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

Abstract

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

Description

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

technical field

The present invention belongs to the technical field of medicine, and particularly relates to novel picolinoyl octahydropyrrolo[3,4-c]pyrrole derivatives and pharmaceutical compositions containing these compounds, as well as methods and uses thereof. In particular, the novel pyridinoyl octahydropyrrolo[3,4-c]pyrrole derivatives described in the present invention can be used to activate 5-HT _1F receptors for the prevention, treatment or alleviation of the interaction with 5-HT _1F receptors related diseases, especially migraine.

Background technique

Migraine is a type of episodic and often unilateral throbbing headache, often accompanied by nausea and vomiting, is a common chronic neurovascular disease, mostly in children and adolescence, the peak incidence in young and middle-aged, It is more common in women, the ratio of male to female patients is about 1:2 to 3, the prevalence rate in the population is 5% to 10%, and there is often a genetic background.

Although migraine is not a fatal disease, it can seriously affect the social life of patients. The socioeconomic burden of migraine in the United States ranges from $1.0 billion to $1.7 billion. In my country, there are also a large number of patients whose work, study and life are affected by migraine. With the accelerated 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 have an average of more than one migraine attack per year. In addition, many people have a genetic predisposition to migraine.

The pathogenesis of migraine is complex and diverse, mainly including vascular origin theory, neurogenesis theory, trigeminal neurovascular theory, biochemical factors and genetic factors. The drugs currently used to treat migraine are mainly 5-HT _1B/D receptor agonists triptans, but because triptans can constrict blood vessels, they are contraindicated in patients with cardiovascular, cerebrovascular and peripheral vascular diseases. In addition, 40% to 70% of migraine patients have poor response to triptans, and one-third of patients who respond to initial treatment often experience headache recurrence. The efficacy of triptans in patients with moderate to severe headaches significantly reduced. To overcome these adverse effects of triptans, calcitonin gene-related peptide (CGRP) receptor antagonists and selective 5-HT _1F receptor agonist anti-migraine drugs have emerged. However, CGRP receptor antagonists still have many defects. For example, olcagepant can only be used intravenously instead of orally. Long-term use of telcagepant can cause liver enzymes to increase. BI-44370 has been discontinued due to its interaction with cytochrome P450. development. Therefore, there is an urgent need to develop new acute-phase therapeutic drugs. The development of selective 5-HT _1F receptor agonist anti-migraine drugs has always been considered a new promising approach.

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

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

SUMMARY OF THE INVENTION

The present invention provides a class of novel pyridinoyl octahydropyrrolo[3,4-c]pyrrole derivatives as 5-HT _1F receptor agonists with different chemical and receptor binding properties that can be used to activate The 5-HT _1F receptor inhibits the extravasation of neuronal proteins while avoiding significant vasoconstrictor activity, and therefore, can be used for the treatment of diseases mediated by the 5-HT _1F receptor, especially for the treatment of migraine. And through experiments, it is found that the picolinyl octahydropyrrolo[3,4-c]pyrrole derivatives of the present invention have stable properties, good safety, 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 clinical application prospects. In addition, the compounds of the present invention are well soluble and thus highly adaptable in preferred formulations such as sublingual, buccal and/or intranasal formulations.

The present invention also provides methods for preparing such compounds, pharmaceutical compositions containing such compounds, and the use of such compounds and pharmaceutical compositions comprising such compounds 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 the compound represented by formula (I). , a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

in:

L is -C(=O)-, -C(=S)- or -S(=O) ₂ -;

R ¹ is a C ₁ -C ₄ alkyl group, a C ₃ -C ₆ cycloalkyl group, a 3-6-membered heterocyclic group, a C ₆ -C ₁₀ -membered aryl group or a 5-10-membered heteroaryl group, wherein R ¹ is optional is substituted with 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 _4alkoxy ), 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 heterocyclyl, _C6 - _C10 aryl or 5-10 membered heteroaryl;

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

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 hydroxy Substituted C ₁ -C ₄ alkyl.

In some embodiments, R ¹ is phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl , pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl, wherein R1 is optionally selected by ¹ , 2, 3, 4 or 5 from ^R1a , R ^1b , R ^1c , R ^1d and R ^1e are substituted;

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 of formula (IIIa-1) or formula (IIIa-2), or a compound of formula (IIIa-1) or formula (IIIa-2) the stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug 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 meaning as described in the present invention.

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

R ³ , R ⁴ and R ⁵ are each independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, methyl, ethyl, n-propyl, isopropyl group, -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 compositions of the present invention further comprise pharmaceutically acceptable excipients, carriers, adjuvants or any combination thereof.

In yet another aspect, the present invention relates to the use of the compounds of formula (I), (IIIa-1) or (IIIa-2) disclosed in the present invention or their pharmaceutical compositions in the preparation of medicaments for prevention and treatment Or alleviate diseases related to 5-HT _1F receptors.

In some embodiments, the disease associated with the 5-HT _1F receptor is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression disorder, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder , ADHD, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss, or dementia.

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

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I), (IIIa-1) or (IIIa-2).

The biological test results show that the compounds of the present invention can activate 5-HT _1F receptors, inhibit the extravasation of neuronal proteins, and can be used as better 5-HT _1F receptor agonists.

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

The foregoing has outlined only certain aspects of the invention, but is not limited to these aspects. These and other aspects are described in more detail 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 will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention as defined by the claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein 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, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of multiple separate embodiments, can 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, can also be provided separately or in any suitable subcombination.

Unless otherwise stated, the following definitions used herein shall apply. For the purposes of the present invention, chemical elements are in accordance with the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry may be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, Its entire contents 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 stated otherwise or otherwise clearly contradicted by context. Thus, as used herein, these articles 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 for use or use in the implementation of the described embodiments.

The term "stereoisomers" refers to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups 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 with its mirror image; whereas an "achiral molecule" refers to a molecule that is superimposable with its mirror image.

The term "enantiomer" refers to two nonsuperimposable, but mirror-image isomers of a compound.

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

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

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, that is, 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 about one or more of its chiral centers. The prefixes d and 1 or (+) and (-) are symbols used to designate the rotation of plane polarized light by the 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, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched forms, such as (R)-, (S)- or (R,S)-configurations 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 70% enantiomeric excess in the (R)- or (S)-configuration 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 may be present as one of the possible isomers or as mixtures thereof, such as racemates and diastereoisomeric mixtures (depending on the number of asymmetric carbon atoms) ) in the form of. 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, the cycloalkyl substituent may have the cis or trans configuration.

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

Any resulting racemate of the final product or intermediate can be resolved into the optical enantiomers by known methods by methods familiar to those skilled in the art, eg, by performing diastereomeric salts thereof obtained. separation. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see 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, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of NotreDame 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 of different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, protontautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.

"Pharmaceutically acceptable" means compounds, materials, compositions, and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergy, or compatibility with reasonable The benefit/risk ratio is symmetric with other problems and complications and is effective for the intended use.

The term "optionally substituted by" is used interchangeably with the term "unsubstituted or substituted by", ie the structure is unsubstituted or substituted by one or more of the present invention Substituents in the present invention include, but are not limited to, D, F, Cl, Br, I, N ₃ , -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -CONH ₂ , -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 with a specified substituent. Unless otherwise indicated, a substituent may be substituted at each reasonable position in the group that is substitutable. When more than one position in a given formula can be substituted by one or more specific substituents selected from the group, the substituents may be substituted identically or differently at each reasonable position in the formula.

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

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. A subject, for example, also refers to primates (eg, 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 humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

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

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " _{C1 - C6} alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, _C4 alkyl, _C5 alkyl and _C6 alkyl groups.

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

The term "D" represents a single deuterium atom.

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

The term "alkyl" or "alkyl group" used in the present invention refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1-20 carbon atoms, wherein the alkyl group can be optionally is substituted with one or more 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, _-CH3 ), ethyl (Et, -CH2CH3), n _{- propyl} (n _- Pr, _{-CH2CH2CH3 )} ), 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 ) ( _CH3 ) ₂ ), sec-butyl (s-Bu, -CH( _CH3 ) _CH2CH3 ), tert-butyl (t-Bu, -C( _{CH3 )3 )} , and the like.

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., 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" positions, or the "E" and "Z" positions. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, and the like.

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

The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, 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 The group contains 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-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), etc.

The term "alkylthio" means that an alkyl group is attached to the remainder of the molecule through a sulfur atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylthio group contains 1-12 carbon atoms. In one embodiment, the alkylthio group contains 1-6 carbon atoms; in another embodiment, the alkylthio group contains 1-4 carbon atoms; in yet another embodiment, the alkylthio group The group contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described 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 group is independently substituted with one or two alkyl groups, respectively, where the alkyl group has the meaning as defined in the present invention. Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N -Diethylamino, etc. The alkylamino group is optionally substituted with one or more substituents described herein.

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

The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, _-CF3 , -CH ₂ CF ₃ , -CHFCH ₃ , -CH ₂ CH ₂ F, -CF ₂ CH ₃ and the like. In one embodiment, C ₁ -C ₆ haloalkyl comprises fluorine substituted C ₁ -C ₆ 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 group comprises a fluorine substituted C ₁ -C ₂ alkyl group.

The term "haloalkoxy" means that an alkoxy group is substituted with one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, 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 fluoro substituted C ₁ -C ₆ alkoxy; in another embodiment, C ₁ -C ₄ haloalkoxy comprises fluoro substituted C ₁ -C ₄ alkoxy; in yet another embodiment, _{C1 -} C2 haloalkoxy comprises fluorine substituted _{C1 -} C2 alkoxy.

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

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, the cycloalkyl group contains 3-10 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3-6 carbon atoms carbon atom. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein, and both refer to a non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein , the bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. wherein one or more atoms on the ring are independently replaced by heteroatoms having the meanings as defined herein. In one embodiment, the heterocyclyl group is a monocyclic heterocyclyl 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 with one or more oxygen atoms to give groups like SO, SO2, PO, _{PO2 )} ; in another embodiment, the heterocyclyl group is composed of 7-12 ring atoms The bicyclic heterocyclyl group (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to obtain a compound 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 the heterocyclyl group may be a carbon group or a heteroatom group. wherein the _-CH2- 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 heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, etc. Examples of heterocyclyl groups where the _-CH2- group is substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxomorpholinyl, and the like. The heterocyclyl group is optionally substituted with one or more substituents described herein.

The term "aryl" refers to 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 of a family in which each ring system contains a ring of 3 to 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" is 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" refers to 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 of 5-7 atoms. A 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 "heteroaromatic", "aromatic heterocycle" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazolyl, tetrazolyl, triazolyl, and the like; also Included, but in no way limited to, the following bicycles: indolyl, quinolinyl, and the like.

As described in the present invention, the ring system formed by the substituent R ⁷ attached to the central octahydropyrrolo[3,4-c]pyrrole ring by a bond (shown in formula f) represents that the substituent R ⁷ can be in the octahydropyrrolo[3,4-c]pyrrole ring. The hydrogen pyrrolo[3,4-c]pyrrole ring is substituted at any substitutable position, as shown in formula f ^1-6 .

The term "protecting group" or "PG" refers to a substituent group that is commonly used to block or protect specific functionality when it reacts with other functional groups. 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, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethoxycarbonyl (Fmoc). Similarly, a "hydroxy 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" means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference is made 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", as used in the present invention, represents the in vivo conversion of a compound of formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), ( The compound represented by IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5). Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.

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

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as 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 including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malonate, Malonate, Mesylate, 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 quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible 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 appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _C1 -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. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association in which the solvent molecule is water.

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

The term "treating" any disease or disorder, in some of these embodiments, refers to ameliorating the disease or disorder (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 a physical parameter that may not be perceived by a patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.

The terms "prevent" or "prevent" refer to a reduction in the risk of acquiring a disease or disorder (ie: stopping the development of at least one clinical symptom of a disease in a subject who may be facing or predisposed to facing the disease, but also not experience or exhibit symptoms of disease).

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

In a structure disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the present invention and are included in the present invention as compounds disclosed herein . When stereochemistry is indicated by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of that structure are so 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 nitrogen-containing basic species can be accomplished 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 in dichloromethane , ethyl acetate or methyl acetate react with peracetic acid, or react with 3-chloroperoxybenzoic acid in chloroform or dichloromethane to prepare nitrogen oxides of the compounds of the present invention.

Formula (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), ( The compounds represented by IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) may exist in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated with it. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, but can be used in 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), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) enantiomeric intermediates of compounds.

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

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

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) Intermediates of compounds represented by , (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5).

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

Description of Compounds of the Invention

The pyridinoyl octahydropyrrolo[3,4-c]pyrrole derivatives, the pharmaceutically acceptable salts, the pharmaceutical preparations and the compositions thereof involved in the present invention can be used for activating 5-HT _1F receptors and inhibiting neurons Protein extravasation has potential use in the treatment of 5-HT _1F receptor-related diseases, especially migraine. The present invention further describes methods of synthesizing the compounds. The compounds of the present invention show 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 the compound represented by formula (I). , a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

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

In one embodiment, L is -C(=O)-, -C(=S)- or -S(=O) _2- .

In one embodiment, R ¹ is C ₁ -C ₆ alkyl, 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 with 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 as 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, _-NO2 , _-NH2 , -OH, -SH, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) ₂ , -C(=O)-( _C1 - _C6 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 heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl.

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 alkanes group, 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, R6 is H, D, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) 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 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 with 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 as described in the present invention.

^In another embodiment, R1 is phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazole radical, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl, wherein R is optionally selected from ¹ , 2, 3, 4 or 5 R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are substituted; wherein R ^1a , R ^1b , R ^1c , R ^1d and R ^1e have the meanings as 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, _-NO2 , _-NH2 , -OH, -SH, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) ₂ , -C(=O)-( _C1 - _C4 alkyl), -C(=O)-(C ₁ -C _4alkoxy ), 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 heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl.

In another embodiment, R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are each independently H, D, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -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, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, Pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazole group, 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 alkanes group, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or hydroxy substituted C ₁ -C ₄ alkyl.

^In another embodiment, ^R3 , R4 and R5 are each independently H, D, F, ^Cl , Br, I, -CN, _-NO2 , _-NH2 , -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 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, R6 is H, D, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) 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, R6 is H, D, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) 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, cyclopentane base, cyclohexyl, azetidine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, tris Azazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

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

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

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

Wherein, each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meaning as 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 isomer of a compound represented by formula (IIIa-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 meaning as 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 isomer of a compound represented by formula (IIIa-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 meaning as 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 isomer of a compound represented by formula (IIIa-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 meaning as 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 isomer of a compound represented by formula (IIIa-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 meaning as 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 isomer of a compound represented by formula (IIIa-5) Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Among them, each of R ^1b , R ^1c , R ^1d , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meaning as described in the present invention.

In yet other embodiments, the present invention relates to a compound that is a compound of formula (IIIb-1), or a stereoisomer, tautomer, nitrogen isomer of a compound of 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 meaning as described in the present invention.

In yet other embodiments, the present invention relates to a compound that is a compound of formula (IIIb-2), or a stereoisomer, tautomer, nitrogen isomer of a compound of 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 meaning as described in the present invention.

In yet other embodiments, the present invention relates to a compound that is a compound of formula (IIIb-3), or a stereoisomer, tautomer, nitrogen isomer of a compound of 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 meaning as described in the present invention.

In yet other embodiments, the present invention relates to a compound that is a compound of formula (IIIb-4), or a stereoisomer, tautomer, nitrogen isomer of a compound of 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 meaning as described in the present invention.

In yet other embodiments, the present invention relates to a compound that is a compound of formula (IIIb-5), or a stereoisomer, tautomer, nitrogen isomer of a compound of formula (IIIb-5) Oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof,

Among them, each of R ^1b , R ^1c , R ^1d , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ has the meaning as 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, solvent of a compound having one of the following structures compounds, metabolites, pharmaceutically acceptable salts or prodrugs thereof, but in no way limited to:

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

In one embodiment, the pharmaceutical composition involved in 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 Use of a compound represented by -5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) or a pharmaceutical composition thereof in the preparation of a medicament, said Drugs are used to prevent, treat or alleviate diseases associated with the 5-HT _1F receptor.

In one embodiment, the disease associated with the 5-HT _1F receptor is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression disorder, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder , ADHD, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss, or dementia.

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

In a further aspect, the present invention relates to formulas (I), (IIa), (IIb), (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa) disclosed in the present invention Use of a compound represented by -5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) or a pharmaceutical composition thereof in the preparation of a medicament, said Drugs are used to activate the 5-HT _1F receptor.

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

PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND ADMINISTRATION OF THE 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), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5) compounds or their individual stereoisomers, the elimination of isomers either a racemic or non-racemic mixture 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 present invention can be determined by the particular compound selected, the type of pharmacokinetic profile desired for the route of administration, and the state of the patient.

Formulations suitable for oral, sublingual, intranasal or injectable administration are prepared by 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 ingredients (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, given The formulation is diluted or enclosed in a carrier which may be in the form of a capsule, sachet, paper or other container. When an excipient serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, carrier or medium for the active ingredient. Thus, the formulations may be tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either in solid or in liquid media), containing, for example, up to 10 Ointments, soft and hard capsules, gels, suppositories, sterile injectable solutions and sterile encapsulated powders of % by weight active compound.

In the preparation of formulations, it may be necessary to grind the active compound to provide a suitable particle size prior to mixing with the other ingredients. If the active compound is substantially insoluble, it is generally ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, its particle size is adjusted by milling to provide a uniform particle size distribution in the formulation, eg, about 40 mesh. In one embodiment of the present 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 in, for example, Ansel H.C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al. , Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

"Pharmaceutically acceptable excipient" as used in the present invention means a pharmaceutically acceptable material, admixture or vehicle that is relevant to the consistency of the administered dosage form or pharmaceutical composition. Each excipient must, when mixed, be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would greatly reduce the efficacy of the disclosed compounds when administered to a patient and would result in a pharmaceutical composition that is not pharmaceutically acceptable Interaction. In addition, 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 based on their particular function in the composition. For example, certain pharmaceutically acceptable excipients can be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected which aid in carrying or transporting the compounds of the present 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 may be selected to enhance patient compliance.

Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, Polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants (such as talc, magnesium stearate and mineral oil), adjuvants. 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, moisturizing agent, Chelating agents, plasticizers, tackifiers, antioxidants, preservatives (such as methyl and propyl parabens), stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may serve more than one function, and provide alternative functions, depending on how much of that excipient is present in the formulation and what other excipients are present in the formulation. agent. The compounds of the present invention can be formulated by methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.

The skilled artisan possesses the knowledge and skills in the art to enable them to select appropriate amounts of suitable pharmaceutically acceptable excipients for use in the present invention. In addition, there are numerous resources available to the skilled artisan describing pharmaceutically acceptable excipients and for use 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 using the compounds described in this invention, pharmaceutically acceptable carriers can be solid or liquid carriers. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may contain from about 5 to about 95% of the active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of preparing various compositions can be found in: A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th ^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, MarcelDekker, New York The various carriers used to formulate pharmaceutically acceptable compositions, and well-known techniques for their preparation, the contents of each of these documents are incorporated herein by reference. Except for any commonly used carriers that are incompatible with the compounds of the present invention, such as by producing any undesired biological effects, or interacting in a deleterious manner with any other ingredient of the pharmaceutically acceptable composition, concerns for their use are within the scope of the present invention. scope of invention.

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

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

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by 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 suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes , sprays, foams and gels.

It will also be recognized that certain compounds of the present invention may exist in free form for use in therapy or, if appropriate, in the form of their pharmaceutically acceptable derivatives. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or can provide, directly or indirectly, the invention described herein 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 present invention are effective as injectable and oral compositions.

For transdermal administration, a transdermal delivery device ("patch") is required. Such transdermal patches may be used for continuous or intermittent infusion of controlled amounts of the compounds of the present invention. The construction and use of transdermal patches for drug delivery are well known in the art. See, for example, US 5,023,252. The patch can be made to release the drug continuously, pulsatilely, or on demand.

It is often desirable or necessary to introduce pharmaceutical compositions directly or indirectly into the brain. Direct techniques typically 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. The delivery of hydrophilic drugs can be enhanced by intra-arterial infusion of hypertonic solutions that instantaneously open the blood-brain barrier.

In a preferred embodiment of the present invention, pharmaceutical formulations are provided which contain at least one of the abovementioned active compounds and are suitable for buccal and/or sublingual or nasal administration. This embodiment provides for administration of the active compound in a manner that avoids gastric complications (eg, by first bypassing the gastric system and/or first being metabolized by the liver). 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 favorable solubility profile, which facilitates sublingual/buccal formulations. Such formulations generally require relatively high concentrations of active ingredient in order to deliver sufficient active ingredient to the limited surface of the sublingual/buccal mucosa for the relatively short duration of time the formulation is in contact with the sublingual/buccal mucosal surface so that active components are absorbed. Therefore, the extremely high activity of the compounds of the present 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, an amount sufficient to treat, cure or reduce symptoms of a disease is administered or brought into balance in the body. The effective amount required for a particular treatment regimen will depend on a number of factors, including the disease being treated, the severity of the disease, the activity of the particular drug used, the mode of administration, the clearance of the particular drug, the duration of treatment, the combination of medications, age , weight, gender, diet and patient health, etc. Additional considerations in the art regarding a "therapeutically effective amount" can be found in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8th ^ed ., Pergamon Press, 1990; Remington's Pharmaceutical Sciences, ^17th ed., Mack Publishing Company, Easton, Pa., 1990.

The compounds of formula I are preferably formulated in unit dosage form, each dosage containing from about 0.001 to 100 mg of active ingredient, more usually from about 1.0 to 30 mg of active ingredient. The term "unit dosage form" refers to 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 above agent.

The active compounds are generally effective over a wide dosage range. For example, the daily dose is generally about 0.0001-30 mg/kg body weight. For adult treatment, a particularly preferred dose (single or divided dose) is about 0.1-15 mg/kg/day. It should be understood, however, that the actual amount of compound to be administered will be determined by the attending physician according to the circumstances, including the disease being treated, the route of administration chosen, the compound or compounds actually to be administered, the 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, dose levels below the lower end of the above-mentioned dose range may be more appropriate, while in other cases, higher doses may be used that do not produce any adverse effects, provided that such larger doses are first administered Divide into several smaller doses for administration throughout the day.

The term "administration" refers to the provision of a therapeutically effective amount of a drug to an individual by means of 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, pills, 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, acacia, 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 clinical characteristics, dosage changes must depend on the condition of the patient being treated, and the appropriate dosage will be determined by the physician on a case-by-case basis. The therapeutically effective amount per unit dose depends on body weight, physiology and the chosen vaccination regimen. Compound per unit dose refers to the weight of the compound per administration, excluding the weight of the carrier (which is contained in the drug).

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

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

In one embodiment, the methods of treatment of the present invention comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments of the present invention encompass the treatment of diseases referred to 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 present invention or a pharmaceutical composition comprising a compound of the present invention may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal, and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular and subcutaneous injection or infusion. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, inhalation and intranasal administration. In one embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered orally. In another embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered by inhalation. In yet another embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered intranasally.

In one embodiment, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention may be administered once, or several times at different time intervals over a specified period of time, depending on the dosing regimen. For example, it is administered once, twice, three times or four times per day. In one embodiment, the administration is once a day. In yet another embodiment, the administration is twice daily. Administration can be performed until the desired therapeutic effect is achieved or maintained indefinitely. A suitable dosing regimen for a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled artisan. In addition, a suitable dosing regimen for a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention, including the duration for which the regimen is carried out, depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated , the medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, etc., factors within the knowledge and experience of the skilled person. Such skilled artisans will also appreciate that adjustments to appropriate dosing regimens may be required as individual patient responses to dosing regimens change, or as individual patient needs change over time.

The compounds of the present invention may be administered concurrently with, before or after one or more other therapeutic agents. The compounds of the present invention can be administered separately with other therapeutic agents by the same or different route of administration, or in 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 the compounds of the invention (within the dosage ranges described herein) and the other pharmaceutically active agents (within their dosage ranges).

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

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 compounds of the present invention in prodrug form, those skilled in the art can implement one or more of the following methods: (a) altering the in vivo onset time of the compound; (b) altering the in vivo duration of action of the compound; (c) altering 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 compounds that are chemically or enzymatically cleaved in vivo. These variants, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

Use of the Compounds and Pharmaceutical Compositions of the Invention

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

In particular, the compounds or pharmaceutical compositions of the invention are present in an amount effective to detectably selectively activate the 5-HT _1F receptor.

In particular, the compounds or pharmaceutical compositions of the invention are present in an amount effective to detectably selectively inhibit neuronal protein extravasation.

The compounds of the present invention can be applied, but in no way limited to, the prevention, treatment or alleviation of diseases associated with 5-HT _1F receptors by administering to a patient an effective amount of the compounds or pharmaceutical compositions of the present invention. The diseases related to 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 disorder, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, disruptive behavior disorder, impulse control disorder , ADHD, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss, and dementia.

In addition to their therapeutic benefits in humans, the compounds and pharmaceutical compositions of the present invention can also be used in veterinary treatment of mammals in pets, introduced breeds, and farm animals. Examples of other animals include horses, dogs and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

General synthetic steps

To illustrate the invention, the following examples are set forth. It is to be understood, however, that the invention is not limited to these examples, but merely provides methods of practicing the invention.

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I), (IIa), (IIb), (IIIa-1), ( IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb- 5) shown. The following reaction schemes and examples are used to further illustrate the content of the present invention.

Those skilled in the art will recognize that the chemical reactions described in this invention can be used to suitably prepare many other compounds of this invention, and that other methods for preparing compounds of this invention are considered to be within the scope of this 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 by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.

In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. 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.

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing with 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 are generally carried out under positive nitrogen or argon pressure or a drying tube is set over anhydrous solvent (unless otherwise indicated), the reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.

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. ^1H NMR spectra were performed with CDC13, _{DMSO -} d6, _CD3OD or acetone _- d6 as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are present, the following abbreviations are 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, double triplet), td (triplet of doublets, triple doublet), tt (triplet of triplet, triple triplet). The coupling constant, J, is expressed in Hertz (Hz).

The measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min. Mobile phase: 5 %-95% ( _CH3CN with 0.1% formic acid) in ( _H2O with 0.1% formic acid) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.

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

The following abbreviations are used throughout this disclosure:

CH ₂ Cl ₂ , DCM Dichloromethane mL, ml mL

CDC1 ₃ deuterated chloroform μL, μl μl

DMSO Dimethyl sulfoxide nL, nl nanoliter

DMSO-d ₆ deuterated dimethyl sulfoxide min min

EtOAc, EA ethyl acetate h h

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

N ₂ Nitrogen Pargyline

nM nanomolar PEI polyethyleneimine

μM Micromolar Serotonin Serotonin, Serotonin, 5-HT

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

Ng nanogram EDTA-K ₂ dipotassium ethylenediaminetetraacetate

Mg Microgram Solutol Polyethylene Glycol-15-Hydroxystearate

Mg mg MTBE methyl tert-butyl ether

G Gram PEG400 Polyethylene Glycol 400

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

The following synthetic schemes describe steps for preparing the compounds disclosed herein, wherein each of ^R1a , ^R1b , ^R1c , ^R1d , ^R1e , ^R3 , R4 and ^R5 has the definitions described herein unless otherwise indicated ^.

Synthesis Scheme 1

where X is CR ^1a or N.

The compound represented by the formula ( 6 ) can be prepared by the following process: the compound represented by the formula ( 1 ) reacts with the compound represented by the formula ( 2 ) to obtain the product represented by the formula ( 3 ); then the compound represented by the formula ( 3 ) The compound 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 with reference to the examples.

Example

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

Step 1) 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-neck round bottom flask at 0°C, Add benzoyl chloride (848 mg, 6.03 mmol) dropwise, transfer to 25 ° C to react for 12 hours; after the reaction, pour the reaction solution into water (30 mL), extract with dichloromethane (40 mL), collect the organic phase, reduce Spin to dryness and separate by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a pale yellow liquid (414 mg, 35.4%).

MS(ESI, pos.ion) m/z: 257.2[M+H] ⁺ ;

¹ H NMR (400 MHz, 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

Methyl 6-benzamidopyridine-2-carboxylate (820 mg, 3.20 mmol), water (2 mL) and methanol (10 mL) were added to a 100 mL single-neck round bottom flask at 25°C, and monohydrate was added Lithium (165 mg, 3.93 mmol) was continued to react for 3 hours; the reaction was stopped, methanol was removed by rotary evaporation under reduced pressure, water (10 mL) was added, then concentrated hydrochloric acid was added to adjust to pH=2, filtered, and the obtained solid was dried at 60 °C to obtain the title compound as White solid (620 mg, 80%).

MS(ESI, pos.ion) m/z: 243.0 [M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 11.02 (s, 1H), 8.36 (d, J=8.4 Hz, 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

6-Benzamidopyridine-2-carboxylic acid (243 mg, 1.0 mmol) and dichloromethane (10 mL) were added to a 100 mL one-neck flask at 0°C, and N,N-diisopropylethylamine (194 mg, 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 ℃ React for 3 hours; stop the reaction, add water (20 mL), and extract with dichloromethane (30 mL×2), collect the organic phase, add anhydrous sodium sulfate (1 g) to dry, filter, and spin dry the filtrate under reduced pressure. Column chromatography Purification (dichloromethane/methanol (v/v)=40/1) gave the title compound as a pale 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-fluorobenzoylamino)pyridine-2-carboxylate

The title compound of this step was prepared according to the method described in Example 1, Step 1, namely, 6-aminopyridine-2-carboxylate (200 mg, 1.31 mmol), triethylamine (0.3 mL, 2.0 mmol) and 4- Fluorobenzoyl chloride (0.25 mL, 2.12 mmol) was prepared by reaction in dichloromethane (10 mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to give 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 (400 MHz, 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-fluorobenzoylamino)pyridine-2-carboxylic acid

The title compound in this step was prepared according to the method described in Example 1, Step 2, that is, methyl 6-(4-fluorobenzamido)pyridine-2-carboxylate (340 mg, 1.24 mmol), hydrogen monohydrate Lithium oxide (55 mg, 1.31 mmol) was prepared by reaction in 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 in this step was prepared according to the method described in step 3 of Example 1, that is, 6-(4-fluorobenzamido)pyridine-2-carboxylic acid (180 mg, 0.69 mmol), N,N-diisopropyl Ethylamine (0.18 mL, 1.09 mmol), HATU (420 mg, 1.1 mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (135 mg, 1.07 mmol) were reacted in dichloromethane (10 mL) Preparation, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to give the title compound as a pale yellow solid (62 mg, 24.3%).

MS(ESI, pos.ion) m/z: 369.1[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.53-8.38 (m, 1H), 8.10-7.82 (m, 3H), 7.54 (d, J=7.2 Hz, 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-chlorobenzoylamino)pyridine-2-carboxylate

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

MS(ESI, pos.ion) m/z: 291.9 [M+H] ⁺ ;

¹ H NMR (400 MHz, 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-chlorobenzoylamino)pyridine-2-carboxylic acid

The title compound in this step was prepared according to the method described in Example 1, Step 2, that is, methyl 6-(4-chlorobenzamido)pyridine-2-carboxylate (362 mg, 1.25 mmol), hydrogen monohydrate Lithium oxide (55 mg, 1.31 mmol) was prepared by reaction in 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 (400 MHz, DMSO-d ₆ ) δ (ppm) 11.13 (s, 1H), 8.34 (d, J=8.4 Hz, 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 in this step was prepared according to the method described in step 3 of Example 1, namely 6-(4-chlorobenzamido)pyridine-2-carboxylic acid (200 mg, 0.72 mmol), N,N-diisopropylethyl acetate Prepared by reaction of amine (0.18 mL, 1.09 mmol), HATU (420 mg, 1.1 mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (140 mg, 1.11 mmol) 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 (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 in this step was prepared according to the method described in Example 1, Step 1, namely, 6-aminopyridine-2-carboxylate (300 mg, 1.97 mmol), triethylamine (0.3 mL, 2.0 mmol) and 4- Bromobenzoyl chloride (660 mg, 3.0 mmol) was prepared by reaction in dichloromethane (10 mL), 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 (400 MHz, 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-bromobenzoylamino)pyridine-2-carboxylic acid

The title compound in this step was prepared according to the method described in Example 1, Step 2, that is, methyl 6-(4-bromobenzamido)pyridine-2-carboxylate (600 mg, 1.79 mmol), hydrogen monohydrate Lithium oxide (75 mg, 1.79 mmol) was prepared by reaction in 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 in this step was prepared according to the method described in step 3 of Example 1, that is, 6-(4-bromobenzamido)pyridine-2-carboxylic acid (200 mg, 0.63 mmol), N,N-diisopropyl Ethylethylamine (0.16 mL, 0.97 mmol), HATU (350 mg, 0.92 mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (120 mg, 0.95 mmol) were reacted in dichloromethane (10 mL) Preparation, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to give the title compound as a pale yellow solid (130 mg, 48.6%).

MS(ESI, pos.ion) m/z: 429.0 [M+H] ⁺ ;

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm) 8.06 (d, J=7.6 Hz, 1H), 7.69 (dd, J=16.0, 8.0 Hz, 3H), 7.44 (d, J=8.4 Hz, 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 according to the method described in step 1 of Example 1, that is, 6-aminopyridine-2-carboxylate (500 mg, 3.29 mmol), triethylamine (0.9 mL, 6.0 mmol) and 2, 4-Difluorobenzoyl chloride (550 mg, 3.12 mmol) was prepared by reaction in dichloromethane (10 mL), 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 (400 MHz, 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 in this step was prepared according to the method described in Example 1, Step 2, that is, methyl 6-(2,4-difluorobenzamido)pyridine-2-carboxylate (340 mg, 1.24 mmol), Lithium hydroxide monohydrate (55 mg, 1.31 mmol) was prepared by reaction in 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 in this step was prepared according to the method described in step 3 of Example 1, that is, 6-(2,4-difluorobenzamido)pyridine-2-carboxylic acid (290 mg, 1.04 mmol), N,N- Diisopropylethylamine (0.26 mL, 1.57 mmol), HATU (600 mg, 1.58 mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (300 mg, 2.38 mmol) in dichloromethane (10 mL) ), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to give the title compound as a pale yellow solid (184 mg, 45.7%).

MS(ESI, pos.ion) m/z: 387.3 [M+H] ⁺ ;

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

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

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

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

MS(ESI, pos.ion) m/z: 309.0 [M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 9.06 (d, J=10.8 Hz, 1H), 8.59-8.54 (m, 1H), 8.06 (t, J=8.4 Hz, 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 in this step was prepared according to the method described in Example 1, Step 2, namely, methyl 6-(4-chloro-2-fluorobenzamido)pyridine-2-carboxylate (309 mg, 1.0 mmol) , lithium hydroxide monohydrate (45 mg, 1.1 mmol) was prepared by reaction 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 in this step was prepared according to the method described in step 3 of Example 1, that is, 6-(4-chloro-2-fluorobenzamido)pyridine-2-carboxylic acid (180 mg, 0.61 mmol), N,N - Diisopropylethylamine (0.15 mL, 0.91 mmol), HATU (350 mg, 0.92 mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (120 mg, 0.95 mmol) in dichloromethane ( 10 mL), the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to give the title compound as a pale yellow solid (98 mg, 39.8%).

MS(ESI, pos.ion) m/z: 403.2[M+H] ⁺ ;

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

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

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

The title compound of this step was prepared according to the method described in step 1 of Example 1, that is, 6-aminopyridine-2-carboxylate (450 mg, 2.96 mmol), triethylamine (0.9 mL, 6.0 mmol) and 2, 4,6-Trifluorobenzoyl chloride (530 mg, 2.72 mmol) was prepared by reacting in dichloromethane (10 mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) Purification gave the title compound as a pale yellow oil (374 mg, 44.2%).

MS(ESI, pos.ion) m/z: 311.2[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.86 (s, 1H), 8.57 (dd, J=7.6, 1.2 Hz, 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 in this step was prepared according to the method described in Example 1, Step 2, that is, methyl 6-(2,4,6-trifluorobenzamido)pyridine-2-carboxylate (178 mg, 0.57 mmol ), lithium hydroxide monohydrate (25 mg, 0.6 mmol) was prepared by reaction in methanol (5 mL) and water (1 mL) to give the title compound as a white solid (160 mg, 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 in this step was prepared according to the method described in step 3 of Example 1, namely 6-(2,4,6-trifluorobenzamido)pyridine-2-carboxylic acid (160 mg, 0.54 mmol), N,N- Diisopropylethylamine (0.15 mL, 0.91 mmol), HATU (350 mg, 0.92 mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (120 mg, 0.95 mmol) in dichloromethane (10 mL) ), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to give the title compound as a pale yellow solid (110 mg, 50.4%).

MS(ESI, pos.ion) m/z: 405.1[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.33 (d, J=8.4 Hz, 1H), 7.82 (t, J=8.0 Hz, 1H), 7.48 (d, J=7.2 Hz, 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 in this step was prepared according to the method described in Example 1, Step 1, namely, 6-aminopyridine-2-carboxylate (600 mg, 3.94 mmol), triethylamine (1.0 mL, 7.2 mmol) and 5- Fluoropyridine-2-carbonyl chloride (600 mg, 3.76 mmol) was prepared by reacting in dichloromethane (10 mL), 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 (400 MHz, CDCl ₃ ) δ (ppm) 10.52 (s, 1H), 8.66-8.62 (m, 1H), 8.47 (d, J=2.4 Hz, 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-carboxamido)pyridine-2-carboxylic acid

The title compound in this step was prepared according to the method described in Example 1, Step 2, that is, methyl 6-(5-fluoropyridine-2-carboxamido)pyridine-2-carboxylate (370 mg, 1.34 mmol), Lithium hydroxide monohydrate (60 mg, 1.43 mmol) was prepared by reaction in 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 in this step was prepared according to the method described in step 3 of Example 1, namely 6-(5-fluoropyridine-2-carboxamido)pyridine-2-carboxylic acid (106 mg, 0.41 mmol), 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 give the title compound as a white solid (57 mg, 38%).

MS(ESI, pos.ion) m/z: 370.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 10.26 (s, 1H), 8.55-8.43 (m, 2H), 8.36 (q, J=4.4 Hz, 1H), 7.91 (t, J=7.6 Hz, 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 in this step was prepared according to the method described in Example 1, Step 1, namely, 6-aminopyridine-2-carboxylate (450 mg, 2.96 mmol), triethylamine (0.9 mL, 6.0 mmol) and 5- Chloropyridine-2-carbonyl chloride (500 mg, 2.84 mmol) was prepared by reaction in dichloromethane (10 mL), 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 (400 MHz, CDCl ₃ ) δ (ppm) 10.54 (s, 1H), 8.66-8.61 (m, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.24 (d, J=8.4 Hz, 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-carboxamido)pyridine-2-carboxylic acid

The title compound in this step was prepared according to the method described in Example 1, Step 2, that is, methyl 6-(5-chloropyridine-2-carboxamido)pyridine-2-carboxylate (490 mg, 1.68 mmol), Prepared by reaction of lithium hydroxide monohydrate (84 mg, 2.0 mmol) in 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 in this step was prepared according to the method described in step 3 of Example 1, that is, 6-(5-chloropyridine-2-carboxamido)pyridine-2-carboxylic acid (198 mg, 0.71 mmol), N,N- Diisopropylethylamine (0.17 mL, 1.03 mmol), HATU (410 mg, 1.08 mmol) and 2-methyloctahydropyrrolo[3,4-c]pyrrole (140 mg, 1.11 mmol) in dichloromethane (10 mL) ), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to give the title compound as a white solid (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: Nonselective Rat ₅ -HT1 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 pH=7.4. 15 mg of cell membrane samples were incubated 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 at 25°C , 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 nonspecific binding values were determined using 10 μM 5-HT.

After incubation, the reaction was terminated by rapid filtration through a glass fiber filter presoaked in 0.3% PEI and rinsed 3 times with pre-chilled 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. By testing the data of a series of concentrations of 5-HT, the inhibition rate is calculated (inhibition rate=100-(the affinity result of the sample hole/the affinity result of the control hole)*100), and the concentration- The inhibition rate competition curve was used to calculate the _IC50 .

The results are shown in Table A.

Table A: The results of the affinity test of the compounds of the present invention to rat 5-HT ₁ receptors

Example number IC₅₀(μM) Example 5 6.98

The experimental results show that the compounds of the present invention have high affinity for rat 5-HT ₁ receptors.

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

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% _CO2 incubator with human 5-HT _1F and Ga15 plasmids. HEK293 cells were transfected and incubated for 24 hours at 37°C, 5% _CO2 .

(2) FLIPR experiment

HEK293 cells transfected for 24 hours were digested and seeded at a density of 2 x 10^4 cells/well in 384-well plates and incubated at 37°C, 5% _CO2 for 16-20 hours. 20 [mu]l of 2X Fluo-4Direct ^(TM) dye was added per well and incubated at 37[deg.]C, 5% _CO2 for 50 minutes and room temperature for 10 minutes. Prepare dose curve plates with different concentrations of compounds, transfer the compounds from the dose curve plates to the cell plate using the FLIPR instrument, and read the fluorescence signal immediately. The binding of Ca ²⁺ to the dye induced by different concentrations of compounds 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-maximal response was expressed as the EC ₅₀ value.

The experimental results show that the compounds of the present invention have strong 5-HT _1F receptor agonistic activity.

Example C: Pharmacokinetic evaluation of the compounds of the present invention by intravenous or gavage in rats and dogs

The inventors conducted pharmacokinetic evaluation of the compounds of the present invention in rats and dogs. The animal information is shown in Table 1.

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

germline grade gender weight age source SD rat SPF male 170-250g 6-9 weeks Hunan Slack Laboratory Animal Co., Ltd. Beagle dog clean grade male 8～10kg 6-7 weeks Hunan Slack Laboratory 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% physiological saline solution or 5% DMSO+60% PEG400+35% physiological saline solution, and the animals were fasted for 12 hours before administration. Free access to water. For the intravenous injection group, the dose was 1 mg/kg, and blood was collected at the following time points after administration (about 0.15 mL of blood): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h, EDTA-K ₂ was pre-added into the blood collection tube as an anticoagulant, the blood samples were centrifuged at 12,000 rpm for 2 minutes, and the plasma was collected and stored at -20°C or -70°C. For the intragastric administration group, the administration dose was 5 mg/kg, and intravenous blood was collected at the following time points (about 0.15 mL of blood) after administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h , EDTA-K ₂ was pre-added into the blood collection tube as an anticoagulant, the blood samples were centrifuged at 12,000 rpm for 2 minutes, the plasma was collected, and stored at -20°C or -70°C. The positive control is Lasmiditan (its structure is

The plasma samples collected above were processed (take 30 μL of plasma, add 120 μL of internal standard aqueous solution, mix evenly, extract with 0.9 mL of MTBE, take 0.7 mL of air-dried and reconstitute with 220 μL of methanol water (v/v=1/1)) Afterwards, the concentrations of the compounds in the plasma were analyzed using LC-MS/MS. The analysis results show that the compounds of the present invention have good pharmacokinetic properties in rats and dogs.

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

ND: Indicates no test data.

It can be seen from the results in Table C1 that the compounds of the present invention have 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 compounds of the present invention have better pharmacokinetic properties in dogs than Lasmiditan.

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

Although the embodiments of the present invention have been shown and described above, it should be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (10)

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

Wherein:

L is-C (=O)-,-C (=S)-or-S (=O)₂-；

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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