WO2021097781A1 - 吡啶亚甲基哌啶衍生物及其用途 - Google Patents

吡啶亚甲基哌啶衍生物及其用途 Download PDF

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WO2021097781A1
WO2021097781A1 PCT/CN2019/120076 CN2019120076W WO2021097781A1 WO 2021097781 A1 WO2021097781 A1 WO 2021097781A1 CN 2019120076 W CN2019120076 W CN 2019120076W WO 2021097781 A1 WO2021097781 A1 WO 2021097781A1
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alkyl
present
compound
group
alkoxy
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PCT/CN2019/120076
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English (en)
French (fr)
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金传飞
钟文和
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广东东阳光药业有限公司
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Priority to PCT/CN2019/120076 priority Critical patent/WO2021097781A1/zh
Priority to CN201980102135.XA priority patent/CN114728929A/zh
Publication of WO2021097781A1 publication Critical patent/WO2021097781A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention belongs to the field of pharmaceutical technology, and specifically relates to novel pyridine methylene piperidine derivatives and pharmaceutical compositions containing these compounds, as well as methods of use and uses thereof.
  • the novel pyridine methylene piperidine derivatives of the present invention can be used to activate 5-HT 1F receptors for the prevention, treatment or alleviation of 5-HT 1F receptor-related diseases, especially bias headache.
  • Migraine is a type of episodic and often unilateral pulsating headache, often accompanied by nausea and vomiting. It is a common chronic neurovascular disease. It usually starts in children and adolescence, and reaches the peak of the disease in the young and middle-aged. It is more common in women, the ratio of male to female patients is about 1:2 to 3, and the prevalence rate in the population is 5% to 10%, often with genetic background.
  • migraine Although migraine is not a fatal disease, it can seriously affect the social life of patients. In the United States, the socio-economic burden caused by migraines is between $1 and $1.7 billion. In our country, there are also a large number of patients with migraine that affect their work, study and life. As the pace of life accelerates, the incidence of migraine is gradually increasing. A recent survey found that about 5.7% of men and 17.6% of women had an average of more than one migraine attack per year. In addition, there are still many people with a genetic predisposition to migraine.
  • migraine The pathogenesis of migraine is complex and diverse, mainly including vascular origin theory, neurogenic theory, trigeminal neurovascular theory, biochemical factors and genetic factors.
  • the drugs used to treat migraine are mainly 5-HT 1B/D receptor agonists triptans, but because triptans can constrict blood vessels, they are contraindicated for patients with cardiovascular and peripheral vascular diseases.
  • 40% to 70% of migraine patients have poor efficacy in the treatment of triptans, and 1/3 of patients with effective initial treatment often encounter headache recurrences.
  • the efficacy of triptans in patients with moderate to severe headaches Significantly reduced.
  • anti-migraine drugs such as calcitonin gene-related peptide (CGRP) receptor antagonists and selective 5-HT 1F receptor agonists have emerged.
  • CGRP receptor antagonists still have many shortcomings. For example, olcagepant can only be used intravenously rather than taken orally. Long-term use of telcagepant can cause increased liver enzymes, and BI-44370 has been discontinued because of its interaction with cytochrome P450. Development. Therefore, there is an urgent need to develop new acute-phase therapeutic drugs. The development of selective 5-HT 1F receptor agonist anti-migraine drugs has always been considered a new and promising approach.
  • Serotonin receptors also known as serotonin receptors or 5-HT receptors
  • 5-HT receptors are a group of G protein-coupled receptors that appear in the center of the central nervous system and around the peripheral nervous system. They can be divided into seven subfamilies5 -HT 1 , 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 respectively mediate different physiological activities.
  • 5-HT 1 receptor is the largest family in the 5-HT receptor family. There are currently five types of 5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 1E and 5-HT 1F Subtype.
  • 5-HT 1F 5-HT 1 receptor subtypes
  • the pharmacological activity shown by the 5-HT 1F receptor is significantly different from any serotonin receptor that has been disclosed. They found that in addition to the above-mentioned strong affinity for 5-HT 1B and 5-HT ID receptors, sumatan also has an affinity for this receptor subtype, with a Ki of about 23 nM. This suggests that the 5-HT 1F receptor may play a role in migraine.
  • 5-HT 1F receptors are mainly expressed in the mesenteric, uterus and brain, but also in various parts of the trigeminal nerve vasculature such as cerebral blood vessels, trigeminal ganglia and trigeminal caudate nucleus, as well as the cerebellum, hippocampus and neocerebral cortex. Like other 5-HT receptors, 5-HT 1F receptors are not only expressed in neurons, but also in glial cells.
  • the activation of the presynaptic 5-HT 1F receptor can inhibit the release of calcitonin gene-related peptide (CGRP) and block neuronal signal transduction in the caudate nucleus of the trigeminal nerve, resulting in an anti-migraine effect, and this selectivity
  • CGRP calcitonin gene-related peptide
  • the inventors After continuous hard research, the inventors have obtained an unexpected new class of selective 5-HT 1F agonists, which have different chemical and receptor binding properties, can inhibit peptide extravasation, and can avoid obvious blood vessels at the same time. Contractile activity, so it can be used to treat migraine and other 5-HT 1F receptor-related diseases. Moreover, the compounds of the present invention have good solubility, and therefore have high adaptability in preferred formulations (such as formulations for sublingual, buccal and/or intranasal administration).
  • the present invention provides a new type of pyridine methylene piperidine derivatives as 5-HT 1F receptor agonists, which can be used to activate 5-HT 1F receptors and inhibit neuronal protein extravasation. Therefore, it can be used It is used to treat diseases mediated by 5-HT 1F receptor, especially for the treatment of migraine.
  • the picolinylidene piperidine derivatives of the present invention have stable properties, good safety, and good pharmacodynamics and pharmacokinetic properties, such as a good brain plasma ratio, Good bioavailability or good metabolic stability, etc. Therefore, it has good clinical application prospects.
  • the present invention also provides methods for preparing such compounds, pharmaceutical compositions containing such compounds, and uses of such compounds and pharmaceutical compositions containing such compounds in preparing medicines.
  • the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of a compound represented by formula (I) , Metabolites, pharmaceutically acceptable salts or its prodrugs,
  • X is N or CR x ;
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by formula (I) disclosed in the present invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.
  • the present invention relates to the use of the compound represented by formula (I) or its pharmaceutical composition disclosed in the present invention in the preparation of medicines for the prevention, treatment or alleviation of 5-HT 1F receptor-related diseases .
  • the disease related to 5-HT 1F receptor is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression Disorders, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder , Attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, excessive appetite, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss or dementia.
  • the present invention relates to the use of the compound represented by formula (I) or its pharmaceutical composition disclosed in the present invention in the preparation of medicines, which are used to activate 5-HT 1F receptors.
  • the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I).
  • any embodiment of any aspect of the present invention can be combined with other embodiments as long as they do not appear contradictory.
  • any technical feature can be applied to the technical feature in other embodiments, as long as they do not conflict.
  • the articles “a”, “an” and “said” used in the present invention are intended to include “at least one” or “one or more”. Therefore, these articles used in the present invention refer to articles of one or more than one (ie, at least one) object.
  • a component refers to one or more components, that is, more than one component may be considered to be adopted or used in the embodiment of the described embodiment.
  • stereoisomers refers to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .
  • chiral molecule refers to a molecule that has the property of not being able to overlap with its mirror image; and "achiral molecule” refers to a molecule that can overlap with its mirror image.
  • enantiomers refers to two isomers of a compound that cannot overlap but are mirror images of each other.
  • racemate or “racemic mixture” refers to an equimolar mixture of two enantiomers which lacks optical activity.
  • diastereomers refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • the prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by a compound, where (-) or l indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called 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 (for example, carbon, etc.) of the compound disclosed in the present invention may exist in a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration form exist.
  • each asymmetric atom has at least 50% enantiomeric excess, 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 present invention can be used as one of the possible isomers or their mixtures, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms).
  • 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 have an E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may have a cis or trans configuration.
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • racemate of any final product or intermediate obtained can be resolved into optical enantiomers by a method familiar to those skilled in the art using known methods, for example, by performing diastereomeric salts of the obtained diastereomers. Separate.
  • the racemic product 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, refer to 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 with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • “Pharmaceutically acceptable” refers to such compounds, raw materials, compositions and/or dosage forms, which are within the scope of reasonable medical judgment and are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions or reasonable The benefit/risk ratio is commensurate with other problems and complications, and is effectively used for the intended purpose.
  • Substituents in the present invention include, but are not limited to D, F, Cl, Br, I, N 3 , -CN, -NO 2 , -NH 2 , -OH, -SH, -COOH, -CONH 2.
  • substituted means that one or more hydrogen atoms in a given structure or group are replaced by a specific substituent. Unless otherwise indicated, a substituent can be substituted at every reasonable substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more specific substituents selected, then the substituents can be substituted at each reasonable position in the structural formula with the same or different substitutions.
  • subject used in the present invention refers to an animal. Typically the animal is a mammal.
  • the subject also refers to primates (such as humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • C 1 -C 6 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • D represents a single deuterium atom.
  • halogen and “halo” are used interchangeably in the present invention and refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • heteroatom refers to O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or on the nitrogen atom in the heterocyclic ring
  • the form in which hydrogen is substituted for example, N (like the N in 3,4-dihydro-2H-pyrrolyl), NH (like the NH in the pyrrolidinyl group) or NR (like the N-substituted pyrrolidinyl group NR, R are the substituents described in the present invention).
  • alkyl or “alkyl group” used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1-20 carbon atoms, wherein the alkyl group may optionally Ground is substituted by one or more substituents described in this invention.
  • the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in another 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 ), etc.
  • alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp 2 double bond, wherein the alkenyl group
  • the group may be optionally substituted with one or more substituents described in the present invention, which includes the positioning of "cis” and “trans”, or the positioning of "E” and "Z”.
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted by one or more substituents described in the present invention.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (ie, propynyl, -C ⁇ C -CH 3 ), etc.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-propyloxy, n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (isopropyloxy, 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-butoxy (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.
  • alkylthio means that the alkyl group is connected to the rest of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkylthio group contains 1-12 carbon atoms. In one embodiment, the alkylthio group contains 1-6 carbon atoms; in another embodiment, the alkylthio group contains 1-4 carbon atoms; in another embodiment, the alkylthio group The group contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described in the present invention.
  • alkylthio groups include, but are not limited to, methylthio (MeS, -SCH 3 ), ethylthio (EtS, -SCH 2 CH 3 ), 1-propylthio (n-PrS, n- Propylthio, -SCH 2 CH 2 CH 3 ), 2-propylthio (i-PrS, i-propylthio, -SCH(CH 3 ) 2 ), 1-butylthio (n-BuS, n- Butylthio, -SCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propylthio (i-BuS, i-butylthio, -SCH 2 CH(CH 3 ) 2 ), 2-butyl Sulfuryl (s-BuS, s-butylthio, -SCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propylthio (t-BuS, t-butylthio, -SC(CH 3
  • alkylamino or “alkylamino” includes “N-alkylamino” and “N,N-dialkylamino” in which the amino groups are independently substituted with one or two alkyl groups, respectively, Wherein the alkyl group has the meaning as described in the present invention.
  • Suitable alkylamino groups can be monoalkylamino or dialkylamino. Examples of such include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N, N -Dimethylamino (dimethylamino), N,N-diethylamino (diethylamino) and so on.
  • the alkylamino group is optionally substituted with one or more substituents described in the present invention.
  • hydroxy-substituted alkyl means that the alkyl group is substituted by one or more hydroxy groups, wherein the alkyl group has the meaning as described in the present invention; such examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2,3-dihydroxypropyl, etc.
  • haloalkyl means that an alkyl group is substituted by one or more halogen atoms, where the alkyl group has the meaning as described in the present invention. Examples of this include, but are not limited to, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CHF 2 , -CH 2 CF 3 , -CHFCH 3 , -CH 2 CH 2 F, -CF 2 CH 3 , -CH 2 CF 2 CHF 2 etc. .
  • the C 1 -C 6 haloalkyl group comprises a fluorine-substituted C 1 -C 6 alkyl group; in another embodiment, the C 1 -C 4 haloalkyl group comprises a fluorine-substituted C 1 -C 4 alkyl group ; In yet another embodiment, the C 1 -C 2 haloalkyl group comprises a fluorine-substituted C 1 -C 2 alkyl group.
  • haloalkoxy means that an alkoxy group is substituted by one or more halogen atoms, wherein the alkoxy group has the meaning as described in the present invention. Examples of this include, but are not limited to, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , -OCHFCH 3 , -OCH 2 CH 2 F, -OCF 2 CH 3 , -OCH 2 CF 2 CHF 2 etc.
  • the C 1 -C 6 haloalkoxy group comprises a fluorine-substituted C 1 -C 6 alkoxy group; in another embodiment, the C 1 -C 4 haloalkoxy group comprises a fluorine-substituted C 1 -C 4 alkoxy; in still another embodiment, C 1 -C 2 haloalkoxy containing fluorine-substituted C 1 -C 2 alkoxy.
  • n is an integer, typically describing the number of ring atoms in a molecule, and the number of ring atoms in the molecule is n.
  • a 5-10 membered heteroaryl group means a heteroaryl group composed of 5, 6, 7, 8, 9 or 10 ring atoms.
  • piperidinyl is a heterocyclic group composed of 6 ring atoms or a 6-membered heterocyclic group
  • pyridyl is a heteroaryl group composed of 6 ring atoms or a 6-membered heteroaryl group.
  • Carbocyclic group or "carbocyclic ring” means a monovalent or multivalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms.
  • Carbobicyclic groups include spirocarbonbicyclic groups and fused carbobicyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • carbocyclic groups further include, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl Group, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
  • the carbocyclyl group is optionally substituted with one or more substituents described in the present invention.
  • cycloalkyl means a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms.
  • the bicyclic or tricyclic ring system may include fused rings, bridged rings, and spiro rings.
  • the cycloalkyl group contains 3-10 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in another embodiment, the cycloalkyl group contains 3-6 carbon atoms. carbon atom.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group is optionally substituted with one or more substituents described in this invention.
  • heterocyclic group and “heterocyclic ring” are used interchangeably herein, and both refer to a non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, wherein ,
  • the bicyclic or tricyclic ring system may include fused ring, bridged ring and spiro ring.
  • One or more atoms in the ring are independently replaced by heteroatoms, and the heteroatoms have the meaning as described in the present invention.
  • the heterocyclic group is a monocyclic heterocyclic group composed of 3-8 ring atoms (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, in This S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO 2 , PO, PO 2 ); in another embodiment, the heterocyclic group is composed of 3-6 ring atoms The monocyclic heterocyclic group (2-5 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain Groups like SO, SO 2 , PO, PO 2 ); in another embodiment, the heterocyclic group is a bicyclic heterocyclic group composed of 7-12 ring atoms (4-9 carbon atoms and selected from N, 1-3 heteroatoms of O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO 2 , PO, PO 2 ).
  • the heterocycly composed
  • the heterocyclic group may be a carbon group or a heteroatom group.
  • the sulfur atom of the ring is optionally oxidized to S-oxide
  • the nitrogen atom of the ring is optionally oxidized to N- Oxygen compounds.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, disulfide ring Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Dioxanyl, Dithianyl, Thioxanyl, Homopiperazinyl, Homopiperidin
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like.
  • the heterocyclic group is optionally substituted by one or more substituents described in the present invention.
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring composed of 3-7 atoms.
  • the aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group.
  • aryl can be used interchangeably with the terms "aromatic ring” or "aromatic ring”. Examples of aryl groups may include phenyl, indenyl, naphthyl, and anthracenyl.
  • the aryl group is optionally substituted with one or more substituents described in the present invention.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, in which at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 5-7 atoms.
  • the heteroaryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the heteroaryl group.
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring", “aromatic heterocyclic ring” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described in the present invention.
  • the 5-10 atom heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • 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 (such as 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
  • protecting group refers to when a substituent reacts with other functional groups, it is usually used to block or protect specific functionality.
  • amino protecting group refers to a substituent connected to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, and tert-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to a substituent of a hydroxyl group used to block or protect the functionality of the hydroxyl group.
  • Suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl.
  • Carboxyl protecting group refers to the substituent of the carboxyl group used to block or protect the functionality of the carboxyl group.
  • General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) Phosphonyl) ethyl, nitroethyl, etc.
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters. For example, these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • Metal refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 -Phenylpropylprop
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the quaternary ammonium salt formed by any compound containing the N group.
  • 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.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or mixtures thereof.
  • hydrate refers to the association formed by the solvent molecule being water.
  • hydrate When the solvent is water, the term "hydrate" may be used.
  • a molecule of the compound of the present invention may be combined with a water molecule, such as a monohydrate; in another embodiment, a molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate In another embodiment, a compound molecule of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrate of the present invention retains the bioavailability of the compound in its non-hydrated form.
  • treating any disease or condition, in some embodiments refers to ameliorating the disease or condition (ie, slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treatment” refers to the regulation of the disease or condition physically (e.g., stabilizing the perceptible symptoms) or physiologically (e.g., stabilizing the parameters of the body) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • prevention refers to the reduction of the risk of acquiring a disease or disorder (ie: stopping the development of at least one clinical symptom of the disease in the subject, who may face or predispose to face the disease, but still Did not experience or show symptoms of the disease).
  • the nitrogen oxides of the compounds of the present invention are also included in the scope of the present invention. It can be done by using common oxidants (such as hydrogen peroxide) at elevated temperature, in the presence of acids such as acetic acid, to oxidize the corresponding nitrogen-containing basic substances, or by reacting with peracids in a suitable solvent, such as in dichloromethane , Ethyl acetate or methyl acetate with peracetic acid, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare the nitrogen oxide of the compound of the present invention.
  • common oxidants such as hydrogen peroxide
  • acids such as acetic acid
  • the compound represented by 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 to be treated with it.
  • the salt is not necessarily a pharmaceutically acceptable salt, and may be used for preparing and/or purifying the compound represented by formula (I) and/or for separating the compound represented by formula (I) Enantiomer intermediate.
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. Generally speaking, such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxide, carbonate, bicarbonate, etc.) of Na, Ca, Mg or K, or by reacting These compounds are prepared by reacting the free base form of these compounds 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 suitable base such as hydroxide, carbonate, bicarbonate, etc.
  • 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 in the present invention is also intended to represent the non-isotopically enriched form and the isotopically enriched form of these compounds.
  • the isotope-enriched compound has the structure described by the general formula given in the present invention, except that one or more atoms are replaced by atoms having the selected atomic weight or mass number.
  • Exemplary isotopes that can be introduced into the compounds of the present 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 present invention relates to intermediates for the preparation of compounds represented by formula (I).
  • the present invention provides a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition of the present invention further includes a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
  • the pyridine methylene piperidine derivatives, their pharmaceutically acceptable salts, pharmaceutical preparations and their compositions related to the present invention can be used to activate 5-HT 1F receptors and inhibit neuronal protein extravasation.
  • the treatment of HT 1F receptor-related diseases, especially migraine, has potential applications.
  • the present invention further describes the method of synthesizing the compound.
  • the compounds of the present invention show good biological activity.
  • the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of a compound represented by formula (I) , Metabolites, pharmaceutically acceptable salts or its prodrugs,
  • each of R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 4 , R 5 , R 6 and X has the meaning as described in the present invention.
  • X is N or CR x ; wherein R x has the meaning as described in the present invention.
  • the compound of the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvent of a compound having one of the following structures
  • Compounds, metabolites, pharmaceutically acceptable salts or its prodrugs but not limited to:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by formula (I) disclosed in the present invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.
  • the present invention relates to the use of the compound represented by formula (I) or its pharmaceutical composition disclosed in the present invention in the preparation of medicines for the prevention, treatment or alleviation of 5-HT 1F receptor-related diseases .
  • the disease related to 5-HT 1F receptor is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression Disorders, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder , Attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, excessive appetite, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss or dementia.
  • the 5-HT 1F receptor-related disease is migraine.
  • the present invention relates to the use of the compound represented by formula (I) or its pharmaceutical composition disclosed in the present invention in the preparation of medicines, which are used to activate 5-HT 1F receptors.
  • the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I) or its individual stereoisomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates thereof .
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and/or preventive components.
  • the dosage form of the compound used in the method of the present invention can be determined by the specific compound selected, the type of pharmacokinetic distribution required by the route of administration, and the state of the patient.
  • a preparation suitable for oral, sublingual, intranasal or injection administration is prepared according to a well-known method in the pharmaceutical field, and the preparation contains at least one active compound. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCE (16th ed. 1980).
  • the preparation of the present invention includes the active ingredient (the compound represented by formula (I)), which is usually mixed with excipients, diluted by excipients, or encapsulated in capsules, sachets, paper or other materials.
  • the active ingredient the compound represented by formula (I)
  • excipients the compound represented by formula (I)
  • a container-like carrier When the excipient is used as a diluent, it can be a solid, semi-solid or liquid material, which acts as an excipient, carrier or medium for the active ingredient.
  • the formulation can be a tablet, pill, powder, lozenge, sachet, cachet, elixirs, suspension, emulsion, solution, syrup, aerosol (in a solid or in a liquid medium), containing, for example, up to 10 Ointments, soft and hard capsules, gels, suppositories, sterile injections and sterile encapsulated powders of the weight% active compound.
  • the active compound In the preparation of the formulation, it may be necessary to grind the active compound before mixing with other ingredients to provide a suitable particle size. If the active compound is substantially insoluble, it is usually ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, its particle size is adjusted by grinding to provide a uniform particle size distribution in the formulation, for example, about 40 mesh. In one embodiment of the present invention, the particle size is about 0.1-100 ⁇ m.
  • Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel HCet 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.
  • “Pharmaceutically acceptable excipient” used in the present invention means a pharmaceutically acceptable material, mixture or vehicle related to the consistency of the dosage form or the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would greatly reduce the efficacy of the compound disclosed in the present invention when administered to a patient and/or would result in a drug that is not pharmaceutically acceptable The interaction of the composition.
  • each excipient must be pharmaceutically acceptable, for example, with sufficiently high purity.
  • Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected.
  • pharmaceutically acceptable excipients can be selected according to their specific functions in the composition. For example, certain pharmaceutically acceptable excipients can be selected that can help produce a uniform dosage form. Certain pharmaceutically acceptable excipients can be selected that can help produce a stable dosage form. Certain pharmaceutically acceptable excipients can be selected that help to carry or transport the compound of the invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients can be selected to enhance patient compliance.
  • excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, Polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose.
  • Suitable pharmaceutically acceptable excipients also include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants (such as talc, magnesium stearate and mineral oil), auxiliary Flowing agents, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, Chelating agents, plasticizers, tackifiers, antioxidants, preservatives (such as methyl hydroxybenzoate and propyl hydroxybenzoate), stabilizers, surfactants, and buffers.
  • excipients such as talc, magnesium stearate and mineral oil
  • auxiliary Flowing agents such as talc, magnesium stearate and mineral oil
  • granulating agents such as talc, magnesium stearate and mineral oil
  • auxiliary Flowing agents such as
  • pharmaceutically acceptable carriers may be solid or liquid carriers.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may contain from about 5% to about 95% active ingredient.
  • Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be obtained in the following: A.Gennaro (ed.), Remington 's Pharmaceutical Sciences, 18 th ed, 1990, Mack Publishing Company Co., Easton, Pennsylvania..
  • composition disclosed in the present invention is prepared using techniques and methods known to those skilled in the art. For descriptions of some commonly used methods in this field, please refer to Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the present invention relates to a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed in the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or a combination thereof, the process comprising Mix the various ingredients.
  • the pharmaceutical composition containing the compound disclosed in the present invention can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
  • dosage forms include those suitable for the following routes of administration: (1) Oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, Solutions, emulsions, sachets and cachets; (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.
  • Oral administration such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, Solutions, emulsions, sachets and cachets
  • Parenteral administration such as sterile solutions, suspensions and reconstituted powders
  • Transdermal administration such
  • compositions of the present invention may exist in free form for treatment, or may exist in the form of their pharmaceutically acceptable derivatives if appropriate.
  • pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, and salts of these esters, or can directly or indirectly provide the present invention when administered to patients in need Any additional adducts or derivatives of the compound or its metabolites or residues.
  • the compounds disclosed in the present invention can be formulated into oral dosage forms. In another embodiment, the compounds disclosed in the present invention can be formulated into an inhalation dosage form. In another embodiment, the compounds disclosed in the present invention can be formulated for nasal administration. In yet another embodiment, the compounds disclosed in the present invention can be formulated into a transdermal dosage form. In yet another embodiment, the compounds disclosed in the present invention can be formulated for topical administration.
  • the pharmaceutical composition provided by the present invention can be provided as compressed tablets, developed tablets, chewable lozenges, fast-dissolving tablets, multiple compressed tablets, enteric-coated tablets, sugar-coated or film-coated tablets.
  • Enteric-coated tablets are compressed tablets coated with substances that can resist the action of gastric acid but dissolve or disintegrate in the intestine, thereby preventing the active ingredients from contacting the acidic environment of the stomach.
  • Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate.
  • Sugar-coated tablets are compressed tablets surrounded by sugar coating, which can help to hide unpleasant taste or odor and prevent oxidation of the tablet.
  • Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance.
  • Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating is endowed with the same general characteristics as sugar coating.
  • Multiple compressed tablets are compressed tablets prepared after more than one compression cycle, including multi-layer tablets, compression-coated or dry-coated tablets.
  • Tablet dosage forms can be prepared by the active ingredient in the form of powder, crystals or granules alone or in combination with one or more carriers or excipients described in the present invention.
  • the carriers and excipients include binders and disintegrating agents. Decomposers, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful when forming chewable tablets and lozenges.
  • the pharmaceutical composition provided by the present invention can be provided in a soft capsule or a hard capsule, which can be prepared from gelatin, methylcellulose, starch or calcium alginate.
  • the hard gelatin capsules also called dry-filled capsules (DFC), consist of two segments, one segment is stuffed into the other segment, thus completely encapsulating the active ingredient.
  • Soft elastic capsules SEC are soft, spherical shells, such as gelatin shells, which are plasticized by adding glycerin, sorbitol, or similar polyols.
  • the soft gelatin shell may contain preservatives to prevent the growth of microorganisms. Suitable preservatives are those described in this invention, including methyl paraben and propyl paraben, and sorbic acid.
  • liquid, semi-solid and solid dosage forms provided by the present invention can be encapsulated in capsules.
  • suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides.
  • Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545.
  • the capsules can also be coated as known to those skilled in the art to improve or maintain the dissolution of the active ingredients.
  • the pharmaceutical composition provided by the present invention can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups.
  • Emulsion is a two-phase system in which one liquid is completely dispersed in the other liquid in the form of pellets, which can be oil-in-water or water-in-oil.
  • Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives.
  • Suspensions may include pharmaceutically acceptable suspending agents and preservatives.
  • the aqueous alcohol solution may include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as Propylene glycol and ethanol.
  • acetals such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as Propylene glycol and ethanol.
  • the elixirs are clear, sweet, hydroalcoholic solutions.
  • Syrups are aqueous solutions of concentrated sugars such as sucrose, and may also contain preservatives.
  • a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier such as water for precise and convenient administration.
  • the pharmaceutical composition provided by the present invention can be formulated into any dosage form suitable for inhalation administration to patients, such as dry powder, aerosol, suspension or solution composition.
  • the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for inhaled administration to a patient with a dry powder.
  • the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for inhalation administration to a patient through a nebulizer.
  • the dry powder composition delivered to the lungs by inhalation usually contains the compound disclosed in the present invention in a fine powder form and one or more finely powdered pharmaceutically acceptable excipients.
  • excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared by, for example, micronization and grinding. Generally, the size-reduced (e.g. micronised) compound can be (e.g., as measured by laser diffraction method) is defined by the D 50 value from about 1 to 10 microns.
  • the pharmaceutical composition suitable for transdermal administration can be prepared as a discontinuous patch, intended to maintain close contact with the patient's epidermis for an extended period of time.
  • the active ingredient can be delivered from the patch by ion penetration, as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • ointments, creams and gels can be formulated with water or oil bases, and suitable thickeners and/or gels and/or solvents.
  • bases may include, water, and/or oils such as liquid paraffin and vegetable oils (such as peanut oil or castor oil), or solvents such as polyethylene glycol.
  • Thickeners and gelling agents used according to the nature of the matrix include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxyvinyl and cellulose derivatives, and/or mono Glyceryl stearate and/or non-ionic emulsifier.
  • the compounds of the present invention can also be combined with soluble polymers as targeted drug carriers.
  • soluble polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylasparagine phenol, or polyoxyethylene polylysine substituted with palmitoyl residues.
  • the compounds disclosed in the present invention can be combined with a class of biodegradable polymers used in achieving controlled release of drugs, such as polylactic acid, poly ⁇ -caprolactone, polyhydroxybutyric acid, and polyorthoesters.
  • the pharmaceutical composition provided by the present invention can be administered parenterally by injection, infusion or implantation for local 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.
  • the pharmaceutical composition provided by the present invention can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and suitable for being in liquid before injection. Make a solid form of a solution or suspension.
  • dosage forms can be prepared according to conventional methods known to those skilled in the field of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, ibid.).
  • the pharmaceutical composition intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, anti- Microbial agents or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting agents or emulsifiers, complexing agents, multivalent Chelating agent or chelating agent, antifreeze, cryoprotectant, thickener, pH adjuster and inert gas.
  • aqueous carriers water-miscible carriers
  • non-aqueous carriers non-aqueous carriers
  • anti- Microbial agents or antimicrobial growth preservatives stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting agents or emulsifiers, complexing agents, multivalent Chelating
  • the pharmaceutical composition provided by the present invention can be administered by rectal suppository, by mixing the drug with a suitable non-irritating excipient (such as cocoa butter, polyethylene glycol synthetic glyceride), and then solid at room temperature. Liquifies or dissolves in the rectal cavity to release the drug. Due to individual differences, the severity of symptoms will vary greatly, and each medicine has its own unique therapeutic characteristics. Therefore, the precise administration method, dosage form and treatment plan for each individual should be determined by a medical practitioner. determination.
  • a suitable non-irritating excipient such as cocoa butter, polyethylene glycol synthetic glyceride
  • the pharmaceutical composition provided by the present invention can be formulated into immediate or modified release dosage forms, including delayed-, sustained-release, pulse-, controlled-, targeted- and programmed release forms.
  • the compound of the present invention can be directly administered without any preparation, the compound of the present invention is usually administered in the form of a pharmaceutical preparation containing a pharmaceutically acceptable excipient and at least one active ingredient.
  • a pharmaceutical preparation containing a pharmaceutically acceptable excipient and at least one active ingredient.
  • These formulations can be administered by various routes, including oral, buccal, rectal, intranasal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal administration. Many of the compounds used in the methods of the present invention are effective as injection and oral compositions.
  • transdermal delivery device For transdermal administration, a transdermal delivery device ("patch") is required. Such transdermal patches can be used to continuously or intermittently inject a controlled amount of the compound of the present invention.
  • the structure and application of transdermal patches for drug delivery are well known in the art. For example, see, US 5,023,252. This patch can be made to release the drug continuously, pulsating or on-demand.
  • Direct techniques usually involve placing a drug delivery catheter in the host's ventricular system to bypass the blood-brain barrier.
  • a drug delivery catheter in the host's ventricular system to bypass the blood-brain barrier.
  • Such an implantable delivery system is described in US5,011,472 for delivering biological factors to specific anatomical regions of the body.
  • Intra-arterial infusion of a hypertonic solution that can instantly open the blood-brain barrier can enhance the delivery of hydrophilic drugs.
  • a pharmaceutical preparation containing at least one of the above-mentioned active compounds and suitable for buccal and/or sublingual or nasal administration is provided.
  • This embodiment provides a way to avoid gastric complications (eg, bypassing the gastric system metabolism first and/or first passing through the liver metabolism) to administer the active compound.
  • This route of administration can also reduce the adsorption time, thereby bringing the therapeutic effect faster.
  • the compounds of the present invention can also provide a particularly advantageous solubility distribution, which is advantageous for sublingual/buccal administration formulations.
  • Such formulations generally require a relatively high concentration of active ingredients in order to deliver a sufficient amount of active ingredients to the limited surface of the sublingual/buccal mucosa within a short period of time during which the formulation is in contact with the sublingual/buccal mucosa surface, so that it is active
  • the components are absorbed. Therefore, the extremely high activity and high solubility of the compounds of the present invention make them suitable for the preparation of sublingual/buccal administration formulations.
  • terapéuticaally effective amount refers to the total amount of each active ingredient sufficient to show a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate the symptoms of the disease is administered or brought into balance in the body.
  • the effective amount required for a particular treatment regimen depends on many factors, including the disease to be treated, the severity of the disease, the activity of the specific drug used, the method of administration, the clearance rate of the specific drug, the duration of treatment, the combination of drugs, and age , Weight, gender, diet and patient’s health, etc.
  • the compound of formula (I) is formulated in a unit dosage form, each dosage containing about 0.001-100 mg of active ingredient, and more often about 1.0-30 mg of active ingredient.
  • unit dosage form refers to a physically separated unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect and appropriate pharmaceutically acceptable excipients as described above Agent.
  • the active compound is usually effective over a wide dosage range.
  • the daily dose is generally about 0.0001-30 mg/kg body weight.
  • a particularly preferred dose is about 0.1-15 mg/kg/day.
  • the amount of compound actually administered will be determined by the attending physician according to the relevant circumstances, including the disease being treated, the route of administration chosen, the one or more compounds to be actually administered, the age, weight and The response and the severity of the patient's symptoms, therefore, the above dosage range should not limit the scope of the present invention in any way.
  • a dosage level lower than the lower limit of the above-mentioned dosage range may be more appropriate.
  • a higher dosage that does not produce any side effects can be used, provided that the larger dosage is first used. Divide into several smaller doses for administration throughout the day.
  • administration refers to providing a therapeutically effective amount of a drug to an individual.
  • the administration methods include oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, supradural, intraocular, and intracranial, Inhalation, rectum, vagina, etc.
  • Dosage forms include ointment, lotion, tablet, capsule, pill, dispersible powder, granule, suppository, pill, lozenge, injection, sterile solution or non-aqueous solution, suspension, emulsion, patch ⁇ etc.
  • Active ingredients and non-toxic pharmaceutically acceptable carriers such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea) , Dextran, etc.
  • non-toxic pharmaceutically acceptable carriers such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea
  • the preferred route of administration will vary with clinical characteristics, and the dose must vary depending on the condition of the patient being treated. The doctor will determine the appropriate dose according to the individual patient.
  • the therapeutically effective amount per unit dose depends on body weight, physiological function and the chosen vaccination schedule.
  • the compound per unit dose refers to the weight of the compound per administration, excluding the weight of the carrier (the drug contains the carrier).
  • the pharmaceutical composition provided by the present invention can be formulated for single-dose or multiple-dose administration.
  • the single-dose preparation is packaged in ampoules, vials or syringes.
  • the multi-dose parenteral preparation must contain an antimicrobial agent at a bacteriostatic or fungicidal concentration. All parenteral preparations must be sterile, as known and practiced in the art.
  • the pharmaceutical composition provided by the present invention can be formulated with other active ingredients that do not impair the expected therapeutic effect, or with a substance that supplements the expected effect.
  • the treatment method of the present invention includes administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need.
  • the various embodiments of the present invention include the treatment of the diseases mentioned in the present invention by administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need.
  • the compound of the present invention or a pharmaceutical composition containing the compound of the present invention can be administered by any suitable route of administration, including systemic administration and local administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration and rectal administration.
  • Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular and subcutaneous injection or infusion administration.
  • Topical administration includes application to the skin as well as intraocular, ear, intravaginal, inhalation and intranasal administration.
  • the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention may be administered orally.
  • the compound of the present invention or a pharmaceutical composition containing the compound of the present invention may be administered by inhalation.
  • the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention may be administered intranasally.
  • the compound of the present invention or a pharmaceutical composition containing the compound of the present invention may be administered at one time, or according to the dosage regimen, administered several times at different time intervals within a specified period of time. For example, it is administered once, twice, three times or four times a day. In one embodiment, it is administered once a day. In yet another embodiment, the administration is twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely.
  • the appropriate dosage regimen of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, which can be determined by the skilled person.
  • the appropriate dosage regimen of the compound of the present invention or the pharmaceutical composition containing the compound of the present invention depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated , The medical history of the patient being treated, the nature of simultaneous therapy, the desired therapeutic effect, and other factors within the scope of the technical staff’s knowledge and experience.
  • Such a skilled person should also understand that the response of an individual patient to the dosing regimen, or when the individual patient's needs change over time, may require adjustment of an appropriate dosing regimen.
  • the compounds of the present invention can be administered simultaneously with one or more other therapeutic agents, or before or after them.
  • the compound of the present invention and other therapeutic agents can be administered separately through the same or different administration routes, or they can be administered in the same pharmaceutical composition. This is selected by those skilled in the art according to the actual physical conditions of the patient, such as the health, age, and weight of the patient. If formulated as a fixed dose, this combination product uses the compound of the present invention (within the dosage range described herein) and other pharmaceutically active agents (within the dosage range).
  • the present invention includes a combination drug, which includes a certain amount of at least one compound of the present invention or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof and an effective amount of one or more additional Therapeutic agent.
  • the compounds of the present invention can be administered in the form of prodrugs.
  • the "prodrug" of the compound of the present invention is a functional derivative that can finally release the compound of the present invention in the body when administered to a patient.
  • administering the compound of the present invention in the form of a prodrug those skilled in the art can implement one or more of the following ways: (a) change the in vivo onset time of the compound; (b) change the duration of the compound in vivo; The in vivo delivery or distribution of the compound; (d) changing the in vivo solubility of the compound; and (e) overcoming the side effects or other difficulties faced by the compound.
  • Typical functional derivatives used to prepare prodrugs include variants of compounds that are cleaved chemically or enzymatically in the body. These variants involving the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates are well known to those skilled in the art.
  • the compounds and pharmaceutical compositions provided by the present invention can be used to prepare medicines for activating 5-HT 1F receptors, and can also be used to prepare medicines for preventing, treating or alleviating 5-HT 1F receptor-related diseases, especially biases. Medicines for headaches.
  • the compound of the present invention or the amount of the compound in the pharmaceutical composition can effectively and detectably activate the 5-HT 1F receptor selectively.
  • the compound of the present invention or the amount of the compound in the pharmaceutical composition can effectively and detectably selectively inhibit neuronal protein extravasation.
  • the compound of the present invention can be applied, but is not limited to, the effective amount of the compound or pharmaceutical composition of the present invention is administered to a patient to prevent, treat or alleviate diseases related to 5-HT 1F receptors.
  • the diseases related to the 5-HT 1F receptor further include, but are not limited to, migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression Disorders, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder , Attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, excessive appetite, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss and dementia.
  • the compound and pharmaceutical composition of the present invention can also be applied to 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 present invention include pharmaceutically acceptable derivatives thereof.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless there are further instructions, wherein the definition of the substituents is as shown in formula (I).
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained by refluxing and drying with sodium metal.
  • Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are dried in advance with anhydrous sodium sulfate.
  • reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
  • the glassware is all dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
  • 1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.
  • the 1 H NMR spectrum uses CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), and uses TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard.
  • the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1x 30mm, 3.5 microns, 6min, flow rate 0.6mL/min.
  • Mobile phase 5
  • the ratio of %-95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid) was measured by electrospray ionization (ESI) at 210 nm/254 nm and UV detection.
  • ESI electrospray ionization
  • the pure compound uses Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80mm DAC), and UV detection at 210nm/254nm.
  • Ru is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl.
  • the compound represented by the formula ( 7 ) can be prepared by the following process: the compound represented by the formula (1 ) reacts with the compound represented by the formula ( 2 ) to obtain the compound represented by the formula ( 3 ); then the compound represented by the formula ( 3 ) The compound shown is condensed with the compound represented by formula (4 ) to obtain the compound represented by formula ( 5 ). The Boc protecting group of the compound represented by formula ( 5 ) is removed to obtain the compound represented by formula ( 6 ); in the presence of a reducing agent (for example, sodium cyanoborohydride), the piperidine ring of the compound represented by formula (6) NH and corresponding aldehyde The Borch reductive amination reaction occurs to obtain the target product represented by formula (7).
  • a reducing agent for example, sodium cyanoborohydride
  • Ru is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl.
  • the compound represented by the formula ( 13 ) can be prepared by the following process: the compound represented by the formula (8 ) reacts with the compound represented by the formula ( 4 ) to obtain the compound represented by the formula ( 9 ); then the compound represented by the formula ( 9 ) The compound shown is reacted with the compound represented by formula ( 10 ) to obtain the compound represented by formula ( 11 ).
  • the Boc protecting group of the compound represented by formula ( 11 ) is removed to obtain the compound represented by formula ( 12 ); in the presence of a reducing agent (for example, sodium cyanoborohydride), the piperidine ring of the compound represented by formula (12) NH and corresponding aldehyde A Borch reductive amination reaction occurs to obtain the target product represented by formula (13).
  • a reducing agent for example, sodium cyanoborohydride
  • 6-Bromopyridin-2-amine 350mg, 2.02mmol
  • triethylamine 0.6mL, 4.34mmol
  • dichloromethane 10mL
  • 4- Fluorobenzoyl chloride 0.3mL, 2.5mmol
  • the title compound in this step was prepared by referring to the method described in step 3 of Example 1, that is, tert-butyl 4-((6-(4-chlorobenzamide)pyridin-2-yl)methyl)piperidine-1-carboxy Ester (450mg, 1.05mmol) and hydrogen chloride ethyl acetate solution (2M, 4mL) were prepared by reacting in methanol (5mL).
  • methanol methanol
  • the title compound in this step was prepared by referring to the method described in step 2 of Example 1, namely tert-butyl 4-methylene piperidine-1-carboxylate (700mg, 3.5mmol), 9-boronbicyclo[3.3.1] Nonane (8.0mL, 0.5M tetrahydrofuran solution), N-(6-bromopyridin-2-yl)-2,4-difluorobenzamide (900mg, 2.88mmol), (1,1'-bis( ⁇ ) Phenylphosphino)ferrocene]palladium dichloride (70mg, 0.09mmol), sodium hydroxide (350mg, 8.75mmol) are prepared by reacting in tetrahydrofuran (5mL) and water (5mL).
  • the title compound in this step was prepared by referring to the method described in step 2 of Example 1, namely tert-butyl 4-methylene piperidine-1-carboxylate (700mg, 3.5mmol), 9-boronbicyclo[3.3.1] Nonane (8.0mL, 0.5M tetrahydrofuran solution), N-(6-bromopyridin-2-yl)-2,4,6-trifluorobenzamide (950mg, 2.88mmol), (1,1'-bis (Diphenylphosphino)ferrocene]palladium dichloride (70mg, 0.09mmol), sodium hydroxide (350mg, 8.75mmol) are prepared by reacting in tetrahydrofuran (5mL) and water (5mL).
  • the title compound in this step was prepared by referring to the method described in step 3 of Example 1, that is, tert-butyl 4-((6-(5-fluoropyridinamide)pyridin-2-yl)methyl)piperidine-1-carboxylic acid
  • the ester (320mg, 0.77mmol) and hydrogen chloride ethyl acetate solution (2M, 6mL) were prepared by reacting in dichloromethane (10mL).
  • the title compound in this step was prepared by referring to the method described in step 3 of Example 1, that is, tert-butyl 4-((6-(5-chloropyridineamide)pyridin-2-yl)methyl)piperidine-1-carboxylic acid
  • the ester (426mg, 0.99mmol) and hydrogen chloride ethyl acetate solution (2M, 6mL) were prepared by reacting in dichloromethane (10mL).
  • Example A Evaluation of the agonistic effect of the compounds of the present invention on human 5-HT 1F receptors transfected with CHO-K1 cells
  • Table A Test results of the agonistic effect of the compounds of the present invention on human 5-HT 1F receptors transfected with CHO-K1 cells
  • the experimental results show that the compound of the present invention has strong 5-HT 1F receptor agonistic activity.
  • Example B Quantitative pharmacokinetic evaluation of the compound of the invention by intravenous injection or gavage in rats and dogs
  • the inventors conducted pharmacokinetic evaluation of the compounds of the present invention in rats and dogs. Among them, the animal information is shown in Table 1.
  • Table 1 Information table of the tested animal of the present invention
  • the compound of the present invention is administered to the test animal in the form of 5% DMSO + 60% PEG400 + 35% Saline solution or 10% DMSO + 10% Kolliphor HS15 + 30% PEG400 + 50% Saline solution. Animals are forbidden before administration Eat for 12 hours and drink freely.
  • the dosage is 0.5mg/kg or 1mg/kg, and blood will be taken from the vein at the following time points after administration (the blood volume is about 0.15mL): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0 , 6.0, 8.0 and 24h (dogs) or 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rats), pre-add EDTA-K 2 as an anticoagulant in the blood collection tube, and centrifuge the blood sample at 12,000 rpm 2 Minutes, collect plasma and store at -20°C or -70°C.
  • the dosage is 2.5mg/kg or 5mg/kg.
  • blood will be collected from the vein at the following time points (the blood volume is about 0.15mL): 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dogs) or 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rats), pre-add EDTA-K 2 as an anticoagulant in the blood collection tube, centrifuge the blood sample at 12,000rpm for 2 minutes, and collect Plasma is stored at -20°C or -70°C.

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Abstract

本发明提供了吡啶亚甲基哌啶衍生物及其用途，具体地，本发明提供了一类新颖的吡啶亚甲基哌啶衍生物以及包含该类化合物的药物组合物，可用于激活5-HT 1F受体。本发明还提供了制备这类化合物和药物组合物的方法，以及它们在制备治疗与5-HT 1F受体有关的疾病，特别是偏头痛的药物中的用途。

Description

吡啶亚甲基哌啶衍生物及其用途 技术领域
本发明属于药物技术领域，具体涉及新颖的吡啶亚甲基哌啶衍生物和包含这些化合物的药物组合物，及其使用方法和用途。特别地，本发明所述的新颖的吡啶亚甲基哌啶衍生物，可用于激活5-HT 1F受体，用于预防、治疗或减轻与5-HT 1F受体有关的疾病，尤其是偏头痛。
背景技术
偏头痛是一类发作性且常为单侧的搏动性头痛，常伴有恶心、呕吐，是一种常见的慢性神经血管性疾患，多起病于儿童和青春期，中青年期达发病高峰，女性多见，男女患者比例约为1：2～3，人群中患病率为5％～10％，常有遗传背景。
偏头痛虽然不是致命的疾病，但能严重影响患者的社会生活。在美国，偏头痛造成的社会经济负担为10～17亿美元。在我国也有大量患者因偏头痛而影响工作、学习和生活。随着生活节奏的加快，偏头痛的发病率呈逐渐增加的趋势。最近调查发现大约5.7％的男性、17.6％的妇女平均每年有1次以上的偏头痛发作。此外，尚有许多人具有偏头痛的遗传发病倾向。
偏头痛的发病机制复杂多样，主要有血管源学说、神经源学说、三叉神经血管学说、生化因素和遗传因素。目前用于治疗偏头痛的药物主要为5-HT 1B/D受体激动剂曲坦类药物，但由于曲坦类药物会使血管收缩，因此对于心脑血管和周围血管疾病患者禁用。此外，40％～70％的偏头痛患者对曲坦类药物治疗疗效较差，1/3初始治疗有效的患者也会经常遇到头痛复发的情况，曲坦类药物对中重度头痛患者的疗效显著降低。为了克服曲坦类药物的这些不良反应，降钙素基因相关肽(CGRP)受体拮抗剂和选择性5-HT 1F受体激动剂类抗偏头痛药物应运而生。然而，CGRP受体拮抗剂仍存在诸多缺陷，如olcagepant只能静注使用而不宜口服，telcagepant长期使用会引起肝酶升高，BI-44370则因会与细胞色素P450发生相互作用而中止了临床开发。因此，迫切需要开发新的急性期治疗药物。而开发选择性5-HT 1F受体激动剂类抗偏头痛药物，一直被认为是一条新的很有希望的途径。
自1938年以来，Graham和Wolff的工作(Arch.Neurol.Psychiatry,39:737-63,1938)在有关偏头痛病理生理学的理论中一直占据主导地位。他们提出，偏头痛的原因是颅外血管的血管舒张。这种观点得到如下证据的支持：麦角生物碱和舒马坦，作为一种不能穿越血-脑屏障的吸水性5-HT 1激动剂，能使头部血管平滑肌收缩，并能有效治疗偏头痛(Humphrey,et al.,Ann.NY Acad.Sci.,600:587-600,1990)。但是，Moskowitz研究小组的工作表明，偏头痛的发生与血管直径改变无关(Cephalalgia,12:5-7,1992)。
Moskowitz研究小组提出，目前未知的疼痛触发器刺激了三叉神经节(三叉神经节使头部组织内的脉管系统受神经支配)，导致脉管系统上的轴索释放血管活性神经肽。然后，这些释放的神经肽激活了一系列事件，从而导致疼痛。这种神经原性炎症被麦角生物碱和舒马坦阻断，其阻断机制涉及5-HT受体，并与位于三叉神经血管纤维上的5-HT 1D亚型密切相关(Neurology,43(supp1.3):S16-S20,1993)。实际上，舒马坦对5-HT 1B和5-HT 1D受体具有高亲和力，Ki分别为10.3nM和5.1nM，该活性表现出血管收缩活性。
5-羟色胺受体，也被称为血清素受体或5-HT受体，是一群于中枢神经系统中央处和末梢神经系统周边出现的G蛋白偶联受体，可分为七个亚科5-HT 1、5-HT 2、5-HT 3、5-HT 4、5-HT 5、5-HT 6和5-HT 7，分别介导不同的生理活性。其中，5-HT 1受体是5-HT受体家族中最庞大的一科，目前有5-HT 1A、5-HT 1B、5-HT 1D、5-HT 1E和5-HT 1F五种亚型。Kao研究小组分离出表达这些5-HT 1受体亚型之一(称为5-HT 1F)的人类基因(Proc.Natl.Acad.Sci.USA,90:408-412,1993)。该5-HT 1F受体显示出的药理学活性明显不同于已公开的任何血清素受体。他们发现，舒马坦除了对5-HT 1B和5-HT ID受体具有上述强亲和力外，还对这种受体亚型具有亲和力，其Ki约为23nM。这表明5-HT 1F受体在偏头痛中可能起作用。
5-HT 1F受体主要表达于肠系膜、子宫和脑部，也存在于大脑血管、三叉神经节和三叉神经尾核等三叉神经脉 管系统中各部分以及小脑、海马及新大脑皮层。与其他5-HT受体一样，5-HT 1F受体不仅表达在神经元，也可表达于神经胶质细胞。突触前5-HT 1F受体的激活可抑制降钙素基因相关肽(CGRP)的释放，并阻滞三叉神经尾核内神经元信号传导，从而产生抗偏头痛作用，且这种选择性5-HT 1F受体激动作用，极大地降低了曲坦类药物引发的血管收缩相关副作用。
随后开发出对5-HT 1F受体亚型具有相对选择性的各种5-HT 1F受体激动剂，并且这种选择性通常会降低用作治疗偏头痛及相关疾病潜药的其它化合物所特有的血管收缩活性。
经过持续不断地努力研究，发明人得到了一类意想不到的新的选择性5-HT 1F激动剂，其具有不同的化学和受体结合特性，能抑制肽外渗，同时能避免明显的血管收缩活性，因而可用于治疗偏头痛和其它与5-HT 1F受体相关的疾病。而且，本发明化合物的溶解性好，因而在优选制剂(如舌下、经颊和/或鼻内给药制剂)中的适应性高。
发明内容
本发明提供了一类作为5-HT 1F受体激动剂的新颖的吡啶亚甲基哌啶衍生物，其可以用于激活5-HT 1F受体、抑制神经元蛋白质外渗，因此，可以用于治疗由5-HT 1F受体介导的疾病，特别是用于治疗偏头痛。并且通过实验发现，本发明的吡啶亚甲基哌啶衍生物的性质稳定，安全性良好，具有良好的药效学和药代动力学性质，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，其具备良好的临床应用前景。
本发明还提供了制备这类化合物的方法、含有这类化合物的药物组合物以及这类化合物和包含这类化合物的药物组合物在制备药物中的用途。
一方面，本发明涉及一种化合物，其为式(I)所示的化合物，或者式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2019120076-appb-000001
其中：
X为N或CR x；
各R 1a、R 1b、R 1c、R 1d和R x独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 6烷基)、-C(＝O)-(C 1-C 6烷氧基)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷硫基、C 1-C 6烷氨基、羟基取代的C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基；
R 2为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基或羟基取代的C 1-C 6烷基；
R 3、R 4和R 5各自独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基或羟基取代的C 1-C 6烷基；和
R 6为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 6烷基)、-C(＝O)-(C 1-C 6烷氧基)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷硫基、C 1-C 6烷氨基、羟基取代的C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基。
在一实施方案中，各R 1a、R 1b、R 1c、R 1d和R x独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 4烷基)、-C(＝O)-(C 1-C 4烷氧基)、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 1-C 4烷硫基、C 1-C 4烷氨基、羟基取代的C 1-C 4烷基、C 3-C 6环烷基、3-6元杂环基、C 6-C 10芳基或5-10元杂芳基；
R 2为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基或羟基取代的C 1-C 4烷基；
R 3、R 4和R 5各自独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基或羟基取代的C 1-C 4烷基。
在另一实施方案中，各R 1a、R 1b、R 1c、R 1d和R x独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-OCH 3、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲硫基、乙硫基、甲氨基、二甲氨基、乙氨基、羟甲基、2-羟基乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、茚基、萘基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、吲哚基或喹啉基；
R 2为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、-CF 3、-CH 2CF 3、甲氧基、乙氧基、正丙基氧基或异丙基氧基；
R 3、R 4和R 5各自独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、-CF 3、-CH 2CF 3、甲氧基、乙氧基、正丙基氧基或异丙基氧基。
在一实施方案中，R 6为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 4烷基)、-C(＝O)-(C 1-C 4烷氧基)、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 1-C 4烷硫基、C 1-C 4烷氨基、羟基取代的C 1-C 4烷基、C 3-C 6环烷基、3-6元杂环基、C 6-C 10芳基或5-10元杂芳基。
在另一实施方案中，R 6为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-OCH 3、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲硫基、乙硫基、甲氨基、二甲氨基、乙氨基、羟甲基、2-羟基乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、茚基、萘基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、吲哚基或喹啉基。
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式(I)所示化合物。
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。
又一方面，本发明涉及本发明公开的式(I)所示化合物或其药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻与5-HT 1F受体有关的疾病。
在一实施方案中，所述的与5-HT 1F受体有关的疾病为偏头痛、一般性疼痛、三叉神经痛、牙痛或颞下颌关节机能障碍疼痛、孤独症、强迫症、恐慌症、抑郁症、社交恐惧症、焦虑、广泛性焦虑症、睡眠障碍、创伤后综合征、慢性疲劳综合征、经前综合征或后黄体期综合征、边缘型人格障碍、破坏性行为障碍、冲动控制障碍、注意力缺陷多动障碍、酒精中毒、烟草滥用、缄默症、拔毛发癖、食欲过盛、神经性厌食症、早泄、勃起机能障碍、 记忆丧失或痴呆。
再一方面，本发明涉及本发明公开的式(I)所示化合物或其药物组合物在制备药物中的用途，所述药物用于激活5-HT 1F受体。
另一方面，本发明涉及式(I)所示化合物的制备、分离和纯化的方法。
生物试验结果表明，本发明化合物可以激活5-HT 1F受体、抑制神经元蛋白质外渗，并可作为较好的5-HT 1F受体激动剂。
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他方面的内容将在下面作更加具体完整的描述。本说明书中的所有参考文献通过整体引用于此。当本说明书的公开内容与引用文献有差异时，以本说明书的公开内容为准。
本发明的详细说明书
定义和一般术语
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，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,New York:2007中的描述，其全部内容通过引用并入本发明。
除非另有说明或者上下文中有明显的冲突，本发明所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本发明所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
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。
术语“手性分子”是具有与其镜像不能重叠性质的分子；而“非手性分子”是指与其镜像可以重叠的分子。
术语“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
术语“外消旋物”或“外消旋混合物”是指两个对映异构体的等摩尔混合物，该混合物缺少光学活性。
术语“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
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。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 ndEd.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.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。
“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、变态反应或与合理的利益/风险比相对称的其他问题和并发症，并有效用于既定用途。
术语“任选地被…….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、Br、I、N 3、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-CONH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-烷基、-C(＝O)-烷氧基、烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、烷硫基、烷氨基、羟基取代的烷基、环烷基、杂环基、芳基、杂芳基等等。
一般而言，术语“取代的”表示所给结构或基团中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个取代基可以在基团各个可取代的合理的位置进行取代。当所给出的结构式中不止一个位置能被选自的一个或多个具体取代基所取代，那么取代基可以相同或不同地在结构式中各个合理的位置进行取代。
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。
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。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。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。
术语“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。
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“C 1-C 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
术语“D”表示单个氘原子。
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)。
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，R为本发明所述的取代基)。
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、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2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2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，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＝CH 2)、烯丙基(-CH 2CH＝CH 2)、1-丙烯基(即，丙烯基，-CH＝CH-CH 3)，等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，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(-CH 2C≡CH)、1-丙炔基(即，丙炔基，-C≡C-CH 3)，等等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，1-丙氧基(正丙基氧基、n-PrO、n-丙氧基、-OCH 2CH 2CH 3)，2-丙氧基(异丙基氧基、i-PrO、i-丙氧基、-OCH(CH 3) 2)，1-丁氧基(n-BuO、n-丁氧基、-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH 3) 3)，等等。
术语“烷硫基”表示烷基基团通过硫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，所述烷硫基基团含有1-12个碳原子。在一实施方案中，烷硫基基团含有1-6个碳原子；在另一实施方案中，烷硫基基团含有1-4个碳原子；在又一实施方案中，烷硫基基团含有1-3个碳原子。所述烷硫基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷硫基基团的实例包括，但并不限于，甲硫基(MeS、-SCH 3)，乙硫基(EtS、-SCH 2CH 3)，1-丙硫基(n-PrS、n-丙硫基、-SCH 2CH 2CH 3)，2-丙硫基(i-PrS、i-丙硫基、-SCH(CH 3) 2)，1-丁硫基(n-BuS、n-丁硫基、-SCH 2CH 2CH 2CH 3)，2-甲基-l-丙硫基(i-BuS、i-丁硫基、-SCH 2CH(CH 3) 2)，2-丁硫基(s-BuS、s-丁硫基、-SCH(CH 3)CH 2CH 3)，2-甲基-2-丙硫基(t-BuS、t-丁硫基、-SC(CH 3) 3)，等等。
术语“烷氨基”或“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代，其中烷基基团具有如本发明所述的含义。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基(甲氨基)，N-乙氨基(乙氨基)，N,N-二甲氨基(二甲氨基)，N,N-二乙氨基(二乙氨基)等等。所述烷氨基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“羟基取代的烷基”表示烷基基团被一个或多个羟基所取代，其中烷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，羟甲基、2-羟基乙基、2-羟基-1-丙基、3-羟基-1-丙基、2,3-二羟基丙基等等。
术语“卤代烷基”表示烷基基团被一个或多个卤素原子所取代，其中烷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，-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CHF 2、-CH 2CF 3、-CHFCH 3、-CH 2CH 2F、-CF 2CH 3、-CH 2CF 2CHF 2等。在一实施方案中，C 1-C 6卤代烷基包含氟取代的C 1-C 6烷基；在另一实施方案中，C 1-C 4卤代烷基包含氟取代的C 1-C 4烷基；在又一实施方案中，C 1-C 2卤代烷基包含氟取代的C 1-C 2烷基。
术语“卤代烷氧基”表示烷氧基基团被一个或多个卤素原子所取代，其中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，-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CHF 2、-OCH 2CF 3、-OCHFCH 3、-OCH 2CH 2F、-OCF 2CH 3、-OCH 2CF 2CHF 2等。在一实施方案中，C 1-C 6卤代烷氧基包含氟取代的C 1-C 6烷氧基；在另一实施方案中，C 1-C 4卤代烷氧基包含氟取代的C 1-C 4烷氧基；在又一实施方案中，C 1-C 2卤代烷氧基包含氟取代的C 1-C 2烷氧基。
术语“n个原子组成的”或“n元”在此处可交换使用，其中n是整数，典型地描述分子中成环原子的数目，在所述分子中成环原子的数目是n。例如，5-10元杂芳基表示5、6、7、8、9或10个环原子组成的杂芳基。再例如，哌啶基是6个环原子组成的杂环基或6元杂环基，而吡啶基是6个环原子组成的杂芳基或6元杂芳基。
术语“碳环基”或“碳环”表示含有3-12个碳原子的，单价或多价的非芳香性的饱和或部分不饱和单环、双环或者三环体系。碳双环基包括螺碳双环基和稠合碳双环基，合适的碳环基基团包括，但并不限于，环烷基、环烯基和环炔基。碳环基基团的实例进一步包括，环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-1-烯基、1-环己基-2-烯基、1-环己基-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基，等等。所述碳环基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。双环或三环体系可以包括稠环、桥环和螺环。在一实施方案中，环烷基包含3-10个碳原子；在另一实施方案中，环烷基包含3-8个碳原子；在又一实施方案中，环烷基包含3-6个碳原子。环烷基基团的实例包含，但并不限于，环丙基、环丁基、环戊基、环己基，等等。所述环烷基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的，非芳香性的饱和或部分不饱和的单环、双环或三环体系，其中，所述双环或三环体系可以包括稠环、桥环和螺环。其中环上一个或多个原子独立地被杂原子所替换，所述杂原子具有如本发明所述的含义。在一实施方案中，杂环基是3-8个环原子组成的的单环杂环基(2-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得 到像SO，SO 2，PO，PO 2的基团)；在又一实施方案中，杂环基是3-6个环原子组成的的单环杂环基(2-5个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO 2，PO，PO 2的基团)；在另一实施方案中，杂环基是7-12个环原子组成的双环杂环基(4-9个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO 2，PO，PO 2的基团)。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。
杂环基可以是碳基或杂原子基。其中，环的-CH 2-基团任选地被-C(＝O)-替代，环的硫原子任选地被氧化成S-氧化物，环的氮原子任选地被氧化成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 PCTCN2019120076-appb-000002
基，二氮杂
Figure PCTCN2019120076-appb-000003
基，硫氮杂
Figure PCTCN2019120076-appb-000004
基，2-氧杂-5-氮杂双环[2.2.1]庚-5-基，等等。杂环基中-CH 2-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。所述的杂环基基团任选地被一个或多个本发明所描述的取代基所取代。
术语“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，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环。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、茚基、萘基和蒽基。所述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。
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，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含5-7个原子组成的环。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”，“芳杂环”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个原子组成的杂芳基包含1，2，3或4个独立选自O，S和N的杂原子。
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)、三唑基(如2-三唑基和5-三唑基)、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、1,2,3-三唑基、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；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]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基，等等。
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-CH 2CH 2SO 2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：Greene et al., Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)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。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，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 +(C 1-4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，C 1-C 8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸、乙醇胺或其混合物。术语“水合物”是指溶剂分子是水所形成的缔合物。
当所述溶剂为水时，可以使用术语“水合物”。在一实施方案中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另一实施方案中，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物；在又一实施方案中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。
术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
术语“防止”或“预防”指获病或障碍的风险的减少(即：使疾病的至少一种临床症状在主体内停止发展，该主体可能面对或预先倾向面对这种疾病，但还没有经历或表现出疾病的症状)。
除非另作说明，本发明的化合物所有合适的同位素变化、立体异构体、互变异构体、溶剂化物、代谢产物、盐和药学上可接受的前药都包含在本发明范围内。
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体都考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(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。
本发明化合物的氮氧化物也包含在本发明的范围之内。可以通过在升温下使用常用氧化剂(例如过氧化氢)，在有例如乙酸的酸存在下，氧化相应的含氮碱性物质，或者通过在适合的溶剂中与过酸反应，例如在二氯甲烷、乙酸乙酯或乙酸甲酯中与过乙酸反应，或在氯仿或二氯甲烷中与3-氯过氧苯甲酸反应，制备本发明化合物的氮氧化物。
式(I)所示化合物可以以盐的形式存在。在一实施方案中，所述盐是指药学上可接受的盐。术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。在另一实施方案中，所述盐不一定是药学上可接受的盐，可以是用于制备和/或提纯式(I)所示化合物和/或用于分离式(I)所示化合物的对映体的中间体。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company,Easton,Pa.,(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts:Properties,Selection,and Use)”,Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H、 3H、 11C、 13C、 14C、 15N、 17O、 18O、 18F、 31P、 32P、 35S、 36Cl和 125I。
另一方面，本发明涉及制备式(I)所示化合物的中间体。
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物。在一实施方案中，本发明所述药物组合物，更进一步包括药学上可接受的载体、赋形剂、佐剂、溶媒或它们的组合。在另一实施方案中，药物组合物可以是液体、固体、半固体、凝胶或喷雾剂型。
本发明化合物的描述
本发明涉及的吡啶亚甲基哌啶衍生物，其药学上可接受的盐，药物制剂及其组合物，可以用于激活5-HT 1F受体、抑制神经元蛋白质外渗，对与5-HT 1F受体有关的疾病，特别是偏头痛的治疗有潜在的用途。本发明又进一步描述了合成所述化合物的方法。本发明的化合物显示出良好的生物活性。
一方面，本发明涉及一种化合物，其为式(I)所示的化合物，或者式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2019120076-appb-000005
其中，各R 1a、R 1b、R 1c、R 1d、R 2、R 3、R 4、R 5、R 6和X具有如本发明所述的含义。
在一实施方案中，X为N或CR x；其中，R x具有如本发明所述的含义。
在一实施方案中，各R 1a、R 1b、R 1c、R 1d和R x独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 6烷基)、-C(＝O)-(C 1-C 6烷氧基)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷硫基、C 1-C 6烷氨基、羟基取代的C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基。
在一实施方案中，R 2为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基或羟基取代的C 1-C 6烷基。
在一实施方案中，R 3、R 4和R 5各自独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基或羟基取代的C 1-C 6烷基。
在一实施方案中，R 6为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 6烷基)、-C(＝O)-(C 1-C 6烷氧基)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷硫基、C 1-C 6烷氨基、羟基取代的C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基。
在一实施方案中，各R 1a、R 1b、R 1c、R 1d和R x独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 4烷基)、-C(＝O)-(C 1-C 4烷氧基)、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 1-C 4烷硫基、C 1-C 4烷氨基、羟基取代的C 1-C 4烷基、C 3-C 6环烷基、3-6元杂环基、C 6-C 10芳基或5-10元杂芳基。
在另一实施方案中，各R 1a、R 1b、R 1c、R 1d和R x独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-OCH 3、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲硫基、乙硫基、甲氨基、二甲氨基、乙氨基、羟甲基、2-羟基乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、茚基、萘基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、吲哚基或喹啉基。
在一实施方案中，R 2为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基或羟基取代的C 1-C 4烷基。
在另一实施方案中，R 2为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、-CF 3、-CH 2CF 3、甲氧基、乙氧基、正丙基氧基或异丙基氧基。
在一实施方案中，R 3、R 4和R 5各自独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基或羟基取代的C 1-C 4烷基。
在另一实施方案中，R 3、R 4和R 5各自独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、-CF 3、-CH 2CF 3、甲氧基、乙氧基、正丙基氧基或异丙基氧基。
在一实施方案中，R 6为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 4烷基)、-C(＝O)-(C 1-C 4烷氧基)、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 1-C 4烷硫基、C 1-C 4烷氨基、羟基取代的C 1-C 4烷基、C 3-C 6环烷基、3-6元杂环基、C 6-C 10芳基或5-10元杂芳基。
在另一实施方案中，R 6为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-OCH 3、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔 基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲硫基、乙硫基、甲氨基、二甲氨基、乙氨基、羟甲基、2-羟基乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、茚基、萘基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、吲哚基或喹啉基。
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、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，但绝不限于：
Figure PCTCN2019120076-appb-000006
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式(I)所示化合物。
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。
又一方面，本发明涉及本发明公开的式(I)所示化合物或其药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻与5-HT 1F受体有关的疾病。
在一实施方案中，所述的与5-HT 1F受体有关的疾病为偏头痛、一般性疼痛、三叉神经痛、牙痛或颞下颌关节机能障碍疼痛、孤独症、强迫症、恐慌症、抑郁症、社交恐惧症、焦虑、广泛性焦虑症、睡眠障碍、创伤后综合征、慢性疲劳综合征、经前综合征或后黄体期综合征、边缘型人格障碍、破坏性行为障碍、冲动控制障碍、注意力缺陷多动障碍、酒精中毒、烟草滥用、缄默症、拔毛发癖、食欲过盛、神经性厌食症、早泄、勃起机能障碍、 记忆丧失或痴呆。
在另一实施方案中，所述的与5-HT 1F受体有关的疾病为偏头痛。
再一方面，本发明涉及本发明公开的式(I)所示化合物或其药物组合物在制备药物中的用途，所述药物用于激活5-HT 1F受体。
另一方面，本发明涉及式(I)所示化合物的制备、分离和纯化的方法。
本发明化合物的药物组合物、制剂和给药
本发明提供一种药物组合物，包括式(I)所示化合物或其单独的立体异构体，异构体的外消旋或非外消旋混合物或其药学上可接受的盐或溶剂化物。在本发明的一个实施方式中，所述药物组合物进一步包含至少一种药学上可接受的载体、辅剂或赋形剂，以及任选地，其它的治疗和/或预防成分。
本发明方法中使用的化合物的给药剂型可以通过所选择的特定化合物、给药途径所要求的药物动力学分布类型及患者的状态来确定。
按制药领域的公知方法制备适合于经口、舌下、鼻内或注射给药的制剂，并且所述制剂含有至少一种活性化合物。参见，例如，REMINGTON′S PHARMACEUTICAL SCIENCES(16th ed.1980)。
一般而言，本发明的制剂包括活性组份(式(I)所示化合物)，并通常与赋型剂混合、被赋型剂稀释或包封在可呈胶囊、小药囊、纸或其它容器状的载体中。当赋型剂用作稀释剂时，其可以是固体、半固体或液体物料，对活性组份起赋型剂、载体或介质的作用。因此，制剂可以是片剂、丸剂、粉剂、锭剂、香囊、扁囊剂、酏剂、悬浮液、乳剂、溶液、糖浆、气溶胶(为固体或在液体介质中)、含有例如高达10重量％活性化合物的软膏、软和硬胶囊、凝胶、栓剂、无菌注射液和无菌封装粉剂。
在制剂的制备中，在与其它组份混合之前，可能需要研磨活性化合物，以提供合适的粒度。如果活性化合物基本不溶，则通常将其研磨至小于200目的粒度。如果活性化合物基本上是水溶性的，则通过研磨调节其粒度，以使制剂中具有均匀粒度分布，例如，约40目。在本发明的一个实施方案中，粒度为大约0.1-100μm。
合适的载体、辅剂和赋形剂对于本领域技术人员是熟知的并且详细描述于例如Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia；Gennaro A.R.et al.,Remington：The Science and Practice of Pharmacy(2000)Lippincott,Williams&Wilkins,Philadelphia；和Rowe R.C.,Handbook of Pharmaceutical Excipients(2005)Pharmaceutical Press,Chicago中。
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/或会导致不是药学上可接受的药物组合物的相互作用。此外，每种赋形剂必须是药学上可接受的，例如，具有足够高的纯度。
合适的药学上可接受的赋形剂会依所选具体剂型而不同。此外，可根据它们在组合物中的特定功能来选择药学上可接受的赋形剂。例如，可选择能有助于生产均一剂型的某些药学上可接受的赋形剂。可选择能有助于生产稳定剂型的某些药学上可接受的赋形剂。可选择对患者给药时有助于携带或运输本发明化合物从身体的一个器官或部分到身体的另一个器官或部分的某些药学上可接受的赋形剂。可选择增强患者依从性的某些药学上可接受的赋形剂。
一些合适的赋型剂实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、西黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。合适的药学上可接受的赋形剂还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(诸如滑石粉、硬脂酸镁和矿物油)、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(诸如羟基苯甲酸甲酯和羟基苯甲酸丙酯)、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。可以采用本领域的已知方法来配制本发明化合物，以便对患者给药后能快速、持续或延缓释放出活性组份。
技术人员掌握本领域的知识和技能，以使他们能选择用于本发明的适当量的合适的药学上可接受的赋形剂。此外，存在大量技术人员可获得的资源，他们描述药学上可接受的赋形剂，并用于选择合适的药学上可接受的赋形剂。实例包括Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
为了用本发明所描述的化合物来制备药物组合物，药学上可接受的载体可以是固体或液体载体。固体形式制剂包括粉剂，片剂，可分散的颗粒剂，胶囊剂，扁囊剂和栓剂。粉剂和片剂可以包含大约5％至大约95％的活性组分。合适的固体载体在本领域是已知的，例如，碳酸镁，硬脂酸镁，滑石粉，糖或乳糖。片剂、粉剂、扁囊剂和胶囊剂可以用作适合于口服的固体剂型。制备各种组合物的可药用载体和方法的例子可以在下列中得到：A.Gennaro(ed.),Remington's Pharmaceutical Sciences,18 th ed.,1990,Mack Publishing Company Co.,Easton,Pennsylvania。
在Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York中披露了用于配置药学上可接受的组合物的各种载体，和用于其制备的公知技术，这些文献各自的内容通过引用并入本发明。除任何诸如因产生任何不期望的生物作用，或以有害方式与药学上可接受组合物中的任何其它成分发生相互作用而与本发明化合物不相容的任何常用载体外，关注其应用属于本发明的范围。
本发明公开的药物组合物使用本领域技术人员已知的技术和方法来制备。本领域一些常用方法的描述可参见Remington's Pharmaceutical Sciences(Mack Publishing Company)。
因此，另一方面，本发明涉及制备药物组合物的工艺，所述药物组合物包含本发明公开化合物和药学上可接受的赋形剂，载体，辅剂，溶媒或它们的组合，该工艺包括混合各种成分。包含本发明公开化合物的药物组合物，可以在例如环境温度和大气压下混合来制备。
本发明公开的化合物通常被配制成适合于通过所需途径对患者给药的剂型。例如，剂型包括那些适合于以下给药途径的剂型：(1)口服给药，例如片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、香包剂和扁囊剂；(2)胃肠外给药，例如无菌溶液剂、混悬剂和复溶粉末；(3)透皮给药，例如透皮贴片剂；(4)直肠给药，例如栓剂；(5)吸入，例如气雾剂、溶液剂和干粉剂；和(6)局部给药，例如乳膏剂、油膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂和凝胶剂。
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。
在一实施方案中，本发明公开的化合物可以配制成口服剂型。在另一实施方案中，本发明公开的化合物可以配制成吸入剂型。在另一实施方案中，本发明公开的化合物可以配制成经鼻给药剂型。在又一实施方案中，本发明公开的化合物可以配制成透皮给药剂型。还在一实施方案中，本发明公开的化合物可以配制成局部给药剂型。
本发明提供的药物组合物可以以压制片、研制片、可咀嚼锭剂、速溶片、复压片、肠溶片、糖衣或薄膜衣片来提供。肠溶片是用能抗胃酸作用但在肠中溶解或崩解的物质包衣的压制片，从而防止了活性成分接触胃的酸性环境。肠包衣包括，但不限于，脂肪酸、脂肪、水杨酸苯酯、蜡、紫胶、氨化紫胶和邻苯二甲酸乙酸纤维素酯。糖衣片为糖衣包围的压制片，其可利于掩盖令人不愉快的味道或气味并且能防止片剂氧化。薄膜包衣片为用水溶 性物质的薄层或薄膜覆盖的压制片。薄膜包衣包括，但不限于，羟乙基纤维素、羧甲基纤维素钠、聚乙二醇4000和邻苯二甲酸乙酸纤维素酯。薄膜包衣赋有和糖包衣相同的一般特性。复压片为经过超过一个压缩周期制备的压制片，包括多层片、压制包衣或干包衣片。
片剂剂型可以由呈粉末、结晶或颗粒状的活性成分单独的或与本发明描述的一种或多种载体或赋形剂组合来制备，所述载体和赋形剂包括粘合剂、崩解剂、控释聚合物、润滑剂、稀释剂和/或着色剂。增香剂和甜味剂在形成咀嚼片和锭剂时特别有用。
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。所述硬明胶胶囊也称为干填充胶囊(DFC)，由两段组成，一段塞入另一段中，因此完全包封了活性成分。软弹性胶囊(SEC)是软的、球形壳，比如明胶壳，其通过加入甘油、山梨醇或类似的多元醇塑化。软明胶壳可以包含防腐剂来预防微生物生长。合适的防腐剂为如本发明所述的那些，包括尼泊金甲酯和尼泊金丙酯，以及山梨酸。本发明提供的液体、半固体和固体剂型可以包囊在胶囊中。合适的液体和半固体剂型包括在碳酸丙烯酯、植物油或甘油三酯中的溶液和混悬剂。包含这样的溶液的胶囊可以如在美国专利U.S.Pat.Nos.4,328,245；4,409,239和4,410,545中描述的来制备。所述胶囊也可以采用如本领域技术人员已知的涂层，从而改善或维持活性成分的溶出。
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。乳剂为二相系统，其中一种液体以小球形式完全分散在另一种液体中，其可以是水包油型或油包水型。乳剂可以包括药学上可接受的非水液体和溶剂、乳化剂和防腐剂。混悬剂可以包括药学上可接受的助悬剂和防腐剂。含水醇溶液可以包括药学上可接受的缩醛，比如低级烷基醛的二(低级烷基)缩醛，例如乙醛二乙基缩醛；和具有一个或多个羟基的水溶性溶剂，比如丙二醇和乙醇。酏剂是透明的、甜味的水醇溶液。糖浆剂是浓的糖例如蔗糖的水溶液，并且还可以包含防腐剂。对于液体剂型，例如，在聚乙二醇中的溶液可以用足量的药学上可接受的液体载体例如水稀释，以精确方便地给药。
本发明提供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。在一实施方案中，本发明所公开的药物组合物可以配制成适于用干粉剂对患者吸入给药的剂型。在又一实施方案中，本发明所公开的药物组合物可以配制成适于通过喷雾器对患者吸入给药的剂型。通过吸入递送至肺的干粉组合物通常包含精细粉末状的本发明所公开的化合物和一种或多种精细粉末状的药学上可接受的赋形剂。特别适合用作干粉剂的药学上可接受的赋形剂为本领域技术人员所知晓，其包括乳糖、淀粉、甘露醇、和单-、二-和多糖。精细粉末可通过例如微粉化和研磨制备得到。一般来说，尺寸减小的(如微粉化的)化合物可以通过约1至10微米的D 50值(例如，用激光衍射法测量的)来定义。
适合于透皮给药的药物组合物可制备成不连续的贴片剂，意在与患者的表皮保持紧密接触一段延长的时间。例如，可通过离子渗透从贴片剂中递送活性成分，如Pharmaceutical Research,3(6),318(1986)中的一般描述。
适合于局部给药的药物组合物可以被配制成油膏剂、乳膏剂、混悬剂、洗剂、粉剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。例如，油膏剂、乳膏剂和凝胶剂可以用水或油基质，和适合的增稠剂和/或凝胶剂和/或溶剂来配置。这样的基质可以包括，水，和/或油例如液体石蜡和植物油(例如花生油或蓖麻油)，或溶剂例如聚乙二醇。根据基质性质使用的增稠剂和凝胶剂包括软石蜡、硬脂酸铝、鲸蜡硬脂醇、聚乙二醇、羊毛脂、蜂蜡、聚羧乙烯和纤维素衍生物，和/或单硬脂酸甘油脂和/或非离子型乳化剂。
本发明化合物也可以与作为靶向药物载体的可溶性聚合物结合。这样的聚合物包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-苯酚、聚羟乙基天冬酰胺苯酚或棕榈酰残基取代的聚氧乙烯聚赖氨酸。此外，本发明所公开的化合物可以与在实现药物的控制释放中使用的一类生物可降解的聚合物结合，例如，聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。
本发明提供的药物组合物可以通过注射、输注或植入肠胃外给药，用于局部或全身给药。如本发明使用的肠 胃外给药包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内、滑膜内和皮下给药。
本发明提供的药物组合物可以配制成适于肠胃外给药的任何剂型，包括溶液、混悬剂、乳剂、胶束、脂质体、微球、纳米体系和适于在注射前在液体中制成溶液或混悬液的固体形式。这样的剂型可以根据药物科学领域的技术人员已知的常规方法来制备(参见Remington:The Science和Practice of Pharmacy,同上)。
预期用于肠胃外给药的药物组合物可以包括一种或多种药学上可接受的载体和赋形剂，包括，但不限于，含水运载体、水混溶性运载体、非水运载体、抗微生物剂或抗微生物生长的防腐剂、稳定剂、溶解增强剂、等渗剂、缓冲剂、抗氧剂、局部麻醉剂、助悬剂和分散剂、湿润剂或乳化剂、络合剂、多价螯合剂或螯合剂、防冻剂、冷冻保护剂、增稠剂、pH调节剂和惰性气体。
本发明提供的药物组合物可以通过直肠栓剂给药，通过将药物与合适的无刺激性的赋形剂(如可可油，聚乙烯乙二醇合成的甘油酯)混合，常温下为固体，然后在直肠腔内液化或溶解释放药物。由于个体差异，症状的严重程度会呈现比较大的变化，而且每种药都有其独特的治疗特性，因此，对于每个个体的精确的给药方式，剂型和治疗方案都应该由执业医生来判定。
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。
虽然可以不用任何制剂而直接施用本发明的化合物，但本发明化合物通常是以含可药用赋型剂和至少一种活性组分的药物制剂的形式服用。这些制剂可以通过各种途径施用，包括经口、颊、直肠、鼻内、透皮、皮下、静脉内、肌内和鼻内给药。本发明方法中使用的许多化合物作为注射和口服组合物是有效的。
为了经皮给药，需要一种透皮释放装置(“贴剂”)。这种透皮贴剂可用来连续或间断注入控制量的本发明化合物。用于传送药物的透皮贴剂的结构和应用是本领域公知的。例如，参见，US5,023,252。这种贴剂可制成连续、脉动或按需释放药物。
常常希望或需要将药物组合物直接或间接引入脑中。直接技术通常涉及将药物传输导管置于宿主的心室系统以绕过血-脑屏障。在US5,011,472中描述了这样一种可植入输送系统，用于向躯体特定解剖学区域传送生物学因子。通过动脉内输注能够瞬间打开血-脑屏障的高渗溶液，可以增强亲水性药物的输送。
在本发明的一个优选实施方案中，提供了含有至少一种上述活性化合物并适于经颊和/或舌下或经鼻给药的药物制剂。该实施方案提供了以避免胃并发症的方式(如，首先绕过胃系统代谢和/或首先经过肝脏代谢)施用活性化合物。这种给药途径还可以降低吸附时间，从而更快地带来治疗效果。本发明化合物还可以提供特别有利的溶解性分布，有利于舌下/经颊给药制剂。这种制剂一般需要相对高的活性组分浓度，以便在制剂与舌下/颊粘膜表面接触的较短延续时间内，对舌下/颊粘膜的有限表面传送足量的活性组分，使得活性组分被吸收。因此，本发明化合物的极高活性及其高溶解性促使其适用于制备舌下/经颊给药制剂。
本文所使用的术语“治疗有效量”是指足以显示出有益的治疗效果的各活性组分的总量。例如，给药或使体内达到平衡的足以治疗、治愈或减轻疾病的症状的量。特殊的治疗方案所需的有效量依赖于多种因素，包括治疗的疾病，疾病的严重程度，使用的特定药物的活性，给药方式，特定药物的清除率，治疗持续时间，联合用药，年龄，体重，性别，饮食和病人的健康等。本领域关于“治疗有效量”需要考虑的其他因素的描述可参见Gilman et al.,eds.,Goodman And Gilman’s:The Pharmacological Bases of Therapeutics,8 th ed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17 th ed.,Mack Publishing Company,Easton,Pa.,1990。
优选将式(I)化合物配制成单位剂型，每剂含大约0.001-100mg活性组分，更经常是含约1.0-30mg活性组分。术语“单位剂型”是指适合作为人类患者和其它哺乳动物的单位剂量的物理分离单元，每个单元含有经计算能产生所需治疗效果的预定量活性组分以及合适的上述可药用赋型剂。
活性化合物通常在很大剂量范围内有效。例如，每天的剂量一般为约0.0001-30mg/kg体重。对于成人治疗，特别优选的剂量(单次剂量或均分剂量)为约0.1-15mg/kg/天。然而，应当理解，实际给药的化合物量将由主治 医师根据有关情况决定，包括所治疗的疾病、所选择的给药途径、实际要服用的一种或多种化合物、具体患者的年龄、体重和响应以及患者症状的严重程度，因此，以上剂量范围不应以任何方式限制本发明范围。在某些情况下，低于上述剂量范围低限的剂量水平可能更为合适，而在其它情况下，可以采用不产生任何副作用的更高剂量，其前提条件是，首先将这种较大剂量分成数个较小剂量供全天给药。
术语“给药”指给个体提供治疗有效量的药物，给药方式包括口服，舌下，静脉，皮下，经皮，肌内，皮内，鞘内，硬膜上，眼内，颅内，吸入，直肠，阴道等。给药剂型包括膏剂，洗剂，片剂，胶囊剂，丸剂，飞散性粉末剂，颗粒剂，栓剂，丹剂，锭剂，注射剂，无菌溶液或非水溶液剂，悬浮剂，乳剂，贴片剂等。活性组分与无毒的药学上可接受的载体(如葡萄糖，乳糖，阿拉伯树胶，明胶，甘露醇，淀粉糊，三硅酸镁，滑石粉，玉米淀粉，角蛋白，硅胶，土豆淀粉，尿素，右旋糖酐等)复合。
优选的给药途径会随着临床特征而变化，剂量的变化必须依赖于正在治疗的病人的情况，医生会根据个体患者来确定合适的剂量。每单位剂量的治疗有效量取决于体重，生理机能和选择的接种方案。每单位剂量的化合物是指每次给药时化合物的重量，不包括载体的重量(药物里含有载体)。
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。
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。
在一实施方案中，本发明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化合物或包含本发明化合物的药物组合物，来治疗本发明提及的疾病。
在一实施方案中，本发明化合物或包含本发明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。全身给药包括口服给药、胃肠外给药、透皮给药和直肠给药。典型的胃肠外给药是指通过注射或输注给药，包括静脉内、肌内和皮下注射或输注给药。局部给药包括施用于皮肤以及眼内、耳、阴道内、吸入和鼻内给药。在一个实施方案中，本发明化合物或包含本发明化合物的药物组合物可以是口服给药。在另一实施方案中，本发明化合物或包含本发明化合物的药物组合物可以是吸入给药。还在一实施方案中，本发明化合物或包含本发明化合物的药物组合物可以是经鼻内给药。
在一实施方案中，本发明化合物或包含本发明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。在一实施方案中，每天给药一次。在又一实施方案中，每天给药两次。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。本发明化合物或包含本发明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，本发明化合物或包含本发明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，可要求调整适宜的给药方案。
本发明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，或与之以同一药物组合物形式给药。这由本领域技术人员根据患者的健康、年龄、体重等身体的实际情况选择。如果配制为固定剂量，这种联用产品使用本发明的化合物(在本文所描述的剂量范围之内)和其他药学活性剂(在其剂量范围之内)。
相应地，在一个方面，本发明包括联合用药，其包括一定数量的至少一种本发明的化合物或其可药用盐、溶 剂化物、酯或前体药物和有效量的一种或多种附加治疗剂。
此外，本发明化合物可以以前药形式给药。在本发明中，本发明化合物的“前药”是对患者给药时，最终能在体内释放出本发明化合物的功能性衍生物。以前药形式给予本发明化合物时，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。
本发明化合物和药物组合物的用途
本发明提供的化合物和药物组合物可用于制备用于激活5-HT 1F受体的药品，也可以用于制备用于预防、治疗或减轻与5-HT 1F受体有关的疾病，特别是偏头痛的药品。
具体而言，本发明的化合物或药物组合物中化合物的量可以有效地可探测地选择性地激活5-HT 1F受体。
具体而言，本发明的化合物或药物组合物中化合物的量可以有效地可探测地选择性地抑制神经元蛋白质外渗。
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药物组合物的有效量对患者给药来预防、治疗或减轻与5-HT 1F受体有关的疾病。所述与5-HT 1F受体有关的疾病，进一步包括但并不限于，偏头痛、一般性疼痛、三叉神经痛、牙痛或颞下颌关节机能障碍疼痛、孤独症、强迫症、恐慌症、抑郁症、社交恐惧症、焦虑、广泛性焦虑症、睡眠障碍、创伤后综合征、慢性疲劳综合征、经前综合征或后黄体期综合征、边缘型人格障碍、破坏性行为障碍、冲动控制障碍、注意力缺陷多动障碍、酒精中毒、烟草滥用、缄默症、拔毛发癖、食欲过盛、神经性厌食症、早泄、勃起机能障碍、记忆丧失和痴呆。
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。
一般合成步骤
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。 1H NMR谱以CDC1 3、DMSO-d 6、CD 3OD或丙酮-d 6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)，q(quartet，四重峰)，m(multiplet，多重峰)，br(broadened，宽峰)，brs(broadened singlet，宽的单峰)，dd(doublet of doublets，双二重峰)，ddd(doublet of doublet of doublets，双双二重峰)，dt(doublet of triplets，双三重峰)，td(triplet of doublets，三双重峰)，tt(triplet of triplets，三三重峰)。偶合常数J，用赫兹(Hz)表示。
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-M(柱子型号：Zorbax SB-C18,2.1x 30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH 3CN)在(含0.1％甲酸的H 2O)中的比例，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。
纯的化合物使用Agilent 1260 pre-HPLC或Calesep pump 250 pre-HPLC(柱子型号：NOVASEP 50/80mm DAC)，在210nm/254nm用UV检测。
下面简写词的使用贯穿本发明：
CH 2Cl 2、DCM  二氯甲烷               mg            毫克
CDC1 3        氘代氯仿               g             克
DMSO         二甲基亚砜             mL、ml        毫升
DMSO-d 6      氘代二甲基亚砜         μL、μl      微升
EtOAc、EA    乙酸乙酯               nL、nl        纳升
CH 3OH、MeOH  甲醇                   min           分钟
CD 3OD        氘代甲醇               h             小时
nM           纳摩尔每升             PE            石油醚(60-90℃)
μM          微摩尔每升             RT、rt、r.t.  室温
mM           毫摩尔每升             EDTA-K 2       乙二胺四乙酸二钾
M            摩尔每升               PEG400        聚乙二醇400
ng           纳克                   Boc、BOC      叔丁氧羰基
μg          微克                   cAMP          Cyclic adenosine monophosphate、环磷酸腺苷
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R 1a、R 1b、R 1c、R 1d和R x具有本发明所述的定义。
合成方案1
Figure PCTCN2019120076-appb-000007
其中，R u为H、C 1-C 6烷基、C 1-C 6卤代烷基或C 3-C 8环烷基。
式( 7)所示的化合物可以通过下列过程制备得到：式( 1)所示的化合物与式( 2)所示的化合物反应，得到 式( 3)所示的化合物；然后式( 3)所示的化合物与式( 4)所示的化合物缩合，得到式( 5)所示的化合物。式( 5)所示的化合物脱除Boc保护基得到式( 6)所示的化合物；在还原剂(例如，氰基硼氢化钠)存在下，式( 6)所示的化合物的哌啶环的NH与相应的醛
Figure PCTCN2019120076-appb-000008
发生Borch还原胺化反应，得到式( 7)所示的目标产物。
合成方案2
Figure PCTCN2019120076-appb-000009
其中，R u为H、C 1-C 6烷基、C 1-C 6卤代烷基或C 3-C 8环烷基。
式( 13)所示的化合物可以通过下列过程制备得到：式( 8)所示的化合物与式( 4)所示的化合物反应，得到式( 9)所示的化合物；然后式( 9)所示的化合物与式( 10)所示的化合物反应，得到式( 11)所示的化合物。式( 11)所示的化合物脱除Boc保护基得到式( 12)所示的化合物；在还原剂(例如，氰基硼氢化钠)存在下，式( 12)所示的化合物的哌啶环的NH与相应的醛
Figure PCTCN2019120076-appb-000010
发生Borch还原胺化反应，得到式( 13)所示的目标产物。
以下结合实施例对本发明提供的化合物、药物组合物及其应用进行进一步说明。
实施例
实施例1 4-氟-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000011
步骤1)N-(6-溴吡啶-2-基)-4-氟苯甲酰胺的合成
Figure PCTCN2019120076-appb-000012
在0℃下将6-溴吡啶-2-胺(350mg,2.02mmol)，三乙胺(0.6mL,4.34mmol)和二氯甲烷(10mL)加入到100mL单口圆底烧瓶中，滴加入4-氟苯甲酰氯(0.3mL,2.5mmol)，转移至25℃下反应12小时；反应结束后，将反应液倒入水(20mL)中，用二氯甲烷萃取(20mL)，收集有机相，减压旋干，柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/1)得到标题化合物为淡黄色固体(588mg,98.5％)。
MS(ESI,pos.ion)m/z:295.0[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.33(d,J＝8.4Hz,1H),7.96–7.89(m,2H),7.62(t,J＝8.0Hz,1H),7.27(d,J＝ 7.2Hz,1H),7.21–7.16(m,2H).
步骤2)叔丁基4-((6-(4-氟苯甲酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯的合成
Figure PCTCN2019120076-appb-000013
将叔丁基4-亚甲基哌啶-1-羧酸酯(440mg,2.2mmol)和9-硼双环[3.3.1]壬烷(5.5mL,0.5M四氢呋喃溶液)加入到100mL单口圆底烧瓶中，氮气保护下油浴70℃反应7小时；然后冷却至25℃，加入N-(6-溴吡啶-2-基)-4-氟苯甲酰胺(578mg,1.96mmol)、四氢呋喃(5mL)、水(5mL)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(60mg,0.08mmol)和氢氧化钠(250mg,6.25mmol)，氮气保护下油浴70℃继续反应14小时；停止反应，加入水(20mL)，再用二氯甲烷萃取(30mL×2)，收集有机相，加入无水硫酸钠(2g)干燥，过滤，滤液减压旋干，柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝5/1)得到标题化合物为黄色油状物(365mg,45.1％)。
MS(ESI,pos.ion)m/z:414.3[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.17(d,J＝8.0Hz,1H),7.98–7.92(m,2H),7.65(t,J＝8.0Hz,1H),7.16(t,J＝8.0Hz,2H),6.88(d,J＝7.6Hz,1H),4.13–3.94(m,2H),2.68–2.59(m,4H),1.92–1.77(m,3H),1.61–1.57(m,2H),1.44(s,9H).
步骤3)4-氟-N-(6-(哌啶-4-基甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000014
在25℃下将叔丁基4-((6-(4-氟苯甲酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯(350mg,0.85mmol)和甲醇(5mL)加入到50mL单口圆底烧瓶中，加入氯化氢乙酸乙酯溶液(2M，3mL)，继续搅拌反应2小时；停止反应，减压旋干，加入饱和碳酸氢钠溶液(20mL)，然后加入二氯甲烷(20mL)萃取；分液，有机相用无水硫酸钠(1g)干燥；过滤，滤液减压旋干，柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)即得到标题化合物为白色固体(0.12g,45.2％)。
MS(ESI,pos.ion)m/z:314.2[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.12–8.08(m,2H),7.99(d,J＝8.0Hz,1H),7.75(t,J＝8.0Hz,1H),7.33(t,J＝8.8Hz,2H),7.04(d,J＝7.6Hz,1H),3.19(d,J＝12.8Hz,2H),2.81–2.73(m,2H),2.64(d,J＝6.8Hz,2H),2.03–1.95(m,1H),1.72–1.69(m,2H),1.49–1.39(m,2H).
步骤4)4-氟-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000015
在25℃将4-氟-N-(6-(哌啶-4-基甲基)吡啶-2-基)苯甲酰胺(110mg,0.35mmol)和甲醇(5mL)加入到50mL单口圆底烧瓶中，加入醋酸(0.06mL,1.0mmol)；加入甲醛(40％,0.04mL,0.7mmol)，然后将氰基硼氢化钠(75mg,1.2mmol)分批加入到反应液中。继续反应3小时后，加入饱和碳酸氢钠溶液(20mL)淬灭，然后用二氯甲烷萃取(20mL×2)。合并有机相，无水硫酸钠(2g)干燥；过滤，滤液减压旋干，柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)得到标题化合物为白色固体(80mg,69.9％)。
MS(ESI,pos.ion)m/z:328.2[M+H] +；
1H NMR(400MHz,CD 3OD)δ(ppm)7.93(t,J＝8.0Hz,1H),7.87(dd,J＝8.6,5.3Hz,2H),7.75(d,J＝8.5Hz,1H), 7.13(d,J＝7.6Hz,1H),7.04(t,J＝8.6Hz,2H),3.27(d,J＝12.1Hz,2H),2.77–2.70(m,4H),2.60(s,3H),1.74–1.70(m,2H),1.44–1.35(m,2H).
实施例2 4-氯-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000016
步骤1)N-(6-溴吡啶-2-基)-4-氯苯甲酰胺的合成
Figure PCTCN2019120076-appb-000017
本步骤标题化合物参照实施例1步骤1所描述的方法制备得到，即将6-溴吡啶-2-胺(350mg,2.02mmol)，三乙胺(0.6mL,4.34mmol)和4-氯苯甲酰氯(0.31mL,2.4mmol)在二氯甲烷(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物为淡黄色固体(616mg,98.4％)。
MS(ESI,pos.ion)m/z:310.9[M+H] +；
步骤2)叔丁基4-((6-(4-氯苯甲酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯的合成
Figure PCTCN2019120076-appb-000018
本步骤标题化合物参照实施例1步骤2所描述的方法制备得到，即将叔丁基4-亚甲基哌啶-1-羧酸酯(800mg,4.0mmol)、9-硼双环[3.3.1]壬烷(8.0mL,0.5M四氢呋喃溶液)、N-(6-溴吡啶-2-基)-4-氯苯甲酰胺(600mg,1.93mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(60mg,0.08mmol)、氢氧化钠(250mg,6.25mmol)在四氢呋喃(5mL)和水(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝4/1)，得到标题化合物为淡黄色固体(560mg,67.6％)。
MS(ESI,pos.ion)m/z:430.4[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.56(s,1H),8.16(d,J＝8.4Hz,1H),7.87(d,J＝8.4Hz,2H),7.65(t,J＝8.0Hz,1H),7.46(d,J＝8.4Hz,2H),6.88(d,J＝7.6Hz,1H),4.05(brs,2H),2.67–2.59(m,4H),1.90–1.83(m,1H),1.60–1.57(m,2H),1.44(s,9H),1.22–1.12(m,2H).
步骤3)4-氯-N-(6-(哌啶-4-基甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000019
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将叔丁基4-((6-(4-氯苯甲酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯(450mg,1.05mmol)和氯化氢乙酸乙酯溶液(2M，4mL)在甲醇(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为淡黄色固体(294mg,85％)。
MS(ESI,pos.ion)m/z:330.3[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.62(s,1H),8.18(d,J＝8.4Hz,1H),7.90(d,J＝8.8Hz,2H),7.66(t,J＝8.0Hz,1H),7.47(d,J＝8.4Hz,2H),6.87(d,J＝7.2Hz,1H),3.46(d,J＝12.0Hz,2H),2.83(t,J＝10.4Hz,2H),2.68(d,J＝6.8Hz,2H),2.03(br,1H),1.78(br,4H).
步骤4)4-氯-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000020
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将4-氯-N-(6-(哌啶-4-基甲基)吡啶-2-基)苯甲酰胺(500mg,1.52mmol)、氰基硼氢化钠(222mg,3.7mmol)和甲醛(40％,0.27mL,3.7mmol)在甲醇(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为白色固体(502mg,95.9％)。
MS(ESI,pos.ion)m/z:344.4[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.20(d,J＝8.0Hz,1H),7.92(d,J＝8.4Hz,2H),7.69(t,J＝8.0Hz,1H),7.48(d,J＝8.8Hz,2H),6.90(d,J＝7.6Hz,1H),3.52(d,J＝6.4Hz,2H),3.12(q,J＝7.6Hz,1H),2.78(s,3H),2.72(br,4H),2.04–1.98(m,2H),1.85–1.82(m,2H).
实施例3 2,4-二氟-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000021
步骤1)N-(6-溴吡啶-2-基)-2,4-二氟苯甲酰胺的合成
Figure PCTCN2019120076-appb-000022
本步骤标题化合物参照实施例1步骤1所描述的方法制备得到，即将6-溴吡啶-2-胺(500mg,2.88mmol)，三乙胺(0.84mL,6.0mmol)和2,4-二氟苯甲酰氯(0.45mL,3.7mmol)在二氯甲烷(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物为白色固体(0.9g,99.5％)。
MS(ESI,pos.ion)m/z:313.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.32(d,J＝8.4Hz,1H),7.61(t,J＝8.0Hz,1H),7.27(d,J＝6.8Hz,1H),7.09–7.00(m,2H),6.99–6.91(m,2H).
步骤2)叔丁基4-((6-(2,4-二氟苯甲酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯的合成
Figure PCTCN2019120076-appb-000023
本步骤标题化合物参照实施例1步骤2所描述的方法制备得到，即将叔丁基4-亚甲基哌啶-1-羧酸酯(700mg,3.5mmol)、9-硼双环[3.3.1]壬烷(8.0mL,0.5M四氢呋喃溶液)、N-(6-溴吡啶-2-基)-2,4-二氟苯甲酰胺(900mg,2.88mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(70mg,0.09mmol)、氢氧化钠(350mg,8.75mmol)在四氢呋喃(5mL)和水(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝4/1)，得到标题化合物为淡黄色固体(440mg,35.5％)。
MS(ESI,pos.ion)m/z:432.4[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.87(d,J＝12.4Hz,1H),8.22–8.10(m,2H),7.64(t,J＝8.0Hz,1H),7.07–7.01(m,1H),6.98–6.91(m,1H),6.89(d,J＝7.2Hz,1H),4.06(brs,2H),2.72–257(m,4H),1.96–1.84(m,1H),1.62– 1.59(m,2H),1.44(s,9H),1.24–1.12(m,2H).
步骤3)2,4-二氟-N-(6-(哌啶-4-基甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000024
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将叔丁基4-((6-(2,4-二氟苯甲酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯(430mg,1.0mmol)和氯化氢乙酸乙酯溶液(2M,3mL)在甲醇(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为白色固体(320mg,96.9％)。
MS(ESI,pos.ion)m/z:332.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.90(d,J＝12.8Hz,1H),8.20–8.12(m,2H),7.64(t,J＝8.0Hz,1H),7.07–7.00(m,1H),6.98–6.90(m,1H),6.87(d,J＝7.6Hz,1H),3.29(d,J＝12.8Hz,2H),2.77–2.60(m,4H),2.05–1.98(m,1H),1.77–1.74(m,2H),1.61–1.47(m,2H).
步骤4)2,4-二氟-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000025
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将2,4-二氟-N-(6-(哌啶-4-基甲基)吡啶-2-基)苯甲酰胺(353mg,1.07mmol)、氰基硼氢化钠(204mg,3.4mmol)和甲醛(40％,0.16mL,2.2mmol)在甲醇(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为白色固体(310mg,84.3％)。
MS(ESI,pos.ion)m/z:346.1[M+H] +；
1H NMR(400MHz,CD 3OD)δ(ppm)8.13(d,J＝8.4Hz,1H),8.08(td,J＝8.8,6.8Hz,1H),7.69(t,J＝7.6Hz,1H),7.08–7.01(m,1H),7.00–6.93(m,2H),3.44(d,J＝12.4Hz,2H),2.91(t,J＝12.0Hz,2H),2.82(s,3H),2.69(d,J＝7.2Hz,2H),1.90(d,J＝14.8Hz,2H),1.62(td,J＝15.2,3.6Hz,2H).
实施例4 4-氯-2-氟-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000026
步骤1)N-(6-溴吡啶-2-基)-4-氯-2-氟苯甲酰胺的合成
Figure PCTCN2019120076-appb-000027
本步骤标题化合物参照实施例1步骤1所描述的方法制备得到，即将6-溴吡啶-2-胺(500mg,2.88mmol)，三乙胺(0.84mL,6.0mmol)和4-氯-2-氟苯甲酰氯(530mg,2.7mmol)在二氯甲烷(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物为白色固体(472mg,53.2％)。
MS(ESI,pos.ion)m/z:329.0[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.32(d,J＝8.0Hz,1H),8.08(t,J＝8.4Hz,1H),7.61(t,J＝8.0Hz,1H),7.32(dd,J＝8.8,2.0Hz,1H),7.29–7.23(m,2H),7.22–7.14(m,1H).
步骤2)叔丁基4-((6-(4-氯-2-氟苯甲酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯的合成
Figure PCTCN2019120076-appb-000028
本步骤标题化合物参照实施例1步骤2所描述的方法制备得到，即将叔丁基4-亚甲基哌啶-1-羧酸酯(600mg,3.0mmol)、9-硼双环[3.3.1]壬烷(6.0mL,0.5M四氢呋喃溶液)、N-(6-溴吡啶-2-基)-4-氯-2-氟苯甲酰胺(472mg,1.44mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(40mg,0.05mmol)、氢氧化钠(200mg,5.0mmol)在四氢呋喃(5mL)和水(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝4/1)，得到标题化合物为淡黄色固体(328mg,51.1％)。
MS(ESI,pos.ion)m/z:448.3[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.91(d,J＝12.8Hz,1H),8.17(d,J＝8.0Hz,1H),8.11(t,J＝8.8Hz,1H),7.67(t,J＝8.0Hz,1H),7.33(dd,J＝8.4,1.6Hz,1H),7.26(dd,J＝11.2,2.4Hz,1H),6.91(d,J＝7.6Hz,1H),4.08(brs,2H),2.74–2.60(m,4H),1.98–1.89(m,1H),1.63(d,J＝12.4Hz,2H),1.47(s,9H),1.26–1.16(m,2H).
步骤3)4-氯-2-氟-N-(6-(哌啶-4-基甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000029
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将叔丁基4-((6-(4-氯-2-氟苯甲酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯(318mg,0.71mmol)和氯化氢乙酸乙酯溶液(2M,3mL)在二氯甲烷(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为白色固体(0.24g,97.2％)。
MS(ESI,pos.ion)m/z:348.3[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.99(d,J＝12.4Hz,1H),8.18(d,J＝8.3Hz,1H),8.08(t,J＝8.4Hz,1H),7.66(t,J＝8.4Hz,1H),7.31(dd,J＝8.4,1.6Hz,1H),7.23(d,J＝1.6Hz,1H),6.89(d,J＝7.2Hz,1H),3.35(d,J＝12.4Hz,2H),3.01(q,J＝7.2Hz,1H),2.77(t,J＝10.8Hz,2H),2.67(d,J＝7.2Hz,2H),1.80–1.76(m,2H),1.62–1.53(m,2H).
步骤4)4-氯-2-氟-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000030
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将4-氯-2-氟-N-(6-(哌啶-4-基甲基)吡啶-2-基)苯甲酰胺(263mg,0.76mmol)、氰基硼氢化钠(150mg,2.5mmol)和甲醛(40％,0.13mL,1.8mmol)在甲醇(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为白色固体(0.16g,58.2％)。
MS(ESI,pos.ion)m/z:362.4[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.17(d,J＝8.4Hz,1H),8.07(t,J＝8.4Hz,1H),7.67(t,J＝8.0Hz,1H),7.31(dd,J＝8.4,1.6Hz,1H),7.24(dd,J＝11.6,1.6Hz,1H),6.90(d,J＝7.2Hz,1H),3.51(d,J＝11.6Hz,2H),3.11(q,J＝6.8Hz,1H),2.76(s,3H),2.73–2.62(m,4H),2.05–1.98(m,2H),1.83–1.80(m,2H).
实施例5 2,4,6-三氟-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000031
步骤1)N-(6-溴吡啶-2-基)-2,4,6-三氟苯甲酰胺的合成
Figure PCTCN2019120076-appb-000032
本步骤标题化合物参照实施例1步骤1所描述的方法制备得到，即将6-溴吡啶-2-胺(500mg,2.88mmol)，三乙胺(0.84mL,6.0mmol)和2,4,6-三氟苯甲酰氯(0.46mL,3.5mmol)在二氯甲烷(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2/1)，得到标题化合物为白色固体(0.95g,99.3％)。
MS(ESI,pos.ion)m/z:331.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)9.13(s,1H),8.35(d,J＝8.0Hz,1H),7.67–7.61(m,2H),7.46–7.39(m,1H),7.30(d,J＝7.6Hz,1H).
步骤2)叔丁基4-((6-(2,4,6-三氟苯甲酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯的合成
Figure PCTCN2019120076-appb-000033
本步骤标题化合物参照实施例1步骤2所描述的方法制备得到，即将叔丁基4-亚甲基哌啶-1-羧酸酯(700mg,3.5mmol)、9-硼双环[3.3.1]壬烷(8.0mL,0.5M四氢呋喃溶液)、N-(6-溴吡啶-2-基)-2,4,6-三氟苯甲酰胺(950mg,2.88mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(70mg,0.09mmol)、氢氧化钠(350mg,8.75mmol)在四氢呋喃(5mL)和水(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝4/1)，得到标题化合物为淡黄色固体(0.37g,28.7％)。
MS(ESI,pos.ion)m/z:450.4[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.38(s,1H),8.14(d,J＝8.4Hz,1H),7.66(t,J＝8.0Hz,1H),6.90(d,J＝7.2Hz,1H),6.79–6.73(m,2H),4.05(brs,2H),2.69–2.55(m,4H),1.85(dd,J＝8.0,4.3Hz,1H),1.60–1.56(m,2H),1.43(s,9H),1.21–1.12(m,2H).
步骤3)2,4,6-三氟-N-(6-(哌啶-4-基甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000034
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将叔丁基4-((6-(2,4,6-三氟苯甲酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯(360mg,0.8mmol)和氯化氢乙酸乙酯溶液(2M,3mL)在甲醇(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为白色固体(0.27g,96.5％)。
MS(ESI,pos.ion)m/z:350.3[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.83(s,1H),8.16(d,J＝8.0Hz,1H),7.66(t,J＝7.6Hz,1H),6.89(d,J＝7.2Hz,1H),6.75(t,J＝8.4Hz,2H),3.29(d,J＝11.6Hz,2H),2.92(q,J＝7.2Hz,1H),2.70(t,J＝12.0Hz,2H),2.61(d,J＝6.4Hz,2H),1.73(d,J＝12.0Hz,2H),1.63–1.45(m,2H).
步骤4)2,4,6-三氟-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)苯甲酰胺的合成
Figure PCTCN2019120076-appb-000035
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将2,4,6-三氟-N-(6-(哌啶-4-基甲基)吡啶-2-基)苯甲酰胺(296mg,0.85mmol)、氰基硼氢化钠(168mg,2.8mmol)和甲醛(40％,0.13mL,1.8mmol)在甲醇(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为淡黄色油状物(0.2g,64.9％)。
MS(ESI,pos.ion)m/z:364.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.36(s,1H),8.15(d,J＝8.2Hz,1H),7.65(t,J＝8.0Hz,1H),6.92(d,J＝7.4Hz,1H),6.79–6.72(m,2H),3.53(d,J＝11.8Hz,2H),3.12(q,J＝6.8Hz,1H),2.77(s,3H),2.72–2.62(m,4H),2.07–1.99(m,2H),1.84–1.80(m,2H).
实施例6 5-氟-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)吡啶甲酰胺的合成
Figure PCTCN2019120076-appb-000036
步骤1)叔丁基4-((6-溴吡啶-2-基)甲基)哌啶-1-羧酸酯的合成
Figure PCTCN2019120076-appb-000037
本步骤标题化合物参照实施例1步骤2所描述的方法制备得到，即将叔丁基4-亚甲基哌啶-1-羧酸酯(460mg,2.3mmol)、9-硼双环[3.3.1]壬烷(6.0mL,0.5M四氢呋喃溶液)、2,6-二溴吡啶(500mg,2.1mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(60mg,0.08mmol)、氢氧化钠(260mg,6.5mmol)在四氢呋喃(5mL)和水(5mL)中反应制备，粗产物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝4/1)，得到标题化合物为淡黄色油状物(0.226g,30.1％)。
MS(ESI,pos.ion)m/z:299.1[M+H-56] +；
1H NMR(400MHz,CDCl 3)δ(ppm)7.46–7.41(m,1H),7.30(d,J＝7.6Hz,1H),7.03(d,J＝7.6Hz,1H),4.05(brs,2H),2.67–2.65(m,4H),1.98–1.89(m,1H),1.59–1.56(m,2H),1.44(s,9H),1.22–1.10(m,2H).
步骤2)叔丁基4-((6-(5-氟吡啶酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯的合成
Figure PCTCN2019120076-appb-000038
将叔丁基4-((6-溴吡啶-2-基)甲基)哌啶-1-羧酸酯(450mg,1.27mmol)、5-氟吡啶-2-甲酰胺(271mg,1.9mmol)、碳酸钾(1.3g,9.42mmol)、碘化亚铜(260mg,1.4mmol)、(1R,2R)-N 1,N 2-二甲基环己烷-1,2-二胺(110mg,0.8mmol)、水(1.1mL)和甲苯(10mL)加入到100mL单口烧瓶中，氮气保护下115℃继续反应12小时；停止反应，加入水(20mL)，再用二氯甲烷萃取(30mL×2)，收集有机相，加入无水硫酸钠(1.5g)干燥，过滤，滤液减压旋干，柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝4/1)得到标题化合物为白色固体(0.33g,62.9％)。
MS(ESI,pos.ion)m/z:415.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)10.23(s,1H),8.47(d,J＝2.4Hz,1H),8.33(dd,J＝8.8,4.4Hz,1H),8.20(d,J＝8.4Hz,1H),7.65(t,J＝8.0Hz,1H),7.59(td,J＝8.4,2.8Hz,1H),6.88(d,J＝7.6Hz,1H),4.06(s,2H),2.73–2.59(m, 4H),1.99–1.89(m,1H),1.63–1.59(m,2H),1.44(s,9H),1.25–1.13(m,2H).
步骤3)5-氟-N-(6-(哌啶-4-基甲基)吡啶-2-基)吡啶甲酰胺的合成
Figure PCTCN2019120076-appb-000039
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将叔丁基4-((6-(5-氟吡啶酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯(320mg,0.77mmol)和氯化氢乙酸乙酯溶液(2M,6mL)在二氯甲烷(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为白色固体(0.23g,94.6％)。MS(ESI,pos.ion)m/z:315.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)10.22(s,1H),8.49(d,J＝2.4Hz,1H),8.33(dd,J＝8.8,4.4Hz,1H),8.21(d,J＝8.4Hz,1H),7.66(t,J＝7.6Hz,1H),7.59(td,J＝8.0,2.4Hz,1H),6.88(d,J＝7.2Hz,1H),3.32(d,J＝12.4Hz,2H),2.75(t,J＝12.0Hz,2H),2.68(d,J＝7.2Hz,2H),2.10–2.02(m,1H),1.80–1.76(m,2H),1.63–1.52(m,2H).
步骤4)5-氟-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)吡啶甲酰胺的合成
Figure PCTCN2019120076-appb-000040
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将5-氟-N-(6-(哌啶-4-基甲基)吡啶-2-基)吡啶甲酰胺(293mg,0.93mmol)、氰基硼氢化钠(114mg,1.9mmol)和甲醛(40％,0.14mL,2.0mmol)在甲醇(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为黄色固体(0.245g,80.1％)。
MS(ESI,pos.ion)m/z:329.3[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.47(s,1H),8.32(dd,J＝8.8,4.4Hz,1H),8.20(d,J＝8.4Hz,1H),7.65(t,J＝7.6Hz,1H),7.59(t,J＝8.0Hz,1H),6.87(d,J＝7.2Hz,1H),3.50(brs,2H),3.10(s,3H),2.75–2.70(m,6H),1.83(brs,2H).
实施例7 5-氯-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)吡啶甲酰胺的合成
Figure PCTCN2019120076-appb-000041
步骤1)叔丁基4-((6-(5-氯吡啶酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯的合成
Figure PCTCN2019120076-appb-000042
将叔丁基4-((6-溴吡啶-2-基)甲基)哌啶-1-羧酸酯(500mg,1.4mmol)、5-氯吡啶-2-甲酰胺(368mg,2.4mmol)、碳酸钾(1.5g,10.9mmol)、碘化亚铜(260mg,1.4mmol)、(1R,2R)-N 1,N 2-二甲基环己烷-1,2-二胺(130mg,0.9mmol)、水(1.2mL)和甲苯(10mL)加入到100mL单口烧瓶中，氮气保护下115℃继续反应12小时；停止反应，加入水(20mL)，再用二氯甲烷萃取(30mL×2)，收集有机相，加入无水硫酸钠(1.5g)干燥，过滤，滤液减压旋干，柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝4/1)得到标题化合物为白色固体(0.436g,71.9％)。
MS(ESI,pos.ion)m/z:431.3[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)10.24(s,1H),8.58(d,J＝2.0Hz,1H),8.23(dd,J＝13.2,8.4Hz,2H),7.88(dd,J＝8.4,2.4Hz,1H),7.65(t,J＝8.0Hz,1H),6.89(d,J＝7.6Hz,1H),4.06(brs,2H),2.89–2.73(m,4H),2.00–1.88(m,1H),1.61(d,J＝12.8Hz,2H),1.44(s,9H),1.25–1.17(m,2H).
步骤2)5-氯-N-(6-(哌啶-4-基甲基)吡啶-2-基)吡啶甲酰胺的合成
Figure PCTCN2019120076-appb-000043
本步骤标题化合物参照实施例1步骤3所描述的方法制备得到，即将叔丁基4-((6-(5-氯吡啶酰胺)吡啶-2-基)甲基)哌啶-1-羧酸酯(426mg,0.99mmol)和氯化氢乙酸乙酯溶液(2M,6mL)在二氯甲烷(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20/1)，得到标题化合物为黄色固体(0.32g,97.9％)。
MS(ESI,pos.ion)m/z:331.2[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)10.25(s,1H),8.61(d,J＝2.0Hz,1H),8.24(t,J＝8.4Hz,2H),7.89(dd,J＝8.4,2.0Hz,1H),7.67(t,J＝7.6Hz,1H),6.89(d,J＝7.6Hz,1H),3.37(d,J＝12.4Hz,2H),2.78(t,J＝11.2Hz,2H),2.70(d,J＝7.2Hz,2H),2.09(brs,1H),1.81(d,J＝12.8Hz,2H),1.69–1.58(m,2H).
步骤3)5-氯-N-(6-((1-甲基哌啶-4-基)甲基)吡啶-2-基)吡啶甲酰胺的合成
Figure PCTCN2019120076-appb-000044
本步骤标题化合物参照实施例1步骤4所描述的方法制备得到，即将5-氯-N-(6-(哌啶-4-基甲基)吡啶-2-基)吡啶甲酰胺(320mg,0.97mmol)、氰基硼氢化钠(132mg,2.2mmol)和甲醛(40％,0.14mL,2.0mmol)在甲醇(10mL)中反应制备，粗产物经硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30/1)，得到标题化合物为白色固体(0.306g,91.3％)。
MS(ESI,pos.ion)m/z:345.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm)8.59(s,1H),8.23(t,J＝8.0Hz,2H),7.89(dd,J＝8.0,1.6Hz,1H),7.68(t,J＝8.0Hz,1H),6.92(d,J＝7.2Hz,1H),3.74(brs,2H),3.51(brs,2H),2.83(s,3H),2.73(d,J＝7.2Hz,2H),1.95–1.73(m,4H).
生物试验
实施例A：评价本发明化合物对CHO-K1细胞转染的人源5-HT 1F受体的激动作用
实验目的：使用HitHunter cAMP检测试剂盒，评价本发明化合物对CHO-K1细胞转染的人源5-HT 1F受体的激动作用。
实验简要流程：将CHO-K1细胞培养于384微孔板中，细胞培养基(AssayComplete TM Cell Plating Reagent,DIscoverX)体积为20μL，细胞密度为10,000/孔，置于37℃、5％CO 2过夜培养。然后移除培养基，每孔先加入15μL cAMP Assay Buffer(DIscoverX)，然后加入5μL共含有4X供试品(测试化合物或5-HT)和4X毛猴素(毛猴素终浓度为15μM)的测试样品，微孔板置于37℃培养30分钟。然后加入5μL cAMP Antibody Reagent(DiscoverX)和20μL cAMP Working Detection Solution(DiscoverX)避光孵育1小时，然后加入20μL cAMP Solution A，避光孵育3小时。将微孔板置于酶标仪(PerkinElmer EnvisionTM)读取发光信号强度。通过测试不同浓度的化合物，得到相应的发光信号强度，以此计算出激动率((1-(Y/Z))*100％＝激动率，其中，Y表示加测试样品的发光信号强度，Z表示只加毛猴素的发光信号强度)，再通过Prism软件计算化合物剂量-效果曲线，产生半最大响应的激动剂浓度 以EC 50值表示。结果见表A。本实验采用5-HT作为阳性对照药，以确保实验体系正常。
表A：本发明化合物对CHO-K1细胞转染的人源5-HT 1F受体的激动作用测定结果
实施例号 EC 50(μM)
实施例3 0.92
实施例5 0.32
实验结果显示，本发明化合物具有较强的5-HT 1F受体激动活性。
实施例B：大鼠、犬静注或灌胃定量本发明化合物的药代动力学评价
发明人在大鼠、犬体内对本发明的化合物进行了药代动力学评估。其中，动物信息详见表1。
表1：本发明受试动物信息表
种系 等级 性别 体重 年龄 来源
SD大鼠 SPF 雄性 180-350g 6-11周 湖南斯莱克景达实验动物有限公司
Beagle犬 普通级 雄性 8～12kg 6-12月 北京玛斯生物技术有限公司
实验方法
将本发明化合物以5％DMSO+60％PEG400+35％Saline溶液或10％DMSO+10％Kolliphor HS15+30％PEG400+50％Saline溶液形式，对受试动物进行给药，给药前动物禁食12h，自由饮水。对于静脉注射给药组，给药剂量为0.5mg/kg或1mg/kg，给药后在以下时间点静脉取血(取血量约0.15mL)：0.083、0.25、0.5、1.0、2.0、4.0、6.0、8.0和24h(犬)或0.083、0.25、0.5、1.0、2.0、5.0、7.0和24h(大鼠)，采血管内预先加入EDTA-K 2作为抗凝剂，血样在12,000rpm下离心2分钟，收集血浆，并于-20℃或-70℃下保存。对于灌胃给药组，给药剂量为2.5mg/kg或5mg/kg，给药后在以下时间点进行静脉取血(取血量约0.15mL)：0.25、0.5、1.0、2.0、4.0、6.0、8.0和24h(犬)或0.25、0.5、1.0、2.0、5.0、7.0和24h(大鼠)，采血管内预先加入EDTA-K 2作为抗凝剂，血样在12,000rpm下离心2分钟，收集血浆，并于-20℃或-70℃下保存。
对上述收集的血浆样品进行处理(冰冻血浆于室温下融化后，涡旋15s混匀，取10-20μL血浆，加入含内标的乙腈溶液120-150μL，涡旋5min混匀，4,000rpm下离心5分钟，取上清液100μL，加入120-150μL甲醇-水(v/v＝1/1)混匀)后，采用LC-MS/MS分析血浆中化合物的浓度。分析结果表明，本发明化合物在大鼠、犬体内均具有较好的药代动力学性质。说明本发明化合物成药性更好，具有更好的临床应用前景。
在本说明书的描述中，参考术语“一个实施例”、“一实施方案”、“一些实施例”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例、实施方案或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例、实施方案或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例、实施方案或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例、实施方案或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例、实施方案或示例以及不同实施例、实施方案或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (10)

  1. 一种化合物，其为式(I)所示的化合物，或者式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
    Figure PCTCN2019120076-appb-100001
    其中：
    X为N或CR x；
    各R 1a、R 1b、R 1c、R 1d和R x独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 6烷基)、-C(＝O)-(C 1-C 6烷氧基)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷硫基、C 1-C 6烷氨基、羟基取代的C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基；
    R 2为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基或羟基取代的C 1-C 6烷基；
    R 3、R 4和R 5各自独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基或羟基取代的C 1-C 6烷基；和
    R 6为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 6烷基)、-C(＝O)-(C 1-C 6烷氧基)、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 1-C 6烷硫基、C 1-C 6烷氨基、羟基取代的C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基。
  2. 根据权利要求1所述的化合物，其中各R 1a、R 1b、R 1c、R 1d和R x独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 4烷基)、-C(＝O)-(C 1-C 4烷氧基)、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 1-C 4烷硫基、C 1-C 4烷氨基、羟基取代的C 1-C 4烷基、C 3-C 6环烷基、3-6元杂环基、C 6-C 10芳基或5-10元杂芳基；
    R 2为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基或羟基取代的C 1-C 4烷基；
    R 3、R 4和R 5各自独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、C 1-C 4烷基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基或羟基取代的C 1-C 4烷基。
  3. 根据权利要求1或2所述的化合物，其中各R 1a、R 1b、R 1c、R 1d和R x独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-OCH 3、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲硫基、乙硫基、甲氨基、二甲氨基、乙氨基、羟甲基、2-羟基乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、茚基、萘基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、吲哚基或喹啉基；
    R 2为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、-CF 3、-CH 2CF 3、甲氧基、乙氧基、正丙基氧基或异丙基氧基；
    R 3、R 4和R 5各自独立地为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-COOH、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、-CF 3、-CH 2CF 3、甲氧基、乙氧基、正丙基氧基或异丙基氧基。
  4. 根据权利要求1所述的化合物，其中R 6为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-(C 1-C 4烷基)、-C(＝O)-(C 1-C 4烷氧基)、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 1-C 4卤代烷基、C 1-C 4烷氧基、C 1-C 4卤代烷氧基、C 1-C 4烷硫基、C 1-C 4烷氨基、羟基取代的C 1-C 4烷基、C 3-C 6环烷基、3-6元杂环基、C 6-C 10芳基或5-10元杂芳基。
  5. 根据权利要求1或4所述的化合物，其中R 6为H、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-SH、-COOH、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)N(CH 3) 2、-C(＝O)-CH 3、-C(＝O)-OCH 3、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF 2、-CF 3、-CHFCH 2F、-CF 2CHF 2、-CH 2CHF 2、-CH 2CF 3、-CH 2CF 2CHF 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF 2、-OCF 3、-OCHFCH 2F、-OCF 2CHF 2、-OCH 2CF 3、-OCH 2CF 2CHF 2、甲硫基、乙硫基、甲氨基、二甲氨基、乙氨基、羟甲基、2-羟基乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、茚基、萘基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、吲哚基或喹啉基。
  6. 根据权利要求1所述的化合物，其为具有下列之一结构的化合物或具有下列之一结构的化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它的前药：
    Figure PCTCN2019120076-appb-100002
    Figure PCTCN2019120076-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
    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。
  8. 权利要求1-6任意一项所述的化合物或权利要求7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、治疗或减轻与5-HT 1F受体有关的疾病。
  9. 根据权利要求8所述的用途，其中所述的与5-HT 1F受体有关的疾病为偏头痛、一般性疼痛、三叉神经痛、牙痛或颞下颌关节机能障碍疼痛、孤独症、强迫症、恐慌症、抑郁症、社交恐惧症、焦虑、广泛性焦虑症、睡眠障碍、创伤后综合征、慢性疲劳综合征、经前综合征或后黄体期综合征、边缘型人格障碍、破坏性行为障碍、冲动控制障碍、注意力缺陷多动障碍、酒精中毒、烟草滥用、缄默症、拔毛发癖、食欲过盛、神经性厌食症、早泄、勃起机能障碍、记忆丧失或痴呆。
  10. 权利要求1-6任意一项所述的化合物或权利要求7所述的药物组合物在制备药物中的用途，所述药物用于激活5-HT 1F受体。
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