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

Substituted phenylethylamine compound and preparation method and use thereof Download PDF

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Publication number
WO2019144805A1
WO2019144805A1 PCT/CN2019/071063 CN2019071063W WO2019144805A1 WO 2019144805 A1 WO2019144805 A1 WO 2019144805A1 CN 2019071063 W CN2019071063 W CN 2019071063W WO 2019144805 A1 WO2019144805 A1 WO 2019144805A1
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alkyl
alkylene
group
compound
cycloalkyl
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PCT/CN2019/071063
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French (fr)
Chinese (zh)
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朱加望
宋智泉
郝小余
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Publication of WO2019144805A1 publication Critical patent/WO2019144805A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C07C13/45—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing nine carbon atoms
    • C07C13/465—Indenes; Completely or partially hydrogenated indenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C07C13/47—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing ten carbon atoms
    • C07C13/48—Completely or partially hydrogenated naphthalenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/02—Monocyclic hydrocarbons
    • C07C15/04—Benzene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/04—Ortho-condensed systems

Definitions

  • the present invention relates to a substituted phenethylamine compound as a ⁇ 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).
  • 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 are a class of drugs that are effective in the treatment of pain, especially in the treatment of moderate and severe pain.
  • 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 ⁇ opioid receptor ( ⁇ OR), kappa opioid receptor ( ⁇ OR), and ⁇ opioid Receptor ( ⁇ opioid receptor, ⁇ OR), opioid receptors, etc. and their subtypes.
  • GPCRs G-protein coupled receptors
  • opioid receptor agonists 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.
  • the present invention provides a novel substituted phenethylamine compound for use as a ⁇ opioid receptor agonist, which has excellent agonistic activity against ⁇ opioid receptors and weaker recruitment of ⁇ -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):
  • 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.
  • A is selected from the group consisting of a C 6-14 aromatic ring and a 5-14 membered heteroaryl ring;
  • 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.
  • 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;
  • n 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.
  • compositions 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.
  • a pharmaceutically acceptable salt for example, a pharmaceutically acceptable salt of a pharmaceutical composition of the invention.
  • the form, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or mixtures thereof, are combined with one or more pharmaceutically acceptable carriers.
  • kits 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
  • 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 ⁇ 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.
  • alkyl refers to a saturated straight or branched chain hydrocarbon group.
  • C1-6 alkyl refers to a straight or branched chain hydrocarbon radical having from 1 to 6 carbon atoms.
  • alkylene refers to a saturated straight or branched divalent hydrocarbon group.
  • C1-6 alkylene refers to a straight or branched divalent hydrocarbon radical having from 1 to 6 carbon atoms.
  • methylene, ethylene, propylene or butylene For example, methylene, ethylene, propylene or butylene.
  • haloalkyl refers to an alkyl group, optionally substituted with one or more (such as 1 to 3) halo.
  • 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.
  • alkenyl refers to a straight or branched chain hydrocarbon radical having one or more carbon-carbon double bonds.
  • 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.
  • 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.
  • cycloalkyl 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • 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.).
  • 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.
  • 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.
  • halo or halogen group, as used herein, is defined to include F, Cl, Br or I.
  • 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.
  • 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.
  • 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.
  • each substituent is selected independently of the other.
  • each substituent may be the same or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • a point of attachment of a substituent may come from any suitable position of the substituent.
  • 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.
  • 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.
  • 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
  • phosphorus isotope eg 32 P
  • sulfur isotope eg 35 S
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • 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).
  • 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.
  • 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.
  • solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • 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.
  • compositions of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • 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.
  • 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.
  • esters 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.
  • 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.
  • N-oxides 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.
  • MCPBA chloroperoxybenzoic acid
  • Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines.
  • 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.
  • 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.
  • 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 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):
  • 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.
  • A is selected from the group consisting of a C 6-14 aromatic ring and a 5-14 membered heteroaryl ring;
  • 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.
  • 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;
  • n 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.
  • 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).
  • 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.
  • 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 .
  • 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.
  • 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)),
  • 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,
  • 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 cycloal
  • 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.
  • 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.
  • 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.
  • 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-
  • 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 alkylene)-
  • n is an integer of 0, 1, 2 or 3. In a more preferred embodiment, n is an integer of 0, 1 or 2.
  • p is an integer of 0, 1, 2 or 3. In a more preferred embodiment, p is 0 or 1.
  • q is an integer of 0, 1, 2 or 3. In a more preferred embodiment, q is 0, 1 or 2.
  • the compounds of the invention have the structure of formula (II):
  • n is an integer of 0, 1, or 2;
  • the compound of the invention has the structure of formula (II'):
  • n is an integer of 0, 1, or 2;
  • the present invention encompasses compounds obtained by any combination of the various embodiments.
  • 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:
  • the invention provides a pharmaceutical composition
  • 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 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.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler 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.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler filler
  • lubricant wetting agent
  • osmotic pressure regulator stabilizer
  • Glidants osmotic pressure regulator
  • flavoring agents preservatives
  • suspending agents coating materials
  • fragrances anti
  • 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.
  • various suitable dosage forms can be prepared depending on the route of administration.
  • 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.
  • 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.
  • suitable emulsifying and suspending agents may also be added to the above oral formulation forms.
  • the pharmaceutical compositions 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.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopic label thereof
  • 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.
  • 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.
  • 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.
  • 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.
  • "effective amount&quot 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.
  • 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.
  • treating 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.).
  • improved pharmacokinetic properties eg improved bioavailability, appropriate half-life and duration of action
  • the MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • 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
  • TLC thin layer chromatography
  • LC-MS 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.
  • 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.
  • 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.
  • the present invention provides a process for the synthesis of a compound of formula (I) according to the procedure described 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 comprises reacting an alkylating agent with compound S-1 in the presence of a base to form compound IM-1.
  • the base is potassium carbonate.
  • the alkylating agent is an alkyl halide.
  • this step comprises reductive amination of the aldehyde and reducing agent with compound S-1 to form compound IM-1.
  • the aldehyde is formaldehyde.
  • the reducing agent is sodium borohydride.
  • this step comprises reacting an acylating reagent with compound S-1 in the presence of a base to form compound IM-1.
  • the base is triethylamine.
  • the acylating agent is (Boc) 2 O.
  • Step 2 comprises reducing the reagent treatment of compound IM-1 to yield compound IM-2.
  • the reducing agent is diisobutylaluminum hydride.
  • this step involves reacting a metal reagent with compound IM-1 to form compound IM-2.
  • the metal reagent is a Grignard reagent.
  • this step comprises the treatment of IM-1 by a reducing reagent treatment and an oxidizing reagent to form compound IM-2.
  • the reducing agent is lithium aluminum hydride.
  • the oxidizing agent is IBX.
  • this step involves the Wittig reaction of the phospho-ylide reagent with compound IM-2 to yield compound IM-3.
  • the phosphorus ylide reagent is ethoxycarbonylmethylenetriphenylphosphine.
  • this step comprises the Adol reaction of the ester with compound IM-2 in the presence of a base to form compound IM-3.
  • the base is sodium hydride.
  • the ester is ethyl acetate.
  • Step 4 comprises the compound IM-3 undergoing a metal catalyzed hydrogenation reaction to form compound IM-4.
  • the metal is Pd/C.
  • the hydrogenation reagent is hydrogen.
  • this step involves the addition reaction of an addition reagent with IM-3 to form compound IM-4.
  • the addition reagent is an alkylamine.
  • Step 5 comprises treating compound IM-4 with a base and an alkylating agent to form compound IM-5.
  • the base is potassium carbonate.
  • the alkylating agent is an alkyl halide.
  • Step 6 comprises reacting IM-5 with a alkylating agent in the presence of a base after deprotection to form compound IM-6.
  • the base is potassium carbonate.
  • the alkylating agent is an alkyl halide.
  • this step comprises reductive amination of IM-5 with a aldehyde and a reducing reagent after deprotection to form compound IM-6.
  • the aldehyde is formaldehyde.
  • the reducing agent is sodium borohydride.
  • this step comprises reacting IM-5 with a acylating reagent in the presence of a base after deprotection to form compound IM-6.
  • the base is triethylamine.
  • the acylating reagent is acetyl chloride.
  • Step 7 comprises treating compound IM-6 with a base for deprotection to yield compound IM-7.
  • the base is sodium hydroxide.
  • the reaction is carried out in a solvent, preferably methanol.
  • Step 8 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).
  • the condensation reagent is HATU.
  • 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%).
  • Step 6 Preparation of (R)-4-((tert-Butoxycarbonyl)amino)-5-(4-hydroxyphenyl)pentanoic acid ethyl ester (SM-1-7)
  • Step 8 Preparation of (R)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanoic acid ethyl ester (SM-1-9)
  • 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.
  • EtOAc EtOAc EtOAc
  • Step 5 Preparation of (R)-4-(dimethylamino)-5-phenylpentanoic acid ethyl ester (10-6)
  • 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. .
  • 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).
  • 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, EtOAcjjjjjjj
  • 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%).
  • 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%)
  • 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%).
  • 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.
  • This assay was to test the agonistic effects of compounds on the ⁇ opioid receptor ( ⁇ OR) G protein signaling pathway.
  • Activation of the ⁇ 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 ⁇ M 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.
  • 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 ⁇ L of stimulation buffer (STB) and 5 ⁇ L of h ⁇ OR/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 ⁇ L system were 100 ⁇ M and 1.5 ⁇ M, 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.
  • STB stimulation buffer
  • h ⁇ OR/CHO cell suspension 10000 cells/well
  • the levels of the agonistic ⁇ OR 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 ⁇ M full agonist DAMGO).
  • the compounds of the present invention have strong agonistic activity on the ⁇ opioid receptor ( ⁇ OR) G protein signaling pathway.
  • This assay was to test the activity of the ⁇ opioid receptor ( ⁇ OR) to recruit ⁇ inhibitory protein 2 after activation by the compounds of the invention.
  • the mu opioid receptor ( ⁇ OR) was detected by enzyme fragment complementation (EFC) to recruit ⁇ inhibitory protein 2 after activation by the compound.
  • EFC enzyme fragment complementation
  • the agonist binds to the ⁇ opioid receptor ( ⁇ OR) overexpressing the ⁇ -gal fragment and recruits the ⁇ -inhibitor-coupled ⁇ -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 ⁇ inhibitory protein 2 recruitment.
  • 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.
  • 20 ⁇ L 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.
  • 6 ⁇ L 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.
  • Test compound activated ⁇ OR recruitment ⁇ 2 inhibitory protein level E max.
  • the compounds of the present invention have a weaker level of recruitment of ⁇ -inhibitor 2 after activation of the ⁇ opioid receptor ( ⁇ OR).

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

取代的苯乙胺化合物及其制备方法和用途Substituted phenethylamine compound, preparation method and use thereof 发明领域Field of invention
本发明涉及作为μ阿片受体激动剂的取代的苯乙胺化合物，包含其的药物组合物、其制备方法及其用于预防和/或治疗μ阿片受体相关疾病(包括但不限于疼痛类疾病)的用途。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).
发明背景Background of the invention
目前上市的治疗疼痛的药物包括非甾体类抗感染药、阿片类激动剂、钙离子通道阻断剂、抗抑郁药物等，它们在控制疼痛方面有一定的疗效，但是同时也带来了许多令人担忧的副作用，因此寻找一类安全有效的治疗疼痛的药物仍是尚未完成的、具有挑战性的研发目标。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.
阿片类药物(例如***)是一类能够有效治疗疼痛的药物，尤其在治疗中度和重度疼痛方面有很好的效果。然而阿片类药物有严重的耐受性、成瘾性、呼吸抑制、恶心、便秘等副作用(Williams，JT等人，Pharacol.Rev.，65，223-254(2013))，还存在被滥用的社会问题。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.
阿片类药物能激活跨膜的阿片G蛋白偶联受体(GPCR)，该受体的亚型包括μ阿片受体(μopioid receptor，μOR)、κ阿片受体(κopioid receptor，κOR)、δ阿片受体(δopioid receptor，δOR)、类阿片受体等及其亚型。目前临床上使用的阿片受体激动剂绝大部分是***的衍生物，也有小分子化合物以及肽类化合物，它们对于亚型的选择性、对相关GPCR的选择性以及药物在体内的分布和代谢都与其产生的药效和副作用有一定的关系。最近对于G蛋白偶联受体的偏向性(biased)作用的发现进一步提高了人们对G蛋白偶联受体信号转导的认知，揭示了新的G蛋白偶联受体药理学作用。通过配体激动G蛋白偶联受体但不激活对β抑制蛋白的募集，能够控制受体产生某种特定的生物反应，得到不同的药理效果(Wisler J.W.等人Curr.Opin.Cell Biol.27，18-24(2014))。具体而言，在μ阿片受体激动过程中募集β抑制蛋白2可能与呼吸抑制或便秘等副作用有关(Bohn，LM等人，Science，286，2495-2498(1999))。近年来该领域的研究越来越引起人们的关注，已有多个偏向性阿片受体配体见诸报道(Edward，RS等人，Curr.Opin.Pharm.32，77-84(2017)；Manglik，A；Lin，H；Aryal，DK等人，Nature，537，185-190，(2016)；WO2017007695A；和WO2017161017A1)。开发新型的具有一定μ阿片受体选择性同时具有较弱的对β抑制蛋白的募集作用的配体化合物为降低副作用(即避免呼吸抑制、便秘和/或改善成瘾性)，发现更安全有效的止痛药物带来了希望。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.
发明概述Summary of invention
本发明提供新型的用作μ阿片受体激动剂的取代的苯乙胺化合物，其具有优异的对μ阿片受体的激动活性而较弱的对β抑制蛋白的募集作用，且具有更好的止痛药的成药性能。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.
本发明的一个方面提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(I)的结构：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):
Figure PCTCN2019071063-appb-000001
Figure PCTCN2019071063-appb-000001
其中：among them:
R 1选自H、卤素、-OR h、氰基、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-COOR h、-CON(R h) 2、-SO 3H、-S(＝O) gR h、-O-C(＝O)-(C 1-6烷基)、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-N(R h) 2、3-10元杂环基、C 6-14芳基和5-14元杂芳基； 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;
R 2在每次出现时各自独立地选自H、卤素、-OR h、氰基、硝基、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、C 2-5烯基、-COOR h、-CON(R h) 2、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、-N(R h) 2和3-10元杂环基： 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和R 10b在每次出现时各自独立地选自H、卤素、-OR h、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、氰基、-COOR h、-CON(R h) 2、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-N(R h) 2和3-10元杂环基；条件是当R 6a和R 6b之一为-OH时，另一者不是H； 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和R 5b各自独立地选自H、卤素、-OR h、-C(＝O)R h、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-C 1-6亚烷基-OR h、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)和3-10元杂环基；或者，R 5a与R 5b连同其所连接的氮原子共同形成5-10元含氮杂环； 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选自直接键、CR 11aR 11b、C(＝O)、O、NR 11a和S(＝O) g； W is selected from direct bonds, CR 11a R 11b , C(=O), O, NR 11a and S(=O) g ;
R 11a和R 11b各自独立地选自H、卤素、-OR h、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、氰基、-COOR h、-CON(R h) 2、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-N(R h) 2和3-10元杂环基； 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选自C 6-14芳环和5-14元杂芳环； A is selected from the group consisting of a C 6-14 aromatic ring and a 5-14 membered heteroaryl ring;
R 12在每次出现时各自独立地选自H、卤素、-OR h、氰基、硝基、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、C 2-5烯基、-COOR h、-CON(R h) 2、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、-N(R h) 2和3-10元杂环基； 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;
上述烷基、亚烷基、环烷基、烯基、含氮杂环、杂环基、芳基、芳环、杂芳基和杂芳环各自任选地被一个或多个各自独立地选自卤素、＝O、-R h、-OR h、-COOR h、-CON(R h) 2、-S(＝O) gR h和-N(R h) 2的取代基取代； 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在每次出现时各自独立地选自H、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、3-10元杂环基、C 6-10芳基和5-10元杂芳基，且多个R h彼此之间可以相同或不同； 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在每次出现时各自独立地表示0、1或2的整数；g each independently represents an integer of 0, 1 or 2 at each occurrence;
m在每次出现时各自独立地表示1-10中的任意整数，包括端值；并且m each independently represents any integer in 1-10, including the end value;
n、p和q各自独立地为0、1、2、3或4的整数。n, p and q are each independently an integer of 0, 1, 2, 3 or 4.
本发明的另一方面提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。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.
本发明的另一方面提供制备本发明的药物组合物的方法，所述方法包括将本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、或者它们的混合物与一种或多种药学上可接受的载体混合。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.
本发明的另一方面提供药盒，其包含本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者它们的混合物，或者本发明的药物组合物。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.
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物在制备用于预防或治疗μ阿片受体相关疾病的药物中的用途。所述药物用于预防或治疗疼痛类疾病。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.
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物，其用于预防或治疗μ阿片受体相关疾病。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.
本发明的另一方面提供预防或治疗μ阿片受体相关疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物。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.
上述μ阿片受体相关疾病包括但不限于疼痛类疾病，所述疾病进一步优选为中度到重度的疼痛类疾病。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.
发明详细描述Detailed description of the invention
定义definition
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。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.
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。The terms "comprising," "comprising," "having," "containing," Or method steps.
如本文中所使用，术语“烷基”指饱和的直链或支链烃基。例如，如本文中所使用，术语“C 1-6烷 基”指具有1-6个碳原子饱和的直链或支链烃基。例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基等。 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.
如本文中所使用，术语“亚烷基”指饱和的直链或支链的二价烃基。例如，如本文中所使用，术语“C 1-6亚烷基”指具有1-6个碳原子饱和的直链或支链的二价烃基。例如亚甲基、亚乙基、亚丙基或亚丁基等。 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.
如本文中所使用，术语“卤代烷基”指任选地被1个或多个(诸如1至3个)卤素取代的烷基。例如，如本文中所使用，术语“卤代C 1-6烷基”指任选地被1个或多个(诸如1至3个)卤素取代的C 1-6烷基。例如CH 2F、CHF 2、CF 3、CCl 3、C 2F 5、C 2Cl 5、CH 2CF 3、CH 2Cl或CH 2CH 2CF 3等。 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.
如本文中所使用，术语“烯基”指具有一个或多个碳碳双键的直链或支链烃基。例如，如本文中所使用，术语“C 2-6烯基”指具有2-6个碳原子以及一个、两个或三个碳碳双键的直链或支链烃基，优选含有一个碳碳双键的C 2-6烯基。例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基等。 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.
如本文中所使用，术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连***(诸如双环[1 -1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等))，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基可具有3至10个碳原子。例如，术语“C 3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。 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.
如本文中所使用，术语“烃环”是指具有例如5-10个(适合地具有5-8个，更适合地具有5-6个)环碳原子的饱和或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环，其包括但不限于环丙基环、环丁基环、环戊基环、环己基环、环庚基环、环辛基环、环壬基环、环己烯基环等。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.
如本文中所使用，术语“杂环基”或“杂环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环原子，其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即“杂环烷基”)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团，其任选地被1或多个(诸如1至3个)适合的取代基取代。例如，如本文中所使用，术语“3-10元杂环基”是具有2-9个(如2、3、4、5、6、7、8或9个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和杂环基。杂环基或杂环的实例包括但不限于：环氧乙烷基、氮丙啶基、氮杂环丁基(azetidinyl)、氧杂环丁基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。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.
如本文中所使用，术语“芳基”或“芳环”指具有共轭π电子***的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C 6-14芳基”或“C 6-14芳环”指含有6至14个碳原子的芳族基团，诸如苯基(环)或萘基(环)。芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。 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.).
如本文中所使用，术语“杂芳基”或“杂芳环”指含有至少一个选自N、O和S的杂原子的单环、双环或三环芳族环系，其优选具有5、6、8、9、10、11、12、13或14个环原子，特别是含有1或2或3或4或5或6或9或10个碳原子，并且，另外在每一种情况下可为苯并稠合的。例如，杂芳基或杂芳环可选自噻吩基(环)、呋喃基(环)、吡咯基(环)、噁唑基(环)、噻唑基(环)、咪唑基(环)、吡唑基(环)、异噁唑基(环)、异噻唑基(环)、噁二唑基(环)、***基(环)、噻二唑基(环)等，以及它们的苯并衍生物；或吡啶基(环)、哒嗪基(环)、嘧啶基(环)、吡嗪基(环)、三嗪基(环)等，以及它们的苯并衍生物。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.
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。The term "halo" or "halogen" group, as used herein, is defined to include F, Cl, Br or I.
如本文中所使用，术语“含氮杂环”指饱和或部分不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C(＝O)、S、S(＝O)和S(＝O) 2的环成员，其通过所述含氮杂环中的氮原子以及任一其余环原子与分子的其余部分连接，所述含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接。含氮杂环的实例包括但不限于：氮丙啶环、氮杂环丁烷环、吡咯烷环、咪唑烷环、噁唑烷环、噻唑烷环、吡唑烷环、吡咯啉环、哌啶环或哌嗪环。 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.
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合 物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。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.
如果取代基被描述为“任选地...被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。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.
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。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.
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。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.
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。Unless otherwise indicated, a point of attachment of a substituent, as used herein, may come from any suitable position of the substituent.
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。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.
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘( 2H)、氚( 3H))；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。 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).
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。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.
本文中可使用实线
Figure PCTCN2019071063-appb-000002
实楔形
Figure PCTCN2019071063-appb-000003
或虚楔形
Figure PCTCN2019071063-appb-000004
描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。 Solid lines can be used in this article
Figure PCTCN2019071063-appb-000002
Solid wedge
Figure PCTCN2019071063-appb-000003
Virtual wedge
Figure PCTCN2019071063-appb-000004
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).
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。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.
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。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.
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。The pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括盐酸盐、乙酸盐、天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、葡庚糖酸盐、葡糖酸盐、硝酸盐、乳清酸盐、棕榈酸盐及其它类似的盐。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.
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、镁盐及其它类似的盐。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.
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts：Properties，Selection，and Use”(Wiley-VCH，2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。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.
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。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.
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合 物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。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.
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和问氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist，Comprehensive Organic Synthesis，vol.7，pp 748-750；A.R.Katritzky和A.J.Boulton，Eds.，Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry，vol.22，pp 390-392，A.R.Katritzky和A.J.Boulton，Eds.，Academic Press。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.
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。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.
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier，1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。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.
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene&P.G.M.Wuts，Protective Groups in Organic Synthesis，John Wiley&Sons，1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。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.
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.
化合物Compound
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(I)的结构：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):
Figure PCTCN2019071063-appb-000005
Figure PCTCN2019071063-appb-000005
其中：among them:
R 1选自H、卤素、-OR h、氰基、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-COOR h、-CON(R h) 2、-SO 3H、-S(＝O) gR h、-O-C(＝O)-(C 1-6烷基)、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-N(R h) 2、3-10元杂环基、C 6-14芳基和5-14元杂芳基； 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;
R 2在每次出现时各自独立地选自H、卤素、-OR h、氰基、硝基、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、C 2-5烯基、-COOR h、-CON(R h) 2、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、-N(R h) 2和3-10元杂环基； 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和R 10b在每次出现时各自独立地选自H、卤素、-OR h、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、氰基、-COOR h、-CON(R h) 2、C 1-6烷基、 C 3-6环烷基、C 2-5烯基、-N(R h) 2和3-10元杂环基；条件是当R 6a和R 6b之一为-OH时，另一者不是H； 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和R 5b各自独立地选自H、卤素、-OR h、-C(＝O)R h、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-C 1-6亚烷基-OR h、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)和3-10元杂环基；或者，R 5a与R 5b连同其所连接的氮原子共同形成5-10元含氮杂环； 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选自直接键、CR 11aR 11b、C(＝O)、O、NR 11a和S(＝O) g； W is selected from direct bonds, CR 11a R 11b , C(=O), O, NR 11a and S(=O) g ;
R 11a和R 11b各自独立地选自H、卤素、-OR h、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、氰基、-COOR h、-CON(R h) 2、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-N(R h) 2和3-10元杂环基； 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选自C 6-14芳环和5-14元杂芳环； A is selected from the group consisting of a C 6-14 aromatic ring and a 5-14 membered heteroaryl ring;
R 12在每次出现时各自独立地选自H、卤素、-OR h、氰基、硝基、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、C 2-5烯基、-COOR h、-CON(R h) 2、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、-N(R h) 2和3-10元杂环基； 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;
上述烷基、亚烷基、环烷基、烯基、含氮杂环、杂环基、芳基、芳环、杂芳基和杂芳环各自任选地被一个或多个各自独立地选自卤素、＝O、-R h、-OR h、-COOR h、-CON(R h) 2、-S(＝O) gR h和-N(R h) 2(优选F、Cl、＝O、C 1-4烷基、C 3-6环烷基、-CF 3、-CHF 2、-OH、-OCF 3、-OCHF 2、-O-(C 1-6烷基)、-COOH、-CONH 2、-NH 2、-NH(C 1-4烷基)和-N(C 1-4烷基) 2)的取代基取代； 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在每次出现时各自独立地选自H、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、3-10元杂环基、C 6-10芳基和5-10元杂芳基，且多个R h彼此之间可以相同或不同； 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在每次出现时各自独立地表示0、1或2的整数；g each independently represents an integer of 0, 1 or 2 at each occurrence;
m在每次出现时各自独立地表示1-10中的任意整数，包括端值；并且m each independently represents any integer in 1-10, including the end value;
n、p和q各自独立地为0、1、2、3或4的整数。n, p and q are each independently an integer of 0, 1, 2, 3 or 4.
在优选的实施方案中，R 1选自H、卤素、-OH、-O-(C 1-4烷基)、氰基、C 1-4烷基、C 3-6环烷基、-COOH、-CONH 2、-O-C(＝O)-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-SH、-S(＝O) g-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2和3-6元杂环基，其中所述烷基、亚烷基、环烷基和杂环基各自任选地被一个或多个各自独立地选自F、Cl、C 1-4烷基、C 3-6环烷基、-CF 3、-CHF 2、-OH、-OCF 3、-OCHF 2、-O-(C 1-6烷基)、-COOH、-CONH 2、-NH 2、-NH(C 1-4烷基)和-N(C 1-4烷基) 2的取代基取代；g为0、1或2的整数；并且m为1、2、3或4的整数。在更优选的实施方案中，R 1选自H、F、Cl、氰基、C 1-4烷基、C 3-6环烷基、-CF 3、-CHF 2、-OH、-OCH 3、-OCF 3、-OCHF 2、-O-C(＝O)-(C 1-4烷基)、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-COOH和-CONH 2；其中，m为1或2的整数。在特别优选的实施方案中，R 1选自H、F、Cl、-CF 3、-CH 3、-CH 2CH 3、-CH(CH 3) 2、-OH、-OCH 3、-OCF 3、-OC(＝O)CH 3、-CH 2-OCH 3和-O-CH 2CH 2-O-CH 3。 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 .
在优选的实施方案中，R 2在每次出现时各自独立地选自H、卤素、-CF 3、-CHF 2、-OH、-OCF 3、-OCHF 2、-O(C 1-4烷基)、氰基、C 1-4烷基、C 3-6环烷基、-COOH、-CONH 2、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2和3-6元杂环基；其中，m为1、2、3或4的整数。在更优选的实施方案中，R 2在每次出现时各自独立地选自H、F、Cl、-OH、-CF 3、-OCF 3、-OCH 3、氰基、C 1-4烷基、C 3-6环烷基、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)和-N(C 1-4烷基) 2；其中m为1、2、3或4的整数。在特别优选的实施方案中，R 2在每次出现时各自独立地选自H、F、Cl、-OH、-CF 3、-OCF 3、-OCH 3、C 1-3烷基、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(C 1-3亚烷基)-O-(C 1-3烷基)和-N(C 1-3烷基) 2。 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 .
在优选的实施方案中，R 3a、R 3b、R 4、R 6a、R 6b、R 7a、R 7b、R 8、R 9a、R 9b、R 10a和R 10b在每次出现时各自独立地选自H、F、Cl、-OH、-O-(C 1-4烷基)、-O-(卤代C 1-4烷基)、氰基、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-COOH、-CONH 2、C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、-S(＝O) g-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2和3-6元杂环基；其中，g为0、1或2的整数；并且m为1、2、3或4的整数。 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.
在更优选的实施方案中，R 3a、R 3b、R 4、R 6a、R 6b、R 7a、R 7b、R 8、R 9a、R 9b、R 10a和R 10b在每次出现时各自独立地选自H、F、Cl、氰基、C 1-4烷基(优选C 1-3烷基，更优选甲基)、C 3-6环烷基、-CF 3、-CHF 2、-OH、-OCF 3、-OCHF 2、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)(优选-O-(C 1-4亚烷基)-O-(C 1-4烷基))、-NH 2、-NH(C 1-4烷基)(优选-NH(C 1-3烷基))、-N(C 1-4烷基) 2(优选-N(C 1-3烷基) 2)、-COOH和-CONH 2；其中，m为1或2的整数。 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.
在优选的实施方案中，R 5a和R 5b各自独立地选自H、F、Cl、-OH、-O-(C 1- 4烷基)(优选-O-(C 1-3烷基))、C 1-6烷基(优选C 1-4烷基，更优选甲基或乙基)、C 3-6环烷基、-C 1-4亚烷基-OH(优选-C 1-3亚烷基-OH)、C 2-5烯基(优选乙烯基、丙烯基或烯丙基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)和3-6元杂环基；或者，R 5a与R 5b连同其所连接的氮原子共同形成5-7元含氮杂环(优选5-6元含氮杂环)；其中，m为 1或2的整数；并且所述烷基、亚烷基、环烷基、烯基、含氮杂环和杂环基各自任选地被一个或多个各自独立地选自F、Cl、-CF 3、-OH、＝O、-OCF 3、C 1-3烷基、-O-C 1-4烷基和-N(C 1-3烷基) 2的取代基取代。 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 .
在优选的实施方案中，R 11a和R 11b各自独立地选自H、F、Cl、-OH、-O-(C 1-4烷基)、氰基、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-COOH、-CONH 2、C 1-4烷基、C 3-6环烷基、-S(＝O) g-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2和3-6元杂环基，其中所述烷基、亚烷基、环烷基和杂环基各自任选地被一个或多个各自独立地选自F、Cl、-CF 3、-CHF 2、-OH、-OCF 3、-OCHF 2、C 1-4烷基、C 3-6环烷基、-O-C 1-4烷基、-COOH、-CONH 2、-S(＝O) g-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)和-N(C 1-3烷基) 2的取代基取代；g为0、1或2的整数；m为1、2、3或4的整数。在更优选的实施方案中，R 11a和R 11b各自独立地选自H、F、Cl、氰基、C 1-4烷基(优选C 1-3烷基，更优选甲基或乙基)、C 3-6环烷基、-CF 3、-CHF 2、-OH、-OCF 3、-OCHF 2、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)(优选-O-(C 1-3亚烷基)-O-(C 1-3烷基))、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-COOH和-CONH 2；m为1或2的整数。 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.
在优选的实施方案中，W选自直接键、CH 2、CHF、CF 2、CHOH、CHCH 3、C(CH 3) 2、C(＝O)、NCH 3、NCH 2CH 3、O、S、S(＝O)和S(＝O) 2；优选地，W选自直接键、CH 2、CHF、CF 2、CHOH、CHCH 3、C(CH 3) 2、C(＝O)、NCH 3、O、S、S(＝O)和S(＝O) 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 ;
优选地，W选自直接键、CH 2、CHF、CF 2、CHOH、CHCH 3、C(CH 3) 2、C(＝O)、NCH 3、NCH 2CH 3、O、S和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 .
在优选的实施方案中，A选自苯环和5-6元杂芳环。在更优选的实施方案中，A为苯环、噻吩环、吡嗪环、嘧啶环或吡啶环。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.
在优选的实施方案中，R 12在每次出现时各自独立地选自H、卤素、-CF 3、-CHF 2、-OH、-O-(C 1-4烷基)、-OCF 3、-OCHF 2、氰基、C 1-4烷基、C 3-6环烷基、-COOH、-CONH 2、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2和3-6元杂环基；并且m为1、2、3或4的整数。在更优选的实施方案中，R 12在每次出现时各自独立地选自H、F、Cl、Br、-OH、-O-(C 1-3烷基)、-CF 3、-OCF 3、氰基、C 1-3烷基、C 3-6环烷基、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-3亚烷基)-O] m-(C 1-3烷基)、-NH 2、-NH(C 1-3烷基)和-N(C 1-3烷基) 2；更优选地，R 12在每次出现时各自独立地选自H、F、Cl、-OH、-O-(C 1-3烷基)、-CF 3、-OCF 3、氰基、C 1-3烷基、C 3-6环烷基、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-3亚烷基)-O] m-(C 1-3烷基)、-NH 2、-NH(C 1-3烷基)和-N(C 1-3烷基) 2；并且m为1或2的整数。在特别优选的实施方案中，R 12在每次出现时各自独立地选自H、F、Cl、Br、-OH、-CF 3、-OCF 3、氰基、-CH 3、-CH 2CH 3、-CH(CH 3) 2、-OCH 3、-O-CH(CH 3) 2、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(C 1-3亚烷基)-O-(C 1-3烷基)和-N(C 1-3烷基) 2；更优选地，R 12在每次出现时各自独立地选自H、F、Cl、-OH、-CF 3、-OCF 3、氰基、-CH 3、-CH 2CH 3、-CH(CH 3) 2、-OCH 3、-O-CH(CH 3) 2、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(C 1-3亚烷基)-O-(C 1-3烷基)和-N(C 1-3烷基) 2；优选地，R 12在每次出现时各自独立地选自H、F、Br、Cl、-OH、氰基、-CH 3和-OCH 3。 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 .
在优选的实施方案中，n为0、1、2或3的整数。在更优选的实施方案中，n为0、1或2的整数。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.
在优选的实施方案中，p为0、1、2或3的整数。在更优选的实施方案中，p为0或1。In a preferred embodiment, p is an integer of 0, 1, 2 or 3. In a more preferred embodiment, p is 0 or 1.
在优选的实施方案中，q为0、1、2或3的整数。在更优选的实施方案中，q为0、1或2。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.
在优选的实施方案中，本发明的化合物具有式(II)的结构：In a preferred embodiment, the compounds of the invention have the structure of formula (II):
Figure PCTCN2019071063-appb-000006
Figure PCTCN2019071063-appb-000006
其中：among them:
n为0、1或2的整数；并且n is an integer of 0, 1, or 2;
其余各基团如上文所定义。The remaining groups are as defined above.
在更优选的实施方案中，本发明的化合物具有式(II’)结构：In a more preferred embodiment, the compound of the invention has the structure of formula (II'):
Figure PCTCN2019071063-appb-000007
Figure PCTCN2019071063-appb-000007
其中：among them:
n为0、1或2的整数；并且n is an integer of 0, 1, or 2;
其余各基团如上文所定义。The remaining groups are as defined above.
本发明涵盖对各个实施方案进行任意组合所得的化合物。The present invention encompasses compounds obtained by any combination of the various embodiments.
在优选的实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：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:
Figure PCTCN2019071063-appb-000008
Figure PCTCN2019071063-appb-000008
Figure PCTCN2019071063-appb-000009
Figure PCTCN2019071063-appb-000009
Figure PCTCN2019071063-appb-000010
Figure PCTCN2019071063-appb-000010
Figure PCTCN2019071063-appb-000011
Figure PCTCN2019071063-appb-000011
药物组合物和药盒Pharmaceutical compositions and kits
在一些实施方案中，本发明提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。。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. .
本文中所述药学上可接受的载体是指生产药品和调配处方时使用的赋形剂和附加剂，是指除活性成分外，在安全性方面已进行了合理的评估，并且包含在药物制剂中的物质。药学上可接受的载体可用于赋型、充当载体、提高稳定性，还可具有增溶、助溶、缓控释等重要功能，是可能会影响到药品的质量、安全性和有效性的重要成分。根据其来源可分为天然物、半合成物和全合成物。根据其作用与用途可分为：溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、湿润剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏着剂、抗氧剂、螯合剂、渗透促进剂、pH调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂等；根据其给药途径可分为口服、注射、黏膜、经皮或局部给药、经鼻或口腔吸入给药和眼部给药等。具体的药学上可接受的载体包括水、乳糖、葡萄糖、果糖、蔗糖、山梨糖醇、甘露醇、聚乙二醇、丙二醇、淀粉、橡胶、凝胶、藻酸盐、硅酸钙、磷酸钙、纤维素、水性糖浆、甲基纤维素、聚乙烯基吡咯烷酮、对羟基苯并山梨酸烷基酯、滑石、硬脂酸镁、硬脂酸、甘油、芝麻油、橄榄油、大豆油等。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.
所述药物组合物可以以任意形式施用，只要其实现预防、减轻、防止或者治愈人类或动物患者的症状。例如，可根据给药途径制成各种适宜的剂型。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.
当口服用药时，所述药物组合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊剂、颗粒剂、丸剂、糖浆剂、口服溶液剂、口服混悬剂和口服乳剂等。其中，片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。口服混悬剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。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.
当经皮或局部施用时，所述药物组合物可制成适当的软膏、洗剂或搽剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或搽剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。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.
所述药物组合物还可以注射剂形式用药，包括注射液、注射用无菌粉末与注射用浓溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。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.
在另一个实施方案中，本发明提供进一步包含另外的治疗剂的药物组合物，所述另外的治疗剂选自但不限于：非甾体类抗感染药、其它阿片类激动剂、钙离子通道阻断剂、抗抑郁药物，或其组合。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.
本发明亦包括一种制品。本文所用的制品意图包括但不限于药盒和包装。本发明的制品包含：(a)第一容器；(b)位于第一容器中的药物组合物，其中所述组合物包含：第一治疗剂，包括：本发明的化合物或其药学上可接受盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、或者它们的混合物；和(c)包装说明书，其说明所述药物组合物可用于治疗疼痛病症(如前文所定义)。在另一些实施方案中，所述包装说明书说明所述药物组合物可与第二治疗剂联用(如前文所定义)以治疗疼痛病症。所述制品可进一步包含：(d)第二容器，其中组分(a)和(b)位于所述第二容器内，而组分(c)位于所述第二容器之内或之外。位于第一和第二容器内意味着各容器将物品保留在其边界之内。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.
所述第一容器为用于容纳药物组合物的容器。此容器可用于制备、储存、运输和/或独立/批量销售。第一容器意图涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如用于乳膏制品)，或者用于制备、容纳、储存或分配药物产品的任何其它容器。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.
所述第二容器为用于容纳所述第一容器和任选存在的包装说明书的容器。所述第二容器的实例包括但不限于盒(例如纸盒或塑料盒)、箱、纸箱、袋(例如纸袋或塑料袋)、小袋和粗布袋。所述包装说明书可经由扎带、胶水、U形钉或别的粘附方式物理粘附于所述第一容器的外部，或者其可放在所述第二容器的内部，而无需与所述第一容器粘附的任何物理工具。或者，所述包装说明书位于所述第二容器的外面。当位于所述第二容器的外面时，优选的是所述包装说明书经由扎带、胶水、U形钉或别的粘附方式物理粘附。或者，其可邻接或接触所述第二容器的外部，而无需物理粘附。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.
所述包装说明书为商标、标签、标示等，其列举了与位于所述第一容器内的药物组合物相关的信息。所列出的信息通常由管辖待销售所述制品的区域的管理机构(例如美国食品与药品管理局)决定。优选所述包装说明书具体列出了所述药物组合物获准用于的适应症。所述包装说明书可由任何材料制成，可从所述材料上读取包含于其中或其上的信息。优选所述包装说明书为可印刷材料(例如纸、塑料、卡纸板、箔、胶粘纸或塑料等)，其上可形成(例如印刷或施涂)所需信息。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).
治疗方法和用途Treatment and use
在一些实施方案中，本发明提供本发明的化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、或者它们的混合物或者本发明的药物组合物在制备用于预防或治疗μ阿片受体相关疾病的药物中的用途。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.
在另一些实施方案中，本发明提供本发明的化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、或者它们的混合物或者本发明的药物组合物，其用于预防或治疗μ阿片受体相关疾病。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.
在另一些实施方案中，本发明提供预防或治疗μ阿片受体相关疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、或者它们的混合物，或者本发明的药物组合物。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.
根据本发明的一个实施方案，可使用本发明的化合物进行预防或治疗的μ阿片受体相关疾病包括但不限于疼痛类疾病，所述疾病进一步优选为中度到重度的疼痛类疾病。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.
如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的 化合物的量。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.
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。可以通过临床领域的普通技术人员容易地确定所述药物组合物的施用量和施用方案。本发明的组合物或化合物一般为每天两次至每3天给药1次，优选每天给药1次，并且给药总量0.01～1000mg/次。一般地，治疗的剂量是变化的，这取决于所考虑的事项，例如：待治疗患者的年龄、性别和一般健康状况；治疗的频率和想要的效果的性质；组织损伤的程度；症状的持续时间；以及可由各个医师调整的其它变量。可以以一次或多次施用想要的剂量，以获得想要的结果。也可以以单位剂量形式提供根据本发明的药物组合物。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.
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。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.
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。"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.).
发明的有益效果Advantageous effects of the invention
本发明发现了一类新型高活性的μ阿片受体激动剂，能够实现下述至少一种技术效果：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)具有μ阿片受体高激动活性；(1) having a high agonistic activity of μ opioid receptor;
(2)具有μ阿片受体选择性；(2) having μ opioid receptor selectivity;
(3)较弱的对β抑制蛋白的募集作用；(3) weaker recruitment of β-inhibitory protein;
(4)更好的物理化学性质(例如溶解度、物理和/或化学稳定性)；(4) better physicochemical properties (eg solubility, physical and/or chemical stability);
(5)改善的药物代谢动力学性质(例如改善的生物利用度、合适的半衰期和作用持续时间)；以及(5) improved pharmacokinetic properties (eg improved bioavailability, appropriate half-life and duration of action);
(6)改善的安全性(较低的毒性和/或较少的副作用，较宽的治疗窗)等。(6) Improved safety (lower toxicity and/or fewer side effects, wider treatment window) and the like.
具体实施方式Detailed ways
以下列举实施例和实验例，进而详细地说明本发明，但它们不限制本发明的范围，另外在不脱离本发明的范围下可进行变化。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.
MS的测定使用Agilent(ESI)质谱仪，生产商：Agilent，型号：Agilent 6120B。The MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
制备高效液相色谱法使用岛津LC-8A制备液相色谱仪(YMC，ODS，250×20mm色谱柱)。Preparative high performance liquid chromatography using Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 x 20 mm column).
薄层色谱法纯化采用的是烟台产GF 254(0.4～0.5nm)硅胶板。Thin layer chromatography was performed using a GF 254 (0.4-0.5 nm) silica gel plate from Yantai.
反应的监测采用薄层色谱法(TLC)或LC-MS，使用的展开剂体系包括但不限于：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系和石油醚和乙酸乙酯体系，根据化合物的极性不同调节溶剂的体积比，或者加入三乙胺等进行调节。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.
柱色谱法一般使用青岛海洋200～300目硅胶为固定相。洗脱剂体系包括但不限于二氯甲烷和甲醇体系以及正己烷和乙酸乙酯体系，根据化合物的极性不同调节溶剂的体积比，也可以加入少量的三乙胺等进行调节。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.
如实施例中无特殊说明，则反应的温度为室温(20℃～30℃)。The temperature of the reaction is room temperature (20 ° C to 30 ° C) unless otherwise specified in the examples.
实施例中所使用的试剂购自Acros Organics、Aldrich Chemical Company或者特伯化学等公司。The reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.
如本文中所使用的缩写具有以下含义：Abbreviations as used herein have the following meanings:
Figure PCTCN2019071063-appb-000012
Figure PCTCN2019071063-appb-000012
Figure PCTCN2019071063-appb-000013
Figure PCTCN2019071063-appb-000013
本发明的化合物可以有机合成领域的技术人员已知的多种方式制备。本发明的化合物可使用下文描述的方法以及合成有机化学领域中已知的合成方法或本领域技术人员所了解的其变化形式来合成。优选方法包括(但不限于)下文所述那些。反应可在适于所使用的试剂和材料且适合于实现转化的溶剂或溶剂混合物中进行。有机合成领域的技术人员应了解，分子上存在的官能团应与所提出的转化一致。这有时将需要以下判断：修改合成步骤的顺序或相对于一种方法路线选择另一特定方法路线以获得本发明的所需化合物。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.
还应认识到，本领域中设计任何合成途径的另一主要考虑因素是正确选择用于保护本发明中所述化合物中存在的反应性官能团的保护基团。向受过训练的相关人士描述许多替代方案的权威说明为Greene等人(Protective Groups in Organic Synthesis，第4版，Wiley-Interscience(2006))。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)).
除非另外说明，以下路线中化合物的取代基如上文所定义。本领域技术人员会明白，根据期望获得的产物结构，可省略以下路线中的一个或多个步骤。本领域技术人员也可根据需要适当地调整反应步骤的顺序。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.
路线1Route 1
本发明提供根据路线1所描述步骤合成式(I)化合物的方法。The present invention provides a process for the synthesis of a compound of formula (I) according to the procedure described in Scheme 1.
在路线1中，R 1P与R 1相同，或者R 1P表示被保护基保护的R 1；PG 1和PG 2各自独立地表示羧基保护基，如C 1-6烷基(优选甲基或乙基)、取代的硅烷基和苄基等；R 5ap与R 5a相同，或者R 5ap为氨基保护基(优选Boc)；R 5bp与R 5b相同，或者R 5bp为氨基保护基(优选Boc)。 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).
步骤一：在一些实施方案中，本步骤包括在碱的存在下烷基化试剂与化合物S-1反应生成化合物IM-1。在一些实施例中，所述碱为碳酸钾。在一些实施方案中，所述烷基化试剂为烷基卤化物。在一些实施方案中，本步骤包括醛和还原试剂与化合物S-1进行还原胺化反应生成化合物IM-1。在一些实施方案中，所述醛为甲醛。在一些实施方案中，所述还原试剂为醋酸硼氢化钠。在一些实施方案中，本步骤包括在碱的存在下酰化试剂与化合物S-1反应生成化合物IM-1。在一些实施方案中，所述碱为三乙胺。在一些实施方案中，所述酰化试剂为(Boc) 2O。 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.
步骤二：在一些实施方案中，本步骤包括还原试剂处理化合物IM-1生成化合物IM-2。在一些实施方案中，所述还原试剂为二异丁基氢化铝。在一些实施方案中，本步骤包括金属试剂与化合物IM-1反应生成化合物IM-2。在一些实施方案中，所述金属试剂为Grignard试剂。在一些实施方案中，本步骤包括IM-1经过还原试剂处理和氧化试剂处理生成化合物IM-2。在一些实施方案中，所述还原试剂为四氢铝锂。在一些实施方案中，所述氧化试剂为IBX。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.
步骤三：在一些实施方案中，本步骤包括磷叶立德试剂与化合物IM-2进行Wittig反应生成化合物IM-3。在一些实施方案中，所述磷叶立德试剂为乙氧甲酰基亚甲基三苯基膦。在一些实施方案中，本步骤包括在碱的存在下酯与化合物IM-2进行Adol反应以生成化合物IM-3。在一些实施方案中，所述碱为氢化钠。在一些实施方案中，所述酯为乙酸乙酯。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.
步骤四：在一些实施方案中，本步骤包括化合物IM-3进行金属催化的氢化反应生成化合物IM-4。在一些实施方案中，所述金属为Pd/C。在一些实施方案中，所述氢化试剂为氢气。在一些实施方案中，本步骤包括加成试剂与IM-3进行Michael加成反应生成化合物IM-4。在一些实施方案中，所述加成试剂为烷基胺。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.
步骤五：在一些实施方案中，本步骤包括用碱和烷基化试剂处理化合物IM-4以生成化合物IM-5。在一些实施方案中，所述碱为碳酸钾。在一些实施方案中，所述烷基化试剂为烷基卤化物。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.
步骤六：在一些实施方案中，本步骤包括IM-5经过脱保护反应后在碱的存在下与烷基化试剂反应生成化合物IM-6。在一些实施方案中，所述碱为碳酸钾。在一些实施方案中，所述烷基化试剂为烷基卤化物。在一些实施方案中，本步骤包括IM-5经过脱保护反应后与醛和还原试剂进行还原胺化反应生成化合物IM-6。在一些实施方案中，所述醛为甲醛。在一些实施方案中，所述还原试剂为醋酸硼氢化钠。在一些实施方案中，本步骤包括IM-5经过脱保护反应后在碱的存在下与酰化试剂反应生成化合物IM-6。在一些实施方案中，所述碱为三乙胺。在一些实施方案中，所述酰化试剂为乙酰氯。当R 5ap与R 5a相同且R 5bp与R 5b相同时，本步骤省略。 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.
步骤七：在一些实施方案中，本步骤包括用碱处理化合物IM-6进行脱保护反应生成化合物IM-7。在一些实施方案中，所述碱为氢氧化钠。在一些实施方案中，所述反应在溶剂(优选为甲醇)中进行。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.
步骤八：在一些实施方案中，本步骤包括化合物IM-7在缩合试剂的存在下进行缩合反应，然后经过脱保护反应生成式(I)化合物。在一些实施方案中，所述缩合试剂为HATU。当R 1P与R 1相同时，未进行脱保护反应。 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.
本领域技术人员会明白，可根据需要调整上述步骤的顺序以及省略其中一个或多个反应步骤。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.
Figure PCTCN2019071063-appb-000014
Figure PCTCN2019071063-appb-000014
本发明中式(II)和式(II’)的化合物等均可以与上述路线中类似的方法合成。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.
实施例Example
实施例A：(R)-4-(二甲基氨基)-5-(4-羟基苯基)戊酸(SM-1)的制备Example A: Preparation of (R)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanoic acid (SM-1)
Figure PCTCN2019071063-appb-000015
Figure PCTCN2019071063-appb-000015
第一步：(S)-2-((叔丁氧羰基)氨基)-3-(4-羟基苯基)丙酸甲酯(SM-1-2)的制备First step: Preparation of (S)-2-((tert-Butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoic acid methyl ester (SM-1-2)
室温下，将酪氨酸甲酯(SM-1-1)(10.00g，51.2mmol)溶于二氯甲烷(250mL)，分别加入三乙胺(14.20mL，102.4mmol)和(Boc) 2O(12.93mL，56.3mmol)。在室温下，将反应物搅拌4小时。将反应物浓缩，将粗产品经硅胶柱色谱法纯化得化合物(SM-1-2)(13.20g，收率87％)。 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%).
第二步：(S)-3-(4-(苄氧基)苯基)-2-((叔丁氧羰基)氨基)丙酸甲酯(SM-1-3)的制备Second step: Preparation of (S)-3-(4-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid methyl ester (SM-1-3)
室温下，将化合物(SM-1-2)(13.00g，44mmol)溶于DMF(100mL)，分别加入K 2CO 3(12.16g，88.0mmol)和溴化苄(10.45mL，88.0mmol)。将反应物在室温下搅拌4小时。将反应物浓缩，将粗产品经硅胶柱色谱法纯化得化合物(SM-1-3)(13.00g，收率77％)。 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%).
第三步：(S)-(1-(4-(苄氧基)苯基)-3-羟基丙-2-基)氨基甲酸叔丁酯(SM-1-4)的制备Third step: Preparation of (S)-(1-(4-(benzyloxy)phenyl)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester (SM-1-4)
0℃下，将化合物(SM-1-3)(12.00g，31.13mmol)溶于四氢呋喃(150mL)中，将四氢铝锂(1.77g，46.70mmol)分批加入，室温反应5小时。加入少量水(1.80mL)和15％的氢氧化钠溶液(1.80mL)，然后再次加入水(6.00mL)，将反应物抽滤，浓缩，将粗产品经硅胶柱色谱法纯化得化合物(SM-1-4)(8.80g，收率79％)。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%).
第四步：(S)-(1-(4-(苄氧基)苯基)-3-氧代丙-2-基)氨基甲酸叔丁酯(SM-1-5)的制备Fourth step: Preparation of (S)-(1-(4-(benzyloxy)phenyl)-3-oxopropan-2-yl)carbamic acid tert-butyl ester (SM-1-5)
在室温下，将化合物(SM-1-4)(7.0g，19.58mmol)溶解于乙酸乙酯(80mL)，将IBX(6.58g，23.50mmol)加入。将反应物加热回流，反应4小时。将反应物抽滤，浓缩得到粗产品(SM-1-5)(6.96g，收率94％)。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.
第五步：(S)-5-(4-(苄氧基)苯基)-4-((叔丁氧羰基)氨基)戊-2-烯酸乙酯(SM-1-6)的制备Step 5: Preparation of (S)-5-(4-(benzyloxy)phenyl)-4-((tert-butoxycarbonyl)amino)pent-2-enoate (SM-1-6)
在室温下，将化合物(SM-1-5)(6.60g，18.57mmol)溶解于二氯甲烷(70.0mL)，加入乙氧甲酰基亚甲基三苯基膦(6.46g，18.57mmol)。于室温下反应4小时。将反应物浓缩，将粗产品经硅胶柱色谱法纯化得化合物(SM-1-6)(7.90g，收率89％)。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%).
第六步：(R)-4-((叔丁氧羰基)氨基)-5-(4-羟基苯基)戊酸乙酯(SM-1-7)的制备Step 6: Preparation of (R)-4-((tert-Butoxycarbonyl)amino)-5-(4-hydroxyphenyl)pentanoic acid ethyl ester (SM-1-7)
在室温下，将化合物(SM-1-6)(5.00g，11.75mmol)溶于乙醇(100.0mL)中，加入钯碳(含量10％)(1.00g)，用氢气置换。于常压氢气氛围下，在50℃反应10小时。将反应物抽滤，浓缩，直接进行下步反应。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.
第七步：(R)-4-氨基-5-(4-羟基苯基)戊酸乙酯(SM-1-8)的制备Step 7: Preparation of (R)-4-amino-5-(4-hydroxyphenyl)pentanoic acid ethyl ester (SM-1-8)
在室温下，将化合物(SM-1-7)(2.00g，5.93mmol)溶于氯化氢乙酸乙酯溶液(2M)(10.0mL)中，室温反应5小时。将反应体系浓缩，得到标题化合物(SM-1-8)(1.60g，收率95％)。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%).
第八步：(R)-4-(二甲基氨基)-5-(4-羟基苯基)戊酸乙酯(SM-1-9)的制备Step 8: Preparation of (R)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanoic acid ethyl ester (SM-1-9)
在室温下，将化合物(SM-1-8)(1.60g，5.86mmol)溶于乙腈(20.0mL)，加入甲醛水溶液(10.0mL)，然后加入醋酸硼氢化钠(5.09g，24.0mmol)。调节反应液pH为碱性，用乙酸乙酯萃取，浓缩，将粗产品经硅胶柱色谱法纯化得化合物(SM-1-9)(1.33g，收率85％)。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%).
第九步：(R)-4-(二甲基氨基)-5-(4-羟基苯基)戊酸(SM-1)的制备Step 9: Preparation of (R)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanoic acid (SM-1)
在室温下，将化合物(SM-1-9)(1.33g，5.0mmol)溶于甲醇(10.0mL)，加入NaOH(1M)(5mL)，于室温搅拌8小时。调节反应液pH为酸性，将反应体系冻干，得到标题化合物(SM-1)(1.0g，收率84％)，直接进行下步反应。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%).
实施例1：(4R)-N-(2，3-二氢-1H-茚-1-基)-4-(二甲基氨基)-5-(4-羟基苯基)戊酰胺(TM1)的制备Example 1: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanamide (TM1) Preparation
Figure PCTCN2019071063-appb-000016
Figure PCTCN2019071063-appb-000016
在室温下，将化合物(SM-1)(25.0mg，0.10mmol)溶于DMF(2.0mL)，加入二异丙基乙基胺(33.0μL，0.20mmol)，然后加入2，3-二氢-1H-茚-1-胺(SM-2)(15.0mg，0.11mmol)和HATU(76.0mg，0.20mmol)，于室温下反应3小时，经制备HPLC纯化得到标题化合物(TM1)(8mg，收率20％)。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] + MS m/z (ESI): 353.3 [M+H] +
1H 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＝8.4，2.9Hz，2H)，6.66(dd，J＝8.4，2.3Hz，2H)，5.22(q，J＝8.0Hz，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). 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).
实施例2：(R)-4-(二甲基氨基)-5-(4-羟基苯基)-N-((S)-1，2，3，4-四氢萘-1-基)戊酰胺(TM2)的制备Example 2: (R)-4-(Dimethylamino)-5-(4-hydroxyphenyl)-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl) Preparation of valeramide (TM2)
Figure PCTCN2019071063-appb-000017
Figure PCTCN2019071063-appb-000017
在室温下，将化合物(SM-1)(25.0mg，0.10mmol)溶于DMF(2mL)，加入(S)-1，2，3，4-四氢萘-1-胺(SM-3)(18.61mg，0.13mmol)，然后加入二异丙基乙基胺(20.90μL，0.12mmol)和HATU(48.10mg，0.12mmol)，于室温反应4小时，经制备HPLC纯化得到标题化合物(TM2)(2mg，收率7％)。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] + MS m/z (ESI): 367.3 [M+H] +
1H 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＝8.0Hz，2H)，6.74(d，J＝8.0Hz，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). 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) ).
实施例3：(R)-4-(二甲基氨基)-N-((1R，2S)-2-羟基-2，3-二氢-1H-茚-1-基)-5-(4-羟基苯基)戊酰胺(TM3)的制备Example 3: (R)-4-(Dimethylamino)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4 Of -hydroxyphenyl)pentanamide (TM3)
Figure PCTCN2019071063-appb-000018
Figure PCTCN2019071063-appb-000018
在室温下，将化合物(SM-1)(50.0mg，0.21mmol)溶于DMF(2mL)，加入(1R，2S)-1-氨基-2，3-二氢-1H-茚-2-醇(SM-4)(31.44mg，0.21mmol)，再加入三乙胺(58.58μL，0.42mmol)和HATU(96.10mg，0.25mmol)，于室温反应4小时，经制备HPLC纯化得到标题化合物(TM3)(62mg，收率75％)。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] + MS m/z (ESI): 369.3 [M+H] +
1H NMR(400MHz，CD 3OD)δ7.24-7.21(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＝5.2Hz，1H)，4.54-4.51(m，1H)，3.12(dd，J＝16.4，5.2Hz，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). 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).
实施例4：(4R)-N-(2，3-二氢-1H-茚-1-基)-4-(二甲基氨基)-5-苯基戊酰胺(TM10)的制备Example 4: Preparation of (4R)-N-(2,3-dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-phenylpentanamide (TM10)
Figure PCTCN2019071063-appb-000019
Figure PCTCN2019071063-appb-000019
第一步：(S)-2-(二甲基氨基)-3-苯基丙酸甲酯(10-2)的制备First step: Preparation of (S)-methyl 2-(dimethylamino)-3-phenylpropanoate (10-2)
室温下，将(S)-苯丙氨酸甲酯盐酸盐(10-1)(2.16g，10mmol)溶于乙腈(20mL)，加入甲醛水溶液(10mL)和醋酸硼氢化钠(8.69g，41mmol)。室温下反应过夜。将反应体系pH调节至碱性，乙酸乙酯萃取三次，合并有机相，浓缩。粗产品经柱色谱法纯化得标题化合物(10-2)(2.00g，收率96％)。(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
第二步：(S)-2-(二甲基氨基)-3-苯基丙-1-醇(10-3)的制备Second step: Preparation of (S)-2-(dimethylamino)-3-phenylpropan-1-ol (10-3)
室温下，将化合物(10-2)(2.00g，9.65mmol)溶于THF(10mL)，分批加入LiAlH 4(366mg，9.65mmol)。室温下反应3小时后，加水淬灭，抽滤，乙酸乙酯萃取三次，浓缩得到标题化合物(10-3)的粗产品(1.5g，收率86％)。 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
第三步：(S)-2-(二甲基氨基)-3-苯基丙醛(10-4)的制备The third step: preparation of (S)-2-(dimethylamino)-3-phenylpropanal (10-4)
-78℃下，将草酰氯(0.64mL，7.53mmol)加入二氯甲烷(5.0mL)，10min后，将DMSO(1.43mL，20mmol)的二氯甲烷(5.0mL)溶液滴加入反应体系。在-78℃下，搅拌1小时后，将化合物(10-3)(0.9g，5.0mmol)的二氯甲烷(5.0mL)溶液滴加入反应体系。在-78℃下，搅拌1小时后，将三乙胺(1.40mL，10.0mmol)滴加入反应体系。在-78℃下，搅拌1小时后，转移至室温，加水淬灭，乙酸乙酯萃取三次，将有机相合并，浓缩，得到标题化合物(10-4)的粗产品(0.5g，收率56％)，直接进行下步反应。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.
第四步：(S)-4-(二甲基氨基)-5-苯基戊-2-烯酸乙酯(10-5)的制备Fourth step: Preparation of ethyl (S)-4-(dimethylamino)-5-phenylpent-2-enoate (10-5)
室温下，将化合物(10-4)(0.88g，5.0mmol)和乙氧甲酰基亚甲基三苯基膦(1.74g，5.0mmol)溶解于甲苯(10.0mL)。反应于室温下搅拌过夜，浓缩，粗产品经柱色谱法纯化得到标题化合物(10-5)(0.45g，收率36％)。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.
第五步：(R)-4-(二甲基氨基)-5-苯基戊酸乙酯(10-6)的制备Step 5: Preparation of (R)-4-(dimethylamino)-5-phenylpentanoic acid ethyl ester (10-6)
室温下，将化合物(10-5)(0.45g，1.82mmol)溶解于乙酸乙酯(5.0mL)，加入钯/碳(0.22g)。于常压氢气氛围下，在50℃反应10小时。抽滤，浓缩，直接进行下步反应。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.
第六步：(R)-4-(二甲基氨基)-5-苯基戊酸(10-7)的制备Step 6: Preparation of (R)-4-(dimethylamino)-5-phenylpentanoic acid (10-7)
室温下，将化合物(10-6)(0.4g，1.60mmol)溶于MeOH(5.0mL)，加入NaOH水溶液(1N)(1.0mL)。于室温下，反应3小时。调节pH为酸性，将反应体系冻干，得到标题化合物(10-7)(0.3g，收率84％)，直接进行下步反应。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%).
第七步：(4R)-N-(2，3-二氢-1H-茚-1-基)-4-(二甲基氨基)-5-苯基戊酰胺(TM10)的制备Step 7: Preparation of (4R)-N-(2,3-dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-phenylpentanamide (TM10)
室温下，将化合物(10-7)(100mg，0.45mmol)、2，3-二氢-1H-茚-1-胺(SM-2)(60mg，0.45mmol)、HATU(189mg，0.49mmol)和DIEA(0.15mL，0.90mmol)溶于DMF(2.0mL)。于室温下反应3小时，经制备HPLC纯化得到标题化合物(TM10)(28mg，收率90％)。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] + MS m/z (ESI): 337.3 [M+H] +
1H NMR(400MHz，CDCl 3)δ7.36-7.27(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). 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).
实施例5：(4R)-N-(2，3-二氢-1H-茚-1-基)-4-(二甲基氨基)-5-(4-甲氧基苯基)戊酰胺(TM13)的制备Example 5: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-methoxyphenyl)pentanamide ( Preparation of TM13)
Figure PCTCN2019071063-appb-000020
Figure PCTCN2019071063-appb-000020
第一步：(R)-4-((叔丁氧羰基)氨基)-5-(4-甲氧基苯基)戊酸乙酯(13-1)的制备First step: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)amino)-5-(4-methoxyphenyl)pentanoate (13-1)
在室温下，将化合物(SM-1-7)(200.0mg，0.59mmol)溶于DMF(10mL)，依次加入碳酸钾(245mg，1.78mol)和碘甲烷(37μL，0.59mmol)，加完于室温反应过夜。加饱和食盐水稀释后，用EA萃取三次，合并有机相后用饱和食盐水再洗涤三次，无水硫酸钠干燥，过滤，浓缩，硅胶薄层色谱法分离，得到标题化合物(13-1)(177mg，收率85％)。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%).
第二步至第四步：(R)-4-(二甲基氨基)-5-(4-甲氧基苯基)戊酸(13-4)的制备Steps 2 to 4: Preparation of (R)-4-(dimethylamino)-5-(4-methoxyphenyl)pentanoic acid (13-4)
除在本实施例中第二步使用化合物(13-1)代替实施例A中第七步的SM-1-7，采用与实施例A中第七步至第九步所描述的类似方法合成化合物(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).
第五步：(4R)-N-(2，3-二氢-1H-茚-1-基)-4-(二甲基氨基)-5-(4-甲氧基苯基)戊酰胺(TM13)的制备The fifth step: (4R)-N-(2,3-dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-methoxyphenyl)pentanamide ( Preparation of TM13)
在室温下，将化合物(13-4)(35.0mg，0.14mmol)溶于DMF(2mL)，加入2，3-二氢-1H-茚-1-胺(SM-2)(18.55mg，0.1mmol)，再加入HATU(63.50mg，0.17mmol)和DIEA(46μL，0.27mmol)，于室温反应4小时。经制备HPLC纯化得到标题化合物(TM13)(8mg，收率15％)。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] + MS m/z (ESI): 367.2 [M+H] +
1H 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). 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).
实施例6：(4R)-N-(2，3-二氢-1H-茚-1-基)-4-(二甲基氨基)-5-(4-(2-甲氧基乙氧基)苯基)戊酰胺(TM14)的制备Example 6: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-(2-methoxyethoxy) Preparation of phenyl)pentanamide (TM14)
Figure PCTCN2019071063-appb-000021
Figure PCTCN2019071063-appb-000021
除在本实施例中第一步用2-甲氧基-1-溴乙烷代替实施例5中第一步的碘甲烷外，采用与实施例5所描述的类似方法合成标题化合物(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] + MS m/z (ESI): 411.3 [M+H] +
1H NMR(400MHz，CD 3OD)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). 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).
实施例7：(4R)-N-(2，3-二氢-1H-茚-1-基)-4-(二甲基氨基)-5-(4-羟基苯基)-2-甲基戊酰胺(TM15)的制备Example 7: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)-2-methyl Preparation of valeramide (TM15)
Figure PCTCN2019071063-appb-000022
Figure PCTCN2019071063-appb-000022
第一步：(S)-5-(4-(苄氧基)苯基)-4-((叔丁氧羰基)氨基)-2-甲基戊-2-烯酸乙酯(15-1)的制备First step: (S)-5-(4-(Benzyloxy)phenyl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate (15-1 Preparation
在冰浴下，取氢化钠(0.10g，4.22mmol)溶于四氢呋喃(20.0mL)中。然后加入2-(二乙氧基膦酰基)丙酸乙酯(1.01g，4.22mmol)，搅拌反应0.5小时。再将化合物(SM-1-5)(1.00g，2.81mmol)溶解于四氢呋喃(10.0mL)后，滴入反应液中，滴完继续冰浴下反应4小时。反应完毕后加入饱和氯化铵淬灭，分取THF层，将水层再用EA萃取两次，合并有机层浓缩，将粗产品经硅胶柱色谱法纯化得化合物(15-1)(0.3g，收率23％)。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%).
第二步至第五步：(4R)-4-(二甲基氨基)-5-(4-羟基苯基)-2-甲基戊酸(15-5)的制备Steps 2 to 5: Preparation of (4R)-4-(dimethylamino)-5-(4-hydroxyphenyl)-2-methylpentanoic acid (15-5)
除在本实施例中第二步使用化合物(15-1)代替实施例A中第六步的化合物(SM-1-6)，采用与实施例A中第六步至第九步所描述的类似方法合成化合物(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).
第六步：(4R)-N-(2，3-二氢-1H-茚-1-基)-4-(二甲基氨基)-5-(4-羟基苯基)-2-甲基戊酰胺(TM15)的制备Step 6: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)-2-methyl Preparation of valeramide (TM15)
在室温下，将化合物(15-5)(50.0mg，0.20mmol)溶于DMF(2.5mL)，依次加入二异丙基乙基胺(66.0μL，0.40mmol)、HATU(90.8mg，0.24mmol)和2，3-二氢-1H-茚-1-胺(SM-2)(26.5mg，0.20mmol)，加完于室温反应3小时，经制备HPLC纯化得到标题化合物(TM15)(9mg，收率11％)。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] + MS m/z (ESI): 367.3 [M+H] +
1H NMR(400MHz，CD 3OD)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＝15.2，7.6Hz，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＝6.8Hz，1H)，1.03(t，J＝6.8Hz，2H). 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).
实施例8：(R)-4-(二甲基氨基)-N-((1S，2R)-2-羟基-2，3-二氢-1H-茚-1-基)-5-(4-羟基苯基)戊酰胺(TM47)的制备Example 8: (R)-4-(Dimethylamino)-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4 Of -hydroxyphenyl)pentanamide (TM47)
Figure PCTCN2019071063-appb-000023
Figure PCTCN2019071063-appb-000023
在室温下，将化合物(SM-1)(100.0mg，0.42mmol)溶于DMF(4mL)，加入(1S，2R)-1-氨基-2，3-二氢-1H-茚-2-醇(SM-5)(62.87mg，0.42mmol)，再加入DIEA(139.29μL，0.84mmol)和HATU(192.28mg，0.51mmol)，于室温反应4小时，经制备HPLC纯化得到标题化合物(TM47)(16mg，收率9％)。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] + MS m/z (ESI): 369.3 [M+H] +
1H NMR(400MHz，CD 3OD)δ7.24-7.16(m，4H)，7.13(d，J＝8.4Hz，2H)，6.78(d，J＝8.4Hz，2H)，5.28(d，J＝5.2Hz，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＝13.6，9.6Hz，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). 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).
实施例9：(R)-N-((R)-2，3-二氢-1H-茚-1-基)-4-(二甲基氨基)-5-(4-羟基苯基)戊酰胺(TM44)的制备Example 9: (R)-N-((R)-2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentyl Preparation of amide (TM44)
Figure PCTCN2019071063-appb-000024
Figure PCTCN2019071063-appb-000024
在室温下，将化合物(SM-1)(25.0mg，0.10mmol)溶于DMF(2.0mL)，加入(R)-2，3-二氢-1H-茚-1-胺盐酸盐(SM-6)(18.6mg，0.11mmol)，再加入DIEA(33.0μL，0.20mmol)和HATU(58.03mg，0.15mmol)，于室温反应4小时，经制备HPLC纯化得到标题化合物(TM44)(3.0mg，收率8％)。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] + MS m/z (ESI): 353.3 [M+H] +
1H NMR(400MHz，CDCl 3)δ7.19-7.06(m，4H)，6.86(d，J＝8.4Hz，2H)，6.65(d，J＝8.4Hz，2H)，5.34(q，J＝7.6Hz，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). 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).
实施例10：(R)-N-((S)-2，3-二氢-1H-茚-1-基)-4-(二甲基氨基)-5-(4-羟基苯基)戊酰胺(TM43)的制备Example 10: (R)-N-((S)-2,3-Dihydro-1H-indol-1-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentane Preparation of amide (TM43)
Figure PCTCN2019071063-appb-000025
Figure PCTCN2019071063-appb-000025
在室温下，将化合物(SM-1)(25.0mg，0.10mmol)溶于DMF(2mL)，加入HATU(48.00mg，0.12mmol)和三乙胺(44μL，0.32mmol)，最后加入(S)-2，3-二氢-1H-茚-1-胺盐酸盐(SM-7)(18.00mg，0.10mmol)，于室温反应4小时，经制备HPLC纯化得到标题化合物(TM43)(5mg，收率14％)。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] + MS m/z (ESI): 353.3 [M+H] +
1H NMR(400MHz，CD 3OD)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＝7.6Hz，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). 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).
实施例11：(4R)-N-(2，3-二氢苯并呋喃-3-基)-4-(二甲基氨基)-5-(4-羟基苯基)戊酰胺(TM27)的制备Example 11: (4R)-N-(2,3-Dihydrobenzofuran-3-yl)-4-(dimethylamino)-5-(4-hydroxyphenyl)pentanamide (TM27) preparation
Figure PCTCN2019071063-appb-000026
Figure PCTCN2019071063-appb-000026
在室温下，将化合物(SM-1)(25.0mg，0.10mmol)溶于DMF(2mL)，加入HATU(48.00mg，0.12mmol)和三乙胺(44μL，0.32mmol)，最后加入2，3-二氢苯并呋喃-3-胺盐酸盐(SM-8)(18.20mg，0.10mmol)，于室温反应4小时，经制备HPLC纯化得到标题化合物(TM27)(22mg，收率59％)。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] + MS m/z (ESI): 355.3 [M+H] +
1H NMR(400MHz，CD 3OD)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). 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).
实施例12：(4R)-N-(6-溴-1-甲基-1，2，3，4-四氢喹啉-4-基)-4-(二甲基氨基)-5-(4-羟基苯基)戊酰胺(TM105)的制备Example 12: (4R)-N-(6-Bromo-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-4-(dimethylamino)-5-( Preparation of 4-hydroxyphenyl)pentanamide (TM105)
Figure PCTCN2019071063-appb-000027
Figure PCTCN2019071063-appb-000027
第一步：6-溴-1-甲基-2，3-二氢喹啉-4(1H)-酮(105-2)的制备First step: Preparation of 6-bromo-1-methyl-2,3-dihydroquinolin-4(1H)-one (105-2)
取6-溴-2，3-二氢喹啉-4(1H)-酮(0.30g，1.26mmol)溶于DMF(6mL)中，依次加入碳酸钾(0.36g，2.52mmol)和碘甲烷(1.07g，7.56mmol)。80℃加热反应16小时，TLC监测反应完毕。将反应液过滤，浓缩除去部分溶剂，残余物再经柱色谱法纯化得标题化合物(0.25g，收率83％)。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
第二步：(Z)-6-溴-1-甲基-2，3-二氢喹啉-4(1H)-酮O-甲基肟(105-3)的制备Second step: Preparation of (Z)-6-bromo-1-methyl-2,3-dihydroquinolin-4(1H)-one O-methylindole (105-3)
取化合物(105-2)(0.25g，1.04mmol)溶于吡啶(25mL)中，再加入O-甲基羟胺(0.25g，5.20mmol)。室温反应16小时，TLC监测反应完毕。将反应液浓缩除去部分溶剂，残余物再经柱色谱法纯化得标题化合物(0.25g，收率89％)。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
第三步：6-溴-1-甲基-1，2，3，4-四氢喹啉-4-胺(105-4)的制备The third step: preparation of 6-bromo-1-methyl-1,2,3,4-tetrahydroquinolin-4-amine (105-4)
取化合物(105-3)(0.10g，0.37mmol)溶于硼烷四氢呋喃溶液(1M)(10mL)。80℃加热反应16小时，TLC监测反应完毕。向反应液中加入2M HCl，升温至80℃淬灭1小时，再加入EA洗去有机杂质，水层用饱和碳酸氢钠调节为碱性，再用EA萃取三次，干燥，浓缩得标题化合物(0.08g，收率89％)。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%).
第四步：(4R)-N-(6-溴-1-甲基-1，2，3，4-四氢喹啉-4-基)-4-(二甲基氨基)-5-(4-羟基苯基)戊酰胺(TM105)的制备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)
取化合物(SM-1)(80.0mg，0.30mmol)溶于DMF(5mL)将化合物，再依次加入HATU(136.9mg，0.36mmol)和N，N-二异丙基乙胺(167μL，1.01mmol)，最后加入化合物(105-4)(82.9mg，0.34mmol)。室温反应4小时，TLC监测反应完毕。再经制备HPLC纯化得到标题化合物(80mg，收率48％)。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] + MS m/z (ESI): 460.2 [M+H] +
1H 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＝12.0，1.6Hz，1H)，6.96-6.93(m，2H)，6.65(d，J＝8.0Hz，2H)，6.54(dd，J＝8.8，1.6Hz，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). 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).
实施例13：(4R)-4-(二甲基氨基)-5-(4-羟基苯基)-N-(1-甲基-1，2，3，4-四氢喹啉-4-基)戊酰胺(TM106)的制备Example 13: (4R)-4-(Dimethylamino)-5-(4-hydroxyphenyl)-N-(1-methyl-1,2,3,4-tetrahydroquinoline-4- Preparation of valeramide (TM106)
Figure PCTCN2019071063-appb-000028
Figure PCTCN2019071063-appb-000028
取TM105(30.0mg，0.07mmol)溶于无水甲醇(15mL)中，再加入Pd/C(30.0mg)。室温反应16小时，TLC监测反应完毕。再经制备HPLC纯化得到标题化合物(4mg，收率14％)。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] + MS m/z (ESI): 382.2 [M+H] +
1H NMR(400MHz，CD 3OD)δ7.09(t，J＝7.2Hz，1H)，6.98(d，J＝8.0Hz，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). 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).
实施例14：(R)-4-氨基-N-((1R，2S)-2-羟基-2，3-二氢-1H-茚-1-基)-5-(4-羟基苯基)戊酰胺(TM69)的制备Example 14: (R)-4-Amino-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl) Preparation of valeramide (TM69)
Figure PCTCN2019071063-appb-000029
Figure PCTCN2019071063-appb-000029
第一步：(R)-4-((叔丁氧羰基)氨基)-5-(4-羟基苯基)戊酸(69-1)的制备First step: Preparation of (R)-4-((tert-butoxycarbonyl)amino)-5-(4-hydroxyphenyl)pentanoic acid (69-1)
将SM-1-7(1.0g，2.96mmol)溶于甲醇(10mL)，再加入15％NaOH(10mL)水溶液，室温反应2小时。TLC监测反应至终点。将反应液浓缩后，加入DCM稀释，分液，水相调pH至3-4，加入DCM/MeOH＝10∶1萃取三次，合并有机相，无水硫酸钠干燥，过滤，旋干溶剂，得到标题化合物(900mg，收率98％)。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%).
第二步：((R)-5-(((1R，2S)-2-羟基-2，3-二氢-1H-茚-1-基)氨基)-1-(4-羟基苯基)-5-氧代戊-2-基)氨基甲酸叔丁酯(69-2)的制备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)
在本步骤中使用(1R，2S)-1-氨基-2，3-二氢-1H-茚-2-醇代替实施例1中的SM-2，使用化合物(69-1)代替SM-1，采用与实施例1所描述的类似方法合成标题化合物(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.
第三步：(R)-4-氨基-N-((1R，2S)-2-羟基-2，3-二氢-1H-茚-1-基)-5-(4-羟基苯基)戊酰胺(TM69)的制备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)
向化合物(69-2)(65mg，0.14mmol)加入5mL盐酸的二氧六环溶液，室温搅拌，TLC监测反应至终点。直接旋干溶剂，得标题化合物(45mg，0.12mmol，收率87％)。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] + MS m/z (ESI): 341.2 [M+H] +
1H NMR(400MHz，CD 3OD)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＝5.2，2.0Hz，1H)，3.13(dd，J＝16.4，5.2Hz，1H)，3.03-2.95(m，1H)，2.91(dd，J＝16.4，2.0Hz，1H)，2.72(dd，J＝5.6Hz，1H)，2.56-2.40(m，3H)，1.95-1.84(m，1H)，1.75-1.64(m，1H). 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).
实施例15：(4R)-N-(2，3-二氢-1H-茚-1-基)-5-(4-羟基苯基)-4-(3-羟基吡咯烷-1-基)戊酰胺(TM35)的制备Example 15: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl)-4-(3-hydroxypyrrolidin-1-yl) Preparation of valeramide (TM35)
Figure PCTCN2019071063-appb-000030
Figure PCTCN2019071063-appb-000030
第一步：(R)-5-(4-(苄氧基)苯基)-4-((叔丁氧羰基)氨基)戊酸乙酯(35-1)的制备First step: Preparation of (R)-5-(4-(benzyloxy)phenyl)-4-((tert-butoxycarbonyl)amino)pentanoic acid ethyl ester (35-1)
将SM-1-7(1.00g，2.96mmol)用MeCN(30mL)溶解，加入碳酸钾(819mg，5.93mmol)及苄溴(608mg，3.56mmol)，85℃回流反应过夜。将反应液浓缩后加水稀释，用EA萃取三次，合并有机相，无水硫酸钠干燥，过滤，旋干溶剂。硅胶柱色谱法纯化得标题化合物(35-1)(820mg，收率64％)。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%)
第二步：(R)-5-(4-(苄氧基)苯基)-4-((叔丁氧羰基)氨基)戊酸(35-2)的制备Second step: Preparation of (R)-5-(4-(benzyloxy)phenyl)-4-((tert-butoxycarbonyl)amino)pentanoic acid (35-2)
将化合物(35-1)(820mg，1.92mmol)用MeOH(10mL)溶解，加入10mLNaOH(15％水溶液)，室 温搅拌反应5小时。将反应液浓缩后，加入DCM稀释，分液，水相调pH至3-4，出现大量沉淀。加入EA萃取三次，合并有机相，无水硫酸钠干燥，过滤，旋干溶剂，得到标题化合物(35-2)(665mg，收率86％)。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).
第三步：((2R)-1-(4-(苄氧基)苯基)-5-((2，3-二氢-1H-茚-1-基)氨基)-5-氧代戊-2-基)氨基甲酸叔丁酯(35-3)的制备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)
将化合物(35-2)(150mg，0.37mmol)用DMF(5mL)溶解，搅拌条件下加入HATU(171mg，0.45mmol)和TEA(76mg，0.75mmol)，最后加入2，3-二氢-1H-茚-1-胺(50mg，0.37mmol)，反应过夜。将反应液浓缩，制备HPLC分离纯化，冻干得标题化合物(35-3)155mg，收率80％)。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.
第四步：(4R)-4-氨基-5-(4-(苄氧基)苯基)-N-(2，3-二氢-1H-茚-1-基)戊酰胺(35-4)的制备The fourth step: (4R)-4-amino-5-(4-(benzyloxy)phenyl)-N-(2,3-dihydro-1H-indol-1-yl)pentanamide (35-4 Preparation
向化合物(35-3)(155mg，0.30mmol)中加入5mL盐酸的二氧六环溶液(4M)，室温搅拌，TLC监测反应至终点。直接旋干溶剂，得标题化合物(35-4)(140mg，收率87％)。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%).
第五步：(4R)-5-(4-(苄氧基)苯基)-N-(2，3-二氢-1H-茚-1-基)-4-(3-羟基吡咯烷-1-基)戊酰胺(35-5)的制备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)
将化合物(35-4)(140mg，0.28mmol)用MeCN(10mL)溶解，加入碳酸钾(119mg，0.86mmol)和碘化钠(43mg，0.29mmol)，再加入1，4-二溴丁-2-醇(80mg，0.37mmol)，85℃回流反应5小时。将反应液浓缩，加水稀释，EA萃取三次，合并有机相，无水硫酸钠干燥，过滤，旋干溶剂。用DCM溶解后，制备薄层色谱法(DCM∶MeOH＝10∶1)分离纯化，得标题化合物(35-5)(78mg，收率56％)。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%).
第六步：(4R)-N-(2，3-二氢-1H-茚-1-基)-5-(4-羟基苯基)-4-(3-羟基吡咯烷-1-基)戊酰胺(TM35)的制备Step 6: (4R)-N-(2,3-Dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl)-4-(3-hydroxypyrrolidin-1-yl) Preparation of valeramide (TM35)
将化合物(35-5)(50mg，0.10mmol)用EtOH(5mL)溶解，加入Pd/C(25mg，0.21mmol)，在氢气氛围下60℃反应过夜，原料全部反应完，抽滤后通过制备HPLC分离纯化，冻干得标题化合物(TM35)(7mg，收率16％)。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] + MS m/z (ESI): 395.3 [M+H] +
1H NMR(400MHz，CD 3OD)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). 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) ).
实施例16：(R)-N-((1R，2S)-2-羟基-2，3-二氢-1H-茚-1-基)-5-(4-羟基苯基)-4-吗啉代戊酰胺(TM73)的制备Example 16: (R)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl)-4-? Preparation of porphyrinamide (TM73)
Figure PCTCN2019071063-appb-000031
Figure PCTCN2019071063-appb-000031
除在本实施例中第一步使用(1R，2S)-1-氨基-2，3-二氢-1H-茚-2-醇代替实施例15中第三步的2，3-二氢-1H-茚-1-胺，并且在本实施例中第三步使用化合物2，2′-二溴二***代替实施例15中第五步的化合物1，4-二溴丁-2-醇，采用与实施例15中第三步至第六步所描述的类似方法合成标题化合物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] + MS m/z (ESI): 411.2 [M+H] +
1H NMR(400MHz，CD 3OD)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). 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).
实施例17：(R)-N-((1R，2S)-2-羟基-2，3-二氢-1H-茚-1-基)-5-(4-羟基苯基)-4-(吡咯烷-1-基)戊酰胺(TM74)的制备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)
Figure PCTCN2019071063-appb-000032
Figure PCTCN2019071063-appb-000032
除在本实施例中第一步使用1，4-二溴丁烷代替实施例15中第五步的化合物1，4-二溴丁-2-醇，采用与实施例15中第五步至第六步所描述的类似方法合成标题化合物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] + MS m/z (ESI): 395.2 [M+H] +
1H NMR(400MHz，CD 3OD)δ7.26-7.14(m，4H)，7.06(d，J＝8.4Hz，2H)，6.72(d，J＝8.4Hz，2H)，5.26(d，J＝4.8Hz，1H)，4.52(td，J＝5.2，2.0Hz，1H)，3.12(dd，J＝16.4，5.2Hz，1H)，3.00-2.88(m，2H)，2.88-2.69(m，5H)，2.54(dd，J＝13.2，9.6Hz，1H)，2.41-2.33(m，2H)，1.91-1.76(m，6H). 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).
实施例18：(R)-N-((1R，2S)-2-羟基-2，3-二氢-1H-茚-1-基)-5-(4-羟基苯基)-4-(甲基氨基)戊酰胺(TM75)的制备Example 18: (R)-N-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-5-(4-hydroxyphenyl)-4-( Preparation of methylamino)pentanamide (TM75)
Figure PCTCN2019071063-appb-000033
Figure PCTCN2019071063-appb-000033
第一步：(R)-5-(4-(苄氧基)苯基)-N-((1R，2S)-2-羟基-2，3-二氢-1H-茚-1-基)-4-((4-甲氧苄基)氨基)戊酰胺(75-1)的制备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)
将化合物(73-2)(150.0mg，0.29mmol)用MeOH(10mL)溶解，加入TEA(29.5mg，0.29mmol)和对甲氧基苯甲醛(47.7mg，0.35mmol)，氮气保护，室温反应1小时。加入三乙酰氧基硼氢化钠(185.3mg，0.86mmol)，室温反应2小时。将反应液浓缩后加水稀释，EA萃取三次，合并有机相，无水硫酸钠干燥，过滤，除去溶剂，硅胶柱色谱法分离纯化，得到标题化合物(100.0mg，收率63％)。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
第二步：(R)-5-(4-(苄氧基)苯基)-N-((1R，2S)-2-羟基-2，3-二氢-1H-茚-1-基)-4-((4-甲氧苄基)(甲基)氨基)戊酰胺(75-2)的制备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)
将化合物(75-1)(100.0mg，0.15mmol)用MeOH(10mL)溶解，加入甲醛水溶液(92.7mg，0.93mmol)，室温搅拌30分钟，加入三乙酰氧基硼氢化钠(163.6mg，0.77mmol)，室温反应4小时。将反应液浓缩后加水稀释，加EA萃取三次，合并有机相，无水硫酸钠干燥，过滤，浓缩，硅胶柱色谱法分离纯化，得到标题化合物(52.1mg，收率60％)。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.
第三步：(R)-N-((1R，2S)-2-羟基-2，3-二氢-1H-茚-1-基)-5-(4-羟基苯基)-4-(甲基氨基)戊酰胺(TM75)的制备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)
将化合物(75-2)(52.1mg，92.1μmol)用EtOH(25mL)溶解，加入Pd/C(25mg)，氢气置换，60℃加热反应过夜。将反应液过滤，旋干，通过制备HPLC分离纯化，冻干得标题化合物(TM-75)(18.1mg，收率19％)。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] + MS m/z (ESI): 355.2 [M+H] +
1H NMR(400MHz，CD 3OD)δ7.25-7.17(m，4H)，7.05(d，J＝8.4Hz，2H)，6.74(d，J＝8.4Hz，2H)，5.28(d，J＝5.2Hz，1H)，4.54(ddd，J＝5.2，5.2，2.0Hz，1H)，3.12(dd，J＝16.0，5.2Hz，1H)，2.92(dd，J＝16.4，2.0Hz，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). 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).
采用上述实施例中类似的合成方法，合成了下述化合物，具体信息见下表。The following compounds were synthesized by a similar synthesis method in the above examples, and the specific information is shown in the following table.
Figure PCTCN2019071063-appb-000034
Figure PCTCN2019071063-appb-000034
Figure PCTCN2019071063-appb-000035
Figure PCTCN2019071063-appb-000035
Figure PCTCN2019071063-appb-000036
Figure PCTCN2019071063-appb-000036
Figure PCTCN2019071063-appb-000037
Figure PCTCN2019071063-appb-000037
Figure PCTCN2019071063-appb-000038
Figure PCTCN2019071063-appb-000038
Figure PCTCN2019071063-appb-000039
Figure PCTCN2019071063-appb-000039
Figure PCTCN2019071063-appb-000040
Figure PCTCN2019071063-appb-000040
Figure PCTCN2019071063-appb-000041
Figure PCTCN2019071063-appb-000041
Figure PCTCN2019071063-appb-000042
Figure PCTCN2019071063-appb-000042
生物学评价Biological evaluation
实验例1Experimental example 1
1.1试验目的1.1 Purpose of the test
本试验的目的是为了测试化合物对μ阿片受体(μOR)G蛋白信号通路的激动作用。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试验原理1.2 Test principle
激活μOR的G蛋白信号通路可以调节细胞内的cAMP水平，通过均相时间分辨荧光(HTRF)的方法测定细胞内cAMP水平变化可以反映化合物的激动活性。根据化合物引起cAMP水平变化的最大效应E max(以1μM完全激动剂DAMGO(H-Tyr-D-Ala-Gly-N-MePhe-Gly-OH)的最大效应为100％)及引起最大效应一半时的化合物浓度EC 50评价化合物的体外活性。 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试验方法1.3 Test methods
1.3.1试验材料及仪器1.3.1 Test materials and instruments
名称name 品牌Brand
hμOR/CHO细胞株hμOR/CHO cell line HDBHDB
HEPESHEPES InvitrogenInvitrogen
HBSS(+/+)HBSS (+/+) InvitrogenInvitrogen
IBMXIBMX SigmaSigma
NKH477NKH477 TocrisTocris
DMSODMSO SigmaSigma
cAMP Dynamic 2试剂盒cAMP Dynamic 2 Kit CisbioCisbio
384孔LDV板384-well LDV board LabcyteLabcyte
低容量384白板Low capacity 384 whiteboard CorningCorning
Echo 550Echo 550 LabcyteLabcyte
BravoBravo Agilent TechnologiesAgilent Technologies
Multidrop CombiMultidrop Combi Thermo ScientificThermo Scientific
Envision酶标仪Envision microplate reader PerkinElmerPerkinElmer
1.3.2试验步骤1.3.2 Test procedure
在384孔LDV板上配制系列稀释浓度的待测化合物样品，使用Echo机器将样品稀释序列转移至实验板(Corning-3824)，每孔转移30nL，同时转移30nL阳性对照DAMGO(HPE)和阴性对照DMSO(ZPE)至相应孔。然后依次向实验板各孔加入5μL刺激缓冲液(STB)和5μL hμOR/CHO细胞悬浮液(10000细胞/孔)，10μL体系中IBMX和NKH477的化合物终浓度分别为100μM和1.5μM。将实验板置于37℃恒温孵箱内孵育40min。然后按照cAMP Dynamic 2试剂盒说明书检测cAMP水平。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测试结果1.4 test results
所测试化合物激动μOR G蛋白信号通路的水平通过以上试验进行测定，测得的EC 50及E max结果见表1(以1μM完全激动剂DAMGO的最大效应为100％)。 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).
表1.测试化合物激动μOR G蛋白信号通路影响cAMP水平的EC 50和E max Table 1. Test compound Inflammatory μOR G protein signaling pathways influence the level of cAMP EC 50 and E max
化合物IDCompound ID EC 50(nM) EC 50 (nM) E max(％) E max (%)
TM1TM1 3.3±0.93.3 ± 0.9 85.0±2.085.0±2.0
TM2TM2 14.2±1.214.2±1.2 110.4±1.2110.4±1.2
TM3TM3 6.2±0.56.2±0.5 102.9±1.1102.9±1.1
TM10TM10 33.1±2.133.1±2.1 105.2±1.1105.2±1.1
TM43TM43 2.3±0.32.3±0.3 105.3±1.2105.3±1.2
TM27TM27 43.1±5.143.1±5.1 81.9±1.681.9±1.6
TM105TM105 47.8±7.347.8 ± 7.3 80.4±2.280.4±2.2
TM106TM106 4.9±1.04.9±1.0 100.6±2.6100.6±2.6
TM74TM74 26.7±1.226.7±1.2 107.7±0.7107.7±0.7
TM75TM75 17.0±2.817.0±2.8 98.7±2.398.7±2.3
TM48TM48 3.1±0.43.1±0.4 100.1±1.9100.1 ± 1.9
TM70TM70 2.9±0.32.9±0.3 108.0±0.9108.0±0.9
TM71TM71 7.5±0.67.5±0.6 102.4±1.4102.4±1.4
TM72TM72 22.1±2.022.1±2.0 98.7±1.398.7±1.3
TM76TM76 1.5±0.31.5±0.3 97.6±2.097.6±2.0
TM77TM77 7.0±0.67.0±0.6 98.2±1.098.2±1.0
TM78TM78 2.4±0.42.4±0.4 96.4±1.596.4±1.5
TM80TM80 2.7±0.42.7±0.4 97.8±1.397.8±1.3
TM8TM8 23.5±1.623.5±1.6 109.8±1.1109.8±1.1
TM61TM61 15.6±1.515.6±1.5 102.3±1.4102.3±1.4
TM107TM107 38.1±2.938.1±2.9 79.2±1.279.2±1.2
TM108TM108 31.6±3.631.6±3.6 71.9±1.371.9±1.3
TM83TM83 7.2±0.57.2±0.5 104.8±1.0104.8±1.0
TM84TM84 1.1±0.31.1±0.3 106.4±1.6106.4±1.6
TM85TM85 55.2±5.455.2±5.4 98.9±1.698.9±1.6
TM86TM86 1.9±0.21.9±0.2 104.4±1.3104.4±1.3
TM87TM87 0.7±0.10.7±0.1 121.3±1.2121.3±1.2
TM89TM89 7.4±2.37.4±2.3 92.7±3.392.7±3.3
TM91TM91 61.3±5.361.3±5.3 102.3±1.5102.3±1.5
TM95TM95 44.7±6.844.7±6.8 88.7±2.388.7±2.3
TM98TM98 0.5±0.10.5±0.1 100.9±1.9100.9±1.9
TM99TM99 41.3±4.241.3±4.2 108.3±2.0108.3±2.0
TM100TM100 4.0±0.54.0±0.5 97.8±1.397.8±1.3
TM101TM101 47.1±5.447.1±5.4 102.6±2.0102.6±2.0
TM103TM103 13.9±1.613.9±1.6 100.4±1.8100.4±1.8
结论：本发明化合物对μ阿片受体(μOR)G蛋白信号通路具有较强的激动活性。Conclusion: The compounds of the present invention have strong agonistic activity on the μ opioid receptor (μOR) G protein signaling pathway.
实验例2Experimental example 2
2.1试验目的2.1 Purpose of the test
本试验的目的是为了测试μ阿片受体(μOR)被本发明化合物激活后募集β抑制蛋白2的活性。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试验原理2.2 Test principle
通过酶片段互补法(EFC)检测μ阿片受体(μOR)被化合物激活后募集β抑制蛋白2的活性。激动剂与过表达偶联β-gal片段的μ阿片受体(μOR)结合后会募集β抑制蛋白偶联的β-gal互补片段形成完整有催化活性的酶，进而催化底物而产生化学发光。根据化合物引起β抑制蛋白2募集水平的最大效应E max(以1μM完全激动剂DAMGO的最大效应为100％)评价化合物的体外活性。 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试验方法2.3 Test methods
2.3.1试验材料及仪器2.3.1 Test materials and instruments
名称name 品牌Brand
人μ阿片β抑制蛋白U2OS/OPRM1细胞株Human μ opioid β inhibitor protein U2OS/OPRM1 cell line DiscoveRXDiscoveRX
PathHunter检测试剂盒PathHunter Test Kit DiscoveRXDiscoveRX
MEM培养基MEM medium GibcoGibco
DMSODMSO SigmaSigma
384孔LDV板384-well LDV board LabcyteLabcyte
384孔板，白色，TC处理，平底，带盖384-well plate, white, TC treated, flat bottom, with lid PerkinElmerPerkinElmer
Echo 550Echo 550 LabcyteLabcyte
BravoBravo Agilent TechnologiesAgilent Technologies
Multidrop CombiMultidrop Combi Thermo ScientificThermo Scientific
Envision酶标仪Envision microplate reader PerkinElmerPerkinElmer
2.3.2试验步骤2.3.2 Test procedure
在384孔LDV板上配制系列稀释浓度的待测化合物样品，使用Echo机器将样品稀释序列转移至实验板(PerkinElmer)，每孔转移60nL，同时转移60nL阳性对照DAMGO(HPE)和阴性对照DMSO(ZPE)至相应孔。然后向实验板各孔加入20μL U2OS/OPRM1细胞悬浮液(7500细胞/孔)，300rpm离心30s，室温孵育2小时。然后按照PathHunter检测试剂盒说明向实验板各孔加入6μL PathHunter检测试剂，室温静置60分钟后在Envision上读数。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测试结果2.4 test results
所测试化合物激活μOR后募集β抑制蛋白2的水平通过以上试验进行测定，测得的E max结果见表2(以1μM完全激动剂DAMGO的最大效应为100％)。 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).
表2.测试化合物激活μOR后募集β抑制蛋白2水平的E max。 Table 2. Test compound activated μOR recruitment β 2 inhibitory protein level E max.
化合物IDCompound ID E max(％) E max (%)
TM1TM1 7.8±0.47.8±0.4
TM47TM47 ＜3<3
TM27TM27 ＜3<3
TM105TM105 6.2±1.26.2±1.2
TM80TM80 20.4±1.120.4 ± 1.1
TM8TM8 19.9±119.9±1
TM107TM107 ＜3<3
TM108TM108 3.7±0.43.7±0.4
TM89TM89 15.7±0.715.7±0.7
TM95TM95 11.4±0.611.4±0.6
TM100TM100 20.0±0.620.0 ± 0.6
结论：本发明化合物激活μ阿片受体(μOR)后募集β抑制蛋白2的水平较弱。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).
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。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. 化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(I)的结构：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):
    Figure PCTCN2019071063-appb-100001
    Figure PCTCN2019071063-appb-100001
    其中：among them:
    R 1选自H、卤素、-OR h、氰基、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-COOR h、-CON(R h) 2、-SO 3H、-S(＝O) gR h、-O-C(＝O)-(C 1-6烷基)、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-N(R h) 2、3-10元杂环基、C 6-14芳基和5-14元杂芳基； 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;
    R 2在每次出现时各自独立地选自H、卤素、-OR h、氰基、硝基、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、C 2-5烯基、-COOR h、-CON(R h) 2、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、-N(R h) 2和3-10元杂环基； 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和R 10b在每次出现时各自独立地选自H、卤素、-OR h、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、氰基、-COOR h、-CON(R h) 2、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-N(R h) 2和3-10元杂环基；条件是当R 6a和R 6b之一为-OH时，另一者不是H； 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和R 5b各自独立地选自H、卤素、-OR h、-C(＝O)R h、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-C 1-6亚烷基-OR h、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)和3-10元杂环基；或者，R 5a与R 5b连同其所连接的氮原子共同形成5-10元含氮杂环； 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选自直接键、CR 11aR 11b、C(＝O)、O、NR 11a和S(＝O) g； W is selected from direct bonds, CR 11a R 11b , C(=O), O, NR 11a and S(=O) g ;
    R 11a和R 11b各自独立地选自H、卤素、-OR h、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、氰基、-COOR h、-CON(R h) 2、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-N(R h) 2和3-10元杂环基； 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选自C 6-14芳环和5-14元杂芳环； A is selected from the group consisting of a C 6-14 aromatic ring and a 5-14 membered heteroaryl ring;
    R 12在每次出现时各自独立地选自H、卤素、-OR h、氰基、硝基、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、C 2-5烯基、-COOR h、-CON(R h) 2、-O-[(C 1-6亚烷基)-O] m-(C 1-6烷基)、-S(＝O) gR h、-N(R h) 2和3-10元杂环基； 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;
    上述烷基、亚烷基、环烷基、烯基、含氮杂环、杂环基、芳基、芳环、杂芳基和杂芳环各自任选地被一个或多个各自独立地选自卤素、＝O、-R h、-OR h、-COOR h、-CON(R h) 2、-S(＝O) gR h和-N(R h) 2的取代基取代； 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在每次出现时各自独立地选自H、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、3-10元杂环基、C 6-10芳基和5-10元杂芳基，且多个R h彼此之间可以相同或不同； 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在每次出现时各自独立地表示0、1或2的整数；g each independently represents an integer of 0, 1 or 2 at each occurrence;
    m在每次出现时各自独立地表示1-10中的任意整数，包括端值；并且m each independently represents any integer in 1-10, including the end value;
    n、p和q各自独立地为0、1、2、3或4的整数。n, p and q are each independently an integer of 0, 1, 2, 3 or 4.
  2. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 1选自H、卤素、-OH、-O-(C 1-4烷基)、氰基、C 1-4烷基、C 3-6环烷基、-COOH、-CONH 2、-O-C(＝O)-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-SH、-S(＝O) g-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2和3-6元杂环基，其中所述烷基、亚烷基、环烷基和杂环基各自任选地被一个或多个各自独立地选自F、Cl、C 1-4烷基、C 3-6环烷基、-CF 3、-CHF 2、-OH、-OCF 3、-OCHF 2、-O-(C 1-6烷基)、-COOH、-CONH 2、-NH 2、-NH(C 1-4烷基)和-N(C 1-4烷基) 2的取代基取代；g为0、1或2的整数；并且m为1、2、3或4的整数； 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;
    优选地，R 1选自H、F、Cl、氰基、C 1-4烷基、C 3-6环烷基、-CF 3、-CHF 2、-OH、-OCH 3、-OCF 3、-OCHF 2、-O-C(＝O)-(C 1-4烷基)、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-NH 2、 -NH(C 1-4烷基)、-N(C 1-4烷基) 2、-COOH和-CONH 2；其中，m为1或2的整数；并且 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;
    更优选地，R 1选自H、F、Cl、-CF 3、-CH 3、-CH 2CH 3、-CH(CH 3) 2、-OH、-OCH 3、-OCF 3、-OC(＝O)CH 3、-CH 2-OCH 3和-O-CH 2CH 2-O-CH 3。 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. 权利要求1或2的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 2在每次出现时各自独立地选自H、卤素、-CF 3、-CHF 2、-OH、-OCF 3、-OCHF 2、-O(C 1-4烷基)、氰基、C 1-4烷基、C 3-6环烷基、-COOH、-CONH 2、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2和3-6元杂环基；其中m为1、2、3或4的整数； 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;
    优选地，R 2在每次出现时各自独立地选自H、F、Cl、-OH、-CF 3、-OCF 3、-OCH 3、氰基、C 1-4烷基、C 3-6环烷基、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)和-N(C 1-4烷基) 2；其中m为1、2、3或4的整数；并且 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;
    更优选地，R 2在每次出现时各自独立地选自H、F、Cl、-OH、-CF 3、-OCF 3、-OCH 3、C 1-3烷基、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(C 1-3亚烷基)-O-(C 1-3烷基)和-N(C 1-3烷基) 2。 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. 权利要求1-3中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 3a、R 3b、R 4、R 6a、R 6b、R 7a、R 7b、R 8、R 9a、R 9b、R 10a和R 10b在每次出现时各自独立地选自H、F、Cl、-OH、-O-(C 1-4烷基)、-O-(卤代C 1-4烷基)、氰基、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-COOH、-CONH 2、C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、-S(＝O) g-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2和3-6元杂环基；其中，g为0、1或2的整数；并且m为1、2、3或4的整数；并且 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;
    优选地，R 3a、R 3b、R 4、R 6a、R 6b、R 7a、R 7b、R 8、R 9a、R 9b、R 10a和R 10b在每次出现时各自独立地选自H、F、Cl、氰基、C 1-4烷基(优选C 1-3烷基，更优选甲基)、C 3-6环烷基、-CF 3、-CHF 2、-OH、-OCF 3、-OCHF 2、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)(优选-O-(C 1-4亚烷基)-O-(C 1-4烷基))、-NH 2、-NH(C 1-4烷基)(优选-NH(C 1-3烷基))、-N(C 1-4烷基) 2(优选-N(C 1-3烷基) 2)、-COOH和-CONH 2；其中，m为1或2的整数。 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. 权利要求1-4中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 5a和R 5b各自独立地选自H、F、Cl、-OH、-O-(C 1-4烷基)(优选-O-(C 1-3烷基))、C 1-6烷基(优选C 1-4烷基，更优选甲基或乙基)、C 3-6环烷基、-C 1-4亚烷基-OH(优选-C 1-3亚烷基-OH)、C 2-5烯基(优选乙烯基、丙烯基或烯丙基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)和3-6元杂环基；或者，R 5a与R 5b连同其所连接的氮原子共同形成5-7元含氮杂环(优选5-6元含氮杂环)；其中，m为1或2的整数；并且所述烷基、亚烷基、环烷基、烯基、含氮杂环和杂环基各自任选地被一个或多个各自独立地选自F、Cl、-CF 3、-OH、＝O、-OCF 3、C 1-3烷基、-O-C 1-4烷基和-N(C 1-3烷基) 2的取代基取代。 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. 权利要求1-5中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 11a和R 11b各自独立地选自H、F、Cl、-OH、-O-(C 1-4烷基)、氰基、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-COOH、-CONH 2、C 1-4烷基、C 3-6环烷基、-S(＝O) g-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2和3-6元杂环基，其中所述烷基、亚烷基、环烷基和杂环基各自任选地被一个或多个各自独立地选自F、Cl、-CF 3、-CHF 2、-OH、-OCF 3、-OCHF 2、C 1-4烷基、C 3-6环烷基、-O-C 1-4烷基、-COOH、-CONH 2、-S(＝O) g-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)和-N(C 1-3烷基) 2的取代基取代；g为0、1或2的整数；m为1、2、3或4的整数；并且 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;
    优选地，R 11a和R 11b各自独立地选自H、F、Cl、氰基、C 1-4烷基(优选C 1-3烷基，更优选甲基或乙基)、C 3-6环烷基、-CF 3、-CHF 2、-OH、-OCF 3、-OCHF 2、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)(优选-O-(C 1-3亚烷基)-O-(C 1-3烷基))、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2、-COOH和-CONH 2；m为1或2的整数。 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. 权利要求1-6中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中W选自直接键、CH 2、CHF、CF 2、CHOH、CHCH 3、C(CH 3) 2、C(＝O)、NCH 3、NCH 2CH 3、O、S、S(＝O)和S(＝O) 2； 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 ;
    优选地，W选自直接键、CH 2、CHF、CF 2、CHOH、CHCH 3、C(CH 3) 2、C(＝O)、NCH 3、O、S、 S(＝O)和S(＝O) 2；或者 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选自直接键、CH 2、CHF、CF 2、CHOH、CHCH 3、C(CH 3) 2、C(＝O)、NCH 3、NCH 2CH 3、O、S和S(＝O) 2。 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. 权利要求1-7中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中A选自苯环和5-6元杂芳环；优选地，A为苯环、噻吩环、吡嗪环、嘧啶环或吡啶环。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. 权利要求1-8中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 12在每次出现时各自独立地选自H、卤素、-CF 3、-CHF 2、-OH、-O-(C 1-4烷基)、-OCF 3、-OCHF 2、氰基、C 1-4烷基、C 3-6环烷基、-COOH、-CONH 2、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-4亚烷基)-O] m-(C 1-4烷基)、-NH 2、-NH(C 1-4烷基)、-N(C 1-4烷基) 2和3-6元杂环基；并且m为1、2、3或4的整数； 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;
    优选地，R 12在每次出现时各自独立地选自H、F、Cl、Br、-OH、-O-(C 1-3烷基)、-CF 3、-OCF 3、氰基、C 1-3烷基、C 3-6环烷基、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-3亚烷基)-O] m-(C 1-3烷基)、-NH 2、-NH(C 1-3烷基)和-N(C 1-3烷基) 2；更优选地，R 12在每次出现时各自独立地选自H、F、Cl、-OH、-O-(C 1-3烷基)、-CF 3、-OCF 3、氰基、C 1-3烷基、C 3-6环烷基、-(C 1-4亚烷基)-O-(C 1-4烷基)、-O-[(C 1-3亚烷基)-O] m-(C 1-3烷基)、-NH 2、-NH(C 1-3烷基)和-N(C 1-3烷基) 2；并且m为1或2的整数；并且 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;
    更优选地，R 12在每次出现时各自独立地选自H、F、Cl、Br、-OH、-CF 3、-OCF 3、氰基、-CH 3、-CH 2CH 3、-CH(CH 3) 2、-OCH 3、-O-CH(CH 3) 2、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(C 1-3亚烷基)-O-(C 1-3烷基)和-N(C 1-3烷基) 2；更优选地，R 12在每次出现时各自独立地选自H、F、Cl、-OH、-CF 3、-OCF 3、氰基、-CH 3、-CH 2CH 3、-CH(CH 3) 2、-OCH 3、-O-CH(CH 3) 2、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(C 1-3亚烷基)-O-(C 1-3烷基)和-N(C 1-3烷基) 2；或者 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在每次出现时各自独立地选自H、F、Br、Cl、-OH、氰基、-CH 3、和-OCH 3。 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. 权利要求1-9中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(II)的结构：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):
    Figure PCTCN2019071063-appb-100002
    Figure PCTCN2019071063-appb-100002
    其中：among them:
    n为0、1或2的整数；并且n is an integer of 0, 1, or 2;
    其余各基团如权利要求1-9中任一项所定义。The remaining groups are as defined in any one of claims 1-9.
  11. 权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(II’)的结构：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'):
    Figure PCTCN2019071063-appb-100003
    Figure PCTCN2019071063-appb-100003
    其中：among them:
    n为0、1或2的整数；并且n is an integer of 0, 1, or 2;
    其余各基团如权利要求1-9中任一项所定义。The remaining groups are as defined in any one of claims 1-9.
  12. 权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：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:
    Figure PCTCN2019071063-appb-100004
    Figure PCTCN2019071063-appb-100004
    Figure PCTCN2019071063-appb-100005
    Figure PCTCN2019071063-appb-100005
    Figure PCTCN2019071063-appb-100006
    Figure PCTCN2019071063-appb-100006
    Figure PCTCN2019071063-appb-100007
    Figure PCTCN2019071063-appb-100007
  13. 药物组合物，其包含预防或治疗有效量的权利要求1-12中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。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. 权利要求1-12中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物在制备用于预防或治疗μ阿片受体相关疾病的药物中的用途。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. 权利要求14的用途，其中所述μ阿片受体相关疾病为疼痛类疾病，所述疾病优选为中度到重度的疼痛类疾病。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.
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