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WO2021027304A1 - Composé analgésique, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Composé analgésique, son procédé de préparation et son utilisation pharmaceutique Download PDF

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Publication number
WO2021027304A1
WO2021027304A1 PCT/CN2020/084773 CN2020084773W WO2021027304A1 WO 2021027304 A1 WO2021027304 A1 WO 2021027304A1 CN 2020084773 W CN2020084773 W CN 2020084773W WO 2021027304 A1 WO2021027304 A1 WO 2021027304A1
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Prior art keywords
alkyl
ring
substituted
membered saturated
unsubstituted
Prior art date
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English (en)
Chinese (zh)
Inventor
刘力锋
胡斌
谢婧
石晓永
赵金柱
何宛
郭淑春
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
Original Assignee
Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Priority to CN202080003851.5A priority Critical patent/CN112789276B/zh
Publication of WO2021027304A1 publication Critical patent/WO2021027304A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a class of biheterocyclic methylethylamine substituted oxaspiro derivatives, a preparation method thereof, a pharmaceutical composition containing the derivatives, and a therapeutic agent, especially as a MOR receptor agonist and in preparation Use in medicines for the treatment and prevention of pain and pain related diseases.
  • Opioid receptors are an important type of G protein-coupled receptor (GPCR), which is the target for the binding of endogenous opioid peptides and opioid drugs.
  • GPCR G protein-coupled receptor
  • Endogenous opioid peptides are naturally produced in mammals.
  • Opioid active substances, currently known endogenous opioid peptides are roughly divided into enkephalins, endorphins, dynorphins and neoorphins.
  • opioid receptors in the central nervous system namely ⁇ (MOR), ⁇ (DOR), ⁇ (KOR) receptors and so on.
  • MOR ⁇
  • DOR ⁇
  • KOR KOR
  • GPCR mediates and regulates physiological functions through two main pathways: the G protein pathway and the ⁇ -arrestin pathway.
  • the traditional GPCR agonist binds to the receptor, it activates the G protein signal pathway, including calcium ion and other second messenger systems, adenyl cyclase (AC), and mitogen-activated protein kinase (mitogen-activated protein).
  • AC adenyl cyclase
  • mitogen-activated protein kinase mitogen-activated protein kinase
  • kinases, MAPK), etc. and ⁇ -arrestin preferential ligands mainly activate the ⁇ -arrestin pathway.
  • the ⁇ -arrestin-mediated GPCR reaction mainly includes three aspects: 1) As a negative regulator, it interacts with G protein-coupled receptor kinase (GRK) to desensitize GPCRs and stop G protein signal transduction. 2) As a scaffold protein, it recruits endocytosis proteins and induces GPCR endocytosis; 3) As a linker protein, it forms a complex with downstream signal molecules of GPCRs and activates signal transduction molecules in a G protein-independent manner, Such as MAPK, Src protein tyrosine kinase and Akt. The difference of ligand-stimulated G protein signal and/or ⁇ -arrestin signal ultimately determines the ligand-specific cellular biological effects of GPCR.
  • GRK G protein-coupled receptor kinase
  • MOR is the target of opioid analgesics such as endogenous enkephalin and morphine.
  • opioid analgesics such as endogenous enkephalin and morphine.
  • endogenous enkephalins and the opioid drug etorphine can stimulate G protein and trigger receptor endocytosis, but morphine does not trigger receptor endocytosis at all. This is because morphine stimulates MOR phosphorylation.
  • the ability is too weak and can only recruit a small amount of ⁇ -arrestin on the membrane (Zhang et al., Proc Natl Acad Sci USA, 1998, 95(12): 7157-7162).
  • Such ligands perform their physiological functions entirely through the G protein signaling pathway instead of the ⁇ -arrestin pathway.
  • MOR agonists include WO2017106547, WO2017063509, WO2012129495, WO2017106306, and so on.
  • drugs can be designed based on the negative ⁇ -arrestin preference ligand of MOR to reduce the side effects mediated by ⁇ -arrestin and enhance the therapeutic effect.
  • the purpose of the present invention is to provide a compound with a novel structure that can be used as a MOR receptor agonist.
  • the first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:
  • R 0 is hydrogen or substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl);
  • R 1 and R 2 are each independently hydrogen, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1- 3 alkyl);
  • R 1 , R 2 and the connected carbon atoms together form a 3 to 6 membered saturated or unsaturated monocyclic ring or a 3 to 6 membered saturated or unsaturated monocyclic ring; the 3 to 6 membered saturated or unsaturated monocyclic ring,
  • the 3- to 6-membered saturated or unsaturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10 alkoxy (preferably C 1-6 alkoxy, more Preferably C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogen (C 1-6 alkyl, more preferably halogenated C 1-3 alkyl);
  • R 3 and R 4 are each independently hydrogen, hydroxy, cyano, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted Substituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 Alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), substituted or unsubstituted C 3-8 cycloalkyl (Preferably substituted or unsubstituted C 3-6 cycloalkyl), NR 11 R 12 , or substituted or unsubstituted 4 to 6-membered saturated monocyclic heterocyclic ring;
  • R 3 , R 4 and the connected carbon atoms together form a 3 to 6 membered saturated or unsaturated monocyclic ring or a 3 to 6 membered saturated or unsaturated monocyclic ring; the 3 to 6 membered saturated or unsaturated monocyclic ring,
  • the 3- to 6-membered saturated or unsaturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10 alkoxy (preferably C 1-6 alkoxy, more Preferably C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogen (C 1-6 alkyl, more preferably halogenated C 1-3 alkyl);
  • R 11 and R 12 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkane Group), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), substituted or unsubstituted C 3-8 cycloalkyl (preferably Is a substituted or unsubstituted C 3-6 cycloalkyl), or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic heterocyclic ring; or R 11 , R 12 and the connected nitrogen atom form a substituted or unsubstituted 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring;
  • X is O or NR c ;
  • R c is hydrogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
  • R a , R b and the connected carbon atoms together form a substituted or unsubstituted C 6-10 aromatic ring, or a substituted or unsubstituted 5 or 6-membered monocyclic heteroaromatic ring, the C 6-10 aromatic ring or 5 Or a 6-membered monocyclic heteroaromatic ring and the connected heterocyclic ring form a fused bicyclic ring;
  • substitution means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents independently selected from Group A; the substituents of Group A are selected from: cyano, acetyl, hydroxyl, Hydroxymethyl, hydroxyethyl, carboxyl, halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably F or Cl ), nitro, C 6-10 aryl (preferably phenyl), 5- or 6-membered monocyclic heteroaryl, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 Alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkane Group), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl
  • the group A substituent is selected from: cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halogenated C 1-3 alkyl, halogen (preferably F or Cl ), nitro, phenyl, 5- or 6-membered monocyclic heteroaryl, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, NR a0 R b0 , -CONR a0 R b0 , -C(O)OC 1-3 alkyl, -CHO, -OC(O)C 1-3 alkane Group, -SO 2 C 1-3 alkyl, -SO 2 -phenyl, -CO-phenyl, 4 to 6 membered saturated or unsaturated monocyclic ring or 4 to 6 membered saturated or unsaturated monocyclic ring, wherein R
  • R 0 is hydrogen or C 1-3 alkyl (preferably methyl).
  • R 0 is hydrogen
  • R 1 and R 2 are each independently hydrogen or C 1-3 alkyl (preferably methyl).
  • R 1 and R 2 are each independently hydrogen.
  • the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring in the substituent group A is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole , Piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2- Dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4 -Dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
  • the 4- to 6-membered saturated or unsaturated monocyclic ring in the substituent group A is selected from: cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl Ring, cyclohexadienyl ring.
  • the 5- or 6-membered monocyclic heteroaryl group in the group A substituent is selected from: thiophene, N-alkyl pyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, three Azole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1 , 2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or Pyrazine.
  • the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R 1 , R 2 and the connected carbon atoms is selected from: aziridine, ethylene oxide, azetidine, oxa Cyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2- Dihydroazetadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2 ,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran
  • the 3- to 6-membered saturated or unsaturated monocyclic ring formed by R 1 , R 2 and the connected carbon atoms is selected from: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclopentenyl ring , Cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
  • the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R 3 , R 4 and the connected carbon atoms is selected from: aziridine, ethylene oxide, azetidine, oxa Cyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2- Dihydroazetadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2 ,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran
  • the 3- to 6-membered saturated or unsaturated monocyclic ring formed by R 3 , R 4 and the connected carbon atoms is selected from: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclopentenyl ring , Cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
  • the 4- to 6-membered saturated monocyclic heterocyclic ring in R 3 and R 4 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine Pyridine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran.
  • the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R 11 , R 12 and the connected nitrogen atom is selected from: azetidine, tetrahydropyrrole, piperidine, piperazine, Morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, 1,2-dihydroazetidine, 2,5-dihydro-1H-pyrrole, 2,3-dihydro -1H-pyrrole, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine.
  • the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring in R 11 and R 12 is selected from: aziridine, ethylene oxide, azetidine, and oxetane , Tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydronitrogen Cyclobutadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3- Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6 -Tetra
  • the 5- or 6-membered monocyclic heteroaryl group described in the substituent group A is selected from the following structures:
  • the above-mentioned 5- to 6-membered monocyclic heteroaryl group is optionally substituted with 1, 2 or 3 substituents each independently selected from Group A.
  • the C 6-10 aromatic ring formed by Ra , R b and the connected carbon atoms is a benzene ring.
  • the 5- or 6-membered monocyclic heteroaromatic ring formed by Ra , Rb and the connected carbon atoms is thiophene or furan.
  • the C 3-8 cycloalkyl group in R 11 and R 12 is selected from the group consisting of cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclohexyl ring.
  • the C 3-8 cycloalkyl group in R 3 and R 4 is selected from the group consisting of cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclohexyl ring.
  • the 5- or 6-membered monocyclic heteroaromatic ring formed by Ra , Rb and the connected carbon atoms is selected from the following structures:
  • the two ring atoms connected are represented by adjacent pairs of atoms shared when fused with other rings.
  • the 5- or 6-membered monocyclic heteroaromatic ring is unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from Group A.
  • R 3 and R 4 are each independently hydrogen, C 1-3 alkyl, C 1-3 alkyl substituted with C 1-3 alkoxy, C 3-6 cycloalkyl, NH 2. NH(C 1-3 alkyl) or N(C 1-3 alkyl) 2 ;
  • R 3 , R 4 and the connected carbon atoms together form a 4- to 6-membered saturated monocyclic ring or a 3- to 6-membered saturated monocyclic ring; the 4- to 6-membered saturated monocyclic ring or a 3- to 6-membered saturated monocyclic ring is not Substituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-3 alkoxy, C 1-3 alkyl, halo C 1-3 alkyl.
  • R 3 and R 4 are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, N(CH 3 ) 2 , methoxyethyl, cyclopropyl, and cyclopropyl. Butyl or cyclopentyl; or R 3 , R 4 and the connected carbon atoms together form a tetrahydropyran ring, a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring or a cyclohexyl ring.
  • X is O or NR c ; R c is hydrogen or methyl.
  • X is O.
  • R 0 , R 3 , and R 4 are as defined in the specification.
  • the 3- to 6-membered or 4- to 6-membered saturated monocyclic heterocyclic ring is selected from the following structures:
  • the hydrogen atoms on the above-mentioned 3- to 6-membered or 4- to 6-membered saturated monocyclic heterocyclic ring are optionally substituted with 1, 2 or 3 substituents each independently selected from Group A.
  • the compound is selected from Table A, wherein the compound of Table A is selected from the following group:
  • the compound is selected from:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and a pharmaceutically acceptable a.
  • the third aspect of the present invention provides the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to the second aspect of the present invention in the preparation of preventive and / Or use in drugs for treating related diseases mediated by MOR receptor agonists.
  • the fourth aspect of the present invention provides the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, or the pharmaceutical composition according to the second aspect of the present invention is prepared for Use in drugs that agonize or antagonize MOR receptors.
  • the fifth aspect of the present invention provides the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to the second aspect of the present invention in the preparation of prevention and / Or use in medicines for the treatment of pain and pain-related diseases.
  • the related diseases mediated by the MOR receptor agonist are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases, preferably pain.
  • the pain is selected from postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation.
  • the cancer is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.
  • the sixth aspect of the present invention provides a method for preventing and/or treating related diseases mediated by MOR receptor agonists, comprising administering to a patient a therapeutically effective amount of the compound according to the first aspect of the present invention or its pharmacy Above acceptable salt, stereoisomer or solvate, or pharmaceutical composition as described in the second aspect of the invention.
  • the seventh aspect of the present invention provides a method for preventing and/or treating pain and pain-related diseases, comprising administering to a patient a therapeutically effective amount of the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof , Stereoisomers or solvates, or pharmaceutical compositions as described in the second aspect of the present invention.
  • the related diseases mediated by the MOR receptor agonist are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases, preferably pain.
  • the pain is selected from postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation.
  • the cancer is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.
  • bi-heterocyclic methyl ethylamine-substituted oxaspiro derivatives not only have excellent analgesic effects, but also have good preference.
  • the compound of the invention has excellent pharmacokinetic properties. Therefore, the series of compounds are expected to be developed as drugs for the treatment and prevention of pain and pain-related diseases. On this basis, the inventor completed the present invention.
  • alkyl refers to linear and branched saturated aliphatic hydrocarbon groups
  • C 1-10 alkyl is an alkyl group containing 1 to 10 carbon atoms, preferably C 1-6 alkyl, more preferably It is a C 1-3 alkyl group with similar definitions; non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , N-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl
  • cycloalkyl and “cycloalkyl ring” are used interchangeably, and both refer to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group, and "C 3-8 cycloalkyl” refers to containing 3 to 8
  • the carbon atom cyclic hydrocarbon group is preferably a C 3-6 cycloalkyl group, and the definition is similar.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl , Cyclooctyl, etc., preferably cyclopropyl, cyclopentyl, and cyclohexenyl.
  • C 1-10 alkoxy refers to -O-(C 1-10 alkyl), where the definition of alkyl is as described above.
  • C 1-6 alkoxy is preferable, and C 1-3 alkoxy is more preferable.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy and the like.
  • C 3-8 cycloalkoxy refers to -O-(C 3-8 cycloalkyl), wherein cycloalkyl is defined as described above. Preferred is C 3-6 cycloalkoxy. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • C 6-10 aryl and C 6-10 aryl ring are used interchangeably, and both refer to all-carbon monocyclic or fused polycyclic rings with a conjugated ⁇ -electron system (that is, sharing adjacent The ring) group of a carbon atom pair refers to an aryl group containing 6 to 10 carbon atoms; phenyl and naphthyl are preferred, and phenyl is more preferred.
  • a bond means that two groups connected by it are connected by a covalent bond.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo refers to the replacement of one or more (eg, 1, 2, 3, 4, or 5) hydrogens in a group with halogen.
  • halo C 1-10 alkyl means that an alkyl group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, where the definition of alkyl is as described above. It is selected as a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-8 alkyl examples include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
  • halogenated C 1-10 alkoxy means that the alkoxy group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of alkoxy is as described above. It is preferably a halogenated C 1-6 alkoxy group, and more preferably a halogenated C 1-3 alkoxy group. Including (but not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy and the like.
  • halo C 3-8 cycloalkyl refers to a cycloalkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of cycloalkyl is as described above. Preferably, it is a halogenated C 3-6 cycloalkyl group. Including (but not limited to) trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl and the like.
  • amino refers to NH 2
  • cyano refers to the CN
  • Niro refers to NO 2
  • benzyl refers to -CH 2 - phenyl
  • carboxy Refers to -C(O)OH
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • Hydroxy refers to -OH
  • thiol refers to SH
  • the structure of "cyclopropylene” is:
  • heteroaryl ring and “heteroaryl” are used interchangeably and refer to having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl ;
  • the ring array shares 6, 10 or 14 ⁇ electrons; and in addition to carbon atoms, there are groups with 1 to 5 heteroatoms.
  • Heteroatom refers to nitrogen, oxygen, or sulfur.
  • 3 to 6 membered (4 to 6 membered) saturated or partially unsaturated monocyclic ring refers to a saturated or partially unsaturated all-carbon monocyclic ring containing 3 to 6 ring atoms.
  • 3 to 6-membered saturated or partially unsaturated monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, ring Hexadienyl ring and so on.
  • 3 to 6 membered (4 to 6 membered) saturated or partially unsaturated monocyclic heterocyclic ring means that 1, 2 or 3 carbon atoms in the 3 to 6 membered monocyclic ring are selected from nitrogen, oxygen or S (O) t (where t is an integer of 0 to 2) substituted by heteroatoms, but not including the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6 members, more It is preferably 5 to 6 yuan.
  • 3- to 6-membered saturated or partially unsaturated monocyclic heterocycles include (but are not limited to) propylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrrole Morpholine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-di Hydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2, 3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyr
  • 5- to 6-membered monocyclic heteroaryl ring and “5- to 6-membered monocyclic heteroaryl” are used interchangeably, and both refer to a mono-heteroaryl ring containing 5 to 6 ring atoms
  • Examples include (but are not limited to): thiophene ring, N-alkane pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole Ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole
  • substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently substituted with each other Ground is substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • substituted by a substituent means that when more than one hydrogen on a group is substituted by a substituent, the types of the substituents may be the same or different, so The selected substituents are of independent types.
  • L is (CR 01 R 02 ) s , when s is 2, that is, L is (CR 01 R 02 )-(CR 01 R 02 ), and the two R 01 or R 02 can be the same or different.
  • L can be C(CH 3 )(CN)-C(CH 2 CH 3 )(OH), C(CH 3 )(CN)-C(CH 3 )(OH) or C(CN) (CH 2 CH 3 )-C(OH)(CH 2 CH 3 ).
  • any group herein may be substituted or unsubstituted.
  • the substituents are preferably 1 to 5 or less groups independently selected from CN, halogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 Alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1- 6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, amino, halogenated C 1-8 alkyl substituted amino, acetyl Group, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, nitro, C 6-10 ary
  • the “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts of inorganic bases such as sodium, potassium, calcium and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salt, triethylamine salt, lysine salt, arginine salt and the like.
  • solvate refers to a complex formed by the compound of the present invention and a solvent. They either react in a solvent or precipitate or crystallize out of the solvent. For example, a complex formed with water is called a "hydrate”. Solvates of compounds of formula (I) fall within the scope of the present invention.
  • the compound represented by formula (I) or formula (II) of the present invention may contain one or more chiral centers and exist in different optically active forms.
  • a compound contains a chiral center
  • the compound contains enantiomers.
  • the present invention includes these two isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • diastereomers may exist.
  • the present invention includes the resolved optically pure specific isomers and mixtures of diastereomers. Diastereoisomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the present invention includes prodrugs of the aforementioned compounds.
  • Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released through enzymatic reactions to obtain the parent compound.
  • Specific preparation methods of prodrugs please refer to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DMBioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • the compound of the present invention or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer, or prodrug can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (for example, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.
  • the compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like.
  • the above-mentioned dosage forms can be prepared from the active compound and one or more carriers or excipients through general pharmaceutical methods.
  • the above-mentioned carrier needs to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or a suspension with the aforementioned carriers.
  • composition of the present invention is formulated, quantified and administered in a manner that conforms to medical practice standards.
  • the "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual to be treated, the cause of the condition, the target of the drug, and the mode of administration.
  • therapeutically effective amount refers to the amount of the compound of the present invention that will cause an individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc. the amount.
  • the therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof contained in the pharmaceutical composition of the present invention is preferably 0.1 mg-5 g/kg (body weight).
  • pharmaceutically acceptable carrier refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of excipient, which is compatible with the patient and most It is preferably a mammal, more preferably a human, which is suitable for delivering the active agent to the target target without terminating the activity of the agent.
  • patient refers to an animal, preferably a mammal, and more preferably a human.
  • mammal refers to warm-blooded spinal mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • treating refers to reducing, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing one or more symptoms of the disease or condition, preventing its development, or alleviating to a certain degree.
  • the compound represented by the following formula (I) can be prepared by a known method, for example, by the following method, a method equivalent thereto, or the method described in the examples.
  • the raw material compound may be in the form of a salt
  • the salt may be any pharmaceutically acceptable salt exemplified by the compound represented by formula (I) of the present invention.
  • the compound represented by formula (I) can be prepared according to the following method: (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl) Acetaldehyde and the compound represented by the formula (Ia) undergo a reductive amination reaction to prepare the compound represented by the formula (I).
  • the reductive amination reaction conditions are known and can be, for example, in an organic solvent (such as DCM, DCE or THF, etc.), under the catalysis of a catalyst (such as tetraisopropyl titanate), using a reducing agent (such as boron) Sodium hydride), the carbonyl group undergoes reductive amination reaction with amine.
  • an organic solvent such as DCM, DCE or THF, etc.
  • a catalyst such as tetraisopropyl titanate
  • a reducing agent such as boron
  • the compound having an amino group, a carboxyl group, or a hydroxyl group used in the present invention can be prepared by using a compound that has been protected by a protective group commonly used for this group as required. After passing through the reaction process of the above-mentioned reaction scheme, a known desorption can be carried out. Protection response.
  • a series of oxaspiro derivatives substituted with biheterocyclic methylethylamine with novel structures are provided, which have higher inhibitory activity on cAMP, higher Emax value, and excellent analgesic effect.
  • the present invention The compound has a lower Emax value for ⁇ -arrestin, and has a good bias. Therefore, it can be developed into drugs for the treatment and prevention of pain and pain-related diseases.
  • DMB 2,4-dimethoxybenzyl
  • THF tetrahydrofuran
  • EA ethyl acetate
  • PE petroleum ether
  • Ac 2 O acetic anhydride
  • NBS N-bromosuccinimide
  • DCM dichloromethane
  • AIBN azobisisobutyronitrile
  • Pd(dppf)Cl 2 is 1,1'-bis(diphenylphosphorferrocene]palladium dichloride
  • TFA is trifluoroacetic acid
  • TBSCl Is tert-butyldimethylchlorosilane
  • NCS N-chlorosuccinimide
  • DHP dihydrotetrahydropyran
  • LiAlH 4 is lithium aluminum hydride
  • PMB p-methoxybenzyl
  • LiHMDS is two (Trimethylsilyl) lithium amide
  • Pd 2 (dba) 3 tris(dibenzylideneacetone
  • room temperature refers to about 20-25°C.
  • Step 1 Dissolve methyl 2-(thiophen-3-yl)acetate (300mg, 1.92mmol) in 10mL of anhydrous tetrahydrofuran, cool to -70°C with a dry ice-ethanol bath, and add hexamethyldisilylamine dropwise Lithium (1M tetrahydrofuran solution, 2.1mL, 2.1mmol), after the addition is complete, continue stirring for 1 hour, add 1,4-dibromobutane (412mg, 1.92mmol) dropwise, warm to 0°C and continue stirring for 2 hours, Recool to -70°C, add dropwise lithium hexamethyldisilazide (1M tetrahydrofuran solution, 2.1mL, 2.1mmol), warm to 0°C and continue stirring for 2 hours, then use saturated aqueous ammonium chloride solution (50mL) for the reaction Quench, extract twice with ethyl acetate (50mL X 2).
  • Step 2 Dissolve methyl 1-(thiophen-3-yl)cyclopentanecarboxylate (400mg) in 10mL of anhydrous tetrahydrofuran, cool to 0°C in an ice water bath, and add tetrahydrolithium aluminum (217mg, 5.71mmol) ). The reaction solution was stirred overnight at room temperature and then recooled to 0°C, quenched with ethyl acetate (5mL) and sodium sulfate decahydrate (400mg), stirred for 10 minutes, filtered, and concentrated under reduced pressure to obtain crude product (1-(thiophen-3) -Cyclopentyl) methanol (300 mg, yellow oil), used directly in the next reaction. Yield: 86%. MS m/z(ESI): 183.1[M+1].
  • Step 3 Combine (1-(thiophen-3-yl)cyclopentyl)methanol (300mg, 1.65mmol), 2,2-diethoxyethylamine (438mg, 3.30mmol), trifluoromethanesulfonic acid (2mL A mixture of) and 1,4-dioxane (10 mL) was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was poured into a cold saturated aqueous sodium bicarbonate solution, extracted twice with ethyl acetate (50mL x 2), combined the organic phases, washed with brine (50mL), dried with anhydrous sodium sulfate, and filtered.
  • Step 4 Combine (5',7'-dihydrospirocyclopentane-1,4'-thieno[2,3-c]pyran]-7'-yl)methylamine (50mg) and (R )-2-(9-(pyridin-2-yl)-6-oxospiro[4.5]dec-9-yl)acetaldehyde (58mg, 0.22mmol), sodium cyanoborohydride (42 mg, 0.67mmol) The mixture of methanol and methanol (5mL) was stirred overnight at room temperature, concentrated under reduced pressure, and separated and purified by liquid phase preparation to obtain the target product N-((5'H,7'H-spirocyclo[cyclopentane-1,4' -Thieno[2,3-c]pyran]-7'-yl)methyl)-2-((R)-9-(pyridin-2-yl)-6-oxospiro[4.5]dec- 9-yl)ethylamine H-1
  • Step 1 Dissolve methyl 2-(thiophen-3-yl)acetate (1.56g, 0.01mol) in 40mL N,N-dimethylformamide, add 1,5-diiodopentane (4.86g, 0.015mol), cooling to 2-5°C, adding NaH (60%, 1.2g, 0.03mol) in batches, and stirring at room temperature for 1 hour.
  • Step 4 Add N-((5'H,7'H-spiro[cyclohexane-1,4'-thieno[2,3-c]pyran]-7'-yl)methylamine (60mg , 0.25mmol) and (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (66mg, 0.25mmol) dissolved in 8mL1,2 -To dichloroethane, add 0.5 mL of tetraisopropyl titanate and stir for 18 hours at 45°C.
  • the preparation method is the same as in Example 1, except that the 1,4-dibromobutane in step 1 is replaced with 1,3-dibromopropane, MS m/z(ESI): 453.2[M+1].
  • Step 1 Dissolve 2-(thiophen-3-yl)ethanol (1g, 7.25mmol) in 1,4-dioxane (15ml), add 2,2-dimethoxyethylamine (1.17g, 10.87 mmol) and sulfuric acid (1.7ml), stirring at room temperature for 2 hours. The organic phase was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography to obtain (4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)carboxamide (20 mg) as Rate: 1%. MS m/z(ESI): 170.1[M+1].
  • Step 2 Dissolve (4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)carboxamide (20mg, 0.118mmol) in chloroform (4ml) solution and add (R)-2-(9-(pyridin-2-yl)-6-oxospiro[4.5]dec-9-yl)acetaldehyde (31mg, 0.118mmol), trifluoroacetic acid (1 drop) and cyano Sodium borohydride (20mg, 0.236mmol) was stirred at room temperature and reacted overnight.
  • Step 1 Dissolve methyl 2-(thiophen-3-yl)acetate (1.56g, 0.01mol) in 40mL N,N-dimethylformamide, add methyl iodide (4.26g, 0.03mol), and cool to 2-5 degrees, add NaH (60%, 1.6 g, 0.04 mol) in batches, and stir at room temperature for 1 hour.
  • Step 3 Add 2-methyl-2-(thiophen-3-yl)propan-1-ol (1g, 6.4mmol) and 2,2-dimethoxyethylamine (0.74g, 7.04mmol) to dioxy Slowly add trifluoromethanesulfonic acid (2ml) solution to the six-ring (30ml) solution. The mixture was stirred at room temperature for 1.5 hours. 40mL of ice water was added to the reaction solution. The pH was adjusted to 9-10 with saturated potassium carbonate.
  • Step 4 Combine (4,4-dimethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methylamine (60mg, 0.3mmol) and (R) -2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (78mg, 0.3mmol) was dissolved in 8mL 1,2-dichloroethane and added 0.5 mL of tetraisopropyl titanate was stirred at 45°C for 18 hours.
  • Step 1 Dissolve methyl 2-(thiophen-3-yl)acetate (1.56g, 0.01mol) in 40mL N,N-dimethylformamide, add ethyl iodide (2.34g, 0.015mol), and cool At 2-5°C, NaH (60%, 1.6 g, 0.04 mol) was added in batches, and stirred at room temperature for 1 hour.
  • Step 2 Slowly add methyl 2-(thiophen-3-yl)butyrate (1.1g, 5.98mmol) to the suspension of lithium tetrahydroaluminum (0.45g, 11.96mmol) in methyl tert-butyl ether (35ml) )
  • Step 4 Combine (4-ethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methylamine (59mg, 0.3mmol) and (R)-2- (9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (78mg, 0.3mmol) was dissolved in 8mL 1,2-dichloroethane and 0.5mL was added Tetraisopropyl titanate was stirred and reacted at 45°C for 18 hours.
  • Example 7 The preparation method of Example 7 refers to Example 6, except that the ethyl iodide in step 1 is replaced with methyl iodide.
  • Example 8 The preparation method of Example 8 refers to Example 5, except that the methyl iodide in step 1 is replaced with ethyl iodide.
  • Example 9 refers to Example 6, except that the ethyl iodide in step 1 is replaced with 2-iodopropane.
  • Example 10 The preparation method of Example 10 refers to Example 6, except that the ethyl iodide in step 1 is replaced with 1-iodopropane.
  • Step 1 Dissolve methyl 2-(thiophen-3-yl)acetate (500mg, 3.20mmol) in 10mL of dimethylformamide, add potassium tert-butoxide (539mg, 4.80mmol) at 0°C, and stir for reaction 30 Then, bromocyclobutane (475 mg, 3.52 mmol) was added, and the reaction was stirred at room temperature for 2 hours. 80 mL of ethyl acetate was added to the reaction solution, and washed with saturated sodium chloride solution (30 mL ⁇ 3) and water (30 mL) in sequence.
  • Step 2 Dissolve methyl 2-cyclobutyl-2-(thiophen-3-yl)acetate (498mg, 2.37mmol) in 10mL of tetrahydrofuran, cool to 0°C under nitrogen protection, and add lithium aluminum hydride (135mg, 3.56 mmol), the reaction was stirred at 0°C for 1 hour. The reaction solution was poured into 70 mL saturated ammonium chloride solution for quenching, and extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 3 Dissolve 2-cyclobutyl-2-(thiophen-3-yl)ethanol (205mg, 1.12mmol) and aminoacetaldehyde dimethylacetal (176mg, 1.67mmol) in 5mL 1,4-dioxane Add 0.5 mL of trifluoromethanesulfonic acid while cooling under the protection of nitrogen, and stir and react at room temperature for 1 hour. After neutralization with potassium hydroxide aqueous solution, 30 mL of saturated sodium bicarbonate solution was added and extracted with ethyl acetate (30 mL ⁇ 3).
  • Step 4 Combine (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (50mg, 0.193mmol) and (4-cyclobutane 4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methylamine (47 mg, 0.21 mmol) was dissolved in 10 mL of methanol, a drop of acetic acid was added, and the reaction was stirred for 30 minutes. Sodium cyanoborohydride (49 mg, 0.78 mmol) was added to the reaction solution, and the reaction was stirred overnight.
  • Step 1 Dissolve 2-(1,3-dioxoisoindolin-2-yl)acetic acid (10g, 48mmol) in 80mL tetrahydrofuran, add oxalyl chloride (6.2mL, 73mmol) in sequence at 0°C to catalyze The amount of N,N-dimethylformamide. The reaction was stirred at 0°C for 2 hours. Concentrated under reduced pressure to obtain the product 2-(1,3-dioxoisoindolin-2-yl)acetyl chloride (10.7 g, yellow liquid), yield: 100%. MS m/z(ESI): 224.0[M+1] (quenched with methanol, sample delivery).
  • Step 2 2-(1,3-dioxoisoindolin-2-yl)acetyl chloride (10.7g, 48mmol) was added to 100mL of anhydrous dichloromethane, and 2-phenyl- 1-Ethylamine (5.8 g, 48 mmol), triethylamine (13.4 mL, 96 mmol). The reaction was stirred at room temperature for 2 hours.
  • Step 3 Dissolve 2-(1,3-dioxoisoindolin-2-yl)-N-phenethylacetamide (8g, 259mmol) in 80mL acetonitrile, add phosphorus oxychloride (7.25mL , 778mmol), the reaction was stirred at 80°C for 80 hours.
  • Step 4 Dissolve 2-((3,4-dihydroisoquinolin-1-yl)methyl)isoindole-1,3-dione (1.45mg, 50mmol) in 15mL dichloromethane and add Sodium triacetylborohydride (3.18g, 150mmol), catalytic amount of acetic acid, stirred at room temperature for 3 hours.
  • Step 5 2-((1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindole-1,3-dione (1.4g, 4.78mmol) was added to 10mL methanol , Add 2-phenyl-1-amine (0.29g, 9.6mmol), catalytic amount of acetic acid. The reaction was stirred at 80°C for 2 hours.
  • Step 6 2-((2-Methyl-1,2,3,4-tetrahydroisoquin-1-yl)methyl)isoindole-1,3-dione (0.6g, 1.96mmol ) was added to 5 mL of ethanol, and hydrazine hydrate (0.39 g, 7.84 mmol) was added. The reaction was stirred at 80°C for 2 hours.
  • Step 7 Dissolve (2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methylamine (78mg, 0.3mmol) in 5mL methanol, add (R)-2-( 9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (54mg, 0.3mmol), sodium cyanoborohydride (95mg, 1.5mmol), and a catalytic amount of acetic acid. The reaction was stirred at 70°C for 3 hours.
  • Example 13 The preparation method of Example 13 refers to Example 4, except that the 2,2-dimethoxyethylamine in step 1 is replaced with 1,1-dimethoxy-2-propylamine.
  • Example 14 refers to Example 4, except that the 2,2-dimethoxyethylamine in step 1 is replaced with 1,1-dimethoxy-2-methylpropane-2-amine.
  • Example 15 refers to Example 4, except that the 2,2-dimethoxyethylamine in step 1 is replaced with 2,2-dimethoxypropane-1-amine.
  • Example 16 The preparation method of Example 16 refers to Example 4, except that the 2-(thiophen-3-yl)ethanol in step 1 is replaced with 2-(thiophen-2-yl)ethanol.
  • Example 17 The preparation method of Example 17 refers to Example 4, except that the 2-(thiophen-3-yl)ethanol in step 1 is replaced with 2-(furan-3-yl)ethanol.
  • Step 1 Refer to Step 6 of Example 12, except that the raw material 2-((2-methyl-1,2,3,4-tetrahydroisoquin-1-yl)methyl)isoindoline The -1,3-dione was replaced with 2-((1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindole-1,3-dione.
  • Step 2 Refer to Step 7 of Example 12, except that (2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methylamine was replaced with (3,4-dihydro Isoquinolin-1-yl)methylamine.
  • Step 3 Refer to Step 4 of Example 12, except that 2-((3,4-dihydroisoquinolin-1-yl)methyl)isoindole-1,3-dione was replaced with (R )-N-((3,4-Dihydroisoquinolin-1-yl)methyl)-2(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl) -Ethylamine.
  • Example 19 refers to steps 2 to 4 of Example 11. The difference is that methyl 2-cyclobutyl-2-(thiophen-3-yl)acetate in step 2 is replaced with 2-dimethylamino- Ethyl 2-(thiophen-3-yl)acetate.
  • Example 20 refers to Example 6, except that the iodoethane in step 1 is replaced with 1-iodo-2-methoxyethane.
  • Example 21 refers to Example 6, except that the iodoethane in step 1 is replaced with 1,1'-oxybis[2-iodoethane].
  • Step 1 Dissolve methyl 2-(thiophen-2-yl)acetate (1.5g, 9.6mmol) in DMF (30ml), add sodium hydride (60%, 1.15g, 28.8mmol) at 0 degree, 0 degree After stirring for half an hour, methyl iodide (4.1 g, 28.8 mmol) was added, and the mixture was stirred at room temperature for 4 hours.
  • Step 2 Dissolve methyl 2-methyl-2-(thiophen-2-yl)propionate (300mg, 1.63mmol) in tetrahydrofuran (10ml), add tetrahydrolithium aluminum (186mg, 4.89mmol) at 0°C , Stir at 0 degrees for 1 hour. Sodium sulfate decahydrate (200 mg) was added, stirred at room temperature for half an hour, filtered, and the organic phase was concentrated under reduced pressure to obtain 2-methyl-2-(thiophen-2-yl)propanol (210 mg) with a yield of 82.3%. MS m/z(ESI): 157.1[M+1].
  • Step 3 Dissolve 2-methyl-2-(thiophen-2-yl)propanol (60mg, 0.38mmol) in 1,4-dioxane (5ml) and add 2,2-dimethoxyethane Amine (62mg, 0.58mmol) and trifluoromethanesulfonic acid (0.2ml) were stirred at room temperature for 2 hours.
  • the organic phase was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography to obtain the crude compound (7,7-dimethyl-6,7-dihydro-4H-thiophene[3,2-c]pyran-4- Yl) formamide (60 mg).
  • Step 4 Dissolve (7,7-dimethyl-6,7-dihydro-4H-thiophene[3,2-c]pyran-4-yl)carboxamide (60mg, 0.3mmol) in chloroform (6ml) solution, add (R)-2-(9-(pyridin-2-yl)-6-oxospiro[4.5]dec-9-yl)acetaldehyde (78mg, 0.3mmol), trifluoroacetic acid (1 drop) and sodium cyanoborohydride (57mg, 0.9mmol), stirred at room temperature overnight.
  • Example 23 refers to Example 4, except that the 2-(thiophen-3-yl)ethanol in step 1 is replaced with 2-(5-chloro-thiophen-3-yl)ethanol.
  • Example 24 refers to Example 1, except that the methyl 1-(thiophen-3-yl)cyclopentanecarboxylate in step 2 is replaced with 2-(5-fluoro-thiophen-3-yl)acetic acid Methyl ester.
  • Example 25 refers to Example 4, except that the 2-(thiophen-3-yl)ethanol in step 1 is replaced with 2-(5-methylthiophen-3-yl)ethanol.
  • Example 26 refers to Example 4, except that the 2-(thiophen-3-yl)ethanol in step 1 is replaced with 2-(4-methylthiophen-3-yl)ethanol.
  • Example 27 refers to Example 4, except that the 2-(thiophen-3-yl)ethanol in step 1 is replaced with 2-(4-chloro-thiophen-3-yl)ethanol.
  • Example 28 refers to Example 4, except that the 2-(thiophen-3-yl)ethanol in step 1 is replaced with 2-phenyl-1-ol.
  • Step 1-2 Refer to Steps 2 and 3 of Example 12, except that 2-phenyl-1-ethylamine is replaced with 2-thiophen-1-ethylamine.
  • Step 3 Refer to Step 6 of Example 12, except that the raw material 2-((2-methyl-1,2,3,4-tetrahydroisoquin-1-yl)methyl)isoindoline The -1,3-dione was replaced with 2-((1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindole-1,3-dione.
  • Step 4 Refer to Step 7 of Example 12, except that (2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methylamine is replaced with (6,7-dihydro Thieno[3,2-c]pyridin-4-yl)methylamine.
  • Step 5 Refer to Step 4 of Example 12, except that 2-((3,4-dihydroisoquinolin-1-yl)methyl)isoindole-1,3-dione was replaced with (R )-N-(((6,7-Dihydrothieno[3,2-c]pyridin-4-yl)methyl)-2(9-(pyridin-2-yl)-6-oxaspiro[ 4.5] Dec-9-yl)-ethylamine.
  • Example 30 refers to Example 12, except that the 2-phenyl-1-amine in step 2 is replaced with 2-(thiophen-2-yl)-ethylamine.
  • Step 1-2 Refer to Steps 2 and 3 of Example 12, except that 2-phenyl-1-ethylamine is replaced with 2-thiophene-3-ethylamine.
  • Step 3 Refer to Step 6 of Example 12, except that the raw material 2-((2-methyl-1,2,3,4-tetrahydroisoquin-1-yl)methyl)isoindoline
  • the -1,3-dione was replaced with 2-((4,5-dihydrothieno[2,3-c]pyridin-7-yl)methyl)isoindole-1,3-dione.
  • Step 4 Refer to Step 7 of Example 12, except that (2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methylamine is replaced with (4,5-dihydro Thieno[2,3-c]pyridin-7-yl)methylamine.
  • Step 5 Refer to Step 4 of Example 12, except that 2-((3,4-dihydroisoquinolin-1-yl)methyl)isoindole-1,3-dione was replaced with (R )-N-(((4,5-Dihydrothieno[2,3-c]pyridin-7-yl)methyl)-2(9-(pyridin-2-yl)-6-oxaspiro[ 4.5] Dec-9-yl)-ethylamine.
  • Example 32 The preparation method of Example 32 refers to Example 12, except that the 2-phenyl-1-amine in step 2 is replaced with 2-(thiophen-3-yl)-ethylamine.
  • Example 33 refers to Example 1, except that the 1,4-dibromobutane in step 1 is replaced with 1,2-dibromoethane.
  • Example 34 The preparation method of Example 34 was prepared by referring to the above method.
  • Example 35 refers to Example 1, except that the 1,4-dibromobutane in step 1 is replaced with 1,3-dibromopropane, and the methyl 2-(thiophen-3-yl)acetate is replaced with Methyl 2-(thiophen-2-yl)acetate.
  • Example 36 refers to Example 6, except that the ethyl iodide in step 1 is replaced with 2-iodopropane, and methyl 2-(thiophen-3-yl)acetate is replaced with 2-(thiophen-2- Base) methyl acetate.
  • Example 37 The preparation method of Example 37 refers to Example 1, except that the 1,4-dibromobutane in step 1 is replaced with 1,2-dibromoethane, and the methyl 2-(thiophen-3-yl)acetate is replaced with Into 2-(thiophen-2-yl) methyl acetate.
  • the cell line used in the following test example is CHO-K1OPRM1 ⁇ -Arrestin Cell Line, source: DiscoverX, number: 93-0213C2, batch number: 13K0402.
  • 1 ⁇ Stimulation buffer Take 1ml of 5 ⁇ Stimulation buffer and add it to 4ml of distilled water and mix well.
  • 50uM NK477 1ml Take 1ul 50mM NKH477 storage solution and add it to 999ul 1 ⁇ Stimulation buffer solution, shake and mix well.
  • cAMP-Cryptate (donor, lyophilized) reaction solution Take 1ml 5 ⁇ cAMP-Cryptate stock solution and add it to 4ml 1 ⁇ Lysis&Detection Buffer solution, and mix gently.
  • Anti-cAMP-d2 (acceptor, lyophilized) reaction solution Take 1ml 5 ⁇ Anti-cAMP-d2 storage solution and add it to 4ml 1 ⁇ Lysis&Detection Buffer solution, and mix gently.
  • the test results of the example compounds are shown in Table 1:
  • the compound Before the compound is diluted, the compound is dissolved in DMSO to a storage concentration of 10mM.
  • the best fit curve is log(agonist) vs. response.
  • the test results of the example compounds are shown in Table 2:
  • the representative compound of the present invention has a higher inhibitory activity on cAMP and a higher Emax value.
  • the compound of the present invention has a lower Emax value for ⁇ -arrestin, and has a good bias.

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Abstract

La présente invention concerne un dérivé oxaspiro substitué de méthyléthylamine bi-hétérocyclique, son procédé de préparation, et une utilisation pharmaceutique de celui-ci. En particulier, l'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable, un stéréoisomère ou un solvate de celui-ci, son procédé de préparation et son utilisation. La définition de chaque groupe dans la formule est détaillée dans la description et les revendications.
PCT/CN2020/084773 2019-08-14 2020-04-14 Composé analgésique, son procédé de préparation et son utilisation pharmaceutique Ceased WO2021027304A1 (fr)

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WO2022206706A1 (fr) * 2021-03-29 2022-10-06 上海枢境生物科技有限公司 Dérivé contenant un spiro, son procédé de préparation et son utilisation
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JP2024511828A (ja) * 2021-03-29 2024-03-15 シューチン バイオファーマ カンパニー リミテッド スピロ環含有誘導体、その調製方法及び使用
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CN117126146A (zh) * 2022-05-25 2023-11-28 天地恒一制药股份有限公司 阿片受体激动剂及其制备方法和用途
WO2024067542A1 (fr) * 2022-09-27 2024-04-04 上海枢境生物科技有限公司 Sel ou forme cristalline contenant un dérivé spirocyclique, son procédé de préparation et son utilisation
CN119894904A (zh) * 2022-09-27 2025-04-25 上海枢境生物科技有限公司 一种含螺环类衍生物的盐、晶型及其制备方法和应用

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