CN110272425B

CN110272425B - Pyridyloxyl octahydropyrrolo [3,4-c ] pyrrole derivatives and uses thereof

Info

Publication number: CN110272425B
Application number: CN201910592056.3A
Authority: CN
Inventors: 金传飞; 钟文和; 许腾飞; 张英俊
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2018-07-02
Filing date: 2019-07-02
Publication date: 2022-11-04
Anticipated expiration: 2039-07-02
Also published as: CN110272425A

Abstract

The invention discloses pyridine acyl octahydropyrrolo [3, 4-c)]The invention relates to pyrrole derivatives and application thereof, in particular to novel pyridine acyl octahydropyrrolo [3,4-c ]]Pyrrole derivatives and pharmaceutical compositions containing them useful for the activation of 5-HT _1F A 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 _1F The use in the manufacture of a medicament for the treatment of a condition associated with a receptor, in particular migraine.

Description

Pyridyloxyl octahydropyrrolo [3,4-c ] pyrrole derivatives and uses thereof

Technical Field

The invention belongs to the technical field of medicaments, and particularly relates to novel pyridine acyl octahydropyrrolo [3,4-c ]]Pyrrole derivatives and pharmaceutical compositions comprising these compounds, and methods of use and uses thereof. Specially for treating diabetesIn particular, the novel pyridinoacyl octahydropyrrolo [3,4-c ] compounds of the present invention]Pyrrole derivatives useful for activating 5-HT _1F Receptor for the prevention, treatment or alleviation of 5-HT _1F A 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 of the population is 5% -10%, and the genetic background is common.

Migraine, while not a fatal disease, can severely impact a patient's social life. Migraine headache imposes a socio-economic burden of $ 10 to $ 17 billion in the united states. In China, a large number of patients influence work, study and life due to migraine. With the increase of the rhythm of life, the incidence rate of migraine tends to increase gradually. 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 migraine treatment is mainly 5-HT _1B/D Receptor 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 of 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 _1F Receptor agonists are produced by the administration of anti-migraine drugs. However, CGRP receptor antagonists suffer from a number of drawbacks, such as the fact that olcagepant can only be administered intravenously and not orally, telcagepant causes elevated liver enzymes for long term use, and BI-44370 for its long term useInteraction with cytochrome P450 has been discontinued and clinical development has been discontinued. Therefore, the development of new acute phase therapeutic drugs is urgently required. To develop selective 5-HT _1F The receptor agonist anti-migraine drugs have been considered as a new promising approach.

5-HT _1F Receptors are mainly expressed in the mesentery, uterus and brain, and also in the cerebral vessels, trigeminal ganglia, trigeminal caudate nuclei and other trigeminal vasculature, as well as in the cerebellum, hippocampus and neocerebral cortex. 5-HT as other 5-HT receptors _1F Receptors are expressed not only in neurons but also in glial cells. Presynaptic 5-HT _1F The 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 _1F The receptor inhibition effect greatly reduces the side effect related to vasoconstriction caused by triptan medicaments.

At present, a para-5-HT has been developed _1F Various 5-HT receptors with relative selectivity for receptor subtypes _1F Receptor agonists, and studies have indicated this to 5-HT _1F Receptor selectivity generally reduces the vasoconstrictive activity characteristic of other compounds used as potential drugs for migraine and related diseases, but no therapeutic drugs related to the target are clinically available, so that the development of more safe and reliable selective 5-HT is still needed _1F A receptor agonist drug.

Disclosure of Invention

The invention provides a class as 5-HT _1F Novel pyridinoyl octahydropyrrolo [3,4-c ] receptor agonists]Pyrrole derivatives with different chemical and receptor binding properties useful for the activation of 5-HT _1F Receptor, inhibition of neuronal protein extravasation while avoiding significant vasoconstrictive activity and, therefore, may be used in the treatment of the disease caused by 5-HT _1F Receptor-mediated diseases, in particular for the treatment of migraine. And found through experiments that the pyridine acyl octahydropyrrolo [3,4-c ] of the invention]Pyrrole derivatives have stable properties, good safety, good pharmacodynamic and pharmacokinetic properties, for exampleSuch as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability, etc. Therefore, the method has good clinical application prospect. Furthermore, the compounds of the present invention have good solubility and thus high suitability in preferred formulations (e.g. sublingual, buccal and/or intranasal formulations).

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, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

wherein:

l is-C (= O) -, -C (= S) -or-S (= O) ₂ -；

R ¹ Is C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl, wherein R ¹ Optionally substituted by 1,2,3, 4 or 5 substituents selected from R ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Substituted with a group of (a);

R ^1a 、R ^1b 、R ^1c 、R ^1d and R ^1e Each independently of the other is H, D, F, cl, br, I, -CN, -NO ₂ 、-NH ₂ 、-OH、-SH、-COOH、-C(＝O)NH ₂ 、-C(＝O)NHCH ₃ 、-C(＝O)N(CH ₃ ) ₂ 、-C(＝O)-(C ₁ -C ₄ Alkyl), -C (= O) - (C) ₁ -C ₄ Alkoxy group), C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy, C ₁ -C ₄ Alkylthio radical, C ₁ -C ₄ Alkylamino, hydroxy-substituted C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl;

R ² is H, D, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl or hydroxy-substituted C ₁ -C ₄ An alkyl group;

R ³ 、R ⁴ and R ⁵ Each independently of the other is H, D, F, cl, br, I, -CN, -NO ₂ 、-NH ₂ 、-OH、C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy or hydroxy substituted C ₁ -C ₄ An alkyl group;

R ⁶ is H, D, -COOH, -C (= O) NH ₂ 、-C(＝O)NHCH ₃ 、-C(＝O)N(CH ₃ ) ₂ 、-C(＝O)-(C ₁ -C ₄ Alkyl), -C (= O) - (C) ₁ -C ₄ Alkoxy group), C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl, C ₁ -C ₄ Haloalkyl, or hydroxy-substituted C ₁ -C ₄ An alkyl group; and

R ⁷ is H, D, F, cl, br, I, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy or hydroxy substituted C ₁ -C ₄ An alkyl group.

In some embodiments, R ¹ Is phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolyl, wherein R is ¹ Optionally substituted by 1,2,3, 4 or 5 substituents selected from R ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Substituted with a group of (a);

R ^1a 、R ^1b 、R ^1c 、R ^1d and R ^1e Each independently is H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CH ₂ CF ₂ CHF ₂ Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ 、-OCH ₂ CF ₂ CHF ₂ Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, or 2-hydroxyethyl.

In some embodiments, the invention relates to a compound of formula (IIIa-1) or formula (IIIa-2), or a stereoisomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (IIIa-1) or formula (IIIa-2),

wherein each R is ^1a 、R ^1b 、R ^1c 、R ^1d 、R ^1e 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Have the meaning as described in the present invention.

In some embodiments, R ² Is H, D, methyl, ethyl, n-propyl, isopropyl, -CF ₃ or-CH ₂ CF ₃ ；

R ³ 、R ⁴ And R ⁵ Each independently is H, D, F, cl, br, I, -CN, -NO ₂ 、-NH ₂ -OH, methyl, ethyl, n-propyl, isopropyl, -CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propyloxy or isopropyloxy;

R ⁷ is H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, -CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In some embodiments, R ⁶ Is H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl or-CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CH ₂ CF ₂ CHF ₂ Hydroxymethyl or 2-hydroxyethyl.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), (IIIa-1) or (IIIa-2) disclosed herein.

In some embodiments, 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), (IIIa-1) or (IIIa-2) or a pharmaceutical composition thereof as disclosed in the present invention for the preparation of a medicament for the prevention, treatment or alleviation of 5-HT _1F A receptor associated disease.

In some embodiments, the treatment is with 5-HT _1F The 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, plucking hairCraving, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss, or dementia.

In a further aspect, the invention relates to the use of a compound of formula (I), (IIIa-1) or (IIIa-2) or a pharmaceutical composition thereof as disclosed in the present invention for the preparation of a medicament for activating 5-HT _1F A receptor.

In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound of formula (I), (IIIa-1) or (IIIa-2).

Biological test results show that the compound can activate 5-HT _1F Receptors, inhibit neuronal protein extravasation, and may be preferred as 5-HT _1F A 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 shall control.

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 from or contradict this application (including but not limited to defined terminology, terminology application, described techniques, and so on), 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 CAS version of the periodic Table of the elements, and with 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 herein or clearly contradicted by context. Thus, the articles are used herein to 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 to be employed or used 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 lacking optical activity.

The term "diastereomer" refers to a stereoisomer that has two or more chiral neutrals 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. A 50.

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). The optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the 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", is used interchangeably with the term "unsubstituted or substituted", i.e., the structure is unsubstituted or substituted with one or more of the substituents described herein, including, but not limited to, D, F, cl, br, I, N ₃ 、-CN、-NO ₂ 、-NH ₂ 、-OH、-SH、-COOH、-CONH ₂ 、-C(＝O)NHCH ₃ 、-C(＝O)N(CH ₃ ) ₂ -C (= O) -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 description of "each of" \8230 ", independently" and "\8230", independently "used in the present invention are interchangeable and should be understood in a broad sense, which means that specific options expressed between the same symbols in different groups do not affect each other, and that specific options 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 "C ₁ -C ₆ Alkyl "in particular denotes independently disclosed methyl, ethyl, C ₃ Alkyl radical, C ₄ Alkyl radical, C ₅ Alkyl and C ₆ An 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 this variable recites "alkyl" or "aryl," it is to be understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "D" denotes a single deuterium atom.

The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state form of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which the 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).

The term "alkyl" or "alkyl group" as used herein, means a saturated straight or branched chain monovalent hydrocarbon radical containing 1 to 20 carbon atoms, wherein said alkyl radical may be optionally substituted with one or more substituents 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 (Et, -CH) ₂ CH ₃ ) N-propyl (n-Pr, -CH) ₂ CH ₂ CH ₃ ) Isopropyl group (i-Pr, -CH (CH) ₃ ) ₂ ) N-butyl (n-Bu, -CH) ₂ CH ₂ CH ₂ CH ₃ ) Isobutyl (i-Bu, -CH) ₂ CH(CH ₃ ) ₂ ) Sec-butyl (s-Bu, -CH (CH) ₃ )CH ₂ CH ₃ ) Tert-butyl (t-Bu, -C (CH) ₃ ) ₃ ) And 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 sp ² A 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". Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, and the like.

The term "alkynyl" 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. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

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) ₂ CH ₃ ) 1-propoxy (n-PrO, n-propoxy, -OCH) ₂ CH ₂ CH ₃ ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) ₃ ) ₂ ) 1-butoxy (n-BuO, n-butoxy, -OCH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) ₂ CH(CH ₃ ) ₂ ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) ₃ )CH ₂ CH ₃ ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) ₃ ) ₃ ) And so on.

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 1-3 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) ₂ CH 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, N-ethylamino, N-dimethylamino, N-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 with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, -CF ₃ 、-CH ₂ CF ₃ 、-CHFCH ₃ 、-CH ₂ CH ₂ F、-CF ₂ CH ₃ And the like. In one embodiment, C ₁ -C ₆ Haloalkyl comprises fluorine-substituted C ₁ -C ₆ An alkyl group; in another embodiment, C ₁ -C ₄ The haloalkyl group containing a fluorine-substituted C ₁ -C ₄ An alkyl group; in yet another embodiment, C ₁ -C ₂ The haloalkyl group containing a fluorine-substituted C ₁ -C ₂ An 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, -OCF ₃ 、-OCH ₂ CF ₃ 、-OCHFCH ₃ 、-OCH ₂ CH ₂ F、-OCF ₂ CH ₃ And the like. In one embodiment, C ₁ -C ₆ Haloalkoxy comprises fluorine substituted C ₁ -C ₆ An alkoxy group; in another embodiment, C ₁ -C ₄ Haloalkoxy comprises fluorine substituted C ₁ -C ₄ An alkoxy group; in yet another embodiment, C ₁ -C ₂ Haloalkoxy comprises fluorine substituted C ₁ -C ₂ An alkoxy group.

The term "n-member" or "n-member" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is 6-atom heterocyclyl or 6-membered heterocyclyl, and cyclohexyl is 6-atom cycloalkyl or 6-membered cycloalkyl.

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 systems can include fused, bridged, and spiro rings. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. 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 a compound like SO, SO ₂ ，PO，PO ₂ A 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, SO ₂ ，PO，PO ₂ The group of (1). The heterocyclyl group is optionally substituted with one or more substituents described herein. The ring atoms of the heterocyclic group may be carbon-based or heteroatom-based. Wherein, is cyclic-CH ₂ The group is optionally replaced by-C (= O) -the sulphur atom of the ring is optionally oxidised to S-oxide and the nitrogen atom of the ring is optionally oxidised to N-oxygen compound. Heterocyclic ringsExamples of radicals include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, and the like. In heterocyclic radicals-CH ₂ Examples of-groups substituted with-C (= O) -include, but are not limited to, 2-oxopyrrolidinyl, oxomorpholinyl, 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, naphthyl, and anthracene. 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 5-10 atom composed heteroaryl group contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N. Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, and the like; the following bicyclic rings are also included, but are in no way limited to these: indolyl, quinolinyl, and the like.

As described herein, substituent R ⁷ Octahydropyrrolo [3,4-c ] s linked to the center by a bond]The ring system formed on the pyrrole ring (shown as the formula f) represents a substituent R ⁷ Can be in octahydropyrrolo [3,4-c ]]Optionally substituted in the pyrrole ring, as in formula f ^1-6 As shown.

The term "protecting group" or "PG" refers to a substituent which, 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-CH ₂ CH ₂ SO ₂ Ph, 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 means a compound which is converted in vivo to a compound of formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5). Such conversion is subject to prodrug hydrolysis in blood or tissueInfluence of enzymatic conversion to the parent structure. 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 descriptive pharmaceutical acceptable salts in detail in J. Pharmaceutical Sciences,1977, 66. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or salts obtained by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonatesCyclopentyl propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl radical) ₄ A salt. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group 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, C ₁ -C ₈ Sulfonates 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 with 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 the 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 does not yet experience or exhibit 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), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) 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 can be an intermediate useful for preparing and/or purifying a compound of formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) and/or for isolating the enantiomer of a compound of formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, using 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 e.g. "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 indicate that the compounds are not isotopically enrichedAnd isotopically enriched forms. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁵ S、 ³⁶ Cl and ¹²⁵ I。

in another aspect, the invention relates to intermediates for the preparation of compounds of formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5).

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 invention relates to pyridine acyl octahydropyrrolo [3,4-c ]]Pyrrole derivatives, pharmaceutically acceptable salts thereof, pharmaceutical preparations and compositions thereof, useful for activating 5-HT _1F Receptor, inhibition of neuronal protein extravasation, and antagonism of 5-HT _1F The 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.

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 each R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ And L has the meaning as described in the present invention.

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

In one embodiment, R ¹ Is C ₁ -C ₆ Alkyl radical, C ₃ -C ₈ Cycloalkyl, 3-8 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein R ¹ Optionally substituted by 1,2,3, 4 or 5 substituents selected from R ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Substituted with a group of (a); wherein R is ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Have the meaning as described in the present invention.

In one embodiment, R ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Each independently is H, D, F, cl, br, I, -CN, -NO ₂ 、-NH ₂ 、-OH、-SH、-COOH、-C(＝O)NH ₂ 、-C(＝O)NHCH ₃ 、-C(＝O)N(CH ₃ ) ₂ 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (= O) - (C) ₁ -C ₆ Alkoxy group), C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy, C ₁ -C ₆ Alkylthio radical, C ₁ -C ₆ Alkylamino, hydroxy-substituted C ₁ -C ₆ Alkyl radical, C ₃ -C ₈ Cycloalkyl, 3-8 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl.

In one embodiment, R ² Is H, D, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkyl halidesBase, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy or hydroxy substituted C ₁ -C ₆ An alkyl group.

In one embodiment, R ³ 、R ⁴ And R ⁵ Each independently is H, D, F, cl, br, I, -CN, -NO ₂ 、-NH ₂ 、-OH、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy or hydroxy substituted C ₁ -C ₆ An alkyl group.

In one embodiment, R ⁶ Is H, D, -COOH, -C (= O) NH ₂ 、-C(＝O)NHCH ₃ 、-C(＝O)N(CH ₃ ) ₂ 、-C(＝O)-(C ₁ -C ₆ Alkyl), -C (= O) - (C) ₁ -C ₆ Alkoxy group), C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, hydroxy-substituted C ₁ -C ₆ Alkyl radical, C ₃ -C ₈ Cycloalkyl, 3-8 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl.

In one embodiment, R ⁷ Is H, D, F, cl, br, I, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy or hydroxy substituted C ₁ -C ₆ An alkyl group.

In one embodiment, R ¹ Is C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl, wherein R ¹ Optionally substituted by 1,2,3, 4 or 5 substituents selected from R ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Substituted with a group of (a); wherein R is ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Have the meaning as described in the present invention.

In another embodiment, R ¹ Is phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolyl, wherein R is ¹ Optionally substituted by 1,2,3, 4 or 5 substituents selected from R ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Substituted with a group of (a); wherein R is ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Have the meaning as described in the present invention.

In one embodiment, R ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Each independently of the other is H, D, F, cl, br, I, -CN, -NO ₂ 、-NH ₂ 、-OH、-SH、-COOH、-C(＝O)NH ₂ 、-C(＝O)NHCH ₃ 、-C(＝O)N(CH ₃ ) ₂ 、-C(＝O)-(C ₁ -C ₄ Alkyl), -C (= O) - (C) ₁ -C ₄ Alkoxy group), C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy, C ₁ -C ₄ Alkylthio radical, C ₁ -C ₄ Alkylamino, hydroxy-substituted C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl.

In another embodiment, R ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Each independently is H, D, F, cl, br, I, -CN, -NO ₂ 、-NH ₂ 、-OH、-SH、-COOH、-C(＝O)NH ₂ 、-C(＝O)NHCH ₃ 、-C(＝O)N(CH ₃ ) ₂ 、-C(＝O)-CH ₃ 、-C(＝O)-OCH ₃ Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CH ₂ CF ₂ CHF ₂ Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ 、-OCH ₂ CF ₂ CHF ₂ Methylthio, 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, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In one embodiment, R ² Is H, D, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl or hydroxy-substituted C ₁ -C ₄ An alkyl group.

In another embodiment, R ² Is H, D, methyl, ethyl, n-propyl, isopropyl, -CF ₃ or-CH ₂ CF ₃ 。

In one embodiment, R ³ 、R ⁴ And R ⁵ Each independently is H, D, F, cl, br, I, -CN, -NO ₂ 、-NH ₂ 、-OH、C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy or hydroxy substituted C ₁ -C ₄ An alkyl group.

In another embodiment, R ³ 、R ⁴ And R ⁵ Each independently is H, D, F, cl, br, I, -CN, -NO ₂ 、-NH ₂ -OH, methyl, ethyl, n-propyl, isopropyl, -CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R ⁷ Is H, D, F, cl, br, I, C ₁ -C ₄ Alkyl radical, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy or hydroxy substituted C ₁ -C ₄ An alkyl group.

In another embodiment, R ⁷ Is H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, -CF ₃ 、-CH ₂ CF ₃ Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R ⁶ Is H, D, -COOH, -C (= O) NH ₂ 、-C(＝O)NHCH ₃ 、-C(＝O)N(CH ₃ ) ₂ 、-C(＝O)-(C ₁ -C ₄ Alkyl), -C (= O) - (C) ₁ -C ₄ Alkoxy group), C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl, C ₁ -C ₄ Haloalkyl, hydroxy-substituted C ₁ -C ₄ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl.

In another embodiment, R ⁶ Is H, D, -COOH, -C (= O) NH ₂ 、-C(＝O)NHCH ₃ 、-C(＝O)N(CH ₃ ) ₂ 、-C(＝O)-CH ₃ 、-C(＝O)-OCH ₃ Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CH ₂ CF ₂ CHF ₂ Hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In some embodiments, the invention relates to a compound that is a compound of formula (IIa), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (IIa), or prodrug thereof,

wherein each R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Have the meaning as described in the present invention.

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

In other embodiments, the invention relates to a compound of formula (IIIa-1), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof of a compound of formula (IIIa-1),

In other embodiments, the invention relates to a compound of formula (IIIa-2), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (IIIa-2), or a prodrug thereof,

wherein each R is ^1b 、R ^1c 、R ^1d 、R ^1e 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Have the meaning as described in the present invention.

In other embodiments, the invention relates to a compound of formula (IIIa-3), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein each R is ^1a 、R ^1c 、R ^1d 、R ^1e 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Have the meaning as described in the present invention.

In other embodiments, the invention relates to a compound of formula (IIIa-4), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (IIIa-4), or a prodrug thereof,

wherein each R is ^1a 、R ^1b 、R ^1d 、R ^1e 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Have the meaning as described in the present invention.

In other embodiments, the invention relates to a compound of formula (IIIa-5), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein each R is ^1b 、R ^1c 、R ^1d 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ And R ⁷ Have the meaning as described in the present invention.

In still other embodiments, the invention relates to a compound of formula (IIIb-1), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (IIIb-1), or a prodrug thereof,

In still other embodiments, the invention relates to a compound of formula (IIIb-2), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (IIIb-2), or a prodrug thereof,

In still other embodiments, the invention relates to a compound of formula (IIIb-3), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (IIIb-3), or a prodrug thereof,

In still other embodiments, the invention relates to a compound of formula (IIIb-4), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (IIIb-4), or a prodrug thereof,

In still other embodiments, the invention relates to a compound of formula (IIIb-5), or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (IIIb-5), or a prodrug thereof,

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 another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) 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), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) disclosed herein or a pharmaceutical composition thereof for the manufacture of a medicament for preventing, treating or ameliorating and/or treating 5-HT _1F A receptor associated disease.

In one embodiment, the compound is conjugated to 5-HT _1F The receptor-related diseases are migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, phobiaPanic 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 disorders, impulse control disorders, 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 conjugated to 5-HT _1F The receptor-related disorder is migraine.

In a further aspect, the invention relates to the use of a compound of formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) disclosed herein or a pharmaceutical composition thereof for the manufacture of a medicament for activating 5-HT _1F A receptor.

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5).

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

The invention provides a pharmaceutical composition, which comprises compounds shown in formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) or individual stereoisomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or solvates 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 (1691h ed.1980).

In general, the formulations of the invention comprise the active ingredient (a compound of formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5)) in admixture with, diluted by an excipient 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 medium 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 milled 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 must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and interactions that 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 that can 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 that enhance patient compliance may be selected.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants (such as talc, magnesium stearate and mineral oil), 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, tackifiers, 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 quick, 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% 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 and Wilkins, philadelphia, and Encyclopedia of Pharmaceutical technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, 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 of the other ingredients of 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, for example, by mixing 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., as a suppository; (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.

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 administration of 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 means sufficient to effectThe total amount of each active ingredient that exhibits 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 upon a variety of factors including the disease being treated, the severity of the disease, the activity of the particular drug employed, the mode of administration, the clearance of the particular drug, the duration of the treatment, the combination, the age, body weight, sex, diet and patient health, among others. Other factors that may be considered in The art for a "therapeutically effective amount" are described in Gilman et al, eds., goodman And Gilman's: the Pharmacological Bases of Therapeutics,8 ^th ed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17 ^th ed.,Mack Publishing Company,Easton,Pa.,1990。

Preferably, the compounds of formula I are formulated in unit dosage forms containing from about 0.001 to 100mg of active ingredient per dose, more often from about 1.0 to 30mg of 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 described above.

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 cases, dosage levels below the lower limit of the dosage range recited above may be more than adequate, while in other cases still higher doses may be employed without causing any side effects, provided that the larger dose is 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 as well as intraocular, otic, intravaginal, inhalational 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 invention or a pharmaceutical composition comprising a compound of the 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 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. Such combination products, if formulated as a fixed dose, 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 of the aforementioned additional therapeutic agents.

In addition, the compounds of the present invention may be administered in prodrug form. 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, including 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 _1F Pharmaceutical compositions of receptors, and their use in the preparation of a medicament for the prevention, treatment or alleviation of 5-HT _1F A pharmaceutical product for a disease associated with a receptor, in particular migraine.

In particular, the compounds of the inventionOr in a pharmaceutical composition, in an amount effective to detectably selectively activate 5-HT _1F A receptor.

In particular, the amount of compound in the compound or pharmaceutical composition of the 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 amelioration of 5-HT in a patient using an effective amount of a compound or pharmaceutical composition of the present invention _1F A receptor associated disease. The and 5-HT _1F Receptor-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 describe the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples, but is provided only to practice the invention.

In general, the compounds of the invention can be prepared by the processes described in the present application, where the substituents are, unless otherwise stated, defined as shown in formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5). 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, all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, arco Chemical Company and Alfa Chemical Company and used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical plant, guangdong Guanghua chemical plant, guangzhou chemical plant, tianjin Haojiuyu Chemicals Co., ltd, tianjin Shuichun chemical plant, wuhan Xin Huayuan science and technology development Co., ltd, qingdao Tenglong chemical reagent Co., ltd, and Qingdao maritime chemical plant.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide 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. Glassware was dried.

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

¹ H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer. ¹ H NMR spectrum with CDC1 ₃ 、DMSO-d ₆ 、CD ₃ OD or acetone-d ₆ TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplets), q (quatets, quartets), m (multiplets ), br (broadpededwideams), brs (broadpedsinglets, wideadlets), dd (doublets ), ddd (doublets, doublets), dt (doublets, triplets, doublets), td (triplets of doublets, triplets), tt (triplets of triplets, 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 0.6mL/min. Mobile phase: 5% -95% (CH with 0.1% formic acid) ₃ CN) in (H containing 0.1% formic acid) ₂ O) 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:

CH ₂ Cl ₂ DCM dichloromethane mL, mL mL

CDC1 ₃ mu.L, mu.l of deuterated chloroform

Nl, nL nanoliter of DMSO dimethyl sulfoxide

DMSO-d ₆ Deuterated dimethyl sulfoxide for min

EtOAc, EA ethyl acetate h hours

CH ₃ OH, meOH methanol CaCl ₂ Calcium chloride

CD ₃ OD deuterated methanol Na ₂ SO ₄ Sodium sulfate

H ₂ O water PE Petroleum ether (60-90 ℃ C.)

DIPEA N, N-diisopropylethylamine RT, RT, r.t. Room temperature

Et ₃ N Triethylamine HCl concentrated hydrochloric acid

LiOH·H ₂ Ascorbic Acid as lithium hydroxide O monohydrate

N ₂ Nitrogen Pargyline bagrine

nM nanomolar PEI polyethyleneimine

mu.M micromolar Serotonin, 5-hydroxytryptamine, 5-HT

mmol, mM mmol Tris-HCl Tris (hydroxymethyl) aminomethane-hydrochloric acid

Ng nanogram EDTA-K ₂ Ethylenediaminetetraacetic acid dipotassium salt

μ m g of Solutol polyethylene glycol-15-hydroxystearate

Mg Mg MTBE methyl tert-butyl ether

G G PEG400 polyethylene glycol 400

HATU 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

The following synthetic schemes describe the procedures for preparing the compounds disclosed herein, except as otherwise indicated, wherein each R is ^1a 、R ^1b 、R ^1c 、R ^1d 、R ^1e 、R ³ 、R ⁴ And R ⁵ Having the definitions set forth herein.

Synthesis scheme 1

Wherein X is CR ^1a Or N.

Formula (A), (B) and6) The compound shown can be prepared by the following steps: formula (A), (B) and1) A compound of the formula2) The compound is reacted to obtain the compound of the formula (A)3) The product shown; then the formula (A), (B)3) Hydrolyzing the compound shown in the formula (A) to obtain a compound shown in the formula (B)4) The product shown; formula (A), (B) and4) A compound of the formula5) By condensation of the compounds shown to give (6) 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- (5-Methylooctahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) pyridin-2-yl) benzamide

Step 1) Synthesis of methyl 6-benzoylaminopyridine-2-carboxylate

Methyl 6-aminopyridine-2-carboxylate (710mg, 4.67mmol), triethylamine (1.3mL, 9.40mmol) and dichloromethane (10 mL) were added to a 100mL single-neck round-bottom flask at 0 ℃, benzoyl chloride (848mg, 6.03mmol) 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 (30 mL), extracted with dichloromethane (40 mL), and the organic phase was collected, dried under reduced pressure, and separated by column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to obtain the title compound as a pale yellow liquid (414mg, 35.4%).

MS(ESI,pos.ion)m/z:257.2[M+H] ⁺ ；

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

Step 2) Synthesis of 6-benzoylaminopyridine-2-carboxylic acid

Methyl 6-benzoylaminopyridine-2-carboxylate (820mg, 3.20mmol), water (2 mL) and methanol (10 mL) were added to a 100mL single-necked round-bottomed flask at 25 ℃, and lithium hydroxide monohydrate (165mg, 3.93mmol) was added to continue the reaction for 3 hours; the reaction was stopped, methanol was removed by rotary evaporation under reduced pressure, water (10 mL) was added, then concentrated hydrochloric acid was added to adjust pH =2, filtered, and the resulting solid was dried at 60 ℃ to give the title compound as a white solid (620mg, 80%).

MS(ESI,pos.ion)m/z:243.0[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)11.02(s,1H),8.36(d,J＝8.4Hz,1H),8.08–7.99(m,3H),7.82(d,J＝7.6Hz,1H),7.60(t,J＝7.6Hz,1H),7.51(t,J＝7.6Hz,2H).

Step 3) N- (6- (5-Methylooctahydropyrrolo [3, 4-c)]Synthesis of pyrrole-2-carbonyl) pyridin-2-yl) benzamides Become into

6-benzoylaminopyridine-2-carboxylic acid (243mg, 1.0mmol) and dichloromethane (10 mL) were added to a 100mL single-neck flask at 0 ℃, N-diisopropylethylamine (194mg, 1.5mmol) and HATU (600mg, 1.5mmol) were added, and the reaction was continued for half an hour under nitrogen protection; then 2-methyloctahydropyrrolo [3,4-c ] is added]Pyrrole (190mg, 1.51mmol), transferred to 25 ℃ for 3 h; the reaction was stopped, water (20 mL) was added, followed by extraction with dichloromethane (30 mL × 2), the organic phase was collected, dried by adding anhydrous sodium sulfate (1 g), filtered, the filtrate was spin-dried under reduced pressure, and column chromatography purification (dichloromethane/methanol (v/v) = 40/1) gave the title compound as a pale yellow solid (94mg, 26.7%). MS (ESI, pos.ion) m/z:351.1[ m ] +H] ⁺ ；

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

Example 2 Synthesis of 4-fluoro-N- (6- (5-methyloctahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) pyridin-2-yl) benzamide

Step 1) Synthesis of methyl 6- (4-fluorobenzamido) pyridine-2-formate

The title compound of this step was prepared by the method described in example 1, step 1, by reacting 6-aminopyridine-2-carboxylate (200mg, 1.31mmol), triethylamine (0.3 mL,2.0 mmol) and 4-fluorobenzoyl chloride (0.25mL, 2.12mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a white solid (350mg, 97.1%).

MS(ESI,pos.ion)m/z:275.1[M+H] ⁺ ；

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

Step 2) Synthesis of 6- (4-fluorobenzamido) pyridine-2-formic acid

This step was performed by the method described in example 1, step 2, i.e., reacting methyl 6- (4-fluorobenzamido) pyridine-2-carboxylate (340mg, 1.24mmol), lithium hydroxide monohydrate (55mg, 1.31mmol) in methanol (10 mL) and water (2 mL) to give the title compound as a white solid (279mg, 86.5%).

MS(ESI,pos.ion)m/z:261.2[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)11.06(s,1H),8.34(d,J＝8.0Hz,1H),8.12(dd,J＝8.8,5.2Hz,2H),8.02(t,J＝8.0Hz,1H),7.82(d,J＝7.6Hz,1H),7.34(t,J＝8.8Hz,2H).

Step 3) 4-fluoro-N- (6- (5-methyloctahydropyrrolo [3, 4-c)]Pyrrole-2-carbonyl) pyridin-2-yl) benzoyl Synthesis of amines

This title compound was prepared as described in example 1, step 3, by reacting 6- (4-fluorobenzamido) pyridine-2-carboxylic acid (180mg, 0.69mmol), N-diisopropylethylamine (0.18mL, 1.09mmol), HATU (420mg, 1.1mmol) and 2-methyloctahydropyrrolo [3,4-c ] pyrrole (135mg, 1.07mmol) in dichloromethane (10 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 40/1) to give the title compound as a pale yellow solid (62mg, 24.3%).

MS(ESI,pos.ion)m/z:369.1[M+H] ⁺ ；

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

EXAMPLE 3 Synthesis of 4-chloro-N- (6- (5-methyloctahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) pyridin-2-yl) benzamide

Step 1) Synthesis of methyl 6- (4-chlorobenzoylamino) pyridine-2-carboxylate

The title compound of this step was prepared by the method described in example 1, step 1, by reacting 6-aminopyridine-2-carboxylate (200mg, 1.31mmol), triethylamine (0.3 mL,2.0 mmol) and 4-chlorobenzoyl chloride (0.25mL, 1.96mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a white solid (362mg, 94.7%).

MS(ESI,pos.ion)m/z:291.9[M+H] ⁺ ；

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

Step 2) Synthesis of 6- (4-chlorobenzoylamino) pyridine-2-carboxylic acid

The title compound was prepared as described in example 1, step 2, by reacting methyl 6- (4-chlorobenzoylamino) pyridine-2-carboxylate (362mg, 1.25mmol), lithium hydroxide monohydrate (55mg, 1.31mmol) in methanol (10 mL) and water (2 mL) to give the title compound as a white solid (228mg, 66.2%).

MS(ESI,pos.ion)m/z:277.0[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)11.13(s,1H),8.34(d,J＝8.4Hz,1H),8.10–7.98(m,3H),7.82(d,J＝7.6Hz,1H),7.58(d,J＝8.4Hz,2H).

Step 3) 4-chloro-N- (6- (5-methyloctahydropyrrolo [3, 4-c)]Pyrrole-2-carbonyl) pyridin-2-yl) benzoyl Synthesis of amines

The title compound of this step was prepared by the method described in step 3 of example 1 by reacting 6- (4-chlorobenzoylamino) pyridine-2-carboxylic acid (200mg, 0.72mmol), N-diisopropylethylamine (0.18mL, 1.09mmol), HATU (420mg, 1.1mmol) and 2-methyloctahydropyrrolo [3,4-c ] pyrrole (140mg, 1.11mmol) in dichloromethane (10 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 40/1) to give the title compound as a pale yellow solid (130mg, 46.7%).

MS(ESI,pos.ion)m/z:385.1[M+H] ⁺ ；

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

EXAMPLE 4 Synthesis of 4-bromo-N- (6- (5-methyloctahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) pyridin-2-yl) benzamide

Step 1) synthesis of methyl 6- (4-bromobenzoylamino) pyridine-2-formate

The title compound of this step was prepared by the method described in example 1, step 1, by reacting 6-aminopyridine-2-carboxylate (300mg, 1.97mmol), triethylamine (0.3 mL,2.0 mmol) and 4-bromobenzoyl chloride (660mg, 3.0 mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a white solid (609mg, 92.1%).

MS(ESI,pos.ion)m/z:335.0[M+H] ⁺ ；

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

Step 2) synthesis of 6- (4-bromobenzoylamino) pyridine-2-carboxylic acid

This step title compound was prepared as described in example 1, step 2 by reacting methyl 6- (4-bromobenzoylamino) pyridine-2-carboxylate (600mg, 1.79mmol), lithium hydroxide monohydrate (75mg, 1.79mmol) in methanol (10 mL) and water (2 mL) to give the title compound as a white solid (510mg, 88.7%).

MS(ESI,pos.ion)m/z:321.1[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)11.14(s,1H),8.34(d,J＝8.0Hz,1H),8.05–7.95(m,3H),7.88–7.80(m,1H),7.74–7.68(m,2H).

Step 3) 4-bromo-N- (6- (5-methyloctahydropyrrolo [3, 4-c)]Pyrrole-2-carbonyl) pyridin-2-yl) benzoyl Synthesis of amines

The title compound of this step was prepared by the method described in example 1, step 3, by reacting 6- (4-bromobenzoylamino) pyridine-2-carboxylic acid (200mg, 0.63mmol), N-diisopropylethylamine (0.16mL, 0.97mmol), HATU (350mg, 0.92mmol) and 2-methyloctahydropyrrolo [3,4-c ] pyrrole (120mg, 0.95mmol) in dichloromethane (10 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 40/1) to give the title compound as a pale yellow solid (130mg, 48.6%).

MS(ESI,pos.ion)m/z:429.0[M+H] ⁺ ；

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

Example 5 Synthesis of 2, 4-difluoro-N- (6- (5-methyloctahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) pyridin-2-yl) benzamide

Step 1) Synthesis of methyl 6- (2, 4-difluorobenzoylamino) pyridine-2-carboxylate

The title compound was prepared as described in example 1, step 1, by reacting 6-aminopyridine-2-carboxylate (500mg, 3.29mmol), triethylamine (0.9mL, 6.0mmol) and 2, 4-difluorobenzoyl chloride (550mg, 3.12mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a white solid (654mg, 71.8%).

MS(ESI,pos.ion)m/z:293.2[M+H] ⁺ ；

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

Step 2) Synthesis of 6- (2, 4-difluorobenzoylamino) pyridine-2-carboxylic acid

This step was made by the method described in reference to example 1, step 2, i.e., methyl 6- (2, 4-difluorobenzamido) pyridine-2-carboxylate (340mg, 1.24mmol), lithium hydroxide monohydrate (55mg, 1.31mmol) was reacted in methanol (10 mL) and water (2 mL) to give the title compound as a white solid (278mg, 86.5%).

MS(ESI,pos.ion)m/z:279.2[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)11.15(s,1H),8.37(d,J＝8.4Hz,1H),8.03(t,J＝7.6Hz,1H),7.84–7.74(m,2H),7.42–7.34(m,1H),7.20(td,J＝8.4,1.6Hz,1H).

Step 3) 2, 4-difluoro-N- (6- (5-methyloctahydropyrrolo [3, 4-c)]Pyrrole-2-carbonyl) pyridin-2-yl) benzene Synthesis of formamide

This step was prepared by the method described in example 1, step 3, i.e., 6- (2, 4-difluorobenzoylamino) pyridine-2-carboxylic acid (290mg, 1.04mmol), N-diisopropylethylamine (0.26mL, 1.57mmol), HATU (600mg, 1.58mmol), and 2-methyloctahydropyrrolo [3,4-c ] pyrrole (300mg, 2.38mmol) were reacted in dichloromethane (10 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 40/1) to give the title compound as a pale yellow solid (184mg, 45.7%).

MS(ESI,pos.ion)m/z:387.3[M+H] ⁺ ；

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

EXAMPLE 64 Synthesis of chloro-2-fluoro-N- (6- (5-methyloctahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) pyridin-2-yl) benzamide

Step 1) Synthesis of methyl 6- (4-chloro-2-fluorobenzamido) pyridine-2-formate

The title compound was prepared by the method described in example 1, step 1, reacting 6-aminopyridine-2-carboxylate (400mg, 2.63mmol), triethylamine (0.9mL, 6.0mmol) and 4-chloro-2-fluorobenzoyl chloride (500mg, 2.59mmol) in dichloromethane (10 mL), and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a white solid (632mg, 79%).

MS(ESI,pos.ion)m/z:309.0[M+H] ⁺ ；

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

Step 2) Synthesis of 6- (4-chloro-2-fluorobenzamido) pyridine-2-formic acid

This step was performed by the method described in reference to example 1, step 2, i.e., reacting methyl 6- (4-chloro-2-fluorobenzamido) pyridine-2-carboxylate (309mg, 1.0 mmol), lithium hydroxide monohydrate (45mg, 1.1mmol) in methanol (10 mL) and water (2 mL) to give the title compound as a white solid (168mg, 56.8%).

MS(ESI,pos.ion)m/z:295.0[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)11.23(s,1H),8.37(d,J＝8.4Hz,1H),8.03(t,J＝8.0Hz,1H),7.83(d,J＝7.6Hz,1H),7.72(t,J＝8.0Hz,1H),7.58(d,J＝10.0Hz,1H),7.40(d,J＝8.4Hz,1H).

Step 3) 4-chloro-2-fluoro-N- (6- (5-methyloctahydropyrrolo [3, 4-c)]Pyrrole-2-carbonyl) pyridin-2-yl) benzenes Synthesis of formamide

The title compound was prepared by the method described in example 1, step 3, by reacting 6- (4-chloro-2-fluorobenzamido) pyridine-2-carboxylic acid (180mg, 0.61mmol), N-diisopropylethylamine (0.15mL, 0.91mmol), HATU (350mg, 0.92mmol) and 2-methyloctahydropyrrolo [3,4-c ] pyrrole (120mg, 0.95mmol) in dichloromethane (10 mL), and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 40/1) to give the title compound as a pale yellow solid (98mg, 39.8%).

MS(ESI,pos.ion)m/z:403.2[M+H] ⁺ ；

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

Example 72, synthesis of 4, 6-trifluoro-N- (6- (5-methyloctahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) pyridin-2-yl) benzamide

Step 1) Synthesis of methyl 6- (2, 4, 6-trifluorobenzoylamino) pyridine-2-carboxylate

This step title compound was prepared as described in example 1, step 1 by reacting 6-aminopyridine-2-carboxylate (450mg, 2.96mmol), triethylamine (0.9ml, 6.0mmol) and 2,4, 6-trifluorobenzoyl chloride (530mg, 2.72mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow oil (374mg, 44.2%).

MS(ESI,pos.ion)m/z:311.2[M+H] ⁺ ；

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

Step 2) Synthesis of 6- (2, 4, 6-trifluorobenzamide) pyridine-2-carboxylic acid

The title compound was prepared as described in step 2 of example 1 by reacting methyl 6- (2, 4, 6-trifluorobenzoylamino) pyridine-2-carboxylate (178mg, 0.57mmol), lithium hydroxide monohydrate (25mg, 0.6 mmol) in methanol (5 mL) and water (1 mL) to give the title compound as a white solid (160mg, 94.1%).

MS(ESI,pos.ion)m/z:297.0[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)11.71(s,1H),8.37(d,J＝8.4Hz,1H),8.05(t,J＝8.0Hz,1H),7.85(d,J＝7.6Hz,1H),7.32(t,J＝8.8Hz,2H).

Step 3) 2,4, 6-trifluoro-N- (6- (5-methyloctahydropyrrolo [3, 4-c)]Pyrrole-2-carbonyl) pyridin-2-yl Synthesis of benzamide

The title compound was prepared by the method described in example 1, step 3, i.e. 6- (2, 4, 6-trifluorobenzoylamino) pyridine-2-carboxylic acid (160mg, 0.54mmol), N-diisopropylethylamine (0.15ml, 0.91mmol), HATU (350mg, 0.92mmol) and 2-methyloctahydropyrrolo [3,4-c ] pyrrole (120mg, 0.95mmol) were reacted in dichloromethane (10 mL) and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 40/1) to give the title compound as a pale yellow solid (110mg, 50.4%).

MS(ESI,pos.ion)m/z:405.1[M+H] ⁺ ；

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

EXAMPLE 8 Synthesis of 5-fluoro-N- (6- (5-methyloctahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) pyridin-2-yl) pyridine-2-carboxamide

Step 1) Synthesis of methyl 6- (5-fluoropyridine-2-carboxamido) pyridine-2-carboxylate

The title compound of this step was prepared as described in example 1, step 1, by reacting 6-aminopyridine-2-carboxylate (600mg, 3.94mmol), triethylamine (1.0mL, 7.2mmol) and 5-fluoropyridine-2-carbonyl chloride (600mg, 3.76mmol) in dichloromethane (10 mL), and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (760mg, 73.4%).

MS(ESI,pos.ion)m/z:276.2[M+H] ⁺ ；

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

Step 2) Synthesis of 6- (5-fluoropyridine-2-carboxamido) pyridine-2-carboxylic acid

This step was performed by the method described in reference to example 1, step 2, i.e., methyl 6- (5-fluoropyridine-2-carboxamido) pyridine-2-carboxylate (370mg, 1.34mmol), lithium hydroxide monohydrate (60mg, 1.43mmol) was reacted in methanol (10 mL) and water (2 mL) to give the title compound as a white solid (313mg, 89.1%).

MS(ESI,pos.ion)m/z:262.0[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.43(s,1H),8.77(d,J＝2.8Hz,1H),8.44(d,J＝8.4Hz,1H),8.30(dd,J＝8.8,4.8Hz,1H),8.09(t,J＝8.0Hz,1H),8.03(td,J＝8.4,2.8Hz,1H),7.85(d,J＝7.6Hz,1H).

Step 3) 5-fluoro-N- (6- (5-methyloctahydropyrrolo [3, 4-c)]Pyrrole-2-carbonyl) pyridin-2-yl) pyridine-2- Synthesis of formamide

The title compound was prepared as described in example 1, step 3 by reacting 6- (5-fluoropyridine-2-carboxamido) pyridine-2-carboxylic acid (106mg, 0.41mmol), N-diisopropylethylamine (0.11mL, 0.67mmol), HATU (250mg, 0.66mmol) and 2-methyloctahydropyrrolo [3,4-c ] pyrrole (75mg, 0.59mmol) in dichloromethane (10 mL) and purifying the crude product by silica gel column chromatography (dichloromethane/methanol (v/v) = 40/1) to give the title compound as a white solid (57mg, 38%).

MS(ESI,pos.ion)m/z:370.3[M+H] ⁺ ；

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

EXAMPLE 9 Synthesis of 5-chloro-N- (6- (5-methyloctahydropyrrolo [3,4-c ] pyrrole-2-carbonyl) pyridin-2-yl) pyridine-2-carboxamide

Step 1) Synthesis of methyl 6- (5-chloropyridine-2-carboxamido) pyridine-2-carboxylate

This title compound was prepared as described in example 1, step 1, by reacting 6-aminopyridine-2-carboxylate (450mg, 2.96mmol), triethylamine (0.9mL, 6.0mmol) and 5-chloropyridine-2-carbonyl chloride (500mg, 2.84mmol) in dichloromethane (10 mL), and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a pale yellow solid (496mg, 59.9%).

MS(ESI,pos.ion)m/z:292.1[M+H] ⁺ ；

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

Step 2) Synthesis of 6- (5-chloropyridine-2-formylamino) pyridine-2-carboxylic acid

This step was performed by the method described in reference to example 1, step 2, i.e., reacting methyl 6- (5-chloropyridine-2-carboxamido) pyridine-2-carboxylate (490mg, 1.68mmol), lithium hydroxide monohydrate (84mg, 2.0 mmol) in methanol (10 mL) and water (2 mL) to give the title compound as a white solid (379mg, 81.3%).

MS(ESI,pos.ion)m/z:278.0[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)10.45(s,1H),8.82(d,J＝1.2Hz,1H),8.44(d,J＝8.4Hz,1H),8.26–8.18(m,2H),8.09(t,J＝7.6Hz,1H),7.85(d,J＝7.2Hz,1H).

Step 3) 5-chloro-N- (6- (5-methyloctahydropyrrolo [3, 4-c)]Pyrrole-2-carbonyl) pyridin-2-yl) pyridine-2- Synthesis of formamide

The title compound was prepared as described in example 1, step 3, by reacting 6- (5-chloropyridine-2-carboxamido) pyridine-2-carboxylic acid (198mg, 0.71mmol), N-diisopropylethylamine (0.17mL, 1.03mmol), HATU (410mg, 1.08mmol), and 2-methyloctahydropyrrolo [3,4-c ] pyrrole (140mg, 1.11mmol) in dichloromethane (10 mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 40/1) to give the title compound as a white solid (110mg, 40%).

MS(ESI,pos.ion)m/z:386.2[M+H] ⁺ ；

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

Biological assay

Example A: non-selective rat 5-HT ₁ Receptor radioligand affinity assay

Experimental methods

Cell membranes were prepared from the cerebral cortex of 175 ± 25g male Wistar rats in Tris-HCl buffer pH = 7.4. Under the condition of 25 deg.C, mixing 15mg of a cell membrane sample with 1nM [ 2 ] ³ H]-5-HT in buffer (50 mM Tris-HCl (pH = 7.4), 0.1% Ascortic acid, 10. Mu.M Pargyline,4mM CaCl ₂ ) And incubated for 60 minutes under which conditions the test compound is added to complete the radioligand binding assay.

Test compounds were dissolved in 100% DMSO and tested at 6 concentrations (0.1 nM, 1nM, 10nM, 100nM, 1. Mu.M, 10. Mu.M) and nonspecific binding was determined using 10. Mu.M 5-HT.

After the incubation was complete, the reaction was terminated by rapid filtration through a glass fiber filter pre-soaked with 0.3% PEI, and washed 3 times in a 96-well cell harvester using a pre-cooled 50mM Tris-HCl solution. After drying, scintillation fluid is added and the residual radioactivity is measured in a liquid scintillation counter.

The results of the experiment are expressed as percent inhibition of radioligand specific binding relative to control wells.

The standard reference compound was 5-HT, and the inhibition rate (inhibition rate =100- (wells affinity result/control wells affinity result) × 100) was calculated by testing the data for a series of concentrations of 5-HT, and the IC was calculated from the concentration-inhibition rate competition curve ₅₀ 。

The results are shown in Table A.

Table a: compounds of the invention on rat 5-HT ₁ Results of receptor affinity assay

Example No. 1	IC ₅₀ (μM)
		Example 5	6.98

The experimental results show that the compound of the invention is used for treating 5-HT of rats ₁ The receptor has a high affinity.

Example B:5-HT _1F Acceptor Ca ²⁺ Migration measurement method

Experimental methods

(1) Transient experiment

Seeding HEK293 cells grown to 90% in 6-well plates at a density of 1.5X 10^6 cells/well 5% CO at 37% ₂ Culturing overnight in incubator with human-derived 5-HT _1F Co-transfection of HEK293 cells with Ga15 plasmid and 5% CO at 37 ℃% ₂ The mixture was incubated for 24 hours.

(2) FLIPR experiment

Digestion of 24-hour transfected HEK293 cells in 384-well plates at a density of 2X 10^4 cells/well and 5% CO at 37% ₂ The following incubations were carried out for 16-20 hours. Add 20. Mu.l 2X Fluo-4Direct per well ^TM Dye and 5% CO at 37% ₂ The mixture was incubated at room temperature for 50 minutes and at room temperature for 10 minutes. Dose curves for different concentrations of compound were prepared, compounds were transferred from dose curves to cell plates using a FLIPR instrument, and fluorescence signals were read immediately. Ca induced by different concentrations of Compounds ²⁺ Fluorescence signals of different intensities were generated in combination with dyes, dose-effect curves of the compounds were calculated by Prism software, and agonist concentrations giving half maximal response were calculated as EC ₅₀ The values are expressed.

The experimental result shows that the compound of the invention has stronger 5-HT _1F Receptor agonistic activity.

Example C: rat, dog intravenous injection or gavage quantification of pharmacokinetic evaluation of Compounds of the invention

The inventors have performed pharmacokinetic evaluation of the compounds of the invention in rats, dogs. 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(s)	Source
						SD rat	SPF	Male(s)	170-250g	6-9 weeks	Hunan Slek laboratory animals Co., ltd
Beagle dog	Cleaning stage	Male(s)	8～10kg	6-7 weeks	Hunan Slek laboratory animals Co., ltd

Experimental methods

The compounds of the present invention are administered to the test animals in the form of 5% DMSO +5% aqueous solution of solutol +90% normal saline or 5% DMSO +60% aqueous solution of PEG400+35% normal saline, with the animals fasted for 12h before administration and with free drinking water. For the group administered by intravenous injection, the dose was 1mg/kg, and blood was taken intravenously (blood volume taken was about 0.15 mL) at the following time points after administration: 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours, EDTA-K is added in advance into the blood sampling tube ₂ As 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 5mg/kg, and venous blood sampling (approximately 0.15mL in blood volume) was performed at the following time points after the administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours, EDTA-K is added in advance in the blood sampling tube ₂ As an anticoagulant, blood samples were centrifuged at 12,000rpm for 2 minutes, plasma was collected and stored at-20 ℃ or-70 ℃. The positive control is Lasmidinan (the structure is

The plasma samples collected above were processed (30. Mu.L of plasma, 120. Mu.L of aqueous internal standard solution added, mixed, extracted with 0.9mL of MTBE, 0.7mL dried, and reconstituted with 220. Mu.L of methanol in water (v/v = 1/1)), and then the concentration of the compound in the plasma was analyzed by LC-MS/MS. Analysis results show that the compound has better pharmacokinetic properties in rats and dogs.

Table C1: pharmacokinetic parameters of Compounds of the invention in rats

ND: indicating no test data.

As can be seen from the results in table C1, the compounds of the present invention have better pharmacokinetic properties in rats than lasiditan.

Table C2: pharmacokinetic parameters of Compounds of the invention in dogs

ND: indicating no test data.

As can be seen from the results in table C2, the compounds of the present invention have better pharmacokinetic properties in dogs than lasiditan.

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:

l is-C (= O) -;

R ¹ is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein R ¹ Optionally substituted by 1,2,3, 4 or 5 substituents selected from R ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Substituted with a group of (a);

R ^1a 、R ^1b 、R ^1c 、R ^1d and R ^1e Each independently is H, D, F, cl, br, I, C ₁ -C ₄ Alkyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₄ Alkynyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy radical, C ₁ -C ₄ Haloalkoxy, C ₁ -C ₄ Alkylthio radical, C ₁ -C ₄ Alkylamino or hydroxy substituted C ₁ -C ₄ An alkyl group;

R ² is H, D or C ₁ -C ₄ An alkyl group;

R ³ 、R ⁴ and R ⁵ Each independently of the other is H, D, F, cl, br, I or C ₁ -C ₄ An alkyl group;

R ⁶ is H, D or C ₁ -C ₄ An alkyl group; and

R ⁷ is H, D, F, cl, br, I or C ₁ -C ₄ An alkyl group.

2. The compound of claim 1, wherein R ^1a 、R ^1b 、R ^1c 、R ^1d And R ^1e Each independently is H, D, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ 、-CF ₃ 、-CHFCH ₂ F、-CF ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CH ₂ CF ₂ CHF ₂ Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF ₂ 、-OCF ₃ 、-OCHFCH ₂ F、-OCF ₂ CHF ₂ 、-OCH ₂ CF ₃ 、-OCH ₂ CF ₂ CHF ₂ Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, or 2-hydroxyethyl.

3. The compound of claim 1 or 2, which is a compound of formula (IIIa-1) or formula (IIIa-2), or a pharmaceutically acceptable salt of a compound of formula (IIIa-1) or formula (IIIa-2),

4. the compound of claim 1, wherein R ² Is H, D, methyl, ethyl, n-propyl or isopropyl;

R ³ 、R ⁴ and R ⁵ Each independently is H, D, F, cl, br, I, methyl, ethyl, n-propyl or isopropyl;

R ⁷ is H, D, F, cl, br, I, methyl, ethyl, n-propyl or isopropyl.

5. The compound of claim 1, wherein R ⁶ H, D, 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 _1F A receptor associated disease.

9. The use according to claim 8, wherein said treatment is with 5-HT _1F The receptor-associated disorder is migraine, general pain, trigeminal neuralgia, pain associated with toothache or temporomandibular joint dysfunction, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, a sleep disorder, 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 _1F A receptor.