CN111187252B - Pyridinoyl azaspiroheptane derivatives and their use - Google Patents

Abstract

The invention discloses pyridine acyl azaspiroheptane derivatives and application thereof, in particular to novel pyridine acyl azaspiroheptane derivatives and a pharmaceutical composition containing the same, which can be used for activating 5-HT _1F A receptor. The invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in the preparation of therapeutic and 5-HT _1F Use in medicine of receptor-related diseases, in particular migraine.

Description

Pyridoylazaspiroheptane derivatives and uses thereof

Technical Field

The present invention belongs to the field of pharmaceutical technology, and specifically relates to novel pyridoyl azaspiroheptane derivatives and pharmaceutical compositions containing these compounds, and methods and uses thereof. In particular, the novel pyridoyl azaspiroheptane derivatives of the present invention can be used to activate 5-HT _1F receptors, and to prevent, treat or alleviate diseases related to 5-HT _1F receptors, especially migraine.

Background Art

Migraine is a type of paroxysmal and often unilateral throbbing headache, often accompanied by nausea and vomiting. It is a common chronic neurovascular disease that often begins in childhood and adolescence, reaches a peak in middle-aged and young people, is more common in females, with a male-to-female ratio of about 1:2-3. The prevalence rate in the population is 5% to 10%, and often has a genetic background.

Although migraine is not a fatal disease, it can seriously affect the social life of patients. In the United States, the socioeconomic burden caused by migraine is 1 to 1.7 billion US dollars. In my country, a large number of patients are also affected by migraine in their work, study and life. With the acceleration of the pace of life, the incidence of migraine is gradually increasing. Recent surveys have 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 tendency to develop migraine.

The pathogenesis of migraine is complex and diverse, mainly including the vascular origin theory, neurogenic theory, trigeminovascular theory, biochemical factors and genetic factors. The drugs currently used to treat migraine are mainly 5-HT _1B/D receptor agonist triptans, but because triptans can cause vasoconstriction, they are contraindicated for patients with cardiovascular and peripheral vascular diseases. In addition, 40% to 70% of migraine patients have poor efficacy in the treatment of triptans, and 1/3 of patients who are initially effective in treatment will often experience headache recurrence. The efficacy of triptans for patients with moderate to severe headaches is significantly reduced. In order to overcome these adverse reactions of triptans, calcitonin gene-related peptide (CGRP) receptor antagonists and selective 5-HT _1F receptor agonists have emerged as anti-migraine drugs. However, CGRP receptor antagonists still have many defects, such as olcagepant can only be used intravenously and is not suitable for oral administration, long-term use of telcagepant can cause elevated liver enzymes, and BI-44370 has been discontinued in clinical development due to its interaction with cytochrome P450. Therefore, there is an urgent need to develop new acute treatment drugs. The development of selective 5-HT _1F receptor agonists has been considered a new and promising approach to anti-migraine drugs.

Since 1938, the work of Graham and Wolff (Arch. Neurol. Psychiatry, 39:737-63, 1938) has dominated the theory of migraine pathophysiology. They proposed that the cause of migraine is vasodilation of extracranial blood vessels. This view is supported by the following evidence: ergot alkaloids and sumatriptan, a hydrophilic 5-HT ₁ agonist that cannot cross the blood-brain barrier, can contract the smooth muscle of the head vessels and effectively treat migraine (Humphrey, et al., Ann. NY Acad. Sci., 600:587-600, 1990). However, the work of Moskowitz's research group showed that the occurrence of migraine is not related to changes in blood vessel diameter (Cephalalgia, 12:5-7, 1992).

The Moskowitz research group proposed that the currently unknown pain trigger stimulated the trigeminal ganglion (the trigeminal ganglion innervates the vasculature in the head tissue), causing the axons on the vasculature to release vasoactive neuropeptides. These released neuropeptides then activated a series of events, leading to pain. This neurogenic inflammation was blocked by ergot alkaloids and sumatan, whose blocking mechanism involves 5-HT receptors and is closely related to the 5-HT _1D subtype located on the trigeminal nerve vascular fibers (Neurology, 43 (supp1.3): S16-S20, 1993). In fact, sumatan has a high affinity for 5-HT _1B and 5-HT _1D receptors, with Ki of 10.3nM and 5.1nM respectively, and this activity exhibits vasoconstrictive activity.

5-HT receptors, also known as serotonin receptors or 5-HT receptors, are a group of G protein-coupled receptors that appear in the central nervous system and the peripheral nervous system. They can be divided into seven subfamilies, 5-HT ₁ , 5-HT ₂ , 5-HT ₃ , 5-HT ₄ , 5-HT ₅ , 5-HT ₆ , and 5-HT ₇ , which mediate different physiological activities. Among them, 5-HT ₁ receptors are the largest family in the 5-HT receptor family, and there are currently five subtypes, 5-HT _1A , 5-HT _1B , 5-HT _1D , 5-HT _1E , and 5-HT _1F . Kao's research group isolated a human gene that expresses one of these 5-HT ₁ receptor subtypes (called 5-HT _1F ) (Proc. Natl. Acad. Sci. USA, 90: 408-412, 1993). The pharmacological activity displayed by this 5-HT _1F receptor is significantly different from any published serotonin receptor. They found that in addition to the strong affinity for 5-HT _1B and 5-HT _ID receptors mentioned above, sumatan also has affinity for this receptor subtype, with a Ki of approximately 23nM. This suggests that the 5-HT _1F receptor may play a role in migraine.

5-HT _1F receptors are mainly expressed in the mesentery, uterus and brain, and are also present in various parts of the trigeminal vasculature such as cerebral blood vessels, trigeminal ganglia and trigeminal nucleus caudalis, as well as in the cerebellum, hippocampus and neocortex. Like other 5-HT receptors, 5-HT _1F receptors are expressed not only in neurons but also in glial cells. Activation of presynaptic 5-HT _1F receptors can inhibit the release of calcitonin gene-related peptide (CGRP) and block neuronal signaling in the trigeminal nucleus caudalis, thereby producing an anti-migraine effect. This selective 5-HT _1F receptor agonism greatly reduces the vasoconstriction-related side effects caused by triptan drugs.

Subsequently, various 5-HT _1F receptor agonists were developed that were relatively selective for the 5-HT _1F receptor subtype, and this selectivity generally reduced the vasoconstrictive activity characteristic of other compounds used as potential drugs for the treatment of migraine and related disorders.

Through continuous and diligent research, the inventors have obtained an unexpected new class of selective 5-HT _1F agonists, which have different chemical and receptor binding properties, can inhibit peptide extravasation, and can avoid obvious vasoconstriction activity, so that they can be used to treat migraine and other diseases related to 5-HT _1F receptors. In addition, the compounds of the present invention have good solubility and are therefore highly adaptable in preferred formulations (such as sublingual, buccal and/or intranasal formulations).

Summary of the invention

The present invention provides a novel pyridoyl azaspiroheptane derivative as a 5-HT _1F receptor agonist, which can be used to activate the 5-HT _1F receptor and inhibit neuronal protein extravasation, and therefore can be used to treat diseases mediated by the 5-HT _1F receptor, especially for treating migraine. And through experiments, it is found that the pyridoyl azaspiroheptane derivative of the present invention has 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.

The present invention also provides methods for preparing the compounds, pharmaceutical compositions containing the compounds, and uses of the compounds and pharmaceutical compositions containing the compounds in preparing drugs.

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, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I),

in:

X is N or CR ^x ;

Each of R ^1a , R ^1b , R ^1c , R ^1d and R ^x is independently H, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-(C ₁ -C ₆ alkyl), -C(=O)-(C ₁ -C ₆ alkoxy), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkyl substituted with hydroxy, C ₃ -C 6 _8- membered cycloalkyl, 3-8-membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10-membered heteroaryl;

^R2 is H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -COOH, -C(=O) _NH2 , C1 _{- C6} alkyl, C1- _C6 haloalkyl, _{C1 - C6} alkoxy, _C1 - _C6 haloalkoxy, or _C1 - _C6 alkyl substituted with hydroxy;

R ³ , R ⁴ and R ⁵ are each independently H, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -COOH, -C(=O)NH ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C 6 haloalkoxy or C ₁ -C ₆ alkyl _substituted with hydroxy; and

^R6 is H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -SH, -COOH, -C( _{=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2 , -C (} =O)-( _{C1- C6} alkyl) _, -C(=O)-( _{C1 - C6} alkoxy), C1- _C6 alkyl, C2- _C6 alkenyl, _{C2 - C6} alkynyl, C1 _{- C6} haloalkyl, C1- _C6 alkoxy, _C1 - _{C6 haloalkoxy, C1-C6 alkylthio , C1} - _C6 alkylamino, C1 _{- C6} alkyl substituted with hydroxy, _C3 - _C8 cycloalkyl, 3-8 membered heterocyclyl, _C6 -C _10- membered aryl or 5-10-membered heteroaryl.

In one embodiment, each of R ^1a , R ^1b , R ^1c , R ^1d and R ^x is independently H, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-(C ₁ -C ₄ alkyl), -C(=O)-(C ₁ -C ₄ alkoxy), C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C _{1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino, C 1 -C 4 alkyl substituted with hydroxy ,} C ₃ -C 4 _6- membered cycloalkyl, 3-6-membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10-membered heteroaryl;

^R2 is H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -COOH, -C(=O) _NH2 , C1 _{- C4} alkyl, C1- _C4 haloalkyl, _{C1 - C4} alkoxy, _C1 - _C4 haloalkoxy, or _C1 - _C4 alkyl substituted with hydroxy;

R ³ , R ⁴ and R ⁵ are each independently H, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -COOH, -C(=O)NH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C 4 haloalkoxy or C ₁ -C ₄ alkyl substituted with _hydroxy .

In another embodiment, each of R ^1a , R ^1b , R ^1c , R ^1d and R ^x is independently H, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-OCH ₃ , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ , -CF ₃ , -CHFCH ₂ F, -CF ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CF ₂ CHF ₂ , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF ₂ , -OCF ₃ , -OCHFCH ₂ F, -OCF ₂ CHF ₂ , -OCH ₂ CF ₃ , -OCH ₂ CF ₂ CHF ₂ , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl;

R ² is H, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -COOH, -C(=O)NH ₂ , methyl, ethyl, n-propyl, isopropyl, -CF ₃ , -CH ₂ CF ₃ , methoxy, ethoxy, n-propyloxy or isopropyloxy;

^R3 , ^R4 and ^R5 are each independently H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -COOH, -C ₍ =O) _NH2 , methyl, ethyl, n-propyl, isopropyl, _-CF3 , _-CH2CF3 , methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, ^R6 is H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -SH, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) ₂ , -C(=O)-(C1-C4 alkyl), -C(=O)-(C1-C4 alkoxy), _C1 -C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1- _C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1- _C4 alkylthio, _C1 -C4 alkylamino, hydroxy-substituted _C1 -C4 alkyl, _C3 -C6 cycloalkyl, 3-6 membered _heterocyclyl , C6-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1- _C4 haloalkyl, C1 _{- C4} alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1 _{- C4} alkylamino, hydroxy-substituted _{C1 - C4} alkyl, _C3 -C6 cycloalkyl, _3-6 membered heterocyclyl, C6- _C4 alkyl, C2- _C4 alkenyl, C2 _- C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1- _{C4 haloalkoxy, C1-C4} alkylthio, C1- _C4 alkylamino, hydroxy-substituted C1 _{- C4} alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, _C6 -C4 _10- membered aryl or 5-10-membered heteroaryl.

In another embodiment, ^R6 is H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -SH, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) ₂ , -C(=O _{) -CH3} , -C( ₌ O)-OCH3, methyl, ethyl _{, n -propyl , isopropyl ,} allyl, propenyl, propargyl, propynyl, -CHF2 _{, -CF3 ,} -CHFCH2F _, -CF2CHF2, -CH2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, _ethoxy , n-propyloxy, isopropyloxy, _-OCHF2 , _-OCF3 , _-OCHFCH2F , _{-OCF2CHF 2} , _-OCH2CF3 , _-OCH2CF2CHF2 , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, ₂ -hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, _{tetrahydrofuranyl} , piperidinyl, piperazinyl, morpholinyl, phenyl _, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

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

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

In another aspect, the present invention relates to the use of the compound of formula (I) or a pharmaceutical composition thereof disclosed in the present invention in the preparation of a drug for preventing, treating or alleviating diseases associated with 5-HT _1F receptors.

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

In another aspect, the present invention relates to the use of the compound represented by formula (I) or the pharmaceutical composition thereof disclosed in the present invention in the preparation of a drug, wherein the drug is used to activate 5-HT _1F receptors.

In another aspect, the present invention relates to methods for preparing, separating and purifying the compound represented by formula (I).

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

Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical features in other embodiments, as long as they do not conflict.

The foregoing content only summarizes certain aspects of the present invention, but is not limited to these aspects. The content of these aspects and other aspects will be described in more detail and completely below. All references in this specification are hereby incorporated by reference in their entirety. When there is a difference between the disclosure of this specification and the cited documents, the disclosure of this specification shall prevail.

Detailed description of the present invention

Definitions and general terms

Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is by no means limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

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

Unless otherwise indicated, the following definitions used in the present invention shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found 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, the entire contents of which are incorporated herein by reference.

Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

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

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

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

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

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

The stereochemical definitions and rules used in the present invention generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its one or more chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. 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 a racemate and this may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

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

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

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

Any racemate of the final product or intermediate obtained can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the diastereoisomeric salts obtained thereof. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis ( ^2nd 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 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

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

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

The term "optionally substituted with..." can be used interchangeably with the term "unsubstituted or substituted with...", i.e., the structure is unsubstituted or substituted with one or more substituents described in the present invention, and the substituents described in the present invention include, but are not limited to D, F, Cl, Br, I, _N3 , -CN, _-NO2 , _-NH2 , -OH, -SH, -COOH, _-CONH2 , -C(=O)NHCH3, -C(=O)N( _CH3 ) ₂ , -C(=O)-alkyl, -C(=O)-alkoxy, alkyl, alkenyl, alkynyl, haloalkyl _, alkoxy, haloalkoxy, alkylthio, alkylamino, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced by a specific substituent. Unless otherwise indicated, a substituent can be substituted at each reasonable position of the group. When more than one position in the given structural formula can be substituted by one or more specific substituents selected, the substituent can be substituted at each reasonable position in the structural formula in the same or different manner.

In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

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

The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is specifically pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C ₁ -C ₆ alkyl" specifically refers to the independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl.

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

The term "D" refers to a single deuterium atom.

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

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

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

The term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp2 ^double bond, wherein the alkenyl group may be optionally substituted with one or more substituents as described herein, including "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH= _CH2 ), allyl ( _-CH2CH = _CH2 ), 1-propenyl (i.e., propenyl, -CH=CH- _CH3 ), and the like.

The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2 to 8 carbon atoms; in another embodiment, the alkynyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (i.e., propynyl, -C≡C-CH ₃ ), and the like.

The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 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 contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, _-OCH3 ), ethoxy (EtO, _-OCH2CH3 ), 1-propoxy (n-propyloxy, n-PrO, n-propoxy, _-OCH2CH2CH3 ), ₂ -propoxy (isopropyloxy _, i-PrO, i-propoxy, -OCH(CH3 _{) 2} ), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), _{2 -} methyl-1-propoxy ( _i - _BuO , i-butoxy, _-OCH2CH ( _CH3 ) ₂ ) _, 2-butoxy (s-BuO, s-butoxy, -OCH( _CH3 ) _CH2CH3 ), 2-methyl-2-propoxy (t- _BuO , t-butoxy, -OC( _CH3 ) ₃ ),etc.

The term "alkylthio" means an alkyl group attached to the rest of the molecule via a sulfur atom, wherein the alkyl group has a 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 contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents as described herein.

Examples of alkylthio groups include, but are not limited to, methylthio (MeS, -SCH ₃ ), ethylthio (EtS, -SCH ₂ CH ₃ ), 1-propylthio (n-PrS, n-propylthio, -SCH ₂ CH ₂ CH ₃ ), 2-propylthio (i-PrS, i-propylthio, -SCH(CH ₃ ) ₂ ), 1-butylthio (n-BuS, n-butylthio, -SCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propylthio (i-BuS, i-butylthio, -SCH ₂ CH(CH ₃ ) ₂ ), 2-butylthio (s-BuS, s-butylthio, -SCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propylthio (t-BuS, t-butylthio, -SC(CH _{3 )} ) ₃ ), and so on.

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

The term "hydroxy-substituted alkyl" means an alkyl group 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 that an alkyl group is substituted by one or more halogen atoms, wherein the alkyl group has the meaning as described herein, and _such examples include, but are not limited to _{, -CHF2} , _-CF3 , -CHFCH2F, _-CF2CHF2 , _-CH2CHF2 , _-CH2CF3 , _{-CHFCH3 , -CH2CH2F , -CF2CH3 , -CH2CF2CHF2 , etc.} In one embodiment, C1 _{- C6} haloalkyl includes fluorine-substituted _C1 - _C6 alkyl; in _{another embodiment, C1-C4 haloalkyl includes fluorine-substituted C1-C4 alkyl; in yet another embodiment, C1-C2 haloalkyl includes fluorine - substituted C1 - C2 alkyl} .

The term "haloalkoxy" means an alkoxy group substituted by one or more halogen atoms, wherein the alkoxy group has the meaning as described in the present invention, _such examples include, but are not limited to, _-OCHF2 , -OCF3, _-OCHFCH2F , _-OCF2CHF2 , _-OCH2CHF2 , _{-OCH2CF3 , -OCHFCH3} , _-OCH2CH2F , _-OCF2CH3 , _{-OCH2CF2CHF2 , etc.} In one embodiment, C1 _{- C6} haloalkoxy _includes fluorine _- substituted _C1 - _C6 alkoxy; in _{another embodiment, C1-C4 haloalkoxy includes fluorine-substituted C1-C4 alkoxy; in yet another embodiment, C1-C2 haloalkoxy includes fluorine - substituted C1 -C2 alkoxy .}

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

The term "carbocyclyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic system of monovalent or polyvalent non-aromatic containing 3-12 carbon atoms.Carbobicyclic radicals include spirocarbobicyclic radicals and fused carbobicyclic radicals, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. The carbocyclyl group is optionally substituted by one or more substituents described in the present invention.

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

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. One or more atoms in the ring are independently replaced by heteroatoms, and the heteroatoms have the meanings as described herein. In one embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3-8 ring atoms (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give groups such as SO, _SO2 , PO, _PO2 ); in another embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3-6 ring atoms (2-5 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give groups such as SO, _SO2 , PO, _PO2 ); in another embodiment, heterocyclyl is a bicyclic heterocyclyl consisting of 7-12 ring atoms (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give groups such as SO, _SO2 , PO, _PO2 ). The heterocyclyl groups are optionally substituted with one or more substituents described herein.

基，二氮杂

基，硫氮杂

基，2-氧杂-5-氮杂双环[2.2.1]庚-5-基，等等。杂环基中-CH₂-基团被-C(＝O)-取代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基、嘧啶二酮基，等等。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、硫代吗啉基1,1-二氧化物，等等。所述的杂环基基团任选地被一个或多个本发明所描述的取代基所取代。The heterocyclic group may be a carbon group or a heteroatom group, wherein the -CH ₂ - group of the ring is optionally replaced by -C(=O)-, the sulfur atom of the ring is optionally oxidized to an S-oxide, and the nitrogen atom of the ring is optionally oxidized to an N-oxide. Examples of heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine

Base, diazepine

Base, thiazolin

Examples of heterocyclic groups in which the -CH ₂ - group is replaced by -C(═O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. The heterocyclic group is optionally substituted by one or more substituents described herein.

The term "aryl" refers to a monocyclic, bicyclic and tricyclic carbon ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, and wherein each ring system contains a ring consisting of 3-7 atoms. The aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups can include phenyl, indenyl, naphthyl and anthracenyl. The aryl group is optionally substituted by one or more substituents described in the present invention.

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 consisting of 5-7 atoms. The heteroaryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 atom heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl , 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

The term "protecting group" or "PG" refers to a substituent that reacts with other functional groups, usually to block or protect a particular functionality. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group that is used to block or protect the functionality of the hydroxy group. Suitable protecting groups include trialkylsilyl, acetyl, benzoyl and benzyl. " _Carboxyl protecting group" refers to a carboxyl substituent used to block or protect the functionality of the carboxyl group. Typical carboxyl protecting groups include _-CH2CH2SO2Ph , _cyanoethyl , 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, etc. For a general description of protecting groups, reference may be 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" used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, the esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.

"Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

The "pharmaceutically acceptable salt" used in the present invention refers to organic salts 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 salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ ( _C1-4alkyl ) ₄ salts. The present invention also contemplates quaternary ammonium salts formed by any compound containing N groups. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _C1 - _C8 sulfonates and aromatic sulfonates.

The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or a mixture thereof. The term "hydrate" refers to an association formed when 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 combined with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.

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

The terms "prevent" or "prevention" refer to a reduction in the risk of acquiring a disease or disorder (i.e., halting the development of at least one clinical symptom of a disease in a subject who may be exposed or predisposed to the disease but does not yet experience or display symptoms of the disease).

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

In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the present invention and are included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of the structure are unambiguous and defined.

Nitrogen oxides of the compounds of the invention are also included within the scope of the invention. Nitrogen oxides of the compounds of the invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) at elevated temperatures in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

The compound shown in formula (I) may exist in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, and may be an intermediate for preparing and/or purifying the compound shown in formula (I) and/or for separating the enantiomers of the compound shown in formula (I).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic part by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "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) can be found in a list of other suitable salts.

Any structural formula provided by the present invention is also intended to represent the isotopically unenriched form and isotopically enriched form of these compounds. Isotopically enriched compounds have the structure described by the general formula provided by the present invention, except that one or more atoms are replaced by atoms with selected atomic weight or mass number. Exemplary isotopes that can be introduced 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 an intermediate for preparing the compound represented by formula (I).

On the other hand, 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, solvent or a combination thereof. In another embodiment, the pharmaceutical composition can be a liquid, solid, semi-solid, gel or spray formulation.

Description of the compounds of the present invention

The pyridoylazaspiroheptane derivatives, pharmaceutically acceptable salts thereof, pharmaceutical preparations and compositions thereof of the present invention can be used to activate 5-HT _1F receptors and inhibit neuronal protein extravasation, and have potential uses in the treatment of diseases related to 5-HT _1F receptors, especially migraine. The present invention further describes a method for 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, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I),

wherein each of R ^1a , R ^1b , R ^1c , R ^1d , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X has the same meaning as defined in the present invention.

In one embodiment, X is N or CR ^x ; wherein R ^x has the meaning as described herein.

In one embodiment, each of R ^1a , R ^1b , R ^1c , R ^1d and R ^x is independently H, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-(C ₁ -C ₆ alkyl), -C(=O)-(C ₁ -C ₆ alkoxy), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C _{1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 1 -C 6 alkyl substituted with hydroxy ,} C ₃ -C 6 _8- membered cycloalkyl, 3-8-membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10-membered heteroaryl.

In one embodiment, ^R2 is H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -COOH, -C(=O) _NH2 , _C1 - _C6 alkyl, C1- _C6 haloalkyl, _{C1 - C6} alkoxy, C1 _{- C6} haloalkoxy, or _C1 - _C6 alkyl substituted with hydroxy.

In one embodiment, R ³ , R ⁴ and R ⁵ are each independently H, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -COOH, -C(=O)NH ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, or C ₁ -C ₆ alkyl substituted with hydroxy.

In one embodiment, ^R6 is H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -SH, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) ₂ , -C(=O)-( _C1 - _C6 alkyl), -C(=O)-( _C1 - _C6 alkoxy), _{C1 -C6} alkyl, _C2 - _C6 alkenyl, _{C2 - C6} alkynyl, C1-C6 haloalkyl, C1- _C6 alkoxy, _{C1 - C6} haloalkoxy, C1 _{- C6} alkylthio, _C1 - _C6 alkylamino, hydroxy-substituted C1 _{- C6} alkyl, _C3 - _C8 cycloalkyl, 3-8 membered heterocyclyl, C6 _{-C6 alkyl 10-} membered aryl or 5-10-membered heteroaryl.

In one embodiment, each of R ^1a , R ^1b , R ^1c , R ^1d and R ^x is independently H, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-(C ₁ -C ₄ alkyl), -C(=O)-(C ₁ -C ₄ alkoxy), C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C _{1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylamino, C 1 -C 4 alkyl substituted with hydroxy ,} C ₃ -C 4 The invention also includes _{a C 6-6} cycloalkyl group, a 3-6 membered heterocyclyl group, a C ₆ -C ₁₀ aryl group or a 5-10 membered heteroaryl group.

In another embodiment, each of R ^1a , R ^1b , R ^1c , R ^1d and R ^x is independently H, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-OCH ₃ , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ , -CF ₃ , -CHFCH ₂ F, -CF ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CF ₂ CHF ₂ , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF ₂ , -OCF ₃ , _-OCHFCH2F , -OCF2CHF2 _{, -OCH2CF3} , -OCH2CF2CHF2, methylthio _, ethylthio _, methylamino, dimethylamino, ethylamino, hydroxymethyl, _{2 -} hydroxyethyl _, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, _indenyl , naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In one embodiment, ^R2 is H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -COOH, -C(=O) _NH2 , _C1 - _C4 alkyl, C1- _C4 haloalkyl, _{C1 - C4} alkoxy, C1 _{- C4} haloalkoxy, or _C1 - _C4 alkyl substituted with hydroxy.

In another embodiment, ^R2 is H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -COOH, -C(=O) _NH2 , methyl, ethyl, n-propyl, _isopropyl , _-CF3 , _-CH2CF3 , methoxy, ethoxy, n-propyloxy, or isopropyloxy.

In one embodiment, R ³ , R ⁴ and R ⁵ are each independently H, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -COOH, -C(=O)NH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, or C ₁ -C ₄ alkyl substituted with hydroxy.

In another embodiment, ^R3 , ^R4 and ^R5 are each independently H, F, Cl, Br _, I, -CN, _-NO2 , _-NH2 , -OH, -COOH, -C(=O) _NH2 , methyl, ethyl, n-propyl, isopropyl, _-CF3 , _-CH2CF3 , methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, ^R6 is H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -SH, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) ₂ , -C(=O)-(C1-C4 alkyl), -C(=O)-(C1-C4 alkoxy), _C1 -C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1- _C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1- _C4 alkylthio, _C1 -C4 alkylamino, hydroxy-substituted _C1 -C4 alkyl, _C3 -C6 cycloalkyl, 3-6 membered _heterocyclyl , C6-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1- _C4 haloalkyl, C1 _{- C4} alkoxy, C1-C4 haloalkoxy, C1- _C4 alkylthio, C1 _- C4 alkylamino, hydroxy-substituted _{C1 - C4} alkyl, C3-C6 cycloalkyl, _3-6 membered heterocyclyl, C6- _C4 alkyl, C2- _C4 alkenyl, C2 _- C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1- _{C4 haloalkoxy, C1-C4} alkylthio, C1- _C4 alkylamino, hydroxy-substituted C1 _{- C4} alkyl, C3- _C6 cycloalkyl, 3-6 membered heterocyclyl, _C6 -C4 _10- membered aryl or 5-10-membered heteroaryl.

In another embodiment, ^R6 is H, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -SH, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) ₂ , -C(=O _{) -CH3} , -C( ₌ O)-OCH3, methyl, ethyl _{, n -propyl , isopropyl ,} allyl, propenyl, propargyl, propynyl, -CHF2 _{, -CF3 ,} -CHFCH2F _, -CF2CHF2, -CH2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, _ethoxy , n-propyloxy, isopropyloxy, _-OCHF2 , _-OCF3 , _-OCHFCH2F , _{-OCF2CHF 2} , _-OCH2CF3 , _-OCH2CF2CHF2 , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, ₂ -hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, _{tetrahydrofuranyl} , piperidinyl, piperazinyl, morpholinyl, phenyl _, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

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

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

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

In another aspect, the present invention relates to the use of the compound of formula (I) or a pharmaceutical composition thereof disclosed in the present invention in the preparation of a drug for preventing, treating or alleviating diseases associated with 5-HT _1F receptors.

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

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

In another aspect, the present invention relates to the use of the compound represented by formula (I) or a pharmaceutical composition thereof disclosed in the present invention in the preparation of a drug, wherein the drug is used to activate a 5-HT _1F receptor.

In another aspect, the present invention relates to methods for preparing, separating and purifying the compound represented by formula (I).

Pharmaceutical compositions, preparations and administration of the compounds of the present invention

The present invention provides a pharmaceutical composition, comprising a compound represented by formula (I) or a single stereoisomer thereof, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and/or preventive ingredients.

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

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

In general, the formulations of the present invention include an active ingredient (a compound of formula (I)), usually mixed with an excipient, diluted by an excipient or enclosed in a carrier which may be in the form of a capsule, sachet, paper or other container. When an excipient is used as a diluent, it may be a solid, semisolid or liquid material which acts as an excipient, carrier or medium for the active ingredient. Thus, the formulation may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (either solid or in a liquid medium), ointment containing, for example, up to 10% by weight of the active compound, soft and hard capsules, gels, suppositories, sterile injections and sterile encapsulated powders.

In the preparation of the formulation, it may be necessary to grind the active compound before mixing with the other components to provide a suitable particle size. 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 grinding to have a uniform particle size distribution in the formulation, for example, about 40 mesh. In one embodiment of the invention, the particle size is about 0.1-100 μm.

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

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or solvent that is relevant to the consistency of the dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would significantly reduce the efficacy of the disclosed compounds when administered to a patient and/or interactions that would result in a pharmaceutical composition that is not pharmaceutically acceptable. In addition, each excipient must be pharmaceutically acceptable, for example, have a sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. In addition, pharmaceutically acceptable excipients may be selected based on their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can help produce a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected that can help produce a stable dosage form. Certain pharmaceutically acceptable excipients may be selected that help carry or transport the compounds of the invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected to enhance patient compliance.

Some suitable excipient examples include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. Suitable pharmaceutically acceptable excipients also include excipients of the following types: diluents, fillers, binders, disintegrants, lubricants (such as talc, magnesium stearate and mineral oil), glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives (such as methyl hydroxybenzoate and propyl hydroxybenzoate), stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function and may provide alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation. The compounds of the invention may be formulated using methods known in the art so as to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.

The skilled person has the knowledge and skill in the art to enable them to select a suitable pharmaceutically acceptable excipient for the appropriate amount of the present invention. In addition, there are a large number of resources available to the skilled person that describe pharmaceutically acceptable excipients and are used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

To prepare pharmaceutical compositions using the compounds described herein, pharmaceutically acceptable carriers may 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 may be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing various compositions may be found in: A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18 ^th ed., 1990, Mack Publishing Company Co., Easton, Pennsylvania.

In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York discloses various carriers for configuring pharmaceutically acceptable compositions, and the known technology for its preparation, and the respective contents of these documents are incorporated into the present invention by reference. Except any conventional carriers such as any undesirable biological effects are produced, or any other components in the pharmaceutically acceptable compositions are interacted in a harmful manner and are incompatible with the compounds of the present invention, it is concerned that its application belongs to the scope of the present invention.

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

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

The compounds disclosed herein are generally formulated into dosage forms suitable for administration to a patient via a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, 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 should also be recognized that certain compounds of the present invention may be used in free form for treatment, or, if appropriate, in the form of pharmaceutically acceptable derivatives thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or any other adducts or derivatives that can directly or indirectly provide the compounds of the present invention or their metabolites or residues when administered to a patient in need thereof.

In one embodiment, the compounds disclosed herein can be formulated into oral dosage forms. In another embodiment, the compounds disclosed herein can be formulated into inhalation dosage forms. In another embodiment, the compounds disclosed herein can be formulated into nasal dosage forms. In yet another embodiment, the compounds disclosed herein can be formulated into transdermal dosage forms. In yet another embodiment, the compounds disclosed herein can be formulated into topical dosage forms.

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

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

The pharmaceutical composition provided by the present invention can be provided in a soft capsule or a hard capsule, which can be prepared by gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also referred to as a dry-filled capsule (DFC), consists of two sections, one section is inserted into the other section, and thus the active ingredient is completely encapsulated. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by adding glycerol, sorbitol or similar polyols. The soft gelatin shell can contain a preservative to prevent microbial growth. Suitable preservatives are those described in the present invention, including methylparaben and propylparaben, and sorbic acid. Liquid, semisolid and solid dosage forms provided by the present invention can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or sustain dissolution of the active ingredient.

The pharmaceutical compositions provided by the present invention can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in another liquid in the form of globules, which can be oil-in-water or water-in-oil. Emulsions can include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are transparent, sweet-tasting aqueous alcoholic solutions. Syrups are concentrated sugars such as sucrose in aqueous solutions, and can also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with sufficient pharmaceutically acceptable liquid carriers such as water for accurate and convenient administration.

The pharmaceutical composition provided by the present invention can be formulated into any dosage form suitable for inhalation administration to patients, such as dry powder, aerosol, suspension or solution composition. In one embodiment, the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for inhalation administration to patients with dry powder. In another embodiment, the pharmaceutical composition disclosed in the present invention can be formulated into a dosage form suitable for inhalation administration to patients by a nebulizer. The dry powder composition delivered to the lung by inhalation generally comprises a fine powder of the disclosed compound of the present invention and one or more fine powder pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art, including lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared by, for example, micronization and grinding. In general, the size-reduced (such as micronized) compound can be defined by a D ₅₀ value of about 1 to 10 microns (e.g., measured by laser diffraction).

Pharmaceutical compositions suitable for transdermal administration can be prepared as discontinuous patches, intended to remain in close contact with the patient's epidermis for an extended period of time. For example, active ingredients can be delivered from the patch by ion permeation, as generally described in Pharmaceutical Research, 3(6), 318(1986).

The pharmaceutical composition that is suitable for topical administration can be formulated into ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.For example, ointment, cream and gel can be configured with water or oil base, and applicable thickener and/or gel and/or solvent.Such matrix can include, water, and/or oil such as liquid paraffin and vegetable oil (such as peanut oil or castor oil), or solvent such as polyethylene glycol.Thickener and gel used according to matrix properties include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxyvinyl polyol and cellulose derivative, and/or glyceryl monostearate and/or nonionic emulsifier.

The compounds of the present invention can also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or the polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the compounds disclosed in the present invention can be combined with a class of biodegradable polymers used in realizing the controlled release of drugs, for example, crosslinked or amphiphilic block copolymers of polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

Pharmaceutical composition provided by the invention can be administered parenterally by injection, infusion or implantation, for local or systemic administration. Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

Pharmaceutical composition provided by the invention can be formulated into any dosage form suitable for parenteral administration, including solution, suspension, emulsion, micelle, liposome, microsphere, nano system and the solid form suitable for making solution or suspension in liquid before injection. Such dosage form can be prepared according to the conventional method known to the technicians in the field of pharmaceutical science (referring to Remington:The Science and Practice of Pharmacy, the same).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solution enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestrants or chelating agents, antifreeze agents, cryoprotectants, thickeners, pH adjusters and inert gases.

The pharmaceutical composition provided by the present invention can be administered via rectal suppositories, by mixing the drug with a suitable non-irritating excipient (such as cocoa butter, glyceride synthesized from polyethylene glycol), which is solid at room temperature, and then liquefying or dissolving in the rectal cavity to release the drug. Due to individual differences, the severity of symptoms will show a relatively large variation, and each drug has its own unique therapeutic properties. Therefore, the precise administration method, dosage form and treatment plan for each individual should be determined by a practicing physician.

The pharmaceutical compositions provided herein can be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

Although the compounds of the present invention can be administered directly without any formulation, the compounds of the present invention are usually administered in the form of pharmaceutical formulations containing pharmaceutically acceptable excipients 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 administration. Many of the compounds used in the methods of the present invention are effective as injection and oral compositions.

For transdermal administration, a transdermal delivery device ("patch") is needed. This transdermal patch can be used to continuously or intermittently inject a controlled amount of the compound of the present invention. The structure and application of transdermal patches for delivering drugs are well known in the art. For example, see, US5,023,252. This patch can be made into a continuous, pulsating or on-demand release drug.

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

In a preferred embodiment of the present invention, a pharmaceutical preparation containing at least one of the above-mentioned active compounds and suitable for buccal and/or sublingual or nasal administration is provided. This embodiment provides a way to avoid gastric complications (e.g., first bypassing gastric system metabolism and/or first passing through liver metabolism) to administer the active compound. This route of administration can also reduce the adsorption time, thereby bringing about a therapeutic effect more quickly. The compounds of the present invention can also provide a particularly advantageous solubility distribution, which is conducive to sublingual/buccal administration preparations. Such preparations generally require a relatively high concentration of active ingredients, so that within the short duration of the preparation contacting the sublingual/buccal mucosal surface, sufficient active ingredients are transmitted to the limited surface of the sublingual/buccal mucosa, so that the active ingredients are absorbed. Therefore, the extremely high activity of the compounds of the present invention and their high solubility make them suitable for preparing sublingual/buccal administration preparations.

As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to show a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate the symptoms of a disease that is administered or allowed to reach equilibrium in the body. The effective amount required for a particular treatment regimen depends on a variety of factors, including the disease being treated, the severity of the disease, the activity of the specific drug used, the method of administration, the clearance rate of the specific drug, the duration of treatment, combined medication, age, weight, sex, diet and health of the patient, etc. For a description of other factors that need to be considered in the field of "therapeutically effective amount", see Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8 ^th ed., Pergamon Press, 1990; Remington's Pharmaceutical Sciences, 17 ^th ed., Mack Publishing Company, Easton, Pa., 1990.

The compound of formula (I) is preferably formulated into a unit dosage form, each dose containing about 0.001-100 mg of active ingredient, more usually about 1.0-30 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human patients and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect and a suitable pharmaceutically acceptable excipient as described above.

Active compounds are usually effective in a wide range of dosages. For example, the daily dosage is generally about 0.0001-30 mg/kg body weight. For adult treatment, a particularly preferred dosage (single dose or divided dose) is about 0.1-15 mg/kg/day. However, it should be understood that the actual amount of compound administered will be determined by the attending physician according to relevant circumstances, including the disease being treated, the selected route of administration, the actual one or more compounds to be taken, the age, body weight and response of the specific patient, and the severity of the patient's symptoms, and therefore, the above dosage range should not limit the scope of the invention in any way. In some cases, a dosage level lower than the lower limit of the above dosage range may be more appropriate, and in other cases, a higher dosage without any side effects can be used, with the prerequisite that this larger dose is first divided into several smaller doses for administration throughout the day.

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

The preferred route of administration will vary with clinical characteristics, and the change in dosage must depend on the condition of the patient being treated. The doctor will determine the appropriate dosage based on the individual patient. The therapeutically effective amount per unit dose depends on body weight, physiological function and the selected vaccination regimen. The compound per unit dose refers to the weight of the compound at each administration, excluding the weight of the carrier (the drug contains a carrier).

The pharmaceutical composition provided by the present invention can be formulated into single dose or multiple dose administration. The single dose preparation is packaged in an ampoule, a vial or a syringe. The multiple dose parenteral preparation must contain an antimicrobial agent at a bacteriostatic or antifungal concentration. All parenteral preparations must be sterile, as known and practiced in the art.

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

In one embodiment, the treatment method of the present invention comprises administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need thereof. Various embodiments of the present invention include treating the diseases mentioned in the present invention by administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need thereof.

In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, ear, vaginal, inhalation and intranasal administration. In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be oral administration. In another embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be inhalation administration. In another embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention can be intranasal administration.

In one embodiment, the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention can be administered once, or several times at different time intervals within a specified time period according to a dosing regimen. For example, once, twice, three times or four times a day. In one embodiment, it is administered once a day. In another embodiment, it is administered twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosing regimen of the compound of the present invention or a pharmaceutical composition comprising the 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 a technician. In addition, the appropriate dosing regimen of the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, including the duration of the implementation of the regimen, 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., within the knowledge and experience of the technician. Such a technician should also understand that for individual patients' responses to the dosing regimen, or when individual patients' needs change over time, it may be required to adjust the appropriate dosing regimen.

The compounds of the present invention can be administered simultaneously with one or more other therapeutic agents, or before or after them. The compounds of the present invention can be administered separately with other therapeutic agents by the same or different routes of administration, or in the form of the same pharmaceutical composition. This is selected by those skilled in the art based on the actual physical conditions of the patient, such as health, age, weight, etc. If formulated as a fixed dose, this combination product uses the compounds of the present invention (within the dosage range described herein) and other pharmaceutically active agents (within its dosage range).

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

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

Uses of the compounds and pharmaceutical compositions of the present invention

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

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

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

The compounds of the present invention can be applied to, but are not limited to, the use of the compounds of the present invention or the effective amount of the pharmaceutical composition administered to patients to prevent, treat or alleviate diseases related to the 5-HT _1F receptor. The diseases related to the 5-HT _1F receptor further include, but are not limited to, migraine, general pain, trigeminal neuralgia, toothache or pain in temporomandibular joint dysfunction, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, destructive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss and dementia.

The compounds and pharmaceutical compositions of the present invention are useful for human treatment and can also be used in veterinary treatment of pets, introduced species of animals and mammals in farm animals. Other examples of animals include horses, dogs and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

General synthetic steps

To describe the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following reaction schemes and examples are provided to further illustrate the present invention.

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

In the examples described below, all temperatures are set forth 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. Common reagents were purchased 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 ether were obtained by drying under reflux with sodium metal. Anhydrous dichloromethane and chloroform were obtained by drying under reflux 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 were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.

The chromatographic column used was a silica gel column, and the silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

¹ H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz NMR spectrometer. ¹ H NMR spectra were recorded using CDCl ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as solvents (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), ddd (doublet of doublet ofdoublets), dt (doublet of triplets), td (triplet of doublets), tt (triplet of triplets). The coupling constant, J, is expressed in Hertz (Hz).

The determination conditions of low-resolution mass spectrometry (MS) data were: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1x30mm, 3.5 microns, 6min, flow rate 0.6mL/min. Mobile phase: 5%-95% (CH ₃ CN containing 0.1% formic acid) in (H ₂ O containing 0.1% formic acid), electrospray ionization (ESI), at 210nm/254nm, with UV detection.

The pure compounds were analyzed using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80 mm DAC) with UV detection at 210 nm/254 nm.

The following abbreviations are used throughout this invention:

CH ₂ Cl ₂ , DCM dichloromethane mg

CDC1 _3- deuterated chloroform g

DMSO dimethyl sulfoxide mL, ml milliliter

DMSO-d _6- deuterated dimethyl sulfoxide μL, μl microliter

EtOAc, EA Ethyl acetate nL, nl Nanoliter

CH ₃ OH, MeOH methanol min minutes

CD ₃ OD deuterated methanol h hours

nM nanomole per liter PE petroleum ether (60-90℃)

μM micromoles per liter RT, rt, r.t. room temperature

mM millimole per liter EDTA-K _2- ethylenediaminetetraacetic acid dipotassium

M moles per liter PEG400 polyethylene glycol 400

ng nanogram Boc, BOC tert-butyloxycarbonyl

μg microgram cAMP Cyclic adenosine monophosphat

e. cyclic adenosine monophosphate

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

The following synthetic schemes describe procedures for preparing compounds disclosed herein, wherein each R ^1a , R ^1b , R ^1c , R ^1d and X has the meanings described herein unless otherwise stated.

Synthesis Scheme 1

Wherein, R ^u is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₃ -C ₈ cycloalkyl.

发生Borch还原胺化反应，得到式(8)所示的目标产物。The compound represented by formula ( 8 ) can be prepared by the following process: the compound represented by formula ( 1 ) is reacted with methoxymethylamine hydrochloride to obtain the compound represented by formula ( 2 ); then the compound represented by formula ( 2 ) is reacted with the compound represented by formula ( 3 ) to obtain the compound represented by formula ( 4 ). The compound represented by formula ( 4 ) is reacted with the compound represented by formula ( 5 ) to obtain the compound represented by formula ( 6 ). The compound represented by formula ( 6 ) is deprotected from the Boc protecting group to obtain the compound represented by formula ( 7 ); in the presence of a reducing agent (e.g., sodium cyanoborohydride), the NH of the azaspiro[3.3]heptane of the compound represented by formula ( 7 ) reacts with the corresponding aldehyde.

Borch reduction amination reaction occurs to obtain the target product represented by formula ( 8 ).

The compounds, pharmaceutical compositions and applications of the present invention are further described below in conjunction with the examples.

Example

Example 1 Synthesis of 4-fluoro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)benzamide

Step 1) Synthesis of tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate

2-(tert-Butyloxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (1.5 g, 6.2 mmol) and dichloromethane (15 mL) were added to a 100 mL single-necked flask at 0°C, and N,N-diisopropylethylamine (3 mL, 18.2 mmol) and HATU (4.7 g, 11.7 mmol) were added, and the reaction was continued for half an hour under nitrogen protection; then methoxymethylamine hydrochloride (1.2 g, 12.3 mmol) was added, and the reaction was transferred to 25°C for 3 hours; the reaction was stopped, water (20 mL) was added, and then extracted with dichloromethane (30 mL×2), the organic phase was collected, anhydrous sodium sulfate (1 g) was added for drying, filtered, the filtrate was decompressed and dried, and the title compound was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to obtain the title compound as a light yellow oil (1.67 g, 94.0%).

MS(ESI,pos.ion)m/z:285.1[M+H] ⁺ ;

Step 2) Synthesis of tert-butyl 6-(6-bromopyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate

2,6-Dibromopyridine (2.8 g, 11.8 mmol) and dichloromethane (20 mL) were added to a 100 mL single-necked flask at -78 °C, and n-butyllithium (2.5 M, 4.2 mL) was added dropwise under nitrogen protection. After stirring for 1 hour, tert-butyl 6-(methoxy(methyl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.67 g, 5.87 mmol) was added, and the stirring reaction was continued for 2 hours. Then, water (20 mL) was added to quench the reaction, and the liquids were separated. The organic phase was collected, and the mixture was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 5/1) after decompression and drying. The title compound was obtained as a red oil (1.2 g, %).

MS(ESI,pos.ion)m/z:325.3[M+H-56] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.00 (dd, J = 7.3, 0.9Hz, 1H), 7.68 (dt, J = 7.8, 7.4Hz, 2H), 4.31 (quint, J = 8.4Hz, 1H), 4.04 (s, 2H), 3.86 (s, 2H), 2.50 (dd, J = 8.3, 4.8Hz, 4H), 1.44 (s, 9H).

Step 3) tert-butyl 6-(6-((4-fluorobenzoyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3]heptane- Synthesis of 2-carboxylates

Tert-butyl 6-(6-bromopyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (600 mg, 1.57 mmol), 4-fluorobenzamide (350 mg, 2.51 mmol), potassium carbonate (1.5 g, 10.9 mmol), cuprous iodide (100 mg, 0.52 mmol), (1R, 2R)-N ₁ ,N ₂ -Dimethylcyclohexane-1,2-diamine (135 mg, 0.95 mmol), water (1.5 mL) and toluene (10 mL) were added to a 100 mL single-necked flask, and the reaction was continued at 90 ° C for 12 hours under nitrogen protection; the reaction was stopped, water (20 mL) was added, and then extracted with dichloromethane (30 mL×2), the organic phase was collected, anhydrous sodium sulfate (1.5 g) was added for drying, filtered, the filtrate was dried under reduced pressure, and the title compound was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to obtain the title compound as a white solid (0.3 g, 43.4%).

MS(ESI,pos.ion)m/z:440.2[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.00 (dd, J = 7.3, 0.9Hz, 1H), 7.68 (dt, J = 7.8, 7.4Hz, 2H), 4.31 (quint, J = 8.4Hz, 1H), 4.04 (s, 2H), 3.86 (s, 2H), 2.50 (dd, J = 8.3, 4.8Hz, 4H), 1.44 (s, 9H).

Step 4) Synthesis of N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-4-fluorobenzamide

At 25°C, tert-butyl 6-(6-((4-fluorobenzoyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (430 mg, 0.98 mmol) and dichloromethane (10 mL) were added to a 100 mL single-necked round-bottom flask, and methanesulfonic acid (0.3 mL, 4.8 mmol) was added, and the reaction was continued to stir for 10 hours; the reaction was stopped, the mixture was evaporated under reduced pressure, saturated sodium bicarbonate solution (40 mL) was added, and then dichloromethane was added for extraction (40 mL); the liquids were separated, and the organic phase was dried over anhydrous sodium sulfate (1 g); filtered, and the filtrate was evaporated under reduced pressure to obtain the title compound as a light yellow solid (320 mg, 86%).

MS(ESI,pos.ion)m/z:340.2[M+H] ⁺ ;

Step 5) Preparation of 4-fluoro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)benzamide synthesis

At 25°C, N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-4-fluorobenzamide (320 mg, 0.94 mmol) and methanol (5 mL) were added to a 50 mL single-mouth round-bottom flask, and acetic acid (0.18 mL, 3.0 mmol) was added; formaldehyde (40%, 0.2 mL, 3.5 mmol) was added, and then sodium cyanoborohydride (188 mg, 3.0 mmol) was added to the reaction solution in batches. After continuing the reaction for 3 hours, saturated sodium bicarbonate solution was added to quench (20 mL), and then extracted with dichloromethane (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate (2 g); filtered, the filtrate was decompressed and dried, and purified by column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain the title compound as a white solid (210 mg, 63.2%).

MS(ESI,pos.ion)m/z:354.3[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.56 (d, J = 12.7Hz, 1H), 8.52 (d, J = 7.8Hz, 1H), 7.98 (s, 2H), 7.92–7.86 (m, 1H),7.80(d,J＝6.8Hz,1H),7.23(d,J＝7.4Hz,2H),4.28–4.15(m,1H),3.32(br,5H),2.53–2.29(m,6H) ).

Example 2 Synthesis of 4-chloro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)benzamide

Step 1) tert-butyl 6-(6-((4-chlorobenzoyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3]heptane- Synthesis of 2-carboxylates

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, i.e., tert-butyl 6-(6-bromopyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (600 mg, 1.57 mmol), 4-chlorobenzamide (370 mg, 2.38 mmol), potassium carbonate (1.5 g, 10.9 mmol), cuprous iodide (180 mg, 0.95 mmol), (1R,2R)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (130 mg, 0.91 mmol) and water (1.5 mL) were reacted in toluene (10 mL). The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to obtain the title compound as a white solid (470 mg, 65.5%).

MS(ESI,pos.ion)m/z:456.4[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.56 (d, J = 8.2Hz, 1H), 8.48 (s, 1H), 7.97–7.88 (m, 3H), 7.84 (d, J = 7.5Hz, 1H),7.52(d,J＝8.6Hz,2H),4.28(p,J＝8.2Hz,1H),4.05(s,2H),3.88(s,2H),2.58–2.43(m,4H), 1.45(s,9H).

Step 2) Synthesis of N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-4-chlorobenzamide

The title compound of this step was prepared by referring to the method described in Step 4 of Example 1, i.e., tert-butyl 6-(6-((4-chlorobenzoyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (470 mg, 1.03 mmol) and methanesulfonic acid (0.6 mL, 9.6 mmol) were reacted in dichloromethane (5 mL) to obtain the title compound as a light yellow solid (360 mg, 98.1%).

MS(ESI,pos.ion)m/z:356.1[M+H] ⁺ ;

Step 3) Preparation of 4-chloro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)benzamide synthesis

The title compound of this step was prepared by referring to the method described in Step 5 of Example 1, i.e., N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-4-chlorobenzamide (360 mg, 1.01 mmol), acetic acid (100 mg, 1.67 mmol), sodium cyanoborohydride (160 mg, 2.53 mmol) and formaldehyde (40%, 0.65 mL, 9 mmol) were reacted in methanol (5 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (210 mg, 56.1%).

MS(ESI,pos.ion)m/z:370.1[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.66–8.38 (m, 2H), 7.93–7.89 (m, 3H), 7.81 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 8.4 Hz,2H),4.24(quint,J＝8.4Hz,1H),3.47–3.13(m,4H),2.49–2.44(m,4H),2.31(s,3H).

Example 3 Synthesis of 2,4-difluoro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)benzamide

Step 1) tert-butyl 6-(6-((2,4-difluorobenzoyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3]heptyl Synthesis of Alkane-2-Carboxylates

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, i.e., tert-butyl 6-(6-bromopyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (700 mg, 1.84 mmol), 2,4-difluorobenzamide (600 mg, 3.82 mmol), potassium carbonate (1.7 g, 12.3 mmol), cuprous iodide (200 mg, 1.05 mmol), (1R,2R)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (160 mg, 1.12 mmol) and water (1.5 mL) were reacted in toluene (10 mL), and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to obtain the title compound as a white solid (0.5 g, 59.5%).

MS(ESI,pos.ion)m/z:458.1[M+H] ⁺ ;

Step 2) Synthesis of N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-2,4-difluorobenzamide become

The title compound of this step was prepared by referring to the method described in Step 4 of Example 1, i.e., tert-butyl 6-(6-((2,4-difluorobenzoyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 1.09 mmol) and methanesulfonic acid (0.32 mL, 5.2 mmol) were reacted in dichloromethane (5 mL) to obtain the title compound as a light yellow solid (390 mg, 99%).

MS(ESI,pos.ion)m/z:358.1[M+H] ⁺ ;

Step 3) 2,4-difluoro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)benzoyl Synthesis of amines

The title compound of this step was prepared by referring to the method described in Step 5 of Example 1, i.e., N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-2,4-difluorobenzamide (390 mg, 1.09 mmol), acetic acid (100 mg, 1.67 mmol), sodium cyanoborohydride (82 mg, 1.31 mmol) and formaldehyde (40%, 0.65 mL, 9 mmol) were reacted in methanol (5 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (170 mg, 41.9%).

MS(ESI,pos.ion)m/z:372.3[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.98 (d, J = 12.9 Hz, 1H), 8.54 ( d, J = 8.1 Hz, 1H), 8.18 ( dd, J = 15.4, 8.6 Hz, 1H) ,7.90(t,J＝7.8Hz,1H),7.84–7.74(m,1H),7.08(t,J＝7.3Hz,1H),7.04–6.93(m,1H),4.55–3.86(m,5H ), 2.80 (s, 3H), 2.64 (d, J = 6.5Hz, 4H).

Example 4 4-Chloro-2-fluoro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)benzene Synthesis of formamide

Step 1) tert-butyl 6-(6-((4-chloro-2-fluorobenzoyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3] Synthesis of Heptane-2-Carboxylate

The title compound of this step was prepared by the method described in Step 3 of Example 1, i.e., tert-butyl 6-(6-bromopyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 1.31 mmol), 4-chloro-2-fluorobenzamide (350 mg, 2.02 mmol), potassium carbonate (1.5 g, 10.9 mmol), cuprous iodide (100 mg, 0.53 mmol), (1R,2R)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (135 mg, 0.95 mmol) and water (1.5 mL) were reacted in toluene (10 mL). The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to obtain the title compound as a white solid (415 mg, 66.8%).

MS(ESI,pos.ion)m/z:474.0[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 9.00 (d, J = 13.8Hz, 1H), 8.56 (d, J = 8.2Hz, 1H), 8.16 (t, J = 8.5Hz, 1H), 7.93 (t,J＝7.9Hz,1H),7.89–7.81(m,1H),7.38(dd,J＝8.5,1.7Hz,1H),7.31(dd,J＝11.7,1.8Hz,1H),4.28( quint,J＝8.4Hz,1H),4.06(s,2H),3.88(s,2H),2.58–2.44(m,4H),1.46(s,9H).

Step 2) Synthesis of N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-4-chloro-2-fluorobenzamide become

The title compound of this step was prepared by referring to the method described in Step 4 of Example 1, i.e., tert-butyl 6-(6-((4-chloro-2-fluorobenzoyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (510 mg, 1.07 mmol) and methanesulfonic acid (0.35 mL, 5.7 mmol) were reacted in dichloromethane (5 mL) to obtain the title compound as a light yellow solid (400 mg, 99%).

MS(ESI,pos.ion)m/z:374.1[M+H] ⁺ ;

Step 3) 4-chloro-2-fluoro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)benzene Synthesis of amides

The title compound of this step was prepared by referring to the method described in Step 5 of Example 1, i.e., N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-4-chloro-2-fluorobenzamide (400 mg, 1.07 mmol), acetic acid (100 mg, 1.67 mmol), sodium cyanoborohydride (80 mg, 1.27 mmol) and formaldehyde (40%, 0.65 mL, 9 mmol) were reacted in methanol (5 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to obtain the title compound as a white solid (0.21 mg, 50.6%).

MS(ESI,pos.ion)m/z:388.2[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 9.00 (d, J = 13.4Hz, 1H), 8.54 (d, J = 8.1Hz, 1H), 8.14 (t, J = 8.5Hz, 1H), 7.91 (t,J＝7.8Hz,1H),7.84(d,J＝7.4Hz,1H),7.36(d,J＝8.4Hz,1H),4.33–4.17(m,1H),3.49–3.16(m, 4H), 2.48 (d, J = 8.4Hz, 4H), 2.35 (s, 3H).

Example 5 Synthesis of 2,4,6-trifluoro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)benzamide

Step 1) tert-butyl 6-(6-((2,4,6-trifluorobenzoyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3] Synthesis of Heptane-2-Carboxylate

The title compound of this step was prepared by referring to the method described in step 3 of Example 1, i.e., tert-butyl 6-(6-bromopyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (600 mg, 1.57 mmol), 2,4,6-trifluorobenzamide (350 mg, 2.0 mmol), potassium carbonate (1.5 g, 10.9 mmol), cuprous iodide (100 mg, 0.53 mmol), (1R,2R)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (135 mg, 0.95 mmol) and water (1.5 mL) were reacted in toluene (10 mL). The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to obtain the title compound as a white solid (0.51 g, 68.2%).

MS(ESI,pos.ion)m/z:476.2[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.53 (d, J = 8.1Hz, 1H), 8.37 (s, 1H), 7.94 (t, J = 7.9Hz, 1H), 7.86 (d, J = 7.5Hz,1H),6.83(dd,J＝14.5,6.2Hz,2H),4.23(quint,J＝8.3Hz,1H),4.03(s,2H),3.86(s,2H),2.53–2.43( m,4H),1.44(s,9H).

Step 2) Preparation of N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-2,4,6-trifluorobenzamide synthesis

The title compound of this step was prepared by referring to the method described in Step 4 of Example 1, i.e., tert-butyl 6-(6-((2,4,6-trifluorobenzoyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (510 mg, 1.07 mmol) and methanesulfonic acid (0.32 mL, 5.2 mmol) in dichloromethane (5 mL) to obtain the title compound as a light yellow solid (0.39 g, 97%).

MS(ESI,pos.ion)m/z:376.1[M+H] ⁺ ;

Step 3) 2,4,6-trifluoro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)benzene Synthesis of amides

The title compound of this step was prepared by referring to the method described in Step 5 of Example 1, i.e., N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-2,4,6-trifluorobenzamide (390 mg, 1.04 mmol), acetic acid (100 mg, 1.67 mmol), sodium cyanoborohydride (80 mg, 1.27 mmol) and formaldehyde (40%, 0.65 mL, 9 mmol) were reacted in methanol (5 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to obtain the title compound as a white solid (0.22 g, 54.4%).

MS(ESI,pos.ion)m/z:390.1[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.98 (d, J = 12.9 Hz, 1H), 8.54 ( d, J = 8.1 Hz, 1H), 8.18 ( dd, J = 15.4, 8.6 Hz, 1H) ,7.90(t,J＝7.8Hz,1H),7.84–7.74(m,1H),7.08(t,J＝7.3Hz,1H),7.04–6.93(m,1H),4.55–3.86(m,5H ), 2.80 (s, 3H), 2.64 (d, J = 6.5Hz, 4H).

Example 6 Synthesis of 5-fluoro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)picolinamide

Step 1) tert-butyl 6-(6-((5-fluoropyridine-2-carbonyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3] Synthesis of Heptane-2-Carboxylate

The title compound of this step was prepared by the method described in step 3 of Example 1, i.e., tert-butyl 6-(6-bromopyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (600 mg, 1.57 mmol), 5-fluoropyridine-2-carboxamide (330 mg, 2.36 mmol), potassium carbonate (1.5 g, 10.9 mmol), cuprous iodide (180 mg, 0.95 mmol), (1R,2R)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (135 mg, 0.95 mmol) and water (1.5 mL) were reacted in toluene (10 mL). The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to obtain the title compound as a white solid (0.43 g, 62.0%).

MS(ESI,pos.ion)m/z:441.4[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 10.30 (s, 1H), 8.59 (dd, J = 12.3, 5.4Hz, 2H), 8.38 (dd, J = 8.7, 4.5Hz, 1H), 7.92 ( t,J＝7.9Hz,1H),7.87–7.80(m,1H),7.65(td,J＝8.3,2.7Hz,1H),4.36(quint,J＝8.4Hz,1H),4.08(s,2H ), 3.87 (s, 2H), 2.53 (d, J = 8.4Hz, 4H), 1.46 (s, 9H).

Step 2) Synthesis of N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-5-fluoropyridine-2-carboxamide become

The title compound of this step was prepared by referring to the method described in Step 4 of Example 1, i.e., tert-butyl 6-(6-((5-fluoropyridine-2-carbonyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (430 mg, 0.98 mmol) and methanesulfonic acid (0.3 mL, 4.88 mmol) were reacted in dichloromethane (5 mL) to obtain the title compound as a light yellow solid (0.33 g, 99%).

MS(ESI,pos.ion)m/z:341.1[M+H] ⁺ ;

Step 3) Preparation of 5-fluoro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)pyridineamide synthesis

The title compound of this step was prepared by referring to the method described in Step 5 of Example 1, i.e., N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-5-fluoropyridine-2-carboxamide (330 mg, 0.97 mmol), acetic acid (100 mg, 1.67 mmol), sodium cyanoborohydride (70 mg, 1.11 mmol) and formaldehyde (40%, 0.65 mL, 9 mmol) were reacted in methanol (5 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (207 mg, 60.3%).

MS(ESI,pos.ion)m/z:355.3[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.98 (d, J = 12.9 Hz, 1H), 8.54 ( d, J = 8.1 Hz, 1H), 8.18 ( dd, J = 15.4, 8.6 Hz, 1H) ,7.90(t,J＝7.8Hz,1H),7.84–7.74(m,1H),7.08(t,J＝7.3Hz,1H),7.04–6.93(m,1H),4.55–3.86(m,5H ), 2.80 (s, 3H), 2.64 (d, J = 6.5Hz, 4H).

Example 7 Synthesis of 5-chloro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)picolinamide

Step 1) tert-butyl 6-(6-((5-chloropyridine-2-carbonyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3] Synthesis of Heptane-2-Carboxylate

The title compound of this step was prepared by referring to the method described in step 3 of example 1, i.e., tert-butyl 6-(6-bromopyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (600 mg, 1.57 mmol), 5-chloropyridine-2-carboxamide (350 mg, 2.23 mmol), potassium carbonate (1.5 g, 10.9 mmol), cuprous iodide (100 mg, 0.53 mmol), (1R,2R)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (135 mg, 0.95 mmol) and water (1.5 mL) were reacted in toluene (10 mL). The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a white solid (0.44 g, 61.2%).

MS(ESI,pos.ion)m/z:457.3[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 10.32 (s, 1H), 8.69 (d, J = 1.9Hz, 1H), 8.61 (d, J = 8.1Hz, 1H), 8.29 (t, J = 7.2Hz,1H),7.99–7.88(m,2H),7.85(d,J＝7.5Hz,1H),4.37(quint,J＝8.4Hz,1H),4.09(s,2H),3.89(s, 2H), 2.54 (d, J = 8.4Hz, 4H), 1.46 (s, 9H).

Step 2) Synthesis of N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-5-chloropyridine-2-carboxamide become

The title compound of this step was prepared by referring to the method described in Step 4 of Example 1, i.e., tert-butyl 6-(6-((5-chloropyridine-2-carbonyl)amino)pyridine-2-carbonyl)-2-azaspiro[3.3]heptane-2-carboxylate (440 mg, 0.96 mmol) and methanesulfonic acid (0.6 g, 6.2 mmol) were reacted in dichloromethane (5 mL) to obtain the title compound as a light yellow solid (0.34 g, 98.9%).

MS(ESI,pos.ion)m/z:357.1[M+H] ⁺ ;

Step 3) 5-chloro-N-(6-(2-methyl-2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)pyridineamide synthesis

The title compound of this step was prepared by referring to the method described in Step 5 of Example 1, i.e., N-(6-(2-azaspiro[3.3]heptane-6-carbonyl)pyridin-2-yl)-5-chloropyridine-2-carboxamide (340 mg, 0.95 mmol), acetic acid (100 mg, 1.67 mmol), sodium cyanoborohydride (50 mg, 0.79 mmol) and formaldehyde (40%, 0.65 mL, 9 mmol) were reacted in methanol (5 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30/1) to give the title compound as a white solid (195 mg, 55.2%).

MS(ESI,pos.ion)m/z:371.1[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 10.28 (s, 1H), 8.65 (s, 1H), 8.57 (d, J = 8.2Hz, 1H), 8.26 (d, J = 8.4Hz, 1H) ,7.90(dt,J＝16.0,5.4Hz,2H),7.80(d,J＝7.5Hz,1H),4.33(quint,J＝8.4Hz,1H),3.60(s,2H),3.42(s, 2H),2.54–2.51(m,4H),2.45(s,3H).

Biological tests

Example A: Evaluation of the agonist effect of the compounds of the present invention on human 5-HT _1F receptors transfected with CHO-K1 cells

Experimental purpose: Use HitHunter cAMP detection kit to evaluate the agonist effect of the compounds of the present invention on human 5-HT _1F receptors transfected with CHO-K1 cells.

Brief experimental process: CHO-K1 cells were cultured in a 384-well microplate with a volume of 20 μL of cell culture medium (AssayComplete ^TM Cell Plating Reagent, DIscoverX) and a cell density of 10,000/well, and cultured overnight at 37°C and 5% CO _2. Then the culture medium was removed, and 15 μL of cAMP Assay Buffer (DIscoverX) was added to each well, followed by 5 μL of a test sample containing 4X test substance (test compound or 5-HT) and 4X monkey tin (monkey tin final concentration of 15 μM), and the microplate was cultured at 37°C for 30 minutes. Then 5 μL of cAMP Antibody Reagent (DiscoverX) and 20 μL of cAMP Working Detection Solution (DiscoverX) were added and incubated in the dark for 1 hour, and then 20 μL of cAMPSolution A was added and incubated in the dark for 3 hours. The microplate was placed in a microplate reader (PerkinElmer EnvisionTM) to read the luminescent signal intensity. By testing different concentrations of compounds, the corresponding luminescent signal intensity is obtained, and the excitation rate is calculated ((1-(Y/Z))*100%=excitation rate, where Y represents the luminescent signal intensity of the test sample, and Z represents the luminescent signal intensity of only adding monkey horn), and then the compound dose-effect curve is calculated by Prism software, and the agonist concentration that produces half-maximal response is expressed as EC ₅₀ value. The results are shown in Table A. In this experiment, 5-HT was used as a positive control drug to ensure that the experimental system is normal.

Table A: Results of the agonist effect of the compounds of the present invention on human 5-HT _1F receptors transfected with CHO-K1 cells

Example No. _EC50 (μM) Example 3 +++ Example 4 +++ Example 5 +++

Note: +++ means 1μM < EC ₅₀ < 10μM

The experimental results show that the compound of the present invention has strong 5-HT _1F receptor agonist activity.

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

The inventors have conducted pharmacokinetic evaluations on the compounds of the present invention in rats and dogs. The animal information is detailed in Table 1.

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

Germline grade gender weight age source SD rats SPF male 180-350g 6-11 weeks Hunan Slake Jingda Experimental Animal Co., Ltd. Beagle General male 8～12kg June-December Beijing Masi Biotechnology Co., Ltd.

Experimental methods

The compound of the present invention was administered to the test animals in the form of 5% DMSO + 60% PEG400 + 35% Saline solution or 10% DMSO + 10% Kolliphor HS15 + 30% PEG400 + 50% Saline solution. The animals were fasted for 12 hours before administration and had free access to water. For the intravenous administration group, the dosage was 0.5 mg/kg or 1 mg/kg, and blood was collected venously at the following time points after administration (blood volume was about 0.15 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (dog) or 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 h (rats). EDTA-K ₂ was pre-added to the blood collection tube as an anticoagulant, and the blood samples were centrifuged at 12,000 rpm for 2 minutes to collect plasma and store at -20°C or -70°C. For the oral gavage administration group, the administration dose was 2.5 mg/kg or 5 mg/kg, and venous blood was collected at the following time points after administration (blood volume was about 0.15 mL): 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (dog) or 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 h (rats). EDTA-K ₂ was pre-added to the blood collection tube as an anticoagulant, and the blood samples were centrifuged at 12,000 rpm for 2 minutes to collect plasma and store at -20°C or -70°C.

After processing the above collected plasma samples (after the frozen plasma is thawed at room temperature, vortex for 15 seconds to mix, take 10-20 μL of plasma, add 120-150 μL of acetonitrile solution containing internal standard, vortex for 5 minutes to mix, centrifuge at 4,000 rpm for 5 minutes, take 100 μL of supernatant, add 120-150 μL of methanol-water (v/v=1/1) to mix), LC-MS/MS was used to analyze the concentration of the compound in plasma. The analysis results show that the compounds of the present invention have good pharmacokinetic properties in rats and dogs. This shows that the compounds of the present invention have better drugability and better clinical application prospects.

In the description of this specification, the description with reference to the terms "one embodiment", "an implementation", "some embodiments", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment, implementation or example are included in at least one embodiment, implementation or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment, implementation or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments, implementations or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments, implementations or examples described in this specification and the features of different embodiments, implementations or examples, without contradiction.

Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims (10)

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

wherein:

x is N or CR ^x ；

Each R is ^1a 、R ^1b 、R ^1c 、R ^1d And R is ^x H, F, cl, br, I or C independently ₁ -C ₆ An alkyl group;

R ² is H;

R ³ 、R ⁴ and R is ⁵ Each independently is H, F, cl, br, I or C ₁ -C ₆ An alkyl group; and

R ⁶ is H or C ₁ -C ₆ An alkyl group.

2. The compound of claim 1, wherein each R ^1a 、R ^1b 、R ^1c 、R ^1d And R is ^x H, F, cl, br, I or C independently ₁ -C ₄ An alkyl group;

R ² is H;

R ³ 、R ⁴ and R is ⁵ Each independently is H, F, cl, br, I or C ₁ -C ₄ An alkyl group.

3. The compound according to claim 1 or 2, wherein each R ^1a 、R ^1b 、R ^1c 、R ^1d And R is ^x H, F, cl, br, I, methyl, ethyl, n-propyl or isopropyl;

R ² is H;

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

4. The compound of claim 1, wherein R ⁶ Is H or C ₁ -C ₄ An alkyl group.

5. The compound of claim 1 or 4, wherein R ⁶ Is H, methyl, ethyl, n-propyl or isopropyl.

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

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

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

8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the prevention, treatment or alleviation of 5-HT _1F Receptor-related diseases.

9. The use according to claim 8, wherein said peptide is associated with 5-HT _1F The receptor-related disorder is migraine, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive compulsive disorder, panic disorder, depression, social phobia, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual or post-luteal phase syndrome, borderline personality disorder, destructive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, hair-plucking nodules, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss or dementia.

10. Use of a compound according to any one of claims 1-6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for activating 5-HT _1F A receptor.