CN110272425B - Pyridinyl octahydropyrrolo[3,4-c]pyrrole derivatives and uses thereof - Google Patents

Abstract

The invention discloses pyridinoyl octahydropyrrolo[3,4-c]pyrrole derivatives and uses thereof, in particular, the present invention relates to a novel picolinyl octahydropyrrolo[3,4-c]pyrrole derivative And the pharmaceutical composition containing the compound can be used to activate the 5-HT _1F receptor. The present invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in the preparation of medicaments for the treatment of diseases related to 5-HT _1F receptors, especially migraine.

Description

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

technical field

The invention belongs to the technical field of medicines, and in particular relates to novel pyridyl octahydropyrrolo[3,4-c]pyrrole derivatives and pharmaceutical compositions containing these compounds, as well as their use and application. In particular, the novel pyridinoyloctahydropyrrolo[3,4-c]pyrrole derivatives described in the present invention can be used to activate 5-HT _1F receptors for preventing, treating or alleviating the effects of 5-HT _1F receptors related diseases, especially migraines.

Background technique

Migraine is a kind of paroxysmal and often unilateral throbbing headache, often accompanied by nausea and vomiting. It is a common chronic neurovascular disease. It is more common in women, and the ratio of male to female patients is about 1:2 to 3. The prevalence rate in the population is 5% to 10%, and it often has a genetic background.

Although migraine is not a fatal disease, it can seriously affect the social life of patients. In the United States, the socioeconomic burden of migraine is $1.0 to $1.7 billion. There are also a large number of patients in my country who affect work, study and life because of migraine. With the quickening pace of life, the incidence of migraine is gradually increasing. A recent survey found that about 5.7% of men and 17.6% of women had more than one migraine attack per year on average. In addition, many people have a genetic predisposition to migraine.

The pathogenesis of migraine is complex and diverse, mainly including angiogenic theory, neurogenic theory, trigeminal neurovascular theory, biochemical factors and genetic factors. The drugs currently used to treat migraine are mainly 5-HT _1B/D receptor agonist triptans, but because triptans can constrict blood vessels, they are contraindicated for patients with cardiovascular and cerebrovascular and peripheral vascular diseases. In addition, 40% to 70% of migraine patients have poor curative effect on triptans, and 1/3 of patients who are effective in initial treatment will often experience headache recurrence. The curative effect of triptans on patients with moderate to severe headache Significantly lower. In order to overcome these adverse reactions of triptans, calcitonin gene-related peptide (CGRP) receptor antagonists and selective 5-HT _1F receptor agonists have emerged as anti-migraine drugs. However, there are still many defects in CGRP receptor antagonists. For example, olcagepant can only be used by intravenous injection and is not suitable for oral administration; develop. Therefore, there is an urgent need to develop new drugs for the treatment of acute phase. The development of selective 5-HT _1F receptor agonist anti-migraine drugs has been considered as a new promising approach.

The 5-HT _1F receptor is mainly expressed in the mesentery, uterus and brain, and also exists in various parts of the trigeminal vasculature such as cerebral blood vessels, trigeminal ganglion and trigeminal caudate nucleus, as well as the cerebellum, hippocampus and neocortex. Like other 5-HT receptors, 5-HT _1F receptors are expressed not only in neurons, but also in glial cells. Activation of presynaptic 5-HT _1F receptors inhibits calcitonin gene-related peptide (CGRP) release and blocks neuronal signaling in the caudate nucleus of the trigeminal nerve, resulting in an antimigraine effect, and this selective The 5-HT _1F receptor inhibitory effect greatly reduces the vasoconstriction-related side effects caused by triptans.

Currently, various 5-HT _1F receptor agonists with relative selectivity for 5-HT _1F receptor subtypes have been developed, and studies indicate that this selectivity for 5-HT _1F receptors is generally reduced as The unique vasoconstriction activity of other compounds that are potential drugs for the treatment of migraine and related diseases, but there is still no therapeutic drug related to this target in clinical practice. Therefore, more safe and reliable selective 5-HT _1F receptor agonists still need to be developed doses of drugs.

Contents of the invention

The present invention provides a class of novel pyridyloctahydropyrrolo[3,4-c]pyrrole derivatives as 5-HT _1F receptor agonists, which have different chemical and receptor binding properties and can be used to activate 5-HT _1F receptors inhibit neuronal protein extravasation while avoiding significant vasoconstrictor activity, therefore, they can be used in the treatment of diseases mediated by 5-HT _1F receptors, especially in the treatment of migraine. And it is found through experiments that the pyridyl octahydropyrrolo[3,4-c]pyrrole derivatives of the present invention are stable in properties, good in safety, and have good pharmacodynamics and pharmacokinetic properties, such as good brain/ Plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability, etc. Therefore, it has good prospects for clinical application. In addition, the compounds of the present invention have good solubility and thus high adaptability in preferred formulations such as sublingual, buccal and/or intranasal formulations.

The present invention also provides a method for preparing the compound, a pharmaceutical composition containing the compound, and the use of the compound and the pharmaceutical composition containing the compound in the preparation of medicaments.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of a compound represented by formula (I) , metabolites, pharmaceutically acceptable salts or prodrugs thereof,

in:

L is -C(=O)-, -C(=S)- or -S(=O) ₂ -;

R ¹ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, wherein, R ¹ is optionally is substituted by 1, 2, 3, 4 or 5 groups selected from R ^1a , R ^1b , R ^1c , R ^1d and R ^1e ;

R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are each independently 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), C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylamino, hydroxy substituted C ₁ -C ₄ alkyl, C ₃ -C ₆ ring Alkyl, 3-6 membered heterocyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl;

R ² is H, D, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or C ₁ -C ₄ alkyl substituted by hydroxy;

R ³ , R ⁴ and R ⁵ are each independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or hydroxy substituted C ₁ -C ₄ alkyl;

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), C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl, or hydroxy substituted C ₁ -C ₄ alkyl; and

R ⁷ is H, D, F, Cl, Br, I, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or hydroxyl Substituted C ₁ -C ₄ alkyl.

^In some embodiments, R is phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl , pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl, wherein R is optionally ¹ , 2, 3, 4 or 5 selected from R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are replaced by groups;

R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are each independently 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, ethyl Thio, methylamino, dimethylamino, ethylamino, hydroxymethyl or 2-hydroxyethyl.

In some embodiments, the present invention relates to a compound, which is a compound shown in formula (IIIa-1) or formula (IIIa-2), or a compound shown in formula (IIIa-1) or formula (IIIa-2) Stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings 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 are each independently 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-propyl oxy or isopropyloxy.

In some embodiments, R ⁶ is H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ , -CF ₃ , _-CHFCH2F , _-CF2CHF2 , _-CH2CF3 , _-CH2CF2CHF2 , _{hydroxymethyl} or _{2 - hydroxyethyl} .

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

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 present invention relates to the use of the compound represented by formula (I), (IIIa-1) or (IIIa-2) disclosed in the present invention or its pharmaceutical composition in the preparation of medicines, which are used for prevention, treatment Or alleviate diseases related to 5-HT _1F receptor.

In some embodiments, the 5-HT _1F receptor-associated disease 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 disturbance, post-traumatic syndrome, chronic fatigue syndrome, premenstrual or postluteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder , ADHD, alcoholism, tobacco abuse, mutism, trichotillomania, hyperphagia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss, or dementia.

In yet another aspect, the present invention relates to the use of the compound represented by formula (I), (IIIa-1) or (IIIa-2) disclosed in the present invention or its pharmaceutical composition in the preparation of medicines for activating 5- HT _1F receptor.

In another aspect, the present invention relates to methods for preparing, isolating and purifying compounds represented by formula (I), (IIIa-1) or (IIIa-2).

Biological test results show that the compound of the invention can activate 5-HT _1F receptors, inhibit neuronal protein extravasation, and can be used as a better 5-HT _1F receptor agonist.

Any embodiment of any aspect of the present invention may be combined with other embodiments as long as they do not contradict each other. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as there is no contradiction between them.

The preceding description merely outlines certain aspects of the invention, but is not intended to be limiting. These and other aspects will be described more specifically and fully below. All references in this specification are hereby incorporated by reference in their entirety. When there is a discrepancy between the disclosure content of this specification and the cited documents, the disclosure content of this specification shall prevail.

Detailed Description of the Invention

Definitions and General Terms

Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could 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 literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this Application shall prevail.

It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple 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.

As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the descriptions in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and JerryMarch, John Wiley & Sons, New York: 2007, The entire contents of which are incorporated herein by reference.

As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless otherwise stated or clearly contradicted by context. Therefore, these articles used in the present invention refer to articles of one or more than one (ie at least one) object. For example, "a component" refers to one or more components, ie there may be more than one component contemplated to be employed or used in the practice of the described embodiment.

The term "stereoisomer" refers to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .

The term "chiral molecule" is a molecule that has the property of being non-superimposable to its mirror image; whereas "achiral molecule" refers to a molecule that is superimposable to its mirror image.

The term "enantiomer" refers to two non-superimposable isomers of a compound that are mirror images of each other.

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

The term "diastereomer" refers to stereoisomers that have two or more chiral neutralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, ie 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 the molecule with respect to its chiral center or centers. The prefixes d and 1 or (+) and (-) are symbols used to designate rotation of plane polarized light by a compound, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration exist. 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.

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

The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.

The racemates of any resulting final products or intermediates can be resolved into the optical antipodes by known methods by methods familiar to those skilled in the art, e.g., by subjecting the obtained diastereomeric salts thereof to separate. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers may be prepared by asymmetric synthesis, see for example Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enol isomerization Amine isomerization.

"Pharmaceutically acceptable" means compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic The benefit/risk ratio is proportionate to other concerns and complications, and effective for the intended purpose.

The term "optionally substituted" may be used interchangeably with the term "unsubstituted or substituted", that is, the structure in question is either unsubstituted or replaced by one or more of the present The substituents described in the invention are substituted, and the substituents described in the invention include, but are 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 have been replaced by a particular substituent. Unless otherwise indicated, a substituent may be substituted at each substitutable reasonable position of the group. When more than one position in a given structural formula can be substituted by one or more specific substituents selected, the substituents can be substituted at each reasonable position in the structural formula either identically or differently.

In addition, it should be noted that, unless otherwise clearly stated, the descriptions used in the present invention "each...independently are" can be interchanged with "...independently" and "...independently". It should be understood in a broad sense. It can mean that in different groups, the specific options expressed between the same symbols do not affect each other, and it can also mean that in the same group, the specific options expressed between the same symbols do not affect each other.

The term "subject" as used in the present invention refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (such as humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

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

The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C ₁ -C ₆ alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl.

In various sections of the invention linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl," it is understood that "alkyl" or "aryl" respectively represents the linking group. An alkylene group or an arylene group.

The term "D" denotes a single deuterium atom.

The term "heteroatom" refers to O, S, N, P, and Si, including forms in any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or Hydrogen-substituted forms, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidinyl NR).

The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1-20 carbon atoms, wherein the alkyl group can be optionally substituted by one or more of the substituents described herein. In one embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1-4 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), and the like.

The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp ² double bond, wherein the alkenyl group A group can be optionally substituted with one or more substituents described herein, including the "cis" and "trans" orientations, or the "E" and "Z" orientations. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, and the like.

The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more substituents described herein. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

The term "alkoxy" denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein. Unless specified otherwise, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group Groups contain 1-3 carbon atoms. The alkoxy groups 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-butane Oxygen (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), and so on.

The term "alkylthio" denotes an alkyl group attached to the rest of the molecule through a sulfur atom, wherein the alkyl group has the meaning described herein. Unless specified otherwise, the alkylthio groups contain 1-12 carbon atoms. In one embodiment, an alkylthio group contains 1-6 carbon atoms; in another embodiment, an alkylthio group contains 1-4 carbon atoms; in yet another embodiment, an alkylthio group Groups contain 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, _-SCH3 ), ethylthio ( _EtS , _-SCH2CH3 ), and the like.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are independently substituted by one or two alkyl groups, Wherein the alkyl group has the meaning as described in the present invention. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- -Diethylamino and the like. The alkylamino group is optionally substituted with one or more substituents described herein.

The term "hydroxyl-substituted alkyl" means that an alkyl group is substituted by one or more hydroxyl groups, wherein the alkyl group has a meaning as described herein; examples of such include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2,3-dihydroxypropyl, etc.

The term "haloalkyl" means that an alkyl group is substituted by one or more halogen atoms, wherein the alkyl group has the meaning described in the present invention, such examples include, but are not limited to, -CF ₃ , -CH ₂ CF ₃ , -CHFCH ₃ , -CH ₂ CH ₂ F, -CF ₂ CH ₃ , etc. In one embodiment, C ₁ -C ₆ haloalkyl comprises fluorine substituted C ₁ -C ₆ alkyl; in another embodiment, C ₁ -C ₄ haloalkyl comprises fluorine substituted C ₁ -C ₄ alkyl ; In yet another embodiment, the C ₁ -C ₂ haloalkyl comprises a fluorine substituted C ₁ -C ₂ alkyl.

The term "haloalkoxy" means that an alkoxy group is substituted by one or more halogen atoms, wherein the alkoxy group has the meaning as described in the present invention, such examples 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 alkoxy; in another embodiment, C ₁ -C ₄ haloalkoxy comprises fluorine substituted C ₁ -C ₄ alkoxy; In yet another embodiment, the C ₁ -C ₂ haloalkoxy comprises a fluorine substituted C ₁ -C ₂ alkoxy.

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

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused, bridged and spiro rings. In one embodiment, cycloalkyl contains 3-10 carbon atoms; In another embodiment, cycloalkyl contains 3-8 carbon atoms; In yet another embodiment, cycloalkyl contains 3-6 carbon atom. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, wherein , the bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. Where one or more atoms on the ring are independently replaced by heteroatoms, said heteroatoms have the meanings as described in the present invention. In one embodiment, the heterocyclic group is a monocyclic heterocyclic group consisting of 3-8 ring atoms (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, in This S or P is optionally substituted by one or more oxygen atoms to obtain a group like SO, SO ₂ , PO, PO ₂ ); in another embodiment, the heterocyclyl is composed of 7-12 ring atoms The bicyclic heterocyclyl (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain like SO , SO ₂ , PO, PO ₂ groups). The heterocyclyl group is optionally substituted with one or more substituents described herein. The ring atoms of a heterocyclyl group can be carbyl or heteroatomyl. wherein the -CH ₂ - group of the ring is optionally replaced by -C(=O)-, the sulfur atom of the ring is optionally oxidized to S-oxide, and the nitrogen atom of the ring is optionally oxidized to N- Oxygen compounds. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, Piperidinyl, morpholinyl, piperazinyl, etc. Examples of _-CH2- groups in heterocyclic groups substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxomorpholinyl, and the like. Said heterocyclyl groups are optionally substituted with one or more substituents described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic family in which each ring system contains rings consisting of 3-7 atoms. The aryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the aryl group. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups 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 5-12 ring atoms, or 5-10 ring atoms, or 5-6 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 composed of 5-7 atoms. The heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl", "heteroaromatic ring" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl group of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, and the like; The following bicyclic rings are included, but are by no means limited to: indolyl, quinolinyl, and the like.

As described in the present invention, the substituent R ⁷ is connected to the central octahydropyrrolo[3,4-c]pyrrole ring by a bond to form a ring system (as shown in formula f) to represent the substituent R ⁷ can be in eight Any position that can be substituted on the hydropyrrolo[3,4-c]pyrrole ring is substituted, as shown in formula f ^1-6 .

The term "protecting group" or "PG" refers to a substituent that reacts with other functional groups, usually to block or protect specific functionality. For example, "amino-protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group. Suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. "Carboxyl protecting group" refers to the substituent of carboxyl to block or protect the functionality of carboxyl. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane base) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl phosphino)ethyl, nitroethyl, etc. For a general description of protecting groups, refer to: Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups, Thieme, Stuttgart, 2005.

The term "prodrug" used in the present invention represents that a compound is converted into formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), ( A compound represented by IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5). Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug with phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters. For example, a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups.

"Metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C ₁ -C ₈ sulfonates and aromatic sulfonates.

A "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, dimethylsulfoxide, 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, one molecule of the compound of the present invention can be combined with one water molecule, such as monohydrate; in another embodiment, one molecule of the compound of the present invention can be combined with more than one water molecule, such as dihydrate substances; in yet another embodiment, one molecule of a compound of the invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the bioavailability of the non-hydrated form of the compound.

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

The term "prevention" 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 who may be or is predisposed to face the disease, but who not experiencing or showing symptoms of disease).

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

In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of the structure are contemplated and included in the invention as disclosed compounds . When stereochemistry is indicated by a solid wedge or a dashed line indicating a particular configuration, then a stereoisomer of that structure is identified and defined.

Nitrogen oxides of the compounds of the present invention are also included within the scope of the present invention. Oxidation of the corresponding nitrogenous basic species can be achieved by using common oxidizing agents such as hydrogen peroxide at elevated temperature in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent such as dichloromethane , ethyl acetate or methyl acetate with peracetic acid, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare the nitrogen oxides of the compounds of the invention.

Formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), ( The compound represented by IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) may exist in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or with the mammal being treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, but may be used for the preparation and/or purification 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 the separation of formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa- 5), an intermediate of an enantiomer of the compound represented by (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5).

The pharmaceutically acceptable salts of this invention can be synthesized from the parent compound, a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg or K hydroxides, carbonates, bicarbonates, etc.), or by They are prepared by reacting the free base forms of these compounds with stoichiometric amounts of the appropriate acid. Such reactions are usually carried out in water or organic solvents or a mixture of both. Generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile will be required where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use )", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) can find some other list of suitable salts.

Any structural formulas given herein are also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the present invention relates to the preparation of formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5) , (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or intermediates of compounds represented by (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 includes a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or a combination thereof. In another embodiment, the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.

DESCRIPTION OF THE COMPOUNDS OF THE INVENTION

The pyridyl octahydropyrrolo[3,4-c]pyrrole derivatives involved in the present invention, their pharmaceutically acceptable salts, pharmaceutical preparations and compositions thereof, can be used to activate 5-HT _1F receptors and inhibit neurons Protein extravasation, with potential use in the treatment of diseases associated with 5-HT _1F receptors, especially migraine. The present invention further describes methods of synthesizing said compounds. The compounds of the present invention exhibit good biological activity.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvate of a compound represented by formula (I) , metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and L has the meanings 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, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, Wherein, R ¹ is optionally substituted by 1, 2, 3, 4 or 5 groups selected from R ^1a , R ^1b , R ^1c , R ^1d and R ^1e ; wherein, R ^1a , R ^1b , R ^1c , R ^1d and R ^1e have the meanings described in the present invention.

In one embodiment, R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are each independently 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), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, hydroxy substituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocyclic group, C ₆ -C ₁₀ aryl group or 5-10 membered heteroaryl group.

In one embodiment, R ² is H, D, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy or hydroxy substituted C ₁ -C ₆ alkyl.

In one embodiment, R ³ , R ⁴ and R ⁵ are each independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, C ₁ -C ₆ alkane radical, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ alkyl substituted by hydroxy.

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), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, hydroxy-substituted C ₁ -C ₆ alkyl, 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, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C 6 ₆ haloalkoxy or hydroxy substituted C ₁ -C ₆ alkyl.

In one embodiment, R ¹ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, Wherein, R ¹ is optionally substituted by 1, 2, 3, 4 or 5 groups selected from R ^1a , R ^1b , R ^1c , R ^1d and R ^1e ; wherein, R ^1a , R ^1b , R ^1c , R ^1d and R ^1e have the meanings described in the present invention.

^In another embodiment, R is phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazole Base, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl, wherein R is optionally ¹ , 2, 3, 4 or 5 selected from R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are substituted by groups; wherein, R ^1a , R ^1b , R ^1c , R ^1d and R ^1e have the meanings described in the present invention.

In one embodiment, R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are each independently 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), C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylamino, hydroxy substituted C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocyclic group, C ₆ -C ₁₀ aryl group or 5-10 membered heteroaryl group.

In another embodiment, R ^1a , R ^1b , R ^1c , R ^1d , and R ^1e are each independently 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, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazole base, indolyl or quinolinyl.

In one embodiment, R ² is H, D, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or hydroxy substituted C ₁ -C ₄ alkyl.

^In another embodiment, R2 is H, D, methyl, ethyl, n- _propyl , isopropyl, _-CF3 or _-CH2CF3 .

In one embodiment, R ³ , R ⁴ and R ⁵ are each independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, C ₁ -C ₄ alkane radical, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or C ₁ -C ₄ alkyl substituted by hydroxy.

In another embodiment, R ³ , R ⁴ and R ⁵ are each independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, methyl, ethyl , n- _propyl , isopropyl, _-CF3 , _-CH2CF3 , methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R ⁷ is H, D, F, Cl, Br, I, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C 4 ₄ haloalkoxy or hydroxy substituted C ₁ -C ₄ alkyl.

In another embodiment, ^R7 is H, D, F, Cl, Br, I, methyl, ethyl, n- _propyl , isopropyl, _-CF3 , _-CH2CF3 , 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), C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl, hydroxy-substituted C ₁ -C ₄ alkyl, 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 Base, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, tri Azazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (IIa), or a stereoisomer, tautomer, nitrogen oxide, or hydrate of a compound represented by formula (IIa) , solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In some embodiments, the present invention relates to a compound, which is a compound represented by formula (IIb), or a stereoisomer, tautomer, nitrogen oxide, or hydrate of a compound represented by formula (IIb) , solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In other embodiments, the present invention relates to a compound, which is a compound represented by formula (IIIa-1), or a stereoisomer, tautomer, nitrogen Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In other embodiments, the present invention relates to a compound, which is a compound represented by formula (IIIa-2), or a stereoisomer, tautomer, nitrogen Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ^1b , R ^1c , R ^1d , R ^1e , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In other embodiments, the present invention relates to a compound, which is a compound represented by formula (IIIa-3), or a stereoisomer, tautomer, nitrogen Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ^1a , R ^1c , R ^1d , R ^1e , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In other embodiments, the present invention relates to a compound, which is a compound represented by formula (IIIa-4), or a stereoisomer, tautomer, nitrogen Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ^1a , R ^1b , R ^1d , R ^1e , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In other embodiments, the present invention relates to a compound, which is a compound represented by formula (IIIa-5), or a stereoisomer, tautomer, nitrogen Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ^1b , R ^1c , R ^1d , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In some other embodiments, the present invention relates to a compound, which is a compound represented by formula (IIIb-1), or a stereoisomer, a tautomer, a nitrogen compound represented by formula (IIIb-1) Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In some other embodiments, the present invention relates to a compound, which is a compound represented by formula (IIIb-2), or a stereoisomer, a tautomer, a nitrogen compound represented by formula (IIIb-2) Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ^1b , R ^1c , R ^1d , R ^1e , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In some other embodiments, the present invention relates to a compound, which is a compound represented by formula (IIIb-3), or a stereoisomer, a tautomer, a nitrogen compound represented by formula (IIIb-3) Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ^1a , R ^1c , R ^1d , R ^1e , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In some other embodiments, the present invention relates to a compound, which is a compound represented by formula (IIIb-4), or a stereoisomer, a tautomer, a nitrogen compound represented by formula (IIIb-4) Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ^1a , R ^1b , R ^1d , R ^1e , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In some other embodiments, the present invention relates to a compound, which is a compound represented by formula (IIIb-5), or a stereoisomer, tautomer, nitrogen Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Wherein, each of R ^1b , R ^1c , R ^1d , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meanings described in the present invention.

In one embodiment, the compound described in the present invention is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvent of a compound having one of the following structures compounds, metabolites, pharmaceutically acceptable salts or its prodrugs, but by no means limited to:

In another aspect, the present invention relates to a pharmaceutical composition comprising the formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa) disclosed in the present invention -3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) compounds.

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 present invention relates to formulas (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa) disclosed in the present invention -5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) compounds or pharmaceutical compositions thereof in the preparation of medicines, the The medicine is used for preventing, treating or alleviating diseases related to 5-HT _1F receptors.

In one embodiment, the disease associated with 5-HT _1F receptors 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 disturbance, post-traumatic syndrome, chronic fatigue syndrome, premenstrual or postluteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder , ADHD, alcoholism, tobacco abuse, mutism, trichotillomania, hyperphagia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss, or dementia.

In another embodiment, the disease associated with 5-HT _1F receptor is migraine.

In yet another aspect, the present invention relates to formulas (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa) disclosed in the present invention -5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) compounds or pharmaceutical compositions thereof in the preparation of medicines, the Drugs used to activate 5-HT _1F receptors.

In another aspect, the present invention relates to formulas (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) compound shown in the preparation, isolation and purification methods.

Pharmaceutical Compositions, Formulations and Administration of Compounds of the Invention

The present invention provides a pharmaceutical composition, comprising formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa- 5), the compound shown in (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) or its individual stereoisomers, and the racemization of isomers or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and/or prophylactic ingredients.

The dosage form for administration of the compounds used in the methods of the invention will be determined by the particular compound selected, the desired pharmacokinetic profile by the route of administration, and the condition of the patient.

Formulations suitable for oral, sublingual, intranasal or parenteral administration are prepared according to methods well known in the art of pharmacy and contain at least one active compound. See, eg, REMINGTON'S PHARMACEUTICAL SCIENCES (16thed. 1980).

In general, the formulations of the present invention comprise the active ingredient (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) compounds), and usually mixed with excipients, A formulation is diluted or enclosed in a carrier which may be in the form of a capsule, sachet, paper or other container. When the excipient acts as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the formulation can be a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), containing, for example, up to 10 % by weight of active compound in ointments, soft and hard capsules, gels, suppositories, sterile injectable solutions and sterile encapsulated powders.

In preparation of a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it is usually ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is adjusted by milling to provide a uniform particle size distribution in the formulation, eg, about 40 mesh. In one embodiment of the invention, the particle size is about 0.1-100 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, Philadelphia; 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.

The "pharmaceutically acceptable excipient" used in the present invention means a pharmaceutically acceptable material, mixture or vehicle related to the consistency of the administered dosage form or pharmaceutical composition. 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 compounds disclosed in this invention when administered to a patient and would result in a pharmaceutical composition that is not pharmaceutically acceptable Interaction. Furthermore, each excipient must be pharmaceutically acceptable, eg, of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected according to their specific function in the composition. For example, certain pharmaceutically acceptable excipients can be selected to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients can be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients can be selected to aid in the carrying or transport of the compounds of the invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients can be selected to enhance patient compliance.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, Polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. Suitable pharmaceutically acceptable excipients also include excipients of the following types: diluents, fillers, binders, disintegrants, lubricants (such as talc, magnesium stearate, and mineral oil), auxiliary Flow agent, granulating agent, coating agent, wetting agent, solvent, co-solvent, suspending agent, emulsifier, sweetener, flavoring agent, taste masking agent, coloring agent, anti-caking agent, humectant, Chelating agents, plasticizers, tackifiers, antioxidants, preservatives (such as methylparaben and propylparaben), stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may serve more than one function, and may serve alternative functions, depending on how much of that excipient and which other excipients are present in the formulation. agent. 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 using methods known in the art.

The skilled artisan possesses the knowledge and skill in the art to enable them to select appropriate pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. Furthermore, there are numerous resources available to the skilled artisan which describe pharmaceutically acceptable excipients and are useful in selecting 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 preparing pharmaceutical compositions from the compounds described by this invention, pharmaceutically acceptable carriers can be either solid or liquid carriers. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may contain from about 5 to about 95% active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 ^ed ., 1990, Mack Publishing Company Co., Easton, Pennsylvania.

Disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York Various carriers for formulating pharmaceutically acceptable compositions, and known techniques for their preparation, the contents of each of these documents are incorporated herein by reference. Concern about the use of any carrier other than any conventionally used carrier that is incompatible with the compounds of the present invention, such as producing any undesired biological effects, or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, falls within the scope of this invention. the scope of the invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Descriptions of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Therefore, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition, said pharmaceutical composition comprising a compound disclosed in the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof, the process comprising Mix the various ingredients. Pharmaceutical compositions comprising compounds disclosed herein can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in dosage forms suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, 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, such as suppository; (5) inhalation, such as aerosol, solution and dry powder; and (6) topical administration, such as cream, ointment, lotion, solution, paste , sprays, foams and gels.

It will also be recognized that some of the compounds of the invention may exist in free form for use in therapy or, if appropriate, as a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or the ability to directly or indirectly provide the present invention when administered to a patient in need thereof. Any additional adducts or derivatives of the compound or its metabolites or residues.

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

For transdermal administration, a transdermal delivery device ("patch") is required. Such transdermal patches may be used for continuous or discontinuous infusion of controlled amounts of the compounds of the invention. The construction and use of transdermal patches for drug delivery is well known in the art. See, eg, US 5,023,252. The patches are available in continuous, pulsatile, or demand-release medications.

Often it is desirable or necessary to introduce a pharmaceutical composition directly or indirectly into the brain. Direct techniques generally involve placing a drug delivery catheter in the host's ventricular system to bypass the blood-brain barrier. Such an implantable delivery system for delivering biological agents to specific anatomical regions of the body is described in US 5,011,472. Delivery of hydrophilic drugs can be enhanced by intra-arterial infusion of hypertonic solutions that transiently open the blood-brain barrier.

In a preferred embodiment of the present invention there are provided pharmaceutical formulations containing at least one active compound as described above and suitable for buccal and/or sublingual or nasal administration. This embodiment provides for administering the active compound in a manner that avoids gastric complications (eg, bypasses gastric systemic metabolism first and/or undergoes hepatic metabolism first). This route of administration also reduces adsorption time, resulting in a faster therapeutic effect. The compounds of the present invention may also provide a particularly advantageous solubility profile, which facilitates sublingual/buccal formulations. Such formulations generally require a relatively high concentration of active ingredient in order to deliver sufficient active ingredient to the limited surface of the sublingual/buccal mucosa for the short duration of time the formulation is in contact with the sublingual/buccal mucosal surface so that the active Components are absorbed. Therefore, the very high activity of the compounds of the invention and their high solubility make them suitable for the preparation of sublingual/buccal formulations.

As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, administering or bringing into equilibrium an amount sufficient to treat, cure or alleviate the symptoms of a disease. The effective amount required for a particular treatment regimen will depend on a variety of factors, including the disease being treated, the severity of the disease, the activity of the specific drug being used, the mode of administration, the clearance of the specific drug, duration of treatment, concomitant drugs, age , weight, sex, diet and patient's health, etc. A description in the art of other factors to be considered for a "therapeutically effective amount" can be found in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8 ^th ed., Pergamon Press, 1990; Remington's Pharmaceutical Sciences, 17 ^th ed., Mack Publishing Company, Easton, Pa., 1990.

The compounds of formula I are preferably formulated in unit dosage form, each dose containing about 0.001-100 mg active ingredient, more usually about 1.0-30 mg active ingredient. The term "unit dosage form" means physically discrete units suitable as unitary dosages for human patients 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. agent.

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

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

The preferred route of administration will vary with the clinical features, and the dosage must be varied depending on the condition of the patient being treated, and the physician will determine the appropriate dosage according to the individual patient. The therapeutically effective amount per unit dose will depend on body weight, physiology and the chosen vaccination regimen. Compound per unit dose refers to the weight of compound per administration, excluding the weight of carrier (which is included in the drug).

The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration. The single-dose formulations are packaged in ampoules, vials or syringes. Such multiple dose parenteral formulations must contain the antimicrobial agent in bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

The pharmaceutical compositions provided herein can be 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 method of treatment of the present invention comprises 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 include treating 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 ocular, 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 present invention or a pharmaceutical composition comprising a compound of the present invention may be administered at one time, or several times at different time intervals within a specified period of time according to the dosing regimen. For example, once, twice, three or four times per day. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. Administration can be until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. A suitable dosing regimen for a compound of the invention or a pharmaceutical composition comprising a compound of the invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled artisan. Furthermore, suitable dosing regimens for the compounds of the invention or pharmaceutical compositions comprising the compounds of the invention, including the duration for which the regimen is carried out, depend on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated , the medical history of the patient being treated, the nature of the concomitant therapy, the desired therapeutic effect, etc. factors within the knowledge and experience of the skilled person. Such skilled artisans will also understand that the response of an individual patient to the dosing regimen, or as the individual patient's needs change over time, may require adjustment of the appropriate dosing regimen.

A compound of the invention may be administered simultaneously with, or preceded or followed by, one or more other therapeutic agents. The compound of the present invention can be administered separately with other therapeutic agents by the same or different routes of administration, or in the form of the same pharmaceutical composition. This is selected by those skilled in the art according to the actual conditions of the patient's health, age, weight and other physical conditions. If formulated as a fixed dose, such combination products employ a compound of the invention (within the dosage range described herein) and the other pharmaceutically active agent (within its dosage range).

Accordingly, in one aspect, the present invention includes combinations comprising a certain amount of at least one compound of the present invention or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof and an effective amount of one or more of the above-mentioned Additional treatments.

In addition, the compounds of the present invention may be administered in prodrug form. In the present invention, the "prodrug" of the compound of the present invention is a functional derivative that can finally release the compound of the present invention in vivo when administered to a patient. When administering the compound of the present invention in the form of a prodrug, those skilled in the art can implement one or more of the following methods: (a) change the in vivo onset time of the compound; (b) change the in vivo action duration of the compound; (c) change 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 compound. Typical functional derivatives used to prepare prodrugs include variants of the compound that are chemically or enzymatically cleaved in vivo. These variations, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

Uses of the compounds and pharmaceutical compositions of the present invention

The compounds and pharmaceutical compositions provided by the present invention can be used to prepare medicines for activating 5-HT _1F receptors, and can also be used to prepare drugs for preventing, treating or alleviating diseases related to 5-HT _1F receptors, especially partial Medicines for headaches.

In particular, the compound of the invention or the amount of the compound in the pharmaceutical composition is effective to detectably and selectively activate the 5-HT _1F receptor.

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

The compounds of the present invention can be used, but not limited to, to prevent, treat or alleviate diseases related to 5-HT _1F receptors by administering an effective amount of the compounds or pharmaceutical compositions of the present invention to patients. The diseases associated with 5-HT _1F receptors further include, but are not limited to, migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression social phobia, anxiety, generalized anxiety disorder, sleep disturbance, post-traumatic syndrome, chronic fatigue syndrome, premenstrual or postluteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder , ADHD, alcoholism, tobacco abuse, mutism, trichotillomania, hyperphagia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss, and dementia.

In addition to being useful in human therapy, the compounds and pharmaceutical compositions of the present invention are also useful in the veterinary treatment of mammals in pets, imported breeds and farm animals. Examples of additional animals include horses, dogs and cats. Here, the compounds of the present invention include their pharmaceutically acceptable derivatives.

General Synthetic Procedure

In order to describe the present invention, examples are listed below. However, it should be understood that the present invention is not limited to these examples, but only provides a method of practicing the present invention.

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless there are further instructions, wherein the substituents are defined as 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) as shown. The following reaction schemes and examples serve to further illustrate the present invention.

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

In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory can be purchased.

Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by reflux drying over sodium metal. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

The following reactions were generally carried out under a positive pressure of nitrogen or argon or over anhydrous solvents with a dry tube (unless otherwise indicated), the reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.

¹ H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. ¹ H NMR spectrum uses CDC1 ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as the solvent (in ppm), and TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, Multiplet), br (broadened, broad peak), brs (broadened singlet, broad singlet), dd (doublet of doublets, double doublet), ddd (doublet of doublet of doublets, double double doublet), dt ( doublet of triplets, doublet of triplets), td (triplet of doublets, triplet of doublets), tt (triplet of triplets, triplet of triplets). Coupling constant J expressed in Hertz (Hz).

The measurement conditions of low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1x 30mm, 3.5 microns, 6min, flow rate is 0.6mL/min. Mobile phase: 5 %-95% (CH ₃ CN with 0.1% formic acid) in (H ₂ O with 0.1% formic acid) by electrospray ionization (ESI) at 210 nm/254 nm 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 abbreviations are used throughout this disclosure:

CH ₂ Cl ₂ , DCM dichloromethane mL, ml ml

CDC1 ₃ deuterated chloroform μL, μl microliter

DMSO Dimethyl Sulfoxide nL, nl Nanoliter

DMSO-d ₆ deuterated dimethyl sulfoxide min minutes

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℃)

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

Et ₃ N Triethylamine HCl Concentrated hydrochloric acid

LiOH·H ₂ O Lithium Hydroxide Monohydrate Ascortic Acid Ascorbic Acid

N ₂ Nitrogen Pargyline Pargyline

nM nanomolar PEI polyethyleneimine

μM Micromolar Serotonin Serotonin, Serotonin, 5-HT

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

Ng nanograms of EDTA-K ₂ dipotassium ethylenediaminetetraacetic acid

MG microgram Solutol macrogol-15-hydroxystearate

Mg milligram MTBE methyl tert-butyl ether

G grams PEG400 Macrogol 400

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

The following synthetic schemes describe the steps for preparing the compounds disclosed in the present invention, wherein each of R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ³ , R ⁴ and R ⁵ has the definition described herein unless otherwise stated.

Synthetic scheme 1

Wherein, X is CR ^1a or N.

The compound shown in the formula ( 6 ) can be prepared by the following process: the compound shown in the formula ( 1 ) reacts with the compound shown in the formula ( 2 ) to obtain the product shown in the formula ( 3 ); then the compound shown in the formula ( 3 ) The compound of formula ( 4 ) is hydrolyzed to obtain the product represented by formula (4); the compound represented by formula ( 4 ) is condensed with the compound represented by formula ( 5 ) to obtain the target product represented by ( 6 ).

The compounds, pharmaceutical compositions and applications provided by the present invention will be further described below in conjunction with the examples.

Example

Example 1N-(6-(5-methyl octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridin-2-yl)synthesis of benzamide

Step 1) the synthesis of methyl 6-benzamidopyridine-2-carboxylate

Methyl 6-aminopyridine-2-carboxylate (710 mg, 4.67 mmol), triethylamine (1.3 mL, 9.40 mmol) and dichloromethane (10 mL) were added to a 100 mL single-necked round bottom flask at 0 °C, Benzoyl chloride (848mg, 6.03mmol) was added dropwise, transferred to 25°C and reacted for 12 hours; after the reaction, the reaction solution was poured into water (30mL), extracted with dichloromethane (40mL), the organic phase was collected, and After being spun to dryness and separated by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), the title compound was obtained as a light yellow liquid (414 mg, 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, 2.4 Hz, 1H), 7.97–7.88 (m, 4H), 7.58 (t, J = 7.2 Hz,1H),7.51(t,J=8.0Hz,2H),4.01(s,3H).

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

Add methyl 6-benzamidopyridine-2-carboxylate (820mg, 3.20mmol), water (2mL) and methanol (10mL) into a 100mL single-necked round-bottom flask at 25°C, add monohydrate hydrogen Lithium (165mg, 3.93mmol), continue to react for 3 hours; stop the reaction, remove methanol by rotary evaporation under reduced pressure, add water (10mL), then add concentrated hydrochloric acid to adjust to pH = 2, filter, and dry the obtained solid at 60°C to obtain the title compound: White solid (620 mg, 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 = 7.6 Hz,1H),7.60(t,J=7.6Hz,1H),7.51(t,J=7.6Hz,2H).

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

Add 6-benzamidopyridine-2-carboxylic acid (243mg, 1.0mmol) and dichloromethane (10mL) into a 100mL one-necked flask at 0°C, add N,N-diisopropylethylamine (194mg, 1.5mmol) and HATU (600mg, 1.5mmol), continue to react for half an hour under nitrogen protection; then add 2-methyloctahydropyrrolo[3,4-c]pyrrole (190mg, 1.51mmol), transfer to 25°C React for 3 hours; stop the reaction, add water (20mL), then extract with dichloromethane (30mL×2), collect the organic phase, add anhydrous sodium sulfate (1g) to dry, filter, the filtrate is spin-dried under reduced pressure, column chromatography Purification (dichloromethane/methanol (v/v)=40/1) gave the title compound as a light yellow solid (94 mg, 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-carboxylate

The title compound of this step was prepared by referring to the method described in step 1 of Example 1, that is, 6-aminopyridine-2-carboxylate (200mg, 1.31mmol), triethylamine (0.3mL, 2.0mmol) and 4- Fluorobenzoyl chloride (0.25mL, 2.12mmol) was prepared by reaction in dichloromethane (10mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title The compound was a white solid (350 mg, 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, 2.4 Hz, 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-carboxylic acid

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, methyl 6-(4-fluorobenzamido)pyridine-2-carboxylate (340mg, 1.24mmol), hydrogen monohydrate Lithium oxide (55 mg, 1.31 mmol) was prepared by reacting methanol (10 mL) and water (2 mL) to give the title compound as a white solid (279 mg, 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 Amine Synthesis

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, 6-(4-fluorobenzamido)pyridine-2-carboxylic acid (180mg, 0.69mmol), N,N-diisopropyl Reaction of ethylethylamine (0.18mL, 1.09mmol), HATU (420mg, 1.1mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (135mg, 1.07mmol) in dichloromethane (10mL) Preparation, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to obtain the title compound as a pale yellow solid (62 mg, 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=7.2 Hz,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-chlorobenzamido)pyridine-2-carboxylate

The title compound of this step was prepared by referring to the method described in step 1 of Example 1, that is, 6-aminopyridine-2-carboxylate (200mg, 1.31mmol), triethylamine (0.3mL, 2.0mmol) and 4- Chlorobenzoyl chloride (0.25mL, 1.96mmol) was prepared by reaction in dichloromethane (10mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title The compound was 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, 2.8 Hz, 1H), 7.93–7.85 (m, 4H), 7.48 (d, J = 8.8 Hz,2H),4.00(s,3H).

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

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, methyl 6-(4-chlorobenzamido)pyridine-2-carboxylate (362mg, 1.25mmol), hydrogen monohydrate Lithium oxide (55 mg, 1.31 mmol) was prepared by reacting methanol (10 mL) and water (2 mL) to give the title compound as a white solid (228 mg, 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 = 7.6 Hz,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 Amine Synthesis

The title compound of this step was prepared by referring to the method described in Step 3 of Example 1, that is, 6-(4-chlorobenzamido)pyridine-2-carboxylic acid (200mg, 0.72mmol), N,N-diisopropylethyl Prepared by reacting amine (0.18mL, 1.09mmol), HATU (420mg, 1.1mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (140mg, 1.11mmol) in dichloromethane (10mL), The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to obtain the title compound as a pale yellow solid (130 mg, 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-bromobenzamido)pyridine-2-carboxylate

The title compound of this step was prepared by referring to the method described in step 1 of Example 1, that is, 6-aminopyridine-2-carboxylate (300mg, 1.97mmol), triethylamine (0.3mL, 2.0mmol) and 4- Bromobenzoyl chloride (660mg, 3.0mmol) was prepared by reaction in dichloromethane (10mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound As a white solid (609 mg, 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, 2.4 Hz, 1H), 7.92–7.88 (m, 2H), 7.82 (d, J = 8.8 Hz,2H),7.64(d,J=8.4Hz,2H),3.99(s,3H).

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

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, methyl 6-(4-bromobenzamido)pyridine-2-carboxylate (600mg, 1.79mmol), hydrogen monohydrate Lithium oxide (75 mg, 1.79 mmol) was prepared by reacting methanol (10 mL) and water (2 mL) to give the title compound as a white solid (510 mg, 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 Amine Synthesis

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, 6-(4-bromobenzamido)pyridine-2-carboxylic acid (200mg, 0.63mmol), N,N-diisopropyl Diethylethylamine (0.16mL, 0.97mmol), HATU (350mg, 0.92mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (120mg, 0.95mmol) were reacted in dichloromethane (10mL) Preparation, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to obtain the title compound as a pale yellow solid (130 mg, 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-difluorobenzamido)pyridine-2-carboxylate

The title compound of this step was prepared by referring to the method described in step 1 of Example 1, that is, 6-aminopyridine-2-carboxylate (500mg, 3.29mmol), triethylamine (0.9mL, 6.0mmol) and 2, 4-Difluorobenzoyl chloride (550mg, 3.12mmol) was prepared by reaction in dichloromethane (10mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), The title compound was obtained as a white solid (654 mg, 71.8%).

MS(ESI,pos.ion)m/z:293.2[M+H] ⁺ ;

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

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

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, methyl 6-(2,4-difluorobenzamido)pyridine-2-carboxylate (340mg, 1.24mmol), Lithium hydroxide monohydrate (55 mg, 1.31 mmol) was prepared by reacting methanol (10 mL) and water (2 mL) to give the title compound as a white solid (278 mg, 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

The title compound of this step was prepared by referring to the method described in Step 3 of Example 1, that is, 6-(2,4-difluorobenzamido)pyridine-2-carboxylic acid (290mg, 1.04mmol), N,N- Diisopropylethylamine (0.26mL, 1.57mmol), HATU (600mg, 1.58mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (300mg, 2.38mmol) in dichloromethane (10mL ), the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to obtain the title compound as a pale yellow solid (184 mg, 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).

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

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

The title compound of this step was prepared by referring to the method described in Step 1 of Example 1, that is, 6-aminopyridine-2-carboxylate (400mg, 2.63mmol), triethylamine (0.9mL, 6.0mmol) and 4- Chloro-2-fluorobenzoyl chloride (500mg, 2.59mmol) was prepared by reaction in dichloromethane (10mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) , the title compound was obtained as a white solid (632 mg, 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-carboxylic acid

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, methyl 6-(4-chloro-2-fluorobenzamido)pyridine-2-carboxylate (309mg, 1.0mmol) , prepared by reacting lithium hydroxide monohydrate (45 mg, 1.1 mmol) in methanol (10 mL) and water (2 mL) to give the title compound as a white solid (168 mg, 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)benzene Synthesis of formamide

The title compound of this step was prepared by referring to the method described in Step 3 of Example 1, that is, 6-(4-chloro-2-fluorobenzamido)pyridine-2-carboxylic acid (180mg, 0.61mmol), N,N -Diisopropylethylamine (0.15mL, 0.91mmol), HATU (350mg, 0.92mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (120mg, 0.95mmol) in dichloromethane ( 10 mL), the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to obtain the title compound as a pale yellow solid (98 mg, 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-methyl octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridin-2-yl)benzamide

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

The title compound of this step was prepared by referring to the method described in step 1 of Example 1, that is, 6-aminopyridine-2-carboxylate (450mg, 2.96mmol), triethylamine (0.9mL, 6.0mmol) and 2, 4,6-Trifluorobenzoyl chloride (530mg, 2.72mmol) was prepared by reaction in dichloromethane (10mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) Purification afforded the title compound as a light yellow oil (374 mg, 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 of this step was prepared by referring to the method described in step 2 of Example 1, that is, methyl 6-(2,4,6-trifluorobenzamido)pyridine-2-carboxylate (178mg, 0.57mmol ), lithium hydroxide monohydrate (25mg, 0.6mmol) was prepared by reacting methanol (5mL) and water (1mL) 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 of this step was prepared by referring to the method described in Step 3 of Example 1, that is, 6-(2,4,6-trifluorobenzamido)pyridine-2-carboxylic acid (160mg, 0.54mmol), N,N- Diisopropylethylamine (0.15mL, 0.91mmol), HATU (350mg, 0.92mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (120mg, 0.95mmol) in dichloromethane (10mL ), the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to obtain the title compound as a pale yellow solid (110 mg, 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 by referring to the method described in step 1 of Example 1, that is, 6-aminopyridine-2-carboxylate (600mg, 3.94mmol), triethylamine (1.0mL, 7.2mmol) and 5- Fluoropyridine-2-carbonyl chloride (600mg, 3.76mmol) was prepared by reaction in dichloromethane (10mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), The title compound was obtained as a pale yellow solid (760 mg, 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, 4.5 Hz, 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-formylamino)pyridine-2-carboxylic acid

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, methyl 6-(5-fluoropyridine-2-carboxamido)pyridine-2-carboxylate (370mg, 1.34mmol), Lithium hydroxide monohydrate (60 mg, 1.43 mmol) was prepared by reacting methanol (10 mL) and water (2 mL) to give the title compound as a white solid (313 mg, 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 of this step was prepared by referring to the method described in step 3 of Example 1, that is, 6-(5-fluoropyridine-2-carboxamido)pyridine-2-carboxylic acid (106mg, 0.41mmol), N,N-diiso Propylethylamine (0.11 mL, 0.67 mmol), HATU (250 mg, 0.66 mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (75 mg, 0.59 mmol) in dichloromethane (10 mL) The reaction was prepared, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to obtain the title compound as a white solid (57 mg, 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

The title compound of this step was prepared by referring to the method described in Step 1 of Example 1, that is, 6-aminopyridine-2-carboxylate (450mg, 2.96mmol), triethylamine (0.9mL, 6.0mmol) and 5- Chloropyridine-2-carbonyl chloride (500mg, 2.84mmol) was prepared by reaction in dichloromethane (10mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1), The title compound was obtained as a pale yellow solid (496 mg, 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

The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, methyl 6-(5-chloropyridine-2-carboxamido)pyridine-2-carboxylate (490mg, 1.68mmol), Lithium hydroxide monohydrate (84 mg, 2.0 mmol) was prepared by reacting methanol (10 mL) and water (2 mL) to give the title compound as a white solid (379 mg, 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 of this step was prepared by referring to the method described in Step 3 of Example 1, that is, 6-(5-chloropyridine-2-carboxamido)pyridine-2-carboxylic acid (198mg, 0.71mmol), N,N- Diisopropylethylamine (0.17mL, 1.03mmol), HATU (410mg, 1.08mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (140mg, 1.11mmol) in dichloromethane (10mL ), the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to obtain the title compound as a white solid (110 mg, 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 test

Example A: Non-selective Rat 5-HT ₁ Receptor Radioligand Affinity Experiment

experimental method

Cell membranes were prepared from the cerebral cortex of 175±25 g male Wistar rats, and placed in Tris-HCl buffer solution with pH=7.4. At 25°C, incubate 15 mg of cell membrane samples with 1 nM [ ³ H]-5-HT in buffer (50 mM Tris-HCl (pH=7.4), 0.1% Ascortic Acid, 10 μM Pargyline, 4 mM CaCl ₂ ) for 60 minutes , under this condition, the test compound was added to complete the radioligand binding experiment.

Test compounds were dissolved in 100% DMSO and tested at 6 concentrations (0.1 nM, 1 nM, 10 nM, 100 nM, 1 μM, 10 μM), and non-specific binding values were determined using 10 μM 5-HT.

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

Experimental results are expressed as percent inhibition of radioligand-specific binding relative to control wells.

The standard reference compound is 5-HT, and the inhibition rate is calculated by testing the data of 5-HT at a series concentration (inhibition rate=100-(affinity result of the sample well/affinity result of the control well)*100), and the concentration- Inhibition rate competition curve, so as to calculate IC ₅₀ .

The results are shown in Table A.

Table A: The results of the compound of the present invention to the rat 5-HT ₁ receptor affinity experiment

Example number IC₅₀(μM) Example 5 6.98

Experimental results show that the compound of the present invention has higher affinity to rat 5-HT ₁ receptors.

Example B: 5-HT _1F Receptor Ca ²⁺ Mobility Assay Method

experimental method

(1) Transient experiment

HEK293 cells grown to 90% were seeded in 6-well plates at a density of 1.5×10^6 cells/well and cultured overnight in a 37°C, 5% CO ₂ incubator, using human 5-HT _1F and Ga15 plasmids together HEK293 cells were transfected and incubated at 37°C, 5% CO ₂ for 24 hours.

(2) FLIPR experiment

HEK293 cells transfected for 24 hours were digested and seeded in 384-well plates at a density of 2×10^4 cells/well and incubated at 37° C., 5% CO ₂ for 16-20 hours. 20 μl of 2X Fluo-4Direct ^™ dye was added per well and incubated at 37°C, 5% CO ₂ for 50 minutes, room temperature for 10 minutes. Prepare a dose curve plate with different concentrations of the compound, use the FLIPR instrument to transfer the compound from the dose curve plate to the cell plate, and read the fluorescence signal immediately. The combination of Ca ²⁺ induced by different concentrations of compounds and dyes can produce fluorescent signals of different intensities. The compound dose-effect curve was calculated by Prism software, and the agonist concentration that produced the half-maximum response was expressed as the EC ₅₀ value.

Experimental results show that the compound of the present invention has strong 5-HT _1F receptor agonistic activity.

Example C: Pharmacokinetic evaluation of quantitative compound of the present invention by intravenous injection or intragastric administration of rats and dogs

The inventors evaluated the pharmacokinetics of the compound of the present invention in rats and dogs. Among them, animal information is shown in Table 1.

Table 1: Information table of the tested animals of the present invention

germline grade gender weight age source SD rat SPF male 170-250g 6-9 weeks Hunan Slack Experimental Animal Co., Ltd. beagle dog clean level male 8～10kg 6-7 weeks Hunan Slack Experimental Animal Co., Ltd.

experimental method

The compound of the present invention was administered to the test animals in the form of 5% DMSO+5% Solutol+90% normal saline solution or 5% DMSO+60% PEG400+35% normal saline solution, and the animals were fasted for 12 hours before administration. Drink water freely. For the intravenous injection group, the dosage was 1 mg/kg, and blood was taken from the vein at the following time points after administration (the blood volume was about 0.15 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and At 24 hours, EDTA-K ₂ was pre-added into the blood collection tube as an anticoagulant, and the blood sample was centrifuged at 12,000 rpm for 2 minutes to collect the plasma and store it at -20°C or -70°C. For the intragastric administration group, the administration dose was 5 mg/kg, and blood was collected from the vein at the following time points after administration (about 0.15 mL blood volume): 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours , pre-added EDTA-K ₂ as an anticoagulant into the blood collection tube, centrifuged the blood sample at 12,000rpm for 2 minutes, collected the plasma, and stored it at -20°C or -70°C. The positive control is Lasmiditan (its structure is

Process the plasma sample collected above (take 30 μL plasma, add 120 μL internal standard aqueous solution, mix well and extract with 0.9 mL MTBE, take 0.7 mL to dry and reconstitute with 220 μL methanol water (v/v=1/1)) Afterwards, the concentrations of compounds in plasma were analyzed by LC-MS/MS. The analysis results show that the compound of the present invention has good pharmacokinetic properties in rats and dogs.

Table C1: Pharmacokinetic parameters of the compounds of the present invention in rats

ND: Indicates no test data.

It can be seen from the results in Table C1 that the compound of the present invention has better pharmacokinetic properties in rats than Lasmiditan.

Table C2: Pharmacokinetic parameters of compounds of the present invention in dogs

ND: Indicates no test data.

It can be seen from the results in Table C2 that the compound of the present invention has better pharmacokinetic properties in dogs than Lasmiditan.

In the description of this specification, descriptions referring to the terms "one embodiment", "an embodiment", "some embodiments", "examples", "specific examples" or "some examples" mean that the embodiments, Embodiment or Example A specific feature, structure, material or characteristic described is included in at least one example, embodiment or example of the invention. In this specification, the schematic representations of the above terms are not necessarily referring to the same embodiment, implementation or illustration. Furthermore, the specific features, structures, materials or characteristics described may be combined in any suitable manner in any one or more of the embodiments, implementations or examples. In addition, those skilled in the art may combine and combine different embodiments, implementations or examples and features of different embodiments, implementations or examples described in this specification without conflicting with each other.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.

Claims (10)

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.