CN110272425A

CN110272425A - Pyridine acyl octahydro pyrrolo- [3,4-c] azole derivatives and application thereof

Info

Publication number: CN110272425A
Application number: CN201910592056.3A
Authority: CN
Inventors: 金传飞; 钟文和; 许腾飞; 张英俊
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2018-07-02
Filing date: 2019-07-02
Publication date: 2019-09-24
Anticipated expiration: 2039-07-02
Also published as: CN110272425B

Abstract

The invention discloses pyridine acyl octahydro pyrrolo-es [3; 4-c] azole derivatives and application thereof, in particular it relates to a kind of novel pyridine acyl octahydro pyrrolo- [3; 4-c] azole derivatives and the pharmaceutical composition comprising such compound, it can be used for activating 5-HT_1FReceptor.The invention further relates to the method for preparing this kind of compound and pharmaceutical composition and they preparation treatment and 5-HT_1FPurposes in the drug of receptor related disease, especially migraine.

Description

Pyridine acyl octahydro pyrrolo- [3,4-c] azole derivatives and application thereof

Technical field

The invention belongs to technical field of pharmaceuticals, and in particular to novel pyridine acyl octahydro pyrrolo- [3,4-c] pyrroles spreads out Biology and the pharmaceutical composition comprising these compounds and its application method and purposes.Particularly, of the present invention novel Pyridine acyl octahydro pyrrolo- [3,4-c] azole derivatives can be used for activating 5-HT_1FReceptor, for prevent, treat or mitigate with 5-HT_1FReceptor related disease, especially migraine.

Background technique

Migraine is a kind of ictal and is often unilateral pulsatile headache, is often accompanied by Nausea and vomiting, is a kind of common Chronic forms vascular illness, a lot of diseases reach onset peak in children and puberty, young and middle-aged phase, and women is common, men and women patient Ratio is about 1:2~3, and illness rate is 5%~10% in crowd, often there is genetic background.

Although migraine is not fatal disease, the social life of patient can be seriously affected.In the U.S., migraine is caused Social economical burden be 10~1,700,000,000 dollars.Also there are a large amount of patients to influence work, studying and living because of migraine in China. With the quickening pace of modern life, the disease incidence of migraine is in the trend gradually increased.The male of investigation discovery recently about 5.7% Property, 17.6% women have 1 time or more migraine every year on average.In addition, still there are many heredity that people has migraine Morbidity tendency.

The complicated multiplicity of the pathogenesis of migraine, mainly there is blood vessel source theory, neurogenic theory, trigemino-vascular It says, biochemical factors and inherent cause.Drug currently used for treating migraine is mainly 5-HT_1B/DReceptor stimulating agent triptan medicine Object, but since triptan drug can make vessel retraction, cardiovascular and cerebrovascular and peripheral vascular disease patient are disabled.In addition, 40%~70% migraineur is poor to triptan drug therapy curative effect, and the 1/3 effective patient of initial treatment also can be frequent The case where encountering headache recurrence, the reduction significant in efficacy of triptan drug centering severe headache.In order to overcome triptan medicine These adverse reactions of object, calcitonin gene-related peptide (CGRP) receptor antagonist and selectivity 5-HT_1FReceptor stimulating agent class is anti- Migraine remedy comes into being.However, Cgrp receptor antagonist is there are still many defects, such as olcagepant can only intravenous use And should not take orally, telcagepant long-time service can cause liver enzyme to increase, and BI-44370 with Cytochrome P450 then because that can occur It interacts and has ceased clinical development.Therefore, there is an urgent need to develop new acute stages treated drugs.And develop selectivity 5- HT_1FReceptor stimulating agent class antimigraine drug has always been considered as being the new approach got a good chance of.

5-HT_1FReceptor is mainly expressed in mesenterium, uterus and brain, exists in cerebral blood vessel, gasserian ganglion and three Pitch each section and cerebellum, hippocampus and neopallium in the trigeminal neuralgias vascular systems such as neural tail core.With other 5-HT receptors Equally, 5-HT_1FReceptor is not only expressed in neuron, and Deiter's cells can also be expressed in.Presynaptic 5-HT_1FThe activation of receptor It can inhibit the release of calcitonin gene-related peptide (CGRP), and block neuron signal in trigeminal neuralgia tail core and conduct, to produce Raw anti-migraine effect, and this selectivity 5-HT_1FReceptor inhibiting effect significantly reduces the blood vessel of triptan drug initiation Shrink related side effects.

Currently, having developed to 5-HT_1FReceptor subtype has the various 5-HT of relative selectivity_1FReceptor stimulating agent, and Research is pointed out this to 5-HT_1FThe selectivity of receptor would generally reduce otherization for being used as treatment migraine and related disease pro-drug Vasoconstrictor activity specific to object is closed, but clinically still without the relevant therapeutic agent of the target spot, therefore, still needs to develop more peaces Complete reliable selectivity 5-HT_1FThe drug of receptor stimulating agent.

Summary of the invention

The present invention provides one kind to be used as 5-HT_1FThe novel pyridine acyl octahydro pyrrolo- [3,4-c] of receptor stimulating agent Azole derivatives can be used for activating 5-HT with different chemistry and receptor-binding characteristic_1FReceptor inhibits neuron egg White matter extravasation, while being avoided that apparent vasoconstrictor activity, therefore, it can be used for treating by 5-HT_1FReceptor-mediated disease, Especially for treating migraine.And it is found through experiments that, pyridine acyl octahydro pyrrolo- [3,4-c] pyrroles of the invention spreads out The property of biology is stablized, good security, has good pharmacodynamics and pharmacokinetic property, such as good brain/blood plasma Than (brain plasma ratio), good bioavilability or good metabolic stability etc..Therefore, have good Potential applicability in clinical practice.In addition, the dissolubility of the compounds of this invention is good, thus it is (such as sublingual, buccal and/or intranasal in preferred formulation Drug-delivery preparation) in adaptability it is high.

The present invention also provides prepare the method for this kind of compound, the pharmaceutical composition containing this kind of compound and this kind of Compound and the purposes of pharmaceutical composition in medicine preparation comprising this kind of compound.

On the one hand, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I) Stereoisomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or Its prodrug,

Wherein:

L is-C (=O)-,-C (=S)-or-S (=O)₂-；

R¹For C₁-C₄Alkyl, C₃-C₆Naphthenic base, 3-6 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 unit's heteroaryl, wherein R¹Appoint Selection of land is selected from R by 1,2,3,4 or 5^1a、R^1b、R^1c、R^1dAnd R^1eGroup replaced；

R^1a、R^1b、R^1c、R^1dAnd R^1eIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、-SH、- COOH ,-C (=O) NH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂,-C (=O)-(C₁-C₄Alkyl) ,-C (=O)-(C₁-C₄Alkane Oxygroup), C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy, C₁- C₄Alkylthio group, C₁-C₄The C that alkylamino, hydroxyl replace₁-C₄Alkyl, C₃-C₆Naphthenic base, 3-6 circle heterocyclic ring base, C₆-C₁₀Aryl or 5- 10 unit's heteroaryls；

R²For H, D, C₁-C₄Alkyl, C₁-C₄The C that halogenated alkyl or hydroxyl replace₁-C₄Alkyl；

R³、R⁴And R⁵It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、C₁-C₄Alkyl, C₁-C₄It is halogenated Alkyl, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl；

R⁶For H, D ,-COOH ,-C (=O) NH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂,-C (=O)-(C₁-C₄Alkane Base) ,-C (=O)-(C₁-C₄Alkoxy), C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl or hydroxyl replace C₁-C₄Alkyl；With

R⁷For H, D, F, Cl, Br, I, C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy or The C that hydroxyl replaces₁-C₄Alkyl.

In some embodiments, R¹For phenyl, indenyl, naphthalene, pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, four Nitrogen oxazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, Yin Diindyl base or quinolyl, wherein R¹Optionally R is selected from by 1,2,3,4 or 5^1a、R^1b、R^1c、R^1dAnd R^1eGroup replaced；

R^1a、R^1b、R^1c、R^1dAnd R^1eIt is each independently H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, alkene Propyl, acrylic, propargyl, propinyl ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxy Base, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、- OCH₂CF₂CHF₂, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, methylol or 2- hydroxyethyl.

It in some embodiments, is shown in formula (IIIa-1) or formula (IIIa-2) the present invention relates to a kind of compound Compound or formula (IIIa-1) or formula (IIIa-2) shown in compound stereoisomer, tautomer, nitrogen oxidation Object, hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,

Wherein, each R^1a、R^1b、R^1c、R^1d、R^1e、R²、R³、R⁴、R⁵、R⁶And R⁷With meaning as described in the present invention.

In some embodiments, R²For H, D, methyl, ethyl, n-propyl, isopropyl ,-CF₃Or-CH₂CF₃；

R³、R⁴And R⁵It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH, methyl, ethyl, n-propyl, Isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup；

R⁷For H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, N-propyl oxygroup or isopropyl oxygroup.

In some embodiments, R⁶For H, D, methyl, ethyl, n-propyl, isopropyl, allyl, acrylic, alkynes third Base, propinyl ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methylol or 2- hydroxyethyl.

On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes formula disclosed by the invention (I), compound shown in (IIIa-1) or (IIIa-2).

In some embodiments, pharmaceutical composition of the present invention further includes pharmaceutically acceptable figuration Agent, carrier, adjuvant or their any combination.

Another aspect, the present invention relates to compound shown in formula disclosed by the invention (I), (IIIa-1) or (IIIa-2) or its The purposes of pharmaceutical composition in medicine preparation, the drug is used to prevent, treat or mitigate and 5-HT_1FReceptor related disease Disease.

In some embodiments, described and 5-HT_1FReceptor related disease is migraine, general pain, trident Neuralgia, toothache or remporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, coke Worry, generalized anxiety disorder, sleep disturbance, posttraumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or rear luteal phase are comprehensive Sign, borderline personality disorder, disruptive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, cigarette Careless abuse, mutism, trichologia, bulimia nerovsa, anorexia nervosa, premature ejaculation, erectile dysfunction, the loss of memory or silly It is slow-witted.

In another aspect, the present invention relates to compound shown in formula disclosed by the invention (I), (IIIa-1) or (IIIa-2) or its The purposes of pharmaceutical composition in medicine preparation, the drug is for activating 5-HT_1FReceptor.

On the other hand, the present invention relates to the preparations of compound shown in formula (I), (IIIa-1) or (IIIa-2), separation and pure The method of change.

Biological results show that the compounds of this invention can activate 5-HT_1FReceptor inhibits neuronal protein extravasation, And it can be used as preferable 5-HT_1FReceptor stimulating agent.

Any embodiment in either present invention face can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention The technical characteristic in scheme is applied, as long as they are not in contradiction.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its Content in terms of him will make more specific complete description below.All bibliography in this specification pass through whole reference In this.When the disclosure of the specification and citation are variant, it is subject to the disclosure of the specification.

Detailed description of the invention book

Definition and general terms

It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case where (including but not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is subject to the application.

It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.

Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With the periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can With reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry Description in March, John Wiley&Sons, New York:2007, entire contents are incorporated by reference into the present invention.

There is apparent conflict unless otherwise indicated or in context, the article " one " used in the present invention, " one (kind) " and " described " are intended to include "at least one" or " one or more ".Therefore, these articles used in the present invention refer to The article of one or more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more It uses or uses in the embodiment that one component is taken into account in the embodiment.

Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (rotational isomer), geometry are different Structure body (cis/trans isomers), atropisomer, etc..

Term " chiral molecules " be with its mirror image cannot be overlapped property molecule；And " achiral molecule " refers to and it The molecule that mirror image can be overlapped.

Term " enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.

Term " racemate " or " racemic mixture " be optically active two enantiomters of hypodactylia etc. rub That mixture.

Term " diastereoisomer " refer to there are two or multiple chiral centres and its molecule not solid of mirror image each other Isomers.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereo-isomerism Body mixture can be operated such as electrophoresis and chromatography, such as HPLC by high resolution analysis and be separated.

Stereochemical definitions used in the present invention and rule generally follow 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.Many organic compounds exist with optical active forms, i.e., they, which have, makes the flat of linearly polarized light The ability that face rotates.When describing optically active compound, indicate molecule about one using prefix D and L or R and S A or multiple chiral centers absolute configurations.Prefix d and l or (+) and (-) are revolved for linearly polarized light caused by appointed compound The symbol turned, wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.It is a kind of specific Stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter: 50 mixtures are known as racemic mixture or racemic modification, when in chemical reaction or in the process without stereoselectivity or three-dimensional spy When anisotropic, such case may occur in which.

Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.

According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.

The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.

The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer to 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)。

Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.

" pharmaceutically acceptable " refers to compounds some in this way, raw material, composition and/or dosage form, they are cured rationally Learn judgement in the range of, be suitable for contacted with patient tissue and without excessive toxicity, irritation, allergy or with reasonable benefit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.

Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced .. " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group packet of the present invention It includes, but is not limited to D, F, Cl, Br, I, N₃、-CN、-NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂,-C (=O) NHCH₃,-C (= O)N(CH₃)₂,-C (=O)-alkyl ,-C (=O)-alkoxy, alkyl, alkenyl, alkynyl, halogenated alkyl, alkoxy, haloalkoxy Base, alkylthio group, alkylamino, the alkyl of hydroxyl substitution, naphthenic base, heterocycle, aryl, heteroaryl etc..

In general, term it is " substituted " indicate specifically replaced to one or more hydrogen atoms in structure or group Replaced base.Unless otherwise indicated, a substituent group can be replaced in each substitutive reasonable position of group. Replaced the specific substituent group of one or more that more than one position can be selected from given structural formula, then substituent group It can each reasonable position be replaced in structural formula identical or differently.

In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.

Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by Trying object is people.

Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.

Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.

It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C₁-C₆Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.

Term " D " indicates single D-atom.

Term " hetero atom " refers to O, S, N, P and Si, the form including any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole base N), NH (as the NH in pyrrolidinyl) or NR (NR in pyrrolidinyl replaced as N-).

Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1-20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.In one embodiment, alkyl group contains 1-6 carbon atom；In another embodiment, alkyl group contains 1-4 A carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-propyl (n-Pr ,-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,-CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), tert-butyl (t-Bu ,-C (CH₃)₃), etc..

Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp²Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention Replaced the substituent group stated comprising the positioning of " cis " and " trans ", or the positioning of " E " and " Z ".The example of alkenyl group Include, but is not limited to, vinyl, 1- acrylic, 2- acrylic, etc..

Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is tri- key of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention Replaced the substituent group stated.The example of alkynyl group includes, but is not limited to, acetenyl, 1- propinyl, 2-propynyl, etc..

Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more Replaced the substituent group that the present invention describes.

The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH₃), ethyoxyl (EtO ,- OCH₂CH₃), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH₂CH₂CH₃), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH₃)₂), 1- butoxy (n-BuO, n- butoxy ,-OCH₂CH₂CH₂CH₃), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH₂CH(CH₃)₂), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH₃)CH₂CH₃), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH₃)₃), etc..

Term " alkylthio group " indicates that alkyl group is connected by sulphur atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkylthio radicals contain 1-12 carbon atom.In an embodiment party In case, alkylthio radicals contain 1-6 carbon atom；In another embodiment, alkylthio radicals contain 1-4 carbon atom；? In another embodiment, alkylthio radicals contain 1-3 carbon atom.The alkylthio radicals can be optionally one or more Replaced the substituent group that the present invention describes.The example of alkylthio radicals includes, but is not limited to, methyl mercapto (MeS ,-SCH₃), second Sulfenyl (EtS ,-SCH₂CH₃) etc..

Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.It closes Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N- first ammonia Base, N- ethylamino, N, N- dimethylamino, N, N- lignocaine etc..The alkylamino radicals are optionally by one or more sheets It invents replaced described substituent group.

Term " alkyl that hydroxyl replaces " indicates alkyl group replaced one or more hydroxyls, and wherein alkyl group has There is meaning as described in the present invention；Such example includes, but is not limited to, methylol, 2- hydroxyethyl, 2- hydroxyl -1- third Base, 3- hydroxyl -1- propyl, 2,3- dihydroxypropyl etc..

Term " halogenated alkyl " indicates alkyl group replaced one or more halogen atoms, and wherein alkyl group has Meaning as described in the present invention, such example includes, but is not limited to ,-CF₃、-CH₂CF₃、-CHFCH₃、-CH₂CH₂F、- CF₂CH₃Deng.In one embodiment, C₁-C₆Halogenated alkyl includes fluorine-substituted C₁-C₆Alkyl；In another embodiment, C₁- C₄Halogenated alkyl includes fluorine-substituted C₁-C₄Alkyl；In yet another embodiment, C₁-C₂Halogenated alkyl includes fluorine-substituted C₁-C₂ Alkyl.

Term " halogenated alkoxy " indicate alkoxy base replaced one or more halogen atoms, wherein alkoxy base Group has meaning as described in the present invention, and such example includes, but is not limited to ,-OCF₃、-OCH₂CF₃、-OCHFCH₃、- OCH₂CH₂F、-OCF₂CH₃Deng.In one embodiment, C₁-C₆Halogenated alkoxy includes fluorine-substituted C₁-C₆Alkoxy；Another In embodiment, C₁-C₄Halogenated alkoxy includes fluorine-substituted C₁-C₄Alkoxy；In yet another embodiment, C₁-C₂Alkyl halide Oxygroup includes fluorine-substituted C₁-C₂Alkoxy.

Term " n former molecular " or " n member ", wherein n is integer, typically describes the number of ring member nitrogen atoms in molecule Mesh, the number of ring member nitrogen atoms is n in the molecule.For example, piperidyl is the molecular heterocycle of 6 originals or 6 circle heterocyclic ring bases, And cyclohexyl is the molecular naphthenic base of 6 originals or 6 yuan of naphthenic base.

Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies System.Bicyclic or three-ring system may include condensed ring, bridged ring and loop coil.In one embodiment, naphthenic base includes that 3-10 carbon is former Son；In another embodiment, naphthenic base includes 3-8 carbon atom；In yet another embodiment, naphthenic base includes 3-6 carbon Atom.The group of naphthene base is optionally replaced one or more substituent groups described in the invention.

Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to comprising 3-12 annular atom, non-aromatic The unsaturated monocyclic, bicyclic or tricyclic system of saturation or part of property, wherein described bicyclic or three-ring system may include thick Ring, bridged ring and loop coil.One or more atoms are independently replaced by hetero atom in its middle ring, and the hetero atom has such as this hair The bright meaning.In one embodiment, heterocycle is monocyclic heterocycles base (the 2-6 carbon atom of 3-8 annular atom composition With selected from N, O, P, the 1-3 hetero atom of S is optionally obtained replaced one or more oxygen atoms in this S or P as SO, SO₂, PO, PO₂Group)；In another embodiment, heterocycle is bicyclic heterocyclic radical (4-9 of 7-12 annular atom composition Carbon atom and it is selected from N, O, P, the 1-3 hetero atom of S optionally obtain picture replaced one or more oxygen atoms in this S or P SO, SO₂, PO, PO₂Group).The heterocyclyl groups are optionally taken by one or more substituent groups described in the invention Generation.The annular atom of heterocycle can be carbon-based or heteroatom group.Wherein ,-the CH of ring₂Group is optionally substituted by-C (=O)-, The sulphur atom of ring is optionally oxidized to S- oxide, and the nitrogen-atoms of ring is optionally oxidized to N- oxygen compound.Heterocycle Example includes, but are not limited to Oxyranyle, azelidinyl, oxetanylmethoxy, pyrrolidinyl, pyrazolidinyl, imidazolidine Base, tetrahydrofuran base, tetrahydro-thienyl, piperidyl, morpholinyl, piperazinyl, etc..- CH in heterocycle₂Group quilt-C (= O)-substitution example includes, but are not limited to 2- oxo-pyrrolidine base, oxo-morpholine, etc..The heterocyclyl groups are appointed Selection of land is replaced one or more substituent groups described in the invention.

Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one ring system be it is aromatic, wherein each ring system include 3-7 original Molecular ring.Aryl group by the armaticity ring of aryl group with parent molecule in general, but unnecessarily connect.Term " aryl " can be used interchangeably with term " aromatic rings " or " aromatic ring ".The example of aryl group may include phenyl, naphthalene and anthracene. The aryl group is optionally replaced one or more substituent groups described in the invention.

Monocycle of term " heteroaryl " expression containing 5-12 annular atom or 5-10 annular atom or 5-6 annular atom, Bicyclic and three-ring system, wherein at least one ring system are aromatic, and at least one ring system includes one or more miscellaneous Atom, wherein each ring system includes 5-7 former molecular ring.Heteroaryl groups are in general, but unnecessarily pass through heteroaryl The armaticity ring of base group is connect with parent molecule.Term " heteroaryl " can be with term " hetero-aromatic ring ", " heteroaromatic " or " heteroaryl Compounds of group " is used interchangeably.The heteroaryl groups are optionally replaced one or more substituent groups described in the invention. In one embodiment, 5-10 former molecular heteroaryl includes 1,2,3 or 4 hetero atom for being independently selected from O, S and N.It is miscellaneous The example of aryl group includes, but is not limited to, furyl, imidazole radicals, oxazolyl, pyrrole radicals, pyridyl group, pyrimidine radicals, pyridazine Base, thiazolyl, tetrazole radical, triazolyl etc.；It also include below bicyclic, but it is bicyclic to be not limited to these: indyl, quinolyl, Etc..

As described in the present invention, substituent R⁷It is keyed to by one on octahydro pyrrolo- [3,4-c] pyrrole ring at center The ring system (as shown in formula f) of formation represents substituent R⁷It can arbitrarily be taken on octahydro pyrrolo- [3,4-c] pyrrole ring The position in generation is replaced, such as formula f^1-6It is shown.

When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group be used to block or protect the functionality of hydroxyl, suitable blocking group includes trialkylsilkl, acetyl group, benzene Formoxyl and benzyl." carboxy protective group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, general Carboxyl-protecting group includes-CH₂CH₂SO₂Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy Ylmethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro second Base, etc..Description general for blocking group can refer to document: Greene et al., Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al., Protecting Groups,Thieme,Stuttgart,2005。

Term " prodrug " used in the present invention, represent a compound be converted into vivo formula (I), (IIa), (IIb), (IIIa-1)、(IIIa-2)、(IIIa-3)、(IIIa-4)、(IIIa-5)、(IIIb-1)、(IIIb-2)、(IIIb-3)、 (IIIb-4) or (IIIb-5) compound represented.Such conversion is hydrolyzed by pro-drug in blood or in blood or tissue It is middle through enzymatic conversion be precursor structure influence.Pro-drug compounds of the present invention can be ester, and ester can in existing invention Using the phenyl ester class that has as pro-drug, aliphatic (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates And amino acid esters.Such as a compound in the present invention includes hydroxyl, it can is acylated to obtain prodrug form Compound.Other prodrug forms include phosphate, if these phosphate compounds are through the hydroxyl phosphorus on parent What acidification obtained.

" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C₁-C₈Sulphonic acid compound and aromatic sulphonic acid compound.

" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Or mixtures thereof acid, ethanol amine.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.

When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, such as dihydrate；In yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.

Any disease of term " treatment " or illness refer to that improving disease or illness (slows down in some of these embodiments Or prevent or mitigate disease or the development of its at least one clinical symptoms).In other embodiments, " treatment " refer to mitigation or Improve at least one body parameter, including the body parameter that may not be discovered by patient.In other embodiments, it " controls Treat " refer in terms of (such as stablizing perceptible symptom) on body or physiologically (such as parameter of stable body) or above-mentioned two Adjust disease or illness.In other embodiments, " treatment " refers to the breaking-out, generation or evil for preventing or delaying disease or illness Change.

Term " preventing " or " prevention " refer to that the reduction for obtaining the risk of disease or obstacle (that is: makes at least one clinical condition of disease Shape stops development in main body, which may face or be inclined in advance in face of this disease, but without undergoing or show The symptom of disease).

Unless otherwise mentioned, all suitable isotope variations of the compound of the present invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.

In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.

The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.

Formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb- 1), compound shown in (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) can exist in a salt form.Implement one In scheme, the salt refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to that substance or composition must be with Other ingredients comprising preparation and/or compatible chemically and/or in toxicology with the mammal of its treatment.In another embodiment party In case, the salt is not necessarily pharmaceutically acceptable salt, can be used to prepare and/or purify formula (I), (IIa), (IIb), (IIIa-1)、(IIIa-2)、(IIIa-3)、(IIIa-4)、(IIIa-5)、(IIIb-1)、(IIIb-2)、(IIIb-3)、 (IIIb-4) or compound shown in (IIIb-5) and/or for separate formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), shown in (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) The intermediate of the enantiomer of compound.

Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list that other is suitable for salt can be found in.

Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

On the other hand, the present invention relates to preparation formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), in compound shown in (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) Mesosome.

On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or their combination.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.

The description of the compounds of this invention

Pyridine acyl octahydro pyrrolo- [3,4-c] azole derivatives of the present invention, pharmaceutically acceptable salt, medicine Object preparation and combinations thereof can be used for activating 5-HT_1FReceptor, inhibit neuronal protein extravasation, to 5-HT_1FReceptor has The treatment of the disease of pass, especially migraine has potential purposes.The present invention further describes the synthesis compound Method.The compound of the present invention shows good bioactivity.

Wherein, each R¹、R²、R³、R⁴、R⁵、R⁶、R⁷There is meaning as described in the present invention with L.

In one embodiment, L is-C (=O)-,-C (=S)-or-S (=O)₂-。

In one embodiment, R¹For C₁-C₆Alkyl, C₃-C₈Naphthenic base, 3-8 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 member Heteroaryl, wherein R¹Optionally R is selected from by 1,2,3,4 or 5^1a、R^1b、R^1c、R^1dAnd R^1eGroup replaced；Wherein, R^1a、 R^1b、R^1c、R^1dAnd R^1eWith meaning as described in the present invention.

In one embodiment, R^1a、R^1b、R^1c、R^1dAnd R^1eIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、- NH₂,-OH ,-SH ,-COOH ,-C (=O) NH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂,-C (=O)-(C₁-C₆Alkyl) ,-C (=O)-(C₁-C₆Alkoxy), C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆ Halogenated alkoxy, C₁-C₆Alkylthio group, C₁-C₆The C that alkylamino, hydroxyl replace₁-C₆Alkyl, C₃-C₈Naphthenic base, 3-8 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 unit's heteroaryl.

In one embodiment, R²For H, D, C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆Haloalkoxy The C that base or hydroxyl replace₁-C₆Alkyl.

In one embodiment, R³、R⁴And R⁵It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、C₁- C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁-C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl.

In one embodiment, R⁶For H, D ,-COOH ,-C (=O) NH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂、-C (=O)-(C₁-C₆Alkyl) ,-C (=O)-(C₁-C₆Alkoxy), C₁-C₆Alkyl, C₂-C₆Alkenyl, C₂-C₆Alkynyl, C₁-C₆Alkyl halide The C that base, hydroxyl replace₁-C₆Alkyl, C₃-C₈Naphthenic base, 3-8 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 unit's heteroaryl.

In one embodiment, R⁷For H, D, F, Cl, Br, I, C₁-C₆Alkyl, C₁-C₆Halogenated alkyl, C₁-C₆Alkoxy, C₁- C₆The C that halogenated alkoxy or hydroxyl replace₁-C₆Alkyl.

In one embodiment, R¹For C₁-C₄Alkyl, C₃-C₆Naphthenic base, 3-6 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 member Heteroaryl, wherein R¹Optionally R is selected from by 1,2,3,4 or 5^1a、R^1b、R^1c、R^1dAnd R^1eGroup replaced；Wherein, R^1a、 R^1b、R^1c、R^1dAnd R^1eWith meaning as described in the present invention.

In another embodiment, R¹For phenyl, indenyl, naphthalene, pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, four Nitrogen oxazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, Yin Diindyl base or quinolyl, wherein R¹Optionally R is selected from by 1,2,3,4 or 5^1a、R^1b、R^1c、R^1dAnd R^1eGroup replaced；Its In, R^1a、R^1b、R^1c、R^1dAnd R^1eWith meaning as described in the present invention.

In one embodiment, R^1a、R^1b、R^1c、R^1dAnd R^1eIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、- NH₂,-OH ,-SH ,-COOH ,-C (=O) NH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂,-C (=O)-(C₁-C₄Alkyl) ,-C (=O)-(C₁-C₄Alkoxy), C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄ Halogenated alkoxy, C₁-C₄Alkylthio group, C₁-C₄The C that alkylamino, hydroxyl replace₁-C₄Alkyl, C₃-C₆Naphthenic base, 3-6 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 unit's heteroaryl.

In another embodiment, R^1a、R^1b、R^1c、R^1dAnd R^1eIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、- NH₂,-OH ,-SH ,-COOH ,-C (=O) NH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂,-C (=O)-CH₃,-C (=O)- OCH₃, methyl, ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, propinyl ,-CHF₂、-CF₃、-CHFCH₂F、- CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup ,-OCHF₂、-OCF₃、- OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, hydroxyl Methyl, 2- hydroxyethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperazine Piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthalene, pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, tetrazole base, furans Base, thienyl, thiazolyl, oxazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, indyl or quinoline Base.

In one embodiment, R²For H, D, C₁-C₄Alkyl, C₁-C₄The C that halogenated alkyl or hydroxyl replace₁-C₄Alkyl.

In another embodiment, R²For H, D, methyl, ethyl, n-propyl, isopropyl ,-CF₃Or-CH₂CF₃。

In one embodiment, R³、R⁴And R⁵It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、C₁- C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl.

In another embodiment, R³、R⁴And R⁵It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、 Methyl, ethyl, n-propyl, isopropyl ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.

In one embodiment, R⁷For H, D, F, Cl, Br, I, C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁- C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl.

In another embodiment, R⁷For H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl ,-CF₃、- CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.

In one embodiment, R⁶For H, D ,-COOH ,-C (=O) NH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂、-C (=O)-(C₁-C₄Alkyl) ,-C (=O)-(C₁-C₄Alkoxy), C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Alkyl halide The C that base, hydroxyl replace₁-C₄Alkyl, C₃-C₆Naphthenic base, 3-6 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 unit's heteroaryl.

In another embodiment, R⁶For H, D ,-COOH ,-C (=O) NH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂、- C (=O)-CH₃,-C (=O)-OCH₃, methyl, ethyl, n-propyl, isopropyl, allyl, acrylic, propargyl, propinyl ,- CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methylol, 2- hydroxyethyl, cyclopropyl, cyclobutyl, Cyclopenta, cyclohexyl, azelidinyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, phenyl, indenyl, Naphthalene, pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, tetrazole base, furyl, thienyl, thiazolyl, oxazolyl, pyridine Base, pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, indyl or quinolyl.

In some embodiments, the present invention relates to a kind of compounds, are formula (IIa) compound represented or formula (IIa) stereoisomer of compound shown in, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmacy Upper acceptable salt or its prodrug,

Wherein, each R¹、R²、R³、R⁴、R⁵、R⁶And R⁷With meaning as described in the present invention.

In some embodiments, the present invention relates to a kind of compounds, are formula (IIb) compound represented or formula (IIb) stereoisomer of compound shown in, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmacy Upper acceptable salt or its prodrug,

In other embodiments, the present invention relates to a kind of compounds, are formula (IIIa-1) compound represented, or The stereoisomer of compound shown in person's formula (IIIa-1), tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug,

In other embodiments, the present invention relates to a kind of compounds, are formula (IIIa-2) compound represented, or The stereoisomer of compound shown in person's formula (IIIa-2), tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug,

Wherein, each R^1b、R^1c、R^1d、R^1e、R²、R³、R⁴、R⁵、R⁶And R⁷With meaning as described in the present invention.

In other embodiments, the present invention relates to a kind of compounds, are formula (IIIa-3) compound represented, or The stereoisomer of compound shown in person's formula (IIIa-3), tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug,

Wherein, each R^1a、R^1c、R^1d、R^1e、R²、R³、R⁴、R⁵、R⁶And R⁷With meaning as described in the present invention.

In other embodiments, the present invention relates to a kind of compounds, are formula (IIIa-4) compound represented, or The stereoisomer of compound shown in person's formula (IIIa-4), tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug,

Wherein, each R^1a、R^1b、R^1d、R^1e、R²、R³、R⁴、R⁵、R⁶And R⁷With meaning as described in the present invention.

In other embodiments, the present invention relates to a kind of compounds, are formula (IIIa-5) compound represented, or The stereoisomer of compound shown in person's formula (IIIa-5), tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug,

Wherein, each R^1b、R^1c、R^1d、R²、R³、R⁴、R⁵、R⁶And R⁷With meaning as described in the present invention.

In other embodiment, it to be formula (IIIb-1) compound represented that the present invention relates to a kind of compounds, or The stereoisomer of compound shown in person's formula (IIIb-1), tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug,

In other embodiment, it to be formula (IIIb-2) compound represented that the present invention relates to a kind of compounds, or The stereoisomer of compound shown in person's formula (IIIb-2), tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug,

In other embodiment, it to be formula (IIIb-3) compound represented that the present invention relates to a kind of compounds, or The stereoisomer of compound shown in person's formula (IIIb-3), tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug,

In other embodiment, it to be formula (IIIb-4) compound represented that the present invention relates to a kind of compounds, or The stereoisomer of compound shown in person's formula (IIIb-4), tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug,

In other embodiment, it to be formula (IIIb-5) compound represented that the present invention relates to a kind of compounds, or The stereoisomer of compound shown in person's formula (IIIb-5), tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug,

In one embodiment, compound of the present invention for the compound with one of following structure or has The stereoisomer of the compound of one of following structure, tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug, but be not limited to:

On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes formula disclosed by the invention (I)、(IIa)、(IIb)、(IIIa-1)、(IIIa-2)、(IIIa-3)、(IIIa-4)、(IIIa-5)、(IIIb-1)、(IIIb- 2), compound shown in (IIIb-3), (IIIb-4) or (IIIb-5).

In one embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable excipient, Carrier, adjuvant or their any combination.

Another aspect, the present invention relates to formula disclosed by the invention (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), shown in (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) The purposes of compound or its pharmaceutical composition in medicine preparation, the drug is used to prevent, treat or mitigate and 5-HT_1FReceptor Related disease.

In one embodiment, described and 5-HT_1FReceptor related disease is migraine, general pain, trident mind Dysmenorrhoea, toothache or remporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, coke Worry, generalized anxiety disorder, sleep disturbance, posttraumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or rear luteal phase are comprehensive Sign, borderline personality disorder, disruptive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, cigarette Careless abuse, mutism, trichologia, bulimia nerovsa, anorexia nervosa, premature ejaculation, erectile dysfunction, the loss of memory or silly It is slow-witted.

In another embodiment, described and 5-HT_1FReceptor related disease is migraine.

In another aspect, the present invention relates to formula disclosed by the invention (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), shown in (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) The purposes of compound or its pharmaceutical composition in medicine preparation, the drug is for activating 5-HT_1FReceptor.

On the other hand, the present invention relates to formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), the system of compound shown in (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) Standby, separation and purifying method.

Pharmaceutical composition, preparation and the administration of the compounds of this invention

The present invention provides a kind of pharmaceutical composition, including formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), shown in (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) Compound or its individual stereoisomer, the racemic or non-racemic mixture or its pharmaceutically acceptable salt of isomers Or solvate.In an embodiment of the invention, described pharmaceutical composition further includes at least one and pharmaceutically may be used Carrier, adjuvant or the excipient of receiving, and optionally, others treatment and/or prevention ingredient.

The form of administration of compound used in the method for the present invention can pass through selected specific compound, administration route The state of required pharmacokinetics distribution pattern and patient determines.

It is suitable for oral, sublingual, intranasal or drug administration by injection preparation by the known method preparation of pharmaceutical field, and described Preparation contains at least one reactive compound.See, e.g., REMINGTON ' S PHARMACEUTICAL SCIENCES (16th ed.1980)。

In general, preparation of the invention includes active constituent (formula (I), (IIa), (IIb), (IIIa-1), (IIIa- 2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) institute Show compound), and usually mixed with excipients, by excipient dilution agent or to be encapsulated in can be in capsule, sachet, paper or other containers In the carrier of shape.When excipients are used as diluent, solid, semisolid or liquid material can be, active constituent is risen and is assigned Type agent, the effect of carrier or medium.Therefore, preparation can be tablet, pill, pulvis, pastille, sachet, cachet, elixir, hang Supernatant liquid, solution, syrup, aerosol (for solid or in liquid medium), contains such as up to 10 weight % active ingredients at emulsion The ointment of object, soft hard capsule, gel, suppository, aseptic parenteral solution and sterile packaged pulvis.

In the preparation of preparation, before being mixed with other components, it may be necessary to reactive compound is ground, it is suitable to provide Granularity.If reactive compound is substantially insoluble, it is usually ground to the granularity less than 200 mesh.If reactive compound It is substantially water-soluble, then its granularity is adjusted by grinding, so as to there is uniform particle size distribution, for example, about 40 mesh in preparation. In one embodiment of the invention, granularity is about 0.1-100 μm.

It is that suitable carrier, adjuvant and excipient are well known to those skilled in the art and be described in detail in for example 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；With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) In Pharmaceutical Press, Chicago.

" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid will be greatly reduced disclosed compound of present invention when administering to a patient and will lead to not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.

Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Certain pharmaceutically acceptable excipient.The certain pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.Facilitate to carry or transport the compounds of this invention when may be selected to administer to a patient from an organ of body or partially to body Another organ or partial certain pharmaceutically acceptable excipient.May be selected enhancing patient compliance it is certain pharmaceutically Acceptable excipient.

Some suitable excipients examples include lactose, glucose, sucrose, D-sorbite, mannitol, starch, I Primary glue, calcium phosphate, alginates, tragacanth glue, gelatin, calcium silicates, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, Syrup and methylcellulose.Suitable pharmaceutically acceptable excipient further includes following kind of excipient: diluent, filling Agent, adhesive, disintegrating agent, lubricant (such as talcum powder, magnesium stearate and mineral oil), glidant, granulating agent, coating agent, profit Humectant, solvent, cosolvent, suspending agent, emulsifier, sweetener, corrigent, odor mask, colorant, anticaking agent, moisturizer, chela Mixture, tackifier, antioxidant, preservative (such as methyl hydroxybenzoate and nipasol), is stablized plasticiser Agent, surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation there are which other Excipient.The compounds of this invention can be prepared using the known method of this field, so as to after administering to a patient can quickly, continue Or delay to release active constituent.

Technical staff grasps the knowledge and skills of this field, so that they can select for the suitable of appropriate amount of the invention Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes 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)。

In order to prepare pharmaceutical composition with compound described in the invention, pharmaceutically acceptable carrier can be solid Body or liquid-carrier.Solid form preparations include pulvis, tablet, dispersible granule, capsule, cachet and suppository.Powder Agent and tablet may include the active component of about 5 to about 95%.Suitable solid carrier is known in the art, example Such as, magnesium carbonate, magnesium stearate, talcum powder, sugar or lactose.Tablet, pulvis, cachet and capsule may be used as be suitble to it is oral Solid dosage forms.The example of pharmaceutical acceptable carrier and method for preparing various compositions can obtain in following: A.Gennaro (ed.),Remington's Pharmaceutical Sciences,18^th ed.,1990,Mack Publishing Company Co.,Easton,Pennsylvania。

In 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 The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Well-known technique, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object effect, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of compound, pays close attention to its application and belong to the scope of the present invention.

Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。

Therefore, on the other hand, the present invention relates to the technique of preparation pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination, the technique include that mixing is each Kind ingredient.Pharmaceutical composition comprising disclosed compound of present invention can mix under such as environment temperature and atmospheric pressure to make It is standby.

Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes those dosage forms for being suitable for following administration route: (1) being administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) it sucks, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.

It will also be appreciated that certain compounds of the invention can exist for treating in a free form, or if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.

Although can not have to any preparation and directly apply the compound of the present invention, the compounds of this invention is usually to contain The form of pharmaceutically acceptable excipients and the pharmaceutical preparation of at least one active component is taken.These preparations can be applied by all means With, including oral, cheek, rectum, intranasal, transdermal, subcutaneous, intravenous, intramuscular and intranasal administration.Permitted used in the method for the present invention More compounds are effective as injection and Orally administered composition.

For percutaneous dosing, a kind of transdermal delivery device (" patch ") is needed.This transdermal patch can be used to it is continuous or The compounds of this invention of disconnected injection control amount.Structure and application for transmitting the transdermal patch of drug are well known in the art. For example, with reference to, US5,023,252.This patch can be made into continuous, pulsation or discharge drug on demand.

It is often desirable to or needs for pharmaceutical composition to be directly or indirectly introduced into brain.Direct technology, which is usually directed to, passes drug Conducting tube is placed in the ventricular system of host around blood brain barrier.Described in US5,011,472 it is such a can plant it is defeated System is sent, for transmitting biological factor to body particular anatomical region.Moment blood-brain can be opened by endoarterial infusion The conveying of hydrophilic medicament can be enhanced in the hypertonic solution of barrier.

In a preferred embodiment of the invention, it provides containing at least one above-mentioned reactive compound and is suitable for warp Cheek and/or sublingual or nose administration pharmaceutical preparation.This embodiment provides for the modes to avoid stomach complication (e.g., first Liver metabolism is metabolized and/or first passed around around gastric system) application reactive compound.This administration route can also reduce absorption Time, to quickly bring therapeutic effect.The compounds of this invention can also provide particularly advantageous dissolubility distribution, be conducive to Sublingual/buccal drug-delivery preparation.This preparation generally requires relatively high active component concentration, so as to viscous in preparation and sublingual/cheek In the shorter perdurabgility of film surface contact, enough active components are transmitted to the limited surface of sublingual/buccal mucosa, so that active Component is absorbed.Therefore, the compounds of this invention it is high activity and its highly dissoluble promote it is suitable for prepare it is sublingual/buccal to Medicine preparation.

Term as used herein " therapeutically effective amount " refers to each active component for being enough to show beneficial therapeutic effect Total amount.For example, being administered or making the amount for the symptom for being enough to treat, curing or mitigating disease for reaching balance in vivo.Special controls Effective quantity needed for treatment scheme depends on many factors, the disease including treatment, the severity of disease, the certain drug used Activity, administration mode, the clearance rate of certain drug, duration for the treatment of, drug combination, the age, weight, gender, diet and The health etc. of patient.This field description as described in " therapeutically effective amount " other factors in need of consideration can be found in 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。

It is preferred that compound of formula I is configured to unit dosage forms, every dose of active component containing about 0.001-100mg is more often Containing about 1.0-30mg active component.Term " unit dosage forms " refers to the unit dose for being suitable as human patients and other mammals The physical separation unit of amount, each unit contain be computed can generate needed for the predetermined amount active component of therapeutic effect and suitable Above-mentioned pharmaceutically acceptable excipients.

Reactive compound is effective usually in very large dosage of range.For example, daily dosage is typically about 0.0001- 30mg/kg weight.For adult treatment, particularly preferred dosage (single dose or divided doses) is about 0.1-15mg/kg/ It.It will be appreciated, however, that the chemical combination object amount being actually administered will be determined by attending physician according to related situation, including what is treated Disease, selected administration route are actually subjected to the one or more compounds taken, age, weight and the response of specific patient And the severity of patient symptom, therefore, the above dosage range should not in any way limit the scope of the invention.In certain feelings Under condition, the dosage level lower than above-mentioned dosage range lower bound is likely more properly, and in other cases, it can use and not generate The higher doses of any side effect, precondition be, first by this larger dose be divided into several smaller doses for whole day to Medicine.

Term " administration " shows individual and provides the drug of therapeutically effective amount, and administration mode includes oral, sublingual, vein, skin Under, it is percutaneously, intramuscular, it is intradermal, it is intrathecal, on dura mater, intraocularly, and encephalic, sucking, rectum, vagina etc..Form of administration includes paste, is washed Agent, tablet, capsule, pill, dustability powder agent, granule, suppository, sublimed preparation, pastille, injection, sterile solution or non-aqueous Solution, suspending agent, emulsion, patch agent etc..Active component and nontoxic pharmaceutically acceptable carrier (such as glucose, lactose, Gum arabic, gelatin, mannitol, gelatinized corn starch, magnesium trisilicate, talcum powder, cornstarch, keratin, silica gel, potato starch, Urea, dextran etc.) it is compound.

Preferred administration route can change with Clinical symptoms, and the variation of dosage is necessarily dependent upon patient being treated The case where, doctor can determine suitable dosage according to individual patient.The therapeutically effective amount of per unit dose depends on weight, raw Manage the vaccination regimen of function and selection.The weight of compound when the compound of per unit dose refers to each administration does not include carrying The weight (containing carrier in drug) of body.

Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multi-dose parenteral administration must comprising it is antibacterial or fungistatic concentrations resist it is micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.

Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect It prepares, or the substance co-formulation with the expected effect of supplement.

In one embodiment, treatment method of the invention includes that this hair of safe and effective amount is given to patient in need Bright compound or pharmaceutical composition comprising the compounds of this invention.Each embodiment of the present invention includes by patient in need It gives the compounds of this invention of safe and effective amount or the pharmaceutical composition comprising the compounds of this invention, is referred to treat the present invention Disease.

In one embodiment, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be by any Suitable administration route is administered, including Formulations for systemic administration and local administration.Formulations for systemic administration include oral administration, parenteral, Cutaneous penetration and rectally.Typical parenteral refers to through injection or administered by infusion, including intravenous, intramuscular and skin Lower injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and intranasal administration.One In a embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be oral administration.Another In embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalation.It is also real one It applies in scheme, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be intranasal administration.

In one embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can disposably give Medicine, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, daily administration one It is secondary, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, it is taken twice daily. It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.The compounds of this invention or comprising The appropriate dosage regimen of the pharmaceutical composition of the compounds of this invention depends on the pharmacokinetic property of the compound, such as inhales Receipts, distribution and half-life period, these can be by determination of technical staff.In addition, the compounds of this invention or including the compounds of this invention The appropriate dosage regimen of pharmaceutical composition, the duration including implementing the program are treated disease depending on treated disease The severity of disease, the age of patient under consideration and physical condition, the medical history of patient under consideration while the property of therapy are thought The factor within the scope of technical staff's knowledge and experience such as therapeutic effect wanted.Such technical staff should also be understood that for Reaction of the individual patient to dosage regimen, or when individual patient needs to change as time goes by it may require that adjust it is suitable to Prescription case.

The compounds of this invention can be administered simultaneously, or before it or later with one or more other therapeutic agents.This hair Bright compound can be administered with other therapeutic agents by identical or different administration route respectively, or therewith with same pharmaceutical composition Form administration.This is selected by those skilled in the art according to the actual conditions of the bodies such as the health of patient, age, weight.If It is formulated as fixed dosage, this combination product uses the compound of the present invention (within dosage range described herein) and its His forms of pharmacologically active agents (within its dosage range).

Correspondingly, in one aspect, the present invention includes drug combination comprising a certain number of at least one of the invention Compound or pharmaceutically acceptable salt thereof, solvate, ester or pro-drug and a effective amount of one or more above-mentioned additional therapeutic agents.

In addition, the compounds of this invention can be administered with prodrug forms.In the present invention, " prodrug " of the compounds of this invention is When administering to a patient, the functional derivatives of the compounds of this invention can be finally released in vivo.This hair is given with prodrug forms When bright compound, one of implementable following manner of those skilled in the art or more: the internal action of compound (a) is changed Time；(b) the internal acting duration of compound is changed；(c) the internal conveying or distribution of compound are changed；(d) modification Close the internal solubility of object；And the side effect or other difficult points for (e) overcoming compound to be faced.It is used to prepare the typical of prodrug Functional derivatives, comprising in vivo chemically or the variant of compound that cracks of the mode of enzyme.Comprising prepare phosphate, Amide, ester, monothioester, carbonate and carbaminate these variants be well-known to those skilled in the art.

The purposes of the compounds of this invention and pharmaceutical composition

Compound provided by the invention and pharmaceutical composition can be used for preparing for activating 5-HT_1FThe drug of receptor, can also To be used to prepare for preventing, treating or mitigating and 5-HT_1FThe drug of receptor related disease, especially migraine.

Specifically, the amount of compound effectively can be selected detectably in the compound of the present invention or pharmaceutical composition Activate 5-HT to property_1FReceptor.

Specifically, the amount of compound effectively can be selected detectably in the compound of the present invention or pharmaceutical composition Inhibit neuronal protein extravasation to property.

The compound of the present invention can be applied to, but be not limited to, and use the compound of the present invention or pharmaceutical composition Effective quantity administers to a patient to prevent, treat or mitigate and 5-HT_1FReceptor related disease.Described and 5-HT_1FReceptor related Disease further comprises but is not limited to that migraine, general pain, trigeminal neuralgia, toothache or remporomandibular joint function hinder Hinder pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, generalized anxiety disorder, sleep disturbance, wound Syndrome, chronic fatigue syndrome, premenstrual syndrome or rear luteal phase syndrome, borderline personality disorder, destructive behavior afterwards Obstacle, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichologia, appetite mistake Sheng, anorexia nervosa, premature ejaculation, erectile dysfunction, the loss of memory and dementia.

The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.

General synthesis step

For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only Method of the invention is practiced in offer.

Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, the wherein definition of substituent group such as formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa- 4), shown in (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5).Following reaction scheme With embodiment for the contents of the present invention to be further illustrated.

The professional of fields will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.

Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.

¹H H NMR spectroscopy is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.¹H H NMR spectroscopy is with CDC1₃、 DMSO-d₆、CD₃OD or acetone-d₆For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as referring to mark It is quasi-.When there is multiplet, following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t will be used (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), brs (broadened singlet, wide is unimodal), dd (doublet of doublets, double doublet), ddd (doublet of Doublet of doublets, in pairs doublet), dt (doublet of triplets, double triplets), td (triplet Of doublets, three doublets), tt (triplet of triplets, three triplets).Coupling constant J, with hertz (Hz) table Show.

The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-M of Agilent (column model: Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase: 5%-95% (contains 0.1% The CH of formic acid₃CN) in (H containing 0.1% formic acid₂O the ratio in), using electrospray ionisation (ESI), at 210nm/254nm, It is detected with UV.

Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar type Number: NOVASEP 50/80mm DAC), detected in 210nm/254nm with UV.

The use of logogram word below is through the present invention:

CH₂Cl₂, mL, ml milliliters of DCM methylene chloride

CDC1₃Deuterated chloroform μ L, μ l microlitres

DMSO dimethyl sulfoxide nL, nl nanoliter

DMSO-d₆Deuterated dimethyl sulfoxide min minutes

EtOAc, EA ethyl acetate h hours

CH₃OH, MeOH methanol CaCl₂Calcium chloride

CD₃OD deuterated methanol Na₂SO₄Sodium sulphate

H₂O water PE petroleum ether (60-90 ℃)

DIPEA N, N- diisopropylethylamine RT, rt, r.t. room temperature

Et₃N triethylamine HCl concentrated hydrochloric acid

LiOH·H₂O Lithium hydroxide monohydrate Ascortic Acid ascorbic acid

N₂The pargyline nitrogen Pargyline

NM nanomole PEI polyethyleneimine

μM micromole Serotonin thrombocytin, 5- hydroxyl Tryptamines, 5-HT

Mmol, mM mMs of Tris-HCl tri- (methylol) ammonia Methylmethane-hydrochloric acid

Ng nanogram EDTA-K₂Ethylenediamine tetra-acetic acid Dipotassium

Μ g microgram Solutol polyethylene glycol -15- Hydroxy stearic acid ester

Mg milligrams of MTBE methyl tertiary butyl ether(MTBE)s

G grams of PEG400 polyethylene glycol 400

HATU 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester

Following synthetic schemes describes the step of preparation disclosed compound of present invention, unless otherwise stated, wherein each R^1a、 R^1b、R^1c、R^1d、R^1e、R³、R⁴And R⁵With definition of the present invention.

Synthetic schemes 1

Wherein, X CR^1aOr N.

Formula (6) compound represented can be prepared by following process: formula (1) compound represented and formula (2) institute Show compound react, obtain formula (3) shown in product；Then formula (3) compound represented hydrolysis, obtain formula (4) shown in produce Object；Formula (4) compound represented and formula (5) compound represented condensation, obtain (6) shown in target product.

Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.

Embodiment

Embodiment 1N- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) benzamide Synthesis

The synthesis of step 1) methyl 6- benzene carbon amide yl pyridines -2- formic acid esters

At 0 DEG C by methyl 6- aminopyridine -2- formic acid esters (710mg, 4.67mmol), triethylamine (1.3mL, 9.40mmol) it is added in 100mL single necked round bottom flask with methylene chloride (10mL), dropwise addition chlorobenzoyl chloride (848mg, 6.03mmol), it is transferred at 25 DEG C and reacts 12 hours；After reaction, reaction solution is poured into water (30mL), uses methylene chloride It extracts (40mL), collects organic phase, decompression is spin-dried for, and column chromatography for separation (petrol ether/ethyl acetate (v/v)=2/1) obtains title Compound is weak yellow liquid (414mg, 35.4%).

MS(ESI,pos.ion)m/z:257.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.90 (s, 1H), 8.63 (dd, J=6.8,2.4Hz, 1H), 7.97- 7.88 (m, 4H), 7.58 (t, J=7.2Hz, 1H), 7.51 (t, J=8.0Hz, 2H), 4.01 (s, 3H)

The synthesis of step 2) 6- benzene carbon amide yl pyridines -2- formic acid

By methyl 6- benzene carbon amide yl pyridines -2- formic acid esters (820mg, 3.20mmol), water (2mL) and methanol at 25 DEG C (10mL) is added in 100mL single necked round bottom flask, is added Lithium hydroxide monohydrate (165mg, 3.93mmol), and it is 3 small that the reaction was continued When；Stop reaction, vacuum rotary steam removes methanol, is added water (10mL), and concentrated hydrochloric acid is then added and is adjusted to pH=2, filters, gained It is white solid (620mg, 80%) that 60 DEG C of solid, which are dried to obtain title compound,.

MS(ESI,pos.ion)m/z:243.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 11.02 (s, 1H), 8.36 (d, J=8.4Hz, 1H), 8.08-7.99 (m, 3H), 7.82 (d, J=7.6Hz, 1H), 7.60 (t, J=7.6Hz, 1H), 7.51 (t, J=7.6Hz, 2H)

The conjunction of step 3) N- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) benzamide At

6- benzene carbon amide yl pyridines -2- formic acid (243mg, 1.0mmol) and methylene chloride (10mL) are added at 0 DEG C In 100mL single-necked flask, n,N-diisopropylethylamine (194mg, 1.5mmol) and HATU (600mg, 1.5mmol), nitrogen is added The reaction was continued under protection half an hour；Then 2- methyl octahydro pyrrolo- [3,4-c] pyrroles (190mg, 1.51mmol), transfer is added It is reacted 3 hours to 25 DEG C；Stop reaction, be added water (20mL), then (30mL × 2) are extracted with dichloromethane, collects organic phase, Anhydrous sodium sulfate (1g) is added to dry, filter, filtrate decompression is spin-dried for, column chromatographic purifying (methylene chloride/methanol (v/v)=40/1) Obtaining title compound is faint yellow solid (94mg, 26.7%).MS(ESI,pos.ion)m/z:351.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.46(s,1H),8.04–7.78(m,3H),7.63–7.46(m,4H), 4.16–3.50(m,6H),3.26–3.06(m,3H),2.89(s,3H),2.74–2.71(m,1H)。

The fluoro- N- of 2 4- of embodiment (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) benzene first The synthesis of amide

The synthesis of step 1) methyl 6- (4- fluorobenzoylamino) pyridine -2- formic acid esters

This step title compound method referring to described in 1 step 1 of embodiment is prepared, that is, by 6- aminopyridine- 2- formic acid esters (200mg, 1.31mmol), triethylamine (0.3mL, 2.0mmol) and 4- fluorobenzoyl chloride (0.25mL, 2.12mmol) The reaction preparation in methylene chloride (10mL), crude product are purified through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), Obtaining title compound is white solid (350mg, 97.1%).

MS(ESI,pos.ion)m/z:275.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.59 (dd, J=6.8,2.4Hz, 1H), 7.99-7.94 (m, 2H), 7.92–7.87(m,2H),7.21–7.14(m,2H),3.99(s,3H).

The synthesis of step 2) 6- (4- fluorobenzoylamino) pyridine -2- formic acid

This step title compound method referring to described in 1 step 2 of embodiment is prepared, that is, by methyl 6- (4- fluorine Benzamido) pyridine -2- formic acid esters (340mg, 1.24mmol), Lithium hydroxide monohydrate (55mg, 1.31mmol) is in methanol Reaction preparation in (10mL) and water (2mL), obtaining title compound is white solid (279mg, 86.5%).

MS(ESI,pos.ion)m/z:261.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 11.06 (s, 1H), 8.34 (d, J=8.0Hz, 1H), 8.12 (dd, J =8.8,5.2Hz, 2H), 8.02 (t, J=8.0Hz, 1H), 7.82 (d, J=7.6Hz, 1H), 7.34 (t, J=8.8Hz, 2H)

The fluoro- N- of step 3) 4- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) benzoyl The synthesis of amine

This step title compound method referring to described in 1 step 3 of embodiment is prepared, that is, by 6- (4- fluorobenzene first Acylamino-) pyridine -2- formic acid (180mg, 0.69mmol), N, N- diisopropylethylamine (0.18mL, 1.09mmol), HATU (420mg, 1.1mmol) and 2- methyl octahydro pyrrolo- [3,4-c] pyrroles (135mg, 1.07mmol) are at methylene chloride (10mL) Middle reaction preparation, crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=40/1), and obtaining title compound is Faint yellow solid (62mg, 24.3%).

MS(ESI,pos.ion)m/z:369.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.53-8.38 (m, 1H), 8.10-7.82 (m, 3H), 7.54 (d, J= 7.2Hz, 1H), 7.18 (d, J=7.2Hz, 2H), 4.22-3.62 (m, 6H), 3.29-3.10 (m, 3H), 2.92 (s, 3H), 2.77–2.67(m,1H).

The chloro- N- of 3 4- of embodiment (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) benzene first The synthesis of amide

The synthesis of step 1) methyl 6- (4- chIorobenzoyIamino) pyridine -2- formic acid esters

This step title compound method referring to described in 1 step 1 of embodiment is prepared, that is, by 6- aminopyridine- 2- formic acid esters (200mg, 1.31mmol), triethylamine (0.3mL, 2.0mmol) and 4- chlorobenzoyl chloride (0.25mL, 1.96mmol) The reaction preparation in methylene chloride (10mL), crude product are purified through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), Obtaining title compound is white solid (362mg, 94.7%).

MS(ESI,pos.ion)m/z:291.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.86 (s, 1H), 8.59 (dd, J=6.4,2.8Hz, 1H), 7.93- 7.85 (m, 4H), 7.48 (d, J=8.8Hz, 2H), 4.00 (s, 3H)

The synthesis of step 2) 6- (4- chIorobenzoyIamino) pyridine -2- formic acid

This step title compound method referring to described in 1 step 2 of embodiment is prepared, that is, by methyl 6- (4- chlorine Benzamido) pyridine -2- formic acid esters (362mg, 1.25mmol), Lithium hydroxide monohydrate (55mg, 1.31mmol) is in methanol Reaction preparation in (10mL) and water (2mL), obtaining title compound is white solid (228mg, 66.2%).

MS(ESI,pos.ion)m/z:277.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 11.13 (s, 1H), 8.34 (d, J=8.4Hz, 1H), 8.10-7.98 (m, 3H), 7.82 (d, J=7.6Hz, 1H), 7.58 (d, J=8.4Hz, 2H)

The chloro- N- of step 3) 4- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) benzoyl The synthesis of amine

This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 6- (4- chlorobenzene first Acylamino-) pyridine -2- formic acid (200mg, 0.72mmol), N, N- diisopropylethylamine (0.18mL, 1.09mmol), HATU (420mg, 1.1mmol) and 2- methyl octahydro pyrrolo- [3,4-c] pyrroles (140mg, 1.11mmol) are at methylene chloride (10mL) Middle reaction preparation, crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=40/1), and obtaining title compound is Faint yellow solid (130mg, 46.7%).

MS(ESI,pos.ion)m/z:385.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.48–8.40(m,1H),8.01–7.85(m,3H),7.57–7.42(m, 3H),4.20–3.75(m,6H),3.28–3.11(m,3H),2.91(s,3H),2.78–2.69(m,1H)。

The bromo- N- of 4 4- of embodiment (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) benzene first The synthesis of amide

The synthesis of step 1) methyl 6- (4- Bromophenacyl amino) pyridine -2- formic acid esters

This step title compound method referring to described in 1 step 1 of embodiment is prepared, that is, by 6- aminopyridine- 2- formic acid esters (300mg, 1.97mmol), triethylamine (0.3mL, 2.0mmol) and 4- bromo-benzoyl chloride (660mg, 3.0mmol) exist Reaction preparation in methylene chloride (10mL), crude product are purified through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1), are obtained It is white solid (609mg, 92.1%) to title compound.

MS(ESI,pos.ion)m/z:335.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.91 (s, 1H), 8.59 (dd, J=6.8,2.4Hz, 1H), 7.92- 7.88 (m, 2H), 7.82 (d, J=8.8Hz, 2H), 7.64 (d, J=8.4Hz, 2H), 3.99 (s, 3H)

The synthesis of step 2) 6- (4- Bromophenacyl amino) pyridine -2- formic acid

This step title compound method referring to described in 1 step 2 of embodiment is prepared, that is, by methyl 6- (4- bromine Benzamido) pyridine -2- formic acid esters (600mg, 1.79mmol), Lithium hydroxide monohydrate (75mg, 1.79mmol) is in methanol Reaction preparation in (10mL) and water (2mL), obtaining title compound is white solid (510mg, 88.7%).

MS(ESI,pos.ion)m/z:321.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 11.14 (s, 1H), 8.34 (d, J=8.0Hz, 1H), 8.05-7.95 (m,3H),7.88–7.80(m,1H),7.74–7.68(m,2H).

The bromo- N- of step 3) 4- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) benzoyl The synthesis of amine

This step title compound method referring to described in 1 step 3 of embodiment is prepared, that is, by 6- (4- bromobenzene first Acylamino-) pyridine -2- formic acid (200mg, 0.63mmol), N, N- diisopropylethylamine (0.16mL, 0.97mmol), HATU (350mg, 0.92mmol) and 2- methyl octahydro pyrrolo- [3,4-c] pyrroles (120mg, 0.95mmol) are at methylene chloride (10mL) Middle reaction preparation, crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=40/1), and obtaining title compound is Faint yellow solid (130mg, 48.6%).

MS(ESI,pos.ion)m/z:429.0[M+H]⁺；

¹H NMR(400MHz,CD₃OD) δ (ppm) 8.06 (d, J=7.6Hz, 1H), 7.69 (dd, J=16.0,8.0Hz, 3H), 7.44 (d, J=8.4Hz, 2H), 7.34 (d, J=7.2Hz, 1H), 3.80-3.35 (m, 6H), 3.12 (br, 4H), 2.72 (s,3H).

The fluoro- N- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) of 5 2,4- of embodiment bis- The synthesis of benzamide

The synthesis of step 1) methyl 6- (2,4 difluorobenzene formamido group) pyridine -2- formic acid esters

This step title compound method referring to described in 1 step 1 of embodiment is prepared, that is, by 6- aminopyridine- 2- formic acid esters (500mg, 3.29mmol), triethylamine (0.9mL, 6.0mmol) and 2,4- difluoro benzoyl chloride (550mg, 3.12mmol) the reaction preparation in the methylene chloride (10mL), crude product through silica gel column chromatography (petrol ether/ethyl acetate (v/v)= 2/1) it purifies, obtaining title compound is white solid (654mg, 71.8%).

MS(ESI,pos.ion)m/z:293.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 9.06 (d, J=11.2Hz, 1H), 8.58-8.54 (m, 1H), 8.17- 8.08 (m, 1H), 7.91 (d, J=4.4Hz, 2H), 7.08-7.01 (m, 1H), 6.99-6.92 (m, 1H), 4.00 (s, 3H)

The synthesis of step 2) 6- (2,4 difluorobenzene formamido group) pyridine -2- formic acid

This step title compound method referring to described in 1 step 2 of embodiment is prepared, that is, by methyl 6- (2,4- Difluorobenzoyl amino) pyridine -2- formic acid esters (340mg, 1.24mmol), Lithium hydroxide monohydrate (55mg, 1.31mmol) is in first Reaction preparation in alcohol (10mL) and water (2mL), obtaining title compound is white solid (278mg, 86.5%).

MS(ESI,pos.ion)m/z:279.2[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 11.15 (s, 1H), 8.37 (d, J=8.4Hz, 1H), 8.03 (t, J= 7.6Hz, 1H), 7.84-7.74 (m, 2H), 7.42-7.34 (m, 1H), 7.20 (td, J=8.4,1.6Hz, 1H)

The fluoro- N- of step 3) 2,4- bis- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) benzene The synthesis of formamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, that is, by 6- (2,4- difluoros Benzamido) pyridine -2- formic acid (290mg, 1.04mmol), N, N- diisopropylethylamine (0.26mL, 1.57mmol), HATU (600mg, 1.58mmol) and 2- methyl octahydro pyrrolo- [3,4-c] pyrroles (300mg, 2.38mmol) are at methylene chloride (10mL) Middle reaction preparation, crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=40/1), and obtaining title compound is Faint yellow solid (184mg, 45.7%).

MS(ESI,pos.ion)m/z:387.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.97 (d, J=13.5Hz, 1H), 8.41 (d, J=8.3Hz, 1H), 8.24-8.18 (m, 1H), 7.86 (t, J=7.9Hz, 1H), 7.53 (d, J=7.5Hz, 1H), 7.13-7.04 (m, 1H), 7.02- 6.90(m,1H),4.10–3.97(m,1H),3.94–3.87(m,1H),3.67–3.58(m,2H),2.91(brs,2H),2.71– 2.63(m,1H),2.62–2.54(m,1H),2.55–2.47(m,1H),2.44–2.37(m,1H),2.34(s,3H).

The fluoro- N- of the chloro- 2- of embodiment 64- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) The synthesis of benzamide

The synthesis of step 1) methyl 6- (the chloro- 2- fluorobenzoylamino of 4-) pyridine -2- formic acid esters

This step title compound method referring to described in 1 step 1 of embodiment is prepared, that is, by 6- aminopyridine- 2- formic acid esters (400mg, 2.63mmol), triethylamine (0.9mL, 6.0mmol) and the chloro- 2- fluorobenzoyl chloride of 4- (500mg, 2.59mmol) the reaction preparation in the methylene chloride (10mL), crude product through silica gel column chromatography (petrol ether/ethyl acetate (v/v)= 2/1) it purifies, obtaining title compound is white solid (632mg, 79%).

MS(ESI,pos.ion)m/z:309.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 9.06 (d, J=10.8Hz, 1H), 8.59-8.54 (m, 1H), 8.06 (t, J=8.4Hz, 1H), 7.94-7.90 (m, 2H), 7.32 (dd, J=8.4,1.6Hz, 1H), 7.26 (dd, J=11.4,1.6Hz, 1H),4.00(s,3H).

The synthesis of step 2) 6- (the chloro- 2- fluorobenzoylamino of 4-) pyridine -2- formic acid

This step title compound method referring to described in 1 step 2 of embodiment is prepared, that is, by methyl 6- (4- Chloro- 2- fluorobenzoylamino) pyridine -2- formic acid esters (309mg, 1.0mmol), Lithium hydroxide monohydrate (45mg, 1.1mmol) is in first Reaction preparation in alcohol (10mL) and water (2mL), obtaining title compound is white solid (168mg, 56.8%).

MS(ESI,pos.ion)m/z:295.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 11.23 (s, 1H), 8.37 (d, J=8.4Hz, 1H), 8.03 (t, J= 8.0Hz, 1H), 7.83 (d, J=7.6Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.58 (d, J=10.0Hz, 1H), 7.40 (d, J=8.4Hz, 1H)

The fluoro- N- of the chloro- 2- of step 3) 4- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) benzene The synthesis of formamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, that is, by 6- (the chloro- 2- of 4- Fluorobenzoylamino) pyridine -2- formic acid (180mg, 0.61mmol), N, N- diisopropylethylamine (0.15mL, 0.91mmol), HATU (350mg, 0.92mmol) and 2- methyl octahydro pyrrolo- [3,4-c] pyrroles (120mg, 0.95mmol) are in methylene chloride Reaction preparation in (10mL), crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=40/1), are obtained titled Conjunction object is faint yellow solid (98mg, 39.8%).

MS(ESI,pos.ion)m/z:403.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.36 (d, J=8.0Hz, 1H), 7.97 (t, J=8.4Hz, 1H), 7.85 (t, J=8.0Hz, 1H), 7.54 (d, J=7.2Hz, 1H), 7.29-7.17 (m, 2H), 4.13-3.59 (m, 6H), 3.33-3.21 (m,2H),3.10–2.94(m,2H),2.86(s,3H).

The fluoro- N- of embodiment 72,4,6- tri- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) The synthesis of benzamide

The synthesis of step 1) methyl 6- (2,4,6- trifluoromethyl benzonitrile acylamino-) pyridine -2- formic acid esters

This step title compound method referring to described in 1 step 1 of embodiment is prepared, that is, by 6- aminopyridine- 2- formic acid esters (450mg, 2.96mmol), triethylamine (0.9mL, 6.0mmol) and 2,4,6- trifluorobenzoyl chlorides (530mg, 2.72mmol) the reaction preparation in the methylene chloride (10mL), crude product through silica gel column chromatography (petrol ether/ethyl acetate (v/v)= 2/1) it purifies, obtaining title compound is light yellow oil (374mg, 44.2%).

MS(ESI,pos.ion)m/z:311.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.86 (s, 1H), 8.57 (dd, J=7.6,1.2Hz, 1H), 7.96- 7.89(m,2H),6.78–6.70(m,2H),3.97(s,3H).

The synthesis of step 2) 6- (2,4,6- benzamide trifluoroacetate) pyridine -2- formic acid

This step title compound method referring to described in 1 step 2 of embodiment is prepared, that is, by methyl 6- (2,4, 6- trifluoromethyl benzonitrile acylamino-) pyridine -2- formic acid esters (178mg, 0.57mmol), Lithium hydroxide monohydrate (25mg, 0.6mmol) is in first Reaction preparation in alcohol (5mL) and water (1mL), obtaining title compound is white solid (160mg, 94.1%).

MS(ESI,pos.ion)m/z:297.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 11.71 (s, 1H), 8.37 (d, J=8.4Hz, 1H), 8.05 (t, J= 8.0Hz, 1H), 7.85 (d, J=7.6Hz, 1H), 7.32 (t, J=8.8Hz, 2H)

The fluoro- N- of step 3) 2,4,6- tri- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) The synthesis of benzamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 6- (2,4,6- tri- Fluorobenzoylamino) pyridine -2- formic acid (160mg, 0.54mmol), N, N- diisopropylethylamine (0.15mL, 0.91mmol), HATU (350mg, 0.92mmol) and 2- methyl octahydro pyrrolo- [3,4-c] pyrroles (120mg, 0.95mmol) are in methylene chloride Reaction preparation in (10mL), crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=40/1), are obtained titled Conjunction object is faint yellow solid (110mg, 50.4%).

MS(ESI,pos.ion)m/z:405.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 8.33 (d, J=8.4Hz, 1H), 7.82 (t, J=8.0Hz, 1H), 7.48 (d, J=7.2Hz, 1H), 6.74 (t, J=8.4Hz, 2H), 3.94-3.64 (m, 4H), 3.10-2.89 (m, 4H)), 2.80- 2.71(m,2H),2.55(s,3H).

The fluoro- N- of 8 5- of embodiment (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) pyridine - The synthesis of 2- formamide

The synthesis of step 1) methyl 6- (5- fluorine pyridine -2- formamido group) pyridine -2- formic acid esters

This step title compound method referring to described in 1 step 1 of embodiment is prepared, that is, by 6- aminopyridine- 2- formic acid esters (600mg, 3.94mmol), triethylamine (1.0mL, 7.2mmol) and 5- fluorine pyridine -2- formyl chloride (600mg, 3.76mmol) the reaction preparation in the methylene chloride (10mL), crude product through silica gel column chromatography (petrol ether/ethyl acetate (v/v)= 2/1) it purifies, obtaining title compound is faint yellow solid (760mg, 73.4%).

MS(ESI,pos.ion)m/z:276.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 10.52 (s, 1H), 8.66-8.62 (m, 1H), 8.47 (d, J=2.4Hz, 1H), 8.33 (dd, J=8.7,4.5Hz, 1H), 7.93-7.89 (m, 2H), 7.60 (td, J=8.0,2.8Hz, 1H), 4.02 (s, 3H).

The synthesis of step 2) 6- (5- fluorine pyridine -2- formamido group) pyridine -2- formic acid

This step title compound method referring to described in 1 step 2 of embodiment is prepared, that is, by methyl 6- (5- fluorine Pyridine -2- formamido group) pyridine -2- formic acid esters (370mg, 1.34mmol), Lithium hydroxide monohydrate (60mg, 1.43mmol) is in first Reaction preparation in alcohol (10mL) and water (2mL), obtaining title compound is white solid (313mg, 89.1%).

MS(ESI,pos.ion)m/z:262.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 10.43 (s, 1H), 8.77 (d, J=2.8Hz, 1H), 8.44 (d, J= 8.4Hz, 1H), 8.30 (dd, J=8.8,4.8Hz, 1H), 8.09 (t, J=8.0Hz, 1H), 8.03 (td, J=8.4,2.8Hz, 1H), 7.85 (d, J=7.6Hz, 1H)

The fluoro- N- of step 3) 5- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) pyridine -2- The synthesis of formamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 6- (5- fluorine pyridine- 2- formamido group) pyridine -2- formic acid (106mg, 0.41mmol), N, N- diisopropylethylamine (0.11mL, 0.67mmol), HATU (250mg, 0.66mmol) and 2- methyl octahydro pyrrolo- [3,4-c] pyrroles (75mg, 0.59mmol) are at methylene chloride (10mL) Middle reaction preparation, crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=40/1), and obtaining title compound is White solid (57mg, 38%).

MS(ESI,pos.ion)m/z:370.3[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 10.26 (s, 1H), 8.55-8.43 (m, 2H), 8.36 (q, J=4.4Hz, 1H), 7.91 (t, J=7.6Hz, 1H), 7.68-7.58 (m, 2H), 4.06 (br, 4H), 3.74-3.66 (m, 2H), 3.32 (br, 2H),2.91(s,3H),2.69(br,2H).

The chloro- N- of 9 5- of embodiment (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) pyridine - The synthesis of 2- formamide

The synthesis of step 1) methyl 6- (5- chloropyridine -2- formamido group) pyridine -2- formic acid esters

This step title compound method referring to described in 1 step 1 of embodiment is prepared, that is, by 6- aminopyridine- 2- formic acid esters (450mg, 2.96mmol), triethylamine (0.9mL, 6.0mmol) and 5- chloropyridine -2- formyl chloride (500mg, 2.84mmol) the reaction preparation in the methylene chloride (10mL), crude product through silica gel column chromatography (petrol ether/ethyl acetate (v/v)= 2/1) it purifies, obtaining title compound is faint yellow solid (496mg, 59.9%).

MS(ESI,pos.ion)m/z:292.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 10.54 (s, 1H), 8.66-8.61 (m, 1H), 8.59 (d, J=1.9Hz, 1H), 8.24 (d, J=8.4Hz, 1H), 7.93-7.90 (m, 2H), 7.88 (dd, J=8.4,2.0Hz, 1H), 4.02 (s, 3H)

The synthesis of step 2) 6- (5- chloropyridine -2- formamido group) pyridine -2- formic acid

This step title compound method referring to described in 1 step 2 of embodiment is prepared, that is, by methyl 6- (5- chlorine Pyridine -2- formamido group) pyridine -2- formic acid esters (490mg, 1.68mmol), Lithium hydroxide monohydrate (84mg, 2.0mmol) is in first Reaction preparation in alcohol (10mL) and water (2mL), obtaining title compound is white solid (379mg, 81.3%).

MS(ESI,pos.ion)m/z:278.0[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆) δ (ppm) 10.45 (s, 1H), 8.82 (d, J=1.2Hz, 1H), 8.44 (d, J= 8.4Hz, 1H), 8.26-8.18 (m, 2H), 8.09 (t, J=7.6Hz, 1H), 7.85 (d, J=7.2Hz, 1H)

The chloro- N- of step 3) 5- (6- (5- methyl octahydro pyrrolo- [3,4-c] pyrroles -2- carbonyl) pyridine -2- base) pyridine -2- The synthesis of formamide

This step title compound method referring to described in 1 step 3 of embodiment is prepared, that is, by 6- (5- chlorine pyrrole Pyridine -2- formamido group) pyridine -2- formic acid (198mg, 0.71mmol), N, N- diisopropylethylamine (0.17mL, 1.03mmol), HATU (410mg, 1.08mmol) and 2- methyl octahydro pyrrolo- [3,4-c] pyrroles (140mg, 1.11mmol) are in methylene chloride Reaction preparation in (10mL), crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=40/1), are obtained titled Conjunction object is white solid (110mg, 40%).

MS(ESI,pos.ion)m/z:386.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃) δ (ppm) 10.29 (s, 1H), 8.61 (d, J=2.0Hz, 1H), 8.48 (d, J= 8.0Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.92 (d, J=6.0Hz, 2H), 7.63 (d, J=7.2Hz, 1H), 4.16- 4.07(m,4H),3.87(br,2H),3.65(br,2H),3.19–3.13(m,2H),2.93(s,3H).

Biologic test

Embodiment A: non-selective rat 5-HT₁Experiment that Receptor Radioligand is affine

Experimental method

Cell membrane is prepared using the Cerebral cortex of 175 ± 25g male Wistar rat, the Tris-HCl for being placed in pH=7.4 is slow In fliud flushing.Under the conditions of 25 DEG C, by 15mg cell membrane sample and 1nM [³H] -5-HT is in buffer (50mM Tris-HCl (pH= 7.4), 0.1%Ascortic Acid, 10 μM of Pargyline, 4mM CaCl₂) middle incubation 60 minutes, it is added under this condition Test-compound completes radioligand-binding study.

Test-compound is dissolved in 100%DMSO, and at 6 concentration (0.1nM, 1nM, 10nM, 100nM, 1 μM, 10 μM) Under tested, measure non-specific binding values using 10 μM of 5-HT.

After incubation, termination reaction is quickly filtered by the glass fiber filter of pre-soaking 0.3%PEI, and 96 It is rinsed 3 times in the cell harvestor of hole using the 50mM Tris-HCl solution of pre-cooling.After drying, scintillation solution is added, in liquid scintillation Remaining radioactivity is measured in counter.

Experimental result is indicated with the suppression percentage specifically bound relative to control wells radioligand.

Standard reference compound is 5-HT, by the data of the 5-HT of test series concentration, inhibiting rate is calculated and (inhibits Rate=100- (well is affine the affine result of result/control wells) * 100), it obtains concentration-inhibiting rate and competes linearity curve, to count Calculate IC₅₀。

It the results are shown in Table A.

Table A: the compounds of this invention is to rat 5-HT₁Experimental result that receptor is affine

Example No.	IC₅₀(μM)
		Embodiment 5	6.98

Experimental result shows that the compounds of this invention is to rat 5-HT₁Receptor compatibility with higher.

Embodiment B:5-HT_1FReceptor Ca²⁺Migrate measuring method

Experimental method

(1) wink turns experiment

By the HEK293 cell for growing to 90% with the density kind of 1.5 × 10^6 cells/well in 6 orifice plates 37 DEG C, 5%CO₂It is incubated overnight in incubator, with source of people 5-HT_1FWith the common transfected HEK 293 of Ga15 plasmid and in 37 DEG C, 5% CO₂It is lower to incubate 24 hours.

(2) FLIPR is tested

To transfect 24 hours HEK293 cell dissociations with the density kind of 2 × 10^4 cells/well in 384 orifice plates and In 37 DEG C, 5%CO₂Lower incubation 16-20 hours.20 μ l 2X Fluo-4Direct are added in every hole^TMDyestuff and in 37 DEG C, 5% CO₂It is lower to incubate 50 minutes, it is placed at room temperature for 10 minutes.Prepare compound various concentration dose curve plate, with FLIPR instrument from Transfer compounds read fluorescence signal into cell plates immediately in dose curve plate.The Ca of various concentration compound induction²⁺With dye Material combines the fluorescence signal that can produce varying strength, calculates compound dose-effect curve by Prism software, generates partly most The agonist concentration responded greatly is with EC₅₀Value indicates.

Experimental result shows that the compounds of this invention has stronger 5-HT_1FReceptor agonist activity.

Embodiment C: rat, dog intravenous or stomach-filling quantify the Pharmacokinetic Evaluation of the compounds of this invention

Inventor has carried out pharmcokinetic evaluation to the compound of the present invention in rat, dog body.Wherein, animal information See Table 1 for details.

Table 1: animal subject information table of the present invention

Germline	Grade	Gender	Weight	Age	Source
						SD rat	SPF	Male	170-250g	6-9 weeks	Hunan Si Laike experimental animal Co., Ltd
Beagle dog	Cleaning grade	Male	8~10kg	6-7 weeks	Hunan Si Laike experimental animal Co., Ltd

Experimental method

By the compounds of this invention with 5%DMSO+5%Solutol+90% normal saline solution or 5%DMSO+60% PEG400+35% normal saline solution form, is administered animal subject, animal fasting 12h, free water before being administered.It is right In intravenous injection administration group, dosage 1mg/kg puts venous blood sampling (amount for taking blood about 0.15mL) at the following time after administration: 0.083,0.25,0.5,1.0,2.0,4.0,6.0,8.0 and for 24 hours, EDTA-K is previously added in heparin tube₂As anti-coagulants, blood Sample is centrifuged 2 minutes at 12,000rpm, collects blood plasma, and save at -20 DEG C or -70 DEG C.For gastric infusion group, administration Dosage is 5mg/kg, clicks through row vein after administration at the following time and takes blood (amount for taking blood about 0.15mL): 0.25,0.5,1.0,2.0, 4.0,6.0,8.0 and for 24 hours, EDTA-K is previously added in heparin tube₂As anti-coagulants, blood sample is centrifuged 2 points at 12,000rpm Clock is collected blood plasma, and is saved at -20 DEG C or -70 DEG C.Positive control is that (its structure is Lasmiditan

The plasma sample of above-mentioned collection is handled and (takes 30 μ L blood plasma, target aqueous solution in 120 μ L is added, after mixing Extracted with 0.9mL MTBE, redissolved after taking 0.7mL to dry up with 220 μ L methanol-waters (v/v=1/1)) after, it is analyzed using LC-MS/MS The concentration of compound in blood plasma.Analysis the result shows that, the compounds of this invention all has preferable medicine for power in rat, dog body Learn property.

Table C1: the compounds of this invention is in the intracorporal pharmacokinetic parameter of rat

ND: no test data is indicated.

The compound of the present invention has more preferable relative to Lasmiditan in rat body it can be seen from table C1 result Pharmacokinetic property.

Table C2: the compounds of this invention is in the intracorporal pharmacokinetic parameter of dog

ND: no test data is indicated.

The compound of the present invention has better relative to Lasmiditan in dog body it can be seen from table C2 result Pharmacokinetic property.

In the description of this specification, reference term " one embodiment ", " embodiment ", " some embodiments ", " show The description of example ", specific examples or " some examples " etc. means to combine the specific spy of the embodiment, embodiment or example description Sign, structure, material or feature are contained at least one embodiment of the present invention, embodiment or example.In this specification In, schematic expression of the above terms are necessarily directed to identical embodiment, embodiment or example.Moreover, description Particular features, structures, materials, or characteristics can be in any one or more embodiments, embodiment or example with suitable Mode combines.In addition, without conflicting with each other, those skilled in the art can be by difference described in this specification Embodiment, embodiment or example and different embodiments, embodiment or exemplary feature are combined.

Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modifies, replacement and variant.

Claims

1. a kind of compound, the stereoisomer for being compound shown in formula (I) compound represented or formula (I), mutually variation Structure body, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,

Wherein:

L is-C (=O)-,-C (=S)-or-S (=O)₂-；

R¹For C₁-C₄Alkyl, C₃-C₆Naphthenic base, 3-6 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 unit's heteroaryl, wherein R¹Optionally R is selected from by 1,2,3,4 or 5^1a、R^1b、R^1c、R^1dAnd R^1eGroup replaced；

R^1a、R^1b、R^1c、R^1dAnd R^1eIt is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、-SH、-COOH、-C (=O) NH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂,-C (=O)-(C₁-C₄Alkyl) ,-C (=O)-(C₁-C₄Alkoxy), C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy, C₁-C₄Alkane sulphur Base, C₁-C₄The C that alkylamino, hydroxyl replace₁-C₄Alkyl, C₃-C₆Naphthenic base, 3-6 circle heterocyclic ring base, C₆-C₁₀Aryl or 5-10 member are miscellaneous Aryl；

R³、R⁴And R⁵It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂、-OH、C₁-C₄Alkyl, C₁-C₄Alkyl halide Base, C₁-C₄Alkoxy, C₁-C₄The C that halogenated alkoxy or hydroxyl replace₁-C₄Alkyl；

R⁶For H, D ,-COOH ,-C (=O) NH₂,-C (=O) NHCH₃,-C (=O) N (CH₃)₂,-C (=O)-(C₁-C₄Alkyl) ,-C (=O)-(C₁-C₄Alkoxy), C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₁-C₄The C that halogenated alkyl or hydroxyl replace₁-C₄ Alkyl；With

R⁷For H, D, F, Cl, Br, I, C₁-C₄Alkyl, C₁-C₄Halogenated alkyl, C₁-C₄Alkoxy, C₁-C₄Halogenated alkoxy or hydroxyl Substituted C₁-C₄Alkyl.

2. compound according to claim 1, wherein R¹For phenyl, indenyl, naphthalene, pyrrole radicals, pyrazolyl, imidazole radicals, three Nitrogen oxazolyl, tetrazole base, furyl, thienyl, thiazolyl, oxazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, benzo Imidazole radicals, indyl or quinolyl, wherein R¹Optionally R is selected from by 1,2,3,4 or 5^1a、R^1b、R^1c、R^1dAnd R^1eGroup institute Replace；

R^1a、R^1b、R^1c、R^1dAnd R^1eBe each independently H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, allyl, Acrylic, propargyl, propinyl ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, methoxyl group, second Oxygroup, n-propyl oxygroup, isopropyl oxygroup ,-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、- OCH₂CF₂CHF₂, methyl mercapto, ethylmercapto group, methylamino, dimethylamino, ethylamino, methylol or 2- hydroxyethyl.

3. compound according to claim 1 or 2 is formula (IIIa-1) or formula (IIIa-2) compound represented, or It is the stereoisomer of compound shown in person's formula (IIIa-1) or formula (IIIa-2), tautomer, nitrogen oxides, hydrate, molten Agent compound, metabolite, pharmaceutically acceptable salt or its prodrug,

4. compound according to claim 1 to 3, wherein R²For H, D, methyl, ethyl, n-propyl, isopropyl Base ,-CF₃Or-CH₂CF₃；

R³、R⁴And R⁵It is each independently H, D, F, Cl, Br, I ,-CN ,-NO₂、-NH₂,-OH, methyl, ethyl, n-propyl, isopropyl Base ,-CF₃、-CH₂CF₃, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup；

5. compound according to any one of claims 1-4, wherein R⁶For H, D, methyl, ethyl, n-propyl, isopropyl, Allyl, acrylic, propargyl, propinyl ,-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂, hydroxyl Methyl or 2- hydroxyethyl.

6. compound described in -5 any one according to claim 1 for the compound with one of following structure or has The stereoisomer of the compound of one of following structure, tautomer, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or its prodrug:

7. a kind of pharmaceutical composition includes compound as claimed in any one of claims 1 to 6；With

Described pharmaceutical composition optionally further includes pharmaceutically acceptable excipient, carrier, adjuvant or theirs is any Combination.

8. compound as claimed in any one of claims 1 to 6 or pharmaceutical composition as claimed in claim 7 are in medicine preparation Purposes, the drug is for preventing, treating or mitigating and 5-HT_1FReceptor related disease.

9. purposes according to claim 8, wherein described and 5-HT_1FReceptor related disease is migraine, generality Pain, trigeminal neuralgia, toothache or remporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social activity Neurosis, anxiety, generalized anxiety disorder, sleep disturbance, posttraumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or after Luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, wine Smart poisoning, tobacco abuse, mutism, trichologia, bulimia nerovsa, anorexia nervosa, premature ejaculation, erectile dysfunction, memory It loses or dull-witted.

10. compound as claimed in any one of claims 1 to 6 or pharmaceutical composition as claimed in claim 7 are in medicine preparation Purposes, the drug is for activating 5-HT_1FReceptor.