CN109776373B - Amide-substituted pyrrolidine amide derivatives and uses thereof - Google Patents

Abstract

The invention discloses amide-substituted pyrrolidine amide derivatives and application thereof, and particularly relates to novel amide-substituted pyrrolidine amide derivatives and pharmaceutical compositions containing the compounds, which can be used for activating β 3-adrenergic receptors, and also relates to a method for preparing the compounds and the pharmaceutical compositions, and application of the compounds and the pharmaceutical compositions in preparing medicaments for treating diseases or symptoms mediated by activation of β 3-adrenergic receptors, particularly overactive bladder.

Description

Amide-substituted pyrrolidine amide derivatives and uses thereof

Technical Field

In particular, the novel amide-substituted pyrrolidine amide derivatives of the present invention are useful for activating β 3-adrenergic receptors, for preventing, treating or alleviating diseases or conditions mediated by activation of β 3-adrenergic receptors, particularly overactive bladder.

Background

Overactive bladder (OAB) is a syndrome characterized by symptoms of urgency, often accompanied by frequency and nocturia, with or without urge incontinence, and with urodynamics manifested as detrusor overactivity, or other forms of urethral-bladder dysfunction. Both men and women occur, and women are common, and the incidence of OAB increases with age. In recent years, with the progress of our country into an aging society and the increase of diabetes and nervous system impairment diseases, the incidence of overactive bladder, which is a secondary related disease, has also increased year by year. In the united states and europe, the incidence of OAB is estimated to be 16% to 17% in women and men over 18 years of age. OAB seriously affects the daily life and social activities of patients, has become a disease that afflicts people, and affects the quality of life of millions of people worldwide.

In the past decades, muscarinic receptor antagonists (anticholinergics) have been the commonly used drugs for treating overactive bladder and are capable of alleviating various symptoms caused by overactive bladder, however, muscarinic receptor antagonists have no effect on some portions of OAB, and such drugs have adverse effects such as constipation, sleepiness, dry mouth, blurred vision, and the like, which have limited their widespread use to some extent.

Adrenergic Receptors (AR) are a class of G-protein coupled receptors that mediate the action of catecholamines and can be classified into α and β.

β -adrenergic receptors (β -AR), initially divided into two subtypes β and β depending on their physiological effects, in 1989 Emorine et al first isolated and cloned an atypical adrenergic receptor gene in human adipocytes, this receptor being designated β -3-adrenergic receptor (β -AR) (Emorine LJ, Marullo S, Briend-vitren MM, axial molecular characterization of the human beta 3-adrenoceptor [ J ] Science,1989,245(4922): 1118-.

β -AR is widely present in various human tissues such as bladder, gastrointestinal tract, adipose tissue, cardiovascular system, etc., but the distribution thereof is related to species classes, and β -AR three subtypes (β -AR, β -AR and β 3-AR) are expressed in human bladder. analysis of the expression of mRNA of β -AR of three subtypes in bladder by the quantitative reverse transcription polymerase chain reaction (RT-PCR) method revealed that expression of mRNA of β -AR in bladder under normal and pathological conditions is significantly higher than that of mRNA of other two subtypes (MichelMC. β -acquired receptor subtypes [ J ] Handb ExPharmacol, (202): 307; 318) Otsuka et al further study revealed that β -AR is expressed in various human tissues including urinary tract epithelium, interstitial cells and detrusor (Otsuka A, shiyboto R. RTH. 2011. RTM. and Shisanorum. 12. urinary tract of human bladder 4. environmental diseases of urinary tract of human bladder.

The contraction of bladder detrusor muscle is coordinated contraction mediated by contractile transmitters released by cholinergic nerves (acetylcholine and ATP), while voluntary contraction during the storage phase is mediated by mechanosensitive afferent nerves. it is presently believed that β -AR agonists inhibit voluntary contraction primarily by acting on β -AR on the detrusor muscle during storage, thereby mediating increased bladder compliance and delayed micturition reflex (Aizawa N, Homma Y, Igawa Y.Effects of mirabegron, alpha beta 3-adrenoceptor agonist, on marprimadware activity and nerve responses in complex with effects of antagonists of oxidative insults [ J ] Eur Urr Ur, 62(6): 5. microcontroceptors in the urinary tract of urinary tract [ J ] Eur 633. extracellular agonists, 5. 7. omega. 5. 7. multidrug. gamma. the intracellular receptor agonistic receptor activation, intracellular phosphorylation of intracellular receptor, intracellular receptor kinase, intracellular receptor activation, intracellular phosphorylation, intracellular receptor activation, and intracellular receptor phosphorylation of intracellular receptor, intracellular receptor phosphorylation, intracellular receptor activation, and other intracellular receptor activation, intracellular receptor phosphorylation, intracellular receptor activation, and other intracellular receptor activation, intracellular receptor phosphorylation, and other intracellular receptor activation, intracellular receptor phosphorylation, and other cellular receptor activation of intracellular receptor phosphorylation, and other intracellular receptor activation, and other receptor activation, intracellular receptor activation, and intracellular receptor activation of intracellular receptor phosphorylation, and other cellular receptor activation, and intracellular receptor activation of intracellular receptor phosphorylation, intracellular receptor activation, and intracellular receptor activation, intracellular receptor activation of intracellular receptor phosphorylation, and intracellular receptor activation of intracellular receptor phosphorylation, intracellular receptor phosphorylation, and other receptor activation.

β 3-AR agonist as a new drug for treating OAB has definite effect, good safety and tolerance, and wide application prospect, the following patent documents disclose compounds as β 3-AR agonist:

WO 9920607A 1 discloses amide derivatives as β 3-AR agonists, pharmaceutical compositions thereof and their use for activating β 3-AR and for preventing or treating diabetes and obesity.

GB 2356197A discloses amide derivatives as β 3-AR agonists, pharmaceutical compositions thereof and their use for activating β 3-AR and for the prevention or treatment of diabetes and obesity.

JP 2012020961 a discloses hydroxymethylpyrrolidine derivatives as β 3-AR agonists, pharmaceutical compositions thereof and their use for activating β 3-AR and for preventing or treating diseases or disorders mediated by activation of β 3-adrenergic receptors, including overactive bladder.

WO 2009123870 a1 discloses hydroxymethylpyrrolidine derivatives as β 3-AR agonists, pharmaceutical compositions thereof and their use for activating β 3-AR and for preventing or treating diseases or disorders mediated by the activation of β 3-adrenergic receptors, including overactive bladder.

WO 2012012314 a1 discloses novel pyrrolidine derivatives as β 3-AR agonists, pharmaceutical compositions thereof and their use for activating β 3-AR and for preventing or treating diseases or disorders mediated by the activation of β 3-adrenergic receptors, including overactive bladder.

JP 10218861 a discloses phenethyl alcohol derivatives as β 3-AR agonists, pharmaceutical compositions thereof and their use for activating β 3-AR and for preventing or treating diabetes.

Disclosure of Invention

The invention provides a novel class of amide-substituted pyrrolidine amide derivatives which are β 3-AR agonists, and can be used for activating β 3-AR, and therefore, can be used for treating diseases or disorders mediated by β 3-adrenergic receptor activation, in particular for treating overactive bladder.

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:

in one embodiment, X is CR^xOr N; wherein R is^xHave the meaning as described in the present invention.

In one embodiment, each R is⁴And R⁵Independently H, D, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-to 10-membered heteroaryl, wherein, said C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl and 5-10 membered heteroaryl are independently optionally substituted with 1,2 or 3R^ySubstituted by radicals, or, R⁴、R⁵And the nitrogen atom to which they are attached, together form a 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl is independently optionally substituted with 1,2 or 3R^ySubstituted by a group; wherein R is^yHave the meaning as described in the present invention.

In one embodiment, each R is^yIndependently D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R^1a、R^1b、R^1c、R^1dAnd R^xEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₆Alkyl), -C (═ O) - (C)₁-C₆Alkoxy group), C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₁-C₆Alkylthio radical, C₁-C₆Alkylamino, hydroxy-substituted C₁-C₆Alkyl radical, C₃-C₈Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In one embodiment, R^2a、R^2b、R^2c、R^2d、R^2eAnd R^2fEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, R^3a、R^3b、R^3cAnd R^3dEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy or hydroxy substituted C₁-C₆An alkyl group.

In one embodiment, each R is⁴And R⁵Independently H, D, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-to 10-membered heteroaryl, wherein, said C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl and 5-10 membered heteroaryl are independently optionally substituted with 1,2 or 3R^ySubstituted by radicals, or, R⁴、R⁵And the nitrogen atom to which they are attached, together form a 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is independently optionally substituted with 1,2 or 3R^ySubstituted by a group; wherein R is^yHave the meaning as described in the present invention.

In another embodiment, each R is⁴And R⁵Independently H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthaleneAryl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl and quinolinyl are independently optionally substituted with 1,2 or 3R^ySubstituted by radicals, or, R⁴、R⁵And the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl group, wherein said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl groups are independently optionally substituted with 1,2, or 3R^ySubstituted by a group; wherein R is^yHave the meaning as described in the present invention.

In one embodiment, each R is^yIndependently D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, each R is^yIndependently D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R^1a、R^1b、R^1c、R^1dAnd R^xEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-(C₁-C₄Alkyl), -C (═ O) - (C)₁-C₄Alkoxy group), C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino, hydroxy-substituted C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In another embodiment, R^1a、R^1b、R^1c、R^1dAnd R^xEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-SH、-COOH、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-C(＝O)-CH₃、-C(＝O)-OCH₃Methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂Methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-OCH₂CF₃、-OCH₂CF₂CHF₂Methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl, 2-hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In one embodiment, R^2a、R^2b、R^2c、R^2d、R^2eAnd R^2fEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R^2a、R^2b、R^2c、R^2d、R^2eAnd R^2fEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

In one embodiment, R^3a、R^3b、R^3cAnd R^3dEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group.

In another embodiment, R^3a、R^3b、R^3cAnd R^3dEach independently is H, D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

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

wherein each R is^1a、R^1b、R^1c、R^1d、R^3a、R^3b、R^3c、R^3d、R⁴、R⁵And X has the meaning as described in the present invention.

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

wherein each R is^1a、R^1b、R^1c、R^1d、R^3a、R^3b、R^3c、R^3d、R⁴、R⁵And X has the meaning as described in the present invention.

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

in another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), (IIa) or (IIb) 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 another embodiment, the invention relates to a pharmaceutical composition further comprising an additional therapeutic agent, wherein said additional therapeutic agent is a overactive bladder agent, a 5-hydroxytryptamine reuptake inhibitor, an anti-obesity compound, a feeding behavior modifier, an α -glucosidase inhibitor, a sulfonylurea, an insulin or insulin mimetic, an insulin sensitizer, a cholesterol lowering agent, a PPAR α agonist, a PPAR δ agonist, a PPAR γ antagonist, or a combination thereof.

In yet another aspect, the invention relates to the use of a compound of formula (I), (IIa) or (IIb) disclosed herein, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention, treatment or alleviation of a disease or a condition mediated by activation of the β 3-adrenergic receptor.

In one embodiment, the disease or disorder mediated by activation of β 3-adrenergic receptors is overactive bladder, urinary incontinence, urge urinary incontinence, urinary urgency, diabetes, obesity, hyperglycemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, depression, atherosclerosis, gastrointestinal disorders, irritable bowel syndrome and other disorders requiring reduced intestinal activity, neurogenic inflammation of the airways, ocular hypertension, glaucoma, diabetic retinopathy, prostatosis or preterm labor;

wherein the atherosclerosis is atherosclerosis of coronary arteries, atherosclerosis of cerebrovascular arteries, or atherosclerosis of peripheral arteries;

wherein the gastrointestinal disorder is gastritis, esophagitis, duodenitis, intestinal ulcer, gastrointestinal ulcer or peptic ulcer;

wherein the neurogenic inflammation of the airway is cough or asthma.

In another embodiment, the disease or condition mediated by activation of β 3-adrenergic receptors is overactive bladder.

In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound of formula (I), (IIa) or (IIb).

Biological test results show that the compound can activate β 3-adrenergic receptor and can be used as a better β 3-adrenergic 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 found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and JerryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

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-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, 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, racemases and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(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 (lowenergy 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 … …", mayUsed interchangeably with the term "unsubstituted or substituted ….," i.e., a structure is unsubstituted or substituted with one or more substituents described herein, including but not limited to D, F, Cl, Br, I, N₃、-CN、-NO₂、-NH₂、-OH、-SH、-COOH、-CONH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂-C (═ O) -alkyl, -C (═ O) -alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylamino, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, 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, an alkyl groupThe groups contain 1-4 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 "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) 1-propenyl (i.e., propenyl, -CH ═ CH-CH)₃) And so on.

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

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)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, -SCH₂CH₂CH₂CH₃) 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 "hydroxy-substituted alkyl" denotes an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2, 3-dihydroxypropyl, and the like.

The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, -CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-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 atomSubstituted C₁-C₂An alkyl group.

The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, wherein the alkoxy group has the meaning as described herein, examples of which include, but are not limited to, -OCHF₂、-OCF₃、-OCHFCH₂F、-OCF₂CHF₂、-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" and "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, a 3-8 membered heterocyclyl group means a heterocyclyl group consisting of 3,4, 5, 6, 7 or 8 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 "carbocyclyl" or "carbocycle" denotes a monovalent or multivalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl group is optionally substituted with one or more substituents described herein.

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, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system can include fused, bridged, and spiro rings. Wherein one or more atoms of the ring are independently replaced by a heteroatom having the meaning as described herein. In one embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 8 ring atoms (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give 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 4 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 ring atoms of the heterocyclic group may be carbon-based or heteroatom-based. 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, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, oxazepanyl, oxazepinyl, and oxazepinyl

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, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-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, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, 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-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), (IIa) or (IIb). 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, e.g. compounds of these phosphate estersThe compound is obtained by phosphorylation of hydroxyl 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, descriptive acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as 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, pectates, salts of these acids, and mixtures thereofSalts, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, 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), (IIa) or (IIb) 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), (IIa) or (IIb) and/or in the isolation of an enantiomer of a compound of formula (I), (IIa) or (IIb).

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), (IIa) or (IIb).

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), (IIa) or (IIb) 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).

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^thed.,1990,Mack PublishingCompany Co.,Easton,Pennsylvania。

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. sup. 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.

The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, for example, carriers such as water, glycols, alcohols, oils, coloring agents, preservatives, flavoring agents and the like in the case of liquid oral preparations such as solutions, elixirs and suspensions; or in the case of solid oral preparations such as tablets, powders, hard and soft capsules, using carriers such as sugars, starches, binders, lubricants, diluents, disintegrants, granulating agents, microcrystalline cellulose and the like, wherein the solid oral preparations are superior to the liquid oral preparations.

Examples of solid compositions of the invention for oral administration are tablets, pills, capsules, granules and diluted powders. In such solid compositions, one or more active substances are mixed with at least one inert excipient, such as starch, lactose, glucose, mannitol, agar, pectin, magnesium aluminate, magnesium metasilicate aluminate, microcrystalline cellulose, hydroxypropyl cellulose and polyvinylpyrrolidone. The composition may also comprise additives other than inert excipients: disintegrants such as calcium glycolate; stabilizers such as lactose; lubricants such as magnesium stearate; and a secondary solubilizer such as aspartic acid or glutamic acid. If necessary, tablets and pills may be coated with a sugar coating such as sucrose, gelatin, phthalic acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc., or with a gastric or intestinal coating film.

Liquid compositions for oral administration include pharmaceutically acceptable solutions, emulsions, syrups, medicaments and suspensions, and contain conventional inert excipients, such as purified water or ethanol. In addition to inert excipients, the compositions may also contain adjuvants such as suspending agents, taste agents, sweeteners, humectants, preservatives and fragrances. Injections for parenteral administration include emulsions, suspensions, non-aqueous solutions and sterile aqueous solutions. Suspensions and non-aqueous solutions include, for example, distilled water and physiological saline solutions for injection. Examples of solvents for the suspension and non-aqueous solution include: propylene glycol; polyethylene glycol; vegetable oils such as sesame oil, olive oil and cocoa butter; alcohols, such as ethanol; gum arabic; and a polycolvate 80. Such compositions may also contain adjuvants such as wetting agents, isotonicity agents, emulsifying agents, dispersing agents, preservatives, stabilizers such as lactose, and co-solubilizers such as aspartic acid or glutamic acid. For example, filtration may be through a bacteria preservation filter, or disinfection may be by mixing with a bactericide or irradiation. These may also be used to make sterile solid compositions which are then dissolved in sterile water or sterile solvent for injection prior to use.

Tablets and capsules are easy to administer and are the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1% of active compound. Of course, the percentage of active compound in these compositions may vary and may conveniently be from about 2% to about 60% by weight of the unit. The amount of active compound in such therapeutically useful compositions is that amount which will provide an effective dosage. The active compounds may also be administered intranasally, for example as a spray or as liquid drops.

Tablets, capsules, pills and the like may also contain binders such as gelatin, tragacanth, corn starch or acacia; excipients, such as dicalcium phosphate; disintegrating agents, such as alginic acid, potato starch, corn starch; lubricants, such as magnesium stearate; and sweetening agents such as saccharin, lactose or sucrose. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

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.

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 prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.

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.

Various other materials may be present in the tablet dosage form as coatings or to modify the physical form of the unit dosage form. For example, tablets may be coated with sugar and/or shellac. Elixirs or syrups may contain, in addition to the active ingredient: preservatives such as methylparaben or propylparaben, sweetening agents such as sucrose, flavouring agents such as cherry flavouring or orange flavouring, dyes.

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.

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. 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).

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 dosage forms for parenteral administration of the pharmaceutical compositions provided by the present invention may be prepared as suspensions or solutions of these active compounds in water suitably mixed with a surfactant such as hydroxypropylcellulose, or as dispersions in liquid polyethylene glycols, glycerol and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the dosage form must be sterile and fluid to the extent that easy injection is achieved. It must be stable under the conditions of manufacture and storage and must be preserved against the contamination of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

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.

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. Other factors that may be considered in The art for a "therapeutically effective amount" are described in Gilman et al, eds., Goodman And Gilman's: The pharmaceutical Bases of Therapeutics,8^thed.,Pergamon Press,1990；Remington's Pharmaceutical Sciences,17^thed.,MackPublishing Company,Easton,Pa.,1990。

The dose can be appropriately determined according to each specific case while taking into consideration the symptoms, age, sex, and the like of the patient. In the case of oral administration, the daily dose for an adult is usually about 0.01mg/kg to 100mg/kg, administered once daily or administered 2 to 4 times daily in divided doses. When administered intravenously according to symptoms, the daily dose for adults is usually about 0.001mg/kg to 10mg/kg, administered once daily or administered 2 or more times daily in divided doses.

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), (IIa) or (IIb) 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.

In the treatment of overactive bladder (OAB) either together with or alone with other anti-OAB agents, satisfactory results are generally obtained when the compounds of the invention are administered in daily doses of from 0.01mg to about 100mg per kg of animal body weight, preferably as a single dose or in divided doses from 2 to 6 times per day, or in sustained release dosage forms. In the case of a 70kg adult, the total daily dose will generally be from about 0.7mg to about 3500mg, or, more specifically, from about 0.7mg to about 2000 mg. Such dosing regimens may be adjusted to provide the optimal therapeutic response.

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 of the additional therapeutic agents described above.

The compounds of formula (I), (IIa) or (IIb) may be combined with other agents useful in the prevention, treatment or alleviation of diseases or conditions for which the compounds of formula (I), (IIa) or (IIb) are indicated. These other drugs may be administered by their usual routes and amounts, simultaneously or sequentially with the compound of formula (I), (IIa) or (IIb). When a compound of formula (I), (IIa) or (IIb) is used concomitantly with one or more other drugs, pharmaceutical unit dosage forms containing such other drugs as well as a compound of formula (I), (IIa) or (IIb) are preferred. Accordingly, the pharmaceutical compositions of the present invention comprise one or more further active ingredients in addition to the compounds of formula (I), (IIa) or (IIb). Examples of other active ingredients that may be used in combination (either separately or in the same pharmaceutical composition) with a compound of formula (I), (IIa) or (IIb) include, but are not limited to:

(1) overactive bladder drugs including (a) muscarinic receptor antagonists (e.g., tolterodine, fesoterodine, oxybutynin, imidafenacin, solifenacin, darifenacin, trospium chloride, propantheline, propiverine, tilmicoline, hyoscyamine and other anticholinergic agents), (b) α adrenergic receptor antagonists (e.g., alfuzosin, tamsulosin, etc.), (c) serotonergic and/or norepinephrine reuptake inhibitors (e.g., duloxetine), (D) selective norepinephrine reuptake inhibitors, (e) dopamine D1 receptor agonists (e.g., pergolide), (f)5-HT_2CAgonists, (g) neuromuscular junction inhibitors of acetylcholine release (e.g., botulinum toxin), (h) NK-1 or NK-2 antagonists (e.g., cizolirtine, aprepitant, etc.), (i) potassium channel openers (e.g., pinacidil, clocarine, etc.), (j) ATP-sensitive potassium ion openers, (k) calcium channel blockers (e.g., verapamil, nifedipine, diltiazem, etc.), (l) voltage-gated sodium channel blockers, (m) capsaicin and other afferent neuromodulators-agonists and antagonists (e.g., resiniferatoxin, capsaicin (capsaicin), etc.), (n) gamma aminobutyric acid receptor antagonists (e.g., baclofen), (o) prostaglandin synthesis inhibitors (e.g., flurbiprofen), (P) vaginal estrogen preparations, (q) PAR2 inhibitors, (r) P2X purine receptor antagonists (e.g., P2X1 or P2X3 antagonists), and(s) phosphodiesterase inhibitors (e.g., PDE 1), PDE4 and PDE5 inhibitors);

(2) 5-hydroxytryptamine reuptake inhibitors such as sertraline and fluoxetine;

(3) anti-obesity compounds such as orlistat, fenfluramine;

(4) feeding performance modifiers, such as neuropeptide Y antagonists (e.g., neuropeptide Y5);

(5) α -glucosidase inhibitors (e.g. acarbose);

(6) sulfonylureas, such as glipizide and tolbutamide;

(7) insulin or insulin mimetics;

(8) insulin sensitizers including (i) biguanides such as phenformin and metformin, (ii) PPAR γ agonists such as glitazones (e.g., englitazone, pioglitazone, etc.);

(9) cholesterol lowering agents such as (a) HMG-CoA reductase inhibitors (atorvastatin, lovastatin and other statins), (b) cholesterol absorption inhibitors such as β -sitosterol and ezetimibe and (acyl CoA: cholesterol acyltransferase) inhibitors such as melinamide, (c) proliferator-activator receptor α agonists such as fenofibric acid derivatives (fenofibrate, gemfibrozil), (d) nicotinyl alcohol, nicotinic acid or a salt thereof, (E) chelators (colestipol, cholestyramine), (f) vitamin E, (g) probucol and (h) thyromimetics;

(10) PPAR α agonists;

(11) PPAR δ agonists;

(l2) PPAR γ antagonists.

In one embodiment, the compounds of the present invention and the additional therapeutic agents described above are used in the manufacture of a medicament for the prevention, treatment, or amelioration of diseases or conditions mediated by activation of the β 3-adrenergic receptor.

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.

Of the Compounds and pharmaceutical compositions of the inventionUse of

The compounds and pharmaceutical compositions provided by the present invention are useful for the preparation of medicaments for activating β 3-adrenergic receptors, and for the preparation of medicaments for the prevention, treatment or alleviation of diseases or conditions mediated by β 3-adrenergic receptor activation, particularly overactive bladder.

In particular, the amount of the compound or compounds in the pharmaceutical compositions of the present invention is effective to detectably selectively activate β 3-adrenergic receptors.

The diseases or disorders mediated by activation of β -adrenergic receptors further include, but are not limited to, overactive bladder, urinary incontinence, urge urinary incontinence, urinary urgency, diabetes, obesity, hyperglycemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, depression, atherosclerosis, gastrointestinal disorders, irritable bowel syndrome and other disorders requiring reduced intestinal activity, neurogenic inflammation of the airways, ocular hypertension, glaucoma, diabetic retinopathy, prostatosis or preterm labor.

The atherosclerosis is atherosclerosis of coronary artery, atherosclerosis of cerebrovascular artery or atherosclerosis of peripheral artery.

The gastrointestinal disorder is gastritis, esophagitis, duodenitis, intestinal ulcer (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis), gastrointestinal ulcer or peptic ulcer.

The neurogenic inflammation of the airway is cough or asthma.

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 invention can be prepared by the processes described herein, unless otherwise indicated, wherein the substituents are as defined in formula (I), (IIa) or (IIb). 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 (singleton, singlet), d (doublet ), t (triplet, triplet), q (quatet, quartet), m (multiplet ), br (broadded, broad), brs (broadded singleton, broad singlet), dd (doublet of doublets), ddd (doublet of doublets ), ddt (doublet of doublets, doublet of triplets), dt (doublet of triplets ), td (triplet of doublets, triplet of triplets), 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 of mL or mL

DMSO dimethyl sulfoxide mu L, mu L microliter

DMSO-d₆Nano liter of deuterated dimethyl sulfoxide nL and nL

CH₃OH, MeOH methanol s sec

H₂Water for min

HCOONH₄Ammonium formate h hours

FA formic acid EDTA-K2 dipotassium ethylene diamine tetraacetate

nM, nmol/L nanomole per liter Solutol polyethylene glycol-15-hydroxystearate

Mu M, mu mol/L micromoles per liter PEG400 polyethylene glycol 400

mM, mmol/L mmole/L PBS phosphate buffersaline, phosphate buffered saline

M, mol/L mol cAMP Cyclic adenosine monophosphate per liter

ng Nanke DMEM Dulbecco's Modified Eagle Medium

Microgram (Boc)₂Boc anhydride, di-tert-butyl dicarbonate

mg of Pd (OH)₂Palladium hydroxide

g of HOBT 1-hydroxybenzotriazole

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

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

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

The following synthetic schemes describe the procedures for preparing the presently disclosed compounds, wherein R is, unless otherwise indicated^1b、R⁴And R⁵Having the definitions set out in the present invention.

Synthesis scheme 1

Wherein Boc is tert-butyloxycarbonyl

Cbz is benzyloxycarbonyl

Compound (A) to (B)11) Can be prepared by the following steps: compound (A) to (B)1) And 4-nitrophenylethylamine hydrochloride to obtain a compound (A)2) Compound (A) to (B)2) To obtain a compound (b)3) Compound (A) to (B)3) The Boc protecting group on the amino group of (1) to give a compound of (a)4) Compound (A) to (B)4) Reduction of the nitro group to give a compound5) Compound (A) to (B)5) Carrying out condensation reaction with (2S) -1- ((benzyloxy) carbonyl) pyrrolidine-2-carboxylic acid to obtain a compound (6) Compound (A) to (B)6) Removing the Cbz protecting group to obtain a compound (7) Compound (A) to (B)7) Reacting with (4-nitrophenyl) chloroformate or phenylchloroformate to obtain compound (A), (B)8) Compound (A) to (B)8) And a compound of (A), (B), (C), (9) Nucleophilic substitution reaction to obtain compound (A)10) Compound (A) to (B)10) Removing Boc protecting group to obtain target compound (11)。

Synthesis scheme 2

Wherein Boc is tert-butyloxycarbonyl

Cbz is benzyloxycarbonyl

Compound (A) to (B)11’) Can be prepared by the following steps: compound (A) to (B)5) With (2R) -1- ((benzyloxy) carbonyl) pyrrolidine-2-carboxylic acidBy condensation reaction to give a compound (6’) Compound (A) to (B)6’) Removing the Cbz protecting group to obtain a compound (7’) Compound (A) to (B)7’) Reacting with (4-nitrophenyl) chloroformate or phenylchloroformate to obtain compound (A), (B)8’) Compound (A) to (B)8’) And a compound of (A), (B), (C), (9) Nucleophilic substitution reaction to obtain compound (A)10’) Compound (A) to (B)10’) Removing Boc protecting group to obtain target compound (11’)。

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

Examples

Example 1(S) -N¹-cyclopropyl-N²Synthesis of- (4- (2- (((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) pyrrolidine-1, 2-dicarboxamide

Step 1 Synthesis of (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide

(2R) -2-hydroxy-2-phenyl-acetic acid (2.70g,18.00mmol) and 4-nitrophenylethylamine hydrochloride (3g,14.81mmol) were weighed into a 100mL single vial, N-dimethylformamide (30mL), triethylamine (2.50mL,18.00mmol) were added, HOBT (2.45g,17.8mmol) and EDCI (3.44g,17.8mmol) were then added, the reaction was stirred at room temperature for 2 hours, ethyl acetate (150mL) was added, the reaction mixture was washed with water (50mL × 3) and brine (30mL × 2), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the title compound as a pale yellow solid (3g, 67%).

MS(ESI,pos.ion)m/z:301.20[M+H]⁺.

Step 2 Synthesis of) (R) -2- ((4-Nitrophenylethyl) amino) -1-phenylethane-1-ol

(R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide was weighed into a 100mL single-neck flask, anhydrous tetrahydrofuran (30mL) was added, sodium borohydride (935mg,24.2mmol) was added under ice-bath, boron trifluoride diethyl ether (3.15mL,24.2mmol) was slowly added dropwise, after completion of the addition, the mixture was stirred for three minutes under ice-bath stirring and heated to 70 ℃ to stir for 1 day, ice water (2mL) was added dropwise to quench the reaction under ice-bath, ethyl acetate (100mL) was added, the organic phase after separation was washed with water (30 mL. times.2), dried over anhydrous sodium sulfate and concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the title compound as a pale yellow liquid (2.2g, 79%).

MS(ESI,pos.ion)m/z:287.20[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.80(s,2H),8.22(d,J＝8.6Hz,2H),7.56(d,J＝8.6Hz,2H),7.40(t,J＝6.0Hz,3H),4.92(dd,J＝10.3,2.5Hz,1H),3.38–2.93(m,6H).

Step 3) (Synthesis of tert-butyl (R) - (2-hydroxy-2-phenylethyl) (4-nitrophenylethyl) carbamate

(R) -2- ((4-nitrophenylethyl) amino) -1-phenylethane-1-ol (1.71g,5.97mmol) was weighed into a 100mL one-neck flask, then tetrahydrofuran (15mL), triethylamine (2.5mL,18mmol) were added, Boc anhydride (1.7mL,7.3mmol, dissolved in 10mL of anhydrous tetrahydrofuran) was added at room temperature, the reaction was stirred at room temperature for 1 hour to stop the reaction, the reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a pale yellow oil (2g, 87%).

MS(ESI,pos.ion)m/z:409.30[M+Na]⁺.

Step 4 Synthesis of tert-butyl (R) - (4-aminophenylethyl) (2-hydroxy-2-phenylethyl) carbamate

Tetrahydrofuran (20mL), ethanol (20mL) and then ammonium chloride (780mg,14.58mmol) were dissolved in water (4mL) and added to a 100mL single-neck flask containing tert-butyl (R) - (2-hydroxy-2-phenylethyl) (4-nitrophenylethyl) carbamate (2.8g,7.2mmol), and finally iron powder (2g,35.81mmol) was added, the reaction was stopped by refluxing at 75 ℃ for 4 hours, the reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a pale yellow liquid (2.4g, 93%).

¹H NMR(400MHz,CDCl₃)δ(ppm)7.32(t,J＝15.1Hz,5H),6.91(s,2H),6.61(d,J＝8.3Hz,2H),4.87(d,J＝6.4Hz,1H),3.44–3.04(m,4H),2.63(s,2H),1.47(s,9H).

Step 5) (S) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) amino) ethyl) benzene Group) carbamoyl) pyrrolidine-1-carboxylic acid benzyl ester synthesis

(2S) -1- ((benzyloxy) carbonyl) pyrrolidine-2-carboxylic acid (0.42g,1.7mmol) was charged in a 100mL single-neck flask, methylene chloride (5mL) and N, N-diisopropylethylamine (0.98mL,5.6mmol) were added, HATU (0.7g,2mmol) was added after cooling at 20 ℃ and stirring for 1 hour, then tert-butyl (R) - (4-aminophenylethyl) (2-hydroxy-2-phenylethyl) carbamate (0.5g,1mmol) was added, the reaction was stopped after 1 hour by transferring to room temperature for 3 hours, water (5mL) was added and quenched, then extracted with methylene chloride (20 mL. times.2), the organic phase was collected, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a pale red liquid (0.5g, 99%).

MS(ESI,pos.ion)m/z:610.20[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.37(d,J＝5.0Hz,12H),7.06(s,2H),5.24(d,J＝12.0Hz,2H),4.90(s,1H),4.51(s,1H),3.69–3.13(m,7H),2.68(d,J＝26.0Hz,2H),1.72(s,4H),1.50(s,9H).

Step 6) tert-butyl ((R) -2-hydroxy-2-phenylethyl) (4- ((S) -pyrrolidine-2-carboxamido) phenylethyl) Synthesis of carbamates

Benzyl (S) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (4.5g,7.7mmol) and methanol (40mL) were added to a 100mL single neck flask, followed by acetic acid (0.44mL) and Pd (OH)₂(0.5g,4mmol) was reacted at room temperature under hydrogen atmosphere for 4 hours. Quenched by the addition of sodium carbonate (0.811g), concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the title compound as a white solid (4.5g, 92%).

MS(ESI,pos.ion)m/z:454.25[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.52(d,J＝8.3Hz,2H),7.36(d,J＝4.5Hz,5H),7.09(s,2H),4.89(s,1H),3.94(dd,J＝9.1,5.4Hz,1H),3.59–3.16(m,5H),3.15–2.97(m,2H),2.71(s,2H),2.24(dt,J＝16.4,7.7Hz,1H),2.06–2.00(m,1H),1.86–1.73(m,2H),1.49(s,9H).

Step 7) (S) -4-Nitrophenyl 2- ((4- (2- ((tert-Butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) ammonia) Synthesis of yl) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylic acid esters

Tert-butyl ((R) -2-hydroxy-2-phenylethyl) (4- ((S) -pyrrolidine-2-carboxamido) phenethyl) carbamate (1.00g,2.21mmol) was weighed into a 100mL single-neck flask, dissolved in dichloromethane (20mL), added triethylamine (0.61mL,4.40mmol) and then cooled at 0 ℃ to room temperature, and (4-nitrophenyl) chloroformate (0.49g,2.42mmol) was slowly added dropwise to the reaction mixture to react for 1 hour, and the reaction mixture was transferred to room temperature to react for 15 hours to stop the reaction, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow oil (900mg, 70%).

MS(ESI,pos.ion)m/z:519.15[M-100+H]⁺.

Step 8) (4- ((S) -1- (cyclopropylcarbamoyl) pyrrolidine-2-carboxamido) phenethyl) ((R) -2-hydroxy Synthesis of tert-butyl 2-phenylethyl) carbamate

Cyclopropylamine (2mL) and (S) -4-nitrophenyl 2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (0.25g,0.40mmol) were added to a 50mL one-necked flask, reacted at room temperature for 20 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (200mg, 90%).

MS(ESI,pos.ion)m/z:559.20[M+Na]⁺.

^{1 2}Step 9) (S) -N-cyclopropyl-N- (4- (2- (((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) pyrrole Synthesis of alkane-1, 2-dicarboxamides

To a 50mL single-neck flask containing tert-butyl (4- ((S) -1- (cyclopropylcarbamoyl) pyrrolidine-2-carboxamido) phenethyl) ((R) -2-hydroxy-2-phenylethyl) carbamate (200mg,0.37mmol) was added dichloromethane (3mL), followed by dropwise addition of a solution of hydrogen chloride in ethyl acetate (2.0mL,4M), stirring at room temperature for 1 hour to stop the reaction, concentration of the reaction mixture, dissolution in methanol (5mL), stirring with sodium carbonate (118mg,1.11mmol) for 10 minutes, concentration of the reaction mixture, and purification of the residue by column chromatography (dichloromethane/methanol (v/v) ═ 7/1) to give the title compound as a white solid (160mg, 98%).

MS(ESI,pos.ion)m/z:437.25[M+H]⁺；

HPLC:95.47％；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.33(s,1H),7.28(s,2H),7.23(d,J＝7.6Hz,2H),7.18(d,J＝6.9Hz,1H),7.14(s,1H),7.01(d,J＝8.0Hz,2H),4.75(d,J＝9.2Hz,1H),4.42–4.31(m,1H),3.56(dt,J＝20.3,14.0Hz,4H),3.40–3.27(m,2H),2.93–2.79(m,3H),2.73(dd,J＝19.8,9.6Hz,3H),2.21(d,J＝9.2Hz,1H),2.07–1.97(m,1H),1.91(d,J＝9.4Hz,2H),0.79(d,J＝7.6Hz,1H),0.61(d,J＝6.0Hz,2H),0.41(s,2H).

EXAMPLE 2 Synthesis of (S) -N- (4- (2- (((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) -1- (pyrrolidine-1-carbonyl) pyrrolidine-2-carboxamide

Step 1) tert-butyl ((R) -2-hydroxy-2-phenylethyl) (4- ((S) -1- (pyrrolidine-1-carbonyl) pyrrolidine-2- Synthesis of carboxamido) phenethyl) carbamates

Pyrrolidine (2mL) and (S) -4-nitrophenyl 2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (0.30g,0.50mmol) were added to a 50mL one-necked flask, reacted at room temperature for 2 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a white solid (250mg, 90%).

MS(ESI,pos.ion)m/z:573.20[M+Na]⁺.

Step 2) (S) -N- (4- (2- (((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) -1- (pyrrolidine-1- Carbonyl) pyrrolidine-2-carboxamide synthesis

To a 50mL one-neck flask containing tert-butyl ((R) -2-hydroxy-2-phenylethyl) (4- ((S) -1- (pyrrolidine-1-carbonyl) pyrrolidine-2-carboxamido) phenethyl) carbamate (250mg,0.45mmol) was added dichloromethane (3mL), followed by dropwise addition of a solution of hydrogen chloride in ethyl acetate (2.0mL,4M), stirring at room temperature for 1 hour to stop the reaction, concentration of the reaction solution, dissolution with methanol (5mL), stirring with sodium carbonate (143mg,1.11mmol) for 10 minutes, concentration of the reaction solution, and purification of the residue by column chromatography (dichloromethane/methanol (v/v) ═ 7/1) to give the title compound as a white solid (170mg, 83%).

MS(ESI,pos.ion)m/z:451.25[M+H]⁺；

HPLC:98.94％；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.36(dd,J＝10.9,4.5Hz,4H),7.32–7.23(m,2H),7.02(d,J＝8.3Hz,2H),6.94(s,1H),4.82(dd,J＝9.5,2.9Hz,1H),4.70(dd,J＝7.9,4.3Hz,1H),3.68–3.65(m,1H),3.56–3.49(m,2H),3.40(ddd,J＝18.3,10.7,6.8Hz,6H),2.98–2.83(m,3H),2.80–2.73(m,3H),2.21(ddt,J＝23.1,20.2,7.7Hz,2H),2.00(dd,J＝13.0,6.8Hz,2H),1.96–1.88(m,2H),1.87–1.79(m,2H).

EXAMPLE 3 Synthesis of (S) -N- (4- (2- (((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) -1- (morpholine-4-carbonyl) pyrrolidine-2-carboxamide

Step 1) tert-butyl ((R) -2-hydroxy-2-phenylethyl) (4- ((S) -1- (morpholine-4-carbonyl) pyrrolidine-2-carboxylic acid methyl ester Amido) phenethyl) carbamate synthesis

Morpholine (4mL) and (S) -4-nitrophenyl 2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (0.30g,0.50mmol) were added to a 50mL one-necked flask, reacted at room temperature for 20 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a colorless oil (170mg, 62%).

MS(ESI,pos.ion)m/z:589.30[M+Na]⁺.

Step 2) (S) -N- (4- (2- (((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) -1- (morpholine-4-carbonyl Yl) Synthesis of pyrrolidine-2-carboxamides

To a 50mL single-neck flask containing tert-butyl ((R) -2-hydroxy-2-phenylethyl) (4- ((S) -1- (morpholine-4-carbonyl) pyrrolidine-2-carboxamido) phenethyl) carbamate (170mg,0.30mmol) was added dichloromethane (3mL), followed by dropwise addition of a solution of hydrogen chloride in ethyl acetate (2.0mL,4M), stirring at room temperature for 1 hour to stop the reaction, concentration of the reaction solution, dissolution in methanol (5mL), stirring with sodium carbonate (95mg,0.90mmol) for 10 minutes, concentration of the reaction solution, and purification of the residue by column chromatography (dichloromethane/methanol (v/v) ═ 7/1) to give the title compound as a white solid (130mg, 93%).

MS(ESI,pos.ion)m/z:467.30[M+H]⁺；

HPLC:98.35％；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.33(dd,J＝16.8,7.8Hz,6H),7.28–7.22(m,1H),7.01(d,J＝7.9Hz,2H),4.89(d,J＝2.4Hz,2H),3.75(dd,J＝16.4,4.9Hz,5H),3.64(d,J＝5.3Hz,4H),3.55(dd,J＝13.9,6.2Hz,4H),2.94(dd,J＝27.4,8.5Hz,3H),2.86–2.76(m,3H),2.17(s,2H),2.01(s,1H),1.85(s,1H).

Example 4(S) -N²- (4- (2- (((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) -N¹Synthesis of (cyclopropyl) pyrrolidine-1, 2-dicarboxamide

Step 1 Synthesis of (R) -2- (3-chlorophenyl) -2-hydroxy-N- (4-nitrophenylethyl) acetamide

(2R) -2- (3-chlorophenyl) -2-hydroxy-acetic acid (3.3g,18mmol) and 4-nitrophenylethylamine hydrochloride (3g,14.8mmol) were weighed into a 100mL single-neck flask, N-dimethylformamide (30mL) and triethylamine (2.5mL,18mmol) were added, HOBT (2.45g,17.8mmol) and EDCI (3.44g,17.8mmol) were then added, the reaction was stirred at room temperature for 2 hours to stop the reaction, ethyl acetate (150mL) was added, the mixture was washed with water (100mL) and saturated brine (100mL) in this order, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated and purified by column chromatography (dichloromethane/methanol (v/v) ═ 30/1) to give the title compound as a pale yellow liquid (4.5g, 91%).

MS(ESI,pos.ion)m/z:335.20[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.09(d,J＝8.6Hz,2H),7.31(dd,J＝14.1,7.2Hz,3H),7.21(t,J＝7.6Hz,3H),6.27(s,1H),4.98(s,1H),3.57(ddt,J＝16.9,13.7,6.8Hz,2H),2.89(ddd,J＝13.8,8.6,5.0Hz,2H).

Step 2 Synthesis of (R) -1- (3-chlorophenyl) -2- ((4-nitrophenylethyl) amino) ethanol

(R) -2- (3-chlorophenyl) -2-hydroxy-N- (4-nitrophenylethyl) acetamide (2g,5.9mmol) was weighed into a 100mL single-neck flask, anhydrous tetrahydrofuran (25mL) was added, sodium borohydride (346mg,8.96mmol) was added in ice bath, boron trifluoride diethyl ether (1.94mL,14.9mmol) was slowly added dropwise, the reaction was stopped by heating to 70 ℃ for three minutes with stirring in ice bath, the reaction was quenched by adding ice water (2mL) in ice bath, ethyl acetate (80mL) was added, the organic phase after separation was washed with water (50 mL. times.2), dried over anhydrous sodium sulfate and concentrated to give the title compound as a pale yellow oil (1.8g, 94%).

MS(ESI,pos.ion)m/z:321.10[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)8.19(d,J＝8.6Hz,2H),7.54(d,J＝8.6Hz,2H),7.49–7.23(m,4H),5.98(s,1H),4.81(dd,J＝9.2,3.1Hz,1H),3.15–2.87(m,6H).

Step 3) Synthesis of tert-butyl (R) - (2- (3-chlorophenyl) -2-hydroxyethyl) (4-nitrophenylethyl) carbamate

(R) -1- (3-chlorophenyl) -2- ((4-nitrophenylethyl) amino) ethanol (1.92g,5.97mmol) was weighed into a 100mL single vial, tetrahydrofuran (15mL), triethylamine (2.5mL,18mmol) were added, then Boc anhydride (1.7mL,7.3mmol, dissolved in 10mL of anhydrous tetrahydrofuran) was added at room temperature, the reaction was stirred at room temperature for 1 hour, the reaction was stopped, the reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a pale yellow oil (2.35g, 93.5%).

MS(ESI,pos.ion)m/z:443.30[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)8.15(d,J＝8.4Hz,2H),7.42–7.13(m,6H),4.90(s,1H),3.39(s,4H),3.06–2.66(m,2H),1.43(s,9H).

Step 4) Synthesis of tert-butyl (R) - (4-Aminophenylethyl) (2- (3-chlorophenyl) -2-hydroxyethyl) carbamate

To a 100mL single neck flask containing tert-butyl (R) - (2- (3-chlorophenyl) -2-hydroxyethyl) (4-nitrophenylethyl) carbamate (2.35g,5.58mmol) was added tetrahydrofuran (20mL), ethanol (20mL), then ammonium chloride (597mg,11.16mmol) was dissolved in water (5mL) and added to the reaction flask, and finally iron powder (1.56g,27.9mmol) was added, the reaction was stopped by refluxing at 75 ℃ for 2 hours, the reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a pale yellow solid (1.8g, 82%).

MS(ESI,pos.ion)m/z:413.10[M+Na]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm)7.34(s,1H),7.26–7.17(m,3H),6.90(d,J＝6.0Hz,2H),6.62(d,J＝8.2Hz,2H),4.82(d,J＝6.7Hz,1H),3.36(dd,J＝83.9,10.5Hz,4H),2.61(d,J＝21.6Hz,2H),1.47(s,9H).

Step 5) (S) -2- ((4- (2- ((tert-Butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethane Synthesis of phenyl) carbamoyl) pyrrolidine-1-carboxylic acid benzyl ester

(2S) -1- ((benzyloxy) carbonyl) pyrrolidine-2-carboxylic acid (0.48g,2.0mmol) was charged in a 100mL single neck flask, methylene chloride (5mL) and N, N-diisopropylethylamine (0.70mL,4.0mmol) were added, HATU (0.7g,2mmol) was added after cooling in an ice bath and stirring for 1 hour, then tert-butyl (R) - (4-aminophenylethyl) (2- (3-chlorophenyl) -2-hydroxyethyl) carbamate (0.39g,1mmol) was added, the reaction was stopped after 1 hour by transferring to room temperature for 3 hours, water (5mL) was added and quenched, then extracted with methylene chloride (20 mL. times.2), the organic phase was collected, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a red liquid (0.49g, 79%).

MS(ESI,pos.ion)m/z:622.20[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.36(d,J＝5.0Hz,12H),7.06(s,1H),5.25(d,J＝12.0Hz,2H),4.92(s,1H),4.51(s,1H),3.69–3.13(m,7H),2.68(d,J＝26.0Hz,2H),1.72(s,4H),1.50(s,9H).

Step 6) (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((S) -pyrrolidine-2-carboxamido) phenethyl) amino Synthesis of tert-butyl formate

Benzyl (S) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (3.1g,5mmol) and methanol (40mL) were added to a 100mL single neck flask, followed by acetic acid (0.40mL) and Pd (OH)₂(0.5g,4mmol), reacted at room temperature under hydrogen atmosphere for 1 hour, quenched by addition of sodium carbonate (0.80g), concentrated under reduced pressure, and the residue purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the title compound as a white solid (2.1g, 86%).

MS(ESI,pos.ion)m/z:488.25[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.53(d,J＝8.3Hz,2H),7.37(d,J＝4.5Hz,4H),7.10(s,2H),4.90(s,1H),3.94(dd,J＝9.1,5.4Hz,1H),3.59–3.16(m,5H),3.15–2.97(m,2H),2.71(s,2H),2.24(dt,J＝16.4,7.7Hz,1H),2.06–2.00(m,1H),1.86–1.73(m,2H),1.49(s,9H).

Step 7) (S) -4-Nitrophenyl 2- ((4- (2- ((tert-Butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxy) Synthesis of ethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylic acid ester

Tert-butyl (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((S) -pyrrolidine-2-carboxamido) phenethyl) carbamate (1.00g,2.05mmol) was weighed into a 100mL single vial, dissolved in dichloromethane (20mL), and after addition of triethylamine (0.61mL,4.40mmol), cooled at 0 ℃ to room temperature, and (4-nitrophenyl) chloroformate (0.49g,2.42mmol) was slowly added dropwise to the reaction mixture to react for 1 hour, and then transferred to room temperature to react for 15 hours, thereby stopping the reaction, the reaction mixture was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow oil (1.00g, 75%).

MS(ESI,pos.ion)m/z:675.25[M+Na]⁺.

Step 8) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((S) -1- (cyclopropylcarbamoyl) pyrrolidine- Synthesis of 2-formylamino) phenethyl) carbamic acid tert-butyl ester

Cyclopropylamine (2mL) and (S) -4-nitrophenyl 2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (0.26g,0.40mmol) were added to a 50mL one-necked flask, reacted at room temperature for 20 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (200mg, 88%).

MS(ESI,pos.ion)m/z:593.20[M+Na]⁺.

^{2 1}Step 9) (S) -N- (4- (2- (((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) -N-cyclopropyl Synthesis of pyrrolidine-1, 2-dicarboxamide

To contain(Dichloromethane (3mL) was added to a 50mL single-neck flask of tert-butyl (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((S) -1- (cyclopropylcarbamoyl) pyrrolidine-2-carboxamido) phenethyl) carbamate (200mg,0.35mmol), then an ethyl acetate solution of hydrogen chloride (2.0mL,4M) was added dropwise, the reaction was stopped by stirring at room temperature for 1 hour, the reaction solution was concentrated, methanol (5mL) was added and dissolved, sodium carbonate (115mg,1.05mmol) was added and stirred for 10 minutes, the reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 7/1) to give the title compound as a white solid (160mg, 97%).

MS(ESI,pos.ion)m/z:471.20[M+H]⁺；

HPLC:96.88％；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.34(s,1H),7.29(s,2H),7.24(d,J＝7.6Hz,2H),7.19(d,J＝6.9Hz,1H),7.02(d,J＝8.0Hz,2H),4.76(d,J＝9.2Hz,1H),4.42–4.31(m,1H),3.56(dt,J＝20.3,14.0Hz,4H),3.40–3.27(m,2H),2.93–2.79(m,3H),2.75(dd,J＝19.8,9.6Hz,3H),2.22(d,J＝9.2Hz,1H),2.07–1.97(m,1H),1.90(d,J＝9.4Hz,2H),0.79(d,J＝7.6Hz,1H),0.61(d,J＝6.0Hz,2H),0.41(s,2H).

EXAMPLE 5 Synthesis of (S) -N- (4- (2- (((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) -1- (pyrrolidine-1-carbonyl) pyrrolidine-2-carboxamide

Step 1) (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((S) -1- (pyrrolidine-1-carbonyl) pyrrolidine-2-carboxylic acid methyl ester Amido) phenethyl) carbamic acid tert-butyl ester synthesis

Pyrrolidine (2mL) and (S) -4-nitrophenyl 2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (0.33g,0.50mmol) were added to a 50mL one-necked flask, reacted at room temperature for 2 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a white solid (245mg, 84%).

MS(ESI,pos.ion)m/z:607.20[M+Na]⁺.

Step 2) (S) -N- (4- (2- (((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) -1- (pyrrole Synthesis of alkane-1-carbonyl) pyrrolidine-2-carboxamide

To a 50mL single neck flask containing tert-butyl (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((S) -1- (pyrrolidine-1-carbonyl) pyrrolidine-2-carboxamido) phenethyl) carbamate (245mg,0.42mmol) was added dichloromethane (3mL), then a solution of hydrogen chloride in ethyl acetate (2.0mL,4M) was added dropwise, the reaction was stopped by stirring at room temperature for 1 hour, the reaction solution was concentrated, methanol (5mL) was added to dissolve, sodium carbonate (134mg,1.26mmol) was added to stir for 10 minutes, the reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 7/1) to give the title compound as a white solid (175mg, 86%).

MS(ESI,pos.ion)m/z:485.20[M+H]⁺；

HPLC:98.68％；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.37(dd,J＝10.9,4.5Hz,4H),7.30–7.21(m,1H),7.03(d,J＝8.3Hz,2H),6.95(s,1H),4.83(dd,J＝9.5,2.9Hz,1H),4.71(dd,J＝7.9,4.3Hz,1H),3.68–3.65(m,1H),3.56–3.49(m,2H),3.42(ddd,J＝18.3,10.7,6.8Hz,6H),2.98–2.83(m,3H),2.80–2.73(m,3H),2.21(ddt,J＝23.1,20.2,7.7Hz,2H),2.01(dd,J＝13.0,6.8Hz,2H),1.96–1.88(m,2H),1.87–1.79(m,2H).

EXAMPLE 6 Synthesis of (S) -N- (4- (2- (((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) -1- (morpholine-4-carbonyl) pyrrolidine-2-carboxamide

Step 1) (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((S) -1- (morpholine-4-carbonyl) pyrrolidine-2-carboxylic acid Synthesis of amino) phenethyl) carbamic acid tert-butyl ester

Morpholine (4mL) and 4-nitrophenyl (S) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (0.33g,0.50mmol) were added to a 50mL one-necked flask, reacted at room temperature for 20 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 50/1) to give the title compound as a colorless oil (258mg, 86%).

MS(ESI,pos.ion)m/z:623.30[M+Na]⁺.

Step 2) (S) -N- (4- (2- (((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) -1- (morpholino) Synthesis of quinoline-4-carbonyl) pyrrolidine-2-formamide

To a 50mL single neck flask containing tert-butyl (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((S) -1- (morpholine-4-carbonyl) pyrrolidine-2-carboxamido) phenethyl) carbamate (258mg,0.43mmol) was added dichloromethane (3mL), followed by dropwise addition of a solution of hydrogen chloride in ethyl acetate (2.0mL,4M), stirring at room temperature for 1 hour to stop the reaction, concentration of the reaction mixture, dissolution with methanol (5mL), stirring with sodium carbonate (134mg,1.26mmol) for 10 minutes, concentration of the reaction mixture, and purification of the residue by column chromatography (dichloromethane/methanol (v/v) ═ 7/1) to give the title compound as a white solid (205mg, 95%).

MS(ESI,pos.ion)m/z:501.30[M+H]⁺；

HPLC:98.69％；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.34(dd,J＝16.8,7.8Hz,5H),7.29–7.23(m,1H),7.02(d,J＝7.9Hz,2H),4.90(d,J＝2.4Hz,2H),3.76(dd,J＝16.4,4.9Hz,5H),3.64(d,J＝5.3Hz,4H),3.55(dd,J＝13.9,6.2Hz,4H),2.94(dd,J＝27.4,8.5Hz,3H),2.86–2.76(m,3H),2.18(s,2H),2.01(s,1H),1.87(s,1H).

Example 7(R) -N¹-cyclopropyl-N²Synthesis of- (4- (2- (((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) pyrrolidine-1, 2-dicarboxamide

Step 1) (R) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) amino) ethyl) benzene Group) carbamoyl) pyrrolidine-1-carboxylic acid benzyl ester synthesis

(2R) -1- ((benzyloxy) carbonyl) pyrrolidine-2-carboxylic acid (0.84g,3.37mmol) was charged in a 100mL single neck flask, methylene chloride (10mL) and N, N-diisopropylethylamine (2.40mL,14mmol) were added, HATU (1.39g,3.65mmol) was added after cooling at 20 ℃ and stirring for 1 hour, then tert-butyl (R) - (4-aminophenylethyl) (2-hydroxy-2-phenylethyl) carbamate (1.0g,2.80mmol) was added, the reaction was stopped after 1 hour by transferring to room temperature for 3 hours, water (5mL) was added and quenched, then extracted with methylene chloride (20 mL. times.2), the organic phase was collected, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a pale red liquid (1.55g, 94%).

MS(ESI,pos.ion)m/z:588.20[M+H]⁺.

Step 2) tert-butyl ((R) -2-hydroxy-2-phenylethyl) (4- ((R) -pyrrolidine-2-carboxamido) phenylethyl) Synthesis of carbamates

Benzyl (R) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (1.50g,2.60mmol) and methanol (15mL) were added to a 100mL single-neck flask, followed by acetic acid (0.15mL) and Pd (OH)₂(300mg,2mmol) under hydrogen at room temperature for 4 hr, adding sodium carbonate (0.81g), quenching, concentrating under reduced pressure, and separating the residue by column chromatographyThe reaction (dichloromethane/methanol (v/v) ═ 25/1) gave the title compound as a white solid (1.11g, 96%).

MS(ESI,pos.ion)m/z:454.20[M+H]⁺.

Step 3) (R) -4-Nitrophenyl 2- ((4- (2- ((tert-Butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) ammonia) Synthesis of yl) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylic acid esters

Tert-butyl ((R) -2-hydroxy-2-phenylethyl) (4- ((R) -pyrrolidine-2-carboxamido) phenethyl) carbamate (1.00g,2.21mmol) was weighed into a 100mL single-neck flask, dissolved in dichloromethane (20mL), added triethylamine (0.61mL,4.40mmol) and then cooled at 0 ℃ to room temperature, and (4-nitrophenyl) chloroformate (0.49g,2.42mmol) was slowly added dropwise to the reaction mixture to react for 1 hour, and the reaction mixture was transferred to room temperature to react for 15 hours to stop the reaction, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow oil (1.00g, 78%).

MS(ESI,pos.ion)m/z:519.25[M-100+H]⁺.

Step 4) (4- ((R) -1- (cyclopropylcarbamoyl) pyrrolidine-2-carboxamido) phenethyl) ((R) -2-hydroxy Synthesis of tert-butyl 2-phenylethyl) carbamate

Cyclopropylamine (2mL) and (R) -4-nitrophenyl 2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (0.25g,0.40mmol) were added to a 50mL one-necked flask, reacted at room temperature for 20 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (215mg, 97%).

MS(ESI,pos.ion)m/z:559.35[M+Na]⁺.

^{1 2}Step 5) (R) -N-cyclopropyl-N- (4- (2- (((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) pyrrole Synthesis of alkane-1, 2-dicarboxamides

To a 50mL one-neck flask containing tert-butyl (4- ((R) -1- (cyclopropylcarbamoyl) pyrrolidine-2-carboxamido) phenethyl) ((R) -2-hydroxy-2-phenylethyl) carbamate (210mg,0.39mmol) was added dichloromethane (3mL), followed by dropwise addition of a solution of hydrogen chloride in ethyl acetate (2.0mL,4M), stirring at room temperature for 1 hour to stop the reaction, concentration of the reaction mixture, dissolution in methanol (5mL), stirring with sodium carbonate (125mg,1.18mmol) for 10 minutes, concentration of the reaction mixture, and purification of the residue by column chromatography (dichloromethane/methanol (v/v) ═ 7/1) to give the title compound as a white solid (155mg, 91%).

MS(ESI,pos.ion)m/z:437.40[M+H]⁺；

HPLC:99.63％；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.33(s,1H),7.28(s,2H),7.23(d,J＝7.6Hz,2H),7.18(d,J＝6.9Hz,1H),7.14(s,1H),7.01(d,J＝8.0Hz,2H),4.75(d,J＝9.2Hz,1H),4.42–4.31(m,1H),3.56(dt,J＝20.3,14.0Hz,4H),3.40–3.27(m,2H),2.93–2.79(m,3H),2.73(dd,J＝19.8,9.6Hz,3H),2.21(d,J＝9.2Hz,1H),2.07–1.97(m,1H),1.91(d,J＝9.4Hz,2H),0.79(d,J＝7.6Hz,1H),0.61(d,J＝6.0Hz,2H),0.41(s,2H).

Example 8(R) -N²- (4- (2- (((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) -N¹Synthesis of (cyclopropyl) pyrrolidine-1, 2-dicarboxamide

Step 1) (R) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethane) Synthesis of phenyl) carbamoyl) pyrrolidine-1-carboxylic acid benzyl ester

(2R) -1- ((benzyloxy) carbonyl) pyrrolidine-2-carboxylic acid (0.84g,3.37mmol) was charged in a 100mL single-neck flask, methylene chloride (10mL) and N, N-diisopropylethylamine (2.40mL,14mmol) were added, HATU (1.39g,3.65mmol) was added after cooling at 20 ℃ and stirring for 1 hour, then tert-butyl (R) - (4-aminophenylethyl) (2- (3-chlorophenyl) -2-hydroxyethyl) carbamate (1.09g,2.80mmol) was added, the reaction was stopped after 1 hour by transferring to room temperature for 3 hours, water (5mL) was added and quenched, then extracted with methylene chloride (20 mL. times.2), the organic phase was collected, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 3/1) to give the title compound as a red liquid (1.50g, 86%).

MS(ESI,pos.ion)m/z:644.30[M+Na]⁺.

Step 2) (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((R) -pyrrolidine-2-carboxamido) phenethyl) amino Synthesis of tert-butyl formate

Benzyl (R) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (1.50g,2.40mmol) and methanol (15mL) were added to a 100mL single neck flask, followed by acetic acid (0.15mL) and Pd (OH)₂(300mg,2mmol), reacted at room temperature for 0.5 hour under hydrogen atmosphere, quenched by addition of sodium carbonate (0.81g), concentrated under reduced pressure, and the residue purified by column chromatography (dichloromethane/methanol (v/v) ═ 25/1) to give the title compound as a white solid (1.05g, 90%).

MS(ESI,pos.ion)m/z:488.20[M+H]⁺.

Step 3) (R) -4-Nitrophenyl 2- ((4- (2- ((tert-Butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxy) Synthesis of ethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylic acid ester

Tert-butyl (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((R) -pyrrolidine-2-carboxamido) phenethyl) carbamate (1.00g,2.05mmol) was weighed into a 100mL single vial, dissolved in dichloromethane (20mL), and after addition of triethylamine (0.61mL,4.40mmol), cooled at 0 ℃ to room temperature, and (4-nitrophenyl) chloroformate (0.49g,2.42mmol) was slowly added dropwise to the reaction mixture to react for 1 hour, and then transferred to room temperature to react for 15 hours to stop the reaction, the reaction mixture was concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a yellow oil (1.10g, 85%).

MS(ESI,pos.ion)m/z:553.25[M-100+H]⁺.

Step 4) (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((R) -1- (cyclopropylcarbamoyl) pyrrolidine-2- Synthesis of t-butyl carboxamido) phenethyl) carbamate

Cyclopropylamine (2mL) and (R) -4-nitrophenyl 2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (0.26g,0.40mmol) were added to a 50mL one-necked flask, reacted at room temperature for 20 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2/1) to give the title compound as a white solid (200mg, 89%).

MS(ESI,pos.ion)m/z:593.35[M+Na]⁺.

^{2 1}Step 5) (R) -N- (4- (2- (((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) -N-cyclopropyl Synthesis of pyrrolidine-1, 2-dicarboxamide

To a 50mL single neck flask containing tert-butyl (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((R) -1- (cyclopropylcarbamoyl) pyrrolidine-2-carboxamido) phenethyl) carbamate (195mg,0.34mmol) was added dichloromethane (3mL), followed by dropwise addition of a solution of hydrogen chloride in ethyl acetate (1.0mL,4M), stirring at room temperature for 1 hour to stop the reaction, concentration of the reaction mixture, dissolution in methanol (5mL), stirring with sodium carbonate (108mg,1.02mmol) for 10 minutes, concentration of the reaction mixture, and purification of the residue by column chromatography (dichloromethane/methanol (v/v) ═ 7/1) to give the title compound as a white solid (145mg, 91%).

MS(ESI,pos.ion)m/z:471.40[M+H]⁺；

HPLC:99.75％；

¹H NMR(400MHz,CDCl₃)δ(ppm)7.34(s,1H),7.29(s,2H),7.24(d,J＝7.6Hz,2H),7.19(d,J＝6.9Hz,1H),7.02(d,J＝8.0Hz,2H),4.76(d,J＝9.2Hz,1H),4.42–4.31(m,1H),3.56(dt,J＝20.3,14.0Hz,4H),3.40–3.27(m,2H),2.93–2.79(m,3H),2.75(dd,J＝19.8,9.6Hz,3H),2.22(d,J＝9.2Hz,1H),2.07–1.97(m,1H),1.90(d,J＝9.4Hz,2H),0.79(d,J＝7.6Hz,1H),0.61(d,J＝6.0Hz,2H),0.41(s,2H).

Example 9(S) -N²Synthesis of- (4- (2- (((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) pyrrolidine-1, 2-dicarboxamide

Step 1) (S) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) amino) ethyl) benzene Yl) carbamoyl) pyridineSynthesis of pyrrolidine-1-carboxylic acid phenyl ester

Tert-butyl ((R) -2-hydroxy-2-phenylethyl) (4- ((S) -pyrrolidine-2-carboxamido) phenethyl) carbamate (0.85g,1.90mmol) was weighed into a 100mL single-neck flask, dichloromethane (8mL) and triethylamine (0.52mL,3.75mmol) were added thereto, and then the mixture was cooled at 0 ℃ to give phenylchloroformate (0.32g,2.00mmol) which was slowly added to the reaction mixture to react for 1 hour, and then the mixture was allowed to react at room temperature for 3 hours to stop the reaction, and the reaction mixture was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 100/1) to give the title compound as a yellow oil (900mg, 80%).

MS(ESI,pos.ion)m/z:596.40[M+Na]⁺.

Step 2) (4- ((S) -1-carbamoylpyrrolidine-2-carboxamido) phenethyl) ((R) -2-hydroxy-2-phenyl Synthesis of Ethyl) carbamic acid tert-butyl ester

A methanol solution of ammonia (5mL) and phenyl (S) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (0.25g,0.44mmol) were added to a 50mL one-necked flask, reacted at room temperature for 24 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (170mg, 80%).

MS(ESI,pos.ion)m/z:519.20[M+Na]⁺.

²Step 3) (S) -N- (4- (2- (((R) -2-hydroxy-2-phenylethyl) amino) ethyl) phenyl) pyrrolidine-1, 2-bis Synthesis of formamide

To a 50mL single neck flask containing tert-butyl (4- ((S) -1-carbamoylpyrrolidine-2-carboxamido) phenethyl) ((R) -2-hydroxy-2-phenylethyl) carbamate (170mg,0.34mmol) was added dichloromethane (3mL), then a solution of hydrogen chloride in ethyl acetate (1.0mL,4M) was added dropwise, stirring was started at room temperature for 1 hour to stop the reaction, the reaction was concentrated, methanol (5mL) was added to dissolve, sodium carbonate (118mg,1.11mmol) was added and stirred for 10 minutes, the reaction was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 7/1) to give the title compound as a white solid (118mg, 87%).

MS(ESI,pos.ion)m/z:397.20[M+H]⁺；

HPLC:98.30％；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.42(d,J＝8.4Hz,2H),7.33(d,J＝6.5Hz,4H),7.28–7.20(m,1H),7.06(d,J＝8.3Hz,2H),6.90(s,1H),4.69(dd,J＝8.4,3.8Hz,1H),4.29–4.20(m,1H),3.59(dd,J＝10.1,5.7Hz,2H),3.44(dd,J＝18.4,11.2Hz,4H),2.87–2.64(m,6H),2.04(dd,J＝16.4,8.3Hz,1H),1.88(ddd,J＝16.5,10.9,5.4Hz,3H).

Example 10(S) -N²Synthesis of- (4- (2- (((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) pyrrolidine-1, 2-dicarboxamide

Step 1) (S) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) Synthesis of ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylic acid phenyl ester

Tert-butyl (R) -2- (3-chlorophenyl) -2-hydroxyethyl) (4- ((S) -pyrrolidine-2-carboxamido) phenethyl) carbamate (0.93g,1.90mmol) was weighed into a 100mL single vial, dichloromethane (8mL) and triethylamine (0.52mL,3.75mmol) were added thereto, followed by cooling at 0 ℃ to give a solution, phenylchloroformate (0.32g,2.00mmol) was slowly added to the reaction solution and reacted for 1 hour, the reaction solution was allowed to stand at room temperature for 3 hours to stop the reaction, the reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 100/1) to give the title compound as a yellow solid (890mg, 77%).

MS(ESI,pos.ion)m/z:608.40[M+H]⁺.

Step 2) (4- ((S) -1-carbamoylpyrrolidine-2-carboxamido) phenethyl) ((R) -2- (3-chlorophenyl) - Synthesis of tert-butyl 2-hydroxyethyl) carbamate

A methanol solution of ammonia (5mL) and phenyl (S) -2- ((4- (2- ((tert-butoxycarbonyl) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (0.30g,0.49mmol) were added to a 50mL one-necked flask, reacted at room temperature for 24 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 20/1) to give the title compound as a white solid (230mg, 88%).

MS(ESI,pos.ion)m/z:553.35[M+Na]⁺.

²Step 3) (S) -N- (4- (2- (((R) -2- (3-chlorophenyl) -2-hydroxyethyl) amino) ethyl) phenyl) pyrrolidine- Synthesis of 1, 2-dicarboxamides

To a 50mL single neck flask containing tert-butyl (4- ((S) -1-carbamoylpyrrolidine-2-carboxamido) phenethyl) ((R) -2- (3-chlorophenyl) -2-hydroxyethyl) carbamate (225mg,0.42mmol) was added dichloromethane (3mL), followed by dropwise addition of a solution of hydrogen chloride in ethyl acetate (1.0mL,4M), stirring at room temperature for 1 hour to stop the reaction, concentration of the reaction mixture, dissolution in methanol (5mL), stirring with sodium carbonate (134mg,1.26mmol) for 10 minutes, concentration of the reaction mixture, and purification of the residue by column chromatography (dichloromethane/methanol (v/v) ═ 7/1) to give the title compound as a white solid (158mg, 88%).

MS(ESI,pos.ion)m/z:431.20[M+H]⁺；

HPLC:97.88％；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)7.43(d,J＝8.4Hz,1H),7.34(d,J＝6.5Hz,4H),7.28–7.20(m,1H),7.07(d,J＝8.3Hz,2H),6.91(s,1H),4.69(dd,J＝8.4,3.8Hz,1H),4.28–4.21(m,1H),3.58(dd,J＝10.1,5.7Hz,2H),3.44(dd,J＝18.4,11.2Hz,4H),2.87–2.64(m,6H),2.04(dd,J＝16.4,8.3Hz,1H),1.88(ddd,J＝16.5,10.9,5.4Hz,3H).

Biological assay

EXAMPLE A evaluation of the agonistic action of the Compounds of the invention at the human β 3-adrenergic receptor

Experimental methods

The experimental system adopts human recombinant β 3-adrenergic receptor, is expressed in HEK-293 cell line, and the HEK-293 cell is inoculated in a culture plate with the density of 1.25 multiplied by 10⁵cell/ml. The medium was changed to Modified HBSS solution at pH 7.4, and test compounds and solvents (PBS containing 0.1% DMSO) were added at different concentrations and incubated at 37 ℃ for 20min, the concentrations of the test compounds were: 10. mu.M, 1. mu.M, 0.1. mu.M, 10nM, 1nM, 0.1 nM. The concentration of cAMP (cyclic adenosine monophosphate) in the medium was detected by TR-FRET method. This experimentUsing isoprotenol (Isoproterenol, 1mM) as a control, a test compound is considered to have β 3-adrenergic receptor agonistic activity if it induces cAMP production by cells in an amount greater than 50% of the amount of cAMP production by Isoproterenol (1mM) induced by cells₅₀By using MathIQ^TM(ID Businesses solutions Ltd., UK) was calculated by analysis of a nonlinear, least squares regression equation. The results are shown in Table A.

TABLE A results of the agonist action of the compounds of the present invention on human β 3-adrenergic receptor

Example No. 2	EC50(μM)
		Example 1	1～10
Example 2	1～10
		Example 6	1～10
Example 9	1～10

The experimental result shows that the compound has stronger β 3-adrenergic receptor agonistic activity.

Example B: pharmacokinetic evaluation of rats and dogs following intravenous or intragastric dosing of Compounds of the invention

(1) Test animal

The tested animals are rats and dogs, and the specific conditions are shown in table 1:

TABLE 1

Germling	Grade	Sex	Body weight	The week of the year	Origin of origin
						SD rat	Cleaning stage	Male sex	180～220g	8 weeks	Changzhou Kavens
Beagle dog	Cleaning stage	Male sex	8～10kg	6-7 weeks	Hunan Slek laboratory animals Co., Ltd

(2) Analytical method

The LC/MS system for analysis included an Agilent 1200 series vacuum degasser, a quaternary pump, an orifice plate autosampler, a thermostatted column oven, an API4000Qtrap triple quadrupole mass spectrometer with an electrospray ionization source (ESI). The quantitative analysis was performed in MRM mode, where the source parameters of the MRM transitions are shown in table 2:

TABLE 2

Air curtain air/CUR:	30psi
		atomizing gas/GS 1:	60psi
auxiliary heating gas/GS 2:	55psi
		ion transmission voltage is (v)/nc (ma):	5500
atomization temperature/TEM:	550℃

assay A0.5. mu.L sample was injected using waters xbridge C18UPLC, 2.1X 50mm, 3.5. mu.M column. Analysis conditions were as follows: the mobile phase is H₂O+2mM HCOONH₄(ammonium formate) + 0.1% FA (formic acid) (mobile phase A) and MeOH (methanol) +2mM MHCOONH₄(ammonium formate) + 0.1% FA (formic acid) (mobile phase B). The flow rate was 0.7 mL/min. The mobile phase gradients are shown in table 3:

TABLE 3

Time of day	Flow ofGradient of phase B
		0.3min	30％
0.8min	90％
		1.9min	90％
2.0min	30％
		2.5min	Stop

(3) Experimental methods

The compounds of the invention were evaluated for pharmacokinetics in rats and dogs by the following specific steps:

the experiments were divided into two groups: one group was administered by intravenous injection and one group was administered by intragastric gavage. The compounds of the invention are administered to the test animals as a 5% Solutol + 60% PEG400 solution. For the group administered by intravenous injection, the dose was 1mg/kg, then blood was taken intravenously (0.3mL) at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours after administration, the anticoagulant EDTA-K2 was added to the blood, and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃. For the gavage administration group, the administration dose was 5mg/kg, then blood (0.3mL) was taken intravenously at time points of 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours after administration, the anticoagulant EDTA-K2 was added to the blood, and centrifuged at 3,000 or 4,000rpm for 10 minutes, and the plasma solution was collected and stored at-20 ℃ or-70 ℃.

Add 150. mu.L IS working solution to 10. mu.L plasma and vortex for 2 min. The mixed solution was then centrifuged at 12,000rpm for 2 min. Taking 100 mu L ofAdding 100 μ L H into the clear solution₂And O, swirling for 2min, and taking 20 mu L of sample injection LC-MS/MS system. And (3) detecting the concentration of the target compound by adopting an LC-MS/MS method, and calculating pharmacokinetic parameters by adopting a non-compartmental model. The analysis result shows that the compound of the invention has better pharmacokinetic property in rats and dogs.

Example C: electrophysiological manual patch clamp for detecting inhibition effect of compound on hERG potassium ion channel

Experimental methods

The test system is HEK-293 cells over-expressing hERG potassium ion channels. The cell culture medium consists of: DMEM, 15% fetal bovine serum and 1% 100 xpicillin-streptomycin. The stably transformed cells were dropped on a round slide and placed in a petri dish with a cell density below 50% and cultured overnight. The experimental cells were transferred to an approximately 1ml bath embedded in an inverted microscope platform and perfused with extracellular fluid at a perfusion rate of 2.7 ml/min. The experiment was started after 5 minutes of stabilization. Membrane currents were recorded using a HEKA EPC-10 patch clamp amplifier and PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrrecht, Pfalz, Germany). All experiments were performed at room temperature (22-24 ℃). The electrode (BF150-110-10) was straightened using a P-97 microelectrode stretcher (setter Instrument Company, One Digital Drive, Novato, CA 94949). The inner diameter of the electrode is 1-1.5mm, and the water inlet resistance after the electrode is filled with the internal liquid is 2-4M omega.

The electrophysiological stimulation scheme of the hERG potassium channel is that firstly, the membrane voltage is clamped at-80 mV, the cells are given with 2s, +20mV voltage stimulation to activate the hERG potassium channel, then the cell is repolarized to-50 mV and 5s continuously to generate outward tail current, and the stimulation frequency is once every 15 s.

The current value is the peak value of the tail current.

In the experiment, the whole cell recording mode is adopted to record the hERG potassium ion channel current. Extracellular fluid (approximately 2ml per minute) was first perfused and continuously recorded, and the current was waited for stabilization (current decay (Run-Down) less than 5% in 5 minutes) at which time the tail current peak was the control current value. Then perfusing the extracellular fluid containing the test compound (the concentrations of the test compound are respectively 30. mu.M, 10. mu.M, 3.3. mu.M, 1.1. mu.M and 0.37. mu.M) and continuously recording until the inhibition effect of the test compound on hERG current reaches a stable state, wherein the peak value of the tail current is the current value after the test compound is added. The steady state criterion is determined by whether the nearest consecutive 3 current traces coincide. After reaching a steady state, perfusion testing can continue for other concentrations or other test compounds if the hERG current returns to or near the magnitude before addition of the test compound after perfusion washing with extracellular fluid. 30 μ M Quinidine (Quinidine) was used in the experiment as a positive control to ensure that the cell response used was normal.

Parameter analysis: the effect of the test compound on the inhibition of the hERG potassium channel at the test concentration was evaluated by measuring the maximum current values of the control and test compound groups and calculating the ratio of the maximum current value of the test compound group to the maximum current value of the control group.

The results of the experiments show that the compounds of the invention have little inhibitory effect (IC) on the hERG potassium channel in the tested concentration range₅₀>30 μ M), indicating that the compounds of the invention are almost free of cardiac risk due to their effect on the hERG potassium channel.

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 (8)

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

wherein:

x is CR^xOr N;

each R⁴And R⁵Independently H, D, C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl or 3-6 membered heterocyclyl, wherein, said C is₃-C₆Cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted with 1,2 or 3R^ySubstituted by radicals, or, R⁴、R⁵And the nitrogen atom to which they are attached, together form a 3-6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is independently optionally substituted with 1,2 or 3R^ySubstituted by a group;

each R^yIndependently D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂、C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy or hydroxy substituted C₁-C₄An alkyl group;

R^1a、R^1c、R^1dand R^xEach independently is H;

R^1bis H, D, F, Cl, Br, I, C₁-C₄Alkyl or C₁-C₄A haloalkyl group;

R^2a、R^2b、R^2c、R^2d、R^2eand R^2fEach independently is H;and

R^3a、R^3b、R^3cand R^3dEach independently is H.

2. The compound of claim 1, wherein each R⁴And R⁵Independently H, D, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, or morpholinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl are independently optionally substituted with 1,2, or 3R^ySubstituted by radicals, or, R⁴、R⁵And the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl group, wherein said azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl groups are independently optionally substituted with 1,2, or 3R^ySubstituted by a group;

each R^yIndependently D, F, Cl, Br, I, -CN, -NO₂、-NH₂、-OH、-COOH、-C(＝O)NH₂Methyl, ethyl, n-propyl, isopropyl, -CF₃、-CH₂CF₃Methoxy, ethoxy, n-propyloxy or isopropyloxy.

3. The compound of claim 1, wherein R^1bIs H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl or-CHF₂、-CF₃、-CHFCH₂F、-CF₂CHF₂、-CH₂CF₃or-CH₂CF₂CHF₂。

4. The compound of claim 1, which is a compound of formula (IIa) or formula (IIb), or a tautomer or pharmaceutically acceptable salt of a compound of formula (IIa) or formula (IIb),

5. the compound of claim 1 or 4, which is a compound having one of the following structures or a tautomer 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. The pharmaceutical composition of claim 6, further comprising an additional therapeutic agent, wherein the additional therapeutic agent is a bladder overactivity drug, a 5-hydroxytryptamine resorption inhibitor, an anti-obesity compound, a feeding behavior modifier, an α -glucosidase inhibitor, a sulfonylurea, insulin or an insulin mimetic, an insulin sensitizer, a cholesterol lowering agent, a PPAR α agonist, a PPAR δ agonist, a PPAR γ antagonist, or a combination thereof.

8. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to any one of claims 6 to 7 in the manufacture of a medicament for the prevention, treatment or alleviation of a disease or a condition mediated by activation of the β 3-adrenergic receptor;

wherein said disease or condition mediated by β 3-adrenergic receptor activation is overactive bladder, urinary incontinence, urinary urgency, diabetes, obesity, hyperglycemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, depression, atherosclerosis, gastrointestinal disorders, irritable bowel syndrome and other conditions requiring reduced intestinal activity, neurogenic inflammation of the airways, ocular hypertension, glaucoma, diabetic retinopathy, prostatosis or preterm labor;

wherein the atherosclerosis is atherosclerosis of coronary arteries, atherosclerosis of cerebrovascular arteries, or atherosclerosis of peripheral arteries;

wherein the gastrointestinal disorder is gastritis, esophagitis, duodenitis, intestinal ulcer, gastrointestinal ulcer or peptic ulcer;

wherein the neurogenic inflammation of the airway is cough or asthma.