WO2021088920A1 - 苯并噻吩类衍生物调节剂、其制备方法和应用 - Google Patents

苯并噻吩类衍生物调节剂、其制备方法和应用 Download PDF

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WO2021088920A1
WO2021088920A1 PCT/CN2020/126735 CN2020126735W WO2021088920A1 WO 2021088920 A1 WO2021088920 A1 WO 2021088920A1 CN 2020126735 W CN2020126735 W CN 2020126735W WO 2021088920 A1 WO2021088920 A1 WO 2021088920A1
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group
substituted
alkyl
unsubstituted
alkoxy
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PCT/CN2020/126735
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English (en)
French (fr)
Inventor
苏熠东
李松
陈晓坡
汪军
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Application filed by Jiangsu Hansoh Pharmaceutical Group Co Ltd, Shanghai Hansoh Biomedical Co Ltd filed Critical Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority to KR1020227018220A priority Critical patent/KR102947882B1/ko
Priority to US17/755,711 priority patent/US12459931B2/en
Priority to EP20884416.7A priority patent/EP4056568A4/en
Priority to JP2022525866A priority patent/JP7810643B2/ja
Priority to CN202080006349.XA priority patent/CN113166135B/zh
Publication of WO2021088920A1 publication Critical patent/WO2021088920A1/zh
Anticipated expiration legal-status Critical
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a nitrogen-containing ring derivative regulator, and a preparation method and application thereof.
  • Dopamine D3 receptor is a member of the G protein-coupled receptor family. It is a subtype of dopamine receptors. It belongs to the same D2-like inhibitory receptors as dopamine D2 and D4 receptors. After binding to DA, it decreases by inhibiting G-protein. cAMP level. D3 receptors are mainly distributed in the midbrain limbic system, especially the nucleus accumbens, olfactory nodules and calleja islands that are not related to motor function. Highly active D3 receptor modulators may have good anti-schizophrenia activities. D3 receptors are closely related to mood, cognition, mentality, addiction, etc., and can better improve the negative symptoms of patients with schizophrenia. D3 receptor may play a regulatory role on cognition by regulating the release of acetylcholine and regulating glutamate receptors, and partial activation of D3 receptors can improve cognition.
  • the serotonin 2A receptor (5-HT2A) receptor is a member of the G protein-coupled receptor family and is a major excitatory receptor subtype of the 5-HT receptor. It is distributed in the center and periphery. Mental, emotional, learning and memory are closely related. Highly active 5-HT2A receptor inhibitors have a significant anti-schizophrenia effect and can reduce the side effects of the extrapyramidal tract.
  • Schizophrenia is a kind of mental illness with the highest prevalence. It has a slow course and is prone to recurring, aggravating or worsening. It causes a serious burden of disease and adverse consequences for patients and their families. Psychiatric patients will have positive symptoms such as delusions, hallucinations, thoughts, language and behavior disorders, lack of emotion and expression, poor speech, lack of pleasure and other negative symptoms, as well as symptoms such as cognitive impairment.
  • anti-schizophrenia drugs Although the research and development and clinical application of anti-schizophrenia drugs have been greatly developed in the past few decades, traditional antipsychotics (first generation) (haloperidol, droperidol, thioridazine, etc.) and Atypical antipsychotics (second generation) (clozapine, risperidone, olanzapine, aripiprazole, etc.) are all effective in treating positive symptoms, but are not ideal for improving negative symptoms and cognitive impairment, so There is an urgent need to develop anti-schizophrenia drugs that can improve not only positive symptoms, but also negative symptoms and cognitive impairment. Highly active dopamine D3 receptor modulators can improve the negative symptoms, positive symptoms and cognitive impairment of patients with schizophrenia, and have no side effects such as extrapyramidal tract and weight gain of the first and second generation antipsychotic drugs .
  • D3 receptor antagonists or partial agonists have a good effect on improving the positive symptoms, negative symptoms and cognitive dysfunction of schizophrenia.
  • International applications WO2007093540A, WO2009013212A2, WO2010031735A1 and WO2012117001A1 report D3 receptor and 5-HT2A dual modulator compounds, but most of the compounds have binding activities Ki of D3 receptor and 5-HT2A above 10 nM;
  • Jiangsu Hengyi Patent WO2014086098A1 reported a selective inhibitor of D3, but there was no study on the binding activity of 5-HT2A; the D3 antagonist Cariprazine developed by Gedeon Richter was listed in 2015 and applied for an international patent WO2005012266A1.
  • Cariprazine has a strong D3 receptor Agonist activity, used in the treatment of schizophrenia has a significant advantage over existing drugs for negative symptoms, but Cariprazine has a weaker inhibitory activity on 5-HT2A receptors, resulting in a more serious extrapyramidal system (ESP) side effect. Therefore, there is an urgent need to develop D3 receptor modulators with high activity and optimized 5-HT2A binding activity to reduce extrapyramidal side effects and improve the effect of negative symptoms of schizophrenia and cognitive improvement.
  • ESP extrapyramidal system
  • the object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:
  • M is selected from N or CR aa ;
  • Ring A is selected from aryl or heteroaryl
  • two R 2 on the same carbon atom or different carbon atoms are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkyl, heterocyclyl, aryl and heteroaryl group Group, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, Thio, nitro, cyano, hydroxy, ester, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted Or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted
  • two R 3 on the same carbon atom or different carbon atoms are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, the cycloalkyl, heterocyclyl, aryl and heteroaryl group Group, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, Thio, nitro, cyano, hydroxy, ester, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted Or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted
  • R 4 and R 5 are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl , Cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 C(O)R aa , -C(O)(CH 2 ) n1 R aa , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 S( O) m1 NR aa R bb , -(CH 2 ) n
  • R 4 and R 5 are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from hydrogen , Deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano , Hydroxy, ester, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted Or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubsti
  • R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro , Hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, halogen , Hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano
  • R aa and R bb are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from hydrogen , Deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano , Hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted Is substituted by one or more substituents in the heterocyclic group, substitute
  • n 0, 1 or 2;
  • x 0, 1, 2, 3 or 4;
  • y is 0, 1, 2, 3 or 4;
  • z 0, 1, 2, 3 or 4;
  • n1 0, 1 or 2;
  • n1 0, 1, 2, 3, 4 or 5;
  • ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl, preferably benzene Group, 5-6 membered monocyclic heteroaryl group, benzo 5-6 membered heteroaryl group or benzo 3-6 membered heterocyclic group.
  • the present invention also provides a preferred solution.
  • R 4 is selected from hydrogen or C 1-6 alkyl, preferably hydrogen or methyl;
  • R 4 and R 5 are linked to form a 3-8 membered heterocyclic group or 5-14 membered heteroaryl group.
  • the 3-8 membered heterocyclic group and 5-14 membered heteroaryl group are optionally further selected From hydrogen, C 1-6 alkyl, halogen, amino, oxo, thio, cyano, hydroxy, C 3-8 alkoxy, C 3-8 haloalkoxy, C 3-8 hydroxyalkyl , -C(O)R cc and -C(O)NR cc R dd are substituted by one or more substituents;
  • heterocyclic group or heteroaryl group is selected from heterocyclic groups or heteroaryl groups containing 1-2 nitrogen, oxygen or sulfur atoms;
  • R aa and R bb are each independently selected from hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycle Group, C 6-14 aryl group or 5-14 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 3-8 cycloalkane Group, 3-8 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group, optionally further selected from halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1 One or more substitutions of -6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl Substituted by
  • the R aa and R bb are each independently selected from hydrogen, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3 -6 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group, said amino group, C 1-3 alkyl group, C 1-3 haloalkyl group, C 1-3 alkoxy group, C 3-6 ring Alkyl, 3-6 membered heterocyclic group, phenyl and 5-6 membered heteroaryl, optionally further selected from halogen, hydroxy, cyano, oxo, C 1-3 alkyl, C 1-3 haloalkane Substituted by one or more substituents in the group, C 1-3 alkoxy group, C 3-6 cycloalkyl group, 3-6 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group;
  • R cc and R dd are each independently selected from hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycle Group, C 6-14 aryl group or 5-14 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 3-8 cycloalkane Group, 3-8 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group, optionally further selected from hydrogen, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, Substituted by one or more substituents in C 1-6 haloalkyl and C 1-6 alkoxy; and
  • n1 0, 1, 2, or 3.
  • the present invention also provides a preferred solution.
  • the compound, its stereoisomer or pharmaceutically acceptable salt thereof, the general formula (IV) is as shown in the general formula (IV-A):
  • R 2 is selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • two R 2s on the same carbon atom or different carbon atoms are linked to form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group, the C 3-8 cycloalkyl group and a 3-8 membered Heterocyclic group, optionally further selected from deuterium atom, C 1-6 alkyl, halogen, amino, oxo, thio, cyano, hydroxyl, C 3-8 alkoxy, C 3-8 haloalkane Substituted by one or more substituents in the oxy group and C 3-8 hydroxyalkyl group;
  • R 3 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy, cyano, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 4 is selected from hydrogen or C 1-6 alkyl
  • R 4 and R 5 are linked to form a 3-8 membered heterocyclic group or 5-14 membered heteroaryl group, optionally further selected from C 1-6 alkyl, halogen, amino, oxo, thio , Cyano, hydroxyl, C 3-8 alkoxy, C 3-8 haloalkoxy, C 3-8 hydroxyalkyl, one of -C(O)R cc and -C(O)NR cc R dd Or substituted by multiple substituents;
  • R aa and R bb are each independently selected from hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycle Group, C 6-14 aryl group or 5-14 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 3-8 cycloalkane Group, 3-8 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group, optionally further selected from halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C One or more of 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl Substituted by substituents,
  • R aa and R bb and adjacent nitrogen atoms form a 4-10 membered heterocyclic group, optionally further selected from halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 Substituted by one or more substituents in haloalkyl, C 1-6 alkoxy, and C 1-6 hydroxyalkyl;
  • R cc and R dd are each independently selected from hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycle Group, C 6-14 aryl group or 5-14 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 3-8 cycloalkane Group, 3-8 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group, optionally further selected from halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C Substituted by one or more substituents in 1-6 haloalkyl and C 1-6 alkoxy;
  • n 1 or 2;
  • n1 0, 1, 2, or 3.
  • the present invention also provides a preferred solution.
  • the compound, its stereoisomers or pharmaceutically acceptable salts thereof, the general formula (IV-A) is as shown in the general formula (IX-B):
  • R 2 is selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • R 3 is selected from hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 4 is selected from hydrogen or C 1-6 alkyl
  • R 4 and R 5 are linked to form a 3-8 membered heterocyclic group or 5-10 membered heteroaryl group, optionally further selected from C 1-6 alkyl, halogen, amino, oxo, thio , Cyano, hydroxy, C 3-8 alkoxy, C 3-8 haloalkoxy, C 3-8 hydroxyalkyl substituted by one or more substituents;
  • R aa and R bb are each independently selected from hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycle Group, C 6-14 aryl group or 5-10 membered heteroaryl group containing 1-2 selected from N, O or S, optionally further selected from halogen, hydroxyl, cyano, oxo, C 1- 6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group Is substituted by one or more substituents,
  • R aa and R bb and adjacent nitrogen atoms form a 4-6 membered heterocyclic group, optionally further selected from halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 One or more substituents in haloalkyl, C 1-6 alkoxy, and C 1-6 hydroxyalkyl are substituted.
  • the present invention also provides a preferred solution, the compound represented by general formula (IX-B), its stereoisomers or pharmaceutically acceptable salts thereof, wherein:
  • R 2 is selected from hydrogen, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl;
  • R 3 is selected from hydrogen, halogen or C 1-3 alkyl
  • R 4 is selected from hydrogen or C 1-3 alkyl
  • R 5 is selected from -(CH 2 ) n1 R aa , -C(O)R aa , -C(O)NR aa R bb , -S(O) 2 R aa or -S(O) m1 NR aa R bb ;
  • R aa and R bb are each independently selected from hydrogen, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl or containing 1-2 selected A 5-6 membered heteroaryl group from N, O or S, optionally further selected from halogen, hydroxyl, cyano, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 Substituted by one or more substituents in alkoxy and C 3-6 cycloalkyl,
  • R aa and R bb and adjacent nitrogen atoms form a 4-6 membered nitrogen-containing heterocyclic group, optionally further selected from halogen, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1 -3 substituted by one or more substituents in the alkoxy group;
  • R 5 is not hydrogen and butoxycarbonyl
  • R 5 is not a methyl group.
  • the present invention also provides a preferred solution, the compound represented by general formula (IX-B), its stereoisomers or pharmaceutically acceptable salts thereof, wherein:
  • R 2 is selected from hydrogen, cyano, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, trifluoromethyl or cyclopropyl;
  • R 3 is selected from hydrogen, fluorine, chlorine, bromine, methyl or ethyl
  • R 4 is selected from hydrogen or methyl
  • R 5 is selected from -R aa , -C(O)R aa or -C(O)NR aa R bb ;
  • R aa and R bb are each independently selected from hydrogen, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, furanyl , Oxazolyl, isoxazolyl, optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy,
  • R aa and R bb and adjacent nitrogen atoms form azetidinyl, pyrrolidinyl or piperidinyl, optionally further selected from halogen, hydroxyl, C 1-3 alkyl, C 1-3 haloalkane Substituted by one or more substituents in the alkoxy group and C 1-3 alkoxy group.
  • the present invention also provides a preferred solution.
  • the specific structure of the compound, its stereoisomer or its pharmaceutically acceptable salt is as shown in the general formula (XII):
  • Ring B is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclic group or 5-10 membered heteroaryl;
  • R 2 is selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • R 4 is selected from hydrogen or C 1-6 alkyl
  • R 6 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy, cyano, C 2-6 alkenyl or C 2-6 alkynyl;
  • hydrogen or halogen Preferably hydrogen or fluorine; more preferably hydrogen or fluorine;
  • R 17 is selected from hydrogen, halogen, amino, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic group, C 6-14 aryl group or 5-14 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 3-8 ring Alkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally further selected from hydrogen, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl , Substituted by one or more substituents in C 1-6 haloalkyl and C 1-6 alkoxy;
  • v is an integer of 0-5; 0, 1, 2 or 3 is preferred.
  • the present invention also provides a preferred solution.
  • the present invention also provides a preferred solution.
  • the present invention also provides a preferred solution, any one of the compounds represented by the general formulae, its stereoisomers or pharmaceutically acceptable salts thereof, wherein:
  • R 1 is selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 3-6 cycloalkyl;
  • R 2 is selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • two R 2s on the same carbon atom or different carbon atoms are linked to form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group, the C 3-8 cycloalkyl group and a 3-8 membered Heterocyclic group, optionally further selected from hydrogen, deuterium atom, C 1-6 alkyl, halogen, amino, oxo, thio, cyano, hydroxyl, C 3-8 alkoxy, C 3- 8 substituted by one or more substituents in haloalkoxy and C 3-8 hydroxyalkyl;
  • R 3 is selected from hydrogen atom, halogen, hydroxyl, C 1-6 alkyl or C 1-6 alkoxy;
  • two R 3 on the same carbon atom or different carbon atoms are linked to form a C 3-8 cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 cycloalkyl and 3-8 membered Heterocyclic group, optionally further selected from hydrogen, deuterium, C 1-6 alkyl, halogen, amino, oxo, thio, cyano, hydroxy, C 3-8 alkoxy, C 3-8 Substituted by one or more substituents in the halogenated alkoxy group and the C 3-8 hydroxyalkyl group;
  • R 4 is selected from hydrogen or C 1-6 alkyl
  • R 4 and R 5 are linked to form a 3-8 membered heterocyclic group or 5-14 membered heteroaryl group.
  • the 3-8 membered heterocyclic group and 5-14 membered heteroaryl group are optionally further selected From hydrogen, C 1-6 alkyl, halogen, amino, oxo, thio, cyano, hydroxy, C 3-8 alkoxy, C 3-8 haloalkoxy, C 3-8 hydroxyalkyl , -C(O)R cc and -C(O)NR cc R dd are substituted by one or more substituents;
  • R aa is selected from hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered Heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally further selected from hydrogen, halogen, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy and 5-14 membered heteroaryl group substituted by one or more substituents;
  • R bb is selected from hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-14 Aryl or 6-14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8
  • the membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group are optionally further selected from hydrogen atom, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkane Substituted by one or more substituents in the C 1-6 alkoxy group;
  • R aa and R bb are linked to form a heterocyclic group, wherein the heterocyclic group is optionally further selected from a hydrogen atom, a C 1-6 alkyl group, a halogen, an amino group, an oxo group, a thio group, and a cyano group. Substituted by one or more substituents in the group, hydroxy, C 3-8 alkoxy, C 3-8 haloalkoxy and C 3-8 hydroxyalkyl;
  • R cc and R dd are each independently selected from hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycle Group, C 6-14 aryl group or 5-14 membered heteroaryl group, the amino group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 3-8 cycloalkane Group, 3-8 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group, optionally further selected from hydrogen, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy are substituted by one or more substituents.
  • the present invention provides a method for preparing a compound represented by general formula (IX-B) or a stereoisomer and a pharmaceutically acceptable salt thereof, which is characterized in that it comprises the following steps:
  • the general formula (IX-B1) reacts with the acid chloride, amine, carboxylic acid or sulfonyl chloride represented by the general formula (II-2) to obtain the compound represented by the general formula (VIII) or its stereoisomer and its pharmaceutically acceptable salt;
  • the general formula (II-2) represents R 5 X, R 5 OH or R 5 NH 2 ;
  • X is halogen; preferably fluorine, chlorine or bromine;
  • Pg is a hydrogen or amino protecting group, selected from allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, methoxycarbonyl, p-toluenesulfonyl Acyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl or p-methoxyphenyl; preferably tert-butoxycarbonyl.
  • the present invention also relates to a technical solution, a pharmaceutical composition, which comprises a compound of general formula (I) shown in any one of the therapeutically effective doses, a compound of general formula shown in any one, and stereoisomers thereof Body or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a pharmaceutical composition which comprises a compound of general formula (I) shown in any one of the therapeutically effective doses, a compound of general formula shown in any one, and stereoisomers thereof Body or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to a technical solution, any one of the compound of the general formula (I) and any one of the compound of the general formula, and its stereoisomers or pharmaceutically acceptable salts thereof, or Application of the pharmaceutical composition in the preparation of G protein-coupled receptor modulators, in particular, in dopamine D3 receptor modulators and 5-HT2A receptor modulator drugs.
  • the present invention further relates to a method for preparing the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment of inflammatory diseases.
  • the present invention also relates to a method for the treatment, prevention and/or treatment of central nervous system diseases and/or mental diseases or disorders, which comprises administering to a patient a therapeutically effective dose of a compound represented by general formula (I) or its stereoisomers or Its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the present invention also provides methods for using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions related to G protein-coupled receptor modulators.
  • the present invention also relates to a method for treating nervous system diseases and/or mental diseases in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, Solvate, hydrate or derivative.
  • the method involves the treatment of conditions such as cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease, and heart disease.
  • the method involves the treatment or prevention of central nervous system disease and/or mental disease or disorder selected from the group consisting of schizophrenia, sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders, and / Or cognitive impairment, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and/or withdrawal syndrome, tinnitus, depression, autism, Alzheimer's Disease, Alzheimer’s disease, seizures, neuralgia or detoxification symptoms, severe depression and mania.
  • central nervous system disease and/or mental disease or disorder selected from the group consisting of schizophrenia, sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders, and / Or cognitive impairment, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and/or withdrawal syndrome, tinnitus, depression, autism, Alzheimer's Disease, Alzheimer’s disease, seizures, neuralgia or detoxification symptoms, severe depression and mania.
  • the treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound of the invention.
  • the present invention provides a method of treating a mammal including a neurological disease and/or psychiatric disease. The method includes administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.
  • the compound of the present invention or its pharmaceutical composition not only has potent D3 receptor agonistic activity, but also has significantly better 5-HT2A inhibitory activity than Cariprazine. It is clinically expected to have good therapeutic effects such as negative symptoms of schizophrenia and can significantly reduce the side effects of EPS The risk of occurrence.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms More preferred are lower alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • Alkyl groups may be substituted or unsubstituted.
  • substituents When substituted, substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, the present invention is preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl , Deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
  • alkylene means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "Butylene” refers to -(CH 2 ) 4 -, etc.
  • alkenyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. The alkenyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 Carbon atoms, most preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Cycloalkyl, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl, more preferably cyclopropyl Group, cyclobutyl and cyclohexyl.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugation. ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a dispirocycloalkyl group, or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • spirocycloalkyl group in which a single spirocycloalkyl and a heterocycloalkyl share a spiro atom
  • non-limiting examples include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups preferably bicyclic or tricyclic, more preferably 4-membered/4-membered, 5-membered/5-membered or 5-membered/6-membered Bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptanyl group, etc. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, boron, phosphorus, S(O) m (where m is an integer from 0 to 2) or P(O) n (where n is an integer from 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS- ,
  • the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, oxetanyl, pyrrolidinyl, oxazolidin-2-onyl, azepyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophene Dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.
  • Oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, oxazolidin-2-onyl, morpholinyl, piperazinyl and azepinyl are preferred. More preferred are oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, azetyl and oxazolidin-2-onyl.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between 3 to 20-membered monocyclic rings, wherein one or more ring atoms are nitrogen, oxygen, boron, phosphorus, and S (O) m (where m is an integer from 0 to 2) or P(O) n (where n is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 3-membered/5-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • Non-limiting examples of spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, where one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group preferably bicyclic or tricyclic, more preferably 3-membered/5-membered, 4-membered/5-membered or 5-membered/6-membered Bicyclic fused heterocyclic group.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxy, or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, isoxazole, oxadiazole, pyrazinyl, etc., preferably pyridyl, oxazolyl, isoxazole, oxadiazole, tetrazole, triazole, Thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl, furyl, pyri
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxy
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • alkenyl refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio Group, carboxyl group or carboxylate group.
  • Alkynyl refers to (CH ⁇ C-), where the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxy or carboxylate group.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH 2 .
  • Cyano refers to -CN.
  • Niro refers to -NO 2 .
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc refers to ethyl acetate
  • MeOH means methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • MeCN means Otoharu.
  • DMA refers to N,N-dimethylacetamide.
  • Et 2 O means diethyl ether
  • DCE refers to 1,2-dichloroethane.
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone) dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi refers to methyl lithium
  • N-BuLi refers to n-butyl lithium
  • X is selected from A, B, or C
  • X is selected from A, B and C
  • X is A, B or C
  • X is A, B and C
  • other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.
  • the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in units of parts per million (ppm).
  • the NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification used for TLC is 0.15mm ⁇ 0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by using or following methods known in the art.
  • the first step (trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)tert-butyl carbamate
  • the first step (trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)tert-butyl carbamate
  • the first step tert-butyl bis(fluoromethyl) carbamate
  • the third step 3-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-di (Fluoromethyl)urea
  • the first step tert-butyl bis(fluoromethyl) carbamate
  • the third step 3-(trans-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-bis( (Fluoromethyl)urea
  • the first step tert-butyl methyl (trifluoromethyl) carbamate
  • the first step preparation of trans-4-allyl-4-hydroxycyclohexyl) tert-butyl carbamate
  • Step 2 Preparation of (trans-4-hydroxy-4-(2-acetaldehyde)cyclohexyl) tert-butyl carbamate
  • the fifth step 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate and 2-(4-((tert- (Butoxycarbonyl) amino) cyclohex-1-en-1-yl) ethyl 4-methylbenzene sulfonate preparation
  • Step 6 Preparation of tert-butyl (cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)carbamate
  • Step 7 Preparation of cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexane-1-amine
  • the eighth step 3-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1,1- Preparation of dimethylurea
  • Cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexane-1-amine (210mg, TFA salt, about 0.147 mmol) was dissolved in dry dichloromethane (5 mL), DIPEA (0.1 mL) and dimethylcarbamoyl chloride (1 drop) were added. The reaction solution was stirred overnight at room temperature. Water (5 mL) was added to the reaction solution, and dichloromethane (10 mL) was added for extraction. The organic phase is dried and spin-dried.
  • Cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluorocyclohexane-1-amine (100mg, TFA salt, 0.21mmol ) was dissolved in anhydrous DMF (3 mL), and 1H-indole-2-carboxylic acid (52 mg, 0.32 mmol), HATU (160 mg, 0.42 mmol) and DIEA (0.2 mL) were added respectively. The reaction was stirred overnight at room temperature.
  • reaction solution was filtered and purified by prep-HPLC to obtain N-(cis-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-fluoro ring Hexyl)-1H-indole-2-carboxamide (25mg, yield 23%)
  • the first step preparation of trans-4-allyl-4-hydroxycyclohexyl) tert-butyl carbamate
  • Step 2 Preparation of (trans-4-hydroxy-4-(2-acetaldehyde)cyclohexyl) tert-butyl carbamate
  • the fifth step 2-(cis-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)ethyl 4-methylbenzenesulfonate and 2-(4-((tert- (Butoxycarbonyl) amino) cyclohex-1-en-1-yl) ethyl 4-methylbenzene sulfonate preparation
  • Step 7 Preparation of cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexane-1-amine
  • the eighth step 3-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-1, Preparation of 1-dimethylurea
  • Cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexane-1-amine is soluble in anhydrous two Methyl chloride, add DIPEA and dimethylcarbamoyl chloride. The reaction solution was stirred overnight at room temperature. Like adding water to the reaction solution, then adding dichloromethane for extraction. The organic phase is dried and spin-dried.
  • the first step 1-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexyl)-3- Preparation of ethyl urea
  • Step 1 Preparation of ethyl (1r,4r)-4-(1,3-dicarbonylisoindolin-2-yl)cyclohexane-1-carboxylate
  • Step 2 Preparation of ethyl 4-(1,3-dicarbonylisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate
  • the third step Preparation of 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindole-1,3-dione
  • the fourth step preparation of 4-(1,3-dicarbonylisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde
  • Step 7 Preparation of 2-(4-(1,3-dicarbonylisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate
  • reaction solution was spin-dried, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate: 50/1 ⁇ 1/1) to obtain 2-(4-(1,3-dicarbonylisoindolin-2-yl) )-1-Methylcyclohexyl)ethyl 4-methylbenzenesulfonate (1.5g).
  • reaction solution was filtered, spin-dried, and the crude product was separated by column chromatography (petroleum ether/ethyl acetate: 50/1 ⁇ 1/1) to obtain 2-(4-(2-(4-(2,3-dichlorobenzene) (Yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl)isoindole-1,3-dione (1.4g).
  • Step 9 Preparation of 4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexane-1-amine
  • reaction solution was spin-dried, water (50mL) was added, the aqueous phase was extracted with ethyl acetate (50mL x 2), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 4-(2-(4-(2) ,3-Dichlorophenyl)piperazin-1-yl)ethyl)-4-methylcyclohexane-1-amine (0.6g).
  • Step 1 Preparation of ethyl (1r,4r)-4-(1,3-dicarbonylisoindolin-2-yl)cyclohexane-1-carboxylate
  • Step 2 Preparation of ethyl 4-(1,3-dicarbonylisoindolin-2-yl)-1-methylcyclohexane-1-carboxylate
  • the third step Preparation of 2-(4-(hydroxymethyl)-4-methylcyclohexyl)isoindole-1,3-dione
  • the fourth step preparation of 4-(1,3-dicarbonylisoindolin-2-yl)-1-methylcyclohexane-1-carbaldehyde
  • Step 7 Preparation of 2-(4-(1,3-dicarbonylisoindolin-2-yl)-1-methylcyclohexyl)ethyl 4-methylbenzenesulfonate
  • reaction solution was spin-dried, and the crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate: 50/1 ⁇ 1/1) to obtain 2-(4-(1,3-dicarbonylisoindolin-2-yl) )-1-Methylcyclohexyl)ethyl 4-methylbenzenesulfonate (1.5g).
  • the ninth step 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl-1-amine
  • reaction solution was spin-dried, water (50mL) was added, the aqueous phase was extracted with ethyl acetate (50mL x 2), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 3-(4-(2-(4) -(Benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-methylcyclohexyl-1-amine (0.6 g).
  • the first step 1-(4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-3-ethylurea preparation
  • the first step 3-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-methylcyclohexyl)-1,1- Preparation of dimethylurea
  • the third step (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl)carbamic acid Tert-butyl ester
  • the fifth step 3-(trans-4-(2-((R)-4-(2,3-dichlorophenyl)-2-methylpiperazin-1-yl)ethyl)cyclohexyl) -1,1-Dimethylurea
  • Example 30 Using 4-bromobenzo[b]thiophene and (R)-3-cyclopropylpiperazine-1-carboxylic acid tert-butyl ester as raw materials, refer to Example 30 to obtain 3-(trans-4-(2-((R )-4-(benzo[b]thiophen-4-yl)-3-cyclopropylpiperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea.
  • the fourth step 3-(trans-4-(2-(5-(benzo[b]thiophen-4-yl)-2,5-diazabicyclo[4.2.0]octane-2- (Yl)ethyl)cyclohexyl)-1,1-dimethylurea
  • the third step (trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl)carbamic acid Tert-butyl ester
  • the fifth step 3-(trans-4-(2-((R)-4-(2,3-dichlorophenyl)-3-methylpiperazin-1-yl)ethyl)cyclohexyl) -1,1-Dimethylurea
  • trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclohexane -1-amine as the raw material.
  • trans-4-(2-((S)-4-(benzo[b]thiophen-4-yl)-3-(trifluoromethyl)piperazin-1-yl)ethyl)cyclohexane -1-amine as the raw material.
  • Example 2 Using 1-(benzo[b]thiophen-4-yl)-1,4-diazoheptan ring as a raw material, refer to Example 2 in the first to third steps to obtain N-(trans-4-(2-( 4-(Benzo(b)thiophen-4-yl)-1,4-diazoheptan-1-yl)ethyl)cyclohexyl)-3,3-difluoroazetidine-1-carboxamide .
  • the third step 3-(cis-4-(2-(4-(benzo[b]thiophen-4-yl)-1,4-diazoheptan-1-yl)ethyl)-4 -Fluorocyclohexyl)-1,1-dimethylurea preparation
  • Step 2 Preparation of cis-4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-4-fluorocyclohexane-1-amine
  • the first step trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexane- 1-amine
  • Trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)cyclohexane-1-amine Dissolve in N,N-dimethylformamide, add potassium carbonate and 2-chloropyrimidine-5-carbonitrile as raw materials to react and stir overnight at room temperature. The solvent was spin-dried, and the crude product was separated by high performance liquid chromatography. Refer to Example 26 to prepare 2-((trans-4-(2-((R)-4-(benzo[b]thiophen-4-yl)) -2-Methylpiperazin-1-yl)ethyl)cyclohexyl)amino)pyrimidine-5-carbonitrile.
  • the first step is to obtain N-(4-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-fluorocyclohexyl)furan -2-carboxamide.
  • Test Example 1 Determination of the binding ability of the compound of the present invention to dopamine D3 receptor
  • test case The purpose of this test case is to measure the affinity of the compound to the dopamine D3 receptor.
  • Pipette tips (Axygen; T-300-R-S, T-200-Y-R-S, T-1000-B-R-S);
  • Tris-base (Sigma, 77-86-1);
  • Experimental buffer 50mM Tris-HCl pH 7.4, 10mm MgCl 2.
  • Washing solution 50mM Tris-HCl pH 7.4, stored at 4°C; 0.5% PEI solution: 0.5g PEI dissolve in 100mL ddH 2 O, 4°C storage of spare .
  • the binding activity of the compound of the present invention to D3 was determined by the above test, and the measured IC 50 value is shown in Table 1.
  • Table 1 The compound of the present invention has an IC 50 binding activity to D3
  • the compound of the present invention has good affinity with dopamine receptor D3.
  • Test Example 2 Determination of the binding ability of the compound of the present invention to 5-HT2A receptor
  • test case The purpose of this test case is to measure the affinity of the compound to the 5-HT2A receptor.
  • Pipette tips (Axygen; T-300-R-S, T-200-Y-R-S, T-1000-B-R-S);
  • Tris-base (Sigma, 77-86-1);
  • Experimental buffer 50mM Tris-HCl pH 7.4, 4mM CaCl 2 .
  • Washing solution 50mM Tris-HCl pH 7.4, stored at 4°C
  • 0.5% PEI solution 0.5g PEI dissolve in 100mL ddH 2 O, 4°C storage of spare
  • the binding activity of the compound of the present invention to 5-HT2A was determined by the above test, and the measured IC 50 value is shown in Table 2.
  • the compound of the present invention has an IC 50 binding activity to 5-HT2A
  • the compound of the present invention has a good affinity for 5-HT2A.
  • Test Example 1 Determination of the effect of the compound of the present invention on cAMP content in cells stably expressing D3 receptor
  • the activation effect of the compound on the D3 receptor is measured.
  • BSA stabilizer (Perkin Elmer; CR84-100);
  • Buffer preparation 1*HBSS+20mM HEPES+0.1%BSA+500 ⁇ M IBMX.
  • Test Example 2 Determination of the influence of the compound of the present invention on the calcium ion mobility in cells stably expressing 5-HT2A receptor
  • the inhibitory effect of the compound on the 5-HT2A receptor was measured.
  • DMEM (Invitrogen; 11965);
  • Hygromycin B (CABI°CHEM, 400052);
  • Buffer preparation 1x HBSS, 20mM HEPES, 2.5mM probeecid (probenecid is 400mM st°C in 1M NaOH), 0.1% BSA. Probenecid and BSA were freshly added on the day of the experiment.
  • Experiment buffers include dye buffers and compound dilution buffers.
  • Cell culture medium Ham's F-12K+10% fetal bovine serum+600ug/ml hygromycin B+1*penicillin and streptomycin; inoculation medium: Ham's F-12K+10% dialysis serum; Assay buffer: 1x HBSS+20mM HEPES; cell line: Flp-In-CHO-5HT2A stable pool.
  • the cell line is cultured in complete medium at 37°C, 5% CO 2 to 70%-90% confluence. After the cells were trypsinized with TrypLE, they were seeded on a 384-well test plate at a density of 1 ⁇ 10 4 cells/well and incubated for 16-24 hours (at least overnight).
  • DMSO to prepare working solution (6X) of the compound to be tested. Take out the cell culture plate and let it stand at room temperature for 10 minutes, add 10 ⁇ L/well of 6x compound to be tested into a 384-well test plate, and incubate for 35 minutes at room temperature in the dark.
  • the calculated output result of each sampling time point in the experiment is the ratio of the wavelength signal of 340/510nm and 380/510nm.
  • the calculation of the maximum value minus the minimum value is derived from the ratio signal curve.
  • GraphPad prism to fit percent inhibition rate and ten-point concentration data to a parameter nonlinear logic formula, the IC 50 value of the compound was calculated.
  • Table 4 The IC 50 value of the compounds on the calcium ion mobility in cells stably expressing 5-HT2A receptors
  • mice were used as test animals to study the pharmacokinetic behavior of the compounds of the examples of the present invention, administered orally at a dose of 5 mg/kg in mice (plasma and brain tissue).
  • the example compounds of the present invention are self-made.
  • Balb/C mice were 12 males in each group; p.o. after fasting overnight, the dose was 5 mg/kg, and the administration volume was 10 mL/kg.
  • mice were sacrificed with CO 2 at 1, 2, 4, 8 and 24 hours.
  • 0.2 mL of blood was collected from the heart, placed in an EDTA-K 2 test tube, and centrifuged at 4°C at 6000 rpm for 6 min to separate the plasma. Store at -80°C; after the whole brain tissue is taken out and weighed, it is placed in a 2mL centrifuge tube and stored at -80°C.
  • Acid aqueous solution, B solution is acetonitrile

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Abstract

一种含氮环类衍生物调节剂、其制备方法和应用。特别地，涉及通式(I)所示的化合物、其制备方法及含有该化合物的药物组合物，及其作为G蛋白耦联受体调节剂在治疗或预防中枢神经系统疾病和/或精神疾病的用途。

Description

苯并噻吩类衍生物调节剂、其制备方法和应用 技术领域
本发明属于药物合成领域，具体涉及一种含氮环类衍生物调节剂及其制备方法和应用。
背景技术
多巴胺D3受体是G蛋白耦联受体家族成员，是多巴胺受体的一种亚型，与多巴胺D2和D4受体同属D2样抑制性受体，与DA结合后，通过抑制G-蛋白降低cAMP水平。D3受体主要分布于中脑边缘系统，特别是与运动功能无关的伏隔核、嗅结节和calleja岛，高活性D3受体调节剂可能会有很好的抗精神分裂活性。D3受体与情绪、认知、精神、成瘾等关系密切，可较好改善精神分裂症患者的阴性症状。D3受体可能是通过调节乙酰胆碱的释放和调节谷氨酸受体起到对认知的调控作用，部分激动D3受体起到改善认知的作用。
5-羟色胺2A受体(5-HT2A)受体是G蛋白耦联受体家族成员，是5-HT受体的一种主要的兴奋性受体亚型，在中枢及外周均有分布，与精神、情绪、学习与记忆等密切相关，高活性5-HT2A受体抑制剂具有显著的抗精神分裂症作用，并能降低锥体外束的副作用。
精神分裂症是患病率最高的一种精神病，病程缓慢，容易反复发作、加重或恶化，对患者及患者家属所造成了严重的疾病负担和不良后果。精神病患者会出现妄想，幻觉，思想语言和行为紊乱等阳性症状，无情绪和表情，言语贫乏，缺乏愉悦感等阴性症状以及认知障碍等症状。虽然在过去的几十年中，抗精神分裂症药物的研发和临床应用有了很大发展，但传统抗精神病药(一代)(氟哌啶醇，氟哌利多，甲硫哒嗪等)及非典型抗精神病药(二代)(氯氮平、利培酮、奥氮平和阿立哌唑等)都是对阳性症状治疗效果较好，对阴性症状和认知障碍改善效果不理想，所以急需开发不仅能够改善阳性症状，也能改善阴性症状和认知障碍的抗精神分裂症的药物。高活性多巴胺D3受体调节剂对精神分裂症患者的阴性症状、阳性症状和认知障碍均有改善作用，且无第一代和第二代抗精神类药物的锥体外束和体重增加等副作用。
D3受体拮抗剂或部分激动剂，对改善精神分裂症的阳性症状、阴性症状及认知功能障碍具有良好的疗效。国际申请WO2007093540A、WO2009013212A2、WO2010031735A1和WO2012117001A1报道了D3受体和5-HT2A双调节剂化合物，但其中的化合物对D3受体和5-HT2A的结合活性Ki大部分都在10nM以上；江苏恒宜专利WO2014086098A1报道了D3选择性抑制剂，但未有5-HT2A的结合活性研究；由Gedeon Richter公司开发的D3拮抗剂Cariprazine已于2015年上市，申请了国际专利WO2005012266A1，Cariprazine具有较强的D3受体激 动剂活性，用于精神分裂症的治疗对阴性症状具有优于现有药物的显著优势，但Cariprazine对5-HT2A受体的抑制活性较弱，导致其具有较严重的锥体外系(ESP)副作用。因此迫切需要开发具有高活性的D3受体调节剂，同时能具有优化的5-HT2A的结合活性，以降低锥体外系副作用同时提高对精神分裂症阴性症状和认知改善的效果。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其中通式(I)所示的化合物结构如下：
Figure PCTCN2020126735-appb-000001
其中：
Figure PCTCN2020126735-appb-000002
选自单键或双键；
M选自N或CR aa；
环A选自芳基或杂芳基；
R 1选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
R 2选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
或，相同碳原子或者不相同碳原子上的两个R 2链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未 取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、-(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；
R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1S(O)(＝NR aa)R bb、-(CH 2) n1S(O) m1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
或，相同碳原子或者不相同碳原子上的两个R 3链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、-(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；
R 4和R 5各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1C(O)R aa、-C(O)(CH 2) n1R aa、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1S(O) m1R aa、-(CH 2) n1S(O) m1NR aaR bb、-(CH 2) n1OR aa、-C(O)NR aa(CH 2) n1R bb、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O)(＝NR aa)R bb、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，所述的烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、羟基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基和杂芳基，任选进一步被选自氢、氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、 -(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；
或，R 4和R 5链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、-(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；
R aa、R bb、R cc和R dd各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、取代或未取代的烷基、取代或未取代的卤代烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
或者，R aa和R bb链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氢、氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基中的一个或多个取代基所取代；
m为0、1或2；
x为0、1、2、3或4；
y为0、1、2、3或4；
z为0、1、2、3或4；
m1为0、1或2；且
n1为0、1、2、3、4或5；
其中，通式(I)不包含化合物
Figure PCTCN2020126735-appb-000003
Figure PCTCN2020126735-appb-000004
本发明还提供了一种优选方案，所述的化合物、其立体异构体或其药学上可接受的盐，环A选自C 6-10芳基或5-10元杂芳基，优选苯基、5-6元单环杂芳基、苯并5-6元杂芳基或苯并3-6元杂环基。
本发明还提供了一种优选方案，所述的化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2020126735-appb-000005
选自
Figure PCTCN2020126735-appb-000006
Figure PCTCN2020126735-appb-000007
本发明还提供了一种优选方案，所述的化合物、其立体异构体或其药学上可接受的盐，R 4选自氢或C 1-6烷基，优选氢或甲基；
R 5选自氢、C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-C(O)R aa、-C(O)NR aaR bb、-C(O)(CH 2) n1R aa、-C(O)NR aa(CH 2) n1R bb、-S(O) 2R aa、-(CH 2) n1S(O)(＝NR aa)R bb、-S(O) m1NR aaR bb或-C(O)OR aa，所述的C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氢、氰基、卤素、C 1-6烷基和C 1-6烷氧基中的一个或多个取代基所取代；
优选-R aa、-C(O)(CH 2) n1R aa、-C(O)NR aa(CH 2) n1R bb或-S(O) 2R aa；
或，R 4和R 5链接形成一个3-8元杂环基或5-14元杂芳基，所述的3-8元杂 环基和5-14元杂芳基，任选进一步被选自氢、C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基、C 3-8羟烷基、-C(O)R cc和-C(O)NR ccR dd中的一个或多个取代基所取代；
其中，所述杂环基或杂芳基选自含有1-2个氮、氧或硫原子的杂环基或杂芳基；
R aa和R bb各自独立地选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代，
优选地，所述R aa和R bb各自独立地选自氢、氨基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、苯基或5-6元杂芳基，所述的氨基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-6环烷基、3-6元杂环基、苯基和5-6元杂芳基，任选进一步被选卤素、羟基、氰基、氧代基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-6环烷基、3-6元杂环基、苯基或5-6元杂芳基中的一个或多个取代基所取代；
R cc和R dd各自独立地选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选氢、卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基中的一个或多个取代基所取代；且
n1为0、1、2或3。
本发明还提供了一种优选方案，所述的化合物、其立体异构体或其药学上可接受盐，通式(IV)如通式(IV-A)所示：
Figure PCTCN2020126735-appb-000008
R 2选自氢、氰基、卤素、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基；
或，相同碳原子或者不相同碳原子上的两个R 2链接形成一个C 3-8环烷基或3-8元杂环基，所述的C 3-8环烷基和3-8元杂环基，任选进一步被选自氘原子、C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基和C 3-8羟烷基中的一个或多个取代基所取代；
R 3选自氢、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、羟基、氰基、C 2-6烯基或C 2-6炔基；
R 4选自氢或C 1-6烷基；
R 5选自氢、C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-C(O)R aa、-C(O)NR aaR bb、-C(O)(CH 2) n1R aa、-C(O)NR aa(CH 2) n1R bb、-S(O) 2R aa、-(CH 2) n1S(O)(＝NR aa)R bb、-S(O) m1NR aaR bb或-C(O)OR aa，所述的C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氰基、卤素、C 1-6烷基和C 1-6烷氧基中的一个或多个取代基所取代；
或，R 4和R 5链接形成一个3-8元杂环基或5-14元杂芳基，任选进一步被选自C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基、C 3-8羟烷基、-C(O)R cc和-C(O)NR ccR dd中的一个或多个取代基所取代；
R aa和R bb各自独立地选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代，
或者，R aa和R bb与相邻的氮原子形成4-10元杂环基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基中的一个或多个取代基所取代；
R cc和R dd各自独立地选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基中的一个或多个取代基所取代；
m为1或2；且
n1为0、1、2或3。
本发明还提供了一种优选方案，所述的化合物、其立体异构体或其药学上可接受盐，通式(IV-A)如通式(IX-B)所示：
Figure PCTCN2020126735-appb-000009
R 2选自氢、氰基、卤素、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基；
R 3选自氢、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6 卤代烷氧基；
R 4选自氢或C 1-6烷基；
R 5选自氢、C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-C(O)R aa、-C(O)NR aaR bb、-C(O)(CH 2) n1R aa、-C(O)NR aa(CH 2) n1R bb、-S(O) 2R aa、-(CH 2) n1S(O)(＝NR aa)R bb、-S(O) m1NR aaR bb或-C(O)OR aa，所述的C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氰基、卤素、C 1-6烷基和C 1-6烷氧基中的一个或多个取代基所取代；
或，R 4和R 5链接形成一个3-8元杂环基或5-10元杂芳基，任选进一步被选自C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基、C 3-8羟烷基中的一个或多个取代基所取代；
R aa和R bb各自独立地选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或含1-2个选自N、O或S的5-10元杂芳基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代，
或者，R aa和R bb与相邻的氮原子形成4-6元杂环基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基中的一个或多个取代基所取代。
本发明还提供了一种优选方案，通式(IX-B)所示的化合物、其立体异构体或其药学上可接受盐，其中：
R 2选自氢、氰基、卤素、C 1-3烷基、C 1-3卤代烷基或C 3-6环烷基；
R 3选自氢、卤素或C 1-3烷基；
R 4选自氢或C 1-3烷基；
R 5选自-(CH 2) n1R aa、-C(O)R aa、-C(O)NR aaR bb、-S(O) 2R aa或-S(O) m1NR aaR bb；
R aa和R bb各自独立地选自氢、氨基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-6环烷基或含1-2个选自N、O或S的5-6元杂芳基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-6环烷基中的一个或多个取代基所取代，
或者，R aa和R bb与相邻的氮原子形成4-6元含氮杂环基，任选进一步被选自卤素、羟基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基中的一个或多个取代基所取代；
其中，当R 2、R 3和R 4为氢时，R 5不为氢和书丁氧羰基；
当当R 2和R 3，R 4为甲基时，R 5不为甲基。
本发明还提供了一种优选方案，通式(IX-B)所示的化合物、其立体异构体或其药学上可接受盐，其中：
R 2选自氢、氰基、氟、氯、溴、甲基、乙基、三氟甲基、三氟甲基或环丙 基；
R 3选自氢、氟、氯、溴、甲基或乙基；
R 4选自氢或甲基；
R 5选自-R aa、-C(O)R aa或-C(O)NR aaR bb；
R aa和R bb各自独立地选自氢、C 1-3烷基、C 1-3氟代烷基、C 1-3烷氧基、环丙基、环丁基、环戊基、呋喃基、噁唑基、异噁唑基，任选进一步被选自卤素、羟基、氰基、C 1-3烷基、C 1-3烷氧基中的一个或多个取代基所取代，
或者，R aa和R bb与相邻的氮原子形成氮杂环丁基、吡咯烷基或哌啶基，任选进一步被选自卤素、羟基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基中的一个或多个取代基所取代。
本发明还提供了一种优选方案，所述的化合物、其立体异构体或其药学上可接受盐，其具体结构如通式(XII)所示：
Figure PCTCN2020126735-appb-000010
其中：
环B选自C 3-8环烷基、3-8元杂环基或5-10元杂芳基；
优选环丙基、氮杂环丁烷基、吡咯烷酮基、呋喃基、噁唑基或异噁唑基；
R 2选自氢、氰基、卤素、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基；
优选氢或C 1-6卤代烷基；更优选氢或三氟甲基；
R 4选自氢或C 1-6烷基；
优选氢或甲基；
R 6选自氢、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、羟基、氰基、C 2-6烯基或C 2-6炔基；
优选氢或卤素；更优选氢或氟；
R 17选自氢、卤素、氨基、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基，任选进一步被选氢、卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基中的一个或多个取代基所取代；
优选氢、氨基、卤素、氨基、羟基、氰基、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基；
更优选氢、氟、氯、羟基、氰基、甲基或甲氧基；且
v为0～5的整数；优选0、1、2或3。
本发明还提供了一种优选方案，任一项所述的化合物、其立体异构体或其药学上可接受盐，其中：
Figure PCTCN2020126735-appb-000011
选自如下基团：
Figure PCTCN2020126735-appb-000012
Figure PCTCN2020126735-appb-000013
Figure PCTCN2020126735-appb-000014
本发明还提供了一种优选方案，任一项所述的各通式所示的化合物、其立体异构体或其药学上可接受盐，其中：环A进一步为
Figure PCTCN2020126735-appb-000015
本发明还提供了一种优选方案，任一项所述的各通式所示的化合物、其立体异构体或其药学上可接受盐，其中：
R 1选自氢、氰基、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 3-6环烷基；
R 2选自氢、氰基、卤素、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基；
或，相同碳原子或者不相同碳原子上的两个R 2链接形成一个C 3-8环烷基或3-8元杂环基，所述的C 3-8环烷基和3-8元杂环基，任选进一步被选自氢、氘原子、C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基和C 3-8羟烷基中的一个或多个取代基所取代；
R 3选自氢原子、卤素、羟基、C 1-6烷基或C 1-6烷氧基；
或，相同碳原子或者不相同碳原子上的两个R 3链接形成一个C 3-8环烷基或3-8元杂环基，所述的C 3-8环烷基和3-8元杂环基，任选进一步被选自氢、氘、C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基和C 3-8羟烷基中的一个或多个取代基所取代；
R 4选自氢或C 1-6烷基；
R 5选自氢、C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-C(O)R aa、-C(O)NR aaR bb、-C(O)(CH 2) n1R aa、-C(O)NR aa(CH 2) n1R bb、-S(O) 2R aa、-(CH 2) n1S(O)(＝NR aa)R bb、-S(O) m1NR aaR bb或-C(O)OR aa，所述的C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氢、氰基、卤素、C 1-6烷基和C 1-6烷氧基中的一个或多个取代基所取代；
或，R 4和R 5链接形成一个3-8元杂环基或5-14元杂芳基，所述的3-8元杂环基和5-14元杂芳基，任选进一步被选自氢、C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基、C 3-8羟烷基、-C(O)R cc和-C(O)NR ccR dd中的一个或多个取代基所取代；
R aa选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8 元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选氢、卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基和5-14元杂芳基中的一个或多个取代基所取代；
R bb选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或6-14元杂芳基，其中所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基任选进一步被选氢原子、卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基中的一个或多个取代基所取代；
或，R aa和R bb链接形成一个杂环基，其中所述的杂环基任选进一步被选自氢原子、C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基和C 3-8羟烷基中的一个或多个取代基所取代；
R cc和R dd各自独立地选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选氢、卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基中的一个或多个取代基所取代。
另一方面，本发明提供制备一种通式(IX-B)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于，包含以下步骤，
Figure PCTCN2020126735-appb-000016
通式(IX-B3)脱保护得到通式(IX-B1)所示化合物或其立体异构体及其药学上可接受盐；
通式(IX-B1)与通式(II-2)所示的酰氯、胺、羧酸或磺酰氯反应，得到通式(VIII)所示化合物或其立体异构体及其药学上可接受盐；
通式(II-2)表示R 5X、R 5OH或R 5NH 2；
X为卤素；优选氟、氯或溴；
Pg为氢或氨基保护基，选自烯丙氧羰基、三氟乙酰基、2,4-二甲氧基苄基、硝基苯磺酰基、三苯甲基、笏甲氧羰基、对甲苯磺酰基、甲酸酯、乙酰基、苄氧羰基、叔丁氧羰基、苄基或对甲氧苯基；优选叔丁氧羰基。
本发明还涉及一种技术方案，一种药用组合物，其包括治疗有效剂量的任一项所示的通式(I)化合物和任一项所示的通式化合物、及其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明还涉及一种技术方案，任一项所述的通式(I)化合物和任一项所示的 通式化合物、及其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备G蛋白耦联受体调节剂，特别地，在多巴胺D3受体调节剂和5-HT2A受体调节剂药物中的应用。
本发明进一步涉及通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗炎性疾病的方法。
本发明还涉及一种治疗预防和/或治疗中枢神经系统疾病和/或精神疾病或病症的方法，其包括向患者施用治疗有效剂量的通式(I)所示的化合物其立体异构体或其药学上可接受的盐，或其药物组合物。
本发明还提供了使用本发明的化合物或药物组合物治疗疾病状况的方法，该疾病状况包括但不限于与G蛋白耦联受体调节剂有关的状况。
本发明还涉及治疗哺乳动物中的神经系统疾病和/或精神疾病的方法，其包括向所述哺乳动物施用治疗有效量的本发明的化合物或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物。
在一些实施方案中，本方法涉及诸如癌症、骨病、炎性疾病、免疫疾病、神经系统疾病、代谢性疾病、呼吸性疾病和心脏病等病症的治疗。
在一些实施方案中，本方法涉及所述治疗或预防中枢神经系统疾病和/或精神疾病或病症选自精神分裂症、睡眠障碍、心境障碍、精神分裂症谱系障碍、痉挛性障碍、记忆障碍和/或认知障碍、运动障碍、人格障碍、自闭症谱系障碍、疼痛、外伤性脑损伤、血管疾病、物质滥用障碍和/或戒断综合征、耳鸣、抑郁症、自闭症、老年痴呆症、阿尔兹海默症、癫痫发作、神经痛或戒毒症状重度抑郁症和狂躁症等疾病。
本文提供的治疗方法包括向受试者施用治疗有效量的本发明的化合物。在一个实施方案中，本发明提供了治疗哺乳动物中包括神经系统疾病和/或精神疾病症的方法。该方法包括向所述哺乳动物施用治疗有效量的本发明的化合物，或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物。
本发明化合物或者其药物组合物不仅具有强效的D3受体激动活性，而且对5-HT2A抑制活性显著优于Cariprazine，临床预计具有良好的精神分裂症阴性症状等治疗疗效并能显著减低EPS副作用的发生风险。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基 丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH 2-、“亚乙基”指-(CH 2) 2-、“亚丙基”指-(CH 2) 3-、“亚丁基”指-(CH 2) 4-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至8个碳原子，最优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基，更优选环丙基、环丁基和环己基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环 烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2020126735-appb-000017
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：
Figure PCTCN2020126735-appb-000018
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为4元/4元、5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2020126735-appb-000019
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2020126735-appb-000020
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至 20个环原子，其中一个或多个环原子为选自氮、氧、硼、磷、S(O) m(其中m是整数0至2)或P(O) n(其中n是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优选包含3至8个环原子。单环杂环基的非限制性实例包括氧杂环丁基、氧杂环丁基、吡咯烷基、恶唑烷-2-酮基、吖庚基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选氧杂环丁基、四氢呋喃基、吡咯烷基、吡唑烷基、哌嗪基、恶唑烷-2-酮基、吗啉基、哌嗪基和吖庚基。更优选氧杂环丁基、吡咯烷基、哌啶基、哌嗪基、吖庚基和恶唑烷-2-酮基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。
术语“螺杂环基”指3至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为氮、氧、硼、磷、S(O) m(其中m是整数0至2)或P(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2020126735-appb-000021
等。
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/5元、4元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2020126735-appb-000022
Figure PCTCN2020126735-appb-000023
等。
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2020126735-appb-000024
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2020126735-appb-000025
Figure PCTCN2020126735-appb-000026
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就 是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2020126735-appb-000027
Figure PCTCN2020126735-appb-000028
等。
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、异噁唑、噁二唑、吡嗪基等，优选为吡啶基、噁唑基、异噁唑、噁二唑、四氮唑、三氮唑基、噻吩基、咪唑基、吡唑基或嘧啶基、噻唑基；更优选吡唑基、呋喃基、吡啶基、噁唑基、异噁唑、呋喃基和嘧啶基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2020126735-appb-000029
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
“烯基”指链烯基，又称烯烃基，其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“炔基”指(CH≡C-)，其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“羟基”指-OH基团。
“卤素”指氟、氯、溴或碘。
“氨基”指-NH 2。
“氰基”指-CN。
“硝基”指-NO 2。
“羧基”指-C(O)OH。
“THF”指四氢呋喃。
“EtOAc”指乙酸乙酯。
“MeOH”指甲醇。
“DMF”指N,N-二甲基甲酰胺。
“DIPEA”指二异丙基乙胺。
“TFA”指三氟乙酸。
“MeCN”指乙晴。
“DMA”指N,N-二甲基乙酰胺。
“Et 2O”指乙醚。
“DCE”指1,2-二氯乙烷。
“DIPEA”指N,N-二异丙基乙胺。
“NBS”指N-溴代琥珀酰亚胺。
“NIS”指N-碘代丁二酰亚胺。
“Cbz-Cl”指氯甲酸苄酯。
“Pd 2(dba) 3”指三(二亚苄基丙酮)二钯。
“Dppf”指1,1’-双二苯基膦二茂铁。
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。
“KHMDS”指六甲基二硅基胺基钾。
“LiHMDS”指双三甲基硅基胺基锂。
“MeLi”指甲基锂。
“n-BuLi”指正丁基锂。
“NaBH(OAc) 3”指三乙酰氧基硼氢化钠。
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是 用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1200 Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。
实施例1
N-(反式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)环己基)-3,3-二氟吖丁啶-1-甲酰胺
Figure PCTCN2020126735-appb-000030
第一步：(反式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)环己基)氨基甲酸叔丁酯
Figure PCTCN2020126735-appb-000031
100mL圆底烧瓶中将1-(2,3-二氯苯基)哌嗪(460mg，2mmol)溶于10毫升乙腈中，2-(反式-4-((叔-丁氧基羰基)氨基)环己基)乙基4-甲基苯磺酸酯(794mg，2mmol)和碳酸钾(834mg，6mmol)加入反应体系。反应于80℃下并搅拌12小时。反应完成后，反应体系冷却至室温，水淬灭反应，乙酸乙酯(10mL*3)萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(石油醚/乙酸乙酯＝1/1冲洗)得到(反式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)环己基)氨基甲酸叔丁酯(550mg，白色固体，产率：60.5％)。
MS m/z(ESI):456.2[M+H] +.
第二步：反式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)环己烷-1-胺
Figure PCTCN2020126735-appb-000032
100mL圆底烧瓶中将(反式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)环己基)氨基甲酸叔丁酯(550mg，1.2mmol)溶于5毫升二氯甲烷中，然后加入盐酸乙酸乙酯溶液(4M,1mL，4mmol)。反应于室温下下并搅拌12小时。反应完成后，反应体系浓缩，饱和碳酸氢钠溶液淬灭反应，乙酸乙酯(10mL*3)萃取。有机相无水硫酸钠干燥。过滤，旋干得到反式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)环己烷-1-胺(400mg，白色固体，产率：91.3％)。
MS m/z(ESI):356.1[M+H] +.
第三步：N-(反式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)环己基)-3,3-二氟吖丁啶-1-甲酰胺
Figure PCTCN2020126735-appb-000033
反式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)环己烷-1-胺(80mg，0.22mmol)溶于3mL二氯甲烷溶液中，加入三乙胺(67mg，0.66mmol)，N,N'-羰基二咪唑(43mg，0.27mmol)反应液在室温下搅拌3小时，然后3,3-二氟吖丁啶盐酸盐(42mg，0.34mmol)加入到反应液中，在室温下反应12小时。反应液用水洗三次(2mL*3),有机相浓缩后用prep-HPLC制备得产品N-(反式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)环己基)-3,3-二氟吖丁啶-1-甲酰胺(69mg，白色固体，产率64.6％)。
MS m/z(ESI):475.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.19–7.11(m,2H),7.00–6.94(m,1H),4.24(t,J＝12.1Hz,4H),3.98(d,J＝8.1Hz,1H),3.63–3.50(m,1H),3.24–3.03(m,4H),2.85–2.61(m,4H),2.56–2.43(m,2H),2.08–1.95(m,2H),1.84–1.75(m,2H),1.56–1.43(m,2H),1.28–1.22(m,1H),1.16–1.01(m,4H).
实施例2
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-3,3-二氟吖丁啶-1-甲酰胺
Figure PCTCN2020126735-appb-000034
第一步：(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)氨基甲酸叔丁酯
Figure PCTCN2020126735-appb-000035
100mL圆底烧瓶中将1-(苯并[b]噻吩-4-基)哌嗪(440mg，2mmol)溶于10毫升乙腈中，2-(反式-4-((叔-丁氧基羰基)氨基)环己基)乙基4-甲基苯磺酸酯(794mg，2mmol)和碳酸钾(834mg，6mmol)加入反应体系。反应于80℃下并搅拌12小时。反应完成后，反应体系冷却至室温，水淬灭反应，乙酸乙酯(10mL*3)萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(石油醚/乙酸乙酯＝1/1冲洗)得到叔丁基(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)氨基甲酸酯(500mg，白色固体，产率：55.9％)。
MS m/z(ESI):444.2[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝8.0Hz,1H),7.41–7.37(m,1H),7.30–7.25(m,2H),6.90(d,J＝7.6Hz,1H),4.44–4.24(m,1H),3.46–3.31(m,1H),3.29–3.19(m,4H),2.95–2.63(m,4H),2.61–2.42(m,2H),2.09–1.94(m,2H),1.87–1.72(m,2H),1.58–1.49(m,2H),1.44(s,9H),1.30–1.20(m,1H),1.16–0.98(m,4H).
第二步：反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺
Figure PCTCN2020126735-appb-000036
100mL圆底烧瓶中将(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)氨基甲酸叔丁酯(500mg，1.13mmol)溶于5毫升二氯甲烷中，然后加入盐酸乙酸乙酯溶液(4M，1mL，4mmol)。反应于室温下下并搅拌12小时。反应完成后，反应体系浓缩，饱和碳酸氢钠溶液淬灭反应，乙酸乙酯(10mL*3)萃取。有机相无水硫酸钠干燥。过滤，旋干得到反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺(350mg，白色固体，产率：90.4％)。
MS m/z(ESI):344.2[M+H] +.
第三步：N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-3,3-二氟吖丁啶-1-甲酰胺
Figure PCTCN2020126735-appb-000037
反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺(50mg，0.15 mmol)溶于3mL二氯甲烷溶液中，加入三乙胺(45mg，0.45mmol)，N,N'-羰基二咪唑(28mg，0.17mmol)反应液在室温下搅拌3小时，然后3,3-二氟吖丁啶盐酸盐(28mg，0.22mmol)加入到反应液中，在室温下反应12小时。反应液用水洗三次(2mL*3)，有机相浓缩后用prep-HPLC制备得产品N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-3,3-二氟吖丁啶-1-甲酰胺(22mg，白色固体，产率32.1％)。
MS m/z(ESI):463.2[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.56(d,J＝8.0Hz,1H),7.45–7.36(m,2H),7.31–7.26(m,1H),6.91(d,J＝7.6Hz,1H),4.24(t,J＝12.1Hz,4H),3.99(d,J＝8.1Hz,1H),3.64–3.51(m,1H),3.37–3.14(m,4H),2.94–2.67(m,4H),2.64–2.51(m,2H),2.08–1.96(m,2H),1.89–1.76(m,2H),1.59–1.48(m,2H),1.29–1.23(m,1H),1.19–1.04(m,4H).
实施例3
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-3-羟基-3-甲基吖丁啶-1-甲酰胺
Figure PCTCN2020126735-appb-000038
反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺(50mg，0.15mmol)溶于3mL二氯甲烷溶液中，加入三乙胺(45mg，0.45mmol)，N,N'-羰基二咪唑(28mg，0.17mmol)反应液在室温下搅拌3小时，然后3-甲基吖丁啶-3-醇盐酸盐(27mg，0.22mmol)加入到反应液中，在室温下反应12小时。反应液用水洗三次(2mL*3),有机相浓缩后用prep-HPLC制备得产品N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-3-羟基-3-甲基吖丁啶-1-甲酰胺(23.5mg，白色固体，产率35.3％)。
MS m/z(ESI):457.3[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝8.0Hz,1H),7.44–7.35(m,2H),7.32–7.26(m,1H),6.90(d,J＝7.6Hz,1H),3.93–3.76(m,5H),3.63–3.49(m,1H),3.32–3.13(m,4H),3.00–2.87(m,1H),2.83–2.64(m,4H),2.57–2.44(m,2H),2.05–1.93(m,3H),1.87–1.73(m,2H),1.53(s,3H),1.52–1.43(m,2H),1.16–1.00(m,4H).
实施例4
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-3-甲氧基-3-甲基吖丁啶-1-甲酰胺
Figure PCTCN2020126735-appb-000039
反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺(50mg，0.15mmol)溶于3mL二氯甲烷溶液中，加入三乙胺(45mg，0.45mmol)，N,N'-羰基二咪唑(28mg，0.17mmol)反应液在室温下搅拌3小时，然后3-甲氧基-3-甲基吖丁啶盐酸盐(30mg，0.22mmol)加入到反应液中，在室温下反应12小时。反应液用水洗三次(2mL*3),有机相浓缩后用prep-HPLC制备得产品N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-3-甲氧基-3-甲基吖丁啶-1-甲酰胺(22mg，白色固体，产率32.1％)。
MS m/z(ESI):471.2[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝8.0Hz,1H),7.44–7.35(m,2H),7.29–7.23(m,1H),6.90(d,J＝7.4Hz,1H),3.88(dd,J＝11.6,8.0Hz,3H),3.65(d,J＝8.0Hz,2H),3.61–3.51(m,1H),3.33–3.13(m,7H),2.86–2.63(m,4H),2.55–2.42(m,2H),2.07–1.94(m,2H),1.85–1.75(m,2H),1.56–1.42(m,5H),1.30–1.19(m,1H),1.19–0.99(m,4H).
实施例5
3-(反式-4-(2-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)乙基)环己基)-1,1-二(氟甲基)脲
Figure PCTCN2020126735-appb-000040
第一步：叔-丁基二(氟甲基)氨基甲酸酯
Figure PCTCN2020126735-appb-000041
将氨基甲酸叔丁酯(500mg，4.3mmol)溶于10mL DMF中，0℃下加入NaH(427mg，10.7mmol)，0℃下搅拌0.5小时，加入氟碘甲烷(1.7g，3.8mmol)， 室温搅拌过夜。水淬灭反应，乙酸乙酯(20mL*3)萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(石油醚/乙酸乙酯＝10/1冲洗)得到叔-丁基二(氟甲基)氨基甲酸酯(150mg，无色液体，产率：19％)。
第二步：二(氟甲基)胺盐酸盐
Figure PCTCN2020126735-appb-000042
将叔-丁基二(氟甲基)氨基甲酸酯(150mg)溶于盐酸乙酸乙酯溶液(4M,2mL)，室温搅拌过夜。旋干得到粗产物二(氟甲基)胺盐酸盐(97mg，99％)。
第三步：3-(反式-4-(2-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)乙基)环己基)-1,1-二(氟甲基)脲
Figure PCTCN2020126735-appb-000043
参考实施例1得到产物3-(反式-4-(2-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)乙基)环己基)-1,1-二(氟甲基)脲。
MS m/z(ESI):452.2[M+H] +.
实施例6
3-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1-(氟甲基)-1-甲基脲
Figure PCTCN2020126735-appb-000044
第一步：(氟甲基)(甲基)氨基甲酸叔丁酯
Figure PCTCN2020126735-appb-000045
将甲基氨基甲酸叔丁酯(500mg，3.8mmol)溶于10mL DMF中，0℃下加入NaH(228mg，5.7mmol)，0℃下搅拌0.5小时，加入氟碘甲烷(610mg，3.8mmol)，室温搅拌过夜。水淬灭反应，乙酸乙酯(20mL*3)萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(石油醚/乙酸乙酯＝10/1冲洗)得到(氟甲基)(甲基)氨基甲酸叔丁酯(50mg，无色液体，产率：8.1％)。
第二步：1-氟-N-甲基甲胺盐酸盐
Figure PCTCN2020126735-appb-000046
将(氟甲基)(甲基)氨基甲酸叔丁酯(50mg)溶于盐酸乙酸乙酯溶液(4M,2mL)，室温搅拌过夜。旋干得到粗产物1-氟-N-甲基甲胺盐酸盐(30mg，99％)。第三步：3-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1-(氟甲基)-1-甲基脲
Figure PCTCN2020126735-appb-000047
反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺(50mg，0.15mmol)溶于3mL二氯甲烷溶液中，加入三乙胺(45mg，0.45mmol)，N,N'-羰基二咪唑(28mg，0.17mmol)反应液在室温下搅拌3小时，然后1-氟-N-甲基甲胺盐酸盐(30mg，0.3mmol)加入到反应液中，在室温下反应12小时。反应液用水洗三次(2mL*3)，有机相浓缩后用prep-HPLC制备得产品3-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1-(氟甲基)-1-甲基脲(12mg，白色固体，产率18.5％)。
MS m/z(ESI):433.2[M+H] +.
实施例7
3-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1,1-二(氟甲基)脲
Figure PCTCN2020126735-appb-000048
第一步：叔-丁基二(氟甲基)氨基甲酸酯
Figure PCTCN2020126735-appb-000049
将氨基甲酸叔丁酯(500mg，4.3mmol)溶于10mL DMF中，0℃下加入NaH(427mg，10.7mmol)，0℃下搅拌0.5小时，加入氟碘甲烷(1.7g，3.8mmol)，室温搅拌过夜。水淬灭反应，乙酸乙酯(20mL*3)萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(石油醚/乙酸乙酯＝10/1冲洗)得到叔-丁基二(氟甲基)氨基甲酸酯(150mg，无色液体，产率：19％)。
第二步：二(氟甲基)胺盐酸盐
Figure PCTCN2020126735-appb-000050
将叔-丁基二(氟甲基)氨基甲酸酯(150mg)溶于盐酸乙酸乙酯溶液(4M,2mL)， 室温搅拌过夜。旋干得到粗产物二(氟甲基)胺盐酸盐(97mg，99％)。
第三步：3-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1,1-二(氟甲基)脲
Figure PCTCN2020126735-appb-000051
参考实施例5得到3-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1,1-二(氟甲基)脲。
MS m/z(ESI):451.2[M+H] +.
实施例8
3-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1-甲基-1-(三氟甲基)脲
Figure PCTCN2020126735-appb-000052
第一步：甲基(三氟甲基)氨基甲酸叔丁酯
Figure PCTCN2020126735-appb-000053
将甲基氨基甲酸叔丁酯(500mg，3.8mmol)溶于10mL DMF中，0℃下加入NaH(228mg，5.7mmol)，0℃下搅拌0.5小时，加入三氟碘甲烷(2.98g，3.8mmol，25％in DMF)，室温搅拌过夜。水淬灭反应，乙酸乙酯(10mL*3)萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(石油醚/乙酸乙酯＝10/1冲洗)得到甲基(三氟甲基)氨基甲酸叔丁酯(40mg，无色液体，产率：5.3％)。
第二步：1,1,1-三氟-N-甲基甲胺盐酸盐
Figure PCTCN2020126735-appb-000054
将甲基(三氟甲基)氨基甲酸叔丁酯(40mg)溶于盐酸乙酸乙酯溶液(4M,2mL)，室温搅拌过夜。旋干得到粗产物1,1,1-三氟-N-甲基甲胺盐酸盐(25mg，99％)。
第三步：3-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1-甲基-1-(三氟甲基)脲
Figure PCTCN2020126735-appb-000055
反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺(50mg，0.15mmol)溶于3mL二氯甲烷溶液中，加入三乙胺(45mg，0.45mmol)，N,N'-羰基二咪唑(28mg，0.17mmol)反应液在室温下搅拌3小时，然后1,1,1-三氟-N-甲基甲胺盐酸盐(25mg，0.18mmol)加入到反应液中，在室温下反应12小时。反应液用水洗三次(2mL*3)，有机相浓缩后用prep-HPLC制备得产品3-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1-甲基-1-(三氟甲基)脲(8mg，白色固体，产率11.3％)。
MS m/z(ESI):469.2[M+H] +.
实施例8
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)二甲基磺酰胺
Figure PCTCN2020126735-appb-000056
将反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺和三乙胺溶解在二氯甲烷中，然后滴加二甲基氨基磺酰氯在室温搅拌16小时，向反应液中加水，用乙酸乙酯萃取，合并有机相用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，经过制备色谱分离，得到白色固体N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)二甲基磺酰胺。
同实施例10，MS m/z(ESI):451.2[M+H] +.
实施例10
N-(反式-4-(2-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)乙基)环己基)二甲基磺酰胺
Figure PCTCN2020126735-appb-000057
第一步：N-(反式-4-(2-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)乙基)环己基)二甲基磺酰胺
Figure PCTCN2020126735-appb-000058
将反式-4-(2-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)乙基)环己烷-1-胺(60mg，0.17mmol)和三乙胺(52mg，0.51mmol)溶解在二氯甲烷(3mL)中，然后滴加二甲基氨基磺酰氯(49mg，0.34mmol)在室温搅拌16小时，向反应液中加水(20mL)，用乙酸乙酯萃取(20mLx3)，合并有机相用饱和食盐水(30mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，经过制备色谱分离，得到白色固体N-(反式-4-(2-(4-(苯并[d]异噻唑-3-基)哌嗪-1-基)乙基)环己基)二甲基磺酰胺(33mg，产率：43％)
MS m/z(ESI):452.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.90(d,J＝8.2Hz,1H),7.81(d,J＝8.1Hz,1H),7.47(t,J＝7.4Hz,1H),7.35(t,J＝7.5Hz,1H),3.97(d,J＝8.0Hz,1H),3.59(s,4H),3.19-3.09(m,1H),2.79(s,6H),2.69(s,4H),2.52–2.39(m,2H),2.10-2.01(m,2H),1.82(d,J＝12.3Hz,2H),1.50-1.44(m,2H),1.34–0.97(m,4H).
实施例11
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)吡啶-3-磺酰胺
Figure PCTCN2020126735-appb-000059
参考实施例10得到N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)吡啶-3-磺酰胺。
MS m/z(ESI):485.2[M+H] +.
实施例12
3-(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000060
第一步：反式-4-烯丙基-4-羟基环己基)氨基甲酸叔丁酯的制备
Figure PCTCN2020126735-appb-000061
(4-羰基环己基)氨基甲酸叔丁酯(18.0g，84.40mmol)溶于无水THF(400mL)中，在-70℃，慢慢滴加烯丙基溴化镁(254mL，254mmol，1M in THF)。滴加结束后，反应液继续搅拌1小时。水(100mL)慢慢滴加至反应液中，淬灭反应，再加入乙酸乙酯(500mL*2)萃取。有机相干燥后浓缩。粗产品通过柱层析纯化(石油醚/乙酸乙酯＝55/45)，得到(反式-4-烯丙基-4-羟基环己基)氨基甲酸叔丁酯(5.4g，收率25％)。MS m/z(ESI):256.2[M+H] +。
第二步：(反式-4-羟基-4-(2-乙醛)环己基)氨基甲酸叔丁酯的制备
Figure PCTCN2020126735-appb-000062
(反式-4-烯丙基-4-羟基环己基)氨基甲酸叔丁酯(5.4g，21.15mmol)溶于THF(100mL)，加入水(100mL)。K 2OsO 4 .2H 2O(779mg，2.11mmol)和NaIO 4(18.09g，84.59mmol)分别加入到反应液中。该反应在室温搅拌过夜。饱和Na 2S 2O 4水溶液(50mL)加入到溶液中，再加入乙酸乙酯(400mL)，搅拌5分钟。有机相收集后干燥和浓缩得到(反式-4-羟基-4-(2-乙醛)环己基)氨基甲酸叔丁酯(4.8g，收率88％)。MS m/z(ESI):258.1[M+H] +。
第三步：(反式-4-羟基-4-(2-乙醇)环己基)氨基甲酸叔丁酯的制备
Figure PCTCN2020126735-appb-000063
(反式-4-羟基-4-(2-乙醛)环己基)氨基甲酸叔丁酯(4.8g，18.65mmol)溶于无水THF(100mL)，分批加入NaBH 4(1.41g，37.31mmol)。加完，反应液在室温下搅拌2小时。水(50mL)慢慢加入反应液淬灭反应，再加入乙酸乙酯(200mL*2)萃取。有机相干燥后浓缩。粗产品通过柱层析纯化(乙酸乙酯/MeOH＝95/5)得到(反式-4-羟基-4-(2-乙醇)环己基)氨基甲酸叔丁酯(3.2g，收率66％)。
MS m/z(ESI):260.2[M+H] +。
第四步：2-(反式-4-((叔-丁氧基羰基)氨基)-1-羟基环己基)乙基4-甲基苯磺酸酯的制备
Figure PCTCN2020126735-appb-000064
(反式-4-羟基-4-(2-乙醇)环己基)氨基甲酸叔丁酯(3.2g，12.34mmol)溶于无水二氯甲烷(50mL)中，加入DMAP(151mg，1.23mmol)和DIPEA(3.19g，24.68mmol)。反应液冷却至0℃，加入TsCl(2.82g，14.81mmol)。该反应升至30℃，并且搅拌过夜。加入水(50mL)和二氯甲烷(100mL)分液。有机相干燥后旋干。粗产品通过柱层析纯化(石油醚/乙酸乙酯＝1/2)，得到2-(反式-4-((叔-丁氧基羰基)氨基)-1-羟基环己基)乙基4-甲基苯磺酸(2.0g，收率39％)。
MS m/z(ESI):414.1[M+H] +。
第五步：2-(顺式-4-((叔-丁氧基羰基)氨基)-1-氟环己基)乙基4-甲基苯磺酸酯和2-(4-((叔-丁氧基羰基)氨基)环己-1-烯-1-基)乙基4-甲基苯磺酸酯的制备
Figure PCTCN2020126735-appb-000065
2-(反式-4-((叔-丁氧基羰基)氨基)-1-羟基环己基)乙基4-甲基苯磺酸(2g，4.84mmol)溶于无水二氯甲烷(50mL)，在-70℃慢慢滴加DAST(4.68g，29.02mmol)。加完以后，该反应在-70℃继续搅拌2小时。水(10mL)慢慢滴加来淬灭反应，再加入饱和NaHCO 3溶液(10mL)来调节pH至弱碱性。二氯甲烷(100mL)加入混合液萃取。有机相干燥并旋干。粗产品通过柱层析纯化(石油醚/乙酸乙酯＝3/2)得到2-(顺式-4-((叔-丁氧基羰基)氨基)-1-氟环己基)乙基4-甲基苯磺酸酯(630mg，收率31％)和2-(4-((叔-丁氧基羰基)氨基)环己-1-烯-1-基)乙基4-甲基苯磺酸酯(600mg，收率31％)。
2-(顺式-4-((叔-丁氧基羰基)氨基)-1-氟环己基)乙基4-甲基苯磺酸酯：
MS m/z(ESI):416.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.79(d,J＝8.2Hz,2H),7.36(d,J＝8.0Hz,2H),4.39(s,1H),4.21–4.12(m,2H),3.45–3.30(m,1H),2.45(s,3H),2.06–1.75(m,7H),1.52–1.46(m,1H),1.44(s,9H),1.41–1.31(m,2H).
2-(4-((叔-丁氧基羰基)氨基)环己-1-烯-1-基)乙基4-甲基苯磺酸酯：
MS m/z(ESI):396.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.78(d,J＝8.2Hz,2H),7.35(d,J＝8.0Hz,2H),5.32(s,1H),4.49(s,1H),4.13–4.00(m,2H),3.75-3.61(m,1H),2.45(s,3H),2.30-2.27(m,2H),1.99-1.94(m,1H),1.85–1.76(m,2H),1.70–1.64(m,1H),1.56–1.50(m,1H),1.45(s,9H).
第六步：(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)氨基甲酸叔丁酯的制备
Figure PCTCN2020126735-appb-000066
2-(顺式-4-((叔-丁氧基羰基)氨基)-1-氟环己基)乙基4-甲基苯磺酸酯(390mg，0.94mmol)溶于乙腈(20mL)，加入1-(2,3-二氯苯基)哌嗪(260mg，1.13mmol)和碳酸钾(389mg，2.82mmol)。该反应在90℃搅拌过夜。水(20mL)加入反应液，再加入乙酸乙酯(50mL)萃取。有机相干燥后浓缩。粗产品通过柱层析纯化(石油醚/乙酸乙酯＝1/9)得到(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)氨基甲酸叔丁酯(210mg，收率47％)。
MS m/z(ESI):474.2[M+H] +。
第七步：顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺的制备
Figure PCTCN2020126735-appb-000067
(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)氨基甲酸叔丁酯(210mg，0.442mmol)溶于25％TFA/二氯甲烷(10mL)。反应液室温搅拌2小时后，直接浓缩干得到顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺(210mg，TFA盐)。MS m/z(ESI):374.2[M+H] +。
第八步：3-(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)-1,1-二甲基脲的制备
Figure PCTCN2020126735-appb-000068
顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺(210mg，TFA盐，约0.147mmol)溶于无水二氯甲烷(5mL)，加入DIPEA(0.1mL)和二甲基氨甲酰氯(1滴)。反应液在室温搅拌过夜。水(5mL)加入反应液，再加入二氯甲烷(10mL)萃取。有机相干燥后旋干。粗产品通过prep-HPLC纯化得到3-(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)-1,1-二甲基脲(21.1mg，收率32％)。
MS m/z(ESI):445.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.20–7.12(m,2H),6.97(dd,J＝7.1,2.3Hz,1H),4.18(d,J＝7.7Hz,1H),3.75–3.60(m,1H),3.27–3.03(m,4H),2.89(s,6H),2.86–2.51(m,6H),2.04–1.81(m,6H),1.64–1.53(m,1H),1.52–1.40(m,3H).
实施例13
N-(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)-1H-吲哚-2-甲酰胺
Figure PCTCN2020126735-appb-000069
第一步：N-(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)-1H-吲哚-2-甲酰胺的制备
Figure PCTCN2020126735-appb-000070
顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺(100mg，TFA盐，0.21mmol)溶于无水DMF(3mL)，分别加入1H-吲哚-2-羧酸(52mg，0.32mmol)，HATU(160mg，0.42mmol)和DIEA(0.2mL)。该反应在室温下搅拌过夜。反应液过滤后通过prep-HPLC纯化，得到N-(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)-1H-吲哚-2-甲酰胺(25mg，收率23％)
MS m/z(ESI):517.2[M+H] +.
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.28(d,J＝8.0Hz,1H),7.59(d,J＝8.0Hz,1H),7.42(d,J＝8.2Hz,1H),7.35–7.24(m,2H),7.22–7.10(m,3H),7.02(t,J＝7.4Hz,1H),3.95–3.79(m,1H),3.08–2.92(m,4H),2.67–2.51(m,6H),1.99–1.87(m,2H),1.86–1.51(m,8H).
实施例14
N-(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)呋喃-2-甲酰胺
Figure PCTCN2020126735-appb-000071
第一步：N-(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)呋喃-2-甲酰胺的制备
Figure PCTCN2020126735-appb-000072
以顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺和呋喃-2-羧酸为原料参考实施例13第一步得到N-(顺式-4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-氟环己基)呋喃-2-甲酰胺(类白色固体，收率36％)。
MS m/z(ESI):468.2[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝8.1Hz,1H),7.80(d,J＝1.7Hz,1H),7.63(d,J＝5.6Hz,1H),7.48(d,J＝8.1Hz,1H),7.44(d,J＝5.6Hz,1H),7.21(t,J＝7.9Hz,1H),7.10(d,J＝3.5Hz,1H),6.84(d,J＝7.8Hz,1H),6.60(dd,J＝3.5,1.7Hz,1H),3.83–3.72(m,1H),3.55–3.38(m,4H),2.98–2.55(m,6H),2.06–1.92(m,2H),1.92–1.72(m,4H),1.72–1.62(m,4H),1.58–1.48(m,1H).
实施例15
3-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000073
第一步：反式-4-烯丙基-4-羟基环己基)氨基甲酸叔丁酯的制备
Figure PCTCN2020126735-appb-000074
(4-羰基环己基)氨基甲酸叔丁酯(18.0g，84.40mmol)溶于无水THF(400mL)中，在-70℃，慢慢滴加烯丙基溴化镁(254mL，254mmol，1M in THF)。滴加结束后，反应液继续搅拌1小时。水(100mL)慢慢滴加至反应液中，淬灭反应，再加入乙酸乙酯(500mL*2)萃取。有机相干燥后浓缩。粗产品通过柱层析纯化(石油醚/乙酸乙酯＝55/45)，得到(反式-4-烯丙基-4-羟基环己基)氨基甲酸叔丁酯(5.4g，收率25％)。MS m/z(ESI):256.2[M+H] +。
第二步：(反式-4-羟基-4-(2-乙醛)环己基)氨基甲酸叔丁酯的制备
Figure PCTCN2020126735-appb-000075
(反式-4-烯丙基-4-羟基环己基)氨基甲酸叔丁酯(5.4g，21.15mmol)溶于THF(100mL)，加入水(100mL)。K 2OsO 4 .2H 2O(779mg，2.11mmol)和NaIO 4(18.09g，84.59mmol)分别加入到反应液中。该反应在室温搅拌过夜。饱和Na 2S 2O 4水溶液(50mL)加入到溶液中，再加入乙酸乙酯(400mL)，搅拌5分钟。有机相收集后干燥和浓缩得到(反式-4-羟基-4-(2-乙醛)环己基)氨基甲酸叔丁酯(4.8g，收率88％)。MS m/z(ESI):258.1[M+H] +。
第三步：(反式-4-羟基-4-(2-乙醇)环己基)氨基甲酸叔丁酯的制备
Figure PCTCN2020126735-appb-000076
(反式-4-羟基-4-(2-乙醛)环己基)氨基甲酸叔丁酯(4.8g，18.65mmol)溶于无水THF(100mL)，分批加入NaBH 4(1.41g，37.31mmol)。加完，反应液在室温下搅拌2小时。水(50mL)慢慢加入反应液淬灭反应，再加入乙酸乙酯(200mL*2)萃取。有机相干燥后浓缩。粗产品通过柱层析纯化(乙酸乙酯/MeOH＝95/5)得到(反式-4-羟基-4-(2-乙醇)环己基)氨基甲酸叔丁酯(3.2g，收率66％)。
MS m/z(ESI):260.2[M+H] +。
第四步：2-(反式-4-((叔-丁氧基羰基)氨基)-1-羟基环己基)乙基4-甲基苯磺酸酯的制备
Figure PCTCN2020126735-appb-000077
(反式-4-羟基-4-(2-乙醇)环己基)氨基甲酸叔丁酯(3.2g，12.34mmol)溶于无水二氯甲烷(50mL)中，加入DMAP(151mg，1.23mmol)和DIPEA(3.19g，24.68mmol)。反应液冷却至0℃，加入TsCl(2.82g，14.81mmol)。该反应升至30℃，并且搅拌过夜。加入水(50mL)和二氯甲烷(100mL)分液。有机相干燥后旋干。粗产品通过柱层析纯化(石油醚/乙酸乙酯＝1/2)，得到2-(反式-4-((叔-丁氧基羰基)氨基)-1-羟基环己基)乙基4-甲基苯磺酸(2.0g，收率39％)。
MS m/z(ESI):414.1[M+H] +。
第五步：2-(顺式-4-((叔-丁氧基羰基)氨基)-1-氟环己基)乙基4-甲基苯磺酸酯和2-(4-((叔-丁氧基羰基)氨基)环己-1-烯-1-基)乙基4-甲基苯磺酸酯的制备
Figure PCTCN2020126735-appb-000078
2-(反式-4-((叔-丁氧基羰基)氨基)-1-羟基环己基)乙基4-甲基苯磺酸(2g，4.84mmol)溶于无水二氯甲烷(50mL)，在-70℃慢慢滴加DAST(4.68g，29.02mmol)。加完以后，该反应在-70℃继续搅拌2小时。水(10mL)慢慢滴加来淬灭反应，再加入饱和NaHCO 3溶液(10mL)来调节pH至弱碱性。二氯甲烷(100mL)加入混合液萃取。有机相干燥并旋干。粗产品通过柱层析纯化(石油醚/乙酸乙酯＝3/2)得到2-(顺式-4-((叔-丁氧基羰基)氨基)-1-氟环己基)乙基4-甲基苯磺酸酯(630mg，收率31％)和2-(4-((叔-丁氧基羰基)氨基)环己-1-烯-1-基)乙基4-甲基苯磺酸酯(600mg，收率31％)。
2-(顺式-4-((叔-丁氧基羰基)氨基)-1-氟环己基)乙基4-甲基苯磺酸酯：
MS m/z(ESI):416.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.79(d,J＝8.2Hz,2H),7.36(d,J＝8.0Hz,2H),4.39(s,1H),4.21–4.12(m,2H),3.45–3.30(m,1H),2.45(s,3H),2.06–1.75(m,7H),1.52–1.46(m,1H),1.44(s,9H),1.41–1.31(m,2H).
2-(4-((叔-丁氧基羰基)氨基)环己-1-烯-1-基)乙基4-甲基苯磺酸酯：
MS m/z(ESI):396.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.78(d,J＝8.2Hz,2H),7.35(d,J＝8.0Hz,2H),5.32(s,1H),4.49(s,1H),4.13–4.00(m,2H),3.75-3.61(m,1H),2.45(s,3H),2.30-2.27(m,2H),1.99-1.94(m,1H),1.85–1.76(m,2H),1.70–1.64(m,1H),1.56–1.50(m,1H),1.45(s,9H).
第六步：(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)氨基甲酸叔丁酯的制备
Figure PCTCN2020126735-appb-000079
以2-(顺式-4-((叔-丁氧基羰基)氨基)-1-氟环己基)乙基4-甲基苯磺酸酯溶于乙腈(20mL)，加入1-(苯并[b]噻吩-4-基)哌嗪和碳酸钾(389mg，2.82mmol)。该反应在90℃搅拌过夜。加入反应液中加入水(20mL)，再加入乙酸乙酯(50mL)萃取。有机相干燥后浓缩。粗产品通过柱层析纯化(石油醚/乙酸乙酯＝1/9)为原料参考实施例12第六步得到(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)氨基甲酸叔丁酯(180mg，收率70％)。
MS m/z(ESI):462.2[M+H] +.
第七步：顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺的制备
Figure PCTCN2020126735-appb-000080
以(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)氨基甲酸叔丁酯溶于25％TFA/二氯甲烷(10mL)。反应液室温搅拌2小时后，直接浓缩干得到为原料参考实施例12第七步得到顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺(180mg，TFA盐)。
MS m/z(ESI):362.1[M+H] +.
第八步：3-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)-1,1- 二甲基脲的制备
Figure PCTCN2020126735-appb-000081
顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺为溶于无水二氯甲烷，加入DIPEA和二甲基氨甲酰氯。反应液在室温搅拌过夜。像反应液中加入水，再加入二氯甲烷萃取。有机相干燥后旋干。粗产品通过prep-HPLC纯化原料参考实施例12第八步得到3-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)-1,1-二甲基脲(18.0mg，收率32％)。
MS m/z(ESI):433.2[M+H] +.
1H NMR(400MHz,DMSO)δ7.69(d,J＝5.5Hz,1H),7.61(d,J＝8.0Hz,1H),7.40(d,J＝5.5Hz,1H),7.27(t,J＝7.8Hz,1H),6.90(d,J＝7.6Hz,1H),5.96(d,J＝7.9Hz,1H),3.52–3.38(m,1H),3.16–2.98(m,4H),2.76(s,6H),2.70–2.56(m,4H),2.49–2.44(m,2H),1.94–1.72(m,4H),1.67–1.60(m,2H),1.60–1.43(m,4H).
实施例16
1-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)-3-乙基脲
Figure PCTCN2020126735-appb-000082
第一步：1-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)-3-乙基脲的制备
Figure PCTCN2020126735-appb-000083
将顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺和三乙胺溶解在无水二氯甲烷中，然后滴加和异氰酸基乙烷为在室温搅拌1小时，向反应液中加水，用乙酸乙酯萃取，合并有机相用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，经过制备色谱分离，或者原料参考实施例12第八步得到1-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)-3-乙基脲(37.2mg，收率66％)。
MS m/z(ESI):433.2[M+H] +.
1H NMR(400MHz,DMSO)δ7.69(d,J＝5.5Hz,1H),7.61(d,J＝8.0Hz,1H),7.40(d,J＝5.5Hz,1H),7.27(t,J＝7.8Hz,1H),6.94–6.87(m,1H),5.74(d,J＝7.9Hz,1H),5.62(t,J＝5.5Hz,1H),3.44–3.34(m,1H),3.14–3.03(m,4H),3.03– 2.94(m,2H),2.71–2.55(m,4H),2.46(s,2H),1.88–1.73(m,4H),1.71–1.61(m,2H),1.61–1.43(m,2H),1.40–1.26(m,2H),0.97(t,J＝7.2Hz,3H).
实施例17
N-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)吡咯烷-1-甲酰胺
Figure PCTCN2020126735-appb-000084
以顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺和吡咯盐酸盐为原料参考实施例8第三步得到N-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)吡咯烷-1-甲酰胺。
MS m/z(ESI):459.2[M+H] +.
实施例18
1-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)-3-环丙基脲
Figure PCTCN2020126735-appb-000085
以顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺和环丙胺盐酸盐为原料参考实施例8第三步得到1-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)-3-环丙基脲。
MS m/z(ESI):445.2[M+H] +.
实施例19
3-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-甲基环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000086
第一步：乙基(1r,4r)-4-(1,3-二羰基异二氢吲哚-2-基)环己烷-1-羧酸酯的制备
Figure PCTCN2020126735-appb-000087
将乙基(1r,4r)-4-氨基环己烷-1-羧酸酯(5g，29mmol)溶于甲苯(200mL)，加入三乙胺(8.8g，88mmol)和异苯并呋喃-1,3-二酮(5.2g，35mmol)，反应在140℃下搅拌8小时。冷却至室温，溶剂旋干，加入水(50mL)，搅拌半小时，有固体析出，过滤，收集固体，旋干，得到乙基(1r,4r)-4-(1,3-二羰基异二氢吲哚-2-基)环己烷-1-羧酸酯(3g)。
MS m/z(ESI):302.2[M+H] +.
第二步：4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-羧酸乙酯的制备
Figure PCTCN2020126735-appb-000088
将(1r,4r)-4-(1,3-二羰基异二氢吲哚-2-基)环己烷-1-羧酸乙酯(3g，10mmol)溶于四氢呋喃(50mL)，冷却至-78℃，加入二异丙基氨基锂(11mL,11mmol)，在此温度下搅拌半小时。再加入碘甲烷(1.7g，12mmol)，反应缓慢升至室温搅拌过夜。加入氯化铵的水溶液(50mL)，搅拌半小时，水相用乙酸乙酯(100mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-羧酸乙酯(3.0g，产率：100％crude)。
第三步：2-(4-(羟甲基)-4-甲基环己基)异二氢吲哚-1,3-二酮的制备
Figure PCTCN2020126735-appb-000089
将4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-羧酸乙酯(3g，9.5mmol)溶于四氢呋喃(30mL)，冷却至0℃，加入四氢铝锂(0.43g，11mmol)，在此温度下搅拌2小时。加入3M氢氧化钠的水溶液(5mL)淬灭反应，加入水(50mL)，水相用乙酸乙酯(100mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得2-(4-(羟甲基)-4-甲基环己基)异二氢吲哚-1,3-二酮(2.6g，产率：100％crude)。
第四步：4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-甲醛的制备
Figure PCTCN2020126735-appb-000090
将2-(4-(羟甲基)-4-甲基环己基)异二氢吲哚-1,3-二酮(2.6g，9.5mmol)溶于二氯甲烷(30mL)，加入PCC(4.1g，19mmol)，在室温下搅拌2小时。反应液旋干，粗品用柱层析分离(石油醚/乙酸乙酯：50/1～1/1)纯化得到4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-甲醛(1.5g)。
MS m/z(ESI):272.2[M+H] +.
第五步：2-(4-甲基-4-乙烯基环己基)异二氢吲哚-1,3-二酮的制备
Figure PCTCN2020126735-appb-000091
将溴化甲基三苯基磷(2.9g，8.3mmol)溶于四氢呋喃(50mL)，置换N 2，冷却至0℃，加入叔丁醇钾(1.1g，10mmol)，反应在室温下搅拌2小时。冷却至0℃，加入4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-甲醛(1.5g，5.5mmol)的四氢呋喃溶液(10mL)。反应在室温下搅拌2小时，再在50℃下搅拌过夜。加水(100mL)淬灭反应，水相用乙酸乙酯(100mL)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，粗品用柱层析分离(石油醚/乙酸乙酯：50/1～1/1)纯化得到2-(4-甲基-4-乙烯基环己基)异二氢吲哚-1,3-二酮(1.2g)。
MS m/z(ESI):270.2[M+H] +.
第六步：2-(4-(2-羟基乙基)-4-甲基环己基)异二氢吲哚-1,3-二酮的制备
Figure PCTCN2020126735-appb-000092
将2-(4-甲基-4-乙烯基环己基)异二氢吲哚-1,3-二酮(1.2g，4.5mmol)溶于无水四氢呋喃(20mL)，冷却至0℃，滴加BH 3/THF(13.5mL,13.5mmol)。反应在室温搅拌3小时，TLC显示反应完全。反应冷却至0℃，缓慢加入3M NaOH水溶液(4mL)，再加入水 2(3mL)，反应在室温搅拌2小时，TLC显示反应完全。加入乙酸乙酯(50mL)，用饱和Na 2S 2O 3水溶液(30mL)洗，再用水(30mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩，得粗品(1.2g，产率：100％crude)，直接用于下一步反应。
MS m/z(ESI):288.2[M+H] +.
第七步：2-(4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己基)乙基4-甲基苯磺酸酯的制备
Figure PCTCN2020126735-appb-000093
将2-(4-(2-羟基乙基)-4-甲基环己基)异二氢吲哚-1,3-二酮(1.2g，4.5mmol)溶于二氯甲烷(20mL)，加入三乙胺(1.4g，13.4mmol)和对甲苯磺酰氯(1.0g，5.4mmol)，反应在室温下搅拌过夜。反应液旋干，粗品用柱层析分离(石油醚/乙酸乙酯：50/1～1/1)纯化得到2-(4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己基)乙基4-甲基苯磺酸酯(1.5g)。
MS m/z(ESI):442.2[M+H] +.
第八步：2-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-甲基环己基)异二氢吲哚-1,3-二酮的制备
Figure PCTCN2020126735-appb-000094
将2-(4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己基)乙基4-甲基苯磺酸酯(1.5g，3.4mmol)，1-(2,3-二氯苯基)哌嗪(0.79g，3.4mmol)和碳酸钾(1.4g，10.2mmol)溶于乙腈(30mL)，反应在80℃下搅拌过夜。反应液过滤，旋干，粗品用柱层析分离(石油醚/乙酸乙酯：50/1～1/1)纯化得到2-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-甲基环己基)异二氢吲哚-1,3-二酮(1.4g)。
MS m/z(ESI):500.2[M+H] +.
第九步：4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-甲基环己烷-1-胺的制备
Figure PCTCN2020126735-appb-000095
将2-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-甲基环己基)异二氢吲哚-1,3-二酮(1.4g，2.8mmol)溶于乙醇(50mL)，加入水合肼(0.35mL,7.0mmol)，反应在80℃下搅拌过夜。反应液旋干，加入水(50mL)，水相用乙酸乙酯(50mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-甲基环己烷-1-胺(0.6g)。
MS m/z(ESI):370.2[M+H] +.
第十步：3-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-甲基环己基)-1,1-二甲基脲的制备
Figure PCTCN2020126735-appb-000096
将4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-甲基环己烷-1-胺(50mg，0.14mmol)溶于二氯甲烷(5mL)，加入三乙胺(71mg，0.7mmol)和二甲基氨甲氯化(299mg，2.3mmol)，反应在室温下搅拌过夜。溶剂旋干，粗品用高效液相色谱柱分离，得到3-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-4-甲基环己基)-1,1-二甲基脲(10.0mg)。
MS m/z(ESI):441.2[M+H] +.
实施例20
3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-甲基环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000097
第一步：乙基(1r,4r)-4-(1,3-二羰基异二氢吲哚-2-基)环己烷-1-羧酸酯的制备
Figure PCTCN2020126735-appb-000098
将乙基(1r,4r)-4-氨基环己烷-1-羧酸酯(5g，29mmol)溶于甲苯(200mL)，加入三乙胺(8.8g，88mmol)和异苯并呋喃-1,3-二酮(5.2g，35mmol)，反应在140℃下搅拌8小时。冷却至室温，溶剂旋干，加入水(50mL)，搅拌半小时，有固体析出，过滤，收集固体，旋干，得到乙基(1r,4r)-4-(1,3-二羰基异二氢吲哚-2-基)环己烷-1-羧酸酯(3g)。
MS m/z(ESI):302.2[M+H] +.
第二步：4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-羧酸乙酯的制备
Figure PCTCN2020126735-appb-000099
将(1r,4r)-4-(1,3-二羰基异二氢吲哚-2-基)环己烷-1-羧酸乙酯(3g，10mmol)溶于四氢呋喃(50mL)，冷却至-78℃，加入二异丙基氨基锂(11mL,11mmol)，在此温度下搅拌半小时。再加入碘甲烷(1.7g，12mmol)，反应缓慢升至室温搅拌 过夜。加入氯化铵的水溶液(50mL)，搅拌半小时，水相用乙酸乙酯(100mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-羧酸乙酯(3.0g，产率：100％crude)。
第三步：2-(4-(羟甲基)-4-甲基环己基)异二氢吲哚-1,3-二酮的制备
Figure PCTCN2020126735-appb-000100
将4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-羧酸乙酯(3g，9.5mmol)溶于四氢呋喃(30mL)，冷却至0℃，加入四氢铝锂(0.43g，11mmol)，在此温度下搅拌2小时。加入3M氢氧化钠的水溶液(5mL)淬灭反应，加入水(50mL)，水相用乙酸乙酯(100mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得2-(4-(羟甲基)-4-甲基环己基)异二氢吲哚-1,3-二酮(2.6g，产率：100％crude)。
第四步：4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-甲醛的制备
Figure PCTCN2020126735-appb-000101
将2-(4-(羟甲基)-4-甲基环己基)异二氢吲哚-1,3-二酮(2.6g，9.5mmol)溶于二氯甲烷(30mL)，加入PCC(4.1g，19mmol)，在室温下搅拌2小时。反应液旋干，粗品用柱层析分离(石油醚/乙酸乙酯：50/1～1/1)纯化得到4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-甲醛(1.5g)。
MS m/z(ESI):272.2[M+H] +.
第五步：2-(4-甲基-4-乙烯基环己基)异二氢吲哚-1,3-二酮的制备
Figure PCTCN2020126735-appb-000102
将溴化甲基三苯基磷(2.9g，8.3mmol)溶于四氢呋喃(50mL)，置换N 2，冷却至0℃，加入叔丁醇钾(1.1g，10mmol)，反应在室温下搅拌2小时。冷却至0℃，加入4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己烷-1-甲醛(1.5g，5.5mmol)的四氢呋喃溶液(10mL)。反应在室温下搅拌2小时，再在50℃下搅拌过夜。加水(100mL)淬灭反应，水相用乙酸乙酯(100mL)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，粗品用柱层析分离(石油醚/乙酸乙酯：50/1～1/1)纯化得到2-(4-甲基-4-乙烯基环己基)异二氢吲哚-1,3-二酮(1.2g)。
MS m/z(ESI):270.2[M+H] +.
第六步：2-(4-(2-羟基乙基)-4-甲基环己基)异二氢吲哚-1,3-二酮的制备
Figure PCTCN2020126735-appb-000103
将2-(4-甲基-4-乙烯基环己基)异二氢吲哚-1,3-二酮(1.2g，4.5mmol)溶于无水四氢呋喃(20mL)，冷却至0℃，滴加BH 3/THF(13.5mL,13.5mmol)。反应在室温搅拌3小时，TLC显示反应完全。反应冷却至0℃，缓慢加入3M NaOH水溶液(4mL)，再加入水 2(3mL)，反应在室温搅拌2小时，TLC显示反应完全。加入乙酸乙酯(50mL)，用饱和Na 2S 2O 3水溶液(30mL)洗，再用水(30mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩，得粗品(1.2g，产率：100％crude)，直接用于下一步反应。
MS m/z(ESI):288.2[M+H] +.
第七步：2-(4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己基)乙基4-甲基苯磺酸酯的制备
Figure PCTCN2020126735-appb-000104
将2-(4-(2-羟基乙基)-4-甲基环己基)异二氢吲哚-1,3-二酮(1.2g，4.5mmol)溶于二氯甲烷(20mL)，加入三乙胺(1.4g，13.4mmol)和对甲苯磺酰氯(1.0g，5.4mmol)，反应在室温下搅拌过夜。反应液旋干，粗品用柱层析分离(石油醚/乙酸乙酯：50/1～1/1)纯化得到2-(4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己基)乙基4-甲基苯磺酸酯(1.5g)。
MS m/z(ESI):442.2[M+H] +.
第八步：3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-甲基环己基)异二氢吲哚-1,3-二酮的制备
Figure PCTCN2020126735-appb-000105
将2-(4-(1,3-二羰基异二氢吲哚-2-基)-1-甲基环己基)乙基4-甲基苯磺酸酯(1.5g，3.4mmol)，1-(苯并[b]噻吩-4-基)哌嗪(0.79g，3.4mmol)和碳酸钾(1.4g，10.2mmol)溶于乙腈(30mL)，反应在80℃下搅拌过夜。反应液过滤，旋干，粗品用柱层析分离(石油醚/乙酸乙酯：50/1～1/1)纯化得到3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-甲基环己基)异二氢吲哚-1,3-二酮(1.4g)。
MS m/z(ESI):500.2[M+H] +.
第九步：3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-甲基环己基-1-胺
Figure PCTCN2020126735-appb-000106
将3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-甲基环己基)异二氢吲哚-1,3-二酮(1.4g，2.8mmol)溶于乙醇(50mL)，加入水合肼(0.35mL,7.0mmol)，反应在80℃下搅拌过夜。反应液旋干，加入水(50mL)，水相用乙酸乙酯(50mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-甲基环己基-1-胺(0.6g)。
MS m/z(ESI):370.2[M+H] +.
第十步：3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-甲基环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000107
将3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-甲基环己基-1-胺(50mg，0.14mmol)溶于二氯甲烷(5mL)，加入三乙胺(71mg，0.7mmol)和二甲基氨甲氯化(299mg，2.3mmol)，反应在室温下搅拌过夜。溶剂旋干，粗品用高效液相色谱柱分离，参考实施例19，得到3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-甲基环己基)-1,1-二甲基脲(20.0mg)。
MS m/z(ESI):429.2[M+H] +.
实施例21
3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000108
第一步：叔-丁基(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-基)氨基甲酸酯的制备
Figure PCTCN2020126735-appb-000109
以2-(4-((叔-丁氧基羰基)氨基)环己-1-烯-1-基)乙基4-甲基苯磺酸酯和1-(苯 并[b]噻吩-4-基)哌嗪为原料参考实施例12第六步得到叔-丁基(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-基)氨基甲酸酯(400mg，收率72％)。
MS m/z(ESI):442.2[M+H] +.
第二步：4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-胺的制备
Figure PCTCN2020126735-appb-000110
以叔-丁基(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-基)氨基甲酸酯为原料参考实施例12第七步得到4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-胺(280mg，收率91％)。
MS m/z(ESI):342.1[M+H] +.
第三步：3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-基)-1,1-二甲基脲的制备
Figure PCTCN2020126735-appb-000111
以4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-胺为原料参考实施例12第八步得到3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-基)-1,1-二甲基脲。
MS m/z(ESI):413.2[M+H] +.
实施例22
1-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-基)-3-丙基脲
Figure PCTCN2020126735-appb-000112
第一步：1-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-基)-3-丙基脲的制备
Figure PCTCN2020126735-appb-000113
以4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-胺和异氰酸基丙烷为原料参考实施例12第八步或者参考实施例16得到1-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己-3-烯-1-基)-3-丙基脲。
MS m/z(ESI):427.2[M+H] +.
实施例23
3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-2-氟环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000114
以4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-2-氟环己烷-1-胺和二甲基氨甲酰氯为原料参考实施例12第八步得到3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-2-氟环己基)-1,1-二甲基脲。
MS m/z(ESI):[M+H] +.433.2
实施例24
1-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-2-氟环己基)-3-乙基脲
Figure PCTCN2020126735-appb-000115
以4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-2-氟环己烷-1-胺和异氰酸基乙烷为原料参考实施例12第八步或者参考实施例16得到1-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-2-氟环己基)-3-乙基脲。
MS m/z(ESI):[M+H] +.433.2
实施例25
1-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己基)-3-乙基脲
Figure PCTCN2020126735-appb-000116
第一步：1-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己基)-3-乙基脲的制备
Figure PCTCN2020126735-appb-000117
将4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己烷-1-胺(60mg，0.16mmol)溶于二氯甲烷(3mL)，加入三乙胺(48.5mg，0.48mmol)，反应在室温下搅拌5分钟，再加入异氰酸基乙烷(17.3mg，0.24mmol)，反应在室温下搅拌过夜。 溶剂旋干，粗品用高效液相色谱柱分离，得到1-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己基)-3-乙基脲(11.9mg，收率：17％)。
MS m/z(ESI):441.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.21–7.11(m,2H),7.01–6.95(m,1H),4.25–4.00(m,2H),3.26–3.13(m,5H),2.91–2.52(m,6H),2.19–2.11(m,1H),1.94–1.86(m,1H),1.69–1.55(m,5H),1.37–1.10(m,11H).
实施例26
N-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己基)-5-氟嘧啶-2-胺
Figure PCTCN2020126735-appb-000118
第一步：N-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己基)-5-氟嘧啶-2-胺的制备
Figure PCTCN2020126735-appb-000119
将4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己烷-1-胺(50mg，0.14mmol)溶于N,N-二甲基甲酰胺(3mL)，加入碳酸钾(41mg，0.4mmol)和2-氯-5-氟嘧啶(40mg，0.3mmol)，反应在室温下搅拌过夜。溶剂旋干，粗品用高效液相色谱柱分离，得到N-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己基)-5-氟嘧啶-2-胺。
MS m/z(ESI):466.1[M+H] +.
实施例27
N-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己基)-1H-吲哚-2-甲酰胺
Figure PCTCN2020126735-appb-000120
第一步：N-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己基)-1H-吲哚-2-甲酰胺的制备
Figure PCTCN2020126735-appb-000121
将4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己烷-1-胺(50mg，0.14mmol)溶于N,N-二甲基甲酰胺(3mL)，加入1H-吲哚-2-羧酸(27mg，0.17mmol)，HATU(74mg，0.2mmol)和二异丙基乙胺(39mg，0.3mmol)，反应在室温下搅拌过夜。溶剂旋干，粗品用高效液相色谱柱分离，得到N-(4-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1-甲基环己基)-1H-吲哚-2-甲酰胺。
MS m/z(ESI):513.2[M+H] +.
实施例28
3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-1-甲基环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000122
第一步：3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-1-甲基环己基)-1,1-二甲基脲的制备
Figure PCTCN2020126735-appb-000123
将3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-1-甲基环己基)-1-胺溶于N,N-二甲基甲酰胺，加入二甲基氨基甲酸，HATU和二异丙基乙胺，反应在室温下搅拌过夜。溶剂旋干，粗品用高效液相色谱柱分离，参考实施例27，得到3-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-1-甲基环己基)-1,1-二甲基脲。
MS m/z(ESI):429.2[M+H] +.
实施例29
1-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-1-甲基环己基)-3-乙基脲
Figure PCTCN2020126735-appb-000124
参考实施例25，得到1-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-1-甲基环 己基)-3-乙基脲
MS m/z(ESI):429.2[M+H] +.
实施例30
3-(反式-4-(2-((R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-基)乙基)环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000125
第一步：(R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-羧酸叔丁酯
Figure PCTCN2020126735-appb-000126
50mL圆底烧瓶中将1-溴-2,3-二氯苯(1.35g，6mmol)，(R)-2-甲基哌嗪-1-羧酸叔丁酯(836mg，5mmol)，三(二亚苄基丙酮)二钯(228mg，0.25mmol)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(289mg，0.5mmol)，叔丁醇钠(1.44g，15mmol)溶于20毫升甲苯中，反应液用氮气置换。反应于80℃下并在氮气保护下搅拌12小时。反应完成后，反应体系冷却至室温，水淬灭反应，乙酸乙酯(10mL*3)萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(石油醚/乙酸乙酯＝4/1冲洗)得到(R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-羧酸叔丁酯(1.0g，黄色固体，产率：48.3％)。
MS m/z(ESI):345.1[M+H] +.
第二步：(R)-1-(2,3-二氯苯基)-3-甲基哌嗪
Figure PCTCN2020126735-appb-000127
50mL圆底烧瓶中将叔-丁基(R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-羧酸酯(1g，2.89mmol)溶于10mL二氯甲烷中，然后加入三氟乙酸(4mL)。反应于室温下下并搅拌12小时。反应完成后，反应体系浓缩，饱和碳酸氢钠溶液淬灭反应，乙酸乙酯(10mL*3)萃取。有机相无水硫酸钠干燥。过滤，旋干得到(R)-1-(2,3-二氯苯基)-3-甲基哌嗪(600mg，白色固体，产率：84.7％)。
MS m/z(ESI):245.1[M+H] +.
第三步：(反式-4-(2-((R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-基)乙基)环己基)氨 基甲酸叔丁酯
Figure PCTCN2020126735-appb-000128
以(R)-1-(2,3-二氯苯基)-3-甲基哌嗪和2-(反式-4-((叔-丁氧基羰基)氨基)环己基)乙基4-甲基苯磺酸酯为原料参考实施例2第一步得到叔丁基(反式-4-(2-((R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-基)乙基)环己基)氨基甲酸酯(100mg，黄色固体，产率：26.0％)。
MS m/z(ESI):470.1[M+H] +.
第四步：反式-4-(2-((R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-基)乙基)环己烷-1-胺
Figure PCTCN2020126735-appb-000129
以(反式-4-(2-((R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-基)乙基)环己基)氨基甲酸叔丁酯为原料参考实施例2第二步得到反式-4-(2-((R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-基)乙基)环己烷-1-胺(75mg，黄色固体，产率：95.2％)。
MS m/z(ESI):370.1[M+H] +.
第五步：3-(反式-4-(2-((R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-基)乙基)环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000130
反式-4-(2-((R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-基)乙基)环己烷-1-胺(60mg，0.16mmol)溶于3mL二氯甲烷溶液中，加入三乙胺(50mg，0.5mmol)，然后二甲氨基甲酰氯(35mg，0.32mmol)加入到反应液中，在室温下反应12小时。反应液用水洗三次(2mL*3)，有机相浓缩后用prep-HPLC制备得产品得到3-(反式-4-(2-((R)-4-(2,3-二氯苯基)-2-甲基哌嗪-1-基)乙基)环己基)-1,1-二甲基脲(8.3mg，白色固体，产率：13.9％)。
MS m/z(ESI):441.2[M+H] +.
1H NMR(400MHz,Methanol-d 4)δ7.39–7.17(m,2H),7.13–7.01(m,1H),3.59–3.45(m,2H),3.28–3.15(m,2H),3.08–2.93(m,2H),2.89(s,6H),2.78–2.57(m,3H),2.52–2.41(m,1H),1.97–1.77(m,4H),1.55–1.39(m,2H),1.37–1.21(m,3H),1.17(d,J＝6.0Hz,3H),1.13–1.03(m,2H).
实施例31
3-(反式-4-(2-((R)-4-(苯并[b]噻吩-4-基)-3-环丙基哌嗪-1-基)乙基)环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000131
以4-溴苯并[b]噻吩和(R)-3-环丙基哌嗪-1-甲酸叔丁酯为原料参考实施例30得3-(反式-4-(2-((R)-4-(苯并[b]噻吩-4-基)-3-环丙基哌嗪-1-基)乙基)环己基)-1,1-二甲基脲。
MS m/z(ESI):455.2[M+H] +.
实施例32
3-(反式-4-(2-((S)-4-(苯并[b]噻吩-4-基)-3-氰基哌嗪-1-基)乙基)环己基)-1,1-二甲基脲的制备
Figure PCTCN2020126735-appb-000132
参考实施例30得到3-(反式-4-(2-((S)-4-(苯并[b]噻吩-4-基)-3-氰基哌嗪-1-基)乙基)环己基)-1,1-二甲基脲。
MS m/z(ESI):440.2[M+H] +.
实施例33
3-(反式-4-(2-((R)-4-(苯并[b]噻吩-4-基)-3-甲基哌嗪-1-基)乙基)环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000133
以4-溴苯并[b]噻吩和(R)-3-甲基哌嗪-1-羧酸叔丁酯为原料参考实施例30得产品3-(反式-4-(2-((R)-4-(苯并[b]噻吩-4-基)-3-甲基哌嗪-1-基)乙基)环己基)-1,1-二甲基脲。
MS m/z(ESI):429.2[M+H] +.
实施例34
3-(反式-4-(2-(5-(苯并[b]噻吩-4-基)-2,5-二氮杂二环[4.2.0]辛烷-2-基)乙基)环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000134
第一步：2-(苯并[b]噻吩-4-基)-2,5-二氮杂二环[4.2.0]辛烷
Figure PCTCN2020126735-appb-000135
以4-溴苯并[B]噻吩和2,5-二氮杂二环[4.2.0]辛烷为原料参考实施例30第一步得到2-(苯并[b]噻吩-4-基)-2,5-二氮杂二环[4.2.0]辛烷(290mg，白色固体，产率：48％)。
MS m/z(ESI):245.1[M+H] +.
第二步：(反式-4-(2-(5-(苯并[b]噻吩-4-基)-2,5-二氮杂二环[4.2.0]辛烷-2-基)乙基)环己基)氨基甲酸叔丁酯
Figure PCTCN2020126735-appb-000136
以2-(苯并[b]噻吩-4-基)-2,5-二氮杂二环[4.2.0]辛烷为原料参考实施例30第三步得到(反式-4-(2-(5-(苯并[b]噻吩-4-基)-2,5-二氮杂二环[4.2.0]辛烷-2-基)乙基)环己基)氨基甲酸叔丁酯(301mg，白色固体，产率：54％)。
MS m/z(ESI):470.3[M+H] +.
第三步：反式-4-(2-(5-(苯并[b]噻吩-4-基)-2,5-二氮杂二环[4.2.0]辛烷-2-基)乙基)环己烷-1-胺
Figure PCTCN2020126735-appb-000137
以(反式-4-(2-(5-(苯并[b]噻吩-4-基)-2,5-二氮杂二环[4.2.0]辛烷-2-基)乙基)环己基)氨基甲酸叔丁酯为原料参考实施例12第七步得到反式-4-(2-(5-(苯并[b]噻吩 -4-基)-2,5-二氮杂二环[4.2.0]辛烷-2-基)乙基)环己烷-1-胺的三氟甲磺酸盐(299mg，产率：99％)。
MS m/z(ESI):370.2[M+H] +.
第四步：3-(反式-4-(2-(5-(苯并[b]噻吩-4-基)-2,5-二氮杂二环[4.2.0]辛烷-2-基)乙基)环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000138
以反式-4-(2-(5-(苯并[b]噻吩-4-基)-2,5-二氮杂二环[4.2.0]辛烷-2-基)乙基)环己烷-1-胺为原料参考实施例12第八步得到3-(反式-4-(2-(5-(苯并[b]噻吩-4-基)-2,5-二氮杂二环[4.2.0]辛烷-2-基)乙基)环己基)-1,1-二甲基脲(23mg，白色固体，产率：35％)。
MS m/z(ESI):441.3[M+H] +.
实施例35
3-(反式-4-(2-((R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-基)乙基)环己基)-1,1-二甲
基脲
Figure PCTCN2020126735-appb-000139
第一步：(R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-羧酸叔丁酯
Figure PCTCN2020126735-appb-000140
以1-溴-2,3-二氯苯和(R)-3-甲基哌嗪-1-羧酸叔丁酯为原料参考实施例30第一步得到叔-丁基(R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-羧酸酯(600mg，黄色固体，产率：32.6％)。
MS m/z(ESI):345.1[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.26–7.21(m,1H),7.21–7.11(m,1H),7.11–6.94(m,1H),3.99–3.00(m,7H),1.49(s,9H),0.91(d,J＝6.3Hz,3H).
第二步：(R)-1-(2,3-二氯苯基)-2-甲基哌嗪
Figure PCTCN2020126735-appb-000141
以(R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-羧酸叔-酯为原料参考实施例30第二步得到(R)-1-(2,3-二氯苯基)-2-甲基哌嗪(420mg，黄色固体，产率：98.8％)。
MS m/z(ESI):245.1[M+H] +.
1H NMR(400MHz,Methanol-d4)δ7.36–7.29(m,1H),7.27–7.16(m,2H),3.60–3.44(m,1H),3.42–3.27(m,2H),3.21–3.13(m,2H),3.02–2.81(m,2H),0.88(d,J＝6.3Hz,3H).
第三步：(反式-4-(2-((R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-基)乙基)环己基)氨基甲酸叔丁酯
Figure PCTCN2020126735-appb-000142
以(R)-1-(2,3-二氯苯基)-2-甲基哌嗪和2-(反式-4-((叔-丁氧基羰基)氨基)环己基)乙基4-甲基苯磺酸酯为原料参考实施例2第一步得到(反式-4-(2-((R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-基)乙基)环己基)氨基甲酸叔丁酯(100mg，黄色固体，产率：26.0％)。
MS m/z(ESI):470.1[M+H] +.
第四步：反式-4-(2-((R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-基)乙基)环己烷-1-胺
Figure PCTCN2020126735-appb-000143
以(反式-4-(2-((R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-基)乙基)环己基)氨基甲酸叔丁酯为原料参考实施例2第二步得到反式-4-(2-((R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-基)乙基)环己烷-1-胺(75mg，黄色固体，产率：95.2％)。
MS m/z(ESI):370.1[M+H] +.
第五步：3-(反式-4-(2-((R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-基)乙基)环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000144
以反式-4-(2-((R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-基)乙基)环己烷-1-胺为原料参考实施例30第五步得到3-(反式-4-(2-((R)-4-(2,3-二氯苯基)-3-甲基哌嗪-1-基)乙基)环己基)-1,1-二甲基脲(25mg，白色固体，产率：35.0％)。
MS m/z(ESI):441.2[M+H] +.
1H NMR(400MHz,Methanol-d 4)δ7.38–7.15(m,3H),3.56–3.44(m,1H),3.36(s,2H),3.12(d,J＝11.6Hz,1H),2.93(s,1H),2.87(s,6H),2.77–2.67(m,1H),2.52–2.34(m,3H),2.17–2.02(m,1H),1.96–1.75(m,4H),1.57–1.42(m,2H),1.37–1.21(m,3H),1.15–0.99(m,2H),0.87(d,J＝6.1Hz,3H).
实施例36
3-(反式-4-(2-((S)-4-(苯并[b]噻吩-4-基)-3-(三氟甲基)哌嗪-1-基)乙基)环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000145
以反式-4-(2-((S)-4-(苯并[b]噻吩-4-基)-3-(三氟甲基)哌嗪-1-基)乙基)环己烷-1-胺为原料参考实施例30第五步得到3-(反式-4-(2-((S)-4-(苯并[b]噻吩-4-基)-3-(三氟甲基)哌嗪-1-基)乙基)环己基)-1,1-二甲基脲。
MS m/z(ESI):483.2[M+H] +.
实施例37
N-(反式-4-(2-((S)-4-(苯并[b]噻吩-4-基)-3-(三氟甲基)哌嗪-1-基)乙基)环己基)噁唑-2-甲酰胺
Figure PCTCN2020126735-appb-000146
以反式-4-(2-((S)-4-(苯并[b]噻吩-4-基)-3-(三氟甲基)哌嗪-1-基)乙基)环己烷-1-胺为原料参考实施例30第五步得到N-(反式-4-(2-((S)-4-(苯并[b]噻吩-4-基)-3-(三氟甲基)哌嗪-1-基)乙基)环己基)噁唑-2-甲酰胺。
MS m/z(ESI):507.2[M+H] +.
实施例38
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)-1,4-重氮基庚环-1-基)乙基)环己基)-3,3-二氟吖丁啶-1-甲酰胺
Figure PCTCN2020126735-appb-000147
以1-(苯并[b]噻吩-4-基)-1,4-重氮基庚环为原料参考实施例2第一至第三步得N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)-1,4-重氮基庚环-1-基)乙基)环己基)-3,3-二氟吖丁啶-1-甲酰胺。
MS m/z(ESI):477.2[M+H] +.
实施例39
3-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)-1,4-重氮基庚环-1-基)乙基)-4-氟环己基)-1,1-二甲基脲
Figure PCTCN2020126735-appb-000148
第一步：叔-丁基(顺式-4-(2-(4-(苯并[b]噻吩-4-基)-1,4-重氮基庚环-1-基)乙基)-4-氟环己基)氨基甲酸酯的制备
Figure PCTCN2020126735-appb-000149
以2-(顺式-4-((叔-丁氧基羰基)氨基)-1-氟环己基)乙基4-甲基苯磺酸酯和1-(苯并[b]噻吩-4-基)-1,4-重氮基庚环为原料参考实施例12第六步得到叔-丁基(顺式-4-(2-(4-(苯并[b]噻吩-4-基)-1,4-重氮基庚环-1-基)乙基)-4-氟环己基)氨基甲酸酯。
MS m/z(ESI):476.2[M+H] +.
第二步：顺式-4-(2-(4-(苯并[b]噻吩-4-基)-1,4-重氮基庚环-1-基)乙基)-4-氟环己烷-1-胺的制备
Figure PCTCN2020126735-appb-000150
以叔-丁基(顺式-4-(2-(4-(苯并[b]噻吩-4-基)-1,4-重氮基庚环-1-基)乙基)-4-氟 环己基)氨基甲酸酯为原料参考实施例12第七步得到顺式-4-(2-(4-(苯并[b]噻吩-4-基)-1,4-重氮基庚环-1-基)乙基)-4-氟环己烷-1-胺。
MS m/z(ESI):376.2[M+H] +.
第三步：3-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)-1,4-重氮基庚环-1-基)乙基)-4-氟环己基)-1,1-二甲基脲的制备
Figure PCTCN2020126735-appb-000151
以顺式-4-(2-(4-(苯并[b]噻吩-4-基)-1,4-重氮基庚环-1-基)乙基)-4-氟环己烷-1-胺为原料参考实施例12第八步得到3-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)-1,4-重氮基庚环-1-基)乙基)-4-氟环己基)-1,1-二甲基脲。
MS m/z(ESI):447.2[M+H] +.
1H NMR(400MHz,DMSO-d6)δ7.63(d,J＝5.6Hz,1H),7.47(d,J＝7.5Hz,1H),7.44(d,J＝5.6Hz,1H),7.21(t,J＝7.8Hz,1H),6.83(d,J＝7.9Hz,1H),5.96(d,J＝7.9Hz,1H),3.55–3.37(m,5H),2.90–2.78(m,2H),2.75(s,6H),2.71–2.51(m,4H),2.58(s,4H),2.05–1.90(m,2H),1.89–1.71(m,4H),1.66–1.58(m,2H),1.58–1.40(m,4H).
实施例40
N-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)呋喃-2-甲酰胺
Figure PCTCN2020126735-appb-000152
第一步：叔-丁基(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)氨基甲酸酯的制备
Figure PCTCN2020126735-appb-000153
以2-(顺式-4-((叔-丁氧基羰基)氨基)-1-氟环己基)乙基4-甲基苯磺酸酯和1-(苯并[b]噻吩-4-基)哌嗪为原料参考实施例12第六步得到叔-丁基(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)氨基甲酸酯(180mg，收率70％)。
MS m/z(ESI):462.2[M+H] +.
第二步：顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺的制备
Figure PCTCN2020126735-appb-000154
以叔-丁基(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)氨基甲酸酯为原料参考实施例12第七步得到顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺(180mg，TFA盐)。
MS m/z(ESI):362.2[M+H] +.
第三步：N-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)呋喃-2-甲酰胺的制备
Figure PCTCN2020126735-appb-000155
以顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己烷-1-胺和呋喃-2-甲酰氯为原料参考实施例12第八步得到N-(顺式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-4-氟环己基)呋喃-2-甲酰胺(33.3mg，收率56％)。
MS m/z(ESI):456.2[M+H] +.
1H NMR(400MHz,DMSO)δ8.20(d,J＝8.1Hz,1H),7.81(s,1H),7.70(d,J＝5.5Hz,1H),7.62(d,J＝8.0Hz,1H),7.40(d,J＝5.5Hz,1H),7.28(t,J＝7.8Hz,1H),7.11(d,J＝3.3Hz,1H),6.90(d,J＝7.6Hz,1H),6.66–6.57(m,1H),3.86–3.72(m,1H),3.15–2.97(m,4H),2.74–2.57(m,4H),2.50–2.43(m,2H),1.98–1.75(m,4H),1.72–1.48(m,6H).
实施例41
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-2-羟基-2-甲基丙酰胺
Figure PCTCN2020126735-appb-000156
以反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺和2-羟基-2-甲基丙酸为原料参考实施例27得到N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-2-羟基-2-甲基丙酰胺。
MS m/z(ESI):430.2[M+H] +.
实施例42
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1-羟基环丙烷-1-甲酰胺
Figure PCTCN2020126735-appb-000157
第一步：N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1-羟基环丙烷-1-甲酰胺
Figure PCTCN2020126735-appb-000158
反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺(100mg，0.291mmol)溶于无水DMF(5ml)，分别加入1-羟基环丙烷-1-羧酸(59mg，0.582mmol)、DIEA(301mg，2.328mmol)和HATU(221mg，0.582mmol)。反应室温下搅拌过夜。水加入反应液，再加入乙酸乙酯萃取。有机相干燥后旋干。粗产品通过prep-HPLC纯化，得到N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1-羟基环丙烷-1-甲酰胺(38.4mg，收率31％)。
1H NMR(400MHz,DMSO-d6)δ7.69(d,J＝5.5Hz,1H),7.61(d,J＝8.0Hz,1H),7.49(d,J＝8.5Hz,1H),7.39(d,J＝5.5Hz,1H),7.27(t,J＝7.8Hz,1H),6.90(d,J＝7.6Hz,1H),6.21(s,1H),3.61–3.47(m,1H),3.16–2.96(m,4H),2.73–2.53(m,4H),2.39(t,J＝7.5Hz,2H),1.85–1.67(m,4H),1.45–1.35(m,2H),1.35–1.19(m,3H),1.07–0.90(m,4H),0.84–0.74(m,2H).
MS m/z(ESI):428.2[M+H] +.
实施例43
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)噁唑-2-甲酰胺
Figure PCTCN2020126735-appb-000159
以反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺和噁唑-2-羧酸为原料参考实施例27得到N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)噁唑-2-甲酰胺。
MS m/z(ESI):439.2[M+H] +.
1H NMR(400MHz,Methanol-d 4)δ8.05(s,1H),7.55(d,J＝8.1Hz,1H),7.51(d,J＝5.6Hz,1H),7.42(d,J＝5.5Hz,1H),7.33(s,1H),7.27(t,J＝7.8Hz,1H),6.94(d,J＝7.6Hz,1H),3.90–3.75(m,1H),3.25–3.05(m,4H),2.89–2.65(m, 4H),2.59–2.45(m,2H),2.07–1.94(m,2H),1.94–1.84(m,2H),1.55–1.29(m,6H),1.23–1.08(m,1H).
实施例44
2-((反式-4-(2-((R)-4-(苯并[b]噻吩-4-基)-2-甲基哌嗪-1-基)乙基)环己基)氨基)嘧啶-5-甲腈
Figure PCTCN2020126735-appb-000160
第一步：反式-4-(2-((R)-4-(苯并[b]噻吩-4-基)-2-甲基哌嗪-1-基)乙基)环己烷-1-胺
Figure PCTCN2020126735-appb-000161
以4-溴苯并[B]噻吩为原料参考实施例35第一至第三步得到反式-4-(2-((R)-4-(苯并[b]噻吩-4-基)-2-甲基哌嗪-1-基)乙基)环己烷-1-胺。
MS m/z(ESI):358.2[M+H] +.
第二步：(R)-4-(2-(4-(苯并[b]噻吩-4-基)-2-甲基哌嗪-1-基)乙基)环己烷-1-胺
Figure PCTCN2020126735-appb-000162
以反式-4-(2-((R)-4-(苯并[b]噻吩-4-基)-2-甲基哌嗪-1-基)乙基)环己烷-1-胺溶于N,N-二甲基甲酰胺，加入碳酸钾和和2-氯嘧啶-5-甲腈为原料反应在室温下搅拌过夜。溶剂旋干，粗品用高效液相色谱柱分离，参考实施例26制备得到2-((反式-4-(2-((R)-4-(苯并[b]噻吩-4-基)-2-甲基哌嗪-1-基)乙基)环己基)氨基)嘧啶-5-甲腈。
MS m/z(ESI):461.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.62(s,1H),8.43(s,1H),7.55(d,J＝8.0Hz,1H),7.40(dd,J＝11.2,5.5Hz,2H),7.29-7.26(m,1H),6.89(d,J＝7.6Hz,1H),5.59(d,J＝8.0Hz,1H),3.86–3.83(m,1H),3.37-3.30(m,2H),3.06-3.04(m,2H),2.88-2.80(m,3H),2.65(s,1H),2.48(s,1H),2.11(d,J＝11.1Hz,2H),1.88(s,2H),1.51(d,J＝6.4Hz,2H),1.30-1.13(m,8H).
实施例45
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)呋喃-2-甲酰胺
Figure PCTCN2020126735-appb-000163
以反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺为原料参考实施例27得产品N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)呋喃-2-甲酰胺。
MS m/z(ESI):438.2[M+H] +.
1H NMR(400MHz,Methanol-d 4)δ7.64(dd,J＝1.8,0.8Hz,1H),7.56(d,J＝8.0Hz,1H),7.51(d,J＝5.5Hz,1H),7.42(dd,J＝5.6,0.8Hz,1H),7.27(t,J＝7.8Hz,1H),7.09(dd,J＝3.5,0.8Hz,1H),6.94(d,J＝7.6Hz,1H),6.56(dd,J＝3.5,1.8Hz,1H),3.89–3.74(m,1H),3.26–3.08(m,4H),2.90–2.67(m,4H),2.61–2.49(m,2H),2.02–1.81(m,4H),1.58–1.48(m,2H),1.47–1.26(m,4H),1.23–1.06(m,2H).
实施例46
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-5-甲基呋喃-2-甲酰胺
Figure PCTCN2020126735-appb-000164
以反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺为原料参考实施例27得产品N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-5-甲基呋喃-2-甲酰胺。
MS m/z(ESI):452.2[M+H] +.
1H NMR(400MHz,Methanol-d 4)δ7.62–7.47(m,2H),7.42(dd,J＝5.6,0.8Hz,1H),7.27(t,J＝7.9Hz,1H),7.06–6.88(m,2H),6.17(dd,J＝3.3,1.1Hz,1H),3.91–3.70(m,1H),3.26–3.07(m,4H),2.90–2.65(m,4H),2.62–2.47(m,2H),2.36(s,3H),2.00–1.79(m,4H),1.67–1.49(m,2H),1.47–1.25(m,4H),1.23–1.05(m,2H).
实施例47
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-2-甲氧基乙酰胺
Figure PCTCN2020126735-appb-000165
参考实施例12第八步得到N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-2-甲氧基乙酰胺(21mg)。
MS m/z(ESI):416.2[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.56(d,J＝8.0Hz,1H),7.33–7.24(m,2H),6.91(d,J＝7.6Hz,1H),6.34(d,J＝8.6Hz,1H),3.87(s,2H),3.83–3.72(m,1H),3.41(s,3H),3.35–3.18(m,4H),2.91–2.67(m,4H),2.66–2.51(m,2H),2.00(d,J＝10.9Hz,2H),1.82(d,J＝11.8Hz,2H),1.61–1.50(m,2H),1.35–1.23(m,2H),1.20–1.12(m,3H).
实施例48
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-3-羟基-3-甲基丁酰胺
Figure PCTCN2020126735-appb-000166
以反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺为原料参考实施例27得产品N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-3-羟基-3-甲基丁酰胺。
MS m/z(ESI):444.2[M+H] +.
1H NMR(400MHz,Methanol-d 4)δ7.55(d,J＝8.1Hz,1H),7.50(d,J＝5.6Hz,1H),7.42(d,J＝5.5Hz,1H),7.26(t,J＝7.9Hz,1H),6.93(d,J＝7.6Hz,1H),3.71–3.54(m,1H),3.24–3.06(m,4H),2.86–2.64(m,4H),2.57–2.46(m,2H),2.30(s,2H),1.99–1.80(m,4H),1.55–1.45(m,2H),1.39–1.18(m,10H),1.17–1.03(m,2H).
实施例49
N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-5-氟嘧啶-2-胺
Figure PCTCN2020126735-appb-000167
以反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺为原料参考实施例26得产品N-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-5-氟嘧啶-2-胺。
MS m/z(ESI):440.2[M+H] +.
1H NMR(400MHz,Methanol-d 4)δ8.19(s,2H),7.59–7.48(m,2H),7.42(d,J＝5.6Hz,1H),7.27(t,J＝7.8Hz,1H),6.94(d,J＝7.6Hz,1H),3.70–3.60(m,1H),3.23–3.15(m,4H),2.84–2.70(m,4H),2.59–2.50(m,2H),2.22–2.16(m,1H), 2.10–1.98(m,3H),1.91–1.82(m,2H),1.65–1.49(m,3H),1.21–1.10(m,2H).
实施例50
3-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1-甲氧基-1-甲基脲
Figure PCTCN2020126735-appb-000168
以反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己烷-1-胺为原料参考实施例1第三步得产品3-(反式-4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)环己基)-1-甲氧基-1-甲基脲。
MS m/z(ESI):431.2[M+H] +.
1H NMR(400MHz,Methanol-d 4)δ7.62–7.48(m,2H),7.42(dd,J＝5.6,0.8Hz,1H),7.26(t,J＝7.9Hz,1H),6.93(dd,J＝7.7,0.8Hz,1H),3.63(s,3H),3.57–3.41(m,1H),3.26–3.10(m,4H),3.03(s,3H),2.86–2.65(m,4H),2.60–2.46(m,2H),1.97–1.80(m,4H),1.56–1.42(m,2H),1.40–1.25(m,4H),1.20–1.02(m,2H).
实施例51
N-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-2-氟环己基)呋喃-2-甲酰胺
Figure PCTCN2020126735-appb-000169
以4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-2-氟环己烷-1-胺和呋喃-2-羧酸为原料参考实施例14第一步得到N-(4-(2-(4-(苯并[b]噻吩-4-基)哌嗪-1-基)乙基)-2-氟环己基)呋喃-2-甲酰胺。
MS m/z(ESI):456.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.56(d,J＝8.0Hz,1H),7.46-7.42(m,1H),7.29(d,J＝7.9Hz,1H),7.14-7.09(m,1H),6.91(d,J＝7.6Hz,1H),6.65–6.54(m,1H),6.50(d,J＝5.1Hz,1H),6.33-6.16(m,1H),4.93-4.73(m,1H),4.38–3.96(m,1H),3.24(s,4H),2.78(s,4H),2.13–1.95(m,2H),1.88-1.83(m,2H),1.75–1.54(m,4H),1.34–1.12(m,3H).
生物学测试评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
一、放射性配体受体结合实验
测试例1、本发明化合物对多巴胺D3受体结合能力的测定
1.实验目的：
该测试例的目的是测量化合物和多巴胺D3受体的亲和力。
2.实验仪器和试剂：
2.1实验仪器：
涡旋混合器(IKA；MS3 basic)；
电热恒温培养箱(上海一恒；DHP-9032)；
微板振动筛(VWR；12620-928)；
TopCount(PerkinElmer；NTX)；
Universal Harvester(PerkinElmer；UNIFILTER-96)。
2.2实验试剂和耗材：
[ 3H]-methylspiperone(PerkinElmer；NET856250UC)；
Human Dopamine D3 Receptor membrane(PerkinElmer；ES-173-M400UA)；
GR 103691(Sigma；162408-66-4)；
ULTIMA GOLD(Perkin Elmer；77-16061)；
96 round deep well plate 1.1mL(Perkin Elmer；P-DW-11-C)；
UNIFILTER-96 GF/B filter plate(PerkinElmer；6005174)；
聚乙烯亚胺，branched(Sigma；408727)；
离心管(BD，352096；352070)；
Loading slot(JET BIOFIL；LTT001050)；
移液枪头(Axygen；T-300-R-S，T-200-Y-R-S，T-1000-B-R-S)；
氯化镁(Sigma，7786-30-3)；
Tris-base(Sigma，77-86-1)；
HCl(Beijing XingJing Precision Chemical Technology CO.,LTD)。
3.实验方法：
实验缓冲液：50mM Tris-HCl pH 7.4,10mm MgCl 2.；洗液：50mM Tris-HCl pH 7.4，4℃存储；0.5％PEI solution：0.5g PEI dissolve in 100mL ddH 2O，4℃storage of spare。
在96孔-试验板中加入5μL待测化合物(0.005nM-100nM，共10个浓度)及100μL缓冲液。每孔中加入1μL细胞膜及300μL缓冲液，600rpm震荡5min。每孔加入100μL缓冲液与[ 3H]-methylspiperone(终浓度为0.5nM)的混合液到反应体系中，600rpm震荡5min，27℃孵育30min。将加入0.5％PEI预先孵育1h的UNIFILTER-96 GF/B filter plate用1mL/well缓冲液洗涤2次，并将细胞膜混悬液加入UNIFILTER-96 GF/B filter plate，并洗涤4次，55℃孵育10min。每孔加入40μL ULTIMA GOLD，进行液闪计数。
4.实验数据处理方法：
通过TopCount读取CPM(Counts per minute)值。根据High control(DMSO对照物)和Low control(100nM阳性化合物)实验组的读值计算的百分比抑制[ 3H]-methylspiperone结合的数据{％抑制率＝(CPM sample-CPM low control)/(CPM high  control-CPM low control)×100}。化合物的浓度经过反应体系稀释3倍后的10个浓度为100nM至0.005nM。使用GraphPad prism拟合百分比抑制率和十点浓度数据至参数非线性逻辑公式计算出化合物的IC 50值。
5.实验结果：
本发明中化合物对D3结合活性通过以上的试验进行测定，测得的IC 50值见表1。
表1本发明中化合物对D3结合活性IC 50
Figure PCTCN2020126735-appb-000170
6.实验结论：
本发明化合物与多巴胺受体D3具有良好的亲和力。
测试例2、本发明化合物对5-HT2A受体结合能力的测定
1.实验目的：
该测试例的目的是测量化合物和5-HT2A受体的亲和力。
2.实验仪器和试剂：
2.1实验仪器：
涡旋混合器(IKA；MS3 basic)；
电热恒温培养箱(上海一恒；DHP-9032)；
微板振动筛(VWR；12620-928)；
TopCount(PerkinElmer；NTX)；
Universal Harvester(PerkinElmer；UNIFILTER-96)。
2.2实验试剂和耗材：
[ 3H]-Ketanserin(PerkinElmer NET791)；
Human Dopamine 5-HT2A Receptor membrane(PerkinElmer)；
ULTIMA GOLD(Perkin Elmer；77-16061)；
96 round deep well plate 1.1mL(Perkin Elmer；P-DW-11-C)；
UNIFILTER-96 GF/B filter plate(PerkinElmer；6005174)；
聚乙烯亚胺，branched(Sigma；408727)；
离心管(BD，352096；352070)；
Loading slot(JET BIOFIL；LTT001050)；
移液枪头(Axygen；T-300-R-S，T-200-Y-R-S，T-1000-B-R-S)；
氯化钙(Sigma)；
Tris-base(Sigma，77-86-1)；
HCl(Beijing XingJing Precision Chemical Technology CO.,LTD)；
L-Ascorbic acid(Tianjin Guangfu)。
3.实验方法：
实验缓冲液：50mM Tris-HCl pH 7.4,4mM CaCl 2.；洗液：50mM Tris-HCl pH 7.4，4℃存储；0.5％PEI solution：0.5g PEI dissolve in 100mL ddH 2O，4℃storage of spare
在96孔-试验板中加入5μL待测化合物(0.005nM-100nM，共10个浓度)及100μL缓冲液。每孔中加入1.5μL细胞膜及300μL缓冲液。600rpm震荡5min。每孔中加入100μL缓冲液与[ 3H]-Ketanserin(终浓度为2nM)的混合液到反应体系中，600rpm震荡5min，27℃孵育30min。将加入0.5％PEI预先孵育1h的UNIFILTER-96 GF/B filter plate用1mL/well缓冲液洗涤2次，并将细胞膜混悬液加入UNIFILTER-96 GF/B filter plate，并洗涤4次，55℃孵育10min。每孔加入40μL ULTIMA GOLD，进行液闪计数。
4.实验数据处理方法：
通过TopCount读取CPM(Counts per minute)值，根据High control(DMSO对照物)和Low control(100nM阳性化合物)实验组的读值计算的百分比抑制[ 3H]-Ketanserin结合的数据{％抑制率＝(CPM sample-CPM low control)/(CPM high control-CPM low  control)×100}，化合物的浓度经过反应体系稀释3倍后的10个浓度为100nM至0.005nM，使用GraphPad prism拟合百分比抑制率和十点浓度数据至参数非线性逻辑公 式计算出化合物的IC 50值。
5.实验结果：
本发明中化合物对5-HT2A结合活性通过以上的试验进行测定，测得的IC 50值见表2。
表2本发明中化合物对5-HT2A结合活性IC 50
Figure PCTCN2020126735-appb-000171
6.实验结论：
本发明化合物对5-HT2A具有良好的亲和力。
二、细胞功能实验
测试例1、本发明化合物在稳定表达D3受体细胞对cAMP含量影响的测定
1.实验目的：
测量化合物对D3受体的激活作用。
2.实验仪器和试剂：
2.1实验仪器：
384孔-试验板(Perkin Elmer；6007680)；
96-well conical btm PP Plt nature RNASE/Dnase-free plate(ThermoFisher；249944)；
EnVision(Perkin Elmer)。
2.2实验试剂：
Fetal Bovine Serum(Gibco，10999141)；
Ham's F-12K(Kaighn's)Medium(Hyclone；SH30526.01)；
Penicillin-Streptomycin，Liquid(Gibco；15140122)；
G418(invitrogen；0131-027)；
Forskolin(Selleck，S2449)；
BSA stabilizer(Perkin Elmer；CR84-100)；
cAMP kit(Cisbio；62AM4PEC)；
IBMX(Sigma；I5879)；
HEPES(Gibco；15630080)；
HBSS(Gibco；14025076)；
TrypLE(ThermoFisher；12604021)。
3.实验方法：
1.缓冲液制备：1*HBSS+20mM HEPES+0.1％BSA+500μM IBMX。
完全培养基：Ham's F12K+10％胎牛血清+1*青霉素链霉素+400μg/mLG418。
2.将CHO-D3细胞株培养于37℃，5％CO 2环境下的完全培养基中；TrypLE消化处理后将细胞重悬于实验buffer中，种到384细胞培养板中，接种密度8000每孔。
3.准备实验buffer:1*HBSS，0.1％BSA，20mM HEPES及500μM IBMX；将化合物用buffer稀释；每孔加入2.5μL的化合物，37℃培养10分钟；用实验缓冲液将forskolin稀释至8μM(8*)；加入2.5μL稀释好的8*forskolin，于37℃孵育30分钟；冻融cAMP-d2和Anti-cAMP-Eu3+，用lysis buffer将其稀释20倍；加入10μL cAMP-d2至实验孔，然后加入10μL Anti-cAMP-Eu3+至实验孔中；将反应板于室温200g离心30s，25℃静置1h后，利用Envision收集数据
4.实验数据处理方法：
1)Z’factor＝1-3*(SDMax+SDMin)/(MeanMax-MeanMin)；
2)CVMax＝(SDMax/MeanMax)*100％；
3)CVMin＝(SDMin/MeanMin)*100％；
4)S/B＝Singal/Background；
5)利用GraphPad非线性拟合公式计算化合物EC 50:
Y＝Bottom+(Top-Bottom)/(1+10^((LogEC 50-X)*HillSlope))
X：化合物浓度log值；Y：Activation％
5.实验结果：
表3化合物在稳定表达D3受体细胞对cAMP含量的EC 50值
实施例编号 EC 50(nM)
卡利拉嗪 1.7
42 1.1
43 0.1
6.实验结论：
从表中数据可以看出，本发明所示的实施例化合物在稳定表达D3受体细胞对cAMP影响实验中显示出良好的激动活性。
测试例2、本发明化合物在稳定表达5-HT2A受体细胞中对钙离子流动能力影响的测定
1.实验目的：
测量化合物对5-HT2A受体的抑制作用。
2.实验仪器和试剂：
2.1实验仪器：
384孔-试验板(Corning；3712)；
移液管(Axygen)；
FLIPR(Molecular Devices)。
2.2实验试剂：
DMEM(Invitrogen；11965)；
胎牛血清(Biowest；S1810-500)；
透析血清(S-FBS-AU-065；Serana)；
青霉素及链霉素(Biowest；L0022-100)；
潮霉素B(CABI℃HEM，400052)；
Matrigel(BD；354230)；
DMSO(Sigma；D2650)；
HBSS(Invitrogen；14065)；
HEPES(Invitrogen；15630080)；
Probenecid(Sigma；P8761)；
BSA(renview；FA016)；
TrypLE(ThermoFisher；12604021)。
3.实验方法：
1)缓冲液制备：1x HBSS，20mM HEPES，2.5mM probenecid(probenecid为400mM st℃k in 1M NaOH)，0.1％BSA。实验当天新鲜加入Probenecid和BSA。实验缓冲液包括染料缓冲液和化合物稀释缓冲液等。
2)细胞培养基：Ham's F-12K+10％胎牛血清+600ug/ml潮霉素B+1*青霉素及链霉素；接种培养基：Ham's F-12K+10％透析血清；Assay buffer：1x HBSS+20mM HEPES；细胞株：Flp-In-CHO-5HT2A stable pool。
3)细胞株培养于完全培养基，于37℃，5％CO 2至70％-90％融合度。细胞用TrypLE胰蛋白酶消化后，以1×10 4个细胞/well的密度播种到384孔-试验板孵育16-24小时(至少过夜)。
4)冻融20X Component A至室温，用实验缓冲液将其稀释至2X工作浓度含5mM Probenecid，置于室温待用。
5)取出细胞培养板，室温静置10min，利用Apricot和实验缓冲液将FBS的浓度稀释至0.03％，最终剩20μL于3764培养板中，随后加入20μL 2X Component A含5mM Probenecid至各实验孔中，200g，RT离心3-5sec，于37℃孵育2hr。6)丢弃培养液，并加入20μL染料。37℃避光孵育60min，读取钙信号。
7)实验前制备拮抗剂：DMSO配制待测化合物工作液(6X)。取出细胞培养板于室温静置10分钟，将10μL/well浓度6x待测化合物加入384孔-试验板中，室温下避光孵育35min。
8)用实验缓冲液将5HT稀释至6nΜ(6X)，转移50μL至384孔板(Corning,3657)，置于室温待用。将试验板转移至FLIPR，加入5uL/well 6x浓度的激动剂化合物。使用FLIPR加入10μL稀释好的5HT至各实验孔中，读取数值并保存数据。总化验体积为30μL，包括20μL/well染料缓冲液、5μL/well 5x浓度的试验化合物和5μL/well 6x浓度的激动剂化合物。
4.实验数据处理方法：
通过FLIPR读取钙信号值。实验中每个采样时间点的计算后的输出结果是340/510nm与380/510nm波长信号的比值。最大值减去最小值的计算来源自比值信号曲线。使用GraphPad prism拟合百分比抑制率和十点浓度数据至参数非线性逻辑公式计算出化合物的IC 50值。
5.实验结果：
表4：化合物在稳定表达5-HT2A受体细胞对钙离子流动能力的IC 50值
实施例编号 IC 50(nM)
卡利拉嗪 551.0
40 3.16
42 3.42
6.实验结论：
从表中数据可以看出，本发明实施例化合物在稳定表达5-HT2A细胞功能钙流试验中显示出良好的抑制活性。
三、Balb/C小鼠药代动力学测定
1.研究目的：
以Balb/C小鼠为受试动物，研究本发明实施例化合物，在5mg/kg剂量下口服给药在小鼠体内(血浆和脑组织)的药代动力学行为。
2.实验方案：
2.1实验药品：
本发明实施例化合物，自制。
2.2实验动物：
Balb/C小鼠，每组12只，雄性，上海杰思捷实验动物有限公司，动物生产许可证号(SCXK(沪)2013-0006N0.311620400001794)。
2.3制剂处方：
0.5％CMC-Na(1％Tween80)，超声溶解，配制为澄清溶液或均一混悬液。
2.4给药：
Balb/C小鼠每组12只，雄性；禁食一夜后分别p.o.，剂量为5mg/kg，给药体积10mL/kg。
2.5样品采集：
小鼠给药前和给药后，在1、2、4、8和24小时，采用CO 2处死，心脏采血0.2mL，置于EDTA-K 2试管中，4℃6000rpm离心6min分离血浆，于-80℃保存；全脑组织取出称重后，置于2mL离心管中，于-80℃保存。
2.6样品处理：
1)血浆样品40uL加入160uL乙腈沉淀，混合后3500×g离心5～20分钟。
2)血浆和脑匀浆样品30μL加入90μL含内标(100ng/mL)乙腈沉淀，混合后13000rpm离心8分钟。
3)取处理后上清溶液70uL加入70μL水，涡旋混合10分钟，随后取20μL进行LC/MS/MS分析待测化合物的浓度，LC/MS/MS分析仪器：AB Sciex API 4000 Qtrap。
2.7液相分析：
●液相条件：Shimadzu LC-20AD泵
●色谱柱：Agilent ZORBAX XDB-C18(50×2.1mm,3.5μm)移动相：A液为0.1％甲
酸水溶液，B液为乙腈
●流速：0.4mL/min
●洗脱时间：0-4.0分钟，洗脱液如下：
Figure PCTCN2020126735-appb-000172
3.实验结果与分析：
药代动力学主要参数用WinNonlin 6.1计算得到，小鼠药代实验结果见下表5所示：
表5：小鼠药代实验结果
Figure PCTCN2020126735-appb-000173
Figure PCTCN2020126735-appb-000174
4.实验结论：
从表中小鼠药代实验结果可以看出：本发明实施例化合物表现出良好的代谢性质，暴露量AUC和最大血药浓度C max都表现良好。
四、体外肝微粒体稳定性实验
1.实验目的：
评价本发明化合物体外肝微粒体的代谢稳定性情况。
2.实验仪器和试剂：
2.1仪器：
仪器 品牌 型号
涡旋仪 IKA Vortex
恒温混和器 SpecificAction Incubation-micro mixer
离心机 Eppendorf Centrifuge 5804R
液相 岛津 LC-30 AD
质谱 AB Sciex API5500
2.2试剂：
试剂 品牌 货号
7-羟基香豆素 百灵威 153384
DMSO Sigma 34869
PBS Gibco 10010-023
CD-1小鼠肝微粒体 BD M1000
NADPH 毕得 BD11658
UDPGA Sigma U6751
阿维菌素 百灵威 622045
3.实验步骤：
3.1.配制化合物工作液
化合物的工作液配制：将2μL化合物储备溶液加入998μL磷酸缓冲液，终浓度为20μM。
对照化合物(7-Hydroxycoumarin)工作液配制：同化合物的配制过程保持一致。
3.2.配制肝微粒体工作液
78.1μL 20mg/mL微粒体，用100mM磷酸缓冲液稀释到2.5mL，混匀，终浓度为0.625mg/mL。
3.3.准备NADPH和UDPGA
称取33.3mg的NADPH和25.8mg的UDPGA，加入2mL的100mM磷酸缓冲液，终浓度均为20mM。
3.4.准备打孔剂(Alamethicin)
称取1mg Alamethicin加入200μL DMSO，配制成5mg/mL的溶液。再从该溶液中取出10μL，加入990μL磷酸缓冲液中(pH 7.4)，终浓度为50μg/mL。
3.5.配制反应终止液
终止液：含有100ng/mL的盐酸拉贝洛尔和400ng/mL甲苯磺丁脲为内标的冷乙腈，储存在2-8℃冰箱。
3.6.孵育流程
在96孔板中依次加入400μL配制好的肝微粒体、25μL化合物工作液(10μM)和25μL Alamethicin(50μg/mL)，于37℃预孵育10min。随后加入50μL配制好的NADPH/UDPGA启动反应，37℃孵育，反应体系的总体积为500μL，各成分最终含量如下：
成分 含量
肝微粒体 0.5mg/mL
化合物 1μM
NADPH 2mM
UDPGA 2mM
Alamethicin 2.5μg/mL
分别在0min、5min、10min、20min、30min和60min时间点取出50μL，加入200μL含有内标的冷终止液终止样品反应，4000g离心10min，取上清液进LC-MS/MS分析。
4.实验结果：
表6体外肝微粒体稳定性
Figure PCTCN2020126735-appb-000175
备注：
Figure PCTCN2020126735-appb-000176
5.实验结论：
以上数据显示，本发明实施例化合物在小鼠肝微粒体中为中等代谢。
五、大鼠主动逃避实验药效模型
1.实验目的：
利用大鼠主动逃避实验药效模型评价化合物的抗精神分裂作用。
实验仪器与试剂：
2.1仪器：
序号 设备名称 设备型号 来源 生产厂商
1 主被动穿梭装置 MED-APA-D1R 进口 Med Associates，Inc.
2 恒温磁力搅拌器 85-2 国产 上海司乐仪器有限公司
3 漩涡仪 H-101 国产 上海康禾光电仪器有限公司
4 超声波清洗器 KQ3200DE 国产 昆山市超声仪器有限公司
2.2试剂：
序号 名称 纯度 批号 保存条件 生产厂商
1 CMC-Na 100％ SLBV9664 RT Sigma
2 Tween 80 100％ BCBV8843 RT Sigma
2.3受试化合物：
本发明实施例化合物，自制。
3.实验动物：
动物种属 品系 年龄 性别 供应商
大鼠 F344 6-8weeks 雄性 北京维通利华
4.溶媒和化合物配制：
4.1溶媒(0.5％CMC-Na+1％Tween80)
称取一定质量(如1.0g)的CMC-Na于玻璃瓶中，加入一定体积(如200mL)的纯化水，搅拌使其分散均匀，根据溶液体积加入1％(v/v)的Tween80，搅拌过夜得到澄清、均匀的澄清溶液，2-8℃保存备用。
4.2化合物配制：
称取处方量的化合物加入处方体积的0.5％CMC-Na+1％Tween80溶液，给药前配制，2-8℃保存，4天内用使。
化合物溶液配制及给药时均需计算实际样品量，折算公式如下：化合物实际样品量＝理论称样量*纯度/盐系数。
5.实验操作：
动物到达实验设施后，适应一周后开始实验。
5.1药效模型建立：
5.1.1动物放入穿梭箱，适应5秒后开始给予10秒的声音和光照刺激；
5.1.2如果动物在10秒声音和光照刺激下躲避至另一侧，则不会进行电击，记录为主动逃避(avoids)，单次训练结束；
5.1.3如果10秒声音和光照刺激结束后，动物未移动至另一侧，则给予电击，电流强度为0.6mA，持续时间为10秒，电击持续的10秒内若动物逃至另一侧，电击停止，记录为被动逃避(escapes)，单次训练结束；
5.1.4如果动物在电击的10秒内一直未躲避，则电击停止，记录为逃避失败(escape failures)，单次训练结束；
5.1.5每只动物每天训练30次，训练结束后，放回笼中，共训练6天。
5.2 Baseline测试及分组
化合物筛选测试的前一天，需要进行baseline测试，测试流程同5.1.1～5.1.3，baseline测试次数为20次，主动逃避次数达到16次(80％)的动物根据主动逃避次数进行分组，每组10只；第一组口服给予溶媒，其余组按照实验设计给予相应的受试化合物。
5.3化合物筛选测试
测试开始前一小时给药，给药方式为口服，5mL/kg；
测试流程同5.1.1～5.1.4，测试次数为20次。
6.数据处理：
软件采集以下数据用于数据分析：
动物的主动逃避次数(avoids)；
动物逃避失败的次数(escape failures)；
动物被动逃避的潜伏期(escape latency)；
所有计量资料均以均数±标准误(Mean±SEM)表示，采用Graphpad 6统计软件中作检验分析，差异的显著性以p﹤0.05被认为有显著性差异。
7.实验结果：
表7
Figure PCTCN2020126735-appb-000177
8.实验结论：
以上数据可知，本发明实施例化合物在大鼠主动逃避实验药效模型中表现出较好的作用，表示其具有抗精神分裂症的作用。
六、SD大鼠重复灌胃14天毒性试验
6.1实验目的
本研究的目的是考察化合物重复灌胃给予SD大鼠14天后可能出现的毒性反应。
6.2实验材料和仪器：
6.2.1供试品
供试品1：实施例42化合物。
6.2.2溶媒：
名称：0.5％CMC-Na(1％tween80)水溶液
6.2.3动物信息：
种属&品系：Sprague-Dawley(SD)大鼠
动物等级：SPF级
动物数量和性别：60只，雌雄各半
6.3实验方法：
将60只大鼠(30只/性别)分性别区段按照体重分为20组，40只大鼠用作毒理研究(1～4组，5只/性别/组)和24只大鼠用作毒代研究(5～8组，3只/性别/组)，第1和5组动物灌胃给予0.5％CMC-Na(1％tween80)水溶液作为溶媒对照组，第2和6、3和7、4和8组动物分别灌胃给予2、10和30mg/kg剂量的实施例42；动物每天给药1次，连续给药14天。给药容量均为10mL/kg。试验期间对临床观察、体重、食量、体温、临床病理指标(血细胞计数、凝血功能、血液生化)、毒代动力学等项目进行检查。所有动物于D15实施安乐死。试验期间对1-4组动物均进行大体解剖观察，对异常组织及脑、肾、肾上腺、肺和支气管、前列腺、睾丸和附睾进行组织病理学检查。
6.4试验数据列表
6.4.1濒死/死亡
试验期间，各组动物均未见死亡/濒死。
6.4.2毒代动力学
实施例42在D1和D14的各剂量组雌性和雄性动物的平均系统暴露量(以AUC last计)比率在0.83至2.52之间，表明实施例42在雌性动物体内的暴露量整体高于雄性动物。分别对D1和D14各剂量组雌性和雄性动物的平均系统暴露量(以AUC last计)做双单侧t检验，结果显示雌雄动物间差异均无统计学意义(P﹥0.05)。
D1和D14雌性和雄性动物体内实施例42的平均暴露量均随剂量的增加而增大，且平均暴露量增大的比例大于剂量增加的比例。
分别按照2、10、30mg/kg的剂量重复灌胃给药14天后，实施例42各剂量 组雌雄动物末次给药(D14)与首次给药(D1)的平均AUC last比值在1.03至2.12之间，未见蓄积。
6.5实验结论：
在本试验条件下，供试品实施例42以2、10和30mg/kg剂量重复灌胃给予SD大鼠两周(1次/天)，主要毒性反应为：体重、食量和体温的降低，血细胞计数：WBC、Lymph、Retic和PLT降低；凝血功能：FIB降低，APTT缩短；主要的毒性靶器官为肺脏和肾上腺。在本试验条件下，供试品实施例42的最大耐受剂量(MTD)为30mg/kg。

Claims (16)

  1. 一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2020126735-appb-100001
    其中：
    Figure PCTCN2020126735-appb-100002
    选自单键或双键；
    M选自N或CR aa；
    环A选自芳基或杂芳基；
    R 1选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
    R 2选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
    或，相同碳原子或者不相同碳原子上的两个R 2链接形成一个环烷基、杂环基、芳基或杂芳基，任选进一步被选自氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、-(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；
    R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、 -NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1S(O)(＝NR aa)R bb、-(CH 2) n1S(O) m1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
    或，相同碳原子或者不相同碳原子上的两个R 3链接形成一个环烷基、杂环基、芳基或杂芳基，任选进一步被选自氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、-(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；
    R 4和R 5各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1C(O)R aa、-C(O)(CH 2) n1R aa、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1S(O) m1R aa、-(CH 2) n1S(O) m1NR aaR bb、-(CH 2) n1OR aa、-C(O)NR aa(CH 2) n1R bb、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O)(＝NR aa)R bb、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，所述的烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、羟基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基和杂芳基，任选进一步被选自氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、-(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；
    或，R 4和R 5链接形成一个环烷基、杂环基、芳基或杂芳基，任选进一步被选自氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、 -(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、-(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；
    R aa、R bb、R cc和R dd各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、取代或未取代的烷基、取代或未取代的卤代烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
    或者，R aa和R bb链接形成一个环烷基、杂环基、芳基或杂芳基，任选进一步被选自氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基中的一个或多个取代基所取代；
    m为0、1或2；
    x为0、1、2、3或4；
    y为0、1、2、3或4；
    z为0、1、2、3或4；
    m1为0、1或2；且
    n1为0、1、2、3、4或5。
  2. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，
    环A选自C 6-10芳基或5-10元杂芳基，优选苯基、5-6元单环杂芳基、苯并5-6元杂芳基或苯并3-6元杂环基。
  3. 根据权利要求1或2所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，
    Figure PCTCN2020126735-appb-100003
    选自
    Figure PCTCN2020126735-appb-100004
    Figure PCTCN2020126735-appb-100005
  4. 根据权利要求1或2所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，
    R 4选自氢或甲基；
    R 5选自-R aa、-C(O)(CH 2) n1R aa、-C(O)NR aa(CH 2) n1R bb或-S(O) 2R aa；
    或，R 4和R 5链接形成一个3-8元杂环基或5-14元杂芳基，所述的3-8元杂环基和5-14元杂芳基，任选进一步被选自C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基、C 3-8羟烷基、-C(O)R cc和-C(O)NR ccR dd中的一个或多个取代基所取代；
    其中，所述杂环基或杂芳基选自含有1-2个氮、氧或硫原子的杂环基或杂芳基；
    R aa和R bb各自独立地选自氢、氨基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、苯基或5-6元杂芳基，所述的氨基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-6环烷基、3-6元杂环基、苯基和5-6元杂芳基，任选进一步被选卤素、羟基、氰基、氧代基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-6环烷基、3-6元杂环基、苯基或5-6元杂芳基中的一个或多个取代基所取代；
    R cc和R dd各自独立地选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基和 C 1-6烷氧基中的一个或多个取代基所取代；且
    n1为0、1、2或3。
  5. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(IV-A)所示：
    Figure PCTCN2020126735-appb-100006
    其中：
    R 2选自氢、氰基、卤素、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基；
    或，相同碳原子或者不相同碳原子上的两个R 2链接形成一个C 3-8环烷基或3-8元杂环基，所述的C 3-8环烷基和3-8元杂环基，任选进一步被选自氘、C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基和C 3-8羟烷基中的一个或多个取代基所取代；
    R 3选自氢、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、羟基、氰基、C 2-6烯基或C 2-6炔基；
    R 4选自氢或C 1-6烷基；
    R 5选自氢、C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-C(O)R aa、-C(O)NR aaR bb、-C(O)(CH 2) n1R aa、-C(O)NR aa(CH 2) n1R bb、-S(O) 2R aa、-(CH 2) n1S(O)(＝NR aa)R bb、-S(O) m1NR aaR bb或-C(O)OR aa，所述的C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氰基、卤素、C 1-6烷基和C 1-6烷氧基中的一个或多个取代基所取代；
    或，R 4和R 5链接形成一个3-8元杂环基或5-14元杂芳基，任选进一步被选自C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基、C 3-8羟烷基、-C(O)R cc和-C(O)NR ccR dd中的一个或多个取代基所取代；
    R aa和R bb各自独立地选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代，
    或者，R aa和R bb与相邻的氮原子形成4-10元杂环基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基中的一个或多个取代基所取代；
    R cc和R dd各自独立地选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基中的一个或多个取代基所取代；
    m为1或2；且
    n1为0、1、2或3；
    其中，通式(IV-A)不包含化合物
    Figure PCTCN2020126735-appb-100007
    Figure PCTCN2020126735-appb-100008
  6. 根据权利要求5所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(IX-B)所示：
    Figure PCTCN2020126735-appb-100009
    R 2选自氢、氰基、卤素、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基；
    R 3选自氢、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6卤代烷氧基；
    R 4选自氢或C 1-6烷基；
    R 5选自氢、C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-C(O)R aa、-C(O)NR aaR bb、-C(O)(CH 2) n1R aa、-C(O)NR aa(CH 2) n1R bb、-S(O) 2R aa、-(CH 2) n1S(O)(＝NR aa)R bb、-S(O) m1NR aaR bb或-C(O)OR aa，所述的C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氰基、卤素、C 1-6烷基和C 1-6烷氧基中的一个或多个取代基所取代；
    或，R 4和R 5链接形成一个3-8元杂环基或5-10元杂芳基，任选进一步被选自C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基、C 3-8羟烷基中的一个或多个取代基所取代；
    R aa和R bb各自独立地选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或含1-2个选自N、O或S的5-10元杂芳 基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；
    或者，R aa和R bb与相邻的氮原子形成4-6元杂环基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6羟烷基中的一个或多个取代基所取代。
  7. 根据权利要求5或6所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，
    R 2选自氢、氰基、卤素、C 1-3烷基、C 1-3卤代烷基或C 3-6环烷基；
    R 3选自氢、卤素或C 1-3烷基；
    R 4选自氢或C 1-3烷基；
    R 5选自-(CH 2) n1R aa、-C(O)R aa、-C(O)NR aaR bb、-S(O) 2R aa或-S(O) m1NR aaR bb；
    R aa和R bb各自独立地选自氢、氨基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-6环烷基或含1-2个选自N、O或S的5-6元杂芳基，任选进一步被选自卤素、羟基、氰基、氧代基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 3-6环烷基中的一个或多个取代基所取代；
    或者，R aa和R bb与相邻的氮原子形成4-6元含氮杂环基，任选进一步被选自卤素、羟基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基中的一个或多个取代基所取代。
  8. 根据权利要求5或6所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，
    R 2选自氢、氰基、氟、氯、溴、甲基、乙基、三氟甲基、三氟甲基或环丙基；
    R 3选自氢、氟、氯、溴、甲基或乙基；
    R 4选自氢或甲基；
    R 5选自-R aa、-C(O)R aa或-C(O)NR aaR bb；
    R aa和R bb各自独立地选自氢、C 1-3烷基、C 1-3氟代烷基、C 1-3烷氧基、环丙基、环丁基、环戊基、呋喃基、噁唑基、异噁唑基，任选进一步被选自卤素、羟基、氰基、C 1-3烷基、C 1-3烷氧基中的一个或多个取代基所取代；
    或者，R aa和R bb与相邻的氮原子形成氮杂环丁基、吡咯烷基或哌啶基，任选进一步被选自卤素、羟基、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基中的一个或多个取代基所取代。
  9. 根据权利要求1～8所述的化合物、其立体异构体或其药学上可接受的盐， 其特征在于，
    Figure PCTCN2020126735-appb-100010
    选自如下基团：
    Figure PCTCN2020126735-appb-100011
    Figure PCTCN2020126735-appb-100012
  10. 根据权利要求1～9中任一项所述的各通式、其立体异构体或其药学上可接受的盐，其特征在于，
    R 1选自氢、氰基、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 3-6环烷基；
    R 2选自氢、氰基、卤素、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基；
    或，相同碳原子或者不相同碳原子上的两个R 2链接形成一个C 3-8环烷基或3-8元杂环基，所述的C 3-8环烷基和3-8元杂环基，任选进一步被选自氢、氘原子、C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基和C 3-8羟烷基中的一个或多个取代基所取代；
    R 3选自氢原子、卤素、羟基、C 1-6烷基或C 1-6烷氧基；
    或，相同碳原子或者不相同碳原子上的两个R 3链接形成一个C 3-8环烷基或3-8元杂环基，所述的C 3-8环烷基和3-8元杂环基，任选进一步被选自氢、氘、C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基和C 3-8羟烷基中的一个或多个取代基所取代；
    R 4选自氢或C 1-6烷基；
    R 5选自氢、C 1-6烷基、C 3-8环烷基、3-8元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-C(O)R aa、-C(O)NR aaR bb、-C(O)NR aa(CH 2) n1R bb、-S(O) 2R aa、-(CH 2) n1S(O)(＝NR aa)R bb、-S(O) m1NR aaR bb或-C(O)OR aa，所述的C 1-6烷基、C 3-8环 烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氢、氰基、卤素、C 1-6烷基和C 1-6烷氧基中的一个或多个取代基所取代；
    或，R 4和R 5链接形成一个杂环基，所述的杂环基，任选进一步被选自氢、C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基、C 3-8羟烷基中的一个或多个取代基所取代；
    R aa选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选氢、卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基中的一个或多个取代基所取代；
    R bb选自氢、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或6-14元杂芳基，其中所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基和5-14元杂芳基任选进一步被选氢原子、卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基中的一个或多个取代基所取代；
    或，R aa和R bb链接形成一个杂环基，其中所述的杂环基任选进一步被选自氢原子、C 1-6烷基、卤素、氨基、氧代基、硫代基、氰基、羟基、C 3-8烷氧基、C 3-8卤代烷氧基和C 3-8羟烷基中的一个或多个取代基所取代。
  11. 根据权利要求1或5所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(XII)所示：
    Figure PCTCN2020126735-appb-100013
    其中：
    环B选自C 3-8环烷基、3-8元杂环基或5-10元杂芳基；
    优选环丙基、氮杂环丁烷基、吡咯烷酮基、呋喃基、噁唑基或异噁唑基；
    R 2选自氢、氰基、卤素、C 1-6烷基、C 1-6卤代烷基或C 3-6环烷基；
    优选氢或C 1-6卤代烷基；更优选氢或三氟甲基；
    R 4选自氢或C 1-6烷基；
    优选氢或甲基；
    R 6选自氢、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、羟基、氰基、C 2-6烯基或C 2-6炔基；
    优选氢或卤素；更优选氢或氟；
    R 17选自氢、卤素、氨基、羟基、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-14芳基或5-14元杂芳基，所述的氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-10芳基和5-10元杂芳基，任选进一步被选氢、卤素、羟基、氰基、氧代基、C 1-6烷基、C 1-6卤代烷基和C 1-6烷氧基中的一个或多个取代基所取代；
    优选氢、氨基、卤素、氨基、羟基、氰基、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基；
    更优选氢、氟、氯、羟基、氰基、甲基或甲氧基；且
    v为0～5的整数；优选0、1、2或3。
  12. 根据权利要求1～11中任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述化合物的具体结构如下：
    Figure PCTCN2020126735-appb-100014
    Figure PCTCN2020126735-appb-100015
  13. 一种制备权利要求6所述的通式(IX-B)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于，包含以下步骤，
    Figure PCTCN2020126735-appb-100016
    通式(IX-B3)脱保护得到通式(IX-B1)所示化合物或其立体异构体及其药学上可接受盐；
    通式(IX-B1)与通式(II-2)所示的酰氯、胺、羧酸或磺酰氯反应，得到通式(VIII)所示化合物或其立体异构体及其药学上可接受盐；
    通式(II-2)表示R 5X、R 5OH或R 5NH 2；
    X为卤素；
    Pg为氢或氨基保护基，选自烯丙氧羰基、三氟乙酰基、2,4-二甲氧基苄基、硝基苯磺酰基、三苯甲基、笏甲氧羰基、对甲苯磺酰基、甲酸酯、乙酰基、苄氧羰基、叔丁氧羰基、苄基或对甲氧苯基；优选叔丁氧羰基。
  14. 一种药物组合物，其包括治疗有效剂量的权利要求1～12中任一项所述的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
  15. 根据权利要求1～12中任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求14所述的药物组合物在制备G蛋白耦联受体调节剂，优选地，在多巴胺D3受体调节剂和5-HT2A受体调节剂药物中的应用。
  16. 根据权利要求1～12中任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求14所述的药物组合物在制备治疗或预防中枢神经系统疾病和/或精神疾病的药物中的用途；神经系统疾病和/或精神疾病优选精神分裂症、睡眠障碍、心境障碍、精神分裂症谱系障碍、痉挛性障碍、记忆障碍和/或认知障碍、运动障碍、人格障碍、自闭症谱系障碍、疼痛、外伤性脑损伤、血管疾病、物质滥用障碍和/或戒断综合征、耳鸣、抑郁症、自闭症、老年痴呆症、阿尔兹海默症、癫痫发作、神经痛或戒毒症状重度抑郁症和狂躁症疾病。
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US12459931B2 (en) 2025-11-04
CN112778183B (zh) 2024-05-10
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