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WO2021143803A1 - 光学纯的氧杂螺环取代的吡咯并吡唑衍生物、其制法与医药上的用途 - Google Patents

光学纯的氧杂螺环取代的吡咯并吡唑衍生物、其制法与医药上的用途 Download PDF

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Publication number
WO2021143803A1
WO2021143803A1 PCT/CN2021/072018 CN2021072018W WO2021143803A1 WO 2021143803 A1 WO2021143803 A1 WO 2021143803A1 CN 2021072018 W CN2021072018 W CN 2021072018W WO 2021143803 A1 WO2021143803 A1 WO 2021143803A1
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alkyl
compound
ring
formula
methyl
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PCT/CN2021/072018
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English (en)
French (fr)
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胡斌
张凯
关慧平
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Application filed by 上海海雁医药科技有限公司, 扬子江药业集团有限公司 filed Critical 上海海雁医药科技有限公司
Priority to AU2021207143A priority Critical patent/AU2021207143B2/en
Priority to US17/758,899 priority patent/US20230147833A1/en
Priority to JP2022543554A priority patent/JP7481458B2/ja
Priority to CN202180001786.7A priority patent/CN114269751B/zh
Priority to KR1020227028456A priority patent/KR20220128429A/ko
Priority to CA3164581A priority patent/CA3164581A1/en
Priority to CN202410198917.0A priority patent/CN118221680A/zh
Priority to EP21740741.0A priority patent/EP4092032A4/en
Publication of WO2021143803A1 publication Critical patent/WO2021143803A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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]
    • 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
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a class of optically pure oxaspiro ring-substituted pyrrolopyrazole derivatives, a preparation method thereof, and pharmaceutical compositions containing the derivatives as well as therapeutic agents, especially as MOR receptor agonists 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 of 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.
  • GPCR mediates and regulates physiological functions mainly through two 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 the second messenger system such as calcium ion, adenyl cyclase (AC), and mitogen-activated protein kinase (mitogen-activated protein).
  • the second messenger system such as calcium ion, adenyl cyclase (AC), and mitogen-activated protein kinase (mitogen-activated protein).
  • MAPK mitogen-activated protein kinases
  • ⁇ -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 GPCR downstream signal molecules to activate signal transduction molecules in a G protein-independent manner, Such as MAPK, Src protein tyrosine kinase and Akt. The difference in the ligand-stimulated G protein signal and/or ⁇ -arrestin signal ultimately determines the ligand-specific cellular biological effects of the 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 enkephalin 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 only a small amount of ⁇ -arrestin can be recruited 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.
  • the currently published patent applications for 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 thereof, or a solvate thereof, or a prodrug thereof:
  • R a and R b are each independently hydrogen, halogen (preferably F or Cl), C 1-6 alkyl (preferably C 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl) or halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy); or R a , R b and the connected carbon atoms together form a 4 to 6-membered saturated monomer A heterocyclic ring or a 3 to 6-membered saturated monocyclic ring; wherein the 4- to 6-membered saturated monocyclic ring and a 3 to 6-membered saturated monocyclic ring are each unsubstituted or by 1, 2 or 3 substituents selected from the following group Substitution: cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C 1-3 alkoxy, C 1-3 alkyl, -COC 1-3 alkyl, -CONR a1 R b1 , NR a1 R
  • R c is hydrogen, halogen (preferably F or Cl), C 1-6 alkyl (preferably C 1-3 alkyl), C 2-6 alkenyl (preferably C 2-4 alkenyl), C 2 -6 alkynyl (preferably C 2-4 alkynyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably halogenated C 1- 3 alkyl), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy), -COC 1-6 alkyl (preferably -COC 1-3 alkyl), -CONR a1 R b1 , NR a1 R b1 , -NHCOC 1-6 alkyl (preferably -NHCOC 1-3 alkyl), -NHCONR a1 R b1 , -NHSO 2 C 1-3 alkyl, -NHSO 2 N R a1 R b1 , -NHSO 2 C 3-6 cycloalkyl,
  • R a1 and R b1 are each independently hydrogen, C 1-6 alkyl (preferably C 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), C 3-6 cycloalkyl or 4 to 6 membered saturated monocyclic ring; or R a1 , R b1 and the connected nitrogen atom form a 4 to 6 membered saturated monocyclic ring; wherein the 4 to 6 membered saturated monocyclic ring is not Substituted or substituted with 1, 2 or 3 C 1-3 alkyl groups; and
  • the compound of formula (I) has a structure represented by formula (I-a) or formula (I-b):
  • the 4- to 6-membered saturated monocyclic heterocycle formed by Ra , Rb and the connected carbon atoms is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiophene Hydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran.
  • the 3- to 6-membered saturated monocyclic ring formed by Ra , Rb and the connected carbon atoms is selected from the group consisting of cyclopropyl ring, cyclobutyl ring, cyclopentyl ring and cyclohexyl ring.
  • the 5- or 6-membered monocyclic heteroaryl group in R c is selected from: thiophene, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole Azole, 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 4- to 6-membered saturated monocyclic heterocycle in R c is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine , Morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran.
  • the 4- to 6-membered saturated monocyclic heterocyclic ring described in R a1 and R b1 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine Pyridine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran.
  • the 4- to 6-membered saturated monocyclic heterocycle formed by R a1 , R b1 and the connected nitrogen atom is selected from: azetidine, tetrahydropyrrole, piperidine, piperazine, morpholine, sulfur Morpholine and thiomorpholine-1,1-dioxide.
  • R a, R b are each independently hydrogen, halo or C 1-3 alkyl; or R a, R b together with the carbon atom form a 3 to 6-membered saturated monocyclic ring.
  • R a and R b are each independently hydrogen, fluorine, methyl or ethyl.
  • R a, R b together with the carbon atom form a cyclopropyl ring, cyclobutyl or cyclopentyl ring.
  • R c is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl.
  • R c is hydrogen, fluorine, methyl, ethyl, methoxy or trifluoromethyl.
  • R a and R b are each independently hydrogen, fluorine or methyl; R c is hydrogen, fluorine, methyl, ethyl, methoxy or trifluoromethyl.
  • R a and R b are methyl; R c is hydrogen, fluorine, methyl, ethyl, methoxy or trifluoromethyl.
  • R a, R b is fluorine
  • R c is hydrogen, fluorine, methyl or ethyl.
  • R a and R b are hydrogen; R c is hydrogen, fluorine, methyl, ethyl or trifluoromethyl.
  • R a is hydrogen; R b is methyl; R c is methyl or ethyl.
  • R a and R b form a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring together with the connected carbon atoms;
  • R c is hydrogen, fluorine, methyl, ethyl, methoxy or tri Fluoromethyl.
  • the second aspect of the present invention provides a compound represented by formula (II), or a pharmaceutically acceptable salt, or a solvate thereof, or a prodrug thereof:
  • R 1 and R 2 are each independently hydrogen, halogen (preferably F or Cl), C 1-6 alkyl (preferably C 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl) or halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy); or R 1 , R 2 and the connected carbon atoms together form a 4 to 6-membered saturated monomer A heterocyclic ring or a 3 to 6-membered saturated monocyclic ring; wherein the 4- to 6-membered saturated monocyclic ring and a 3 to 6-membered saturated monocyclic ring are each unsubstituted or by 1, 2 or 3 substituents selected from the following group Substitution: cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C 1-3 alkoxy, C 1-3 alkyl, -COC 1-3 alkyl, -CONR 11 R 12 , NR 11 R 12 , -NHCOC 1-3 al
  • R 3 is hydrogen, halogen (preferably F or Cl), C 1-6 alkyl (preferably C 1-3 alkyl), C 2-6 alkenyl (preferably C 2-4 alkenyl), C 2 -6 alkynyl (preferably C 2-4 alkynyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably halogenated C 1- 3 alkyl), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy), -COC 1-6 alkyl (preferably -COC 1-3 alkyl), -CONR 11 R 12 , NR 11 R 12 , -NHCOC 1-6 alkyl (preferably -NHCOC 1-3 alkyl), -NHCONR 11 R 12 , -NHSO 2 C 1-3 alkyl, -NHSO 2 NR 11 R 12 , -NHSO 2 C 3-6 cycloalkyl, -SO 2 C 1-3 alkyl, -SO 2 NR 11
  • R 11 and R 12 are each independently hydrogen, C 1-6 alkyl (preferably C 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), C 3-6 cycloalkyl or 4 to 6 membered saturated monocyclic ring; or R 11 , R 12 and the connected nitrogen atom form a 4 to 6 membered saturated monocyclic ring; wherein the 4 to 6 membered saturated monocyclic ring is Substituted or substituted with 1, 2 or 3 C 1-3 alkyl groups; and
  • the compound of formula (II) has a structure represented by formula (II-a) or formula (II-b):
  • the 4- to 6-membered saturated monocyclic ring formed by R 1 , R 2 and the connected carbon atoms is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiophene Hydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran.
  • the 3 to 6-membered saturated monocyclic ring formed by R 1 , R 2 and the connected carbon atoms is selected from the group consisting of cyclopropyl ring, cyclobutyl ring, cyclopentyl ring and cyclohexyl ring.
  • the 5- or 6-membered monocyclic heteroaryl group in R 3 is selected from: thiophene, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole Azole, 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 and pyrazine.
  • the 4- to 6-membered saturated monocyclic heterocycle in R 3 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine , Morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran.
  • the 4- to 6-membered saturated monocyclic heterocyclic ring described in R 11 and R 12 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine Pyridine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide and tetrahydropyran.
  • the 4- to 6-membered saturated monocyclic ring formed by R 11 , R 12 and the connected nitrogen atom is selected from: azetidine, tetrahydropyrrole, piperidine, piperazine, morpholine, sulfur Morpholine and thiomorpholine-1,1-dioxide.
  • R 1, R 2 are each independently hydrogen, halo or C 1-3 alkyl; or R a, R b together with the carbon atom form a 3 to 6-membered saturated monocyclic ring.
  • R 1 and R 2 are each independently hydrogen, fluorine, methyl or ethyl.
  • R 1 , R 2 and the connected carbon atoms together form a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring.
  • R 3 is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl.
  • R 3 is hydrogen, fluorine, methyl, ethyl, methoxy or trifluoromethyl.
  • R 1 and R 2 are each independently hydrogen, fluorine or methyl; R 3 is hydrogen, fluorine, methyl, ethyl, methoxy or trifluoromethyl.
  • R 1 and R 2 are methyl; R 3 is hydrogen, fluorine, methyl, ethyl, methoxy or trifluoromethyl.
  • R 1 and R 2 are fluorine; R 3 is hydrogen, fluorine, methyl or ethyl.
  • R 1 and R 2 are hydrogen; R 3 is hydrogen, fluorine, methyl, ethyl or trifluoromethyl.
  • R 1 is hydrogen; R 2 is methyl; R 3 is methyl or ethyl.
  • R 1 , R 2 and the connected carbon atoms together form a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring;
  • R 3 is hydrogen, fluorine, methyl, ethyl, methoxy or tri Fluoromethyl.
  • the 4- to 6-membered saturated monocyclic heterocyclic ring is selected from the following structures:
  • the hydrogen atoms on the above 4- to 6-membered saturated monocyclic heterocyclic ring are optionally substituted with 1, 2 or 3 substituents each independently selected from the following group: cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen , C 1-3 alkoxy, C 1-3 alkyl, -COC 1-3 alkyl, -CONR a1 R b1 , NR a1 R b1 , -NHCOC 1-3 alkyl, -NHCONR a1 R b1 ,- NHSO 2 C 1-3 alkyl, -NHSO 2 NR a1 R b1 and -NHSO 2 C 3-6 cycloalkyl.
  • substituents each independently selected from the following group: cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen , C 1-3 alkoxy, C 1-3 alkyl, -COC 1-3 alkyl, -CONR a1 R b1 , NR
  • the 5- to 6-membered monocyclic heteroaryl group described in R c or R 3 is selected from the following structures:
  • the above 5- to 6-membered monocyclic heteroaryl group is optionally substituted with 1, 2 or 3 substituents each independently selected from the following group: cyano, hydroxy, hydroxymethyl, cyanomethyl, halogen, C 1 -3 alkoxy, C 1-3 alkyl, -COC 1-3 alkyl, -CONR a1 R b1 , NR a1 R b1 , -NHCOC 1-3 alkyl, -NHCONR a1 R b1 , -NHSO 2 C 1-3 alkyl, -NHSO 2 NR a1 R b1 and -NHSO 2 C 3-6 cycloalkyl.
  • substituents each independently selected from the following group: cyano, hydroxy, hydroxymethyl, cyanomethyl, halogen, C 1 -3 alkoxy, C 1-3 alkyl, -COC 1-3 alkyl, -CONR a1 R b1 , NR a1 R b1 ,
  • the compound is selected from the following group:
  • the third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof ; And a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, or a solvate thereof, or a prodrug thereof, or a pharmaceutical combination as described in the third aspect of the present invention
  • the fifth aspect of the present invention provides a compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, or a solvate thereof, or a prodrug thereof, or a pharmaceutical combination according to the third aspect of the present invention In the preparation of drugs for agonizing or antagonizing MOR receptors.
  • the sixth aspect of the present invention provides a compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, or a solvate thereof, or a prodrug thereof, or a pharmaceutical combination according to the third aspect of the present invention In the preparation of medicines for the prevention and/or 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 seventh 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 described in the first or second aspect of the present invention, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or the pharmaceutical composition according to the third aspect of the present invention.
  • the eighth aspect of the present invention provides a method for preventing and/or treating pain and pain-related diseases, which comprises administering to a patient a therapeutically effective amount of the compound according to the first or second aspect of the present invention, or pharmaceutically acceptable The accepted salt, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition as described in the third 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.
  • the ninth aspect of the present invention provides a method for preparing a compound of formula (I), including the steps:
  • the compound 1b is subjected to a reductive amination reaction with a compound of formula (I-1),
  • the compound of formula (I-1) has a structure represented by formula (I-1a) or (I-1b):
  • R a and R b are each independently hydrogen, fluorine or methyl; or R a and R b and the connected carbon atoms together form a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring; R c is hydrogen, fluorine, methyl, ethyl, methoxy or trifluoromethyl.
  • the reductive amination reaction is carried out in a reaction system of an inert solvent and a reducing agent.
  • the inert solvent is C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform , 1,2-Dichloroethane, ethyl acetate, acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, etc., or a combination thereof.
  • the reducing agent is selected from: tetrabutylamine borohydride, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, boron Lithium hydride, potassium borohydride, borane.
  • the tenth aspect of the present invention provides a method for preparing a compound of formula (II), including the steps:
  • the compound 1b is subjected to a reductive amination reaction with a compound of formula (II-1),
  • the compound of formula (II-1) has a structure represented by formula (II-1a) or (II-1b):
  • R 1 and R 2 are each independently hydrogen, fluorine or methyl; or R 1 , R 2 and the connected carbon atoms together form a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring; R 3 is hydrogen, fluorine, methyl, ethyl, methoxy or trifluoromethyl.
  • the reductive amination reaction is carried out in a reaction system of an inert solvent and a reducing agent.
  • the inert solvent is C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform , 1,2-Dichloroethane, ethyl acetate, acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, etc., or a combination thereof.
  • the reducing agent is selected from: tetrabutylamine borohydride, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, boron Lithium hydride, potassium borohydride and borane.
  • the eleventh aspect of the present invention provides a compound represented by formula (III), or its salt, or its enantiomer, or its diastereomer, or its racemate, or its non- Enantiomeric mixture:
  • R 1a and R 1b are each independently hydrogen, halogen (preferably F or Cl), C 1-6 alkyl (preferably C 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl) or halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy); or R 1a , R 1b and the connected carbon atoms together form a 4 to 6-membered saturated monomer A heterocyclic ring or a 3 to 6-membered saturated monocyclic ring; wherein the 4- to 6-membered saturated monocyclic ring and a 3 to 6-membered saturated monocyclic ring are each unsubstituted or substituted by 1, 2 or 3 substituents selected from the following group Substitution: cyano, hydroxyl, hydroxymethyl, cyanomethyl, halogen, C 1-3 alkoxy, C 1-3 alkyl, -COC 1-3 alkyl, -CONR a1 R b1 , NR a1
  • R 1c is hydrogen, halogen (preferably F or Cl), C 1-6 alkyl (preferably C 1-3 alkyl), C 2-6 alkenyl (preferably C 2-4 alkenyl), C 2 -6 alkynyl (preferably C 2-4 alkynyl), C 1-6 alkoxy (preferably C 1-3 alkoxy), halogenated C 1-6 alkyl (preferably halogenated C 1- 3 alkyl), halogenated C 1-6 alkoxy (preferably halogenated C 1-3 alkoxy), -COC 1-6 alkyl (preferably -COC 1-3 alkyl), -CONR a1 R b1 , NR a1 R b1 , -NHCOC 1-6 alkyl (preferably -NHCOC 1-3 alkyl), -NHCONR a1 R b1 , -NHSO 2 C 1-3 alkyl, -NHSO 2 N R a1 R b1 , -NHSO 2 C 3-6 cycloalkyl,
  • R a1 and R b1 are each independently hydrogen, C 1-6 alkyl (preferably C 1-3 alkyl), halogenated C 1-6 alkyl (preferably halogenated C 1-3 alkyl), C 3-6 cycloalkyl or 4 to 6 membered saturated monocyclic ring; or R a1 , R b1 and the connected nitrogen atom form a 4 to 6 membered saturated monocyclic ring; wherein the 4 to 6 membered saturated monocyclic ring is not Substituted or substituted with 1, 2 or 3 C 1-3 alkyl groups.
  • R 1a and R 1b are each independently hydrogen, halogen, or C 1-3 alkyl; or R 1a and R 1b and the connected carbon atoms together form a 3- to 6-membered saturated monocyclic ring.
  • R 1a and R 1b are each independently hydrogen, fluorine, methyl, or ethyl.
  • R 1a , R 1b and the connected carbon atoms together form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring.
  • R 1c is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, or halo C 1-3 alkyl.
  • R 1c is hydrogen, fluorine, methyl, ethyl, methoxy, or trifluoromethyl.
  • R 1a and R 1b are each independently hydrogen, fluorine, or methyl; R 1c is hydrogen, fluorine, methyl, ethyl, methoxy, or trifluoromethyl.
  • R 1a and R 1b are methyl; R 1c is hydrogen, fluorine, methyl, ethyl, methoxy, or trifluoromethyl.
  • R 1a and R 1b are fluorine; R 1c is hydrogen, fluorine, methyl, or ethyl.
  • R 1a and R 1b are hydrogen; R 1c is hydrogen, fluorine, methyl, ethyl, or trifluoromethyl.
  • R 1a is hydrogen; R 1b is methyl; R 1c is methyl or ethyl.
  • R 1a and R 1b form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring together with the connected carbon atoms;
  • R 1c is hydrogen, fluorine, methyl, ethyl, methoxy or trifluoro methyl.
  • the compound of formula (III) has a structure represented by formula (I-1) or formula (II-1):
  • R a , R b , R c in formula (I-1) are as defined in the compound of formula (I); R 1 , R 2 , and R 3 in formula (II-1) are as defined in the compound of formula (II) ;
  • the asterisk * represents that the chiral carbon atom is in the R or S configuration.
  • the compound of formula (I-1) is of formula (I-1a) or formula (I-1b); the compound of formula (II-1) is of formula (II-1a) or formula (II- 1b) Shown structure:
  • the compound of formula (I-1a) is selected from the following structures:
  • the compound of formula (I-1b) is selected from the following structures:
  • the compound of formula (II-1a) is selected from the following structures:
  • the compound of formula (II-1b) is selected from the following structures:
  • the present invention also relates to a method for preparing compounds or salts of formula (Ia), formula (Ib), formula (II-a) and formula (II-b), thereby synthesizing a substantially optically pure oxa A spiro-substituted pyrrolopyrazole derivative, which contains substantially no other stereoisomers. It is desirable to prepare such compounds in the form of substantially pure stereoisomers, with an isomer purity of at least 98% ee, and most preferably at least 99% ee. The isomer excess value provides a quantitative measurement of the percentage of the major isomer exceeding the percentage of the minor isomer coexisting with it. It can be easily measured by appropriate methods established and well-known in the art, such as Chiral High Pressure Liquid Chromatography (HPLC), Chiral Gas Chromatography (GC), Nuclear Magnetic Resonance (NMR) using chiral shift reagents, etc.
  • HPLC Chiral High Pressure Liquid Chromatography
  • GC Chiral Gas Chr
  • Figure 1 is a single crystal structure diagram of compound V5
  • Figure 2 is a single crystal structure diagram of compound V6.
  • the present inventors unexpectedly discovered that such optically pure oxaspiro ring-substituted pyrrolopyrazole derivatives not only have excellent analgesic effects, but also have good bias.
  • the invention 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
  • alkenyl groups include ethenyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, hexenyl, and the like.
  • alkynyl refers to straight-chain and branched unsaturated aliphatic hydrocarbon groups with carbon-carbon triple bonds, preferably having 2-10 (C 2-10 ), more preferably 2-6 (C 2 -6 ), more preferably 2-4 (C 2-4 ) carbon atoms.
  • alkynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, and the like.
  • cycloalkyl and “cycloalkyl ring” are used interchangeably, and both refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, and "C 3-8 cycloalkyl” means to contain 3
  • the cyclic hydrocarbon group of up to 8 carbon atoms 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.
  • spiro ring refers to a polycyclic group that shares one carbon atom (called a spiro atom) between single rings. These can contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system. According to the number of rings, spiro rings are classified into double spiro rings or multi spiro rings, preferably double spiro rings. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro ring. E.g:
  • spiro heterocyclic ring refers to a polycyclic hydrocarbon sharing one atom (called a spiro atom) between single rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer 0 to 2) of heteroatoms, and the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. According to the number of rings, spiro heterocycles are classified into dispiro heterocycles or polyspiro heterocycles, and dispiro heterocycles are preferred. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro heterocyclic ring. E.g:
  • bridged ring refers to a polycyclic group that shares two or more carbon atoms.
  • the shared carbon atoms are called bridgehead carbons.
  • the two bridgehead carbons can be a carbon chain or a bond. , Called the bridge. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. Preferably it is a double ring or a triple ring bridged ring.
  • bridged heterocycle refers to a polycyclic group that shares two or more atoms, where one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (where n is an integer from 0 to 2 ), the rest of the ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. Preferably, it is a bicyclic or tricyclic bridged heterocyclic ring. E.g:
  • 8 to 10 membered bicyclic ring refers to a bridged ring containing two rings containing 8 to 10 ring atoms.
  • the bicyclic ring may be a saturated all-carbon bicyclic ring or a partially unsaturated all-carbon bicyclic ring, and an 8- to 10-membered bicyclic ring Examples include (but are not limited to):
  • 8 to 10 membered bicyclic heterocyclic ring refers to a bridged heterocyclic ring containing two rings containing 8 to 10 ring atoms, in which 1, 2, 3, 4, or 5 ring carbon atoms are selected from nitrogen , Oxygen or sulfur heteroatoms.
  • 8- to 10-membered biheterocycles include, but are not limited to, tetrahydroquinoline ring, tetrahydroisoquinoline ring, decahydroquinoline ring, and the like.
  • C 1-8 alkoxy refers to -O-(C 1-8 alkyl), where the definition of alkyl is as described above.
  • a C 1-6 alkoxy group is preferred, a C 1-4 alkoxy group is preferred, and a C 1-3 alkoxy group is more preferred.
  • Non-limiting examples of alkoxy groups 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 the definition of cycloalkyl is as described above. Preferred is C 3-6 cycloalkoxy.
  • Non-limiting examples of cycloalkoxy 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 an all-carbon monocyclic or fused polycyclic ring with a conjugated ⁇ -electron system (that is, sharing adjacent The ring) group of carbon atom pairs 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 the 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 the alkyl group is as described above. It is preferably a halogenated C 1-8 alkyl group, more preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-4 alkyl group, and even more preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-6 alkyl examples include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
  • halo-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 1-8 alkoxy group, more preferably a halogenated C 1-6 alkoxy group, more preferably a halogenated C 1-4 alkoxy group, and more preferably a halogenated C 1-3 alkoxy group .
  • Haloalkoxy includes, but is not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
  • halogenated C 3-8 cycloalkyl refers to cycloalkyl 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.
  • deuterated C 1-8 alkyl refers to an alkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) deuterium atoms, where the definition of the alkyl group is as described above. It is preferably a deuterated C 1-6 alkyl group, and more preferably a deuterated C 1-3 alkyl group. Examples of deuterated alkyl groups include, but are not limited to, mono-deuterated methyl, mono-deuterated ethyl, di-deuterated methyl, di-deuterated ethyl, tri-deuterated methyl, tri-deuterated ethyl, 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, sharing 6, 10, or 14 ⁇ electrons in the ring array; and in addition to carbon atoms, Groups with 1 to 5 heteroatoms.
  • Heteroatom refers to nitrogen, oxygen, or sulfur. It is preferably a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group.
  • 3 to 7 membered (4 to 7 membered) saturated monocyclic ring refers to a saturated all-carbon monocyclic ring containing 3 to 7 ring atoms, preferably 3 to 6 membered saturated monocyclic ring.
  • saturated monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, cycloheptyl ring, cyclooctyl ring and the like.
  • 3 to 7 membered (4 to 7 membered) saturated monocyclic heterocyclic ring means that 1, 2 or 3 carbon atoms in the 3 to 7 membered saturated monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer of 0 to 2) replaced by heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6-membered saturated monocyclic heterocycles, More preferred is a 5- to 6-membered saturated monocyclic heterocyclic ring.
  • saturated monocyclic heterocycles include, but are not limited to, propylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine , Dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, etc.
  • 5- or 6-membered monocyclic heteroaryl ring and “5- or 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, 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 ring, thiadiazole
  • 8 to 10 membered bicyclic heteroaryl ring and “8 to 10 membered bicyclic heteroaryl ring” are used interchangeably, and both refer to a bicyclic heteroaryl ring containing 8 to 10 ring atoms, for example including (But not limited to): benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, Phthalazine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8 -Naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphth
  • 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 having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., 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, hydroxyl, hydroxymethyl, hydroxyethyl, carboxy, nitro, C 6-10
  • 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 the compound of formula (I) fall within the scope of the present invention.
  • 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 a pharmaceutically acceptable salt thereof, or a solvate, or prodrug thereof 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 common pharmacological 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 used in 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 conforming to medical practice standards.
  • the "therapeutically effective amount" of the compound to be 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.
  • terapéuticaally effective amount refers to the amount of the compound of the present invention that will cause a biological or medical response of an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc. quantity.
  • the effective dose of the compound of the present invention for therapeutic use may vary greatly in the practice of the present invention, depending on the specific application, disease or disease state involved, the dose can be easily determined by those skilled in the art .
  • the pharmaceutical composition of the present invention contains the compound of formula (I) or formula (II) or
  • the appropriate therapeutically effective dose of its pharmaceutically acceptable salt, or its solvate, or its prodrug is typically 0.1 ⁇ g to 5 g per kilogram of patient body weight per day, preferably 1 mg to 1000 mg per kilogram of body weight per day.
  • the required dose is preferably administered in two, three, four, five, six or more sub-doses at appropriate intervals within a day.
  • These sub-doses can be administered in a unit dosage form, for example, each unit dosage contains 10 ⁇ g to 1000 mg, preferably 50 ⁇ g to 500 mg, more preferably 50 ⁇ g to 250 mg, and most preferably 50 ⁇ g to 10 mg of the active ingredient.
  • the dose can be administered as a continuous infusion.
  • pharmaceutically acceptable carrier refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, packaging material or auxiliary preparation or any type of excipient, which is compatible with the patient, 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 compounds represented by formula (I) and formula (II) of the present invention can be prepared by known methods, 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) and formula (II) of the present invention.
  • the compound represented by the formula (I) can be prepared according to the following method: the compound of the formula I-1 and the compound 1b are subjected to a reductive amination reaction to obtain the compound of the formula (I).
  • the reductive amination reaction is carried out in an inert solvent at a certain temperature (e.g. -20°C to 80°C, preferably 0°C to 60°C, more preferably 20°C to 60°C), the compound of formula (I-1), compound 1b reacts with the reducing agent for a period of time (such as 0.5 hour to 48 hours, preferably 0.5 hour to 5 hours) to obtain the compound of formula (I).
  • the inert solvent and reducing agent may be known in the art, and the reducing agent may be selected from, for example, tetrabutylamine borohydride, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride , Sodium borohydride, lithium borohydride, potassium borohydride, borane and so on.
  • the inert solvent can be selected from , for example, C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloro Ethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a combination thereof.
  • the compound of formula I-1 can be prepared by reaction scheme (a-1) or by reaction scheme (a-2).
  • the compound represented by the formula (i-2) can be obtained by the condensation reaction of the compound of the formula (i-1) and (S)-2-methylpropane-2-sulfenamide (using a catalyst, for example: tetraethyl titanate) Ester, tetraisopropyl titanate); the compound represented by formula (i-2) uses a reducing agent (for example: sodium borohydride, lithium tri-sec-butyl borohydride, sodium cyanoborohydride, diisobutyl aluminum hydride ) Reduction and separation by high performance liquid chromatography to obtain two single isomers, namely compounds represented by formulas (i-3a) and (i-3b); compounds represented by formulas (i-3a) and (i-3b) Deaminization of the protective group with acid (for example: hydrogen chloride) yields compounds represented by formula (I-1a) and (I-1b), respectively.
  • a reducing agent for example: sodium borohydride, lithium tri-sec-butyl borohydr
  • the compound represented by the formula (i-2) can be obtained by the condensation reaction of the compound of the formula (i-1) and (S)-2-methylpropane-2-sulfenamide (using a catalyst, for example: tetraethyl titanate) Ester, tetraisopropyl titanate); the compound represented by formula (i-2) uses chiral resolution to obtain two single isomer compounds represented by formula (i-2a) and formula (i-2b); The compounds represented by (i-2a) and formula (i-2b) are respectively reduced with reducing agents (for example: sodium borohydride, lithium tri-sec-butyl borohydride, sodium cyanoborohydride, diisobutyl aluminum hydride) to obtain Compounds represented by formulas (i-3a) and (i-3b); compounds represented by formulas (i-3a) and (i-3b) are deaminated with an acid (e.g., hydrogen chloride) to obtain a protective group of formula (I-1a), respectively ) And
  • the chiral adjuvant (S)-2-methylpropane-2-sulfenamide in reaction schemes (a-1) and (a-2) can also be replaced with other chiral adjuvants with the same chiral inducing effect , For example (S)-methylbenzylamine.
  • the compound represented by the formula (II) can also be prepared according to the following method: the compound represented by the formula II-1 and the compound 1b are subjected to a reductive amination reaction to obtain the compound represented by the formula (II).
  • the reductive amination reaction is carried out in an inert solvent at a certain temperature (such as -20°C to 80°C, preferably at 0°C to 60°C, more preferably at 20°C to 60°C), the compound of formula (II-1), compound 1b reacts with the reducing agent for a period of time (such as 0.5 hour to 48 hours, preferably 0.5 hour to 5 hours) to obtain the compound of formula (II).
  • the inert solvent and reducing agent may be known in the art, and the reducing agent may be selected from, for example, tetrabutylamine borohydride, sodium malonyloxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride , Sodium borohydride, lithium borohydride, potassium borohydride, borane and so on.
  • the inert solvent can be selected from , for example, C 1-4 alkyl alcohol, toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-dichloro Ethane, ethyl acetate, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, etc., or a combination thereof.
  • the compound of formula II-1 can be prepared by reaction scheme (b-1) or by reaction scheme (b-2).
  • the compound represented by the formula (ii-2) can be reacted by the condensation reaction of the compound of the formula (ii-1) with (R)-2-methylpropane-2-sulfenamide (using a catalyst, for example: tetraethyl titanate Ester, tetraisopropyl titanate); the compound represented by formula (ii-2) uses a reducing agent (for example: sodium borohydride, lithium tri-sec-butyl borohydride, sodium cyanoborohydride, diisobutyl aluminum hydride) ) Reduction and separation by HPLC to prepare the compounds represented by formulas (ii-3a) and (ii-3b); the compounds represented by formulas (ii-3a) and (ii-3b) use acids (for example: hydrogen chloride) Deaminization of the protecting group yields compounds represented by formula (II-1a) and (II-1b), respectively.
  • a catalyst for example: tetraethyl titanate Ester, tetrais
  • the compound represented by the formula (ii-2) can be reacted by the condensation reaction of the compound of the formula (ii-1) with (R)-2-methylpropane-2-sulfenamide (using a catalyst, for example: tetraethyl titanate Ester, tetraisopropyl titanate); the compound represented by formula (ii-2) uses chiral resolution to obtain two single isomer compounds represented by formula (ii-2a) and formula (ii-2b); The compounds represented by (ii-2a) and formula (ii-2b) are respectively reduced with reducing agents (for example: sodium borohydride, lithium tri-sec-butyl borohydride, sodium cyanoborohydride, diisobutyl aluminum hydride) to obtain Compounds represented by formulas (ii-3a) and (ii-3b); compounds represented by formulas (ii-3a) and (ii-3b) are deaminated with an acid (e.g., hydrogen chloride) to obtain a protective
  • the chiral adjuvant (R)-2-methylpropane-2-sulfenamide in reaction schemes (b-1) and (b-2) can also be replaced with other chiral adjuvants with the same chiral inducing effect , For example (R)-methylbenzylamine.
  • the compound having an amino group, a carboxyl group, or a hydroxyl group used in the present invention can be prepared 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 optically pure oxaspiro ring substituted pyrrolopyrazole derivatives with novel structures are provided, which have high inhibitory activity on cAMP (EC 50 is 1nM to 50nM, more preferably 1nM to 30nM, the best Is 1nM to 10nM), and higher Emax value (Emax is greater than 50%, more preferably Emax is greater than 80%), has excellent analgesic effect, in addition, the compound of the present invention has a lower Emax value for ⁇ -arrestin (Emax is less than 50%, more preferably Emax is less than 20%, and the best Emax is less than 10%), good bias. Therefore, it can be developed into drugs for the treatment and prevention of pain and pain-related diseases.
  • LC-MS Agilent 1290HPLC System/6130/6150MS liquid mass spectrometer (manufacturer: Agilent), column Waters BEH/CHS, 50 ⁇ 2.1mm, 1.7 ⁇ m.
  • Single crystal detection uses Bruker's D8venture X-ray single crystal diffractometer for testing.
  • ISCO Combiflash-Rf75 or Rf200 type automatic column instrument Agela 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.
  • the known starting materials can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. and Darui Chemicals, etc. company.
  • thin layer chromatography can be used to monitor the progress of the reaction, and column chromatography can be used to purify the compound.
  • the developing agent system used in column chromatography or TLC can be selected from: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system and acetone system, etc.
  • the volume ratio of the solvent is based on the polarity of the compound Adjust differently.
  • DCE 1,2-dichloroethane
  • THF tetrahydrofuran
  • EA ethyl acetate
  • PE petroleum ether
  • DCM dichloromethane
  • n-BuLi n-butyllithium
  • HATU 2-( 7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • DMF is dimethylformamide
  • DMSO dimethyl sulfoxide
  • DIEA or DIPEA is N,N-diisopropylethylamine
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DIBAL-H diisobutylaluminum hydride.
  • room temperature refers to about 20-25°C.
  • Step 1 Add 1-methylcyclopropanecarboxylic acid (10mg, 0.10mol) and N,O-dimethylhydroxylamine hydrochloride (14.6g, 0.15mol) into 80mL DMF, and then add HATU (45.6g, 0.12 mol) and DIEA (50mL, 0.30mol) at room temperature overnight. Add EA (500 mL).
  • Step 2 Dissolve compound V2-1 (14.5 g, 101 mmol) in 90 mL of ether, cool to -78°C, and slowly add 1M diisobutylaluminum hydride (152 mL, 152 mmol) dropwise. After reacting at -78°C for 2 hours, add 1M HCl (16mL) to quench the reaction, and then add 1M HCl (16mL) after heating to 0°C. Drying with anhydrous sodium sulfate (70 g) and filtering to obtain compound V2-2.
  • 1M diisobutylaluminum hydride 152 mL, 152 mmol
  • Step 5 Dissolve compound V2-4 (12.3 g, 55.3 mmol) in 50 mL of THF and 20 mL of methanol, add lithium hydroxide monohydrate (3.6 g, 85.7 mmol) and 30 mL of water, and stir for reaction at room temperature for 2 hours. Adjust the pH value of the reaction solution to 3 with 6M hydrochloric acid solution, spin off the organic solvent under reduced pressure, extract the aqueous phase with DCM (100mL ⁇ 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • the compound V2-5 (9.2 g, colorless oily liquid) was obtained by phase chromatography, and the yield was 86%. MS m/z(ESI): 195.0[M+1].
  • Step 1 Add triethylphosphonoacetate (476mL, 2.4mol), DBU (365g, 2.4mol), lithium chloride (127g, 3mol) and acetonitrile (1.2L) into a 3L single-neck flask, protected by argon Stir at room temperature for 20 minutes. Cool to 0°C (internal temperature), and slowly add isobutyraldehyde (144g, 2mol) dropwise. Stir at room temperature for 12 hours. LCMS showed that the reaction was complete, filtered, and the filter cake was washed with EA (100 mL x 2). Add water (1L), extract with EA (1.5L x2), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and spin dry to obtain compound V3-1 (175g, colorless liquid).
  • Step 2 Add DMF (1L) to a 3L single-neck flask containing compound V3-1 (300g, 2.1mol), add potassium carbonate (579g, 4.2mol), pyrazole (287g, 4.2mol), 65 After stirring for 18 hours at °C, LCMS showed that the reaction was complete, and it was spin-dried directly. The remaining solid was slurried with acetonitrile (150 ml) and the white solid was filtered. Filter and wash the filter cake with EA (500mL x2).
  • Step 3 Add water (200 mL) to potassium hydroxide (133 g, 3.32 mol) to dissolve, and pre-cool to (5° C.). Add compound V3-2 (465g, 2.21mol), methanol (0.5L), and THF (0.5L) into a 3L flask, then add pre-cooled potassium hydroxide aqueous solution, stir for 2 hours, and adjust the pH to about 3 with concentrated hydrochloric acid. , Extracted with DCM (800ml x2), combined all the organic phases, washed with saturated brine, dried and concentrated to obtain compound V3-3 (410.5g, Y: 100%, white solid). MS m/z(ESI): 183.1[M+1].
  • Step 4 Under the protection of nitrogen, add compound V3-3 (10.2 g, 0.055 mol), THF (200 mL) to a three-necked flask (500 mL), and cool to -75°C. Slowly add 2.5M n-butyllithium (55mL, 0.137mol) in THF solution dropwise. After the dropwise addition is completed, slowly raise the temperature to -10°C and continue stirring for 3 hours. Quench with saturated ammonium chloride, add water (100mL), extract with EA (400ml x2), combine the organic phases, wash with saturated brine, dry, and concentrate to obtain a brown liquid. Purification by column chromatography (PE containing 30% EA as mobile phase) gave compound V3 (4g, Y: 22.2%, white solid), MS m/z (ESI): 165.1[M+1].
  • Step 2 Compound V4-1 (8g, 4.06mmol) was dissolved in a THF (100ml) solution, DIBAL-H (1.0M, 60ml, 6.1mmol) was added at -78°C, and stirred at -78°C for 1 hour. Sodium sulfate decahydrate was added, stirred for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound V4-2.
  • Step 5 Dissolve compound V4-4 (3.3 g, 12 mmol) in a solution of methanol (20 ml) and water (5 ml), add lithium hydroxide (0.55 g, 24 mmol), and stir at room temperature for 2 hours.
  • the solution was added with hydrochloric acid (3N) solution to adjust the pH to 2, DCM/methanol (10/1) solution was extracted, the organic phase was distilled under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain compound V4-5 (1.8g). The rate is 61%.
  • Step 6 Compound V4-5 (1.8g, 7.26mmol) was dissolved in THF (30ml) solution, and n-butyllithium (2.5M, 7.3ml, 18.1mmol) solution was added at -78°C, and stirred at -20°C for 30 minute.
  • Preparation of compound V5 single crystal take a small amount of compound V5 into a small beaker and dissolve it with ethyl acetate, seal the small beaker with a film, and pierce some small holes in the film. Put petroleum ether in a large beaker, then place a small beaker in a large beaker, seal the large beaker, and let stand at room temperature to crystallize, and crystals will precipitate in the solution.
  • the single crystal X-ray analysis of the crystal by Bruker's D8venture X-ray single crystal diffractometer confirmed that its absolute configuration is (4S, 6S) configuration, and its structure diagram is shown in Figure 1. Therefore, the absolute configuration of compound 3-3a can be inferred from the single crystal structure of compound V5 as (4S, 6S) configuration.
  • Compound V6 can be prepared by referring to the method of compound V5. MS m/z(ESI): 384.1[M+1].
  • Preparation of compound V6 single crystal take a small amount of compound V6 into a small beaker and dissolve it with ethyl acetate, seal the small beaker with a film, and pierce some small holes in the film. Put petroleum ether into a large beaker, then place a small beaker in a large beaker, seal the large beaker, and let stand at room temperature to crystallize, and crystals will precipitate in the solution.
  • the single crystal X-ray analysis of the crystal by Bruker's D8venture X-ray single crystal diffractometer confirmed that its absolute configuration is (4R, 6R) configuration, and its structure diagram is shown in Figure 2.
  • Example 1 (4S,6S)-6-tert-butyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl )Ethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-amine (H-1a) and (4S,6R)-6-tert-butyl-N-( 2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-5,6-dihydro-4H-pyrrolo[1, 2-b)pyrazol-4-amine (H-1b)
  • Step 1 Dissolve compound V1 (1g, 5.6mmol) and (R)-2-methylpropane-2-sulfenamide (1g, 8.4mmol) in 70ml of toluene, add 3mL of tetraisopropyl titanate, 120 The reaction was stirred at °C for 1 hour.
  • Step 2 Take compound 1-1 (0.8g) through preparative chromatography (preparation conditions, preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm gradient: 30%-60% Acetonitrile change) purification to obtain two single-configuration products 1-2a (340mg, retention time of 9.5min) and 1-2b (300mg, retention time of 10.5min).
  • Step 3 Dissolve compound 1-2a (0.3g, 1mmol) in 15ml DCM, add 4M hydrochloric acid dioxane solution, stir and react at room temperature for 1 hour. Concentrated to obtain compound 1-3a (179 mg, yellow solid), yield: 100%. MS m/z(ESI): 180.1[M+1].
  • Step 4 Dissolve compound 1-3a (179 mg, 1 mmol) and compound 1b (259 mg, 1 mmol) in 30 mL of methanol, and stir and react at room temperature for 1 hour. Add sodium cyanoborohydride (248mg, 4mmol) and stir for 5 hours, add 5mL of water to the reaction solution, stir for 0.5 minutes, filter, and concentrate the filtrate under reduced pressure, preparative chromatography (preparation conditions, preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm gradient: 30%-60% acetonitrile change) purified to obtain a single configuration compound H-1a (110 mg, white solid), yield: 31%.
  • Step 5 Referring to the preparation method of step 3, compound 1-3b is prepared using compound 1-2b as a raw material.
  • Step 6 Referring to the preparation method of Step 4, compound H-1b (110 mg, white solid) was prepared using compound 1-3b as a raw material, and the yield: 31%.
  • Step 2 Compound 2-1 (612 mg, 2.19 mmol) was added to 50 mL methanol. After cooling to 0°C, sodium borohydride (166 mg, 4.39 mmol) was added, and the reaction was stirred at room temperature for 2 hours. Concentrate under reduced pressure and use preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH 4 HCO 3 H 2 O; wavelength: 254/214nm; gradient: 30%-60% acetonitrile change) to obtain two single isoforms Structure 2-2a (254mg, colorless oily liquid, retention time: 9min) yield: 41%; 2-2b (242mg, colorless oily liquid, retention time: 10min), yield: 39%. MS m/z (ESI): 282.1 [M+1].
  • Step 3 Compound 2-2a (254 mg, 0.90 mmol) was added to 20 mL methanol. 4M hydrochloric acid 1,4-dioxane solution (4.5 mL, 18 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Concentrate under reduced pressure, add 30mL saturated sodium bicarbonate solution, extract with DCM and methanol (15:1) (50mL ⁇ 4), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a single isomer compound The yield of 2-3a (151 mg, pale yellow oily liquid): 94%. MS m/z(ESI): 178.1[M+1].
  • Step 4 Add compound 2-3a (151 mg, 0.85 mmol), compound 1b (243 mg, 0.94 mmol) and sodium cyanoborohydride (268 mg, 4.26 mmol) into 20 mL of methanol. After reacting at 40°C for 4 hours, the reaction was stirred overnight at room temperature. Concentrate under reduced pressure, and purify the resulting residue by preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH 4 HCO 3 H 2 O; wavelength: 254/214nm; gradient: 30%-60% acetonitrile change), Compound H-2a (186.25 mg, white solid) was obtained, and the yield was 52%.
  • Step 5 Compound 2-2b (242 mg, 0.86 mmol) was added to 20 mL of methanol. 4M hydrochloric acid 1,4-dioxane solution (4.3 mL, 17.2 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Concentrate under reduced pressure, add 30mL saturated sodium bicarbonate solution, extract with DCM and methanol (15:1) (50mL ⁇ 4), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a single isomer compound The yield of 2-3b (151 mg, light yellow oily liquid): 99%. MS m/z(ESI): 178.1[M+1].
  • Step 6 Add compound 2-3b (151 mg, 0.85 mmol), compound 1b (243 mg, 0.94 mmol) and sodium cyanoborohydride (267 mg, 4.25 mmol) into 10 mL of methanol. After reacting at 40°C for 4 hours, the reaction was stirred overnight at room temperature. Concentrate under reduced pressure, and purify the resulting residue by preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH 4 HCO 3 H 2 O; wavelength: 254/214nm; gradient: 30%-60% acetonitrile change), Compound H-2b (215.62 mg, white solid) was obtained, yield: 60%.
  • Example 3 (4S, 6S)-6-isopropyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl )Ethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-amine (H-3a) and (4S,6R)-6-isopropyl-N-( 2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-5,6-dihydro-4H-pyrrolo[1, 2-b)pyrazol-4-amine (H-3b)
  • Step 1 Dissolve compound V3 (17g, 103.5mmol) in 250 (mL) toluene, add (R)-2-methylpropane-2-sulfenamide (18.8g, 155mmol) and tetraisopropyl titanate (117g, 414mmol), the reaction was stirred at 110°C for 16 hours. Cool to room temperature, add 80 mL of water and 600 mL of DCM to the reaction solution, filter, wash the filter cake with DCM (100 mL), separate the layers, wash the organic phase with saturated brine (100 mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate was purified by column chromatography (PE containing 30% EA as the mobile phase) to obtain compound 3-1 (20.3 g, Y: 73.5%, brown liquid). MS m/z(ESI): 268.1[M+1].
  • Step 2 Add compound 3-1 (0.39g, 1.45mmol) and methanol (5mL) into a single-neck flask, cool to 0°C, and slowly add sodium borohydride (0.11g, 2.9mmol). Stir at room temperature for 1.5 hours. Cool to 0 degrees, add 20 mL of ice water, wash and extract with DCM (50 mL x 2).
  • Step 3 Add compound 3-2a (120mg, 0.45mmol), methanol (3mL) to a single-neck flask, cool to 0°C, and slowly add methanol hydrochloric acid gas (1.2mL, 4.5mmol, 4mol/L). Stir at room temperature for 1.5 hours. Adjust the pH to about 8 with saturated sodium bicarbonate, extract with DCM (50ml x2), combine all the organic phases, wash with saturated brine, dry, and concentrate to obtain compound 3-3a (70mg, Y: 95.12%, yellow liquid). MS m/z(ESI): 166.1[M+1].
  • Step 4 Dissolve compound 3-3a (50mg, 0.3mmol) in methanol (5mL), add compound 1b (78.3mg, 0.3mmol) and sodium cyanoborohydride (94mg, 1.5mmol), stir and react at 20°C 3. Hour.
  • Step 5 Add compound 3-2b (100mg, 0.37mmol) and methanol (3mL) into a single-neck flask, cool to 0°C, and slowly add methanol hydrochloric acid gas (0.93mL, 3.7mmol, 4mol/L). Stir at room temperature for 1.5 hours. Adjust the pH to about 8 with saturated sodium bicarbonate, extract with DCM (50ml x2), combine all the organic phases, wash with saturated brine, dry, and concentrate to obtain compound 3-3b (50mg, Y: 81.2%, yellow liquid). MS m/z(ESI):166.1[M+1]
  • Step 6 Dissolve compound 3-3b (50mg, 0.3mmol) in 5 (mL) methanol, add compound 1b (78.3mg, 0.3mmol) and sodium cyanoborohydride (94mg, 1.5mmol), stir and react at 20°C 3 hours.
  • Step 2 Compound 4-1 (600 mg, 1.8 mmol) was dissolved in a methanol (10 ml) solution, sodium borohydride (205 mg, 5.4 mmol) was added at zero degree, and the mixture was stirred at room temperature for 2 hours.
  • Step 3 Compound 4-2a (150 mg, 0.45 mmol) was dissolved in methanol (10 ml), hydrogen chloride THF solution (4M, 2 ml) was added, and the mixture was stirred at room temperature for 4 hours. DCM (50ml) was added, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain compound 4-3a (100mg).
  • Step 4 Compound 1b (112mg, 0.43mmol) was dissolved in methanol (10ml) solution, compound 4-3a (100mg, 0.43mmol) and sodium cyanoborohydride (55mg, 0.86mmol) were added, and stirred at 40°C for 4 hours. Water was added, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography to obtain compound H-4a (72.70 mg) with a yield of 36%.
  • Step 5 Referring to the preparation method of step 3, compound 4-3b is prepared using compound 4-2b as a raw material.
  • Step 6 Referring to the preparation method of Step 4, compound H-4b (90.52 mg) was prepared with compound 4-3b as a raw material, and the yield was 44%.
  • Example 7 (4R, 6S)-6-isopropyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl )Ethyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-amine (H-7a) and (4R,6R)-6-isopropyl-N-( 2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-5,6-dihydro-4H-pyrrolo[1, 2-b)pyrazol-4-amine (H-7b)
  • Example 3 Refer to the preparation method of Example 3, the difference is that the compound (S)-2-methylpropane-2-sulfenamide is used instead of the compound (R)-2-methylpropane-2-sulfenamide to obtain a single Configuration compounds H-7a and H-7b, MS m/z(ESI): 409.3[M+1].
  • Example 8 (4R,6S)-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-6 -(1-(Trifluoromethyl)cyclopropyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-amine (H-8a) and (4R,6R) -N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-6-(1-(trifluoromethyl) )Cyclopropyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-4-amine (H-8b)
  • the cell line used in the following test example is CHO-K1OPRM1 ⁇ -Arrestin Cell Line, source: DiscoverX, number: 93-0213C2, batch number: 13K0402.
  • the cells are digested and subcultured with cell digestion solution.
  • 1 ⁇ Stimulation buffer Take 1ml of 5 ⁇ Stimulation buffer and add it to 4ml of distilled water, and mix well.
  • 50uM NK477 1ml Take 1 ⁇ l 50mM NKH477 storage solution and add it to 999 ⁇ l 1 ⁇ Stimulation buffer solution, shake and mix well.
  • cAMP-Cryptate (donor, lyophilized) reaction solution Take 1ml of 5 ⁇ cAMP-Cryptate storage solution and add it to 4ml of 1 ⁇ Lysis&Detection Buffer, and mix gently.
  • Anti-cAMP-d2 (acceptor, lyophilized) reaction solution Take 1ml of 5 ⁇ Anti-cAMP-d2 storage solution and add it to 4ml of 1 ⁇ Lysis&Detection Buffer, and mix gently.
  • the cells are digested and subcultured with cell digestion solution.
  • 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.
  • Table 2 The results 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

光学纯的氧杂螺环取代的吡咯并吡唑衍生物、其制法与医药上的用途，所述化合物为式(I)和式(Ⅱ)所示的化合物或其药学上可接受的盐，或其溶剂化物，或其前药，及其制备方法和应用。

Description

光学纯的氧杂螺环取代的吡咯并吡唑衍生物、其制法与医药上的用途 技术领域
本发明涉及一类光学纯的氧杂螺环取代的吡咯并吡唑衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂，特别是作为MOR受体激动剂和在制备治疗和预防疼痛和疼痛等相关疾病的药物中的用途。
背景技术
阿片受体是一类重要的G蛋白偶联受体(G protein coupled receptor,GPCR)，是内源性阿片肽及阿片类药物结合的靶点，内源性阿片肽是哺乳动物体内天然生成的阿片样活性物质，目前已知的内源性阿片肽大致分为脑啡肽、内啡肽、强啡肽和新啡肽几类。中枢神经系统中存在其相应的阿片受体，即μ(MOR)、δ(DOR)、κ(KOR)受体等。研究发现，内源性阿片肽镇痛作用的强弱，主要取决于阿片受体表达的多少，阿片受体是阿片类药物以及内源性阿片肽镇痛作用的靶点。
目前的研究认为，GPCR介导及调控生理功能，主要经由两条途径：G蛋白途径和β-arrestin途径。传统的GPCR激动剂与受体结合后，激活G蛋白信号途径，包括钙离子等第二信使系统、腺苷酸环化酶(adenyl cyclase，AC)、丝裂原活化蛋白激酶(mitogen-activated protein kinases，MAPK)等，而β-arrestin偏爱性配体则主要激活β-arrestin途径。而β-arrestin介导的GPCR反应主要包括3个方面：1)作为负性调控因子，与G蛋白偶联受体激酶(GRK)作用，使GPCRs发生受体脱敏反应，中止G蛋白信号转导；2)作为支架蛋白(scaffold protein)，募集胞吞蛋白，诱导GPCR内吞；3)作为接头蛋白，与GPCR下游信号分子形成复合物，以G蛋白非依赖的方式激活信号转导分子，如MAPK、Src蛋白酪氨酸激酶和Akt等。配体刺激G蛋白信号和/或β-arrestin信号的差异，最终决定了GPCR的配体特异性细胞生物学效应。
MOR是内源性脑啡肽和吗啡等阿片类镇痛药物的作用靶点。早期研究显示，内源性脑啡肽和阿类药物埃托啡可以激动G蛋白并引发受体内吞，但是吗啡却完全不会引发受体的内吞，这是因为吗啡激动MOR磷酸化的能力太弱，仅能募集微量的β-arrestin于膜上(Zhang等，Proc Natl Acad Sci USA,1998,95(12):7157-7162)。此类配体完全通过G蛋白信号通路而不是β-arrestin途径来发挥其生理功能。研究发现给β-arrestin2基因敲除小鼠注射吗啡后，由G蛋白信号介导的镇痛效果更强且维持时间更长(Bohn等，Science，1999年)。可以预见，如果此类配体的负性β-arrestin偏爱性更强，甚至可以逃脱β-arrestin介导的受体脱敏，则可导致G蛋白信号传递时间延长，产生更强大的镇痛作用。
目前公开的MOR激动剂专利申请包括WO2017106547、WO2017063509、WO2012129495、WO2017106306等。
阿片类药物长期使用会产生耐受以及呼吸抑制、便秘等副作用，而这些副作用被证明与β-arrestin的功能密切相关。为了减小阿片类药物的副作用，可基于MOR的负性β-arrestin偏爱性配体设计药物，使β-arrestin介导的副作用降低，增强治疗效果。
发明内容
本发明的目的是提供一种结构新颖的可作为MOR受体激动剂的化合物。
本发明第一方面提供了一种式(I)所示的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药：
Figure PCTCN2021072018-appb-000001
其中，
R a、R b各自独立地为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)或卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)；或者R a、R b与相连的碳原子共同形成4至 6元饱和单杂环或3至6元饱和单环；其中所述4至6元饱和单杂环和3至6元饱和单环各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1和-NHSO 2C 3-6环烷基；
R c为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、C 2-6烯基(优选为C 2-4烯基)、C 2-6炔基(优选为C 2-4炔基)、C 1-6烷氧基(优选为C 1-3烷氧基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)、-COC 1-6烷基(优选为-COC 1-3烷基)、-CONR a1R b1、NR a1R b1、-NHCOC 1-6烷基(优选为-NHCOC 1-3烷基)、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2N R a1R b1、-NHSO 2C 3-6环烷基、-SO 2C 1-3烷基、-SO 2NR a1R b1、4至6元饱和单杂环、C 6-10芳基或5或6元单环杂芳基；其中所述4至6元饱和单杂环、C 6-10芳基和5或6元单环杂芳基各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1和-NHSO 2C 3-6环烷基；
R a1、R b1各自独立地为氢、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、C 3-6环烷基或4至6元饱和单杂环；或者R a1、R b1与相连的氮原子形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-3烷基取代；以及
*为R或S构型。
在另一优选例中，式(I)化合物为式(I-a)或式(I-b)所示结构：
Figure PCTCN2021072018-appb-000002
在另一优选例中，R a、R b与相连的碳原子共同形成的4至6元饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物和四氢吡喃。
在另一优选例中，R a、R b与相连的碳原子共同形成的3至6元饱和单环选自：环丙基环、环丁基环、环戊基环和环己基环。
在另一优选例中，R c中所述5或6元单环杂芳基选自：噻吩、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-恶二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪。
在另一优选例中，R c中所述4至6元饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物和四氢吡喃。
在另一优选例中，R a1和R b1中所述的4至6元饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物和四氢吡喃。
在另一优选例中，R a1、R b1与相连的氮原子形成的4至6元饱和单杂环选自：氮杂环丁烷、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉和硫代吗啉-1,1-二氧化物。
在另一优选例中，R a、R b各自独立地为氢、卤素或C 1-3烷基；或者R a、R b与相连的碳原子共同形成3至6元饱和单环。
在另一优选例中，R a、R b各自独立地为氢、氟、甲基或乙基。
在另一优选例中，R a、R b与相连的碳原子共同形成环丙基环、环丁基环或环戊基环。
在另一优选例中，R c为氢、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基。
在另一优选例中，R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在另一优选例中，R a、R b各自独立地为氢、氟或甲基；R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在另一优选例中，R a、R b为甲基；R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在另一优选例中，R a、R b为氟；R c为氢、氟、甲基或乙基。
在另一优选例中，R a、R b为氢；R c为氢、氟、甲基、乙基或三氟甲基。
在另一优选例中，R a为氢；R b为甲基；R c为甲基或乙基。
在另一优选例中，R a、R b与相连的碳原子共同形成环丙基环、环丁基环或环戊基环；R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
本发明第二方面提供了一种式(II)所示的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药：
Figure PCTCN2021072018-appb-000003
其中，
R 1、R 2各自独立地为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)或卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)；或者R 1、R 2与相连的碳原子共同形成4至6元饱和单杂环或3至6元饱和单环；其中所述4至6元饱和单杂环和3至6元饱和单环各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR 11R 12、NR 11R 12、-NHCOC 1-3烷基、-NHCONR 11R 12、-NHSO 2C 1-3烷基、-NHSO 2NR 11R 12和-NHSO 2C 3-6环烷基；
R 3为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、C 2-6烯基(优选为C 2-4烯基)、C 2-6炔基(优选为C 2-4炔基)、C 1-6烷氧基(优选为C 1-3烷氧基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)、-COC 1-6烷基(优选为-COC 1-3烷基)、-CONR 11R 12、NR 11R 12、-NHCOC 1-6烷基(优选为-NHCOC 1-3烷基)、-NHCONR 11R 12、-NHSO 2C 1-3烷基、-NHSO 2NR 11R 12、-NHSO 2C 3-6环烷基、-SO 2C 1-3烷基、-SO 2NR 11R 12、4至6元饱和单杂环、C 6-10芳基或5或6元单环杂芳基；其中所述4至6元饱和单杂环、C 6-10芳基和5或6元单环杂芳基各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR 11R 12、NR 11R 12、-NHCOC 1-3烷基、-NHCONR 11R 12、-NHSO 2C 1-3烷基、-NHSO 2NR 11R 12和-NHSO 2C 3-6环烷基；
R 11、R 12各自独立地为氢、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、C 3-6环烷基或4至6元饱和单杂环；或者R 11、R 12与相连的氮原子形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-3烷基取代；以及
*为R或S构型。
在另一优选例中，式(II)化合物为式(II-a)或式(II-b)所示结构：
Figure PCTCN2021072018-appb-000004
在另一优选例中，R 1、R 2与相连的碳原子共同形成的4至6元饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物和四氢吡喃。
在另一优选例中，R 1、R 2与相连的碳原子共同形成的3至6元饱和单环选自：环丙基环、环丁基环、环戊基环和环己基环。
在另一优选例中，R 3中所述5或6元单环杂芳基选自：噻吩、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-恶二唑、噻二唑、吡啶、哒嗪、嘧啶和吡嗪。
在另一优选例中，R 3中所述4至6元饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻 吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物和四氢吡喃。
在另一优选例中，R 11和R 12中所述的4至6元饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物和四氢吡喃。
在另一优选例中，R 11、R 12与相连的氮原子形成的4至6元饱和单杂环选自：氮杂环丁烷、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉和硫代吗啉-1,1-二氧化物。
在另一优选例中，R 1、R 2各自独立地为氢、卤素或C 1-3烷基；或者R a、R b与相连的碳原子共同形成3至6元饱和单环。
在另一优选例中，R 1、R 2各自独立地为氢、氟、甲基或乙基。
在另一优选例中，R 1、R 2与相连的碳原子共同形成环丙基环、环丁基环或环戊基环。
在另一优选例中，R 3为氢、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基。
在另一优选例中，R 3为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在另一优选例中，R 1、R 2各自独立地为氢、氟或甲基；R 3为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在另一优选例中，R 1、R 2为甲基；R 3为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在另一优选例中，R 1、R 2为氟；R 3为氢、氟、甲基或乙基。
在另一优选例中，R 1、R 2为氢；R 3为氢、氟、甲基、乙基或三氟甲基。
在另一优选例中，R 1为氢；R 2为甲基；R 3为甲基或乙基。
在另一优选例中，R 1、R 2与相连的碳原子共同形成环丙基环、环丁基环或环戊基环；R 3为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在另一优选例中，所述4至6元饱和单杂环选自以下结构：
Figure PCTCN2021072018-appb-000005
Figure PCTCN2021072018-appb-000006
上述4至6元饱和单杂环上的氢原子任选地被1、2或3个各自独立地选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1和-NHSO 2C 3-6环烷基。
在另一优选例中，R c或R 3中所述的5至6元单环杂芳基选自以下结构：
Figure PCTCN2021072018-appb-000007
Figure PCTCN2021072018-appb-000008
上述5至6元单环杂芳基任选地被1、2或3个各自独立地选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1和-NHSO 2C 3-6环烷基。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2021072018-appb-000009
Figure PCTCN2021072018-appb-000010
本发明第三方面提供了一种药物组合物，所述药物组合物包括本发明第一或第二方面所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药；以及药学上可接受的载体。
本发明第四方面提供了本发明第一或第二方面所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，或如本发明第三方面所述药物组合物在制备预防和/或治疗MOR受体激动剂介导的相关疾病的药物中的用途。
本发明第五方面提供了本发明第一或第二方面所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，或如本发明第三方面所述药物组合物在制备用于激动或拮抗MOR受体的药物中的用途。
本发明第六方面提供了本发明第一或第二方面所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，或如本发明第三方面所述药物组合物在制备预防和/或治疗疼痛和疼痛相关疾病的药物中的用途。
在另一优选例中，所述MOR受体激动剂介导的相关疾病选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神疾病、泌尿和生殖疾病、心血管疾病和呼吸道疾病，优选疼痛。
在另一优选例中，所述疼痛选自术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛和炎症引起的疼痛。
在另一优选例中，所述癌症选自乳腺癌、子宫内膜癌、宫颈癌、皮肤癌、前列腺癌、卵巢癌、输卵管肿瘤、卵巢瘤、血友病和白血病。
本发明第七方面提供了一种预防和/或治疗MOR受体激动剂介导的相关疾病的方法，包括给予所需患者治疗有效量的本发明第一或第二方面方面所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，或如本发明第三方面所述药物组合物。
本发明第八方面体提供了一种预防和/或治疗疼痛和疼痛相关疾病的方法，包括给予所需患者治疗有效量的本发明第一或第二方面所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，或如本发明第三方面所述药物组合物。
在另一优选例中，所述MOR受体激动剂介导的相关疾病选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神疾病、泌尿和生殖疾病、心血管疾病和呼吸道疾病，优选疼痛。
在另一优选例中，所述疼痛选自术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛和炎症引起的疼痛。
在另一优选例中，所述癌症选自乳腺癌、子宫内膜癌、宫颈癌、皮肤癌、前列腺癌、卵巢癌、输卵管肿瘤、卵巢瘤、血友病和白血病。
本发明第九方面体提供了一种式(I)化合物的制备方法，包括步骤：
将化合物1b与式(I-1)化合物进行还原胺化反应，
Figure PCTCN2021072018-appb-000011
得到所述式(I)化合物，其中各式中基团如说明书中所定义。
在另一优选例中，式(I-1)化合物为式(I-1a)或(I-1b)所示结构：
Figure PCTCN2021072018-appb-000012
在另一优选例中，R a、R b各自独立地为氢、氟或甲基；或者R a、R b与相连的碳原子共同形成环丙基环、环丁基环或环戊基环；R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在另一优选例中，所述还原胺化反应在惰性溶剂和还原剂的反应体系下进行。
在另一优选例中，所述惰性溶剂为C 1-4烷基醇，甲苯、二甲苯、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、乙醚、二氯甲烷、氯仿、1，2-二氯乙烷、乙酸乙酯、乙腈、二甲亚砜、N,N-二甲基甲酰胺等，或其组合。
在另一优选例中，所述还原剂选自：硼氢化四丁基胺盐，丙二酰氧基硼氢化钠，三乙酰氧基硼氢化钠，氰基硼氢化钠，硼氢化钠，硼氢化锂，硼氢化钾，硼烷。
本发明第十方面体提供了一种式(II)化合物的制备方法，包括步骤：
将化合物1b与式(II-1)化合物进行还原胺化反应，
Figure PCTCN2021072018-appb-000013
得到所述式(II)化合物，其中各式中基团如说明书中所定义。
在另一优选例中，式(II-1)化合物为式(II-1a)或(II-1b)所示结构：
Figure PCTCN2021072018-appb-000014
在另一优选例中，R 1、R 2各自独立地为氢、氟或甲基；或者R 1、R 2与相连的碳原子共同形成环丙基环、环丁基环或环戊基环；R 3为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在另一优选例中，所述还原胺化反应在惰性溶剂和还原剂的反应体系下进行。
在另一优选例中，所述惰性溶剂为C 1-4烷基醇，甲苯、二甲苯、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、乙醚、二氯甲烷、氯仿、1，2-二氯乙烷、乙酸乙酯、乙腈、二甲亚砜、N,N-二甲基甲酰胺等，或其组合。
在另一优选例中，所述还原剂选自：硼氢化四丁基胺盐，丙二酰氧基硼氢化钠，三乙酰氧基硼氢化钠，氰基硼氢化钠，硼氢化钠，硼氢化锂，硼氢化钾和硼烷。
本发明第十一方面提供了一种式(Ⅲ)所示的化合物，或其盐，或其对映异构体，或其非对映异构体，或其外消旋体，或其非对映异构体混合物：
Figure PCTCN2021072018-appb-000015
Figure PCTCN2021072018-appb-000016
其中，
R 1a、R 1b各自独立地为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)或卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)；或者R 1a、R 1b与相连的碳原子共同形成4至6元饱和单杂环或3至6元饱和单环；其中所述4至6元饱和单杂环和3至6元饱和单环各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1和-NHSO 2C 3-6环烷基；
R 1c为氢、卤素(优选为F或Cl)、C 1-6烷基(优选为C 1-3烷基)、C 2-6烯基(优选为C 2-4烯基)、C 2-6炔基(优选为C 2-4炔基)、C 1-6烷氧基(优选为C 1-3烷氧基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、卤代C 1-6烷氧基(优选为卤代C 1-3烷氧基)、-COC 1-6烷基(优选为-COC 1-3烷基)、-CONR a1R b1、NR a1R b1、-NHCOC 1-6烷基(优选为-NHCOC 1-3烷基)、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2N R a1R b1、-NHSO 2C 3-6环烷基、-SO 2C 1-3烷基、-SO 2NR a1R b1、4至6元饱和单杂环、C 6-10芳基或5或6元单环杂芳基；其中所述4至6元饱和单杂环、C 6-10芳基和5或6元单环杂芳基各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1和-NHSO 2C 3-6环烷基；
R a1、R b1各自独立地为氢、C 1-6烷基(优选为C 1-3烷基)、卤代C 1-6烷基(优选为卤代C 1-3烷基)、C 3-6环烷基或4至6元饱和单杂环；或者R a1、R b1与相连的氮原子形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-3烷基取代。
在一些实施例中，R 1a、R 1b各自独立地为氢、卤素或C 1-3烷基；或者R 1a、R 1b与相连的碳原子共同形成3至6元饱和单环。
在一些实施例中，R 1a、R 1b各自独立地为氢、氟、甲基或乙基。
在一些实施例中，R 1a、R 1b与相连的碳原子共同形成环丙基环、环丁基环或环戊基环。
在一些实施例中，R 1c为氢、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基。
在一些实施例中，R 1c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在一些实施例中，R 1a、R 1b各自独立地为氢、氟或甲基；R 1c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在一些实施例中，R 1a、R 1b为甲基；R 1c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在一些实施例中，R 1a、R 1b为氟；R 1c为氢、氟、甲基或乙基。
在一些实施例中，R 1a、R 1b为氢；R 1c为氢、氟、甲基、乙基或三氟甲基。
在一些实施例中，R 1a为氢；R 1b为甲基；R 1c为甲基或乙基。
在一些实施例中，R 1a、R 1b与相连的碳原子共同形成环丙基环、环丁基环或环戊基环；R 1c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
在一些实施例中，式(Ⅲ)化合物为式(I-1)或式(II-1)所示结构：
Figure PCTCN2021072018-appb-000017
其中式(I-1)中R a、R b、R c如式(Ⅰ)化合物中所定义；式(II-1)中R 1、R 2、R 3如式(Ⅱ)化合物中所定义；星号*代表手性碳原子为R或S构型。
在一些实施例中，式(I-1)化合物为式(I-1a)或式(I-1b)所示结构；式(II-1)化合物为式(II-1a)或式(II-1b)所示结构：
Figure PCTCN2021072018-appb-000018
在一些实施方案中，式(I-1a)化合物选自以下结构：
Figure PCTCN2021072018-appb-000019
在一些实施方案中，式(I-1b)化合物选自以下结构：
Figure PCTCN2021072018-appb-000020
在一些实施方案中，式(II-1a)化合物选自以下结构：
Figure PCTCN2021072018-appb-000021
在一些实施方案中，式(II-1b)化合物选自以下结构：
Figure PCTCN2021072018-appb-000022
本发明也涉及一种用于制备式(I-a)、式(I-b)、式(II-a)和式(II-b)化合物或盐的方法，从而合成一种基本上为光学纯的氧杂螺环取代的吡咯并吡唑衍生物，该衍生物基本上不含有其他立体异构体。希望制备的这种化合物基本上为纯的立体异构体形式，异构体纯度为至少98％ee，最优选为至少99％ee。异构体过量值提供的是主要异构体的百分量超过与其同时存在的次要异构体的百分量的定量测量，可容易地通过本领域所建立的和公知的适当方法进行测量，例如手性高压液相色谱法(HPLC)、手性气相色谱法(GC)、使用手性位移试剂的核磁共振(NMR)等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为化合物V5的单晶结构图；
图2为化合物V6的单晶结构图。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现了这类光学纯的氧杂螺环取代的吡咯并吡唑衍生物，不仅具有优异的镇痛效果，还具有较好的偏向性，此外本发明的化合物具有优异的药代动力学特性。因此该系列化合物有望开发成为用于治疗和预防疼痛和疼痛相关疾病的药物。在此基础上，发明人完成了本发明。
术语定义
如本文所用，“烷基”指直链和支链的饱和的脂族烃基，C 1-10烷基为包含1至10个碳原子的烷基，优 选为C 1-6烷基，更优选为C 1-3烷基，定义类似；烷基的非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等更优选。
如本文所用，“烯基”指直链或支链的具有碳碳双键(C＝C)的不饱和脂族烃基，优选具有2-10个(C 2-10)，较优选为2-6个(C 2-6)，更优选为2-4个(C 2-4)碳原子。烯基的非限制性实施例包括乙烯基、丙烯基、异丙烯基、正丁烯基、异丁烯基、戊烯基、己烯基等。
如本文所用，“炔基”指直链和支链的具有碳碳三键的不饱和脂族烃基，优选具有2-10个(C 2-10)，较优选为2-6个(C 2-6)，更优选为2-4个(C 2-4)碳原子。炔基的非限制性实施例包括乙炔基、丙炔基、正丁炔基、异丁炔基、戊炔基、己炔基等。
如本文所用，“环烷基”和“环烷基环”可互换使用，均指饱和或部分不饱和单环或多环环状烃基，“C 3-8环烷基”是指包含3至8个碳原子的环烃基，优选为C 3-6环烷基，定义类似。环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环戊基、环己烯基。
如本文所用，“螺环”是指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺环分为双螺环或多螺环，优选为双螺环。更优选为4元/5元、5元/5元或5元/6元双螺环。例如：
Figure PCTCN2021072018-appb-000023
如本文所用，“螺杂环”指单环之间共用一个原子(称螺原子)的多环烃，其中一个或两个环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺杂环分为双螺杂环或多螺杂环，优选双螺杂环。更优选为4元/5元、5元/5元或5元/6元双螺杂环。例如：
Figure PCTCN2021072018-appb-000024
如本文所用，“桥环”是指共用两个或两个以上碳原子的多环基团，共用的碳原子称为桥头碳，两个桥头碳之间可以是碳链，也可以是一个键，称为桥。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥环。例如：
Figure PCTCN2021072018-appb-000025
Figure PCTCN2021072018-appb-000026
如本文所用，“桥杂环”指共用两个或两个以上原子的多环基团，其中一个或多个环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥杂环。例如：
Figure PCTCN2021072018-appb-000027
如本文所用，“8至10元双环”是指含8至10个环原子的含两个环的桥环，双环可为饱和全碳双环或部分不饱和的全碳双环，8至10元双环的实例包括(但不限于)：
Figure PCTCN2021072018-appb-000028
如本文所用，“8至10元双杂环”是指含8至10个环原子的含两个环的桥杂环，其中1、2、3、4或5个环碳原子被选自氮、氧或硫的杂原子所取代。8至10元双杂环的实例包括(但不限于)四氢喹啉环、四氢异喹啉环、十氢喹啉环等。
如本文所用，“C 1-8烷氧基”指-O-(C 1-8烷基)，其中烷基的定义如上所述。优选C 1-6烷氧基，优选C 1-4烷氧基，更优选C 1-3烷氧基。烷氧基的非限制性实施例包含甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。
如本文所用，“C 3-8环烷氧基”指-O-(C 3-8环烷基)，其中环烷基的定义如上所述。优选C 3-6环烷氧基。环烷氧基的非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。
如本文所用，“C 6-10芳基”和“C 6-10芳环”可互换使用，均指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，指含有6至10个碳原子的芳基；优选苯基和萘基，更优选苯基。
如本文所用，“一个键”指由其连接的两个基团通过一个共价键连接。
如本文所用，“卤素”指氟、氯、溴或碘。
如本文所用，“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。
例如，“卤代C 1-10烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。优选为卤代C 1-8烷基，较优优选为卤代C 1-6烷基，较优选为卤代C 1-4烷基，更优选为卤代C 1-3烷基。卤代C 1-6烷基的例子包括(但不限于)一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。
又例如，“卤代C 1-10烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C 1-8烷氧基，较优选为卤代C 1-6烷氧基，较优选为卤代C 1-4烷氧基，更优选为卤代C 1-3烷氧基。卤代烷氧基包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。
又例如，“卤代C 3-8环烷基”指环烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中环烷基的定义如上所述。优选为卤代C 3-6环烷基。包括(但不限于)三氟环丙基、一氟环丙基、一氟环己基、二氟环丙基、二氟环己基等。
如本文所用，“氘代C 1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)氘原子取代，其中烷基的定义如上所述。优选为氘代C 1-6烷基，更优选为氘代C 1-3烷基。氘代烷基的例子包括(但不限于)单氘代甲基、单氘代乙基、二氘代甲基、二氘代乙基、三氘代甲基、三氘代乙基等。
如本文所用，“氨基”指NH 2，“氰基”指CN，“硝基”指NO 2，“苄基”指-CH 2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“乙酰基”指-C(O)CH 3，“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或-CHOHCH 3，“羟基”指-OH，“硫醇”指SH，“亚环丙基”结构为：
Figure PCTCN2021072018-appb-000029
如本文所用，“杂芳基环”与“杂芳基”可互换使用，是指具有5到10个环原子，环阵列中共享6、10或14个π电子；且除碳原子外还具有1到5个杂原子的基团。“杂原子”是指氮、氧或硫。优选为5或6元单环杂芳基或8至10元双环杂芳基。
如本文所用，“3至7元(4至7元)饱和单环”是指含3至7个环原子的饱和全碳单环，优选为3至6元饱和单环。饱和单环的实例包括(但不限于)：环丙基环、环丁基环、环戊基环、环己基环、环庚基环、环辛基环等。
如本文所用，“3至7元(4至7元)饱和单杂环”是指3至7元饱和单环中的1、2或3个碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳；优选4至6元饱和单杂环，更优选5至6元饱和单杂环。饱和单杂环的实例包括(但不限于)环氧丙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、吡咯啉、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃等。
如本文所用，“5或6元单环杂芳基环”和“5或6元单环杂芳基”可互换使用，均是指含5至6个环原子的单杂芳基环，例如包括(但不限于)：噻吩环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等。
如本文所用，“8至10元双环杂芳基环”和“8至10元双环杂芳基”可互换使用，均是指含8至10个环原子的双杂芳基环，例如包括(但不限于)：苯并呋喃、苯并噻吩、吲哚、异吲哚、喹啉、异喹啉、吲唑、苯并噻唑、苯并咪唑、喹唑啉、喹喔啉、噌啉、酞嗪、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶。
如本文所用，“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
除非另有定义，本发明所述“各自独立地选自……的取代基”是指当基团上的一个以上的氢被取代基取代时，所述的取代基种类可以相同或不同，所选自的取代基为各自独立的种类。
除非另有定义，本发明所述“……相同或不同，且各自独立地为……”是指当通式中存在一个以上的相同取代基团时，该基团可以相同或不同，为各自独立的种类。例如L为(CR 01R 02) s，当s为2时，即L为(CR 01R 02)-(CR 01R 02)，其中的两个R 01或R 02可以相同或不同，为各自独立的种类，例如L可以为C(CH 3)(CN)-C(CH 2CH 3)(OH)，C(CH 3)(CN)-C(CH 3)(OH)或C(CN)(CH 2CH 3)-C(OH)(CH 2CH 3)。
除非另有定义，本文任一基团可以是取代的或未取代的。上述基团被取代时，取代基优选为1至5个以下基团，独立地选自CN、卤素、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷基取代的胺基、胺基、卤代C 1-8烷基取代的胺基、乙酰基、羟基、羟甲基、羟乙基、羧基、硝基、C 6-10芳基(优选苯基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优 选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)、4至6元饱和或不饱和单杂环、4至6元饱和或不饱和单环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环，其中R a0、R b0各自独立地为氢或C 1-3烷基。
本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。
本文所述的4至6元(5至6元)饱和单杂环被取代时，取代基的位置可处在它们可能的化学位置，示例性的单杂环的代表性的取代情况如下所示：
Figure PCTCN2021072018-appb-000030
Figure PCTCN2021072018-appb-000031
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2021072018-appb-000032
表示与其他原子的连接。
除非另有定义，当本发明所述的4至6元饱和单杂环为取代基时，其自身也可以为取代或被1、2或3个选自下组的取代基所取代：卤素、羟基、C 1-3烷基、O＝、NR a0R b0、羟甲基、羟乙基、羧基、-C(O)OC 1-3烷基、乙酰基、卤代C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环；其中R a0、R b0各自独立地为氢或C 1-3烷基。
所述“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其他副作用的，与无机酸或有机酸所形成的盐。
“药学上可接受的碱加成盐”，包括但不限于无机碱的盐如钠盐，钾盐，钙盐和镁盐等。包括但不限于有机碱的盐，比如铵盐，三乙胺盐，赖氨酸盐，精氨酸盐等。
本发明中提及的“溶剂化物”是指本发明的化合物与溶剂形成的配合物。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，一个与水形成的配合物称为“水合物”。式(I)化合物的溶剂化物属于 本发明范围之内。
本发明包括上述化合物的前药。前药包括已知的氨基保护基和羧基保护基，在生理条件下被水解或经由酶反应释放得到母体化合物。具体的前药制备方法可参照(Saulnier，M.G.；Frennesson，D.B.；Deshpande，M.S.；Hansel，S.B and Vysa，D.M.Bioorg.Med.Chem Lett.1994，4，1985-1990；和Greenwald，R.B.；Choe，Y.H.；Conover，C.D.；Shum，K.；Wu，D.；Royzen，M.J.Med.Chem.2000，43，475.)。
通常，本发明化合物或其药学上可接受的盐，或其溶剂化物，或前药可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。
如本文所用，“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。
通常，尽管用于治疗用途的本发明化合物的有效剂量在本发明的实践中可有很大的不同，这取决于具体应用、疾病或涉及的疾病状态，该剂量可由本领域技术人员容易地决定，但是对于本文所述的每种有关组合物，以及为了达到对本文所述的每种疾病的治疗效果，本发明的药物组合物中含有的本发明式(I)或式(II)化合物或其药学上可接受的盐、或其溶剂化物、或其前药的适当的治疗有效剂量典型地每天每千克患者体重为0.1μg到5g，优选每天每千克体重为1mg到1000mg。
需要的剂量优选在一天之内以适当的间隔内以二、三、四、五、六或更多次的亚剂量给药。这些亚剂量可以单位剂量形式给药，如，每单位剂量包括10μg到1000mg，优选50μg到500mg，更优选50μg到250mg，而最优选50μg到10mg的活性成分。或者，如果患者疾病需要的话，剂量可以以连续灌输进行施用。
如本文所用，“药学上可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。
如本文所用，“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。
如本文所用，“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。
制备方法
下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。
除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
用于本发明的化合物的制备方法：
本发明式(I)和式(II)所示化合物可通过已知的方法制备，例如，通过下述方法、与之等同的方法或实施例中所述的方法。在下面的制备方法中，原料化合物可以是盐的形式，该盐可以是本发明式(I)和式(II)表示的化合物所示例的任何药学上可接受的盐。
反应方案(a)
Figure PCTCN2021072018-appb-000033
(在上述方案的各式中，星号*代表手性碳原子为R或S构型(下同)，所有基团定义如说明书中所述。)
具体地，式(I)表示的化合物可按照以下方法制得：将式I-1化合物和化合物1b发生还原胺化反应制得式(I)化合物。还原胺化反应在惰性溶剂中，在一定温度(如-20℃至80℃，优选在0℃至60℃，更优选在20℃至60℃)下，将式(I-1)化合物、化合物1b与还原剂反应一段时间(如0.5小时至48小时，优选0.5小时至5小时)，从而得到式(I)化合物。其中惰性溶剂和还原剂可以是本领域已知的，其中还原剂可选自如硼氢化四丁基胺盐，丙二酰氧基硼氢化钠，三乙酰氧基硼氢化钠，氰基硼氢化钠，硼氢化钠，硼氢化锂，硼氢化钾，硼烷等。惰性溶剂可选自如C 1-4烷基醇，甲苯、二甲苯、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、乙醚、二氯甲烷、氯仿、1，2-二氯乙烷、乙酸乙酯、乙腈、二甲亚砜、N,N-二甲基甲酰胺等，或其组合。
其中式I-1化合物可通过反应方案(a-1)进行制备，或通过反应方案(a-2)进行制备。
反应方案(a-1)
Figure PCTCN2021072018-appb-000034
(在上述方案的各式中，所有基团定义如说明书中所述。)
具体地，式(i-2)表示的化合物可通过式(i-1)化合物与(S)-2-甲基丙烷-2-亚磺酰胺的缩合反应(使用催化剂,例如：钛酸四乙酯、钛酸四异丙酯)制备；式(i-2)表示的化合物用还原剂(例如:硼氢化钠、三仲丁基硼氢化锂、氰基硼氢化钠、二异丁基氢化铝)还原，通过高效液相制备色谱分离制得两个单一异构体即式(i-3a)和(i-3b)表示的化合物；式(i-3a)和(i-3b)表示的化合物用酸(例如:氯化氢)脱氨基保护基，分别得到式(I-1a)和(I-1b)表示的化合物。
反应方案(a-2)
Figure PCTCN2021072018-appb-000035
(在上述方案的各式中，所有基团定义如说明书中所述。)
具体地，式(i-2)表示的化合物可通过式(i-1)化合物与(S)-2-甲基丙烷-2-亚磺酰胺的缩合反应(使用催化剂,例如：钛酸四乙酯、钛酸四异丙酯)制备；式(i-2)表示的化合物利用手性拆分方式得到两个单一异构体式(i-2a)和式(i-2b)表示的化合物；式(i-2a)和式(i-2b)表示的化合物分别用还原剂(例如:硼氢化钠、三仲丁基硼氢化锂、氰基硼氢化钠、二异丁基氢化铝)还原，得到式(i-3a)和(i-3b)表示的化合物；式(i-3a)和(i-3b)表示的化合物用酸(例如:氯化氢)脱氨基保护基，分别得到式(I-1a) 和(I-1b)表示的化合物。
反应方案(a-1)和(a-2)中的手性辅剂(S)-2-甲基丙烷-2-亚磺酰胺也可替换为其他具有同样手性诱导作用的手性辅剂，例如(S)-甲基苄胺。
反应方案(b)
Figure PCTCN2021072018-appb-000036
(在上述方案的各式中，*为R或S构型，所有基团定义如说明书中所述。)
具体地，式(Ⅱ)表示的化合物也可按照以下方法制得：将式II-1表示的化合物和化合物1b发生还原胺化反应制得式(Ⅱ)表示的化合物。还原胺化反应在惰性溶剂中，在一定温度(如-20℃至80℃，优选在0℃至60℃，更优选在20℃至60℃)下，将式(II-1)化合物、化合物1b与还原剂反应一段时间(如0.5小时至48小时，优选0.5小时至5小时)，从而得到式(II)化合物。其中惰性溶剂和还原剂可以是本领域已知的，其中还原剂可选自如硼氢化四丁基胺盐，丙二酰氧基硼氢化钠，三乙酰氧基硼氢化钠，氰基硼氢化钠，硼氢化钠，硼氢化锂，硼氢化钾，硼烷等。惰性溶剂可选自如C 1-4烷基醇，甲苯、二甲苯、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、乙醚、二氯甲烷、氯仿、1，2-二氯乙烷、乙酸乙酯、乙腈、二甲亚砜、N,N-二甲基甲酰胺等，或其组合。
其中式II-1化合物可通过反应方案(b-1)进行制备或通过反应方案(b-2)进行制备。
反应方案(b-1)
Figure PCTCN2021072018-appb-000037
(在上述方案的各式中，所有基团定义如说明书中所述。)
具体地，式(ii-2)表示的化合物可通过式(ii-1)化合物与(R)-2-甲基丙烷-2-亚磺酰胺的缩合反应(使用催化剂,例如：钛酸四乙酯、钛酸四异丙酯)制备；式(ii-2)表示的化合物用还原剂(例如:硼氢化钠、三仲丁基硼氢化锂、氰基硼氢化钠、二异丁基氢化铝)还原，通过高效液相制备色谱分离制得式(ii-3a)和(ii-3b)表示的化合物；式(ii-3a)和(ii-3b)表示的化合物用酸(例如:氯化氢)脱氨基保护基，分别得到式(II-1a)和(II-1b)表示的化合物。
反应方案(b-2)
Figure PCTCN2021072018-appb-000038
(在上述方案的各式中，所有基团定义如说明书中所述。)
具体地，式(ii-2)表示的化合物可通过式(ii-1)化合物与(R)-2-甲基丙烷-2-亚磺酰胺的缩合反应(使用催化剂,例如：钛酸四乙酯、钛酸四异丙酯)制备；式(ii-2)表示的化合物利用手性拆分方式得到两个单一异构体式(ii-2a)和式(ii-2b)表示的化合物；式(ii-2a)和式(ii-2b)表示的化合物分别用还原剂(例如:硼氢化钠、三仲丁基硼氢化锂、氰基硼氢化钠、二异丁基氢化铝)还原，得到式(ii-3a)和(ii-3b)表示的化合物；式(ii-3a)和(ii-3b)表示的化合物用酸(例如:氯化氢)脱氨基保护基，分别得到式(II-1a)和(II-1b)表示的化合物。
反应方案(b-1)和(b-2)中的手性辅剂(R)-2-甲基丙烷-2-亚磺酰胺也可替换为其他具有同样手性诱导作用的手性辅剂，例如(R)-甲基苄胺。
用于本发明的具有氨基、羧基或羟基的化合物可使用根据需要已通过常用于该基团的保护基进行保护的化合物来制备，在通过上述反应方案的反应过程后，可进行已知的脱保护反应。
与现有技术相比，本发明的主要优点在于：
提供了一系列结构新颖的光学纯的氧杂螺环取代的吡咯并吡唑衍生物，其对cAMP具有较高的抑制活性(EC 50为1nM至50nM，更佳地为1nM至30nM，最佳的为1nM至10nM)，以及较高的Emax值(Emax大于50％，更佳地Emax大于80％)，具有优异的镇痛效果，此外本发明的化合物对β-arrestin具有较低的Emax值(Emax小于50％，更佳地Emax小于20％，最佳的Emax小于10％)，偏向性好。因此可开发成为用于治疗和预防疼痛和疼痛相关疾病的药物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
试剂与仪器
1HNMR：Bruker AVANCE-400核磁仪，内标为四甲基硅烷(TMS)；
LC-MS：Agilent 1290HPLC System/6130/6150MS液质联用质谱仪(生产商：安捷伦)，柱子Waters BEH/CHS，50×2.1mm，1.7μm。
单晶检测采用布鲁克公司D8venture X射线单晶衍射仪进行测试。
制备高效液相色谱(pre-HPLC)：GX-281(生产商：吉尔森)。
采用ISCO Combiflash-Rf75或Rf200型自动过柱仪，Agela 4g、12g、20g、40g、80g、120g一次性硅胶柱。
已知的起始原料可以采用或按照本领域已知的方法来合成，或可以购自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)和达瑞化学品等公司。
实施例中，反应进程的监测可采用薄层色谱法(TLC)，化合物纯化可采用柱层析。柱层析或TLC所用的展开剂体系可选自：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系、石油醚和乙酸乙酯体系和丙酮体系等，溶剂的体积比根据化合物的极性不同而进行调节。
如本文所用，DCE为1,2-二氯乙烷，THF为四氢呋喃，EA为乙酸乙酯，PE为石油醚，DCM为二氯甲烷，n-BuLi为正丁基锂，HATU为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，DMF为二甲基甲酰胺，DMSO为二甲基亚砜，DIEA或DIPEA为N,N-二异丙基乙胺，DBU为1,8-二氮杂二环[5.4.0]十一碳-7-烯，DIBAL-H为二异丁基氢化铝。
如本文所用，室温是指约为20-25℃。
中间体1b
Figure PCTCN2021072018-appb-000039
将(R)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸基-9-基)乙腈(11g，43mmol，购于上海予成医药科技有限公司，CAS编号1401031-38-6)溶于DCM(100ml)溶液中，在-78度下滴加二异丁基氢化铝溶液(1.0M，86ml)，-78度下搅拌1小时。反应液加入十水合硫酸钠(30g)，室温搅拌半小时，过滤，减压浓缩滤液得到黄色油状中间体。将中间体溶于乙醇(100ml)溶液中，加入盐酸(6N，100ml)溶液，100度搅拌36小时。减压浓缩，用制备液相色谱纯化所得残余物，得到(R)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸基-9-基)乙醛1b(6.5g)，收率59％。MS m/z(ESI):260.2[M+1]。
中间体V1
Figure PCTCN2021072018-appb-000040
步骤1：将新戊醛(17.2g，0.2mol)溶解于400mL乙腈中，加入磷酰基乙酸三乙酯(48g，0.21mol)和氯化锂(8.8g，0.21mol)，冷却至2-5℃，慢加入DBU(30.4g，0.2mol)，室温18小时。反应液浓缩，用EA稀释(300mL)，用水洗(100ml×2)，用饱和食盐水洗涤(80mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法纯化(PE/EA＝10/1)，得到化合物V1-1(25.6g，黄色油状液体)，产率：82％。MS m/z(ESI):157.2[M+1]
步骤2：向装有化合物V1-1(7.8g，50mmol)和吡唑(5.1g，75mmol)的封管中加入乙腈溶液(80ml)和DBU(11.4g，75mmol)，在100℃下搅拌48小时，冷却至室温，浓缩，剩余物用EA(150ml)稀释，用水洗(60ml×1)，用饱和食盐水洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法纯化(PE/EA＝6/1)，得到化合物V1-2(8.96g，黄色油状液体)，产率：80％。MS m/z(ESI):225.1[M+1]。
步骤3：化合物V1-2(8.96g，40mmol)溶解于甲醇/水(100ml/20ml)中，加入氢氧化钠(3.2g，80mmol)，室温搅拌1小时，反应完全。浓缩，剩余物用水(70ml)溶解，用2M盐酸调节PH＝3-4，用DCM萃取(90mlx3)，合并的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物V1-3(7g，黄色油状液体)，产率：90％。MS m/z(ESI):197.2[M+1]。
步骤4：化合物V1-3(7g，35.7mmol)溶解在干燥的THF(120ml)，氮气保护下，冷却至-70℃，慢慢滴加2.5M的丁基锂的THF溶液(35.7ml，89.2mmol)。滴加完毕，反应液缓慢升温至-40℃，搅拌45分钟。反应液用3ml水淬灭，过滤，浓缩。用硅胶柱色谱法纯化(PE/EA＝6/1)，得到化合物V1(4.76g，黄色油状液体)，产率：15％。MS m/z(ESI):179.2[M+1]。
中间体V2
Figure PCTCN2021072018-appb-000041
步骤1：将1-甲基环丙烷甲酸(10mg，0.10mol)和N,O-二甲基羟胺盐酸盐(14.6g，0.15mol)加入80mL DMF中，然后依次加入HATU(45.6g，0.12mol)和DIEA(50mL，0.30mol)，室温反应过夜。 加入EA(500mL)。有机相用1N盐酸(100mL x 2)和饱和氯化钠溶液(50mL x 2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA＝1/0～1/1)纯化所得残余物，得到化合物V2-1(11.3g，淡黄色油状物)，产率：79％。MS m/z(ESI):144.1[M+1]。
步骤2：将化合物V2-1(14.5g,101mmol)溶解于90mL乙醚，冷却到-78℃，缓慢滴加入1M二异丁基氢化铝(152mL，152mmol)。-78℃下反应2小时后，加入1M HCl(16mL)淬灭反应，升温到0℃后再加入1M HCl(16mL)。无水硫酸钠(70g)干燥，过滤，得到化合物V2-2。
步骤3：将氯化锂(6.5g，153mmol)加入60mL乙腈中，然后依次加入三乙基膦酰乙酸酯(24.5mL，122mmol)和DBU(18.1mL，121mmol)，冷却到0℃后，滴入化合物V2-2(8.5g)，室温反应过夜。加入150mL水，EA萃取(150mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝1/0～10/1)纯化所得残余物，得到化合物V2-3(10.5g,无色油状液体)，产率：68％。MS m/z(ESI):155.0[M+1]。
步骤4：将化合物V2-3(10.5g,0.068mol)，吡唑(9.3g，0.137mol)和碳酸钾(18.8g，0.136mol)加入50mL DMF中，65℃反应45小时。冷却到室温，加入300mL EA，用水(100mL)和饱和氯化钠溶液(100mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝1/0～5/1)纯化所得残余物，得到化合物V2-4(12.3g,无色油状液体)，产率：82％。MS m/z(ESI):223.1[M+1]。
步骤5：将化合物V2-4(12.3g，55.3mmol)溶解于50mL THF和20mL甲醇中，加入一水合氢氧化锂(3.6g，85.7mmol)和30mL水，室温搅拌反应2小时。用6M盐酸溶液调整反应液pH值至3，减压旋去有机溶剂，水相用DCM萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备液相色谱得到化合物V2-5(9.2g,无色油状液体)，产率：86％。MS m/z(ESI):195.0[M+1]。
步骤6：将化合物V2-5(3.05g,15.7mmol)溶解于80mL THF，冷却到-78℃，缓慢滴加入2.5M正丁基锂(15.7mL，39.3mmol)，-78℃反应0.5小时，-45℃反应1小时。用30mL饱和氯化铵溶液淬灭，EA萃取(50mL×4)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝1/0～3/1)纯化所得残余物，得到化合物V2(460mg,无色油状液体)。产率：16.7％。MS m/z(ESI):177.0[M+1]。
中间体V3
Figure PCTCN2021072018-appb-000042
步骤1：向3L单口瓶中加入三乙基膦酰乙酸酯(476mL,2.4mol)，DBU(365g，2.4mol)，氯化锂(127g，3mol)和乙腈(1.2L)，氩气保护下室温搅拌20分钟。冷却到0℃(内温)，缓慢滴加异丁醛(144g，2mol)。室温搅拌12小时。LCMS显示反应完全，过滤，滤饼用EA洗涤(100mL x2)。加入水(1L),用EA萃取(1.5L x2)，饱和氯化钠洗，无水硫酸钠干燥，旋干得化合物V3-1(175g，无色液体)。
步骤2：向装有化合物V3-1(300g,2.1mol)的3L单口瓶中加入DMF(1L)，搅拌下，加入碳酸钾(579g,4.2mol)，吡唑(287g,4.2mol)，65℃，搅拌18小时，LCMS显示反应完全，直接旋干，剩余固体用乙腈(150ml)打浆，过滤的白色固体。过滤，滤饼用EA洗涤(500mL x2)。饱和食盐水洗(300mL x3),无水硫酸钠干燥，旋干，柱层析纯化(PE含5％EA为流动相)得到化合物V3-2(258g,Y:58％，无色液体)。MS m/z(ESI):211.1[M+1]。
步骤3：将水(200mL)加入到氢氧化钾(133g，3.32mol)中溶解，预冷到(5℃)。在3L烧瓶中加入化合物V3-2(465g，2.21mol)，甲醇(0.5L)，,THF(0.5L)，再加入预冷的氢氧化钾水溶液，搅拌2小时，浓盐酸调PH约到3，用DCM萃取(800ml x2)，合并所有的有机相，饱和食盐水洗，干燥，浓缩得到化合物V3-3(410.5g,Y:100％，白色固体)。MS m/z(ESI):183.1[M+1]。
步骤4：在氮气保护下，向三口瓶(500mL)中加入化合物V3-3(10.2g，0.055mol)，THF(200mL),降温到-75℃。缓慢滴加2.5M的正丁基锂(55mL,0.137mol)的THF溶液，滴加完毕，缓慢升至-10℃，继续搅拌3小时。饱和氯化铵淬灭，加入水(100mL),用EA(400ml x2)萃取，合并有机相，饱和食盐水洗，干燥，浓缩得棕色液体。柱层析纯化(PE含30％EA为流动相)得到化合物V3(4g,Y:22.2％，白 色固体)，MS m/z(ESI):165.1[M+1]。
中间体V4
Figure PCTCN2021072018-appb-000043
步骤1：将1-(三氟甲基)环丙烷-1-羧酸(6.8g，44mmol)溶于DMF(100ml)溶液中，加入二甲羟胺盐酸盐(5.14g，53mmol)，HATU(25g，66mmol)和三乙胺(13.3g，132mmol)溶液，室温搅拌过夜。加入EA(400ml)，饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，有机相减压浓缩，用薄层层析以洗脱剂(PE：EA＝1:1)纯化所得残余物，得到化合物V4-1(8g)，收率92％。MS m/z(ESI):198.1[M+1]
步骤2：化合物V4-1(8g，4.06mmol)溶于THF(100ml)溶液中，在-78℃下加入DIBAL-H(1.0M，60ml，6.1mmol)，-78℃下搅拌1小时。加入十水合硫酸钠，搅拌30分钟，过滤，滤液减压浓缩得到化合物V4-2。
步骤3:化合物V4-2(5.6g，40.6mmol)溶于乙腈(100ml)溶液中，加入二乙氧基氧膦基甲酸乙酯(13.64g，60.9mmol)，DBU(12.34g，81.2mmol)和氯化锂(3.4g，81.2mmol)，室温搅拌过夜。加入EA(300ml)，饱和盐水溶液洗涤，无水硫酸钠干燥，有机相减压浓缩，用薄层层析以洗脱剂(PE：EA＝2:1)纯化所得残余物，得到化合物V4-3(4g)，收率47％。MS m/z(ESI):209.1[M+1]。
步骤4：将吡唑(2.61g，38.5mmol)溶于DMF(100ml)溶液中，加入化合物V4-3(4g，19.2mmol)和碳酸钾(7.95g，57.6mmol)，60℃搅拌过夜。加入EA(300ml)，饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，有机相减压浓缩，用薄层层析以洗脱剂(PE：EA＝1:1)纯化所得残余物，得到化合物V4-4(3.3g)，产率：62％。MS m/z(ESI):277.1[M+1]
步骤5：将化合物V4-4(3.3g,12mmol)溶于甲醇(20ml)和水(5ml)溶液中，加入氢氧化锂(0.55g，24mmol)，在室温下搅拌2小时。溶液加入盐酸(3N)溶液调整pH至2，DCM/甲醇(10/1)溶液萃取，有机相减压蒸馏，用制备液相色谱纯化所得残余物，得到化合物V4-5(1.8g)，产率61％。MS m/z(ESI):249.1[M+1]
步骤6：化合物V4-5(1.8g,7.26mmol)溶于THF(30ml)溶液中，在-78℃下加入正丁基锂(2.5M,7.3ml，18.1mmol)溶液，-20℃搅拌30分钟。反应液加入氯化钠水溶液，EA溶液萃取，有机相减压浓缩，用薄层层析以洗脱剂(PE：EA＝1:2)纯化所得残余物，得到化合物V4(700mg)，产率42％。MS m/z(ESI):231.1[M+1]。
化合物V5
Figure PCTCN2021072018-appb-000044
将化合物3-3a(0.11g，0.67mmol)溶于二氯甲烷(8ml)，在0度下加入三乙胺(0.2g，2mmol)和4-溴苯磺酰氯(0.204g，0.804mmol)，0度下搅拌1小时，加入二氯甲烷(10ml)，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，有机相减压浓缩，用制备液相色谱纯化所得残余物，得到白色固体4-溴-N-((4S，6S)-6-异丙基-5,6-二氢-4H-吡咯[1,2-b]吡唑-4-基)苯磺酰胺V5(0.06g)产率23.3％。MS m/z(ESI):384.1[M+1]。
化合物V5单晶的制备：取少量化合物V5放入小烧杯中，并用乙酸乙酯溶解，用薄膜密封小烧杯，在薄膜上扎些小孔。将石油醚放入大烧杯中，再将小烧杯置于大烧杯中，密封大烧杯，室温静置结晶，溶 液中析出晶体。通过布鲁克公司D8venture X射线单晶衍射仪对该晶体进行单晶X-ray分析证实其绝对构型为(4S，6S)构型，其结构图如图1所示。因此化合物3-3a可由化合物V5的单晶结构推断其绝对构型为(4S，6S)构型。
仪器参数：
Figure PCTCN2021072018-appb-000045
化合物V6
Figure PCTCN2021072018-appb-000046
化合物V6可参考化合物V5的方法制备获得。MS m/z(ESI):384.1[M+1]。
化合物V6单晶的制备：取少量化合物V6放入小烧杯中，并用乙酸乙酯溶解，用薄膜密封小烧杯，在薄膜上扎些小孔。将石油醚放入大烧杯中，再将小烧杯置于大烧杯中，密封大烧杯，室温静置结晶，溶液中析出晶体。通过布鲁克公司D8venture X射线单晶衍射仪对晶体进行单晶X-ray分析证实其绝对构型为(4R，6R)构型，其结构图如图2所示。
仪器参数：
Figure PCTCN2021072018-appb-000047
实施例1：(4S,6S)-6-叔丁基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-1a)和(4S,6R)-6-叔丁基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-1b)
Figure PCTCN2021072018-appb-000048
步骤1：将化合物V1(1g，5.6mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(1g，8.4mmol)溶解于70ml甲苯中，加入3mL钛酸四异丙酯，120℃搅拌反应1小时。冷却至室温，向反应液加入水(10ml)，搅拌20分钟，过滤，滤液中加入硼氢化钠(425mg，11.2mmol)，搅拌0.5小时，向反应液中加入5mL水，搅拌0.5分钟，过滤，滤液减压浓缩，用硅胶柱色谱法纯化(PE/EA＝4/1)，得到化合物1-1(1.26g，黄色固体)，产率：85％。MS m/z(ESI):284.1[M+1]。
步骤2：取化合物1-1(0.8g)经制备色谱(制备条件，制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O，波长：254/214nm梯度：30％-60％乙腈变化)纯化得到两个单一构型的产物1-2a(340mg，保留时间为9.5min)和1-2b(300mg，保留时间为10.5min)。
步骤3：将化合物1-2a(0.3g，1mmol)溶解于15ml DCM中，加入4M的盐酸二氧六环溶液，室温搅拌反应1小时。浓缩得到化合物1-3a(179mg，黄色固体)，产率：100％。MS m/z(ESI):180.1[M+1]。
步骤4：将化合物1-3a(179mg，1mmol)和化合物1b(259mg，1mmol)溶解于30mL甲醇中，室温搅拌反应1小时。加入氰基硼氢化钠(248mg，4mmol)搅拌5小时，向反应液中加入5mL水，搅拌0.5分钟，过滤，滤液减压浓缩，制备色谱(制备条件，制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O，波长：254/214nm梯度：30％-60％乙腈变化)纯化得到单一构型化合物H-1a(110mg，白色固体)，产率：31％。MS m/z(ESI):423.2[M+1]； 1H NMR(400MHz,DMSO-d6)δ8.52-8.50(m,1H),7.70-7.68(m,1H),7.45-7.42(m,1H),7.30(d,J＝1.8Hz,1H),7.17-7.15(m,1H),5.71(d,J＝1.7Hz,1H),3.85-3.81(m,2H),3.57-3.55(m,2H),2.57-2.55(m,1H),2.46–2.38(m,2H),2.32-2.30(m,1H),2.01–1.88(m,1H),1.91–1.63(m,4H),1.67–1.21(m,9H),0.91(s,9H),0.62-0.59(m,1H)。
步骤5：参考步骤3的制备方法，以化合物1-2b为原料制备得到化合物1-3b。
步骤6：参考步骤4的制备方法，以化合物1-3b为原料制备得到化合物H-1b(110mg，白色固体)，产率：31％。MS m/z(ESI):423.2[M+1]； 1H NMR(400MHz,DMSO-d6)δ8.51-8.48(m,1H),7.71-7.69(m,1H),7.45-7.43(m,1H),7.29(d,J＝1.8Hz,1H),7.18-7.16(m,1H),5.64(d,J＝1.8Hz,1H),3.83-3.81(m,2H),3.58(d,J＝3.0Hz,2H),2.54-2.51(m,1H),2.45–2.26(m,3H),1.99-1.97(m,1H),1.89–1.64(m,4H),1.65–1.23(m,9H),0.91(s,9H),0.58-0.56(m,1H).
实施例2：(4S,6S)-6-(1-甲基环丙基)-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-2a)和(4S,6R)-6-(1-甲基环丙基)-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-2b)
Figure PCTCN2021072018-appb-000049
步骤1：将化合物V2(460mg，2.61mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(475mg，3.92mmol)加入20mL甲苯中，然后加入钛酸四乙酯(2mL，9.54mmol)，120℃搅拌反应2小时。用5mL水淬灭，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝1/0～1/1)得到化合物2-1(612mg,黄色油状液体)，产率：84％。MS m/z(ESI):280.1[M+1]。
步骤2：将化合物2-1(612mg，2.19mmol)加入50mL甲醇中。冷却到0℃，加入硼氢化钠(166mg，4.39mmol)，室温搅拌反应2小时。减压浓缩，用制备液相色谱(制备柱：21.2X250mm C18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：30％-60％乙腈变化)得到两个单一异构体2-2a(254mg,无色油状液体，保留时间为9min)产率：41％；2-2b(242mg,无色油状液体，保留时间为10min)，产率：39％。MS m/z(ESI):282.1[M+1]。
步骤3：将化合物2-2a(254mg，0.90mmol)加入20mL甲醇中。加入4M盐酸的1,4-二氧六环溶液(4.5mL，18mmol)，室温搅拌反应1小时。减压浓缩，加入30mL饱和碳酸氢钠溶液，用DCM和甲醇(15:1)萃取(50mL×4)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到单一异构体化合物2-3a(151mg,淡黄色油状液体)产率：94％。MS m/z(ESI):178.1[M+1]。
步骤4：将化合物2-3a(151mg，0.85mmol)、化合物1b(243mg,0.94mmol)和氰基硼氢化钠(268mg，4.26mmol)加入20mL甲醇中。40℃下反应4小时后，室温搅拌反应过夜。减压浓缩，用制备液相色谱(制备柱：21.2X250mm C18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：30％-60％乙腈变化)纯化所得残余物，得到化合物H-2a(186.25mg,白色固体)，产率：52％。MS m/z(ESI):421.1[M+1]； 1H NMR(400MHz,CD 3OD)δ8.53-8.48(m,1H),7.79-7.72(m,1H),7.50(d,J＝8.1Hz,1H),7.43(d,J＝1.8Hz,1H),7.24-7.21(m,1H),5.89(dd,J＝1.9,0.7Hz,1H),4.02(t,J＝7.8Hz,1H),3.77-3.71(m,2H),3.49 (t,J＝7.8Hz,1H),2.81-2.73(m,1H),2.70–2.59(m,1H),2.53(d,J＝11.7Hz,1H),2.41(dd,J＝13.7,1.9Hz,1H),2.11-2.00(m,3H),1.91(d,J＝13.8Hz,1H),1.77-1.38(m,8H),1.13-1.06(m,1H),0.84(s,3H),0.76-0.69(m,2H),0.60-0.55(m,1H),0.51-0.42(m,1H),0.38-0.29(m,1H)。
步骤5：将化合物2-2b(242mg,0.86mmol)加入20mL甲醇中。加入4M盐酸的1,4-二氧六环溶液(4.3mL，17.2mmol)，室温搅拌反应1小时。减压浓缩，加入30mL饱和碳酸氢钠溶液，用DCM和甲醇(15:1)萃取(50mL×4)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到单一异构体化合物2-3b(151mg,淡黄色油状液体)产率：99％。MS m/z(ESI):178.1[M+1]。
步骤6：将化合物2-3b(151mg，0.85mmol)、化合物1b(243mg,0.94mmol)和氰基硼氢化钠(267mg，4.25mmol)加入10mL甲醇中。40℃下反应4小时后，室温搅拌反应过夜。减压浓缩，用制备液相色谱(制备柱：21.2X250mm C18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：30％-60％乙腈变化)纯化所得残余物，得到化合物H-2b(215.62mg,白色固体)，产率：60％。MS m/z(ESI):421.1[M+1]；NMR(400MHz,CD 3OD)δ8.54–8.49(m,1H),7.78-7.74(m,1H),7.51(d,J＝8.1Hz,1H),7.42(d,J＝1.9Hz,1H),7.25-7.22(m,1H),5.91–5.80(m,1H),4.02(t,J＝7.8Hz,1H),3.82–3.66(m,2H),3.49(t,J＝7.8Hz,1H),2.79-2.72(m,1H),2.63–2.47(m,2H),2.41(dd,J＝13.7,1.9Hz,1H),2.16-1.97(m,3H),1.91(d,J＝13.8Hz,1H),1.79–1.35(m,9H),1.12-1.06(m,1H),0.83(s,3H),0.74-0.69(m,2H),0.61–0.53(m,1H),0.49-0.44(m,1H),0.38–0.29(m,1H).
实施例3：(4S，6S)-6-异丙基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-3a)和(4S，6R)-6-异丙基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-3b)
Figure PCTCN2021072018-appb-000050
步骤1：将化合物V3(17g，103.5mmol)溶解于250(mL)甲苯中，加入(R)-2-甲基丙烷-2-亚磺酰胺(18.8g，155mmol)和钛酸四异丙酯(117g，414mmol),110℃搅拌反应16小时。冷却至室温，向反应液中加入80mL水，600mL DCM，过滤，滤饼用DCM(100mL)洗，分层，有机相用饱和食盐水(100mL)洗，无水硫酸钠干燥，减压浓缩，浓缩物柱层析纯化(PE含30％EA为流动相)得到化合物3-1(20.3g,Y:73.5％，棕色液体)。MS m/z(ESI):268.1[M+1]。
步骤2：单口瓶中加入化合物3-1(0.39g,1.45mmol)，甲醇(5mL)，冷却到0度，缓慢加入硼氢化钠(0.11g,2.9mmol)。室温搅拌1.5小时。冷却到0度，加入20毫升冰水，用DCM洗涤萃取(50mL x2)。饱和食盐水洗(20mL),无水硫酸钠干燥，旋干，制备色谱法制备(制备条件，制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O，波长：254/214nm梯度：28％-30％乙腈变化)得到单一非对映异构体化合物3-2a(150mg,Y:38.4％，白色固体，保留时间为9.5min)，MS m/z(ESI):270.0[M+1]。和化合物3-2b(100mg,Y:25.6％，白色固体，保留时间为10.5min)，MS m/z(ESI):270.0[M+1]。
步骤3：单口瓶中加入化合物3-2a(120mg,0.45mmol)，甲醇(3mL)，冷却到0度，缓慢加入甲醇盐酸气(1.2mL,4.5mmol，4mol/L)。室温搅拌1.5小时。饱和碳酸氢钠调PH约到8，用DCM萃取(50ml x2)，合并所有的有机相，饱和食盐水洗，干燥，浓缩得到化合物3-3a(70mg,Y:95.12％，黄色液体)。MS m/z(ESI):166.1[M+1]。
步骤4：将化合物3-3a(50mg，0.3mmol)溶解于(5mL)甲醇中，加入化合物1b(78.3mg，0.3mmol)和氰基硼氢化钠(94mg，1.5mmol),20℃搅拌反应3小时。向反应液中加入20mL水，用DCM(30mL×2)萃取，无水硫酸钠干燥，减压浓缩，浓缩物用制备色谱法纯化(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)，得到单一构型化合物H-3a(10.12mg,Y:8.26％)， 白色固体。化合物H-3a的绝对构型是通过化合物V5的绝对构型推断确定。MS m/z(ESI):409.2[M+1]； 1H NMR(400MHz,CD 3OD)δ8.51(ddd,J＝4.9,1.8,0.8Hz,1H),7.79–7.71(m,1H),7.50(d,J＝8.1Hz,1H),7.41(d,J＝1.9Hz,1H),7.22(ddd,J＝7.5,4.9,1.0Hz,1H),5.87(dd,J＝1.9,0.6Hz,1H),4.07(ddd,J＝21.0,11.7,6.2Hz,2H),3.81–3.69(m,2H),2.73–2.58(m,2H),2.52(dd,J＝14.0,2.3Hz,1H),2.48–2.35(m,2H),2.12–1.97(m,2H),1.95–1.82(m,2H),1.78–1.65(m,3H),1.64–1.36(m,5H),1.14–1.04(m,1H),0.99(d,J＝7.0Hz,3H),0.79–0.65(m,4H).
步骤5：单口瓶中加入化合物3-2b(100mg,0.37mmol)，甲醇(3mL)，冷却到0度，缓慢加入甲醇盐酸气(0.93mL,3.7mmol，4mol/L)。室温搅拌1.5小时。饱和碳酸氢钠调PH约到8，用DCM萃取(50ml x2)，合并所有的有机相，饱和食盐水洗，干燥，浓缩得到化合物3-3b(50mg,Y:81.2％，黄色液体)。MS m/z(ESI):166.1[M+1]
步骤6：将化合物3-3b(50mg，0.3mmol)溶解于5(mL)甲醇中，加入化合物1b(78.3mg，0.3mmol)和氰基硼氢化钠(94mg，1.5mmol),20℃搅拌反应3小时。向反应液中加入20mL水，用DCM(30mL×2)萃取，无水硫酸钠干燥，减压浓缩，浓缩物用制备色谱法纯化(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)，得到单一构型化合物H-3b(30.01mg,Y:24.5％)，白色固体。MS m/z(ESI):409.3[M+1]； 1H NMR(400MHz,CD 3OD)δ8.59–8.52(m,1H),7.79(td,J＝8.0,1.9Hz,1H),7.54(d,J＝8.1Hz,1H),7.43(d,J＝1.8Hz,1H),7.27(ddd,J＝7.4,4.9,0.9Hz,1H),5.86(dd,J＝1.9,0.7Hz,1H),4.11(ddd,J＝15.3,10.4,6.3Hz,2H),3.86–3.71(m,2H),2.69(dt,J＝13.1,7.8Hz,1H),2.63–2.51(m,2H),2.50–2.39(m,2H),2.15(td,J＝11.4,4.7Hz,1H),2.09–1.98(m,1H),1.91(ddd,J＝15.3,13.5,8.6Hz,2H),1.83–1.38(m,8H),1.16–1.08(m,1H),1.02(d,J＝7.0Hz,3H),0.81–0.64(m,4H).
实施例4:(4S,6S)-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-6-(1-(三氟甲基)环丙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺H-4a和(4S,6R)-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-6-(1-(三氟甲基)环丙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺H-4b
Figure PCTCN2021072018-appb-000051
步骤1：化合物V4(700mg，3.04mmol)溶于甲苯(10ml)溶液中，加入(R)-2-甲基丙烷-2-亚磺胺(442mg，3.65mmol)和钛酸四异丙酯(0.5ml)，在120℃搅拌2小时。有机相减压浓缩，用薄层层析以洗脱剂(PE：EA＝3:7)纯化所得残余物，得到化合物4-1(600mg)，产率49％。MS m/z(ESI):334.1[M+1]。
步骤2：化合物4-1(600mg，1.8mmol)溶于甲醇(10ml)溶液中，在零度下加入硼氢化钠(205mg，5.4mmol)，室温搅拌2小时。加水，过滤，滤液减压浓缩，用制备液相色谱纯化(制备条件，制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O，波长：254/214nm梯度：28％-30％乙腈变化)所得残余物，纯化得到两个单一构型的化合物4-2a(150mg，保留时间为8.5min)和4-2b(150mg，保留时间为9.5min)，产率25％。MS m/z(ESI):336.1[M+1]
步骤3：化合物4-2a(150mg，0.45mmol)溶于甲醇(10ml)，加入氯化氢THF溶液(4M，2ml)，室温搅拌4小时。加入DCM(50ml)，饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，有机相减压浓缩得到化合物4-3a(100mg)。
步骤4：化合物1b(112mg,0.43mmol)溶于甲醇(10ml)溶液中，加入化合物4-3a(100mg,0.43mmol)和氰基硼氢化钠(55mg，0.86mmol)，40℃搅拌4小时。加水，过滤，滤液减压浓缩，用制备液相色谱纯化所得残余物，得到化合物H-4a(72.70mg)，产率36％。MS m/z(ESI):475.1[M+1]； 1H NMR(400MHz,CD 3OD):δ8.51-8.50(m,1H),7.70-7.67(m,1H),7.45-7.43(d,J＝8Hz,1H),7.35(s,1H),7.18-7.15(m,1H),5.75(d,J＝1.2Hz,1H),4.42-4.38(t,J＝8Hz,1H),3.84-3.82(m,1H),3.57-3.52(m,2H),2.93-2.89(m,1H),2.42-2.30(m,3H),1.97-1.74(m,5H),1.57-1.31(m,10H),1.02-0.80(m,2H),0.61-0.55(m,1H).
步骤5：参考步骤3的制备方法，以化合物4-2b为原料制备得到化合物4-3b。
步骤6:参考步骤4的制备方法，以化合物4-3b为原料制备得到化合物H-4b(90.52mg)，产率44％。MS m/z(ESI):475.1[M+1]； 1H NMR(400MHz,CD 3OD):δ8.51-8.49(m,1H),7.72-7.68(m,1H),7.44-7.42(d,J＝8Hz,1H),7.34(s,1H),7.18-7.16(m,1H),5.70(d,J＝1.2Hz,1H),4.41-4.37(t,J＝8Hz,1H),3.86-3.84(m,1H),3.58-3.56(m,2H),2.90-2.87(m,1H),2.32-2.29(m,3H),2.00-1.74(m,5H),1.64-1.30(m,9H),0.97-0.90(m,3H),0.81-0.78(m,1H).
实施例5：(4R,6S)-6-叔丁基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-5a)和(4R,6R)-6-叔丁基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-5b)
Figure PCTCN2021072018-appb-000052
参考实施例1的制备方法，不同之处在于用化合物(S)-2-甲基丙烷-2-亚磺酰胺替代化合物(R)-2-甲基丙烷-2-亚磺酰胺，分别得到单一构型化合物H-5a和H-5b，MS m/z(ESI):423.2[M+1]。
实施例6：(4R,6S)-6-(1-甲基环丙基)-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-6a)和(4R,6R)-6-(1-甲基环丙基)-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-6b)
Figure PCTCN2021072018-appb-000053
参考实施例2的制备方法，不同之处在于用化合物(S)-2-甲基丙烷-2-亚磺酰胺替代化合物(R)-2-甲基丙烷-2-亚磺酰胺，分别得到单一构型化合物H-6a和H-6b，MS m/z(ESI):421.1[M+1]。
实施例7：(4R，6S)-6-异丙基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-7a)和(4R，6R)-6-异丙基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-7b)
Figure PCTCN2021072018-appb-000054
参考实施例3的制备方法，不同之处在于用化合物(S)-2-甲基丙烷-2-亚磺酰胺替代化合物(R)-2-甲基丙烷-2-亚磺酰胺，分别得到单一构型化合物H-7a和H-7b，MS m/z(ESI):409.3[M+1]。
实施例8:(4R,6S)-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-6-(1-(三氟甲基)环丙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-8a)和(4R,6R)-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-6-(1-(三氟甲基)环丙基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-胺(H-8b)
Figure PCTCN2021072018-appb-000055
参考实施例4的制备方法，不同之处在于用化合物(S)-2-甲基丙烷-2-亚磺酰胺替代化合物(R)-2-甲基丙烷-2-亚磺酰胺，分别得到单一构型化合物H-8a和H-8b，MS m/z(ESI):475.1[M+1]。
生物测试
以下测试例所使用的细胞株为
Figure PCTCN2021072018-appb-000056
CHO-K1OPRM1β-Arrestin Cell Line，来源：DiscoverX，编号：93-0213C2,批号：13K0402。
所使用的试剂、其供应商、货号和存储温度如下：
Assay Complete TM Cell Culture Kit 107，DiscoverX，92-3107G，-20℃；
AssayComplete TM Thawing Reagent，DiscoverX，92-4002TR，-20℃；
AssayComplete TM Cell Detachment Reagent，DiscoverX，92-0009，-20℃；
Assay Complete TM Cell Plating Reagent，DiscoverX，93-0563R2，-20℃；
PathhunterDetection Kit，DiscoverX，93-0001，-20℃；
PBS(1×)0.0067M(PO4)，Hyclone，SH30256.01，4℃；
DMSO，Sigma，D5879-100ML，常温；
NKH477，Sigma，1603，-20℃；
IBMX，Tocris，I5879，-20℃。
所使用的仪器、其型号和供应商如下：
Countsatr BioMed，IM1200，ALIT；
Microscope，IX51，OLYMPUS；
Centrifuge，5804，Eppendorf；
Thermostatic Water Bath，DK-S420，ShanghaiShenxian thermostatic equipment factory；
Cell Incubator，3111，Thermo；
Biological Safety Cabinet，BSC-1300IIA2，AIRTECH；
OptiPlate-384White Opaque，6007290，Perkin Elmer；
Multimode plate Reader，Victor X5，PerkinElmer；
Culture Plate-384White Opaque,TC-treated，6007680，PerkinElmer。
测试例一 HTRF-cAMP细胞实验
实验方法和步骤
一、细胞复苏
1、将复苏液从4℃冰箱中取出放37℃水浴锅中预热15分钟。
2、从液氮罐中取出P6代细胞，将冰冻的细胞冻存管迅速放在37℃水浴锅中轻轻晃动30秒到1分钟，直到看见小冰晶或细胞即将完全融化。
3、用70％的酒精进行彻底的消毒擦干。
4、离心去除冻存液，用预先预热的新鲜复苏液重悬细胞。
a、吸取3ml预先预热的细胞复苏液到15ml离心管。
b、1300rpm离心3分钟。
c、去除上清冻存液，用4ml预热的复苏液重悬细胞。
5、将细胞混悬液转移到T25细胞培养瓶中培养24小时，37℃，5％CO2。
6、培养24小时后，将细胞培养瓶中的复苏液换成预热好的细胞培养基。
二、细胞传代
1、当细胞在T25培养瓶中的生长密度>70％时,用细胞消化液对细胞进行消化传代培养。
a、吸出培养瓶中的培养基，加入4ml预先预热的PBS，轻轻晃动润洗细胞，吸弃PBS。
b、吸取1ml细胞消化液加入到T25培养瓶中。
c、反复摇晃培养瓶使消化液彻底覆盖培养瓶，放在37℃,5％CO2培养箱中5分钟。
d、取出细胞培养瓶，在显微镜下观察细胞，看细胞是否被分离。
e、加入3ml预热好的细胞培养基，终止消化。
f、用细胞培养基反复轻轻冲洗培养瓶，收集细胞悬液到15ml离心管。
g、1300rpm离心3分钟，去除上清。
h、用3ml细胞培养基重悬。
2、按1：3的比例进行细胞传代(每瓶加入1ml的细胞重悬液+3ml的细胞培养基，传至T25瓶)。
三、细胞种板
1、重复步骤2.2.1(a-h)，直到细胞传到P8代。细胞计数，然后用2×/1mM IBMX stimulation buffer液重悬细胞，使细胞密度为1.2*10^6/ml.
2、使用多通道移液器，将1.2*10^6/ml的细胞溶液，以每孔10μl的体积(即每孔12000个细胞)种在384孔板内。
四、c-AMP试验
1、配置相关试剂，按药物稀释配置表，配置化合物。
a、1×Stimulation buffer液：取1ml的5×Stimulation buffer存储液加到4ml的蒸馏水中，混匀。
b、2×/1mM IBMX stimulation buffer液5ml：取10ul 500mM IBMX存储液加到4990μl细胞培养基中，轻轻吹打混匀。
c、阳性药吗啡的梯度稀释配置表：
Figure PCTCN2021072018-appb-000057
Figure PCTCN2021072018-appb-000058
d、化合物稀释之前，先将化合物用DMSO溶解，使其存储浓度为10mM.
阳性药TRV130和各化合物稀释配置表：
Figure PCTCN2021072018-appb-000059
e、50uM NK477 1ml：取1μl 50mM NKH477存储液加到999μl 1×Stimulation buffer液中，震荡混匀。
f、检测试剂
A.cAMP-Cryptate(donor,lyophilized)反应液：取1ml 5×cAMP-Cryptate存储液加到4ml 1×Lysis & Detection Buffer液中，轻轻混匀。
B.Anti-cAMP-d2(acceptor,lyophilized)反应液：取1ml 5×Anti-cAMP-d2存储液加到4ml 1×Lysis & Detection Buffer液中，轻轻混匀。
2、cAMP试验步骤
a、种12000个细胞在10μl含2xIBMX stimulation缓冲液种，每孔。
b、在每孔细胞中加入8μl的化合物样品稀释液。
c、每孔中加入配置好的2μl 10xNKH477液。
d、37℃孵育45mins。
e、加入10μl cAMP-d2和10μl抗cAMP Cryptate反应液。
f、室温避光孵育60mins。
g、HTRF读板。
3、RFU检测读板
孵育60分钟后，所有的样品将通过均相时间分辨荧光的方法检测读板。
数据分析
将数据从多功能读板仪连接的电脑中对应软件导出，包括665nm和620nm两个信号值。比率的计算公式为：比率＝665nm信号值/620nm信号值×10000。用GraphPad Prism软件对数据进行分析。最佳拟合曲线选用log(agonist)vs.response.利用计算机辅助剂量-反应曲线的非线性回归分析方式确定化合物的EC50值；PEC50＝-logEC50(EC50值的单位是摩尔)；％吗啡的最大效应值＝(化合物样品比率-空白孔比率)/TOP×100(注：TOP值是吗啡样品比率-空白孔比率后通过软件Graphpad Prism分析拟合的曲线Top值)。结果如表1所示：
表1 化合物对cAMP的活性
Figure PCTCN2021072018-appb-000060
测试例二 β-Arrestin细胞实验
实验方法和步骤
一、细胞复苏
1、将复苏液从4℃冰箱中取出放37℃水浴锅中预热15分钟。
2、从液氮罐中取出P6代细胞，将冰冻的细胞培养管迅速放在37℃水浴锅中轻轻晃动30秒到1分钟，直到看见小冰晶或细胞即将完全融化。
3、用70％的酒精进行彻底的消毒擦干。
4、离心去除冻存液，用预先预热的新鲜复苏液重悬细胞。
a、吸取3ml预先预热的细胞复苏液到15ml离心管。
b、1300rpm离心3分钟。
c、去除上清，用4ml预热的复苏液重悬细胞。
5、将细胞混悬液转移到T25细胞培养瓶中培养24小时，37℃，5％CO2。
6、培养24小时后，将细胞培养瓶中的复苏液换成预热好的细胞培养基。
二、细胞传代
1、当细胞在T25培养瓶中的生长密度>70％时,用细胞消化液对细胞进行消化传代培养。
a.吸出培养瓶中的培养基，加入4ml预先预热的PBS，轻轻晃动润洗细胞，吸弃PBS。
b.吸取1ml细胞消化液加入到T25培养瓶中。
c.反复摇晃培养瓶使消化液彻底覆盖培养瓶，放在37℃,5％CO2培养箱中5分钟。
d.取出细胞培养瓶，在显微镜下观察细胞，看细胞是否被分离。
e.加入3ml预热好的细胞培养基，终止消化。
f.用细胞培养基反复轻轻冲洗培养瓶，最后将细胞悬液转移到15ml离心管。
g.1300rpm离心3分钟，去除上清。
h.用3ml细胞培养基重悬。
2、按1：3的比例进行细胞传代(每瓶加入1ml的细胞重悬液+3ml的细胞培养基，传至T25瓶)。
3、重复步骤2.2.1(a-h)，直到细胞传到P8代。
三、细胞种板
1、用移液器取20μl的细胞悬液用细胞计数仪测量细胞数。
2、1300rpm离心3分钟，沉淀细胞。
3、去除上清，加入相应细胞铺板液使细胞浓度为2×10^5/ml。
4、使用多通道移液器，根据实验设计，将2×10^5/ml的细胞溶液，以每孔20ul的体积(即每孔4000个细胞)种在384孔板内。
5、将种好细胞的384孔板放到37℃,5％CO2培养箱中培养24h。
四、β-arrestin试验
1、按照下列稀释表配置化合物。
a.阳性药吗啡的梯度稀释配置表：
Figure PCTCN2021072018-appb-000061
b.化合物稀释之前，先将化合物用DMSO溶解，使其存储浓度为10mM.
阳性药TRV130和各化合物稀释配置表：
Figure PCTCN2021072018-appb-000062
2、取5μl上述配置好的各化合物样品稀释液加到384孔板中。
3、加完样后，将384孔板放回37℃,5％CO 2培养箱中培养90分钟。
五、RLU检测
1、化合物孵育结束前，按下列比例配置Working Detection溶液(注意避光)。然后每孔加入12.5μl，避光、常温、摇床孵育1h。
Figure PCTCN2021072018-appb-000063
2、化合物孵育结束，每孔加入12.5μl上述工作液，避光、常温、80rpm摇床孵育1h。
3、孵育结束，运用多功能读板仪进行读板。
数据分析
将数据从多功能读板仪连接的电脑中对应软件导出，用GraphPad Prism软件对数据进行分析。最佳拟合曲线选用log(agonist)vs.response.利用计算机辅助剂量-反应曲线的非线性回归分析方式确定化合物的EC50值；PEC50＝-logEC50(EC50值的单位是摩尔)；％吗啡的最大效应值＝(化合物样品的RLU值-空白孔的RLU值)/TOP×100(注：TOP值是吗啡样品的RLU值-空白孔的RLU值后通过软件Graphpad Prism分析拟合的曲线Top值)。结果如表2所示：
表2 化合物对β-arrestin的测试结果
Figure PCTCN2021072018-appb-000064
从表1和表2可以看出，本发明代表性化合物对cAMP具有较高的抑制活性，以及较高的Emax值。此外本发明的化合物对β-arrestin具有较低的Emax值，偏向性好。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (49)

  1. 一种式(I)所示的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药：
    Figure PCTCN2021072018-appb-100001
    其中，
    R a、R b各自独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基或卤代C 1-6烷氧基；或者R a、R b与相连的碳原子共同形成4至6元饱和单杂环或3至6元饱和单环；其中所述4至6元饱和单杂环和3至6元饱和单环各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1和-NHSO 2C 3-6环烷基；
    R c为氢、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、-COC 1-6烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-6烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2N R a1R b1、-NHSO 2C 3-6环烷基、-SO 2C 1-3烷基、-SO 2NR a1R b1、4至6元饱和单杂环、C 6-10芳基或5或6元单环杂芳基；其中所述4至6元饱和单杂环、C 6-10芳基和5或6元单环杂芳基各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1和-NHSO 2C 3-6环烷基；
    R a1、R b1各自独立地为氢、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基或4至6元饱和单杂环；或者R a1、R b1与相连的氮原子形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-3烷基取代；以及
    *为R或S构型。
  2. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，式(I)化合物为式(I-a)或式(I-b)所示结构：
    Figure PCTCN2021072018-appb-100002
  3. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R a、R b各自独立地为氢、卤素或C 1-3烷基；或者R a、R b与相连的碳原子共同形成3至6元饱和单环。
  4. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R a、R b各自独立地为氢、氟、甲基或乙基。
  5. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R a、R b与相连的碳原子共同形成环丙基环、环丁基环或环戊基环。
  6. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R c为氢、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基。
  7. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  8. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R a、R b各自独立地为氢、氟或甲基；R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  9. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R a、R b为甲基；R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  10. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R a、R b为氟；R c为氢、氟、甲基或乙基。
  11. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R a、R b为氢；R c为氢、氟、甲基、乙基或三氟甲基。
  12. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R a为氢；R b为甲基；R c为甲基或乙基。
  13. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R a、R b与相连的碳原子共同形成环丙基环、环丁基环或环戊基环；R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  14. 一种式(II)所示的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药：
    Figure PCTCN2021072018-appb-100003
    其中，
    R 1、R 2各自独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基或卤代C 1-6烷氧基；或者R 1、R 2与相连的碳原子共同形成4至6元饱和单杂环或3至6元饱和单环；其中所述4至6元饱和单杂环和3至6元饱和单环各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR 11R 12、NR 11R 12、-NHCOC 1-3烷基、-NHCONR 11R 12、-NHSO 2C 1-3烷基、-NHSO 2NR 11R 12和-NHSO 2C 3-6环烷基；
    R 3为氢、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、-COC 1-6烷基、-CONR 11R 12、NR 11R 12、-NHCOC 1-6烷基、-NHCONR 11R 12、-NHSO 2C 1-3烷基、-NHSO 2NR 11R 12、-NHSO 2C 3-6环烷基、-SO 2C 1-3烷基、-SO 2NR 11R 12、4至6元饱和单杂环、C 6-10芳基或5或6元单环杂芳基；其中所述4至6元饱和单杂环、C 6-10芳基和5或6元单环杂芳基各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR 11R 12、NR 11R 12、-NHCOC 1-3烷基、-NHCONR 11R 12、-NHSO 2C 1-3烷基、-NHSO 2NR 11R 12和-NHSO 2C 3-6环烷基；
    R 11、R 12各自独立地为氢、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基或4至6元饱和单杂环；或者R 11、R 12与相连的氮原子形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-3烷基取代；以及
    *为R或S构型。
  15. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，式(II)化合物为式(II-a)或式(II-b)所示结构：
    Figure PCTCN2021072018-appb-100004
  16. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R 1、R 2各自独立地为氢、卤素或C 1-3烷基；或者R 1、R 2与相连的碳原子共同形成3至6元饱和单环。
  17. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R 1、R 2各自独立地为氢、氟、甲基或乙基。
  18. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R 1、R 2与相连的碳原子共同形成环丙基环、环丁基环或环戊基环。
  19. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R 3为氢、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基。
  20. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R 3为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  21. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R 1、R 2各自独立地为氢、氟或甲基；R 3为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  22. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R 1、R 2为甲基；R 3为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  23. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R 1、R 2为氟；R 3为氢、氟、甲基或乙基。
  24. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R 1、R 2为氢；R 3为氢、氟、甲基、乙基或三氟甲基。
  25. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R 1为氢；R 2为甲基；R 3为甲基或乙基。
  26. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，R 1、R 2与相连的碳原子共同形成环丙基环、环丁基环或环戊基环；R 3为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  27. 如权利要求1所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2021072018-appb-100005
  28. 如权利要求14所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2021072018-appb-100006
  29. 一种药物组合物，所述药物组合物包括：权利要求1至28中任一项所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药；以及药学上可接受的载体。
  30. 如权利要求1至28中任一项所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，或如权利要求29所述药物组合物在制备预防和/或治疗MOR受体激动剂介导的相关疾病的药物中的用途。
  31. 如权利要求1至28中任一项所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，或如权利要求29所述药物组合物在制备预防和/或治疗疼痛和疼痛相关疾病的药物中的用途。
  32. 如权利要求1至28中任一项所述的化合物，或其药学上可接受的盐，或其溶剂化物，或其前药，或如权利要求29所述药物组合物在制备激动或拮抗MOR受体的药物中的用途。
  33. 一种式(I)化合物的制备方法，包括：
    将化合物1b与式(I-1)化合物进行还原胺化反应，
    Figure PCTCN2021072018-appb-100007
    得到所述式(I)化合物，其中式(I-1)和式(I)化合物中基团如权利要求1中所定义。
  34. 如权利要求33所述的制备方法，其特征在于，式(I-1)化合物为式(I-1a)或(I-1b)所示结构：
    Figure PCTCN2021072018-appb-100008
  35. 如权利要求33所述的制备方法，其特征在于，R a、R b各自独立地为氢、氟或甲基；或者R a、R b与相连的碳原子共同形成环丙基环、环丁基环或环戊基环；R c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  36. 一种式(II)化合物的制备方法，包括：
    将化合物1b与式(II-1)化合物进行还原胺化反应，
    Figure PCTCN2021072018-appb-100009
    得到所述式(II)化合物，其中式(II-1)和式(II)化合物中基团如权利要求14中所定义。
  37. 如权利要求36所述的制备方法，其特征在于，式(II-1)化合物为式(II-1a)或(II-1b)所示结构：
    Figure PCTCN2021072018-appb-100010
  38. 如权利要求36所述的制备方法，其特征在于，R 1、R 2各自独立地为氢、氟或甲基；或者R 1、R 2与相连的碳原子共同形成环丙基环、环丁基环或环戊基环；R 3为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  39. 如权利要求33或36所述的制备方法，其特征在于，所述还原胺化反应在惰性溶剂和还原剂的反应体系下进行。
  40. 如权利要求33或36所述的制备方法，其特征在于，所述惰性溶剂为C 1-4烷基醇，甲苯、二甲苯、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、乙醚、二氯甲烷、氯仿、1，2-二氯乙烷、乙酸乙酯、乙腈、二甲亚砜、N,N-二甲基甲酰胺等，或其组合。
  41. 如权利要求33或36所述的制备方法，其特征在于，所述还原剂选自：硼氢化四丁基胺盐，丙二酰氧基硼氢化钠，三乙酰氧基硼氢化钠，氰基硼氢化钠，硼氢化钠，硼氢化锂，硼氢化钾和硼烷。
  42. 一种式(Ⅲ)所示的化合物，或其盐，或其对映异构体，或其非对映异构体，或其外消旋体，或其非对映异构体混合物：
    Figure PCTCN2021072018-appb-100011
    其中，
    R 1a、R 1b各自独立地为氢、卤素、C 1-6烷基、卤代C 1-6烷基或卤代C 1-6烷氧基；或者R 1a、R 1b与相连的碳原子共同形成4至6元饱和单杂环或3至6元饱和单环；其中所述4至6元饱和单杂环和3至6元饱和单环各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、 C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1和-NHSO 2C 3-6环烷基；
    R 1c为氢、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、-COC 1-6烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-6烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2N R a1R b1、-NHSO 2C 3-6环烷基、-SO 2C 1-3烷基、-SO 2NR a1R b1、4至6元饱和单杂环、C 6-10芳基或5或6元单环杂芳基；其中所述4至6元饱和单杂环、C 6-10芳基和5或6元单环杂芳基各自为未取代的或被1、2或3个选自下组的取代基取代：氰基、羟基、羟甲基、氰基甲基、卤素、C 1-3烷氧基、C 1-3烷基、-COC 1-3烷基、-CONR a1R b1、NR a1R b1、-NHCOC 1-3烷基、-NHCONR a1R b1、-NHSO 2C 1-3烷基、-NHSO 2NR a1R b1和-NHSO 2C 3-6环烷基；以及
    R a1、R b1各自独立地为氢、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基或4至6元饱和单杂环；或者R a1、R b1与相连的氮原子形成4至6元饱和单杂环；其中所述4至6元饱和单杂环为未取代的或被1、2或3个C 1-3烷基取代。
  43. 如权利要求42所述的化合物，或其盐，或其对映异构体，或其非对映异构体，或其外消旋体，或其非对映异构体混合物，其特征在于，R 1a、R 1b各自独立地为氢、氟或甲基；R 1c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  44. 如权利要求42所述的化合物，或其盐，或其对映异构体，或其非对映异构体，或其外消旋体，或其非对映异构体混合物，其特征在于，R 1a、R 1b为甲基；R 1c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  45. 如权利要求42所述的化合物，或其盐，或其对映异构体，或其非对映异构体，或其外消旋体，或其非对映异构体混合物，其特征在于，R 1a为氢；R 1b为甲基；R 1c为甲基或乙基。
  46. 如权利要求42所述的化合物，或其盐，或其对映异构体，或其非对映异构体，或其外消旋体，或其非对映异构体混合物，其特征在于，R 1a、R 1b与相连的碳原子共同形成环丙基环、环丁基环或环戊基环；R 1c为氢、氟、甲基、乙基、甲氧基或三氟甲基。
  47. 一种氧杂螺环取代的吡咯并吡唑衍生物的中间体，其特征在于，所述中间体为式(I-1)或式(II-1)所示结构：
    Figure PCTCN2021072018-appb-100012
    其中R a、R b、R c如权利要求1中所定义；R 1、R 2、R 3如权利要求14中所定义；星号*代表手性碳原子为R或S构型。
  48. 如权利要求47所述的中间体，其特征在于，式(I-1)化合物为式(I-1a)或式(I-1b)所示结构；式(II-1)化合物为式(II-1a)或式(II-1b)所示结构：
    Figure PCTCN2021072018-appb-100013
  49. 如权利要求48所述的中间体，其特征在于，
    式(I-1a)化合物选自：
    Figure PCTCN2021072018-appb-100014
    式(I-1b)化合物选自：
    Figure PCTCN2021072018-appb-100015
    式(II-1a)化合物选自：
    Figure PCTCN2021072018-appb-100016
    式(II-1b)化合物选自：
    Figure PCTCN2021072018-appb-100017
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