WO2017012579A1 - Substituted indole compounds and use methods and uses thereof - Google Patents

Substituted indole compounds and use methods and uses thereof Download PDF

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Publication number
WO2017012579A1
WO2017012579A1 PCT/CN2016/090985 CN2016090985W WO2017012579A1 WO 2017012579 A1 WO2017012579 A1 WO 2017012579A1 CN 2016090985 W CN2016090985 W CN 2016090985W WO 2017012579 A1 WO2017012579 A1 WO 2017012579A1
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group
compound
och
alkyl
alkoxy
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PCT/CN2016/090985
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French (fr)
Chinese (zh)
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金传飞
梁海平
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 CN201680002185.7A priority Critical patent/CN106795160B/en
Publication of WO2017012579A1 publication Critical patent/WO2017012579A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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. character of. 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 a prodrug thereof,
  • each of R 1 , R a , R b , X, W, V, U, m, n and r has the meaning as described in the present invention.
  • X is CR 2 or N; W is CR 3 or N; V is CR 4 or N; U is CR 5 or N;
  • the precondition is that at most two of X, W, V and U are N at the same time;
  • R 2 , R 3 , R 4 and R 5 have the meanings indicated in the present invention.
  • each of R 1 and R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, C 1 -C 6 alkyl, C 1- C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy, wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkane
  • the oxy group and the C 1 -C 6 haloalkoxy group are each 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.
  • n 0, 1, 2, 3 or 4.
  • r is 0, 1 or 2.
  • p is 1, 2, 3 or 4.
  • each of R 1 and R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy, wherein said C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 The alkoxy group and the C 1 -C 4 haloalkoxy group are each independently optionally substituted by one or more R w ; and each R w has the meaning as described herein.
  • each of R 1 and R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, methyl, ethyl, n-propyl Base, isopropyl, 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 a product, a pharmaceutically acceptable salt or a prodrug thereof:
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein.
  • the invention relates to a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
  • the pharmaceutical composition of the present invention 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 stimulants , a 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 disclosed herein for 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; 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 disclosed herein for the manufacture of a medicament for inhibiting serotonin reuptake.
  • the invention relates to the use of a compound or pharmaceutical 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. Furthermore, in any of the embodiments of any of the aspects of the present invention, any of the technical features may be applied to the technical features in other embodiments as long as they There will be no contradictions.
  • 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. .
  • (-) 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 1-6 carbon atoms; In another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains from 1 to 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 ring system containing from 3 to 12 ring carbon atoms.
  • the cycloalkyl group contains from 3 to 10 ring carbon atoms; in another embodiment, the cycloalkyl group contains from 3 to 8 ring carbon atoms; in yet another embodiment, the cycloalkyl group comprises 3- 6 ring carbon atoms.
  • 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-imidazolyl, 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 (such as 2-thi
  • a ring system formed by a substituent attached to a central ring represents a substituent on the ring (such as the ring B in formula a) which may be substituted or any reasonable The location can be replaced.
  • the formula a represents that any position on the B ring that may be substituted may be substituted by the substituent R, as shown in formula b, formula c and formula d.
  • 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, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3 -Phenylpropionate
  • 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 invention may be combined with more than one water molecule, such as 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 body Parameters, 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 dashed line indicating a particular configuration, then the stereoisomers of the structure are defined and defined herein.
  • 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 may 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, on).
  • 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 agonism.
  • 5-HT 1A receptor drug 5-HT 1A receptor drug.
  • 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.
  • a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered at a time, or several times at different time intervals, over a specified period of time, depending on the dosage regimen. For example, administration once, twice, three times or four times a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the compounds disclosed herein depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, as determined by the skilled artisan.
  • suitable dosage regimens of the disclosed compounds or pharmaceutical compositions comprising the compounds of the present invention including the duration of implementation of the regimen, depend on the condition being treated, the severity of the condition being treated, the age of the subject being treated, and Body shape
  • the medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, etc. are within the knowledge and experience of the skilled person.
  • the dosage regimen for the adjustment may be required for individual patient responses to the dosage regimen, or for individual patient needs to change over time.
  • 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 compound represented by the formula ( 5 ) can be produced by the method described in the synthesis scheme 1: First, the compound ( 1 ) is reacted under the action of POCl 3 to obtain the compound ( 2 ), and then the compound ( 2 ) and piperazine-1-carboxylic acid. The tert-butyl ester is reacted under the action of a base to obtain the compound ( 3 ), and finally the compound ( 3 ) is decarboxylated in a solution of trifluoroacetic acid in dichloromethane or ethyl acetate in ethyl acetate, followed by potassium carbonate or carbonic acid. Under the action of a base such as sodium, a nucleophilic substitution reaction with the compound ( 4 ) gives the target compound ( 5 ).
  • a base such as sodium
  • the compound represented by the formula ( 11 ) and the formula ( 12 ) can be produced by the method described in Synthetic Scheme 2: First, the compound ( 2 ) is reacted under the action of an oxidizing agent such as mCPBA or OXONE to obtain a compound ( 6 ), the compound ( 6 ). The compound ( 7 ) is obtained by reacting in acetic anhydride; then the compound ( 7 ) and the compound ( 8 ) are reacted under the action of a base to obtain a compound ( 9 ), and the compound ( 9 ) is further reacted with piperazine-1-carboxylic acid tert-butyl ester in a base.
  • an oxidizing agent such as mCPBA or OXONE
  • the reaction of the reaction gives the compound ( 10 ); the final compound ( 10 ) is deprotected from the Boc protecting group in a solution of trifluoroacetic acid in dichloromethane or ethyl acetate in ethyl acetate, followed by an alkali such as potassium carbonate or sodium carbonate. Under the action, a nucleophilic substitution reaction with the compound ( 4 ) gives the target compound ( 11 ). Compound ( 11 ) is subjected to hydrolysis of an ester to give another target compound ( 12 ).
  • the compound represented by the formula ( 15 ) can be produced by the method described in Synthesis Scheme 3: first, the compound ( 9 ) is subjected to aminolysis under the action of an aminating agent such as ammonia methanol solution to obtain a compound ( 13 ), and then the compound ( 13 ) is The piperazine-1-carboxylic acid tert-butyl ester is reacted under the action of a base to obtain a compound ( 14 ), and finally the compound ( 14 ) is deprotected from the Boc protecting group in a solution of trifluoroacetic acid in dichloromethane or ethyl acetate in ethyl acetate. Further, a nucleophilic substitution reaction with the compound ( 4 ) by a base such as potassium carbonate or sodium carbonate gives the target compound ( 15 ).
  • an aminating agent such as ammonia methanol solution
  • a base such as potassium carbonate or sodium carbonate
  • 1,6-Naphthyridin-5(6H)-one (3.00 g, 20.53 mmol) was added to phosphorus oxychloride (40 mL).
  • the reaction liquid was elevated in temperature, refluxed for 24 hours, and then cooled to room temperature, and then phosphorus oxychloride was distilled off under reduced pressure. Ice water (20 mL) was added to the reaction mixture, and the pH was adjusted to 8 to 9 with sodium carbonate solid.
  • the mixture was filtered and the filtrate was extracted with dichloromethane (20 mL ⁇ 5).
  • the organic phase was dried over anhydrous sodium sulfate EtOAcjjjjjjjjj g, 91.1%).
  • the title compound of this step was prepared according to the method of the step 3 of Example 1, that is, 4-(1,6-naphthyridin-5-yl)piperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.27 mmol) and hydrogen chloride in ethyl acetate
  • the ester solution (4M, 2 mL) was obtained in methylene chloride (10 mL).
  • EtOAc EtOAc EtOAc EtOAc (EtOAc: EtOAc (21 mg, 0.13 mmol) and sodium carbonate (405 mg, 3.82 mmol) were obtained from EtOAc (EtOAc) (EtOAc)
  • EtOAc EtOAc
  • the title compound of this step is prepared according to the method of the step 3 of Example 1, that is, 4-(2-(2-ethoxy-2-oxoethoxy)-1,6-naphthyridin-5-yl)piperazine
  • the title compound of this step is prepared according to the method of the step 3 of Example 1, that is, 4-(2-(2-ethoxy-2-oxoethoxy)-1,6-naphthyridin-5-yl)piperazine
  • 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 .
  • the compounds of the invention IC on human 5-HT transporter (the SERT) 50 values less than 10 nM
  • the compounds of the invention IC on human 5-HT transporter (the SERT) 50 The value is less than 1 nM; specifically, the compound prepared in Example 1 of the present invention has an IC 50 value of 2.03 nM, and the compound prepared in Example 2 of the present invention has an IC 50 value of 0.61 nM.
  • 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.
  • the compound of the invention binds to the h5-HT 1A receptor with a Ki value of less than 15 nM, and in other embodiments, the compound of the invention binds to the h5-HT 1A receptor with a Ki value of less than 1 nM;
  • the compound prepared in Inventive Example 1 had a Ki value of 0.31 nM, and the compound prepared in Example 2 of the present invention had a Ki value of 13.2 nM.
  • the experimental results show that the compound of the present invention has strong binding affinity to the 5-HT 1A receptor.

Abstract

Disclosed are substituted indole compounds and use methods and uses thereof. The present invention particularly relates to novel indole compounds and pharmaceutical compositions comprising the compounds, for inhibiting re-uptake of 5-hydroxytryptamine and/or excitation of a 5-HT1A receptor. The present invention also relates to methods for preparing these compounds and pharmaceutical compositions, and uses thereof in treatment of dysfunctions of a central nervous system.

Description

取代的吲哚化合物及其使用方法和用途Substituted hydrazine compound and its use and use 技术领域Technical field
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。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. In particular, the invention describes substituted anthraquinone compounds which may act as serotonin reuptake inhibitors and/or 5-HT 1A receptor agonists.
背景技术Background technique
5-羟色胺(5-HT)，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。Serotonin (5-HT), 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. character of. 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.
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)。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).
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.Areview oftheir adverse effects and toxicity in overdose.EmergMedClinNorthAm,2000；18(4):637-54)。Historically, drug therapy for mood disorders began in the 1950s, including tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), which rely primarily on neurotransmitters (dopamine, norepinephrine, and 5). The blocking effect of serotonin is effective. However, the non-selective and undesirable side effects on the target limit their use. By the 1980s, the emergence of selective serotonin reuptake inhibitors (SSRIs) changed this situation. Compared with TCAs, these drugs are equivalent in efficacy, but have few side effects, even if they are taken in excess, the toxicity is small (Sarko J. Andidepressant, old and new. Areview of their adverse effects and toxicity in overdose. EmergMedClinNorthAm, 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。Traditional SSRIs treatment increases the serotonin content by inhibiting the reuptake of serotonin and regulating its transport. However, 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. However, as the time of administration increases, SSRIs cause desensitization of 5-HT 1A autoreceptors, and the activation effect is restrained, thereby exerting a normal regulatory effect. It is concluded that the activation effect of 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.
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)。In contrast to SSRIs, 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).
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。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.
发明摘要Summary of invention
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。The following merely summarizes some aspects of the invention and is not limited thereto. These and other parts are more fully explained later. All references in this specification are hereby incorporated by reference in their entirety. In the event that the disclosure of the specification differs from the cited document, the disclosure of this specification shall control.
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。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.
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。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.
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。The invention also provides methods of preparing such compounds and pharmaceutical compositions containing such compounds.
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它的前药，In one aspect, 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 a prodrug thereof,
Figure PCTCN2016090985-appb-000001
Figure PCTCN2016090985-appb-000001
其中，各R1、Ra、Rb、X、W、V、U、m、n和r具有如本发明所述的含义。Wherein each of R 1 , R a , R b , X, W, V, U, m, n and r has the meaning as described in the present invention.
在一实施方案中，X为CR2或N；W为CR3或N；V为CR4或N；U为CR5或N；In one embodiment, X is CR 2 or N; W is CR 3 or N; V is CR 4 or N; U is CR 5 or N;
前提条件是X、W、V和U中最多两个同时为N；The precondition is that at most two of X, W, V and U are N at the same time;
其中，R2、R3、R4和R5具有本发明所述的含义。Wherein R 2 , R 3 , R 4 and R 5 have the meanings indicated in the present invention.
在一实施方案中，各R1和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。In one embodiment, each of R 1 and R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, C 1 -C 6 alkyl, C 1- C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy, wherein said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkane The oxy group and the C 1 -C 6 haloalkoxy group are each independently optionally substituted by one or more R w ; and each R w has the meaning as described herein.
在一实施方案中，各R2、R3、R4、R5和Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-C(＝O)NH2、-COOH、-C(＝O)CH3、-C(＝O)OCH3、-O-(CH2)p-C(＝O)NH2、-O-(CH2)p-C(＝O)OH、-O-(CH2)p-C(＝O)-(C1-C6烷基)、-O-(CH2)p-C(＝O)-(C1-C6烷氧基)、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)CH3、-C(＝O)OCH3、-O-(CH2)p-C(＝O)NH2、-O-(CH2)p-C(＝O)OH、-O-(CH2)p-C(＝O)-(C1-C6烷基)、-O-(CH2)p-C(＝O)-(C1-C6烷氧基)、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。 In one embodiment, each of R 2 , R 3 , R 4 , R 5 and R b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -C(=O)NH 2 , -COOH, -C(=O)CH 3 , -C(=O)OCH 3 , -O-(CH 2 ) p -C(=O)NH 2 , -O-(CH 2 ) p -C(=O)OH, -O-(CH 2 ) p -C(=O)-(C 1 -C 6 alkyl), -O-(CH 2 ) p - C(=O)-(C 1 -C 6 alkoxy), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1- C 6 alkoxy group, C 1 -C 6 haloalkoxy group, C 3 -C 8 cycloalkyl group, heterocyclic group composed of 3 to 10 ring atoms, C 6 -C 10 aryl group or 5-10 a heteroaryl group composed of a ring atom, wherein the -C(=O)CH 3 , -C(=O)OCH 3 , -O-(CH 2 ) p -C(=O)NH 2 , -O-( CH 2 ) p -C(=O)OH, -O-(CH 2 ) p -C(=O)-(C 1 -C 6 alkyl), -O-(CH 2 ) p -C(=O )-(C 1 -C 6 alkoxy), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 Alkoxy group, C 1 -C 6 haloalkoxy group, C 3 -C 8 cycloalkyl group, heterocyclic group composed of 3 to 10 ring atoms, C 6 -C 10 aryl group and 5-10 ring atoms Heteroaryl is optionally independently A plurality of R w substituted; and each R w is as defined in the present invention.
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)-。In one embodiment, each R w is independently D, F, Cl, Br, I, -NO 2 , -CN, -N 3 , -NH 2 , -OH, -SH, oxo (=O), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylamino, C 1 -C 4 alkylthio, NH 2 -(C 1 -C 4 alkylene)-, HO-(C 1 -C 4 alkylene)-, HS-(C 1- C 4 alkylene)-, (C 1 -C 4 alkoxy)-(C 1 -C 4 alkylene)-, (C 1 -C 4 alkylamino)-(C 1 -C 4 Alkyl)-, (C 1 -C 4 alkylthio)-(C 1 -C 4 alkylene)-, C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)-(C 1 -C 4 alkylene)-, heterocyclic group consisting of 3-7 ring atoms, (heterocyclic group consisting of 3-7 ring atoms)-(C 1 -C 4 alkylene)-, phenyl , phenyl-(C 1 -C 4 alkylene)-, heteroaryl group of 5-6 ring atoms or (heteroaryl group of 5-6 ring atoms)-(C 1 -C 4 -alkylene) base)-.
在一实施方案中，m为0、1、2或3。In one embodiment, m is 0, 1, 2 or 3.
在一实施方案中，n为0、1、2、3或4。In one embodiment, n is 0, 1, 2, 3 or 4.
在一实施方案中，r为0、1或2。In one embodiment, r is 0, 1 or 2.
在一实施方案中，p为1、2、3或4。In one embodiment, p is 1, 2, 3 or 4.
在另一实施方案中，各R1和Ra独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基，其中所述C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基和C1-C4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。In another embodiment, each of R 1 and R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy, wherein said C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 The alkoxy group and the C 1 -C 4 haloalkoxy group are each independently optionally substituted by one or more R w ; and each R w has the meaning as described herein.
在又一实施方案中，各R1和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。In still another embodiment, each of R 1 and R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, methyl, ethyl, n-propyl Base, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CF 3 or -OCF 3 .
在另一实施方案中，各R2、R3、R4、R5和Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-C(＝O)NH2、-COOH、-C(＝O)CH3、-C(＝O)OCH3、-O-(CH2)p-C(＝O)NH2、-O-(CH2)p-C(＝O)OH、-O-(CH2)p-C(＝O)-(C1-C4烷基)、-O-(CH2)p-C(＝O)-(C1-C4烷氧基)、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、5-6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)CH3、-C(＝O)OCH3、-O-(CH2)p-C(＝O)NH2、-O-(CH2)p-C(＝O)OH、-O-(CH2)p-C(＝O)-(C1-C4烷基)、-O-(CH2)p-C(＝O)-(C1-C4烷氧基)、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、5-6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。In another embodiment, each of R 2 , R 3 , R 4 , R 5 and R b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH , -SH, -C(=O)NH 2 , -COOH, -C(=O)CH 3 , -C(=O)OCH 3 , -O-(CH 2 ) p -C(=O)NH 2 , -O-(CH 2 ) p -C(=O)OH, -O-(CH 2 ) p -C(=O)-(C 1 -C 4 alkyl), -O-(CH 2 ) p -C(=O)-(C 1 -C 4 alkoxy), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, a C 1 -C 4 alkoxy group, a C 1 -C 4 haloalkoxy group, a C 3 -C 6 cycloalkyl group, a heterocyclic group consisting of 5 to 6 ring atoms, a phenyl group or 5-6 ring atoms a heteroaryl group wherein -C(=O)CH 3 , -C(=O)OCH 3 , -O-(CH 2 ) p -C(=O)NH 2 , -O-(CH 2 ) p -C(=O)OH, -O-(CH 2 ) p -C(=O)-(C 1 -C 4 alkyl), -O-(CH 2 ) p -C(=O)-(C 1 -C 4 alkoxy), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, a heterocyclic group consisting of a C 1 -C 4 haloalkoxy group, a C 3 -C 6 cycloalkyl group, a heterocyclic group of 5 to 6 ring atoms, a phenyl group and 5 to 6 ring atoms, optionally independently Or replaced by multiple R w And each R w has the meaning as described in the present invention.
在又一实施方案中，各R2、R3、R4、R5和Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-C(＝O)NH2、-COOH、-C(＝O)CH3、-C(＝O)OCH3、-O-CH2-C(＝O)NH2、-O-(CH2)2-C(＝O)NH2、-O-CH2-C(＝O)OH、-O-(CH2)2-C(＝O)OH、-O-CH2-C(＝O)CH3、-O-CH2-C(＝O)CH2CH3、-O-CH2-C(＝O)CH(CH3)2、-O-(CH2)2-C(＝O)CH3、-O-(CH2)2-C(＝O)CH2CH3、-O-(CH2)2-C(＝O)CH(CH3)2、-O-CH2-C(＝O)OCH3、-O-CH2-C(＝O)OCH2CH3、-O-CH2-C(＝O)OCH(CH3)2、-O-(CH2)2-C(＝O)OCH3、-O-(CH2)2-C(＝O)OCH2CH3、-O-(CH2)2-C(＝O)OCH(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。In still another embodiment, each of R 2 , R 3 , R 4 , R 5 and R b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH , -SH, -C(=O)NH 2 , -COOH, -C(=O)CH 3 , -C(=O)OCH 3 , -O-CH 2 -C(=O)NH 2 , -O -(CH 2 ) 2 -C(=O)NH 2 , -O-CH 2 -C(=O)OH, -O-(CH 2 ) 2 -C(=O)OH, -O-CH 2 - C(=O)CH 3 , -O-CH 2 -C(=O)CH 2 CH 3 , -O-CH 2 -C(=O)CH(CH 3 ) 2 , -O-(CH 2 ) 2 -C(=O)CH 3 , -O-(CH 2 ) 2 -C(=O)CH 2 CH 3 , -O-(CH 2 ) 2 -C(=O)CH(CH 3 ) 2 ,- O-CH 2 -C(=O)OCH 3 , -O-CH 2 -C(=O)OCH 2 CH 3 , -O-CH 2 -C(=O)OCH(CH 3 ) 2 , -O- (CH 2 ) 2 -C(=O)OCH 3 , -O-(CH 2 ) 2 -C(=O)OCH 2 CH 3 , -O-(CH 2 ) 2 -C(=O)OCH(CH 3 ) 2 , methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CF 3 , -CH 2 CF 3 , -OCF 3 , -OCH 2 CF 3 or -OCH 2 CF 2 CHF 2 .
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它的前药： In one embodiment, 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 a product, a pharmaceutically acceptable salt or a prodrug thereof:
Figure PCTCN2016090985-appb-000002
Figure PCTCN2016090985-appb-000002
另一方面，本发明涉及一种药物组合物，所述药物组合物包含本发明公开的化合物。 In another aspect, the present invention is directed to a pharmaceutical composition comprising a compound disclosed herein.
在一实施方案中，本发明涉及的药物组合物，进一步包含药学上可接受的赋形剂、载体、佐剂或它们的任意组合。In one embodiment, the invention relates to a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
在一实施方案中，本发明涉及的药物组合物，进一步地包含治疗中枢神经***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。In one embodiment, the pharmaceutical composition of the present invention 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 stimulants , a nicotinic antagonist or any combination thereof.
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。In another embodiment, the medicament for treating central nervous system dysfunction of the present invention is amitriptyline, desipramine, mirtazapine, bupropion, and rebaudioside. Reboxetine, fluoxetine, trazodone, sertraline, duloxetine, fluvoxamine, milnacipran , levomilnacipran, desvenlafaxine, vilazodone, venlafaxine, dapoxetine, nefazodone ), femoxetine, clomipramine, citalopram, escitalopram, paroxetine, lithium carbonate, spirulina Buspirone, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, perospirone, Clozapine, modafinil, mecamylamine, card Cabergoline, adamantane, imipramine, pramipexole, thyroxine, dextromethorphan, quinidine, naltrexone Naltrexone), samidorphan, buprenorphine, melatonin, alprazolam, pipamperone, vestipitant, chlordiazepoxide , perphenazine or any combination thereof.
另一方面，本发明涉及本发明公开的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。In another aspect, the invention relates to the use of a compound or composition disclosed herein for the manufacture of a medicament for the prevention, treatment or amelioration of central nervous system dysfunction. For example, in one embodiment, the medicament is for preventing, treating or ameliorating central nervous system dysfunction in a mammal; in another embodiment, the medicament is for preventing, treating or ameliorating central nervous system dysfunction in a human .
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。In one embodiment, 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.
另一方面，本发明涉及本发明公开的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。In another aspect, the invention relates to the use of a compound or composition disclosed herein for the manufacture of a medicament for inhibiting serotonin reuptake.
另一方面，本发明涉及本发明化合物或药物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。In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the partial activating of a 5-HT 1A receptor.
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。In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound of formula (I).
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。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. A serotonin reuptake inhibitor and/or a 5-HT 1A receptor agonist.
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。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. Furthermore, in any of the embodiments of any of the aspects of the present invention, any of the technical features may be applied to the technical features in other embodiments as long as they There will be no contradictions.
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。The foregoing description merely summarizes certain aspects of the invention, but is not limited thereto. These and other aspects are described in more detail below.
本发明的详细说明书Detailed description of the invention
定义和一般术语Definitions and general terms
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。Some embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and formulas. The invention is intended to cover all alternatives, modifications, and equivalents, which are within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the invention. The invention is in no way limited to the methods and materials described herein. Where one or more of the incorporated literature, patents, and similar materials are different or inconsistent with the present application (including but not limited to defined terms, terminology applications, described techniques, etc.), The application shall prevail.
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。It will be further appreciated that certain features of the invention are described in the various embodiments of the invention, and may be described in combination in a single embodiment. On the contrary, the various features of the invention are described in a single embodiment for the sake of brevity, but may be provided separately or in any suitable sub-combination.
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。Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety.
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。The following definitions used in the present invention should be applied unless otherwise stated. For the purposes of the present invention, chemical elements are consistent with the CAS version of the Periodic Table of the Elements, and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, The entire contents thereof are incorporated herein by reference.
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。The articles "a", "an" and "sai" are used, and are meant to include "at least one" or "one or more", unless otherwise indicated. Thus, the articles used herein are used to refer to one or more than one (i. For example, "a component" refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.
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。The term "subject" as used herein 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.
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。The term "patient" as used herein refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a human.
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。The term "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. .
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,New York,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。The stereochemical definitions and rules used in the present invention generally follow SP 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, New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are used to specify the plane-polarized light rotation caused by the compound. The sign of (-) 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.
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。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. In certain embodiments, 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.
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。Depending on the choice of starting materials and methods, 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.
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。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.
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)。The 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. In particular, 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. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre 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。The term "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. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-ene Amine isomerization.
“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。"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.
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。The term "optional" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and that the description includes instances in which the event or circumstance occurs and where it does not. For example, "optional key" means that the key may or may not be present, and the description includes a single bond, a double bond, or a triple bond.
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。As described herein, 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.
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。The term "optionally substituted with" can be used interchangeably with the term "unsubstituted or substituted.", ie the structure is unsubstituted or substituted by one or more of the present invention. Substituents, the 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.
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。In addition, it should be noted that the descriptions of the "individually" and "individually" and "independently" are interchangeable, unless otherwise explicitly indicated in the present invention. It should be understood in a broad sense, which can mean that the specific options expressed between the same symbols in different groups do not affect each other, and can also represent specific options expressed in the same group and between the same symbols. There is no influence between each other.
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。The term "comprising" is an open-ended expression that includes the subject matter of the invention, but does not exclude other aspects.
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。The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.
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。In each part of the specification, the substituents of the compounds disclosed herein are disclosed in terms of the type or range of groups. In particular, the invention includes each individual sub-combination of each member of the group and range of such groups. For example, the term "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.
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。In various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable recited for that group is understood to be a linking group. For example, if the structure requires a linking group and the definition of the Markush group for the variable is "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represent the attached An alkylene group or an arylene group.
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)。The terms "halogen" and "halo" are used interchangeably herein and refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (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。The term "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. In one embodiment, 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. Examples of 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.
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。The term "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.
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。The term "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". In one embodiment, the alkenyl group contains 2 to 6 carbon atoms; in another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH 2), allyl (-CH 2 CH = CH 2) and the like.
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。The term "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. In one embodiment, the alkynyl group contains 2 to 6 carbon atoms; in another embodiment, the alkynyl group contains 2 to 4 carbon atoms. Examples of 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. .
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。The term "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 1-6 carbon atoms; In another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains from 1 to 3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein.
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。Examples of 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.
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。The term "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.
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。The term "haloalkyl", "haloalkenyl" or "haloalkoxy" 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.
术语“环烷基”表示含有3-12个环碳原子的，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个环碳原子；在另一实施方案中，环烷基包含3-8个环碳原子；在又一实施方案中，环烷基包含3-6个环碳原子。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。The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms. In one embodiment, the cycloalkyl group contains from 3 to 10 ring carbon atoms; in another embodiment, the cycloalkyl group contains from 3 to 8 ring carbon atoms; in yet another embodiment, the cycloalkyl group comprises 3- 6 ring carbon atoms. 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.
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 PCTCN2016090985-appb-000003
基，二氮杂
Figure PCTCN2016090985-appb-000004
基，硫氮杂
Figure PCTCN2016090985-appb-000005
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。The terms "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. Unless otherwise stated, a heterocyclic group can be a carbon or a nitrogen group, and a -CH 2 - group can be optionally substituted with -C(=O)-. 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. Examples of 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 , dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, oxetanyl, thiaheptanyl, oxazepine
Figure PCTCN2016090985-appb-000003
Diaza
Figure PCTCN2016090985-appb-000004
Thioaza
Figure PCTCN2016090985-appb-000005
Base, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and the like. Examples of the -CH 2 - group in the heterocyclic group substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto group, 3,5-dioxopiperidinyl, pyrimidindione, and the like. 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.
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)。The term "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).
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。 The term "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. The term "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.
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。The term "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. The term "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. In one embodiment, 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.
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。Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 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 (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl, etc.; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl (eg 2-indenyl), fluorenyl, Quinolinyl (eg 2-quinolyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (eg 1-isoquinolinyl, 3- Quinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, Imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl,[1,2,4]triazolo[1,5-a Pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.
像本发明所描述的，取代基画一个键连接到中心的环上形成的环体系(如式a所示)代表取代基在环上(如式a中的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和式d所示。As described in the present invention, a ring system formed by a substituent attached to a central ring (as shown in formula a) represents a substituent on the ring (such as the ring B in formula a) which may be substituted or any reasonable The location can be replaced. For example, the formula a represents that any position on the B ring that may be substituted may be substituted by the substituent R, as shown in formula b, formula c and formula d.
Figure PCTCN2016090985-appb-000006
Figure PCTCN2016090985-appb-000006
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。The term "protecting group" or "PG" refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups. For example, "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). Similarly, 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.
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.SymposiumSeries；Roche et al.,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987；Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Reviews 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。The term "prodrug" as used in the present invention 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. In the prior invention, 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. For example, 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. A discussion of the completeness of prodrugs can be found in Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium 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, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al, Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328 -2345, each of which is incorporated herein by reference.
“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。"Metabolic 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.
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，丙二酸盐，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。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. Other pharmaceutically acceptable 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, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3 -Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. 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.
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。"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or mixtures thereof. The term "hydrate" means that the solvent molecule is an association formed by water.
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。When the solvent is water, the term "hydrate" can be used. In one embodiment, 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 invention may be combined with more than one water molecule, such as 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.
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。The term "treating" any disease or condition as used in the present invention, in some embodiments thereof, 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). In other embodiments, "treating" refers to alleviating or ameliorating at least one body Parameters, including physical parameters that may not be perceived by the patient. In other embodiments, "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. In other embodiments, "treating" refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
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。The term "therapeutically 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.
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。The indole compound of the present invention, a pharmaceutically acceptable salt thereof, a pharmaceutical preparation and a composition thereof, 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.
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。All suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are included within the scope of the invention unless otherwise stated.
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(solid wedge)或虚线指明时，则该结构的立体异构体就此明确和定义。In the structures disclosed herein, 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. . When stereochemistry is indicated by a solid wedge or dashed line indicating a particular configuration, then the stereoisomers of the structure are defined and defined herein.
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。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. 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.
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。The compound of the formula (I) may exist in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "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. In another embodiment, 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.
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′sPharmaceutical Sciences”，第20版，Mack Publishing Company,Easton,Pa.,(1985)；和“药用盐手册：性质、选择和应用(Handbook ofPharmaceutical Salts:Properties,Selection,andUse)”,Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. In general, 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. 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. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" A list of additional suitable salts can be found in Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
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。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.
另一方面，本发明涉及制备式(I)所示化合物的中间体。In another aspect, the invention relates to an intermediate for the preparation of a compound of formula (I).
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。In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or a combination thereof. In another implementation In the scheme, the pharmaceutical composition may be in the form of a liquid, solid, semi-solid, gel or spray.
本发明化合物的药物组合物、制剂和给药Pharmaceutical compositions, formulations and administrations of the compounds of the invention
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。The present invention provides 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 . In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally other therapeutic and/or prophylactic ingredients.
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 ofPharmacy(2000)Lippincott,Williams&Wilkins,Philadelphia；和Rowe R.C.,Handbook of Pharmaceutical Excipients(2005)Pharmaceutical Press,Chicago中。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.
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。It will also be appreciated that certain compounds of the invention may exist in free form for treatment or, if appropriate, in the form of their pharmaceutically acceptable derivatives. Some non-limiting embodiments of 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.
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。The pharmaceutical 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. Alternatively, 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. When prepared in unit dosage form, 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.
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。As used 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. In addition, each excipient must be pharmaceutically acceptable, for example, of sufficiently high purity.
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。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.
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。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. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function and provide alternative functionality depending on how many other excipients are present in the formulation and in the formulation. Agent.
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(theAmerican Pharmaceutical Association and the Pharmaceutical Press)。The skilled artisan will have the knowledge and skill in the art to enable them to select the appropriate amount of suitable pharmaceutically acceptable excipient for use in the present invention. In addition, there are a number of resources available to the skilled artisan who describe pharmaceutically acceptable excipients and are used to select suitable pharmaceutically acceptable excipients. Examples include 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)。 The pharmaceutical 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).
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。Accordingly, in another aspect, 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.
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。The compounds disclosed herein are typically formulated in a dosage form suitable for administration to a patient by the desired route. For example, 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.
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。In one embodiment, 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.
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。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.
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。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.
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。The pharmaceutical compositions provided herein can be provided in liquid and semisolid dosage forms including emulsions, solutions, suspensions, elixirs, and syrups.
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。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.
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。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.
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。The pharmaceutical 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.
在所有上述剂型中可以使用着色剂和调味剂。Colorants and flavoring agents can be used in all of the above dosage forms.
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。The compounds disclosed herein can also be combined with soluble polymers as targeted drug carriers.
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。The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-release, pulse-, controlled-, targeted-, and programmed release forms.
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。The pharmaceutical 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.
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。The pharmaceutical 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.
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 ofPharmacy,同 上)。The pharmaceutical 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. A solid form of the solution or suspension. Such 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, on).
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。The pharmaceutical 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.
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。In another aspect, the pharmaceutical 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.
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。Pharmaceutical 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. For example, the active ingredient can be delivered from the patch by ion permeation as generally described in Pharmaceutical Research, 3(6), 318 (1986).
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。Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
本发明化合物和组合物的用途Use of the compounds and compositions of the invention
本发明提供的化合物和药物组合物可用于制备用于预防、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，也可以用于制备用于抑制5-羟色胺再摄取和/或激动5-HT1A受体的药品。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 agonism. 5-HT 1A receptor drug.
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。In particular, 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.
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。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.
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。In addition to being useful for human therapy, 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. Herein, the compounds of the invention include pharmaceutically acceptable derivatives thereof.
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。In one embodiment, 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.
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。In one embodiment, 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.
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一次性给药，或者根据给药方案，在指定时间段内，在不同的时间间隔给药若干次。例如，每天给药一次、两次、三次或四次。可以给药直至达到想要的治疗效果或无限期地维持想要的治疗效果。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的合适给药方案取决于该化合物的药代动力学性质，例如吸收、分布和半衰期，这些可以由技术人员测定。此外，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的合适给药方案，包括实施该方案的持续时间，取决于被治疗的疾病，被治疗疾病的严重程度、被治疗患者的年龄和身体状 况、被治疗患者的医疗史、同时疗法的性质、想要的治疗效果等在技术人员知识和经验范围内的因素。这样的技术人员还应该理解，对于个体患者对给药方案的反应，或随着时间推移个体患者需要变化时，可要求调整事宜的给药方案。In one embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered at a time, or several times at different time intervals, over a specified period of time, depending on the dosage regimen. For example, administration once, twice, three times or four times a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the compounds disclosed herein depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, as determined by the skilled artisan. Furthermore, suitable dosage regimens of the disclosed compounds or pharmaceutical compositions comprising the compounds of the present invention, including the duration of implementation of the regimen, depend on the condition being treated, the severity of the condition being treated, the age of the subject being treated, and Body shape The medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, etc., are within the knowledge and experience of the skilled person. Such skilled artisans will also appreciate that the dosage regimen for the adjustment may be required for individual patient responses to the dosage regimen, or for individual patient needs to change over time.
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。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.
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。Furthermore, the compounds disclosed herein can be administered in the form of a prodrug. In the present invention, 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. When 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.
一般合成步骤General synthetic procedure
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。For the purpose of describing the invention, the examples are set forth below. However, it is to be understood that the invention is not limited to the embodiments, but merely provides a method of practicing the invention.
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。In general, 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.
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。Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of the interfering group, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.
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 andAlfa 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。The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant purchased it.
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。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.
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。The following 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.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。The column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.
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 oftriplets，双三重峰)。偶合常数，用赫兹(Hz)表示。 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz NMR spectrometer. The 1 H NMR spectrum was determined by using CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as a solvent (in ppm) using TMS (0 ppm) or chloroform (7.26 ppm) as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet, single peak), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide) Peak), dd (doublet of doublets), dt (doublet oftriplets, double triplet). Coupling constant, expressed in Hertz (Hz).
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-C18,2.1x 30mm,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。The conditions for the determination of low resolution mass spectrometry (MS) data were: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 micron, 6 min, flow rate 0.6 mL/min. Mobile phase: 5 ratio of 95% (0.1% formic acid in CH 3 CN) in (H containing 0.1% formic acid 2 O) in using electrospray ionization (ESI), at 210nm / 254nm, with UV detection.
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。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.
下面简写词的使用贯穿本发明：The following abbreviations are used throughout the invention:
AcOH、HOAc、CH3COOH  乙酸AcOH, HOAc, CH 3 COOH acetic acid
BOC、Boc  叔丁氧基羰基BOC, Boc tert-butoxycarbonyl
CH2Cl2、DCM  二氯甲烷CH 2 Cl 2 , DCM dichloromethane
CDC13  氘代氯仿CDC1 3 deuterated chloroform
CD3OD  氘代甲醇CD 3 OD deuterated methanol
DMF  N,N-二甲基甲酰胺DMF N,N-dimethylformamide
DMSO  二甲基亚砜DMSO dimethyl sulfoxide
EDTA  乙二胺四乙酸EDTA ethylenediaminetetraacetic acid
Et3N、TEA  三乙胺Et 3 N, TEA triethylamine
EtOAc、EA  乙酸乙酯EtOAc, EA ethyl acetate
g  克g g
h  小时h hours
HCl  氯化氢HCl hydrogen chloride
NaCl  氯化钠NaCl sodium chloride
KCl  氯化钾KCl potassium chloride
MgSO4  硫酸镁MgSO4 magnesium sulfate
MeCN、CH3CN  乙腈MeCN, CH 3 CN acetonitrile
mL、ml  毫升mL, ml ml
PE  石油醚(60-90℃)PE petroleum ether (60-90 ° C)
RT、rt、r.t.  室温RT, rt, r.t. room temperature
Rt  保留时间Rt retention time
TFA  三氟乙酸TFA trifluoroacetic acid
Tris-HCl  三(羟甲基)氨基甲烷-盐酸Tris-HCl Tris(hydroxymethyl)aminomethane-hydrochloric acid
BSA  牛血清蛋白BSA bovine serum albumin
mCPBA  间氯过氧苯甲酸mCPBA m-chloroperoxybenzoic acid
OXONE  过氧单磺酸钾OXONE Potassium Peroxymonosulfonate
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R1和n具有本发明所述的定义，R为C1-C6烷基。 The following synthetic schemes describe the preparation of the compounds disclosed herein, unless otherwise stated, wherein each of R 1 and n has the definitions described herein, and R is C 1 -C 6 alkyl.
合成方案1：Synthetic Scheme 1:
Figure PCTCN2016090985-appb-000007
Figure PCTCN2016090985-appb-000007
式(5)所示的化合物可以通过合成方案1描述的方法制备得到：首先，化合物(1)在POCl3的作用下反应得到化合物(2)，然后化合物(2)与哌嗪-1-甲酸叔丁酯在碱的作用下反应得到化合物(3)，最后化合物(3)在三氟乙酸的二氯甲烷溶液或氯化氢的乙酸乙酯溶液中脱去Boc保护基后，再在碳酸钾或碳酸钠等碱的作用下，与化合物(4)进行亲核取代反应得到目标化合物(5)。The compound represented by the formula ( 5 ) can be produced by the method described in the synthesis scheme 1: First, the compound ( 1 ) is reacted under the action of POCl 3 to obtain the compound ( 2 ), and then the compound ( 2 ) and piperazine-1-carboxylic acid. The tert-butyl ester is reacted under the action of a base to obtain the compound ( 3 ), and finally the compound ( 3 ) is decarboxylated in a solution of trifluoroacetic acid in dichloromethane or ethyl acetate in ethyl acetate, followed by potassium carbonate or carbonic acid. Under the action of a base such as sodium, a nucleophilic substitution reaction with the compound ( 4 ) gives the target compound ( 5 ).
合成方案2:Synthetic Scheme 2:
Figure PCTCN2016090985-appb-000008
Figure PCTCN2016090985-appb-000008
式(11)和式(12)所示的化合物可以通过合成方案2描述的方法制备得到：首先，化合物(2)在氧化剂如mCPBA或OXONE的作用下反应得到化合物(6)，化合物(6)在醋酐中反应得到化合物(7)；然后化合物(7)和化合物(8)在碱的作用下反应得到化合物(9)，化合物(9)再与哌嗪-1-甲酸叔丁酯在碱的作用反应下反应得到化合物(10)；最后化合物(10)在三氟乙酸的二氯甲烷溶液或氯化氢的乙酸乙酯溶液中脱去Boc保护基后，再在碳酸钾或碳酸钠等碱的作用下，与化合物(4)进行亲核取代反应得到目标化合物(11)。化合物(11)进行酯的水解反应得到另一目标化合物(12)。The compound represented by the formula ( 11 ) and the formula ( 12 ) can be produced by the method described in Synthetic Scheme 2: First, the compound ( 2 ) is reacted under the action of an oxidizing agent such as mCPBA or OXONE to obtain a compound ( 6 ), the compound ( 6 ). The compound ( 7 ) is obtained by reacting in acetic anhydride; then the compound ( 7 ) and the compound ( 8 ) are reacted under the action of a base to obtain a compound ( 9 ), and the compound ( 9 ) is further reacted with piperazine-1-carboxylic acid tert-butyl ester in a base. The reaction of the reaction gives the compound ( 10 ); the final compound ( 10 ) is deprotected from the Boc protecting group in a solution of trifluoroacetic acid in dichloromethane or ethyl acetate in ethyl acetate, followed by an alkali such as potassium carbonate or sodium carbonate. Under the action, a nucleophilic substitution reaction with the compound ( 4 ) gives the target compound ( 11 ). Compound ( 11 ) is subjected to hydrolysis of an ester to give another target compound ( 12 ).
合成方案3:Synthetic Scheme 3:
Figure PCTCN2016090985-appb-000009
Figure PCTCN2016090985-appb-000009
Figure PCTCN2016090985-appb-000010
Figure PCTCN2016090985-appb-000010
式(15)所示的化合物可以通过合成方案3描述的方法制备得到：首先，化合物(9)在胺化剂如氨甲醇溶液的作用下氨解得到化合物(13)，然后化合物(13)与哌嗪-1-甲酸叔丁酯在碱的作用下反应得到化合物(14)，最后化合物(14)在三氟乙酸的二氯甲烷溶液或氯化氢的乙酸乙酯溶液中脱去Boc保护基后，再在碳酸钾或碳酸钠等碱的作用下，与化合物(4)进行亲核取代反应得到目标化合物(15)。The compound represented by the formula ( 15 ) can be produced by the method described in Synthesis Scheme 3: first, the compound ( 9 ) is subjected to aminolysis under the action of an aminating agent such as ammonia methanol solution to obtain a compound ( 13 ), and then the compound ( 13 ) is The piperazine-1-carboxylic acid tert-butyl ester is reacted under the action of a base to obtain a compound ( 14 ), and finally the compound ( 14 ) is deprotected from the Boc protecting group in a solution of trifluoroacetic acid in dichloromethane or ethyl acetate in ethyl acetate. Further, a nucleophilic substitution reaction with the compound ( 4 ) by a base such as potassium carbonate or sodium carbonate gives the target compound ( 15 ).
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。The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in conjunction with the examples.
实施例1 3-(4-(4-(1,6-萘啶-5-基)哌嗪-1-基)丁基)-1H-吲哚-5-甲腈Example 1 3-(4-(4-(1,6-naphthyridin-5-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
Figure PCTCN2016090985-appb-000011
Figure PCTCN2016090985-appb-000011
步骤1)5-氯-1,6-萘啶的合成Step 1) Synthesis of 5-chloro-1,6-naphthyridine
将1,6-萘啶-5(6H)-酮(3.00g,20.53mmol)加入到三氯氧磷(40mL)中。反应液升高温度，回流反应24小时后冷却至室温，然后减压蒸馏除去三氯氧磷。向反应混合物中加入冰水(20mL)，并用碳酸钠固体调节pH为8～9。将所得混合物过滤，滤液用二氯甲烷(20mL×5)萃取。有机相用无水硫酸钠干燥，过滤，并减压浓缩得到粗品，所得粗品经硅胶柱层析(二氯甲烷/甲醇(v/v)＝10/1)纯化得到标题化合物为白色固体(3.08g,91.1％)。1,6-Naphthyridin-5(6H)-one (3.00 g, 20.53 mmol) was added to phosphorus oxychloride (40 mL). The reaction liquid was elevated in temperature, refluxed for 24 hours, and then cooled to room temperature, and then phosphorus oxychloride was distilled off under reduced pressure. Ice water (20 mL) was added to the reaction mixture, and the pH was adjusted to 8 to 9 with sodium carbonate solid. The mixture was filtered and the filtrate was extracted with dichloromethane (20 mL×5). The organic phase was dried over anhydrous sodium sulfate EtOAcjjjjjjjjjjj g, 91.1%).
MS(ESI,pos.ion)m/z:165.1(M+H)；MS (ESI, pos.) m/z: 165.1 (M+H);
1H NMR(CDCl3,400MHz)δ(ppm):9.15(dd,J＝4.2,1.5Hz,1H),8.71-8.60(m,1H),8.53(d,J＝5.9Hz,1H),7.90(d,J＝5.8Hz,1H),7.64(dd,J＝8.5,4.3Hz,1H). 1 H NMR (CDCl 3 , 400 MHz) δ (ppm): 9.15 (dd, J = 4.2, 1.5 Hz, 1H), 8.71 - 8.60 (m, 1H), 8.53 (d, J = 5.9 Hz, 1H), 7.90 (d, J = 5.8 Hz, 1H), 7.64 (dd, J = 8.5, 4.3 Hz, 1H).
步骤2)4-(1,6-萘啶-5-基)哌嗪-1-甲酸叔丁酯的合成Step 2) Synthesis of 4-(1,6-naphthyridin-5-yl)piperazine-1-carboxylic acid tert-butyl ester
将5-氯-1,6-萘啶(3.00g,18.23mmol)、哌嗪-1-甲酸叔丁酯(3.73g,20.05mmol)和碳酸钠(2.90g,37.34mmol)加入到乙腈中(30mL)。将混合物升高温度，回流反应10小时后冷却至室温，然后减压浓缩得到粗品，粗品经硅胶柱层析(石油醚/乙酸乙酯(v/v)＝10/1)纯化得到标题化合物为浅黄色固体(4.70g,82.1％)。5-Chloro-1,6-naphthyridine (3.00 g, 18.23 mmol), piperazine-1-carboxylic acid tert-butyl ester (3.73 g, 20.05 mmol) and sodium carbonate (2.90 g, 37.34 mmol) were added to acetonitrile ( 30mL). The mixture was heated to reflux temperature, and the mixture was evaporated to dryness EtOAc (HHHHHHHHHHHHHHH Light yellow solid (4.70 g, 82.1%).
MS(ESI,pos.ion)m/z:315.2(M+H)；MS (ESI, pos.) m/z: 315.2 (M+H);
1H NMR(CDCl3,400MHz)δ(ppm):9.12(dd,J＝4.2,1.6Hz,1H),8.70-8.58(m,1H),8.50(d,J＝6.0Hz,1H),7.88(d,J＝5.8Hz,1H),7.64(dd,J＝8.5,4.4Hz,1H),3.62-3.53(m,4H),3.16-3.05(m,4H),1.49(m,9H). 1 H NMR (CDCl 3 , 400 MHz) δ (ppm): 9.12 (dd, J = 4.2, 1.6 Hz, 1H), 8.70-8.58 (m, 1H), 8.50 (d, J = 6.0 Hz, 1H), 7.88 (d, J = 5.8 Hz, 1H), 7.64 (dd, J = 8.5, 4.4 Hz, 1H), 3.62-3.53 (m, 4H), 3.16-3.05 (m, 4H), 1.49 (m, 9H).
步骤3)3-(4-(4-(1,6-萘啶-5-基)哌嗪-1-基)丁基)-1H-吲哚-5-甲腈的合成Step 3) Synthesis of 3-(4-(4-(1,6-naphthyridin-5-yl)piperazin-1-yl)butyl)-1H-indole-5-carbonitrile
将4-(1,6-萘啶-5-基)哌嗪-1-甲酸叔丁酯(400mg,1.27mmol)溶解在二氯甲烷(10mL)中，加入氯化氢的乙酸乙酯溶液(4M,2mL)，反应液置于室温反应1小时后减压旋干。将所得的盐酸盐固体溶解在乙 腈中(15mL)，并依次加入3-(4-氯丁基)-1H-吲哚-5-甲腈(296mg,1.27mmol)、碘化钾(21mg,0.13mmol)和碳酸钠(405mg,3.82mmol)，然后将反应液升高温度，回流反应过夜。反应结束后，将反应混合物冷却至室温，并减压浓缩得到粗品，粗产品经硅胶柱层析(二氯甲烷/甲醇(v/v)＝50/1)纯化得到标题化合物为淡黄色固体(300mg,57.5％)。4-(1,6-Naphthyridin-5-yl)piperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.27 mmol) was dissolved in dichloromethane (10 mL). 2 mL), the reaction solution was allowed to react at room temperature for 1 hour, and then dried under reduced pressure. Dissolve the resulting hydrochloride solid in B In a nitrile (15 mL), followed by 3-(4-chlorobutyl)-1H-indole-5-carbonitrile (296 mg, 1.27 mmol), potassium iodide (21 mg, 0.13 mmol) and sodium carbonate (405 mg, 3.82 mmol) Then, the reaction solution was elevated in temperature and refluxed overnight. After the reaction, the reaction mixture was cooled to EtOAc (mjqqqqqqq 300 mg, 57.5%).
MS(ESI,pos.ion)m/z:411.0(M+H)；MS (ESI, pos.) m/z: 411.0 (M+H);
1H NMR(CDCl3,600MHz)δ(ppm):8.99(dd,J＝4.2,1.7Hz,1H),8.95(s,1H),8.41-8.37(m,1H),8.33(d,J＝5.9Hz,1H),7.97(s,1H),7.48(d,J＝6.0Hz,1H),7.43(dd,J＝8.4,4.3Hz,1H),7.40(d,J＝0.6Hz,2H),7.15-7.12(m,1H),3.50(t,J＝4.8Hz,4H),2.81(t,J＝7.5Hz,2H),2.73(brs,4H),2.56-2.48(m,2H),1.83-1.75(m,2H),1.72-1.62(m,2H)； 1 H NMR (CDCl 3 , 600 MHz) δ (ppm): 8.99 (dd, J = 4.2, 1.7 Hz, 1H), 8.95 (s, 1H), 8.41 - 8.37 (m, 1H), 8.33 (d, J = 5.9 Hz, 1H), 7.97 (s, 1H), 7.48 (d, J = 6.0 Hz, 1H), 7.43 (dd, J = 8.4, 4.3 Hz, 1H), 7.40 (d, J = 0.6 Hz, 2H) , 7.15-7.12 (m, 1H), 3.50 (t, J = 4.8 Hz, 4H), 2.81 (t, J = 7.5 Hz, 2H), 2.73 (brs, 4H), 2.56-2.48 (m, 2H), 1.83-1.75 (m, 2H), 1.72-1.62 (m, 2H);
13C NMR(CDCl3,150MHz)δ(ppm):161.6,153.6,153.0,144.5,138.1,134.1,127.5,124.7,124.6,123.4,121.0,120.8,117.5,116.8,116.7,112.0,102.0,58.5,53.3,51.3,28.0,26.6,24.8. 13 C NMR (CDCl 3 , 150 MHz) δ (ppm): 161.6, 153.6, 153.0, 144.5, 138.1, 134.1, 127.5, 124.7, 124.6, 123.4, 121.0, 120.8, 117.5, 116.8, 116.7, 112.0, 102.0, 58.5, 53.3, 51.3, 28.0, 26.6, 24.8.
实施例2 3-(3-(4-(1,6-萘啶-5-基)哌嗪-1-基)丙基)-1H-吲哚-5-甲腈Example 2 3-(3-(4-(1,6-naphthyridin-5-yl)piperazin-1-yl)propyl)-1H-indole-5-carbonitrile
Figure PCTCN2016090985-appb-000012
Figure PCTCN2016090985-appb-000012
本步骤标题化合物按照实施例1步骤3的方法制备得到，即将4-(1,6-萘啶-5-基)哌嗪-1-甲酸叔丁酯(400mg,1.27mmol)和氯化氢的乙酸乙酯溶液(4M,2mL)在二氯甲烷(10mL)中反应所得的盐酸盐固体与3-(3-氯丙基)-1H-吲哚-5-甲腈(278mg,1.27mmol)、碘化钾(21mg,0.13mmol)和碳酸钠(405mg,3.82mmol)在乙腈(15mL)中反应制备得到粗品，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浅黄色固体(320mg,63.5％)。The title compound of this step was prepared according to the method of the step 3 of Example 1, that is, 4-(1,6-naphthyridin-5-yl)piperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.27 mmol) and hydrogen chloride in ethyl acetate The ester solution (4M, 2 mL) was obtained in methylene chloride (10 mL). EtOAc EtOAc EtOAc (EtOAc: EtOAc (21 mg, 0.13 mmol) and sodium carbonate (405 mg, 3.82 mmol) were obtained from EtOAc (EtOAc) (EtOAc) The title compound was obtained as a pale yellow solid (320 mg, 63.5%).
MS(ESI,pos.ion)m/z:397.0(M+H)；MS (ESI, pos.) m/z: 397.0 (M+H);
1H NMR(CDCl3,600MHz)δ(ppm):8.99(dd,J＝4.3,1.7Hz,1H),8.85(s,1H),8.40(d,J＝7.9Hz,1H),8.34(d,J＝5.9Hz,1H),8.01(s,1H),7.49(d,J＝5.9Hz,1H),7.45-7.40(m,3H),7.16(d,J＝2.0Hz,1H),3.52(t,J＝4.8Hz,4H),2.85(t,J＝7.5Hz,2H),2.75(t,J＝4.8Hz,4H),2.58-2.53(m,2H),2.01-1.95(m,2H)； 1 H NMR (CDCl 3 , 600 MHz) δ (ppm): 8.99 (dd, J = 4.3, 1.7 Hz, 1H), 8.85 (s, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.34 (d) , J=5.9 Hz, 1H), 8.01 (s, 1H), 7.49 (d, J = 5.9 Hz, 1H), 7.45-7.40 (m, 3H), 7.16 (d, J = 2.0 Hz, 1H), 3.52 (t, J = 4.8 Hz, 4H), 2.85 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 4.8 Hz, 4H), 2.58-2.53 (m, 2H), 2.01-1.95 (m, 2H);
13C NMR(CDCl3,150MHz)δ(ppm):161.7,153.6,153.1,144.5,138.0,134.1,127.6,124.8,124.7,123.5,120.9,120.8,117.4,116.8,116.7,112.0,102.2,58.1,53.3,51.4,27.3,22.6. 13 C NMR (CDCl 3 , 150 MHz) δ (ppm): 161.7, 153.6, 153.1, 144.5, 138.0, 134.1, 127.6, 124.8, 124.7, 123.5, 120.9, 120.8, 117.4, 116.8, 116.7, 112.0, 102.2, 58.1, 53.3, 51.4, 27.3, 22.6.
实施例3 2-((5-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)-1,6-萘啶-2-基)氧基)乙酸乙酯Example 3 2-((5-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-1,6-naphthyridin-2- Ethyl acetate
Figure PCTCN2016090985-appb-000013
Figure PCTCN2016090985-appb-000013
步骤1)5-氯-1,6-萘啶1-氧化物的合成Step 1) Synthesis of 5-chloro-1,6-naphthyridine 1-oxide
将5-氯-1,6-萘啶(3.00g,18.23mmol)溶于二氯甲烷(30mL)中，然后将上述溶液冷却到0℃，并分 批加入间氯过氧苯甲酸(6.29g,36.45mmol)。反应液升温至室温反应3小时后，用饱和碳酸钠水溶液(30mL)洗涤。有机相用无水硫酸钠干燥，过滤，并减压浓缩得到标题化合物为浅黄色固体(2.71g,82.3％)。5-Chloro-1,6-naphthyridine (3.00 g, 18.23 mmol) was dissolved in dichloromethane (30 mL), then the solution was cooled to 0 ° C and divided m-Chloroperoxybenzoic acid (6.29 g, 36.45 mmol) was added in portions. The reaction solution was warmed to room temperature for 3 hours and then washed with saturated aqueous sodium sulfate (30 mL). The organic phase was dried with EtOAc EtOAcjjjjjjj
MS(ESI,pos.ion)m/z:181.0(M+H)；MS (ESI, pos.) m/z: 181.0 (M+H);
1H NMR(CDCl3,600MHz)δ(ppm):8.65(dd,J＝6.0,0.6Hz,1H),8.53(d,J＝6.0Hz,1H),8.45(dd,J＝6.0,0.6Hz,1H),8.12(d,J＝9.0Hz,1H),7.48(dd,J＝9.0,6.6Hz,1H). 1 H NMR (CDCl 3 , 600 MHz) δ (ppm): 8.65 (dd, J = 6.0, 0.6 Hz, 1H), 8.53 (d, J = 6.0 Hz, 1H), 8.45 (dd, J = 6.0, 0.6 Hz) , 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.48 (dd, J = 9.0, 6.6 Hz, 1H).
步骤2)5-氯-1,6-萘啶-2(1H)-酮的合成Step 2) Synthesis of 5-chloro-1,6-naphthyridin-2(1H)-one
将5-氯-1,6-萘啶1-氧化物(2.70mg,14.95mmol)加入到乙酸酐(30mL)中，反应液于130℃反应18小时后冷却至100℃，并加入水(20mL)，然后继续冷却到室温。向所得反应混合物中加入二氯甲烷(50mL)和饱和碳酸氢钠水溶液(50mL)，并搅拌半小时。分离的有机相用无水硫酸钠干燥，过滤，并减压浓缩得到粗品，粗品经硅胶柱层析(二氯甲烷/甲醇(v/v)＝60/1)纯化得到标题化合物为浅黄色固体(1.35g,50.0％)。5-Chloro-1,6-naphthyridinium 1-oxide (2.70 mg, 14.95 mmol) was added to acetic anhydride (30 mL), and the reaction mixture was reacted at 130 ° C for 18 hours, then cooled to 100 ° C, and water (20 mL) ), then continue to cool to room temperature. Dichloromethane (50 mL) and a saturated aqueous solution of sodium hydrogencarbonate (50 mL) were added and the mixture was stirred for half an hour. The separated organic layer was dried with EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (1.35g, 50.0%).
1H NMR(CDCl3,600MHz)δ(ppm):8.33(d,J＝5.4Hz,1H),8.20(d,J＝9.6Hz,1H),7.25(s,1H),6.81(d,J＝9.6Hz,1H). 1 H NMR (CDCl 3 , 600 MHz) δ (ppm): 8.33 (d, J = 5.4 Hz, 1H), 8.20 (d, J = 9.6 Hz, 1H), 7.25 (s, 1H), 6.81 (d, J) =9.6Hz, 1H).
步骤3)2-((5-氯-1,6-萘啶-2-基)氧基)乙酸乙酯的合成Step 3) Synthesis of 2-((5-chloro-1,6-naphthyridin-2-yl)oxy)acetate
将5-氯-1,6-萘啶-2(1H)-酮(800mg,4.43mmol)、2-溴乙酸乙酯(796μL,6.64mmol)和碳酸钾(1.84g,13.29mmol)依次加入到DMF(10mL)中，反应液置于室温反应16小时后，向其中加入水(30mL)，并用乙酸乙酯(15mL×3)萃取。有机相用无水硫酸钠干燥，过滤，并减压浓缩得到粗品，粗品经硅胶柱层析(二氯甲烷/甲醇(v/v)＝80/1)纯化得到标题化合物为浅黄色固体(944mg,80.0％)。5-Chloro-1,6-naphthyridin-2(1H)-one (800 mg, 4.43 mmol), ethyl 2-bromoacetate (796 μL, 6.64 mmol) and potassium carbonate (1.84 g, 13.29 mmol) were sequentially added After reacting the reaction solution for 16 hours at room temperature in DMF (10 mL), water (30 mL) was added, and ethyl acetate (15 mL × 3) was applied. The organic phase was dried over anhydrous sodium sulfate (mjjjjjjjjjj , 80.0%).
MS(ESI,pos.ion)m/z:267.0(M+H)；MS (ESI, pos.) m/z: 267.0 (M+H);
1H NMR(CDCl3,600MHz)δ(ppm):8.34(d,J＝6.0Hz,1H),8.16(dd,J＝10.2,0.6Hz,1H),6.92(d,J＝6.0Hz,1H),6.83(d,J＝9.6Hz,1H),5.01(s,2H),4.25(q,J＝7.2Hz,2H),1.28(t,J＝7.2Hz,3H). 1 H NMR (CDCl 3 , 600 MHz) δ (ppm): 8.34 (d, J = 6.0 Hz, 1H), 8.16 (dd, J = 10.2, 0.6 Hz, 1H), 6.92 (d, J = 6.0 Hz, 1H) ), 6.83 (d, J = 9.6 Hz, 1H), 5.01 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).
步骤4)4-(2-(2-乙氧基-2-氧代乙氧基)-1,6-萘啶-5-基)哌嗪-1-甲酸叔丁酯的合成Step 4) Synthesis of 4-(2-(2-ethoxy-2-oxoethoxy)-1,6-naphthyridin-5-yl)piperazine-1-carboxylic acid tert-butyl ester
本步骤标题化合物按照实施例1步骤2的方法制备得到，即将2-((5-氯-1,6-萘啶-2-基)氧基)乙酸乙酯(940mg,3.52mmol)、哌嗪-1-甲酸叔丁酯(722mg,3.88mmol)和碳酸钠(560mg,5.29mmol)在乙腈中(10mL)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)＝10/1)纯化得到标题化合物为浅黄色固体(1.06g,72.1％)。The title compound of this step was obtained according to the procedure of Step 2 of Example 1, that is, ethyl 2-((5-chloro-1,6-naphthyridin-2-yl)oxy)acetate (940 mg, 3.52 mmol), piperazine The crude product was obtained by the reaction of tert-butyl-l-carboxylate (722 mg, 3.88 mmol) and sodium carbonate (560 mg, 5.29 mmol) in acetonitrile (10 mL). The title compound was obtained as a pale yellow solid (1.06 g, 72.1%).
MS(ESI,pos.ion)m/z:417.2(M+H)；MS (ESI, pos.) m/z: 417.2 (M+H);
1H NMR(CDCl3,600MHz)δ(ppm):8.24(d,J＝6.0Hz,1H),8.16-8.12(m,1H),6.90(d,J＝6.0Hz,1H),6.81(d,J＝9.6Hz,1H),5.00(s,2H),4.25(q,J＝7.2Hz,2H),3.60(brs,4H),3.02(brs,4H),1.48(s,9H),1.29(t,J＝7.2Hz,3H). 1 H NMR (CDCl 3, 600MHz ) δ (ppm): 8.24 (d, J = 6.0Hz, 1H), 8.16-8.12 (m, 1H), 6.90 (d, J = 6.0Hz, 1H), 6.81 (d , J = 9.6 Hz, 1H), 5.00 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 3.60 (brs, 4H), 3.02 (brs, 4H), 1.48 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H).
步骤5)2-((5-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)-1,6-萘啶-2-基)氧基)乙酸乙酯的合成Step 5) 2-((5-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-1,6-naphthyridin-2- Synthesis of Ethyl Acetate
本步骤标题化合物按照实施例1步骤3的方法制备得到，即将4-(2-(2-乙氧基-2-氧代乙氧基)-1,6-萘啶-5-基)哌嗪-1-甲酸叔丁酯(300mg,0.72mmol)和氯化氢的乙酸乙酯溶液(4M,2mL)在二氯甲烷(10mL)中反应所得的盐酸盐固体与3-(4-氯丁基)-1H-吲哚-5-甲腈(168mg,0.72mmol)、碘化钾(12mg,0.07mmol)和碳酸钠(229mg,2.16mmol)在乙腈(15mL)中反应制备得到粗品，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淡黄色固体(210mg,53.0％)。 The title compound of this step is prepared according to the method of the step 3 of Example 1, that is, 4-(2-(2-ethoxy-2-oxoethoxy)-1,6-naphthyridin-5-yl)piperazine The hydrochloride salt solid and 3-(4-chlorobutyl) were obtained by reacting tert-butyl-l-carboxylate (300 mg, 0.72 mmol) and ethyl acetate in ethyl acetate (4M, 2 mL) in dichloromethane (10 mL) -1H-indole-5-carbonitrile (168 mg, 0.72 mmol), potassium iodide (12 mg, 0.07 mmol) and sodium carbonate (229 mg, 2.16 mmol). Purification (methylene chloride / MeOH (v/v) = 50/1)
MS(ESI,pos.ion)m/z:512.9(M+H)；MS (ESI, pos.) m/z: 512.9 (M+H);
1H NMR(CDCl3,600MHz)δ(ppm):8.73(s,1H),8.21(d,J＝6.0Hz,1H),7.94(s,1H),7.89(d,J＝9.6Hz,1H),7.37(s,2H),7.09(s,1H),6.64(d,J＝10.2Hz,1H),6.57(d,J＝6.0Hz,1H),4.99(s,2H),4.23(q,J＝7.2Hz,2H),3.35(t,J＝4.8Hz,4H),2.78(t,J＝7.2Hz,2H),2.65(t,J＝4.8Hz,4H),2.46(t,J＝7.2Hz,2H),1.80-1.69(m,2H),1.67-1.61(m,2H),1.27(t,J＝7.2Hz,3H)； 1 H NMR (CDCl 3 , 600 MHz) δ (ppm): 8.73 (s, 1H), 8.21 (d, J = 6.0 Hz, 1H), 7.94 (s, 1H), 7.89 (d, J = 9.6 Hz, 1H) ), 7.37 (s, 2H), 7.09 (s, 1H), 6.64 (d, J = 10.2 Hz, 1H), 6.57 (d, J = 6.0 Hz, 1H), 4.99 (s, 2H), 4.23 (q) , J = 7.2 Hz, 2H), 3.35 (t, J = 4.8 Hz, 4H), 2.78 (t, J = 7.2 Hz, 2H), 2.65 (t, J = 4.8 Hz, 4H), 2.46 (t, J = 7.2 Hz, 2H), 1.80-1.69 (m, 2H), 1.67-1.61 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H);
13C NMR(CDCl3,150MHz)δ(ppm):167.7,161.9,161.8,148.2,146.7,138.1,136.7,127.4,124.9,124.8,123.4,121.0,119.8,117.5,112.0,107.4,103.3,102.0,62.0,58.5,53.3,51.4,43.9,27.9,26.6,24.8,14.1. 13 C NMR (CDCl 3 , 150 MHz) δ (ppm): 167.7, 161.9, 161.8, 148.2, 146.7, 138.1, 136.7, 127.4, 124.9, 124.8, 123.4, 121.0, 119.8, 117.5, 112.0, 107.4, 103.3, 102.0, 62.0, 58.5, 53.3, 51.4, 43.9, 27.9, 26.6, 24.8, 14.1.
实施例4 2-((5-(4-(3-(5-氰基-1H-吲哚-3-基)丙基)哌嗪-1-基)-1,6-萘啶-2-基)氧基)乙酸乙酯Example 4 2-((5-(4-(3-(5-Cyano-1H-indol-3-yl)propyl)piperazin-1-yl)-1,6-naphthyridin-2- Ethyl acetate
Figure PCTCN2016090985-appb-000014
Figure PCTCN2016090985-appb-000014
本步骤标题化合物按照实施例1步骤3的方法制备得到，即将4-(2-(2-乙氧基-2-氧代乙氧基)-1,6-萘啶-5-基)哌嗪-1-甲酸叔丁酯(300mg,0.72mmol)和氯化氢的乙酸乙酯溶液(4M,2mL)在二氯甲烷(10mL)中反应所得的盐酸盐固体与3-(3-氯丙基)-1H-吲哚-5-甲腈(158mg,0.72mmol)、碘化钾(12mg,0.07mmol)和碳酸钠(229mg,2.16mmol)在乙腈(15mL)中反应制备得到粗品，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淡黄色固体(230mg,64.1％)。The title compound of this step is prepared according to the method of the step 3 of Example 1, that is, 4-(2-(2-ethoxy-2-oxoethoxy)-1,6-naphthyridin-5-yl)piperazine The hydrochloride salt solid and 3-(3-chloropropyl) were obtained by reacting tert-butyl-l-carboxylate (300 mg, 0.72 mmol) and ethyl acetate in ethyl acetate (4M, 2 mL) in dichloromethane (10 mL) -1H-indole-5-carbonitrile (158 mg, 0.72 mmol), potassium iodide (12 mg, 0.07 mmol) and sodium carbonate (229 mg, 2.16 mmol). Purification (methylene chloride / MeOH (v/v) = 50/1)
MS(ESI,pos.ion)m/z:498.9(M+H)；MS (ESI, pos.) m/z: 498.9 (M+H);
1H NMR(CDCl3,600MHz)δ(ppm):8.54(s,1H),8.22(d,J＝5.4Hz,1H),7.98(s,1H),7.89(d,J＝9.6Hz,1H),7.39(s,2H),7.12(s,1H),6.65(d,J＝9.6Hz,1H),6.58(d,J＝6.0Hz,1H),5.00(s,2H),4.24(d,J＝6.6Hz,2H),3.39(t,J＝4.8Hz,4H),2.81(t,J＝6.6Hz,2H),2.68(t,J＝4.8Hz,4H),2.52(brs,2H),1.96(t,J＝6.6Hz,2H),1.28(t,J＝6.6Hz,3H)； 1 H NMR (CDCl 3 , 600 MHz) δ (ppm): 8.54 (s, 1H), 8.22 (d, J = 5.4 Hz, 1H), 7.78 (s, 1H), 7.89 (d, J = 9.6 Hz, 1H) ), 7.39 (s, 2H), 7.12 (s, 1H), 6.65 (d, J = 9.6 Hz, 1H), 6.58 (d, J = 6.0 Hz, 1H), 5.00 (s, 2H), 4.24 (d) , J = 6.6 Hz, 2H), 3.39 (t, J = 4.8 Hz, 4H), 2.81 (t, J = 6.6 Hz, 2H), 2.68 (t, J = 4.8 Hz, 4H), 2.52 (brs, 2H) ), 1.96 (t, J = 6.6 Hz, 2H), 1.28 (t, J = 6.6 Hz, 3H);
13C NMR(CDCl3,150MHz)δ(ppm):167.8,161.9,161.8,148.3,146.9,138.1,136.8,127.6,124.9,124.8,123.5,121.0,120.0,117.3,112.1,107.5,103.5,102.3,62.1,58.1,53.3,51.4,44.0,27.2,22.6,14.2. 13 C NMR (CDCl 3 , 150 MHz) δ (ppm): 167.8, 161.9, 161.8, 148.3, 146.9, 138.1, 136.8, 127.6, 124.9, 124.8, 123.5, 121.0, 120.0, 117.3, 112.1, 107.5, 103.5, 102.3, 62.1, 58.1, 53.3, 51.4, 44.0, 27.2, 22.6, 14.2.
实施例5 2-((5-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)-1,6-萘啶-2-基)氧基)乙酰胺Example 5 2-((5-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-1,6-naphthyridin-2- Ethyloxyacetamide
Figure PCTCN2016090985-appb-000015
Figure PCTCN2016090985-appb-000015
步骤1)2-((5-氯-1,6-萘啶-2-基)氧基)乙酰胺的合成Step 1) Synthesis of 2-((5-chloro-1,6-naphthyridin-2-yl)oxy)acetamide
将2-((5-氯-1,6-萘啶-2-基)氧基)乙酸乙酯(800mg,3.00mmol)加入到氨甲醇溶液(20mL)中，反应液置于常温下反应12小时后，直接减压浓缩得粗品，粗品经硅胶柱层析(二氯甲烷/甲醇(v/v)＝30/1)纯化得到标题化合物为白色固体(642mg,90.0％)。2-((5-Chloro-1,6-naphthyridin-2-yl)oxy)acetic acid ethyl acetate (800 mg, 3.00 mmol) was added to a solution of ammonia methanol (20 mL), and the reaction mixture was allowed to react at room temperature 12 After </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI>
MS(ESI,pos.ion)m/z:238.1(M+H)； MS (ESI, pos.) m/z: 238.1 (M+H);
1H NMR(DMSO-d6,600MHz)δ(ppm):8.36(d,J＝6.0Hz,1H),8.14(d,J＝9.8Hz,1H),7.75(s,1H),7.35(d,J＝5.8Hz,2H),6.82(d,J＝9.8Hz,1H),4.87(s,2H). 1 H NMR (DMSO-d 6 , 600MHz) δ (ppm): 8.36 (d, J = 6.0Hz, 1H), 8.14 (d, J = 9.8Hz, 1H), 7.75 (s, 1H), 7.35 (d , J = 5.8 Hz, 2H), 6.82 (d, J = 9.8 Hz, 1H), 4.87 (s, 2H).
步骤2)4-(2-(2-氨基-2-氧代乙氧基)-1,6-萘啶-5-基)哌嗪-1-甲酸叔丁酯的合成Step 2) Synthesis of tert-butyl 4-(2-(2-amino-2-oxoethoxy)-1,6-naphthyridin-5-yl)piperazine-1-carboxylate
本步骤标题化合物按照实施例1步骤2的方法制备得到，即将2-((5-氯-1,6-萘啶-2-基)氧基)乙酰胺(640mg,2.69mmol)、哌嗪-1-甲酸叔丁酯(225mg,2.96mmol)和碳酸钠(428mg,4.04mmol)在乙腈中(10mL)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)＝10/1)纯化得到标题化合物为浅黄色固体(835mg,80.3％)。The title compound of this step was obtained according to the procedure of Step 2 of Example 1, that is, 2-((5-chloro-1,6-naphthyridin-2-yl)oxy)acetamide (640 mg, 2.69 mmol), piperazine- The crude product was obtained by the reaction of t-butyl 1-carboxylate (225 mg, 2.96 mmol) and sodium carbonate (428 mg, 4.04 mmol) in acetonitrile (10 mL). The title compound was obtained as a pale yellow solid (835 mg, 80.3%).
MS(ESI,pos.ion)m/z:388.2(M+H)；MS (ESI, pos.) m/z: 388.2 (M+H);
1H NMR(DMSO-d6,600MHz)δ(ppm):8.32(d,J＝6.0Hz,1H),8.10(d,J＝9.8Hz,1H),7.72(s,1H),7.35(d,J＝6.0Hz,2H),6.82(d,J＝9.8Hz,1H),4.89(s,2H),3.63-3.58(m,4H),3.04(brs,4H),1.50(s,9H). 1 H NMR (DMSO-d 6 , 600MHz) δ (ppm): 8.32 (d, J = 6.0Hz, 1H), 8.10 (d, J = 9.8Hz, 1H), 7.72 (s, 1H), 7.35 (d , J=6.0 Hz, 2H), 6.82 (d, J=9.8 Hz, 1H), 4.89 (s, 2H), 3.63-3.58 (m, 4H), 3.04 (brs, 4H), 1.50 (s, 9H) .
步骤3)2-((5-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)-1,6-萘啶-2-基)氧基)乙酰胺的合成Step 3) 2-((5-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-1,6-naphthyridin-2- Synthesis of acetoxy)acetamide
本步骤标题化合物按照实施例1步骤3的方法制备得到，即将4-(2-(2-氨基-2-氧代乙氧基)-1,6-萘啶-5-基)哌嗪-1-甲酸叔丁酯(400mg,1.03mmol)和氯化氢的乙酸乙酯溶液(4M,2mL)在二氯甲烷(10mL)中反应所得的盐酸盐固体与3-(4-氯丁基)-1H-吲哚-5-甲腈(240mg,1.03mmol)、碘化钾(17mg,0.10mmol)和碳酸钠(328mg,3.10mmol)在乙腈(15mL)中反应制备得到粗品，粗品经硅胶柱层析(二氯甲烷/甲醇(v/v)＝30/1)纯化得到标题化合物为淡黄色固体(390mg,78.1％)。The title compound of this step was prepared according to the method of Step 3 of Example 1, that is, 4-(2-(2-amino-2-oxoethoxy)-1,6-naphthyridin-5-yl)piperazine-1. -Hydrate tert-butyl ester (400 mg, 1.03 mmol) and a solution of hydrogen chloride in ethyl acetate (4M, 2 mL). - 吲哚-5-carbonitrile (240 mg, 1.03 mmol), potassium iodide (17 mg, 0.10 mmol) and sodium carbonate ( 328 mg, 3.10 mmol). Purification of chloromethane/methanol (v/v) = 30/1)
MS(ESI,pos.ion)m/z:484.9(M+H)；MS (ESI, pos.) m/z: 484.9 (M+H);
1H NMR(DMSO-d6,600MHz)δ(ppm):11.37(s,1H),8.19(d,J＝6.0Hz,1H),8.07(s,1H),7.92(d,J＝9.8Hz,1H),7.71(s,1H),7.50(d,J＝8.4Hz,1H),7.39(dd,J＝8.4,1.3Hz,1H),7.34(d,J＝1.6Hz,1H),7.30(s,1H),6.87(d,J＝6.1Hz,1H),6.60(d,J＝9.8Hz,1H),4.82(s,2H),3.30-3.20(m,4H),2.78-2.72(m,2H),2.76-2.64(m,4H),2.54(brs,2H),1.70-1.65(m,2H),1.58-1.54(m,2H)； 1 H NMR (DMSO-d 6 , 600MHz) δ (ppm): 11.37 (s, 1H), 8.19 (d, J = 6.0Hz, 1H), 8.07 (s, 1H), 7.92 (d, J = 9.8Hz , 1H), 7.71 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.4, 1.3 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.30 (s, 1H), 6.87 (d, J = 6.1 Hz, 1H), 6.60 (d, J = 9.8 Hz, 1H), 4.82 (s, 2H), 3.30-3.20 (m, 4H), 2.78-2.72 ( m, 2H), 2.76-2.64 (m, 4H), 2.54 (brs, 2H), 1.70-1.65 (m, 2H), 1.58-1.54 (m, 2H);
13C NMR(DMSO-d6,150MHz)δ(ppm):168.8,161.5,161.2,147.9,147.4,138.5,136.5,127.5,125.4,124.7,124.0,121.4,120.4,116.3,113.1,107.0,105.2,100.6,57.7,52.8,51.0,49.1,44.9,28.0,24.5. 13 C NMR (DMSO-d 6 , 150 MHz) δ (ppm): 168.8, 161.5, 161.2, 147.9, 147.4, 138.5, 136.5, 127.5, 125.4, 124.7, 124.0, 121.4, 120.4, 116.3, 113.1, 107.0, 105.2, 100.6, 57.7, 52.8, 51.0, 49.1, 44.9, 28.0, 24.5.
实施例6 2-((5-(4-(3-(5-氰基-1H-吲哚-3-基)丙基)哌嗪-1-基)-1,6-萘啶-2-基)氧基)乙酰胺Example 6 2-((5-(4-(3-(5-Cyano-1H-indol-3-yl)propyl)piperazin-1-yl)-1,6-naphthyridin-2- Ethyloxyacetamide
Figure PCTCN2016090985-appb-000016
Figure PCTCN2016090985-appb-000016
本步骤标题化合物按照实施例1步骤3的方法制备得到，即将4-(2-(2-氨基-2-氧代乙氧基)-1,6-萘啶-5-基)哌嗪-1-甲酸叔丁酯(400mg,1.03mmol)和氯化氢的乙酸乙酯溶液(4M,2mL)在二氯甲烷(10mL)中反应所得的盐酸盐固体与3-(3-氯丙基)-1H-吲哚-5-甲腈(226mg,1.03mmol)、碘化钾(17mg,0.10mmol)和碳酸钠(328mg,3.10mmol)在乙腈(15mL)中反应制备得到粗品，粗品经硅胶柱层析(二氯甲烷/甲醇(v/v)＝30/1)纯化得到标题化合物为淡黄色固体(380mg,78.4％)。 The title compound of this step was prepared according to the method of Step 3 of Example 1, that is, 4-(2-(2-amino-2-oxoethoxy)-1,6-naphthyridin-5-yl)piperazine-1. -Hydrate tert-butyl ester (400 mg, 1.03 mmol) and a solution of hydrogen chloride in ethyl acetate (4M, 2 mL). - 吲哚-5-carbonitrile (226 mg, 1.03 mmol), potassium iodide (17 mg, 0.10 mmol) and sodium carbonate ( 328 mg, 3.10 mmol). Purification of chloromethane/methanol (v/v) = 30/1)
MS(ESI,pos.ion)m/z:470.3(M+H)；MS (ESI, pos.) m/z: 470.3 (M+H);
1H NMR(DMSO-d6,600MHz)δ(ppm):11.39(s,1H),8.19(d,J＝6.0Hz,1H),8.10(s,1H),7.93(d,J＝9.6Hz,1H),7.70(s,1H),7.50(d,J＝8.4Hz,1H),7.40(dd,J＝8.4,1.2Hz,1H),7.35(d,J＝1.8Hz,1H),7.29(s,1H),6.85(d,J＝6.0Hz,1H),6.60(d,J＝9.6Hz,1H),4.81(s,2H),3.25(t,J＝4.8Hz,4H),2.75(t,J＝7.2Hz,2H),2.55(t,J＝4.8Hz,4H),2.41(t,J＝6.6Hz,2H),1.91-1.76(m,2H)； 1 H NMR (DMSO-d 6 , 600MHz) δ (ppm): 11.39 (s, 1H), 8.19 (d, J = 6.0Hz, 1H), 8.10 (s, 1H), 7.93 (d, J = 9.6Hz , 1H), 7.70 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 8.4, 1.2 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.29 (s, 1H), 6.85 (d, J = 6.0 Hz, 1H), 6.60 (d, J = 9.6 Hz, 1H), 4.81 (s, 2H), 3.25 (t, J = 4.8 Hz, 4H), 2.75 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 4.8 Hz, 4H), 2.41 (t, J = 6.6 Hz, 2H), 1.91-1.76 (m, 2H);
13C NMR(DMSO-d6,150MHz)δ(ppm):168.3,161.1,161.0,147.5,147.0,138.0,136.1,127.2,125.0,124.3,123.6,121.0,119.8,115.8,112.6,106.5,104.6,100.2,57.4,52.8,51.2,44.5,27.1,22.0. 13 C NMR (DMSO-d 6 , 150 MHz) δ (ppm): 168.3, 161.1, 161.0, 147.5, 147.0, 138.0, 136.1, 127.2, 125.0, 124.3, 123.6, 121.0, 119.8, 115.8, 112.6, 106.5, 104.6, 100.2, 57.4, 52.8, 51.2, 44.5, 27.1, 22.0.
实施例7 2-((5-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)-1,6-萘啶-2-基)氧基)乙酸Example 7 2-((5-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-1,6-naphthyridin-2- Alkyloxyacetic acid
Figure PCTCN2016090985-appb-000017
Figure PCTCN2016090985-appb-000017
将2-((5-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1-基)-1,6-萘啶-2-基)氧基)乙酸乙酯(250mg,0.49mmol)溶于甲醇(10mL)中，并加入碳酸铯(238mg,0.73mmol)。反应液逐渐升高温度到60℃，反应24小时后，减压蒸馏除去溶剂。残留液用稀盐酸调节pH至2～3，然后用二氯甲烷萃取(10mL×3)。有机相用无水硫酸钠干燥，过滤，并减压浓缩得到粗品，粗品经硅胶柱层析(二氯甲烷/甲醇(v/v)＝10/1)纯化得到标题化合物为浅黄色固体(182mg,77.1％)。2-((5-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)-1,6-naphthyridin-2-yl) Ethyl acetate (250 mg, 0.49 mmol) was dissolved in MeOH (10 mL) and EtOAc (EtOAc, EtOAc, The reaction liquid was gradually elevated to 60 ° C, and after reacting for 24 hours, the solvent was distilled off under reduced pressure. The residual liquid was adjusted to pH 2-3 with dilute hydrochloric acid and then extracted with dichloromethane (10 mL×3). The organic phase was dried over anhydrous sodium sulfate EtOAcjjjjjjjjjj , 77.1%).
MS(ESI,pos.ion)m/z:484.9(M+H)；MS (ESI, pos.) m/z: 484.9 (M+H);
1HNMR(CD3OD,600MHz)δ(ppm):8.25(d,J＝6.2Hz,1H),8.08(d,J＝9.8Hz,1H),7.99(s,1H),7.45(d,J＝8.4Hz,1H),7.34(dd,J＝8.4,1.4Hz,1H),7.26(s,1H),7.08(d,J＝6.2Hz,1H),6.69(d,J＝9.8Hz,1H),5.05(s,2H),3.86-3.55(m,4H),3.38(brs,4H),3.29-3.22(m,2H),2.86(t,J＝6.8Hz,2H),1.90-1.79(m,4H)； 1 H NMR (CD 3 OD, 600 MHz) δ (ppm): 8.25 (d, J = 6.2 Hz, 1H), 8.08 (d, J = 9.8 Hz, 1H), 7.99 (s, 1H), 7.45 (d, J) = 8.4 Hz, 1H), 7.34 (dd, J = 8.4, 1.4 Hz, 1H), 7.26 (s, 1H), 7.08 (d, J = 6.2 Hz, 1H), 6.69 (d, J = 9.8 Hz, 1H) ), 5.05 (s, 2H), 3.86-3.55 (m, 4H), 3.38 (brs, 4H), 3.29-3.22 (m, 2H), 2.86 (t, J = 6.8 Hz, 2H), 1.90 - 1.79 ( m, 4H);
13C NMR(CD3OD,150MHz)δ(ppm):169.4,162.3,159.8,147.2,147.1,138.6,136.3,127.2,124.6,123.9,123.7,120.7,120.2,115.4,112.1,108.0,105.6,100.7,56.8,51.5,48.3,43.6,26.9,23.8,23.3. 13 C NMR (CD 3 OD, 150 MHz) δ (ppm): 169.4, 162.3, 159.8, 147.2, 147.1, 138.6, 136.3, 127.2, 124.6, 123.9, 123.7, 120.7, 120.2, 115.4, 112.1, 108.0, 105.6, 100.7 , 56.8, 51.5, 48.3, 43.6, 26.9, 23.8, 23.3.
实施例8 2-((5-(4-(3-(5-氰基-1H-吲哚-3-基)丙基)哌嗪-1-基)-1,6-萘啶-2-基)氧基)乙酸Example 8 2-((5-(4-(3-(5-Cyano-1H-indol-3-yl)propyl)piperazin-1-yl)-1,6-naphthyridin-2- Alkyloxyacetic acid
Figure PCTCN2016090985-appb-000018
Figure PCTCN2016090985-appb-000018
本步骤标题化合物按照实施例7的方法制备得到，即将2-((5-(4-(3-(5-氰基-1H-吲哚-3-基)丙基)哌嗪-1-基)-1,6-萘啶-2-基)氧基)乙酸乙酯(250mg,0.50mmol)和碳酸铯(345mg,0.75mmol)在甲醇(10mL)中反应制备得到粗品，粗品经硅胶柱层析(二氯甲烷/甲醇(v/v)＝10/1)纯化得到标题化合物为浅黄色固体(186mg,78.9％)。The title compound of this step was obtained according to the method of Example 7, that is, 2-((5-(4-(3-(5- cyano-1H-indol-3-yl)propyl)piperazin-1-yl) Ethyl acetate-1,6-naphthyridin-2-yl)oxy) (250 mg, 0.50 mmol) and yttrium carbonate (345 mg, 0.75 mmol). Purification (methylene chloride / MeOH (v/v) = 10/1)
MS(ESI,pos.ion)m/z:471.3(M+H)；MS (ESI, pos.) m/z: 471.3 (M+H);
1H NMR(CD3OD,600MHz)δ(ppm):8.27(d,J＝6.1Hz,1H),8.13(d,J＝9.8Hz,1H),8.07(s,1H),7.50(d,J＝ 8.4Hz,1H),7.39(dd,J＝8.4,1.2Hz,1H),7.35(s,1H),7.08(d,J＝6.1Hz,1H),6.72(d,J＝9.8Hz,1H),5.06(s,2H),3.84-3.60(m,4H),3.50-3.30(m,4H),3.29(d,J＝5.0Hz,2H),2.94(t,J＝7.3Hz,2H),2.29-2.19(m,2H)； 1 H NMR (CD 3 OD, 600 MHz) δ (ppm): 8.27 (d, J = 6.1 Hz, 1H), 8.13 (d, J = 9.8 Hz, 1H), 8.07 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.4, 1.2 Hz, 1H), 7.35 (s, 1H), 7.08 (d, J = 6.1 Hz, 1H), 6.72 (d, J = 9.8 Hz, 1H), 5.06 (s, 2H), 3.84 - 3.60 (m, 4H), 3.50-3.30 (m, 4H), 3.29 (d, J = 5.0 Hz, 2H), 2.94 (t, J = 7.3 Hz, 2H) ), 2.29-2.19 (m, 2H);
13C NMR(CD3OD,150MHz)δ(ppm):169.6,161.4,160.4,148.1,147.2,138.5,136.6,127.3,125.8,124.7,124.2,121.4,120.7,114.8,113.2,107.2,105.9,100.8,56.0,51.3,49.0,48.4,24.4,22.0. 13 C NMR (CD 3 OD, 150 MHz) δ (ppm): 169.6, 161.4, 160.4, 148.1, 147.2, 138.5, 136.6, 127.3, 125.8, 124.7, 124.2, 121.4, 120.7, 114.8, 113.2, 107.2, 105.9, 100.8 , 56.0, 51.3, 49.0, 48.4, 24.4, 22.0.
生物试验Biological test
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Example A: Evaluation of the affinity of compounds for CHO cell transfected humanized 5-HT transporters
实验方法experimental method
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。A mixed system of cell membrane homogenate protein (12 μg), 2 nM [ 3 H] imipramine, and buffer (50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KCl, and 0.1% BSA) at 22 °C The test compound was added or not added for a total of 60 minutes.
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。And in a mixed system of the above conditions, 10 μM of imipramine was added for measurement of non-specific binding value.
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。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.
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。The standard reference compound was imipramine, and a competitive curve was obtained by a series of experimental tests to calculate the IC 50 .
在一些实施例中，本发明化合物对人源5-HT转运体(SERT)的IC50值小于10nM，在另一些实施例中本发明化合物对人源5-HT转运体(SERT)的IC50值小于1nM；具体的，本发明实施例1制备得到的化合物的IC50值为2.03nM，本发明实施例2制备得到的化合物的IC50值为0.61nM。In some embodiments, the compounds of the invention IC on human 5-HT transporter (the SERT) 50 values less than 10 nM, in other embodiments, the compounds of the invention IC on human 5-HT transporter (the SERT) 50 The value is less than 1 nM; specifically, the compound prepared in Example 1 of the present invention has an IC 50 value of 2.03 nM, and the compound prepared in Example 2 of the present invention has an IC 50 value of 0.61 nM.
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。The experimental results show that the compound of the present invention has a strong affinity for a human 5-HT transporter (SERT).
实施例B：h5-HT1A受体结合亲和力试验Example B: h5-HT 1A receptor binding affinity test
实验方法experimental method
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。Human membrane was homogenized (36 μg 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 μg / ml aprotinine) in a mixed system, with or without the addition of test compounds, for a total of 60 minutes.
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。The standard reference compound was 8-OH-DPAT, and 10 μM 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.
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。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.
数据分析data analysis
[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。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.
在一些实施例中，本发明化合物与h5-HT1A受体结合的Ki值小于15nM，在另一些实施例中本发明化 合物与h5-HT1A受体结合的Ki值小于1nM；具体的，本发明实施例1制备得到的化合物的Ki值为0.31nM，本发明实施例2制备得到的化合物的Ki值为13.2nM。In some embodiments, the compound of the invention binds to the h5-HT 1A receptor with a Ki value of less than 15 nM, and in other embodiments, the compound of the invention binds to the h5-HT 1A receptor with a Ki value of less than 1 nM; The compound prepared in Inventive Example 1 had a Ki value of 0.31 nM, and the compound prepared in Example 2 of the present invention had a Ki value of 13.2 nM.
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。The experimental results show that the compound of the present invention has strong binding affinity to the 5-HT 1A receptor.
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。In the description of the present specification, a description with reference to the terms "one embodiment", "an embodiment", "some embodiments", "example", "specific example" or "some examples", etc. Specific features, structures, materials, or characteristics described in the embodiments or examples are included in at least one embodiment, embodiment, or example of the invention. In the present specification, the schematic representation of the above terms is not necessarily directed to the same embodiment, embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments, embodiments or examples. In addition, various embodiments, embodiments, or examples described in the specification, and features of various embodiments, embodiments, or examples may be combined and combined.
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。 Although the embodiments of the present invention have been shown and described, it is understood that the above-described embodiments are illustrative and are not to be construed as limiting the scope of the invention. The embodiments are subject to variations, modifications, substitutions and variations.

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它的前药，a compound which is a stereoisomer, a tautomer, an oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of the formula (I) or a compound of the formula (I). Or its prodrug,
    Figure PCTCN2016090985-appb-100001
    Figure PCTCN2016090985-appb-100001
    其中：among them:
    X为CR2或N；X is CR 2 or N;
    W为CR3或N；W is CR 3 or N;
    V为CR4或N；V is CR 4 or N;
    U为CR5或N；U is CR 5 or N;
    前提条件是X、W、V和U中最多两个同时为N；The precondition is that at most two of X, W, V and U are N at the same time;
    各R1和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；Each of R 1 and R a is independently 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 ;
    各R2、R3、R4、R5和Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-C(＝O)NH2、-COOH、-C(＝O)CH3、-C(＝O)OCH3、-O-(CH2)p-C(＝O)NH2、-O-(CH2)p-C(＝O)OH、-O-(CH2)p-C(＝O)-(C1-C6烷基)、-O-(CH2)p-C(＝O)-(C1-C6烷氧基)、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)CH3、-C(＝O)OCH3、-O-(CH2)p-C(＝O)NH2、-O-(CH2)p-C(＝O)OH、-O-(CH2)p-C(＝O)-(C1-C6烷基)、-O-(CH2)p-C(＝O)-(C1-C6烷氧基)、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；Each of R 2 , R 3 , R 4 , R 5 and R b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -C ( =O)NH 2 , -COOH, -C(=O)CH 3 , -C(=O)OCH 3 , -O-(CH 2 ) p -C(=O)NH 2 , -O-(CH 2 ) p -C(=O)OH, -O-(CH 2 ) p -C(=O)-(C 1 -C 6 alkyl), -O-(CH 2 ) p -C(=O)- (C 1 -C 6 alkoxy), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy a heterocyclic group consisting of a C 1 -C 6 haloalkoxy group, a C 3 -C 8 cycloalkyl group, a 3 to 10 ring atom, a C 6 -C 10 aryl group or a 5-10 ring atom a group wherein -C(=O)CH 3 , -C(=O)OCH 3 , -O-(CH 2 ) p -C(=O)NH 2 , -O-(CH 2 ) p -C (=O)OH, -O-(CH 2 ) p -C(=O)-(C 1 -C 6 alkyl), -O-(CH 2 ) p -C(=O)-(C 1 - C 6 alkoxy), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 8 cycloalkyl, heterocyclic group of 3-10 ring atoms, C 6 -C 10 aryl group and heteroaryl group of 5-10 ring atoms independently The ground is replaced by one or more R w ;
    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)-；Each R w is independently D, F, Cl, Br, I, -NO 2 , -CN, -N 3 , -NH 2 , -OH, -SH, oxo (=O), C 1 -C 4 alkane , C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkane Amino, C 1 -C 4 alkylthio, NH 2 -(C 1 -C 4 alkylene)-, HO-(C 1 -C 4 alkylene)-, HS-(C 1 -C 4 alkylene Base)-, (C 1 -C 4 alkoxy)-(C 1 -C 4 alkylene)-, (C 1 -C 4 alkylamino)-(C 1 -C 4 alkylene)-, ( C 1 -C 4 alkylthio)-(C 1 -C 4 alkylene)-, C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)-(C 1 -C 4 alkylene a heterocyclic group consisting of 3-7 ring atoms, (heterocyclic group consisting of 3-7 ring atoms)-(C 1 -C 4 alkylene)-, phenyl, phenyl-(C 1 -C 4 alkylene)-, heteroaryl group of 5-6 ring atoms or (heteroaryl group of 5-6 ring atoms)-(C 1 -C 4 alkylene)-;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;
    r为0、1或2；和r is 0, 1 or 2; and
    p为1、2、3或4。 p is 1, 2, 3 or 4.
  2. 根据权利要求1所述的化合物，其中各R1和Ra独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基，其中所述C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基和C1-C4卤代烷氧基独立任选地被一个或多个Rw所取代。The compound according to claim 1, wherein each of R 1 and R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, C 1 -C 4 An alkyl group, a C 1 -C 4 haloalkyl group, a C 1 -C 4 alkoxy group or a C 1 -C 4 haloalkoxy group, wherein said C 1 -C 4 alkyl group, C 1 -C 4 haloalkyl group, C 1 The -C 4 alkoxy group and the C 1 -C 4 haloalkoxy group are each independently optionally substituted by one or more R w .
  3. 根据权利要求1所述的化合物，其中各R1和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。The compound according to claim 1, wherein each of R 1 and R a is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, methyl, ethyl , n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CF 3 or -OCF 3 .
  4. 根据权利要求1所述的化合物，其中各R2、R3、R4、R5和Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-C(＝O)NH2、-COOH、-C(＝O)CH3、-C(＝O)OCH3、-O-(CH2)p-C(＝O)NH2、-O-(CH2)p-C(＝O)OH、-O-(CH2)p-C(＝O)-(C1-C4烷基)、-O-(CH2)p-C(＝O)-(C1-C4烷氧基)、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、5-6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)CH3、-C(＝O)OCH3、-O-(CH2)p-C(＝O)NH2、-O-(CH2)p-C(＝O)OH、-O-(CH2)p-C(＝O)-(C1-C4烷基)、-O-(CH2)p-C(＝O)-(C1-C4烷氧基)、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、5-6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。The compound according to claim 1, wherein each of R 2 , R 3 , R 4 , R 5 and R b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -C(=O)NH 2 , -COOH, -C(=O)CH 3 , -C(=O)OCH 3 , -O-(CH 2 ) p -C(=O NH 2 , -O-(CH 2 ) p -C(=O)OH, -O-(CH 2 ) p -C(=O)-(C 1 -C 4 alkyl), -O-(CH 2 ) p -C(=O)-(C 1 -C 4 alkoxy), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 Haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 3 -C 6 cycloalkyl, heterocyclic group consisting of 5-6 ring atoms, phenyl or 5-6 rings a heteroaryl group composed of atoms, wherein -C(=O)CH 3 , -C(=O)OCH 3 , -O-(CH 2 ) p -C(=O)NH 2 , -O-(CH 2 ) p -C(=O)OH, -O-(CH 2 ) p -C(=O)-(C 1 -C 4 alkyl), -O-(CH 2 ) p -C(=O) -(C 1 -C 4 alkoxy), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkane An oxy group, a C 1 -C 4 haloalkoxy group, a C 3 -C 6 cycloalkyl group, a heterocyclic group consisting of 5 to 6 ring atoms, a phenyl group and a heteroaryl group consisting of 5 to 6 ring atoms are independently optional. Ground cover A plurality of R w substituted.
  5. 根据权利要求1所述的化合物，其中各R2、R3、R4、R5和Rb独立地为H、D、F、Cl、Br、I、-CN、-NO2、-NH2、-OH、-SH、-C(＝O)NH2、-COOH、-C(＝O)CH3、-C(＝O)OCH3、-O-CH2-C(＝O)NH2、-O-(CH2)2-C(＝O)NH2、-O-CH2-C(＝O)OH、-O-(CH2)2-C(＝O)OH、-O-CH2-C(＝O)CH3、-O-CH2-C(＝O)CH2CH3、-O-CH2-C(＝O)CH(CH3)2、-O-(CH2)2-C(＝O)CH3、-O-(CH2)2-C(＝O)CH2CH3、-O-(CH2)2-C(＝O)CH(CH3)2、-O-CH2-C(＝O)OCH3、-O-CH2-C(＝O)OCH2CH3、-O-CH2-C(＝O)OCH(CH3)2、-O-(CH2)2-C(＝O)OCH3、-O-(CH2)2-C(＝O)OCH2CH3、-O-(CH2)2-C(＝O)OCH(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。The compound according to claim 1, wherein each of R 2 , R 3 , R 4 , R 5 and R b is independently H, D, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -SH, -C(=O)NH 2 , -COOH, -C(=O)CH 3 , -C(=O)OCH 3 , -O-CH 2 -C(=O)NH 2 , -O-(CH 2 ) 2 -C(=O)NH 2 , -O-CH 2 -C(=O)OH, -O-(CH 2 ) 2 -C(=O)OH, -O- CH 2 -C(=O)CH 3 , -O-CH 2 -C(=O)CH 2 CH 3 , -O-CH 2 -C(=O)CH(CH 3 ) 2 , -O-(CH 2 ) 2 -C(=O)CH 3 , -O-(CH 2 ) 2 -C(=O)CH 2 CH 3 , -O-(CH 2 ) 2 -C(=O)CH(CH 3 ) 2 , -O-CH 2 -C(=O)OCH 3 , -O-CH 2 -C(=O)OCH 2 CH 3 , -O-CH 2 -C(=O)OCH(CH 3 ) 2 , -O-(CH 2 ) 2 -C(=O)OCH 3 , -O-(CH 2 ) 2 -C(=O)OCH 2 CH 3 , -O-(CH 2 ) 2 -C(=O) OCH(CH 3 ) 2 , methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CF 3 , -CH 2 CF 3 , -OCF 3 , -OCH 2 CF 3 or -OCH 2 CF 2 CHF 2 .
  6. 根据权利要求1-5任意一项所述的化合物，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它的前药：The compound according to any one of claims 1 to 5, which is a stereoisomer, a tautomer, an oxynitride, a solvate of a compound having one of the following structures or a compound having one of the following structures; Metabolite, pharmaceutically acceptable salt or its prodrug:
    Figure PCTCN2016090985-appb-100002
    Figure PCTCN2016090985-appb-100002
    Figure PCTCN2016090985-appb-100003
    Figure PCTCN2016090985-appb-100003
  7. 一种药物组合物，包含权利要求1-6任意一项所述的化合物；和A pharmaceutical composition comprising the compound of any of claims 1-6;
    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、佐剂或它们的任意组合。The pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.
  8. 根据权利要求7所述的药物组合物，其进一步地包含治疗中枢神经***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。The pharmaceutical composition according to claim 7, which further comprises a medicament for treating central nervous system dysfunction, wherein said medicament for treating central nervous system dysfunction is amitriptyline, desipramine, mirtazapine, ampoules Fetacrotonone, reboxetine, fluoxetine, trazodone, sertraline, duloxetine, fluvoxamine, milnacipran, levaminatron, desvenlafaxine, vera Oxazolone, venlafaxine, dapoxetine, nefazodone, non-moxetine, clomipramine, citalopram, escitalopram, paroxetine, lithium carbonate, buspirone, ol Nitrogen, quetiapine, risperidone, ziprasidone, aripiprazole, perospirone, clozapine, modafinil, mecamylamine, cabergoline, adamantane, imipramine, Pramipexole, thyroxine, dextromethorphan, quinidine, naltrexone, samidorphan, buprenorphine, melatonin, alprazolam, piperazine, vicipitan, chlordiazepoxide Nai Jing or any combination of them.
  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。Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 8 for the preparation of a medicament for the prevention, treatment or amelioration of central nervous system dysfunction.
  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Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 8 for the preparation of a medicament for inhibiting serotonin reuptake, and/or
    所述药物用于部分激动5-HT1A受体。 The drug is used to partially agonize the 5-HT 1A receptor.
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