CN111004214B

CN111004214B - Pyridylpiperidine derivatives and use thereof

Info

Publication number: CN111004214B
Application number: CN201911152299.1A
Authority: CN
Inventors: 钟文和; 金传飞; 王涛
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2019-11-22
Filing date: 2019-11-22
Publication date: 2021-06-08
Anticipated expiration: 2039-11-22
Also published as: CN111004214A

Abstract

The invention discloses pyridine acyl piperidine derivatives and application thereof, and particularly relates to novel pyridine acyl piperidine derivatives and a pharmaceutical composition containing the same, which can be used for activating 5-HT_1FA receptor. The invention also relates to processes for the preparation of such compounds and pharmaceutical compositions, and their use in the preparation of a medicament for the treatment of 5-HT_1FThe use in the manufacture of a medicament for the treatment of a condition associated with a receptor, in particular migraine.

Description

Pyridylpiperidine derivatives and use thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to novel pyridine acyl piperidine derivatives, a pharmaceutical composition containing the compounds, and a using method and application of the derivatives. In particular, the novel pyridinylpiperidine derivatives of the present invention are useful for activating 5-HT_1FReceptor for the prevention, treatment or alleviation of 5-HT_1FA receptor-related disorder, in particular migraine.

Background

Migraine is a paroxysmal and often unilateral throbbing headache, often accompanied by nausea and vomiting, and is a common chronic neurovascular disease, which is mostly ill in children and adolescence, reaches the peak of onset in middle and young age, is common in women, and has the proportion of male patients to female patients of about 1: 2-3, the prevalence rate in the population is 5% -10%, and the population often has a genetic background.

Migraine, while not a fatal disease, can severely impact a patient's social life. In the United states, the socio-economic burden of migraine is $ 10-17 billion. In China, a large number of patients influence work, study and life due to migraine. With the pace of life increasing, the incidence of migraine tends to increase. Recent investigations have found that about 5.7% of men and 17.6% of women have on average more than 1 migraine attack per year. In addition, many people have a genetic predisposition to migraine.

The pathogenesis of migraine is complex and various, and the pathogenesis mainly comprises an angiogenetic theory, a neurogenic theory, a trigeminal neurovascular theory, biochemical factors and genetic factors. The current drug for the treatment of migraine is mainly 5-HT_1B/DReceptor agonist triptans, but triptans cause vasoconstriction and are therefore contraindicated in patients with cardiovascular and cerebrovascular and peripheral vascular disease. In addition, 40-70% of migraine patients have poor curative effect on triptan medicines, 1/3 patients who are initially treated effectively can often suffer from headache recurrence, and the curative effect of the triptan medicines on patients with moderate and severe headache is obviously reduced. To overcome these adverse effects of triptans, Calcitonin Gene Related Peptide (CGRP) receptor antagonists and selective 5-HT_1FReceptor agonists are produced by the administration of anti-migraine drugs. However, CGRP receptor antagonists still have several drawbacks, such as the fact that olcagepant can only be administered intravenously and not orally, the fact that telcagepant causes elevated liver enzymes in long-term use, and the fact that BI-44370 interacts with cytochrome P450 has led to clinical development discontinuation. Therefore, the development of new acute phase therapeutic drugs is urgently required. To develop selective 5-HT_1FThe receptor agonist anti-migraine drugs have been considered as a new promising approach.

Since 1938 Graham and Wolff's work (Arch. neuron. Psychiatry,39: 737-. They suggested that the cause of migraine headache is vasodilation of extracranial blood vessels. This view is supported by the following evidence: ergot alkaloid and sumatriptan as a water-absorbing 5-HT agent incapable of crossing the blood-brain barrier₁Agonists, capable of contracting the smooth muscle of the head blood vessels and effective in the treatment of hemicraniaHeadache (Humphrey, et al, Ann. NY Acad. Sci.,600: 587-. However, work by the Moskowitz research group showed that migraine development was not associated with altered vessel diameter (Cephalalgia,12:5-7,1992).

The Moskowitz group suggested that currently unknown pain triggers irritate the trigeminal ganglion (which innervates the vasculature within the head tissue), causing axons on the vasculature to release vasoactive neuropeptides. These released neuropeptides then activate a series of events, leading to pain. This neurogenic inflammation is blocked by ergot alkaloids and sumatriptan, whose blocking mechanism involves the 5-HT receptor and interacts with the 5-HT located on the trigeminal neurovascular fibers_1DSubtypes are closely related (Neurology,43(supp1.3): S16-S20,1993). Indeed, sumatriptan pairs 5-HT_1BAnd 5-HT_1DThe receptor has high affinity with Ki of 10.3nM and 5.1nM, respectively, and this activity shows vasoconstrictive activity.

The 5-hydroxytryptamine receptor, also known as serotonin receptor or 5-HT receptor, is a group of G protein-coupled receptors found in the central and peripheral nervous system of the central nervous system and can be divided into seven subfamilies of 5-HT₁、5-HT₂、5-HT₃、5-HT₄、5-HT₅、5-HT₆And 5-HT₇Respectively, mediate different physiological activities. Wherein, 5-HT₁The receptor is the largest family of 5-HT receptors, and 5-HT is currently the most abundant receptor family_1A、5-HT_1B、5-HT_1D、5-HT_1EAnd 5-HT_1FFive subtypes. Isolation of expression of these 5-HT by the Kao group₁One of the receptor subtypes (termed 5-HT)_1F) Human gene (Proc. Natl. Acad. Sci. USA,90:408-412, 1993). The 5-HT_1FThe receptor exhibits pharmacological activity that is significantly different from any of the serotonin receptors disclosed. They found that sumatriptan was found to be other than on 5-HT_1BAnd 5-HT_IDIn addition to the strong affinity described above, the receptor also has an affinity for this receptor subtype with a Ki of approximately 23 nM. This indicates 5-HT_1FReceptors may play a role in migraine.

5-HT_1FReceptors are expressed primarily in the mesentery, uterus and brain,it is also found in the cerebral blood vessels, trigeminal ganglia, trigeminal nerve tail nuclei, and other trigeminal nerve vasculature, as well as in the cerebellum, hippocampus, and neocerebral cortex. 5-HT as other 5-HT receptors_1FReceptors are expressed not only in neurons, but also in glial cells. Presynaptic 5-HT_1FThe receptor activation can inhibit the release of calcitonin gene-related peptide (CGRP) and block neuronal signaling in the tail nucleus of trigeminal nerve, thereby producing an anti-migraine effect, and the selective 5-HT_1FThe receptor agonism greatly reduces the side effect related to vasoconstriction caused by triptan medicaments.

Subsequently, the development of p-5-HT_1FVarious 5-HT receptors with relative selectivity for receptor subtypes_1FReceptor agonists, and this selectivity generally reduces the vasoconstrictive activity characteristic of other compounds useful as potential agents in the treatment of migraine and related disorders.

Through continuous and diligent research, the inventor obtains an unexpected new selective 5-HT_1FAgonists, which have different chemical and receptor binding properties, inhibit peptide extravasation while avoiding significant vasoconstrictive activity, and are therefore useful in the treatment of migraine and other conditions associated with 5-HT_1FA receptor associated disease. Furthermore, the compounds of the present invention have good solubility and thus are highly adaptable in preferred formulations, such as sublingual, buccal and/or intranasal formulations.

Disclosure of Invention

The invention provides a class as 5-HT_1FNovel pyridinylpiperidine derivatives as receptor agonists, which may be used for the activation of 5-HT_1FReceptor, inhibition of neuronal protein extravasation and, therefore, may be used in the treatment of 5-HT_1FReceptor-mediated diseases, in particular for the treatment of migraine. Experiments show that the pyridine acyl piperidine derivative has stable property, good safety, good pharmacodynamics and pharmacokinetic properties, such as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability and the like. Therefore, the method has good clinical application prospect.

The invention also provides processes for the preparation of such compounds, pharmaceutical compositions containing them and the use of such compounds and pharmaceutical compositions containing them in the manufacture of medicaments.

In one aspect, the invention relates to a compound of formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein:

x is N or CR^x；

Each R^1a、R^1b、R^1c、R^1dAnd R^xIndependently H, 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) - (C)₁-C₆Alkoxy group), C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl;

R²is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group;

R³、R⁴and R⁵Each independently is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group; and

R⁶is H, 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) - (C)₁-C₆Alkoxy group), C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In one embodiment, each R is^1a、R^1b、R^1c、R^1dAnd R^xIndependently H, 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) - (C)₁-C₄Alkoxy group), C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl;

R²is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group;

R³、R⁴and R⁵Each independently is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, each R is^1a、R^1b、R^1c、R^1dAnd R^xIndependently H, 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)-OCH₃Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazoylOxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl;

R²is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy;

R³、R⁴and R⁵Each independently is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R⁶Is H, 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) - (C)₁-C₄Alkoxy group), C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In another embodiment, R⁶Is H, 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)-OCH₃Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as disclosed herein.

In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

In yet another aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein for the preparation of a medicament for the prevention, treatment or amelioration of 5-HT_1FA receptor associated disease.

In one embodiment, the compound is conjugated to 5-HT_1FThe receptor-related disorder is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, and so forthDisability, memory loss or dementia.

In a further aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof as disclosed in the present invention for the preparation of a medicament for the activation of 5-HT_1FA receptor.

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).

Biological test results show that the compound can activate 5-HT_1FReceptors, inhibit neuronal protein extravasation, and may be preferred as 5-HT_1FA receptor agonist.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to one or to more than one (i.e., to at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.

The term "chiral molecule" is a molecule having the property of not overlapping its mirror image; and "achiral molecule" refers to a molecule that can overlap with its mirror image.

The term "enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

The term "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers, which mixture lacks optical activity.

The term "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of 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 in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^nd Ed.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.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)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization.

"pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.

The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including but 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, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a particular substituent. Unless otherwise indicated, a substituent may be substituted at any reasonable position in the group that it may be substituted for. When more than one position in a given formula can be substituted with one or more particular substituents selected from the group, then the substituents may be substituted identically or differently at each of the possible positions in the formula.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁-C₆Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "D" denotes a single deuterium atom.

The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R being a substituent as described herein).

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) And so on.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) 1-propenyl (i.e., propenyl, -CH ═ CH-CH)₃) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, whichWherein the alkynyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl (i.e., propynyl, -C.ident.C-CH)₃) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-propyloxy, n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (isopropyloxy, i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) And so on.

The term "alkylthio" means an alkyl group attached to the rest of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1 to 12 carbon atoms. In one embodiment, the alkylthio group contains 1 to 6 carbon atoms; in another embodiment, the alkylthio group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylthio group contains 1 to 3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein.

Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH)₃) Ethylthio (EtS, -SCH)₂CH₃) 1-propylthio (n-PrS, n-propylthio, -SCH)₂CH₂CH₃) 2-propylthio (i-PrS, i-propylthio, -SCH (CH)₃)₂) 1-butylthio (n-BuS, n-butylthio, -SCH)₂CH₂CH₂CH₃) 2-methyl-l-propylthio (i-BuS, i-butylthio, -SCH)₂CH(CH₃)₂) 2-butylthio (s-BuS, s-butylthio, -SCH (CH)₃)CH₂CH₃) 2-methyl-2-propylthio (t-BuS, t-butylthio, -SC (CH)₃)₃) And so on.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups, wherein the alkyl groups have the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N-dimethylamino (dimethylamino), N-diethylamino (diethylamino), and the like. The alkylamino group is optionally substituted with one or more substituents described herein.

The term "hydroxy-substituted alkyl" denotes an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.

The term "haloalkyl" denotes an alkyl group substituted by one or more halogen atoms, wherein the alkyl group has the meaning as described herein, such examplesIncluding, but not limited to, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CHF₂、-CH₂CF₃、-CHFCH₃、-CH₂CH₂F、-CF₂CH₃、-CH₂CF₂CHF₂And the like. In one embodiment, C₁-C₆The haloalkyl group containing a fluorine-substituted C₁-C₆An alkyl group; in another embodiment, C₁-C₄The haloalkyl group containing a fluorine-substituted C₁-C₄An alkyl group; in yet another embodiment, C₁-C₂The haloalkyl group containing a fluorine-substituted C₁-C₂An alkyl group.

The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, examples of which include, but are not limited to, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CHF₂、-OCH₂CF₃、-OCHFCH₃、-OCH₂CH₂F、-OCF₂CH₃、-OCH₂CF₂CHF₂And the like. In one embodiment, C₁-C₆Haloalkoxy comprises fluorine substituted C₁-C₆An alkoxy group; in another embodiment, C₁-C₄Haloalkoxy comprises fluorine substituted C₁-C₄An alkoxy group; in yet another embodiment, C₁-C₂Haloalkoxy comprises fluorine substituted C₁-C₂An alkoxy group.

The terms "n-member of atoms" or "n-member" are used interchangeably herein, where n is an integer typically describing the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, 5-10 membered heteroaryl means heteroaryl consisting of 5, 6, 7, 8, 9 or 10 ring atoms. As another example, piperidinyl is heterocyclyl or 6-membered heterocyclyl consisting of 6 ring atoms, and pyridinyl is heteroaryl or 6-membered heteroaryl consisting of 6 ring atoms.

The term "carbocyclyl" or "carbocycle" denotes a monovalent or multivalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl group is optionally substituted with one or more substituents described herein.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused, bridged and spiro rings. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system can include fused, bridged, and spiro rings. Wherein one or more atoms of the ring are independently replaced by a heteroatom having the meaning as described herein. In one embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 8 ring atoms (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give compounds like SO, SO₂，PO，PO₂A group of (d); in yet another embodiment, heterocyclyl is a group of 3-6 ring atomsMonocyclic heterocyclic groups of (2-5 carbon atoms and 1-3 hetero atoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give compounds like SO, SO₂，PO，PO₂A group of (d); in another embodiment, heterocyclyl is a bicyclic heterocyclyl consisting of 7 to 12 ring atoms (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give the same SO, SO₂，PO，PO₂The group of (1). The heterocyclyl group is optionally substituted with one or more substituents described herein.

The heterocyclic group may be a carbon-based or heteroatom group. Wherein, is cyclic-CH₂The group is optionally replaced by-C (═ O) -, the sulfur atom of the ring is optionally oxidized to S-oxide, and the nitrogen atom of the ring is optionally oxidized to N-oxide. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, oxazepanyl, oxazepinyl, and oxazepinyl

Radical, diaza

Radical, S-N-aza

Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals of-CH₂Examples of-radicals substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinylPyrimidine diketones, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1, 1-dioxide, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms. The aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of the aryl group may include phenyl, indenyl, naphthyl and anthryl. The aryl group is optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms. The heteroaryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5-10 atoms contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene et al, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991and Kocienski et al.,Protecting Groups,Thieme,Stuttgart,2005。

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. OthersPharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, mesylates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C₁-C₈Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association of solvent molecules that is water.

When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.

The term "treating" any disease or condition, in some embodiments refers to ameliorating the disease or condition (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

The term "prevent" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., arresting the development of at least one clinical symptom of a disease in a subject that may be facing or predisposed to facing such a disease, but who has not yet experienced or exhibited symptoms of the disease).

Unless otherwise indicated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are encompassed within the scope of the present invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.

Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

The compounds of formula (I) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salt need not be a pharmaceutically acceptable salt, and may be an intermediate useful in the preparation and/or purification of a compound of formula (I) and/or in the isolation of an enantiomer of a compound of formula (I).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by those having a selected atomic mass or mass numberAnd (4) replacing atoms. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.

Description of the Compounds of the invention

The pyridine acyl piperidine derivative, the pharmaceutically acceptable salt, the pharmaceutical preparation and the composition thereof can be used for activating 5-HT_1FReceptor, inhibition of neuronal protein extravasation, and antagonism of 5-HT_1FThe treatment of receptor-related diseases, in particular migraine, is of potential use. The invention further describes methods for synthesizing the compounds. The compounds of the present invention show good biological activity.

wherein each R is^1a、R^1b、R^1c、R^1d、R²、R³、R⁴、R⁵、R⁶And X has the meaning as described in the present invention.

In one embodiment, X is N or CR^x(ii) a Wherein R is^xHave the meaning as described in the present invention.

In one embodiment, each R is^1a、R^1b、R^1c、R^1dAnd R^xIndependently H, 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) - (C)₁-C₆Alkoxy group), C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In one embodiment, R²Is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R³、R⁴And R⁵Each independently is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R⁶Is H, 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) - (C)₁-C₆Alkoxy group), C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In one embodiment, each R is^1a、R^1b、R^1c、R^1dAnd R^xIndependently H, 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) - (C)₁-C₄Alkoxy group), C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In another embodiment, each R is^1a、R^1b、R^1c、R^1dAnd R^xIndependently H, 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)-OCH₃Methyl, ethyl, n-propyl, isopropyl,Allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In one embodiment, R²Is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R²Is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R³、R⁴And R⁵Each independently is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R³、R⁴And R⁵Each independently is H, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound having one of the following structures, but is by no means limited thereto:

In one embodiment, the compound is conjugated to 5-HT_1FThe receptor-related disorder is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, flushingDyskinesia, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss or dementia.

In another embodiment, said is reacted with 5-HT_1FThe receptor-related disorder is migraine.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I) or an individual stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally other therapeutic and/or prophylactic ingredients.

The dosage form in which the compounds used in the methods of the invention are administered may be determined by the particular compound selected, the type of pharmacokinetic profile required for the route of administration, and the condition of the patient.

Formulations suitable for oral, sublingual, intranasal or injectable administration are prepared according to methods well known in the pharmaceutical art and contain at least one active compound. See, for example, REMINGTON' S PHARMACEUTICAL SCIENCES (16th ed.1980).

In general, the formulations of the present invention comprise the active ingredient (compound of formula (I)) in admixture with, diluted by, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When used as a diluent, the excipient may be a solid, semi-solid or liquid material which acts as an excipient, carrier or vehicle for the active ingredient. Thus, the formulations may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, gels, suppositories, sterile injectable solutions, and sterile packaged powders.

In the preparation of the formulations, it may be necessary to grind the active compound to provide the appropriate particle size prior to mixing with the other components. If the active compound is substantially insoluble, it is typically ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, its particle size is adjusted by milling to provide a uniform particle size distribution in the formulation, e.g., about 40 mesh. In one embodiment of the invention, the particle size is about 0.1 to 100 μm.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, philidelphia; gennaro a.r.et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and/or would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting a compound of the invention from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants (such as talc, magnesium stearate and mineral oil), glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives (such as methyl and propyl hydroxybenzoates), stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation. The compounds of the present invention may be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by methods known in the art.

The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).

For the preparation of pharmaceutical compositions using the compounds described herein, the pharmaceutically acceptable carrier can be a solid or liquid carrier. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may contain from about 5% to about 95% of the active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing the various compositions can be found in: gennaro (ed.), Remington's Pharmaceutical Sciences,18^th ed.,1990,Mack Publishing Company Co.,Easton,Pennsylvania。

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed 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. Annu 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, enteric-coated tablets, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet, including a multi-layered tablet, a press coated or a dry coated tablet, prepared over more than one compression cycle.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension or solution composition. In one embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound of the disclosed invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. Fine powders may be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns₅₀Values (e.g., measured by laser diffraction).

Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.

The compounds of the invention may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

The pharmaceutical compositions provided herein can be administered by rectal suppository by mixing the drug with a suitable non-irritating excipient (e.g., cocoa butter, glycerol esters synthesized with polyethylene glycol), which is solid at ordinary temperatures, and then liquefying or dissolving in the rectal cavity to release the drug. Because of individual variation, the severity of symptoms can vary widely, and each drug has its unique therapeutic properties, the precise mode of administration, dosage form and treatment regimen for each individual should be determined by the practitioner.

The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

Although the compounds of the present invention may be administered directly without any formulation, the compounds of the present invention are generally administered in the form of a pharmaceutical formulation containing a pharmaceutically acceptable excipient and at least one active ingredient. These formulations may be administered by a variety of routes including oral, buccal, rectal, intranasal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal administration. Many of the compounds used in the methods of the invention are effective as injectable and oral compositions.

For transdermal administration, a transdermal delivery device ("patch") is required. Such transdermal patches may be used for continuous or intermittent infusion of controlled amounts of the compounds of the present invention. The structure and use of transdermal patches for delivering drugs is well known in the art. See, for example, US5,023,252. The patch can be made to deliver the drug continuously, in pulses, or on demand.

It is often desirable or necessary to introduce a pharmaceutical composition directly or indirectly into the brain. Direct techniques typically involve placing a drug delivery catheter in the ventricular system of the host to bypass the blood-brain barrier. Such an implantable delivery system for delivering biological factors to specific anatomical regions of the body is described in US5,011,472. Delivery of hydrophilic drugs can be enhanced by intraarterial infusion of hypertonic solutions that can momentarily open the blood-brain barrier.

In a preferred embodiment of the present invention, there is provided a pharmaceutical formulation containing at least one of the above-mentioned active compounds and suitable for buccal and/or sublingual or nasal administration. This embodiment provides for administering the active compound in a manner that avoids gastric complications (e.g., first bypassing the gastric system metabolism and/or first passing through the liver metabolism). This route of administration may also reduce the adsorption time and thus bring about a more rapid therapeutic effect. The compounds of the present invention may also provide a particularly advantageous solubility profile, facilitating sublingual/buccal administration of the formulation. Such formulations generally require a relatively high concentration of active ingredient so that a sufficient amount of the active ingredient is delivered to the limited surface of the sublingual/buccal mucosa to allow the active ingredient to be absorbed over a relatively short duration of time during which the formulation is in contact with the sublingual/buccal mucosal surface. Thus, the extremely high activity of the compounds of the present invention and their high solubility make them suitable for use in the preparation of sublingual/buccal formulations.

The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate symptoms of the disease is administered or allowed to equilibrate in vivo. The effective amount required for a particular treatment regimen will depend on a variety of factors including the condition being treated, the severity of the condition, the activity of the particular drug employed, the mode of administration, the clearance rate of the particular drug, the duration of the treatment, the drug combination, the age, body weight, sex, diet and patient health, etc. Description of other factors to be considered in the art in relation to the "therapeutically effective amountSee Gilman et al, eds., Goodman And Gilman's, The pharmaceutical Bases of Therapeutics,8^thed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17^th ed.,Mack Publishing Company,Easton,Pa.,1990。

Preferably, the compounds of formula (I) are formulated in unit dosage forms containing from about 0.001 to about 100mg of the active ingredient per dose, more often from about 1.0 to about 30mg of the active ingredient per dose. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable excipient as hereinbefore described.

The active compounds are generally effective over a wide dosage range. For example, the daily dose is generally about 0.0001-30mg/kg body weight. For adult human treatment, a particularly preferred dose (single or divided dose) is about 0.1-15 mg/kg/day. It will be understood, however, that the amount of compound actually administered will be determined by the attending physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds to be administered, the age, weight and response of the particular patient, and the severity of the patient's symptoms, and, therefore, the above dosage ranges should not be construed as limiting the scope of the invention in any way. In some instances, dosage levels below the lower limit of the aforesaid dosage range may be more suitable, while in other cases higher doses may be employed without causing any side effects, provided that such larger doses are first divided into several smaller doses for administration throughout the day.

The term "administering" refers to providing a therapeutically effective amount of a drug to an individual by means including oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. The administration forms include ointments, lotions, tablets, capsules, pills, dispersible powders, granules, suppositories, pellets, troches, injections, sterile or non-aqueous solutions, suspensions, emulsions, patches and the like. The active ingredient is compounded with non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, pulvis Talci, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).

The preferred route of administration will vary with clinical characteristics, the dosage will necessarily vary depending upon the condition of the patient being treated, and the physician will determine the appropriate dosage for the individual patient. The therapeutically effective amount per unit dose depends on body weight, physiology and the selected vaccination regimen. The weight of the compound per unit dose, excluding the weight of the carrier (vehicle included in the drug), refers to the weight of the compound per administration.

The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.

The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

In one embodiment, the treatment methods of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments of the present invention encompass the treatment of the diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.

In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered orally. In another embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered by inhalation. In yet another embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered intranasally.

In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the compounds of the invention or pharmaceutical compositions comprising the compounds of the invention depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, the appropriate dosage regimen, including the duration of the regimen, of the compound of the invention or of the pharmaceutical composition containing the compound of the invention depends on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.

The compounds of the present invention may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition. This is selected by the person skilled in the art according to the physical circumstances of the patient, such as health, age, weight, etc. If formulated as a fixed dose, such combination products employ the compounds of the present invention (within the dosage ranges described herein) and the other pharmaceutically active agents (within their dosage ranges).

Accordingly, in one aspect, the present invention includes a combination comprising an amount of at least one compound of the present invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional therapeutic agents.

In addition, the compounds of the present invention may be administered in the form of a prodrug. In the present invention, a "prodrug" of a compound of the present invention is a functional derivative that, when administered to a patient, is ultimately released in vivo from the compound of the present invention. When administering the compounds of the present invention in prodrug form, one skilled in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of action of the compound in vivo; (c) altering the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for preparing prodrugs comprise variants of the compounds which are cleaved in vivo either chemically or enzymatically. These variants, which involve the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

Use of the Compounds and pharmaceutical compositions of the invention

The compounds and pharmaceutical compositions provided by the invention are useful for the preparation of a medicament for activating 5-HT_1FPharmaceutical compositions of receptors, and their use in the preparation of a medicament for the prevention, treatment or alleviation of 5-HT_1FA pharmaceutical product for a disease associated with a receptor, in particular migraine.

In particular, the amount of compound in the compounds or pharmaceutical compositions of the invention is effective to detectably selectively activate 5-HT_1FA receptor.

In particular, the amount of the compound or compounds in the pharmaceutical composition of the present invention is effective to detectably selectively inhibit neuronal protein extravasation.

The compounds of the present invention may be used in, but are in no way limited to, the prevention, treatment, or alleviation of 5-HT by administering to a patient an effective amount of a compound or a pharmaceutical composition of the present invention_1FReceptorsThe associated diseases. The and 5-HT_1FReceptor-related disorders further including, but not limited to, migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss, and dementia.

In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

¹H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer.¹H NMR Spectrum in CDC1₃、DMSO-d₆、CD₃OD or acetone-d₆TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton, singlet), d (doublet ), t (triplet, triplet), q (quatet, quartet), m (multiplet ), br (broad, broad), br (broad singleton), dd (doublet of doublets), ddd (doublet of doublets), dt (doublet of triplets)ts, double triplets), td (triplet of doublets), qd (quatet of doublets, quadruplet), tt (triplet of triplets). Coupling constant J, expressed in Hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18,2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase: 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).

The following acronyms are used throughout the invention:

CH₂Cl₂DCM dichloromethane mg

CDC1₃G of deuterated chloroform

DMSO dimethyl sulfoxide mL, mL

DMSO-d₆mu.L, mu.l microliter of deuterated dimethyl sulfoxide

EtOAc, EA Ethyl acetate nL, nL nanoliter

CH₃OH, MeOH/methanol min

CD₃OD deuterated methanol for h

nM nanomole/liter PE Petroleum Ether (60-90 ℃ C.)

Micromoles per liter RT, RT, r.t. Room temperature

mM millimole per liter EDTA-K₂Ethylenediaminetetraacetic acid dipotassium salt

M mol PEG400 polyethylene glycol 400 per liter

ng Nak Boc, BOC tert-butyloxycarbonyl radical

Mu.g of cAMP Cyclic adenosine monophosphate, adenosine monophosphate

The following synthetic schemes describe the steps for preparing the compounds disclosed herein, wherein each R is, unless otherwise indicated^1a、R^1b、R^1c、R^1dAnd R^xHaving the definitions set out in the present invention.

Synthesis scheme 1

Formula (A), (B) and8) The compound shown can be prepared by the following steps: formula (A), (B) and1) A compound of the formula2) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)3) A compound shown in the specification; then formula (A), (B), (C), (3) A compound of the formula4) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)5) The compounds shown. Formula (A), (B) and5) The Boc protecting group of the compound is removed to obtain a compound of the formula (6) A compound shown in the specification; formula (A), (B) and6) A compound of the formula7) Reacting the compound shown in the formula (A) to obtain a compound shown in the formula (B)8) The target product shown.

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.

Examples

EXAMPLE 1 Synthesis of N- (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) benzenesulfonamide

Step 1) Synthesis of (6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone

2, 6-dibromopyridine (3.1g,13.06mmol) and methyl tert-butyl ether (30mL) were added to a 100mL single-neck flask at-78 deg.C, N-butyllithium (2.5M,5.5mL) was added dropwise under nitrogen, after stirring for 1 hour, N-diethyl-1-methyl-piperidine-4-carboxamide (1.3g,6.6mmol) was added, stirring was continued for 2 hours, then water (20mL) was added to quench the reaction, the organic phase was separated, collected, spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a red oil (1.1g, 59%).

MS(ESI,pos.ion)m/z:283.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.98(dd,J＝7.3,1.1Hz,1H),7.76–7.63(m,2H),3.75(tt,J＝11.4,3.8Hz,1H),2.93(dd,J＝8.7,3.1Hz,2H),2.33(s,3H),2.16(td,J＝11.7,2.5Hz,2H),1.99–1.94(m,2H),1.79(ddd,J＝15.7,12.4,3.8Hz,2H).

Step 2) Synthesis of tert-butyl (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) aminocarboxylate

(6-bromopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (3.3g,11.7mmol), tert-butyl carbamate (2.0g,17.1mmol), cesium carbonate (5.7g,17.5mmol), palladium acetate (280mg,1.18mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (0.75g,1.2mmol), and toluene (80mL) were added to a 250mL single-neck flask, and the reaction was continued for 8 hours at 100 ℃ under nitrogen; the reaction was stopped, water (50mL) was added, extraction was performed with dichloromethane (50mL × 2), the organic phase was collected, dried with anhydrous sodium sulfate (1.5g), filtered, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a brown solid (3.06g, 82%).

MS(ESI,pos.ion)m/z:320.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.12(d,J＝8.3Hz,1H),7.78(t,J＝7.9Hz,1H),7.66(dd,J＝7.5,0.7Hz,1H),7.45(s,1H),3.63(tt,J＝11.0,4.1Hz,1H),2.89(t,J＝14.2Hz,2H),2.29(s,3H),2.08(ddd,J＝14.3,10.0,4.2Hz,2H),1.90–1.72(m,4H),1.53(s,9H).

Step 3) Synthesis of (6-Aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone

Tert-butyl (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) aminocarboxylate (3.06g,9.58mmol) and dichloromethane (60mL) were added to a 250mL single neck round bottom flask at 25 deg.C, an ethyl hydrogen chloride solution in ethyl acetate (22mL,2M) was added, and the reaction was stirred for an additional 12 hours; the reaction was stopped, spin-dried under reduced pressure, and extracted with saturated sodium bicarbonate solution (40mL) followed by dichloromethane (40 mL); the solution was separated, and the organic phase was dried over anhydrous sodium sulfate (1.5 g); filtration, spin-drying of the filtrate under reduced pressure, and purification by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) gave the title compound as a brown oil (1.7g, 81%).

MS(ESI,pos.ion)m/z:220.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.54(t,J＝7.8Hz,1H),7.37(d,J＝7.4Hz,1H),6.66(d,J＝8.1Hz,1H),4.61(s,2H),3.69(tt,J＝11.4,3.8Hz,1H),2.91(d,J＝11.6Hz,2H),2.30(s,3H),2.08(tt,J＝6.7,3.4Hz,2H),1.90(d,J＝11.8Hz,2H),1.76(ddd,J＝15.6,12.4,3.7Hz,2H).

Step 4) Synthesis of N- (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) benzenesulfonamide

(6-Aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (200mg,0.91mmol), triethylamine (0.26mL,1.82mmol) and dichloromethane (10mL) were added to a 100mL single neck round bottom flask at 0 ℃, benzenesulfonyl chloride (193mg,1.09mmol) was added dropwise, and the mixture was transferred to 25 ℃ for reaction for 12 hours; after completion of the reaction, the reaction mixture was poured into water (30mL), extracted with dichloromethane (40mL), and the organic phase was collected, dried under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (142mg, 43.5%).

MS(ESI,pos.ion)m/z:360.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm)7.93(d,J＝7.0Hz,2H),7.77(t,J＝7.9Hz,1H),7.61–7.53(m,3H),7.41(d,J＝7.4Hz,1H),7.12(d,J＝8.2Hz,1H),3.36(tt,J＝11.5,3.6Hz,1H),2.95(d,J＝11.6Hz,2H),2.35(s,3H),2.19(t,J＝11.0Hz,2H),1.70(d,J＝11.9Hz,2H),1.50(qd,J＝12.7,3.6Hz,2H).

EXAMPLE 22 Synthesis of fluoro-N- (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) benzenesulfonamide

The title compound was prepared as described in example 1, step 4 by reacting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (200mg,0.91mmol), triethylamine (0.26mL,1.82mmol), 2-fluorobenzenesulfonyl chloride (185mg,0.95mmol) in dichloromethane (10mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (106mg, 30.9%).

MS(ESI,pos.ion)m/z:378.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.04(dd,J＝10.7,4.2Hz,1H),7.75(t,J＝7.9Hz,1H),7.65(d,J＝7.3Hz,1H),7.59(dd,J＝12.7,6.5Hz,1H),7.51(d,J＝8.2Hz,1H),7.33(t,J＝7.6Hz,1H),7.21–7.14(m,1H),3.20(br,5H),2.80(s,3H),1.27(brs,4H).

EXAMPLE 32 Synthesis of chloro-N- (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) benzenesulfonamide

The title compound was prepared as described in example 1, step 4 by reacting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (200mg,0.91mmol), triethylamine (0.26mL,1.82mmol), 2-chlorobenzenesulfonyl chloride (194mg,0.92mmol) in dichloromethane (10mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (130mg, 36.4%).

MS(ESI,pos.ion)m/z:394.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm)8.20(d,J＝7.7Hz,1H),7.76(t,J＝7.8Hz,1H),7.62–7.53(m,3H),7.37(d,J＝7.4Hz,1H),7.07(d,J＝8.2Hz,1H),3.05(br,3H),2.48(s,3H),2.42–2.32(m,2H),1.73(d,J＝12.1Hz,2H),1.56–1.46(m,2H).

EXAMPLE 43 Synthesis of fluoro-N- (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) benzenesulfonamide

The title compound was prepared as described in example 1, step 4 by reacting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (200mg,0.91mmol), triethylamine (0.26mL,1.82mmol), 3-fluorobenzenesulfonyl chloride (185mg,0.95mmol) in dichloromethane (10mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (207mg, 60.5%).

MS(ESI,pos.ion)m/z:378.0[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm)7.73–7.65(m,3H),7.57(td,J＝8.0,5.7Hz,1H),7.38(td,J＝8.4,2.0Hz,1H),7.32(d,J＝7.2Hz,1H),7.04(d,J＝8.2Hz,1H),3.39(tt,J＝11.3,3.7Hz,1H),3.09(d,J＝11.8Hz,2H),2.49(s,3H),2.43–2.39(m,2H),1.77(d,J＝11.8Hz,2H),1.57(td,J＝15.3,3.6Hz,2H).

EXAMPLE 53 Synthesis of chloro-N- (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) benzenesulfonamide

The title compound was prepared as described in example 1, step 4 by reacting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (200mg,0.91mmol), triethylamine (0.26mL,1.82mmol), 3-chlorobenzenesulfonyl chloride (198mg,0.94mmol) in dichloromethane (10mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (169mg, 47.1%).

MS(ESI,pos.ion)m/z:394.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm)7.94(t,J＝1.7Hz,1H),7.85(d,J＝7.8Hz,1H),7.78(t,J＝7.8Hz,1H),7.66(dd,J＝8.0,1.0Hz,1H),7.59(dd,J＝13.2,5.3Hz,1H),7.41(t,J＝7.3Hz,1H),7.10(d,J＝8.2Hz,1H),3.41(tt,J＝11.1,3.7Hz,1H),3.24(d,J＝12.0Hz,2H),2.67(t,J＝11.9Hz,2H),2.64(s,3H),1.87(d,J＝11.7Hz,2H),1.63(td,J＝14.5,3.4Hz,2H).

EXAMPLE 64 Synthesis of fluoro-N- (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) benzenesulfonamide

The title compound was prepared as described in example 1, step 4 by reacting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (200mg,0.91mmol), triethylamine (0.26mL,1.82mmol), 4-fluorobenzenesulfonyl chloride (177mg,0.91mmol) in dichloromethane (10mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (155mg, 45%).

MS(ESI,pos.ion)m/z:378.1[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm)7.94(dd,J＝8.7,5.3Hz,2H),7.71(t,J＝7.8Hz,1H),7.35(dd,J＝15.8,7.8Hz,3H),7.06(d,J＝8.2Hz,1H),3.42–3.31(m,1H),2.99(d,J＝11.7Hz,2H),2.40(s,3H),2.31–2.19(m,2H),1.74(d,J＝11.9Hz,2H),1.53(qd,J＝13.0,3.6Hz,2H).

EXAMPLE 74 Synthesis of chloro-N- (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) benzenesulfonamide

The title compound of this step was prepared by the method described in example 1, step 4, by reacting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (200mg,0.91mmol), triethylamine (0.26mL,1.82mmol), 4-chlorobenzenesulfonyl chloride (194mg,0.92mmol) in dichloromethane (10mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (108mg, 30.3%).

MS(ESI,pos.ion)m/z:393.9[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.97–7.92(m,2H),7.75(t,J＝7.9Hz,1H),7.64(d,J＝7.4Hz,1H),7.51(d,J＝8.2Hz,1H),7.44–7.39(m,2H),3.60(brs,1H),3.40(br,2H),2.95(brs,2H),2.79(s,3H),2.42–2.29(m,2H),2.13(br,2H).

EXAMPLE 84 Synthesis of methyl-N- (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) benzenesulfonamide

The title compound was prepared as described in example 1, step 4 by reacting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (200mg,0.91mmol), triethylamine (0.26mL,1.82mmol), 4-methylbenzenesulfonyl chloride (173mg,0.91mmol) in dichloromethane (10mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (177mg, 52.3%).

MS(ESI,pos.ion)m/z:373.9[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.81(t,J＝8.0Hz,3H),7.44(d,J＝7.2Hz,1H),7.37(d,J＝8.1Hz,2H),7.14(d,J＝8.2Hz,1H),3.37(tt,J＝11.5,3.7Hz,1H),2.88(d,J＝11.5Hz,2H),2.36(s,3H),2.29(s,3H),2.07(t,J＝11.5Hz,2H),1.68(d,J＝11.6Hz,2H),1.47(qd,J＝12.4,3.6Hz,2H).

Example Synthesis of 92, 4-difluoro-N- (6- (1-methylpiperidine-4-carbonyl) pyridin-2-yl) benzenesulfonamide

The title compound was prepared as described in example 1, step 4 by reacting (6-aminopyridin-2-yl) (1-methylpiperidin-4-yl) methanone (200mg,0.91mmol), triethylamine (0.26mL,1.82mmol), 2, 4-difluorobenzenesulfonyl chloride (195mg,0.92mmol) in dichloromethane (10mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a white solid (130mg, 36.1%).

MS(ESI,pos.ion)m/z:396.2[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm)7.98(dd,J＝15.3,8.3Hz,1H),7.63(t,J＝7.8Hz,1H),7.38–7.30(m,1H),7.29–7.14(m,2H),6.94(d,J＝8.2Hz,1H),3.35–3.30(m,1H),3.08(d,J＝11.2Hz,2H),2.50(s,3H),2.37(br,2H),1.79–1.76(m,2H),1.57–1.51(m,2H).

Biological assay

Example A: evaluation of human 5-HT transfection of CHO-K1 cells with Compounds of the invention_1FAgonism of receptors

Purpose of the experiment: evaluation of human 5-HT transfection of CHO-K1 cells with Compounds of the invention Using HitHunter cAMP detection kit_1FAgonism of the receptor.

Brief experimental procedure: CHO-K1 cells were cultured in 384 microwell plates, cell culture medium (Assaycomplete)^TMCell platinum Reagent, DIscoverX) volume of 20. mu.L, Cell density of 10,000/well, 5% CO at 37 ℃₂The culture was carried out overnight. The medium was then removed and 15. mu.L cAMP Assay Buffer (DIscoverX) was added to each well followed by additionmu.L of test sample containing a total of 4X test substance (test compound or 5-HT) and 4X Macacan (final concentration of 15. mu.M) was incubated at 37 ℃ for 30 minutes. Then 5. mu.L of cAMP Antibody Reagent (discover X) and 20. mu.L of cAMP work Detection Solution (discover X) were added and incubated for 1 hour in the dark, and then 20. mu.L of cAMP Solution A was added and incubated for 3 hours in the dark. The plate was placed in a microplate reader (Perkinelmer envision. TM.) to read the intensity of the luminescence signal. The corresponding luminescence signal intensity was obtained by testing different concentrations of the compound, and from this the rate of excitation ((1- (Y/Z)). times.100%. the rate of excitation, where Y represents the luminescence signal intensity with addition of the test sample and Z represents the luminescence signal intensity with addition of only mao monkey hormone, and then the compound dose-effect curve was calculated by Prism software, and the agonist concentration giving half maximal response was calculated as EC concentration₅₀The values are represented. The results are shown in Table A. In the experiment, 5-HT is used as a positive control drug to ensure that the experiment system is normal.

Table a: human 5-HT transfection of CHO-K1 cells with the compounds of the invention_1FMeasurement of receptor agonism

Example No. 2	EC₅₀(μM)
		Example 6	+++
Example 7	+++
		Example 9	+++

Note: + + + + + denotes 1. mu.M<EC₅₀<10μM

The experimental result shows that the compound of the invention has stronger 5-HT_1FReceptor agonistic activity.

Example B: rat, dog intravenous injection or gavage quantitative pharmacokinetic evaluation of the compounds of the invention

The inventors have performed pharmacokinetic evaluations in rats, dogs, on the compounds of the invention. Wherein, the animal information is detailed in table 1.

Table 1: the invention relates to an information table for tested animals

Germling	Grade	Sex	Body weight	Age (age)	Source
						SD rat	SPF	Male sex	180-350g	6-11 weeks	HUNAN SLAC JINGDA EXPERIMENTAL ANIMAL Co.,Ltd.
Beagle dog	Common stage	Male sex	8～12kg	6-12 months	BEIJING MARSHALL BIOTECHNOLOGY Co.,Ltd.

Experimental methods

The compounds of the invention were administered to the animals in the form of 5% DMSO + 60% PEG400+ 35% Saline solution or 10% DMSO + 10% Kolliphor HS15+ 30% PEG400+ 50% Saline solution, and the animals were fasted for 12h before administration with free water. For the group administered by intravenous injection, the dose was 0.5mg/kg or 1mg/kg, and blood was taken intravenously (blood volume taken was about 0.15mL) at the following time points after administration: 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dog) or 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rat), EDTA-K is added into the blood sampling tube in advance₂As an anticoagulant, blood samples were centrifuged at 12,000rpm for 2 minutes, plasma was collected and stored at-20 ℃ or-70 ℃. For the gavage group, the dose was 2.5mg/kg or 5mg/kg, and venous blood sampling (blood sampling amount about 0.15mL) was performed at the following time points after administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dog) or 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rat), EDTA-K is added into the blood sampling tube in advance₂As an anticoagulant, blood samples were centrifuged at 12,000rpm for 2 minutes, plasma was collected and stored at-20 ℃ or-70 ℃.

The plasma samples collected above were processed (frozen plasma was thawed at room temperature, vortexed for 15s, 10-20. mu.L of plasma was taken, 120-150. mu.L of acetonitrile solution containing the internal standard was added, vortexed for 5min, centrifuged at 4,000rpm for 5min, 100. mu.L of supernatant was taken, and 120-150. mu.L of methanol-water (v/v: 1/1) was added and mixed), and then the concentration of the compound in plasma was analyzed by LC-MS/MS. Analysis results show that the compound has better pharmacokinetic properties in rats and dogs. The compound of the invention has better drugability and better clinical application prospect.

In the description herein, references to the description of the term "one embodiment," "an embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment, or example is included in at least one embodiment, or example of the invention. In this specification, a schematic representation of the above terms does not necessarily refer to the same embodiment, implementation, or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments, implementations, or examples. Furthermore, the various examples, embodiments, or examples described in this specification, as well as features of various examples, embodiments, or examples, may be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. A compound, which is a compound represented by formula (I), or a pharmaceutically acceptable salt of the compound represented by formula (I),

wherein:

x is CR^x；

Each R^1a、R^1b、R^1c、R^1dAnd R^xIndependently H, F, Cl, Br, I, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy or C₁-C₆A haloalkoxy group;

R²is H;

R³、R⁴and R⁵Each independently is H; and

R⁶is C₁-C₆An alkyl group.

2. The compound of claim 1, wherein each R^1a、R^1b、R^1c、R^1dAnd R^xIndependently H, F, Cl, Br, I, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy or C₁-C₄A haloalkoxy group.

3. The compound of claim 1 or 2, wherein each R^1a、R^1b、R^1c、R^1dAnd R^xIndependently H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃or-OCH₂CF₂CHF₂。

4. The compound of claim 1, wherein R⁶Is C₁-C₄An alkyl group.

5. The compound of claim 1 or 4, wherein R⁶Is methyl, ethyl, n-propyl or isopropyl.

6. The compound of claim 1, which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:

7. a pharmaceutical composition comprising a compound of any one of claims 1-6; and

the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the prevention, treatment or alleviation of 5-HT_1FA receptor associated disease.

9. The use according to claim 8, wherein said treatment is with 5-HT_1FThe receptor-related disorder is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss or dementia.

10. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for activating 5-HT_1FA receptor.