WO2019144805A1 - Substituted phenylethylamine compound and preparation method and use thereof - Google Patents

Abstract

Provided are a substituted phenylethylamine compound as a μ opioid receptor agonist, a pharmaceutical composition comprising same, a preparation method therefor and the use of same for preventing and/or treating diseases associated with the μ opioid receptor (including but not limited to painful diseases).

Description

Substituted phenethylamine compound, preparation method and use thereof Field of invention

The present invention relates to a substituted phenethylamine compound as a μ opioid receptor agonist, a pharmaceutical composition comprising the same, a process for the preparation thereof, and a medicament for preventing and/or treating a mu opioid receptor (including but not limited to pain) The use of the disease).

Background of the invention

Currently listed drugs for the treatment of pain include non-steroidal anti-infectives, opioid agonists, calcium channel blockers, antidepressants, etc., which have a certain effect in controlling pain, but also bring a lot of A worrying side effect, so finding a safe and effective treatment for pain remains an unfinished and challenging R&D goal.

Opioids (such as morphine) are a class of drugs that are effective in the treatment of pain, especially in the treatment of moderate and severe pain. However, opioids have serious side effects such as tolerance, addiction, respiratory depression, nausea, and constipation (Williams, JT et al., Pharacol. Rev., 65, 223-254 (2013)), and are also abused. social problem.

Opioids activate transmembrane opioid G-protein coupled receptors (GPCRs), and subtypes of this receptor include μopioid receptor (μOR), kappa opioid receptor (κOR), and δ opioid Receptor (δopioid receptor, δOR), opioid receptors, etc. and their subtypes. Most of the opioid receptor agonists currently in clinical use are derivatives of morphine, small molecule compounds and peptide compounds, their selectivity for subtypes, selectivity for related GPCRs, and drug distribution and metabolism in vivo. They all have a certain relationship with the efficacy and side effects. Recent discoveries on the biased effects of G-protein coupled receptors have further increased the perception of G-protein coupled receptor signaling and revealed the pharmacological effects of the new G-protein coupled receptors. By agonizing G-protein-coupled receptors but not activating the recruitment of β-repressor, it is possible to control the receptor to produce a specific biological response and obtain different pharmacological effects (Wisler JW et al. Curr. Opin. Cell Biol. 27 , 18-24 (2014)). In particular, recruitment of beta inhibitory protein 2 during mu opioid receptor agonism may be associated with side effects such as respiratory depression or constipation (Bohn, LM et al, Science, 286, 2495-2498 (1999)). In recent years, research in this field has attracted more and more attention. Several biased opioid receptor ligands have been reported (Edward, RS et al., Curr. Opin. Pharm. 32, 77-84 (2017); Manglik, A; Lin, H; Aryal, DK et al, Nature, 537, 185-190, (2016); WO2017007695A; and WO2017161017A1). Development of novel ligand compounds with a certain μ opioid receptor selectivity and weaker recruitment of beta inhibitory proteins to reduce side effects (ie avoid respiratory depression, constipation and/or improve addiction) and find safer and more effective The painkillers have brought hope.

Summary of invention

The present invention provides a novel substituted phenethylamine compound for use as a μ opioid receptor agonist, which has excellent agonistic activity against μ opioid receptors and weaker recruitment of β-repressor protein, and has better The drug-making properties of painkillers.

One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or a prodrug wherein the compound has the structure of formula (I):

among them:

R ^{1 is} selected from the group consisting of H, halogen, -OR ^h , cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, -COOR ^h , -CON(R ^h ) ₂ ,- SO ₃ H, -S(=O) _g R ^h , -OC(=O)-(C _1-6 alkyl), -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -N(R ^h ) ₂ , 3-10 membered heterocyclic group, C _6-14 aryl group and 5-14 membered heteroaryl group;

Each occurrence of R ² is independently selected from the group consisting of H, halogen, -OR ^h , cyano, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, halo C _1-6 alkyl, C _2-5 alkenyl, -COOR ^h , -CON(R ^h ) ₂ , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(= O) _g R ^h , -N(R ^h ) ₂ and 3-10 membered heterocyclic group:

R ^3a , R ^3b , R ⁴ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ^9a , R ^9b , R ^10a and R ^10b are each independently selected from H, halogen, - at each occurrence. OR ^h , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(=O) _g R ^h , cyano, -COOR ^h , -CON( R ^h ) ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, -N(R ^h ) ₂ and 3-10 membered heterocyclic; the condition is when R ^6a and R ^When one of ^6b is -OH, the other is not H;

R ^5a and R ^5b are each independently selected from H, halogen, -OR ^h , -C(=O)R ^h , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, - C _1-6 alkylene-OR ^h , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl) and 3-10 membered heterocyclic group; or, R ^5a Forming a 5-10 membered nitrogen-containing heterocycle together with R ^5b together with the nitrogen atom to which it is attached;

W is selected from direct bonds, CR ^11a R ^11b , C(=O), O, NR ^11a and S(=O) _g ;

R ^11a and R ^11b are each independently selected from H, halogen, -OR ^h , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(=O _g R ^h , cyano, -COOR ^h , -CON(R ^h ) ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, -N(R ^h ) ₂ and 3-10 membered heterocyclic group;

A is selected from the group consisting of a C _6-14 aromatic ring and a 5-14 membered heteroaryl ring;

R ¹² is each independently selected from the group consisting of H, halogen, -OR ^h , cyano, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, halo C _1-6 alkyl, C _2-5 alkenyl, -COOR ^h , -CON(R ^h ) ₂ , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(= O) _g R ^h , -N(R ^h ) ₂ and a 3-10 membered heterocyclic group;

The above alkyl, alkylene, cycloalkyl, alkenyl, nitrogen-containing heterocyclic, heterocyclic, aryl, aromatic, heteroaryl and heteroaryl rings are each optionally independently selected by one or more of them. Substituted from a substituent of halogen, =O, -R ^h , -OR ^h , -COOR ^h , -CON(R ^h ) ₂ , -S(=O) _g R ^h and -N(R ^h ) ₂ ;

R ^h is each independently selected from H, C _1-6 alkyl, halo C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 , each occurrence. An aryl group and a 5-10 membered heteroaryl group, and the plurality of ^Rh groups may be the same or different from each other;

g each independently represents an integer of 0, 1 or 2 at each occurrence;

m each independently represents any integer in 1-10, including the end value;

n, p and q are each independently an integer of 0, 1, 2, 3 or 4.

Another aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, a solvate, an N-oxide, an isotope-labeled compound, a metabolite or a prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semi-solid formulation, a liquid formulation or a gaseous state preparation.

Another aspect of the invention provides a method of preparing a pharmaceutical composition of the invention, which comprises administering a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polycrystal thereof, or a pharmaceutically acceptable salt thereof The form, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or mixtures thereof, are combined with one or more pharmaceutically acceptable carriers.

Another aspect of the invention provides a kit comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxidation thereof, or a pharmaceutically acceptable salt thereof a compound, an isotope-labeled compound, a metabolite or a prodrug or a mixture thereof, or a pharmaceutical composition of the invention.

Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled Use of a compound, metabolite or prodrug or a pharmaceutical composition of the invention for the preparation of a medicament for the prevention or treatment of a mu opioid receptor-associated disease. The medicament is for preventing or treating a painful disease.

Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled A compound, metabolite or prodrug or a pharmaceutical composition of the invention for use in the prevention or treatment of a mu opioid receptor-associated disease.

Another aspect of the invention provides a method of preventing or treating a mu opioid receptor-associated disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester or stereoisomer thereof, A construct, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug or a pharmaceutical composition of the invention.

The above-mentioned μ opioid receptor-related diseases include, but are not limited to, pain-related diseases, and the diseases are further preferably moderate-to-severe pain-like diseases.

Detailed description of the invention

definition

Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the invention.

The terms "comprising," "comprising," "having," "containing," Or method steps.

The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon group. For example, as used herein, the term " _C1-6 alkyl" refers to a straight or branched chain hydrocarbon radical having from 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl.

The term "alkylene" as used herein refers to a saturated straight or branched divalent hydrocarbon group. For example, as used herein, the term " _C1-6 alkylene" refers to a straight or branched divalent hydrocarbon radical having from 1 to 6 carbon atoms. For example, methylene, ethylene, propylene or butylene.

The term "haloalkyl" as used herein refers to an alkyl group, optionally substituted with one or more (such as 1 to 3) halo. For example, as used herein, the term "halo C _1-6 alkyl" refers to optionally substituted with one or more (such as one to three) halogen substituted C _1-6 alkyl group. For example, CH ₂ F, CHF ₂ , CF ₃ , CCl ₃ , C ₂ F ₅ , C ₂ Cl ₅ , CH ₂ CF ₃ , CH ₂ Cl or CH ₂ CH ₂ CF ₃ and the like.

As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon radical having one or more carbon-carbon double bonds. For example, as used herein, the term "C _2-6 alkenyl" refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and one, two or three carbon-carbon double bonds, preferably containing one carbon carbon. Double bond C _2-6 alkenyl. For example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl and the like.

The term "cycloalkyl" as used herein refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl). , cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1 _- 1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl Or bicyclo [5.2.0] anthracenyl, decahydronaphthyl, etc.)), which is optionally substituted by one or more (such as 1 to 3) suitable substituents. The cycloalkyl group may have 3 to 10 carbon atoms. For example, the term "C _3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl or ring). Hexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.

As used herein, the term "hydrocarbon ring" refers to a saturated or unsaturated (ie, in the ring) having, for example, 5-10 (suitably 5-8, more suitably 5-6) ring carbon atoms. One or more double bonds and/or triple bonds) monocyclic or polycyclic hydrocarbon rings including, but not limited to, cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclohexyl rings, cycloheptyl rings, rings An octyl ring, a cyclononyl ring, a cyclohexenyl ring, and the like.

The term "heterocyclyl" or "heterocycle" as used herein, refers to having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, at least one of which An atom is a hetero atom selected from N, O and S and the remaining ring atoms are saturated (ie "heterocycloalkyl") or partially unsaturated (ie having one or more double bonds and/or three in the ring) A cyclic group, which is optionally substituted with one or more (such as 1 to 3) suitable substituents. For example, as used herein, the term "3-10 membered heterocyclyl" is taken to have 2-9 (eg, 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and independently selected A saturated or partially unsaturated heterocyclic group of one or more (e.g., 1, 2, 3 or 4) heteroatoms of N, O and S. Examples of heterocyclic or heterocyclic rings include, but are not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxane Alkenyl (dioxolinyl), pyrrolidinyl, pyrrolidinone, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, sulfur? A phenyl group, a piperazinyl group or a trithianyl group.

As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C _6-14 aryl" or "C _6-14 aromatic ring" refers to an aromatic group containing from 6 to 14 carbon atoms, such as phenyl (cyclo) or naphthyl ( ring). The aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO ₂ , C _1-6 alkyl, etc.).

The term "heteroaryl" or "heteroaryl ring" as used herein, refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one hetero atom selected from N, O and S, which preferably has 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular containing 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and additionally in each case It can be benzofused. For example, the heteroaryl or heteroaryl ring may be selected from the group consisting of thienyl (cyclo), furyl (cyclo), pyrrolyl (cyclo), oxazolyl (cyclo), thiazolyl (cyclo), imidazolyl (cyclo), pyridyl Azolyl (cyclo), isoxazolyl (cyclo), isothiazolyl (cyclo), oxadiazolyl (cyclo), triazolyl (cyclo), thiadiazolyl (ring), etc., and their benzo a derivative; or a pyridyl group (cyclo), a pyridazinyl group (cyclo), a pyrimidinyl group (cyclo), a pyrazinyl group (cyclo), a triazinyl group (ring), and the like, and a benzo derivative thereof.

The term "halo" or "halogen" group, as used herein, is defined to include F, Cl, Br or I.

The term "nitrogen-containing heterocyclic ring" as used herein refers to a saturated or partially unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10 in the ring. 11, 12 or 13 carbon atoms and at least one nitrogen atom, which may also optionally comprise one or more (eg one, two, three or four) selected from N, O, C (=O), a ring member of S, S(=O) and S(=O) ₂ which is bonded to the remainder of the molecule by a nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, said nitrogen-containing heterocyclic ring It is optionally benzofused and is preferably attached to the remainder of the molecule by a nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring. Examples of nitrogen-containing heterocycles include, but are not limited to, aziridine rings, azetidine rings, pyrrolidine rings, imidazolidine rings, oxazolidine rings, thiazolidine rings, pyrazolidine rings, pyrroline rings, and piperidines. A pyridine ring or a piperazine ring.

The term "substituted" means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not present at present. The normal valence in the case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.

If a substituent is described as "optionally substituted," the substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.

If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same or different from another (other) substituent.

As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.

Unless otherwise indicated, a point of attachment of a substituent, as used herein, may come from any suitable position of the substituent.

When a bond of a substituent is shown to pass through a bond connecting two atoms in the ring, such a substituent may be bonded to any of the ring-forming atoms in the substitutable ring.

The invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass. Examples of suitable contain a compound of the present invention isotopes include (but are not limited to) isotopes of hydrogen (e.g., deuterium ⁽² H), tritium ⁽³ H)); isotopes of carbon (e.g. ¹¹ C, ¹³ C and ¹⁴ C) Chlorine isotope (eg ³⁶ Cl); fluorine isotopes (eg ¹⁸ F); iodine isotopes (eg ¹²³ I and ¹²⁵ I); nitrogen isotopes (eg ¹³ N and ¹⁵ N); oxygen isotopes (eg ¹⁵ O) , ¹⁷ O and ¹⁸ O); phosphorus isotope (eg ³² P); and sulfur isotope (eg ³⁵ S).

The term "stereoisomer" denotes an isomer formed by at least one asymmetric center. In a compound having one or more (eg, one, two, three or four) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.

Solid lines can be used in this article

Solid wedge

Virtual wedge

The chemical bonds of the compounds of the invention are depicted. The use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.). The use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise indicated, the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist. The compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).

The invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

It will also be understood that certain compounds of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to a patient in need thereof The compound of the invention, or a metabolite or residue thereof, can be provided directly or indirectly after the drug. Thus, when reference is made herein to a "compound of the invention," it is also intended to encompass the various derivative forms described above for the compound.

The pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.

Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate/carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitic acid Salt and other similar salts.

Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts.

For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

As used herein, the term "ester" means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound). The compounds of the invention may also be esters per se.

The compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed. Nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. The synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups. Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: TLGilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; ARKatritzky and AJ Boulton, Eds., Academic Press And GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, ARKatritzky and AJ Boulton, Eds., Academic Press.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.

The invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the invention may, for example, be known by those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups, such as those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.

The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

Compound

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug wherein the compound has the structure of formula (I):

among them:

R ^{1 is} selected from the group consisting of H, halogen, -OR ^h , cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, -COOR ^h , -CON(R ^h ) ₂ ,- SO ₃ H, -S(=O) _g R ^h , -OC(=O)-(C _1-6 alkyl), -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -N(R ^h ) ₂ , 3-10 membered heterocyclic group, C _6-14 aryl group and 5-14 membered heteroaryl group;

Each occurrence of R ² is independently selected from the group consisting of H, halogen, -OR ^h , cyano, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, halo C _1-6 alkyl, C _2-5 alkenyl, -COOR ^h , -CON(R ^h ) ₂ , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(= O) _g R ^h , -N(R ^h ) ₂ and a 3-10 membered heterocyclic group;

R ^3a , R ^3b , R ⁴ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ^9a , R ^9b , R ^10a and R ^10b are each independently selected from H, halogen, - at each occurrence. OR ^h , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(=O) _g R ^h , cyano, -COOR ^h , -CON( R ^h ) ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, -N(R ^h ) ₂ and 3-10 membered heterocyclyl; provided that R ^6a and R ^When one of ^6b is -OH, the other is not H;

R ^5a and R ^5b are each independently selected from H, halogen, -OR ^h , -C(=O)R ^h , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, - C _1-6 alkylene-OR ^h , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl) and 3-10 membered heterocyclic group; or, R ^5a Forming a 5-10 membered nitrogen-containing heterocycle together with R ^5b together with the nitrogen atom to which it is attached;

W is selected from direct bonds, CR ^11a R ^11b , C(=O), O, NR ^11a and S(=O) _g ;

R ^11a and R ^11b are each independently selected from H, halogen, -OR ^h , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(=O _g R ^h , cyano, -COOR ^h , -CON(R ^h ) ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, -N(R ^h ) ₂ and 3-10 membered heterocyclic group;

A is selected from the group consisting of a C _6-14 aromatic ring and a 5-14 membered heteroaryl ring;

R ¹² is each independently selected from the group consisting of H, halogen, -OR ^h , cyano, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, halo C _1-6 alkyl, C _2-5 alkenyl, -COOR ^h , -CON(R ^h ) ₂ , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(= O) _g R ^h , -N(R ^h ) ₂ and a 3-10 membered heterocyclic group;

The above alkyl, alkylene, cycloalkyl, alkenyl, nitrogen-containing heterocyclic, heterocyclic, aryl, aromatic, heteroaryl and heteroaryl rings are each optionally independently selected by one or more of them. From halogen, =O, -R ^h , -OR ^h , -COOR ^h , -CON(R ^h ) ₂ , -S(=O) _g R ^h and -N(R ^h ) ₂ (preferably F, Cl, = O, C _1-4 alkyl, C _3-6 cycloalkyl, -CF ₃ , -CHF ₂ , -OH, -OCF ₃ , -OCHF ₂ , -O-(C _1-6 alkyl), -COOH Substituted with a substituent of -CONH ₂ , -NH ₂ , -NH(C _1-4 alkyl) and -N(C _1-4 alkyl) ₂ );

R ^h is each independently selected from H, C _1-6 alkyl, halo C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 , each occurrence. An aryl group and a 5-10 membered heteroaryl group, and the plurality of ^Rh groups may be the same or different from each other;

g each independently represents an integer of 0, 1 or 2 at each occurrence;

m each independently represents any integer in 1-10, including the end value;

n, p and q are each independently an integer of 0, 1, 2, 3 or 4.

In a preferred embodiment, R ^{1 is} selected from the group consisting of H, halogen, -OH, -O-(C _1-4 alkyl), cyano, C _1-4 alkyl, C _3-6 cycloalkyl, -COOH , -CONH ₂ , -OC(=O)-(C _1-4 alkyl), -O-[(C _1-4 alkylene)-O] _m -(C _1-4 alkyl), -SH , -S(=O) _g -(C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ and 3-6 member a cyclic group wherein each of the alkyl, alkylene, cycloalkyl and heterocyclic groups is optionally independently selected from one or more selected from the group consisting of F, Cl, C _1-4 alkyl, C _3-6 ring Alkyl, -CF ₃ , -CHF ₂ , -OH, -OCF ₃ , -OCHF ₂ , -O-(C _1-6 alkyl), -COOH, -CONH ₂ , -NH ₂ , -NH (C ₁ Substituted with a substituent of _-4 alkyl) and -N(C _1-4 alkyl) ₂ ; g is an integer of 0, 1 or 2; and m is an integer of 1, 2, 3 or 4. In a more preferred embodiment, R ^{1 is} selected from the group consisting of H, F, Cl, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, -CF ₃ , -CHF ₂ , -OH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , -OC(=O)-(C _1-4 alkyl), -(C _1-4 alkylene)-O-(C _1-4 alkyl), -O- [(C _1-4 alkylene)-O] _m -(C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -COOH and -CONH ₂ ; wherein m is an integer of 1 or 2. In a particularly preferred embodiment, R ^{1 is} selected from the group consisting of H, F, Cl, -CF ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OH, -OCH ₃ , -OCF ₃ , -OC(=O)CH ₃ , -CH ₂ -OCH ₃ and -O-CH ₂ CH ₂ -O-CH ₃ .

In a preferred embodiment, each occurrence of R ² is independently selected from the group consisting of H, halogen, —CF ₃ , —CHF ₂ , —OH, —OCF ₃ , —OCHF ₂ , —O(C _1-4 alkane). , cyano, C _1-4 alkyl, C _3-6 cycloalkyl, -COOH, -CONH ₂ , -(C _1-4 alkylene)-O-(C _1-4 alkyl), -O-[(C _1-4 alkylene)-O] _m -(C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkane yl) _2, and 3-6-membered heterocyclyl; wherein, m is an integer of 3 or 4. In a more preferred embodiment, each occurrence of R ² is independently selected from the group consisting of H, F, Cl, -OH, -CF ₃ , -OCF ₃ , -OCH ₃ , cyano, C _1-4 alkyl , C _3-6 cycloalkyl, -(C _1-4 alkylene)-O-(C _1-4 alkyl), -O-[(C _1-4 alkylene)-O] _m - ( C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl) and -N(C _1-4 alkyl) ₂ ; wherein m is an integer of 1, 2, 3 or 4. In a particularly preferred embodiment, R ² is each independently selected from the group consisting of H, F, Cl, -OH, -CF ₃ , -OCF ₃ , -OCH ₃ , C _1-3 alkyl, -( C _1-3 alkylene)-O-(C _1-3 alkyl), -O-(C _1-3 alkylene)-O-(C _1-3 alkyl) and -N(C _{1- 3} alkyl) ₂ .

In a preferred embodiment, R ^3a , R ^3b , R ⁴ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ^9a , R ^9b , R ^10a and R ^10b are each independently present at each occurrence. Selected from H, F, Cl, -OH, -O-(C _1-4 alkyl), -O-(halogenated C _1-4 alkyl), cyano, -(C _1-4 alkylene) -O-(C _1-4 alkyl), -O-[(C _1-4 alkylene)-O] _m -(C _1-4 alkyl), -COOH, -CONH ₂ , C _1-4 Alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, -S(=O) _g -(C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl And -N(C _1-4 alkyl) ₂ and 3-6 membered heterocyclic group; wherein g is an integer of 0, 1 or 2; and m is an integer of 1, 2, 3 or 4.

In a more preferred embodiment, R ^3a , R ^3b , R ⁴ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ^9a , R ^9b , R ^10a and R ^10b are each independently present at each occurrence Selected from H, F, Cl, cyano, C _1-4 alkyl (preferably C _1-3 alkyl, more preferably methyl), C _3-6 cycloalkyl, -CF ₃ , -CHF ₂ , - OH, -OCF ₃ , -OCHF ₂ , -(C _1-3 alkylene)-O-(C _1-3 alkyl), -O-[(C _1-4 alkylene)-O] _m - (C _1-4 alkyl) (preferably -O-(C _1-4 alkylene)-O-(C _1-4 alkyl)), -NH ₂ , -NH(C _1-4 alkyl) ( Preferred is -NH(C _1-3 alkyl)), -N(C _1-4 alkyl) ₂ (preferably -N(C _1-3 alkyl) ₂ ), -COOH and -CONH ₂ ; wherein m is An integer of 1 or 2.

In a preferred embodiment, R ^5a and R ^5b are each independently selected from H, F, Cl, -OH, -O- (C 1 - 4 alkyl) (preferably -O- (C _1-3 alkyl) ), C _1-6 alkyl (preferably C _1-4 alkyl, more preferably methyl or ethyl), C _3-6 cycloalkyl, -C _1-4 alkylene-OH (preferably -C _{1- 3} alkylene-OH), C _2-5 alkenyl (preferably vinyl, propenyl or allyl), -O-[(C _1-4 alkylene)-O] _m - (C _1-4 Alkyl) and a 3-6 membered heterocyclic group; or, R ^5a and R ^5b together with the nitrogen atom to which they are attached form a 5-7 membered nitrogen-containing heterocyclic ring (preferably a 5-6 membered nitrogen-containing heterocyclic ring); m is an integer of 1 or 2; and the alkyl, alkylene, cycloalkyl, alkenyl, nitrogen-containing heterocyclic ring and heterocyclic group are each optionally one or more independently selected from F, Cl Substituent substitution of -CF ₃ , -OH, =O, -OCF ₃ , C _1-3 alkyl, -OC _1-4 alkyl and -N(C _1-3 alkyl) ₂ .

In a preferred embodiment, R ^11a and R ^11b are each independently selected from the group consisting of H, F, Cl, -OH, -O-(C _1-4 alkyl), cyano, -O-[(C _1-4 Alkylene)-O] _m -(C _1-4 alkyl), -COOH, -CONH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, -S(=O) _g -(C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ and 3-6 membered heterocyclic group, wherein the alkyl group, alkylene group The base, cycloalkyl and heterocyclic groups are each optionally one or more independently selected from the group consisting of F, Cl, -CF ₃ , -CHF ₂ , -OH, -OCF ₃ , -OCHF ₂ , C _1-4 Alkyl, C _3-6 cycloalkyl, -OC _1-4 alkyl, -COOH, -CONH ₂ , -S(=O) _g -(C _1-4 alkyl), -NH ₂ , -NH( Substituted with a substituent of C _1-4 alkyl) and -N(C _1-3 alkyl) ₂ ; g is an integer of 0, 1 or 2; m is an integer of 1, 2, 3 or 4. In a more preferred embodiment, R ^11a and R ^11b are each independently selected from H, F, Cl, cyano, C _1-4 alkyl (preferably C _1-3 alkyl, more preferably methyl or ethyl) , C _3-6 cycloalkyl, -CF ₃ , -CHF ₂ , -OH, -OCF ₃ , -OCHF ₂ , -(C _1-3 alkylene)-O-(C _1-3 alkyl), -O-[(C _1-4 alkylene)-O] _m -(C _1-4 alkyl) (preferably -O-(C _1-3 alkylene)-O-(C _1-3 alkyl) )), -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -COOH and -CONH ₂ ; m is an integer of 1 or 2.

In a preferred embodiment, W is selected from the group consisting of a direct bond, CH ₂ , CHF, CF ₂ , CHOH, CHCH ₃ , C(CH ₃ ) ₂ , C(=O), NCH ₃ , NCH ₂ CH ₃ , O, S , S(=O) and S(=O) ₂ ; preferably, W is selected from a direct bond, CH ₂ , CHF, CF ₂ , CHOH, CHCH ₃ , C(CH ₃ ) ₂ , C(=O), NCH ₃ , O, S, S (= O) and S (= O) ₂ ;

Preferably, W is selected from the group consisting of a direct bond, CH ₂ , CHF, CF ₂ , CHOH, CHCH ₃ , C(CH ₃ ) ₂ , C(=O), NCH ₃ , NCH ₂ CH ₃ , O, S and S (= O) ₂ .

In a preferred embodiment, A is selected from the group consisting of a benzene ring and a 5-6 membered heteroaryl ring. In a more preferred embodiment, A is a benzene ring, a thiophene ring, a pyrazine ring, a pyrimidine ring or a pyridine ring.

In a preferred embodiment, R ¹² is each independently selected from the group consisting of H, halo, -CF ₃ , -CHF ₂ , -OH, -O-(C _1-4 alkyl), -OCF ₃ , -OCHF ₂ , cyano, C _1-4 alkyl, C _3-6 cycloalkyl, -COOH, -CONH ₂ , -(C _1-4 alkylene)-O-(C _1-4 alkyl) , -O-[(C _1-4 alkylene)-O] _m -(C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 Alkyl) ₂ and 3-6 membered heterocyclic groups; and m is an integer of 1, 2, 3 or 4. In a more preferred embodiment, R ¹² is each independently selected from the group consisting of H, F, Cl, Br, -OH, -O-(C _1-3 alkyl), -CF ₃ , -OCF ₃ , cyano, C _1-3 alkyl, C _3-6 cycloalkyl, -(C _1-4 alkylene)-O-(C _1-4 alkyl), -O-[(C _1-3 Alkylene)-O] _m -(C _1-3 alkyl), -NH ₂ , -NH(C _1-3 alkyl) and -N(C _1-3 alkyl) ₂ ; more preferably, R ¹² is each independently selected from the group consisting of H, F, Cl, -OH, -O-(C _1-3 alkyl), -CF ₃ , -OCF ₃ , cyano, C _1-3 alkyl, C _3-6 cycloalkyl, -(C _1-4 alkylene)-O-(C _1-4 alkyl), -O-[(C _1-3 alkylene)-O] _m -(C _1-3 alkyl), -NH ₂ , -NH(C _1-3 alkyl) and -N(C _1-3 alkyl) ₂ ; and m is an integer of 1 or 2. In a particularly preferred embodiment, R ¹² is each independently selected from the group consisting of H, F, Cl, Br, -OH, -CF ₃ , -OCF ₃ , cyano, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OCH ₃ , -O-CH(CH ₃ ) ₂ , -(C _1-3 alkylene)-O-(C _1-3 alkyl), -O-( C _1-3 alkylene)-O-(C _1-3 alkyl) and -N(C _1-3 alkyl) ₂ ; more preferably, R ¹² is each independently selected from H, in each occurrence F, Cl, -OH, -CF ₃ , -OCF ₃ , cyano, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OCH ₃ , -O-CH(CH ₃ ) ₂ , -(C _1-3 alkylene)-O-(C _1-3 alkyl), -O-(C _1-3 alkylene)-O-(C _1-3 alkyl) and -N(C _1-3 alkyl) ₂ ; Preferably, R ¹² is each independently selected from the group consisting of H, F, Br, Cl, -OH, cyano, -CH ₃ and -OCH ₃ .

In a preferred embodiment, n is an integer of 0, 1, 2 or 3. In a more preferred embodiment, n is an integer of 0, 1 or 2.

In a preferred embodiment, p is an integer of 0, 1, 2 or 3. In a more preferred embodiment, p is 0 or 1.

In a preferred embodiment, q is an integer of 0, 1, 2 or 3. In a more preferred embodiment, q is 0, 1 or 2.

In a preferred embodiment, the compounds of the invention have the structure of formula (II):

among them:

n is an integer of 0, 1, or 2;

The remaining groups are as defined above.

In a more preferred embodiment, the compound of the invention has the structure of formula (II'):

among them:

n is an integer of 0, 1, or 2;

The remaining groups are as defined above.

The present invention encompasses compounds obtained by any combination of the various embodiments.

In a preferred embodiment, the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled a compound, metabolite or prodrug, wherein the compound is selected from the group consisting of:

Pharmaceutical compositions and kits

In some embodiments, the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, a solvate, an N-oxide, an isotopically labeled compound, a metabolite or a prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semisolid formulation, a liquid formulation Or a gaseous preparation. .

The pharmaceutically acceptable carrier as used herein refers to an excipient and an additive used in the manufacture of a pharmaceutical preparation and formulation, and refers to a reasonable evaluation of safety in addition to the active ingredient, and is included in the pharmaceutical preparation. The substance in it. The pharmaceutically acceptable carrier can be used for prototyping, acting as a carrier, improving stability, and having important functions such as solubilization, solubilization, slow release and release, and is important for affecting the quality, safety and effectiveness of the drug. ingredient. According to its source, it can be divided into natural materials, semi-synthetic materials and total synthetic materials. According to its action and use, it can be divided into: solvent, propellant, solubilizer, cosolvent, emulsifier, colorant, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, Glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, filter aid, release retardant, etc.; For oral, injection, mucosal, transdermal or topical administration, nasal or oral inhalation and ocular administration. Specific pharmaceutically acceptable carriers include water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginate, calcium silicate, calcium phosphate , cellulose, aqueous syrup, methyl cellulose, polyvinyl pyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil, and the like.

The pharmaceutical composition may be administered in any form as long as it achieves prevention, alleviation, prevention or cure of symptoms of a human or animal patient. For example, various suitable dosage forms can be prepared depending on the route of administration.

When administered orally, the pharmaceutical composition can be formulated into any orally acceptable preparation including, but not limited to, tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, and oral emulsions. Wait. Among them, the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added. The diluent used in the capsules generally includes lactose and dried corn starch. Oral suspensions are usually prepared by admixing the active ingredient with suitable emulsifying and suspending agents. Optionally, some sweeteners, fragrances or colorants may also be added to the above oral formulation forms.

When administered transdermally or topically, the pharmaceutical compositions may be in the form of a suitable ointment, lotion or lozenge, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers which can be used in ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and carriers which can be used for lotions or elixirs include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The pharmaceutical composition can also be administered in the form of an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.

In another embodiment, the invention provides a pharmaceutical composition further comprising an additional therapeutic agent selected from the group consisting of, but not limited to, non-steroidal anti-infectives, other opioid agonists, calcium ion channels Blocker, antidepressant, or a combination thereof.

The invention also includes an article of manufacture. Articles used herein are intended to include, but are not limited to, kits and packages. The article of the present invention comprises: (a) a first container; (b) a pharmaceutical composition in the first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of the invention or a pharmaceutically acceptable compound thereof Salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or mixtures thereof; and (c) packaging The instructions illustrate that the pharmaceutical composition can be used to treat a pain condition (as defined above). In other embodiments, the package insert states that the pharmaceutical composition can be used in combination with a second therapeutic agent (as defined above) to treat a pain condition. The article of manufacture may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside the second container. Being located within the first and second containers means that each container retains the item within its boundaries.

The first container is a container for containing a pharmaceutical composition. This container can be used for preparation, storage, transportation, and/or stand-alone/bulk sales. The first container is intended to cover bottles, cans, vials, flasks, syringes, tubes (eg for use in cream products), or any other container used to prepare, contain, store or dispense a pharmaceutical product.

The second container is a container for containing the first container and optionally a package insert. Examples of the second container include, but are not limited to, a box (e.g., a carton or plastic box), a box, a carton, a bag (e.g., a paper bag or a plastic bag), a pouch, and a rag bag. The package insert may be physically adhered to the exterior of the first container via a cable tie, glue, staple or other attachment means, or it may be placed inside the second container without Any physical tool to which the first container adheres. Alternatively, the package insert is located outside of the second container. When located outside of the second container, it is preferred that the package insert is physically adhered via a tie, glue, staple or other attachment means. Alternatively, it may abut or contact the exterior of the second container without physical adhesion.

The package insert is a trademark, label, label, etc., which lists information relating to the pharmaceutical composition located within the first container. The information listed is typically determined by the regulatory agency (eg, the US Food and Drug Administration) that governs the area in which the article is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved for use. The package insert can be made of any material from which information contained therein or thereon can be read. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (e.g., printed or applied).

Treatment and use

In some embodiments, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopic label thereof Use of a compound, metabolite or prodrug, or a mixture thereof, or a pharmaceutical composition of the invention, for the manufacture of a medicament for the prevention or treatment of a mu opioid receptor-associated disease.

In other embodiments, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof A labeled compound, metabolite or prodrug, or a mixture thereof or a pharmaceutical composition of the invention for use in the prevention or treatment of a mu opioid receptor-associated disease.

In other embodiments, the invention provides a method of preventing or treating a mu opioid receptor-associated disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester thereof, Stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or mixtures thereof, or pharmaceutical compositions of the invention.

According to one embodiment of the present invention, a mu opioid receptor-related disease which can be prevented or treated using the compound of the present invention includes, but is not limited to, a pain-like disease, and the disease is further preferably a moderate to severe pain-like disease.

The term "effective amount" as used herein refers to an amount of a compound that, after administration, will relieve to some extent one or more symptoms of the condition being treated.

The dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition. The amount of administration and the administration regimen of the pharmaceutical composition can be readily determined by one of ordinary skill in the clinical arts. The composition or compound of the present invention is generally administered once a day to once every three days, preferably once a day, and the total amount of administration is from 0.01 to 1000 mg per time. Generally, the dosage of the treatment varies, depending on the considerations, such as the age, sex and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the extent of tissue damage; the symptoms Duration; and other variables that can be adjusted by each physician. The desired dose can be administered one or more times to achieve the desired result. The pharmaceutical composition according to the invention may also be provided in unit dosage form.

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or the progression of one or more symptoms of such a condition or condition, or preventing such A condition or condition or one or more symptoms of such condition or condition.

"Individual" as used herein includes human or non-human animals. Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).

Advantageous effects of the invention

The present invention has discovered a novel class of highly active mu opioid receptor agonists that achieve at least one of the following technical effects:

(1) having a high agonistic activity of μ opioid receptor;

(2) having μ opioid receptor selectivity;

(3) weaker recruitment of β-inhibitory protein;

(4) better physicochemical properties (eg solubility, physical and/or chemical stability);

(5) improved pharmacokinetic properties (eg improved bioavailability, appropriate half-life and duration of action);

(6) Improved safety (lower toxicity and/or fewer side effects, wider treatment window) and the like.

Detailed ways

The present invention is further illustrated by the following examples and examples, which are not intended to limit the scope of the invention, and may be modified without departing from the scope of the invention.

The MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

Preparative high performance liquid chromatography using Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 x 20 mm column).

Thin layer chromatography was performed using a GF 254 (0.4-0.5 nm) silica gel plate from Yantai.

The reaction is monitored by thin layer chromatography (TLC) or LC-MS using a developing solvent system including, but not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems, depending on The polarity of the compound is adjusted to adjust the volume ratio of the solvent, or triethylamine or the like is added for adjustment.

Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase. The eluent system includes, but is not limited to, a dichloromethane and methanol system, and a n-hexane and ethyl acetate system. The volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine or the like.

The temperature of the reaction is room temperature (20 ° C to 30 ° C) unless otherwise specified in the examples.

The reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.

Abbreviations as used herein have the following meanings:

The compounds of the invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials employed and suitable for effecting the conversion. Those skilled in the art of organic synthesis should be aware that the functional groups present on the molecule should be consistent with the proposed transformation. This will sometimes require the following determination: modify the order of the synthetic steps or route another specific method route relative to one method to obtain the desired compound of the invention.

It will also be appreciated that another major consideration in designing any synthetic route in the art is the correct selection of protecting groups for protecting the reactive functional groups present in the compounds described herein. An authoritative statement describing many alternatives to trained stakeholders is Greene et al. (Protective Groups in Organic Synthesis, 4th edition, Wiley-Interscience (2006)).

Unless otherwise stated, the substituents of the compounds in the following routes are as defined above. Those skilled in the art will appreciate that one or more of the following routes may be omitted depending on the desired product structure. Those skilled in the art can also appropriately adjust the order of the reaction steps as needed.

Route 1

The present invention provides a process for the synthesis of a compound of formula (I) according to the procedure described in Scheme 1.

In Scheme 1, R ^1P is the same as R ¹ , or R ^1P represents R ¹ protected by a protecting group; PG ¹ and PG ² each independently represent a carboxy protecting group, such as a C _1-6 alkyl group (preferably methyl or B) And a substituted silane group and a benzyl group; R ^5ap is the same as R ^5a or R ^5ap is an amino protecting group (preferably Boc); R ^5bp is the same as R ^5b or R ^5bp is an amino protecting group (preferably Boc).

Step 1: In some embodiments, this step comprises reacting an alkylating agent with compound S-1 in the presence of a base to form compound IM-1. In some embodiments, the base is potassium carbonate. In some embodiments, the alkylating agent is an alkyl halide. In some embodiments, this step comprises reductive amination of the aldehyde and reducing agent with compound S-1 to form compound IM-1. In some embodiments, the aldehyde is formaldehyde. In some embodiments, the reducing agent is sodium borohydride. In some embodiments, this step comprises reacting an acylating reagent with compound S-1 in the presence of a base to form compound IM-1. In some embodiments, the base is triethylamine. In some embodiments, the acylating agent is (Boc) ₂ O.

Step 2: In some embodiments, this step comprises reducing the reagent treatment of compound IM-1 to yield compound IM-2. In some embodiments, the reducing agent is diisobutylaluminum hydride. In some embodiments, this step involves reacting a metal reagent with compound IM-1 to form compound IM-2. In some embodiments, the metal reagent is a Grignard reagent. In some embodiments, this step comprises the treatment of IM-1 by a reducing reagent treatment and an oxidizing reagent to form compound IM-2. In some embodiments, the reducing agent is lithium aluminum hydride. In some embodiments, the oxidizing agent is IBX.

Step 3: In some embodiments, this step involves the Wittig reaction of the phospho-ylide reagent with compound IM-2 to yield compound IM-3. In some embodiments, the phosphorus ylide reagent is ethoxycarbonylmethylenetriphenylphosphine. In some embodiments, this step comprises the Adol reaction of the ester with compound IM-2 in the presence of a base to form compound IM-3. In some embodiments, the base is sodium hydride. In some embodiments, the ester is ethyl acetate.

Step 4: In some embodiments, this step comprises the compound IM-3 undergoing a metal catalyzed hydrogenation reaction to form compound IM-4. In some embodiments, the metal is Pd/C. In some embodiments, the hydrogenation reagent is hydrogen. In some embodiments, this step involves the addition reaction of an addition reagent with IM-3 to form compound IM-4. In some embodiments, the addition reagent is an alkylamine.

Step 5: In some embodiments, this step comprises treating compound IM-4 with a base and an alkylating agent to form compound IM-5. In some embodiments, the base is potassium carbonate. In some embodiments, the alkylating agent is an alkyl halide.

Step 6: In some embodiments, this step comprises reacting IM-5 with a alkylating agent in the presence of a base after deprotection to form compound IM-6. In some embodiments, the base is potassium carbonate. In some embodiments, the alkylating agent is an alkyl halide. In some embodiments, this step comprises reductive amination of IM-5 with a aldehyde and a reducing reagent after deprotection to form compound IM-6. In some embodiments, the aldehyde is formaldehyde. In some embodiments, the reducing agent is sodium borohydride. In some embodiments, this step comprises reacting IM-5 with a acylating reagent in the presence of a base after deprotection to form compound IM-6. In some embodiments, the base is triethylamine. In some embodiments, the acylating reagent is acetyl chloride. When R ^5ap is the same as R ^5a and R ^{5bp is the} same as R ^5b , this step is omitted.

Step 7: In some embodiments, this step comprises treating compound IM-6 with a base for deprotection to yield compound IM-7. In some embodiments, the base is sodium hydroxide. In some embodiments, the reaction is carried out in a solvent, preferably methanol.

Step 8: In some embodiments, this step comprises the compound IM-7 undergoing a condensation reaction in the presence of a condensation reagent followed by a deprotection reaction to form a compound of formula (I). In some embodiments, the condensation reagent is HATU. When R ^{1P is the} same as R ¹ , no deprotection reaction is carried out.

Those skilled in the art will appreciate that the order of the above steps can be adjusted as needed and one or more of the reaction steps can be omitted.

The compounds of the formula (II) and the formula (II') in the present invention can be synthesized in a similar manner to those in the above route.

Example

Example A: Preparation of (R)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanoic acid (SM-1)

First step: Preparation of (S)-2-((tert-Butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoic acid methyl ester (SM-1-2)

Tyrosine methyl ester (SM-1-1) (10.00 g, 51.2 mmol) was dissolved in dichloromethane (250 mL) at room temperature, respectively, triethylamine (14.20 mL, 102.4 mmol) and (Boc) ₂ O (12.93 mL, 56.3 mmol). The reaction was stirred for 4 hours at room temperature. The reactant was concentrated, and the crude product was purified by silica gel column chromatography to afford compound (SM-1-2) (13.20 g, yield 87%).

Second step: Preparation of (S)-3-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid methyl ester (SM-1-3)

Solution of Compound (SM-1-2) (13.00g, 44mmol) was dissolved in DMF (100mL), were added _{K 2 CO 3 (12.16g, 88.0mmol} ) and benzyl bromide (10.45mL, 88.0mmol). The reaction was stirred at room temperature for 4 hours. The reactant was concentrated, and the crude product was purified by silica gel column chromatography to yield Compound (SM-1-3) (13.00 g, yield 77%).

Third step: Preparation of (S)-(1-(4-(benzyloxy)phenyl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester (SM-1-4)

Compound (SM-1-3) (12.00 g, 31.13 mmol) was dissolved in tetrahydrofuran (150 mL), and lithium tetrahydroaluminum (1.77 g, 46.70 mmol) was added portionwise and reacted at room temperature for 5 hours. A small amount of water (1.80 mL) and a 15% sodium hydroxide solution (1.80 mL) were added, then water (6.00 mL) was added again, the reaction was suction filtered, concentrated, and the crude product was purified by silica gel column chromatography. -1-4) (8.80 g, yield 79%).

Fourth step: Preparation of (S)-(1-(4-(benzyloxy)phenyl)-3-oxopropan-2-yl)carbamic acid tert-butyl ester (SM-1-5)

Compound (SM-1-4) (7.0 g, 19.58 mmol) was dissolved in ethyl acetate (80 mL), and IBX (6.58 g, 23.50 mmol) was added. The reaction was heated to reflux and allowed to react for 4 h. The reaction was suction filtered and concentrated to give abr. (m.

Step 5: Preparation of (S)-5-(4-(benzyloxy)phenyl)-4-((tert-butoxycarbonyl)amino)pent-2-enoate (SM-1-6)

Compound (SM-1-5) (6.60 g, 18.57 mmol) was dissolved in dichloromethane (70.0 mL), and EtOAc (EtOAc, EtOAc) The reaction was carried out for 4 hours at room temperature. The reactant was concentrated, and the crude product was purified by silica gel column chromatography to yield Compound (SM-1-6) (7.90 g, yield: 89%).

Step 6: Preparation of (R)-4-((tert-Butoxycarbonyl)amino)-5-(4-hydroxyphenyl)pentanoic acid ethyl ester (SM-1-7)

Compound (SM-1-6) (5.00 g, 11.75 mmol) was dissolved in ethanol (100.0 mL) at room temperature, and palladium carbon (content 10%) (1.00 g) was added and replaced with hydrogen. The reaction was carried out at 50 ° C for 10 hours under a hydrogen atmosphere under normal pressure. The reaction was suction filtered, concentrated, and directly subjected to the next step.

Step 7: Preparation of (R)-4-amino-5-(4-hydroxyphenyl)pentanoic acid ethyl ester (SM-1-8)

The compound (SM-1-7) (2.00 g, 5.93 mmol) was dissolved in ethyl hydrogen chloride (2M) (10.0 mL). The reaction system was concentrated to give the title compound (SM-1-8) (1.60 g, yield 95%).

Step 8: Preparation of (R)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanoic acid ethyl ester (SM-1-9)

Compound (SM-1-8) (1.60 g, 5.86 mmol) was dissolved in acetonitrile (20.0 mL), EtOAc (10.0 mL), and then sodium borohydride (5.09 g, 24.0 mmol). The pH of the reaction mixture was adjusted to be basic, extracted with ethyl acetate, and concentrated, and the crude product was purified by silica gel column chromatography to afford compound (SM-1-9) (1.33 g, yield: 85%).

Step 9: Preparation of (R)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanoic acid (SM-1)

The compound (SM-1-9) (1.33 g, 5.0 mmol) was dissolved in MeOH (10.0 mL). The pH of the reaction mixture was adjusted to be acidic, and the reaction system was lyophilized to give the title compound (SM-1) (1.0 g, yield: 84%).

Example 1: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanamide (TM1) Preparation

Compound (SM-1) (25.0 mg, 0.10 mmol) was dissolved in DMF (2.0 mL), diisopropylethylamine (33.0 μL, 0.20 mmol) was added at room temperature, then 2,3-dihydrogen was added -1H-indol-1-amine (SM-2) (15.0 mg, 0.11 mmol), EtOAc (EtOAc) Yield 20%).

MS m/z (ESI): 353.3 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ9.13 (s, 1H), 8.09 (dd, J = 8.2,3.6Hz, 1H), 7.23-7.14 (m, 3H), 7.10-7.09 (m, 1H), 6.95 (dd, J=8.4, 2.9 Hz, 2H), 6.66 (dd, J=8.4, 2.3 Hz, 2H), 5.22 (q, J=8.0 Hz, 1H), 2.92-2.86 (m, 1H), 2.80- 2.72 (m, 2H), 2.47-2.46 (m, 1H), 2.35-2.28 (m, 1H), 2.25-2.15 (m, 8H), 2.04-1.95 (m, 1H), 1.74-1.68 (m, 1H) ), 1.64-1.44 (m, 2H).

Example 2: (R)-4-(Dimethylamino)-5-(4-hydroxyphenyl)-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl) Preparation of valeramide (TM2)

Compound (SM-1) (25.0 mg, 0.10 mmol) was dissolved in DMF (2 mL) at room temperature, and (S)-1,2,3,4-tetrahydronaphthalen-1-amine (SM-3) was added. (18.61 mg, 0.13 mmol), then diisopropylethylamine (20.90 μL, 0.12 mmol) and HATU (48.10 mg, 0.12 mmol). (2 mg, yield 7%).

MS m/z (ESI): 367.3 [M+H] ⁺

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.39 (d, J = 7.2Hz, 1H), 7.23 (d, J = 7.6Hz, 1H), 7.15-7.12 (m, 2H), 7.09-7.07 (m, 1H), 6.92 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 8.0 Hz, 2H), 5.21-5.11 (m, 1H), 2.88-2.79 (m, 2H), 2.76-2.66 (m) , 2H), 2.43 - 2.35 (m, 1H), 2.28 (s, 1H), 2.18-2.13 (m, 6H), 2.01-1.92 (m, 2H), 1.83 (s, 4H), 1.70 (s, 2H) ).

Example 3: (R)-4-(Dimethylamino)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4 Of -hydroxyphenyl)pentanamide (TM3)

Compound (SM-1) (50.0 mg, 0.21 mmol) was dissolved in DMF (2 mL) at room temperature and (1R,2S)-1-amino-2,3-dihydro-1H-indol-2-ol was added. (SM-4) (31.44 mg, 0.21 mmol), EtOAc (EtOAc, m. ) (62 mg, yield 75%).

MS m/z (ESI): 369.3 [M+H] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 7.24-7.21 (m, 2H), 7.20-7.17 (m, 1H), 7.15-7.13 (m, 1H), 7.01-7.03 (m, 2H), 6.73 6.70 (m, 2H), 5.24 (d, J = 5.2 Hz, 1H), 4.54-4.51 (m, 1H), 3.12 (dd, J = 16.4, 5.2 Hz, 1H), 2.95-2.87 (m, 2H) , 2.81-2.77 (m, 1H), 2.36 (s, 6H), 2.33-2.29 (m, 3H), 1.90 - 1.71 (m, 2H).

Example 4: Preparation of (4R)-N-(2,3-dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-phenylpentanamide (TM10)

First step: Preparation of (S)-methyl 2-(dimethylamino)-3-phenylpropanoate (10-2)

(S)-Phenylalanine methyl ester hydrochloride (10-1) (2.16 g, 10 mmol) was dissolved in acetonitrile (20 mL) at room temperature, and aqueous sodium hydroxide (10 mL) and sodium borohydride (8.69 g, 41mmol). The reaction was allowed to proceed overnight at room temperature. The pH of the reaction system was adjusted to be basic, extracted with ethyl acetate three times, and the organic phases were combined and concentrated. The crude product was purified by EtOAcjjjjjjjj

Second step: Preparation of (S)-2-(dimethylamino)-3-phenylpropan-1-ol (10-3)

At room temperature, the compound (10-2) (2.00g, 9.65mmol) was dissolved in THF (10mL), was added portionwise LiAlH ₄ (366mg, 9.65mmol). After reacting for 3 hours at room temperature, it was quenched with EtOAc (EtOAc)EtOAc

The third step: preparation of (S)-2-(dimethylamino)-3-phenylpropanal (10-4)

Oxalyl chloride (0.64 mL, 7.53 mmol) was added to dichloromethane (5.0 mL) at -78 ° C. After 10 min, a solution of DMSO (1.43 mL, 20 mmol) in dichloromethane (5.0 mL) was added dropwise. After stirring at -78 ° C for 1 hour, a solution of the compound (10-3) (0.9 g, 5.0 mmol) in dichloromethane (5.0 mL) was added dropwise. After stirring at -78 ° C for 1 hour, triethylamine (1.40 mL, 10.0 mmol) was added dropwise to the reaction system. After stirring at -78 °C for 1 hour, it was transferred to EtOAc EtOAc (EtOAc). %), proceed directly to the next step.

Fourth step: Preparation of ethyl (S)-4-(dimethylamino)-5-phenylpent-2-enoate (10-5)

Compound (10-4) (0.88 g, 5.0 mmol) and ethoxycarbonylmethylenetriphenylphosphine (1.74 g, 5.0 mmol) were dissolved in toluene (10.0 mL). The reaction was stirred at rt EtOAc (EtOAc)EtOAc.

Step 5: Preparation of (R)-4-(dimethylamino)-5-phenylpentanoic acid ethyl ester (10-6)

Compound (10-5) (0.45 g, 1.82 mmol) was dissolved in ethyl acetate (5.0 mL), and palladium/carbon (0.22 g) was added. The reaction was carried out at 50 ° C for 10 hours under a hydrogen atmosphere under normal pressure. Filter by suction, concentrate, and proceed directly to the next step.

Step 6: Preparation of (R)-4-(dimethylamino)-5-phenylpentanoic acid (10-7)

Compound (10-6) (0.4 g, 1.60 mmol) was dissolved in MeOH (5.0 mL) EtOAc. The reaction was carried out for 3 hours at room temperature. The pH was adjusted to be acidic, and the reaction system was lyophilized to give the title compound (10-7) (0.3 g, yield: 84%).

Step 7: Preparation of (4R)-N-(2,3-dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-phenylpentanamide (TM10)

Compound (10-7) (100 mg, 0.45 mmol), 2,3-dihydro-1H-indol-1-amine (SM-2) (60 mg, 0.45 mmol), HATU (189 mg, 0.49 mmol) DIEA (0.15 mL, 0.90 mmol) was dissolved in DMF (2.0 mL). The reaction was carried out for 3 hours at rt.

MS m/z (ESI): 337.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.27 (m, 5H), 7.24-7.23 (m, 1H), 7.20-7.04 (m, 3H), 5.49-5.42m, 1H), 3.07-2.97 ( m, 2H), 2.95-2.84 (m, 1H), 2.73-2.68 (m, 1H), 2.62-2.53 (m, 1H), 2.38-2.26 (m, 6H), 2.24 (m, 4H), 1.87- 1.72 (m, 3H).

Example 5: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-methoxyphenyl)pentanamide ( Preparation of TM13)

First step: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)amino)-5-(4-methoxyphenyl)pentanoate (13-1)

The compound (SM-1-7) (200.0 mg, 0.59 mmol) was dissolved in DMF (10 mL), and then potassium carbonate (245 mg, 1.78 mol) and methyl iodide (37 μL, 0.59 mmol) The reaction was carried out at room temperature overnight. After the mixture was diluted with a saturated aqueous solution of EtOAc (3 mL) (EtOAc) 177 mg, yield 85%).

Steps 2 to 4: Preparation of (R)-4-(dimethylamino)-5-(4-methoxyphenyl)pentanoic acid (13-4)

Except that in the second step of the present embodiment, the compound (13-1) was used instead of the SM-1-7 of the seventh step in the example A, and synthesized in a manner similar to that described in the seventh step to the ninth step of the embodiment A. Compound (13-4).

The fifth step: (4R)-N-(2,3-dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-methoxyphenyl)pentanamide ( Preparation of TM13)

Compound (13-4) (35.0 mg, 0.14 mmol) was dissolved in DMF (2 mL) at room temperature and 2,3-dihydro-1H-indol-1-amine (SM-2) (18.55 mg, 0.1 Addition of HATU (63.50 mg, 0.17 mmol) and DIEA (46 μL, 0.27 mmol), and react at room temperature for 4 hours. Purification by preparative HPLC gave the title compound (m.

MS m/z (ESI): 367.2 [M+H] ⁺

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.17-7.08 (m, 4H), 6.97-6.94 (m, 2H), 6.76-6.73 (m, 2H), 5.38-5.31 (m, 1H), 3.72 (s , 3H), 2.91-2.85 (m, 1H), 2.82-2.74 (m, 2H), 2.56-2.42 (m, 2H), 2.23-2.10 (m, 9H), 1.75-1.58 (m, 4H).

Example 6: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-(2-methoxyethoxy) Preparation of phenyl)pentanamide (TM14)

The title compound (TM14) was synthesized in a similar manner to that described in Example 5 except that in the first step, 2-methoxy-1-bromoethane was used instead of the methyl iodide in the first step of Example 5. .

MS m/z (ESI): 411.3 [M+H] ⁺

_{^{1 H NMR (400MHz, CD 3}} OD) δ7.23-7.18 (m, 2H), 7.17-7.15 (m, 2H), 7.09 (dd, J = 8.8,2.8Hz, 2H), 6.87-6.83 (m, 2H), 5.32-5.28 (m, 1H), 4.08-4.05 (m, 2H), 3.75-3.71 (m, 2H), 3.41 (s, 3H), 3.00-2.94 (m, 2H), 2.9-2.79 ( m, 1H), 2.75-2.66 (m, 1H), 2.48-2.39 (m, 1H), 2.33-2.30 (d, J = 11.6, 6H), 2.28-2.10 (m, 3H), 1.82-1.73 (m , 2H), 1.72-1.63 (m, 1H).

Example 7: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)-2-methyl Preparation of valeramide (TM15)

First step: (S)-5-(4-(Benzyloxy)phenyl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate (15-1 Preparation

Sodium hydride (0.10 g, 4.22 mmol) was taken in tetrahydrofuran (20.0 mL). Then ethyl 2-(diethoxyphosphonyl)propanoate (1.01 g, 4.22 mmol) was added and the reaction was stirred for 0.5 h. Further, the compound (SM-1-5) (1.00 g, 2.81 mmol) was dissolved in tetrahydrofuran (10.0 mL), and then added dropwise to the reaction mixture, and the reaction was continued for 4 hours under ice cooling. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride, and the THF layer was separated. The aqueous layer was extracted twice with EA, and the organic layer was concentrated. The crude product was purified by silica gel column chromatography to give compound (15-1) (0.3 g , yield 23%).

Steps 2 to 5: Preparation of (4R)-4-(dimethylamino)-5-(4-hydroxyphenyl)-2-methylpentanoic acid (15-5)

Except that in the second step of the present embodiment, the compound (15-1) is used instead of the compound (SM-1-6) of the sixth step in the embodiment A, and the steps described in the sixth step to the ninth step of the embodiment A are employed. A similar method was used to synthesize the compound (15-5).

Step 6: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)-2-methyl Preparation of valeramide (TM15)

Compound (15-5) (50.0 mg, 0.20 mmol) was dissolved in DMF (2.5 mL), then diisopropylethylamine (66.0 μL, 0.40 mmol), HATU (90.8 mg, 0.24 mmol) And 2,3-dihydro-1H-indol-1-amine (SM-2) (26.5 mg, 0.20 mmol), mp. Yield 11%).

MS m/z (ESI): 367.3 [M+H] ⁺

_{^{1 H NMR (400MHz, CD 3}} OD) δ7.27-7.16 (m, 4H), 7.04 (dd, J = 18.8,8.4Hz, 1H), 6.93 (d, J = 8.4Hz, 1H), 6.71-6.64 (m, 2H), 5.35 (dd, J = 15.2, 7.6 Hz, 1H), 3.03-2.96 (m, 1H), 2.89-2.82 (m, 2H), 2.79-2.76 (m, 1H), 2.51-2.43 (m, 2H), 2.44 - 2.28 (m, 7H), 1.92-1.78 (m, 2H), 1.42-1.35 (m, 1H), 1.14 (d, J = 6.8 Hz, 1H), 1.03 (t, J =6.8Hz, 2H).

Example 8: (R)-4-(Dimethylamino)-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4 Of -hydroxyphenyl)pentanamide (TM47)

Compound (SM-1) (100.0 mg, 0.42 mmol) was dissolved in DMF (4 mL) at room temperature and (1S,2R)-1-amino-2,3-dihydro-1H-indole-2-ol was added. (SM-5) (62.87 mg, 0.42 mmol), EtOAc (EtOAc (EtOAc) 16 mg, yield 9%).

MS m/z (ESI): 369.3 [M+H] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 7.24 - 7.16 (m, 4H), 7.13 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 5.28 (d, J) = 5.2 Hz, 1H), 4.56-4.53 (m, 1H), 3.52 (s, 1H), 3.16-3.08 (m, 2H), 2.94-2.90 (m, 7H), 2.72 (dd, J = 13.6, 9.6 Hz, 1H), 2.60-2.54 (m, 1H), 2.44-2.37 (m, 1H), 2.14-2.04 (m, 1H), 1.93-1.84 (m, 1H).

Example 9: (R)-N-((R)-2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentyl Preparation of amide (TM44)

Compound (SM-1) (25.0 mg, 0.10 mmol) was dissolved in DMF (2.0 mL) at room temperature and (R)-2,3-dihydro-1H-indol-1-amine hydrochloride (SM) -6) (18.6 mg, 0.11 mmol), further added DIEA (33.0 μL, 0.20 mmol) and HATU (58.03 mg, 0.15 mmol). , yield 8%).

MS m/z (ESI): 353.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.19-7.06 (m, 4H), 6.86 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 5.34 (q, J = 7.6 Hz, 1H), 2.94-2.88 (m, 1H), 2.83-2.75 (m, 2H), 2.63 (s, 1H), 2.52-2.44 (m, 1H), 2.34-2.19 (m, 6H), 2.18 -2.13 (m, 3H), 1.75-1.61 (m, 3H).

Example 10: (R)-N-((S)-2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentane Preparation of amide (TM43)

Compound (SM-1) (25.0 mg, 0.10 mmol) was dissolved in DMF (2 mL) at room temperature, HATU (48.00 mg, 0.12 mmol) and triethylamine (44 μL, 0.32 mmol), and finally (S) -2,3-Dihydro-1H-indol-1-amine hydrochloride (SM-7) (18.00 mg, 0.10 mmol). Yield 14%).

MS m/z (ESI): 353.3 [M+H] ⁺

_{^{1 H NMR (400MHz, CD 3}} OD) δ7.21-7.19 (m, 2H), 7.16-7.15 (m, 2H), 7.01-6.9 (m, 2H), 6.72-6.70 (m, 2H), 5.30 ( t, J=7.6 Hz, 1H), 3.01-2.94 (m, 1H), 2.92-2.79 (m, 2H), 2.76-2.67 (m, 1H), 2.49-2.39 (m, 1H), 2.36-2.25 ( m, 7H), 2.24 - 2.13 (m, 2H), 1.83-1.66 (m, 3H).

Example 11: (4R)-N-(2,3-Dihydrobenzofuran-3-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanamide (TM27) preparation

Compound (SM-1) (25.0 mg, 0.10 mmol) was dissolved in DMF (2 mL) at room temperature, HATU (48.00 mg, 0.12 mmol) and triethylamine (44 μL, 0.32 mmol), and finally 2,3 -Dihydrobenzofuran-3-amine hydrochloride (SM-8) (18.20 mg, 0.10 mmol). .

MS m/z (ESI): 355.3 [M+H] ⁺

_{^{1 H NMR (400MHz, CD 3}} OD) δ7.30-7.28 (m, 1H), 7.23-7.19 (m, 1H), 7.10-7.06 (m, 2H), 6.93-6.88 (m, 1H), 6.79- 6.81 (m, 1H), 6.76-6.74 (m, 2H), 5.50-5.47 (m, 1H), 4.65-4.59 (m, 1H), 4.28-4.23 (m, 1H), 3.06-3.01 (m, 1H) ), 2.90-2.78 (m, 7H), 2.67-2.60 (m, 1H), 2.39-2.37 (m, 1H), 2.28-2.17 (m, 1H), 2.02-1.97 (m, 1H), 1.82-1.77 (m, 1H).

Example 12: (4R)-N-(6-Bromo-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-4-(dimethylamino)-5-( Preparation of 4-hydroxyphenyl)pentanamide (TM105)

First step: Preparation of 6-bromo-1-methyl-2,3-dihydroquinolin-4(1H)-one (105-2)

6-Bromo-2,3-dihydroquinolin-4(1H)-one (0.30 g, 1.26 mmol) was dissolved in DMF (6 mL), then potassium carbonate (0.36 g, 2.52 1.07 g, 7.56 mmol). The reaction was heated at 80 ° C for 16 hours, and the reaction was monitored by TLC. The reaction mixture was filtered, EtOAcjjjjjjjj

Second step: Preparation of (Z)-6-bromo-1-methyl-2,3-dihydroquinolin-4(1H)-one O-methylindole (105-3)

Compound (105-2) (0.25 g, 1.04 mmol) was dissolved in pyridine (25 mL). The reaction was allowed to proceed for 16 hours at room temperature, and the reaction was monitored by TLC. The reaction mixture was concentrated to dryness crystals crystals crystals

The third step: preparation of 6-bromo-1-methyl-1,2,3,4-tetrahydroquinolin-4-amine (105-4)

The compound (105-3) (0.10 g, 0.37 mmol) was dissolved in EtOAc (1M) (10 mL). The reaction was heated at 80 ° C for 16 hours, and the reaction was monitored by TLC. 2M HCl was added to the reaction mixture, and the mixture was heated to 80 ° C for 1 hour, and then EA was added to remove organic impurities. The aqueous layer was adjusted to basic with saturated sodium bicarbonate, and then extracted with EA three times. 0.08 g, yield 89%).

The fourth step: (4R)-N-(6-bromo-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-4-(dimethylamino)-5-( Preparation of 4-hydroxyphenyl)pentanamide (TM105)

The compound (SM-1) (80.0 mg, 0.30 mmol) was dissolved in DMF (5 mL). EtOAc (EtOAc, EtOAc, EtOAc Finally, compound (105-4) (82.9 mg, 0.34 mmol) was added. The reaction was carried out for 4 hours at room temperature, and the reaction was monitored by TLC. The title compound (80 mg, yield 48%) was obtained.

MS m/z (ESI): 460.2 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ9.13 (s, 1H), 8.13 (dd, J = 8.4,2.8Hz, 1H), 7.18 (dt, J = 8.8,2.8Hz, 1H), 7.02 ( Dd, J = 12.0, 1.6 Hz, 1H), 6.96-6.93 (m, 2H), 6.65 (d, J = 8.0 Hz, 2H), 6.54 (dd, J = 8.8, 1.6 Hz, 1H), 4.88-4.81 (m, 1H), 3.20-3.13 (m, 2H), 2.82 (s, 3H), 2.75-2.70 (m, 1H), 2.49-2.46 (m, 1H), 2.25-2.13 (m, 8H), 2.08 -2.00 (m, 1H), 1.89-1.83 (m, 1H), 1.77-1.73 (m, 1H), 1.64-1.44 (m, 2H).

Example 13: (4R)-4-(Dimethylamino)-5-(4-hydroxyphenyl)-N-(1-methyl-1,2,3,4-tetrahydroquinoline-4- Preparation of valeramide (TM106)

TM105 (30.0 mg, 0.07 mmol) was dissolved in dry methanol (15 mL) and then Pd/C (30.0 mg). The reaction was allowed to proceed for 16 hours at room temperature, and the reaction was monitored by TLC. The title compound (4 mg, yield 14%)

MS m/z (ESI): 382.2 [M+H] ⁺

¹ H NMR (400 MHz, CD ₃ OD) δ 7.09 (t, J = 7.2 Hz, 1H), 6.98 (d, J = 8.0 Hz, 3H), 6.70-6.59 (m, 4H), 4.69-4.51 (m) , 1H), 3.17-3.13 (m, 2H), 2.89 (s, 3H), 2.84 (s, 1H), 2.62-2.60 (m, 1H), 2.30-2.20 (m, 7H), 2.18-2.07 (m , 2H), 2.01-1.86 (m, 2H), 1.78-1.67 (m, 2H).

Example 14: (R)-4-Amino-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl) Preparation of valeramide (TM69)

First step: Preparation of (R)-4-((tert-butoxycarbonyl)amino)-5-(4-hydroxyphenyl)pentanoic acid (69-1)

SM-1-7 (1.0 g, 2.96 mmol) was dissolved in methanol (10 mL) and then 15% NaOH (10 mL) aqueous solution was then allowed to react at room temperature for 2 hours. The reaction was monitored by TLC to the end point. After concentrating the reaction mixture, the mixture was diluted with DCM, and the mixture was separated, and then the mixture was evaporated to EtOAc. The title compound (900 mg, yield 98%).

Second step: ((R)-5-(((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)amino)-1-(4-hydroxyphenyl) Preparation of tert-butyl-5-oxopentan-2-yl)carbamate (69-2)

In this step, (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol was used instead of SM-2 in Example 1, and compound (69-1) was used instead of SM-1. The title compound (69-2) was synthesized in a similar manner to that described in Example 1.

The third step: (R)-4-amino-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl) Preparation of valeramide (TM69)

To the compound (69-2) (65 mg, 0.14 mmol) was added 5 mL of hydrochloric acid in dioxane, and the mixture was stirred at room temperature, and the reaction was monitored by TLC. The solvent was directly evaporated to give the title compound (45 mg,j.

MS m/z (ESI): 341.2 [M+H] ⁺

_{^{1 H NMR (400MHz, CD 3}} OD) δ7.26-7.17 (m, 4H), 7.07-7.01 (m, 2H), 6.77-6.69 (m, 2H), 5.29 (d, J = 5.2Hz, 1H) , 4.55 (td, J = 5.2, 2.0 Hz, 1H), 3.13 (dd, J = 16.4, 5.2 Hz, 1H), 3.03-2.95 (m, 1H), 2.91 (dd, J = 16.4, 2.0 Hz, 1H) ), 2.72 (dd, J = 5.6 Hz, 1H), 2.56-2.40 (m, 3H), 1.95-1.84 (m, 1H), 1.75-1.64 (m, 1H).

Example 15: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl)-4-(3-hydroxypyrrolidin-1-yl) Preparation of valeramide (TM35)

First step: Preparation of (R)-5-(4-(benzyloxy)phenyl)-4-((tert-butoxycarbonyl)amino)pentanoic acid ethyl ester (35-1)

SM-1-7 (1.00 g, 2.96 mmol) was dissolved in MeCN (30 mL). EtOAc (EtOAc, EtOAc (EtOAc) The reaction mixture was concentrated, diluted with water and EtOAc EtOAc. The title compound (35-1) (820 mg, yield: 64%)

Second step: Preparation of (R)-5-(4-(benzyloxy)phenyl)-4-((tert-butoxycarbonyl)amino)pentanoic acid (35-2)

Compound (35-1) (820 mg, 1.92 mmol) was dissolved in MeOH (10 mL), and then 10 mL NaOH (15% aqueous solution) was added and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction solution, it was diluted with DCM, separated, and the aqueous phase was adjusted to pH 3-4, and a large amount of precipitate appeared. After the addition of EA, EtOAc (3 mL).

The third step: ((2R)-1-(4-(benzyloxy)phenyl)-5-((2,3-dihydro-1H-indol-1-yl)amino)-5-oxopentane Preparation of tert-butyl-2-ylcarbamate (35-3)

Compound (35-2) (150 mg, 0.37 mmol) was dissolved in DMF (5 mL). EtOAc (EtOAc, EtOAc, EtOAc, EtOAc -Indole-1-amine (50 mg, 0.37 mmol), was reacted overnight. The reaction mixture was concentrated, purified by preparative HPLC, and then evaporated to give the title compound (35 g.

The fourth step: (4R)-4-amino-5-(4-(benzyloxy)phenyl)-N-(2,3-dihydro-1H-indol-1-yl)pentanamide (35-4 Preparation

To the compound (35-3) (155 mg, 0.30 mmol) was added 5 mL of aq. The solvent was directly dried to give the title compound (35-4) (140 mg, yield: 87%).

The fifth step: (4R)-5-(4-(benzyloxy)phenyl)-N-(2,3-dihydro-1H-indol-1-yl)-4-(3-hydroxypyrrolidine- Preparation of 1-yl)pentanamide (35-5)

Compound (35-4) (140 mg, 0.28 mmol) was dissolved in MeCN (10 mL), potassium carbonate (119 mg, 0.86 mmol) and sodium iodide (43 mg, 0.29 mmol). 2-Alcohol (80 mg, 0.37 mmol) was refluxed at 85 ° C for 5 hours. The reaction mixture was concentrated, diluted with water and EtOAc EtOAc. After dissolving in DCM, the title compound (35-5) (78 mg, yield: 56%).

Step 6: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl)-4-(3-hydroxypyrrolidin-1-yl) Preparation of valeramide (TM35)

The compound (35-5) (50 mg, 0.10 mmol) was dissolved in EtOH (5 mL), Pd/C (25 mg, 0.21 mmol) was added, and the reaction was carried out under a hydrogen atmosphere at 60 ° C overnight, the whole of the reaction was completed, and the mixture was filtered. The title compound (TM35) (7 mg, yield 16%) was obtained.

MS m/z (ESI): 395.3 [M+H] ⁺

_{^{1 H NMR (400MHz, CD 3}} OD) δ7.25-7.15 (m, 4H), 7.06-6.99 (m, 2H), 6.74-6.67 (m, 2H), 5.36-5.29 (m, 1H), 4.36- 4.26(m,1H), 3.06-2.65(m,8H), 2.52-2.40(m,2H),2.34-2.21(m,2H),2.14-1.96(m,1H),1.85-1.67(m,4H) ).

Example 16: (R)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl)-4-? Preparation of porphyrinamide (TM73)

In addition to the first step in this example, (1R,2S)-1-amino-2,3-dihydro-1H-indol-2-ol was used in place of the 2,3-dihydrogen in the third step of Example 15. 1H-indol-1-amine, and in the third step of this example, the compound 2,2'-dibromodiethyl ether was used instead of the compound 1,4-dibromobutan-2-ol in the fifth step of Example 15, The title compound TM73 was synthesized in a similar manner to that described in the third to sixth steps of Example 15.

MS m/z (ESI): 411.2 [M+H] ⁺

_{^{1 H NMR (400MHz, CD 3}} OD) δ7.27-7.08 (m, 4H), 7.05-6.95 (m, 2H), 6.76-6.66 (m, 2H), 5.29-5.23 (m, 1H), 4.55- 4.48(m,1H),3.71-3.56(m,4H),3.17-3.07(m,1H),2.97-2.86(m,2H),2.73-2.66(m,3H),2.44-2.24(m,4H ), 1.88-1.66 (m, 2H).

Example 17: (R)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl)-4-( Preparation of pyrrolidin-1-yl)pentanamide (TM74)

In addition to the first step in this example, 1,4-dibromobutane was used instead of the compound 1,4-dibromobutan-2-ol of the fifth step of Example 15, using the fifth step of Example 15 to The title compound TM74 was synthesized in a similar manner to that described in the sixth step.

MS m/z (ESI): 395.2 [M+H] ⁺

_{^{1 H NMR (400MHz, CD 3}} OD) δ7.26-7.14 (m, 4H), 7.06 (d, J = 8.4Hz, 2H), 6.72 (d, J = 8.4Hz, 2H), 5.26 (d, J = 4.8 Hz, 1H), 4.52 (td, J = 5.2, 2.0 Hz, 1H), 3.12 (dd, J = 16.4, 5.2 Hz, 1H), 3.00-2.88 (m, 2H), 2.88-2.69 (m, 5H), 2.54 (dd, J = 13.2, 9.6 Hz, 1H), 2.41-2.33 (m, 2H), 1.91-1.76 (m, 6H).

Example 18: (R)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl)-4-( Preparation of methylamino)pentanamide (TM75)

First step: (R)-5-(4-(benzyloxy)phenyl)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl) Preparation of -4-((4-methoxybenzyl)amino)pentanamide (75-1)

Compound (73-2) (150.0 mg, 0.29 mmol) was dissolved in MeOH (10 mL), EtOAc (29.5 mg, 0.29 mmol) and p-methoxybenzaldehyde (47.7 mg, 0.35 mmol) 1 hour. Sodium triacetoxyborohydride (185.3 mg, 0.86 mmol) was added and the mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated, diluted with water and EtOAc EtOAc EtOAcjjjjjjjj

Second step: (R)-5-(4-(benzyloxy)phenyl)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl) Preparation of -4-((4-methoxybenzyl)(methyl)amino)pentanamide (75-2)

Compound (75-1) (100.0 mg, 0.15 mmol) was dissolved in MeOH (10 mL), EtOAc (EtOAc (EtOAc) Methyl), reacted at room temperature for 4 hours. The reaction mixture was concentrated, diluted with water, EtOAc EtOAc m.

The third step: (R)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl)-4-( Preparation of methylamino)pentanamide (TM75)

Compound (75-2) (52.1 mg, 92.1 μmol) was dissolved in EtOH (25 mL), Pd/C (25 mg) was added, and the mixture was replaced with hydrogen and heated at 60 ° C overnight. The reaction mixture was filtered, dried, evaporated, mjjjjjjjj

MS m/z (ESI): 355.2 [M+H] ⁺

_{^{1 H NMR (400MHz, CD 3}} OD) δ7.25-7.17 (m, 4H), 7.05 (d, J = 8.4Hz, 2H), 6.74 (d, J = 8.4Hz, 2H), 5.28 (d, J = 5.2 Hz, 1H), 4.54 (ddd, J = 5.2, 5.2, 2.0 Hz, 1H), 3.12 (dd, J = 16.0, 5.2 Hz, 1H), 2.92 (dd, J = 16.4, 2.0 Hz, 1H) , 2.79-2.71 (m, 1H), 2.71-2.63 (m, 2H), 2.45-2.38 (m, 2H), 2.37 (s, 3H), 1.91-1.72 (m, 2H).

The following compounds were synthesized by a similar synthesis method in the above examples, and the specific information is shown in the following table.

Biological evaluation

Experimental example 1

1.1 Purpose of the test

The purpose of this assay was to test the agonistic effects of compounds on the μ opioid receptor (μOR) G protein signaling pathway.

1.2 Test principle

Activation of the μ protein G signal pathway regulates intracellular cAMP levels, and changes in intracellular cAMP levels by homogeneous time-resolved fluorescence (HTRF) reflect the agonistic activity of the compound. The maximal effect E _max (100% of the maximum effect of 1 μM full agonist DAMGO (H-Tyr-D-Ala-Gly-N-MePhe-Gly-OH)) based on the compound causing changes in cAMP levels and half of the maximum effect The compound concentration EC _{50 was used to} evaluate the in vitro activity of the compounds.

1.3 Test methods

1.3.1 Test materials and instruments

name	Brand
hμOR/CHO cell line	HDB
HEPES	Invitrogen
HBSS (+/+)	Invitrogen
IBMX	Sigma
NKH477	Tocris
DMSO	Sigma
cAMP Dynamic 2 Kit	Cisbio
384-well LDV board	Labcyte
Low capacity 384 whiteboard	Corning
Echo 550	Labcyte
Bravo	Agilent Technologies
Multidrop Combi	Thermo Scientific
Envision microplate reader	PerkinElmer

1.3.2 Test procedure

Serial dilutions of the test compound samples were prepared on 384-well LDV plates, and the sample dilution sequence was transferred to the experimental plate (Corning-3824) using an Echo machine, transferring 30 nL per well, and transferring 30 nL positive control DAMGO (HPE) and negative control. DMSO (ZPE) to the corresponding wells. Then, 5 μL of stimulation buffer (STB) and 5 μL of hμOR/CHO cell suspension (10000 cells/well) were sequentially added to each well of the experimental plate, and the final concentrations of the compounds of IBMX and NKH477 in the 10 μL system were 100 μM and 1.5 μM, respectively. The plate was incubated for 40 min in a 37 ° C incubator. The cAMP levels were then tested according to the cAMP Dynamic 2 kit instructions.

1.4 test results

The levels of the agonistic μOR G protein signaling pathway of the tested compounds were determined by the above assay, and the measured EC ₅₀ and E _max results are shown in Table 1 (100% with a maximum effect of 1 μM full agonist DAMGO).

Table 1. Test compound Inflammatory μOR G protein signaling pathways influence the level of cAMP EC ₅₀ and E _max

Compound ID	EC 50 (nM)	E max (%)
TM1	3.3 ± 0.9	85.0±2.0
TM2	14.2±1.2	110.4±1.2
TM3	6.2±0.5	102.9±1.1
TM10	33.1±2.1	105.2±1.1
TM43	2.3±0.3	105.3±1.2
TM27	43.1±5.1	81.9±1.6
TM105	47.8 ± 7.3	80.4±2.2
TM106	4.9±1.0	100.6±2.6
TM74	26.7±1.2	107.7±0.7
TM75	17.0±2.8	98.7±2.3
TM48	3.1±0.4	100.1 ± 1.9
TM70	2.9±0.3	108.0±0.9
TM71	7.5±0.6	102.4±1.4
TM72	22.1±2.0	98.7±1.3
TM76	1.5±0.3	97.6±2.0
TM77	7.0±0.6	98.2±1.0
TM78	2.4±0.4	96.4±1.5
TM80	2.7±0.4	97.8±1.3

TM8	23.5±1.6	109.8±1.1
TM61	15.6±1.5	102.3±1.4
TM107	38.1±2.9	79.2±1.2
TM108	31.6±3.6	71.9±1.3
TM83	7.2±0.5	104.8±1.0
TM84	1.1±0.3	106.4±1.6
TM85	55.2±5.4	98.9±1.6
TM86	1.9±0.2	104.4±1.3
TM87	0.7±0.1	121.3±1.2
TM89	7.4±2.3	92.7±3.3
TM91	61.3±5.3	102.3±1.5
TM95	44.7±6.8	88.7±2.3
TM98	0.5±0.1	100.9±1.9
TM99	41.3±4.2	108.3±2.0
TM100	4.0±0.5	97.8±1.3
TM101	47.1±5.4	102.6±2.0
TM103	13.9±1.6	100.4±1.8

Conclusion: The compounds of the present invention have strong agonistic activity on the μ opioid receptor (μOR) G protein signaling pathway.

Experimental example 2

2.1 Purpose of the test

The purpose of this assay was to test the activity of the μ opioid receptor (μOR) to recruit β inhibitory protein 2 after activation by the compounds of the invention.

2.2 Test principle

The mu opioid receptor (μOR) was detected by enzyme fragment complementation (EFC) to recruit β inhibitory protein 2 after activation by the compound. The agonist binds to the μ opioid receptor (μOR) overexpressing the β-gal fragment and recruits the β-inhibitor-coupled β-gal complementary fragment to form a fully catalytically active enzyme, which catalyzes the substrate to produce chemiluminescence. . The in vitro activity of the compounds was evaluated based on the maximum effect _Emax (the maximum effect of 1 [mu]M full agonist DAMGO is 100%) at which the compound caused the level of β inhibitory protein 2 recruitment.

2.3 Test methods

2.3.1 Test materials and instruments

name	Brand
Human μ opioid β inhibitor protein U2OS/OPRM1 cell line	DiscoveRX
PathHunter Test Kit	DiscoveRX
MEM medium	Gibco
DMSO	Sigma
384-well LDV board	Labcyte
384-well plate, white, TC treated, flat bottom, with lid	PerkinElmer
Echo 550	Labcyte
Bravo	Agilent Technologies
Multidrop Combi	Thermo Scientific
Envision microplate reader	PerkinElmer

2.3.2 Test procedure

Serial dilutions of the test compound samples were prepared on 384-well LDV plates, and the sample dilution sequence was transferred to a test plate (PerkinElmer) using an Echo machine, 60 nL per well, while transferring 60 nL positive control DAMGO (HPE) and negative control DMSO ( ZPE) to the corresponding hole. Then, 20 μL of U2OS/OPRM1 cell suspension (7500 cells/well) was added to each well of the assay plate, centrifuged at 300 rpm for 30 s, and incubated at room temperature for 2 hours. Then, 6 μL of PathHunter detection reagent was added to each well of the assay plate according to the PathHunter test kit instructions, and allowed to stand on Envision after standing at room temperature for 60 minutes.

2.4 test results

The level of recruitment of β-inhibitor 2 after activation of μOR by the test compound was determined by the above test, and the measured E _max results are shown in Table 2 (100% of the maximum effect of 1 μM full agonist DAMGO).

Table 2. Test compound activated μOR recruitment β 2 inhibitory protein level E _max.

Compound ID	E max (%)
TM1	7.8±0.4
TM47	<3
TM27	<3
TM105	6.2±1.2
TM80	20.4 ± 1.1
TM8	19.9±1
TM107	<3
TM108	3.7±0.4
TM89	15.7±0.7
TM95	11.4±0.6
TM100	20.0 ± 0.6

Conclusion: The compounds of the present invention have a weaker level of recruitment of β-inhibitor 2 after activation of the μ opioid receptor (μOR).

Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each of the references (including all patents, patent applications, journal articles, books, and any other publications) cited in this application are hereby incorporated by reference in their entirety.

Claims (15)

1. a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein Said compound has the structure of formula (I):

   

   among them:

   R ^{1 is} selected from the group consisting of H, halogen, -OR ^h , cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, -COOR ^h , -CON(R ^h ) ₂ ,- SO ₃ H, -S(=O) _g R ^h , -OC(=O)-(C _1-6 alkyl), -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -N(R ^h ) ₂ , 3-10 membered heterocyclic group, C _6-14 aryl group and 5-14 membered heteroaryl group;

   Each occurrence of R ² is independently selected from the group consisting of H, halogen, -OR ^h , cyano, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, halo C _1-6 alkyl, C _2-5 alkenyl, -COOR ^h , -CON(R ^h ) ₂ , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(= O) _g R ^h , -N(R ^h ) ₂ and a 3-10 membered heterocyclic group;

   R ^3a , R ^3b , R ⁴ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ^9a , R ^9b , R ^10a and R ^10b are each independently selected from H, halogen, - at each occurrence. OR ^h , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(=O) _g R ^h , cyano, -COOR ^h , -CON( R ^h ) ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, -N(R ^h ) ₂ and 3-10 membered heterocyclic; the condition is when R ^6a and R ^When one of ^6b is -OH, the other is not H;

   R ^5a and R ^5b are each independently selected from H, halogen, -OR ^h , -C(=O)R ^h , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, - C _1-6 alkylene-OR ^h , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl) and 3-10 membered heterocyclic group; or, R ^5a Forming a 5-10 membered nitrogen-containing heterocycle together with R ^5b together with the nitrogen atom to which it is attached;

   W is selected from direct bonds, CR ^11a R ^11b , C(=O), O, NR ^11a and S(=O) _g ;

   R ^11a and R ^11b are each independently selected from H, halogen, -OR ^h , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(=O _g R ^h , cyano, -COOR ^h , -CON(R ^h ) ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C _2-5 alkenyl, -N(R ^h ) ₂ and 3-10 membered heterocyclic group;

   A is selected from the group consisting of a C _6-14 aromatic ring and a 5-14 membered heteroaryl ring;

   R ¹² is each independently selected from the group consisting of H, halogen, -OR ^h , cyano, nitro, C _1-6 alkyl, C _3-6 cycloalkyl, halo C _1-6 alkyl, C _2-5 alkenyl, -COOR ^h , -CON(R ^h ) ₂ , -O-[(C _1-6 alkylene)-O] _m -(C _1-6 alkyl), -S(= O) _g R ^h , -N(R ^h ) ₂ and a 3-10 membered heterocyclic group;

   The above alkyl, alkylene, cycloalkyl, alkenyl, nitrogen-containing heterocyclic, heterocyclic, aryl, aromatic, heteroaryl and heteroaryl rings are each optionally independently selected by one or more of them. Substituted from a substituent of halogen, =O, -R ^h , -OR ^h , -COOR ^h , -CON(R ^h ) ₂ , -S(=O) _g R ^h and -N(R ^h ) ₂ ;

   R ^h is each independently selected from H, C _1-6 alkyl, halo C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, C _6-10 , each occurrence. An aryl group and a 5-10 membered heteroaryl group, and the plurality of ^Rh groups may be the same or different from each other;

   g each independently represents an integer of 0, 1 or 2 at each occurrence;

   m each independently represents any integer in 1-10, including the end value;

   n, p and q are each independently an integer of 0, 1, 2, 3 or 4.
2. A compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or pre- Medicament wherein R ^{1 is} selected from the group consisting of H, halogen, -OH, -O-(C _1-4 alkyl), cyano, C _1-4 alkyl, C _3-6 cycloalkyl, -COOH, -CONH ₂ , -OC(=O)-(C _1-4 alkyl), -O-[(C _1-4 alkylene)-O] _m -(C _1-4 alkyl), -SH, -S ( =O) _g -(C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ and 3-6 membered heterocyclic group, wherein The alkyl, alkylene, cycloalkyl and heterocyclic groups are each optionally one or more independently selected from the group consisting of F, Cl, C _1-4 alkyl, C _3-6 cycloalkyl, - CF ₃ , -CHF ₂ , -OH, -OCF ₃ , -OCHF ₂ , -O-(C _1-6 alkyl), -COOH, -CONH ₂ , -NH ₂ , -NH(C _1-4 alkyl And a substituent of -N(C _1-4 alkyl) ₂ ; g is an integer of 0, 1 or 2; and m is an integer of 1, 2, 3 or 4;

   Preferably, R ^{1 is} selected from the group consisting of H, F, Cl, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, -CF ₃ , -CHF ₂ , -OH, -OCH ₃ , -OCF ₃ , -OCHF ₂ , -OC(=O)-(C _1-4 alkyl), -(C _1-4 alkylene)-O-(C _1-4 alkyl), -O-[(C _{1- 4} alkylene)-O] _m -(C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -COOH and - CONH ₂ ; wherein m is an integer of 1 or 2;

   More preferably, R ^{1 is} selected from the group consisting of H, F, Cl, -CF ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OH, -OCH ₃ , -OCF ₃ , -OC ( =O)CH ₃ , -CH ₂ -OCH ₃ and -O-CH ₂ CH ₂ -O-CH ₃ .
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or prodrugs, wherein each occurrence of R ² is independently selected from the group consisting of H, halogen, -CF ₃ , -CHF ₂ , -OH, -OCF ₃ , -OCHF ₂ , -O(C _1-4 alkyl) , cyano, C _1-4 alkyl, C _3-6 cycloalkyl, -COOH, -CONH ₂ , -(C _1-4 alkylene)-O-(C _1-4 alkyl), -O -[(C _1-4 alkylene)-O] _m -(C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ and 3-6 membered heterocyclic groups; wherein m is an integer of 1, 2, 3 or 4;

   Preferably, each occurrence of R ² is independently selected from the group consisting of H, F, Cl, -OH, -CF ₃ , -OCF ₃ , -OCH ₃ , cyano, C _1-4 alkyl, C _3-6 Cycloalkyl, -(C _1-4 alkylene)-O-(C _1-4 alkyl), -O-[(C _1-4 alkylene)-O] _m -(C _1-4 alkane a group of -1, -NH ₂ , -NH(C _1-4 alkyl) and -N(C _1-4 alkyl) ₂ ; wherein m is an integer of 1, 2, 3 or 4;

   More preferably, each occurrence of R ² is independently selected from the group consisting of H, F, Cl, -OH, -CF ₃ , -OCF ₃ , -OCH ₃ , C _1-3 alkyl, -(C _1-3 Alkylene)-O-(C _1-3 alkyl), -O-(C _1-3 alkylene)-O-(C _1-3 alkyl) and -N(C _1-3 alkyl) ₂ .
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof, isotope-labeled a compound, metabolite or prodrug wherein R ^3a , R ^3b , R ⁴ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ^9a , R ^9b , R ^10a and R ^10b are each present at each occurrence Independently selected from H, F, Cl, -OH, -O-(C _1-4 alkyl), -O-(halogenated C _1-4 alkyl), cyano, -(C _1-4 alkylene ))-O-(C _1-4 alkyl), -O-[(C _1-4 alkylene)-O] _m -(C _1-4 alkyl), -COOH, -CONH ₂ , C _{1 -4} alkyl, halo C _1-4 alkyl, C _3-6 cycloalkyl, -S(=O) _g -(C _1-4 alkyl), -NH ₂ , -NH(C _1-4 An alkyl group, a -N(C _1-4 alkyl) ₂ and a 3-6 membered heterocyclic group; wherein g is an integer of 0, 1 or 2; and m is an integer of 1, 2, 3 or 4;

   Preferably, R ^3a , R ^3b , R ⁴ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ^9a , R ^9b , R ^10a and R ^10b are each independently selected from H, each occurrence. F, Cl, cyano, C _1-4 alkyl (preferably C _1-3 alkyl, more preferably methyl), C _3-6 cycloalkyl, -CF ₃ , -CHF ₂ , -OH, -OCF ₃ , -OCHF ₂ , -(C _1-3 alkylene)-O-(C _1-3 alkyl), -O-[(C _1-4 alkylene)-O] _m -(C _1-4 Alkyl) (preferably -O-(C _1-4 alkylene)-O-(C _1-4 alkyl)), -NH ₂ , -NH(C _1-4 alkyl) (preferably -NH(C) _1-3 alkyl)), -N(C _1-4 alkyl) ₂ (preferably -N(C _1-3 alkyl) ₂ ), -COOH and -CONH ₂ ; wherein m is an integer of 1 or 2 .
5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof, isotope-labeled a compound, metabolite or prodrug wherein R ^5a and R ^5b are each independently selected from the group consisting of H, F, Cl, -OH, -O-(C _1-4 alkyl) (preferably -O-(C _1-3 alkane) Base)), C _1-6 alkyl (preferably C _1-4 alkyl, more preferably methyl or ethyl), C _3-6 cycloalkyl, -C _1-4 alkylene-OH (preferably -C _1-3 alkylene-OH), C _2-5 alkenyl (preferably vinyl, propenyl or allyl), -O-[(C _1-4 alkylene)-O] _m - (C _{1 -4} alkyl) and 3-6 membered heterocyclic; or, R ^5a and R ^5b together with the nitrogen atom to which they are attached form a 5-7 membered nitrogen-containing heterocycle (preferably a 5-6 membered nitrogen-containing heterocycle); Wherein m is an integer of 1 or 2; and the alkyl, alkylene, cycloalkyl, alkenyl, nitrogen-containing heterocyclic ring and heterocyclic group are each optionally one or more independently selected from F Substituent substitution of Cl, -CF ₃ , -OH, =O, -OCF ₃ , C _1-3 alkyl, -OC _1-4 alkyl and -N(C _1-3 alkyl) ₂ .
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof, isotope-labeled a compound, metabolite or prodrug wherein R ^11a and R ^11b are each independently selected from the group consisting of H, F, Cl, -OH, -O-(C _1-4 alkyl), cyano, -O-[(C _{1 -4} alkylene)-O] _m -(C _1-4 alkyl), -COOH, -CONH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, -S(=O) _g - (C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ and 3-6 membered heterocyclic group, wherein the alkyl group, The alkylene, cycloalkyl and heterocyclyl groups are each optionally one or more independently selected from the group consisting of F, Cl, -CF ₃ , -CHF ₂ , -OH, -OCF ₃ , -OCHF ₂ , C _{1 -4} alkyl, C _3-6 cycloalkyl, -OC _1-4 alkyl, -COOH, -CONH ₂ , -S(=O) _g -(C _1-4 alkyl), -NH ₂ ,- Substituted by a substituent of NH(C _1-4 alkyl) and -N(C _1-3 alkyl) ₂ ; g is an integer of 0, 1 or 2; m is an integer of 1, 2, 3 or 4;

   Preferably, R ^11a and R ^11b are each independently selected from H, F, Cl, cyano, C _1-4 alkyl (preferably C _1-3 alkyl, more preferably methyl or ethyl), C _3-6 Cycloalkyl, -CF ₃ , -CHF ₂ , -OH, -OCF ₃ , -OCHF ₂ , -(C _1-3 alkylene)-O-(C _1-3 alkyl), -O-[( C _1-4 alkylene)-O] _m -(C _1-4 alkyl) (preferably -O-(C _1-3 alkylene)-O-(C _1-3 alkyl)), -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , -COOH and -CONH ₂ ; m is an integer of 1 or 2.
7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof, isotope-labeled a compound, metabolite or prodrug wherein W is selected from the group consisting of a direct bond, CH ₂ , CHF, CF ₂ , CHOH, CHCH ₃ , C(CH ₃ ) ₂ , C(=O), NCH ₃ , NCH ₂ CH ₃ , O , S, S(=O) and S(=O) ₂ ;

   Preferably, W is selected from the group consisting of a direct bond, CH ₂ , CHF, CF ₂ , CHOH, CHCH ₃ , C(CH ₃ ) ₂ , C(=O), NCH ₃ , O, S, S(=O), and S ( =O) ₂ ; or

   W is selected from the group consisting of a direct bond, CH ₂ , CHF, CF ₂ , CHOH, CHCH ₃ , C(CH ₃ ) ₂ , C(=O), NCH ₃ , NCH ₂ CH ₃ , O, S, and S(=O) ₂ .
8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof, isotope-labeled a compound, metabolite or prodrug wherein A is selected from the group consisting of a benzene ring and a 5-6 membered heteroaryl ring; preferably, A is a benzene ring, a thiophene ring, a pyrazine ring, a pyrimidine ring or a pyridine ring.
9. A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof, isotopically labeled a compound, metabolite or prodrug wherein R ¹² is each independently selected from the group consisting of H, halogen, -CF ₃ , -CHF ₂ , -OH, -O-(C _1-4 alkyl), -OCF ₃ , -OCHF ₂ , cyano, C _1-4 alkyl, C _3-6 cycloalkyl, -COOH, -CONH ₂ , -(C _1-4 alkylene)-O-(C _1-4 alkane , O-[(C _1-4 alkylene)-O] _m -(C _1-4 alkyl), -NH ₂ , -NH(C _1-4 alkyl), -N (C _{1 a -4} alkyl) ₂ and 3-6 membered heterocyclic group; and m is an integer of 1, 2, 3 or 4;

   Preferably, each occurrence of R ¹² is independently selected from the group consisting of H, F, Cl, Br, -OH, -O-(C _1-3 alkyl), -CF ₃ , -OCF ₃ , cyano, C _1-3 alkyl, C _3-6 cycloalkyl, -(C _1-4 alkylene)-O-(C _1-4 alkyl), -O-[(C _1-3 alkylene)- O] _m -(C _1-3 alkyl), -NH ₂ , -NH(C _1-3 alkyl) and -N(C _1-3 alkyl) ₂ ; more preferably, R ^{12 is present} at each occurrence Each is independently selected from the group consisting of H, F, Cl, -OH, -O-(C _1-3 alkyl), -CF ₃ , -OCF ₃ , cyano, C _1-3 alkyl, C _3-6 ring Alkyl, -(C _1-4 alkylene)-O-(C _1-4 alkyl), -O-[(C _1-3 alkylene)-O] _m -(C _1-3 alkyl , -NH ₂ , -NH(C _1-3 alkyl) and -N(C _1-3 alkyl) ₂ ; and m is an integer of 1 or 2;

   More preferably, each occurrence of R ¹² is independently selected from the group consisting of H, F, Cl, Br, -OH, -CF ₃ , -OCF ₃ , cyano, -CH ₃ , -CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -OCH ₃ , -O-CH(CH ₃ ) ₂ , -(C _1-3 alkylene)-O-(C _1-3 alkyl), -O-(C _1-3 Alkylene)-O-(C _1-3 alkyl) and -N(C _1-3 alkyl) ₂ ; more preferably, each occurrence of R ¹² is independently selected from H, F, Cl, -OH, -CF ₃ , -OCF ₃ , cyano, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OCH ₃ , -O-CH(CH ₃ ) ₂ , -(C _{1 -3} alkylene)-O-(C _1-3 alkyl), -O-(C _1-3 alkylene)-O-(C _1-3 alkyl) and -N(C _1-3 alkane Base) ₂ ; or

   R ¹² is each independently selected from the group consisting of H, F, Br, Cl, -OH, cyano, -CH ₃ , and -OCH ₃ at each occurrence.
10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof, isotope-labeled a compound, metabolite or prodrug wherein the compound has the structure of formula (II):

    

    among them:

    n is an integer of 0, 1, or 2;

    The remaining groups are as defined in any one of claims 1-9.
11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof, isotope-labeled a compound, metabolite or prodrug wherein the compound has the structure of formula (II'):

    

    among them:

    n is an integer of 0, 1, or 2;

    The remaining groups are as defined in any one of claims 1-9.
12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof, isotope-labeled a compound, metabolite or prodrug, wherein the compound is selected from the group consisting of:

    

    

    

    
13. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, a solvate, an N-oxide, an isotope-labeled compound, a metabolite or a prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semi-solid formulation, a liquid formulation or a gaseous state preparation.
14. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof, isotope-labeled Use of a compound, metabolite or prodrug or a pharmaceutical composition of the invention for the preparation of a medicament for the prevention or treatment of a mu opioid receptor-associated disease.
15. The use according to claim 14, wherein the μ opioid receptor-associated disease is a pain-like disease, and the disease is preferably a moderate to severe pain-like disease.