30mg,8.8％)，为黄色油状物，1H NMR(400MHz,CD3OD)δ8.13-8.09(m,2H),7.36-7.31(m,4H),7.23-7.21(m,2H),4.92-4.87(m,2H),4.52(S,2H),4.43(S,2H),3.6-3.65(m,2H),3.36(S,3H),3.18-3.16(m,2H),3.09-3.05(m,2H),2.87(S,3H),1.99-1.96(m,2H),1.86-1.72(m,1H),1.65-1.62(m,2H).LC-MS(ESI,m/z):442.3[M+H]+.EX42制备1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-3-((4-(甲氧基甲基)环己基)甲基)-1-甲基脲.三氟乙酸(ER10259)
3-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-(4-(methoxymethyl)benzyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 with 1-(4-(methoxymethyl)phenyl)-N-methylmethanamine (100 mg, 0.61 mmol, 0.8 eq) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (300 mg, 1.13 mmol, 1.0 eq) to give the desired product (30 mg, 8.8%) as a yellow oil. 1 H NMR (400 MHz, CD 3 OD) δ8.13-8.09 (m, 2H), 7.36-7.31 (m, 4H), 7.23-7.21 (m, 2H), 4.92-4.87 (m, 2H), 4.52 (S, 2H), 4.43 (S, 2H), 3.6-3.65 (m, 2H), 3.36 (S, 3H), 3.18-3.16 (m, 2H), 3.09-3.05 (m, 2H), 2.87 (S, 3H), 1.99-1.96 (m, 2H), 1.86-1.72 (m, 1H), 1.65-1.62 (m, 2H). LC-MS (ESI, m/z): 442.3 [M+H] + .EX42 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((4-(methoxymethyl)cyclohexyl)methyl)-1-methylurea. Trifluoroacetic acid (ER10259)
1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-3-((4-(甲氧基甲基)环己基)甲基)-1-甲基脲.三氟乙酸在与ER10301类似的条件下制备和纯化，以(4-(甲氧基甲基)环己基)甲胺(47.9mg，0.30mmol)和1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮(100mg，0.38mmol)为原料，得到所需产物(50mg，8.9％)，为黄色固体，1H NMR(400MHz,CD3OD)δ8.12-8.08(m,2H),7.35-7.31(m,2H),4.90(S,2H),3.68(d,J＝16Hz,2H),3.38-3.3.36(m,2H),3.30-3.20(m,2H),3.20-3.19(m,2H),3.12-2.92(m,5H),1.95-1.61(m,15H).LC-MS(ESI,m/z):448.3[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((4-(methoxymethyl)cyclohexyl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from (4-(methoxymethyl)cyclohexyl)methanamine (47.9 mg, 0.30 mmol) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one (100 mg, 0.38 mmol) to give the desired product (50 mg, 8.9%) as a yellow solid. 1 H NMR (400 MHz, CD 3 OD) δ8.12-8.08 (m, 2H), 7.35-7.31 (m, 2H), 4.90 (s, 2H), 3.68 (d, J = 16 Hz, 2H), 3.38-3.3.36 (m, 2H), 3.30-3.20 (m, 2H), 3.20-3.19 (m, 2H), 3.12-2.92 (m, 5H), 1.95-1.61 (m, 15H). LC-MS (ESI, m/z): 448.3 [M+H] + .
EX43制备1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-3-((4-(甲氧基甲基)环己基)甲基)脲.三氟乙酸(ER10261)
EX43 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((4-(methoxymethyl)cyclohexyl)methyl)urea.Trifluoroacetic acid (ER10261)
1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-3-((4-(甲氧基甲基)环己基)甲基)脲.三氟乙酸在与ER10301类似的条件下制备和纯化，以(4-(甲氧基甲基)环己基)甲胺(100mg，0.63mmol，0.8eq)和2-(4-(氨基甲基)哌啶-1-基)-1-(4-氟苯基)乙-1-酮(197mg，0.78mmol，1.0eq)为原料，得到所需产物(20mg，5.8％)，为黄色油状物。1H NMR(400MHz,CD3OD)δ8.12-8.08(m,2H),7.35-7.31(m,2H),4.93(S,2H),3.68(d,J＝12Hz,2H),3.20-3.19(m,2H),3.10-2.96(m,6H),2.21-1.98(m,5H),1.82-1.78(m,5H),1.62-1.57(m,5H).LC-MS(ESI,m/z):433.3[M+H]+.1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((4-(methoxymethyl)cyclohexyl)methyl)urea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from (4-(methoxymethyl)cyclohexyl)methanamine (100 mg, 0.63 mmol, 0.8 eq) and 2-(4-(aminomethyl)piperidin-1-yl)-1-(4-fluorophenyl)ethan-1-one (197 mg, 0.78 mmol, 1.0 eq) to give the desired product (20 mg, 5.8%) as a yellow oil. 1 H NMR (400 MHz, CD 3 OD) δ8.12-8.08 (m, 2H), 7.35-7.31 (m, 2H), 4.93 (s, 2H), 3.68 (d, J=12 Hz, 2H), 3.20-3.19 (m, 2H), 3.10-2.96 (m, 6H), 2.21-1.98 (m, 5H), 1.82-1.78 (m, 5H), 1.62-1.57 (m, 5H). LC-MS (ESI, m/z): 433.3 [M+H] + .
EX44制备3-(4-乙氧基苄基)-1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸(ER10260)
EX44 Preparation of 3-(4-ethoxybenzyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.Trifluoroacetic acid (ER10260)
3-(4-乙氧基苄基)-1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸在类似于ER10301的条件下制备和纯化，以(4-乙氧基苯基)甲胺(136mg，0.90mmol，0.8eq)和1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮(300mg，1.13mmol，1.0eq)为原料，得到所需产物(36mg，7.2％)，为白色固体，1H NMR(400MHz,CD3OD)δ8.12-8.09(m,2H),7.35-7.31(m,2H),7.21-7.19(m,2H),6.85-6.83(m,2H),4.89(S,2H),4.52(S,2H),4.28(S,2H),4.00(q,J＝16HZ,2H),3.98(d,J＝8Hz,2H),3.11-3.08(m,2H),2.95(S,3H),1.95-1.91 9m,3H),1.65-1.61(m,2H),1.366(t,J＝16Hz,3H).LC-MS(ESI,m/z):442.3[M+H]+.3-(4-Ethoxybenzyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10301 starting from (4-ethoxyphenyl)methanamine (136 mg, 0.90 mmol, 0.8 eq) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one (300 mg, 1.13 mmol, 1.0 eq) to give the desired product (36 mg, 7.2%) as a white solid, 1 H NMR (400 MHz, CD 3 OD) δ8.12-8.09 (m, 2H), 7.35-7.31 (m, 2H), 7.21-7.19 (m, 2H), 6.85-6.83 (m, 2H), 4.89 (S, 2H), 4.52 (S, 2H), 4.28 (S, 2H), 4.00 (q, J = 16 Hz, 2H), 3.98 (d, J = 8 Hz, 2H), 3.11-3.08 (m, 2H), 2.95 (S, 3H), 1.95-1.91 9m, 3H), 1.65-1.61 (m, 2H), 1.366 (t, J = 16 Hz, 3H). LC-MS (ESI, m/z): 442.3 [M+H] + .
EX45制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(5-甲氧基吡啶-2-基)-1-甲基脲.三氟乙酸(ER10304)
EX45 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(5-methoxypyridin-2-yl)-1-methylurea.Trifluoroacetic acid (ER10304)
在N2和0℃下，向5-甲氧基吡啶-2-胺(258mg，2.08mmol，1.1equiv)的DMF(10mL)溶液中，加入NaH(54.5mg，2.27mmol，1.2equiv)，所得混合物搅拌1小时。然后加入CDI(337mg，2.08mmol，1.1equiv)并将反应混合物搅拌2小时。在0℃下，将1-(4-氟苯基)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮氯化氢(500mg，1.89mmol，1.0equiv)和TEA(574mg)的DMF(5mL，5.67mmol，3.0equiv))溶液加入反应物中。将所得混合物在室温搅拌过夜，用水(50mL)稀释并用EA(20mL×3)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)和方法A下的prep-HPLC纯化，得到1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-(5-甲氧基吡啶-2-基)-1-甲基脲.三氟乙酸(25.0mg，3.03％)，为淡黄色固体，1H NMR(400MHz,DMSO_d6):δ9.76–9.75(m,1H),8.75–8.70(m,1H),8.17–8.07(m,2H),7.98–7.95(m,1H),7.73–7.71(m,1H),7.51–7.40(m,3H),5.06–4.97(m,2H),3.80(s,3H),3.56–3.53(m,1.5H),3.38–3.29(m,3H),3.07–3.02(m,4.5H),1.86–1.69(m,3H),1.62–1.54(m,2H).LC-MS(ESI,m/z):415.1[M+H]+。To a solution of 5-methoxypyridin-2-amine (258 mg, 2.08 mmol, 1.1 equiv) in DMF (10 mL) under N 2 and 0°C, NaH (54.5 mg, 2.27 mmol, 1.2 equiv) was added and the resulting mixture was stirred for 1 hour. CDI (337 mg, 2.08 mmol, 1.1 equiv) was then added and the reaction mixture was stirred for 2 hours. 1-(4-Fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one hydrochloride (500 mg, 1.89 mmol, 1.0 equiv) and TEA (574 mg) in DMF (5 mL, 5.67 mmol, 3.0 equiv)) were added to the reactant at 0°C. The resulting mixture was stirred at room temperature overnight, diluted with water (50 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=10/1) and prep-HPLC under method A to give 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-(5-methoxypyridin-2-yl)-1-methylurea.trifluoroacetic acid (25.0 mg, 3.03%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ):δ9.76–9.75(m,1H),8.75–8.70(m,1H),8.17–8.07(m,2H),7.98–7.95(m,1H),7.73–7.71(m,1H),7.51–7.40(m,3H),5.06–4.97(m,2H),3.80(s,3H),3.56–3.53(m,1.5H),3.38–3.29(m,3H),3.07–3.02(m,4.5H),1.86–1.69(m,3H),1.62–1.54(m,2H).LC-MS(ESI,m/z):415.1[M+H] + .
EX46制备1-(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)-3-(4-(甲氧基甲基)苄基)-1-甲基脲.三氟乙酸(ER10294)
EX46 Preparation of 1-(1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-3-(4-(methoxymethyl)benzyl)-1-methylurea.trifluoroacetic acid (ER10294)
在50mL圆底烧瓶中装入1-[4-(甲氧基甲基)苯基]甲胺(132mg，0.879mmol，1.10equiv)、1,1'-羰基二咪唑(156mg，0.967mmol，1.21equiv)、四氢呋喃(2mL)。将反应溶液在室温下搅拌2小时，然后加入1-(4-氟苯基)-2-[4-(甲基氨基)哌啶-1-基]乙酮(200mg，0.799mmol，1.00equiv)和N，N-二异丙 基乙胺(516mg，3.99mmol，5.00equiv)的二甲亚砜(3mL)溶液。将反应溶液在室温搅拌过夜，然后减压浓缩。粗产物在方法A条件下通过prep-HPLC纯化以得到1-(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)-3-(4-(甲氧基甲基)苄基)-1-甲基脲.三氟乙酸(74.8mg，产率17.0％)，为黄色半固体，1H-NMR(300MHz,CD3OD)δ8.00-8.22(m,2H),7.22-7.40(m,6H),4.94(s,2H),4.38–4.52(m,5H),3.60-3.74(m,2H),3.35(s,3H),3.11-3.26(m,2H),2.87(s,3H),2.16-2.30(m,2H),1.88-1.92(m,2H).LCMS(ESI,m/z):428[M+H]+.A 50 mL round-bottom flask was charged with 1-[4-(methoxymethyl)phenyl]methylamine (132 mg, 0.879 mmol, 1.10 equiv), 1,1'-carbonyldiimidazole (156 mg, 0.967 mmol, 1.21 equiv), and tetrahydrofuran (2 mL). The reaction solution was stirred at room temperature for 2 hours, and then 1-(4-fluorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethanone (200 mg, 0.799 mmol, 1.00 equiv) and N,N-diisopropyl 1-(1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-3-(4-(methoxymethyl)benzyl)-1-methylurea. Trifluoroacetic acid (74.8 mg, 17.0% yield) was obtained as a yellow semi-solid. 1 H-NMR (300 MHz, CD 3 OD) δ8.00-8.22 (m, 2H), 7.22-7.40 (m, 6H), 4.94 (s, 2H), 4.38–4.52 (m, 5H), 3.60-3.74 (m, 2H), 3.35 (s, 3H), 3.11-3.26 (m, 2H), 2.87 (s, 3H), 2.16-2.30 (m, 2H), 1.88-1.92 (m, 2H). LCMS (ESI, m/z): 428 [M+H] + .
EX47制备1-(1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)-3-(4-甲氧基苄基)-1-甲基脲.三氟乙酸(ER10293)
EX47 Preparation of 1-(1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-3-(4-methoxybenzyl)-1-methylurea trifluoroacetic acid (ER10293)
1-(1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)-3-(4-甲氧基苄基)-1-甲基脲.三氟乙酸在与ER10294类似的条件下制备和纯化，以(4-甲氧基苯基)甲胺(120mg，0.879mmol，1.1equiv)和1-(4-氟苯基)-2-[4-(甲胺)哌啶-1-基]乙酮(200mg，0.799mmol，1equiv)为原料，得到所需产物(70.8mg，16.6％)，为黄色半固体，1H-NMR(300MHz,CD3OD)δ8.04-8.24(m,2H),7.30-7.49(m,2H),7.19–7.23(m,2H),6.83–6.87(m,2H),4.94(s,2H),4.38-4.45(m,1H),4.30(s,2H),3.59-3.76(m,5H),3.21-3.44(m,2H),2.85(s,3H),2.08-2.32(m,2H),1.80-2.00(m,2H).LCMS(ESI,m/z):414[M+H]+。1-(1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)-3-(4-methoxybenzyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10294 starting from (4-methoxyphenyl)methanamine (120 mg, 0.879 mmol, 1.1 equiv) and 1-(4-fluorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethanone (200 mg, 0.799 mmol, 1 equiv) to give the desired product (70.8 mg, 16.6%) as a yellow semisolid, 1 H-NMR (300 MHz, CD 3 OD) δ8.04-8.24 (m, 2H), 7.30-7.49 (m, 2H), 7.19–7.23 (m, 2H), 6.83–6.87 (m, 2H), 4.94 (s, 2H), 4.38-4.45 (m, 1H), 4.30 (s, 2H), 3.59-3.76 (m, 5H), 3.21-3.44 (m, 2H), 2.85 (s, 3H), 2.08-2.32 (m, 2H), 1.80-2.00 (m, 2H). LCMS (ESI, m/z): 414 [M+H] + .
EX48制备1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((5-(甲氧基甲基)噻唑-2-基)甲基)-1-甲基脲.三氟乙酸(ER10282)
EX48 Preparation of 1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((5-(methoxymethyl)thiazol-2-yl)methyl)-1-methylurea.trifluoroacetic acid (ER10282)
1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-3-((5-(甲氧基甲基)噻唑-2-基)甲基)-1-甲基脲.三氟乙酸在与ER10294类似的条件下制备和纯化，以(5-(甲氧基甲基)噻唑-2-基)甲胺(400mg，2.53mmol，1.0equiv)和1-(4-氟苯)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.氯化氢(334mg，1.26mmol，0.5equiv)为原料，得到所需产物(18.7mg，2％)，为淡黄色油状物，1H NMR(300MHz,CDCl3)δ7.91-7.96(m,2H),7.59-7.61(s,1H),7.15-7.21(m,2H),5.56(s,1H),4.70(s,2H),4.69(s,4H),3.66(s,2H),3.38(s,4H),3.27(s,3H),2.98(s,3H),1.82-2.09(m,5H).LC-MS(ESI,m/z):449[M+H]+。1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-3-((5-(methoxymethyl)thiazol-2-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10294 starting from (5-(methoxymethyl)thiazol-2-yl)methanamine (400 mg, 2.53 mmol, 1.0 equiv) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one.hydrogen chloride (334 mg, 1.26 mmol, 0.5 equiv) to give the desired product (18.7 mg, 2%) as a light yellow oil. 1 H NMR (300 MHz, CDCl 3 )δ7.91-7.96(m,2H),7.59-7.61(s,1H),7.15-7.21(m,2H),5.56(s,1H),4.70(s,2H),4.69(s,4H),3.66(s,2H),3.38(s,4H),3.27(s,3H),2.98(s,3H),1.82-2.09(m,5H).LC-MS(ESI,m/z):449[M+H] + .
EX49制备3-((trans-4-乙氧基环己基)甲基)-1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸(ER10276-0)和3-((cis-4-乙氧基环己基)甲基)-1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸(ER10276-0A)

EX49 Preparation of 3-((trans-4-ethoxycyclohexyl)methyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.trifluoroacetic acid (ER10276-0) and 3-((cis-4-ethoxycyclohexyl)methyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.trifluoroacetic acid (ER10276-0A)

3-((trans-4-乙氧基环己基)甲基)-1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸和3-((cis-4-乙氧基环己基)甲基)-1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸在与ER10294类似的条件下制备和纯化，以1-(4-乙氧基环己基)甲胺(170mg，1.08mmol，1.0equiv.)和1-(4-氟苯)-2-(4-((甲基氨基)甲基)哌啶-1-基)乙-1-酮.氯化氢(286mg，1.08mmol，1.0equiv)为原料，得到所需产物，3-((trans-4-乙氧基环己基)甲基)-1-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸(18mg，3％产率)，为浅棕色油状物，1H-NMR(300MHz,Chloroform-d)δ8.07-8.12(m,1H),7.94(s,1H),7.02-7.24(m,2H),4.39-4.71(m,2H),3.42-3.79(m,5H),2.90-3.31(m,9H),1.78-2.12(m,7H),1.32-1.50(m,2H),1.11-1.25(m,6H),0.85-1.11(m,2H).LC-MS(ESI,m/z):448[M+H]+,和3-((cis-4-乙氧基环己基)甲基)-1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸(13mg,2％)为浅黄色油状物，1H-NMR(300MHz,Chloroform-d)δ7.92(s,2H),7.15-7.20(m,2H),4.53-4.60(m,2H),3.30-3.82(m,6H),3.00-3.30(m,5H),2.92(s,3H),1.70-2.12(m,6H),1.30-1.52(m,6H),1.09-1.23(m,4H),0.72-1.08(m,1H).LC-MS(ESI,m/z):448[M+H]+。3-((trans-4-ethoxycyclohexyl)methyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.trifluoroacetic acid and 3-((cis-4-ethoxycyclohexyl)methyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.trifluoroacetic acid were prepared and purified under similar conditions to ER10294 with 1-(4-ethoxycyclohexyl)methanamine (170 mg, 1.08 mmol, 1.0 equiv.) and 1-(4-fluorophenyl)-2-(4-((methylamino)methyl)piperidin-1-yl)ethan-1-one. Hydrogen chloride (286 mg, 1.08 mmol, 1.0 equiv) were used as starting materials to give the desired product, 3-((trans-4-ethoxycyclohexyl)methyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea. Trifluoroacetic acid (18 mg, 3% yield) as a light brown oil, 1 H-NMR (300MHz, Chloroform-d) δ8.07-8.12 (m, 1H), 7.94 (s, 1H), 7.02-7.24 (m, 2H), 4.39-4.71 (m, 2H), 3.42-3.79 (m, 5H), 2.90-3.31 (m, 9H), 1.78-2.12 (m, 7H), 1.32-1.50 (m, 2H), 1.11-1.25 (m, 6H), 0.85-1.11 (m, 2H). LC-MS (ESI, m/z): 448 [M+H] + , and 3-((cis-4-ethoxycyclohexyl)methyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea. Trifluoroacetic acid (13 mg, 2%) was a light yellow oil, 1 H-NMR (300 MHz, Chloroform-d) δ 7.92 (s, 2H), 7.15-7.20 (m, 2H), 4.53-4.60 (m, 2H), 3.30-3.82 (m, 6H), 3.00-3.30 (m, 5H), 2.92 (s, 3H), 1.70-2.12 (m, 6H), 1.30-1.52 (m, 6H), 1.09-1.23 (m, 4H), 0.72-1.08 (m, 1H). LC-MS (ESI, m/z): 448 [M+H] + .
EX50制备3-((6-乙氧基吡啶-3-基)甲基)-1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸(ER10275)
EX50 Preparation of 3-((6-ethoxypyridin-3-yl)methyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.Trifluoroacetic acid (ER10275)
3-((6-乙氧基吡啶-3-基)甲基)-1-((1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基)-1-甲基脲.三氟乙酸在与ER10294类似的条件下制备和纯化，以1-(6-乙氧基吡啶-3-基)甲胺(58.0mg,0.38mmol，1.0equiv)和1-(4-氟苯)-2-(4-((甲胺))甲基)哌啶-1-基)乙烷-1-酮(100mg，0.38mmol，1.0equiv)得到所需产物(38.8mg，18％)，为淡黄色固体，1H NMR(400MHz,CD3OD)δ8.05-8.12(m,3H),7.72(s,1H),7.31-7.35(m,2H),6.80-6.84(m,1H),4.87-4.95(m,2H),4.30(s,4H),3.66(d,J＝12.0Hz,2H),3.48(s,1H),3.28-3.38(m,1H),3.08-3.18(m,2H),2.95(s,3H),1.91-1.99(m,3H),1.61-1.68(m,2H),1.37-1.39(m,3H).LC-MS(ESI,m/z):443[M+H]+.3-((6-ethoxypyridin-3-yl)methyl)-1-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)-1-methylurea.trifluoroacetic acid was prepared and purified under similar conditions to ER10294 with 1-(6-ethoxypyridin-3-yl)methanamine (58.0 mg, 0.38 mmol, 1.0 equiv) and 1-(4-fluorophenyl)-2-(4-((methylamino))methyl)piperidin-1-yl)ethan-1-one (100 mg, 0.38 mmol, 1.0 equiv) to give the desired product (38.8 mg, 18%) as a light yellow solid. 1 H NMR (400 MHz, CD 3 OD) δ8.05-8.12 (m, 3H), 7.72 (s, 1H), 7.31-7.35 (m, 2H), 6.80-6.84 (m, 1H), 4.87-4.95 (m, 2H), 4.30 (s, 4H), 3.66 (d, J＝12.0 Hz, 2H), 3.48 (s, 1H), 3.28-3.38 (m, 1H), 3.08-3.18 (m, 2H), 2.95 (s, 3H), 1.91-1.99 (m, 3H), 1.61-1.68 (m, 2H), 1.37-1.39 (m, 3H). LC-MS (ESI, m/z): 443 [M+H] + .
PEX31：N-(4-(甲氧基甲基)苄基)-2-(哌啶-4-基氧基)乙酰胺的制备
PEX31: Preparation of N-(4-(methoxymethyl)benzyl)-2-(piperidin-4-yloxy)acetamide
步骤1：4-(2-((4-(甲氧基甲基)苄基)氨基)-2-氧代乙氧基)哌啶-1-甲酸叔丁酯的制备
Step 1: Preparation of tert-butyl 4-(2-((4-(methoxymethyl)benzyl)amino)-2-oxoethoxy)piperidine-1-carboxylate
将{[1-(叔丁氧基羰基)哌啶-4-基]氧基}乙酸溶液(500mg,1.93mmol,1.0equiv)，1-[4-(甲氧基甲基)苯基]甲胺(320mg,2.12mmol,1.1equiv)、HOBT(953mg,2.51mmol,1.3equiv)、EDCI(480mg,2.51mmol,1.3equiv)和DIEA(748mg,5.78mmol,3.0equiv)在DCM(10mL)中的溶液，在室温下搅拌过夜并用水(20mL)淬灭。所得混合物用EtOAc(3×100mL)萃取。将合并的有机层用盐水(2×100mL)洗涤，用无水Na2SO4干燥。过滤后，将滤液减压浓缩。将残余物在硅胶柱上用EtOAc/PE(1/1)进行色谱分离，得到4-(2-((4-(甲氧基甲基)苄基)氨基)-2-氧代乙氧基)哌啶-1-甲酸叔丁酯(300mg,39.6％)，为棕色油状物。LC-MS(ESI,m/z):393[M+H]+.A solution of {[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}acetic acid solution (500 mg, 1.93 mmol, 1.0 equiv), 1-[4-(methoxymethyl)phenyl]methanamine (320 mg, 2.12 mmol, 1.1 equiv), HOBT (953 mg, 2.51 mmol, 1.3 equiv), EDCI (480 mg, 2.51 mmol, 1.3 equiv) and DIEA (748 mg, 5.78 mmol, 3.0 equiv) in DCM (10 mL) was stirred at room temperature overnight and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EtOAc/PE (1/1) to give tert-butyl 4-(2-((4-(methoxymethyl)benzyl)amino)-2-oxoethoxy)piperidine-1-carboxylate (300 mg, 39.6%) as a brown oil. LC-MS (ESI, m/z): 393 [M+H] + .
步骤2：N-(4-(甲氧基甲基)苄基)-2-(哌啶-4-基氧基)乙酰胺的制备Step 2: Preparation of N-(4-(methoxymethyl)benzyl)-2-(piperidin-4-yloxy)acetamide
将4-(2-((4-(甲氧基甲基)苄基)氨基)-2-氧代乙氧基)哌啶-1-甲酸叔丁酯(300mg,0.764mmol,1.0equiv)和TFA(1mL)在DCM(6mL)中的溶液室温搅拌1h。将所得混合物减压浓缩，得到N-(4-(甲氧基甲基)苄基)-2-(哌啶-4-基氧基)乙酰胺(180mg粗品)，为无色油状物，无需进一步纯化直接用于下一步。LC-MS(ESI,m/z):293[M+H]+.A solution of tert-butyl 4-(2-((4-(methoxymethyl)benzyl)amino)-2-oxoethoxy)piperidine-1-carboxylate (300 mg, 0.764 mmol, 1.0 equiv) and TFA (1 mL) in DCM (6 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give N-(4-(methoxymethyl)benzyl)-2-(piperidin-4-yloxy)acetamide (180 mg crude) as a colorless oil, which was used in the next step without further purification. LC-MS (ESI, m/z): 293 [M+H] + .
PEX32：哌啶-4-基甲基((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酸酯的制备
PEX32: Preparation of piperidin-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)(methyl)carbamate
步骤1：1-(6-甲氧基吡啶-3-基)-N-甲基甲胺的制备
Step 1: Preparation of 1-(6-methoxypyridin-3-yl)-N-methylmethanamine
向6-甲氧基烟醛(2.00g,14.6mmol)的甲醇(20mL)溶液中加入40％甲胺(2.52g,21.9mmol)的甲醇溶液，然后将所得溶液在65℃搅拌2小时，然后在0℃加入硼氢化钠(1.10g,29.2mmol)。将反应混合物在25℃搅拌4小时。混合物用饱和NH4Cl溶液(50mL)稀释，用DCM(2×20mL)萃取。合并有机层，用无水硫酸钠干燥并真空蒸发，得到粗产物1-(6-甲氧基吡啶-3-基)-N-甲基甲胺(1.00g，40.41％)，为黄色油状物。1H NMR(400MHz,CDCl3)δ8.06–8.05(m,1H),7.58–7.54(m,1H),6.72–6.70(m,1H),3.91(s,3H),3.66(s,2H),2.43(s,3H),1.63(s,1H).To a solution of 6-methoxynicotinaldehyde (2.00 g, 14.6 mmol) in methanol (20 mL) was added a 40% methanol solution of methylamine (2.52 g, 21.9 mmol), and the resulting solution was stirred at 65 °C for 2 hours, and then sodium borohydride (1.10 g, 29.2 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 4 hours. The mixture was diluted with saturated NH 4 Cl solution (50 mL) and extracted with DCM (2×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate and evaporated in vacuo to give the crude product 1-(6-methoxypyridin-3-yl)-N-methylmethanamine (1.00 g, 40.41%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.06–8.05 (m, 1H), 7.58–7.54 (m, 1H), 6.72–6.70 (m, 1H), 3.91 (s, 3H), 3.66 (s, 2H), 2.43 (s, 3H), 1.63 (s, 1H).
步骤2：制备4-硝基苯基((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酸酯
Step 2: Preparation of 4-nitrophenyl((6-methoxypyridin-3-yl)methyl)(methyl)carbamate
在氮气保护和0℃下，向氯甲酸4-硝基苯酯(951mg,4.73mmol)的THF(8mL)溶液中滴加(6-甲氧基吡啶-3-基)甲基](甲基)胺(360mg,2.37mmol)和DIEA(611mg,4.73mmol)的THF(2mL)溶液。然后将反应混合物在20℃搅拌1小时。将混合物用水(30mL)稀释并用EA(3×10mL)萃取。将合并的有机层用无水硫酸钠干燥并真空蒸发得到粗产物，将其通过快速色谱法(PE/EtOAc＝10/1)纯化得到4-硝基苯基((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酸酯(520mg,63.2％)，为淡黄色固体。LC-MS(ESI,m/z):318.1[M+H]+.Under nitrogen protection and 0°C, a solution of (6-methoxypyridin-3-yl)methyl](methyl)amine (360 mg, 2.37 mmol) and DIEA (611 mg, 4.73 mmol) in THF (2 mL) was added dropwise to a solution of 4-nitrophenyl chloroformate (951 mg, 4.73 mmol) in THF (8 mL). The reaction mixture was then stirred at 20°C for 1 hour. The mixture was diluted with water (30 mL) and extracted with EA (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo to give a crude product, which was purified by flash chromatography (PE/EtOAc=10/1) to give 4-nitrophenyl ((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (520 mg, 63.2%) as a light yellow solid. LC-MS (ESI, m/z): 318.1 [M+H] + .
步骤3：制备4-(((((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酰基)氧基)甲基)哌啶-1-羧酸苄酯
Step 3: Preparation of benzyl 4-(((((6-methoxypyridin-3-yl)methyl)(methyl)carbamoyl)oxy)methyl)piperidine-1-carboxylate
在氮气保护0℃下，向氯甲酸4-硝基苯酯(470mg,1.48mmol)和1-(苄氧基)-O-[4-(羟甲基)哌啶-1-基]甲酮(371mg,1.48mmol)在THF(10mL)的溶液中滴加1M HMDSK(2.96mL，2.96mmol)。然后将反应混合物在20℃搅拌1小时。混合物用饱和NH4Cl溶液(20mL)稀释，并用EA(3×20mL)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。将残余物通过prep-TLC(DCM/MeOH＝15/1)纯化，得到产物4-(((((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酰基)氧基)甲基)哌啶-1-羧酸苄基酯(290mg,42.6％)，为黄色油状物。LC-MS(ESI,m/z):428.2[M+H]+.1M HMDSK (2.96 mL, 2.96 mmol) was added dropwise to a solution of 4-nitrophenyl chloroformate (470 mg, 1.48 mmol) and 1-(benzyloxy)-O-[4-(hydroxymethyl)piperidin-1-yl]methanone (371 mg, 1.48 mmol) in THF (10 mL) under nitrogen at 0°C. The reaction mixture was then stirred at 20°C for 1 hour. The mixture was diluted with saturated NH 4 Cl solution (20 mL) and extracted with EA (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo to give a crude product. The residue was purified by prep-TLC (DCM/MeOH=15/1) to give the product, benzyl 4-(((((6-methoxypyridin-3-yl)methyl)(methyl)carbamoyl)oxy)methyl)piperidine-1-carboxylate (290 mg, 42.6%), as a yellow oil. LC-MS (ESI, m/z): 428.2 [M+H] + .
步骤4：哌啶-4-基甲基((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酸酯的制备
Step 4: Preparation of piperidin-4-ylmethyl((6-methoxypyridin-3-yl)methyl)(methyl)carbamate
将{1-[(E)-[(苄氧基)亚甲基]氧代]哌啶-4-基}甲基N-[(6-甲氧基吡啶-3-基)甲基]-N-甲基氨基甲酸酯(300mg,0.700mmol)和Pd/C(60.0mg,10％)的THF(3mL)溶液的混合物在氢气下于20℃搅拌3小时。过滤混合物，真空蒸发滤液，得到粗品哌啶-4-基甲基((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酸酯(170mg，75.9％)，为黄色油状物。LC-MS(ESI,m/z):294.2[M+H]+.A mixture of {1-[(E)-[(benzyloxy)methylene]oxy]piperidin-4-yl}methyl N-[(6-methoxypyridin-3-yl)methyl]-N-methylcarbamate (300 mg, 0.700 mmol) and Pd/C (60.0 mg, 10%) in THF (3 mL) was stirred at 20°C for 3 hours under hydrogen. The mixture was filtered and the filtrate was evaporated in vacuo to give crude piperidin-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (170 mg, 75.9%) as a yellow oil. LC-MS (ESI, m/z): 294.2 [M+H] + .
PEX33：哌啶-4-基甲基((6-甲氧基吡啶-3-基)甲基)氨基甲酸酯的制备
PEX33: Preparation of piperidin-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)carbamate
哌啶-4-基甲基((6-甲氧基吡啶-3-基)甲基)氨基甲酸酯的制备方法与哌啶-4-基甲基((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酸酯的制备方法相似，以(6-甲氧基吡啶-3-基)甲基氨基作为原料。 The preparation method of piperidin-4-ylmethyl((6-methoxypyridin-3-yl)methyl)carbamate is similar to the preparation method of piperidin-4-ylmethyl((6-methoxypyridin-3-yl)methyl)(methyl)carbamate, using (6-methoxypyridin-3-yl)methylamino as the starting material.
PEX34 1-(4-氟苯基)-2-(4-(羟甲基)哌啶-1-基)乙-1-酮的制备
PEX34 Preparation of 1-(4-fluorophenyl)-2-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one
将2-氯-1-(4-氟苯基)乙酮(500mg,2.90mmol,1.0equiv)、哌啶-4-基甲醇(434mg,3.77mmol,1.3equiv)、KI(96.2mg,0.579mmol,0.2equiv)和K2CO3(1.20g，8.69mmol，3.0equiv)的混合物在DMF(10mL)中的混合溶液在60℃搅拌2h后，用水(20mL)淬灭。所得混合物用EtOAc(3×30mL)萃取。合并的有机层用盐水(2×100mL)洗涤，经无水Na2SO4干燥。过滤后，将滤液减压浓缩。将残余物在硅胶柱上用EtOAc/PE(3/2)进行色谱分离，得到1-(4-氟苯基)-2-(4-(羟甲基)哌啶-1-基)乙-1-酮(400mg，55％)，为棕色油状物。LC-MS(ESI,m/z):252[M+H]+.A mixture of 2-chloro-1-(4-fluorophenyl)ethanone (500 mg, 2.90 mmol, 1.0 equiv), piperidin-4-ylmethanol (434 mg, 3.77 mmol, 1.3 equiv), KI (96.2 mg, 0.579 mmol, 0.2 equiv) and K 2 CO 3 (1.20 g, 8.69 mmol, 3.0 equiv) in DMF (10 mL) was stirred at 60 ° C for 2 h and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EtOAc/PE (3/2) to give 1-(4-fluorophenyl)-2-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one (400 mg, 55%) as a brown oil. LC-MS (ESI, m/z): 252 [M+H] + .
EX51：2-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)氧基)-N-(4-(甲氧基甲基)苄基)乙酰胺·2,2,2-三氟乙酸盐的制备(ER10300)
EX51: Preparation of 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)oxy)-N-(4-(methoxymethyl)benzyl)acetamide 2,2,2-trifluoroacetate (ER10300)
将N-(4-(甲氧基甲基)苄基)-2-(哌啶-4-基氧基)乙酰胺(200mg,0.68mmol,1.0equiv)，2-氯-1-(4-氟苯基)乙酮(118mg，0.684mmol，1.0equiv)、K2CO3(283mg，2.05mmol，3.0equiv)和KI(22.7mg，0.137mmol，0.2equiv)在DMF(8mL)中的溶液在60℃搅拌2h，用水(20mL)淬灭。所得混合物用EtOAc(3×30mL)萃取。合并的有机层用盐水(50mL)洗涤，用无水Na2SO4干燥。过滤后，将滤液减压浓缩。将残余物在硅胶柱上用CH2Cl2/MeOH(96:4)进行色谱分离，得到粗残余物，通过prep-HPLC(在方法A条件下)纯化，得到2-((1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)氧基)-N-(4-(甲氧基甲基)苄基)乙酰胺·2,2,2-三氟乙酸盐(24.5mg,8.3％)，为无色油状物。1H NMR(300MHz,CD3OD)δ8.08-8.13(m,2H),7.36-7.37(m,2H),7.30-7.35(m,4H),4.85-4.91(m,2H),4.42-4.45(m,4H),4.10(s,2H),3.72-3.88(m,2H),3.46-3.54(m,2H),3.32(s,3H),3.07-3.30(m,1H),1.98-2.41(m,4H).LC-MS(ESI,m/z):429[M+H]+。A solution of N-(4-(methoxymethyl)benzyl)-2-(piperidin-4-yloxy)acetamide (200 mg, 0.68 mmol, 1.0 equiv), 2-chloro-1-(4-fluorophenyl)ethanone (118 mg, 0.684 mmol, 1.0 equiv), K 2 CO 3 (283 mg, 2.05 mmol, 3.0 equiv) and KI (22.7 mg, 0.137 mmol, 0.2 equiv) in DMF (8 mL) was stirred at 60 °C for 2 h and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column with CH2Cl2 /MeOH (96:4) to give a crude residue, which was purified by prep-HPLC (under Method A conditions) to give 2-((1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)oxy)-N-(4-(methoxymethyl)benzyl)acetamide 2,2,2-trifluoroacetate (24.5 mg, 8.3%) as a colorless oil. 1 H NMR (300 MHz, CD 3 OD) δ 8.08-8.13 (m, 2H), 7.36-7.37 (m, 2H), 7.30-7.35 (m, 4H), 4.85-4.91 (m, 2H), 4.42-4.45 (m, 4H), 4.10 (s, 2H), 3.72-3.88 (m, 2H), 3.46-3.54 (m, 2H), 3.32 (s, 3H), 3.07-3.30 (m, 1H), 1.98-2.41 (m, 4H). LC-MS (ESI, m/z): 429 [M+H] + .
EX52：(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基-((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酸酯的制备(ER10344)
EX52: Preparation of (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl-((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (ER10344)
在氮气保护0℃下，向哌啶-4-基甲基((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酸酯(170mg，0.580mmol)的DMF(1mL)溶液中加入K2CO3(120mg，0.869mmol)和2-溴-1-(4-氟苯基)乙酮(126mg,0.580mmol)。然后 将混合物在20℃搅拌1小时，用水(20mL)稀释并用EA(3×5mL)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。通过Prep-TLC(DCM/MeOH＝15/1)纯化残余物，得到(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酸酯(150mg，47.1％)，为黄色油状物。1H NMR(400MHz,DMSO_d6)δ9.80(brs,1H),8.13–8.06(m,3H),7.60–7.46(m,3H),6.84–6.82(m,1H),5.01–5.00(m,2H),5.00–4.37(m,2H),4.00–3.95(m,2H),3.83(s,3H),3.52–2.82(m,4H),2.67–2.51(m,3H),1.99–1.72(m,3H),1.65–1.24(m,2H).LC-MS(ESI,m/z):430.2[M+H]+.To a DMF (1 mL) solution of piperidin-4-ylmethyl ((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (170 mg, 0.580 mmol) was added K 2 CO 3 (120 mg, 0.869 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (126 mg, 0.580 mmol) under nitrogen at 0°C. The mixture was stirred at 20°C for 1 hour, diluted with water (20 mL) and extracted with EA (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo to give a crude product. The residue was purified by Prep-TLC (DCM/MeOH=15/1) to give (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (150 mg, 47.1%) as a yellow oil. 1 H NMR (400 MHz, DMSO_d 6 ) δ 9.80 (brs, 1H), 8.13–8.06 (m, 3H), 7.60–7.46 (m, 3H), 6.84–6.82 (m, 1H), 5.01–5.00 (m, 2H), 5.00–4.37 (m, 2H), 4.00–3.95 (m, 2H), 3.83 (s, 3H), 3.52–2.82 (m, 4H), 2.67–2.51 (m, 3H), 1.99–1.72 (m, 3H), 1.65–1.24 (m, 2H). LC-MS (ESI, m/z): 430.2 [M+H] + .
EX53：(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酸酯的制备(ER10345)
EX53: Preparation of (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (ER10345)
在氮气保护0℃下，向哌啶-4-基甲基((6-甲氧基吡啶-3-基)甲基)氨基甲酸酯(118mg，0.422mmol)的DMF(10mL)溶液中加入K2CO3(87.6mg，0.634mmol)和2-溴-1-(4-氟苯基)乙酮(91.7mg,0.422mmol)。将混合物在20℃搅拌1小时，用水(30mL)稀释并用DCM(3×10mL)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。通过prpe-TLC(DCM/MeOH＝15/1)纯化残余物，得到(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基((6-甲氧基吡啶-3-基)甲基)(甲基)氨基甲酸酯(70.0mg，31.2％)，为黄色油状物。1H NMR(400MHz,DMSO_d6)δ9.83(brs,1H),8.09–8.05(s,3H),7.51–7.49(m,1H),7.47(m,1H),7.27(m,2H),6.81–6.79(m,1H),5.03–5.00(s,2H),4.14(m,2H),3.90(m,2H),3.83(m,3H),3.55(m,1.5H),3.45(m,1H),3.29(m,1H),3.04(m,1.5H),1.78–1.58(m,3H),1.24(m,2H).LC-MS(ESI,m/z):416.2[M+H]+.To a solution of piperidin-4-ylmethyl((6-methoxypyridin-3-yl)methyl)carbamate (118 mg, 0.422 mmol) in DMF (10 mL) was added K 2 CO 3 (87.6 mg, 0.634 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (91.7 mg, 0.422 mmol) under nitrogen at 0°C. The mixture was stirred at 20°C for 1 hour, diluted with water (30 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo to give a crude product. The residue was purified by prpe-TLC (DCM/MeOH=15/1) to give (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl((6-methoxypyridin-3-yl)methyl)(methyl)carbamate (70.0 mg, 31.2%) as a yellow oil. 1 H NMR (400 MHz, DMSO_d 6 ) δ9.83 (brs, 1H), 8.09–8.05 (s, 3H), 7.51–7.49 (m, 1H), 7.47 (m, 1H), 7.27 (m, 2H), 6.81–6.79 (m, 1H), 5.03–5.00 (s, 2H), 4.14 (m, 2H), 3.90 (m, 2H), 3.83 (m, 3H), 3.55 (m, 1.5H), 3.45 (m, 1H), 3.29 (m, 1H), 3.04 (m, 1.5H), 1.78–1.58 (m, 3H), 1.24 (m, 2H). LC-MS (ESI, m/z): 416.2 [M+H] + .
EX54：(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基(4-(甲氧基甲基)苄基)氨基甲酸酯·2,2,2-三氟乙酸盐的制备(ER10299)
EX54: Preparation of (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl(4-(methoxymethyl)benzyl)carbamate 2,2,2-trifluoroacetate (ER10299)
在0℃下，向1-(4-氟苯基)-2-(4-(羟甲基)哌啶-1-基)乙-1-酮(260mg,1.04mmol,1.0equiv)和Et3N(419mg,4.14mmol,4.0equiv)在DCM(10mL)的溶液中加入4-硝基苯甲酰氯(230mg，1.14mmol，1.1equiv)。将混合物在室温搅拌1小时。添加1-[4-(甲氧基甲基)苯基]甲胺(234mg，1.55mmol，1.5equiv)。将混合物在室温搅拌过夜并减压浓缩。将残余物在硅胶柱上用CH2Cl2/MeOH(96/4)进行色谱分离，得到粗残余物，将其通过prep-HPLC(方法A条件下)纯化，得到(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基(4-(甲氧基甲基)苄基)氨基甲酸·2,2,2-三氟乙酸盐(26.0mg,5.8％)，为无色油状物。1H NMR(300M Hz,CD3OD)δ8.08-8.13(m,2H),7.36-7.36(m,6H),4.86-4.91(m,2H),4.28-4.43(m,4H),4.03(s,2H),3.67-3.70(m,2H),3.31-3.35(m,4H),3.09-3.30(m,2H),2.02-2.06(m,2H),1.68-1.77(m,2H).LC-MS(ES  I,m/z):429[M+H]+.To a solution of 1-(4-fluorophenyl)-2-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one (260 mg, 1.04 mmol, 1.0 equiv) and Et3N (419 mg, 4.14 mmol, 4.0 equiv) in DCM (10 mL) at 0°C was added 4-nitrobenzoyl chloride (230 mg, 1.14 mmol, 1.1 equiv). The mixture was stirred at room temperature for 1 hour. 1-[4-(methoxymethyl)phenyl]methanamine (234 mg, 1.55 mmol, 1.5 equiv) was added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was chromatographed on silica gel column with CH2Cl2 /MeOH (96/4) to give a crude residue which was purified by prep-HPLC (under Method A conditions) to give (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl(4-(methoxymethyl)benzyl)carbamic acid 2,2,2-trifluoroacetate (26.0 mg, 5.8%) as a colorless oil. 1 H NMR (300 MHz, CD 3 OD) δ 8.08-8.13 (m, 2H), 7.36-7.36 (m, 6H), 4.86-4.91 (m, 2H), 4.28-4.43 (m, 4H), 4.03 (s, 2H), 3.67-3.70 (m, 2H), 3.31-3.35 (m, 4H), 3.09-3.30 (m, 2H), 2.02-2.06 (m, 2H), 1.68-1.77 (m, 2H). LC-MS (ES I,m/z):429[M+H] + .
EX55：(1-(2-(4-氟苯基)-2-氧乙基)哌啶-4-基)甲基(甲基)(吡啶-2-基)氨基甲酸酯·2,2,2-三氟乙酸盐的制备(ER10348)
EX55: Preparation of (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl(methyl)(pyridin-2-yl)carbamate 2,2,2-trifluoroacetate (ER10348)
在氮气保护和0℃下，向双(三氯甲基)碳酸酯(960mg，3.24mmol)的THF(20mL)溶液中滴加N-甲基吡啶-2-胺(700mg，6.47mmol)和吡啶(1.02g，12.9mmol)的THF(4mL)溶液。然后将反应混合物在20℃搅拌1小时，用水(20mL)稀释并用EA(3×6mL)萃取。合并的有机层用无水硫酸钠干燥并真空蒸发，得到粗中间体，其不经进一步纯化直接用于下一步骤。Under nitrogen protection and 0°C, a solution of N-methylpyridine-2-amine (700mg, 6.47mmol) and pyridine (1.02g, 12.9mmol) in THF (4mL) was added dropwise to a solution of bis(trichloromethyl) carbonate (960mg, 3.24mmol) in THF (20mL). The reaction mixture was then stirred at 20°C for 1 hour, diluted with water (20mL) and extracted with EA (3×6mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo to give a crude intermediate, which was used directly in the next step without further purification.
在氮气保护和0℃下，向1-(4-氟苯基)-2-(4-(羟甲基)哌啶-1-基)乙-1-酮(921mg,3.67mmol)和TEA(1.11g,11.0mmol)的THF(10mL)溶液中逐滴加入上述粗制中间体(625mg，粗制)的THF(10mL)溶液。然后将反应混合物在50℃搅拌16小时，然后冷却至室温，用水(20mL)稀释，用EtOAc(3×6mL)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。将残余物依次通过prep-TLC(DCM/MeOH＝10/1)，和prep-HPLC(在方法A条件下)纯化，得到(1-(2-(4-氟苯基)-2-氧代乙基)哌啶-4-基)甲基(甲基)(吡啶-2-基)氨基甲酸酯·2,2,2-三氟乙酸盐(38.1mg，1.18％)，为淡黄色固体。1H NMR(400MHz,DMSO_d6)δ9.82(brs,1H),8.42–8.41(m,1H),8.07(m,2H),7.71(m,1H),7.47(m,1H),7.20–7.17(m,2H),6.99(m,1H),5.02–5.01(m,2H),4.13–4.16(m,2H),3.53(m,1.5H),3.36(m,3H),3.17(m,1H),3.05(m,1.5H),1.89–1.80(m,3H),1.73–1.64(m,2H).LC-MS(ESI,m/z):386.1[M+H]+。Under nitrogen protection and 0°C, to a solution of 1-(4-fluorophenyl)-2-(4-(hydroxymethyl)piperidin-1-yl)ethan-1-one (921 mg, 3.67 mmol) and TEA (1.11 g, 11.0 mmol) in THF (10 mL) was added dropwise a solution of the above crude intermediate (625 mg, crude) in THF (10 mL). The reaction mixture was then stirred at 50°C for 16 hours, then cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3×6 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo to give a crude product. The residue was purified sequentially by prep-TLC (DCM/MeOH=10/1) and prep-HPLC (under method A conditions) to give (1-(2-(4-fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl(methyl)(pyridin-2-yl)carbamate 2,2,2-trifluoroacetate (38.1 mg, 1.18%) as a light yellow solid. 1 H NMR (400 MHz, DMSO_d 6 ) δ 9.82 (brs, 1H), 8.42–8.41 (m, 1H), 8.07 (m, 2H), 7.71 (m, 1H), 7.47 (m, 1H), 7.20–7.17 (m, 2H), 6.99 (m, 1H), 5.02–5.01 (m, 2H), 4.13–4.16 (m, 2H), 3.53 (m, 1.5H), 3.36 (m, 3H), 3.17 (m, 1H), 3.05 (m, 1.5H), 1.89–1.80 (m, 3H), 1.73–1.64 (m, 2H). LC-MS (ESI, m/z): 386.1 [M+H] + .
生物活性测试Biological activity test
1、5-HT2A受体拮抗剂活性筛选试验1. 5-HT2A receptor antagonist activity screening test
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。In order to confirm the antagonistic activity of the compounds of the present invention on the 5-HT2A receptor, 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. When the terbium-labeled anti-IP1 antibody binds to the d2-labeled IP1, energy resonance transfer occurs, thereby generating a signal. As the production of IP1 in the cell increases, the free IP1 binds to the antibody more, and the signal gradually decreases.
材料和方法：Materials and methods:
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)。According to the user manual, the Chinese hamster ovary cell transformed cell line (Flp-In ™ -CHO cell line) (purchased from invitrogen, R75807) was generated by transfecting CHO cells with pFRT//acZeo2 and selecting Zeocin ™ resistant clones. The Flp-In ™ -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). Flp-In-CHO-5HT2A cells were obtained by transfection. Stably transfected cell lines were cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone) + 1× Penicilin-Streptomycin + 800μg/ml Hygromycin B (ant-hg-5, Invivogen). To verify the activity of the compound, the Flp-In-CHO-5HT2A stable cell line was cultured in a 384-well plate (7.5K) at 37°C and 5% CO 2 for 20 hours. The compound was diluted to different concentrations with Ham's F-12K medium, and the culture medium that was cultured overnight was replaced with fresh medium at 100μl/well. After the cells were treated with the compound for 30 minutes, 5-HT was added and cultured at 37 degrees Celsius 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).
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。According to the results shown, the 5HT2A receptor activity of the Flp-In-CHO-5HT2A stable cell line was inhibited by the compound, suggesting that the compound has 5HT2A receptor antagonist activity.
2、Sigma2靶点结合性实验2. Sigma2 target binding experiment
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。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 μM 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.
3、hERG膜蛋白特异性结合实验3. hERG membrane protein specific binding experiment
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。The experiment was conducted using a HEK293 cell line that stably expresses hERG (human Ether-a-go-go Related Gene)-encoded potassium channels. In the myocardium, the potassium channels encoded by hERG mediate a delayed rectifier potassium current (IKr), and Ikr inhibition is the most important mechanism for drug-induced QT interval prolongation. Due to its special molecular structure, hERG's functional loss or drug inhibition will affect the cardiac action potential repolarization process and cause QT interval prolongation, and may also induce torsades de pointes, leading to arrhythmias.
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。In this experiment, 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. After incubation for a certain period of time to reach equilibrium, 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. The higher the signal, the weaker the binding ability of the test compound to the hERG membrane protein.
材料和方法：Materials and methods:
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。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). 50 μL of scintillation fluid 20 (6013621, PerkinElmer) was added to each well of the plate and the plate was sealed with a top sealing film (6005250, PerkinElmer). The radioactive signal was detected using a Microbeta plate reader.
4、hERG膜蛋白特异性结合自动膜片钳实验4. hERG membrane protein specific binding automated patch clamp experiment
该实验采用自动膜片钳***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。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.
材料和方法Materials and methods
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))。SyncroPatch 384i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。

The cells in two T175 culture flasks (431082, CORNING) were rinsed with 8 mL DPBS-2 mM EDTA at room temperature and transferred. 3 mL of cell digestion solution was added, and the container was gently shaken to cover the cell surface. After incubation at 37°C for 8-10 minutes, the cells were separated 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 tank with orbital shaking (IKA (MS3digital)). The chip was filled with internal and external solutions on the SyncroPatch 384i instrument (Nanion (384i)) (Nanion (221401, 4xhigh)), and cells were added to the chip. After sealing the cell, the holding potential was set to -90 mV for 500 ms, and the hERG current was induced by depolarization to +30 mV for 4.8 seconds, and then the voltage was taken to -50 mV for 5.2 seconds, and the inactivation tail current was measured by removing inactivation. hERG currents were recorded in the presence of test compounds for at least 5 min and the inhibitory concentration of hERG currents in the presence of the compounds was determined in two independent experiments.

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。 The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (10)

  1. 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，
    A compound of formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
    其中，in,
    X选自N或O，其中，当X为O时，R1不存在；X is selected from N or O, wherein, when X is O, R 1 is absent;
    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；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独立的选自0-4的整数；n and m are independently selected from integers from 0 to 4;
    R3独立地选自氢、卤素、OH、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； R3 is independently selected from hydrogen, halogen, OH, 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选自氢、卤素、OH、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； R4 is selected from hydrogen, halogen, OH, 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;
    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，杂环或杂芳环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代；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 heteroatom in the heterocyclic ring or heteroaromatic ring is selected from one or more of N, O and S; Cy 1 is further substituted by one or more R 5 ;
    R5独立地选自氢、卤素、OH、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、或C1-6亚烷基C6-10芳基； R5 is independently selected from hydrogen , halogen , OH, CN, 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;
    优选，n、m独立的选自0-2的整数；Preferably, n and m are independently selected from integers of 0-2;
    优选，R4选自氢、卤素、C1-3烷基；Preferably, R 4 is selected from hydrogen, halogen, C 1-3 alkyl;
    优选，R4的取代位置为苯环的对位。Preferably, the substitution position of R4 is the para position of the benzene ring.
    优选，Cy1是苯环、吡啶、环己烷、噻唑、噁唑、咪唑；Preferably, Cy 1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, imidazole;
    优选，R5为一个取代基，位于所述环的对位；Preferably, R 5 is a substituent located in the para position of the ring;
    优选，式I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；n、m独立的选自0-2的整数；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选自氢、卤素、C1-3烷基，优选，R4选自氢、F、Cl、甲基；优选，R4的取代位置为苯环的对位；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、吡啶、环己烷、噻唑、噁唑、咪唑；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，位于所述环的对位。Preferably, in Formula I, 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; 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, preferably, R 4 is selected from hydrogen, F, Cl, methyl; preferably, R The substitution position of Cy1 is the para position of the benzene ring; Cy1 represents a non-condensed 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; Cy1 is further substituted by one or more R5 ; preferably, Cy1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, imidazole; R5 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkoxyC1-3 alkylene, C3-7 cycloalkane, C1-3 alkane Preferably , R 5 is a substituent located at the para position of the ring.
  2. 如权利要求1所述的化合物、其药学可接受的盐、溶剂化物、或立体异构体，具有如下式II结构：
    The compound according to claim 1, its pharmaceutically acceptable salt, solvate, or stereoisomer, has the following structure:
    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；wherein 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独立的选自0-4的整数；n and m are independently selected from integers from 0 to 4;
    R3独立地选自氢、卤素、OH、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； R3 is independently selected from hydrogen, halogen, OH, 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选自氢、卤素、OH、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； R4 is selected from hydrogen, halogen, OH, 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;
    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，杂环或杂芳环中环杂原子选自N、O、S中的一个或多个；Cy1进一步被一个或多个R5取代；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 heteroatom in the heterocyclic ring or heteroaromatic ring is selected from one or more of N, O and S; Cy 1 is further substituted by one or more R 5 ;
    R5独立地选自氢、卤素、OH、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、或C1-6亚烷基C6-10芳基； R5 is independently selected from hydrogen , halogen , OH, CN, 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;
    优选，n、m独立的选自0-2的整数；Preferably, n and m are independently selected from integers of 0-2;
    优选，R4选自氢、卤素、C1-3烷基；Preferably, R 4 is selected from hydrogen, halogen, C 1-3 alkyl;
    优选，R4的取代位置为苯环的对位；Preferably, the substitution position of R 4 is the para position of the benzene ring;
    优选，Cy1是苯环、吡啶、环己烷、噻唑、噁唑、咪唑；Preferably, Cy 1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, imidazole;
    优选，R5为一个取代基，位于所述环的对位；Preferably, R 5 is a substituent located in the para position of the ring;
    优选，式II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；n、m独立的选自0-2的整数；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选自氢、卤素、C1-3烷基，优选，R4选自氢、F、Cl、甲基；优选，R4的取代位置为苯环的对位；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、吡啶、环己烷、噻唑、噁唑、咪唑；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，位于所述环的对位。Preferably, in Formula II, 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; 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, preferably, R 4 is selected from hydrogen, F, Cl, methyl; preferably, R The substitution position of Cy1 is the para position of the benzene ring; Cy1 represents a non-condensed 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 ring heteroatoms in the heteroaromatic ring and the heterocyclic ring are selected from one or more of N, O, and S; Cy1 is further substituted by one or more R5 ; preferably, Cy1 is a benzene ring, pyridine, cyclohexane, thiazole, oxazole, and imidazole; 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, preferably, R5 is a substituent located in the para position of the ring.
  3. 如权利要求1所述的化合物、其药学可接受的盐、溶剂化物、或立体异构体，具有如下式IIA结构：
    The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has the following structure:
    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、C1-6亚烷基C6-10芳基；Wherein, 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 1-6 alkylene C 6-10 aryl;
    m、n独立的选自0-4的整数；m and n are independently selected from integers of 0-4;
    R3选自氢、卤素、OH、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基； R3 is selected from hydrogen, halogen, OH, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkylene;
    Cy1选自被一个或多个R5取代的环己烷、苯环、吡啶环、噻唑环、咪唑环、噁唑环；Cy 1 is selected from cyclohexane, benzene ring, pyridine ring, thiazole ring, imidazole ring, oxazole ring substituted with one or more R 5 ;
    R5独立地选自氢、卤素、OH、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、或C1-6亚烷基C6-10芳基； R5 is independently selected from hydrogen , halogen, OH, CN, 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;
    优选，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；Preferably, 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;
    优选，m、n为0、1或2；Preferably, m and n are 0, 1 or 2;
    优选，R3选自氢、氟、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基；Preferably, R 3 is selected from hydrogen, fluorine, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxyC 1-3 alkylene;
    优选，R5选自氢、卤素、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3烷基、C3-7环烷烃、C1-3亚烷基C3-7环烷烃；Preferably, R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkyl, C 3-7 cycloalkane, C 1-3 alkylene C 3-7 cycloalkane;
    优选，R5为一个取代基，位于所述环的对位；Preferably, R 5 is a substituent located in the para position of the ring;
    优选，R1、R2独立地选自氢、C1-3烷基、C3-7环烷烃；m为0或1；n为1；R3选自氢、氟、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基；Cy1为苯环或吡啶；R5为氢，或位于所述环对位的C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3烷基。Preferably, R1 and R2 are independently selected from hydrogen, C1-3 alkyl, C3-7 cycloalkane; m is 0 or 1; n is 1; R3 is selected from hydrogen, fluorine, C1-3 alkyl, C1-3 alkoxy, C1-3 alkoxyC1-3 alkylene; Cy1 is a benzene ring or pyridine; R5 is hydrogen, or a C1-3 alkyl , C1-3 alkoxy or C1-3 alkoxyC1-3 alkyl located in the para position of the ring.
  4. 如权利要求1所述的化合物、其药学可接受的盐、溶剂化物、或立体异构体，具有式III结构：
    The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a structure of Formula III:
    其中，R2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；wherein R 2 is 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独立的选自0-4的整数，例如0，1，2，3或4；n, m are independently selected from integers of 0-4, such as 0, 1, 2, 3 or 4;
    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； 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； 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;
    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，杂芳环或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；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 or 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 ;
    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、或C1-6亚烷基C3-7环烷烃。 R5 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkylene , C3-7 cycloalkane , or C1-6 alkyleneC3-7 cycloalkane.
    优选，R3选自氢、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基；Preferably, R 3 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxyC 1-3 alkylene;
    优选，R4选自氢、卤素、CN、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基；Preferably, R 4 is selected from hydrogen, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxyC 1-3 alkylene;
    优选，R4取代位置位于苯环的对位。Preferably, the substitution position of R4 is located at the para position of the benzene ring.
    优选，Cy1是苯环或吡啶环；Preferably, Cy 1 is a benzene ring or a pyridine ring;
    优选，R5选自氢、卤素、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、或C1-3亚烷基C3-7环烷烃；Preferably, R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, or C 1-3 alkylene C 3-7 cycloalkane;
    优选，n选自1-3的整数；Preferably, n is selected from an integer of 1-3;
    优选，m选自0-2的整数；Preferably, m is selected from an integer of 0-2;
    优选，式III中，R2选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃或C1-3亚烷基C3-7环烷烃；n选自1-3的整数；m选自0-2的整数；R3选自氢、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基；R4选自氢、卤素、CN、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基，优选，R4选自F；优选，R4取代位置位于苯环的对位；Cy1是非稠合的单环，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，杂芳环或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是苯环或吡啶环；R5选自氢、卤素、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、或C1-3亚烷基C3-7环烷烃，优选，R5为一个取代基，取代位置位于Cy1环的对位。Preferably, in formula III, R2 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane or C1-3 alkylene C3-7 cycloalkane; n is selected from an integer of 1-3; m is selected from an integer of 0-2; R3 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy or C1-3 alkoxy C1-3 alkylene; R4 is selected from hydrogen, halogen, CN, C1-3 alkyl, C1-3 alkoxy or C1-3 alkoxy C1-3 alkylene, preferably, R4 is selected from F; preferably, the substitution position of R4 is located at the para position of the benzene ring; Cy1 is 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 heterocyclic ring heteroatoms are selected from one or more of N, O, and S; Cy1 is further substituted by one or more R5 ; preferably, Cy R 1 is a benzene ring or a pyridine ring; R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, or C 1-3 alkylene C 3-7 cycloalkane, preferably, R 5 is a substituent, and the substitution position is located at the para position of the Cy 1 ring.
  5. 如权利要求1所述的化合物、其药学可接受的盐、溶剂化物、或立体异构体，具有式IIIA结构，
    The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having a structure of formula IIIA,
    其中，R2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；wherein R 2 is 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;
    m独立的选自0-4的整数，例如0，1，2，3或4；m is independently selected from an integer of 0-4, such as 0, 1, 2, 3 or 4;
    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； 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;
    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，杂芳环或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； 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 or 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 ;
    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、或C1-6亚烷基C3-7环烷烃； R5 is selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkylene , C3-7 cycloalkane , or C1-6 alkyleneC3-7 cycloalkane;
    优选，R2选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃或C1-3亚烷基C3-7环烷烃；Preferably, R 2 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkylene, C 3-7 cycloalkane or C 1-3 alkylene C 3-7 cycloalkane;
    优选，R3选自氢、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基；Preferably, R 3 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkoxyC 1-3 alkylene;
    优选，Cy1是苯环或吡啶环；Preferably, Cy 1 is a benzene ring or a pyridine ring;
    优选，R5选自氢、卤素、C1-3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、或C1-3亚烷基C3-7环烷烃；Preferably, R 5 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkylene, or C 1-3 alkylene C 3-7 cycloalkane;
    优选，m选自0-2的整数；Preferably, m is selected from an integer of 0-2;
    优选，式IIIA中，R2选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃或C1-3亚烷基C3-7环烷烃；m选自0-2的整数；R3选自氢、C1-3烷基、C1-3烷氧基或C1-3烷氧基C1-3亚烷基；Cy1是非稠合的单环，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，杂芳环或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是苯环或吡啶环；R5选自氢、卤素、C1- 3烷基、C1-3烷氧基、C1-3烷氧基C1-3亚烷基、或C1-3亚烷基C3-7环烷烃，优选，R5为一个取代基，取代位置位于Cy1环的对位。Preferably, in formula IIIA, R2 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane or C1-3 alkylene C3-7 cycloalkane; m is selected from an integer of 0-2; R3 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy or C1-3 alkoxy C1-3 alkylene; Cy1 is a non-condensed 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 or the heterocyclic ring are selected from one or more of N, O and S; Cy1 is further substituted by one or more R5 , preferably, Cy1 is a benzene ring or a pyridine ring; R5 is selected from hydrogen, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkoxy C1-3 alkylene or C1-3 alkylene C3-7 cycloalkane, preferably, R 5 is a substituent, and the substitution position is located at the para position of the Cy 1 ring.
  6. 如权利要求1所述的化合物、其药学可接受的盐、溶剂化物、或立体异构体，具有式IIIB结构，
    The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having a structure of formula IIIB,
    其中，R2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；wherein R 2 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;
    m选自0-4的整数；m is an integer selected from 0 to 4;
    R3选自氢、C1-6烷基、C1-6烷氧基、或C3-7环烷烃；R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or C 3-7 cycloalkane;
    每个独立的表示双键或单键；Each Independent ones represent double or single bonds;
    W、Z1独立的选自C、N、O或S中的一个；优选W、Z1独立的选自C或N；W, Z 1 are independently selected from C, N, O or S; preferably W, Z 1 are independently selected from C or N;
    一个或多个R5连接六元环任意环碳和/或环氮原子上，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、C1-6亚烷基C3-7环烷烃；One or more R 5 are connected to any ring carbon and/or ring nitrogen atom of the six-membered ring, and R 5 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkylene, C 1-6 alkylene C 3-7 cycloalkane;
    优选，式IIIB中，R2选自氢、C1-3烷基、C1-3烷氧基C1-3亚烷基、C3-7环烷烃或C1-3亚烷基C3-7环烷烃；m为0、1或2；R3选自氢、C1-3烷基；每个独立的表示双键；W和Z1均为C，或，W为C且Z1为N，或，W为N且Z1为C；一个或多个R5连接六元环任意环碳和/或环氮原子，R5选自氢、卤素、C1-3烷基、C1- 3烷氧基、C1-3烷氧基C1-3亚烷基、或C1-3亚烷基C3-7环烷烃。Preferably, in Formula IIIB, R2 is selected from hydrogen, C1-3 alkyl, C1-3 alkoxy C1-3 alkylene, C3-7 cycloalkane or C1-3 alkylene C3-7 cycloalkane; m is 0, 1 or 2; R3 is selected from hydrogen, C1-3 alkyl; each Independently represents a double bond; W and Z1 are both C, or, W is C and Z1 is N, or, W is N and Z1 is C; one or more R5 are connected to any ring carbon and/or ring nitrogen atom of the six-membered ring, and R5 is selected from hydrogen, halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 alkoxy C1-3 alkylene, or C1-3 alkylene C3-7 cycloalkane.
  7. 如权利要求1所述的化合物、其药学可接受的盐、溶剂化物、或立体异构体，其选自以下结构：


    The compound according to claim 1, its pharmaceutically acceptable salt, solvate, or stereoisomer, which is selected from the following structures:


  8. 一种制备权利要求1-7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：A method for preparing the compound of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, characterized in that:
    步骤1、当X为N时，将式A结构的胺基化合物、式B化合物与羰基化试剂反应，合成得到式I化合物，
    Step 1: When X is N, react the amino compound of formula A and the compound of formula B with a carbonylating agent to synthesize a compound of formula I.
    或，当X为N时，式A’化合物与式B’化合物反应，得到式I化合物；
    Or, when X is N, the compound of formula A' reacts with the compound of formula B' to obtain a compound of formula I;
    或、当X为O时，将式C结构的胺基化合物与式D化合物反应，合成得到式I化合物，
    Or, when X is O, the amino compound of formula C is reacted with the compound of formula D to synthesize the compound of formula I,
    或，当X为O时，式C化合物、式D’化合物与三氟乙酸反应，得到式I化合物；
    Or, when X is O, the compound of formula C and the compound of formula D' are reacted with trifluoroacetic acid to obtain a compound of formula I;
    或，当X为O时，式E化合物与式F化合物反应，得到式I化合物；Or, when X is O, the compound of formula E reacts with the compound of formula F to obtain a compound of formula I;
    步骤2、如果需要，再根据目标产物的需要，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；Step 2: If necessary, the compound of formula I is functionally modified according to the needs of the target product 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;
    其中，Z为离去基团。Wherein, Z is a leaving group.
  9. 一种药物组合物，其特征在于，包括权利要求1-7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；A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt or solvate or a stereoisomer thereof;
    优选，所述药物组合物进一步含有药学上可接受的载体；Preferably, the pharmaceutical composition further contains a pharmaceutically acceptable carrier;
    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；Preferably, the pharmaceutical composition further contains other drugs for treating related diseases mediated by 5HT2A receptor and/or Sigma2 receptor activity;
    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***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、***、米氮平；Preferably, the other therapeutic drugs are selected from drugs for treating mental illnesses and drugs for treating central nervous system degenerative diseases; preferably, the The mental illness treatment drug is selected from benzodiazepine , barbiturates, chloral hydrate, buspirone, phenothiazines, thioxanthenes, butyrophenones, clozapine, risperidone, tricyclic antidepressants, heterocyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, ketamine, mirtazapine;
    优选，所述中枢神经***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***、金刚烷胺、利血平。Preferably, the drug for treating degenerative diseases of the central nervous system is selected from levodopa, bromocriptine, ergoline, diprophylline, amantadine, and reserpine.
  10. 权利要求1-7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；Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt or solvate or stereoisomer thereof in the preparation of a medicament for treating a disease mediated by Sigma2 receptor activity, a disease mediated by 5HT2A receptor activity, or a disease mediated by both Sigma2 receptor activity and 5HT2A receptor activity;
    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***疾病；Preferably, the related diseases mediated by the activity of 5HT2A receptor and/or Sigma2 receptor are central nervous system diseases;
    优选，所述中枢神经***疾病选自：精神疾病、中枢神经***退行性疾病、中枢神经***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；Preferably, the central nervous system disease is selected from: mental illness, central nervous system degenerative disease, mental disorder symptoms associated with or concurrent with central nervous system degenerative disease, and negative symptoms of mental illness;
    优选，所述精神疾病选自：抑郁症、焦虑症、躁狂症、精神***症、情感性***症、双相精神障碍、失眠、自闭症；Preferably, the mental illness is selected from the group consisting of depression, anxiety, mania, schizophrenia, schizoaffective disorder, bipolar disorder, insomnia, and autism;
    优选，所述中枢神经***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；Preferably, the degenerative disease of the central nervous system is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's disease, and Lewy body dementia;
    优选，所述中枢神经***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。 Preferably, the mental disorder symptoms associated with or concurrent with the degenerative diseases of the central nervous system and the negative symptoms of mental illness are selected from: affective disorders, language dysfunction, hallucinations, loss of interest, emotional blunting, loss of will, lack of pleasure, and social withdrawal.
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