WO2021147818A1 - 5-ht2a receptor antagonist and application thereof in treating central nervous system diseases - Google Patents

5-ht2a receptor antagonist and application thereof in treating central nervous system diseases Download PDF

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WO2021147818A1
WO2021147818A1 PCT/CN2021/072517 CN2021072517W WO2021147818A1 WO 2021147818 A1 WO2021147818 A1 WO 2021147818A1 CN 2021072517 W CN2021072517 W CN 2021072517W WO 2021147818 A1 WO2021147818 A1 WO 2021147818A1
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urea
methyl
ring
fluorobenzyl
benzyl
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PCT/CN2021/072517
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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 CN202010076067.9A external-priority patent/CN113214289B/en
Priority claimed from CN202010076066.4A external-priority patent/CN113214141B/en
Application filed by 瀚远医药有限公司 filed Critical 瀚远医药有限公司
Publication of WO2021147818A1 publication Critical patent/WO2021147818A1/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
    • A61K31/435—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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention belongs to the technical field of medicine, and relates to a 5-HT2A receptor antagonist or inverse agonist with a central nervous system disease treatment effect and applications thereof.
  • the compounds can be used to treat certain mental diseases (such as depression, anxiety, psychosis, schizophrenia, insomnia, autism, etc.) and degenerative diseases of the central nervous system (such as Alzheimer’s disease, Parkinson’s disease, etc.) Disease, Huntington’s disease, Lewy body dementia, etc.) related or concurrent mental disorders.
  • Serotonin or 5-hydroxytryptamine plays an extremely important role in the physiological functions of the human body.
  • 5-HT is an important neurotransmitter and neuromodulator, which regulates a variety of 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) play an extremely important role (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 acts through its receptors. According to the structure (amino acid sequence), biochemical (post-receptor mechanism of signal transduction) and pharmacological differences, 5-HT receptors are divided into 7 families (5-HT 1 ⁇ 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.
  • the 5-HT2A subtype receptors are widely and discretely expressed in the central nervous system, and are highest in the cerebral cortex, limbus, hippocampus, hypothalamus and basal ganglia that are involved in the regulation of higher cognitive and emotional functions. 5-HT2A receptors are expressed on dopamine, GABA, glutamate and Ach neurons and act as dendritic heterogeneous receptors (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 second messenger molecules such as loops.
  • G protein guanine nucleotide binding protein
  • cAMP adenylate
  • inositol phosphates adenylate
  • diacylglycerol adenylate
  • These second messenger molecules regulate the functions of a variety of intracellular enzymes (such as kinases and ion channels), and ultimately affect cell excitability and cell function.
  • 5-HT2A receptors are involved in the molecular mechanism of atypical antipsychotics such as clozapine, olanzapine, and risperidone (Gonzalez -Maeso J, et al., (2009) Trends Neurosci, 32: 225-232; Fricios 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 the treatment of negative symptoms of schizophrenia (such as affective disorders, language loss, etc.) (Blier P, et al., (2005) J Clin Psychiatry 66, Suppl 8, 30-40; Richt and NM, et al., (2008) Prog Brain Res, 172, 141-153; Meltzer, HY (2013) Annu Rev Med 64, 393-406); other studies have confirmed that cortical cones The 5-HT2A receptor regulation pathway of somatic neurons
  • the drugs used to treat mental illness are divided into two categories.
  • "Typical” antipsychotic drugs or the previous generation drugs have little clinical application due to the side effects of motor functions (extrapyramidal side effects, Parkinson's disease, etc.) caused by the previous generation of drugs.
  • Current drugs focus more on “atypical” antipsychotics.
  • Drugs (Prim Cre Companion J Clin Psychiatry. (2007) 9(6): 444-54).
  • the second-generation antipsychotic drugs all have broad-spectrum receptor activity. These compounds act as agonists, competitive antagonists or inverse agonists to modulate a variety of monoaminergic receptors such as 5-HT, dopaminergic, Adrenergic, muscarinic, or histaminergic receptors.
  • 5-HT2A receptor antagonists or inverse agonists especially those with high selectivity and/or no dopamine D2 receptor binding activity, is of great importance for promoting the development of anti-neuropsychiatric drugs.
  • these compounds can treat diseases while avoiding many side effects caused by non-selective receptor interactions.
  • the present invention provides a compound having 5-HT2A receptor antagonistic activity, and a pharmaceutical composition containing the compound for the treatment of central nervous system diseases, and further provides a method for the treatment of central nervous system diseases.
  • the present invention provides a compound having the structure of Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • n is selected from an integer of 0-4, which limits the number of alkylene units of the alkylene chain
  • the ring A group is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-8 membered aromatic ring group, 5-8 membered heteroaromatic ring group, or the above ring is 4-8 membered cycloalkane Group, 4-8 membered heterocycloalkyl group, 4-8 membered aromatic ring group or 4-8 membered heteroaromatic ring group fused to form a fused ring group;
  • n is selected from an integer of 1-4, ring A passes through (CH 2 )n through a ring carbon atom or a ring nitrogen atom.
  • the group is connected to the N atom of the main structure;
  • Any substitution position of the ring where Z is connected selected from -OCH 2 -, -O-, -N-, -S-, -SO 2 -, -CO- or -CH(OH)- group, when Z is -OCH 2 -, R 1 Z forms a R 1 -OCH 2 -structure;
  • R 1 is one or more substituents, independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , Substituted by substituents of C 1-6 alkyl or C 1-6 alkoxy;
  • Substituents R 1 Z can be one or more, located at any substitution position of the ring;
  • R 2 is one or more substituents, located at any substitution position of the ring, R 2 is independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkane Oxy, hydroxy or NO 2 ; the substitution means that the group is further substituted by C 1-6 alkyl, halogen, hydroxy or amino;
  • R 3 is one or more substituents, located at any substitution position of the ring, independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl , Substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylene hydroxy, hydroxyl, NO 2 , substituted or unsubstituted 5-7 membered aromatic ring carbonyl, substituted or unsubstituted 5-7 membered heteroaromatic ring carbonyl, substituted or unsubstituted 5-7 membered cycloalkylcarbonyl, substituted or unsubstituted 5-7 membered aromatic ring carbonyl C 1-6 alkylene, substituted or unsubstituted 5- 7-membered heteroaromatic ring carbonyl C 1-6 alkylene, substituted or unsubstituted 5-7 membered
  • R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkane Oxy, hydroxy, or NO 2 ; the substitution means that the group is further substituted with a C 1-6 alkyl, halogen, hydroxy, or amino group.
  • the ring A group is selected from 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered aromatic ring group, 5-8 membered heteroaromatic ring group, or the above ring is 4-8 membered cycloalkane Group, 4-8 membered heterocycloalkyl group, 4-8 membered aromatic ring group or 4-8 membered heteroaromatic ring group fused to form a condensed ring group; preferably ring A is azetidinyl, pyrrolidinyl, piperidinyl , Imidazolyl, C 4-7 cycloalkyl, quinazinyl, pyridooxazinyl;
  • n is selected from an integer of 1-4, ring A is connected to the main body through a ring carbon atom or a ring nitrogen atom through a (CH 2 )n group Structure N atom;
  • Any substitution position of the ring where Z is connected is selected from -O-, -N-, -S-, -SO 2 -, -CO- or -CH(OH)- group;
  • R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , C 1-6 alkyl or C 1-6 alkoxy substituents are substituted.
  • R 2 is one or more substituents, located at any substitution position of the ring, R 2 is independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkane Oxy, hydroxy or NO 2 ; the substitution means that the group is further substituted by C 1-6 alkyl, halogen, hydroxy or amino;
  • R 3 is one or more substituents, located at any substitution position of the ring, independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl , Substituted or unsubstituted C 1-6 alkoxy, C 1-6 alkylene hydroxy, hydroxy, NO 2 , said substitution means that the group is further substituted by C 1-6 alkyl, halogen, hydroxy or Amino substitution; preferably R 3 is one or more, independently selected from H, halogen, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, C 1-6 alkylene hydroxy, said substitution means that said group is further substituted by C 1-6 alkyl, halogen, hydroxy or amino.
  • R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkane Oxy, hydroxy, or NO 2 ; the substitution means that the group is further substituted with a C 1-6 alkyl, halogen, hydroxy, or amino group.
  • the present invention also provides a compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • n is selected from 0, 1, 2, or 3;
  • Ring X is the ring where X is located, where X is -(CH 2 )m-, and m is 0, 1, 2 or 3, so that X, nitrogen and other ring carbon atoms form a 4, 5, 6 or 7-membered nitrogen heterocycle, Ring X is connected to the alkylene chain of the main structure through a ring nitrogen atom or ring carbon atom;
  • Any substitution position of the ring where Z is connected is selected from -O-, -N-, -S-, -SO 2 -, -CO- or -CH(OH)- group;
  • R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , Substituted by substituents of C 1-6 alkyl or C 1-6 alkoxy;
  • R 2 is one or more substituents, located at any substitution position of the ring, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
  • R 3 is one or more substituents, located at any substitution position of the ring, independently selected from H, halogen, hydroxyl or NO 2 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3- 6-membered cycloalkyl, substituted or unsubstituted C 1-6 alkoxy; the "substituted” means that the group is further substituted with C 1-6 alkyl or halogen.
  • n 0, 1 or 2;
  • Ring X is a 4-6 membered nitrogen-containing heterocyclic ring
  • Z is -O-, -S-, -CO-, or -SO 2 -group
  • R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , C 1-6 alkyl or C 1-6 alkoxy substituent substituted, preferably R 1 is methyl, isobutyl, cyclobutane, oxolane, trifluoroethyl, or 2-hydroxy Isobutyl
  • R 2 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, hydroxyl or NO 2 ; preferably R 2 is halogen, particularly preferably fluorine;
  • R 3 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-6 membered cycloalkyl, Halogenated 3-6 membered cycloalkyl, hydroxy or NO 2 ; preferably C 1-6 alkyl, halogen, fluoro C 1-6 alkyl, 3-6 membered cycloalkyl.
  • n is selected from 1;
  • Ring X is a 4-6 membered nitrogen-containing heterocyclic ring
  • Z is -O-, -S-, -CO-, or -SO 2 -group
  • R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxyl , C 1-6 alkyl or C 1-6 alkoxy substituent substituted, preferably R 1 is methyl, isobutyl, cyclobutane, oxolane, trifluoroethyl, or 2-hydroxy Isobutyl
  • R 2 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, hydroxyl or NO 2 ; preferably R 2 is halogen, particularly preferably fluorine;
  • R 3 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-6 membered cycloalkyl, Hydroxy or NO 2 ; preferably C 1-6 alkyl, halogen, fluoro C 1-6 alkyl, 3-6 membered cycloalkyl.
  • the present invention also provides a compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • X is -(CH 2 ) m -, where m is 0, 1, 2 or 3, so that X, N and other ring carbon atoms form 4, 5, 6 or 7-membered aza Ring, the heterocyclic ring is connected to the N atom of the main structure through the ring C atom;
  • Ring B is condensed with ring X, and ring B is 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl;
  • Any substitution position of the ring where Z is connected is selected from -O-, -N-, -S-, -SO 2 -, -CO- or -CH(OH)- group;
  • R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , Substituted by substituents of C 1-6 alkyl or C 1-6 alkoxy;
  • R 2 is one or more substituents, located at any substitution position of the ring, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
  • R 3 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-6 membered cycloalkyl, Hydroxy or NO 2 ; preferably C 1-6 alkyl, halogen, fluoro C 1-6 alkyl, 3-6 membered cycloalkyl;
  • fused ring of ring X and ring B is selected from the following groups:
  • the present invention also provides a compound having the structure of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
  • p and q are selected from integers from 0 to 4 respectively,
  • Y is a carbon atom or a heteroatom, wherein the heteroatom is selected from O, S, N atoms,
  • Ring Y is the ring where the Y atom is located, and is connected to the main structure of the compound through a ring carbon atom or a ring N atom,
  • R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ;
  • R 3 is 1 or more substituents, located at any substitution position of the ring, R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, NO 2 , 5- 7-membered aromatic ring carbonyl, 5-7 membered heteroaromatic ring carbonyl or 5-7 membered cycloalkanecarbonyl, 5-7 membered aromatic ring carbonyl C 1-6 alkylene, 5-7 membered heteroaromatic ring carbonyl C 1-6 Alkylene or 5-7 membered cycloalkylcarbonyl C 1-6 alkylene, R 3 may be further substituted by H, halogen, C 1-6 alkyl, C 1-6 alkoxy, or hydroxy; preferably R 3 Replace at Y position;
  • R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
  • p is selected from 1, 2 or 3, so that the ring where Y is located corresponds to a 4, 5 or 6-membered ring,
  • q is selected from 0, 1 or 2
  • Y is a C or N atom
  • R 1 OCH 2 - is located at any substitution position of the ring
  • R 1 is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, and the R 1 is further selected from H, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy substituted; preferably R 1 OCH 2 -is located at the para-substitution position of the ring;
  • R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ; preferably R 2 is fluorine;
  • R 3 is 1 or more substituents, located at any substitution position of the ring, R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, NO 2 , 5- A 7-membered aromatic ring carbonyl C 1-6 alkylene group, a 5-7 membered heteroaromatic ring carbonyl C 1-6 alkylene group or a 5-7 membered cycloalkylcarbonyl C 1-6 alkylene group, R 3 may be further replaced by H , Halogen, C 1-6 alkyl, C 1-6 alkoxy, or hydroxy substituted; preferably R 3 is substituted at the Y position;
  • R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
  • p is selected from 1, 2 or 3, so that the ring where Y is located corresponds to a 4, 5 or 6-membered ring,
  • Y is N atom
  • R 1 OCH 2 - is located at any substitution position of the ring, preferably a para position, wherein R 1 is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, and the R 1 further Substitution is selected from H, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
  • R 2 is one or more substituents, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ; preferably substituted at the 2-position and/or 4-position Location;
  • R 3 is substituted at the Y position, and R 3 is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy or phenylcarbonyl C 1-6 alkylene;
  • R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
  • halogen refers to F, Cl, Br or I.
  • alkyl refers to saturated hydrocarbon groups, including straight chain alkyl groups and branched chain alkyl groups.
  • alkylene refers to a divalent alkyl group.
  • Alkylene chain is polymethylene, ie -(CH 2 )x-, where x is a positive integer.
  • cycloalkyl refers to a monocyclic hydrocarbon group that is saturated or contains one or more unsaturated units but is not aromatic.
  • the ring is a 3-20 membered ring, which has a single point of attachment to the rest of the compound .
  • heterocycloalkyl refers to a monocyclic group containing 1 to 5 independently selected from heteroatoms such as N, S, O, etc.
  • the heterocycloalkyl group may be a saturated ring or an unsaturated ring, so The ring is a 3-20 membered ring, including piperidine, pyrrolidine, tetrahydrofuran and the like.
  • aryl refers to a single ring, and the system has 5 to 10 (preferably 5, 6 or 9) ring members in total, and the ring members are ring carbon atoms; (4n+2) ⁇ electrons (where n is a positive integer) are shared in the system to comply with Huckel's rule.
  • heteroaryl and “heteroaryl ring group” refer to having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; (4n+2) ⁇ electrons (where n is a positive integer) to comply with shock Er’s rule; and in addition to carbon atoms, it also has 1 to 5 heteroatoms selected from nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen, For example, pyridine, imidazole group and the like.
  • substitution position in the ring means that the substituent group is located at any position in the ring that can be substituted, including substitution sites such as ring carbon atoms, ring nitrogen, and ring sulfur atoms.
  • substitution positions such as ring carbon atoms, ring nitrogen, and ring sulfur atoms.
  • the substitution position is the ortho, meta and/or para position relative to the substitution position of the main chain, or 2, 3, 4, 5 or 6 position (relative to the position where the benzene ring is connected to the main chain) );
  • the substitution position can be the position of the ring nitrogen, or the ortho, inter or para position of the ring nitrogen position, or the 2, 3, 4 or 5 positions.
  • 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 amino acids with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, etc., or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, lemon Acid, succinic acid, malonic acid, etc., or salts formed by using other methods in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cypionate, gluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, gluconate, hemisulfate, heptanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate , Malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate,
  • the present invention protects the following specific compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof:
  • the present invention protects a method for preparing a compound of formula I, which is characterized in that:
  • Step 1 The isocyanate compound of formula A and the amino compound of formula B are reacted according to the following reaction formula to synthesize the compound of formula I.
  • Step 2 If necessary, according to the needs of the target product, functional group modification is performed on the compound of formula I to convert it into a target product with the structure of formula I, or into a pharmaceutically acceptable salt or precursor compound of the compound.
  • the preparation method is also applicable to the preparation of the compound of formula IA, the compound of formula IB and the compound of formula IC.
  • the compound of formula I, compound of formula IA, compound of formula IB, compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer of the present invention has 5HT2A receptor inhibitory activity or inverse agonist activity, and can be used For the treatment of related diseases mediated by 5HT2A receptor activity.
  • the inhibitory activity of the compound of the present invention on 5HT2A is tested by using a Flp-In-CHO-5HT2A stable cell line and completed by the IP-One experiment.
  • 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. If the compound exhibits EC 50 ⁇ 1 ⁇ M, the compound tested in the above analysis is considered to have 5HT2A inhibitory activity.
  • Preferred compounds of the present invention have EC 50 ⁇ 150 nM, more preferred compounds have EC 50 ⁇ 50 nM, most preferred compounds have EC 50 ⁇ 25 nM, and particularly preferred compounds have EC 50 ⁇ 20 nM.
  • the compound of formula I, compound of formula IA, compound of formula IB, compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer of the present invention has good 5HT2A receptor antagonistic activity. Furthermore, the compounds of the present invention also have good selectivity, especially selectivity to 5HT2B and/or 5HT2C, reduced cardiotoxicity, and/or improved metabolic stability.
  • the present invention provides a compound of formula I, a compound of formula IA, a compound of formula IB, a compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof for preparing medicines for the treatment of related diseases mediated by 5HT2A receptor activity In the use.
  • the related diseases mediated by the 5HT2A receptor activity include, but are not limited to, central nervous system diseases.
  • the central nervous system disease includes but is not limited to: mental disease, central nervous system degenerative disease, central nervous system degenerative disease related or concurrent mental disorder symptoms, and negative symptoms of mental disease.
  • the mental illness includes, but is not limited to: depression, anxiety, mania, schizophrenia, schizoaffective disorder, bipolar disorder, insomnia, autism, etc.
  • the degenerative diseases of the central nervous system include but are not limited to: Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia and the like.
  • the mental disorder symptoms related to or concurrent with degenerative diseases of the central nervous system, and negative symptoms of mental diseases include, but are not limited to: affective disorders, language dysfunction, hallucinations, loss of interest, and the like.
  • the present invention provides a pharmaceutical composition characterized by comprising a compound of formula I, a compound of formula IA, a compound of formula IB, a compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • the pharmaceutical composition can be used to treat related diseases mediated by 5HT2A receptor activity.
  • the definition of the related diseases mediated by the 5HT2A receptor activity is as described above.
  • the pharmaceutical composition further contains a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is various auxiliary materials commonly used or known in the pharmaceutical field, including but not limited to: diluents, binders, antioxidants, pH regulators, preservatives, lubricants, disintegrants, etc. .
  • the diluent examples include lactose, starch, cellulose derivatives, inorganic calcium salts, sorbitol and the like.
  • the binder is, for example, starch, gelatin, sodium carboxymethyl cellulose, polyvinylpyrrolidone and the like.
  • the antioxidants are, for example, vitamin E, sodium bisulfite, sodium sulfite, butylated hydroxyanisole and the like.
  • the pH adjusting agent includes, for example, hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, Tris, acetic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and the like.
  • the preservatives include, for example, methyl paraben, ethyl paraben, m-cresol, benzalkonium chloride and the like.
  • the lubricants are, for example, magnesium stearate, micronized silica gel, talc and the like.
  • the disintegrant is for example: starch, methyl cellulose, xanthan gum, croscarmellose sodium and the like.
  • the pharmaceutical composition contains a compound of formula I, a compound of formula IA, a compound of formula IB, a compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer in an amount of 0.1-1000 mg, preferably 1- 500 mg, more preferably 5-100 mg.
  • the compound of formula I, compound of formula IA, compound of formula IB, compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the pharmaceutical composition accounts for 10%-90% by mass of the pharmaceutical composition %, preferably 20%-80%, more preferably 30%-70%.
  • the dosage form of the pharmaceutical composition can be an oral dosage form, such as tablets, capsules, pills, powders, granules, suspensions, syrups, etc.; it can also be an injection dosage form, such as injections, powder injections, etc. , Administered by intravenous, intraperitoneal, subcutaneous or intramuscular route injection. All dosage forms used are well known to those of ordinary skill in the pharmaceutical arts.
  • the administration route of the pharmaceutical composition includes, but is not limited to: oral; buccal; sublingual; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous and intradermal , Intramuscular, intravenous; by implanting reservoirs or reservoirs.
  • the dosage of the compound of formula I, the compound of formula IA, the compound of formula IB, the compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof will depend on the age, health and weight of the recipient. Type of drug, frequency of treatment, 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 of two, three or four times a day .
  • the dosage can be administered once or multiple times, and the administration time can be from a single day to several months or longer.
  • the dosage of the compound of formula I, compound of formula IA, compound of formula IB, compound of formula IC, 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, and so on.
  • the pharmaceutical composition can be used in combination with other drugs for treating related diseases mediated by 5HT2A receptor activity.
  • the pharmaceutical composition may further contain a second therapeutic agent, and the second therapeutic agent is another drug for treating related diseases mediated by 5HT2A receptor activity.
  • the present invention provides a method for treating related diseases mediated by 5HT2A receptor activity, which is characterized by administering a therapeutically effective amount of a compound of formula I, a compound of formula IA, a compound of formula IB, a compound of formula IC to a patient in need, or A pharmaceutically acceptable salt, solvate, or stereoisomer.
  • the administration route of the compound of formula I, compound of formula IA, compound of formula IB, compound of formula IC or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof includes, but is not limited to: oral; buccal; tongue Subcutaneous; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial; by implanting a reservoir or liquid storage Device.
  • the method further includes administering other drugs for treating related diseases mediated by 5HT2A receptor activity to patients in need.
  • drugs for the treatment of related diseases mediated by 5HT2A receptor activity include but are not limited to: drugs for mental illness, drugs for degenerative diseases of the central nervous system, and the like.
  • the mental illness treatment drugs include but are not limited to: benzodiazepine Class (e.g. methyltriazepam, chlorazide , Clonazepam, diazepam, sulazepam, fluazepam, midazolam, etc.); barbiturates (e.g., phenobarbital, pentobarbital, etc.); chloral hydrate; Cyclic ketones; phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, etc.); thioxanthenes (e.g., Thioxanthene); butyrylbenzenes (e.g., haloperidol ); clozapine; risperidone; tricyclic antidepressants (for example: imipramine, doxepin, nortriptyline, amitriptyline, etc.); heterocyclic antidepressants (for example: a Moxapine, map
  • fluoxetine paroxetine, sertraline, citalopram , Fluvoxamine, etc.
  • monoamine oxidase inhibitors for example: phenelzine, moclobemide, etc.
  • ketamine mirtazapine.
  • the drugs for the treatment of degenerative diseases of the central nervous system include but are not limited to: levodopa, bromocriptine, thipropergoline, propargyl amphetamine, amantadine, and ureteride.
  • DIEA N,N-diisopropylethylamine
  • Pd(PPh3)4 Tetra(triphenylphosphine) palladium
  • Et ethyl
  • Ac acetyl
  • EtOAc is ethyl acetate or ethyl acetate
  • ETOH is ethanol.
  • Triphosgene Triphosgene
  • Non-7-yl)-urea (compound #1): (4-fluoro-benzyl)-(9-methyl-3-oxa-9-aza-bicyclo[3 ,3,1]non-7-yl)amine (1) in anhydrous THF (5ml) was slowly added to 1-isobutoxy-4-(isocyanatomethyl)benzene in DCM (5.0mL ) In solution. The resulting mixture was heated at 40°C for about 10 minutes. The solvent was removed under vacuum. The crude product was purified by high performance liquid chromatography.
  • Octahydro-quinazin-2-one 900 mg of 2-carbonyl-octahydro-quinazine-1-carboxylic acid ethyl ester (5-2) was refluxed in 10 ml of 6N HCl for 20 hours. The reaction mixture was neutralized with solid Na 2 CO 3 and extracted with 3 ⁇ 30 ml of ether. The organic phase was washed with brine and dried with Na 2 SO 4. The solvent was evaporated to obtain 300 mg of crude product (yield 49%).
  • Hexahydro-pyrido[2,1-c][1,4]oxazin-8-one (7-3) The synthesis method is similar to (5-3). Use 8-carbonyl-octahydro-pyrido[2,1-c][1,4]oxazine-9-carboxylic acid ethyl ester (7-2) (900mg, 4.0mmol) to obtain the crude product (300mg, 48 % Yield) used directly in the next reaction.
  • the synthesis method is similar to compound #1. Use 0.76mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) as raw material to react with H001-004 compound to obtain a white solid compound #H001-018 ER10174 (26.2mg, 8% yield).
  • the synthesis method is similar to compound #1.
  • Use 1.0mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) and 1-(1-ethylpyrrolidin-3-yl)-N- (4-fluorobenzyl) methylamine was reacted to obtain the product compound #H001-026ER10177 (80mg, 18% yield).
  • N-(4-fluorobenzyl)-2-(1-methylpyrrolidin-2-yl)ethane-1-amine (H001-031): The synthesis method is similar to (1-1). Using 10 mmol of 2-(1-methylpyrrolidin-2-yl)ethane-1-amine, the intermediate (H001-031) (486 mg, 21% yield) was obtained as a brown oil. LCMS: [M+1] + 237.3.
  • ER10203 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylazetidine-3-yl)methyl)urea (H002-037)
  • the synthesis method of ER10203 is similar to compound #1, using 0.15mmol 1-isobutoxy-4-isocyanatomethyl-benzene(1-4) and N-(4-fluorobenzyl)-1-(1 -Methylazetidine-3-yl)methylamine (H001-057) was reacted to obtain a white solid compound H002-037 ER10203 (20 mg, 29% yield).
  • Example compounds were prepared and purified by the following method, similar to the preparation method of compound #1, containing 1-(2,4-difluorobenzyl)-3-(4-hydroxybenzyl)-1-((1-methyl Piperidin-4-yl)methyl)urea (50mg, 0.124mmol), cesium carbonate (121mg, 0.37mmol), 2,2-dimethyloxirane (89mg, 1.24mmol) and DMF (1.0mL ) The mixture is placed in a sealed tube and heated at 100°C overnight. The resulting mixture was purified by HPLC to obtain the target product (H003-042) ER10248 (13 mg, 22% yield). LCMS: [M+1] + 476.8.
  • the compound of this example uses the preparation and purification method similar to that of Example 58, using (R)-1-(4-fluorobenzyl)-3-(4-hydroxybenzyl)-1-((1-methylpyrrolidine) -3-yl)methyl)urea (50mg, 0.135mmol) as a raw material to obtain (R)-3-(4-(2-hydroxy-2-methylpropoxy)benzyl)-1-(4 -Fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea (H003-035) ER10247 (60 mg, 12%).
  • (2,4-Difluorobenzyl)-(1-(N-tert-butoxycarbonyl)piperidin-4-yl)amine (II-8) is prepared similarly to (4-fluoro-benzyl)- Preparation of (1-methylpiperidin-4-yl)-amine (II-1): Use 9.33mmol (N-tert-butoxycarbonyl)piperidin-4-yl)amine to obtain a colorless oily intermediate (II- 8) The crude product (2.0g) was used directly in the next reaction without further purification.
  • urea (III-7) is similar to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl )
  • Preparation of urea (III-1) use 4-cyclopropoxymethyl-1-benzylamine (I-4) (30mg, 0.182mmol, 1.0equiv.) and N-(2,4-difluoro Benzyl)-1-(1-methylpiperidin-4-yl)methylamine (II-5) (46.2mg, 0.182mmol, 1.0 equiv.), purified by silica gel column to give the final product (20mg, yield 24.0%).
  • LCMS [M+1] + 458.8.
  • urea (III-8) 3-((4-isopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)
  • the preparation of urea (III-8) is similar to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) )
  • Preparation of urea (III-1) use 4-isopropoxymethyl-1-benzylamine (I-1) (30mg, 0.182mmol, 1.0equiv.) and N-(2,4-difluoro Benzyl)-1-(1-methylpiperidin-4-yl)methylamine (II-5) (46.2mg, 0.182mmol, 1.0 equiv.), purified by silica gel column to give the final product (31mg, yield 37.0%).
  • LCMS [M+1] + 460.8.
  • Step 1 3-((4-Methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-(N-tert-butoxycarbonyl)piperidine- Preparation of 4-methyl)urea
  • the ER10152 used is the positive control, and the structural formula is: It is commercially available or synthetically prepared according to the method described in US7601740B2.
  • the IP-One experiment was selected to complete the test.
  • the following experiments were done using 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 IP1 labeled with d2 provided in 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 produced by transfecting CHO cells with pFRT//acZeo2 and selecting Zeocin TM resistant clones to produce Flp- In TM -CHO cell line.
  • 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 with human HTR2A gene ( Human HTR2A, GeneBank, NM_000621) was stably transfected to obtain Flp-In-CHO-5HT2A cells.
  • the stably transfected cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone) + 1 x Penicilin-Streptomycin + 800 ⁇ g/ml Hygromycin B (ant-hg-5, Invivogen).
  • the Flp-In-CHO-5HT2A stable cell line was cultured in a 384-well plate (7.5K) for 20 hours at 37°C and 5% CO 2.
  • the compound was diluted with Ham's F-12K medium to different concentrations, and the medium was replaced with fresh medium at 100 ⁇ l/well for overnight culture.
  • the cells were treated with compound for 30 minutes and 5-HT was added and incubated at 37 degrees Celsius for 45 minutes, then the sequence After adding lysis detection buffer, IP1-d2 and IP1-Ab, incubating for 1 hour at room temperature, read the plate on Envision (HTRF module), and calculate the inhibitory rate of the compound on the cell 5-HT2A receptor.
  • HTRF module plate on Envision
  • the IP-One experiment was selected to complete the test.
  • the following experiments were performed using Flp-In-CHO-5HT2B/2C VGV 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 IP1 labeled with d2 provided in 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 produced by transfecting CHO cells with pFRT//acZeo2 and selecting Zeocin TM resistant clones to produce Flp- In TM -CHO cell line.
  • Flp-In TM -CHO cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Gibco)+1 ⁇ Penicilin-Streptomycin (15140122, Gibco), and then human HTR2B/2C VGV gene (Human HTR2B, GeneBank, NM_000867; Human HTR2C (5-HT2C VGV ), GeneBank, NM_000868) were stably transfected to obtain Flp-In-CHO-5HT2B/2C VGV cells.
  • the stably transfected cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Gibco) + 1 x Penicilin-Streptomycin + 800 ⁇ g/ml Hygromycin B (ant-hg-5, Invivogen).
  • FBS Gibco
  • Penicilin-Streptomycin + 800 ⁇ g/ml Hygromycin B anti-hg-5, Invivogen.
  • the Flp-In-CHO-5HT2B/2C VGV stable cell line was cultured in a 384-well plate (5K, 7.5K) for 20 hours at 37 degrees Celsius and 5% CO 2.
  • the compound was diluted with Ham's F-12K medium to different concentrations, and the medium was replaced with fresh medium at 100 ⁇ l/well for overnight culture.
  • the cells were treated with compound for 30 minutes and 5-HT was added and incubated at 37 degrees Celsius for 45 minutes, then the sequence After adding the lysis detection buffer, IP1-d2 and IP1-Ab, incubating for 1 hour at room temperature, the plate was read on Envision (HTRF module), and the inhibition rate of the compound on the 5-HT2B/2C VGV receptor of the cells was calculated.
  • HTRF module Envision
  • the hERG membrane protein specific binding experiment was selected to complete the detection.
  • the experiment used the HEK293 cell line stably expressing hERG (human Ether-a-go-go Related Gene) encoding potassium channel to complete the experiment.
  • the potassium channel encoded by hERG mediates a delayed rectifier potassium current (IKr), and Ikr inhibition is the most important mechanism for the prolongation of the QT interval caused by drugs.
  • IKr delayed rectifier potassium current
  • hERG's lack of function or drug inhibition will affect the repolarization process of cardiac action potentials and cause the QT interval to prolong. At the same time, it may induce torsade de pointes ventricular tachycardia and lead to arrhythmia.
  • hERG membrane protein, detection compound and a fixed concentration of radioligand are mixed, so that the detection compound and radioligand can competitively bind to hERG membrane protein.
  • vacuum filtration is used to remove no binding to membrane protein.
  • CPM isotope signal
  • the liver is the main organ for the metabolism of endogenous matrix and exogenous drugs.
  • in vitro tools that can help researchers study the metabolism of candidate drugs, including isolated fresh or cryopreserved liver cells, liver slices, and subcellular components such as liver microparticles and S9 components. These subcellular components are prepared from the liver through a series of homogenization and ultracentrifugation methods.
  • the S9 fraction produced by the initial low-speed centrifugation of 10,000g liver homogenate is the fraction in the supernatant obtained by this centrifugation method.
  • the S9 component contains all phase I and phase II enzymes, and the S9 component is further centrifuged at 100,000 g to obtain endoplasmic reticulum-derived microparticles.
  • Microsomes are rich in cytochrome P450 (CYP) and flavin monooxygenase (FMO).
  • CYP cytochrome P450
  • FMO flavin monooxygenase
  • phase II enzymes such as certain glycoside glucuronyltransferase UGT subtypes and cyclohydrolase EH are also present in the microsomes.
  • Microsomes can be used to study the activity of UGT, however, the microsomal membrane restricts the entry of UGT matrix and/or cofactors.
  • the best UGT activity can be achieved by adding MgCl 2 and pore-forming antibiotics (such as propylmethacin). These components allow the glucuronic acid product and the cofactor UDPGA in the microsomal network to be efficiently transported.
  • Individual or combined donor liver microsomes can be used for metabolism-related research. The combined donors can represent population averages or specific research factors such as age, BMI, or the limiting capacity of specific CYP subtypes. The purpose of this study is to evaluate the metabolic stability of the compound in human liver microsomes.
  • the human liver microsomes used in this test system were purchased from Corning (Cat No. 452117) and stored in a refrigerator below -60°C before use.
  • Coenzymes are NADPH (Chem-impex international, Cat. No. 00616) and UDPGA (Sigma, Cat. No. U6751) cofactors.
  • NADPH Chem-impex international, Cat. No. 00616
  • UDPGA Sigma, Cat. No. U6751
  • CL int(mic) 0.693/T 1/2 /microsomal protein content (microsomal protein concentration mg/mL during incubation)
  • CL int(liver) CL int(mic) ⁇ the amount of microsomal protein in the liver (mg/g) ⁇ liver weight-to-weight ratio
  • the intrinsic liver clearance rate and liver clearance rate can be converted by the following formula:

Abstract

A compound of a structure of formula I having a central nervous system disease treatment effect, which has the activity of a 5-HT2A receptor antagonist or an inverse agonist, has high 5-HT2A receptor selectivity, low cardiotoxicity, and good metabolic stability, and can be applied to treat some mental diseases (such as depression, anxiety disorders, psychiatric disorders, schizophrenia, insomnia, and autism) and central nervous system degenerative disorder (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and dementia with Lewy bodies)-related or complicated mental disorders.

Description

5-HT2A受体拮抗剂及其治疗中枢神经***疾病的应用5-HT2A receptor antagonist and its application in the treatment of central nervous system diseases
本申请要求2020年1月21日向中国国家知识产权局提交的专利申请号为202010076067.9，发明名称为“5-HT2A受体拮抗剂及其治疗中枢神经***疾病的应用”和专利申请号为202010076066.4，发明名称为“5-HT2A受体拮抗剂及其制备和应用”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 requires that the patent application number submitted to the State Intellectual Property Office of China on January 21, 2020 is 202010076067.9, the title of the invention is "5-HT2A receptor antagonist and its application in the treatment of central nervous system diseases" and the patent application number is 202010076066.4, Priority of the prior application with the title of "5-HT2A receptor antagonist and its preparation and application". The full text of the prior application is incorporated into this application by reference.
技术领域Technical field
本发明属于医药技术领域，涉及一种具有中枢神经***疾病治疗作用的5-HT2A受体拮抗剂或反向激动剂及其应用。所述化合物可以用于治疗某些精神疾病(如抑郁症，焦虑症，精神病，精神***症，失眠，自闭症等)及与中枢神经***退行性疾病(如阿尔兹海默症，帕金森病，亨廷顿病，路易小体痴呆症等)相关或者并发的精神紊乱症状。The invention belongs to the technical field of medicine, and relates to a 5-HT2A receptor antagonist or inverse agonist with a central nervous system disease treatment effect and applications thereof. The compounds can be used to treat certain mental diseases (such as depression, anxiety, psychosis, schizophrenia, insomnia, autism, etc.) and degenerative diseases of the central nervous system (such as Alzheimer’s disease, Parkinson’s disease, etc.) Disease, Huntington’s disease, Lewy body dementia, etc.) related or concurrent mental disorders.
背景技术Background technique
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-HT 1～5-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 the physiological functions of the human body. In the central nervous system, 5-HT is an important neurotransmitter and neuromodulator, which regulates a variety of 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) play an extremely important role (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 acts through its receptors. According to the structure (amino acid sequence), biochemical (post-receptor mechanism of signal transduction) and pharmacological differences, 5-HT receptors are divided into 7 families (5-HT 1～5). -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。The 5-HT2A subtype receptors are widely and discretely expressed in the central nervous system, and are highest in the cerebral cortex, limbus, hippocampus, hypothalamus and basal ganglia that are involved in the regulation of higher cognitive and emotional functions. 5-HT2A receptors are expressed on dopamine, GABA, glutamate and Ach neurons and act as dendritic heterogeneous receptors (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 second messenger molecules such as loops. The levels of adenylate (cAMP), inositol phosphates, and diacylglycerol increase or decrease. These second messenger molecules regulate the functions of a variety of intracellular enzymes (such as kinases and ion channels), and ultimately affect cell excitability and cell 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 transmission of 5-HT is related to the pathogenesis of a variety of mental diseases, such as mental diseases (depression, panic attacks, schizophrenia, suicidal tendencies, etc.) and neurodegenerative diseases (Alzheimer’s disease, Huntington’s disease, Pa Jinsen disease, etc.) (Fioravanti et al., (1992) Brain Cogn. 18, 116-124; Sinopoli VM, et al., (2017) Neurosci Biobehav Rev, 80: 372-381). In recent years, studies have found that 5-HT2A receptors are closely related to the pathological state of neuropsychiatric diseases. 5-HT2A receptors are involved in the molecular mechanism of atypical antipsychotics 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 the treatment of negative symptoms of schizophrenia (such as affective disorders, language loss, etc.) (Blier P, et al., (2005) J Clin Psychiatry 66, Suppl 8, 30-40; Richt and NM, et al., (2008) Prog Brain Res, 172, 141-153; Meltzer, HY (2013) Annu Rev Med 64, 393-406); other studies have confirmed that cortical cones The 5-HT2A receptor regulation pathway of somatic neurons is essential to mediate signal transduction and behavioral responses triggered by hallucinogens (Gonzalez-Maeso J, et al., (2009) Trends Neurosci, 32: 225-232), It suggests the role of 5-HT2A receptors in the treatment of hallucinations 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、II型糖尿病等副作用的原因。大多数抗精神病药物都具有多巴胺D2受体拮抗作用，现已证明与锥体外系副作用相关(Strange PG.(2001)Pharmacol Rev，53(1)：119-33；Tuppurainen H，et al.，(2010)Nord J Psychiatry，64(4)：233-8；Sykes DA，et al.，(2017)Nat Commun，8(1)：763)。因此，开发更多种5-HT2A受体拮抗剂或反向激动剂，尤其是具有选择性高的，和/或无多巴胺D2受体结合活性等特性，对于推动抗神经精神疾病药物发展有至关重要的作用，这类化合物在治疗疾病同时能够避免由于无选择性受体相互作用导致的诸多副作用。The drugs used to treat mental illness, namely antipsychotics, are divided into two categories. "Typical" antipsychotic drugs or the previous generation drugs have little clinical application due to the side effects of motor functions (extrapyramidal side effects, Parkinson's disease, etc.) caused by the previous generation of drugs. Current drugs focus more on "atypical" antipsychotics. Drugs (Prim Cre Companion J Clin Psychiatry. (2007) 9(6): 444-54). However, the second-generation antipsychotic drugs all have broad-spectrum receptor activity. These compounds act as agonists, competitive antagonists or inverse agonists to modulate a variety of monoaminergic receptors such as 5-HT, dopaminergic, Adrenergic, muscarinic, or histaminergic receptors. This broad-spectrum regulation is likely to cause side effects such as abnormal sedation, abnormal motor function, and type II diabetes. Most antipsychotic drugs have dopamine D2 receptor antagonism, which has been proved to be related to extrapyramidal side effects (Strange PG. (2001) Pharmacol Rev, 53(1): 119-33; Tuppurainen H, et al., ( 2010) Nord J Psychiatry, 64(4): 233-8; Sykes DA, et al., (2017) Nat Commun, 8(1): 763). Therefore, the development of more kinds of 5-HT2A receptor antagonists or inverse agonists, especially those with high selectivity and/or no dopamine D2 receptor binding activity, is of great importance for promoting the development of anti-neuropsychiatric drugs. Importantly, these compounds can treat diseases while avoiding many side effects caused by non-selective receptor interactions.
发明内容Summary of the invention
本发明提供一种具有5-HT2A受体拮抗活性的化合物，及含有该化合物的用 于治疗中枢神经***疾病的药物组合物，并进一步提供中枢神经***疾病的治疗方法。The present invention provides a compound having 5-HT2A receptor antagonistic activity, and a pharmaceutical composition containing the compound for the treatment of central nervous system diseases, and further provides a method for the treatment of central nervous system diseases.
具体而言，本发明提供一种具有式I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：Specifically, the present invention provides a compound having the structure of Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure PCTCN2021072517-appb-000001
Figure PCTCN2021072517-appb-000001
其中，in,
n选自0-4的整数，限定所述亚烷基链的亚烷基单元数量；n is selected from an integer of 0-4, which limits the number of alkylene units of the alkylene chain;
环A基团选自3-8元环烷基、3-8元杂环烷基、5-8元芳环基、5-8元杂芳环基，或上述环被4-8元环烷基，4-8元杂环烷基、4-8元芳环基或4-8元杂芳环基稠合形成的稠合环基；The ring A group is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-8 membered aromatic ring group, 5-8 membered heteroaromatic ring group, or the above ring is 4-8 membered cycloalkane Group, 4-8 membered heterocycloalkyl group, 4-8 membered aromatic ring group or 4-8 membered heteroaromatic ring group fused to form a fused ring group;
当n＝0时，环A通过环碳原子或环N原子与主体结构N原子连接，当n选自1-4的整数时，环A通过环碳原子或环氮原子通过(CH 2)n基团连接主体结构N原子； When n=0, ring A is connected to the N atom of the main structure through a ring carbon atom or a ring N atom. When n is selected from an integer of 1-4, ring A passes through (CH 2 )n through a ring carbon atom or a ring nitrogen atom. The group is connected to the N atom of the main structure;
Z连接所在环任意取代位置，选自-OCH 2-，-O-，-N-，-S-，-SO 2-，-CO-或-CH(OH)-基团，当Z为-OCH 2-时，R 1Z形成R 1-OCH 2-结构； Any substitution position of the ring where Z is connected, selected from -OCH 2 -, -O-, -N-, -S-, -SO 2 -, -CO- or -CH(OH)- group, when Z is -OCH 2 -, R 1 Z forms a R 1 -OCH 2 -structure;
R 1为1或多个取代基，彼此独立选自C 1-6烷基，3-6元环烷基，4-6元杂环烷基，所述R 1被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基的取代基取代； R 1 is one or more substituents, independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , Substituted by substituents of C 1-6 alkyl or C 1-6 alkoxy;
取代基R 1Z可为1或多个，位于所在环的任意取代位置； Substituents R 1 Z can be one or more, located at any substitution position of the ring;
R 2为1或多个取代基，位于所在环的任意取代位置，R 2彼此独立选自H、卤素，取代或未取代的C 1-6烷基，取代或未取代的C 1-6烷氧基、羟基或NO 2；所述取代是指所述基团进一步被C 1-6烷基、卤素、羟基或氨基取代； R 2 is one or more substituents, located at any substitution position of the ring, R 2 is independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkane Oxy, hydroxy or NO 2 ; the substitution means that the group is further substituted by C 1-6 alkyl, halogen, hydroxy or amino;
R 3为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H，卤素，取代或未取代的C 1-6烷基，取代或未取代的3-6元环烷基，取代或未取代的C 1-6烷氧基、取代或未取代的C 1-6亚烷基羟基，羟基，NO 2，取代或未取代的5-7元芳环羰基，取代或未取代的5-7元杂芳环羰基，取代或未取代的5-7元环烷羰基，取代或未取代的5-7元芳环羰基C 1-6亚烷基，取代或未取代的5-7元杂芳环羰基C 1-6亚烷基，取代或未取代的5-7元环烷羰基C 1-6亚烷基；所述取代是指所述基团进一步被H，卤素，C 1-6烷基，C 1-6烷氧基，氨基或羟基取代。 R 3 is one or more substituents, located at any substitution position of the ring, independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl , Substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylene hydroxy, hydroxyl, NO 2 , substituted or unsubstituted 5-7 membered aromatic ring carbonyl, substituted or unsubstituted 5-7 membered heteroaromatic ring carbonyl, substituted or unsubstituted 5-7 membered cycloalkylcarbonyl, substituted or unsubstituted 5-7 membered aromatic ring carbonyl C 1-6 alkylene, substituted or unsubstituted 5- 7-membered heteroaromatic ring carbonyl C 1-6 alkylene, substituted or unsubstituted 5-7 membered cycloalkane carbonyl C 1-6 alkylene; the substitution means that the group is further replaced by H, halogen, C 1-6 alkyl, C 1-6 alkoxy, amino or hydroxy substituted.
R 4为1或多个取代基，位于所在环的任意取代位置，R 4彼此独立选自H、卤素，取代或未取代的C 1-6烷基，取代或未取代的C 1-6烷氧基、羟基或NO 2；所述取代是指所述基团进一步被C 1-6烷基、卤素、羟基或氨基取代。 R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkane Oxy, hydroxy, or NO 2 ; the substitution means that the group is further substituted with a C 1-6 alkyl, halogen, hydroxy, or amino group.
式I化合物中，优选，Among the compounds of formula I, preferably,
环A基团选自4-8元环烷基、4-8元杂环烷基、5-8元芳环基、5-8元杂芳环基，或上述环被4-8元环烷基，4-8元杂环烷基、4-8元芳环基或4-8元杂芳环基稠合形成的稠合环基；优选环A为吖丁啶基，吡咯烷基，哌啶基，咪唑基，C 4-7环烷基，喹嗪基，吡啶并噁嗪基； The ring A group is selected from 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 5-8 membered aromatic ring group, 5-8 membered heteroaromatic ring group, or the above ring is 4-8 membered cycloalkane Group, 4-8 membered heterocycloalkyl group, 4-8 membered aromatic ring group or 4-8 membered heteroaromatic ring group fused to form a condensed ring group; preferably ring A is azetidinyl, pyrrolidinyl, piperidinyl , Imidazolyl, C 4-7 cycloalkyl, quinazinyl, pyridooxazinyl;
当n＝0时，环A通过环碳原子与主体结构N原子连接，当n选自1-4的整数时，环A通过环碳原子或环氮原子通过(CH 2)n基团连接主体结构N原子； When n=0, ring A is connected to the main structure N atom through a ring carbon atom. When n is selected from an integer of 1-4, ring A is connected to the main body through a ring carbon atom or a ring nitrogen atom through a (CH 2 )n group Structure N atom;
Z连接所在环任意取代位置，选自-O-，-N-，-S-，-SO 2-，-CO-或-CH(OH)-基团； Any substitution position of the ring where Z is connected is selected from -O-, -N-, -S-, -SO 2 -, -CO- or -CH(OH)- group;
R 1为1或多个取代基，彼此独立选自C 1-6烷基，4-6元环烷基，4-6元杂环烷基，所述R 1被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基的取代基取代。 R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , C 1-6 alkyl or C 1-6 alkoxy substituents are substituted.
R 2为1或多个取代基，位于所在环的任意取代位置，R 2彼此独立选自H、卤素，取代或未取代的C 1-6烷基，取代或未取代的C 1-6烷氧基、羟基或NO 2；所述取代是指所述基团进一步被C 1-6烷基、卤素、羟基或氨基取代； R 2 is one or more substituents, located at any substitution position of the ring, R 2 is independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkane Oxy, hydroxy or NO 2 ; the substitution means that the group is further substituted by C 1-6 alkyl, halogen, hydroxy or amino;
R 3为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H，卤素，取代或未取代的C 1-6烷基，取代或未取代的3-6元环烷基，取代或未取代的C 1-6烷氧基、C 1-6亚烷基羟基、羟基、NO 2，所述取代是指所述基团进一步被C 1-6烷基、卤素、羟基或氨基取代；优选R 3为1个或多个，彼此独立地选自H、卤素、羟基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、C 1-6亚烷基羟基，所述取代是指所述基团进一步被C 1-6烷基、卤素、羟基或氨基取代。 R 3 is one or more substituents, located at any substitution position of the ring, independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl , Substituted or unsubstituted C 1-6 alkoxy, C 1-6 alkylene hydroxy, hydroxy, NO 2 , said substitution means that the group is further substituted by C 1-6 alkyl, halogen, hydroxy or Amino substitution; preferably R 3 is one or more, independently selected from H, halogen, hydroxyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, C 1-6 alkylene hydroxy, said substitution means that said group is further substituted by C 1-6 alkyl, halogen, hydroxy or amino.
R 4为1或多个取代基，位于所在环的任意取代位置，R 4彼此独立选自H、卤素，取代或未取代的C 1-6烷基，取代或未取代的C 1-6烷氧基、羟基或NO 2；所述取代是指所述基团进一步被C 1-6烷基、卤素、羟基或氨基取代。 R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkane Oxy, hydroxy, or NO 2 ; the substitution means that the group is further substituted with a C 1-6 alkyl, halogen, hydroxy, or amino group.
此外，本发明还提供一种式IA结构化合物，或其药学可接受的盐，溶剂化物，或立体异构体：In addition, the present invention also provides a compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure PCTCN2021072517-appb-000002
Figure PCTCN2021072517-appb-000002
其中，n选自0，1，2，或3；Wherein, n is selected from 0, 1, 2, or 3;
环X为X所在环，其中X为-(CH 2)m-，m为0，1，2或3，从而X、氮与其它环碳原子形成4，5，6或7元氮杂环，X环通过环氮原子或环碳原子与主体结构的亚烷基链连接； Ring X is the ring where X is located, where X is -(CH 2 )m-, and m is 0, 1, 2 or 3, so that X, nitrogen and other ring carbon atoms form a 4, 5, 6 or 7-membered nitrogen heterocycle, Ring X is connected to the alkylene chain of the main structure through a ring nitrogen atom or ring carbon atom;
Z连接所在环任意取代位置，选自-O-，-N-，-S-，-SO 2-，-CO-或-CH(OH)-基团； Any substitution position of the ring where Z is connected is selected from -O-, -N-, -S-, -SO 2 -, -CO- or -CH(OH)- group;
R 1为1或多个取代基，彼此独立选自C 1-6烷基，4-6元环烷基，4-6元杂环烷基，所述R 1被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基的取代基取代； R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , Substituted by substituents of C 1-6 alkyl or C 1-6 alkoxy;
R 2为1或多个取代基，位于所在环的任意取代位置，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 2 is one or more substituents, located at any substitution position of the ring, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
R 3为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H，卤素，羟基或NO 2，取代或未取代的C 1-6烷基，取代或未取代的3-6元环烷基，取代或未取代的C 1-6烷氧基；所述“取代”是指所述基团进一步被C 1-6烷基或卤素取代。 R 3 is one or more substituents, located at any substitution position of the ring, independently selected from H, halogen, hydroxyl or NO 2 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3- 6-membered cycloalkyl, substituted or unsubstituted C 1-6 alkoxy; the "substituted" means that the group is further substituted with C 1-6 alkyl or halogen.
进一步优选：Further preferred:
n为0，1或2；n is 0, 1 or 2;
环X为4-6元含氮杂环；Ring X is a 4-6 membered nitrogen-containing heterocyclic ring;
Z为-O-，-S-，-CO-，或-SO 2-基团； Z is -O-, -S-, -CO-, or -SO 2 -group;
R 1为1或多个取代基，彼此独立选自C 1-6烷基，4-6元环烷基，4-6元杂环烷基，所述R 1被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基的取代基取代，优选R 1为甲基、异丁基、环丁烷、氧杂环戊烷、三氟乙基、或2-羟基异丁基； R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , C 1-6 alkyl or C 1-6 alkoxy substituent substituted, preferably R 1 is methyl, isobutyl, cyclobutane, oxolane, trifluoroethyl, or 2-hydroxy Isobutyl
R 2为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H、卤素、羟基或NO 2；优选R 2为卤素，特别优选为氟； R 2 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, hydroxyl or NO 2 ; preferably R 2 is halogen, particularly preferably fluorine;
R 3为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H，卤素，C 1-6烷基，卤代C 1-6烷基，3-6元环烷基，卤代3-6元环烷基，羟基或NO 2；优选C 1-6烷基，卤素，氟代C 1-6烷基，3-6元环烷基。 R 3 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-6 membered cycloalkyl, Halogenated 3-6 membered cycloalkyl, hydroxy or NO 2 ; preferably C 1-6 alkyl, halogen, fluoro C 1-6 alkyl, 3-6 membered cycloalkyl.
特别优选：Particularly preferred:
n选自1；n is selected from 1;
环X为4-6元含氮杂环；Ring X is a 4-6 membered nitrogen-containing heterocyclic ring;
Z为-O-，-S-，-CO-，或-SO 2-基团； Z is -O-, -S-, -CO-, or -SO 2 -group;
R 1为1或多个取代基，彼此独立选自C 1-6烷基，4-6元环烷基，4-6元杂环烷基，所述R 1被选自H，卤素，羟基，C 1-6烷基或C 1-6烷氧基的取代基取代，优选R 1为甲基、异丁基、环丁烷、氧杂环戊烷、三氟乙基、或2-羟基异丁基； R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxyl , C 1-6 alkyl or C 1-6 alkoxy substituent substituted, preferably R 1 is methyl, isobutyl, cyclobutane, oxolane, trifluoroethyl, or 2-hydroxy Isobutyl
R 2为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H、卤素、羟基或NO 2；优选R 2为卤素，特别优选为氟； R 2 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, hydroxyl or NO 2 ; preferably R 2 is halogen, particularly preferably fluorine;
R 3为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H，卤素，C 1-6烷基，卤代C 1-6烷基，3-6元环烷基，羟基或NO 2；优选C 1-6烷基，卤素，氟代C 1-6烷基，3-6元环烷基。 R 3 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-6 membered cycloalkyl, Hydroxy or NO 2 ; preferably C 1-6 alkyl, halogen, fluoro C 1-6 alkyl, 3-6 membered cycloalkyl.
本发明还提供一种式IB结构化合物，或其药学可接受的盐，溶剂化物，或立体异构体：The present invention also provides a compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure PCTCN2021072517-appb-000003
Figure PCTCN2021072517-appb-000003
其中，X所在的环X中，X为-(CH 2) m-，其中m为0，1，2或3，从而X、N与其它环碳原子形成4，5，6或7元氮杂环，所述杂环通过环C原子与主体结构N原子连接； Wherein, in the ring X where X is located, X is -(CH 2 ) m -, where m is 0, 1, 2 or 3, so that X, N and other ring carbon atoms form 4, 5, 6 or 7-membered aza Ring, the heterocyclic ring is connected to the N atom of the main structure through the ring C atom;
环B与X环稠合，环B为4-7元环烷基或4-7元杂环烷基；Ring B is condensed with ring X, and ring B is 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl;
Z连接所在环任意取代位置，选自-O-，-N-，-S-，-SO 2-，-CO-或-CH(OH)-基团； Any substitution position of the ring where Z is connected is selected from -O-, -N-, -S-, -SO 2 -, -CO- or -CH(OH)- group;
R 1为1或多个取代基，彼此独立选自C 1-6烷基，4-6元环烷基，4-6元杂环烷基，所述R 1被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基的取代基取代； R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , Substituted by substituents of C 1-6 alkyl or C 1-6 alkoxy;
R 2为1或多个取代基，位于所在环的任意取代位置，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 2 is one or more substituents, located at any substitution position of the ring, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
R 3为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H，卤素，C 1-6烷基，卤代C 1-6烷基，3-6元环烷基，羟基或NO 2；优选C 1-6烷基，卤素，氟代C 1-6烷基，3-6元环烷基； R 3 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-6 membered cycloalkyl, Hydroxy or NO 2 ; preferably C 1-6 alkyl, halogen, fluoro C 1-6 alkyl, 3-6 membered cycloalkyl;
进一步，优选环X与环B的稠合环选自如下基团：Further, it is preferable that the fused ring of ring X and ring B is selected from the following groups:
Figure PCTCN2021072517-appb-000004
Figure PCTCN2021072517-appb-000004
本发明还提供一种具有式IC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 invention also provides a compound having the structure of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
Figure PCTCN2021072517-appb-000005
Figure PCTCN2021072517-appb-000005
其中，in,
p，q分别选自0-4的整数，p and q are selected from integers from 0 to 4 respectively,
Y为碳原子或杂原子，其中杂原子选自O，S，N原子，Y is a carbon atom or a heteroatom, wherein the heteroatom is selected from O, S, N atoms,
环Y即Y原子所在环，通过环碳原子或者环N原子与化合物主体结构连接，Ring Y is the ring where the Y atom is located, and is connected to the main structure of the compound through a ring carbon atom or a ring N atom,
取代基R 1OCH 2-为1或多个，位于所在环的任意取代位置，其中，R 1彼此独立选自C 1-6烷基，3-6元环烷基，所述R 1进一步被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基取代；优选，R 1OCH 2-为1个，并位于环的对位取代位置； Substituents R 1 OCH 2 -are 1 or more, located at any substitution position of the ring where R 1 is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, and said R 1 is further Substitution selected from H, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy; preferably, R 1 OCH 2 -is one and is located at the para-substitution position of the ring;
R 2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ;
R 3为1或多个取代基，位于所在环的任意取代位置，R 3彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基，羟基，NO 2，5-7元芳环羰基，5-7元杂芳环羰基或5-7元环烷羰基，5-7元芳环羰基C 1-6亚烷基，5-7元杂芳环羰基C 1-6亚烷基或5-7元环烷羰基C 1-6亚烷基，R 3进一步可被H，卤素，C 1-6烷基，C 1-6烷氧基，或羟基取代； 优选R 3在Y位置取代； R 3 is 1 or more substituents, located at any substitution position of the ring, R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, NO 2 , 5- 7-membered aromatic ring carbonyl, 5-7 membered heteroaromatic ring carbonyl or 5-7 membered cycloalkanecarbonyl, 5-7 membered aromatic ring carbonyl C 1-6 alkylene, 5-7 membered heteroaromatic ring carbonyl C 1-6 Alkylene or 5-7 membered cycloalkylcarbonyl C 1-6 alkylene, R 3 may be further substituted by H, halogen, C 1-6 alkyl, C 1-6 alkoxy, or hydroxy; preferably R 3 Replace at Y position;
R 4为1或多个取代基，位于所在环的任意取代位置，R 4彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2。 R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
优选，p选自1，2或3，使Y所在环对应为4，5或6元环，Preferably, p is selected from 1, 2 or 3, so that the ring where Y is located corresponds to a 4, 5 or 6-membered ring,
q选自0，1或2，q is selected from 0, 1 or 2,
Y为C或N原子，Y is a C or N atom,
取代基R 1OCH 2-位于所在环的任意取代位置，R 1彼此独立选自C 1-6烷基，3-6元环烷基，所述R 1进一步被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基取代；优选R 1OCH 2-位于环的对位取代位置； The substituent R 1 OCH 2 -is located at any substitution position of the ring, R 1 is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, and the R 1 is further selected from H, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy substituted; preferably R 1 OCH 2 -is located at the para-substitution position of the ring;
R 2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2；优选R 2为氟； R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ; preferably R 2 is fluorine;
R 3为1或多个取代基，位于所在环的任意取代位置，R 3彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基，羟基，NO 2，5-7元芳环羰基C 1-6亚烷基，5-7元杂芳环羰基C 1-6亚烷基或5-7元环烷羰基C 1-6亚烷基，R 3进一步可被H，卤素，C 1-6烷基，C 1-6烷氧基，或羟基取代；优选R 3在Y位置取代； R 3 is 1 or more substituents, located at any substitution position of the ring, R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, NO 2 , 5- A 7-membered aromatic ring carbonyl C 1-6 alkylene group, a 5-7 membered heteroaromatic ring carbonyl C 1-6 alkylene group or a 5-7 membered cycloalkylcarbonyl C 1-6 alkylene group, R 3 may be further replaced by H , Halogen, C 1-6 alkyl, C 1-6 alkoxy, or hydroxy substituted; preferably R 3 is substituted at the Y position;
R 4为1或多个取代基，位于所在环的任意取代位置，R 4彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2。 R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
进一步优选，具有式IC结构的化合物，More preferably, the compound having the structure of formula IC,
其中，q＝0或1，Where q=0 or 1,
p选自1，2或3，使Y所在环对应为4，5或6元环，p is selected from 1, 2 or 3, so that the ring where Y is located corresponds to a 4, 5 or 6-membered ring,
Y为N原子，Y is N atom,
取代基R 1OCH 2-位于所在环的任意取代位置，优选为对位取代位置，其中，R 1彼此独立选自C 1-6烷基，3-6元环烷基，所述R 1进一步被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基取代； The substituent R 1 OCH 2 -is located at any substitution position of the ring, preferably a para position, wherein R 1 is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, and the R 1 further Substitution is selected from H, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
R 2为1或多个取代基，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2；优选为2位和/或4位取代位置； R 2 is one or more substituents, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ; preferably substituted at the 2-position and/or 4-position Location;
R 3在Y位取代，R 3选自H、卤素，C 1-6烷基，C 1-6烷氧基，羟基或苯基羰基C 1-6亚烷基； R 3 is substituted at the Y position, and R 3 is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy or phenylcarbonyl C 1-6 alkylene;
R 4为1或多个取代基，位于所在环的任意取代位置，R 4彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2。 R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
本专利提及的“被选自H的取代基取代”，含义为所述取代基为H，实质上意味着所述基团未被其它取代基团取代。"Substituted by a substituent selected from H" mentioned in this patent means that the substituent is H, which essentially means that the group is not substituted by other substituent groups.
术语“卤素”指F、Cl、Br或I。The term "halogen" refers to F, Cl, Br or I.
术语“烷基”是指饱和的烃基，包括直链烷基、分支链烷基。The term "alkyl" refers to saturated hydrocarbon groups, including straight chain alkyl groups and branched chain alkyl groups.
术语“亚烷基”是指二价烷基。“亚烷基链”是聚亚甲基，即-(CH 2)x-，其中x为 正整数。 The term "alkylene" refers to a divalent alkyl group. "Alkylene chain" is polymethylene, ie -(CH 2 )x-, where x is a positive integer.
术语“环烷基”，是指饱和或含有一个或一个以上不饱和单元但非芳香族的单环烃基，所述环为3-20元环，其具有单个连接点与化合物的其余部分相连接。The term "cycloalkyl" refers to a monocyclic hydrocarbon group that is saturated or contains one or more unsaturated units but is not aromatic. The ring is a 3-20 membered ring, which has a single point of attachment to the rest of the compound .
术语“杂环烷基”为含有1个到5个、独立的选自N，S，O等杂原子的单环状基团，所述杂环烷基可以是饱和环或不饱和环，所述环为3-20元环，包括哌啶，吡咯烷，四氢呋喃等。The term "heterocycloalkyl" refers to a monocyclic group containing 1 to 5 independently selected from heteroatoms such as N, S, O, etc. The heterocycloalkyl group may be a saturated ring or an unsaturated ring, so The ring is a 3-20 membered ring, including piperidine, pyrrolidine, tetrahydrofuran and the like.
术语“芳基”、“芳环基”或“芳香环基”，指单环，所述***共具有5至10个(优选5、6或9)环成员，环成员为环碳原子；环系中共享(4n+2)个π电子(其中n是正整数)以符合休克尔规则。The term "aryl", "aromatic ring group" or "aromatic ring group" refers to a single ring, and the system has 5 to 10 (preferably 5, 6 or 9) ring members in total, and the ring members are ring carbon atoms; (4n+2) π electrons (where n is a positive integer) are shared in the system to comply with Huckel's rule.
术语“杂芳基”和“杂芳环基”是指具有5到10个环原子，优选5、6或9个环原子；(4n+2)个π电子(其中n是正整数)以符合休克尔规则；并且除碳原子外，还具有1到5个杂原子，所述杂原子选自氮、氧或硫，并包括氮或硫的任何氧化形式和碱性氮的任何季铵化形式，例如吡啶、咪唑基团等。The terms "heteroaryl" and "heteroaryl ring group" refer to having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; (4n+2) π electrons (where n is a positive integer) to comply with shock Er’s rule; and in addition to carbon atoms, it also has 1 to 5 heteroatoms selected from nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen, For example, pyridine, imidazole group and the like.
术语“彼此独立”在本申请中表示，所述取代彼此独立，不互为关联。The term "independent of each other" in this application means that the substitutions are independent of each other and not related to each other.
术语“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，包括环碳原子、环氮、环硫原子等取代位点。可举例为：所谓环为苯环时，取代位置为相对于主链取代位置的邻、间和/或对位，或2，3，4，5或6位(相对于苯环连接主链位置)；所谓环为含氮5元或6元环时，取代位置可为环氮位置，或环氮位置的邻、间或对位，或2，3，4或5位等。The term "arbitrary substitution position in the ring" means that the substituent group is located at any position in the ring that can be substituted, including substitution sites such as ring carbon atoms, ring nitrogen, and ring sulfur atoms. For example: when the so-called ring is a benzene ring, the substitution position is the ortho, meta and/or para position relative to the substitution position of the main chain, or 2, 3, 4, 5 or 6 position (relative to the position where the benzene ring is connected to the main chain) ); When the so-called ring is a nitrogen-containing 5-membered or 6-membered ring, the substitution position can be the position of the ring nitrogen, or the ortho, inter or para position of the ring nitrogen position, or the 2, 3, 4 or 5 positions.
术语“药学上可接受的盐”包括从适合的无机酸和碱以及有机酸和碱衍生而来的那些盐。药学上可接受的无毒性酸加成盐的实例是氨基与无机酸如盐酸、氢溴酸、磷酸、硫酸和高氯酸等，或者与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸等形成的盐，或者通过使用诸如离子交换等本领域的其他方法形成的盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。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 amino acids with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, etc., or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, lemon Acid, succinic acid, malonic acid, etc., or salts formed by using other methods in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cypionate, gluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, gluconate, hemisulfate, heptanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate , Malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate , Valerate, etc.
更优选，本发明保护如下具体化合物，或其药学可接受的盐，溶剂化物，或立体异构体：More preferably, the present invention protects the following specific compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof:
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(9-甲基-3-氧杂-9-氮杂-二环[3.3.1]壬-7-基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(9-methyl-3-oxa-9-aza-bicyclo[3.3. 1] Non-7-yl)-urea,
1-(3-(吖丁啶-1-基)-丙基)-1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-脲，1-(3-(azetidine-1-yl)-propyl)-1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-urea,
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(1-甲基-吡咯烷-3-基甲基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(1-methyl-pyrrolidin-3-ylmethyl)-urea,
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(1-甲基-吖丁啶-3-基甲基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(1-methyl-azetidine-3-ylmethyl)-urea,
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(八氢-喹嗪-2-基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(octahydro-quinazin-2-yl)-urea,
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(八氢-吡啶并[2，1-c][1，4]噁嗪-8-基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(octahydro-pyrido[2,1-c][1,4]oxazine- 8-yl)-urea,
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(2-(吡咯烷-1-基)-乙基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(2-(pyrrolidin-1-yl)-ethyl)-urea,
3-(4-异丁氧基-苯甲基)-1-(4-氟-苯甲基)-1-[2-(1-甲基-1H-咪唑-4-基)-乙基]-脲，3-(4-isobutoxy-benzyl)-1-(4-fluoro-benzyl)-1-[2-(1-methyl-1H-imidazol-4-yl)-ethyl] -Urea,
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(哌啶-1-基)乙基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(piperidin-1-yl)ethyl)urea,
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-3-基)甲基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-3-yl)methyl)urea,
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-(2-氟乙基)吡咯烷-3-基)甲基)脲，3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-(2-fluoroethyl)pyrrolidin-3-yl)methyl)urea,
3-(4-环丁氧基苯甲基)-1-((1-乙基吡咯烷-3-基)甲基)-1-(4-氟苯甲基)脲，3-(4-Cyclobutoxybenzyl)-1-((1-ethylpyrrolidin-3-yl)methyl)-1-(4-fluorobenzyl)urea,
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-2-基)甲基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-2-yl)methyl)urea,
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(吡咯烷-1-基)乙基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(pyrrolidin-1-yl)ethyl)urea,
3-(4-环丁氧基苯甲基)-1-((1-环丙基吡咯烷-3-基)甲基)-1-(4-氟苯甲基)脲，3-(4-Cyclobutoxybenzyl)-1-((1-cyclopropylpyrrolidin-3-yl)methyl)-1-(4-fluorobenzyl)urea,
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(1-甲基吡咯烷-2-基)乙基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(1-methylpyrrolidin-2-yl)ethyl)urea,
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(1-甲基哌啶-2-基)乙基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(1-methylpiperidin-2-yl)ethyl)urea,
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)urea,
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
(S)-3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(S)-3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
(R)-3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(R)-3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，3-(4-cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
(S)-3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(S)-3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea,
(R)-3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(R)-3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea,
1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)-3-(4-(3-甲基丁酰)苯甲基)脲，1-(4-fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)-3-(4-(3-methylbutyryl)benzyl)urea,
(S)-1-(4-氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(S)-1-(4-fluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea,
(R)-1-(4-氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(R)-1-(4-fluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea,
(S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，(S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) Yl)benzyl)urea,
(R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，(R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) Yl)benzyl)urea,
(S)-1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(S)-1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
(R)-1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(R)-1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲，1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylazetidine-3-yl)methyl)urea,
1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-异丁氧基苯甲基)脲，1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-isobutoxybenzyl)urea,
1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy)benzyl Base) urea,
3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
3-(3-氟-4-甲氧苄基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(3-fluoro-4-methoxybenzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
(R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-异丁氧基苯甲基)脲，(R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-isobutoxybenzyl)urea,
(S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-异丁氧基苯甲基)脲，(S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-isobutoxybenzyl)urea,
(R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，(R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) Yl)benzyl)urea,
(S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，(S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) Yl)benzyl)urea,
3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(3-fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
3-(4-环丁氧基-3-氟苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl) Urea,
1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，1-(2,4-Difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) )Benzyl)urea,
3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
1-(2，4-二氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-(1-甲基哌啶-4-基)脲，1-(2,4-Difluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-(1-methylpiperidin-4-yl)urea,
(R)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，(R)-1-(2,4-Difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-tri Fluoroethoxy)benzyl)urea,
(S)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，(S)-1-(2,4-Difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-tri Fluoroethoxy)benzyl)urea,
(R)-1-(2，4-二氟苯甲基)-3-(3-氟-4-甲氧苄基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-methoxybenzyl)-1-((1-methylpyrrolidin-3-yl)methyl ) Urea,
(R)-3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-3-(3-fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea,
(S)-3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(S)-3-(3-fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea,
3-(3-氟-4-异丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(3-fluoro-4-isobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
(S)-1-(2，4-二氟苯甲基)-3-(3-氟-4-甲氧苄基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(S)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-methoxybenzyl)-1-((1-methylpyrrolidin-3-yl)methyl ) Urea,
3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(3-Fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidine-4 -Base) methyl) urea,
1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-((1-methylpiper (Pyridin-4-yl)methyl)urea,
(R)-1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-((1 -Methylpyrrolidin-3-yl)methyl)urea,
(S)-1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(S)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-((1 -Methylpyrrolidin-3-yl)methyl)urea,
(S)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(S)-3-(3-Fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methyl Pyrrolidin-3-yl)methyl)urea,
(R)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-3-(3-Fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methyl Pyrrolidin-3-yl)methyl)urea,
3-(4-(2-羟基2-甲基丙氧基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-(2-hydroxy-2-methylpropoxy)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl )Methyl)urea,
3-(4-(2-羟基2-甲基丙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-(2-hydroxy-2-methylpropoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl ) Urea,
(R)-3-(4-(2-羟基2-甲基丙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-3-(4-(2-Hydroxy-2-methylpropoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidine-3- Yl)methyl)urea,
3-(4-((四氢呋喃-3-基)-氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-((tetrahydrofuran-3-yl)-oxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl ) Urea,
(R)-3-(4-((四氢呋喃-3-基)-氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-3-(4-((tetrahydrofuran-3-yl)-oxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidine-3- Yl)methyl)urea,
(S)-3-(4-(四氢呋喃-3-基)-氧基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(S)-3-(4-(Tetrahydrofuran-3-yl)-oxy)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidine- 3-yl)methyl)urea,
(S)-3-(4-((四氢呋喃-3-基)-氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(S)-3-(4-((Tetrahydrofuran-3-yl)-oxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidine-3- Yl)methyl)urea,
1-(2-(吖丁啶-1-基)-乙基)-1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-脲。1-(2-(Azetidine-1-yl)-ethyl)-1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-urea.
3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲，3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea,
3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-(((R)-1-(1-甲基吡咯烷-3-基))甲基)脲，3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-(((R)-1-(1-methylpyrrolidin-3-yl )) Methyl) urea,
3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-(((S)-1-(1-甲基吡咯烷-3-基))甲基)脲，3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-(((S)-1-(1-methylpyrrolidin-3-yl )) Methyl) urea,
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea ,
3-((4-乙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-((4-ethoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea ,
3-((4-环丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-((4-Cyclopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl) Urea,
3-((4-异丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-((4-isopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl) Urea,
3-(4-异丙氧基甲基苯甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲，3-(4-isopropoxymethylbenzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea,
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-甲基)脲，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidine-4-methyl)urea,
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(2-苯基羰基乙基)-哌啶-4-甲基)脲，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N-(2-phenylcarbonylethyl)-piperidine -4-methyl)urea,
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(苯基羰基甲基)-哌啶-4-甲基)脲，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N-(phenylcarbonylmethyl)-piperidine-4 -Methyl)urea,
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-基)脲，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidin-4-yl)urea,
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(苯基羰基甲基)-哌啶-4-基)脲，或，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N-(phenylcarbonylmethyl)-piperidine-4 -Based) urea, or,
3-((4-异丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-基)脲。3-((4-isopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidin-4-yl)urea.
本发明保护一种制备式I化合物的方法，其特征在于：The present invention protects a method for preparing a compound of formula I, which is characterized in that:
步骤1、式A结构的异氰酸化合物与式B氨基化合物按如下反应式反应，合成得到式I化合物，Step 1. The isocyanate compound of formula A and the amino compound of formula B are reacted according to the following reaction formula to synthesize the compound of formula I.
Figure PCTCN2021072517-appb-000006
Figure PCTCN2021072517-appb-000006
所述基团定义与前述一致；The definition of the group is consistent with the foregoing;
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, according to the needs of the target product, functional group modification is performed on the compound of formula I to convert it into a target product with the structure of formula I, or into a pharmaceutically acceptable salt or precursor compound of the compound.
所述制备方法同样适用于式IA化合物、式IB化合物和式IC化合物的制备。The preparation method is also applicable to the preparation of the compound of formula IA, the compound of formula IB and the compound of formula IC.
本发明的式I化合物、式IA化合物、式IB化合物、式IC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5HT2A受体抑制活性或反向激动活性，可以用于5HT2A受体活性介导的相关疾病的治疗。The compound of formula I, compound of formula IA, compound of formula IB, compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer of the present invention has 5HT2A receptor inhibitory activity or inverse agonist activity, and can be used For the treatment of related diseases mediated by 5HT2A receptor activity.
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EC 50≤1μM，认为在以上分析中测试的化合物具有5HT2A的抑制活性。本发明优选的化合物具有EC 50≤150nM，更优选的化合物具有EC 50≤50nM，最优选化合物具有EC 50≤25nM，特别优选的化合物具有EC 50≤20nM。 The inhibitory activity of the compound of the present invention on 5HT2A is tested by using a Flp-In-CHO-5HT2A stable cell line and completed by the IP-One experiment. 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. If the compound exhibits EC 50 ≤ 1 μM, the compound tested in the above analysis is considered to have 5HT2A inhibitory activity. Preferred compounds of the present invention have EC 50 ≤ 150 nM, more preferred compounds have EC 50 ≤ 50 nM, most preferred compounds have EC 50 ≤ 25 nM, and particularly preferred compounds have EC 50 ≤ 20 nM.
本发明的式I化合物、式IA化合物、式IB化合物、式IC化合物，或其药学上可接受的盐，溶剂化物，或立体异构体，具有好的5HT2A受体的拮抗活性。进一步的，本发明化合物还具有好的选择性，尤其是对5HT2B和/或5HT2C的选择性，降低的心脏毒性，和/或，提高的代谢稳定性。The compound of formula I, compound of formula IA, compound of formula IB, compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer of the present invention has good 5HT2A receptor antagonistic activity. Furthermore, the compounds of the present invention also have good selectivity, especially selectivity to 5HT2B and/or 5HT2C, reduced cardiotoxicity, and/or improved metabolic stability.
本发明提供式I化合物、式IA化合物、式IB化合物、式IC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 a compound of formula I, a compound of formula IA, a compound of formula IB, a compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof for preparing medicines for the treatment of related diseases mediated by 5HT2A receptor activity In the use.
所述5HT2A受体活性介导的相关疾病包括但不限于中枢神经***疾病。The related diseases mediated by the 5HT2A receptor activity 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 disease includes but is not limited to: mental disease, central nervous system degenerative disease, central nervous system degenerative disease related or concurrent mental disorder symptoms, and negative symptoms of mental disease.
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 illness includes, but is 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 degenerative diseases of the central nervous system include but are not limited to: Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia and the like.
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、兴趣缺失等。The mental disorder symptoms related to or concurrent with degenerative diseases of the central nervous system, and negative symptoms of mental diseases include, but are not limited to: affective disorders, language dysfunction, hallucinations, loss of interest, and the like.
本发明提供一种药物组合物，其特征在于包括式I化合物、式IA化合物、式IB化合物、式IC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, a compound of formula IA, a compound of formula IB, a compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
所述药物组合物可以用于治疗5HT2A受体活性介导的相关疾病。所述5HT2A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 related diseases mediated by 5HT2A receptor activity. The definition of the related diseases mediated by the 5HT2A 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 auxiliary materials 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 and the like. The binder is, for example, starch, gelatin, sodium carboxymethyl cellulose, polyvinylpyrrolidone and the like. The antioxidants are, for example, vitamin E, sodium bisulfite, sodium sulfite, butylated hydroxyanisole and the like. The pH adjusting agent includes, for example, hydrochloric acid, sodium hydroxide, citric acid, tartaric acid, Tris, acetic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, and the like. The preservatives include, for example, methyl paraben, ethyl paraben, m-cresol, benzalkonium chloride and the like. The lubricants are, for example, magnesium stearate, micronized silica gel, talc and the like. The disintegrant is for example: starch, methyl cellulose, xanthan gum, croscarmellose sodium and the like.
所述药物组合物中含有式I化合物、式IA化合物、式IB化合物、式IC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, a compound of formula IA, a compound of formula IB, a compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer in an amount of 0.1-1000 mg, preferably 1- 500 mg, more preferably 5-100 mg.
所述药物组合物中式I化合物、式IA化合物、式IB化合物、式IC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 compound of formula I, compound of formula IA, compound of formula IB, compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the pharmaceutical composition accounts for 10%-90% by mass of the pharmaceutical composition %, preferably 20%-80%, 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 dosage form of the pharmaceutical composition can be an oral dosage form, such as tablets, capsules, pills, powders, granules, suspensions, syrups, etc.; it can also be an injection dosage form, such as injections, powder injections, etc. , Administered by intravenous, intraperitoneal, subcutaneous or intramuscular route injection. All dosage forms used are well known to those of ordinary skill in the pharmaceutical arts.
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 administration route of the pharmaceutical composition includes, but is not limited to: oral; buccal; sublingual; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous and intradermal , Intramuscular, intravenous; by implanting reservoirs or reservoirs.
式I化合物、式IA化合物、式IB化合物、式IC化合物，或其药学上可接受的盐，溶剂化物，或立体异构体的施用剂量将取决于接受者的年龄、健康和体重，联用药物的种类，治疗频率，给药途径等。药物可以单一日剂量施用，每天给药一次、每两天给药一次、每三天给药一次、每四天给药一次，或者总日剂量以每天两次、三次或四次的分开剂量施用。剂量可以施用一次或多次，施药时间可以单日至几个月或更长时间。式I化合物、式IA化合物、式IB化合物、式IC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 the compound of formula I, the compound of formula IA, the compound of formula IB, the compound of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof will depend on the age, health and weight of the recipient. Type of drug, frequency of treatment, 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 of two, three or four times a day . The dosage can be administered once or multiple times, and the administration time can be from a single day to several months or longer. The dosage of the compound of formula I, compound of formula IA, compound of formula IB, compound of formula IC, 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, and so on.
所述药物组合物可以和其他的治疗5HT2A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 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受体活性介导的相关疾病的药物。The pharmaceutical composition may further contain a second therapeutic agent, and the second therapeutic agent is another drug for treating related diseases mediated by 5HT2A receptor activity.
本发明提供一种治疗5HT2A受体活性介导的相关疾病的方法，其特征在于，对有需要的患者施用治疗有效量的式I化合物、式IA化合物、式IB化合物、式IC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 related diseases mediated by 5HT2A receptor activity, which is characterized by administering a therapeutically effective amount of a compound of formula I, a compound of formula IA, a compound of formula IB, a compound of formula IC to a patient in need, or A pharmaceutically acceptable salt, solvate, or stereoisomer.
所述式I化合物、式IA化合物、式IB化合物、式IC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 route of the compound of formula I, compound of formula IA, compound of formula IB, compound of formula IC or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof includes, but is not limited to: oral; buccal; tongue Subcutaneous; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial; by implanting a reservoir or liquid storage Device.
所述方法进一步包括，对有需要的患者给予其他的治疗5HT2A受体活性介导的相关疾病的药物。The method further includes administering other drugs for treating related diseases mediated by 5HT2A receptor activity to patients in need.
其他的治疗5HT2A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 the treatment of related diseases mediated by 5HT2A receptor activity include but are not limited to: drugs for mental illness, drugs for degenerative diseases of the central nervous system, and the like.
所述精神疾病治疗药物包括但不限于：苯二氮
Figure PCTCN2021072517-appb-000007
类(例如：甲基***西泮、氯氮
Figure PCTCN2021072517-appb-000008
、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 mental illness treatment drugs include but are not limited to: benzodiazepine
Figure PCTCN2021072517-appb-000007
Class (e.g. methyltriazepam, chlorazide
Figure PCTCN2021072517-appb-000008
, Clonazepam, diazepam, sulazepam, fluazepam, midazolam, etc.); barbiturates (e.g., phenobarbital, pentobarbital, etc.); chloral hydrate; Cyclic ketones; phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, etc.); thioxanthenes (e.g., Thioxanthene); butyrylbenzenes (e.g., haloperidol ); clozapine; risperidone; tricyclic antidepressants (for example: imipramine, doxepin, nortriptyline, amitriptyline, etc.); heterocyclic antidepressants (for example: a Moxapine, maprotiline, trazodone, bupropion, venfalasine, etc.); selective 5-HT reuptake inhibitors (e.g. fluoxetine, paroxetine, sertraline, citalopram , Fluvoxamine, etc.); monoamine oxidase inhibitors (for example: phenelzine, moclobemide, etc.); ketamine; mirtazapine.
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 the treatment of degenerative diseases of the central nervous system include but are not limited to: levodopa, bromocriptine, thipropergoline, propargyl amphetamine, amantadine, and ureteride.
具体实施方案Specific implementation plan
实施例中使用的化学试剂均为市售化合物，其中The chemical reagents used in the examples are all commercially available compounds, where
DMF：N，N-二甲基甲酰胺；DMF: N,N-dimethylformamide;
DIEA：N，N-二异丙基乙胺；DIEA: N,N-diisopropylethylamine;
Et3N：三乙基胺Et3N: Triethylamine
DCM：二氯甲烷DCM: Dichloromethane
THF：四氢呋喃THF: Tetrahydrofuran
Acetone：丙酮Acetone: Acetone
Pyridine：吡啶Pyridine: Pyridine
Pd(PPh3)4：四(三苯基膦)钯Pd(PPh3)4: Tetra(triphenylphosphine) palladium
Et：乙基，Ac：乙酰基；如EtOAc为乙酸乙酯或醋酸乙酯，ETOH为乙醇。Et: ethyl, Ac: acetyl; for example, EtOAc is ethyl acetate or ethyl acetate, and ETOH is ethanol.
TFA：三氟乙酸TFA: Trifluoroacetic acid
TFE：2，2，2-三氟乙醇TFE: 2,2,2-trifluoroethanol
Triphosgene：三光气Triphosgene: Triphosgene
式IA和式IB化合物的示例性化合物及制备实施例如实施例1-64。Exemplary compounds and preparation examples of compounds of formula IA and formula IB are Examples 1-64.
实施例1：合成1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(9-甲基-3-氧杂-9-氮杂-二环[3.3.1]壬-7-基)-脲(Compound #1)，ER10048Example 1: Synthesis of 1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(9-methyl-3-oxa-9-aza- Bicyclo[3.3.1]non-7-yl)-urea(Compound#1), ER10048
Figure PCTCN2021072517-appb-000009
Figure PCTCN2021072517-appb-000009
(4-氟-苯甲基)-(9-甲基-3-氧杂-9-氮杂-二环[3，3，1]壬-7-基)胺(1-1)：室温下，在9-甲基-3-氧杂-9-氮杂-双环[3，3，1]壬烷-7-酮(125毫克，0.805mmol)的5.0mL二氯甲烷溶液中添加4-氟苯甲基胺(151mg，1.21mmol)，然后分批慢慢加入三乙酰氧基氢硼化物钠(341mg，1.61mmol)，和0.1ml醋酸。混合物在室温下搅拌过夜。加入冰水(10ml)，用10％(v/v)异丙醇/氯仿(30ml×2)提取混合物。有机相Na 2SO 4干燥，在真空条件下过滤和浓缩，得到无色油状中间体(1-1)(181mg，产率85％)。LCMS：[M+1] +265.2。 (4-Fluoro-benzyl)-(9-methyl-3-oxa-9-aza-bicyclo[3,3,1]non-7-yl)amine (1-1): at room temperature , Add 4-fluoro to 9-methyl-3-oxa-9-aza-bicyclo[3,3,1]nonane-7-one (125 mg, 0.805 mmol) in 5.0 mL of dichloromethane solution Benzylamine (151 mg, 1.21 mmol), and then slowly add sodium triacetoxyborohydride (341 mg, 1.61 mmol) and 0.1 ml of acetic acid in batches. The mixture was stirred overnight at room temperature. Ice water (10ml) was added, and the mixture was extracted with 10% (v/v) isopropanol/chloroform (30ml×2). The organic phase was dried over Na 2 SO 4 , filtered and concentrated under vacuum to obtain colorless oily intermediate (1-1) (181 mg, yield 85%). LCMS: [M+1] + 265.2.
Figure PCTCN2021072517-appb-000010
Figure PCTCN2021072517-appb-000010
4-异丁氧基苯甲腈(1-2)：在丙酮(150毫升)中，将碳酸钾(58.0g，420mmol)添加到4-羟基苯甲腈(25.0g，210mmol)和1-溴-2-甲基丙烷(34.5g，252mmol)的混合物中。在60℃下搅拌3天。过滤掉固体，用丙酮(50mL)清洗。在真空条件下去除溶剂后，加入饱和NaHCO 3溶液(100毫升)，用EtOAc(50ml×3)提取混合物。将有机相用盐水(30ml)清洗，Na 2SO 4干燥，在真空下浓缩，得到中间体(1-2)(29.3克，产量80％)。LCMS：[M+1] +176.2。 4-Isobutoxybenzonitrile (1-2): In acetone (150 ml), potassium carbonate (58.0g, 420mmol) was added to 4-hydroxybenzonitrile (25.0g, 210mmol) and 1-bromo -2-methylpropane (34.5g, 252mmol). Stir at 60°C for 3 days. The solid was filtered off and washed with acetone (50 mL). After the solvent was removed under vacuum, saturated NaHCO 3 solution (100 mL) was added, and the mixture was extracted with EtOAc (50 mL×3). The organic phase was washed with brine (30 ml), dried over Na 2 SO 4 and concentrated under vacuum to obtain intermediate (1-2) (29.3 g, yield 80%). LCMS: [M+1] + 176.2.
Figure PCTCN2021072517-appb-000011
Figure PCTCN2021072517-appb-000011
(4-异丁氧基苯基)甲胺(1-3)：氩气保护下，无水THF(200ml)中加入氢化锂铝(3.25g，86mmol)冰浴冷却至0℃。然后慢慢滴加4-异丁氧基-苯甲腈(10.0g，57mmol)的THF溶液(20mL)。混合物室温搅拌过夜，将得到的混合物冷却到0℃，然后滴入2N NaOH的饱和Na 2SO 4水溶液，形成白色悬浮液。过滤掉白色固体并用THF(30毫升)进行洗涤。滤液Na 2SO 4干燥，过滤后，在真空下浓缩，得到无色油状物(10.1克，产率98％)。LCMS：[M+1] +180.2。 (4-Isobutoxyphenyl)methylamine (1-3): Under the protection of argon, lithium aluminum hydride (3.25g, 86mmol) was added to anhydrous THF (200ml) and cooled to 0°C in an ice bath. Then a THF solution (20 mL) of 4-isobutoxy-benzonitrile (10.0 g, 57 mmol) was slowly added dropwise. The mixture was stirred at room temperature overnight, the resulting mixture was cooled to 0°C, and then 2N NaOH saturated Na 2 SO 4 aqueous solution was added dropwise to form a white suspension. The white solid was filtered off and washed with THF (30 mL). The filtrate was dried over Na 2 SO 4 , filtered, and concentrated under vacuum to obtain a colorless oil (10.1 g, yield 98%). LCMS: [M+1] + 180.2.
Figure PCTCN2021072517-appb-000012
Figure PCTCN2021072517-appb-000012
1-异丁氧基-4-(异氰酸基甲基)苯(1-4)：0℃下，三光气(3.3g，11.2mmol)的DCM(10mL)溶液慢慢加入到(4-异丁氧基苯基)甲胺(2.0g，11.2mmol)的DCM溶液(10ml)中。混合物在室温搅拌1小时。加入冰水(20毫升)，用DCM(50ml×2)提取混合物。将有机相用盐水清洗，在Na 2SO 4干燥，在真空下过滤和浓缩，得油状产物(1-4)(2.20g，98％的产率)。LCMS：[M+1] +206.2。 1-Isobutoxy-4-(isocyanatomethyl)benzene (1-4): At 0°C, a solution of triphosgene (3.3g, 11.2mmol) in DCM (10mL) was slowly added to (4- Isobutoxyphenyl) methylamine (2.0 g, 11.2 mmol) in DCM (10 ml). The mixture was stirred at room temperature for 1 hour. Ice water (20 mL) was added, and the mixture was extracted with DCM (50 mL×2). The organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum to obtain oily product (1-4) (2.20 g, 98% yield). LCMS: [M+1] + 206.2.
Figure PCTCN2021072517-appb-000013
Figure PCTCN2021072517-appb-000013
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(9-甲基-3-氧杂-9-氮杂-二环[3.3.1]壬-7-基)-脲(compound #1)：0℃下把(4-氟-苯甲基)-(9-甲基-3-氧杂-9-氮杂-二环[3，3，1]壬-7-基)胺(1)的无水THF(5ml)溶液慢慢加到1-异丁氧基-4-(异氰酸基甲基)苯的DCM (5.0mL)溶液中。生成的混合物在40℃加热约10分钟。在真空下去除溶剂。粗产物高效液相色谱法进行纯化。得到化合物#1 ER10048(149毫克，产量89％)为白色固体。 1H NMR(300MHz，CDCl 3)：δ7.26-7.23(d，J＝9.0Hz，2H)，7.15-6.95(m，4H)，6.82(d，J＝8.5Hz，2H)，4.71-4.85(m，2H)，4.50(s，2H)，4.35(d，J＝5.5Hz，2H)，3.90(d，J＝11.2Hz)，3.71(d，J＝6.5Hz，2H)，3.27(d，J＝11.2Hz，2H)，2.83(d，J＝10.8Hz，2H)，2.57(s，2H)，2.34-2.01(m，2H)，1.62-1.75(m，4H)，1.04(d，J＝6.6hz，6H).LCMS：[M+1] +470.21。 1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(9-methyl-3-oxa-9-aza-bicyclo[3.3. 1] Non-7-yl)-urea (compound #1): (4-fluoro-benzyl)-(9-methyl-3-oxa-9-aza-bicyclo[3 ,3,1]non-7-yl)amine (1) in anhydrous THF (5ml) was slowly added to 1-isobutoxy-4-(isocyanatomethyl)benzene in DCM (5.0mL ) In solution. The resulting mixture was heated at 40°C for about 10 minutes. The solvent was removed under vacuum. The crude product was purified by high performance liquid chromatography. Compound #1 ER10048 (149 mg, yield 89%) was obtained as a white solid. 1 H NMR (300MHz, CDCl 3 ): δ7.26-7.23 (d, J=9.0Hz, 2H), 7.15-6.95 (m, 4H), 6.82 (d, J=8.5Hz, 2H), 4.71-4.85 (m, 2H), 4.50 (s, 2H), 4.35 (d, J = 5.5 Hz, 2H), 3.90 (d, J = 11.2 Hz), 3.71 (d, J = 6.5 Hz, 2H), 3.27 (d , J=11.2Hz, 2H), 2.83(d, J=10.8Hz, 2H), 2.57(s, 2H), 2.34-2.01(m, 2H), 1.62-1.75(m, 4H), 1.04(d, J=6.6hz, 6H). LCMS: [M+1] + 470.21.
实施例2：合成1-(3-(吖丁啶-1-基)-丙基)-1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-脲(Compound #12)，ER10053Example 2: Synthesis of 1-(3-(azetidine-1-yl)-propyl)-1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl) -Urea (Compound #12), ER10053
Figure PCTCN2021072517-appb-000014
Figure PCTCN2021072517-appb-000014
(3-(吖丁啶-1)-基-丙基)-(4-氟-苯甲基)-胺(12-1)：合成方法类似于中间体(1-1)。用0.88mmol 3-(吖丁啶-1-基)-丙基胺与4-氟苯甲醛，得到棕色油状化合物(12-1)(155mg，80％产率)。LCMS：[M+1] +223.3。 (3-(azetidine-1)-yl-propyl)-(4-fluoro-benzyl)-amine (12-1): The synthesis method is similar to the intermediate (1-1). Using 0.88 mmol of 3-(azetidin-1-yl)-propylamine and 4-fluorobenzaldehyde, compound (12-1) (155 mg, 80% yield) was obtained as a brown oil. LCMS: [M+1] + 223.3.
Figure PCTCN2021072517-appb-000015
Figure PCTCN2021072517-appb-000015
1-(3-(吖丁啶-1-基)-丙基)-1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-脲(Compound #12)合成方法类似于compound #1。用0.70mmol(3-(吖丁啶-1)-基-丙基)-(4-氟-苯甲基)-胺(12-1)，与1-异丁氧基-4-(异氰酸基甲基)苯(1-4)反应，得到白色固体compound#12 ER10053(100mg。33％产率)。 1H NMR(300MHz，CDCl 3)：δ7.31(d，J＝6.4Hz，4H)，7.01(t，J＝8.7Hz，2H)，6.93-6.84(m，2H)，4.48(s，2H)，4.41(s，2H)，3.73(d，J＝6.5Hz，2H)，3.245(s，2Hz)，3.02-2.91(m，4H)，2.36(d，J＝5.9Hz，2H)，2.09(dp，J＝12.4，6.1Hz，2H)，1.74(p，J＝7.2Hz，2H)，1.50-1.40(m，2H)，1.03(d，J＝6.6Hz，6H)，LCMS：[M+1] +428.3。 1-(3-(azetidine-1-yl)-propyl)-1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-urea (Compound # 12) The synthesis method is similar to compound #1. Use 0.70mmol (3-(azetidine-1)-yl-propyl)-(4-fluoro-benzyl)-amine (12-1), and 1-isobutoxy-4-(isocyanide Acid-methyl)benzene (1-4) was reacted to obtain compound#12 ER10053 (100 mg, 33% yield) as a white solid. 1 H NMR (300MHz, CDCl 3 ): δ 7.31 (d, J = 6.4 Hz, 4H), 7.01 (t, J = 8.7 Hz, 2H), 6.93-6.84 (m, 2H), 4.48 (s, 2H) ), 4.41(s, 2H), 3.73(d, J=6.5Hz, 2H), 3.245(s, 2Hz), 3.02-2.91(m, 4H), 2.36(d, J=5.9Hz, 2H), 2.09 (dp, J = 12.4, 6.1 Hz, 2H), 1.74 (p, J = 7.2 Hz, 2H), 1.50-1.40 (m, 2H), 1.03 (d, J = 6.6 Hz, 6H), LCMS: [M +1] + 428.3.
实施例3：合成1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(1-甲基-吡咯烷-3-基甲基)-脲(compound #10)，ER10054Example 3: Synthesis of 1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(1-methyl-pyrrolidin-3-ylmethyl)- Urea (compound #10), ER10054
Figure PCTCN2021072517-appb-000016
Figure PCTCN2021072517-appb-000016
(4-氟-苯甲基)-(1-甲基-吡咯烷-3-基甲基)-胺(10-1)：合成方法类似于中间体(1-1)。用(1-甲基-吡咯烷-3-基)-甲胺(100mg，0.87mmol)与4-氟苯甲醛反应，得到黄色油状产物(10-1)(155mg，80％产率)。LCMS：[M+1] +223.4。 (4-Fluoro-benzyl)-(1-methyl-pyrrolidin-3-ylmethyl)-amine (10-1): The synthesis method is similar to the intermediate (1-1). (1-Methyl-pyrrolidin-3-yl)-methylamine (100 mg, 0.87 mmol) was reacted with 4-fluorobenzaldehyde to obtain a yellow oily product (10-1) (155 mg, 80% yield). LCMS: [M+1] + 223.4.
Figure PCTCN2021072517-appb-000017
Figure PCTCN2021072517-appb-000017
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(1-甲基-吡咯烷-3-基甲基)-脲(compound #10)合成方法类似于compound #1。用(4-氟-苯甲基)-(1-甲基-吡咯烷-3-基甲基)-胺(10-1)0.69mmol与1-异丁氧基-4-(异氰酸基甲基)苯(1-4)反应，得到黄色固体compound #10 ER10054(140mg，47％产率)。 1H NMR(300MHz，CDCl 3)：δ7.29-7.17(m，4H)，7.02(dd，J＝9.8，7.5Hz，2H)，6.86(dd，J＝9.1，2.4Hz，2H)，6.37(s，1H)，4.70-4.58(m，2H)，4.44-4.32(m，2H)，3.80(s，2H)，3.72(d，J＝6.4Hz，2H)，3.31(dd，J＝15.2，10.6Hz，2H)，3.08-2.89(m，2H)，2.67(d，J＝9.8Hz，2H)，2.14(s，2H)，2.15-2.01(m，2H)，2.06-1.83(m，1H)，1.44(d，J＝9.0Hz，2H)，1.04(d，J＝6.7Hz，6H).LCMS：[M+1] +428.3。 1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(1-methyl-pyrrolidin-3-ylmethyl)-urea (compound #10 ) The synthesis method is similar to compound #1. Use (4-fluoro-benzyl)-(1-methyl-pyrrolidin-3-ylmethyl)-amine (10-1) 0.69mmol and 1-isobutoxy-4-(isocyanate Methyl)benzene (1-4) was reacted to obtain compound #10 ER10054 (140 mg, 47% yield) as a yellow solid. 1 H NMR (300MHz, CDCl 3 ): δ 7.29-7.17 (m, 4H), 7.02 (dd, J = 9.8, 7.5 Hz, 2H), 6.86 (dd, J = 9.1, 2.4 Hz, 2H), 6.37 (s, 1H), 4.70-4.58 (m, 2H), 4.44-4.32 (m, 2H), 3.80 (s, 2H), 3.72 (d, J = 6.4 Hz, 2H), 3.31 (dd, J = 15.2 , 10.6Hz, 2H), 3.08-2.89(m, 2H), 2.67(d, J=9.8Hz, 2H), 2.14(s, 2H), 2.15-2.01(m, 2H), 2.06-1.83(m, 1H), 1.44 (d, J=9.0 Hz, 2H), 1.04 (d, J=6.7 Hz, 6H). LCMS: [M+1] + 428.3.
实施例4：合成1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-((1-甲基-吖丁啶)-3-基甲基)-脲(Compound #11)，ER10057Example 4: Synthesis of 1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-((1-methyl-azetidine)-3-ylmethyl Base)-urea (Compound #11), ER10057
Figure PCTCN2021072517-appb-000018
Figure PCTCN2021072517-appb-000018
(4-氟-苯甲基)-((1-甲基-吖丁啶)-3-基甲基)-胺(11-1)：合成方法类似于中间体(1-1)。用0.5mmol(1-甲基-吖丁啶-3-基)-甲胺与4-氟苯甲醛反应，得到棕色油状中间体(11-1)(88mg，85％产率)。LCMS：[M+1] +209.3。 (4-Fluoro-benzyl)-((1-methyl-azetidine)-3-ylmethyl)-amine (11-1): The synthesis method is similar to the intermediate (1-1). 0.5 mmol (1-methyl-azetidine-3-yl)-methylamine was reacted with 4-fluorobenzaldehyde to obtain brown oily intermediate (11-1) (88 mg, 85% yield). LCMS: [M+1] + 209.3.
Figure PCTCN2021072517-appb-000019
Figure PCTCN2021072517-appb-000019
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-((1-甲基-吖丁啶)-3-基甲基)-脲(Compound #11)合成方法类似于compound #1。用0.42mmol(4-氟-苯甲基)-((1-甲基-吖丁啶)-3-基甲基)-胺(11-1)与1-异丁氧基-4-(异氰酸基甲基)苯(1-4)反应，得到黄色固体compound #11 ER10057(23mg，14％产率)。LCMS：[M+1] +414.5。 1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-((1-methyl-azetidine)-3-ylmethyl)-urea( Compound #11) The synthesis method is similar to compound #1. Use 0.42mmol (4-fluoro-benzyl)-((1-methyl-azetidine)-3-ylmethyl)-amine (11-1) and 1-isobutoxy-4-(iso Cyanomethyl)benzene (1-4) was reacted to obtain compound #11 ER10057 (23 mg, 14% yield) as a yellow solid. LCMS: [M+1] + 414.5.
实施例5：合成1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(八氢-喹嗪-2-基)-脲(Compound #5)，ER10063Example 5: Synthesis of 1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(octahydro-quinazin-2-yl)-urea (Compound# 5), ER10063
Figure PCTCN2021072517-appb-000020
Figure PCTCN2021072517-appb-000020
2-(1-(3-丙酸乙酯)-哌啶)-2-基)-乙酸乙酯(5/6-1)：在氩气下，室温搅拌2-(哌啶-2-基)乙酸乙酯(500mg，3.0mmol)，丙烯酸乙酯(901mg，9.0mmol)，三乙胺(1800mg，18mmol)混合物的乙醇溶液4天，真空下去除溶剂和过量试剂。获得了粗产品中间体化合物(5/6-1)(600毫克，产率76％)，并在下一步直接使用。2-(1-(3-Ethylpropionate)-piperidin-2-yl)-ethyl acetate (5/6-1): Stir at room temperature under argon ) Ethanol solution of ethyl acetate (500 mg, 3.0 mmol), ethyl acrylate (901 mg, 9.0 mmol), and triethylamine (1800 mg, 18 mmol) mixture for 4 days, the solvent and excess reagents were removed under vacuum. The crude intermediate compound (5/6-1) (600 mg, yield 76%) was obtained and used directly in the next step.
Figure PCTCN2021072517-appb-000021
Figure PCTCN2021072517-appb-000021
2-羰基-八氢-喹嗪-1-甲酸乙基酯(5-2)：在氩气氛下，2-(1-(3-丙酸乙酯)-哌啶)-2-基)-乙酸乙酯(5-1)(810mg，3.0mmol)溶解在6毫升无水THF中。在-78℃下，慢慢滴加1.3M LiHDMS(6.0mmol)的THF溶液。然后-78℃搅拌2小时，加入1毫升6NHCl。回温到室温后，加入30毫升水。用30毫升***提取混合物。调节水层与饱和Na 2CO 3水溶液pH＝8.0～9.0***提取水层。将有机相用盐水清洗，并用Na 2SO 4干燥。减压下浓缩，得到粗产物(5-2)900毫克。在下一步反应中直接使用。 2-Carbonyl-octahydro-quinazine-1-carboxylic acid ethyl ester (5-2): Under argon atmosphere, 2-(1-(3-propionic acid ethyl ester)-piperidin)-2-yl)- Ethyl acetate (5-1) (810 mg, 3.0 mmol) was dissolved in 6 mL of dry THF. At -78°C, a 1.3M LiHDMS (6.0 mmol) THF solution was slowly added dropwise. Then, it was stirred at -78°C for 2 hours, and 1 ml of 6N HCl was added. After warming to room temperature, add 30 ml of water. The mixture was extracted with 30 ml of ether. Adjust the pH of the water layer and saturated Na 2 CO 3 aqueous solution to pH=8.0～9.0 and extract the water layer with ether. The organic phase was washed with brine and dried with Na 2 SO 4 . Concentrate under reduced pressure to obtain 900 mg of crude product (5-2). Used directly in the next reaction.
Figure PCTCN2021072517-appb-000022
Figure PCTCN2021072517-appb-000022
八氢-喹嗪-2-酮(5-3)：900mg 2-羰基-八氢-喹嗪-1-甲酸乙基酯(5-2)在10ml 6NHCl中回流20小时。反应混合物用固体Na 2CO 3中和，***3×30毫升提取，将有机相用盐水清洗并用Na 2SO 4干燥，将溶剂蒸发，得到粗产物300mg(产率49％)。 Octahydro-quinazin-2-one (5-3): 900 mg of 2-carbonyl-octahydro-quinazine-1-carboxylic acid ethyl ester (5-2) was refluxed in 10 ml of 6N HCl for 20 hours. The reaction mixture was neutralized with solid Na 2 CO 3 and extracted with 3×30 ml of ether. The organic phase was washed with brine and dried with Na 2 SO 4. The solvent was evaporated to obtain 300 mg of crude product (yield 49%).
Figure PCTCN2021072517-appb-000023
Figure PCTCN2021072517-appb-000023
(4-氟-苯甲基)-(八氢-喹嗪-2-基)-胺(5-4)：合成方法类似于(1-1)。用0.97mmol八氢-喹嗪-2-酮(5-3)得到无色油状产物(5-4)(215mg，产率85％)。LCMS：[M+1] +263.21。 (4-Fluoro-benzyl)-(octahydro-quinazin-2-yl)-amine (5-4): The synthesis method is similar to (1-1). 0.97 mmol of octahydro-quinazin-2-one (5-3) was used to obtain a colorless oily product (5-4) (215 mg, yield 85%). LCMS: [M+1] + 263.21.
Figure PCTCN2021072517-appb-000024
Figure PCTCN2021072517-appb-000024
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(八氢-喹嗪-2-基)-脲(Compound #5)：合成方法类似于compound #1。用0.83mmol(4-氟-苯甲基)-(八氢-喹嗪-2-基)-胺(5-4)与1-异丁氧基-4-(异氰酸基甲基)苯(1-4)反应，得到白色固体compound #5 ER10063(280mg，73％产率)。 1H NMR(300MHz，CDCl 3)：δ7.19(dd，J＝6.6Hz，2H)，7.03(d，J＝8.5Hz，4H)，6.80(d，J＝8.6Hz，2H)，4.45-4.6(m，2H)，4.43(s，，2H)，4.39-4.25(m，4H)，3.70(d，J＝6.6Hz，2H)，3.14(d，J＝13.4Hz，2H)，2.55(s，1H)，2.08(dt，J＝13.40Hz，1H)，2.04-2.06(m，4H)，1.88(d，J＝13.2Hz，，4H)，1.34(s，2H)，1.31-1.16(m，2H)，1.03(d，J＝6.7Hz，6H)，LCMS：[M+1] +468.10。 1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(octahydro-quinazin-2-yl)-urea (Compound #5): synthetic method Similar to compound #1. Use 0.83mmol (4-fluoro-benzyl)-(octahydro-quinazin-2-yl)-amine (5-4) and 1-isobutoxy-4-(isocyanatomethyl)benzene (1-4) Reaction to obtain compound #5 ER10063 (280 mg, 73% yield) as a white solid. 1 H NMR (300MHz, CDCl 3 ): δ 7.19 (dd, J = 6.6 Hz, 2H), 7.03 (d, J = 8.5 Hz, 4H), 6.80 (d, J = 8.6 Hz, 2H), 4.45 4.6 (m, 2H), 4.43 (s,, 2H), 4.39-4.25 (m, 4H), 3.70 (d, J = 6.6 Hz, 2H), 3.14 (d, J = 13.4 Hz, 2H), 2.55 ( s, 1H), 2.08 (dt, J = 13.40 Hz, 1H), 2.04-2.06 (m, 4H), 1.88 (d, J = 13.2 Hz,, 4H), 1.34 (s, 2H), 1.31-1.16 ( m, 2H), 1.03 (d, J=6.7 Hz, 6H), LCMS: [M+1] + 468.10.
实施例6：合成1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(八氢-吡啶并[2，1-c][1，4]噁嗪-8-基)-脲(Compound #7)，ER10065Example 6: Synthesis of 1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(octahydro-pyrido[2,1-c][1, 4] Oxazine-8-yl)-urea (Compound #7), ER10065
Figure PCTCN2021072517-appb-000025
Figure PCTCN2021072517-appb-000025
3-((3-乙氧基羰基甲基)-吗啉-4-基)丙酸乙酯(7/8-1)：合成方法类似于(5-1)。用2-(吗啉-3-基)-乙酸乙酯(1.0g，5.8mmol)得到粗产物(1.3g，87％产率)直接用于下一步反应。Ethyl 3-((3-ethoxycarbonylmethyl)-morpholin-4-yl)propionate (7/8-1): The synthesis method is similar to (5-1). The crude product (1.3 g, 87% yield) was obtained with 2-(morpholin-3-yl)-ethyl acetate (1.0 g, 5.8 mmol) and used directly in the next reaction.
Figure PCTCN2021072517-appb-000026
Figure PCTCN2021072517-appb-000026
8-羰基-八氢-吡啶并[2，1-c][1，4]噁嗪-9-甲酸乙酯(7-2)：合成方法类似于(5-2)。用3-((3-乙氧基羰基甲基)-吗啉-4-基)丙酸乙酯(7-1)(1.3g，3.9mmol)得到粗产物(900mg，100％产率)直接用于下一步反应。8-Carbonyl-octahydro-pyrido[2,1-c][1,4]oxazine-9-ethyl carboxylate (7-2): The synthesis method is similar to (5-2). Ethyl 3-((3-ethoxycarbonylmethyl)-morpholin-4-yl)propionate (7-1) (1.3g, 3.9mmol) was used to obtain the crude product (900mg, 100% yield) directly Used in the next reaction.
Figure PCTCN2021072517-appb-000027
Figure PCTCN2021072517-appb-000027
六氢-吡啶并[2，1-c][1，4]噁嗪-8-酮(7-3)：合成方法类似于(5-3)。用8-羰基-八氢-吡啶并[2，1-c][1，4]噁嗪-9-羧酸乙基酯(7-2)(900mg，4.0mmol)得到粗产物(300mg，48％产率)直接用于下一步反应。Hexahydro-pyrido[2,1-c][1,4]oxazin-8-one (7-3): The synthesis method is similar to (5-3). Use 8-carbonyl-octahydro-pyrido[2,1-c][1,4]oxazine-9-carboxylic acid ethyl ester (7-2) (900mg, 4.0mmol) to obtain the crude product (300mg, 48 % Yield) used directly in the next reaction.
Figure PCTCN2021072517-appb-000028
Figure PCTCN2021072517-appb-000028
(4-氟-苯甲基)-(八氢吡啶并[2，1-c][1，4]噁嗪-8-基)-胺(7-4)：合成方法类似于(1-1)。用六氢-吡啶并[2，1-c][1，4]噁嗪-8-酮(7-3)(150mg，0.97mmol)与4-氟苯基甲胺得到粗产物(166mg，65％产率)，直接用于下一步反应。LCMS：[M+1] +265.21。 (4-Fluoro-benzyl)-(octahydropyrido[2,1-c][1,4]oxazine-8-yl)-amine (7-4): The synthesis method is similar to (1-1 ). Using hexahydro-pyrido[2,1-c][1,4]oxazine-8-one (7-3) (150mg, 0.97mmol) and 4-fluorophenylmethylamine to obtain the crude product (166mg, 65 % Yield), directly used in the next reaction. LCMS: [M+1] + 265.21.
Figure PCTCN2021072517-appb-000029
Figure PCTCN2021072517-appb-000029
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(八氢吡啶并[2，1-c][1，4]噁嗪-8-基)-脲(Compound #7)：合成方法类似于compound #1。用0.63mmol(4-氟-苯甲基)-(八氢-吡啶并[2，1-c][1，4]噁嗪-8-基)-胺(7-4)与1-异丁氧基-4-(异氰酸基甲基)苯(1-4)反应，得到白色固体#7 ER10065(150mg，58％产率)。 1H NMR(300MHz，CDCl 3)：δ7.19(dt，J＝8.7Hz，4.8Hz，2H)，7.04(dd，J＝8.4Hz，4H)，6.8(s，2H)，4.52(s，2H)，4.38-4.25(m，3H)，3.91-3.73(m，2H)，3.72(s，2Hz)，3.67(d，J＝12.2Hz，2H)，3.58-3.48(m，2H)，3.04(dd，J＝11.3.4.8Hz，2H)，2.91-2.61(m，1H)，2.52-2.20(m，1H)，2.08(dt，J＝13.4，6.6Hz，1H)，1.80(td，J＝14.6，14.0，6.4Hz，2H)，1.31-1.16(m，2H)，1.03(d，J＝6.8Hz，6H)，LCMS：[M+1] +470.11。 1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(octahydropyrido[2,1-c][1,4]oxazine-8 -Base)-urea (Compound #7): The synthesis method is similar to compound #1. Use 0.63mmol (4-fluoro-benzyl)-(octahydro-pyrido[2,1-c][1,4]oxazine-8-yl)-amine (7-4) and 1-isobutyl The oxy-4-(isocyanatomethyl)benzene (1-4) was reacted to obtain #7 ER10065 (150 mg, 58% yield) as a white solid. 1 H NMR (300MHz, CDCl 3 ): δ 7.19 (dt, J = 8.7 Hz, 4.8 Hz, 2H), 7.04 (dd, J = 8.4 Hz, 4H), 6.8 (s, 2H), 4.52 (s, 2H), 4.38-4.25 (m, 3H), 3.91-3.73 (m, 2H), 3.72 (s, 2Hz), 3.67 (d, J=12.2Hz, 2H), 3.58-3.48 (m, 2H), 3.04 (dd, J = 11.3.4.8 Hz, 2H), 2.91-2.61 (m, 1H), 2.52-2.20 (m, 1H), 2.08 (dt, J = 13.4, 6.6 Hz, 1H), 1.80 (td, J =14.6, 14.0, 6.4 Hz, 2H), 1.31-1.16 (m, 2H), 1.03 (d, J=6.8 Hz, 6H), LCMS: [M+1] + 470.11.
实施例7：合成1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(2-(吡咯烷-1-基)-乙基)-脲(compound #53)，ER10066Example 7: Synthesis of 1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(2-(pyrrolidin-1-yl)-ethyl)- Urea (compound #53), ER10066
Figure PCTCN2021072517-appb-000030
Figure PCTCN2021072517-appb-000030
(4-氟-苯甲基)-(2-(吡咯烷-1-基)-乙基)-胺(53-1)：合成方法类似于(1-1)。用1.3mmol2-(吡咯烷-1-基)-乙基胺得到棕色油状(53-1)(213mg，73％产率)。LCMS：[M+1] +223.35 (4-Fluoro-benzyl)-(2-(pyrrolidin-1-yl)-ethyl)-amine (53-1): The synthesis method is similar to (1-1). Using 1.3 mmol of 2-(pyrrolidin-1-yl)-ethylamine, (53-1) was obtained as a brown oil (213 mg, 73% yield). LCMS: [M+1] + 223.35
Figure PCTCN2021072517-appb-000031
Figure PCTCN2021072517-appb-000031
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(2-(吡咯烷-1-基)-乙基)-脲(Compound #53)合成方法类似于compound #1。用0.95mmol(4-氟-苯甲基)-(2-吡咯烷-1-基-乙基)-胺(53-1)与1-异丁氧基-4-(异氰酸基甲基)苯(1-4)反应，得到compound #53 ER10066(210mg，51％产率)。LCMS：[M+1] +428.18。 1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(2-(pyrrolidin-1-yl)-ethyl)-urea (Compound #53 ) The synthesis method is similar to compound #1. Use 0.95mmol (4-fluoro-benzyl)-(2-pyrrolidin-1-yl-ethyl)-amine (53-1) and 1-isobutoxy-4-(isocyanatomethyl ) Benzene (1-4) was reacted to obtain compound #53 ER10066 (210 mg, 51% yield). LCMS: [M+1] + 428.18.
实施例8：合成3-(4-异丁氧基-苯甲基)-1-(4-氟-苯甲基)-1-[2-(1-甲基-1H-咪唑-4-基)-乙基]-脲(compound #55)，ER10117Example 8: Synthesis of 3-(4-isobutoxy-benzyl)-1-(4-fluoro-benzyl)-1-[2-(1-methyl-1H-imidazol-4-yl) )-Ethyl]-urea (compound #55), ER10117
Figure PCTCN2021072517-appb-000032
Figure PCTCN2021072517-appb-000032
(4-氟-苯甲基)-[2-(1-甲基-1H-咪唑-4-基)-乙基]-胺(55-1)合成方法类似于(1-1)。用2-(1-甲基-1H-咪唑-4-基)-乙基胺(250mg，1.26mmol)得到无色油状物(55-1)(176mg，60％产率)。LCMS：[M+1] +234.31。 The synthesis method of (4-fluoro-benzyl)-[2-(1-methyl-1H-imidazol-4-yl)-ethyl]-amine (55-1) is similar to (1-1). 2-(1-Methyl-1H-imidazol-4-yl)-ethylamine (250 mg, 1.26 mmol) was used to obtain a colorless oil (55-1) (176 mg, 60% yield). LCMS: [M+1] + 234.31.
Figure PCTCN2021072517-appb-000033
Figure PCTCN2021072517-appb-000033
1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-[2-(1-甲基-1H-咪唑-4-基)-乙基]-脲(compound #55)合成方法类似于compound #1。用0.76mmol(4-氟-苯甲基)-[2-(1-甲基-1H-咪唑-4-基)-乙基]-胺(55-1)与1-异丁氧基-4-(异氰酸基甲基)苯(1-4)反应，得到黄色固体compound #55 ER10117(75mg，23％产率)。 1H NMR(300MHz，CDCl 3)：δ7.56(s，2H)，7.30(s，2H)，7.30-7.14(m，1H)，7.12-6.85(m，4H)，4.25(d，J＝11.4Hz，2H)，3.77-3.60(m，2H)，3.16(q，J＝6.7Hz，2H)，2.61-2.50(m，1Hz)，2.41(m，4H)，2.26(m，2H)，1.89(p，J＝7.1Hz，2H)，1.38(m，2H)，1.04(s，3H)，1.08-0.94(m，6H)，LCMS：[M+1] +440.08。 1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-[2-(1-methyl-1H-imidazol-4-yl)-ethyl] -Urea (compound #55) synthesis method is similar to compound #1. Use 0.76mmol (4-fluoro-benzyl)-[2-(1-methyl-1H-imidazol-4-yl)-ethyl]-amine (55-1) and 1-isobutoxy-4 -(Isocyanatomethyl)benzene (1-4) was reacted to obtain compound #55 ER10117 (75 mg, 23% yield) as a yellow solid. 1 H NMR (300MHz, CDCl 3 ): δ 7.56 (s, 2H), 7.30 (s, 2H), 7.30-7.14 (m, 1H), 7.12-6.85 (m, 4H), 4.25 (d, J= 11.4Hz, 2H), 3.77-3.60(m, 2H), 3.16(q, J=6.7Hz, 2H), 2.61 to 2.50(m, 1Hz), 2.41(m, 4H), 2.26(m, 2H), 1.89 (p, J=7.1 Hz, 2H), 1.38 (m, 2H), 1.04 (s, 3H), 1.08-0.94 (m, 6H), LCMS: [M+1] + 440.08.
实施例9：合成3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(哌啶-1-基)乙基)脲(H001-017，ER10173)Example 9: Synthesis of 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(piperidin-1-yl)ethyl)urea (H001- 017, ER10173)
Figure PCTCN2021072517-appb-000034
Figure PCTCN2021072517-appb-000034
N-(4-氟苯甲基)-2-(哌啶-1-基)乙烷-1-胺(H001-003)，合成方法类似于(1-1)。用0.9mmol 2-哌啶-1-基-乙基胺得到棕色中间体(H001-003)(104mg，44％产率)。LCMS：[M+1] +237.3。 N-(4-fluorobenzyl)-2-(piperidin-1-yl)ethane-1-amine (H001-003), the synthesis method is similar to (1-1). With 0.9 mmol 2-piperidin-1-yl-ethylamine, the brown intermediate (H001-003) (104 mg, 44% yield) was obtained. LCMS: [M+1] + 237.3.
Figure PCTCN2021072517-appb-000035
Figure PCTCN2021072517-appb-000035
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(哌啶-1-基)乙基)脲(H001-017，ER10173)合成方法类似于compound #1。用0.76mmol 1-环丁氧基-4-异氰酸基甲基苯(37-3)与上述中间体反应，得到白色固体compound ER10173(58.6mg，18％产率)。 1H NMR(400MHz，CDCl 3)：δ7.26-7.23(m，4H)，7.02-6.97(m，2H)，6.72(d，J＝8.5Hz，2H)，5.40(bs，1H)，4.62-4.59(m，1H)，4.42(s，2H)，4.28(s，2H)，3.70(m，2Hz)，3.61(d，J＝6.5Hz，2H)，3.12(m，2H)，2.62(m，2H)，2.45-2.38(m，6H)，2.16-2.12(m，2H)，1.94-1.71(m，2H)，1.68-1.65(m，1H)，1.39(m 1H)。LCMS：[M+1] +440.3。 Synthesis of 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(piperidin-1-yl)ethyl)urea (H001-017, ER10173) The method is similar to compound #1. 0.76 mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) was reacted with the above intermediate to obtain compound ER10173 (58.6 mg, 18% yield) as a white solid. 1 H NMR (400MHz, CDCl 3 ): δ7.26-7.23 (m, 4H), 7.02-6.97 (m, 2H), 6.72 (d, J=8.5Hz, 2H), 5.40 (bs, 1H), 4.62 -4.59(m, 1H), 4.42(s, 2H), 4.28(s, 2H), 3.70(m, 2Hz), 3.61(d, J=6.5Hz, 2H), 3.12(m, 2H), 2.62( m, 2H), 2.45-2.38 (m, 6H), 2.16-2.12 (m, 2H), 1.94-1.71 (m, 2H), 1.68-1.65 (m, 1H), 1.39 (m 1H). LCMS: [M+1] + 440.3.
实施例10：合成3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H001-018)ER10174Example 10: Synthesis of 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea ( H001-018)ER10174
Figure PCTCN2021072517-appb-000036
Figure PCTCN2021072517-appb-000036
N-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H001-004)，合成方法类似于(1-1)。用0.9mmol 2-哌啶-1-基-乙基胺为原料得到棕色中间体(H001-004)(82mg，35％产率)。LCMS：[M+1] +237.3。 N-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)methylamine (H001-004), the synthesis method is similar to (1-1). Using 0.9 mmol 2-piperidin-1-yl-ethylamine as a raw material, a brown intermediate (H001-004) (82 mg, 35% yield) was obtained. LCMS: [M+1] + 237.3.
Figure PCTCN2021072517-appb-000037
Figure PCTCN2021072517-appb-000037
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H001-018)ER101743-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea(H001-018)ER10174
合成方法类似于compound #1.用0.76mmol 1-环丁氧基-4-异氰酸基甲基苯(37-3)为原料与H001-004化合物反应，得到白色固体compound #H001-018 ER10174(26.2mg，8％产率). 1H NMR(400MHz，CDCl3)：δ7.19-7.09(m，2H)，7.04-6.93(m，4H)，6.72(d，J＝8.5Hz，2H)，4.80(bs，1H)，4.42(m，4H)，4.28(s，2H)，3.60(m，2Hz)，3.24(d，J＝6.5Hz，2H)，2.77(s，3H)，2.62(m，2H)，2.45-2.38(m，2H)，2.16-1.94(m，4H)，1.85-1.60(m，4H).LCMS：[M+1] +440.3. The synthesis method is similar to compound #1. Use 0.76mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) as raw material to react with H001-004 compound to obtain a white solid compound #H001-018 ER10174 (26.2mg, 8% yield). 1 H NMR (400MHz, CDCl3): δ7.19-7.09 (m, 2H), 7.04-6.93 (m, 4H), 6.72 (d, J=8.5Hz, 2H) , 4.80(bs, 1H), 4.42(m, 4H), 4.28(s, 2H), 3.60(m, 2Hz), 3.24(d, J=6.5Hz, 2H), 2.77(s, 3H), 2.62( m, 2H), 2.45-2.38 (m, 2H), 2.16-1.94 (m, 4H), 1.85-1.60 (m, 4H). LCMS: [M+1] + 440.3.
实施例11：合成3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-3-基)甲基)脲(H001-019)ER10175Example 11: Synthesis of 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-3-yl)methyl)urea ( H001-019)ER10175
Figure PCTCN2021072517-appb-000038
Figure PCTCN2021072517-appb-000038
N-(4-氟苯甲基)-1-(1-甲基哌啶-3-基)甲胺(H001-007).合成方法类似于(1-1).用7.2mmol(1-甲基哌啶-3-基)甲胺与4-氟苯甲醛反应，得到棕色油状中间体(H001-007)(560mg，33％产率).LCMS：[M+1]+ 237.3N-(4-fluorobenzyl)-1-(1-methylpiperidin-3-yl)methylamine (H001-007). The synthesis method is similar to (1-1). Use 7.2mmol(1-methyl (Hydroxypiperidin-3-yl)methylamine was reacted with 4-fluorobenzaldehyde to obtain a brown oily intermediate (H001-007) (560mg, 33% yield). LCMS: [M+1]+ 237.3
Figure PCTCN2021072517-appb-000039
Figure PCTCN2021072517-appb-000039
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-3-基)甲基)脲(H001-019)ER101753-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-3-yl)methyl)urea(H001-019)ER10175
合成方法类似于compound #1.用0.76mmol 1-环丁氧基-4-异氰酸基甲基苯(37-3)得到白色固体compound #H001-019 ER10175(24.7mg，7％产率). 1H NMR(400MHz，CDCl3)：δ7.19-7.09(m，2H)，7.04-6.93(m，4H)，6.72(d，J＝8.5Hz，2H)，4.80(bs，1H)， 4.57(m，1H)，4.48-4.43(d，J＝8.5Hz，1H)，4.32-4.17(m，3H)，3.77(m，5H)，3.54(m，2Hz)，2.94(m，1H)，2.76(s，3H)，2.54(m，2H)，2.45-2.36(m，3H)，2.16-2.04(m，2H)，2.05-1.60(m，2H).LCMS：[M+1] +440.3. The synthesis method is similar to compound #1. 0.76mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) is used to obtain white solid compound #H001-019 ER10175 (24.7mg, 7% yield) . 1 H NMR (400MHz, CDCl3): δ 7.19-7.09 (m, 2H), 7.04-6.93 (m, 4H), 6.72 (d, J = 8.5 Hz, 2H), 4.80 (bs, 1H), 4.57 (m, 1H), 4.48-4.43 (d, J=8.5Hz, 1H), 4.32-4.17 (m, 3H), 3.77 (m, 5H), 3.54 (m, 2Hz), 2.94 (m, 1H), 2.76 (s, 3H), 2.54 (m, 2H), 2.45-2.36 (m, 3H), 2.16-2.04 (m, 2H), 2.05-1.60 (m, 2H). LCMS: [M+1] + 440.3 .
实施例12：合成3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-(2-氟乙基)吡咯烷-3-基)甲基)脲(H001-024，ER10176)Example 12: Synthesis of 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-(2-fluoroethyl)pyrrolidin-3-yl) Methyl)urea (H001-024, ER10176)
Figure PCTCN2021072517-appb-000040
Figure PCTCN2021072517-appb-000040
叔-丁基3-(((4-氟苯甲基)氨基)甲基)吡咯烷-1-甲酸酯(H001-009)合成方法类似于(1-1).用叔丁基3-(氨基甲基)吡咯烷-1-甲酸酯(390mg，1.29mmol)与4-氟苯甲醛反应，得到无色油状产物(290mg，73％产率).LCMS：[M+1] +209.2. The synthesis method of tert-butyl 3-(((4-fluorobenzyl)amino)methyl)pyrrolidine-1-carboxylate (H001-009) is similar to (1-1). Use tert-butyl 3-((4-fluorobenzyl)amino)methyl)pyrrolidine-1-carboxylate (H001-009). (Aminomethyl)pyrrolidine-1-carboxylate (390mg, 1.29mmol) was reacted with 4-fluorobenzaldehyde to obtain a colorless oily product (290mg, 73% yield). LCMS: [M+1] + 209.2 .
Figure PCTCN2021072517-appb-000041
Figure PCTCN2021072517-appb-000041
叔-丁基3-((3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)脲基)甲基)吡咯烷-1-甲酸酯(H001-020)合成方法类似于(1-1).用3mmol叔-丁基3-(((4-氟苯甲基)氨基)甲基)吡咯烷-1-甲酸酯(H001-009)与1-环丁氧基-4-异氰酸基甲基苯(37-3)反应，得到中间体(H001-020)(600mg，39％产率).LCMS：[M+1] +512.2. Tert-Butyl 3-((3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)ureido)methyl)pyrrolidine-1-carboxylate (H001-020 ) The synthesis method is similar to (1-1). Use 3mmol tert-butyl 3-(((4-fluorobenzyl)amino)methyl)pyrrolidine-1-carboxylate (H001-009) and 1- Cyclobutoxy-4-isocyanatomethylbenzene (37-3) was reacted to obtain intermediate (H001-020) (600 mg, 39% yield). LCMS: [M+1] + 512.2.
Figure PCTCN2021072517-appb-000042
Figure PCTCN2021072517-appb-000042
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(吡咯烷-3-基甲基)脲(H001-022)合成方法类似于(9-1).1mmol叔-丁基3-((3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)脲基)甲基)吡咯烷-1-甲酸酯(H01-020)在二氯甲烷和TFA(2∶1)的混合溶液中搅拌1小时，低压脱溶后得到白色固体(H001-022)(250mg，61％产率).LCMS：[M+1] +412.3 The synthesis method of 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(pyrrolidin-3-ylmethyl)urea (H001-022) is similar to (9- 1).1mmol tert-butyl 3-((3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)ureido)methyl)pyrrolidine-1-carboxylate (H01-020) was stirred in a mixed solution of dichloromethane and TFA (2:1) for 1 hour, and a white solid (H001-022) (250 mg, 61% yield) was obtained after low-pressure desolvation. LCMS: [M+ 1] + 412.3
Figure PCTCN2021072517-appb-000043
Figure PCTCN2021072517-appb-000043
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-(2-氟乙基)吡咯烷-3-基)甲基)脲(H001-024，ER10176)3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-(2-fluoroethyl)pyrrolidin-3-yl)methyl)urea( H001-024, ER10176)
在3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(吡咯烷-3-基甲基)脲(0.39mmol)的无水DMF(2mL)中加入1-氟-2-碘乙烷(0.39mmol)和碳酸铯(0.39mmol)。反应混合物在60℃下搅拌过夜，去除溶剂，用高效液相色谱进行提纯。得到白色固体compound H001-024，ER10176(120mg，67％产率)。 1H NMR(400MHz，CDCl3)：δ7.19-7.09(m，3H)，7.04-6.93(m，3H)，6.72(d，J＝8.5Hz，2H)，4.84(bs，1H)，4.70(m，1H)，4.62-4.53(m，2H)，4.42-4.19(m，5H)，3.86(m，2H)，3.50(m，3Hz)，3.25(m，2H)，3.03(m，1H)，2.80(m，2H)，2.44(m，2H)，2.28-2.05(m，3H)，1.875-1.63(m，3H).LCMS：[M+1] +458.1 In 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(pyrrolidin-3-ylmethyl)urea (0.39mmol) in anhydrous DMF (2mL) Add 1-fluoro-2-iodoethane (0.39 mmol) and cesium carbonate (0.39 mmol). The reaction mixture was stirred overnight at 60°C, the solvent was removed, and the mixture was purified by high performance liquid chromatography. A white solid compound H001-024, ER10176 (120 mg, 67% yield) was obtained. 1 H NMR (400MHz, CDCl3): δ 7.19-7.09 (m, 3H), 7.04-6.93 (m, 3H), 6.72 (d, J = 8.5 Hz, 2H), 4.84 (bs, 1H), 4.70 ( m, 1H), 4.62-4.53 (m, 2H), 4.42-4.19 (m, 5H), 3.86 (m, 2H), 3.50 (m, 3Hz), 3.25 (m, 2H), 3.03 (m, 1H) , 2.80 (m, 2H), 2.44 (m, 2H), 2.28-2.05 (m, 3H), 1.875-1.63 (m, 3H). LCMS: [M+1] + 458.1
实施例13：合成3-(4-环丁氧基苯甲基)-1-((1-乙基吡咯烷-3-基)甲基)-1-(4-氟苯甲基)脲(H001-026)ER10177Example 13: Synthesis of 3-(4-cyclobutoxybenzyl)-1-((1-ethylpyrrolidin-3-yl)methyl)-1-(4-fluorobenzyl)urea ( H001-026)ER10177
Figure PCTCN2021072517-appb-000044
Figure PCTCN2021072517-appb-000044
1-(1-乙基吡咯烷-3-基)-N-(4-氟苯甲基)甲胺(H001-006).合成方法类似于(1-1).用10mmol(1-乙基吡咯烷-3-基)甲胺与4-氟苯甲醛反应，得到棕色油状中间体(H001-006)(300mg，13％产率).LCMS：[M+1] +237.3 1-(1-Ethylpyrrolidin-3-yl)-N-(4-fluorobenzyl)methylamine (H001-006). The synthesis method is similar to (1-1). Use 10mmol(1-ethyl Pyrrolidin-3-yl) methylamine was reacted with 4-fluorobenzaldehyde to obtain brown oily intermediate (H001-006) (300mg, 13% yield). LCMS: [M+1] + 237.3
Figure PCTCN2021072517-appb-000045
Figure PCTCN2021072517-appb-000045
3-(4-环丁氧基苯甲基)-1-((1-乙基吡咯烷-3-基)甲基)-1-(4-氟苯甲基)脲(H001-026)ER101773-(4-Cyclobutoxybenzyl)-1-((1-ethylpyrrolidin-3-yl)methyl)-1-(4-fluorobenzyl)urea(H001-026)ER10177
合成方法类似于compound #1.用1.0mmol 1-环丁氧基-4-异氰酸基甲基苯(37-3)与1-(1-乙基吡咯烷-3-基)-N-(4-氟苯甲基)甲胺反应，得到产物compound #H001-026ER10177(80mg，18％产率). 1H NMR(400MHz，CDCl3)：δ7.19-7.09(m，3H)，7.04- 6.93(m，3H)，6.72(d，J＝8.5Hz，2H)，4.67(bs，1H)，4.58(m，1H)，4.41-4.32(m，2H)，4.27-4.17(m，2H)，3.80(m，2H)，3.75(m，2H)，3.62-3.47(m，2H)，3.31-3.12(m，2H)，2.99-2.65(m，2H)，2.41(m，2H)，2.24-2.05(m，4H)，1.89-1.63(m，1H)，1.35(m，3H).LCMS：[M+1] +440.2 The synthesis method is similar to compound #1. Use 1.0mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) and 1-(1-ethylpyrrolidin-3-yl)-N- (4-fluorobenzyl) methylamine was reacted to obtain the product compound #H001-026ER10177 (80mg, 18% yield). 1 H NMR (400MHz, CDCl3): δ7.19-7.09(m, 3H), 7.04 6.93 (m, 3H), 6.72 (d, J = 8.5 Hz, 2H), 4.67 (bs, 1H), 4.58 (m, 1H), 4.41-4.32 (m, 2H), 4.27-4.17 (m, 2H) , 3.80 (m, 2H), 3.75 (m, 2H), 3.62-3.47 (m, 2H), 3.31-3.12 (m, 2H), 2.99-2.65 (m, 2H), 2.41 (m, 2H), 2.24 -2.05 (m, 4H), 1.89-1.63 (m, 1H), 1.35 (m, 3H). LCMS: [M+1] + 440.2
实施例14：合成3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-2-基)甲基)脲(H001-028)ER10179Example 14: Synthesis of 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-2-yl)methyl)urea ( H001-028)ER10179
Figure PCTCN2021072517-appb-000046
Figure PCTCN2021072517-appb-000046
N-(4-氟苯甲基)-1-(1-甲基哌啶-2-基)甲胺(H001-021)，合成方法类似于(1-1)。用3mmol(1-甲基哌啶-2-基)甲胺得到中间体(H001-021)(453mg，64％产率)。LCMS：[M+1] +237.3。 N-(4-fluorobenzyl)-1-(1-methylpiperidin-2-yl)methylamine (H001-021), the synthesis method is similar to (1-1). The intermediate (H001-021) (453 mg, 64% yield) was obtained with 3 mmol (1-methylpiperidin-2-yl)methylamine. LCMS: [M+1] + 237.3.
Figure PCTCN2021072517-appb-000047
Figure PCTCN2021072517-appb-000047
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-2-基)甲基)脲(H001-028)ER10179，合成方法类似于compound #1。用1.0mmol 1-环丁氧基-4-异氰酸基甲基苯(37-3)与N-(4-氟苯甲基)-1-(1-甲基哌啶-2-基)甲胺(H001-021)反应，得到产物compound #H001-028 ER10179(60mg，14％产率)。 1H NMR(400MHz，CDCl 3)：δ7.12(m，2H)，7.07-6.97(m，4H)，6.70(d，J＝6.7Hz，2H)，5.24(bs，1H)，4.46(s，1H)，4.35-4.18(m，3H)，4.15-3.99(m，1H)，3.59(m，1H)，3.76(m，2H)，3.55(m，2H)，3.45-3.15(m，2H)，2.90-2.72(m，4H)，2.47-2.30(m，3H)，2.20-2.09(m，1H)，1.99-1.78(m，2H)，1.65(m，3H)。LCMS：[M+1] +440.2 3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-2-yl)methyl)urea(H001-028)ER10179 , The synthesis method is similar to compound #1. Use 1.0mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) and N-(4-fluorobenzyl)-1-(1-methylpiperidin-2-yl) Methylamine (H001-021) was reacted to obtain compound #H001-028 ER10179 (60 mg, 14% yield). 1 H NMR (400MHz, CDCl 3 ): δ 7.12 (m, 2H), 7.07-6.97 (m, 4H), 6.70 (d, J = 6.7 Hz, 2H), 5.24 (bs, 1H), 4.46 (s , 1H), 4.35 to 4.18 (m, 3H), 4.15 to 3.99 (m, 1H), 3.59 (m, 1H), 3.76 (m, 2H), 3.55 (m, 2H), 3.45 to 3.15 (m, 2H) ), 2.90-2.72 (m, 4H), 2.47-2.30 (m, 3H), 2.20-2.09 (m, 1H), 1.99-1.78 (m, 2H), 1.65 (m, 3H). LCMS: [M+1] + 440.2
实施例15：合成3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(吡咯烷-1-基)乙基)脲(H001-029)ER10180Example 15: Synthesis of 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(pyrrolidin-1-yl)ethyl)urea (H001- 029)ER10180
Figure PCTCN2021072517-appb-000048
Figure PCTCN2021072517-appb-000048
N-(4-氟苯甲基)-2-(吡咯烷-1-基)乙烷-1-胺(H001-025)，合成方法类似于(1-1)。用 5mmol 2-(吡咯烷-1-基)乙烷-1-胺与4-氟苯甲醛反应，得到中间体(H001-025)(568mg，51％产率)。LCMS：[M+1] +223.3。 N-(4-fluorobenzyl)-2-(pyrrolidin-1-yl)ethane-1-amine (H001-025), the synthesis method is similar to (1-1). 5mmol of 2-(pyrrolidin-1-yl)ethane-1-amine was reacted with 4-fluorobenzaldehyde to obtain intermediate (H001-025) (568 mg, 51% yield). LCMS: [M+1] + 223.3.
Figure PCTCN2021072517-appb-000049
Figure PCTCN2021072517-appb-000049
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(吡咯烷-1-基)乙基)脲(H001-029)ER10180，合成方法类似于compound #1。用1.0mmol 1-环丁氧基-4-异氰酸基甲基苯(37-3)与N-(4-氟苯甲基)-2-(吡咯烷-1-基)乙烷-1-胺(H001-025)反应，得到产物H001-029 ER10180(80mg，18％产率)。 1H NMR(400MHz，CDCl 3)：δ7.14-7.10(m，2H)，7.08-6.99(m，4H)，6.70(d，J＝8.8Hz，2H)，5.32(bs，1H)，4.64-4.56(m，1H)，4.43(s，2H)，4.28(s，2H)，3.90-3.69(m，5H)，3.31-3.25(m，2H)，2.47-2.38(m，2H)，2.19-2.04(m，6H)，1.88-1.80(m，2H)，1.73-1.61(m，1H).LCMS：[M+1] +426.3。 3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(pyrrolidin-1-yl)ethyl)urea (H001-029) ER10180, synthetic The method is similar to compound #1. Use 1.0mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) and N-(4-fluorobenzyl)-2-(pyrrolidin-1-yl)ethane-1 -Amine (H001-025) was reacted to obtain the product H001-029 ER10180 (80 mg, 18% yield). 1 H NMR (400MHz, CDCl 3 ): δ 7.14-7.10 (m, 2H), 7.08-6.99 (m, 4H), 6.70 (d, J=8.8 Hz, 2H), 5.32 (bs, 1H), 4.64 -4.56 (m, 1H), 4.43 (s, 2H), 4.28 (s, 2H), 3.90-3.69 (m, 5H), 3.31-3.25 (m, 2H), 2.47-2.38 (m, 2H), 2.19 -2.04 (m, 6H), 1.88-1.80 (m, 2H), 1.73-1.61 (m, 1H). LCMS: [M+1] + 426.3.
实施例16：合成3-(4-环丁氧基苯甲基)-1-((1-环丙基吡咯烷-3-基)甲基)-1-(4-氟苯甲基)脲(H001-030)ER10181Example 16: Synthesis of 3-(4-cyclobutoxybenzyl)-1-((1-cyclopropylpyrrolidin-3-yl)methyl)-1-(4-fluorobenzyl)urea (H001-030)ER10181
Figure PCTCN2021072517-appb-000050
Figure PCTCN2021072517-appb-000050
3-(4-环丁氧基苯甲基)-1-((1-环丙基吡咯烷-3-基)甲基)-1-(4-氟苯甲基)脲(H001-030)ER10181，40℃下(1-乙氧基环丙氧基)三甲基硅烷(79μl)和TFE(5.0mL)混合搅拌5分钟。然后添加3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(吡咯烷酮-3-基甲基)脲(H001-022)(161mg)。混合物搅拌5分钟后，加入NaBH 4(340.5mg)然后在室温下搅拌过夜。旋转蒸发所有溶剂，用高效液相色谱提纯。得到白色固体compound#H001-030 ER10181(85毫克，产率48％)。 1H NMR(400MHz，CDCl 3)：δ7.18-6.94(m，6H)，6.70(d，J＝8.8Hz，2H)，6.32(bs，1H)，4.59(s，2H)，4.43-4.13(m，3H)，3.90-3.76(m，2H)，3.28-3.08(m，2H)，3.07-2.69(m，4H)，2.564-2.35(m，3H)，2.24-2.04(m，3H)，1.88-1.60(m，2H)，1.31-1.12(m，2H)，0.90-0.71(m，2H)。LCMS：[M+1] +452.2。 3-(4-Cyclobutoxybenzyl)-1-((1-cyclopropylpyrrolidin-3-yl)methyl)-1-(4-fluorobenzyl)urea (H001-030) ER10181, (1-ethoxycyclopropoxy)trimethylsilane (79μl) and TFE (5.0mL) were mixed and stirred for 5 minutes at 40°C. Then 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(pyrrolidone-3-ylmethyl)urea (H001-022) (161 mg) was added. After the mixture was stirred for 5 minutes, NaBH 4 (340.5 mg) was added and then stirred at room temperature overnight. Rotary evaporate all solvents and purify by high performance liquid chromatography A white solid compound #H001-030 ER10181 (85 mg, yield 48%) was obtained. 1 H NMR (400MHz, CDCl 3 ): δ 7.18-6.94 (m, 6H), 6.70 (d, J=8.8 Hz, 2H), 6.32 (bs, 1H), 4.59 (s, 2H), 4.43-4.13 (m, 3H), 3.90-3.76 (m, 2H), 3.28-3.08 (m, 2H), 3.07-2.69 (m, 4H), 2.564-2.35 (m, 3H), 2.24-2.04 (m, 3H) , 1.88-1.60 (m, 2H), 1.31-1.12 (m, 2H), 0.90-0.71 (m, 2H). LCMS: [M+1] + 452.2.
实施例17：合成3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(1-甲基吡咯烷-2-基)乙基)脲(H001-033)ER10182Example 17: Synthesis of 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(1-methylpyrrolidin-2-yl)ethyl) Urea (H001-033) ER10182
Figure PCTCN2021072517-appb-000051
Figure PCTCN2021072517-appb-000051
N-(4-氟苯甲基)-2-(1-甲基吡咯烷-2-基)乙烷-1-胺(H001-031)：合成方法类似于(1-1)。用10mmol 2-(1-甲基吡咯烷-2-基)乙烷-1-胺得到棕色油状中间体(H001-031)(486mg，21％产率)。LCMS：[M+1] +237.3。 N-(4-fluorobenzyl)-2-(1-methylpyrrolidin-2-yl)ethane-1-amine (H001-031): The synthesis method is similar to (1-1). Using 10 mmol of 2-(1-methylpyrrolidin-2-yl)ethane-1-amine, the intermediate (H001-031) (486 mg, 21% yield) was obtained as a brown oil. LCMS: [M+1] + 237.3.
Figure PCTCN2021072517-appb-000052
Figure PCTCN2021072517-appb-000052
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(1-甲基吡咯烷-2-基)乙基)脲(H001-033)ER10182，合成方法类似于compound #1。用0.5mmol 1-环丁氧基-4-异氰酸基甲基苯(37-3)与N-(4-氟苯甲基)-2-(1-甲基吡咯烷-2-基)乙烷-1-胺(H001-031)反应，得到白色固体compound #H001-033 ER10182(190mg，86％产率)。 1H NMR(400MHz，CDCl 3)：δ7.17-7.10(m，2H)，7.08-6.99(m，4H)，6.70(d，J＝8.8Hz，2H)，5.01(bs，1H)，4.64-4.56(m，1H)，4.45-4.24(m，4H)，3.90-3.69(m，3H)，3.38-3.09(m，4H)，2.47-2.26(m，3H)，2.19-1.94(m，6H)，1.92-1.80(m，2H)，1.73-1.61(m，2H)。LCMS：[M+1] +440.3。 3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(1-methylpyrrolidin-2-yl)ethyl)urea (H001-033 ) ER10182, the synthesis method is similar to compound #1. Use 0.5mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) and N-(4-fluorobenzyl)-2-(1-methylpyrrolidin-2-yl) Ethane-1-amine (H001-031) was reacted to obtain compound #H001-033 ER10182 (190 mg, 86% yield) as a white solid. 1 H NMR (400MHz, CDCl 3 ): δ 7.17-7.10 (m, 2H), 7.08-6.99 (m, 4H), 6.70 (d, J=8.8 Hz, 2H), 5.01 (bs, 1H), 4.64 -4.56 (m, 1H), 4.45-4.24 (m, 4H), 3.90-3.69 (m, 3H), 3.38-3.09 (m, 4H), 2.47-2.26 (m, 3H), 2.19-1.94 (m, 6H), 1.92-1.80 (m, 2H), 1.73-1.61 (m, 2H). LCMS: [M+1] + 440.3.
实施例18：合成3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(1-甲基哌啶-2-基)乙基)脲(H001-034)ER10183Example 18: Synthesis of 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(1-methylpiperidin-2-yl)ethyl) Urea (H001-034) ER10183
Figure PCTCN2021072517-appb-000053
Figure PCTCN2021072517-appb-000053
N-(4-氟苯甲基)-2-(1-甲基哌啶-2-基)乙烷-1-胺(H001-032)，合成方法类似于(1-1)。用6.3mmol 2-(1-甲基哌啶-2-基)乙烷-1-胺得到棕色油状中间体(H001-032)(296mg，13％产率)。LCMS：[M+1] +251.3。 N-(4-fluorobenzyl)-2-(1-methylpiperidin-2-yl)ethane-1-amine (H001-032), the synthesis method is similar to (1-1). Using 6.3 mmol of 2-(1-methylpiperidin-2-yl)ethane-1-amine, the intermediate (H001-032) (296 mg, 13% yield) was obtained as a brown oil. LCMS: [M+1] + 251.3.
Figure PCTCN2021072517-appb-000054
Figure PCTCN2021072517-appb-000054
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(1-甲基哌啶-2-基)乙基)脲(H001-034)ER10183，合成方法类似于compound #1。用0.5mmol 1-环丁氧基-4-异氰酸基甲基苯(37-3)反应，得到白色固体compound #H001-034 ER10183(120mg，47％产率)。 1H NMR(400MHz，CDCl 3)：δ7.32-7.21(m，4H)，7.04-6.97(m，2H)，6.70(d，J＝8.8Hz，2H)，4.64-4.56(m，2H)，4.51-4.45(m，1H)，4.33-4.21(m，2H)，4.06-3.99(m，1H)，3.18-3.09(m，1H)，2.88-2.78(m，1H)，2.65-2.56(m，2H)，2.47-2.30(m，3H)，2.20-2.01(m，4H)，1.92-1.60(m，6H)，1.32-1.12(m，4H)，0.90-0.79(m，1H)。LCMS：[M+1] +454.3。 3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(1-methylpiperidin-2-yl)ethyl)urea (H001-034 ) ER10183, the synthesis method is similar to compound #1. It was reacted with 0.5 mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) to obtain compound #H001-034 ER10183 (120 mg, 47% yield) as a white solid. 1 H NMR (400MHz, CDCl 3 ): δ 7.32-7.21 (m, 4H), 7.04-6.97 (m, 2H), 6.70 (d, J=8.8 Hz, 2H), 4.64-4.56 (m, 2H) , 4.51-4.45 (m, 1H), 4.33-4.21 (m, 2H), 4.06-3.99 (m, 1H), 3.18-3.09 (m, 1H), 2.88-2.78 (m, 1H), 2.65-2.56 ( m, 2H), 2.47-2.30 (m, 3H), 2.20-2.01 (m, 4H), 1.92-1.60 (m, 6H), 1.32-1.12 (m, 4H), 0.90-0.79 (m, 1H). LCMS: [M+1] + 454.3.
实施例19：合成3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲(H001-061)ER10188Example 19: Synthesis of 3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)urea (H001-061)ER10188
Figure PCTCN2021072517-appb-000055
Figure PCTCN2021072517-appb-000055
N-(4-氟苯甲基)-1-(1-甲基吖丁啶-3-基)甲胺(H001-057)，合成方法类似于(1-1)。用5.5mmol(1-甲基吖丁啶-3-基)甲胺得到棕色油状中间体(H001-057)(500mg，44％产率)。LCMS：[M+1] +209.2。 N-(4-fluorobenzyl)-1-(1-methylazetidine-3-yl)methylamine (H001-057), the synthesis method is similar to (1-1). Using 5.5 mmol (1-methylazetidine-3-yl) methylamine, intermediate (H001-057) (500 mg, 44% yield) was obtained as a brown oil. LCMS: [M+1] + 209.2.
Figure PCTCN2021072517-appb-000056
Figure PCTCN2021072517-appb-000056
3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲(H001-061)ER10188，合成方法类似于compound #1。用0.2mmol 1-环丁氧基-4-异氰酸基甲基苯(37-3)与N-(4-氟苯甲基)-1-(1-甲基吖丁啶-3-基)甲胺(H001-057)反应，得到白色固体compound #H001-061 ER10188(15mg，15％产率)。LCMS：[M+1] +412.3。 3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)urea (H001-061) ER10188, the synthesis method is similar to compound #1. Use 0.2mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) and N-(4-fluorobenzyl)-1-(1-methylazetidine-3-yl) ) Methylamine (H001-057) was reacted to obtain compound #H001-061 ER10188 (15 mg, 15% yield) as a white solid. LCMS: [M+1] + 412.3.
实施例20：合成(S)-3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-062)ER10189Example 20: Synthesis of (S)-3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl Base) urea (H001-062) ER10189
Figure PCTCN2021072517-appb-000057
Figure PCTCN2021072517-appb-000057
(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-058)，合成方法类似于(1-1)。用8.5mmol(S)-(1-甲基吡咯烷-2-基)甲胺得到棕色油状中间体(H001-058)(720mg，38％产率)。LCMS：[M+1] +223.2。 (S)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-2-yl)methylamine (H001-058), the synthesis method is similar to (1-1). Using 8.5 mmol (S)-(1-methylpyrrolidin-2-yl)methylamine, intermediate (H001-058) (720 mg, 38% yield) was obtained as a brown oil. LCMS: [M+1] + 223.2.
Figure PCTCN2021072517-appb-000058
Figure PCTCN2021072517-appb-000058
(S)-3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-062)ER10189，合成方法类似于compound #1。用0.5mmol 1-环丁氧基-4-异氰酸基甲基苯(37-3)与(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-058)反应，得到白色固体compound #H001-062 ER10189(52mg，26％产率)。LCMS：[M+1] +426.3。 (S)-3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea (H001 -062) ER10189, the synthesis method is similar to compound #1. Use 0.5mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) and (S)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidine- 2-yl)methylamine (H001-058) was reacted to obtain compound #H001-062 ER10189 (52 mg, 26% yield) as a white solid. LCMS: [M+1] + 426.3.
实施例21：合成(R)-3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-063)ER10190Example 21: Synthesis of (R)-3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl Base) urea (H001-063) ER10190
Figure PCTCN2021072517-appb-000059
Figure PCTCN2021072517-appb-000059
(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-059)，合成方法类似于(1-1)。用8.5mmol(R)-(1-甲基吡咯烷-2-基)甲胺得到棕色油状中间体(H001-059)(750mg，40％产率)。LCMS：[M+1] +223.2。 (R)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-2-yl)methylamine (H001-059), the synthesis method is similar to (1-1). Using 8.5 mmol of (R)-(1-methylpyrrolidin-2-yl)methylamine, intermediate (H001-059) (750 mg, 40% yield) was obtained as a brown oil. LCMS: [M+1] + 223.2.
Figure PCTCN2021072517-appb-000060
Figure PCTCN2021072517-appb-000060
(R)-3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-063)ER10190，合成方法类似于compound #1。用0.2mmol 1-环丁氧基-4-异氰酸基甲基苯(37-3)与(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-059)反应，得到白色固体compound #H001-063 ER10190(55mg，28％产率)。LCMS：[M+1] +426.3。 (R)-3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea (H001 -063) ER10190, the synthesis method is similar to compound #1. Use 0.2mmol 1-cyclobutoxy-4-isocyanatomethylbenzene (37-3) and (R)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidine- 2-yl)methylamine (H001-059) was reacted to obtain compound #H001-063 ER10190 (55 mg, 28% yield) as a white solid. LCMS: [M+1] + 426.3.
实施例22：合成(S)-3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-067)ER10194Example 22: Synthesis of (S)-3-(4-cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidine-2 -Yl) methyl) urea (H001-067) ER10194
Figure PCTCN2021072517-appb-000061
Figure PCTCN2021072517-appb-000061
4-环丁氧基-3-氟苯甲腈(H001-037)，合成方法类似于(37-1)。用15mmol 3-氟-4-羟基苯甲腈与1-溴环丁烷反应，得到中间体(H001-037)(1.8g，65％产率)。LCMS：[M+1] +192.2。 4-cyclobutoxy-3-fluorobenzonitrile (H001-037), the synthesis method is similar to (37-1). 15mmol of 3-fluoro-4-hydroxybenzonitrile was reacted with 1-bromocyclobutane to obtain intermediate (H001-037) (1.8g, 65% yield). LCMS: [M+1] + 192.2.
Figure PCTCN2021072517-appb-000062
Figure PCTCN2021072517-appb-000062
(4-环丁氧基-3-氟苯基)甲胺(H002-039)合成方法类似于(1-3)。用5mmol 4-环丁氧基-3-氟苯甲腈(H001-037)还原得到中间体(H002-039)(900mg，89％产率)。LCMS：[M+1] +196.2。 The synthesis method of (4-cyclobutoxy-3-fluorophenyl)methylamine (H002-039) is similar to (1-3). Reduction with 5 mmol 4-cyclobutoxy-3-fluorobenzonitrile (H001-037) gave intermediate (H002-039) (900 mg, 89% yield). LCMS: [M+1] + 196.2.
Figure PCTCN2021072517-appb-000063
Figure PCTCN2021072517-appb-000063
1-环丁氧基-2-氟-4-(异氰酸基甲基)苯(H001-067-1)，合成方法类似于(37-3)。用0.15mmol(4-环丁氧基-3-氟苯基)甲胺(H002-039)与Triphogene反应，得到中间体(H001-067-1)(30mg，89％产率)。LCMS：[M+1] +222.2。 1-Cyclobutoxy-2-fluoro-4-(isocyanatomethyl)benzene (H001-067-1), the synthesis method is similar to (37-3). 0.15mmol (4-cyclobutoxy-3-fluorophenyl)methylamine (H002-039) was reacted with Triphogene to obtain intermediate (H001-067-1) (30mg, 89% yield). LCMS: [M+1] + 222.2.
Figure PCTCN2021072517-appb-000064
Figure PCTCN2021072517-appb-000064
(S)-3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-067)ER10194，合成方法类似于compound #1。用0.5mmol 1-环丁氧基-2-氟-4-异氰酸基甲基苯(H001-067-1)与(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-058)反应，得到白色固体compound #H001-067 ER10194(130mg，59％产率)。LCMS：[M+1] +444.3。 (S)-3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea (H001-067) ER10194, the synthesis method is similar to compound #1. Use 0.5mmol 1-cyclobutoxy-2-fluoro-4-isocyanatomethylbenzene (H001-067-1) and (S)-N-(4-fluorobenzyl)-1-(1 -Methylpyrrolidin-2-yl)methylamine (H001-058) was reacted to obtain compound #H001-067 ER10194 (130mg, 59% yield) as a white solid. LCMS: [M+1] + 444.3.
实施例23：合成(R)-3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-068)ER10195Example 23: Synthesis of (R)-3-(4-cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidine-2 -Yl) methyl) urea (H001-068) ER10195
Figure PCTCN2021072517-appb-000065
Figure PCTCN2021072517-appb-000065
(R)-3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-068)ER10195，合成方法类似于compound #1。用0.5mmol 1-环丁氧基-2-氟-4-(异氰酸基甲基)苯(H002-067-1)与(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-059)反应，得到白色固体compound #H001-068 ER10195(120mg，54％产率)。LCMS：[M+1] +444.3。 (R)-3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea (H001-068) ER10195, the synthesis method is similar to compound #1. Use 0.5mmol 1-cyclobutoxy-2-fluoro-4-(isocyanatomethyl)benzene (H002-067-1) and (R)-N-(4-fluorobenzyl)-1- (1-Methylpyrrolidin-2-yl)methylamine (H001-059) was reacted to obtain compound #H001-068 ER10195 (120 mg, 54% yield) as a white solid. LCMS: [M+1] + 444.3.
实施例24：合成1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)-3-(4-(3-甲基丁酰)苯甲基)脲(H001-069)ER10196Example 24: Synthesis of 1-(4-fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)-3-(4-(3-methylbutyryl)benzene (Methyl) urea (H001-069) ER10196
Figure PCTCN2021072517-appb-000066
Figure PCTCN2021072517-appb-000066
1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)-3-(4-(3-甲基丁酰)苯甲基)脲(H001-069)ER10196，合成方法类似于compound #1。用0.05mmol 1-(3-甲基丁酰)-(4-异氰酸基甲基)苯基(39-5)和N-(4-氟苯甲基)-1-(1-甲基吖丁啶-3-基)甲胺(H001-057)反应得到白色固体compound H001-069 ER10196(7.1mg，33％产率)。LCMS：[M+1] +426.3。 1-(4-Fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)-3-(4-(3-methylbutyryl)benzyl)urea( H001-069) ER10196, the synthesis method is similar to compound #1. Use 0.05mmol 1-(3-methylbutyryl)-(4-isocyanatomethyl)phenyl(39-5) and N-(4-fluorobenzyl)-1-(1-methyl) Azetidine-3-yl)methylamine (H001-057) was reacted to obtain compound H001-069 ER10196 (7.1 mg, 33% yield) as a white solid. LCMS: [M+1] + 426.3.
实施例25：合成(S)-1-(4-氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-070)ER10197Example 25: Synthesis of (S)-1-(4-fluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-((1-methylpyrrolidine-2 -Base) methyl) urea (H001-070) ER10197
Figure PCTCN2021072517-appb-000067
Figure PCTCN2021072517-appb-000067
(S)-1-(4-氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-070)ER10197合成方法类似于compound #1，用0.5mmol 1-(3-甲基丁酰)-(4-异氰酸基甲基)苯基(39-5)与(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-058)反应得到白色固体compound H001-070 ER10197(70mg，32％产率)。LCMS：[M+1] +440.3。 (S)-1-(4-fluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea (H001-070) ER10197 synthesis method is similar to compound #1, using 0.5mmol 1-(3-methylbutyryl)-(4-isocyanatomethyl)phenyl(39-5) and (S )-N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-2-yl)methylamine (H001-058) was reacted to obtain a white solid compound H001-070 ER10197 (70mg, 32% yield ). LCMS: [M+1] + 440.3.
实施例26：合成(R)-1-(4-氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-071)ER10198Example 26: Synthesis of (R)-1-(4-fluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-((1-methylpyrrolidine-2 -Base) methyl) urea (H001-071) ER10198
Figure PCTCN2021072517-appb-000068
Figure PCTCN2021072517-appb-000068
(R)-1-(4-氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H001-071)ER10198合成方法类似于compound #1，用0.3mmol 1-(3-甲基丁酰)-(4-异氰酸基甲基)苯基(39-5)与(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-059)反应得到白色固体compound H001-071 ER10198(60mg，45％产率)。LCMS：[M+1] +440.3。 (R)-1-(4-fluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea (H001-071) ER10198 synthesis method is similar to compound #1, using 0.3mmol 1-(3-methylbutyryl)-(4-isocyanatomethyl)phenyl(39-5) and (R )-N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-2-yl)methylamine (H001-059) was reacted to obtain a white solid compound H001-071 ER10198 (60mg, 45% yield ). LCMS: [M+1] + 440.3.
实施例27：合成(S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H002-027)ER10199Example 27: Synthesis of (S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)-3-(4-(2,2,2 -Trifluoroethoxy)benzyl)urea (H002-027)ER10199
Figure PCTCN2021072517-appb-000069
Figure PCTCN2021072517-appb-000069
4-(2，2，2-三氟乙氧基)苯甲腈(H002-009)，合成方法类似于(37-1)。用6mmol 4-羟基苯甲腈得到中间体(H002-009)(960mg，78％产率)。LCMS：[M+1] +202.2。 4-(2,2,2-Trifluoroethoxy)benzonitrile (H002-009), the synthesis method is similar to (37-1). The intermediate (H002-009) (960 mg, 78% yield) was obtained with 6 mmol 4-hydroxybenzonitrile. LCMS: [M+1] + 202.2.
Figure PCTCN2021072517-appb-000070
Figure PCTCN2021072517-appb-000070
(4-(2，2，2-三氟乙氧基)苯基)甲胺(H002-012)合成方法类似于(1-3)，用5mmol 4-(2，2，2-三氟乙氧基)苯甲腈得到(H002-012)(700mg，71％产率)。LCMS：[M+1] +206.2。 The synthesis method of (4-(2,2,2-trifluoroethoxy)phenyl)methylamine (H002-012) is similar to (1-3), using 5mmol 4-(2,2,2-trifluoroethane) (Oxy)benzonitrile gave (H002-012) (700 mg, 71% yield). LCMS: [M+1] + 206.2.
Figure PCTCN2021072517-appb-000071
Figure PCTCN2021072517-appb-000071
1-(异氰酸基甲基)-4-(2，2，2-三氟乙氧基)苯(H002-027-1)，合成方法类似于(37-3)。用0.15mmol(4-(2，2，2-三氟乙氧基)苯基)甲胺(H002-012)得到中间体(H002-027-1)(30mg，89％产率)。LCMS：[M+1] +232.2。 1-(isocyanatomethyl)-4-(2,2,2-trifluoroethoxy)benzene (H002-027-1), the synthesis method is similar to (37-3). Using 0.15 mmol (4-(2,2,2-trifluoroethoxy)phenyl)methylamine (H002-012), intermediate (H002-027-1) (30 mg, 89% yield) was obtained. LCMS: [M+1] + 232.2.
Figure PCTCN2021072517-appb-000072
Figure PCTCN2021072517-appb-000072
(S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H002-027)ER10199合成方法类似于compound #1。用0.15mmol 1-(异氰酸基甲基)-4-(2，2，2-三氟乙氧基)苯(H002-027-1)与(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-058)反应得到白色固体compound H002-027 ER10199(50mg，75％产率)。LCMS：[M+1] +455.2。 (S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) The synthesis method of phenylmethyl)urea (H002-027)ER10199 is similar to compound #1. Use 0.15mmol 1-(isocyanatomethyl)-4-(2,2,2-trifluoroethoxy)benzene (H002-027-1) and (S)-N-(4-fluorobenzyl) Yl)-1-(1-methylpyrrolidin-2-yl)methylamine (H001-058) was reacted to obtain compound H002-027 ER10199 (50 mg, 75% yield) as a white solid. LCMS: [M+1] + 455.2.
实施例28：合成(R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H002-028)ER10200Example 28: Synthesis of (R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)-3-(4-(2,2,2 -Trifluoroethoxy)benzyl)urea (H002-028)ER10200
Figure PCTCN2021072517-appb-000073
Figure PCTCN2021072517-appb-000073
(R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H002-028)ER10200合成方法类似于compound #1。用0.15mmol 1-(异氰酸基甲基)-4-(2，2，2-三氟乙氧基)苯(H002-027-1)与(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-059)反应得到白色固体compound H002-028 ER10200(40mg，53％产率)。LCMS：[M+1] +455.2。 (R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) The synthesis method of phenylmethyl)urea (H002-028) ER10200 is similar to compound #1. Use 0.15mmol 1-(isocyanatomethyl)-4-(2,2,2-trifluoroethoxy)benzene (H002-027-1) and (R)-N-(4-fluorobenzyl) Yl)-1-(1-methylpyrrolidin-2-yl)methylamine (H001-059) was reacted to obtain compound H002-028 ER10200 (40 mg, 53% yield) as a white solid. LCMS: [M+1] + 455.2.
实施例29：合成(S)-1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H002-035)ER10201Example 29: Synthesis of (S)-1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylpyrrolidin-2-yl)methyl Base) urea (H002-035) ER10201
Figure PCTCN2021072517-appb-000074
Figure PCTCN2021072517-appb-000074
(S)-1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H002-035)ER10201合成方法类似于compound #1，用0.15mmol 1-异丁氧基-4-异氰酸基甲基-苯(1-4)与(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-058)反应得到白色固体H002-035 ER10201(50mg，70％产率)。LCMS：[M+1] +429.3。 (S)-1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea (H002 -035) ER10201 synthesis method is similar to compound #1, using 0.15mmol 1-isobutoxy-4-isocyanatomethyl-benzene (1-4) and (S)-N-(4-fluorobenzyl Yl)-1-(1-methylpyrrolidin-2-yl)methylamine (H001-058) was reacted to obtain H002-035 ER10201 (50 mg, 70% yield) as a white solid. LCMS: [M+1] + 429.3.
实施例30：合成(R)-1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H002-036)ER10202Example 30: Synthesis of (R)-1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylpyrrolidin-2-yl)methyl Base) urea (H002-036) ER10202
Figure PCTCN2021072517-appb-000075
Figure PCTCN2021072517-appb-000075
(R)-1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲(H002-036)ER10202合成方法类似于compound #1。用0.15mmol 1-异丁氧基-4-异氰酸基甲基-苯(1-4)与(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-2-基)甲胺(H001-059)反应得到白色固体compound H002-036 ER10202(50mg，70％产率)。(R)-1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea (H002 -036) ER10202 synthesis method is similar to compound #1. Use 0.15mmol 1-isobutoxy-4-isocyanatomethyl-benzene(1-4) and (R)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidine) -2-yl)methylamine (H001-059) was reacted to obtain compound H002-036 ER10202 (50mg, 70% yield) as a white solid.
实施例31：合成1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲(H002-037)ER10203Example 31: Synthesis of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylazetidine-3-yl)methyl)urea (H002-037)ER10203
Figure PCTCN2021072517-appb-000076
Figure PCTCN2021072517-appb-000076
1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲(H002-037)ER10203合成方法类似于compound #1，用0.15mmol 1-异丁氧基-4-异氰酸基甲基-苯(1-4)与N-(4-氟苯甲基)-1-(1-甲基吖丁啶-3-基)甲胺(H001-057)反应得到白色固体compound H002-037 ER10203(20mg，29％产率)。1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylazetidine-3-yl)methyl)urea (H002-037) The synthesis method of ER10203 is similar to compound #1, using 0.15mmol 1-isobutoxy-4-isocyanatomethyl-benzene(1-4) and N-(4-fluorobenzyl)-1-(1 -Methylazetidine-3-yl)methylamine (H001-057) was reacted to obtain a white solid compound H002-037 ER10203 (20 mg, 29% yield).
实施例32：合成1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-异丁氧基苯甲基)脲(H001-080)ER10204Example 32: Synthesis of 1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-isobutoxybenzyl)urea ( H001-080)ER10204
Figure PCTCN2021072517-appb-000077
Figure PCTCN2021072517-appb-000077
1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-异丁氧基苯甲基)脲(H001-080)ER10204合成方法类似于compound #1，用0.15mmol 1-异丁氧基-4-异氰酸基甲基-苯(1-4)与N-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H001-004)反应得到白色固体compound H001-080 ER10204(50mg，40％产率)。LCMS：[M+1] +442.3。 1-(4-Fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-isobutoxybenzyl)urea(H001-080)ER10204 The synthesis method is similar to compound #1, using 0.15mmol 1-isobutoxy-4-isocyanatomethyl-benzene(1-4) and N-(4-fluorobenzyl)-1-(1- Methylpiperidin-4-yl)methylamine (H001-004) was reacted to obtain compound H001-080 ER10204 (50 mg, 40% yield) as a white solid. LCMS: [M+1] + 442.3.
实施例33：合成1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H001-081)ER10205Example 33: Synthesis of 1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-(2,2,2-trifluoroethane) (Oxy)benzyl)urea (H001-081)ER10205
Figure PCTCN2021072517-appb-000078
Figure PCTCN2021072517-appb-000078
1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H001-081)ER10205合成方法类似于compound #1，用0.15mmol 1-(异氰酸基甲基)-4-(2，2，2-三氟乙氧基)苯(H002-027-1)与N-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H001-004)反应得到白色固体compound H001-081 ER10205(8mg，11％产率)。LCMS：[M+1] +468.2。 1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy)benzyl The synthesis method of urea (H001-081) ER10205 is similar to compound #1, using 0.15mmol 1-(isocyanatomethyl)-4-(2,2,2-trifluoroethoxy)benzene (H002- 027-1) reacted with N-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)methylamine (H001-004) to obtain a white solid compound H001-081 ER10205 (8mg, 11 %Yield). LCMS: [M+1] + 468.2.
实施例34：合成3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H001-082)ER10206Example 34: Synthesis of 3-(4-cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl Base) urea (H001-082) ER10206
Figure PCTCN2021072517-appb-000079
Figure PCTCN2021072517-appb-000079
3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H001-082) ER10206，合成方法类似于compound #1，用0.15mmol 1-环丁氧基-2-氟-4-(异氰酸基甲基)苯(H001-067-1)与N-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H001-004)反应得到白色固体compound #H001-082 ER10206(30mg，44％产率)。LCMS：[M+1] +458.3。 3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea (H001 -082) ER10206, the synthesis method is similar to compound #1, using 0.15mmol 1-cyclobutoxy-2-fluoro-4-(isocyanatomethyl)benzene (H001-067-1) and N-(4 -Fluorobenzyl)-1-(1-methylpiperidin-4-yl)methylamine (H001-004) was reacted to obtain compound #H001-082 ER10206 (30 mg, 44% yield) as a white solid. LCMS: [M+1] + 458.3.
实施例35：合成3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H001-084)ER10207Example 35: Synthesis of 3-(3-fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea (H001-084)ER10207
Figure PCTCN2021072517-appb-000080
Figure PCTCN2021072517-appb-000080
2-氟-4-(异氰酸基甲基)-1-甲氧基苯(H001-084-1)合成方法类似于(H002-012)。用13mmol 3-氟-4-甲氧基苯甲腈得到中间体(H001-084-1)(1.8g，88％产率)。LCMS：[M+1] +182.2。 The synthesis method of 2-fluoro-4-(isocyanatomethyl)-1-methoxybenzene (H001-084-1) is similar to (H002-012). The intermediate (H001-084-1) (1.8 g, 88% yield) was obtained with 13 mmol of 3-fluoro-4-methoxybenzonitrile. LCMS: [M+1] + 182.2.
Figure PCTCN2021072517-appb-000081
Figure PCTCN2021072517-appb-000081
3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H001-084)ER10207，合成方法类似于compound #1，用0.2mmol 2-氟-4-(异氰酸基甲基)-1-甲氧基苯(H001-084-1)与N-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H001-004)反应得到白色固体compound #H001-084 ER10207(9mg，11％产率)。LCMS：[M+1] +418.2。 3-(3-Fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea (H001-084) ER10207, the synthesis method is similar to compound #1, using 0.2mmol 2-fluoro-4-(isocyanatomethyl)-1-methoxybenzene (H001-084-1) and N-(4-fluorobenzyl) Yl)-1-(1-methylpiperidin-4-yl)methylamine (H001-004) was reacted to obtain compound #H001-084 ER10207 (9 mg, 11% yield) as a white solid. LCMS: [M+1] + 418.2.
实施例36：合成(R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-异丁氧基苯甲基)脲(H001-088)ER10209Example 36: Synthesis of (R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-isobutoxybenzyl Base) urea (H001-088) ER10209
Figure PCTCN2021072517-appb-000082
Figure PCTCN2021072517-appb-000082
(R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-异丁氧基苯甲基)脲(H001-088)ER10209合成方法类似于compound #1，用0.28mmol 1-异丁氧基-4-异氰酸基 甲基-苯(1-4)与(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H001-086)反应，得到白色固体compound H001-088 ER10209(25mg，21％产率)。LCMS：[M+1] +428.3。 (R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-isobutoxybenzyl)urea (H001 -088) The synthesis method of ER10209 is similar to compound #1, using 0.28mmol 1-isobutoxy-4-isocyanatomethyl-benzene (1-4) and (S)-N-(4-fluorobenzyl) Yl)-1-(1-methylpyrrolidin-3-yl)methylamine (H001-086) was reacted to obtain compound H001-088 ER10209 (25 mg, 21% yield) as a white solid. LCMS: [M+1] + 428.3.
实施例37：合成(S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-异丁氧基苯甲基)脲(H001-089)ER10210Example 37: Synthesis of (S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-isobutoxybenzyl Base) urea (H001-089) ER10210
Figure PCTCN2021072517-appb-000083
Figure PCTCN2021072517-appb-000083
(S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-异丁氧基苯甲基)脲(H001-089)ER10210合成方法类似于compound #1。用0.28mmol 1-异丁氧基-4-异氰酸基甲基-苯(1-4)与(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H001-087)反应，得到白色固体compound H001-089 ER10210(26mg，22％产率)。LCMS：[M+1] +428.3。 (S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-isobutoxybenzyl)urea (H001 -089) ER10210 synthesis method is similar to compound #1. Use 0.28mmol 1-isobutoxy-4-isocyanatomethyl-benzene(1-4) and (R)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidine) -3-yl)methylamine (H001-087) was reacted to obtain compound H001-089 ER10210 (26 mg, 22% yield) as a white solid. LCMS: [M+1] + 428.3.
实施例38：合成(R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H001-090)ER10211Example 38: Synthesis of (R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2 -Trifluoroethoxy)benzyl)urea (H001-090)ER10211
Figure PCTCN2021072517-appb-000084
Figure PCTCN2021072517-appb-000084
(R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H001-090)ER10211合成方法类似于compound #1，用0.24mmol 1-(异氰酸基甲基)-4-(2，2，2-三氟乙氧基)苯(H002-027-1)与(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H001-086)反应，得到白色固体compound H001-090 ER10211(23mg，21％产率)。LCMS：[M+1] +454.2。 (R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) The synthesis method of phenylmethyl)urea (H001-090)ER10211 is similar to compound #1, using 0.24mmol 1-(isocyanatomethyl)-4-(2,2,2-trifluoroethoxy) Benzene (H002-027-1) reacts with (S)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (H001-086) to obtain a white solid compound H001-090 ER10211 (23mg, 21% yield). LCMS: [M+1] + 454.2.
实施例39：合成(S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H001-091)ER10212Example 39: Synthesis of (S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2 -Trifluoroethoxy)benzyl)urea (H001-091)ER10212
Figure PCTCN2021072517-appb-000085
Figure PCTCN2021072517-appb-000085
(S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H001-091)ER10212合成方法类似于compound #1，用0.24mmol 1-(异氰酸基甲基)-4-(2，2，2-三氟乙氧基)苯(H002-027-1)与(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H001-087)反应，得到白色固体compound H001-091 ER10212(22mg，20％产率)。LCMS：[M+1] +454.2。 (S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) Benzyl) urea (H001-091) ER10212 The synthesis method is similar to compound #1, using 0.24mmol 1-(isocyanatomethyl)-4-(2,2,2-trifluoroethoxy) Benzene (H002-027-1) reacts with (R)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (H001-087) to obtain a white solid compound H001-091 ER10212 (22mg, 20% yield). LCMS: [M+1] + 454.2.
实施例40：合成3-(3-氟-4-甲氧苄基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-071)ER10213Example 40: Synthesis of 3-(3-fluoro-4-methoxybenzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methan Base) urea (H002-071) ER10213
Figure PCTCN2021072517-appb-000086
Figure PCTCN2021072517-appb-000086
N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H002-070)，合成方法类似于(1-1)。用8.8mmol(1-甲基哌啶-4-基)甲胺得到棕色油状中间体(H002-070)(1.5g，75％产率)。LCMS：[M+1] +255.3。 N-(2,4-Difluorobenzyl)-1-(1-methylpiperidin-4-yl)methylamine (H002-070), the synthesis method is similar to (1-1). Using 8.8mmol (1-methylpiperidin-4-yl)methylamine, the intermediate (H002-070) was obtained as a brown oil (1.5g, 75% yield). LCMS: [M+1] + 255.3.
Figure PCTCN2021072517-appb-000087
Figure PCTCN2021072517-appb-000087
3-(3-氟-4-甲氧苄基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-071)ER10213，合成方法类似于compound #1。用0.2mmol 2-氟-4-(异氰酸基甲基)-1-甲氧基苯(H001-084-1)与N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H002-070)反应得到白色固体compound #H002-071 ER10213(46mg，55％产率)。LCMS：[M+1] +436.2。 3-(3-Fluoro-4-methoxybenzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea (H002 -071) ER10213, the synthesis method is similar to compound #1. Use 0.2mmol 2-fluoro-4-(isocyanatomethyl)-1-methoxybenzene (H001-084-1) and N-(2,4-difluorobenzyl)-1-(1 -Methylpiperidin-4-yl)methylamine (H002-070) was reacted to obtain compound #H002-071 ER10213 (46 mg, 55% yield) as a white solid. LCMS: [M+1] + 436.2.
实施例41：合成3-(4-环丁氧基-3-氟苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-072)ER10214Example 41: Synthesis of 3-(4-cyclobutoxy-3-fluorobenzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidine-4- (Base) methyl) urea (H002-072) ER10214
Figure PCTCN2021072517-appb-000088
Figure PCTCN2021072517-appb-000088
3-(4-环丁氧基-3-氟苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-072)ER10214，合成方法类似于compound #1。用0.15mmol 1-环丁氧基-2-氟-4-(异氰酸基甲基)苯(H001-067-1)与N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H002-070)反应得到白色固体compound #H002-072 ER10214(25mg，34％产率)。LCMS：[M+1] +476.3。 3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl) Urea (H002-072) ER10214, the synthesis method is similar to compound #1. Use 0.15mmol 1-cyclobutoxy-2-fluoro-4-(isocyanatomethyl)benzene (H001-067-1) and N-(2,4-difluorobenzyl)-1-( 1-Methylpiperidin-4-yl)methylamine (H002-070) was reacted to obtain compound #H002-072 ER10214 (25 mg, 34% yield) as a white solid. LCMS: [M+1] + 476.3.
实施例42：合成1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H002-073)ER10215Example 42: Synthesis of 1-(2,4-Difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-(2,2,2- Trifluoroethoxy)benzyl)urea (H002-073)ER10215
Figure PCTCN2021072517-appb-000089
Figure PCTCN2021072517-appb-000089
1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H002-073)ER10215，合成方法类似于compound #1。用0.15mmol 1-(异氰酸基甲基)-4-(2，2，2-三氟乙氧基)苯(H002-027-1)与N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H002-070)反应得到白色固体compound #H002-073 ER10215(7.5mg，11％产率)。LCMS：[M+1] +486.2。 1-(2,4-Difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) ) Benzyl) urea (H002-073) ER10215, the synthesis method is similar to compound #1. Use 0.15mmol 1-(isocyanatomethyl)-4-(2,2,2-trifluoroethoxy)benzene (H002-027-1) and N-(2,4-difluorobenzyl) )-1-(1-methylpiperidin-4-yl)methylamine (H002-070) was reacted to obtain compound #H002-073 ER10215 (7.5 mg, 11% yield) as a white solid. LCMS: [M+1] + 486.2.
实施例44：合成1-(2，4-二氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-(1-甲基哌啶-4-基)脲(H002-079)ER10219Example 44: Synthesis of 1-(2,4-Difluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-(1-methylpiperidin-4-yl ) Urea (H002-079) ER10219
Figure PCTCN2021072517-appb-000090
Figure PCTCN2021072517-appb-000090
1-(2，4-二氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-(1-甲基哌啶-4-基)脲(H002-079)ER10219，合成方法类似于compound #1。用0.16mmol 1-(4-异氰酸基甲基-苯基)-3-甲基-丁烷-1-酮(39-5)与N-(2，4-二氟苯甲基)-N-(1-甲基哌啶-4-基)胺(H002-069)反应得到白色固体compound #H002-079 ER10219(36mg，50％产率)。LCMS：[M+1] +458.3。 1-(2,4-Difluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-(1-methylpiperidin-4-yl)urea (H002- 079) ER10219, the synthesis method is similar to compound #1. Use 0.16mmol 1-(4-isocyanatomethyl-phenyl)-3-methyl-butan-1-one (39-5) and N-(2,4-difluorobenzyl)- N-(1-methylpiperidin-4-yl)amine (H002-069) was reacted to obtain compound #H002-079 ER10219 (36 mg, 50% yield) as a white solid. LCMS: [M+1] + 458.3.
实施例45：合成(R)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H002-081)ER10221Example 45: Synthesis of (R)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2, 2,2-Trifluoroethoxy)benzyl)urea (H002-081)ER10221
Figure PCTCN2021072517-appb-000091
Figure PCTCN2021072517-appb-000091
(R)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H002-081)ER10221，合成方法类似于compound #1。用0.15mmol 1-(异氰酸基甲基)-4-(2，2，2-三氟乙氧基)苯(H002-027-1)与(S)-N-(2，4-二氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H002-078)反应，得到白色固体compound #H002-081 ER10221(10mg，15％产率)。LCMS：[M+1] +472.2。 (R)-1-(2,4-Difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-tri Fluoroethoxy)benzyl)urea (H002-081)ER10221, the synthesis method is similar to compound #1. Use 0.15mmol 1-(isocyanatomethyl)-4-(2,2,2-trifluoroethoxy)benzene (H002-027-1) and (S)-N-(2,4-bis Fluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (H002-078) was reacted to obtain compound #H002-081 ER10221 (10 mg, 15% yield) as a white solid. LCMS: [M+1] + 472.2.
实施例46：合成(S)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H002-082)ER10222Example 46: Synthesis of (S)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2, 2,2-Trifluoroethoxy)benzyl)urea (H002-082)ER10222
Figure PCTCN2021072517-appb-000092
Figure PCTCN2021072517-appb-000092
(R)-N-(2，4-二氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H002-077)，合成方法类似于(1-1)。用4mmol(R)-(1-甲基吡咯烷-3-基)甲胺得到棕色油状中间体(H002-077)(0.3g，29％产率)。LCMS：[M+1] +241.3。 (R)-N-(2,4-Difluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (H002-077), the synthesis method is similar to (1-1). 4mmol (R)-(1-methylpyrrolidin-3-yl)methylamine was used to obtain brown oily intermediate (H002-077) (0.3g, 29% yield). LCMS: [M+1] + 241.3.
Figure PCTCN2021072517-appb-000093
Figure PCTCN2021072517-appb-000093
(S)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲(H002-082)ER10222，合成方法类似于compound #1。用0.15mmol 1-(异氰酸基甲基)-4-(2，2，2-三氟乙氧基)苯(H002-027-1)与(R)-N-(2，4-二氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H002-077)合成得到白色固体compound #H002-082 ER10222(18mg，26％产率)。LCMS：[M+1] +472.2。 (S)-1-(2,4-Difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-tri Fluoroethoxy)benzyl)urea (H002-082)ER10222, the synthesis method is similar to compound #1. Use 0.15mmol 1-(isocyanatomethyl)-4-(2,2,2-trifluoroethoxy)benzene (H002-027-1) and (R)-N-(2,4-bis Fluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (H002-077) was synthesized to obtain compound #H002-082 ER10222 (18 mg, 26% yield) as a white solid. LCMS: [M+1] + 472.2.
实施例47：合成(R)-1-(2，4-二氟苯甲基)-3-(3-氟-4-甲氧苄基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-088)ER10224Example 47: Synthesis of (R)-1-(2,4-difluorobenzyl)-3-(3-fluoro-4-methoxybenzyl)-1-((1-methylpyrrolidine-3 -Yl)methyl)urea (H002-088)ER10224
Figure PCTCN2021072517-appb-000094
Figure PCTCN2021072517-appb-000094
(R)-1-(2，4-二氟苯甲基)-3-(3-氟-4-甲氧苄基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-088)ER10224，合成方法类似于compound #1。用0.26mmol 2-氟-4-(异氰酸基甲基)-1-甲氧基苯(H001-084-1)与(S)-N-(2，4-二氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H002-078)反应，得到白色固体compound #H002-088 ER10224(35mg，32％产率)。LCMS：[M+1] +422.8。 (R)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-methoxybenzyl)-1-((1-methylpyrrolidin-3-yl)methyl ) Urea (H002-088) ER10224, the synthesis method is similar to compound #1. Use 0.26mmol 2-fluoro-4-(isocyanatomethyl)-1-methoxybenzene (H001-084-1) and (S)-N-(2,4-difluorobenzyl)- 1-(1-methylpyrrolidin-3-yl)methylamine (H002-078) was reacted to obtain compound #H002-088 ER10224 (35 mg, 32% yield) as a white solid. LCMS: [M+1] + 422.8.
实施例48：合成(R)-3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-089)ER10225Example 48: Synthesis of (R)-3-(3-fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl) (Methyl) urea (H002-089) ER10225
Figure PCTCN2021072517-appb-000095
Figure PCTCN2021072517-appb-000095
(R)-3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-089)ER10225，合成方法类似于compound #1。用0.26mmol 2-氟-4-(异氰酸基甲基)-1-甲氧基苯(H001-084-1)与(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H001-086)反应，得到白色固体compound #H002-089 ER10225(35mg，34％产率)。LCMS：[M+1] +404.9。 (R)-3-(3-Fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea( H002-089) ER10225, the synthesis method is similar to compound #1. Use 0.26mmol 2-fluoro-4-(isocyanatomethyl)-1-methoxybenzene (H001-084-1) and (S)-N-(4-fluorobenzyl)-1-( 1-Methylpyrrolidin-3-yl)methylamine (H001-086) was reacted to obtain compound #H002-089 ER10225 (35 mg, 34% yield) as a white solid. LCMS: [M+1] + 404.9.
实施例49：合成(S)-3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-090)ER10226Example 49: Synthesis of (S)-3-(3-fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl) (Methyl)urea (H002-090)ER10226
Figure PCTCN2021072517-appb-000096
Figure PCTCN2021072517-appb-000096
(S)-3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-090)ER10226，合成方法类似于compound #1。用0.32mmol 2-氟-4-(异氰酸基甲基)-1-甲氧基苯(H001-084-1)与(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H001-087)反应，得到白色固体compound #H002-090 ER10226(57mg，44％产率)。LCMS：[M+1] +403.8。 (S)-3-(3-Fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea( H002-090) ER10226, the synthesis method is similar to compound #1. Use 0.32mmol 2-fluoro-4-(isocyanatomethyl)-1-methoxybenzene (H001-084-1) and (R)-N-(4-fluorobenzyl)-1-( 1-Methylpyrrolidin-3-yl)methylamine (H001-087) was reacted to obtain compound #H002-090 ER10226 (57 mg, 44% yield) as a white solid. LCMS: [M+1] + 403.8.
实施例50：合成3-(3-氟-4-异丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-093)ER10227Example 50: Synthesis of 3-(3-fluoro-4-isobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl Base) urea (H002-093) ER10227
Figure PCTCN2021072517-appb-000097
Figure PCTCN2021072517-appb-000097
2-氟-1-异丁氧基-4-(异氰酸基甲基)苯(H002-093-1)合成方法类似于(37-3)，用0.13mmol(3-氟-4-异丁氧基苯基)甲胺得到中间体(H002-093-1)(28mg，99％产率)。LCMS：[M+1] +224.3。 The synthesis method of 2-fluoro-1-isobutoxy-4-(isocyanatomethyl)benzene (H002-093-1) is similar to (37-3), with 0.13mmol (3-fluoro-4-iso Butoxyphenyl) methylamine gave the intermediate (H002-093-1) (28 mg, 99% yield). LCMS: [M+1] + 224.3.
Figure PCTCN2021072517-appb-000098
Figure PCTCN2021072517-appb-000098
3-(3-氟-4-异丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-093)ER10227合成方法类似于compound #1，用0.13mmol 2-氟-1-异丁氧基-4-(异氰酸基甲基)苯(H002-093-1)与N-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H001-004)反应得到白色固体compound H002-093 ER10227(22mg，37％产率)。LCMS：[M+1] +460.8。 3-(3-Fluoro-4-isobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea (H002 -093) ER10227 synthesis method is similar to compound #1, using 0.13mmol 2-fluoro-1-isobutoxy-4-(isocyanatomethyl)benzene (H002-093-1) and N-(4- Fluorobenzyl)-1-(1-methylpiperidin-4-yl)methylamine (H001-004) was reacted to obtain compound H002-093 ER10227 (22 mg, 37% yield) as a white solid. LCMS: [M+1] + 460.8.
实施例51：合成(S)-1-(2，4-二氟苯甲基)-3-(3-氟-4-甲氧苄基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-094)ER10228Example 51: Synthesis of (S)-1-(2,4-difluorobenzyl)-3-(3-fluoro-4-methoxybenzyl)-1-((1-methylpyrrolidine-3 -Base) methyl) urea (H002-094) ER10228
Figure PCTCN2021072517-appb-000099
Figure PCTCN2021072517-appb-000099
(S)-1-(2，4-二氟苯甲基)-3-(3-氟-4-甲氧苄基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-094)ER10228，合成方法类似于compound #1，用0.19mmol 2-氟-4-(异氰酸基甲基)-1-甲氧基苯(H001-084-1)与(R)-N-(2，4-二氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H002-077)反应，得到白色固体compound #H002-094 ER10228(29mg，36％产率)。LCMS：[M+1] +422.8。 (S)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-methoxybenzyl)-1-((1-methylpyrrolidin-3-yl)methyl ) Urea (H002-094) ER10228, the synthesis method is similar to compound #1, using 0.19mmol 2-fluoro-4-(isocyanatomethyl)-1-methoxybenzene (H001-084-1) and ( R)-N-(2,4-Difluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (H002-077) is reacted to obtain a white solid compound #H002-094 ER10228( 29mg, 36% yield). LCMS: [M+1] + 422.8.
实施例52：合成3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-096)ER10229Example 52: Synthesis of 3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methyl Piperidin-4-yl)methyl)urea (H002-096)ER10229
Figure PCTCN2021072517-appb-000100
Figure PCTCN2021072517-appb-000100
2-氟-4-(异氰酸基甲基)-1-(2，2，2-三氟乙氧基)苯(H002-096-1)合成方法类似于(37-3)，用0.22mmol(3-氟-4-(2，2，2-三氟乙氧基)苯基)甲胺得到中间体(H002-096-1)(55mg，98％产率)。LCMS：[M+1] +249.2。 The synthesis method of 2-fluoro-4-(isocyanatomethyl)-1-(2,2,2-trifluoroethoxy)benzene (H002-096-1) is similar to (37-3), using 0.22 mmol (3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)methylamine gave intermediate (H002-096-1) (55 mg, 98% yield). LCMS: [M+1] + 249.2.
Figure PCTCN2021072517-appb-000101
Figure PCTCN2021072517-appb-000101
3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-096)ER10229合成方法类似于compound #1，用0.22mmol 2-氟-4-(异氰酸基甲基)-1-(2，2，2-三氟乙氧基)苯(H002-096-1)与N-(4-氟苯甲基)-1-(1-甲基哌啶-4-基) 甲胺(H001-004)反应得到白色固体compound H002-096 ER10229(60mg，55％产率)。LCMS：[M+1] +486.7。 3-(3-Fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidine-4 -Yl)methyl)urea (H002-096)ER10229 The synthesis method is similar to compound #1, with 0.22mmol 2-fluoro-4-(isocyanatomethyl)-1-(2,2,2-trifluoro Ethoxy)benzene (H002-096-1) reacts with N-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)methylamine (H001-004) to obtain a white solid compound H002-096 ER10229 (60 mg, 55% yield). LCMS: [M+1] + 486.7.
实施例53：合成1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-097)ER10230Example 53: Synthesis of 1-(2,4-difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(( 1-methylpiperidin-4-yl)methyl)urea (H002-097)ER10230
Figure PCTCN2021072517-appb-000102
Figure PCTCN2021072517-appb-000102
1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H002-097)ER10230合成方法类似于compound #1，用0.22mmol 2-氟-4-(异氰酸基甲基)-1-(2，2，2-三氟乙氧基)苯(H002-096-1)与N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(H002-070)反应得到白色固体compound H002-097 ER10230(45mg，40％产率)。LCMS：[M+1] +504.7。 1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-((1-methylpiper (Pyridin-4-yl)methyl)urea (H002-097)ER10230 The synthesis method is similar to compound #1, with 0.22mmol 2-fluoro-4-(isocyanatomethyl)-1-(2,2,2 -Trifluoroethoxy)benzene (H002-096-1) and N-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)methylamine (H002-070 ) The white solid compound H002-097 ER10230 (45mg, 40% yield) was obtained by the reaction. LCMS: [M+1] + 504.7.
实施例54：合成(R)-1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-098)ER10231Example 54: Synthesis of (R)-1-(2,4-difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)- 1-((1-Methylpyrrolidin-3-yl)methyl)urea (H002-098)ER10231
Figure PCTCN2021072517-appb-000103
Figure PCTCN2021072517-appb-000103
(R)-1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-098)ER10231，合成方法类似于compound #1。用0.13mmol 2-氟-4-(异氰酸基甲基)-1-(2，2，2-三氟乙氧基)苯(H002-096-1)与(S)-N-(2，4-二氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H002-078)反应，得到白色固体compound #H002-098 ER10231(40mg，61％产率)。LCMS：[M+1] +490.7。 (R)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-((1 -Methylpyrrolidin-3-yl)methyl)urea (H002-098)ER10231, the synthesis method is similar to compound #1. Use 0.13mmol 2-fluoro-4-(isocyanatomethyl)-1-(2,2,2-trifluoroethoxy)benzene (H002-096-1) and (S)-N-(2 , 4-Difluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (H002-078) was reacted to obtain a white solid compound #H002-098 ER10231 (40mg, 61% yield) . LCMS: [M+1] + 490.7.
实施例55：合成(S)-1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-099)ER10232Example 55: Synthesis of (S)-1-(2,4-difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)- 1-((1-Methylpyrrolidin-3-yl)methyl)urea (H002-099)ER10232
Figure PCTCN2021072517-appb-000104
Figure PCTCN2021072517-appb-000104
(S)-1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-099)ER10232，合成方法类似于compound #1。用0.13mmol 2-氟-4-(异氰酸基甲基)-1-(2，2，2-三氟乙氧基)苯(H002-096-1)与(R)-N-(2，4-二氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H002-077)反应得到白色固体compound #H002-099 ER10232(31mg，47％产率)。LCMS：[M+1] +490.7。 (S)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-((1 -Methylpyrrolidin-3-yl)methyl)urea (H002-099)ER10232, the synthesis method is similar to compound #1. Use 0.13mmol 2-fluoro-4-(isocyanatomethyl)-1-(2,2,2-trifluoroethoxy)benzene (H002-096-1) and (R)-N-(2 , 4-Difluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (H002-077) was reacted to obtain compound #H002-099 ER10232 (31 mg, 47% yield) as a white solid. LCMS: [M+1] + 490.7.
实施例56：合成(S)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-100)ER10233Example 56: Synthesis of (S)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-( (1-Methylpyrrolidin-3-yl)methyl)urea (H002-100)ER10233
Figure PCTCN2021072517-appb-000105
Figure PCTCN2021072517-appb-000105
(S)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H002-100)ER10233，合成方法类似于compound #1，用0.13mmol 2-氟-4-(异氰酸基甲基)-1-(2，2，2-三氟乙氧基)苯(H002-096-1)与(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H001-087)反应，得到白色固体compound #H002-100 ER10233(12mg，19％产率)。LCMS：[M+1] +472.7。 (S)-3-(3-Fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methyl Pyrrolidin-3-yl)methyl)urea (H002-100)ER10233, the synthesis method is similar to compound #1, with 0.13mmol 2-fluoro-4-(isocyanatomethyl)-1-(2,2 , 2-Trifluoroethoxy)benzene (H002-096-1) and (R)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine ( H001-087) was reacted to obtain white solid compound #H002-100 ER10233 (12 mg, 19% yield). LCMS: [M+1] + 472.7.
实施例57：合成(R)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H003-001)ER10234Example 57: Synthesis of (R)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-( (1-Methylpyrrolidin-3-yl)methyl)urea (H003-001)ER10234
Figure PCTCN2021072517-appb-000106
Figure PCTCN2021072517-appb-000106
(R)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H003-001)ER10234，合成方法类似于compound #1。用0.13mmol 2-氟-4-(异氰酸基甲基)-1-(2，2，2-三氟乙氧基)苯(H002-096-1)与(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(H001-086)反应，得到白色固体compound #H003-001 ER10234(49mg，77％产率)。LCMS：[M+1] +472.7。 (R)-3-(3-Fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methyl Pyrrolidin-3-yl)methyl)urea (H003-001)ER10234, the synthesis method is similar to compound #1. Use 0.13mmol 2-fluoro-4-(isocyanatomethyl)-1-(2,2,2-trifluoroethoxy)benzene (H002-096-1) and (S)-N-(4 -Fluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (H001-086) was reacted to obtain compound #H003-001 ER10234 (49 mg, 77% yield) as a white solid. LCMS: [M+1] + 472.7.
实施例58：合成3-(4-(2-羟基-2-甲基丙氧基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H003-042)ER10248Example 58: Synthesis of 3-(4-(2-hydroxy-2-methylpropoxy)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methyl Piperidin-4-yl)methyl)urea (H003-042)ER10248
Figure PCTCN2021072517-appb-000107
Figure PCTCN2021072517-appb-000107
实施例化合物通过以下方法制备和纯化，与化合物#1制备方法类似，将包含1-(2，4-二氟苄基)-3-(4-羟基苄基)-1-((1-甲基哌啶-4-基)甲基)脲(50mg，0.124mmol)，碳酸铯(121mg，0.37mmol)，2，2-二甲基环氧乙烷(89mg，1.24mmol)和DMF(1.0mL)混合物放置在密封管中，在100℃加热过夜。所得混合物通过HPLC纯化，得到目标产物(H003-042)ER10248(13mg，22％的产率)。LCMS：[M+1] +476.8。 Example compounds were prepared and purified by the following method, similar to the preparation method of compound #1, containing 1-(2,4-difluorobenzyl)-3-(4-hydroxybenzyl)-1-((1-methyl Piperidin-4-yl)methyl)urea (50mg, 0.124mmol), cesium carbonate (121mg, 0.37mmol), 2,2-dimethyloxirane (89mg, 1.24mmol) and DMF (1.0mL ) The mixture is placed in a sealed tube and heated at 100°C overnight. The resulting mixture was purified by HPLC to obtain the target product (H003-042) ER10248 (13 mg, 22% yield). LCMS: [M+1] + 476.8.
实施例59：合成3-(4-(2-羟基-2-甲基丙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H003-030)ER10241Example 59: Synthesis of 3-(4-(2-hydroxy-2-methylpropoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidine- 4-yl)methyl)urea (H003-030) ER10241
Figure PCTCN2021072517-appb-000108
Figure PCTCN2021072517-appb-000108
本实施例化合物使用与实施例58相似制备和纯化方法，使用1-(4-氟苄基)-3-(4-羟基苄基)-1-((1-甲基哌啶-4-基)甲基)脲(30mg，0.078mmol)作为原料，得到3-(4-(2-羟基2-甲基丙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(H003-030)ER10241(36mg，18％)。LCMS：[M+1] +458.8。 The compound of this example used the preparation and purification method similar to that of Example 58, using 1-(4-fluorobenzyl)-3-(4-hydroxybenzyl)-1-((1-methylpiperidin-4-yl) )Methyl)urea (30mg, 0.078mmol) was used as a raw material to obtain 3-(4-(2-hydroxy2-methylpropoxy)benzyl)-1-(4-fluorobenzyl)-1- ((1-Methylpiperidin-4-yl)methyl)urea (H003-030) ER10241 (36 mg, 18%). LCMS: [M+1] + 458.8.
实施例60：合成(R)-3-(4-(2-羟基-2-甲基丙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H003-035)ER10247Example 60: Synthesis of (R)-3-(4-(2-hydroxy-2-methylpropoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methyl Pyrrolidin-3-yl) methyl) urea (H003-035) ER10247
Figure PCTCN2021072517-appb-000109
Figure PCTCN2021072517-appb-000109
本实施例化合物使用与实施例58相似制备和纯化方法，使用(R)-1-(4-氟苄基)-3-(4-羟基苄基)-1-((1-甲基吡咯烷-3-基)甲基)脲(50mg，0.135mmol)作为原料，得到(R)-3-(4-(2-羟基-2-甲基丙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲(H003-035)ER10247(60mg，12％).LCMS：[M+1] +444.8。 The compound of this example uses the preparation and purification method similar to that of Example 58, using (R)-1-(4-fluorobenzyl)-3-(4-hydroxybenzyl)-1-((1-methylpyrrolidine) -3-yl)methyl)urea (50mg, 0.135mmol) as a raw material to obtain (R)-3-(4-(2-hydroxy-2-methylpropoxy)benzyl)-1-(4 -Fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea (H003-035) ER10247 (60 mg, 12%). LCMS: [M+1] + 444.8.
实施例61-64：使用类似方法，合成以下化合物：Examples 61-64: Using similar methods, the following compounds were synthesized:
Figure PCTCN2021072517-appb-000110
Figure PCTCN2021072517-appb-000110
Figure PCTCN2021072517-appb-000111
Figure PCTCN2021072517-appb-000111
式IC化合物的示例性化合物及制备实施例如实施例65-79。Exemplary compounds and preparation examples of the compound of formula IC are Examples 65-79.
其中中间体制备：The intermediate preparation:
4-异丙氧基甲基-1-苯甲基胺(I-1)的制备：Preparation of 4-isopropoxymethyl-1-benzylamine (I-1):
Figure PCTCN2021072517-appb-000112
Figure PCTCN2021072517-appb-000112
步骤一：4-异丙氧基甲基-1-苯腈的制备Step 1: Preparation of 4-isopropoxymethyl-1-benzonitrile
Figure PCTCN2021072517-appb-000113
Figure PCTCN2021072517-appb-000113
在0℃下，向异丙醇(0.40g，7.0mmol，1.3equiv.)的四氢呋喃(20mL)溶液中加入氢化钠(0.37g，30equiv.)，室温搅拌30分钟。向反应混合物中加入4-溴甲基-1-苯腈(1.0g，5.0mmol，1.0equiv.)的四氢呋喃(20mL)溶液。搅拌过夜。加入乙酸乙酯稀释反应混合液，随后用水和饱和食盐水洗。低压下旋蒸掉溶剂，然后 粗产物用柱分离色谱纯化得到白色固体，4-异丙氧基甲基-1-苯腈(0.8g，收率：90％)。At 0° C., sodium hydride (0.37 g, 30 equiv.) was added to a solution of isopropanol (0.40 g, 7.0 mmol, 1.3 equiv.) in tetrahydrofuran (20 mL) and stirred at room temperature for 30 minutes. A solution of 4-bromomethyl-1-benzonitrile (1.0 g, 5.0 mmol, 1.0 equiv.) in tetrahydrofuran (20 mL) was added to the reaction mixture. Stir overnight. The reaction mixture was diluted by adding ethyl acetate, and then washed with water and saturated brine. The solvent was evaporated under low pressure, and then the crude product was purified by column separation chromatography to obtain a white solid, 4-isopropoxymethyl-1-benzonitrile (0.8 g, yield: 90%).
步骤二：4-异丙氧基甲基-1-苯甲基胺(I-1)的制备：Step 2: Preparation of 4-isopropoxymethyl-1-benzylamine (I-1):
Figure PCTCN2021072517-appb-000114
Figure PCTCN2021072517-appb-000114
在氩气的保护下向干燥的反应瓶中加入LiAlH 4(0.35g，2.0equiv.)和无水四氢呋喃(50mL)。冷却至0℃后，向其中慢慢加入4-异丙氧基甲基-1-苯腈(0.8g，1.0equiv.)的四氢呋喃(10mL)溶液。持续搅拌3个小时后，反应溶液用2.0N NaOH和饱和食盐水洗。低压浓缩得到粗产物(0.60g，收率73％)，直接用于下一步的反应。 Under the protection of argon, LiAlH 4 (0.35 g, 2.0 equiv.) and anhydrous tetrahydrofuran (50 mL) were added to the dry reaction flask. After cooling to 0°C, a solution of 4-isopropoxymethyl-1-benzonitrile (0.8 g, 1.0 equiv.) in tetrahydrofuran (10 mL) was slowly added thereto. After continuous stirring for 3 hours, the reaction solution was washed with 2.0N NaOH and saturated brine. Concentrate at low pressure to obtain the crude product (0.60 g, yield 73%), which was directly used in the next reaction.
4-甲氧基甲基-1-苯甲胺(I-2)
Figure PCTCN2021072517-appb-000115
和4-乙氧基甲基-1-苯甲胺(I-3)
Figure PCTCN2021072517-appb-000116
均有商业化供应。 4-methoxymethyl-1-benzylamine (I-2)
Figure PCTCN2021072517-appb-000115
And 4-ethoxymethyl-1-benzylamine (I-3)
Figure PCTCN2021072517-appb-000116
All have commercial supply.
4-环丙氧基甲基-1-苯甲胺(I-4)的制备：
Figure PCTCN2021072517-appb-000117
Preparation of 4-cyclopropoxymethyl-1-benzylamine (I-4):
Figure PCTCN2021072517-appb-000117
4-环丙氧基甲基-1-苯甲胺(I-4)的制备类似于4-异丙氧基甲基-1-苯甲基胺(I-1)的制备：用4-溴甲基-1-苯腈(1.0g，5.0mmol，1.0equiv.)和环丙醇(390mg，1.3equiv.)反应，收率(0.6g，68％)。The preparation of 4-cyclopropoxymethyl-1-benzylamine (I-4) is similar to the preparation of 4-isopropoxymethyl-1-benzylamine (I-1): 4-bromo Methyl-1-benzonitrile (1.0 g, 5.0 mmol, 1.0 equiv.) and cyclopropanol (390 mg, 1.3 equiv.) were reacted with a yield (0.6 g, 68%).
(4-氟-苯甲基)-(1-甲基哌啶-4-基)-胺(II-1)的制备：Preparation of (4-fluoro-benzyl)-(1-methylpiperidin-4-yl)-amine (II-1):
Figure PCTCN2021072517-appb-000118
Figure PCTCN2021072517-appb-000118
室温下，在1-甲基-哌啶-4-基胺(19g，88mmol)的500.0mL二氯甲烷溶液中添加4-氟苯甲醛(11g，90mmol)，然后分批慢慢加入三乙酰氧基氢硼化物钠(33g，180mmol)，及10mL醋酸。混合物在室温下搅拌过夜。加入冰水(500mL)，用10％(v/v)异丙醇/氯仿(500ml×4)提取混合物。有机相用Na 2SO 4干燥，在真空条件下过滤和浓缩，得到无色油状中间体，(4-氟-苯甲基)-(1-甲基哌啶-4-基)-胺(II-1)(12.7g，产率65％)。LCMS：[M+1] +223.4。 At room temperature, add 4-fluorobenzaldehyde (11g, 90mmol) to a 500.0mL dichloromethane solution of 1-methyl-piperidin-4-ylamine (19g, 88mmol), and then slowly add triacetoxy in batches Sodium borohydride (33 g, 180 mmol), and 10 mL of acetic acid. The mixture was stirred overnight at room temperature. Ice water (500 mL) was added, and the mixture was extracted with 10% (v/v) isopropanol/chloroform (500 ml×4). The organic phase was dried with Na 2 SO 4 , filtered and concentrated under vacuum to obtain a colorless oily intermediate, (4-fluoro-benzyl)-(1-methylpiperidin-4-yl)-amine (II -1) (12.7 g, yield 65%). LCMS: [M+1] + 223.4.
N-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(II-2)的制备类似于(4-氟-苯甲基)-(1-甲基哌啶-4-基)-胺(II-1)的制备：用0.9mmol(1-甲基哌啶-4-基)甲胺为原料得到棕色中间体(II-2)(82mg，35％产率)。LCMS：[M+1] +237.3。 The preparation of N-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)methylamine (II-2) is similar to (4-fluoro-benzyl)-(1-methyl) Preparation of ylpiperidin-4-yl)-amine (II-1): Using 0.9mmol (1-methylpiperidin-4-yl)methylamine as raw material to obtain brown intermediate (II-2) (82mg, 35 %Yield). LCMS: [M+1] + 237.3.
Figure PCTCN2021072517-appb-000119
Figure PCTCN2021072517-appb-000119
(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(II-3)类似于(4-氟-苯甲基)-(1-甲基哌啶-4-基)-胺(II-1)的制备：用8.5mmol S-(1-甲基吡咯烷-3-基)甲胺得到棕色油状中间体(II-3)(720mg，38％产率)。LCMS：[M+1] +223.2。 (S)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (II-3) is similar to (4-fluoro-benzyl)-(1 -Methylpiperidin-4-yl)-amine (II-1): Use 8.5mmol S-(1-methylpyrrolidin-3-yl)methylamine to obtain brown oily intermediate (II-3)( 720 mg, 38% yield). LCMS: [M+1] + 223.2.
Figure PCTCN2021072517-appb-000120
Figure PCTCN2021072517-appb-000120
(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(II-4)类似于(4-氟-苯甲基)-(1-甲基哌啶-4-基)-胺(II-1)的制备：用8.5mmol R-(1-甲基吡咯烷-3-基)甲胺得到棕色油状中间体(II-4)(750mg，40％产率)。LCMS：[M+1] +223.2。 (R)-N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (II-4) is similar to (4-fluoro-benzyl)-(1 -Methylpiperidin-4-yl)-amine (II-1): Use 8.5mmol R-(1-methylpyrrolidin-3-yl)methylamine to obtain brown oily intermediate (II-4)( 750 mg, 40% yield). LCMS: [M+1] + 223.2.
Figure PCTCN2021072517-appb-000121
Figure PCTCN2021072517-appb-000121
N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(II-5)的制备类似于(4-氟-苯甲基)-(1-甲基哌啶-4-基)-胺(II-1)的制备：用8.8mmol(1-甲基哌啶-4-基)甲胺得到棕色油状中间体(II-5)(1.5g，75％产率)。LCMS：[M+1] +255.3。 The preparation of N-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)methylamine (II-5) is similar to (4-fluoro-benzyl)-( Preparation of 1-methylpiperidin-4-yl)-amine (II-1): Use 8.8mmol (1-methylpiperidin-4-yl) methylamine to obtain brown oily intermediate (II-5) (1.5 g, 75% yield). LCMS: [M+1] + 255.3.
Figure PCTCN2021072517-appb-000122
Figure PCTCN2021072517-appb-000122
(2，4-二氟苯甲基)-(1-甲基哌啶-4-基)胺(II-6)的制备类似于(4-氟-苯甲基)-(1-甲基哌啶-4-基)-胺(II-1)的制备：用8.8mmol 1-甲基哌啶-4-胺(8.8mmol)得到棕色油状中间体(II-6)(0.8g，产率38％)。LCMS：[M+1] +241.3。 (2,4-Difluorobenzyl)-(1-methylpiperidin-4-yl)amine (II-6) is prepared similarly to (4-fluoro-benzyl)-(1-methylpiperidine) Preparation of pyridin-4-yl)-amine (II-1): Using 8.8mmol 1-methylpiperidin-4-amine (8.8mmol) to obtain brown oily intermediate (II-6) (0.8g, yield 38 %). LCMS: [M+1] + 241.3.
Figure PCTCN2021072517-appb-000123
Figure PCTCN2021072517-appb-000123
N-(2，4-二氟苯甲基)-1-(1-(N-叔丁氧羰基)哌啶-4-基)甲胺(II-7)的制备类似于(4-氟-苯甲基)-(1-甲基哌啶-4-基)-胺(II-1)的制备：用9.33mmol 1-(N-叔丁氧羰基)哌啶-4-基)甲胺得到无色油状中间体(II-7)(2.0g)粗产品，无进一步纯化直接用于下一步反应。The preparation of N-(2,4-difluorobenzyl)-1-(1-(N-tert-butoxycarbonyl)piperidin-4-yl)methylamine (II-7) is similar to that of (4-fluoro- Preparation of benzyl)-(1-methylpiperidin-4-yl)-amine (II-1): Use 9.33mmol 1-(N-tert-butoxycarbonyl)piperidin-4-yl)methylamine to obtain The crude product of colorless oily intermediate (II-7) (2.0 g) was used directly in the next reaction without further purification.
Figure PCTCN2021072517-appb-000124
Figure PCTCN2021072517-appb-000124
(2，4-二氟苯甲基)-(1-(N-叔丁氧羰基)哌啶-4-基)胺(II-8)的制备类似于(4-氟-苯甲基)-(1-甲基哌啶-4-基)-胺(II-1)的制备：用9.33mmol(N-叔丁氧羰基)哌啶-4-基)胺得到无色油状中间体(II-8)(2.0g)粗产品，无进一步纯化直接用于下一步反应。(2,4-Difluorobenzyl)-(1-(N-tert-butoxycarbonyl)piperidin-4-yl)amine (II-8) is prepared similarly to (4-fluoro-benzyl)- Preparation of (1-methylpiperidin-4-yl)-amine (II-1): Use 9.33mmol (N-tert-butoxycarbonyl)piperidin-4-yl)amine to obtain a colorless oily intermediate (II- 8) The crude product (2.0g) was used directly in the next reaction without further purification.
Figure PCTCN2021072517-appb-000125
Figure PCTCN2021072517-appb-000125
实施例65：3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-1)的制备(ER10067)Example 65: 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea (III-1 ) Preparation (ER10067)
Figure PCTCN2021072517-appb-000126
Figure PCTCN2021072517-appb-000126
向三聚光气(49.7mg，0.167mmol，1.0equiv.)的二氯甲烷溶液中逐滴加入4-异丙氧基甲基-1-苯甲基胺(I-1)(30mg，0.167mmol，1.0equiv.)的四氢呋喃溶液(1.0mL)。然后逐滴加入三乙胺(0.070mL，3.0equiv.)的二氯甲烷溶液(2.0mL)。脱溶后，残留物重新溶解在二氯甲烷中(3.0mL)，然后加入(4-氟-苯甲基)-(1-甲基哌啶-4-基)-胺(II-1)(39.6mg，1.0equiv.)的四氢呋喃溶液(2.0mL)。混合物在室温下搅拌2小时。脱溶后，粗产品经过硅胶柱纯化给出最终产物。To the dichloromethane solution of trimer phosgene (49.7mg, 0.167mmol, 1.0 equiv.) was added dropwise 4-isopropoxymethyl-1-benzylamine (I-1) (30mg, 0.167mmol) , 1.0 equiv.) in tetrahydrofuran (1.0 mL). Then triethylamine (0.070 mL, 3.0 equiv.) in dichloromethane (2.0 mL) was added dropwise. After desolvation, the residue was redissolved in dichloromethane (3.0 mL), and then (4-fluoro-benzyl)-(1-methylpiperidin-4-yl)-amine (II-1) was added ( 39.6 mg, 1.0 equiv.) in tetrahydrofuran (2.0 mL). The mixture was stirred at room temperature for 2 hours. After desolvation, the crude product is purified by silica gel column to give the final product.
实施例66：3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(III-2)的制备(ER10235)Example 66: 3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl ) Preparation of Urea (III-2) (ER10235)
Figure PCTCN2021072517-appb-000127
Figure PCTCN2021072517-appb-000127
3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(III-2)的制备类似于3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-1)的制备：用4-异丙氧基甲基-1-苯甲基胺(I-1)(30mg，0.167mmol，1.0equiv.)和N-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(II-2)(39.6mg，0.167mmol，1.0equiv.)，硅胶柱纯化给出最终产物(13mg，收率18％)。LCMS：M+1] +442.8。 3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea(III -2) is similar to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea ( III-1) Preparation: Use 4-isopropoxymethyl-1-benzylamine (I-1) (30mg, 0.167mmol, 1.0 equiv.) and N-(4-fluorobenzyl)- 1-(1-Methylpiperidin-4-yl)methylamine (II-2) (39.6 mg, 0.167 mmol, 1.0 equiv.), purified by silica gel column to give the final product (13 mg, yield 18%). LCMS: M+1] + 442.8.
实施例67：3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-(((R)-1-(1-甲基吡咯烷-3-基))甲基)脲(III-3)的制备(ER10236)Example 67: 3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-(((R)-1-(1-methylpyrrolidine) -3-yl))methyl)urea (III-3) preparation (ER10236)
Figure PCTCN2021072517-appb-000128
Figure PCTCN2021072517-appb-000128
3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-(((R)-1-(1-甲基吡咯烷-3-基))甲基)脲(III-3)的制备类似于3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-1)的制备：用4-异丙氧基甲基-1-苯甲基胺(I-1)(30mg，0.167mmol，1.0equiv.)和(S)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(II-3)(37.2mg，0.167mmol，1.0equiv.)，硅胶柱纯化给出最终产物(5.3mg，收率7.0％)。LCMS：[M+1] +428.8。 3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-(((R)-1-(1-methylpyrrolidin-3-yl ))Methyl)urea (III-3) is similar to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine). Preparation of pyridin-4-yl)urea (III-1): use 4-isopropoxymethyl-1-benzylamine (I-1) (30mg, 0.167mmol, 1.0equiv.) and (S) -N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (II-3) (37.2mg, 0.167mmol, 1.0equiv.), purified by silica gel column to give Final product (5.3 mg, yield 7.0%). LCMS: [M+1] + 428.8.
实施例68：3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-(((S)-1-(1-甲基吡咯烷-3-基))甲基)脲(III-4)的制备(ER10237)Example 68: 3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-(((S)-1-(1-methylpyrrolidine) -3-yl))methyl)urea (III-4) preparation (ER10237)
Figure PCTCN2021072517-appb-000129
Figure PCTCN2021072517-appb-000129
3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-(((S)-1-(1-甲基吡咯烷-3-基))甲基)脲(III-4)的制备类似于3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-1)的制备：用4-异丙氧基甲基-1-苯甲基胺(I-1)(30mg，0.167mmol，1.0equiv.)和(R)-N-(4-氟苯甲基)-1-(1-甲基吡咯烷-3-基)甲胺(II-4)(37.2mg，0.167mmol，1.0equiv.)，硅胶柱纯化给出最终产物(12mg，收率17.0％)。LCMS：[M+1] +428.8。 3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-(((S)-1-(1-methylpyrrolidin-3-yl ))Methyl)urea (III-4) is prepared similarly to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine). Preparation of pyridin-4-yl)urea (III-1): use 4-isopropoxymethyl-1-benzylamine (I-1) (30mg, 0.167mmol, 1.0equiv.) and (R) -N-(4-fluorobenzyl)-1-(1-methylpyrrolidin-3-yl)methylamine (II-4) (37.2mg, 0.167mmol, 1.0equiv.), purified by silica gel column to give The final product (12 mg, yield 17.0%). LCMS: [M+1] + 428.8.
实施例69：3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(III-5)的制备(ER10243)Example 69: 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl) Preparation of methyl)urea (III-5) (ER10243)
Figure PCTCN2021072517-appb-000130
Figure PCTCN2021072517-appb-000130
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(III-5)的制备类似于3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-1)的制备：用4-甲氧基甲基-1-苯甲胺(I-2)(30mg，0.198mmol，1.0equiv.)和N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(II-5)(37.2mg，0.198mmol，1.0equiv.)，硅胶柱纯化给出最终产物(16mg，收率19.0％)。LCMS：[M+1] +432.8。 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea The preparation of (III-5) is similar to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) Preparation of urea (III-1): use 4-methoxymethyl-1-benzylamine (I-2) (30mg, 0.198mmol, 1.0equiv.) and N-(2,4-difluorobenzyl) Yl)-1-(1-methylpiperidin-4-yl)methylamine (II-5) (37.2mg, 0.198mmol, 1.0 equiv.), purified by silica gel column to give the final product (16mg, yield 19.0% ). LCMS: [M+1] + 432.8.
实施例70：3-((4-乙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(III-6)的制备(ER10244)Example 70: 3-((4-Ethoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl) Preparation of methyl)urea (III-6) (ER10244)
Figure PCTCN2021072517-appb-000131
Figure PCTCN2021072517-appb-000131
3-((4-乙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(III-6)的制备类似于3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-1)的制备：用4-乙氧基甲基-1-苯甲胺(I-3)(30mg，0.182mmol，1.0equiv.)和N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(II-5)(46.7mg，0.182mmol，1.0equiv.)，硅胶柱纯化给出最终产物(25mg，收率19.0％)。LCMS：[M+1] +446.8。 3-((4-ethoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea The preparation of (III-6) is similar to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) Preparation of urea (III-1): use 4-ethoxymethyl-1-benzylamine (I-3) (30mg, 0.182mmol, 1.0equiv.) and N-(2,4-difluorobenzyl) Yl)-1-(1-methylpiperidin-4-yl)methylamine (II-5) (46.7mg, 0.182mmol, 1.0 equiv.), purified by silica gel column to give the final product (25mg, yield 19.0% ). LCMS: [M+1] + 446.8.
实施例71：3-((4-环丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(III-7)的制备(ER10245)Example 71: 3-((4-Cyclopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl )Methyl)urea (III-7) Preparation (ER10245)
Figure PCTCN2021072517-appb-000132
Figure PCTCN2021072517-appb-000132
3-((4-环丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(III-7)的制备类似于3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-1)的制备：用4-环丙氧基甲基-1-苯甲胺(I-4)(30mg，0.182mmol，1.0equiv.)和N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(II-5)(46.2mg，0.182mmol，1.0equiv.)，硅胶柱纯化给出最终产物(20mg，收率24.0％)。LCMS：[M+1] +458.8。 3-((4-Cyclopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl) The preparation of urea (III-7) is similar to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl ) Preparation of urea (III-1): use 4-cyclopropoxymethyl-1-benzylamine (I-4) (30mg, 0.182mmol, 1.0equiv.) and N-(2,4-difluoro Benzyl)-1-(1-methylpiperidin-4-yl)methylamine (II-5) (46.2mg, 0.182mmol, 1.0 equiv.), purified by silica gel column to give the final product (20mg, yield 24.0%). LCMS: [M+1] + 458.8.
实施例72：3-((4-异丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(III-8)的制备(ER10246)Example 72: 3-((4-isopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl )Methyl)urea (III-8) Preparation (ER10246)
Figure PCTCN2021072517-appb-000133
Figure PCTCN2021072517-appb-000133
3-((4-异丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲(III-8)的制备类似于3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-1)的制备：用4-异丙氧基甲基-1-苯甲胺(I-1)(30mg，0.182mmol，1.0equiv.)和N-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)甲胺(II-5)(46.2mg，0.182mmol，1.0equiv.)，硅胶柱纯化给出最终产物(31mg，收率37.0％)。LCMS：[M+1] +460.8。 3-((4-isopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl) The preparation of urea (III-8) is similar to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) ) Preparation of urea (III-1): use 4-isopropoxymethyl-1-benzylamine (I-1) (30mg, 0.182mmol, 1.0equiv.) and N-(2,4-difluoro Benzyl)-1-(1-methylpiperidin-4-yl)methylamine (II-5) (46.2mg, 0.182mmol, 1.0 equiv.), purified by silica gel column to give the final product (31mg, yield 37.0%). LCMS: [M+1] + 460.8.
实施例73：3-(4-异丙氧基甲基苯甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-9)的制备(ER10218)Example 73: 3-(4-isopropoxymethylbenzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea ( III-9) Preparation (ER10218)
Figure PCTCN2021072517-appb-000134
Figure PCTCN2021072517-appb-000134
3-(4-异丙氧基甲基苯甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-9)的制备类似于3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-1)的制备：用4-异丙氧基甲基-1-苯甲胺(I-1)(50mg，1.0equiv.)和(2，4-二氟苯甲基)-(1-甲基哌啶-4-基)胺(II-6)(70mg，1.0equiv.)，硅胶柱纯化给出最终纯产物。LCMS：[M+1] +446.3。 1H核磁共振(400MHz，CDCl 3)：δ7.29-7.20(m，2H)，7.19-7.03(m，2H)，6.86-6.74(m，2H)，6.39(s，1H)，4.78(s，1H)，4.67(t，J＝12.4Hz，1H)，4.45(s，2H)，4.33(d，J＝11.1Hz，4H)，3.66(dq，J＝12.2，6.1Hz，1H)，3.57(d，J＝11.9Hz，2H)，2.83(m，2H)，2.76(s，3H)，2.14(q，J＝12.5Hz，2H)，1.88(d，J＝13.6Hz，2H)，1.19(d，J＝6.1Hz，6H)。 3-(4-isopropoxymethylbenzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea(III-9) The preparation is similar to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea (III-1 ) Preparation: Use 4-isopropoxymethyl-1-benzylamine (I-1) (50mg, 1.0equiv.) and (2,4-difluorobenzyl)-(1-methylpiper Pyridin-4-yl)amine (II-6) (70mg, 1.0 equiv.), purified by silica gel column to give the final pure product. LCMS: [M+1] + 446.3. 1 H NMR (400MHz, CDCl 3 ): δ 7.29-7.20 (m, 2H), 7.19-7.03 (m, 2H), 6.86-6.74 (m, 2H), 6.39 (s, 1H), 4.78 (s) , 1H), 4.67 (t, J = 12.4 Hz, 1H), 4.45 (s, 2H), 4.33 (d, J = 11.1 Hz, 4H), 3.66 (dq, J = 12.2, 6.1 Hz, 1H), 3.57 (d, J=11.9Hz, 2H), 2.83 (m, 2H), 2.76 (s, 3H), 2.14 (q, J=12.5Hz, 2H), 1.88 (d, J=13.6Hz, 2H), 1.19 (d, J=6.1 Hz, 6H).
实施例74：3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-甲基)脲(III-10)的制备Example 74: 3-((4-Methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidine-4-methyl)urea ( III-10) Preparation
步骤一：3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-(N-叔丁氧羰基)哌啶-4-甲基)脲的制备Step 1: 3-((4-Methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-(N-tert-butoxycarbonyl)piperidine- Preparation of 4-methyl)urea
Figure PCTCN2021072517-appb-000135
Figure PCTCN2021072517-appb-000135
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-(N-叔丁氧羰基)哌啶-4-甲基)脲的制备类似于3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲(III-1)的制备：用4-甲氧基甲基-1-苯甲胺(I-2)(300mg，1.984mmol，1.0equiv.)和N-(2，4-二氟苯甲基)-1-(1-(N-叔丁氧羰基)哌啶-4-基)甲胺(II-7)(675mg，1.0equiv.)，硅胶柱纯化给出最终纯产物(200mg，19％)。3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-(N-tert-butoxycarbonyl)piperidine-4-methyl The preparation of urea is similar to 3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea ( III-1) Preparation: Use 4-methoxymethyl-1-benzylamine (I-2) (300mg, 1.984mmol, 1.0equiv.) and N-(2,4-difluorobenzyl) -1-(1-(N-tert-butoxycarbonyl)piperidin-4-yl)methylamine (II-7) (675mg, 1.0 equiv.), purified by silica gel column to give the final pure product (200mg, 19%) .
步骤二：3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-甲基)脲(III-10)的制备Step 2: 3-((4-Methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidine-4-methyl)urea(III -10) Preparation
Figure PCTCN2021072517-appb-000136
Figure PCTCN2021072517-appb-000136
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-(N-叔丁氧羰基)哌啶-4-甲基)脲(100mg，0.193mmol，1.0equiv.)溶解于5.0毫升二氯甲烷溶液中，随后逐滴加入4N HCl的二氧杂环己烷(dioxane)(2.0mL)溶液。反应溶液室温搅拌30分钟。真空浓缩反应溶液给出粗产品(80mg，99％)，无进一步纯化，直接用于下一步反应。3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-(N-tert-butoxycarbonyl)piperidine-4-methyl Hydroxyurea (100 mg, 0.193 mmol, 1.0 equiv.) was dissolved in 5.0 mL of dichloromethane solution, and then 4N HCl in dioxane (2.0 mL) was added dropwise. The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated in vacuo to give a crude product (80 mg, 99%), which was used directly in the next reaction without further purification.
实施例75：3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(2-苯基羰基乙基)-哌啶-4-甲基)脲(III-11)的制备(ER10251)Example 75: 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N-(2-phenylcarbonylethyl) )-Piperidine-4-methyl)urea (III-11) Preparation (ER10251)
Figure PCTCN2021072517-appb-000137
Figure PCTCN2021072517-appb-000137
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-甲基)脲(III-10)(40mg，0.096mmol，1.0equiv.)溶解于40mL DMF中，随后分别加入DIPEA(37mg，0.287mmol，3.0equiv.)和3-氯代苯丙酮(3-chloropropiophenone)(16.2mg，0.096mmol，1.0equiv.)。所得溶液在室温搅拌18小时。加入饱和碳酸氢钠，混合物用乙酸乙酯萃取。有机相用无水Na 2SO 4干燥，浓缩，残余物用制备HPLC分离纯化得到目标化合物(28.5mg，收率54％)。LCMS：[M+1] +：550.7。 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidine-4-methyl)urea(III-10) (40mg, 0.096mmol, 1.0equiv.) was dissolved in 40mL DMF, and then DIPEA (37mg, 0.287mmol, 3.0equiv.) and 3-chloropropiophenone (16.2mg, 0.096mmol, 1.0 equiv.). The resulting solution was stirred at room temperature for 18 hours. Saturated sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na 2 SO 4 and concentrated. The residue was separated and purified by preparative HPLC to obtain the target compound (28.5 mg, yield 54%). LCMS: [M+1] + : 550.7.
实施例76：3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(苯基羰基甲基-哌啶-4-甲基)脲(III-12)的制备(ER10252)Example 76: 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N-(phenylcarbonylmethyl-piper Preparation of pyridine-4-methyl)urea (III-12) (ER10252)
Figure PCTCN2021072517-appb-000138
Figure PCTCN2021072517-appb-000138
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(苯基羰基甲基)-哌啶-4-甲基)脲(III-12)的制备相似于3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(2-苯基羰基乙基)-哌啶-4-甲基)脲(III-11)的制备(实施例75)，用3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-甲基)脲(III-10)(40mg，0.096mmol，1.0equiv.)和苯甲酰甲基溴(Phenacyl bromide)(19mg，0.096mmol，1.0equiv.)制备，高效液相色谱纯化给出最终纯产物(28.6mg，56％)。LCMS：[M+1] +：536.7。 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N-(phenylcarbonylmethyl)-piperidine-4 -Methyl)urea (III-12) is prepared similarly to 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1- Preparation of N-(2-phenylcarbonylethyl)-piperidine-4-methyl)urea (III-11) (Example 75), using 3-((4-methoxymethyl)benzyl )-1-(2,4-Difluorobenzyl)-1-(1-piperidine-4-methyl)urea (III-10) (40mg, 0.096mmol, 1.0equiv.) and benzoyl Phenacyl bromide (19 mg, 0.096 mmol, 1.0 equiv.) was prepared and purified by high performance liquid chromatography to give the final pure product (28.6 mg, 56%). LCMS: [M+1] + : 536.7.
实施例77：3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-基)脲(III-13)的制备(ER10250)Example 77: 3-((4-Methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidin-4-yl)urea (III -13) Preparation (ER10250)
Figure PCTCN2021072517-appb-000139
Figure PCTCN2021072517-appb-000139
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-基)脲(III-13)的制备类似于3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-甲基)脲(III-10)的制备(实施例74)，用4-甲氧基甲基-1-苯甲胺(I-2)(200mg，1.323mmol，1.0equiv.)和N-(2，4-二氟苯甲基)-1-(1-(N-叔丁氧羰基)哌啶-4-基)胺(II-8)(431mg，1.323mmol，1.0equiv.)。LCMS：[M+1] +404.8。 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidin-4-yl)urea(III-13) The preparation is similar to 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidine-4-methyl)urea (III -10) (Example 74), using 4-methoxymethyl-1-benzylamine (I-2) (200mg, 1.323mmol, 1.0equiv.) and N-(2,4-difluoro Benzyl)-1-(1-(N-tert-butoxycarbonyl)piperidin-4-yl)amine (II-8) (431 mg, 1.323 mmol, 1.0 equiv.). LCMS: [M+1] + 404.8.
实施例78：3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(苯基羰基甲基)-哌啶-4-基)脲(III-14)的制备(ER10255)Example 78: 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N-(phenylcarbonylmethyl)- Preparation of piperidin-4-yl)urea (III-14) (ER10255)
Figure PCTCN2021072517-appb-000140
Figure PCTCN2021072517-appb-000140
3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(苯基羰基甲基)-哌啶-4-基)脲(III-14)的制备相似于3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(2-苯基羰基乙基)-哌啶-4-甲基)脲(III-11)的制备(实施例75)，用3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-基)脲(III-13)(50mg，0.124mmol，1.0equiv.)和苯甲酰甲基溴(Phenacyl bromide)(24.7mg，0.124mmol，1.0equiv.)制备，高效液相色谱纯化给出最终纯产物(43mg，67％)。LCMS：[M+1] +：522.7。 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N-(phenylcarbonylmethyl)-piperidine-4 -Yl)urea (III-14) is prepared similarly to 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N -(2-Phenylcarbonylethyl)-piperidine-4-methyl)urea (III-11) preparation (Example 75), using 3-((4-methoxymethyl)benzyl) -1-(2,4-Difluorobenzyl)-1-(1-piperidin-4-yl)urea (III-13) (50mg, 0.124mmol, 1.0equiv.) and phenacyl bromide (Phenacyl bromide) (24.7 mg, 0.124 mmol, 1.0 equiv.) was prepared and purified by high performance liquid chromatography to give the final pure product (43 mg, 67%). LCMS: [M+1] + : 522.7.
实施例79：3-((4-异丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-基)脲(III-15)的制备(ER10253)Example 79: 3-((4-isopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidin-4-yl)urea ( III-15) Preparation (ER10253)
Figure PCTCN2021072517-appb-000141
Figure PCTCN2021072517-appb-000141
3-((4-异丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-基)脲(III-15)的制备相似于3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-甲基)脲(III-10)的制备(实施例74)，用4-异丙氧基甲基-1-苯甲胺(I-1)和N-(2，4-二氟苯甲基)-1-(1-(N-叔丁氧羰基)哌啶-4-基)胺(II-8)制备。LCMS：[M+1] +432.8。 3-((4-isopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidin-4-yl)urea(III-15) The preparation is similar to 3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidine-4-methyl)urea ( III-10) preparation (Example 74), using 4-isopropoxymethyl-1-benzylamine (I-1) and N-(2,4-difluorobenzyl)-1-( Preparation of 1-(N-tert-butoxycarbonyl)piperidin-4-yl)amine (II-8). LCMS: [M+1] + 432.8.
生物学活性试验Biological activity test
以下生物学活性试验中，使用的ER10152是阳性对照物，结构式为：
Figure PCTCN2021072517-appb-000142
可商购，或按照US7601740B2中记载的方法合成制备。 In the following biological activity test, the ER10152 used is the positive control, and the structural formula is:
Figure PCTCN2021072517-appb-000142
It is commercially available or synthetically prepared according to the method described in US7601740B2.
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 compound of the present invention on 5-HT2A receptor, the IP-One experiment was selected to complete the test. The following experiments were done using 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 IP1 labeled with d2 provided in the kit compete for the antigen binding site of the anti-IP1 antibody. When the terbium-labeled anti-IP1 antibody binds to the IP1 labeled with d2, energy resonance transfer occurs, thereby generating a signal. The production of intracellular IP1 increases, the binding of free IP1 to antibodies increases, and the signal gradually decreases.
材料和方法：Materials and Method:
依据用户手册，中国地鼠卵巢细胞转化细胞系(Flp-In TM-CHO cell line)(购买于invitrogen，R75807)，通过用pFRT//acZeo2转染CHO细胞并选择Zeocin TM抗性克隆产生Flp-In TM-CHO细胞系。Flp-In TM-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％CO 2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)，计算化合物对细胞5-HT2A受体的抑制率。 According to the user manual, the Chinese hamster ovary cell transformed cell line (Flp-In TM -CHO cell line) (purchased from invitrogen, R75807) was produced by transfecting CHO cells with pFRT//acZeo2 and selecting Zeocin TM resistant clones to produce Flp- In TM -CHO cell line. 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 with human HTR2A gene ( Human HTR2A, GeneBank, NM_000621) was stably transfected to obtain Flp-In-CHO-5HT2A cells. The stably transfected cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Hyclone) + 1 x Penicilin-Streptomycin + 800 μg/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) for 20 hours at 37°C and 5% CO 2. The compound was diluted with Ham's F-12K medium to different concentrations, and the medium was replaced with fresh medium at 100μl/well for overnight culture. The cells were treated with compound for 30 minutes and 5-HT was added and incubated at 37 degrees Celsius for 45 minutes, then the sequence After adding lysis detection buffer, IP1-d2 and IP1-Ab, incubating for 1 hour at room temperature, read the plate on Envision (HTRF module), and calculate the inhibitory rate of the compound on the cell 5-HT2A receptor.
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 antagonistic activity.
化合物编号Compound number 5HT2A EC50(nM)5HT2A EC50(nM) 化合物编号Compound number 5HT2A EC50(nM)5HT2A EC50(nM)
ER10152ER10152 4545 ER10214ER10214 2626
ER10200ER10200 24twenty four ER10215ER10215 1212
ER10205ER10205 1414 ER10221ER10221 1717
ER10207ER10207 21twenty one ER10222ER10222 1616
ER10211ER10211 22twenty two ER10238ER10238 23twenty three
ER10212ER10212 1515 ER10241ER10241 1616
ER10213ER10213 1919 ER10248ER10248 1010
ER10067ER10067 1111 ER10244ER10244 1010
ER10218ER10218 1313 ER10246ER10246 1212
ER10237ER10237 21twenty one ER10250ER10250 23twenty three
ER10243ER10243 1616 ER10253ER10253 99
2、5-HT2B/2C VGV受体拮抗剂活性筛选试验 2. 5-HT2B/2C VGV receptor antagonist activity screening test
为证实本发明化合物对5-HT2B/2C VGV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-5HT2B/2C VGV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 compound of the present invention on the 5-HT2B/2C VGV receptor, the IP-One experiment was selected to complete the test. The following experiments were performed using Flp-In-CHO-5HT2B/2C VGV 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 IP1 labeled with d2 provided in the kit compete for the antigen binding site of the anti-IP1 antibody. When the terbium-labeled anti-IP1 antibody binds to the IP1 labeled with d2, energy resonance transfer occurs, thereby generating a signal. The production of intracellular IP1 increases, the binding of free IP1 to antibodies increases, and the signal gradually decreases.
材料和方法：Materials and Method:
依据用户手册，中国地鼠卵巢细胞转化细胞系(Flp-In TM-CHO cell line)(购买于invitrogen，R75807)，通过用pFRT//acZeo2转染CHO细胞并选择Zeocin TM抗性克隆产生Flp-In TM-CHO细胞系。Flp-In TM-CHO细胞系于加有10％FBS(Gibco)+1×Penicilin-Streptomycin(15140122，Gibco)的Ham’s F-12K完全培养基(Hyclone)中培养，之后以人HTR2B/2C VGV基因 (Human HTR2B，GeneBank， NM_000867；Human HTR2C(5-HT2C VGV)，GeneBank，NM_000868) 稳定转染得到Flp-In-CHO-5HT2B/2C VGV细胞。稳定转染的细胞系培养于加有10％FBS(Gibco)+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-5HT2B/2C VGV稳定细胞系在37摄氏度，5％CO 2条件下，于384孔板中培养(5K，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)，计算化合物对细胞5-HT2B/2C VGV受体的抑制率。 According to the user manual, the Chinese hamster ovary cell transformed cell line (Flp-In TM -CHO cell line) (purchased from invitrogen, R75807) was produced by transfecting CHO cells with pFRT//acZeo2 and selecting Zeocin TM resistant clones to produce Flp- In TM -CHO cell line. Flp-In TM -CHO cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Gibco)+1×Penicilin-Streptomycin (15140122, Gibco), and then human HTR2B/2C VGV gene (Human HTR2B, GeneBank, NM_000867; Human HTR2C (5-HT2C VGV ), GeneBank, NM_000868) were stably transfected to obtain Flp-In-CHO-5HT2B/2C VGV cells. The stably transfected cell line was cultured in Ham's F-12K complete medium (Hyclone) supplemented with 10% FBS (Gibco) + 1 x Penicilin-Streptomycin + 800 μg/ml Hygromycin B (ant-hg-5, Invivogen). To verify the activity of the compound, the Flp-In-CHO-5HT2B/2C VGV stable cell line was cultured in a 384-well plate (5K, 7.5K) for 20 hours at 37 degrees Celsius and 5% CO 2. The compound was diluted with Ham's F-12K medium to different concentrations, and the medium was replaced with fresh medium at 100μl/well for overnight culture. The cells were treated with compound for 30 minutes and 5-HT was added and incubated at 37 degrees Celsius for 45 minutes, then the sequence After adding the lysis detection buffer, IP1-d2 and IP1-Ab, incubating for 1 hour at room temperature, the plate was read on Envision (HTRF module), and the inhibition rate of the compound on the 5-HT2B/2C VGV receptor of the cells was calculated.
将每个化合物对5-HT2B或5-HT2C的EC50值除以其对5-HT2A的EC50值，计算出每个化合物对5-HT2B或5-HT2C的选择性相对于5-HT2A的选择性的倍数：Divide the EC50 value of each compound for 5-HT2B or 5-HT2C by its EC50 value for 5-HT2A to calculate the selectivity of each compound to 5-HT2B or 5-HT2C relative to the selectivity of 5-HT2A Multiples of:
化合物编号Compound number 对2B选择性(倍数)Selectivity to 2B (multiple) 对2C选择性(倍数)Selectivity to 2C (multiple)
ER10152ER10152 8686 44
ER10200ER10200 222222 1818
ER10204ER10204 192192 77
ER10205ER10205 280280 1515
ER10206ER10206 5858 1414
ER10207ER10207 138138 6868
ER10211ER10211 126126 1616
ER10212ER10212 103103 1616
ER10241ER10241 231231 5757
ER10247ER10247 9797 4545
ER10248ER10248 10001000 5252
ER10254ER10254 8484 6969
ER10067ER10067 300300 1212
ER10218ER10218 300300 1212
ER10250ER10250 10001000 4848
3、hERG膜蛋白特异性结合实验3. hERG membrane protein specific binding experiment
为检验本发明化合物对心脏的毒性，选择hERG膜蛋白特异性结合实验完成检测。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。In order to test the toxicity of the compound of the present invention to the heart, the hERG membrane protein specific binding experiment was selected to complete the detection. The experiment used the HEK293 cell line stably expressing hERG (human Ether-a-go-go Related Gene) encoding potassium channel to complete the experiment. In the myocardium, the potassium channel encoded by hERG mediates a delayed rectifier potassium current (IKr), and Ikr inhibition is the most important mechanism for the prolongation of the QT interval caused by drugs. Because of its special molecular structure, hERG's lack of function or drug inhibition will affect the repolarization process of cardiac action potentials and cause the QT interval to prolong. At the same time, it may induce torsade de pointes ventricular tachycardia and lead to arrhythmia.
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, detection compound and a fixed concentration of radioligand are mixed, so that the detection compound and radioligand can competitively bind to hERG membrane protein. After incubating for a certain period of time to reach equilibrium, vacuum filtration is used to remove no binding to membrane protein. After drying the filter plate, add scintillation fluid, and detect the isotope signal (CPM) on Microbeta. The higher the signal, the weaker the binding ability of the detection compound to hERG membrane protein.
材料和方法：Materials and Method:
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。Add the compound, the diluted hERG membrane protein, and the diluted H3-Dofetilide ligand (NET1144100UC, PerkinElmer) to a 96-well plate (3631, Corning) one after another. After the plate is sealed with a sealing membrane, incubate at room temperature with shaking1 After hours, use the PerkinElmer cell harvester to transfer the incubated hERG membrane protein to the GF/B plate (600517, PerkinElmer), and use the washing buffer (20mmol/L HEPES (PH 7.4) (Sigma-H3375)); 10mmol/L chlorine Potassium chloride (Sigma-P9333); 1mmol/L magnesium chloride (Sigma-449172), stored at 4°C) and washed 5 times (4°C, 0.4 mL each time). Then bake the GF/B plate in an oven at 50°C for 30 minutes to fully dry the GF/B plate, seal the bottom of the GF/B plate with a bottom sealing film (6005199, PerkinElmer), and add 50 μL of scintillation fluid 20 ( 6013621, PerkinElmer) and then use the top sealing film (6005250, PerkinElmer) to seal the plate, and read the plate on Microbeta to detect the radioactive signal.
测试化合物以及它们的结合率值Test compounds and their binding rate values
Figure PCTCN2021072517-appb-000143
Figure PCTCN2021072517-appb-000143
4、人肝微粒体代谢稳定性实验4. Metabolic stability test of human liver microsomes
肝脏是内源性基质及外源性药物代谢的主要器官。有几种体外工具可以帮助研究人员研究候选药物的代谢，包括分离的新鲜或冷冻保存的肝细胞、肝脏切片以及肝微粒和S9组分等亚细胞成分。这些亚细胞成分是通过一系列的均质化和超速离心的方式从肝脏中制备出来。The liver is the main organ for the metabolism of endogenous matrix and exogenous drugs. There are several in vitro tools that can help researchers study the metabolism of candidate drugs, including isolated fresh or cryopreserved liver cells, liver slices, and subcellular components such as liver microparticles and S9 components. These subcellular components are prepared from the liver through a series of homogenization and ultracentrifugation methods.
10,000g肝脏匀浆的初始低速离心法产生的S9组分是此离心方法得到的上清液中的组分。S9组分包含所有I相和II相酶，S9组分进一步离心100,000g得到内质网衍生微粒。微粒体富含细胞色素P450(CYP)和黄素单加氧酶(FMO)。此外，一些II相酶(如某些苷葡糖苷酸转移酶UGT亚型和环氧水解酶EH)也在微粒体中存在。微粒体可用于研究UGT的活性，然而，微粒体膜限制UGT基质和/或辅助因子的进入。通过添加MgCl 2以及成孔抗生素(如丙甲菌素)可以达到最佳UGT活性。这些组件使得微粒体网络中的葡萄糖醛酸产物和辅助因子UDPGA能够有效转运。个体或组合的供者肝微粒体可用于进行代谢相关研究。组合的供者可以代表人群平均水平或特定研究因素，如年龄，BMI或特定CYP亚型的限制能力。本研究的目的是评定化合物在人肝微粒体中的代谢稳定性。 The S9 fraction produced by the initial low-speed centrifugation of 10,000g liver homogenate is the fraction in the supernatant obtained by this centrifugation method. The S9 component contains all phase I and phase II enzymes, and the S9 component is further centrifuged at 100,000 g to obtain endoplasmic reticulum-derived microparticles. Microsomes are rich in cytochrome P450 (CYP) and flavin monooxygenase (FMO). In addition, some phase II enzymes (such as certain glycoside glucuronyltransferase UGT subtypes and cyclohydrolase EH) are also present in the microsomes. Microsomes can be used to study the activity of UGT, however, the microsomal membrane restricts the entry of UGT matrix and/or cofactors. The best UGT activity can be achieved by adding MgCl 2 and pore-forming antibiotics (such as propylmethacin). These components allow the glucuronic acid product and the cofactor UDPGA in the microsomal network to be efficiently transported. Individual or combined donor liver microsomes can be used for metabolism-related research. The combined donors can represent population averages or specific research factors such as age, BMI, or the limiting capacity of specific CYP subtypes. The purpose of this study is to evaluate the metabolic stability of the compound in human liver microsomes.
材料和方法Materials and Method
该测试体系用到的人肝微粒体购买自Corning(Cat No.452117)，使用前储存于低于-60℃的冰箱内。辅酶为NADPH(Chem-impex international，Cat.No.00616)和UDPGA(Sigma，Cat.No.U6751)辅因子。将称量好的NADPH粉末和UDPGA粉末溶解在MgCl 2溶液中配置25mM UGPDA和10mM NADPH的工作液。准备八块96孔板(T0，T5，T10，T20，T30，T60，NFC60，BLANK)，使用Apricot自动液体工作站(PP-550DS，USA)，每孔加入10μL化合物工作液(T0，T5，T10，T20，T30，T60，NFC60)，T0板加入冷乙腈终止液，随后向八块板中加入80μL/孔人肝微粒体，37度预孵育10分钟。NCF60板加入10μL/孔100mM磷酸钾缓冲液放入37度水浴锅中孵育计时1小时。其他板在孵育结束后加入10μL/孔NADPH+UDPGA辅因子组合，按照每板设定做不同时间孵育。孵育结束后加入300μL/孔冷乙腈终止反应，封板震荡10分钟后4000rpm，4度离心20分钟。取100μL/孔离心上清液加入到已添加300μL/孔HPLC水的新板中，混匀递交LC-MS/MS生物分析。 The human liver microsomes used in this test system were purchased from Corning (Cat No. 452117) and stored in a refrigerator below -60°C before use. Coenzymes are NADPH (Chem-impex international, Cat. No. 00616) and UDPGA (Sigma, Cat. No. U6751) cofactors. Dissolve the weighed NADPH powder and UDPGA powder in the MgCl 2 solution to prepare a working solution of 25 mM UGPDA and 10 mM NADPH. Prepare eight 96-well plates (T0, T5, T10, T20, T30, T60, NFC60, BLANK), use Apricot automatic liquid workstation (PP-550DS, USA), add 10 μL of compound working solution (T0, T5, T10) to each well , T20, T30, T60, NFC60), T0 plate was added with cold acetonitrile stop solution, and then 80μL/well human liver microsomes were added to eight plates, and pre-incubated at 37°C for 10 minutes. Add 10 μL/well of 100 mM potassium phosphate buffer to the NCF60 plate and place it in a 37-degree water bath and incubate for 1 hour. Add 10μL/well of NADPH+UDPGA cofactor combination to other plates after the incubation, and incubate at different times according to the setting of each plate. After the incubation, 300 μL/well of cold acetonitrile was added to terminate the reaction, the plate was sealed and shaken for 10 minutes, and then centrifuged at 4000 rpm at 4 degrees for 20 minutes. Take 100μL/well of centrifugal supernatant and add it to a new plate to which 300μL/well of HPLC water has been added, mix well and submit to LC-MS/MS bioanalysis.
计算化合物与内标峰面积比值转化成剩余百分比求得供试品和对照化合物体外消除速率常数ke：％剩余量＝任意时间点对照品与内标的峰面积比值/0分钟时对照品与内标的峰面积比值×100％。Calculate the peak area ratio of the compound to the internal standard and convert it into the remaining percentage to obtain the in vitro elimination rate constant ke of the test product and the reference compound:% remaining = the peak area ratio of the reference product and the internal standard at any time point/the ratio of the reference product and the internal standard at 0 minutes Peak area ratio×100%.
CL int(mic)＝0.693/T 1/2/微粒体蛋白含量(孵育时微粒体蛋白浓度mg/mL) CL int(mic) = 0.693/T 1/2 /microsomal protein content (microsomal protein concentration mg/mL during incubation)
CL int(liver)＝CL int(mic)×肝脏中微粒体蛋白量(mg/g)×肝重体重比 CL int(liver) = CL int(mic) × the amount of microsomal protein in the liver (mg/g) × liver weight-to-weight ratio
根据充分搅拌模型(well stir model)，肝固有清除率和肝清除率可以通过下式换算：According to the well stir model, the intrinsic liver clearance rate and liver clearance rate can be converted by the following formula:
CL(Liver)＝(CL int(liver)×Qh)/(CL int(liver)+Qh) CL(Liver)=(CL int(liver) ×Qh)/(CL int(liver) +Qh)
化合物的肝微粒体清除率：Compound clearance rate of liver microsomes:
Figure PCTCN2021072517-appb-000144
Figure PCTCN2021072517-appb-000144
化合物编号Compound number 肝微粒体清除率(mL/min/Kg)Liver microsome clearance rate (mL/min/Kg)
ER10152ER10152 24twenty four
ER10067ER10067 22twenty two
ER10218ER10218 1818
ER10243ER10243 1212
ER10253ER10253 ＜8.6＜8.6

Claims (12)

  1. 一种具有式I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：A compound having the structure of Formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
    Figure PCTCN2021072517-appb-100001
    Figure PCTCN2021072517-appb-100001
    其中，in,
    n选自0-4的整数；n is selected from an integer of 0-4;
    环A基团选自3-8元环烷基、3-8元杂环烷基、5-8元芳环基、5-8元杂芳环基，或上述环被4-8元环烷基，4-8元杂环烷基、4-8元芳环基或4-8元杂芳环基稠合形成的稠合环基；优选，环A基团选自4-8元环烷基、4-8元杂环烷基、5-8元芳环基、5-8元杂芳环基，或上述环被4-8元环烷基，4-8元杂环烷基、4-8元芳环基或4-8元杂芳环基稠合形成的稠合环基；进一步优选，环A为吖丁啶基，吡咯烷基，哌啶基，咪唑基，C 4-7环烷基，喹嗪基，吡啶并噁嗪基； The ring A group is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-8 membered aromatic ring group, 5-8 membered heteroaromatic ring group, or the above ring is 4-8 membered cycloalkane Group, a 4-8 membered heterocycloalkyl group, a 4-8 membered aromatic ring group or a 4-8 membered heteroaromatic ring group fused to form a condensed ring group; preferably, the ring A group is selected from 4-8 membered cycloalkanes Group, 4-8 membered heterocycloalkyl group, 5-8 membered aromatic ring group, 5-8 membered heteroaromatic ring group, or the above ring is 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, 4 -8 membered aromatic ring group or 4-8 membered heteroaromatic ring group fused to form a condensed ring group; further preferably, ring A is azetidinyl, pyrrolidinyl, piperidinyl, imidazolyl, C 4-7 cycloalkane Group, quinazinyl, pyridooxazinyl;
    当n＝0时，环A通过环碳原子或环N原子与主体结构N原子连接，当n选自1-4的整数时，环A通过环碳原子或环氮原子通过(CH 2)n基团连接主体结构N原子； When n=0, ring A is connected to the N atom of the main structure through a ring carbon atom or a ring N atom. When n is selected from an integer of 1-4, ring A passes through (CH 2 )n through a ring carbon atom or a ring nitrogen atom. The group is connected to the N atom of the main structure;
    Z连接所在环任意取代位置，选自-OCH 2-，-O-，-N-，-S-，-SO 2-，-CO-或-CH(OH)-基团，当Z为-OCH 2-时，R 1Z形成R 1-OCH 2-结构；取代基R 1Z可为1或多个，位于所在环的任意取代位置；优选Z选自-O-，-N-，-S-，-SO 2-，-CO-或-CH(OH)-基团； Any substitution position of the ring where Z is connected, selected from -OCH 2 -, -O-, -N-, -S-, -SO 2 -, -CO- or -CH(OH)- group, when Z is -OCH When 2 -, R 1 Z forms a structure of R 1 -OCH 2 -; the substituent R 1 Z can be one or more, located at any substitution position of the ring; preferably Z is selected from -O-, -N-, -S -, -SO 2 -, -CO- or -CH(OH)- group;
    R 1为1或多个取代基，彼此独立选自C 1-6烷基，3-6元环烷基，4-6元杂环烷基，所述R 1被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基的取代基取代；优选R 1为1或多个取代基，彼此独立选自C 1-6烷基，4-6元环烷基，4-6元杂环烷基，所述R 1被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基的取代基取代； R 1 is one or more substituents, independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , C 1-6 alkyl or C 1-6 alkoxy substituents; preferably R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is substituted by a substituent selected from H, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
    R 2为1或多个取代基，位于所在环的任意取代位置，R 2彼此独立选自H、卤素，取代或未取代的C 1-6烷基，取代或未取代的C 1-6烷氧基、羟基或NO 2；所述取代是指所述基团进一步被C 1-6烷基、卤素、羟基或氨基取代； R 2 is one or more substituents, located at any substitution position of the ring, R 2 is independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkane Oxy, hydroxy or NO 2 ; the substitution means that the group is further substituted by C 1-6 alkyl, halogen, hydroxy or amino;
    R 3为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H，卤素，取代或未取代的C 1-6烷基，取代或未取代的3-6元环烷基，取代或未取代的C 1-6烷氧基、取代或未取代的C 1-6亚烷基羟基，羟基，NO 2，取代或未取代的5-7元芳环 羰基，取代或未取代的5-7元杂芳环羰基，取代或未取代的5-7元环烷羰基，取代或未取代的5-7元芳环羰基C 1-6亚烷基，取代或未取代的5-7元杂芳环羰基C 1-6亚烷基，取代或未取代的5-7元环烷羰基C 1-6亚烷基；所述取代是指所述基团进一步被H，卤素，C 1-6烷基，C 1-6烷氧基，氨基或羟基取代；优选R 3为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H，卤素，取代或未取代的C 1-6烷基，取代或未取代的3-6元环烷基，取代或未取代的C 1-6烷氧基、C 1-6亚烷基羟基、羟基、NO 2，所述取代是指所述基团进一步被C 1-6烷基、卤素、羟基或氨基取代；进一步优选R 3为1个或多个，彼此独立地选自H、卤素、羟基、取代或未取代的C 1- 6烷基、取代或未取代的C 1-6烷氧基、C 1-6亚烷基羟基，所述取代是指所述基团进一步被C 1-6烷基、卤素、羟基或氨基取代； R 3 is one or more substituents, located at any substitution position of the ring, independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl , Substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylene hydroxy, hydroxyl, NO 2 , substituted or unsubstituted 5-7 membered aromatic ring carbonyl, substituted or unsubstituted 5-7 membered heteroaromatic ring carbonyl, substituted or unsubstituted 5-7 membered cycloalkylcarbonyl, substituted or unsubstituted 5-7 membered aromatic ring carbonyl C 1-6 alkylene, substituted or unsubstituted 5- 7-membered heteroaromatic ring carbonyl C 1-6 alkylene, substituted or unsubstituted 5-7 membered cycloalkane carbonyl C 1-6 alkylene; the substitution means that the group is further replaced by H, halogen, C 1-6 alkyl, C 1-6 alkoxy, amino or hydroxy substituted; preferably R 3 is one or more substituents, located at any substitution position of the ring, independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, C 1-6 alkylene hydroxy, hydroxyl, NO 2 , the Substitution means that the group is further substituted by C 1-6 alkyl, halogen, hydroxy or amino; more preferably R 3 is one or more, independently selected from H, halogen, hydroxy, substituted or unsubstituted C 1- 6 alkyl group, a substituted or unsubstituted C 1-6 alkoxy, hydroxy C 1-6 alkylene group, a substituted means that the group is further substituted C 1-6 alkyl, halo, hydroxy Or amino substitution;
    R 4为1或多个取代基，位于所在环的任意取代位置，R 4彼此独立选自H、卤素，取代或未取代的C 1-6烷基，取代或未取代的C 1-6烷氧基、羟基或NO 2；所述取代是指所述基团进一步被C 1-6烷基、卤素、羟基或氨基取代。 R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkane Oxy, hydroxy, or NO 2 ; the substitution means that the group is further substituted with a C 1-6 alkyl, halogen, hydroxy, or amino group.
  2. 一种式IA结构化合物，或其药学可接受的盐，溶剂化物，或立体异构体：A compound of formula IA, or a pharmaceutically acceptable salt, solvate, or stereoisomer:
    Figure PCTCN2021072517-appb-100002
    Figure PCTCN2021072517-appb-100002
    其中，n选自0，1，2，或3；Wherein, n is selected from 0, 1, 2, or 3;
    环X为X所在环，X为-(CH 2)m-，m为0，1，2或3；从而X、氮与其它环碳原子形成4，5，6或7元氮杂环，X环通过环氮原子或环碳原子与主体结构的亚烷基链连接； Ring X is the ring where X is located, X is -(CH 2 )m-, and m is 0, 1, 2 or 3; thus X, nitrogen and other ring carbon atoms form a 4, 5, 6 or 7-membered nitrogen heterocycle, X The ring is connected to the alkylene chain of the main structure through a ring nitrogen atom or a ring carbon atom;
    Z连接所在环任意取代位置，选自-O-，-N-，-S-，-SO 2-，-CO-或-CH(OH)-基团； Any substitution position of the ring where Z is connected is selected from -O-, -N-, -S-, -SO 2 -, -CO- or -CH(OH)- group;
    R 1为1或多个取代基，彼此独立选自C 1-6烷基，4-6元环烷基，4-6元杂环烷基，所述R 1被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基的取代基取代； R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , Substituted by substituents of C 1-6 alkyl or C 1-6 alkoxy;
    R 2为1或多个取代基，位于所在环的任意取代位置，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 2 is one or more substituents, located at any substitution position of the ring, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
    R 3为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H，卤素， 羟基或NO 2，取代或未取代的C 1-6烷基，取代或未取代的3-6元环烷基，取代或未取代的C 1-6烷氧基；所述“取代”是指所述基团进一步被C 1-6烷基或卤素取代。 R 3 is one or more substituents, located at any substitution position of the ring, independently selected from H, halogen, hydroxy or NO 2 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3- 6-membered cycloalkyl, substituted or unsubstituted C 1-6 alkoxy; the "substituted" means that the group is further substituted with C 1-6 alkyl or halogen.
  3. 如权利要求2所述化合物，或其药学可接受的盐，溶剂化物，或立体异构体，其中：The compound of claim 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
    n为0，1或2，优选n为1；n is 0, 1 or 2, preferably n is 1;
    环X为4-6元含氮杂环；Ring X is a 4-6 membered nitrogen-containing heterocyclic ring;
    Z为-O-，-S-，-CO-，或-SO 2-基团； Z is -O-, -S-, -CO-, or -SO 2 -group;
    R 1为1或多个取代基，彼此独立选自C 1-6烷基，4-6元环烷基，4-6元杂环烷基，所述R 1被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基的取代基取代，优选R 1为甲基、异丁基、环丁烷、氧杂环戊烷、三氟乙基、或2-羟基异丁基； R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , C 1-6 alkyl or C 1-6 alkoxy substituent substituted, preferably R 1 is methyl, isobutyl, cyclobutane, oxolane, trifluoroethyl, or 2-hydroxy Isobutyl
    R 2为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H、卤素、羟基或NO 2，优选R 2为卤素，特别优选为氟； R 2 is one or more substituents, located at any substitution position of the ring, independently selected from H, halogen, hydroxyl or NO 2 , preferably R 2 is halogen, particularly preferably fluorine;
    R 3为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H，卤素，C 1-6烷基，卤代C 1-6烷基，3-6元环烷基，卤代3-6元环烷基，羟基或NO 2；优选C 1-6烷基，卤素，氟代C 1-6烷基，3-6元环烷基。 R 3 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-6 membered cycloalkyl, Halogenated 3-6 membered cycloalkyl, hydroxy or NO 2 ; preferably C 1-6 alkyl, halogen, fluoro C 1-6 alkyl, 3-6 membered cycloalkyl.
  4. 一种式IB结构化合物，或其药学可接受的盐，溶剂化物，或立体异构体：A compound of formula IB, or a pharmaceutically acceptable salt, solvate, or stereoisomer:
    Figure PCTCN2021072517-appb-100003
    Figure PCTCN2021072517-appb-100003
    其中，X所在的环X中，X为-(CH 2)m-，其中m为0，1，2或3，从而X、N与其它环碳原子形成4，5，6或7元氮杂环，所述杂环通过环C原子与主体结构N原子连接； Wherein, in the ring X where X is located, X is -(CH 2 )m-, where m is 0, 1, 2 or 3, so that X, N and other ring carbon atoms form 4, 5, 6 or 7-membered aza Ring, the heterocyclic ring is connected to the N atom of the main structure through the ring C atom;
    环B与X环稠合，环B为4-7元环烷基或4-7元杂环烷基；Ring B is condensed with ring X, and ring B is 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl;
    Z连接所在环任意取代位置，选自-O-，-N-，-S-，-SO 2-，-CO-或-CH(OH)-基团； Any substitution position of the ring where Z is connected is selected from -O-, -N-, -S-, -SO 2 -, -CO- or -CH(OH)- group;
    R 1为1或多个取代基，彼此独立选自C 1-6烷基，4-6元环烷基，4-6元杂环烷基，所述R 1被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基的取代基取代； R 1 is one or more substituents, independently selected from C 1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, said R 1 is selected from H, halogen, hydroxy , Substituted by substituents of C 1-6 alkyl or C 1-6 alkoxy;
    R 2为1或多个取代基，位于所在环的任意取代位置，R 2彼此独立选自H、卤素， C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 2 is one or more substituents, located at any substitution position of the ring, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ;
    R 3为1或多个取代基，位于所在环的任意取代位置，彼此独立选自H，卤素，C 1-6烷基，卤代C 1-6烷基，3-6元环烷基，羟基或NO 2；优选C 1-6烷基，卤素，氟代C 1-6烷基，3-6元环烷基； R 3 is 1 or more substituents, located at any substitution position of the ring, independently selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, 3-6 membered cycloalkyl, Hydroxy or NO 2 ; preferably C 1-6 alkyl, halogen, fluoro C 1-6 alkyl, 3-6 membered cycloalkyl;
    优选环X与环B的稠合环选自如下基团：Preferably, the fused ring of ring X and ring B is selected from the following groups:
    Figure PCTCN2021072517-appb-100004
    Figure PCTCN2021072517-appb-100004
  5. 一种式IC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，A compound of the structure of formula IC, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
    Figure PCTCN2021072517-appb-100005
    Figure PCTCN2021072517-appb-100005
    其中，in,
    p，q分别选自0-4的整数，p and q are selected from integers from 0 to 4 respectively,
    Y为碳原子或杂原子，其中杂原子选自O，S，N原子，Y is a carbon atom or a heteroatom, wherein the heteroatom is selected from O, S, N atoms,
    环Y即Y原子所在环，通过环碳原子或者环N原子与化合物主体结构连接，Ring Y is the ring where the Y atom is located, and is connected to the main structure of the compound through a ring carbon atom or a ring N atom,
    取代基R 1OCH 2-为1或多个，位于所在环的任意取代位置，其中，R 1彼此独立选自C 1-6烷基，3-6元环烷基，所述R 1进一步被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基取代；优选，R 1OCH 2-为1个，并位于环的对位取代位置； Substituents R 1 OCH 2 -are 1 or more, located at any substitution position of the ring where R 1 is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, and said R 1 is further Substitution selected from H, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy; preferably, R 1 OCH 2 -is one and is located at the para-substitution position of the ring;
    R 2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2； R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ;
    R 3为1或多个取代基，位于所在环的任意取代位置，R 3彼此独立选自H、卤素， C 1-6烷基，C 1-6烷氧基，羟基，NO 2，5-7元芳环羰基，5-7元杂芳环羰基或5-7元环烷羰基，5-7元芳环羰基C 1-6亚烷基，5-7元杂芳环羰基C 1-6亚烷基或5-7元环烷羰基C 1-6亚烷基，R 3进一步可被H，卤素，C 1-6烷基，C 1-6烷氧基，或羟基取代；优选R 3在Y位置取代； R 3 is one or more substituents, located at any substitution position of the ring, R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, NO 2 , 5- 7-membered aromatic ring carbonyl, 5-7 membered heteroaromatic ring carbonyl or 5-7 membered cycloalkanecarbonyl, 5-7 membered aromatic ring carbonyl C 1-6 alkylene, 5-7 membered heteroaromatic ring carbonyl C 1-6 Alkylene or 5-7 membered cycloalkylcarbonyl C 1-6 alkylene, R 3 may be further substituted by H, halogen, C 1-6 alkyl, C 1-6 alkoxy, or hydroxy; preferably R 3 Replace at Y position;
    R 4为1或多个取代基，位于所在环的任意取代位置，R 4彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2。 R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
  6. 如权利要求5所述的式IC化合物，或其药学可接受的盐，溶剂化物，或立体异构体，其特征在于，p选自1，2或3，使Y所在环对应为4，5或6元环，The compound of formula IC according to claim 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is selected from 1, 2 or 3, so that the ring of Y corresponds to 4, 5. Or a 6-membered ring,
    q选自0，1或2，q is selected from 0, 1 or 2,
    Y为C或N原子，Y is a C or N atom,
    取代基R 1OCH 2-位于所在环的任意取代位置，R 1彼此独立选自C 1-6烷基，3-6元环烷基，所述R 1进一步被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基取代；优选R 1OCH 2-位于环的对位取代位置； The substituent R 1 OCH 2 -is located at any substitution position of the ring, R 1 is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, and the R 1 is further selected from H, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy substituted; preferably R 1 OCH 2 -is located at the para-substitution position of the ring;
    R 2为1或多个取代基，位于所在环的任意取代位置，优选为2位和/或4位取代，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2；优选R 2为氟； R 2 is one or more substituents, located at any substitution position of the ring, preferably substituted at the 2-position and/or 4-position, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 Alkoxy, hydroxyl or NO 2 ; preferably R 2 is fluorine;
    R 3为1或多个取代基，位于所在环的任意取代位置，R 3彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基，羟基，NO 2，5-7元芳环羰基C 1-6亚烷基，5-7元杂芳环羰基C 1-6亚烷基或5-7元环烷羰基C 1-6亚烷基，R 3进一步可被H，卤素，C 1-6烷基，C 1-6烷氧基，或羟基取代； R 3 is one or more substituents, located at any substitution position of the ring, R 3 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, NO 2 , 5- 7-membered aromatic ring carbonyl C 1-6 alkylene group, 5-7 membered heteroaromatic ring carbonyl C 1-6 alkylene group or 5-7 membered cycloalkane carbonyl C 1-6 alkylene group, R 3 may be further replaced by H , Halogen, C 1-6 alkyl, C 1-6 alkoxy, or hydroxy substituted;
    R 4为1或多个取代基，位于所在环的任意取代位置，R 4彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2。 R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
  7. 如权利要求5或6所述的式IC化合物，或其药学可接受的盐，溶剂化物，或立体异构体，其特征在于，The compound of formula IC according to claim 5 or 6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, characterized in that:
    q＝0或1，q=0 or 1,
    p选自1，2或3，使Y所在环对应为4，5或6元环，p is selected from 1, 2 or 3, so that the ring where Y is located corresponds to a 4, 5 or 6-membered ring,
    Y为N原子，Y is N atom,
    取代基R 1OCH 2-位于所在环的任意取代位置，优选为对位取代位置，其中，R 1彼此独立选自C 1-6烷基，3-6元环烷基，所述R 1进一步被选自H、卤素、羟基、C 1-6烷基或C 1-6烷氧基取代； The substituent R 1 OCH 2 -is located at any substitution position of the ring, preferably a para position, wherein R 1 is independently selected from C 1-6 alkyl, 3-6 membered cycloalkyl, and the R 1 further Substitution is selected from H, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
    R 2为1或多个取代基，R 2彼此独立选自H、卤素，C 1-6烷基，C 1-6烷氧基、羟基或NO 2；优选为2位和/或4位取代位置； R 2 is one or more substituents, R 2 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 ; preferably substituted at the 2-position and/or 4-position Location;
    R 3在Y位取代，R 3选自H、卤素，C 1-6烷基，C 1-6烷氧基，羟基或苯基羰基C 1-6亚烷基； R 3 is substituted at the Y position, and R 3 is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy or phenylcarbonyl C 1-6 alkylene;
    R 4为1或多个取代基，位于所在环的任意取代位置，R 4彼此独立选自H、卤素， C 1-6烷基，C 1-6烷氧基、羟基或NO 2。 R 4 is one or more substituents, located at any substitution position of the ring, R 4 is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl or NO 2 .
  8. 如权利要求1-7任一项所述的化合物，或其药学可接受的盐，溶剂化物，或立体异构体，选自以下具体化合物，或其药学可接受的盐，溶剂化物，或立体异构体：The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the following specific compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof isomer:
    1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(9-甲基-3-氧杂-9-氮杂-二环[3.3.1]壬-7-基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(9-methyl-3-oxa-9-aza-bicyclo[3.3. 1] Non-7-yl)-urea,
    1-(3-(吖丁啶-1-基)-丙基)-1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-脲，1-(3-(azetidine-1-yl)-propyl)-1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-urea,
    1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(1-甲基-吡咯烷-3-基甲基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(1-methyl-pyrrolidin-3-ylmethyl)-urea,
    1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(1-甲基-吖丁啶-3-基甲基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(1-methyl-azetidine-3-ylmethyl)-urea,
    1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(八氢-喹嗪-2-基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(octahydro-quinazin-2-yl)-urea,
    1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(八氢-吡啶并[2，1-c][1，4]噁嗪-8-基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(octahydro-pyrido[2,1-c][1,4]oxazine- 8-yl)-urea,
    1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-1-(2-(吡咯烷-1-基)-乙基)-脲，1-(4-Fluoro-benzyl)-3-(4-isobutoxy-benzyl)-1-(2-(pyrrolidin-1-yl)-ethyl)-urea,
    3-(4-异丁氧基-苯甲基)-1-(4-氟-苯甲基)-1-[2-(1-甲基-1H-咪唑-4-基)-乙基]-脲，3-(4-isobutoxy-benzyl)-1-(4-fluoro-benzyl)-1-[2-(1-methyl-1H-imidazol-4-yl)-ethyl] -Urea,
    3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(哌啶-1-基)乙基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(piperidin-1-yl)ethyl)urea,
    3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
    3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-3-基)甲基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-3-yl)methyl)urea,
    3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-(2-氟乙基)吡咯烷-3-基)甲基)脲，3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-(2-fluoroethyl)pyrrolidin-3-yl)methyl)urea,
    3-(4-环丁氧基苯甲基)-1-((1-乙基吡咯烷-3-基)甲基)-1-(4-氟苯甲基)脲，3-(4-Cyclobutoxybenzyl)-1-((1-ethylpyrrolidin-3-yl)methyl)-1-(4-fluorobenzyl)urea,
    3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-2-基)甲基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-2-yl)methyl)urea,
    3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(吡咯烷-1-基)乙基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(pyrrolidin-1-yl)ethyl)urea,
    3-(4-环丁氧基苯甲基)-1-((1-环丙基吡咯烷-3-基)甲基)-1-(4-氟苯甲基)脲，3-(4-Cyclobutoxybenzyl)-1-((1-cyclopropylpyrrolidin-3-yl)methyl)-1-(4-fluorobenzyl)urea,
    3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(1-甲基吡咯烷-2-基)乙基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(1-methylpyrrolidin-2-yl)ethyl)urea,
    3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-(2-(1-甲基哌啶-2-基)乙基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-(2-(1-methylpiperidin-2-yl)ethyl)urea,
    3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)urea,
    3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
    (S)-3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(S)-3-(4-Cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
    (R)-3-(4-环丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(R)-3-(4-cyclobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
    3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，3-(4-cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
    (S)-3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(S)-3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea,
    (R)-3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(R)-3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea,
    1-(4-氟苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)-3-(4-(3-甲基丁酰)苯甲基)脲，1-(4-fluorobenzyl)-1-((1-methylazetidine-3-yl)methyl)-3-(4-(3-methylbutyryl)benzyl)urea,
    (S)-1-(4-氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(S)-1-(4-fluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea,
    (R)-1-(4-氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(R)-1-(4-fluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-((1-methylpyrrolidin-2-yl)methyl ) Urea,
    (S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，(S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) Yl)benzyl)urea,
    (R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基) 脲，(R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) Yl)benzyl)urea,
    (S)-1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(S)-1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
    (R)-1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吡咯烷-2-基)甲基)脲，(R)-1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylpyrrolidin-2-yl)methyl)urea,
    1-(4-氟苯甲基)-3-(4-异丁氧基苯甲基)-1-((1-甲基吖丁啶-3-基)甲基)脲，1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-((1-methylazetidine-3-yl)methyl)urea,
    1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-异丁氧基苯甲基)脲，1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-isobutoxybenzyl)urea,
    1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy)benzyl Base) urea,
    3-(4-环丁氧基-3-氟苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
    3-(3-氟-4-甲氧苄基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(3-fluoro-4-methoxybenzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
    (R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-异丁氧基苯甲基)脲，(R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-isobutoxybenzyl)urea,
    (S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-异丁氧基苯甲基)脲，(S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-isobutoxybenzyl)urea,
    (R)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，(R)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) Yl)benzyl)urea,
    (S)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，(S)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) Yl)benzyl)urea,
    3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(3-fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
    3-(4-环丁氧基-3-氟苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-Cyclobutoxy-3-fluorobenzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl) Urea,
    1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，1-(2,4-Difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)-3-(4-(2,2,2-trifluoroethoxy) )Benzyl)urea,
    3-(色烷-6-基甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(Chroman-6-ylmethyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
    1-(2，4-二氟苯甲基)-3-(4-(3-甲基丁酰)苯甲基)-1-(1-甲基哌啶-4-基)脲，1-(2,4-Difluorobenzyl)-3-(4-(3-methylbutyryl)benzyl)-1-(1-methylpiperidin-4-yl)urea,
    (R)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，(R)-1-(2,4-Difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-tri Fluoroethoxy)benzyl)urea,
    (S)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)-3-(4-(2，2，2-三氟乙氧基)苯甲基)脲，(S)-1-(2,4-Difluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)-3-(4-(2,2,2-tri Fluoroethoxy)benzyl)urea,
    (R)-1-(2，4-二氟苯甲基)-3-(3-氟-4-甲氧苄基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-methoxybenzyl)-1-((1-methylpyrrolidin-3-yl)methyl ) Urea,
    (R)-3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-3-(3-fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea,
    (S)-3-(3-氟-4-甲氧苄基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(S)-3-(3-fluoro-4-methoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidin-3-yl)methyl)urea,
    3-(3-氟-4-异丁氧基苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(3-fluoro-4-isobutoxybenzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
    (S)-1-(2，4-二氟苯甲基)-3-(3-氟-4-甲氧苄基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(S)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-methoxybenzyl)-1-((1-methylpyrrolidin-3-yl)methyl ) Urea,
    3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(3-Fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidine-4 -Base) methyl) urea,
    1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-((1-methylpiper (Pyridin-4-yl)methyl)urea,
    (R)-1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-((1 -Methylpyrrolidin-3-yl)methyl)urea,
    (S)-1-(2，4-二氟苯甲基)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-((1-甲基吡咯烷- 3-基)甲基)脲，(S)-1-(2,4-Difluorobenzyl)-3-(3-fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-((1 -Methylpyrrolidine-3-yl)methyl)urea,
    (S)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(S)-3-(3-Fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methyl Pyrrolidin-3-yl)methyl)urea,
    (R)-3-(3-氟-4-(2，2，2-三氟乙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-3-(3-Fluoro-4-(2,2,2-trifluoroethoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methyl Pyrrolidin-3-yl)methyl)urea,
    3-(4-(2-羟基2-甲基丙氧基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-(2-hydroxy-2-methylpropoxy)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl )Methyl)urea,
    3-(4-(2-羟基2-甲基丙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-(2-hydroxy-2-methylpropoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl ) Urea,
    (R)-3-(4-(2-羟基2-甲基丙氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-3-(4-(2-Hydroxy-2-methylpropoxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidine-3- Yl)methyl)urea,
    3-(4-((四氢呋喃-3-基)-氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-(4-((tetrahydrofuran-3-yl)-oxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl ) Urea,
    (R)-3-(4-((四氢呋喃-3-基)-氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(R)-3-(4-((tetrahydrofuran-3-yl)-oxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidine-3- Yl)methyl)urea,
    (S)-3-(4-(四氢呋喃-3-基)-氧基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(S)-3-(4-(Tetrahydrofuran-3-yl)-oxy)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpyrrolidine- 3-yl)methyl)urea,
    (S)-3-(4-((四氢呋喃-3-基)-氧基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基吡咯烷-3-基)甲基)脲，(S)-3-(4-((Tetrahydrofuran-3-yl)-oxy)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpyrrolidine-3- Yl)methyl)urea,
    1-(2-(吖丁啶-1-基)-乙基)-1-(4-氟-苯甲基)-3-(4-异丁氧基-苯甲基)-脲，1-(2-(azetidine-1-yl)-ethyl)-1-(4-fluoro-benzyl)-3-(4-isobutoxy-benzyl)-urea,
    3-(4-异丙氧基甲基苯甲基)-1-(4-氟苯甲基)-1-(1-甲基哌啶-4-基)脲，3-(4-isopropoxymethylbenzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea,
    3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea,
    3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-(((R)-1-(1-甲基吡咯烷-3-基))甲基)脲，3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-(((R)-1-(1-methylpyrrolidin-3-yl )) Methyl) urea,
    3-((4-异丙氧基甲基)苯甲基)-1-(4-氟苯甲基)-1-(((S)-1-(1-甲基吡咯烷-3-基))甲基)脲，3-((4-isopropoxymethyl)benzyl)-1-(4-fluorobenzyl)-1-(((S)-1-(1-methylpyrrolidin-3-yl )) Methyl) urea,
    3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea ,
    3-((4-乙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-((4-ethoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl)urea ,
    3-((4-环丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-((4-Cyclopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl) Urea,
    3-((4-异丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-((1-甲基哌啶-4-基)甲基)脲，3-((4-isopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-((1-methylpiperidin-4-yl)methyl) Urea,
    3-(4-异丙氧基甲基苯甲基)-1-(2，4-二氟苯甲基)-1-(1-甲基哌啶-4-基)脲，3-(4-isopropoxymethylbenzyl)-1-(2,4-difluorobenzyl)-1-(1-methylpiperidin-4-yl)urea,
    3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-甲基)脲，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidine-4-methyl)urea,
    3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(2-苯基羰基乙基)-哌啶-4-甲基)脲，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N-(2-phenylcarbonylethyl)-piperidine -4-methyl)urea,
    3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(苯基羰基甲基)-哌啶-4-甲基)脲，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N-(phenylcarbonylmethyl)-piperidine-4 -Methyl)urea,
    3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-基)脲，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidin-4-yl)urea,
    3-((4-甲氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-N-(苯基羰基甲基)-哌啶-4-基)脲，或，3-((4-methoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-N-(phenylcarbonylmethyl)-piperidine-4 -Based) urea, or,
    3-((4-异丙氧基甲基)苯甲基)-1-(2，4-二氟苯甲基)-1-(1-哌啶-4-基)脲。3-((4-isopropoxymethyl)benzyl)-1-(2,4-difluorobenzyl)-1-(1-piperidin-4-yl)urea.
  9. 权利要求1-8任一项所述的化合物，或其药学可接受的盐，溶剂化物，或立体异构体的制备方法，其特征在于：The method for preparing the compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, characterized in that:
    步骤1、式A结构的异氰酸化合物与式B氨基化合物按如下反应式反应，合成得到式I化合物，Step 1. The isocyanate compound of formula A and the amino compound of formula B are reacted according to the following reaction formula to synthesize the compound of formula I.
    Figure PCTCN2021072517-appb-100006
    Figure PCTCN2021072517-appb-100006
    步骤2、任选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. Optionally, according to the needs of the target product, functional group modification is performed on the compound of formula I to convert it into the target product, or into a pharmaceutically acceptable salt or precursor compound of the compound.
  10. 一种药物组合物，其特征在于包含权利要求1-8任一化合物或其药学上可接受的盐，溶剂化物，或立体异构体。A pharmaceutical composition characterized by comprising any compound of claims 1-8 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
    优选，所述药物组合物进一步包含药学上可接受的载体。Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
    优选，所述药物组合物进一步包含第二种治疗剂，所述第二种治疗剂是其他的治疗5HT2A受体活性介导的相关疾病的药物。Preferably, the pharmaceutical composition further comprises a second therapeutic agent, and the second therapeutic agent is another drug for treating related diseases mediated by 5HT2A receptor activity.
    优选，所述第二种治疗剂选自：苯二氮
    Figure PCTCN2021072517-appb-100007
    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、左旋多巴、溴隐亭、硫丙麦角林、丙炔***、金刚烷胺和利血平。     Preferably, the second therapeutic agent is selected from: benzodiazepine
    Figure PCTCN2021072517-appb-100007
    Class, barbiturates, chloral hydrate, buspirone, phenothiazines, thioxanthenes, butyrylbenzenes, clozapine, risperidone, tricyclic antidepressants, heterocyclics Antidepressants, selective 5-HT reuptake inhibitors, monoamine oxidase inhibitors, ketamine, mirtazapine, levodopa, bromocriptine, thipropergoline, propargyl amphetamine, amantadine, and reserpine.
  11. 权利要求1-8任一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应用。The use of a compound or a pharmaceutically acceptable salt, solvate, or stereoisomer of any one of claims 1-8 in the preparation of a medicament for the treatment of related diseases mediated by 5HT2A receptor activity.
    优选，所述5HT2A受体活性介导的相关疾病是中枢神经***疾病。Preferably, the related disease mediated by the 5HT2A receptor activity is a central nervous system disease.
    优选，所述中枢神经***疾病是精神疾病、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 a mental disease, a central nervous system degenerative disease, a mental disorder symptom associated with or concurrent with a central nervous system degenerative disease, and a negative symptom of a mental disease.
    优选，所述精神疾病是抑郁症、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 depression, anxiety, mania, schizophrenia, schizoaffective disorder, bipolar disorder, insomnia, autism.
    优选，所述中枢神经***退行性疾病是阿尔兹海默症、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 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是情感障碍、语言功能减退、幻觉、兴趣缺失。Preferably, the mental disorder symptoms related to or concurrent with degenerative diseases of the central nervous system, and the negative symptoms of mental diseases are affective disorder, decreased language function, hallucinations, and loss of interest.
  12. 治疗5HT2A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权利要求1-8任一化合物，或其药学上可接受的盐，溶剂化物，或立体异构体。A method for treating related diseases mediated by 5HT2A receptor activity, characterized by administering a therapeutically effective amount of any one of the compounds of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereotaxic compound of any one of claims 1-8 to a patient in need isomer.
    优选，所述方法进一步包括，对有需要的患者给予其他的治疗5HT2A受体活性介导的相关疾病的药物；优选，所述其他的治疗剂选自：苯二氮
    Figure PCTCN2021072517-appb-100008
    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、左旋多巴、溴隐亭、硫丙麦角林、丙炔***、金刚烷胺和利血平。     Preferably, the method further includes administering to the patient in need other drugs for treating related diseases mediated by 5HT2A receptor activity; preferably, the other therapeutic agent is selected from: benzodiazepines
    Figure PCTCN2021072517-appb-100008
    Class, barbiturates, chloral hydrate, buspirone, phenothiazines, thioxanthenes, butyrylbenzenes, clozapine, risperidone, tricyclic antidepressants, heterocyclics Antidepressants, selective 5-HT reuptake inhibitors, monoamine oxidase inhibitors, ketamine, mirtazapine, levodopa, bromocriptine, thipropergoline, propargyl amphetamine, amantadine, and reserpine.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009039461A2 (en) * 2007-09-21 2009-03-26 Acadia Pharmaceuticals, Inc. N-substituted piperidine derivatives as serotonin receptor agents
CN101780080A (en) * 2003-01-16 2010-07-21 阿卡蒂亚药品公司 Selective serotonin 2a/2c receptor inverse agonists as therapeutics for neurodegenerative diseases
WO2010111353A1 (en) * 2009-03-25 2010-09-30 Acadia Pharmaceuticals, Inc. N-substituted piperidine derivatives as serotonin receptor agents
CN109111385A (en) * 2017-06-23 2019-01-01 上海翰森生物医药科技有限公司 5-HT2AAcceptor inhibitor and its preparation method and application
WO2019040107A1 (en) * 2017-08-21 2019-02-28 Acadia Pharmaceuticals Inc. Compounds, salts thereof and methods for treatment of diseases
WO2019040106A2 (en) * 2017-08-21 2019-02-28 Acadia Pharmaceuticals Inc. Compounds, salts thereof and methods for treatment of diseases

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101780080A (en) * 2003-01-16 2010-07-21 阿卡蒂亚药品公司 Selective serotonin 2a/2c receptor inverse agonists as therapeutics for neurodegenerative diseases
WO2009039461A2 (en) * 2007-09-21 2009-03-26 Acadia Pharmaceuticals, Inc. N-substituted piperidine derivatives as serotonin receptor agents
WO2010111353A1 (en) * 2009-03-25 2010-09-30 Acadia Pharmaceuticals, Inc. N-substituted piperidine derivatives as serotonin receptor agents
CN109111385A (en) * 2017-06-23 2019-01-01 上海翰森生物医药科技有限公司 5-HT2AAcceptor inhibitor and its preparation method and application
WO2019040107A1 (en) * 2017-08-21 2019-02-28 Acadia Pharmaceuticals Inc. Compounds, salts thereof and methods for treatment of diseases
WO2019040106A2 (en) * 2017-08-21 2019-02-28 Acadia Pharmaceuticals Inc. Compounds, salts thereof and methods for treatment of diseases

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