CN110963999B - 2, 3-dihydrobenzofuran amide derivative and application thereof - Google Patents

Abstract

The invention discloses 2, 3-dihydrobenzofuran amide derivatives and application thereof, and particularly relates to novel 2, 3-dihydrobenzofuran amide derivatives and a pharmaceutical composition containing the same, which can be used as 5-HT₄A receptor agonist. The invention also relates to processes for the preparation of such compounds and pharmaceutical compositions, and their use in the preparation of a medicament for the treatment of 5-HT₄The use in the manufacture of a medicament for the treatment of a disorder associated with receptor activity, in particular constipation-type irritable bowel syndrome (IBS-C).

Description

2, 3-dihydrobenzofuran amide derivative and application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to novel 2, 3-dihydrobenzofuran amide derivatives, a pharmaceutical composition containing the compounds, and a using method and application thereof. In particular, the novel 2, 3-dihydrobenzofuran amide derivatives of the present invention are useful as 5-HT₄Receptor agonists for the prevention, treatment or alleviation of 5-HT₄A disorder associated with receptor activity, in particular irritable bowel syndrome of constipation type (IBS-C).

Background

Irritable Bowel Syndrome (IBS), also known as Irritable Bowel Syndrome, is a group of Bowel dysfunction diseases with persistent or intermittent episodes of altered abdominal pain, abdominal distension, Bowel habits and/or stool behavior to clinical manifestations, but a lack of structural and biochemical abnormalities in the gastrointestinal tract. Roman III classifies the functional bowel disease as a functional bowel disease, the functional bowel disease accounts for about 10% of the general population, patients mainly take young and middle-aged people, the onset age is usually 20-50 years old, women are more common than men, the family aggregation tendency is generated, and the functional bowel disease is often accompanied with other gastrointestinal dysfunction diseases such as functional dyspepsia. In most cases, more than one symptom can appear in more than half of the cases, and the average duration of the symptom aggravation is 1-5 days. IBS is divided into four clinical types of constipation type, diarrhea type, mixed type and uncertain type according to the stool characteristics, and diarrhea type is the main type in China. IBS is one of the most common functional gastrointestinal diseases, seriously affects the quality of life of patients and is a hot spot of current research.

Epidemiological studies around the world have reported that IBS is a frequently encountered disease worldwide. The prevalence rate of the population in western countries reaches 10% -20%, and epidemiological investigation according to Roman II standard in China shows that the prevalence rate of IBS in community population is 5.7%, wherein 22% of IBS is treated once due to IBS symptoms.

5-hydroxytryptamine (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter that is widely distributed throughout the body, both in the central nervous system and in the peripheral system. 5-HT is a monoamine neurotransmitter of importance in the brain-gut junction, and 95% of the human 5-HT is present in the gut, 90% in enterochromaffin cells and 10% in enteric neurons. Higher postprandial 5-HT serum concentrations have been observed in diarrhea predominant IBS patients. There may be dysfunction in the downstream pain-regulating pathways of IBS patients. Higher concentrations of 5-HT are found in the nucleus of endorphin-mediated analgesic systems, which are believed to act as gates, regulating the processing of afferent signals by the posterior horn of the spinal cord. 5-HT has multiple effects, which can lead to smooth muscle contraction (by stimulation of cholinergic nerves) or relaxation (by stimulation of nitric oxide-releasing inhibitory neurons). 5-HT released via the mucosa stimulates both internal and external sensory neurons, the former probably via 5-HT₄The receptor causes secretion and a peristaltic reflex, the latter via 5-HT₃Receptors modulate sensation. 5-HT also modulates sensory function via spinal vagal afferent nerve fibers.

The 5-hydroxytryptamine receptor, also known as serotonin receptor or 5-HT receptor, is a group of G protein-coupled receptors found in the central and peripheral nervous system of the central nervous system and can be divided into seven subfamilies of 5-HT₁、5-HT₂、5-HT₃、5-HT₄、5-HT₅、5-HT₆And 5-HT₇And the interaction between 5-hydroxytryptamine and these different receptors is associated with various physiological functions. Wherein, 5-HT₄Receptors are present in myenteric plexus neurons, primary afferent neurons, enterochromaffin cells, and smooth muscle cells. These receptors may be in vitroThe role of the drugs that mediate the release of certain neurotransmitters in the colon, including acetylcholine, vasoactive intestinal peptide, calcitonin gene-related peptide that stimulates the peristaltic reflex, and substance P, is complex. 5-HT₄Receptors mediate relaxation and contraction of the circular smooth muscle bundle and have multiple effects on longitudinal smooth muscle. 5-HT₄Receptor activation can also cause secretion of fluids from the colon and small intestine.

In particular, characterization of 5-HT₄Receptors and the identification of drug substances with which interactions occur have been the focus of recent research (see, for example, reviews by Langlois and Fischmeister, j.med.chem.2003, 46, 319-. 5-HT₄Receptor agonists useful in therapy and 5-HT₄Disorders associated with receptor activity, particularly disorders of reduced motility of the gastrointestinal tract. Such disorders include Irritable Bowel Syndrome (IBS), chronic constipation, gastroesophageal reflux disease (GERD), delayed gastric emptying, gastroparesis, functional dyspepsia, delayed drug-induced transport, intestinal pseudo-infarction, and post-operative ileus.

Despite modulation of 5-HT₄The drug substance with receptor activity is widely used, but the clinical treatment effect of IBS is still poor at present, and 5-HT is in clinical application₄Few receptor agonist compounds are available. Cisapride is a widely used agent for the treatment of gastrointestinal motility disorders and has exited the market because of its cardiac side effects. While another drug, prucalopride, has been temporarily discontinued in later clinical trials. Therefore, there is an urgent need to develop novel 5-HT compounds that can achieve the desired therapeutic effects with low side effects₄A receptor agonist. Also, preferred formulations may have improved selectivity, potency, duration of action, and/or drug metabolism properties, among other properties.

5-HT₄The receptor stimulant used as a new medicine for treating IBS has the advantages of exact effect, safety, better tolerance and wide application prospect.

Disclosure of Invention

The invention provides a class as 5-HT₄Novel 2, 3-dihydrobenzofuran amide derivatives of receptor agonists useful in the treatment of 5-HT₄Diseases associated with receptor activity, in particular for the treatment of constipation-predominant irritable bowel syndrome (IBS-C). Experiments show that the 2, 3-dihydrobenzofuran amide derivative has stable property, good safety, good pharmacodynamics and pharmacokinetic properties, such as good brain/plasma ratio (brain plasma ratio), good bioavailability or good metabolic stability. Therefore, the method has good clinical application prospect.

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

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

wherein L and R have the meaning as described herein.

In one embodiment, L is- (CR)¹R²)_n-; wherein R is¹、R²And n has the meaning as described in the present invention.

In one embodiment, n is 1,2,3 or 4.

In one embodiment, each R is¹And R²Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, cyano, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy radical, C_1-6Alkylamino radical, amino radical C_1-6Alkyl, hydroxy C_1-6Alkyl or cyano C_1-6An alkyl group.

In another embodiment, each R is¹And R²Independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, cyano, methyl, ethyl, n-propyl,Isopropyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylamino, dimethylamino, aminomethyl, aminoethyl, hydroxymethyl, hydroxyethyl, cyanomethyl or cyanoethyl.

In one embodiment, R is C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms; wherein said R is optionally substituted with 1,2,3 or 4R^xSubstituted; wherein R is^xHave the meaning as described in the present invention.

In another embodiment, R is C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 6 atoms; wherein said R is optionally substituted with 1,2,3 or 4R^xSubstituted; wherein R is^xHave the meaning as described in the present invention.

In yet another embodiment, R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, tetrahydropyranyl, piperazinyl, tetrahydrothienyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, or pyrazinyl; wherein said R is optionally substituted with 1,2,3 or 4R^xSubstituted; wherein R is^xHave the meaning as described in the present invention.

In one embodiment, each R is^xIndependently is ═ O, deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, carboxy, -C (═ O) NH₂、C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy radical, C_1-6Alkanoyl radical, C_1-6Alkylamino radical, amino radical C_1-6Alkyl, hydroxy C_1-6Alkyl, cyano C_1-6Alkyl radical, C_1-6Alkylamino acyl radical, C_1-6Alkoxyacyl, hydroxy C_1-6Alkanoyl, amino C_1-6Alkanoyl, substituted or unsubstituted C_3-6Cycloalkyl, substituted or unsubstituted heterocyclyl of 3 to 6 atoms, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl of 5 to 6 atoms.

In another embodiment, each R is^xIndependently is ═ O, deuterium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, carboxy, -C (═ O) NH₂Methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、-OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methyl acyl, ethyl acyl, methyl amino, dimethylamino, aminomethyl, aminoethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, cyanoethyl, methylaminoacyl, dimethylaminoacyl, methoxyacyl, ethoxyacyl, hydroxymethylacyl, aminomethylacyl, substituted or unsubstituted C_3-6Cycloalkyl, substituted or unsubstituted heterocyclyl of 3 to 6 atoms, substituted or unsubstituted phenyl, or substituted or unsubstituted heteroaryl of 5 to 6 atoms.

Preferably, R is

Wherein said R is optionally substituted with 1,2,3 or 4R^xSubstituted; wherein R is^xHave the meaning as described in the present invention. Further preferably, R is

Wherein each R is^x0、R^x1、R^x2And R^x3Independently is H or R^x(ii) a k is 0, 1,2,3 or 4; wherein R is^xHave the meaning as described in the present invention. Even more preferably, R is

In one embodiment, the compound of the present invention is a compound having one of the following structures or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt of the compound having one of the following structures, or a prodrug thereof:

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

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

In yet another aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein for the preparation of a medicament for the prevention, treatment or amelioration of 5-HT₄Diseases associated with receptor activity.

In one implementationIn the scheme, the alpha-beta-glucosidase is conjugated with 5-HT₄The diseases associated with receptor activity are Irritable Bowel Syndrome (IBS), chronic constipation, diabetic and idiopathic gastric diseases, gastroesophageal reflux disease (GERD), delayed gastric emptying, gastroparesis, functional dyspepsia, delayed drug-induced transport, intestinal pseudo-infarction or postoperative ileus.

In one embodiment, the Irritable Bowel Syndrome (IBS) is constipation type irritable bowel syndrome (IBS-C), diarrhea type irritable bowel syndrome (IBS-D), mixed irritable bowel syndrome (IBS-M), or indeterminate irritable bowel syndrome (IBS-U).

In a further aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof as disclosed in the present invention for the preparation of a medicament for agonizing 5-HT₄A receptor.

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

Biological test results show that the compound of the invention can stimulate 5-HT₄Receptor, and can be a preferred 5-HT₄A receptor agonist.

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

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

Detailed description of the invention

Definitions and general terms

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

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

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

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

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

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

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

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

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

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

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

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

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

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^nd Ed.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

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

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

The term "optionally substituted with …" used interchangeably with the term "unsubstituted or substituted with …" and as used herein with "substituted or unsubstituted" means that the structure is unsubstituted or substituted with one or more substituents as described herein. Substituents described herein 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, -S (═ O)₂NH₂、-S(＝O)₂NHCH₃、-S(＝O)₂N(CH₃)₂、-S(＝O)₂-alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

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

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

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

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

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

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

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

The term "D" denotes a single deuterium atom.

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

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

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

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has as such an alkyl groupThe meaning of the invention is described. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, i.e., C₁-C₆An alkoxy group; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms, i.e., C₁-C₄An alkoxy group; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms, i.e., C₁-C₃An alkoxy group. The alkoxy group may be optionally substituted with one or more substituents described herein.

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

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

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

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

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

The term "aminoalkyl" or "amino-substituted alkyl" means that the alkyl group is substituted with one or more amino groups, wherein the alkyl group has the meaning as described herein. Examples include, but are not limited to, aminomethyl, aminoethyl (e.g., 2-aminoethyl), and the like.

The term "cyanoalkyl" or "cyano-substituted alkyl" means that an alkyl group is substituted with one or more cyano groups, wherein the alkyl group has the meaning as described herein. Examples include, but are not limited to, cyanomethyl, cyanoethyl (e.g., 2-cyanoethyl), and the like.

The term "acyl" refers to a group

For example, "alkanoyl" or "alkylacyl" refers to an alkyl through group

Attached to the rest of the molecule, for example, methylacyl, ethylaccyl, etc.; similarly, alkylaminoacyl and alkoxyacyl refer to alkylamino and alkoxy groups, respectively, through the radical

Attached to the rest of the molecule, e.g., methylaminoacyl, dimethylaminoacyl, methoxyacyl, ethoxyacyl, etc.; wherein the alkyl, alkylamino and alkoxy groups all have the meaning as defined herein.

The terms "hydroxyalkanoyl" and "aminoalkanoyl" mean that an alkanoyl group is substituted with one or more hydroxy or amino groups, respectively, wherein the alkyl group has the meaning as described herein; for example, hydroxymethylacyl or aminomethylacyl groups.

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

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

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

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic or tricyclic ring systems may include fused, bridged and spiro rings. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms, i.e., C₃-C₈A cycloalkyl group; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms, i.e., C₃-C₆A cycloalkyl group. 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 containing 3 to 12 ring atomsWherein said bicyclic or tricyclic ring system may include fused, bridged and spiro rings. Wherein one or more atoms of the ring are independently replaced by a heteroatom having the meaning as described herein. In one embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 8 ring atoms (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give compounds like SO, SO₂，PO，PO₂A group of (d); in yet another embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give compounds like SO, SO₂，PO，PO₂A group of (d); in another embodiment, heterocyclyl is a bicyclic heterocyclyl consisting of 7 to 12 ring atoms (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give the same SO, SO₂，PO，PO₂The group of (1). The heterocyclyl group is optionally substituted with one or more substituents described herein.

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

Radical, diaza

Radical, S-N-aza

Aryl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, and the like. In heterocyclic radicals of-CH₂Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 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 heterocyclyl group is optionally substituted with one or more substituents described herein.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

Suitable pharmaceutically acceptable carriers depend on the pharmaceutical form and are known to the person skilled in the art.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents and solvent mixtures, coatings, complexing agents, solid carriers, dispersion media, surface active excipients, antibacterial and antifungal agents, isotonic and absorption delaying agents for pharmaceutically active substances, and mixtures thereof, which are also known in the art.

Non-limiting examples for pharmaceutically acceptable carriers include those having a composition selected from the group consisting of: lactose, gelatin, sugar alcohols (e.g. starch, mannitol, corn starch, etc.), vegetable oils, talc, magnesium stearate, colloidal silicon dioxide, carboxymethylcellulose, microcrystalline cellulose, sodium lauryl sulfate, aqueous buffered solutions, copovidone, polysorbates, ethanol, propylene glycol, polyglycols (preferably polyethylene glycols, such as PEG400),

80 (i.e. PEG (20), sorbitol monooleate), DMSO, a mixture of water and a co-solvent, for example an aqueous solution comprising an alcohol such as ethanol and/or a polyglycol such as polyethylene glycol, an ester of a polyol such as glycerol and/or polyethylene glycol with a fatty acid, a surfactant such as an anionic, cationic, nonionic and amphoteric surfactant, a complexing agent such as a cyclodextrin, for example alpha-cyclodextrin (alpha-CD) or hydroxypropyl-beta-cyclodextrin (HP-beta-CD), a bile acid or lipid, for example a salt of an animal or vegetable phospholipid, a micellizing agent, and an oil such as corn oil, or a mixture of two or more of the aforementioned components.

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

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

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

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

The compounds or pharmaceutical compositions of the present invention may be administered in any suitable manner including, but not limited to, oral, rectal, vaginal, nasal, inhalation, topical (including transdermal) and parenteral.

In a preferred embodiment, the pharmaceutical composition of the invention is suitable for oral administration. Suitable pharmaceutical compositions for oral administration may be in the form of capsules, pills, tablets, lozenges, granules, powders, cachets, troches, syrups, elixirs, as oil-in-water or water-in-oil liquid emulsions, solutions or suspensions in aqueous or non-aqueous liquids, and the like. Each of which contains a predetermined amount of the compound of the present invention as an active ingredient.

The pharmaceutical compositions of the present invention are preferably packaged in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable for administration to a patient, i.e., units containing a predetermined quantity of active agent calculated to produce the desired therapeutic effect, alone or in combination with one or more other units. For example, such unit dosage forms can be capsules, pills, tablets, and the like.

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

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

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

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

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

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

Suitable liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Such liquid dosage forms typically comprise the active ingredient and an inert diluent, such as water or other solvent. Solubilizers and emulsifiers such as ethanol, isopropanol, propylene glycol, 1, 3-butylene glycol, glycerol, tetrahydrofuryl alcohol, benzyl alcohol, ethyl carbonate, ethyl acetate, benzyl benzoate, oils (especially germ, peanut, corn, olive, cottonseed, castor, and sesame oils), polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, polyoxyethylene sorbitol and sorbitan esters, ethoxylated isostearyl alcohols, microcrystalline cellulose, agar-agar, bentonite, tragacanth and aluminum metahydroxide (aluminum metahydroxide), and mixtures thereof.

The pharmaceutical compositions of the present invention, when used for administration in solid dosage forms (i.e., as capsules, pills, tablets, etc.), generally comprise a compound of the present invention as an active ingredient in combination with one or more pharmaceutically acceptable carriers, such as dicalcium phosphate or sodium citrate. Such solid dosage forms may optionally or alternatively further comprise: (1) fillers or extenders, such as starches, sucrose, lactose, glucose, microcrystalline cellulose, mannitol, and/or silicic acid; (2) binders such as gelatin, sucrose, alginates, carboxymethylcellulose, polyvinylpyrrolidone and/or acacia; (3) humectants, such as glycerol; (4) wetting agents, such as cetyl alcohol and/or glyceryl monostearate; (5) solution retarding agents such as paraffin; (6) disintegrating agents such as alginic acid, agar-agar, calcium carbonate, tapioca or potato starch, certain silicates and/or sodium carbonate; (7) absorption promoters, such as quaternary ammonium compounds; (8) absorbents such as kaolin and/or bentonite clay; (9) lubricants such as magnesium stearate, calcium stearate, talc, sodium lauryl sulfate, solid polyethylene glycols and/or mixtures thereof; (10) a buffering agent; and (11) a colorant.

Flavoring agents, sweetening agents, flavoring agents, coating agents, releasing agents, preserving agents and antioxidants may also be present in the pharmaceutical compositions of the present invention. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, sodium sulfite, sodium hydrogen sulfate, sodium pyrosulfate, cysteine hydrochloride, and the like; (2) oil-soluble antioxidants such as alpha-tocopherol, lecithin, propyl gallate, ascorbyl palmitate, Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), and the like; and (3) metal chelating agents such as phosphoric acid, tartaric acid, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, and the like. Coating agents for tablets, capsules and the like include those used for enteric coating, such as Cellulose Acetate Phthalate (CAP), carboxymethylethylcellulose (CMEC), Cellulose Acetate Trimellitate (CAT), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate (PVAP), methacrylic acid-methacrylate copolymer and the like.

The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension or solution composition. In one embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Such compositions are generally administered using well known delivery devices such as nebulizers, metered dose inhalers, dry powder inhalation devices, or similar delivery devices. When administered by inhalation using a pressurized container, the pharmaceutical compositions of the present invention generally comprise the active ingredient and a suitable propellant, such as dichlorotetrafluoroethane, dichlorodifluoromethane, trichlorofluoromethane, carbon dioxide or other suitable propellantA gas. Additionally, the pharmaceutical composition may be in the form of a capsule or cartridge (e.g., made from gelatin) comprising a compound of the present invention and a powder suitable for use in a dry powder inhalation device. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound of the disclosed invention and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. Fine powders may be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns₅₀Values (e.g., measured by laser diffraction).

Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986). The compounds of the present invention may also be administered transdermally using well known transdermal delivery systems and excipients. For example, the compounds of the present invention may be mixed with penetration enhancers such as propylene glycol, azacycloalkane-2-ones, polyethylene glycol monolaurate, and the like, and incorporated into a patch or similar delivery system. Additional excipients, including buffers, emulsifiers, gelling agents, and the like, may be used in such transdermal compositions if desired.

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

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

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

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

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

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

The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms. For example, a sustained release dosage form may contemplate the incorporation of the compound therein to an ion exchange resin, which optionally may be coated with a diffusion barrier coating to modify the release properties of the resin.

The pharmaceutical compositions of the present invention may also be formulated to provide sustained or controlled release of the active ingredient using hydroxypropylmethylcellulose or other polymer matrices, microspheres and/or liposomes in varying proportions, if desired.

Furthermore, the pharmaceutical compositions of the present invention may optionally contain opacifying agents and may be formulated such that they release the active ingredient only or, preferably, in a delayed manner, optionally in certain locations of the gastrointestinal tract. Examples of embedding compositions that can be used include waxes and polymers. The active ingredient may also be in microencapsulated form containing one or more of the above excipients.

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

The pharmaceutical compositions of the present invention generally contain a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Typically, such pharmaceutical compositions contain from about 0.1 to about 95% by weight of the active agent, including from about 1 to about 70% by weight, such as from about 5 to about 60% by weight of the active agent.

The present invention provides a method of increasing gastrointestinal motility in a mammal, comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the invention.

The invention also provides methods of treating patients suffering from 5-HT₄A method of treating a disease or condition associated with receptor activity in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.

When used for treating gastrointestinal motility disorder or 5-HT₄Other conditions mediated by the receptor, generally where the compounds of the invention are administered orally in a single daily dose or in multiple doses per day, other forms of administration may also be used. The amount of active agent administered per dose or the total amount administered per day is generally determined by the clinician in view of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

For treating disorders of reduced motility of the gastrointestinal tract or disorders caused by 5-HT₄Suitable dosages for other receptor-mediated disorders are contemplated in the range of about 0.0007 to about 20 mg/kg/day of active agent, including about 0.0007 to about 1 mg/kg/day. For an average 70kg human, the amount is from about 0.05 to about 70 mg/day of active agent.

In one aspect, the compounds of the invention are useful for the treatment of irritable bowel syndrome. When used to treat constipation-type irritable bowel syndrome, the compounds of the present invention are generally administered orally in a single daily dose or in multiple doses per day. The dosage for treating constipation-type irritable bowel syndrome is expected to be from about 0.05 to about 70 mg/day.

In another aspect, the compounds of the invention are useful for treating diabetic gastroparesis. When used to treat diabetic gastroparesis, the compounds of the present invention are generally administered orally in a single daily dose or in multiple doses per day. The dosage for treating diabetic gastroparesis is expected to be from about 0.05 to about 70 mg/day.

In yet another aspect, the compounds of the invention are useful for treating functional dyspepsia. When used to treat functional dyspepsia, the compounds of the present invention are generally administered orally in a single daily dose or in multiple doses per day. The dosage for treating functional dyspepsia is expected to be about 0.05 to about 70 mg/day.

In yet another aspect, the compounds of the present invention are useful for treating chronic constipation. When used to treat chronic constipation, the compounds of the present invention are generally administered orally in a single daily dose or in multiple doses per day. The dosage for treating chronic constipation is expected to be about 0.05 to about 70 mg/day.

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

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

Any suitable route of administration may be employed to provide an effective dose of a compound of the invention to a mammal, especially a human. For example, oral administration, rectal administration, parenteral administration, topical administration, ocular administration, nasal administration, pulmonary administration, and the like can be employed. Dosage forms include tablets, troches, capsules, creams, ointments, suspensions, dispersions, solutions, aerosols, and the like. Preferably, the compound of formula (I) or (II) is administered orally.

The effective dosage of the active ingredient employed will vary with the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages are readily determined by one skilled in the art.

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

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

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

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

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

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

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

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

Use of the Compounds and pharmaceutical compositions of the invention

The compounds and pharmaceutical compositions provided by the invention can be used for preparing medicines for exciting 5-HT₄Pharmaceutical compositions of receptors, and their use in the preparation of a medicament for the prevention, treatment or alleviation of 5-HT₄A disease associated with receptor activity, in particular constipation-type irritable bowel syndrome (IBS-C).

In particular, the amount of compound in the compounds or pharmaceutical compositions of the invention is effective to detectably selectively agonize 5-HT₄A receptor.

The compounds of the present invention may be applied, but are in no way limited, to the use of an effective amount of a compound or pharmaceutical composition of the present inventionAdministration to a patient to prevent, treat or alleviate 5-HT₄Receptor mediated or with 5-HT₄Disorders associated with receptor activity, i.e. by administration of 5-HT₄Diseases ameliorated by treatment with receptor agonists. Such conditions further include, but are not limited to, Irritable Bowel Syndrome (IBS), chronic constipation, diabetic and idiopathic gastric disease, gastroesophageal reflux disease (GERD), delayed gastric emptying, gastroparesis, functional dyspepsia, delayed drug-induced transit, intestinal pseudo-infarction, or post-operative ileus. Wherein the Irritable Bowel Syndrome (IBS) is constipation type irritable bowel syndrome (IBS-C), diarrhea type irritable bowel syndrome (IBS-D), mixed type irritable bowel syndrome (IBS-M) or indeterminate type irritable bowel syndrome (IBS-U). Furthermore, it has been suggested that certain 5-HT₄The receptor agonist compounds may be used to treat central nervous system disorders, including mood disorders, cognitive disorders, and disorders of control of autonomic function.

Preferably, the compounds of the present invention increase the motility of the gastrointestinal tract and are therefore expected to be useful in the prevention, treatment or alleviation of gastrointestinal disorders resulting from decreased motility of the gastrointestinal tract in mammals, including humans. Such disorders of reduced motility of the gastrointestinal tract include constipation-type irritable bowel syndrome (IBS-C), diabetic and idiopathic gastroparesis, functional dyspepsia or chronic constipation.

Particularly preferably, the compounds of the present invention are used for the prevention, treatment or alleviation of constipation-type irritable bowel syndrome (IBS-C).

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

General synthetic procedure

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

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

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

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

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

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

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

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

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

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

The following acronyms are used throughout the invention:

CDC1₃deuterated chloroform mg

DMSO dimethyl sulfoxide g

DMSO-d₆Kg of deuterated dimethyl sulfoxide

nM, nmol/L nanomole per liter mL, mL

μ M, μmol/L micromoles per liter μ L, μ L microliters

mM, mmol/L millimole/L nL, nL nanoliter

M, mol/L mol/L/s sec

mmol min

mm h hours

Mu m micron cAMP cyclic adenosine monophosphate

nm nanometer Hepes 4-hydroxyethyl piperazine ethanesulfonic acid

IBMX 3-isobutyl-1-methylxanthine

HBSS Hank's Balanced Salt Solution, Hank's Balanced Salt Solution

The following intermediate preparation schemes and synthetic schemes describe the steps for preparing the disclosed compounds, unless otherwise indicated, X is Br, Cl, I, etc. halogen; wherein R and L have the definitions described herein.

Synthesis scheme 1

The compound (I) can be prepared by the following steps: the compound (S1) and brominated alcohol compound Br-L-OH are subjected to nucleophilic substitution reaction to obtain a compound (S2), the compound (S2) and a halogenated compound X-R are subjected to nucleophilic substitution reaction to obtain a compound (S3), the compound (S3) is subjected to Boc protection group removal to obtain a compound (S4), and the compound (S4) and 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid are condensed to obtain the target compound (I).

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

Examples

EXAMPLE 14 Synthesis of amino-5-chloro-N- (1- (3- ((5-fluoropyrimidin-2-yl) oxy) propyl) piperidin-4-yl) -2, 3-dihydrobenzofuran-7-carboxamide

Step 1) Synthesis of tert-butyl 1- (3-hydroxypropyl) piperidin-4-yl) carbamate

In a 100mL single-neck bottle, tert-butyl N- (4-piperidinyl) carbamate (2g, 9.99mmol), 3-bromopropan-1-ol (2.08g, 14.98mmol), potassium carbonate (2.78g, 19.97mmol) and acetonitrile (30mL) were added, the reaction was stopped after reacting at 80 ℃ for 12 hours, the reaction was directly concentrated, and the residue was separated by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (1.5g, 59%). MS (ESI, pos. ion) M/z 259.25[ M + H ]]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)4.45(s,1H),3.79–3.73(m,2H),3.45(dd,J＝6.9,5.3Hz,1H),2.95(s,2H),2.61–2.53(m,2H),2.05(t,J＝9.7Hz,2H),1.92(d,J＝11.9Hz,2H),1.68(dt,J＝10.8,5.4Hz,2H),1.41(s,9H),1.26(d,J＝15.8Hz,2H).

Step 2) Synthesis of tert-butyl 1- (3- ((5-fluoropyrimidin-2-yl) oxy) propyl) piperidin-4-yl) carbamate

Tert-butyl (1- (3-hydroxypropyl) piperidin-4-yl) carbamate (300mg, 1.16mmol) was weighed into a 50mL single-necked flask, anhydrous tetrahydrofuran (6mL) and sodium hydride (55mg, 1.39mmol) were added thereto, and stirred for 30 minutes, and then a solution of 2-chloro-5-fluoro-pyrimidine (200mg, 1.51mmol) dissolved in anhydrous tetrahydrofuran (4mL) was added dropwise to the reaction flask and stirred at room temperature for 10 hours. The reaction was stopped, the reaction was concentrated directly and the residue was isolated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a white solid (182mg, 44%).

MS(ESI,pos.ion)m/z:355.20[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.33(s,2H),4.48(dt,J＝24.1,9.4Hz,2H),4.33(t,J＝6.4Hz,1H),3.42(s,1H),2.82(d,J＝11.0Hz,2H),2.55–2.41(m,2H),2.06(t,J＝11.9Hz,2H),2.00–1.82(m,6H),1.41(s,9H).

Step 3) Synthesis of 1- (3- ((5-fluoropyrimidin-2-yl) oxy) propyl) piperidin-4-amine hydrochloride

Tert-butyl (1- (3- ((5-fluoropyrimidin-2-yl) oxy) propyl) piperidin-4-yl) carbamate (160mg, 0.45mmol) was weighed into a 50mL single-necked flask, dichloromethane (3mL) was added, and then a solution of HCl in ethyl acetate (8mL,3.5M) was added dropwise and allowed to stir at room temperature for 1.5 hours. The reaction was stopped, and the solvent was distilled off under reduced pressure to give the title compound as a white solid (115mg, 87%).

MS(ESI,pos.ion)m/z:255.20[M-HCl+H]⁺.

Step 4) 4-amino-5-chloro-N- (1- (3- ((5-fluoropyrimidin-2-yl) oxy) propyl) piperidin-4-yl) -2, 3-di Synthesis of hydrobenzofuran-7-carboxamides

1- (3- ((5-Fluoropyrimidin-2-yl) oxy) propyl) piperidin-4-amine hydrochloride (230mg, 0.79mmol), 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid (200mg, 0.95mmol), N, N-dimethylformamide (10mL), triethylamine (0.33mL, 2.4mmol), 1-hydroxybenzotriazole (0.13g, 0.95mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (0.18g, 0.95mmol) were weighed into a 100mL single vial and stirred at room temperature for 22 hours. The reaction was stopped, ethyl acetate (30mL) and water (20mL) were added, the mixture was stirred for 5 minutes for liquid separation, the organic phase was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a pale yellow solid (130mg, 37%).

MS(ESI,pos.ion)m/z:450.15[M+H]⁺；

HPLC:95.25％；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.36(s,2H),7.86(s,1H),7.27(d,J＝6.3Hz,1H),4.52(dt,J＝24.1,9.4Hz,2H),4.34(t,J＝6.4Hz,1H),3.45(s,1H),2.88(d,J＝11.0Hz,2H),2.57–2.43(m,2H),2.08(t,J＝11.9Hz,2H),2.02–1.84(m,6H).

Example 22 Synthesis of 3- (4- (4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxamido) piperidin-1-yl) propoxy) pyrimidine-4-carboxylic acid

Step 1) preparation of methyl 2- (3- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) propoxy) pyrimidine-4-carboxylate Synthesis of

Tert-butyl (1- (3-hydroxypropyl) piperidin-4-yl) carbamate (300mg, 1.16mmol) was weighed into a 50mL single-necked flask, anhydrous tetrahydrofuran (6mL) and sodium hydride (55mg, 1.39mmol) were added thereto, and stirred for 30 minutes, and then a solution of methyl 2-chloropyrimidine-4-carboxylate (260mg, 1.51mmol) dissolved in anhydrous tetrahydrofuran (4mL) was added dropwise to the reaction flask, and left to stir at room temperature for 10 hours. The reaction was stopped, the reaction was concentrated directly and the residue was isolated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 1/1) to give the title compound as a white solid (160mg, 35%).

MS(ESI,pos.ion)m/z:395.20[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)9.12(s,1H),8.15(s,1H),4.48(dt,J＝24.1,9.4Hz,2H),4.33(t,J＝6.4Hz,1H),3.42(s,1H),3.85(s,3H),2.82(d,J＝11.0Hz,2H),2.55–2.41(m,2H),2.06(t,J＝11.9Hz,2H),2.00–1.82(m,6H),1.41(s,9H).

Step 2) Synthesis of methyl 2- (3- (4-aminopiperidin-1-yl) propoxy) pyrimidine-4-carboxylate hydrochloride

To a 50mL single-necked flask containing methyl 2- (3- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) propoxy) pyrimidine-4-carboxylate (500mg,1.27 mmol) was added dichloromethane (5mL) followed by HCl in ethyl acetate (4mL,3.5M), and after the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was stopped, and the solvent was distilled off under reduced pressure to give the title compound as a pale yellow solid (419mg, 99%).

MS(ESI,pos.ion)m/z:295.30[M-HCl+H]⁺.

Step 3)2- (3- (4- (4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxamido) piperidine-1-yl) propoxy Yl) Synthesis of pyrimidine-4-carboxylic acid methyl ester

Methyl 2- (3- (4-aminopiperidin-1-yl) propoxy) pyrimidine-4-carboxylate hydrochloride (265mg, 0.80mmol), 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid (200mg, 0.95mmol), N, N-dimethylformamide (10mL), triethylamine (0.33mL, 2.4mmol), 1-hydroxybenzotriazole (0.13g, 0.95mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (0.18g, 0.95mmol) were weighed into a 100mL single vial and stirred at room temperature for 22 hours. The reaction was stopped, ethyl acetate (20mL) and water (20mL) were added, stirred for 5 minutes, separated, the organic phase concentrated, and the residue purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a pale yellow solid (153mg, 39%).

MS(ESI,pos.ion)m/z:490.25[M+H]⁺；

1H NMR(400MHz,CDCl3)δ(ppm)9.11(s,1H),8.14(s,1H),7.84(s,1H),7.26(d,J＝6.3Hz,1H),4.50(dt,J＝24.1,9.4Hz,2H),4.35(t,J＝6.4Hz,1H),3.43(s,1H),3.86(s,3H),2.83(d,J＝11.0Hz,2H),2.55–2.43(m,2H),2.11(t,J＝11.9Hz,2H),2.02–1.85(m,6H).

Step 4)2- (3- (4- (4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxamido) piperidin-1-yl) propoxy Group) Synthesis of pyrimidine-4-carboxylic acid

Methyl 2- (3- (4- (4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxamido) piperidin-1-yl) propoxy) pyrimidine-4-carboxylate (153mg, 0.31mmol) was weighed into a 50mL single-necked flask, methanol (5mL) and water (1mL) were added, lithium hydroxide monohydrate (13mg) was further added, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped, the reaction solution was concentrated, water (5mL) was added, hydrochloric acid (2N) was slowly added dropwise to adjust the pH to 6-7, and the filter cake was dried after suction filtration to give the title compound as a white solid (135mg, 92%).

MS(ESI,pos.ion)m/z:476.30[M+H]⁺；

HPLC:96.86％；

1H NMR(400MHz,CDCl3)δ(ppm)9.09(s,1H),8.12(s,1H),7.82(s,1H),7.25(d,J＝6.3Hz,1H),4.49(dt,J＝24.1,9.4Hz,2H),4.33(t,J＝6.4Hz,1H),3.42(s,1H),2.81(d,J＝11.0Hz,2H),2.55–2.43(m,2H),2.10(t,J＝11.9Hz,2H),2.01–1.83(m,6H).

EXAMPLE 34 Synthesis of amino-5-chloro-N- (1- (3- (cyclopentyloxy) propyl) piperidin-4-yl) -2, 3-dihydrobenzofuran-7-carboxamide

Step 1) (Synthesis of tert-butyl 1- (3- (cyclopentyloxy) propyl) piperidin-4-yl) carbamate

Tert-butyl (1- (3-hydroxypropyl) piperidin-4-yl) carbamate (1.00g,3.87mmol) was weighed into a 100mL single-neck flask, dichloromethane (20mL) was added, silver carbonate (3.2g,11.7mmol) and silver perchlorate (250mg,1.21mmol) were added, iodocyclopentane (2.37g,12mmol) was added dropwise, and the reaction was carried out under nitrogen atmosphere and in the dark at room temperature for 7 hours. The reaction was stopped, suction filtered, the filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (989mg, 78%).

MS(ESI,pos.ion)m/z:327.35[M+H]⁺.

¹H NMR(400MHz,CDCl₃)δ(ppm)3.99–3.79(m,1H),3.47(t,J＝6.0Hz,2H),3.32(s,2H),3.18(s,2H),2.88–2.64(m,2H),2.45(t,J＝11.0Hz,2H),2.05(d,J＝11.8Hz,2H),1.85(dd,J＝13.4,6.9Hz,3H),1.79–1.55(m,9H),1.44(s,9H).

Step 2) Synthesis of 1- (3- (cyclopentyloxy) propyl) piperidin-4-amine hydrochloride

Tert-butyl (1- (3- (cyclopentyloxy) propyl) piperidin-4-yl) carbamate (800mg,2.45mmol) was weighed into a 50mL one-necked flask, dichloromethane (5mL) was added, and an ethyl acetate solution of hydrochloric acid (5mL,4M) was added dropwise to the flask and reacted at room temperature for 22 hours. The reaction was stopped and suction filtered to give the title compound as a white solid (464mg, 72%).

MS(ESI,pos.ion)m/z:227.20[M+H]⁺.

Step 3) 4-amino-5-chloro-N- (1- (3- (cyclopentyloxy) propyl) piperidin-4-yl) -2, 3-dihydrobenzofuran Synthesis of pyran-7-carboxamides

In a 50mL single neck flask were added 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid (566mg,2.66mmol), 1- (3- (cyclopentyloxy) propyl) piperidin-4-amine hydrochloride (450mg,1.71mmol), N-dimethylformamide (10mL), triethylamine (0.72mL,5.2mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (664mg,3.37mmol) and 1-hydroxybenzotriazole (473g,3.37mmol), stirred at room temperature for 4 hours to stop the reaction, ethyl acetate (20mL) and water (15mL) were added, separated by stirring for 10 minutes, the organic phase was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 15/1) to give the title compound as a white solid (410mg, 57%).

MS(ESI,pos.ion)m/z:422.30[M+H]⁺；

HPLC:92.68％；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.85(s,1H),7.28(d,J＝6.3Hz,1H),4.77(t,J＝8.7Hz,2H),4.28(s,2H),3.42(t,J＝6.5Hz,2H),3.07(t,J＝8.7Hz,2H),2.85(d,J＝11.2Hz,2H),2.49–2.35(m,2H),2.25–2.09(m,4H),2.01(d,J＝10.5Hz,2H),1.80–1.46(m,12H).

Example Synthesis of 42- (2- (4- (4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxamido) piperidin-1-yl) ethoxy) -4-methylthiazole-5-carboxamide

Step 1) Synthesis of tert-butyl (1- (2-hydroxyethyl) piperidin-4-yl) carbamate

Tert-butylpiperidinbutan-4-ylcarbamate (2g, 9.98mmol), 2-bromoethanol (1.06mL, 14.98mmol) and potassium carbonate (2.79g, 19.97mmol) were weighed into a 100mL single vial, acetonitrile (28mL) was added, the reaction was left at 80 ℃ for 5 hours, the reaction was stopped after completion of the TLC detection, the reaction was directly concentrated, and the residue was separated by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a pale yellow oil (1.9g, 78%).

MS(ESI,pos.ion)m/z:245.20[M+H]⁺.

¹H NMR(600MHz,CDCl₃)δ(ppm)4.44(s,1H),3.58–3.54(m,2H),3.45(s,1H),2.81(d,J＝10.6Hz,2H),2.50–2.47(m,2H),2.15(t,J＝11.1Hz,2H),1.91(d,J＝11.7Hz,2H),1.41(s,9H),1.37(dd,J＝17.5,6.4Hz,2H).

Step 2) (1- (2- (((5-carbamoyl-4-methylthiazol-2-yl) oxy) ethyl) piperidin-4-yl) amino Synthesis of tert-butyl formate

Tert-butyl (1- (2-hydroxyethyl) piperidin-4-yl) carbamate (2.9g, 12mmol) and tetrahydrofuran (50mL) were weighed into a 100mL single neck flask, stirred in an ice bath for 3 minutes, sodium hydride (570mg, 14mmol) was added, after stirring for 20 minutes, 2-bromo-4-methylthiazole-5-carboxamide (3.4g, 15mmol) was added, the reaction was stopped after 24 hours at 50 ℃, the reaction was directly concentrated, and the residue was separated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (2.4g, 52%).

MS(ESI,pos.ion)m/z:385.20[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.35(s,2H),6.73(d,J＝7.5Hz,1H),4.42(t,J＝5.4Hz,2H),3.18(d,J＝7.5Hz,1H),2.82(d,J＝11.7Hz,2H),2.65(t,J＝5.4Hz,2H),2.50(s,2H),2.41(s,3H),2.05–1.96(m,2H),1.65(d,J＝10.5Hz,2H),1.37(s,9H).

Step 3) Synthesis of 2- (2- (2- (4-aminopiperidin-1-yl) ethoxy) -4-methylthiazole-5-carboxamide hydrochloride Become into

Tert-butyl (1- (2- (((5-carbamoyl-4-methylthiazol-2-yl) oxy) ethyl) piperidin-4-yl) carbamate (1g, 2.60mmol) and dichloromethane (18mL) were weighed into a 50mL one-neck flask, followed by dropwise addition of methanesulfonic acid (0.517mL, 7.80mmol), stirring at room temperature for 14H, stopping the reaction after TLC detection reaction was complete, and concentration under reduced pressure to give the title compound as a pale yellow solid (930mg, 100%). MS (ESI, pos.ion) M/z 285.20[ M + H ] M/z]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.45(s,2H),7.19(s,2H),4.04(t,J＝6.8Hz,2H),3.58(d,J＝12.0Hz,2H),3.25(d,J＝4.0Hz,1H),3.16–3.04(m,2H),2.50(s,2H),2.29(s,3H),2.13(d,J＝12.0Hz,2H),1.98(d,J＝12.4Hz,2H).

Step 4)2- (2- (4- (4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxamido) piperidin-1-yl) ethoxy Synthesis of yl) -4-methylthiazole-5-carboxamide

2- (2- (2- (4-aminopiperidin-1-yl) ethoxy) -4-methylthiazole-5-carboxamide hydrochloride (920mg, 2.57mmol) and 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid (500mg, 2.34mmol) were weighed into a 100mL single-necked flask, N-dimethylformamide (20mL) and triethylamine (0.97mL, 7.02mmol) were added, then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (544mg, 2.81mmol) and 1-hydroxybenzotriazole (387mg, 2.81mmol) were added, the reaction was stopped after stirring at room temperature for 16h, dichloromethane (20mL) was added, washing was performed with water (10 mL. times.3), and the residue was subjected to column chromatography (dichloromethane/methanol (v/v) ═ 20/1) ) The title compound was isolated as a white solid (580mg, 52%).

MS(ESI,pos.ion)m/z:480.20[M+H]⁺；

HPLC:98.61％；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.45(s,1H),7.37(s,2H),7.28(d,J＝7.5Hz,1H),5.88(s,2H),4.72(t,J＝8.7Hz,2H),4.48(s,2H),3.76(s,1H),3.07–2.99(m,6H),2.81(d,J＝25.1Hz,2H),2.42(s,3H),1.82(d,J＝9.6Hz,2H),1.48(d,J＝9.4Hz,2H).

Example 52 Synthesis of 3- (4- (4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxamido) piperidin-1-yl) propoxy) -4-methylthiazole-5-carboxamide

Step 1) (1- (3- (((5-carbamoyl-4-methylthiazol-2-yl) oxy) propyl) piperidin-4-yl) amino Synthesis of tert-butyl formate

Tert-butyl (1- (3-hydroxypropyl) piperidin-4-yl) carbamate (1.55g, 6mmol) and tetrahydrofuran (50mL) were weighed into a 100mL single-neck flask, stirred in an ice bath for 3 minutes, added with sodium hydride (280mg, 7mmol, 60%), stirred for 20 minutes, added with 2-bromo-4-methylthiazole-5-carboxamide (1.7g,7.5mmol), reacted at 50 ℃ for 24 hours and stopped, the reaction was directly concentrated, and the residue was separated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (1.0g, 42%).

MS(ESI,pos.ion)m/z:399.25[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.37(s,2H),6.75(d,J＝7.5Hz,1H),4.43(t,J＝5.4Hz,2H),3.19(d,J＝7.5Hz,1H),2.85(d,J＝11.7Hz,2H),2.66(t,J＝5.4Hz,2H),2.53(s,2H),2.43(s,3H),2.05–1.97(m,4H),1.68(d,J＝10.5Hz,2H),1.39(s,9H).

Step 2) Synthesis of 2- (3- (4-aminopiperidin-1-yl) propoxy) -4-methylthiazole-5-carboxamide hydrochloride

Tert-butyl (1- (2- (((5-carbamoyl-4-methylthiazol-2-yl) oxy) ethyl) piperidin-4-yl) carbamate (1.03g, 2.60mmol) and dichloromethane (15mL) were weighed into a 50mL single vial, followed by dropwise addition of methanesulfonic acid (0.517mL, 7.80mmol), stirring at room temperature for 14H, after completion of the TLC detection reaction, the reaction was stopped and concentrated under reduced pressure to give the title compound as a pale yellow solid (868mg, 100%). MS (ESI, pos.ion) M/z 299.20[ M-HCl + H ]: 299.20]⁺.

Step 3)2- (3- (4- (4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxamido) piperidin-1-yl) propoxy Synthesis of yl) -4-methylthiazole-5-carboxamide

Weighing 2- (3- (4-aminopiperidin-1-yl) propoxy) -4-methylthiazole-5-carboxamide hydrochloride (434mg, 1.30mmol) and 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid (250mg, 1.17mmol) in a 100mL single-neck flask, adding N, N-dimethylformamide (10mL) and triethylamine (0.5mL, 3.0mmol), then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (272mg, 1.40mmol) and 1-hydroxybenzotriazole (193mg, 1.40mmol), stirring at room temperature for 16h to stop the reaction, adding dichloromethane (20mL), washing with water (10mL × 3), and separating the residue after concentration by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to obtain the target The title compound was a white solid (250mg, 39%).

MS(ESI,pos.ion)m/z:495.25[M+H]⁺；

HPLC:98.88％.

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.42(s,1H),7.35(s,2H),7.23(d,J＝7.5Hz,1H),5.85(s,2H),4.71(t,J＝8.7Hz,2H),4.45(s,2H),3.75(s,1H),3.05–2.96(m,6H),2.80(d,J＝25.1Hz,2H),2.42(s,3H),1.80(m,4H),1.48(d,J＝9.4Hz,2H).

EXAMPLE 64 Synthesis of amino-5-chloro-N- (1- (2- ((5-fluoropyrimidin-2-yl) oxy) ethyl) piperidin-4-yl) -2, 3-dihydrobenzofuran-7-carboxamide

Step 1) Synthesis of tert-butyl 1- (2- (((5-fluoropyrimidin-2-yl) oxy) ethyl) piperidin-4-yl) carbamate

Tert-butyl (1- (2-hydroxyethyl) piperidin-4-yl) carbamate (1g, 4.09mmol) and tetrahydrofuran (20mL) were weighed into a 100mL single-necked flask, sodium hydride (196mg, 4.91mmol) was added under ice bath, and after stirring for 20 minutes, 2-chloro-5-fluoropyrimidine (705mg, 5.32mmol) was added, followed by reaction at room temperature for 10 hours. The reaction was stopped, the reaction was concentrated directly and the residue was isolated by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (550mg, 40%).

MS(ESI,pos.ion)m/z:341.40[M+H]⁺.

¹H NMR(400MHz,CDCl₃)δ(ppm)8.34(d,J＝3.4Hz,2H),4.43(t,J＝5.9Hz,2H),3.44(s,1H),2.90(d,J＝11.6Hz,2H),2.77(t,J＝5.9Hz,2H),2.21(t,J＝11.2Hz,2H),1.90(d,J＝11.8Hz,2H),1.42(s,9H),1.23(s,2H).

Step 2) Synthesis of 1- (2- ((5-fluoropyrimidin-2-yl) oxy) ethyl) piperidin-4-amine hydrochloride

Tert-butyl (1- (2- (((5-fluoropyrimidin-2-yl) oxy) ethyl) piperidin-4-yl) carbamate (300mg, 0.88mmol), dichloromethane (6mL) were weighed into a 50mL single-necked flask, added to the flask, a solution of HCl in ethyl acetate (4mL, 4M) was added dropwise, the reaction was stopped with stirring in an ice bath for 40min, and concentrated to give the title compound as a white solid (240mg, 99%).

MS(ESI,pos.ion)m/z:241.20[M+H]⁺.

Step 3) 4-amino-5-chloro-N- (1- (2- ((5-fluoropyrimidin-2-yl) oxy) ethyl) piperidin-4-yl) -2, 3-di Synthesis of hydrobenzofuran-7-carboxamides

1- (2- ((5-Fluoropyrimidin-2-yl) oxy) ethyl) piperidin-4-amine hydrochloride (325mg, 1.17mmol), 4-amino-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid (251mg, 1.17mmol), N, N-dimethylformamide (15mL) and triethylamine (0.49mL, 3.52mmol) were weighed into a 100mL single-necked flask, 1-hydroxybenzotriazole (194mg, 1.41mmol) and 1- (3-dimethylamidopropyl) -3-ethylcarbodiimide hydrochloride (273mg, 1.41mmol) were added, the reaction was stopped after stirring at room temperature for 12 hours, ethyl acetate (30mL), water (20mL) were added, liquid separation was carried out after stirring for 3 minutes, the organic phase was collected, the organic phase was washed with a saturated saline solution, after concentration, the residue was isolated by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (150mg, 30%).

MS(ESI,pos.ion)m/z:436.20[M+H]⁺；

HPLC:97.88％；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)9.10(s,1H),9.08(s,1H),7.45(s,1H),7.28(d,J＝7.5Hz,1H),5.88(s,2H),4.72(t,J＝8.7Hz,2H),4.48(s,2H),3.76(s,1H),3.07–2.99(m,3H),2.81(d,J＝25.1Hz,2H),2.42(s,3H),1.82(d,J＝9.6Hz,2H),1.48(d,J＝9.4Hz,2H).

Biological assay

Example A: evaluation of Compounds of the invention human 5-HT transfected in CHO cells (Chinese hamster ovary cells)₄Agonism of receptors

The purpose is as follows: evaluation of human 5-HT of transfection of Compounds of the invention into CHO cells (Chinese hamster ovary cells) by HTRF detection of cAMP₄Agonism of the receptor.

The experimental process comprises the following steps: cells were suspended in HBSS buffer (invitrogen), 20mM Hepes and 50. mu.M IBMX at 2X 10⁴The density of cells/well is averaged into the microwell reaction plate. Then adding the test compound or a blank control solvent or a positive control compound, and incubating for 30min at room temperature. After incubation, the cells were lysed, and D2-cAMP fluorescence energy acceptor and fluorescence energy donor (anti-cAMP antibody labeled with europium cryptate) were added, incubated at room temperature for 60min, and then excited light at 337nm in an enzyme reader (Envison, Perkin Elmer) was used to read the fluorescence intensity at 620nm and 665 nm. The concentration of cAMP was calculated by the ratio of the fluorescence intensity at 665nm to 620 nm. Positive control Compound was 5-HT, and EC was tested for each experiment₅₀To ensure the test system is normal. For comparison, the activation rate was 100% at a concentration of cAMP of 1. mu.M 5-HT. The rate of agonism ((W/Z)). 100% -the rate of agonism (EC) was calculated by testing different concentrations of the compound to obtain the corresponding cAMP concentration_max) Wherein W represents the concentration of cAMP of the test compound and Z represents the concentration of cAMP of 1. mu.M 5-HT). The compound dose-effect curves were then calculated by Prism software, and the agonist concentration giving half maximal response was calculated as EC₅₀The values are represented.

The experimental results show that the compound of the invention can be used for the transfection of human 5-HT in CHO cells (Chinese hamster ovary cells)₄The receptor has stronger agonism. In particular, the EC of the compounds of the examples of the invention₅₀Values of less than 100nM, EC for some compounds₅₀Values less than 50 nM; EC of more preferred example Compounds of the invention₅₀Values were less than 10 nM. Wherein, the table A lists the test results of the agonistic activity of some compounds of the present invention.

Table a: human 5-HT transfection of partial Compounds of the invention into CHO cells₄Measurement of receptor agonism

Example No. 2	EC50(nM)	ECmax
			Example 1	8.9	80％
Example 3	50-100	N/A
			Example 4	2.1	100％

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

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

Claims (9)

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

wherein:

l is- (CR)¹R²)_n-；

n is 1,2,3 or 4;

each R¹And R²Independently hydrogen or deuterium;

r is cyclopentyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl or pyrimidinyl; wherein said R is optionally substituted with 1,2,3 or 4R^xSubstituted;

each R^xIndependently deuterium, F, Cl, Br, I, carboxy, -C (═ O) NH₂Or C_1-6An alkyl group.

2. The compound of claim 1, wherein each R^xIndependently deuterium, F, Cl, Br, I, carboxy, -C (═ O) NH₂Methyl, ethyl, n-propyl, isopropyl or tert-butyl.

3. The compound of claim 1, wherein R is

Wherein said R is optionally substituted with 1,2,3 or 4R^xAnd (4) substituting.

4. The compound of claim 1, wherein R is

Wherein each R is^x0、R^x1、R^x2And R^x3Independently is H or R^x；

k is 0, 1,2,3 or 4.

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

6. a pharmaceutical composition comprising a compound of any one of claims 1-5; and

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

7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the prevention, treatment or alleviation of 5-HT₄Diseases associated with receptor activity.

8. The use according to claim 7, wherein said treatment is with 5-HT₄The diseases related to receptor activity are irritable bowel syndrome, chronic constipation, diabetic and idiopathic gastropathy, gastroesophageal reflux disease, delayed gastric emptying, gastroparesis, functional dyspepsia, delayed drug delivery, intestinal pseudo-infarction or postoperative ileus.

9. The use according to claim 8, wherein the irritable bowel syndrome condition is constipation type irritable bowel syndrome, diarrhea type irritable bowel syndrome, mixed type irritable bowel syndrome, or indeterminate type irritable bowel syndrome.