WO2017025058A1 - 取代的吲哚化合物及其使用方法和用途 - Google Patents

取代的吲哚化合物及其使用方法和用途 Download PDF

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WO2017025058A1
WO2017025058A1 PCT/CN2016/094792 CN2016094792W WO2017025058A1 WO 2017025058 A1 WO2017025058 A1 WO 2017025058A1 CN 2016094792 W CN2016094792 W CN 2016094792W WO 2017025058 A1 WO2017025058 A1 WO 2017025058A1
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group
alkyl
compound
ring atoms
independently
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PCT/CN2016/094792
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English (en)
French (fr)
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金传飞
张英俊
张
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广东东阳光药业有限公司
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Priority to CN201680002302.XA priority Critical patent/CN106795143B/zh
Publication of WO2017025058A1 publication Critical patent/WO2017025058A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the technical field of medicines, and in particular relates to compounds, compositions and methods and uses thereof for treating central nervous system dysfunction.
  • the invention describes substituted anthraquinone compounds which may act as serotonin reuptake inhibitors and/or 5-HT 1A receptor agonists.
  • Serotonin a neurotransmitter that transmits signals in the brain and nervous system, plays an important role in central nervous system (CNS) dysfunction, especially anxiety, depression, aggression, and impulsive emotions. Antagonizing or stimulating certain types of serotonin receptors can effectively modulate central nervous system dysfunction. To date, at least 14 serotonin receptors have been identified. These receptors can be divided into different families, which are classified as 5-HT 1 , 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 , respectively. Different subtypes are distinguished by a, b, and c.
  • Depression is the most important of all indications associated with serotonin dysfunction, as depression has become the fourth most burdensome disease in humans, according to the World Health Organization. It is estimated that by 2020, the disability-adjusted life expectancy of depression will leap to the second place in all diseases. (Bromet E, Andrade LH, Hwang I, et al., Cross-national epidemiology of DSM-IV major depressive episode. BMCMed. 2011, 9:90).
  • TCAs tricyclic antidepressants
  • MAOIs monoamine oxidase inhibitors
  • SSRIs selective serotonin reuptake inhibitors
  • SSRIs Traditional SSRIs treatment increases the serotonin content by inhibiting the reuptake of serotonin and regulating its transport.
  • the use of SSRIs also activates the 5-HT 1A autoreceptor of the presynaptic membrane, resulting in a decrease in the release of serotonin and a decrease in the concentration of synaptic serotonin.
  • SSRIs cause desensitization of 5-HT 1A autoreceptors, and the activation effect is restrained, thereby exerting a normal regulatory effect.
  • 5-HT 1A autoreceptor is an important reason for delaying the efficacy of SSRIs (Celada P, Puig M, Amargos-Bosch M, et al., The therapeutic role of 5-HT 1A and 5) -HT 2A receptors in depression. J Psychiatry Neurosci, 2004, 29(4): 252-65). Therefore, overcoming the negative feedback effect of 5-HT 1A autoreceptor antagonists has the prospect of enhancing and accelerating clinical anti-depression.
  • a 5-HT 1A receptor agonist or partial agonist acts directly on the postsynaptic serotonin receptor to increase serotonin neurotransmission in the SSRI latency phase.
  • Feiger and Wilcox demonstrated that buspirone and gepirone are clinically effective 5-HT 1A partial agonists (Feiger, A. Psychopharmacol. Bull. 1996, 32: 659-65).
  • the addition of buspirone to standard SSRI treatments resulted in significant improvements in patients who had previously not responded to standard treatment for depression (Dimitriou, EJ Clin. Psychopharmacol., 1998, 18: 465-9).
  • the present invention provides a novel compound having selective serotonin reuptake inhibitory activity and/or 5-HT 1A receptor agonistic activity, and has good clinical application prospects.
  • the compounds of the invention have better pharmacological, pharmacological and/or toxicological properties than existing analogous compounds.
  • the present invention relates to a novel class of substituted indole compounds which have strong binding affinity to a 5-HT transporter (SERT) and which selectively inhibit 5-HT reuptake, and which are also associated with 5-HT 1A receptors. It has strong binding affinity and can effectively agonize 5-HT 1A receptor, so it can be used to prepare drugs for treating central nervous system (CNS) dysfunction, and the compound of the present invention has stable properties, good safety, pharmacodynamics and Pharmacokinetic advantages, such as good brain plasma ratio, good bioavailability or good metabolic stability, have good clinical application prospects.
  • SERT 5-HT transporter
  • CNS central nervous system
  • the compounds of the present invention selectively inhibit serotonin reuptake and/or have an agonistic effect on 5-HT 1A receptors, and can be used for the preparation of central nervous system (CNS) dysfunction, such as depression and anxiety. , a drug for bipolar disorder.
  • CNS central nervous system
  • the invention also provides methods of preparing such compounds and pharmaceutical compositions containing such compounds.
  • the invention relates to a compound which is a compound of formula (I) or a stereoisomer, tautomer, oxynitride, solvate, metabolite, a pharmaceutically acceptable salt or prodrug,
  • each of R 1 , R a , R b , Q, L, Cy, m, n and p has the meaning as described in the present invention.
  • Q is CH or N.
  • Cy is an aryl group of 6-10 ring atoms or a heteroaryl group of 5-10 ring atoms, wherein the 6-10 ring atoms consist of an aryl group and 5-10 rings
  • the heteroaryl group consisting of atoms is optionally independently substituted by 1, 2, 3, 4 or 5 R y ; and each R y has the meaning as described in the present invention.
  • R 1 is H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl a C 1 -C 6 alkoxy group or a C 1 -C 6 haloalkoxy group, wherein said C 1 -C 6 alkyl group, C 1 -C 6 haloalkyl group, C 1 -C 6 alkoxy group and C 1 -
  • the C 6 haloalkoxy group is independently optionally substituted by one or more R w ; and each R w has the meaning as described herein.
  • each R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, C 1 -C 6 alkyl, C 1 -C a 6 haloalkyl group, a C 1 -C 6 alkoxy group or a C 1 -C 6 haloalkoxy group, wherein the C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, a C 1 -C 6 alkoxy group, and The C 1 -C 6 haloalkoxy group is, independently, optionally substituted by one or more R w ; and each R w has the meaning as described herein.
  • each R b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, C 1 -C 6 alkyl, C 1 -C a 6 haloalkyl group, a C 1 -C 6 alkoxy group or a C 1 -C 6 haloalkoxy group, wherein the C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, a C 1 -C 6 alkoxy group, and The C 1 -C 6 haloalkoxy group is, independently, optionally substituted by one or more R w ; and each R w has the meaning as described herein.
  • m is 0, 1, 2 or 3.
  • p is 0, 1, 2 or 3.
  • n 0, 1, 2, 3 or 4.
  • each k is independently 0, 1, 2, 3 or 4.
  • each r is independently 0, 1, 2, 3 or 4.
  • Cy is the following substructure:
  • each t is independently 1, 2, 3, 4 or 5; and each R y has the meaning as described in the present invention.
  • R 1 is H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, methyl, ethyl, n-propyl, isopropyl, A Oxy, ethoxy, n-propyloxy, isopropyloxy, -CF 3 or -OCF 3 .
  • each R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, methyl, ethyl, n-propyl, isopropyl Base, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CF 3 or -OCF 3 .
  • each R b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, methyl, ethyl, n-propyl, isopropyl Base, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CF 3 or -OCF 3 .
  • the compound of the present invention is a stereoisomer, tautomer, oxynitride, solvate, metabolism of a compound having one of the following structures or a compound having one of the following structures
  • the invention in another aspect, relates to a pharmaceutical composition comprising a compound of the invention.
  • the invention relates to a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, adjuvant, or any combination thereof.
  • the present invention relates to a pharmaceutical composition, which further comprises a medicament for treating central nervous system dysfunction, wherein the medicament for treating central nervous system dysfunction is an antidepressant, an anxiolytic, and an emotional stabilizer.
  • Lithium salt drugs atypical antipsychotics, antiepileptic drugs, anti-Parkinson's disease drugs, drugs as selective serotonin reuptake inhibitors and/or 5-HT 1A receptor agonists, central nervous system excitability Drug, nicotinic antagonist or any combination thereof.
  • the medicament for treating central nervous system dysfunction of the present invention is amitriptyline, desipramine, mirtazapine, bupropion, and rebaudioside.
  • the invention relates to the use of a compound or composition of the invention in the manufacture of a medicament for the prevention, treatment or amelioration of central nervous system dysfunction.
  • the medicament is for preventing, treating or ameliorating central nervous system dysfunction in a mammal, and in another embodiment, the medicament is for preventing, treating or ameliorating central nervous system dysfunction in a human .
  • the central nervous system dysfunction refers to depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress Obstacle, dyskinesia, sexual dysfunction, musculoskeletal pain, cognitive impairment, memory disorder, Parkinson's disease, Huntington's disease, phobia, substance abuse or addiction, drug addiction withdrawal symptoms or premenstrual tension synthesis disease.
  • the invention relates to the use of a compound or composition of the invention in the manufacture of a medicament for inhibiting serotonin reuptake.
  • the invention relates to the use of a compound or composition of the invention in the manufacture of a medicament for the partial activating of a 5-HT 1A receptor.
  • the invention relates to a process for the preparation, isolation and purification of a compound of formula (I).
  • the results of the biological test indicate that the compound of the present invention has strong affinity for the human 5-HT transporter (SERT); and also has strong binding affinity for the 5-HT 1A receptor; therefore, the compound provided by the present invention can be used as a better choice.
  • SERT human 5-HT transporter
  • a serotonin reuptake inhibitor and/or a 5-HT 1A receptor agonist are included in the compound of the present invention.
  • any of the embodiments of any of the aspects of the invention may be combined with other embodiments as long as they do not contradict each other.
  • any of the technical features may be applied to the technical features in other embodiments as long as they do not contradict each other.
  • subject refers to an animal. Typically the animal is a mammal, including a human. Subjects, for example, also refer to primates (eg, humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In one embodiment, the subject is a primate. In another embodiment, the subject is a human.
  • patient refers to a person (including adults and children) or other animal. In some embodiments, “patient” refers to a human.
  • stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • the prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, At least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert) E.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • proton transfer such as keto-enol isomerization and imine-ene Amine isomerization.
  • “Pharmaceutically acceptable” means a compound, material, composition, and/or dosage form that, within the scope of sound medical judgment, is suitable for contact with a patient's tissue without undue toxicity, irritation, allergies, or reasonable The benefits/risk ratios are commensurate with other problems and complications and are effectively used for the intended use.
  • the compounds of the invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or, as in the examples, specific examples, subclasses, and ones encompassed by the invention Class of compounds.
  • substituents of the present invention include, but are not limited to, D, F, Cl, N 3 , -CN, -OH, -SH, -NH 2 , alkyl, alkoxy, alkylthio, alkylamino , cycloalkyl, heterocyclic, aryl, heteroaryl and the like.
  • C 1 -C 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the definition of the Markush group for the variable is "alkyl” or "aryl”
  • the “alkyl” or “aryl” respectively represent the attached An alkylene group or an arylene group.
  • halogen and “halo” are used interchangeably herein and refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • alkyl or "alkyl group” as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein.
  • the alkyl group contains from 1 to 6 carbon atoms; in another embodiment, the alkyl group contains from 1 to 4 carbon atoms; and in one embodiment, the alkyl group contains 1 - 3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), and the like.
  • alkylene denotes a saturated divalent hydrocarbon radical derived from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, an alkylene group contains from 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in yet another embodiment, the alkylene group The group contains 1-3 carbon atoms; also in one embodiment, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 -) and the like.
  • alkenyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp 2 double bond, wherein the alkenyl group
  • the group may be optionally substituted with one or more substituents described herein, including the positioning of "cis” and “trans”, or the positioning of "E” and "Z”.
  • the alkenyl group contains 2 to 6 carbon atoms; in another embodiment, the alkenyl group contains 2 to 4 carbon atoms.
  • alkynyl means a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more of the substituents described herein.
  • the alkynyl group contains 2 to 6 carbon atoms; in another embodiment, the alkynyl group contains 2 to 4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like. .
  • alkoxy denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains from 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains from 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propyloxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butyl Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ), and so on.
  • alkylamino or “alkylamino” includes “N-alkylamino” and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups, Wherein the alkyl group has the meaning as described herein.
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N, N - Diethylamino and the like.
  • the alkylamino group is optionally substituted with one or more substituents described herein.
  • haloalkyl denotes an alkyl, alkenyl or alkoxy group substituted by one or more halogen atoms, wherein alkyl, alkenyl and alkoxy
  • the group has the meaning as described herein, and such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
  • cycloalkyl denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl contains 3-10 carbon atoms; in another embodiment, the cycloalkyl contains 3-8 carbon atoms; in yet another embodiment, the cycloalkyl contains 3-6 carbon atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group can be optionally substituted with one or more substituents described herein.
  • heterocyclyl and “heterocycle” are used interchangeably herein to refer to a monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring atoms wherein at least one ring atom of the ring is selected from the group consisting of nitrogen and sulfur. And oxygen atoms, the ring may be fully saturated or contain one or more degrees of unsaturation, but none of the aromatic rings.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrroline, 3-pyrrolyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , dioxoal
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group, a thiomorpholino 1,1-dioxide, and the like.
  • the heterocyclyl group is optionally substituted with one or more substituents described herein.
  • heteroatom refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
  • aryl denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring is aromatic .
  • the aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group.
  • aryl can be used interchangeably with the terms "aromatic ring” or "aromatic ring”. Examples of the aryl group may include a phenyl group, a naphthyl group, an anthracene, and the like.
  • the aryl group can be optionally substituted with one or more substituents described herein.
  • heteroaryl denotes a monocyclic, bicyclic, and tricyclic ring system having 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic, and At least one ring contains one or more heteroatoms.
  • a heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of a heteroaryl group.
  • heteroaryl can be used interchangeably with the terms “heteroaryl ring” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • the 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in another embodiment, the heteroaryl group is lower 5-6 membered heteroaryl.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazole , 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl , 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2- Thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3- Thienyl, pyrazolyl (eg
  • a substituent is formed by a bond to the ring to form a ring system which represents a substituent which can be substituted on the ring (such as ring A and ring B in formula a) in any substitutable or any reasonable position.
  • the formula a represents that any of the positions of the A ring and the B ring which may be substituted may be substituted by the substituent R, as shown by the formula b, the formula c, the formula d, the formula e, the formula f, the formula g and the formula h.
  • L linking group such as an L group in the present invention
  • the L linking group "-O-(CH 2 ) k -" may form a structure represented by the formula i or a structure represented by the formula j.
  • protecting group refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups.
  • protecting group of an amino group refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc).
  • a "hydroxy protecting group” refers to a substituent of a hydroxy group used to block or protect the functionality of a hydroxy group.
  • Suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl.
  • Carboxy protecting group means a substituent of a carboxy group used to block or protect the functionality of a carboxy group.
  • Typical carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, nitroethyl, and the like.
  • a general description of protecting groups can be found in Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups, Thieme, Stuttgart, 2005.
  • prodrug denotes a compound which is converted in vivo to a compound of formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug-like compound of the present invention may be an ester.
  • the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters.
  • a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid Salt, picrate, pi
  • Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -C 8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -C 8 sulfonate and aromatic sulfonate.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or mixtures thereof.
  • hydrate means that the solvent molecule is an association formed by water.
  • hydrate can be used.
  • a molecule of the compound of the invention may be combined with a water molecule, such as a monohydrate; in another embodiment, a molecule of the compound of the invention may be combined with more than one water molecule, For example, a dihydrate, in yet another embodiment, a molecule of the compound of the invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the compounds in a non-hydrated form.
  • any disease or condition as used in the present invention refers to ameliorating a disease or condition (ie, slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms).
  • “treating” refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • “treating” refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both.
  • “treating” refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
  • terapéuticaally effective amount means that when administered to a subject to treat a disease, the amount of the compound is sufficient to effect treatment of the disease.
  • the “therapeutically effective amount” can vary with the compound, the disease and severity, and the condition, age, weight, sex, etc. of the subject to be treated.
  • the indole compound of the present invention can be used as a selective serotonin reuptake inhibitor and/or a 5-HT 1A receptor agonist for a human center
  • the treatment of nervous system dysfunction such as depression, anxiety, and bipolar disorder, has potential uses.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the invention, and as disclosed herein are included in the present invention. .
  • stereochemistry is indicated by a solid wedge or a dashed line indicating a particular configuration, the stereoisomers of the structure are thus defined and defined.
  • Nitrogen oxides of the compounds of the invention are also included within the scope of the invention.
  • the corresponding nitrogen-containing basic substance can be oxidized by using a usual oxidizing agent (for example, hydrogen peroxide) at elevated temperature, in the presence of an acid such as acetic acid, or by reacting with a peracid in a suitable solvent, for example, in methylene chloride.
  • a usual oxidizing agent for example, hydrogen peroxide
  • the oxynitride of the compound of the present invention is prepared by reacting with peracetic acid in ethyl acetate or methyl acetate or by reacting with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
  • the compound of the formula (I) may exist in the form of a salt.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal treated therewith.
  • the salt is not necessarily a pharmaceutically acceptable salt, and may be used to prepare and/or purify a compound of formula (I) and/or to isolate a compound of formula (I). The intermediate of the enantiomer.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods.
  • such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • the free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched.
  • Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the invention relates to an intermediate for the preparation of a compound of formula (I).
  • the invention provides a pharmaceutical composition comprising a compound of the invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition can be in the form of a liquid, solid, semi-solid, gel or spray.
  • compositions, formulations and administrations of the compounds of the invention are provided.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a single stereoisomer thereof, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof .
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally other therapeutic and/or prophylactic ingredients.
  • Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel HC et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro ARet Al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
  • compositions of the invention may exist in free form for treatment or, if appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or can be provided directly or indirectly to a patient in need thereof. Any additional adduct or derivative of the compound or its metabolite or residue.
  • compositions disclosed herein can be prepared and packaged in bulk form in which a safe and effective amount of a compound of the invention can be extracted and then administered to a patient in the form of a powder or syrup.
  • the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions disclosed herein can generally contain, for example, from 0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100 mg of the compounds disclosed herein.
  • pharmaceutically acceptable excipient means a pharmaceutically acceptable material, mixture or vehicle that is associated with the administration of a dosage form or pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions which would greatly reduce the efficacy of the compounds disclosed herein when administered to a patient and result in a pharmaceutical composition that is not pharmaceutically acceptable Interaction.
  • each excipient must be pharmaceutically acceptable, for example, of sufficiently high purity.
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, pharmaceutically acceptable excipients can be selected based on their particular function in the composition.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, Preservatives, stabilizers, surfactants and buffers.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents,
  • compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the present invention is directed to a process for preparing a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, the process comprising Mix various ingredients.
  • Pharmaceutical compositions comprising the compounds disclosed herein can be prepared, for example, by mixing at ambient temperature and atmospheric pressure.
  • dosage forms include those suitable for the following routes of administration: (1) oral administration, for example, tablets, capsules, caplets, pills, tablets, powders, syrups, elixirs, suspensions, Solution, emulsion, sachet and cachet; (2) parenteral administration, such as sterile solutions, suspensions and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes , sprays, foams and gels.
  • routes of administration include those suitable for the following routes of administration: (1) oral administration, for example, tablets, capsules, caplets, pills, tablets, powders, syrups, elixirs, suspensions, Solution, emulsion, sachet and cachet; (2) parenteral administration, such as sterile solutions, suspensions and reconstituted powders; (3)
  • the compounds disclosed herein can be formulated into oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhaled dosage form. In another embodiment, the compounds disclosed herein may be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated in a transdermal dosage form. In still another embodiment, the compounds disclosed herein may be formulated for topical administration.
  • the pharmaceutical composition provided by the present invention can be provided as a compressed tablet, a developed tablet, a chewable tablet, a fast-dissolving tablet, a reconstituted tablet, or an enteric coated tablet, a sugar-coated tablet or a film-coated tablet.
  • the pharmaceutical composition provided by the present invention may be provided in a soft capsule or a hard capsule, which may be prepared from gelatin, methylcellulose, starch or calcium alginate.
  • compositions provided herein can be provided in liquid and semisolid dosage forms including emulsions, solutions, suspensions, elixirs, and syrups.
  • Dosage unit formulations for oral administration can be microencapsulated as appropriate. It may also be prepared as a composition for prolonged or sustained release, for example by coating or embedding the particulate material in a polymer, wax or the like.
  • the oral pharmaceutical compositions provided herein can also be provided in the form of liposomes, micelles, microspheres or nanosystems.
  • the micellar dosage form can be prepared by the method described in U.S. Pat. No. 6,350,458.
  • compositions provided herein can be provided as non-effervescent or effervescent granules and powders to reconstitute a liquid dosage form.
  • the pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • the pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Colorants and flavoring agents can be used in all of the above dosage forms.
  • the compounds disclosed herein can also be combined with soluble polymers as targeted drug carriers.
  • compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-release, pulse-, controlled-, targeted-, and programmed release forms.
  • compositions provided herein can be formulated with other active ingredients that do not impair the intended therapeutic effect, or with a substance that complements the intended effect.
  • compositions provided by the present invention can be administered parenterally by injection, infusion or implantation for topical or systemic administration.
  • Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and Subcutaneous administration.
  • compositions provided herein can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and in liquids prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, supra).
  • compositions provided by the present invention may be formulated for administration in single or multiple doses.
  • the single dose formulation is packaged in an ampoule, vial or syringe.
  • the multi-dose parenteral formulation must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as is known and practiced in the art.
  • compositions disclosed herein can be formulated into any dosage form suitable for inhalation administration to a patient, such as a dry powder, aerosol, suspension or solution composition.
  • compositions suitable for transdermal administration can be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time.
  • the active ingredient can be delivered from the patch by ion permeation as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the compounds and pharmaceutical compositions provided by the present invention are useful for the preparation of a medicament for preventing, treating or ameliorating central nervous system dysfunction in mammals, including humans, and for preparing serotonin reuptake and/or agonizing 5-HT 1A. Receptive drugs.
  • the amount of the compound in the composition of the present invention can effectively and selectively detect the reuptake of serotonin and agonize the 5-HT 1A receptor, and the compound of the present invention can be used as a therapeutic human center.
  • Neurological (CNS) dysfunction drugs such as depression and anxiety.
  • the compounds of the invention may be used, but are in no way limited to, the administration of an effective amount of a compound or composition of the invention to a patient to prevent, treat or ameliorate central nervous system dysfunction.
  • the central nervous system dysfunction disease responsive to serotonin receptor regulation further includes, but is not limited to, depression, anxiety, mania, schizophrenia, sleep disorder, bipolar disorder, obsessive concept With behavioral disorders, panic disorder, post-traumatic stress disorder, dyskinesia, sexual dysfunction, musculoskeletal pain, cognitive impairment, memory impairment, Parkinson's disease, Huntington's disease, phobia, substance abuse or addiction, Drug addiction withdrawal symptoms and premenstrual tension syndrome.
  • the compounds and pharmaceutical compositions of the present invention are also useful in veterinary treatment of pets, introduced species of animals, and mammals in farm animals. Other examples of animals include horses, dogs, and cats.
  • the compounds of the invention include pharmaceutically acceptable derivatives thereof.
  • the methods of treatment disclosed herein comprise administering to a patient in need thereof a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
  • Embodiments of the present disclosure include methods of treating the above mentioned diseases by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.
  • a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered by any suitable route of administration, including systemic administration and topical administration.
  • the compounds disclosed herein can be administered simultaneously with, or before or after, one or more other therapeutic agents.
  • the compounds of the invention may be administered separately or in combination with other therapeutic agents by the same or different routes of administration.
  • a prodrug of a compound disclosed herein is a functional derivative which, when administered to a patient, ultimately releases the compound of the present invention in vivo.
  • a compound disclosed herein is administered in a prodrug form
  • one of skill in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of in vivo action of the compound; Changing the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming the side effects or other difficulties faced by the compound.
  • Typical functional derivatives for the preparation of prodrugs including variants of compounds which are cleaved chemically or enzymatically in vivo. These variants comprising the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates are well known to those skilled in the art.
  • the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I).
  • the following reaction schemes and examples are provided to further illustrate the contents of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.
  • reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe.
  • the glassware is dry.
  • the column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
  • MS mass spectrometry
  • the pure compound was detected by UV using an Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80 mm DAC) at 210 nm / 254 nm.
  • the intermediate represented by the formula ( 3 ) can be produced by the synthesis scheme 1: the compound ( 1 ) is subjected to Suzuki coupling reaction with the boronic acid pinacol ester to obtain the compound ( 2 ); the compound ( 2 ) is under the action of sodium perborate. An intermediate compound ( 3 ) is produced.
  • the compound of the formula ( 8 ) can be produced by the synthesis scheme 2: first, the compound ( 4 ) is reacted with sodium methylsulfinate to obtain the compound ( 5 ); then, the compound ( 5 ) and the compound ( 3 ) are in the base. Substituting reaction to form compound ( 6 ); finally, compound ( 6 ) is decarboxylated in ethyl acetate or trifluoroacetic acid, and then substituted with compound ( 7 ) under the action of a base. The target compound ( 8 ) was obtained.
  • the compound represented by the formula ( 12 ) can be produced by the synthesis scheme 3: the compound ( 3 ) and the compound ( 9 ) are subjected to a substitution reaction under the action of a base to obtain a compound ( 10 ); the compound ( 10 ) is dissolved in a methanol solution of ammonia or The compound ( 11 ) is obtained by the action of hydrogen peroxide; the compound ( 11 ) is decarboxylated in ethyl acetate or trifluoroacetic acid, and then the compound ( 7 ) is substituted with a base to obtain a target.
  • 1,4-Di(bromomethyl)benzene (3.10 g, 11.75 mmol) and sodium methylsulfinate (0.40 g, 3.92 mmol) were dissolved in DMF (5 mL), and the reaction was warmed to 80 ° C for 6 hours. After that, it was cooled to room temperature, and then water (20 mL) was added and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic layer was dried with EtOAcjjjjjjjj 0.64g, 62.1%).
  • the title compound of this step was prepared according to the method described in the step 1 of Example 3, that is, 4-(5-hydroxypyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0.70 g, 2.50 mmol), 2- (bromo) Methyl)benzonitrile (0.54 g, 2.75 mmol) and cesium carbonate (2.44 g, 7.49 mmol) were obtained in EtOAc (5 mL). The title compound was obtained as a white solid (0.93 g, 93.9%).
  • the title compound of this step was prepared according to the method described in Step 2 of Example 3, that is, 4-(5-((2-cyanobenzyl)oxy)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester ( 0.90g, 2.28mmol), potassium carbonate (0.10g, 0.72mmol) and hydrogen peroxide (0.46mL, 4.55mmol, 30%) were reacted in dimethyl sulfoxide (15mL) to obtain crude product.
  • Example A Evaluation of the affinity of compounds for CHO cell transfected humanized 5-HT transporters
  • the incubated samples were quickly filtered through a 96-well cell harvester (Unifilter, Packard) under vacuum conditions through a glass fiber filter (GF/B, Packard) pre-impregnated with 0.3% PEI and using ice-cold 50 mM Tris-HCl and Rinse several times with 150 mM NaCl.
  • the filter was dried and the residual radioactivity was calculated in a scintillation counter (Topcount, Packard) using scintillation fluid (Microscint 0, Packard).
  • the experimental results are expressed as a percentage inhibition of radioligand-specific binding relative to the control group.
  • the standard reference compound was imipramine, and a competitive curve was obtained by a series of experimental tests to calculate the IC 50 . See Table A for the experimental results.
  • Example B h5-HT 1A receptor binding affinity test
  • Human membrane was homogenized (36 ⁇ g protein), 0.3 nM [ 3 H]8-OH-DPAT (Perkin-Elmer) and buffer (50 mM Tris-HCl (pH 7.4), 10 mM MgSO at 22 °C. 4 , 0.5 mM EDTA, 2 ⁇ g / ml aprotinine) in a mixed system, with or without the addition of test compounds, for a total of 60 minutes.
  • buffer 50 mM Tris-HCl (pH 7.4), 10 mM MgSO at 22 °C. 4 , 0.5 mM EDTA, 2 ⁇ g / ml aprotinine
  • the standard reference compound was 8-OH-DPAT, and 10 ⁇ M 8-OH-DPAT was added to the mixed system of the above conditions for measurement of non-specific binding value.
  • a competitive curve was obtained by testing the data of a series of concentrations of 8-OH-DPAT in different experiments.
  • the incubated samples were quickly filtered through a 96-well cell harvester (Unifilter, Packard) under vacuum conditions through a glass fiber filter (GF/B, Packard) pre-impregnated with 0.3% PEI and repeated using ice-cold 50 mM Tris-HCl. Rinse several times. The filter was dried and the residual radioactivity was calculated in a scintillation counter (Topcount, Packard) using scintillation fluid (Microscint 0, Packard). The experimental results are expressed as a percentage inhibition of radioligand-specific binding relative to the control group.
  • the binding assay of [ 3 H]8-OH-DPAT (0.3 nM) to the 5-HT 1A receptor in human HEK-293 cells was performed by a scintillation proximity assay of the membrane.
  • the test compound needs to be tested at least three times at a concentration exceeding 6 log, and the data is subjected to nonlinear regression analysis by a Hill equation curve to obtain an IC 50 value, which is then calculated by the Cheng Prusoff equation to obtain a Ki value. See Table B for the experimental results.
  • Example number K i (nM) Example 3 2.14
  • Example 4 1.13
  • Example 5 3.95
  • Example 6 2.16
  • the experimental results show that the compound of the present invention has strong binding affinity to the 5-HT 1A receptor.

Abstract

提供取代的吲哚化合物及其使用方法和用途，具体公开了一类用于抑制5-羟色胺再摄取和/或激动5-HT 1A受体的吲哚化合物及其药物组合物。还提供制备这类化合物和药物组合物的方法，以及它们在治疗中枢神经***功能障碍中的用途。

Description

取代的吲哚化合物及其使用方法和用途 技术领域
本发明属于药物技术领域，具体涉及用于治疗中枢神经***功能障碍的化合物、组合物及其使用方法和用途。特别地，本发明所述的是可以作为5-羟色胺再摄取抑制剂和/或5-HT1A受体激动剂的取代的吲哚化合物。
背景技术
5-羟色胺，一种在大脑和神经***中传递信号的神经递质，在中枢神经***(CNS)功能障碍中，尤其是焦虑、抑郁、侵略和冲动情绪中，扮演着重要的角色。拮抗或激动一定类型的5-羟色胺受体可以有效地调控中枢神经***功能障碍。迄今为止，至少有14种5-羟色胺受体被确认。这些受体可分为不同家族，分别记作5-HT1、5-HT2、5-HT3、5-HT4、5-HT5、5-HT6和5-HT7，而各族中的不同亚型则用a、b和c等区分。
在所有与5-羟色胺功能障碍相关的适应症中，抑郁症是最重要的，因为据世界卫生组织报道，抑郁症已成为人类第四大负担性疾病。预计到2020年，抑郁症的伤残调整寿命年会跃居到所有疾病的第二位。(Bromet E,Andrade LH,Hwang I,et al.,Cross-national epidemiology of DSM-IV major depressive episode.BMCMed.2011,9:90)。
历史上，情绪障碍的药物治疗始于20世纪50年代，包括三环类抗抑郁药(TCAs)和单胺氧化酶抑制剂(MAOIs)，这些药物主要靠对神经递质(多巴胺、去甲肾上腺素和5-羟色胺)的阻断作用来发挥疗效。然而，对靶标的非选择性和不期望的副作用限制了它们的使用。到20世纪80年代，选择性5-羟色胺再摄取抑制剂(SSRIs)的出现，改变了这种情状。与TCAs相比，这类药物疗效相当，但副作用小，即使过量服用，产生的毒性也较小(Sarko J.Andidepressant,old and new.A review oftheir adverse effects and toxicity in overdose.Emerg Med Clin North Am,2000；18(4):637-54)。
传统的SSRIs治疗通过抑制5-羟色胺的再摄取和调节其转运来增加5-羟色胺的含量。但使用SSRIs后，同样会激活突触前膜的5-HT1A自身受体，导致5-羟色胺的释放量减少，使突触间5-羟色胺的浓度降低。不过，随着服药时间的延长，SSRIs会导致5-HT1A自身受体脱敏，激活效应得到克制，从而发挥正常的调节作用。由此推断，对5-HT1A自身受体的激活效应是推迟SSRIs发挥药效的重要原因(Celada P,Puig M,Amargos-Bosch M,et al.,The therapeutic role of 5-HT1A and 5-HT2A receptors in depression.J Psychiatry Neurosci,2004,29(4):252-65)。因此，克服5-HT1A自身受体拮抗剂的负反馈作用有增强和加快临床抗抑郁的前景。
与SSRIs相比，5-HT1A受体激动剂或部分激动剂直接作用于突触后的5-羟色胺受体，以增加SSRI潜伏作用期中的5-羟色胺神经传递。Feiger和Wilcox证明丁螺环酮和吉吡隆是临床上有效的5-HT1A部分激动剂(Feiger,A.Psychopharmacol.Bull.1996,32:659-65)。标准SSRI治疗中加入丁螺环酮，在先前对抑郁的标准治疗无反应的患者中引起显著的改善(Dimitriou,E.J.Clin.Psychopharmacol.,1998,18:465-9)。
本发明提供了一类具有选择性5-羟色胺再摄取抑制活性和/或5-HT1A受体激动活性的新化合物，具备较好的临床应用前景。与已有的同类化合物相比，本发明的化合物具有更好的药效，药代性质和/或毒理特 性。
发明摘要
以下仅概括说明本发明的一些方面，并不局限于此。这些方面和其他部分在后面有更完整的说明。本说明书中的所有参考文献通过整体引用于此。当本说明书的公开内容与引用文献有差异时，以本说明书的公开内容为准。
本发明涉及一类新颖的取代的吲哚化合物，其与5-HT转运体(SERT)具有较强的结合亲和力，能选择性抑制5-HT再摄取，另外其与5-HT1A受体也具有较强的结合亲和力，能有效激动5-HT1A受体，从而可以用于制备治疗中枢神经***(CNS)功能障碍的药物，并且本发明化合物性质稳定，安全性良好，具有药效学和药代动力学优势，例如良好的脑/血浆比(brain plasma ratio)、良好的生物利用度或良好的代谢稳定性等，因此具备较好的临床应用前景。
本发明所述化合物对5-羟色胺再摄取有选择性抑制作用和/或对5-HT1A受体有激动作用，可以用于制备治疗中枢神经***(CNS)功能障碍，比如抑郁症、焦虑症、双相障碍的药物。
本发明还提供制备这类化合物的方法以及含有此类化合物的药物组合物。
一方面，本发明涉及一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2016094792-appb-000001
其中，各R1、Ra、Rb、Q、L、Cy、m、n和p具有如本发明所述的含义。
在一实施方案中，Q为CH或N。
在一实施方案中，L为-O-(CH2)k-、-(CH2)k-O-、-O-(CH2)k-C(＝O)-(CH2)k-、-(CH2)k-C(＝O)-(CH2)k-O-、-S-(CH2)k-、-(CH2)k-S-、-NH-(CH2)k-或-(CH2)k-NH-，其中各k具有如本发明所述的含义。
在一实施方案中，Cy为6-10个环原子组成的芳基或5-10个环原子组成的杂芳基，其中所述6-10个环原子组成的芳基和5-10个环原子组成的杂芳基独立任选地被1、2、3、4或5个Ry所取代；和各Ry具有如本发明所述的含义。
在一实施方案中，R1为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基或C1-C6卤代烷氧基，其中所述C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基独立任选地被一个或多个Rw所取代；和各Rw具有如本发明所述的含义。
在一实施方案中，各Ra独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基或C1-C6卤代烷氧基，其中所述C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基独立任选地被一个或多个Rw所取代；和各Rw具有如本发明所述的含义。
在一实施方案中，各Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基或C1-C6卤代烷氧基，其中所述C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6 卤代烷氧基独立任选地被一个或多个Rw所取代；和各Rw具有如本发明所述的含义。
在一实施方案中，各Ry独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C6烷基)、-C(＝O)-(C1-C6烷氧基)、-(CH2)r-S(＝O)-(C1-C6烷基)、-(CH2)r-S(＝O)2-(C1-C6烷基)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基、3-10个环原子组成的杂环基、C6-C10芳基或5-10个环原子组成的杂芳基，其中所述-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C6烷基)、-C(＝O)-(C1-C6烷氧基)、-(CH2)r-S(＝O)-(C1-C6烷基)、-(CH2)r-S(＝O)2-(C1-C6烷基)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基、3-10个环原子组成的杂环基、C6-C10芳基和5-10个环原子组成的杂芳基独立任选地被一个或多个Rw所取代；和各Rw具有如本发明所述的含义。
在一实施方案中，各Rw独立地为D、F、Cl、Br、I、-NO2、-CN、-N3、-NH2、-OH、-SH、氧代(＝O)、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷氨基、C1-C4烷硫基、NH2-(C1-C4亚烷基)-、HO-(C1-C4亚烷基)-、HS-(C1-C4亚烷基)-、(C1-C4烷氧基)-(C1-C4亚烷基)-、(C1-C4烷氨基)-(C1-C4亚烷基)-、(C1-C4烷硫基)-(C1-C4亚烷基)-、C3-C6环烷基、(C3-C6环烷基)-(C1-C4亚烷基)-、3-7个环原子组成的杂环基、(3-7个环原子组成的杂环基)-(C1-C4亚烷基)-、苯基、苯基-(C1-C4亚烷基)-、5-6个环原子组成的杂芳基或(5-6个环原子组成的杂芳基)-(C1-C4亚烷基)-。
在一实施方案中，m为0、1、2或3。
在一实施方案中，p为0、1、2或3。
在一实施方案中，n为0、1、2、3或4。
在一实施方案中，各k独立地为0、1、2、3或4。
在一实施方案中，各r独立地为0、1、2、3或4。
在一实施方案中，Cy为以下子结构式：
Figure PCTCN2016094792-appb-000002
其中，各t独立地为1、2、3、4或5；和各Ry具有如本发明所述的含义。
在一实施方案中，各Ry独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C4烷基)、-C(＝O)-(C1-C4烷氧基)、-(CH2)r-S(＝O)-(C1-C4烷基)、-(CH2)r-S(＝O)2-(C1-C4烷基)、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C3-C6环烷基、4-6个环原子组成的杂环基、苯基或5-6个环原子组成的杂芳基，其中所述-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C4烷基)、-C(＝O)-(C1-C4烷氧基)、-(CH2)r-S(＝O)-(C1-C4烷基)、-(CH2)r-S(＝O)2-(C1-C4烷基)、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C3-C6环烷基、4-6个环原子组成的杂环基、苯基和5-6个环原子组成的杂芳基独立任选地被一个或多个Rw所取代；和各Rw具有如本发明所述的含义。
在一实施方案中，R1为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CF3或-OCF3。
在一实施方案中，各Ra独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CF3或-OCF3。
在一实施方案中，各Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CF3或-OCF3。
在一实施方案中，各Ry独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)CH3、-C(＝O)OCH3、-CH2-S(＝O)CH3、-CH2-S(＝O)CH2CH3、-CH2-S(＝O)CH(CH3)2、-CH2-S(＝O)2CH3、-CH2-S(＝O)2CH2CH3、-CH2-S(＝O)2CH(CH3)2、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CF3、-CH2CF3、-OCF3、-OCH2CF3或-OCH2CF2CHF2。
在一实施方案中，本发明所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药：
Figure PCTCN2016094792-appb-000003
Figure PCTCN2016094792-appb-000004
另一方面，本发明涉及一种药物组合物，其包含本发明所述化合物。
在一实施方案中，本发明涉及的药物组合物，其进一步包含药学上可接受的赋形剂、载体、辅剂、佐剂或它们的任意组合。
在一实施方案中，本发明涉及的药物组合物，其更进一步包含治疗中枢神经***功能障碍的药物，所述治疗中枢神经***功能障碍的药物为抗抑郁药物、抗焦虑药物、作为情感稳定剂的锂盐类药物、非典型性抗精神病药物、抗癫痫药物、抗帕金森病药物、作为选择性5-羟色胺再摄取抑制剂和/或5-HT1A受体激动剂的药物、中枢神经兴奋药、烟碱拮抗剂或它们的任意组合。
在另一实施方案中，本发明治疗中枢神经***功能障碍的药物为阿米替林(amitriptyline)、地昔帕明(desipramine)、米氮平(mirtazapine)、安非他酮(bupropion)、瑞波西汀(reboxetine)、氟西汀(fluoxetine)、曲唑酮(trazodone)、舍曲林(sertraline)、度洛西汀(duloxetine)、氟伏沙明(fluvoxamine)、米那普仑(milnacipran)、左旋米那普仑(levomilnacipran)、去甲文拉法辛(desvenlafaxine)、维拉唑酮(vilazodone)、文拉法辛(venlafaxine)、达泊西汀(dapoxetine)、奈法唑酮(nefazodone)、非莫西汀(femoxetine)、氯丙咪嗪(clomipramine)、西酞普兰(citalopram)、艾司西酞普兰(escitalopram)、帕罗西汀(paroxetine)、碳酸锂(lithium carbonate)、丁螺环酮(buspirone)、奥氮平(olanzapine)、喹硫平(quetiapine)、利培酮(risperidone)、齐拉西酮(ziprasidone)、阿立哌唑(aripiprazole)、哌罗匹隆(perospirone)、氯氮平(clozapine)、***(modafinil)、美卡拉明(mecamylamine)、卡麦角林(cabergoline)、金刚烷(adamantane)、丙咪嗪(imipramine)、普拉克索(pramipexole)、甲状腺素(thyroxine)、右美沙芬(dextromethorphan)、奎尼丁(quinidine)、纳曲酮(naltrexone)、samidorphan、丁丙诺啡(buprenorphine)、褪黑激素(melatonin)、阿普***(alprazolam)、匹泮哌隆(pipamperone)、维替匹坦(vestipitant)、利眠宁(chlordiazepoxide)、奋乃静(perphenazine)或它们的任意组合。
另一方面，本发明涉及本发明化合物或组合物在制备药物中的用途，所述药物用于预防、治疗或减轻中枢神经***功能障碍。例如，在一实施方案中，所述药物用于预防、治疗或减轻哺乳动物中枢神经***功能障碍，在另一实施方案中，所述药物用于预防、治疗或减轻人的中枢神经***功能障碍。
在一实施方案中，所述的中枢神经***功能障碍是指抑郁症、焦虑症、躁狂症、精神***症、双相障碍、睡眠障碍、强迫观念与行为障碍、惊恐障碍、创伤后应激障碍、运动障碍、性功能障碍、肌肉骨骼疼痛障碍、认知障碍、记忆障碍、帕金森氏病、亨廷顿氏病、恐怖症、物质滥用或成瘾、药物成瘾戒断症状或经前期紧张综合症。
另一方面，本发明涉及本发明化合物或组合物在制备药物中的用途，所述药物用于抑制5-羟色胺再摄取。
另一方面，本发明涉及本发明化合物或组合物在制备药物中的用途，所述药物用于部分激动5-HT1A受体。
另一方面，本发明涉及式(I)所示化合物的制备、分离和纯化的方法。
生物试验结果表明，本发明化合物对人源5-HT转运体(SERT)具有强的亲和力；对5-HT1A受体也具有强的结合亲和力；因此本发明提供的化合物可作为较好的选择性5-羟色胺再摄取抑制剂和/或5-HT1A受体激动剂。
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他方面的内容将在下面作更加具体完整的描述。
本发明的详细说明书
定义和一般术语
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的 替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本发明所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,和“March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,NewYork:2007中的描述，其全部内容通过引用并入本发明。
除非另有说明或者上下文中有明显的冲突，本发明所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本发明所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物，包括人类。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等等。在一实施方案中，所述受试对象是灵长类动物。在另一实施方案中，所述受试对象是人。
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。
术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc,NewYork,1994。许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量， 至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.ofNotre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。
“药学上可接受的”是指这样一些化合物、原料、组合物和/或剂型，它们在合理医学判断的范围内，适用于与患者组织接触而无过度毒性、刺激性、***反应或与合理的利益/风险比相对称的其他问题和并发症，并有效用于既定用途。
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其中它不出现的情况。例如，“任选的键”是指该键可以存在或可以不存在，并且该描述包括单键、双键或三键。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子、子类和本发明所包含的一类化合物。
术语“任选地被…….所取代”，可以与术语“未取代或被…..所取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基取代，本发明所述的取代基包括，但不限于D，F，Cl，N3，-CN，-OH，-SH，-NH2，烷基，烷氧基，烷硫基，烷氨基，环烷基，杂环基，芳基，杂芳基等等。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
术语“不饱和”或“不饱和的”表示部分含有一个或多个不饱和度。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-C6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
术语“卤素”和“卤代”在本发明中可互换使用，是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
本发明使用的术语“烷基”或“烷基基团”，表示含有1-20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。在一实施方案中，烷基基团含有1-6个碳原子；在另一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。烷基基团的实例包含，但并不限于，甲基(Me、-CH3)，乙基(Et、-CH2CH3)，正丙基(n-Pr、-CH2CH2CH3)，异丙基(i-Pr、-CH(CH3)2)，正丁基(n-Bu、-CH2CH2CH2CH3)，异丁基(i-Bu、-CH2CH(CH3)2)，仲丁基(s-Bu、-CH(CH3)CH2CH3)，叔丁基(t-Bu、-C(CH3)3)，等等。
术语“亚烷基”表示从饱和的直链或支链烃中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子。在一实施方案中，亚烷基基团含有1-6个碳原子；在另一实施方案中，亚烷基基团含有1-4个碳原子；在又一实施方案中，亚烷基基团含有1-3个碳原子；还在一实施方案中，亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH2-)，亚乙基(-CH2CH2-)，亚异丙基(-CH(CH3)CH2-)等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“trans”的定位，或者“E”和“Z”的定位。在一实施方案中，烯基基团包含2-6个碳原子；在另一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH2)、烯丙基(-CH2CH＝CH2)等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，炔基基团包含2-6个碳原子；在另一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)、1-丙炔基(-C≡C-CH3)等等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH3)，乙氧基(EtO、-OCH2CH3)，1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH3)2)，1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3)，等等。
术语“烷氨基”或“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代，其中烷基基团具有如本发明所述的含义。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基等等。所述烷氨基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“卤代烷基”、“卤代烯基”或“卤代烷氧基”表示烷基、烯基或烷氧基基团被一个或多个卤素原子所取代，其中烷基、烯基和烷氧基基团具有如本发明所述的含义，这样的实例包含，但并不限于，三氟甲基、三氟甲氧基等。
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。在一实施方案中，环烷基包含3-10个碳原子；在另一实施方案中，环烷基包含3-8个碳原子；在又一实施方案中，环烷基包含3-6个碳原子。环烷基的实例包括，但并不限于，环丙基、环丁基、环戊基、环己基，等等。所述环烷基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的单环、双环或三环体系，其中环上至少一个环原子选自氮、硫和氧原子，环可以是完全饱和的或包含一个或多个不饱和度，但一个芳香性环都不能有。除非另外说明，杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括，但不限于，环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2016094792-appb-000005
基，二氮杂
Figure PCTCN2016094792-appb-000006
基，硫氮杂
Figure PCTCN2016094792-appb-000007
基，2-氧杂-5-氮杂双环[2.2.1]庚-5-基，等等。杂环基中-CH2-基团被-C(＝O)-取代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基、嘧啶二酮基，等等。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、硫代吗啉基1,1-二氧化物，等等。所述杂环基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中至少一个环是芳香族的。芳基基团通常，但不必须地通过芳基基团的芳香性环与母体分子连接。术语“芳基”可以和术语“芳香环”或“芳环”交换使用。芳基基团的实例可以包括苯基、萘基、蒽，等等。所述芳基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环是芳香族的，且至少一个环包含一个或多个杂原子。杂芳基基团通常，但不必须地通过杂芳基基团的芳香性环与母体分子连接。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，5-10元杂芳基包含1、2、3或4个独立选自O、S和N的杂原子；在另一实施方案中，杂芳基基团为较低级的5-6元杂芳基。
杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑 基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、***基(如2-***基和5-***基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-***基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基，等等；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]***并[4,3-b]哒嗪基、[1,2,4]***并[1,5-a]嘧啶基、[1,2,4]***并[1,5-a]吡啶基，等等。
像本发明所描述的，取代基画一个键连接到环上形成的环体系代表取代基在环上(如式a中的A环和B环)任何可取代或任何合理的位置都可以进行取代。例如，式a代表A环和B环上任何可能被取代的位置均可被取代基R取代，如式b、式c、式d、式e、式f、式g和式h所示。
Figure PCTCN2016094792-appb-000008
如本发明所描述的，连接基团(如本发明中的L基团)中的两个连接点可以任意互换。例如，L连接基团“-O-(CH2)k-”既可以形成得到式i所示的结构，也可以形成得到式j所示的结构。
Figure PCTCN2016094792-appb-000009
术语“保护基团”或“PG”是指一个取代基与其他官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC,Boc)，苄氧羰基(CBZ,Cbz)和9-芴甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括三烷基甲硅烷基，乙酰基，苯甲酰基和苄基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH2CH2SO2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：Greene et al.,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：Higuchi et al.,Pro-drugs as Novel Delivery Systems,Vol.14,A.C.S.Symposium Series；Roche et al.,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,NatureReviews Drug Discovery,2008,7,255-270,and Hecker et al,Prodrugs of Phosphates and Phosphonates,J.Med.Chem.,2008,51,2328-2345,每篇文献通过引用包含于此。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-C8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸、乙醇胺或其混合物。术语“水合物”是指溶剂分子是水所形成的缔合物。
当所述溶剂为水时，可以使用术语“水合物”。在一实施方案中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另一实施方案中，一个本发明化合物分子可以与多于一个的水分子相结合， 比如二水合物，在又一实施方案中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
术语“治疗有效量”是指当给药于主体来治疗疾病时，化合物的分量足够对这种疾病的治疗起效。“治疗有效量”可以随着化合物，疾病和严重程度，以及有待治疗的主体的条件，年龄，体重，性别等而改变。
本发明涉及的吲哚化合物，其药学上可接受的盐，药物制剂及其组合物，可以用作选择性5-羟色胺再摄取抑制剂和/或5-HT1A受体激动剂，对人类中枢神经***功能障碍，比如抑郁症，焦虑症、双相障碍的治疗有潜在的用途。
除非另作说明，本发明的化合物所有合适的同位素变化、立体异构体、互变异构体、溶剂化物、代谢产物、盐和药学上可接受的前药都包含在本发明范围内。
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体都考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(solidwedge)或虚线指明时，则该结构的立体异构体就此明确和定义。
本发明化合物的氮氧化物也包含在本发明的范围之内。可以通过在升温下使用常用氧化剂(例如过氧化氢)，在有例如乙酸的酸存在下，氧化相应的含氮碱性物质，或者通过在适合的溶剂中与过酸反应，例如在二氯甲烷、乙酸乙酯或乙酸甲酯中与过乙酸反应，或在氯仿或二氯甲烷中与3-氯过氧苯甲酸反应，制备本发明化合物的氮氧化物。
式(I)所示化合物可以以盐的形式存在。在一实施方案中，所述盐是指药学上可接受的盐。术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。在另一实施方案中，所述盐不一定是药学上可接受的盐，可以是用于制备和/或提纯式(I)所示化合物和/或用于分离本式(I)所示化合物的对映体的中间体。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如***、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company,Easton,Pa.,(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts:Properties,Selection,and Use)”,Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如2H、 3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl和125I。
另一方面，本发明涉及制备式(I)所示化合物的中间体。
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物。在一实施方案中，本发明所述药物组合物，更进一步包括药学上可接受的载体、赋形剂、佐剂、溶媒或它们的组合。在另一实施方案中，药物组合物可以是液体、固体、半固体、凝胶或喷雾剂型。
本发明化合物的药物组合物、制剂和给药
本发明提供一种药物组合物，包括式(I)所示化合物或其单独的立体异构体，异构体的外消旋或非外消旋混合物或其药学上可接受的盐或溶剂化物。在本发明的一个实施方式中，所述药物组合物进一步包含至少一种药学上可接受的载体、辅剂或赋形剂，以及任选地，其它的治疗和/或预防成分。
合适的载体、辅剂和赋形剂剂对于本领域技术人员是熟知的并且详细描述于例如Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al.,Remington：The Science and Practice of Pharmacy(2000)Lippincott,Williams&Wilkins,Philadelphia；和Rowe R.C.,Handbook of Pharmaceutical Excipients(2005)Pharmaceutical Press,Chicago中。
也应认识到，本发明的某些化合物可以以游离形式存在用于治疗，或者如果适当可以以其药学上可接受的衍生物的形式存在。药学上可接受衍生物的一些非限制性的实施方案包括药学上可接受的前药，盐，酯，这些酯的盐，或者对有需要的患者给药时能直接或间接提供本发明所述化合物或其代谢产物或残留物的任何另外的加合物或衍生物。
本发明公开的药物组合物可制备并包装为散装(bulk)形式，其中可提取安全有效量的本发明化合物，然后以粉末或糖浆形式给予患者。或者，本发明公开的药物组合物可制备并包装为单位剂型，其中每个物理上离散的单位含有安全有效量的本发明化合物。当以单位剂型制备时，本发明公开的药物组合物通常可含，例如，0.5mg至1g、或1mg至700mg、或5mg至100mg的本发明公开的化合物。
本发明所用“药学上可接受的赋形剂”意指与给药剂型或药物组合物一致性相关的药学上可接受的材料，混合物或溶媒。每种赋形剂在混合时必须与药物组合物的其它成分相容，以避免对患者给药时会大大降低本发明公开化合物的功效的相互作用和会导致不是药学上可接受的药物组合物的相互作用。此外，每种赋形剂必须是药学上可接受的，例如，具有足够高的纯度。
合适的药学上可接受的赋形剂会依所选具体剂型而不同。此外，可根据它们在组合物中的特定功能来选择药学上可接受的赋形剂。
合适的药学上可接受的赋形剂包括以下类型的赋形剂：稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、甜味剂、矫味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、塑化剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。技术人员可认识到，某些药学上可接受的赋形剂可提供不止一种功能，并提供可供选择的功能，这取决于制剂中存在多少该赋形剂和制剂中存在哪些其他赋形剂。
技术人员掌握本领域的知识和技能，以使他们能选择用于本发明的适当量的合适的药学上可接受的赋形剂。此外，存在大量技术人员可获得的资源，他们描述药学上可接受的赋形剂，并用于选择合适的药学上可接受的赋形剂。实例包括Remington's Pharmaceutical Sciences(Mack Publishing Company),The  Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
本发明公开的药物组合物使用本领域技术人员已知的技术和方法来制备。本领域一些常用方法的描述可参见Remington's Pharmaceutical Sciences(Mack Publishing Company)。
因此，另一方面，本发明涉及制备药物组合物的工艺，所述药物组合物包含本发明公开化合物和药学上可接受的赋形剂，载体，辅剂，溶媒或它们的组合，该工艺包括混合各种成分。包含本发明公开化合物的药物组合物，可以在例如环境温度和大气压下混合来制备。
本发明公开的化合物通常被配制成适合于通过所需途径对患者给药的剂型。例如，剂型包括那些适合于以下给药途径的剂型：(1)口服给药，例如片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、香包剂和扁囊剂；(2)胃肠外给药，例如无菌溶液剂、混悬剂和复溶粉末；(3)透皮给药，例如透皮贴片剂；(4)直肠给药，例如栓剂；(5)吸入，例如气雾剂、溶液剂和干粉剂；和(6)局部给药，例如乳膏剂、油膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂和凝胶剂。
在一实施方案中，本发明公开的化合物可以配制成口服剂型。在另一实施方案中，本发明公开的化合物可以配制成吸入剂型。在另一实施方案中，本发明公开的化合物可以配制成经鼻给药剂型。在又一实施方案中，本发明公开的化合物可以配制成透皮给药剂型。还在一实施方案中，本发明公开的化合物可以配制成局部给药剂型。
本发明提供的药物组合物可以以压制片、研制片、可咀嚼锭剂、速溶片、复压片、或肠溶片、糖衣或薄膜衣片来提供。
本发明提供的药物组合物可以以软胶囊或硬胶囊来提供，其可以由明胶、甲基纤维素、淀粉或海藻酸钙来制备。
本发明提供的药物组合物可以以液体和半固体剂型来提供，包括乳剂、溶液、混悬剂、酏剂和糖浆剂。
适当时，可以将口服给药的剂量单位制剂微囊包封。也可以将其制备成延长或维持释放的组合物，例如通过将微粒材料包衣或包埋在聚合物、蜡或类似物中。
本发明提供的口服药物组合物还可以以脂质体、胶束、微球或纳米体系的形式提供。胶束剂型可以用U.S.Pat.No.6,350,458描述的方法来制备。
本发明提供的药物组合物可以以非泡腾或泡腾的颗粒剂和粉剂来提供，以重构成液体剂型。在非泡腾颗粒剂或粉剂中使用的药学上可接受的载体和赋形剂可以包括稀释剂、甜味剂和润湿剂。在泡腾颗粒剂或粉剂中使用的药学上可接受的载体和赋形剂可以包括有机酸和二氧化碳源。
在所有上述剂型中可以使用着色剂和调味剂。
本发明所公开的化合物也可以与作为靶向药物载体的可溶性聚合物结合。
本发明提供的药物组合物可以配制成立即或改性释放剂型，包括延迟-、缓释-、脉冲-、控制-、靶向-和程序化释放形式。
本发明提供的药物组合物可以与不会损害预期的治疗作用的其它活性成分共同配制，或者与补充预期的作用的物质共同配制。
本发明提供的药物组合物可以通过注射、输注或植入肠胃外给药，用于局部或全身给药。如本发明使用的肠胃外给药包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内、滑膜内和 皮下给药。
本发明提供的药物组合物可以配制成适于肠胃外给药的任何剂型，包括溶液、混悬剂、乳剂、胶束、脂质体、微球、纳米体系和适于在注射前在液体中制成溶液或混悬液的固体形式。这样的剂型可以根据药物科学领域的技术人员已知的常规方法来制备(参见Remington:The Science和Practice of Pharmacy,同上)。
本发明提供的药物组合物可以配制成单剂量或多剂量给药。所述单剂量制剂被包装在安瓿剂、小瓶或注射器中。所述多剂量肠胃外制剂必须包含抑菌或抑真菌浓度的抗微生物剂。所有的肠胃外制剂都必须是无菌的，如本领域已知和实践的。
另一方面，本发明所公开的药物组合物可以配制成适于对患者吸入给药的任何剂型，例如干粉剂、气雾剂、混悬剂或溶液组合物。
适合于透皮给药的药物组合物可制备成不连续的贴片剂，意在与患者的表皮保持紧密接触一段延长的时间。例如，可通过离子渗透从贴片剂中递送活性成分，如Pharmaceutical Research,3(6),318(1986)中的一般描述。
适合于局部给药的药物组合物可以被配制成油膏剂、乳膏剂、混悬剂、洗剂、粉剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。
本发明化合物和组合物的用途
本发明提供的化合物和药物组合物可用于制备预防、治疗或减轻哺乳动物，包括人类的中枢神经***功能障碍的药品，也可以用于制备抑制5-羟色胺再摄取和/或激动5-HT1A受体的药品。
具体而言，本发明的组合物中化合物的量可以有效地可探测地选择性地抑制5-羟色胺的再摄取并对5-HT1A受体有激动作用，本发明的化合物可以作为治疗人类中枢神经***(CNS)功能障碍比如抑郁症、焦虑症的药物。
本发明的化合物可以应用于，但绝不限于，使用本发明的化合物或组合物的有效量对患者给药来预防、治疗或减轻中枢神经***功能障碍性疾病。所述的响应于5-羟色胺受体调控的中枢神经***功能障碍性疾病，进一步包括但并不限于，抑郁症，焦虑症，躁狂症，精神***症，睡眠障碍，双相障碍，强迫观念与行为障碍，惊恐障碍，创伤后应激障碍，运动障碍，性功能障碍，肌肉骨骼疼痛障碍，认知障碍，记忆障碍，帕金森氏病，亨廷顿氏病，恐怖症，物质滥用或成瘾，药物成瘾戒断症状和经前期紧张综合症等。
本发明的化合物及药物组合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物中的哺乳动物。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。
在一实施方案中，本发明公开的治疗方法包括对有需要的患者给予安全有效量的本发明化合物或包含本发明化合物的药物组合物。本发明公开的各实施方案包括通过对有需要的患者给予安全有效量的本发明公开化合物或包含本发明公开化合物的药物组合物，来治疗上面所提到疾病的方法。
在一实施方案中，本发明公开化合物或包含本发明公开化合物的药物组合物可以通过任何适合的给药途径来给药，包括全身给药和局部给药。
本发明公开化合物可以与一种或多种其它治疗剂同时，或在其之前或之后给药。本发明化合物可以与其他治疗剂通过相同或不同给药途径分别给药，或与之以同以药物组合物形式给药。
此外，本发明公开的化合物可以以前药形式给药。在本发明中，本发明公开化合物的“前药”是对患者给药时，最终能在体内释放出本发明公开化合物的功能性衍生物。以前药形式给予本发明公开的化合物时，本领域技术人员可实施下列方式中的一种及以上：(a)变更化合物的体内起效时间；(b)变更化合物的体内作用持续时间；(c)变更化合物的体内输送或分布；(d)变更化合物的体内溶解度；及(e)克服化合物所面临的副作用或其他难点。用于制备前药的典型的功能性衍生物，包含在体内以化学方式或酶的方式裂解的化合物的变体。包含制备磷酸盐、酰胺、酯、硫代酯、碳酸盐及氨基甲酸盐的这些变体对本领域技术人员来讲是众所周知的。
一般合成步骤
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。
无水四氢呋喃，二氧六环，甲苯，***是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。1H NMR谱以CDC13、DMSO-d6、CD3OD或丙酮-d6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、dd(doublet ofdoublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-M(柱子型号：Zorbax SB-C18,2.1x30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH3CN)在(含0.1％甲酸的H2O)中的比例，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。
纯的化合物使用Agilent 1260pre-HPLC或Calesep pump 250pre-HPLC(柱子型号：NOVASEP 50/80mmDAC)，在210nm/254nm用UV检测。
下面简写词的使用贯穿本发明：
BOC、Boc 叔丁氧基羰基
CH2Cl2、DCM 二氯甲烷
CDC13 氘代氯仿
CD3OD 氘代甲醇
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
EDTA 乙二胺四乙酸
Et3N、TEA 三乙胺
EtOAc、EA 乙酸乙酯
MeOH 甲醇
h 小时
HCl 氯化氢
NH3 氨气
H2O2 双氧水
MgSO4 硫酸镁
K2CO3 碳酸钾
NaBO3 过硼酸钠
CH3SO2Na 甲基亚磺酸钠
MeCN、CH3CN 乙腈
mL、ml 毫升
RT、rt、r.t. 室温
TFA 三氟乙酸
Tris-HCl 三(羟甲基)氨基甲烷-盐酸
BSA 牛血清蛋白
下列合成方案描述了制备本发明公开化合物的步骤，除非另外说明，其中各n具有本发明所述的定义，R’为氰基或是甲氧基羰基。
合成方案1：
Figure PCTCN2016094792-appb-000010
式(3)所示的中间体可以通过合成方案1制备得到：化合物(1)与联硼酸频那醇酯进行Suzuki偶联反应得到化合物(2)；化合物(2)在过硼酸钠的作用下生成中间体化合物(3)。
合成方案2：
Figure PCTCN2016094792-appb-000011
式(8)所示的化合物可以通过合成方案2制备得到：首先，化合物(4)与甲基亚磺酸钠作用得到化合物(5)；然后，化合物(5)和化合物(3)在碱的作用下发生取代反应生成化合物(6)；最后，化合物(6)在氯化氢的乙酸乙酯溶液或三氟乙酸中脱去Boc保护基后，再与化合物(7)在碱的作用下发生取代反应得到目标化合物(8)。
合成方案3：
Figure PCTCN2016094792-appb-000012
式(12)所示的化合物可以通过合成方案3制备得到：化合物(3)与化合物(9)在碱的作用下发生取代反应得到化合物(10)；化合物(10)在氨的甲醇溶液或是在双氧水的作用下得到化合物(11)；化合物(11)在氯化氢的乙酸乙酯溶液或三氟乙酸中脱去Boc保护基后，再与化合物(7)在碱的作用下发生取代反应得到目标化合物(12)。
以下结合实施例对本发明提供的化合物、药物组合物及其应用进行进一步说明。
实施例
实例施1 3-(4-(4-(5-((4-((甲基砜基)甲基)苄基)氧基)嘧啶-2-基)哌嗪-1-基)丁基)-1H-吲哚-5-甲腈
Figure PCTCN2016094792-appb-000013
步骤1) 3-(4-氯丁酰基)-1H-吲哚-5-甲腈的合成
0℃下，将4-氯丁酰氯(9.60g,68.00mmol)滴加到含有氯化铝(9.00g,68.00mmol)的二氯甲烷(90mL)溶液中，混合液搅拌30分钟后，继续向其中滴加5-氰基吲哚(8.10g,57.00mmol)的二氯甲烷(800mL)溶液。反应液升温至室温，搅拌2小时后，将反应液缓慢倒入冰/浓盐酸(50g/50mL)的混合物中，然后在室温下继续搅拌20小时。将所得混合物抽滤，并依次用水(10mL)和乙酸乙酯(10mL)洗涤滤饼，滤饼干燥后得到标题化合物为黄色固体(8.90g,63.1％)。
LC-MS(ESI,pos.ion)m/z:247.1(M+1).
步骤2) 3-(4-羟基丁基)-1H-吲哚-5-甲腈的合成
将3-(4-氯丁酰基)-1H-吲哚-5-甲腈(0.49g,2.00mmol)溶于异丙醇(20mL)中，溶液降温至0℃，然后向其中分批加入硼氢化钠(0.23g,6.00mmol)。反应液加热至80℃，搅拌6小时后，冷却至0℃，然后加入饱和碳酸钠水溶液(1mL)淬灭反应。将混合物抽滤，滤液减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝2/1)纯化得到标题化合物为白色固体(343mg,80.0％)。
LC-MS(ESI,pos.ion)m/z:215.2(M+1).
步骤3) 4-(5-氰基-1H-吲哚-3-基)丁基4-甲基苯磺酸酯的合成
将3-(4-羟基丁基)-1H-吲哚-5-甲腈(0.41g,1.90mmol)溶于二氯甲烷(20mL)中，依次向其中加入三乙胺(0.3mL,2.28mmol)和对甲苯磺酰氯(0.43g,2.28mmol)。反应液于室温下搅拌反应4小时后，加水(100mL)淬灭反应。分液，有机相用无水硫酸钠干燥，过滤，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝4/1)纯化得到标题化合物为白色固体(0.56g,80.0％)。
LC-MS(ESI,pos.ion)m/z:369.2(M+1).
步骤4) 4-(5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯的合成
氮气保护下，将4-(5-溴嘧啶-2-基)哌嗪-1-甲酸叔丁酯(4.00g,11.65mmol)、联硼酸频那醇酯(3.26g,12.82mmol)、乙酸钾(3.43g,34.96mmol)和醋酸钯(26mg,0.12mmol)加入到DMF(20mL)中。将反应液升温到85℃反应过夜后冷却至室温，然后向其中加水(20mL)，并用乙酸乙酯(20mL×3)萃取。合并的有机相用无水硫酸钠干燥，过滤，并减压浓缩，所得粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝3/1)纯化得到标题化合物为白色固体(2.52g,55.4％)。
MS(ESI,pos.ion)m/z:391.3(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):8.61(s,2H),3.88(t,J＝4.8Hz,4H),3.50(t,J＝4.8Hz,4H),1.50(s,9H),1.33(s,12H).
步骤5) 4-(5-羟基嘧啶-2-基)哌嗪-1-甲酸叔丁酯的合成
将4-(5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(2.00g,5.12mmol)和四水合过硼酸钠(2.37g,15.37mmol)加入到四氢呋喃(5mL)和水(5mL)的混合溶剂中，反应液于室温搅拌反应后，向其中加入饱和氯化铵水溶液(20mL)，并用乙酸乙酯(20mL×3)萃取。合并的有机相用无水硫酸钠干燥，过滤，并减压浓缩，所得粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝3/1)纯化得到标题化合物为白色固体(1.18g,81.9％)。
MS(ESI,pos.ion)m/z:225.3(M+1-56)；
1H NMR(400MHz,CDCl3)δ(ppm):8.09(s,2H),6.82(brs,1H),3.69(t,J＝4.8Hz,4H),3.50(t,J＝4.8Hz, 4H),1.50(s,9H).
步骤6) 1-(溴甲基)-4-((甲基砜基)甲基)苯的合成
将1,4-二(溴甲基)苯(3.10g,11.75mmol)和甲基亚磺酸钠(0.40g,3.92mmol)溶于DMF(5mL)中，反应液升温至80℃反应6小时后，冷却至室温，然后向其中加水(20mL)，并用乙酸乙酯(20mL×3)萃取。合并的有机相用无水硫酸钠干燥，过滤，并减压浓缩，所得粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝2/1)纯化得到标题化合物为白色固体(0.64g,62.1％)。
MS(ESI,pos.ion)m/z:285.1(M+Na)；
1H NMR(600MHz,CDCl3)δ(ppm):7.47(d,J＝8.0Hz,2H),7.42(d,J＝8.0Hz,2H),4.51(s,2H),4.27(s,2H),2.80(s,3H).
步骤7) 4-(5-((4-((甲基砜基)甲基)苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯的合成
将4-(5-羟基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(0.60g,2.14mmol)、1-(溴甲基)-4-((甲基砜基)甲基)苯(0.63g,2.40mmol)和碳酸铯(2.09g,6.42mmol)加入到DMF(10mL)中，反应液升温至40℃搅拌反应24小时后冷却至室温，然后向其中加水(20mL)，并用乙酸乙酯(20mL×3)萃取。合并的有机相用无水硫酸钠干燥，过滤，并减压浓缩，所得粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化得到标题化合物为白色固体(0.84g,84.8％)。
MS(ESI,pos.ion)m/z:463.1(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):8.14(s,2H),7.47(brs,4H),5.06(s,2H),4.27(s,2H),3.72(t,J＝4.8Hz,4H),3.50(t,J＝4.8Hz,4H),2.79(s,3H),1.50(s,9H).
步骤8) 3-(4-(4-(5-((4-((甲基砜基)甲基)苄基)氧基)嘧啶-2-基)哌嗪-1-基)丁基)-1H-吲哚-5-甲腈的合成
将4-(5-((4-((甲基砜基)甲基)苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.67mmol)加入到氯化氢的乙酸乙酯溶液(4M,3mL)中，混合液于室温搅拌反应1小时后，减压旋干。将所得的固体溶解在乙腈(15mL)中，并依次加入4-(5-氰基-1H-吲哚-3-基)丁基4-甲基苯磺酸酯(271mg,0.74mmol)、碳酸钾(139mg,1.00mmol)和碘化钾(11mg,0.07mmol)，然后将反应液升温，回流反应20小时后，冷却至室温，并减压浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化得到标题化合物为白色固体(200mg,53.5％)。
MS(ESI,pos.ion)m/z:559.1(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.37(brs,1H),8.24(s,2H),8.08(s,1H),7.50(d,J＝7.8Hz,1H),7.47(d,J＝8.4Hz,2H),7.43(d,J＝8.4Hz,2H),7.40(dd,J＝8.4,1.2Hz,1H),7.34(d,J＝1.2Hz,1H),5.11(s,2H),4.49(s,2H),3.60(brs,4H),2.90(s,3H),2.74(t,J＝7.2Hz,2H),2.38(brs,4H),2.34(t,J＝6.5Hz,2H),1.70-1.63(m,2H),1.54-1.50(m,2H).
实例施2 3-(3-(4-(5-((4-((甲基砜基)甲基)苄基)氧基)嘧啶-2-基)哌嗪-1-基)丙基)-1H-吲哚-5-甲腈
Figure PCTCN2016094792-appb-000014
步骤1) 3-(3-羟基丙基)-1H-吲哚-5-甲腈的合成
将4-氰基苯肼盐酸盐(3.53g,20.8mmol)溶解在稀硫酸(4％,50mL)和N,N-二甲基乙酰胺(10mL)的混合溶剂中，向其中滴加3,4-二氢-2H-吡喃(1.90mL,20.80mmol)。反应液加热至100℃，搅拌20小时后，冷却至室温，并用乙酸乙酯(50mL×3)萃取。合并的有机相用水(50mL×3)洗涤，然后用无水硫酸钠干燥，过滤，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝2/1)纯化得到标题化合物为白色固体(1.46g,35.0％)。
LC-MS(ESI,pos.ion)m/z:201.1(M+1).
步骤2) 3-(5-氰基-1H-吲哚-3-基)丙基4-甲基苯磺酸酯的合成
将3-(3-羟基丙基)-1H-吲哚-5-甲腈(1.00g,5.00mmol)溶于二氯甲烷(20mL)中，依次向其中加入三乙胺(0.8mL,6.00mmol)和对甲苯磺酰氯(1.14g,6.00mmol)。反应液于室温下搅拌反应4小时后，加水(100mL)淬灭反应。分液，有机相用无水硫酸钠干燥，过滤，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝4/1)纯化得到标题化合物为白色固体(1.33g,75.0％)。
LC-MS(ESI,pos.ion)m/z:355.1(M+1).
步骤3) 3-(3-(4-(5-((4-((甲基砜基)甲基)苄基)氧基)嘧啶-2-基)哌嗪-1-基)丙基)-1H-吲哚-5-甲腈
将4-(5-((4-((甲基砜基)甲基)苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(300mg,0.67mmol)加入到氯化氢的乙酸乙酯溶液(4M,3mL)中，混合液于室温搅拌反应1小时后，减压旋干。将所得的固体溶解在乙腈(15mL)中，并依次加入3-(5-氰基-1H-吲哚-3-基)丙基4-甲基苯磺酸酯(261mg,0.74mmol)、碳酸钾(139mg,1.00mmol)和碘化钾(11mg,0.07mmol)，然后将反应液升温，回流反应20小时后，冷却至室温，并减压浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化得到标题化合物为白色固体(180mg,49.5％)。
MS(ESI,pos.ion)m/z:545.5(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.38(s,1H),8.25(s,2H),8.10(s,1H),7.50(d,J＝8.4Hz,1H),7.47(d,J＝8.4Hz,2H),7.43(d,J＝7.8Hz,2H),7.40(dd,J＝8.4,1.2Hz,1H),7.35(d,J＝1.2Hz,1H),5.12(s,2H),4.50(s,2H),3.63(brs,4H),2.91(s,3H),2.75(t,J＝7.2Hz,2H),2.40(brs,4H),2.34(t,J＝6.0Hz,2H),1.85-1.80(m,2H).
实例施3 3-(((2-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)甲基)苯甲酰胺
Figure PCTCN2016094792-appb-000015
步骤1) 4-(5-((3-氰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯的合成
氮气保护下，将4-(5-羟基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(600mg,2.14mmol)、K2CO3(592mg,4.28mmol)和3-溴甲基苯甲腈(503mg,2.57mmol)加入到乙腈(10mL)中，反应液升温到95℃反应8小时后冷却至室温，并减压浓缩，所得残留物经硅胶柱层析(PE/EA(v/v)＝5/1)纯化得到标题化合物为白色固体 (732mg,86.5％)。
MS(ESI,pos.ion)m/z:396.4(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):8.28(s,2H),7.91(s,1H),7.82-7.71(m,2H),7.61(t,J＝7.6Hz,1H),5.18(s,2H),3.71(t,J＝4.8Hz,4H),3.48(t,J＝4.8Hz,4H),1.48(s,9H).
步骤2) 4-(5-((3-氨基甲酰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯的合成
将4-(5-((3-氰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(720mg,1.82mmol)和碳酸钾(81mg,0.58mmol)加入到二甲基亚砜(3mL)中，然后向其中缓慢滴加双氧水(372μL,3.64mmol,30％)。反应液于室温反应8小时后，向其中加入水(10mL)淬灭反应，并用二氯甲烷(10mL×3)萃取。合并的有机相用无水硫酸钠干燥，过滤，并减压浓缩，所得粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝2/1)纯化得到标题化合物为白色固体(704mg,93.5％)。
MS(ESI,pos.ion)m/z:414.2(M+1)；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.28(s,2H),8.01(brs,1H),7.95(s,1H),7.83(d,J＝7.6Hz,1H),7.58(d,J＝7.6Hz,1H),7.47(t,J＝7.6Hz,1H),7.39(s,1H),5.15(s,2H),3.60(t,J＝4.8Hz,4H),3.37(t,J＝4.8Hz,4H),1.41(s,9H).
步骤3) 3-(((2-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)甲基)苯甲酰胺的合成
将4-(5-((3-氨基甲酰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(350mg,0.85mmol)加入到氯化氢的乙酸乙酯溶液(4M,3mL)中，混合液于室温搅拌反应1小时后，减压旋干。将所得的固体溶解在乙腈(15mL)中，并依次加入4-(5-氰基-1H-吲哚-3-基)丁基4-甲基苯磺酸酯(343mg,0.93mmol)、碳酸钾(175mg,1.27mmol)和碘化钾(14mg,0.08mmol)，然后将反应液升高温度，回流反应20小时后，冷却至室温，并减压浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化得到标题化合物为黄色固体(220mg,51.0％)。
MS(ESI,pos.ion)m/z:510.4(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.35(s,1H),8.24(s,2H),8.07(s,1H),8.01(brs,1H),7.94(s,1H),7.83(d,J＝7.8Hz,1H),7.57(d,J＝7.8Hz,1H),7.49(d,J＝8.4Hz,1H),7.46(t,J＝8.4Hz,1H),7.40-7.38(m,2H),7.32(d,J＝1.8Hz,1H),5.13(s,2H),3.59(t,J＝4.8Hz,4H),2.72(t,J＝7.2Hz,2H),2.37(brs,4H),2.33(t,J＝6.6Hz,2H),1.68-1.63(m,2H),1.53-1.48(m,2H).
实例施4 3-(((2-(4-(3-(5-氰基-1H-吲哚-3-基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)甲基)苯甲酰胺
Figure PCTCN2016094792-appb-000016
将4-(5-((3-氨基甲酰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(350mg,0.85mmol)加入到氯化氢的乙酸乙酯溶液(4M,3mL)中，混合液于室温搅拌反应1小时后，减压旋干。将所得的固体溶解在乙腈(15mL)中，并依次加入3-(5-氰基-1H-吲哚-3-基)丙基4-甲基苯磺酸酯(330mg,0.93mmol)、碳酸钾(175mg, 1.27mmol)和碘化钾(14mg,0.08mmol)，然后将反应液升高温度，回流反应20小时后，冷却至室温，并减压浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化得到标题化合物为黄色固体(210mg,50.1％)。
MS(ESI,pos.ion)m/z:496.3(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.39(s,1H),8.26(s,2H),8.10(s,1H),8.02(s,1H),7.95(s,1H),7.84(d,J＝7.6Hz,1H),7.58(d,J＝7.6Hz,1H),7.49(d,J＝8.4Hz,1H),7.47(d,J＝7.8Hz,1H),7.40(dd,J＝8.2,1.2Hz,2H),7.35(d,J＝1.2Hz,1H),5.15(s,2H),3.63(brs,4H),2.75(t,J＝7.2Hz,2H),2.42(brs,4H),2.36(brs,2H),1.86-1.81(m,2H).
实例施5 4-(((2-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)甲基)苯甲酰胺
Figure PCTCN2016094792-appb-000017
步骤1) 4-(5-((4-(甲氧基羰基)苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯的合成
氮气保护下，将4-(5-羟基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,1.78mmol)、K2CO3(495mg,3.58mmol)和4-溴甲基苯甲酸甲酯(430mg,1.87mmol)加入到乙腈(10mL)中。将反应液升温到95℃反应8小时后，冷却至室温，并减压浓缩，所得残留物经硅胶柱层析(PE/EA(v/v)＝5/1)纯化得到标题化合物为白色固体(668mg,87.4％)。
MS(ESI,pos.ion)m/z:429.4(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):8.11(s,2H),8.05(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz,2H),5.07(s,2H),3.92(s,3H),3.69(t,J＝4.8Hz,4H),3.47(t,J＝4.8Hz,4H),1.48(s,9H).
步骤2) 4-(5-((4-氨基甲酰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯的合成
将4-(5-((4-(甲氧基羰基)苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(1.10g,2.57mmol)溶于NH3/MeOH(30mL,5％)溶液中，反应液升温到160℃反应8小时后冷却至室温，然后向其中加入水(20mL)淬灭反应，并用二氯甲烷萃取(20mL×3)萃取。合并的有机相用无水硫酸钠干燥，过滤，并减压浓缩，所得粗品经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化得到标题化合物为白色固体(457mg,43.1％)。
MS(ESI,pos.ion)m/z:314.3(M+1-Boc)；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.27(s,2H),7.97(brs,1H),7.87(d,J＝8.0Hz,2H),7.49(d,J＝8.0Hz,2H),7.36(brs,1H),5.16(s,2H),3.60(t,J＝4.8Hz,4H),3.37(t,J＝4.8Hz,4H),1.42(s,9H).
步骤3) 4-(((2-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)甲基)苯甲酰胺的合成
将4-(5-((4-氨基甲酰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(250mg,0.60mmol)加入到氯化氢的乙酸乙酯溶液(4M,3mL)中，混合液于室温搅拌反应1小时后，减压旋干。将所得的固体溶解在乙腈(15mL)中，并依次加入4-(5-氰基-1H-吲哚-3-基)丁基4-甲基苯磺酸酯(245mg,0.67mmol)、碳酸钾(125mg,0.91mmol)和碘化钾(10mg,0.06mmol)，然后将反应液升高温度，回流反应20小时后，冷却至室温，并 减压浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化得到标题化合物为浅黄色固体(140mg,45.5％)。
MS(ESI,pos.ion)m/z:510.3(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.36(s,1H),8.24(s,2H),8.07(s,1H),7.97(s,1H),7.88(d,J＝8.4Hz,2H),7.49(d,J＝8.4Hz,3H),7.39(dd,J＝8.4,1.2Hz,1H),7.37-7.33(m,2H),5.15(s,2H),3.60(brs,4H),2.73(t,J＝7.2Hz,2H),2.42(brs,6H),1.69-1.64(m,2H),1.53(brs,2H).
实例施6 4-(((2-(4-(3-(5-氰基-1H-吲哚-3-基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)甲基)苯甲酰胺
Figure PCTCN2016094792-appb-000018
将4-(5-((4-氨基甲酰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(250mg,0.60mmol)加入到氯化氢的乙酸乙酯溶液(4M,3mL)中，混合液于室温搅拌反应1小时后，减压旋干。将所得的固体溶解在乙腈(15mL)中，并依次加入3-(5-氰基-1H-吲哚-3-基)丙基4-甲基苯磺酸酯(235mg,0.67mmol)、碳酸钾(125mg,0.91mmol)和碘化钾(10mg,0.06mmol)，然后将反应液升高温度，回流反应20小时后，冷却至室温，并减压浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化得到标题化合物为浅黄色固体(160mg,53.3％)。
MS(ESI,pos.ion)m/z:496.3(M+1)；
1HNMR(600MHz,DMSO-d6)δ(ppm):11.39(s,1H),8.26(s,2H),8.10(s,1H),7.99(s,1H),7.89(d,J＝8.4Hz,2H),7.50(d,J＝8.4Hz,3H),7.40(d,J＝8.4Hz,1H),7.38-7.35(m,2H),3.65(s,4H),2.75(t,J＝7.2Hz,2H),2.49-2.42(m,6H),1.86-1.84(m,2H).
实例施7 2-(((2-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)甲基)苯甲酰胺
Figure PCTCN2016094792-appb-000019
步骤1) 4-(5-((2-氰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯的合成
本步骤标题化合物按照实施例3步骤1描述的方法制备得到，即将4-(5-羟基嘧啶-2-基)哌嗪-1-甲酸叔丁酯(0.70g,2.50mmol)、2-(溴甲基)苯甲腈(0.54g,2.75mmol)和碳酸铯(2.44g,7.49mmol)在DMF(5mL)中反应制备得到粗品，粗品经硅胶柱层析(PE/EA(v/v)＝3/1)纯化得到标题化合物为白色固体(0.93g,93.9％)。
MS(ESI,pos.ion)m/z:396.4(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):8.19(s,2H),7.73(d,J＝7.6Hz,1H),7.67-7.66(m,2H),7.50-7.46(m, 1H),5.22(s,2H),3.74(t,J＝4.8Hz,4H),3.51(t,J＝4.8Hz,4H),1.50(s,9H).
步骤2) 4-(5-((2-氨基甲酰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯的合成
本步骤标题化合物按照实施例3步骤2描述的方法制备得到，即将4-(5-((2-氰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(0.90g,2.28mmol)、碳酸钾(0.10g,0.72mmol)和双氧水(0.46mL,4.55mmol,30％)在二甲基亚砜(15mL)中反应制备得到粗品，粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝2/1)纯化得到标题化合物为白色固体(0.87g,92.5％)。
MS(ESI,pos.ion)m/z:414.2(M+1)；
1H NMR(400MHz,DMSO-d6)δ(ppm):8.22(s,2H),7.87(brs,1H),7.54-7.51(m,2H),7.48-7.44(m,2H),7.39(t,J＝7.6Hz,1H),5.29(s,2H),3.60(t,J＝4.8Hz,4H),3.38(t,J＝4.8Hz,4H),1.42(s,9H).
步骤3) 2-(((2-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)嘧啶-5-基)氧基)甲基)苯甲酰胺的合成
将4-(5-((2-氨基甲酰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.97mmol)加入到氯化氢的乙酸乙酯溶液(4M,3mL)中，混合液于室温搅拌反应1小时后，减压旋干。将所得的固体溶解在乙腈(15mL)中，并依次加入4-(5-氰基-1H-吲哚-3-基)丁基4-甲基苯磺酸酯(392mg,1.06mmol)、碳酸钾(200mg,1.45mmol)和碘化钾(16mg,0.10mmol)，然后将反应液升高温度，回流反应20小时后，冷却至室温，并减压浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化得到标题化合物为白色固体(250mg,50.7％)。
MS(ESI,pos.ion)m/z:510.3(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.37(s,1H),8.20(s,2H),8.08(s,1H),7.88(s,1H),7.59-7.52(m,2H),7.50(d,J＝8.4Hz,1H),7.47-7.44(m,2H),7.39(dd,J＝7.2,1.2Hz,2H),7.33(d,J＝1.8Hz,1H),5.28(s,2H),3.60(brs,4H),2.73(t,J＝7.2Hz,2H),2.38(brs,4H),2.33(t,J＝6.0Hz,2H),1.69-1.64(m,2H),1.54-1.49(m,2H).
实例施8 2-(((2-(4-(3-(5-氰基-1H-吲哚-3-基)丙基)哌嗪-1-基)嘧啶-5-基)氧基)甲基)苯甲酰胺
Figure PCTCN2016094792-appb-000020
将4-(5-((2-氨基甲酰基苄基)氧基)嘧啶-2-基)哌嗪-1-甲酸叔丁酯(400mg,0.97mmol)加入到氯化氢的乙酸乙酯溶液(4M,3mL)中，混合液于室温搅拌反应1小时后，减压旋干。将所得的固体溶解在乙腈(15mL)中，并依次加入3-(5-氰基-1H-吲哚-3-基)丙基4-甲基苯磺酸酯(377mg,1.06mmol)、碳酸钾(200mg,1.45mmol)和碘化钾(16mg,0.10mmol)，然后将反应液升高温度，回流反应20小时后，冷却至室温，并减压浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝1/1)纯化得到标题化合物为白色固体(250mg,52.2％)。
MS(ESI,pos.ion)m/z:496.3(M+1)；
1H NMR(600MHz,DMSO-d6)δ(ppm):11.39(s,1H),8.20(s,2H),8.10(s,1H),7.88(s,1H),7.54-7.52(m,2H),7.50(d,J＝8.4Hz,1H),7.46(td,J＝7.8,1.2Hz,2H),7.41-7.38(m,2H),7.35(d,J＝1.6Hz,1H),5.28(s, 2H),3.63(brs,4H),2.75(t,J＝7.2Hz,2H),2.42(brs,4H),2.35(brs,2H),1.85-1.81(m,2H).
生物试验
实施例A：评价化合物对CHO细胞转染的人源化5-HT转运体的亲和力
实验方法
在22℃条件下，向细胞膜匀浆蛋白(12μg)、2nM[3H]丙咪嗪以及缓冲液(50mM Tris-HCl(pH 7.4)、120mM NaCl、5mM KCl和0.1％BSA)形成的混合体系中，加入或不加入测试化合物，共孵育60分钟。
并在上述条件的混合体系中，加入10μM丙咪嗪，用于测得非特异性结合值。
孵育后的样本用96样细胞收集器(Unifilter,Packard)在真空条件下通过预浸过0.3％PEI的玻璃纤维滤膜(GF/B,Packard)快速过滤，并使用冰冷的50mM Tris-HCl和150mM NaCl反复冲洗几次。干燥滤膜，在闪烁计数器(Topcount,Packard)中，用闪烁液(Microscint 0,Packard)计算残留的放射活性。实验结果以相对于对照组放射性配体特异性结合的抑制百分比表示。
标准参照化合物为丙咪嗪，通过系列浓度的实验测试获得竞争性曲线，从而计算出IC50。实验结果参见表A。
表A 本发明化合物对人源5-HT转运体(SERT)的亲和力测定结果
实施例号 IC50(nM)
实施例1 0.76
实施例2 0.65
实施例3 0.79
实施例4 0.45
实施例5 0.89
实施例6 0.63
实施例7 1.0
实施例8 0.85
实验结果显示，本发明化合物对人源5-HT转运体(SERT)具有较强的亲和力。
实施例B：h5-HT1A受体结合亲和力试验
实验方法
在22℃条件下，向人HEK-293细胞膜匀浆(36μg蛋白)，0.3nM[3H]8-OH-DPAT(Perkin-Elmer)和缓冲液(50mM Tris-HCl(pH 7.4),10mM MgSO4,0.5mM EDTA,2μg/ml aprotinine)形成的混合体系中，加入或不加入测试化合物，共孵育60分钟。
标准参照化合物为8-OH-DPAT，在上述条件的混合体系中，加入10μM 8-OH-DPAT，用于测得非特异性结合值。通过不同实验测试系列浓度的8-OH-DPAT的数据，获得竞争性曲线。
孵育后的样本用96样细胞收集器(Unifilter,Packard)在真空条件下通过预浸过0.3％PEI的玻璃纤维滤膜(GF/B,Packard)快速过滤，并使用冰冷的50mM Tris-HCl反复冲洗几次。干燥滤膜，在闪烁计数器(Topcount,Packard)中，用闪烁液(Microscint 0,Packard)计算残留的放射活性。实验结果以相对于对照组放射性配体特异性结合的抑制百分比表示。
数据分析
[3H]8-OH-DPAT(0.3nM)与人HEK-293细胞中5-HT1A受体的结合试验通过膜的闪烁接近检测法来完成。受试化合物需要在浓度超过6log情况下，至少测试三次，数据经Hill方程曲线进行非线性回归分析，得IC50值，再经ChengPrusoff方程式计算，得Ki值。实验结果参见表B。
表B 本发明化合物对5-HT1A受体的结合亲和力实验结果
实施例号 Ki(nM)
实施例3 2.14
实施例4 1.13
实施例5 3.95
实施例6 2.16
实验结果显示，本发明化合物对5-HT1A受体具有较强的结合亲和力。
在本说明书的描述中，参考术语“一个实施例”、“一实施方案”、“一些实施例”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例、实施方案或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例、实施方案或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例、实施方案或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例、实施方案或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例、实施方案或示例以及不同实施例、实施方案或示例的特征进行结合和组合。尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (10)

  1. 一种化合物，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    Figure PCTCN2016094792-appb-100001
    其中：
    Q为CH或N；
    L为-O-(CH2)k-、-O-(CH2)k-C(＝O)-(CH2)k-、-S-(CH2)k-或-NH-(CH2)k-；
    Cy为6-10个环原子组成的芳基或5-10个环原子组成的杂芳基，其中所述6-10个环原子组成的芳基和5-10个环原子组成的杂芳基独立任选地被1、2、3、4或5个Ry所取代；
    各R1、Ra和Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基或C1-C6卤代烷氧基，其中所述C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基独立任选地被一个或多个Rw所取代；
    各Ry独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C6烷基)、-C(＝O)-(C1-C6烷氧基)、-(CH2)r-S(＝O)-(C1-C6烷基)、-(CH2)r-S(＝O)2-(C1-C6烷基)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基、3-10个环原子组成的杂环基、C6-C10芳基或5-10个环原子组成的杂芳基，其中所述-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C6烷基)、-C(＝O)-(C1-C6烷氧基)、-(CH2)r-S(＝O)-(C1-C6烷基)、-(CH2)r-S(＝O)2-(C1-C6烷基)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基、3-10个环原子组成的杂环基、C6-C10芳基和5-10个环原子组成的杂芳基独立任选地被一个或多个Rw所取代；
    各Rw独立地为D、F、Cl、Br、I、-NO2、-CN、-N3、-NH2、-OH、-SH、氧代(＝O)、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷氨基、C1-C4烷硫基、NH2-(C1-C4亚烷基)-、HO-(C1-C4亚烷基)-、HS-(C1-C4亚烷基)-、(C1-C4烷氧基)-(C1-C4亚烷基)-、(C1-C4烷氨基)-(C1-C4亚烷基)-、(C1-C4烷硫基)-(C1-C4亚烷基)-、C3-C6环烷基、(C3-C6环烷基)-(C1-C4亚烷基)-、3-7个环原子组成的杂环基、(3-7个环原子组成的杂环基)-(C1-C4亚烷基)-、苯基、苯基-(C1-C4亚烷基)-、5-6个环原子组成的杂芳基或(5-6个环原子组成的杂芳基)-(C1-C4亚烷基)-；
    m和p各自独立地为0、1、2或3；和
    各n、k和r独立地为0、1、2、3或4。
  2. 根据权利要求1所述的化合物，其中Cy为以下子结构式：
    Figure PCTCN2016094792-appb-100002
    Figure PCTCN2016094792-appb-100003
    其中，各t独立地为1、2、3、4或5。
  3. 根据权利要求1或2所述的化合物，其中各Ry独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C4烷基)、-C(＝O)-(C1-C4烷氧基)、-(CH2)r-S(＝O)-(C1-C4烷基)、-(CH2)r-S(＝O)2-(C1-C4烷基)、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C3-C6环烷基、4-6个环原子组成的杂环基、苯基或5-6个环原子组成的杂芳基，其中所述-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)-(C1-C4烷基)、-C(＝O)-(C1-C4烷氧基)、-(CH2)r-S(＝O)-(C1-C4烷基)、-(CH2)r-S(＝O)2-(C1-C4烷基)、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C3-C6环烷基、4-6个环原子组成的杂环基、苯基和5-6个环原子组成的杂芳基独立任选地被一个或多个Rw所取代。
  4. 根据权利要求1所述的化合物，其中各R1、Ra和Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CF3或-OCF3。
  5. 根据权利要求3所述的化合物，其中各Ry独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-COOH、-C(＝O)NH2、-C(＝O)NHCH3、-C(＝O)N(CH3)2、-C(＝O)CH3、-C(＝O)OCH3、-CH2-S(＝O)CH3、-CH2-S(＝O)CH2CH3、-CH2-S(＝O)CH(CH3)2、-CH2-S(＝O)2CH3、-CH2-S(＝O)2CH2CH3、-CH2-S(＝O)2CH(CH3)2、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-CF3、-CH2CF3、-OCF3、-OCH2CF3或-OCH2CF2CHF2。
  6. 根据权利要求1所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药：
    Figure PCTCN2016094792-appb-100004
    Figure PCTCN2016094792-appb-100005
  7. 一种药物组合物，其包含权利要求1-6任意一项所述的化合物；和
    所述药物组合物任选地进一步包含药学上可接受的赋形剂、载体、辅剂、佐剂或它们的任意组合。
  8. 根据权利要求7所述的药物组合物，其进一步包含治疗中枢神经***功能障碍的药物，所述治疗中枢神经***功能障碍的药物为阿米替林、地昔帕明、米氮平、安非他酮、瑞波西汀、氟西汀、曲唑酮、舍曲林、度洛西汀、氟伏沙明、米那普仑、左旋米那普仑、去甲文拉法辛、维拉唑酮、文拉法辛、达泊西汀、奈法唑酮、非莫西汀、氯丙咪嗪、西酞普兰、艾司西酞普兰、帕罗西汀、碳酸锂、丁螺环酮、奥氮平、喹硫平、利培酮、齐拉西酮、阿立哌唑、哌罗匹隆、氯氮平、***、美卡拉明、卡麦角林、金刚烷、丙咪嗪、普拉克索、甲状腺素、右美沙芬、奎尼丁、纳曲酮、samidorphan、丁丙诺啡、褪黑激素、阿普***、匹泮哌隆、维替匹坦、利眠宁、奋乃静或它们的任意组合。
  9. 权利要求1-6任意一项所述的化合物或权利要求7-8任意一项所述的药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻中枢神经***功能障碍。
  10. 权利要求1-6任意一项所述的化合物或权利要求7-8任意一项所述的药物组合物在制备药物中的用途，所述药物用于抑制5-羟色胺再摄取；和/或
    所述药物用于部分激动5-HT1A受体。
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WO2015169180A1 (en) * 2014-05-04 2015-11-12 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods and use thereof

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US11285153B2 (en) 2017-09-29 2022-03-29 Sunshine Lake Pharma Co., Ltd. Substituted pyrimidine piperazine compound and use thereof
KR20210027218A (ko) * 2019-09-02 2021-03-10 한양대학교 에리카산학협력단 2,5-이치환된 피리미딘 유도체 및 이를 포함하는 약학적 조성물
KR102483492B1 (ko) * 2019-09-02 2023-01-02 한양대학교 에리카산학협력단 2,5-이치환된 피리미딘 유도체 및 이를 포함하는 약학적 조성물
CN112851641A (zh) * 2019-11-28 2021-05-28 广东东阳光药业有限公司 嘧啶苯甲酰胺化合物的盐酸盐及其用途
CN112851643A (zh) * 2019-11-28 2021-05-28 广东东阳光药业有限公司 嘧啶苯甲酰胺化合物的盐酸盐及其用途
CN112851641B (zh) * 2019-11-28 2023-08-15 广东东阳光药业股份有限公司 嘧啶苯甲酰胺化合物的盐酸盐及其用途
CN112851643B (zh) * 2019-11-28 2024-01-16 广东东阳光药业股份有限公司 嘧啶苯甲酰胺化合物的盐酸盐及其用途
CN111533738A (zh) * 2020-05-27 2020-08-14 中国药科大学 含吲哚结构的化合物或其药学上可接受的盐、制备方法和用途

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