WO2023093834A1 - 一种吡咯烷类抗病毒化合物 - Google Patents

一种吡咯烷类抗病毒化合物 Download PDF

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WO2023093834A1
WO2023093834A1 PCT/CN2022/134262 CN2022134262W WO2023093834A1 WO 2023093834 A1 WO2023093834 A1 WO 2023093834A1 CN 2022134262 W CN2022134262 W CN 2022134262W WO 2023093834 A1 WO2023093834 A1 WO 2023093834A1
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Prior art keywords
membered
alkyl
pharmaceutically acceptable
acceptable salt
formula
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PCT/CN2022/134262
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English (en)
French (fr)
Inventor
邹昊
祝伟
刘浪
王伟昆
徐顺
李正涛
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先声再明医药有限公司
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Priority to CN202280077074.8A priority Critical patent/CN118302421A/zh
Publication of WO2023093834A1 publication Critical patent/WO2023093834A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic

Definitions

  • the disclosure relates to the field of medicine, in particular to a novel pyrrolidine compound and a pharmaceutically acceptable salt thereof, and its use as a coronavirus 3CL protease inhibitor in preventing or treating related diseases caused by coronavirus infection.
  • Coronaviruses are a class of RNA viruses that can cause disease in mammals and birds, ranging from mild to severe and even fatal respiratory infections.
  • the epidemics of diseases such as SARS, MERS and SARS-CoV-2 (COVID-19) are all caused by coronaviruses.
  • the SARS-CoV-2 (COVID-19) coronavirus contains four nonstructural proteins: papain-like protease (PLPro) and 3C-like protease (3CLPro), RNA polymerase and helicase.
  • PPro papain-like protease
  • 3CLPro 3C-like protease
  • RNA polymerase RNA polymerase
  • helicase Among them, 3CLpro can hydrolyze viral polyproteins pp1a and pp1ab during coronavirus replication to produce functional proteins. 3C-like proteases are therefore critical for viral replication.
  • 3CL protease inhibition can effectively inhibit virus replication and reduce intracellular and in vivo virus titers, but so far no 3CL protease inhibitor has been approved for clinical use.
  • small molecule antiviral drugs with good effect are imminent in clinical practice, so the research and development of 3CL protease inhibitors with novel structure, low toxicity and high efficiency have great social significance.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 is selected from C 1 -C 10 alkyl, said C 1 -C 10 alkyl is optionally substituted by halogen;
  • R 2 is selected from C 1 -C 10 alkyl or (CH 2 ) n -R 4 , n is selected from 0 or 1, R 4 is selected from C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkenyl, 4-14 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkene Base, 4-14 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by R 2a ;
  • R 3 is selected from 4-14 membered heterocyclic groups or 5-10 membered heteroaryl groups, and the 4-14 membered heterocyclic groups or 5-10 membered heteroaryl groups are optionally substituted by R 3a ;
  • R 1 is selected from C 1 -C 3 alkyl optionally substituted with halogen.
  • R 1 is selected from C 1 -C 3 alkyl optionally substituted with F or Cl.
  • R 1 is selected from CF 3 or CF 2 Cl.
  • R 2 is selected from C 1 -C 6 alkyl or (CH 2 ) n -R 4 , n is selected from 0 or 1, R 4 is selected from C 5 -C 12 cycloalkyl, 4-7 Membered heterocyclic group or C 6 -C 10 aryl group, said C 1 -C 6 alkyl group, C 5 -C 12 cycloalkyl group, 4-7 membered heterocyclic group or C 6 -C 10 aryl group is optionally R 2a is substituted.
  • R 2 is selected from C 1 -C 6 alkyl, C 5 -C 12 cycloalkyl, 4-7 membered heterocyclyl or CH 2 -(C 6 -C 10 aryl), the C 1 -C 6 alkyl, C 5 -C 12 cycloalkyl, 4-7 membered heterocyclyl or CH 2 -(C 6 -C 10 aryl) is optionally substituted by R 2a .
  • R 2 is selected from C 1 -C 4 alkyl, C 6 -C 10 cycloalkyl, 5-6 membered heterocyclyl or CH 2 -(C 6 -C 10 aryl), the C 1 -C 4 alkyl, C 6 -C 10 cycloalkyl, 5-6 membered heterocyclyl or CH 2 -(C 6 -C 10 aryl) is optionally substituted by R 2a .
  • R 2 is selected from C 1 -C 4 alkyl, C 6 -C 10 cycloalkyl or CH 2 -(C 6 -C 10 aryl), said C 1 -C 4 alkyl, C 6 -C 10 cycloalkyl or CH 2 —(C 6 -C 10 aryl) is optionally substituted by R 2a .
  • R 2a is selected from OH, C 1 -C 3 alkyl, or NH 2 optionally substituted with R b .
  • R b is selected from C 1 -C 3 alkyl.
  • R 2a is selected from OH, methyl, or N(CH 3 ) 2 .
  • R 2a is selected from OH or N(CH 3 ) 2 .
  • R is selected from
  • R is selected from
  • R 3 is selected from 4-14 membered heterocyclyls substituted by R 3a .
  • R is selected from 4-7 membered monoheterocyclyl, 6-14 membered fused heterocyclyl, 6-14 membered spiroheterocyclyl or 6-14 membered bridged heterocyclyl, said 4 -7-membered monoheterocyclyl, 6-14 membered fused heterocyclyl, 6-14 membered spiroheterocyclyl or 6-14 membered bridged heterocyclyl is optionally substituted by R 3a .
  • R is selected from 4-7 membered monoheterocyclyl or 6-14 membered fused heterocyclyl, and the 4-7 membered monoheterocyclyl or 6-14 membered fused heterocyclyl is any is substituted by R 3a .
  • R is selected from said optionally substituted by R 3a .
  • R is selected from said optionally substituted by R 3a .
  • R is selected from said Optionally substituted by F, Cl, Br, I, CN or C 1 -C 3 alkyl.
  • R is selected from
  • R is selected from
  • R is selected from
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 are as defined above.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (Ib) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 are as defined above.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (Ic) or a pharmaceutically acceptable salt thereof:
  • R 2 and R 3 are as defined above.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (Id) or a pharmaceutically acceptable salt thereof:
  • R 2 and R 3 are as defined above.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the present disclosure also provides a pharmaceutical composition, which comprises the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
  • the present disclosure relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating coronavirus 3CL protease-related diseases.
  • the present disclosure relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of diseases related to coronavirus 3CL protease.
  • the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating diseases related to coronavirus 3CL protease.
  • the present disclosure also relates to a method for preventing or treating coronavirus 3CL protease-related diseases, the method comprising administering to a patient a therapeutically effective amount of a pharmaceutical preparation comprising the compound of formula (I) described in the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating related diseases caused by coronavirus infection.
  • the present disclosure relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of related diseases caused by coronavirus infection.
  • the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating related diseases caused by coronavirus infection.
  • the present disclosure also relates to a method for preventing or treating related diseases caused by coronavirus infection, the method comprising administering to a patient a therapeutically effective amount of a pharmaceutical preparation comprising a compound of formula (I) described in the present disclosure or a pharmaceutically acceptable salt thereof .
  • the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and 2019 novel coronavirus (2019-nCoV or SARS-CoV- 2).
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • 2019 novel coronavirus 2019-nCoV or SARS-CoV- 2.
  • the coronavirus 3CL protease-associated disease is selected from respiratory tract infection, pneumonia or complications thereof.
  • the related diseases caused by the coronavirus infection are selected from respiratory tract infection, pneumonia or complications thereof.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • Compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. This disclosure encompasses all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof are within the definition of the disclosed compounds.
  • asymmetric carbon atoms there may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included in Compounds of the disclosure are within the definition.
  • Compounds of the present disclosure containing asymmetric atoms can be isolated in optically pure or racemic forms, optically pure forms can be resolved from racemic mixtures, or synthesized by using chiral starting materials or chiral reagents .
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by substituents, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • ethyl is “optionally” substituted with halogen , meaning that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted ( CH2CH2F , CH2CH2Cl , etc.), polysubstituted ( CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc. ) or fully substituted ( CF2CF3 , CF2CCl3 , CCl2CCl3 , etc.) . It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • any variable eg R a , R b
  • its definition is independent at each occurrence. For example, if a group is substituted by 2 R b , each R b has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • linking group mentioned herein does not indicate its linking direction
  • its linking direction is arbitrary.
  • L 1 in is selected from “C 1 -C 3 alkylene-O”
  • L 1 can connect ring Q and R 1 in the direction from left to right to form “ring QC 1 -C 3 alkylene Group -OR 1 "
  • ring Q and R 1 can also be connected from right to left to form “ring QOC 1 -C 3 alkylene-R 1 ".
  • Cm - Cn herein refers to having an integer number of carbon atoms in the range of mn.
  • C 1 -C 10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group having the general formula C n H 2n+1 , and the alkyl group may be straight or branched.
  • C 1 -C 10 alkyl is understood to mean a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 6 alkyl" can be understood as an
  • C 1 -C 3 alkyl is understood to mean a linear or branched saturated alkyl group having 1 to 3 carbon atoms.
  • the "C 1 -C 10 alkyl” may include “C 1 -C 6 alkyl” or “C 1 -C 3 alkyl”, and the “C 1 -C 6 alkyl” may further include “ C 1 -C 3 alkyl”.
  • alkoxy refers to the group produced by the loss of the hydrogen atom on the hydroxyl group of straight-chain or branched alcohols, which can be understood as “alkyloxy” or “alkyl-O-".
  • C 1 -C 10 alkoxy can be understood as “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-”; the term “C 1 -C 6 alkoxy” It can be understood as “C 1 -C 6 alkyloxy” or "C 1 -C 6 alkyl-O-".
  • the "C 1 -C 10 alkoxy” may include “C 1 -C 6 alkoxy” and “C 1 -C 3 alkoxy” and other ranges, and the "C 1 -C 6 alkoxy”"C 1 -C 3 alkoxy” may be further included.
  • cycloalkyl refers to a fully saturated carbocyclic group in the form of a monocyclic ring, a fused ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 20 membered ring.
  • C 3 -C 12 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring carbon atoms, specific examples of the cycloalkyl group Including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo [2.2.2] Octyl, adamantyl, spiro[4.5]decyl, etc.
  • C 3 -C 12 cycloalkyl may include “C 5 -C 12 cycloalkyl”, “C 3 -C 10 cycloalkyl”, “C 6 -C 10 cycloalkyl” and “C 3 - C 6 cycloalkyl” and other ranges.
  • C 5 -C 12 cycloalkyl refers to a cycloalkyl group having 5, 6, 7, 8, 9, 10, 11 or 12 ring carbon atoms.
  • C 3 -C 10 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms.
  • C 6 -C 10 cycloalkyl refers to a cycloalkyl group having 6, 7, 8, 9 or 10 ring carbon atoms.
  • C3 - C6 cycloalkyl refers to a cycloalkyl group having 3, 4, 5 or 6 ring carbon atoms.
  • C 3 -C 6 cycloalkyloxy can be understood as “C 3 -C 6 cycloalkyl-O-”.
  • cycloalkenyl refers to an incompletely saturated non-aromatic carbocyclic group having at least one carbon-carbon double bond and existing in the form of a single ring, a condensed ring, a bridged ring, or a spiro ring.
  • C 4 -C 12 cycloalkenyl refers to a cycloalkenyl group having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, specific examples include but are not limited to cyclopentyl alkenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl and the like.
  • 4-14 membered heterocyclic group refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, and its ring atoms contain 1-5 independently selected from the heteroatoms or heteroatom groups described above.
  • 4-membered heterocyclic groups include but are not limited to azetidinyl or oxetanyl
  • 5-membered heterocyclic groups include but are not limited to tetrahydrofuranyl, dioxolyl , pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl
  • specific examples of 6-membered heterocyclic groups include but Not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridyl or 4H-[1,3,4] Thiadiazinyl
  • specific examples of 7-membered heterocyclyl include, but are not limited to, diazepanyl.
  • the heterocyclic group can also be a bicyclic heterocyclic group and a tricyclic heterocyclic group, wherein specific examples of 5 and 5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl ; Specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2 ,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • the heterocyclic group may be a benzofused cyclic group of the above-mentioned 4-7 membered heterocyclic group, specific examples include but not limited to dihydroisoquinolyl and the like.
  • “4-14 membered heterocyclic group” may include “4-7 membered heterocyclic group", “5-6 membered heterocyclic group”, “4-7 membered monoheterocyclic group”, “6-14 membered fused heterocyclic group” Cyclic group", "6-14 membered spiro heterocyclic group” or "6-14 membered bridged heterocyclic group” and other ranges.
  • 6-14 membered fused heterocyclic group means that the number of ring atoms is 6, 7, 8, 9, 10, 11, 12, 13, 14, and its ring atoms contain 1-5 ring atoms independently selected from the above The fused heterocyclic group of the heteroatom or heteroatom group.
  • 6-14 membered spiroheterocyclyl means that the number of ring atoms is 6, 7, 8, 9, 10, 11, 12, 13, 14, and the ring atoms contain 1-5 independently selected from the above The spiroheterocyclyl of the above-mentioned heteroatom or heteroatom group.
  • 6-14 membered bridged heterocyclic group means that the number of ring atoms is 6, 7, 8, 9, 10, 11, 12, 13, 14, and its ring atoms contain 1-5 independently selected from the above The bridged heterocyclic group of the heteroatom or heteroatom group mentioned above.
  • heterocyclyl in the present disclosure may include “heterocycloalkyl", for example, “4-14 membered heterocyclyl” may include “4-14 membered heterocycloalkyl”.
  • heterocyclyloxy can be understood as “heterocyclyl-O-”.
  • heterocycloalkyl refers to a heterocycloalkyl group with 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1-5 ring atoms independently selected from A heteroatom or heteroatom group as described above.
  • 3--10 membered heterocycloalkyl may include “4-10 membered heterocycloalkyl” or "4-7 membered heterocycloalkyl", wherein specific examples of 4-membered heterocycloalkyl include but are not limited to Azetidinyl, oxetanyl, or thibutanyl; specific examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, iso Thiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydropyrazolyl; specific examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl , piperazinyl, 1,
  • heterocycloalkyloxy is understood to mean “heterocycloalkyl-O-”.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • the aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
  • C 6 -C 20 aryl is understood to mean an aryl group having 6 to 20 carbon atoms.
  • C aryl rings with 6 carbon atoms
  • C aryl such as phenyl; or rings with 9 carbon atoms (“C aryl”), such as indanyl or indenyl; or rings with 10 a ring of 3 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl; or a ring of 13 carbon atoms (“C 13 aryl”), such as fluorenyl; or is a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms.
  • C aryl rings with 6 carbon atoms
  • C aryl such as phenyl
  • C aryl rings with 9 carbon atoms
  • C aryl such as indanyl or indenyl
  • C 10 aryl rings with 10 carbon atoms
  • aryloxy is understood to mean “aryl-O-”.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S.
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazole Linyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
  • heteroaryloxy is understood to mean “heteroaryl-O-”.
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to a -OH group.
  • cyano refers to a -CN group.
  • mercapto refers to a -SH group.
  • amino refers to a -NH2 group.
  • nitro refers to a -NO2 group.
  • terapéuticaally effective amount means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying The amount of a compound of the disclosure required for the onset of one or more symptoms of a particular disease, condition or disorder.
  • the amount of a compound of the present disclosure that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art according to its own knowledge and this disclosure.
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in an individual (eg, a mammal), Especially when such individuals (eg mammals) are susceptible to the disease state, but have not yet been diagnosed as having the disease state.
  • mammals includes mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (such as chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, pigs; domesticated animals , such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • patient and “individual” are used interchangeably.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of pharmaceutically acceptable acids or bases, including salts formed between compounds and inorganic or organic acids, and salts formed between compounds and inorganic or organic bases.
  • composition refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the disclosure also includes isotopically labeled compounds of the disclosure that are identical to those described herein, but with one or more atoms replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotopically labeled compounds of the disclosure are useful in compound and/or substrate tissue distribution assays. Tritiated (ie3H ) and carbon-14 ( ie14C ) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the disclosure can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the pharmaceutical composition of the present disclosure can be prepared by combining the compound of the present disclosure with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present disclosure can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, emulsifying methods, freeze-drying methods and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
  • the daily dosage is 0.01 mg/kg to 200 mg/kg body weight, preferably 0.05 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 30 mg /kg body weight, in single or divided doses.
  • the compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art As an equivalent alternative, preferred embodiments include but are not limited to the examples of the present disclosure.
  • ratios indicated for mixed solvents are volume mixing ratios.
  • % means weight percent wt%.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • the eluent or mobile phase can be a mixed eluent or mobile phase composed of two or more solvents, and the ratio is the volume ratio of each solvent, such as "0-10% methanol/dichloromethane" means a mixed eluent Or the volume ratio of methanol and dichloromethane in the mobile phase is 0:100-10:100.
  • the synthetic route is as follows:
  • Step 1 tert-butyl ((2S)-1-amino-1-oxo-3-(2-oxoindol-3-yl)propan-2-yl)carbamate (1b)
  • compound 1b (0.090g, 0.28mmol) was dissolved in 1,4-dioxane (1mL), and 1,4-dioxane hydrochloride solution (4M, 1mL, 4.0mmol) was added to react The solution was reacted at room temperature for 2 hours. The reaction solution was lyophilized to obtain compound 1c (0.070 g).
  • Step 3 (1R,2S,5S)-N-((2S)-1-Amino-1-carbonyl-3-(2-carbonylindolin-3-yl)propan-2-yl)-3- ((S)-3,3-Dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0] Hexane-2-carboxamide (1e)
  • Step 4 (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-3-((S)-3 ,3-Dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-methanol Amides (1)
  • the retention time (RT) of compound 1-P2 under the following high performance liquid chromatography conditions is 1.64min.
  • HPLC conditions column is Xtimate C18 2.1*50mm, mobile phase A is 0.05% trifluoroacetic acid aqueous solution, mobile phase B is 0.05% trifluoroacetic acid acetonitrile solution, flow rate is 0.7ml/min, B% is 5%- 95%.
  • the synthetic route is as follows:
  • Step 1 (S)-2-(adamantan-1-yl)-2-(2,2,2-trifluoroacetylamino)acetic acid (2b)
  • compound 2a (0.15g, 0.72mmol) was dissolved in methanol (10ml), then triethylamine (0.46g, 3.6mmol), ethyl trifluoroacetate (0.51g, 3.6mmol) were added, and the reaction The solution was heated to 50°C for 16h. The reaction solution was concentrated, and 1M hydrochloric acid was added to adjust the pH to 3-4. Extracted with ethyl acetate (3 x 10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Compound 2b (0.2 g) was obtained. m/z (ESI): 306[M+H] + .
  • Step 2 (1R,2S,5S)-3-((S)-2-(Adamantan-1-yl)-2-(2,2,2-trifluoroacetylamino)acetyl)-N-( (S)-1-amino-1-carbonyl-3-((S)-2-carbonylpyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo [3.1.0] Hexane-2-carboxamide (2d)
  • Step 3 (1R,2S,5S)-3-((S)-2-(Adamantan-1-yl)-2-(2,2,2-trifluoroacetylamino)acetyl)-N-( (S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexyl Alkane-2-carboxamides (2)
  • the synthetic route is as follows:
  • compound 3b (0.81g, 4.41mmol) was dissolved in methanol (20ml), then triethylamine (1.3g, 13mmol) and ethyl trifluoroacetate (3.1g, 22mmol) were added, then heated to Reaction at 50°C for 16h.
  • the reaction solution was concentrated, and 1M hydrochloric acid was added to adjust the pH to 3-4.
  • the reaction solution was extracted with ethyl acetate (3 ⁇ 50ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 3c (0.97g).
  • Step 6 (1R,2S,5S)-6,6-Dimethyl-3-(2-(spiro[3.3]heptan-2-yl)-2-(2,2,2-trifluoroacetylamino ) Acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (3h)
  • Step 7 (1R,2S,5S)-N-((S)-1-amino-1-carbonyl-3-((S)-2-carbonylpyrrolidin-3-yl)propan-2-yl)- 6,6-Dimethyl-3-(2-(spiro[3.3]heptan-2-yl)-2-(2,2,2-trifluoroacetylamino)acetyl)-3-azabicyclo [3.1.0] Hexane-2-carboxamide (3j)
  • Step 7 (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-6,6-dimethyl Base-3-(2-(spiro[3.3]heptane-2-yl)-2-(2,2,2-trifluoroacetylamino)acetyl)-3-azabicyclo[3.1.0]hexyl Alkane-2-carboxamide (3)
  • Step 1 Methyl(1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-2-((1r,3R,5R,7S)-3-hydroxy Adamant-1-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (5b)
  • compound 5a (0.6g, 1.8mmol) and 3f (0.28g, 1.6mmol) were dissolved in anhydrous N,N-dimethylformamide (5mL), and 2-(7-azabenzo Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.68g, 1.8mmol), then add N,N-diisopropylethylamine (0.70g, 5.4mmol) , and the reaction solution was reacted at room temperature for 10 min.
  • N,N-diisopropylethylamine (0.70g, 5.4mmol
  • Step 2 (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-2-((1r,3R,5R,7S)-3-hydroxyadamantane -1-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (5c)
  • Step 3 (1R,2S,5S)-3-((S)-2-Amino-2-((1r,3R,5R,7S)-3-hydroxyadamantan-1-yl)acetyl)-6 ,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (5d)
  • Step 4 (1R,2S,5S)-3-((S)-2-Amino-2-((1r,3R,5R,7S)-3-hydroxyadamantan-1-yl)acetyl)-6 ,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (5e)
  • Compound 5 can be prepared in a similar manner to Example 1 by replacing Compound 1d with Compound 5e.
  • the synthetic route is as follows:
  • Step 1 Methyl 2-((benzyloxy)carbonyl)amino)-2-(4-((tert-butoxycarbonyl)amino)cyclohexylene acetate (6c)
  • Step 4 2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)-2-(2,2,2-trifluoroacetamido)acetic acid (6f)
  • Step 5 tert-butyl (4-(2-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine -3-yl)propyl-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)-2-oxo-1-( 2,2,2-Trifluoroacetamido)ethyl)cyclohexyl)-2-carboxamide (6g)
  • Step 6 (1R,2S,5S)-N-((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propyl-2-yl )-3-(2-(4-(dimethylamino)cyclohexyl)-2-(2,2,2-trifluoroacetamido)acetyl)-6,6-dimethyl-3-nitrogen Heterobicyclo[3.1.0]hexane-2-carboxamide (6h)
  • Step 7 (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(2-( 4-(Dimethylamino)cyclohexane)-2-(2,2,2-trifluoroacetamido)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0] Cyclohexane-2-carboxamide (Compound 6)
  • Step 1 N 6 -(Benzyloxycarbonyl)-N 2 -(2,2,2-trifluoroacetyl)-L-lysine (7b)
  • N 6 -Cbz-L-lysine 7a (1.0 g, 3.6 mmol) was dissolved in anhydrous methanol (3.5 mL), and triethylamine (0.7 g, 7.1 mmol) and ethyl trifluoroacetate (0.6 g, 4.6 mmol), stirred overnight at room temperature, concentrated under reduced pressure, diluted with water and adjusted the pH to 4, extracted 3 times with ethyl acetate, combined the organic phase, washed the organic phase with saturated brine (100 mL) and dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated, and the obtained crude product 7b (1.0 g, yield 74%) was directly used in the next reaction without purification.
  • Step 3 Synthesis of N 6 , N 6 -dimethyl-N 2 -(2,2,2-trifluoroacetyl)-L-lysine (7d)
  • Step 4 (1R,2S,5S)-N-((S)-1-Amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl) -3-(N 6 ,N 6 -Dimethyl-N 2 -(2,2,2-trifluoroacetyl)-L-lysyl)-6,6-dimethyl-3-azabicyclo [3.1.0] Hexane-2-carboxamide (7e)
  • Step 5 (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-(N 6 , N 6 -Dimethyl-N 2 -(2,2,2-trifluoroacetyl)-L-lysyl)-6,6-dimethyl-3-azabicyclo[3.1.0]cyclohexyl Alkane-2-carboxamide (7)
  • Example 8 (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine -3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl- 3-Azabicyclo[3.1.0]hexane-2-carboxamide (compound 8)
  • the synthetic route is as follows:
  • Step 1 Methyl(2S)-2-((tert-butoxycarbonyl)amino)-3-(2-carbonyl-1-((2-(trimethylsilyl)ethoxy)methyl )-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)propionate (8b)
  • N-tert-butoxycarbonyl-O-p-toluenesulfonylserine methyl ester (1.4g, 3.78mmol) was dissolved in anhydrous tetrahydrofuran at -10°C, and sodium hydrogen (0.11g .4.54mmol) and continued to react at this temperature for 30 minutes, and then added the solution dropwise to the above-mentioned 1-[[2-(trimethylsilyl) Ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-2(3H)-one in anhydrous tetrahydrofuran solution, and continue to react at -78°C for 2 hours, and then rise to Reaction at room temperature for another 2 hours.
  • Step 2 (2S)-2-((tert-butoxycarbonyl)amino)-3-(2-carbonyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid (8c)
  • Step 3 tert-butyl((2S)-1-amino-1-oxo-3-(2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2 ,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)propan-2-yl)carbamate (8d)
  • compound 8c (0.7g, 1.6mmol) and ammonium chloride (0.16g, 3.2mmol) were dissolved in anhydrous N,N-dimethylformamide (5mL), and then 2-(7 -Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.88g, 2.3mmol) and N,N-diisopropylethylamine (0.6g, 4.6mmol), react at room temperature for 1 hour.
  • Compound 8 was obtained by replacing compound 1c with compound 8e and using the same preparation method as in Example 1.
  • the synthetic route is as follows:
  • compound 9a (90mg, 0.3mmol) was dissolved in methanol (10ml), then triethylamine (0.11g, 1.1mmol) and ethyl difluorochloroacetate 9b (94mg, 0.6mmol) were added to react The solution was heated to 50°C for 16h. The reaction solution was concentrated, and 1M hydrochloric acid was added to adjust the pH to 3-4. Extracted with ethyl acetate (3 x 10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Compound 9c (65 mg) was obtained. m/z (ESI): 338.1 [M+H] + .
  • Step 2 (1R,2S,5S)-3-((S)-2-(2-Chloro-2,2-difluoroacetamido)-3,3-dimethylbutyryl)-N-(( 1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2 - Formamide (9)
  • the synthetic route is as follows:
  • Step 1 (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-((S)-2-((1R,3R,5R,7S)-3-hydroxyadamantan-1-yl)-2-(2,2,2-trifluoroacetamido)acetyl )-6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (10b)
  • Step 2 (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S )-2-((1R,3R,5R,7S)-3-hydroxyadamantan-1-yl)-2-(2,2,2-trifluoroacetamido)acetyl)-6,6-di Methyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (10)
  • Test example 1 SARS-CoV-2 3CL protease inhibitory activity test
  • the detection is carried out using the BPS kit (3CL Protease, MBP-tagged (SARS-CoV-2) Assay Kit), which contains 3CL protease, fluorescent substrate, and reaction buffer. 3CL protease hydrolyzes the fluorescent substrate to generate a detectable fluorescent product, and the detection of the fluorescent product reflects the activity of the protease.
  • BPS kit (3CL Protease, MBP-tagged (SARS-CoV-2) Assay Kit
  • 3CL protease hydrolyzes the fluorescent substrate to generate a detectable fluorescent product, and the detection of the fluorescent product reflects the activity of the protease.
  • Inhibition rate % (average 0% inhibition well-sample well)/(average 0% inhibition well-average 100% inhibition well) x 100%.
  • HillSlope is the slope coefficient of the curve.

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Abstract

提供了式（I）所示吡咯烷类化合物及其药学上可接受的盐，以及其作为冠状病毒3CL蛋白酶抑制剂在预防或治疗由冠状病毒感染引起的相关疾病中的用途。

Description

一种吡咯烷类抗病毒化合物
本公开要求2021年11月26日向中国国家知识产权局提交的，专利申请号为202111424968.3，发明名称为“一种吡咯烷类抗病毒化合物”的中国专利申请的优先权和权益。上述在先申请的全文通过援引整体并入本文中。
技术领域
本公开涉及医药领域，具体涉及一种新型的吡咯烷类化合物及其药学上可接受的盐，以及其作为冠状病毒3CL蛋白酶抑制剂在预防或治疗由冠状病毒感染引起的相关疾病中的用途。
背景技术
冠状病毒是一类可引起哺乳动物和鸟类的疾病的RNA病毒，可引起从轻微到严重甚至致命的呼吸道感染。SARS、MERS和SARS-CoV-2(COVID-19)等疾病的流行，均由冠状病毒所引起。SARS-CoV-2(COVID-19)冠状病毒包含有四种非结构蛋白：木瓜样蛋白酶(PLPro)和3C样蛋白酶(3CLPro)、RNA聚合酶和解旋酶。其中，3CLpro在冠状病毒复制期间能够水解病毒多聚蛋白pp1a和pp 1ab，以产生功能性蛋白质。因此3C样蛋白酶对病毒的复制至关重要。目前临床前和临床有多项研究表明3CL蛋白酶抑制能够有效抑制病毒复制，且能降低细胞内和体内病毒滴度，但是到目前为止尚无3CL蛋白酶抑制剂获批临床。鉴于冠状病毒导致的严重肺炎疾病严重影响了人们的生命健康，效果好的小分子抗病毒药物在临床上迫在眉睫，因此研究、开发结构新颖、低毒高效的3CL蛋白酶抑制剂具有重大的社会意义。
发明内容
本公开提供一种式(I)所示化合物或其药学上可接受的盐：
Figure PCTCN2022134262-appb-000001
其中，
R 1选自C 1-C 10烷基，所述C 1-C 10烷基任选被卤素取代；
R 2选自C 1-C 10烷基或(CH 2) n-R 4，n选自0或者1，R 4选自C 3-C 12环烷基、C 4-C 12环烯基、4-14元杂环基、C 6-C 10芳基或5-10元杂芳基，所述C 1-C 10烷基、C 3-C 12环烷基、C 4-C 12环烯基、4-14元杂环基、C 6-C 10芳基或5-10元杂芳基任选被R 2a取代；
R 3选自4-14元杂环基或5-10元杂芳基，所述4-14元杂环基或5-10元杂芳基任选被R 3a取代；
每一个R 2a、R 3a独立地选自F、Cl、Br、I、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R b取代；
每一个R b独立地选自F、Cl、Br、I、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R c取代；
每一个R c独立地选自F、Cl、Br、I、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基、4-7元杂环基、C 1-C 6烷氧基、C 3-C 6环烷基氧基或4-7元杂环基氧基；
条件是，式(I)所示化合物不包含
Figure PCTCN2022134262-appb-000002
在一些实施方案中，R 1选自C 1-C 3烷基，所述C 1-C 3烷基任选被卤素取代。
在一些实施方案中，R 1选自C 1-C 3烷基，所述C 1-C 3烷基任选被F或Cl取代。
在一些实施方案中，R 1选自CF 3或CF 2Cl。
在一些实施方案中，R 2选自C 1-C 6烷基或(CH 2) n-R 4，n选自0或者1，R 4选自C 5-C 12环烷基、4-7元杂环基或C 6-C 10芳基，所述C 1-C 6烷基、C 5-C 12环烷基、4-7元杂环基或C 6-C 10芳基任选被R 2a取代。
在一些实施方案中，R 2选自C 1-C 6烷基、C 5-C 12环烷基、4-7元杂环基或CH 2-(C 6-C 10芳基)，所述C 1-C 6烷基、C 5-C 12环烷基、4-7元杂环基或CH 2-(C 6-C 10芳基)任选被R 2a取代。
在一些实施方案中，R 2选自C 1-C 4烷基、C 6-C 10环烷基、5-6元杂环基或CH 2-(C 6-C 10芳基)，所述C 1-C 4烷基、C 6-C 10环烷基、5-6元杂环基或CH 2-(C 6-C 10芳基)任选被R 2a取代。
在一些实施方案中，R 2选自C 1-C 4烷基、C 6-C 10环烷基或CH 2-(C 6-C 10芳基)，所述C 1-C 4烷基、C 6-C 10环烷基或CH 2-(C 6-C 10芳基)任选被R 2a取代。
在一些实施方案中，R 2a选自F、Cl、Br、I、CN、＝O、OH、NH 2或C 1-C 6烷基，所述OH、NH 2或C 1-C 6烷基任选被R b取代。
在一些实施方案中，R 2a选自OH、C 1-C 3烷基或NH 2，所述NH 2任选被R b取代。
在一些实施方案中，R b选自C 1-C 3烷基。
在一些实施方案中，R 2a选自OH、甲基或N(CH 3) 2。
在一些实施方案中，R 2a选自OH或N(CH 3) 2。
在一些实施方案中，R 2选自
Figure PCTCN2022134262-appb-000003
Figure PCTCN2022134262-appb-000004
在一些实施方案中，R 2选自
Figure PCTCN2022134262-appb-000005
Figure PCTCN2022134262-appb-000006
在一些实施方案中，R 3选自4-14元杂环基，所述4-14元杂环基被R 3a取代。
在一些实施方案中，R 3选自4-7元单杂环基、6-14元稠合杂环基、6-14元螺杂环基或6-14元桥杂环基，所述4-7元单杂环基、6-14元稠合杂环基、6-14元螺杂环基或6-14元桥杂环基任选被R 3a取代。
在一些实施方案中，R 3选自4-7元单杂环基或6-14元稠合杂环基，所述4-7元单杂环基或6-14元稠合杂环基任选被R 3a取代。
在一些实施方案中，R 3选自
Figure PCTCN2022134262-appb-000007
Figure PCTCN2022134262-appb-000008
所述
Figure PCTCN2022134262-appb-000009
Figure PCTCN2022134262-appb-000010
任选被R 3a取代。
在一些实施方案中，R 3选自
Figure PCTCN2022134262-appb-000011
所述
Figure PCTCN2022134262-appb-000012
Figure PCTCN2022134262-appb-000013
任选被R 3a取代。
在一些实施方案中，R 3a独立地选自F、Cl、Br、I、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基。
在一些实施方案中，R 3a独立地选自F、Cl、Br、I、CN、＝O或C 1-C 6烷基。
在一些实施方案中，R 3a独立地选自F、Cl或＝O。
在一些实施方案中，R 3a选自＝O。
在一些实施方案中，R 3选自
Figure PCTCN2022134262-appb-000014
Figure PCTCN2022134262-appb-000015
所述
Figure PCTCN2022134262-appb-000016
Figure PCTCN2022134262-appb-000017
任选被F、Cl、Br、I、CN或C 1-C 3烷基取代。
在一些实施方案中，R 3选自
Figure PCTCN2022134262-appb-000018
Figure PCTCN2022134262-appb-000019
Figure PCTCN2022134262-appb-000020
在一些实施方案中，R 3选自
Figure PCTCN2022134262-appb-000021
Figure PCTCN2022134262-appb-000022
在一些实施方案中，R 3选自
Figure PCTCN2022134262-appb-000023
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(Ia)所示化合物或其药学上可接受的盐：
Figure PCTCN2022134262-appb-000024
其中，R 1、R 2、R 3如上文定义。
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(Ib)所示化合物或其药学上可接受的盐：
Figure PCTCN2022134262-appb-000025
其中，R 1、R 2、R 3如上文定义。
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(Ic)所示化合物或其药学上可接受的盐：
Figure PCTCN2022134262-appb-000026
其中，R 2、R 3如上文定义。
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(Id)所示化合物或其药学上可接受的盐：
Figure PCTCN2022134262-appb-000027
其中，R 2、R 3如上文定义。
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：
Figure PCTCN2022134262-appb-000028
Figure PCTCN2022134262-appb-000029
Figure PCTCN2022134262-appb-000030
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：
Figure PCTCN2022134262-appb-000031
Figure PCTCN2022134262-appb-000032
Figure PCTCN2022134262-appb-000033
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：
Figure PCTCN2022134262-appb-000034
Figure PCTCN2022134262-appb-000035
Figure PCTCN2022134262-appb-000036
本公开还提供药物组合物，其包含式(I)所示化合物或其药学上可接受的盐和药学上可接受的辅料。
进一步，本公开涉及式(I)所示的化合物或其药学上可接受的盐，或其药物组合物在制备预防或治疗冠状病毒3CL蛋白酶相关疾病的药物中的用途。
进一步，本公开涉及式(I)所示的化合物或其药学上可接受的盐，或其药物组合物在预防或治疗冠状病毒3CL蛋白酶相关疾病中的用途。
进一步，本公开涉及预防或治疗冠状病毒3CL蛋白酶相关疾病的式(I)化合物或其药学上可接受的盐，或其药物组合物。
本公开还涉及预防或治疗冠状病毒3CL蛋白酶相关疾病的方法，该方法包括给以患者治疗有效量的包含本公开所述的式(I)化合物或其药学上可接受的盐的药物制剂。
进一步，本公开涉及式(I)所示的化合物或其药学上可接受的盐，或其药物组合物在制备预防或治疗由冠状病毒感染引起的相关疾病的药物中的用途。
进一步，本公开涉及式(I)所示的化合物或其药学上可接受的盐，或其药物组合物在预防或治疗由冠状病毒感染引起的相关疾病中的用途。
进一步，本公开涉及预防或治疗由冠状病毒感染引起的相关疾病的式(I)化合物或其药学上可接受的盐，或其药物组合物。
本公开还涉及预防或治疗由冠状病毒感染引起的相关疾病的方法，该方法包括给以患者治疗有效量的包含本公开所述的式(I)化合物或其药学上可接受的盐的药物制剂。
在一些实施方案中，所述冠状病毒选自严重急性呼吸道综合征冠状病毒(SARS-CoV)、中东呼吸综合征冠状病毒(MERS-CoV)和2019新型冠状病毒(2019-nCoV或SARS-CoV-2)。
在一些实施方案中，所述冠状病毒3CL蛋白酶相关疾病选自呼吸道感染、肺炎或其并发症。
在一些实施方案中，所述冠状病毒感染引起的相关疾病选自呼吸道感染、肺炎或其并发症。
术语定义和说明
除非另有说明，本公开中所用的术语具有下列含义，本公开中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
本文中
Figure PCTCN2022134262-appb-000037
表示连接位点。
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚楔键
Figure PCTCN2022134262-appb-000038
表示一个立体中心的绝对构型，用黑实键和虚键
Figure PCTCN2022134262-appb-000039
表示一个立体中心的相对构型(如脂环化合物的顺反构型)。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本公开化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本公开包含化合物的所有互变异构形式。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和非对映异构体。
本公开的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键，因此本公开的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，以及其外消旋混合物或其它混合物，例如对映异构体或非对映体富集的混合物，以上所有这些异构体以及它们的混合物都属于本公开化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子，所有取代基中涉及到的这些异构体以及它们的混合物，也均包括在本公开化合物的定义范围之内。本公开的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来，光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，是指乙基可以是未被取代的(CH 2CH 3)、单取代的(CH 2CH 2F、CH 2CH 2Cl等)、多取代的(CHFCH 2F、CH 2CHF 2、CHFCH 2Cl、CH 2CHCl 2等)或完全被取代的(CF 2CF 3、CF 2CCl 3、CCl 2CCl 3等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
当任何变量(例如R a、R b)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团被2个R b所取代，则每个R b都有独立的选项。
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为键。
当其中一个变量选自化学键或不存在时，表示其连接的两个基团直接相连，比如A-L-Z中L代表键时表示该结构实际上是A-Z。
当本文中涉及到的连接基团若没有指明其连接方向，则其连接方向是任意的。例如当结构单元
Figure PCTCN2022134262-appb-000040
中的L 1选自“C 1-C 3亚烷基-O”时，此时L 1既可以按照与从左到右的方向连接环Q和R 1构成“环Q-C 1-C 3亚烷基-O-R 1”，也可以按照从右到左的方向连接环Q和R 1构成“环Q-O-C 1-C 3亚烷基-R 1”。
本文中的C m-C n是指具有m-n范围中的整数个碳原子。例如“C 1-C 10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
术语“烷基”是指通式为C nH 2n+1的烃基，该烷基可以是直链或支链的。术语“C 1-C 10烷基”可理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和烃基。所述烷基的具体实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等；术语“C 1-C 6烷基”可理解为表示具有1至6个碳原子的烷基，具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等。术语“C 1-C 3烷基”可理解为表示具有1至3个碳原子的直链或支链饱和烷基。所述“C 1-C 10烷基”可以包含“C 1-C 6烷基”或“C 1-C 3烷基”等范围，所述“C 1-C 6烷基”可以进一步包含“C 1-C 3烷基”。
术语“烷氧基”是指直链或支链醇类失去羟基上的氢原子产生的基团，可理解为“烷基氧基”或“烷基-O-”。术语“C 1-C 10烷氧基”可理解为“C 1-C 10烷基氧基”或“C 1-C 10烷基-O-”；术语“C 1-C 6烷氧基”可理解为“C 1-C 6烷基氧基”或“C 1-C 6烷基-O-”。所述“C 1-C 10烷氧基”可以包含“C 1-C 6烷氧基”和“C 1-C 3烷氧基”等范围，所述“C 1-C 6烷氧基”可以进一步包含“C 1-C 3烷氧基”。
术语“环烷基”是指完全饱和的且以单环、稠环、桥环或螺环等形式存在的碳环基团。除非另有指示，该碳环通常为3至20元环。术语“C 3-C 12环烷基”是指具有3、4、5、6、7、8、9、10、11或12个环碳原子的环烷基，所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C 3-C 12环烷基”可以包含“C 5-C 12环烷基”、“C 3-C 10环烷基”、“C 6-C 10环烷基”和“C 3-C 6环烷基”等范围。术语“C 5-C 12环烷基”是指具有5、6、7、8、9、10、11或12个环碳原子的环烷基。术语“C 3-C 10环烷基”是指具有3、4、5、6、7、8、9或10个环碳原子的环烷基。术语“C 6-C 10环烷基”是指具有6、7、8、9或10个环碳原子的环烷基。术语“C 3-C 6环烷基”是指具有3、4、5或6个环碳原子的环烷基。
术语“C 3-C 6环烷基氧基”可理解为“C 3-C 6环烷基-O-”。
术语“环烯基”是指不完全饱和的具有至少一个碳-碳双键且以单环、稠环、桥环或螺环等形式存在的非芳香族碳环基。术语“C 4-C 12环烯基”是指环原子数目为4、5、6、7、8、9、10、 11、12、13、14的环烯基，具体实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基或环庚二烯基等。
术语“杂环基”是指完全饱和的或部分饱和的单环、稠合环、螺环或桥环基团，其环原子中含有1-5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O) 2-、-S(＝O)-、-P(＝O) 2-、-P(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。术语“4-14元杂环基”是指环原子数目为4、5、6、7、8、9、10、11、12、13、14的杂环基，且其环原子中含有1-5个独立选自上文所述的杂原子或杂原子团。其中，4元杂环基的具体实例包括但不限于氮杂环丁烷基或氧杂环丁烷基；5元杂环基的具体实例包括但不限于四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、4,5-二氢噁唑基或2,5-二氢-1H-吡咯基；6元杂环基的具体实例包括但不限于四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基或4H-[1,3,4]噻二嗪基；7元杂环基的具体实例包括但不限于二氮杂环庚烷基。所述杂环基还可以是双环杂环基和三环杂环基，其中，5,5元双环基的具体实例包括但不限于六氢环戊并[c]吡咯-2(1H)-基；5,6元双环基的具体实例包括但不限于六氢吡咯并[1,2-a]吡嗪-2(1H)-基、5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪基或5,6,7,8-四氢咪唑并[1,5-a]吡嗪基。任选地，所述杂环基可以是上述4-7元杂环基的苯并稠合环基，具体实例包括但不限于二氢异喹啉基等。“4-14元杂环基”可以包含“4-7元杂环基”、“5-6元杂环基”、“4-7元单杂环基”、“6-14元稠合杂环基”、“6-14元螺杂环基”或“6-14元桥杂环基”等范围。术语“6-14元稠合杂环基”是指环原子数目为6、7、8、9、10、11、12、13、14，且其环原子中含有1-5个独立选自上文所述的杂原子或杂原子团的稠合杂环基。术语“6-14元螺杂环基”是指环原子数目为6、7、8、9、10、11、12、13、14，且其环原子中含有1-5个独立选自上文所述的杂原子或杂原子团的螺杂环基。术语“6-14元桥杂环基”是指环原子数目为6、7、8、9、10、11、12、13、14，且其环原子中含有1-5个独立选自上文所述的杂原子或杂原子团的桥杂环基。
本公开中的“杂环基”可以包含“杂环烷基”，例如“4-14元杂环基”可以包含“4-14元杂环烷基”。
术语“杂环基氧基”可理解为“杂环基-O-”。
术语“杂环烷基”是指完全饱和的且以单环、稠环、桥环或螺环等形式存在的环状基团，其环的环原子中含有1-5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O) 2-、-S(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。术语“3-10元杂环烷基”是指环原子数目为3、4、5、6、7、8、9或10的杂环烷基，且其环原子中含有1-5个独立选自上文所述的杂原子或杂原子团。术语“3-10元杂环烷基”可以包含“4-10元杂环烷基”或“4-7元杂环烷基”，其中，4元杂环烷基的具体实例包括但不限于吖丁啶基、噁丁环基或噻丁环基；5元杂环烷基的具体实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基或四氢吡唑基；6元杂环烷基的具体实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基或1,4-二噻烷基；7元杂环烷基的具体实例包括但不限于氮杂环庚烷基、氧杂环庚烷基或硫杂环庚烷基。
术语“杂环烷基氧基”可理解为“杂环烷基-O-”。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。术语“C 6-C 20芳基”可理解为具有6～20个碳原子的芳基。特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基；或者具有13个碳原子的环(“C 13芳基”)，例如芴基；或者是具有14个碳原子的环(“C 14芳基”)，例如蒽基。术语“C 6-C 10芳基”可理解为具有6～10个碳原子的芳基。 特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基。
术语“芳基氧基”可理解为“芳基-O-”。
术语“杂芳基”是指具有芳香性的单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基。术语“5-10元杂芳基”可理解为包括这样的单环或双环芳族环系：其具有5、6、7、8、9或10个环原子，特别是5或6或9或10个环原子，且其包含1-5个，优选1-3个独立选自N、O和S的杂原子。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基或噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基或异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基等以及它们的苯并衍生物，例如喹啉基、喹唑啉基或异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基或吩噁嗪基等。
术语“杂芳基氧基”可理解为“杂芳基-O-”。
术语“卤”或“卤素”是指氟、氯、溴或碘。
术语“羟基”是指-OH基团。
术语“氰基”是指-CN基团。
术语“巯基”是指-SH基团。
术语“氨基”是指-NH 2基团。
术语“硝基”是指-NO 2基团。
术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本公开化合物的用量。构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括预防疾病或疾病状态在个体(例如哺乳动物)中出现，特别是当这类个体(例如哺乳动物)易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“个体”包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。术语“患者”和“个体”可互换地使用。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指药学上可接受的酸或碱的盐，包括化合物与无机酸或有机酸形成的盐，以及化合物与无机碱或有机碱形成的盐。
术语“药物组合物”是指一种或多种本公开的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本公开的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising可理解为开放的、非排他性的意义，即“包括但不限于”。
本公开还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于 自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本公开化合物(例如用 3H及 14C标记)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本公开化合物。
本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本公开化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本公开的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本文所述的通式Ⅰ化合物的所有施用方法中，每天给药的剂量为0.01mg/kg到200mg/kg体重，优选为0.05mg/kg到50mg/kg体重，更优选0.1mg/kg到30mg/kg体重，以单独或分开剂量的形式。
本公开的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其它化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本公开的实施例。
本公开具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本公开的化学变化及其所需的试剂和物料。为了获得本公开的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
具体实施方式
下面通过实施例对发明进行详细描述，但并不意味着对本公开任何不利限制。本文已经详细地描述了本公开，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本公开精神和范围的情况下针对本公开具体实施方式进行各种改变和改进将是显而易见的。本公开所使用的所有试剂是市售的，无需进一步纯化即可使用。
除非另作说明，混合溶剂表示的比例是体积混合比例。
除非另作说明，否则，％是指重量百分比wt％。
化合物经手工或
Figure PCTCN2022134262-appb-000041
软件命名，市售化合物采用供应商目录名称。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC 50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
洗脱剂或流动相可由两种或两种以上溶剂组成的混合洗脱剂或流动相，其比值为各溶剂的体积比，如“0～10％甲醇/二氯甲烷”表示混合洗脱剂或流动相中的甲醇与二氯甲烷的体积用量比为0:100～10:100。
实施例1：(1R,2S,5S)-N-((2S)-1-氨基-1-羰基-3-(2-羰基二氢吲哚-3-基)丙烷-2-基)-3-((S)-3,3-二甲基-2-(2,2,2-三氟乙酰氨基)丁酰)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-甲酰胺(化合物1)的制备
合成路线如下：
Figure PCTCN2022134262-appb-000042
步骤1：叔丁基((2S)-1-氨基-1-氧代-3-(2-氧代吲哚-3-基)丙烷-2-基)氨基甲酸酯(1b)
在20℃下，将化合物1a(0.30g,0.90mmol)溶于甲醇(1mL)，加入氨甲醇溶液(7N，3mL)。反应液在40℃反应24小时。将反应液减压蒸馏除去溶剂，所得残余物经反相色谱法纯化(
Figure PCTCN2022134262-appb-000043
C 18快速硅胶柱，0.05％甲酸水溶液：乙腈＝20：1～1：2的条件下梯度洗脱)得化合物1b(0.09g)。
m/z(ESI):320[M+H] +。
步骤2：(2S)-2-氨基-3-(2-羰基二氢吲哚-3-基)丙酰胺盐酸盐(1c)
在20℃下，将化合物1b(0.090g，0.28mmol)溶于1，4-二氧六环(1mL)，加入盐酸1，4-二氧六环溶液(4M,1mL,4.0mmol)，反应液在室温反应2小时。将反应液冻干，得化合物1c(0.070g)。
m/z(ESI):220[M+H] +。
步骤3：(1R,2S,5S)-N-((2S)-1-氨基-1-羰基-3-(2-羰基二氢吲哚-3-基)丙烷-2-基)-3-((S)-3,3-二甲基-2-(2,2,2-三氟乙酰氨基)丁酰)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-甲酰胺(1e)
在20℃下，将2-羟基吡啶-1-氧化物(0.005g,0.082mmol)加入化合物1d(0.10g,0.27mmol)和化合物1c(0.07g,0.27mmol)的N，N-二甲基甲酰胺(2mL)溶液中。依次加入N,N-二异丙基乙胺(0.11g,0.82mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.079g, 0.41mmol)。反应液在25℃下反应12h。反应混合物经反相色谱法纯化(
Figure PCTCN2022134262-appb-000044
C 18快速硅胶柱，0.05％甲酸水溶液：乙腈＝20：1～1：1的条件下梯度洗脱)得化合物1e(0.04g)。m/z(ESI):566[M+H] +。
步骤4：(1R,2S,5S)-N-((1S)-1-氰基-2-(2-羰基二氢吲哚-3-基)乙基)-3-((S)-3,3-二甲基-2-(2,2,2-三氟乙酰氨基)丁酰)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-甲酰胺(1)
在20℃下，将N-(三乙基铵磺酰)氨基甲酸甲酯内盐(0.025g,0.11mmol)加入化合物1e(0.02g,0.035mmol)的二氯甲烷(1mL)溶液中。反应混合物在25℃下反应12h。将反应液减压浓缩，所得残余物经反相色谱法纯化(
Figure PCTCN2022134262-appb-000045
C 18快速硅胶柱，0.05％甲酸水溶液：乙腈＝20:1～1:2条件下梯度洗脱)，依次得到第一个异构体产物1mg(化合物1-P1)和第二个异构体产物7mg(化合物1-P2)。
其中，化合物1-P2在以下高效液相色谱条件下的保留时间(RT)为1.64min。
高效液相色谱条件：柱子为Xtimate C18 2.1*50mm，流动相A为0.05％三氟乙酸水溶液，流动相B为0.05％三氟乙酸的乙腈溶液，流速0.7ml/min，B％为5％-95％。
化合物1-P2的结构表征数据如下：
m/z(ESI):548[M+H] +。
1H NMR:(400MHz,DMSO-d6)δ10.58-10.41(m,1H),9.42-9.00(m,2H),7.39-7.26(m,1H),7.21-7.13(m,1H),7.03-6.78(m,2H),5.30-5.16(m,1H),4.44-4.30(m,1H),4.22(s,1H),4.00-3.86(m,1H),3.75-3.64(m,1H),3.58-3.47(m,1H),2.19-2.05(m,1H),1.63-1.54(m,1H),1.35(d,J＝7.7Hz,1H),1.04(s,3H),1.01-0.96(m,2H),0.94(s,2H),0.90-0.79(m,9H)。
实施例2：(1R,2S,5S)-3-((S)-2-(金刚烷-1-基)-2-(2,2,2-三氟乙酰氨基)乙酰基)-N-((S)-1-氰基-2-((S)-2-羰基吡咯烷-3-基)乙基)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-甲酰胺(化合物2)的制备
合成路线如下：
Figure PCTCN2022134262-appb-000046
步骤1：(S)-2-(金刚烷-1-基)-2-(2,2,2-三氟乙酰氨基)乙酸(2b)
在20℃下，将化合物2a(0.15g,0.72mmol)溶于甲醇(10ml)中，再加入三乙胺(0.46g,3.6mmol)、三氟乙酸乙酯(0.51g,3.6mmol)，反应液加热至50℃反应16h。将反应液浓缩，加入1M盐酸调整pH至3-4。用乙酸乙酯(3×10ml)萃取，有机相经无水硫酸钠干燥，过滤，浓缩。得化合物2b(0.2g)。m/z(ESI):306[M+H] +。
步骤2：(1R,2S,5S)-3-((S)-2-(金刚烷-1-基)-2-(2,2,2-三氟乙酰氨基)乙酰基)-N-((S)-1-氨基-1-羰基-3-((S)-2-羰基吡咯烷-3-基)丙烷-2-基)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-甲酰胺(2d)
在20℃下，将2-羟基吡啶-1-氧化物(0.004g,0.033mmol)加入化合物2b(0.1g,0.33mmol)和化合物2c(0.11g,0.33mmol)的N，N-二甲基甲酰胺(2mL)溶液中，再加入N,N-二异丙基乙胺(0.13g,0.98mmol)和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.094g,0.49mmol)，反应液在20℃下反应12h。反应混合物经反相色谱法纯化
Figure PCTCN2022134262-appb-000047
C 18快速硅胶柱，0.05％甲酸水溶液:乙腈＝20:1～1:1梯度洗脱)得化合物2d(0.018g)。
m/z(ESI):596[M+H] +。
步骤3：(1R,2S,5S)-3-((S)-2-(金刚烷-1-基)-2-(2,2,2-三氟乙酰氨基)乙酰基)-N-((S)-1-氰基-2-((S)-2-羰基吡咯烷-3-基)乙基)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-甲酰胺(2)
在20℃下，将甲基-N-(三乙基氨磺酰)氨基甲酸酯内盐(0.023g,0.091mmol)加入化合物 2d(0.018g,0.03mmol)的二氯甲烷(1mL)溶液中。在20℃反应12h。将反应液减压浓缩，所得残余物经反相色谱法纯化(
Figure PCTCN2022134262-appb-000048
C 18快速硅胶柱，0.05％甲酸水溶液:乙腈＝20:1～1:2条件下梯度洗脱)得化合物2(0.004g)。
m/z(ESI):578[M+H] +。
1HNMR:(400MHz,Chloroform-d)δ9.59(d,J＝3.6Hz,0.4H),8.17(d,J＝6.6Hz,0.6H),6.94(d,J＝9.3Hz,0.4H),6.89(d,J＝9.4Hz,0.6H),5.72(s,1H),4.89(dt,J＝10.3,6.2Hz,0.6H),4.58(dt,J＝12.1,4.0Hz,0.4H),4.41(d,J＝9.4Hz,0.6H),4.28(s,0.6H),4.26(s,0.4H),4.03–3.96(m,0.6H),3.92–3.84(m,0.8H),3.78(d,J＝10.3Hz,0.6H),3.54(d,J＝12.4Hz,0.4H),3.46–3.33(m,2H),3.26–3.16(m,0.4H),2.63–2.51(m,1H),2.49–2.14(m,2H),2.07–1.88(m,5H),1.73–1.64(m,6H),1.60–1.51(m,6H),1.42–1.25(m,2H),1.07(s,1.2H),1.06(s,1.8H),1.03(s,1.2H),0.86(s,1.8H).
实施例3：(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-羰基吡咯烷-3-基)乙基)-6,6-二甲基-3-(2-(螺[3.3]庚烷-2-基)-2-(2,2,2-三氟乙酰氨基)乙酰基)-3-氮杂二环[3.1.0]己烷-2-甲酰胺(化合物3)的制备
合成路线如下：
Figure PCTCN2022134262-appb-000049
步骤1：2-氨基-2-(螺[3.3]庚烷-2-基)乙酸甲酯(3b)
氢气氛下，将化合物3a(1.6g,5.1mmol)溶于乙酸乙酯(100mL)，再加入钯碳(0.32g)，反应液在20℃下反应16小时。将反应液过滤，减压蒸馏除去溶剂，得到化合物3b(0.81g)。m/z(ESI):184[M+H] +。
步骤2：2-(螺[3.3]庚烷-2-基)-2-(2,2,2-三氟乙酰胺)乙酸甲酯(3c)
在20℃下，将化合物3b(0.81g,4.41mmol)溶于甲醇(20ml)中，再加入三乙胺(1.3g,13mmol)和三氟乙酸乙酯(3.1g,22mmol)，然后加热至50℃反应16h。将反应液浓缩，加入1M盐酸调节pH至3-4。反应液用乙酸乙酯(3×50ml)萃取，有机相经无水硫酸钠干燥、过滤和浓缩后得到化合物3c(0.97g)。
m/z(ESI):280[M+H] +。
步骤3：2-氨基-2-(螺[3.3]庚烷-2-基)乙酸锂(3d)
将化合物3c(0.97g，3.5mmol)溶于四氢呋喃(5mL)和水(5mL)中，加入氢氧化锂(0.33g,14mmol)，反应液在20℃下反应2小时。再加入乙酸乙酯(30mL)，过滤得到 化合物3d(0.56g)。
步骤4：2-(螺[3.3]庚烷-2-基)-2-(2,2,2-三氟乙酰胺)乙酸(3e)
室温下，将2-氨基-2-(螺[3.3]庚烷-2-基)乙酸锂(0.56g,3.3mmol)溶于甲醇(20ml)中，再加入三乙胺(1.0g,9.9mmol)和三氟乙酸乙酯(2.3g,16mmol)，然后加热至50℃反应16h。浓缩，加入1M盐酸调节pH至3-4。乙酸乙酯(3×50ml)萃取，有机相经无水硫酸钠干燥，过滤，浓缩得到化合物3e(0.56g)。
m/z(ESI):266[M+H] +。
步骤5：(1R,2S,5S)-6,6-二甲基-3-(2-(螺[3.3]庚烷-2-基)-2-(2,2,2-三氟乙酰氨基)乙酰基)-3-氮杂二环[3.1.0]己烷-2-羧酸甲酯(3g)
在0℃下，将化合物3f(0.15g,0.75mmol)和化合物3e(0.2g,0.75mmol)溶于N,N-二甲基甲酰胺(3mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.43g,1.1mmol)，然后加入N,N-二异丙基乙胺(0.23g,2.3mmol)，反应液在20℃下反应2h。反应混合物经反相色谱法纯化(
Figure PCTCN2022134262-appb-000050
C 18快速硅胶柱，0.05％甲酸水溶液:乙腈＝20:1～1:2条件下梯度洗脱)得化合物3g(0.23g)。
m/z(ESI):417[M+H] +。
步骤6：(1R,2S,5S)-6,6-二甲基-3-(2-(螺[3.3]庚烷-2-基)-2-(2,2,2-三氟乙酰氨基)乙酰基)-3-氮杂二环[3.1.0]己烷-2-羧酸(3h)
将化合物3g(0.23g，0.55mmol)溶于四氢呋喃(5mL)和水(5mL)中，再加入氢氧化锂(0.1g,2.2mmol)，反应液在20℃下反应2小时。加入1M盐酸将反应液调至pH＝7，用乙酸乙酯(3×50ml)萃取，有机相经无水硫酸钠干燥，过滤，浓缩后得到化合物3h(0.18g)。m/z(ESI):403[M+H] +。
步骤7：(1R,2S,5S)-N-((S)-1-氨基-1-羰基-3-((S)-2-羰基吡咯烷-3-基)丙烷-2-基)-6,6-二甲基-3-(2-(螺[3.3]庚烷-2-基)-2-(2,2,2-三氟乙酰氨基)乙酰基)-3-氮杂二环[3.1.0]己烷-2-甲酰胺(3j)
在20℃下，将2-羟基吡啶-1-氧化物(0.004g,0.041mmol)加入化合物3h(0.16g,0.41mmol)和化合物3i(0.07g,0.41mmol)的N，N-二甲基甲酰胺(2mL)溶液中。再加入N,N-二异丙基乙胺(0.12g,1.2mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.096g,0.62mmol)。反应液在20℃下反应12h。反应混合物经反相色谱法纯化(
Figure PCTCN2022134262-appb-000051
C 18快速硅胶柱，0.05％甲酸水溶液：乙腈＝20：1～1：1梯度洗脱)得化合物3j(0.16g)。
m/z(ESI):556[M+H] +。
步骤7：(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-羰基吡咯烷-3-基)乙基)-6,6-二甲基-3-(2-(螺[3.3]庚烷-2-基)-2-(2,2,2-三氟乙酰氨基)乙酰基)-3-氮杂二环[3.1.0]己烷-2-甲酰胺(3)
室温下，将N-(三乙基铵磺酰)氨基甲酸甲酯内盐(0.1g,0.43mmol)加入化合物3j(0.08g,0.14mmol)的二氯甲烷(5mL)溶液中。反应液在20℃反应12h。减压蒸馏除去溶剂，所得残余物经反相色谱法纯化(
Figure PCTCN2022134262-appb-000052
C 18快速硅胶柱，0.05％甲酸水溶液:乙腈＝20:1～1:2条件下梯度洗脱)得化合物3(0.060g)。
m/z(ESI):538[M+H] +。
1HNMR:(400MHz,DMSO-d6)δ9.70(d,J＝6.1Hz,0.6H),9.64(d,J＝8.3Hz,0.4H),8.95(d,J＝8.4Hz,0.6H),8.79(d,J＝8.3Hz,0.4H),7.75–7.67(m,1H),5.02–4.89(m,1H),4.54–4.47(m,0.4H),4.38–4.33(m,0.6H),4.12(s,0.6H),4.06(s,0.4H),3.91(d,J＝5.6Hz,0.4H),3.88(d,J＝5.5Hz,0.6H),3.75(d,J＝10.3Hz,0.6H),3.66(d,J＝11.1Hz,0.4H),3.21–3.06(m,2H),2.47–2.32(m,2H),2.16–2.02(m,2H),1.97–1.82(m,5H),1.81–1.62(m,6H),1.60–1.41(m,2H),1.35–1.27(m,1H),1.06–1.01(m,3H),0.92(s,1.2H),0.87(s,1.8H)。
实施例4：(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-羰基吡咯烷-3-基)乙基)-6,6-二甲基-3-((S)-3-(萘-2-基)-2-(2,2,2-三氟乙酰氨基)丙酰)-3-氮杂二环[3.1.0]己烷-2-甲酰胺(化合物4)
Figure PCTCN2022134262-appb-000053
以化合物4a替换化合物2a,采用与实施例2相同的制备方法，制得化合物4.
Figure PCTCN2022134262-appb-000054
m/z(ESI):584[M+H] +。
1HNMR:(400MHz,DMSO-d 6)δ10.0(d,J＝7.2Hz,1H),8.99(d,J＝8.0Hz,1H),7.89-7.75(m,5H),7.50-7.47(m,3H),5.02-4.96(m,1H),4.77-4.69(m,1H),4.19(s,1H),3.92-3.89(m,1H),3.74(d,J＝10.8Hz,1H),3.25-3.05(m,4H),2.47-2.38(m,1H),2.21-2.10(m,2H),1.83-1.69(m,2H),1.60-1.57(m,1H),1.35(d,J＝8.0Hz,1H),1.04(s,3H),0.89(s,3H).
实施例5:(1R,2S,5S)-N-((1S)-1-氰基-2-(2-羰基二氢吲哚-3-基)乙基)-3-((S)-2-((1r,3R,5R,7S)-3-羟基金刚烷-1-基)-2-(2,2,2-三氟乙酰氨基)乙酰基)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-甲酰胺(化合物5)
Figure PCTCN2022134262-appb-000055
中间体5e合成路线如下：
Figure PCTCN2022134262-appb-000056
步骤1:甲基(1R,2S,5S)-3-((S)-2-((叔-丁氧基羰基)氨基)-2-((1r,3R,5R,7S)-3-羟基金刚烷-1-基)乙酰基)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-羧酸酯(5b)
室温下，将化合物5a(0.6g,1.8mmol)和3f(0.28g,1.6mmol)溶于无水N,N-二甲基甲酰胺(5mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.68g,1.8mmol)，然后加入N,N-二异丙基乙胺(0.70g,5.4mmol)，反应液在室温条件下反应10min。反应混合物直 接经反相色谱法纯化(
Figure PCTCN2022134262-appb-000057
C 18快速硅胶柱，0.05％甲酸水溶液:乙腈＝20:1～1:20梯度洗脱)得化合物5b(0.75g)。m/z(ESI):477[M+H] +.
步骤2:(1R,2S,5S)-3-((S)-2-((叔-丁氧基羰基)氨基)-2-((1r,3R,5R,7S)-3-羟基金刚烷-1-基)乙酰基)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-羧酸(5c)
将化合物5b(0.75g，1.6mmol)溶于四氢呋喃(5.0mL)和水(5.0mL)中，再加入氢氧化锂(0.20g,4.8mmol)，反应液在20℃下反应2小时。加入1M盐酸将反应液调至pH＝3.减压蒸馏除去溶剂，所残余物直接经反相色谱法纯化(
Figure PCTCN2022134262-appb-000058
C 18快速硅胶柱，0.05％甲酸水溶液:乙腈＝20:1～1:20梯度洗脱)得化合物5c(0.72g)。m/z(ESI):463[M+H] +.
步骤3:(1R,2S,5S)-3-((S)-2-氨基-2-((1r,3R,5R,7S)-3-羟基金刚烷-1-基)乙酰基)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-羧酸(5d)
在室温条件下，将化合物5c(0.72g，1.5mmol)溶于1,4-二氧六环(5.0mL)，加入盐酸1,4-二氧六环溶液(4.0M,5.0mL,20mmol)，反应液在室温反应12小时。将反应液冻干直接用于下一步反应。
步骤4:(1R,2S,5S)-3-((S)-2-氨基-2-((1r,3R,5R,7S)-3-羟基金刚烷-1-基)乙酰基)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-羧酸(5e)
在室温条件下，将化合物5d(0.58g,1.5mmol)溶于甲醇(10ml)中，再加入三乙胺(0.76g,7.5mmol)和三氟乙酸乙酯(1.7g,12mmol)，然后加热至50℃反应12h。将反应液浓缩，所残余物直接经反相色谱法纯化(
Figure PCTCN2022134262-appb-000059
C 18快速硅胶柱，0.05％甲酸水溶液:乙腈＝20:1～1:20梯度洗脱)得化合物5c(0.64g)。m/z(ESI):459[M+H] +.
以化合物5e替换化合物1d,采用与实施例1类似的方法可以制得化合物5.
m/z(ESI):642[M+H] +。
1HNMR:(400MHz,DMSO-d 6)δ10.5(s,1H),9.36(d,J＝9.2Hz,1H),9.28(d,J＝9.2Hz,1H),7.39(d,J＝8.0Hz,1H),7.18(t,J＝8.0Hz,1H),6.90(t,J＝8.0Hz,1H),6.82(d,J＝8.0Hz,1H),5.28-5.23(m,1H),4.31(s,1H),4.26(d,J＝7.6Hz,1H),4.20(s,1H),3.92-3.89(m,1H),3.69-3.66(m,1H),3.54-3.47(m,1H),2,34-2.27(m,1H),2.14-1.83(m,2H),1.60-1.28(m,15H),1.04(s,3H),0.86(s,3H).
实施例6:(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-(2-(4-(二甲基氨基)环己烷)-2-(2,2,2-三氟乙酰胺基)乙酰基)-6,6-二甲基-3氮杂双环[3.1.0]环己烷-2-甲酰胺(化合物6)的制备
合成路线如下:
Figure PCTCN2022134262-appb-000060
步骤1:甲基2-((苄氧基)羰基)胺基)-2-(4-((叔丁氧基羰基)胺基)亚环己基乙酸酯(6c)
将苄氧基羰基-α-膦酰甘氨酸三甲酯6b(1.7g,5.3mmol)溶于乙酸乙酯(15mL)中，加入四甲基胍(0.8g,6.8mmol)，室温搅拌半小时后加入4-N-Boc-氨基环己酮6a(1.7g,7.9mmol)的乙酸乙酯溶液(5mL),然后在室温条件下反应3天。反应液浓缩，所得残留物直接经反相色谱柱纯化(C18,0.05％氨水:乙腈＝20:1～1:20)得产物6c(1.1g,收率49％)。
m/z(ESI):419[M+H] +。
步骤2:甲基2-胺基-2-(4-((叔丁氧基羰基)胺基)环己基乙酸酯(6d)
将化合物6c(0.14g,0.3mmol)溶入乙酸乙酯(3mL)和甲醇(3mL)中，加入10％钯碳(0.04g,0.2mmol)，用氢气球置换3次氢气，室温常压搅拌12小时。过滤除去钯碳，滤液旋干，所得粗产物6d(90mg,产率93％)可不经纯化直接用于下一步反应。
m/z(ESI):287[M+H] +。
步骤3:2-胺基-2-(4-((叔丁氧基羰基)胺基)环己基)乙酸(6e)
室温下，将化合物6d(95mg,0.33mmol),氢氧化锂(15mg,0.66mmol)溶于四氢呋喃(2mL)/水(0.5mL)的混合溶液中,室温反应3小时。减压除去THF，用少量水稀释，用盐酸(1M)调pH至中性，冻干得化合物6e(85mg,产率94％)。m/z(ESI):273[M+H] +。
步骤4:2-(4-((叔丁氧基羰基)胺基)环己基)-2-(2,2,2-三氟乙酰胺基)乙酸(6f)
将化合物6e(90mg,0.33mmol)溶于甲醇(2mL)并加入三乙胺(0.20g,1.98mmol),搅拌5分钟后再加入三氟乙酸乙酯(140mg,1.00mmol),50℃条件下反应3小时。待反应液冷却至室温，减压蒸馏除去溶剂，所得残余物经反向色谱柱(C18,0.05％甲酸:乙腈＝20:1～1:20)得化合物6f(60mg,产率49％)。
m/z(ESI):369[M+H] +。
步骤5:叔丁基(4-(2-((1R,2S,5S)-2-(((S)-1-胺基-1-氧-3-((S)-2-氧吡咯烷-3-基)丙基-2-基)氨甲酰基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-3-基)-2-氧-1-(2,2,2-三氟乙酰胺基)乙基)环己基)-2-甲酰胺(6g)
将化合物6f(0.12g,0.32mmol),化合物2c(0.13g,0.38mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.15g,0.38mmol)溶于无水N,N-二甲基甲酰胺(1.5mL)并加入二异丙基乙胺(0.16g,1.3mmol),室温搅拌1小时。反应液直接经反向色谱柱纯化(C18, 0.05％水:乙腈＝20:1～1:20)得化合物6g(70mg,产率32％)。
m/z(ESI):659.3[M+H] +。
步骤6:(1R,2S,5S)-N-((S)-1-胺基-1-氧-3-((S)-2-氧吡咯烷-3-基)丙基-2-基)-3-(2-(4-(二甲胺基)环己基)-2-(2,2,2-三氟乙酰胺基)乙酰基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-甲酰胺(6h)
将化合物6g(70mg,0.11mmol)溶于二氯甲烷(1.0mL)并加入盐酸二氧六环(1mL),室温搅拌3小时后减压除去溶剂。所得残余物重新溶解于甲醇(2.0mL)并向其中加入37％甲醛水溶液(0.1mL)，室温搅拌10分钟后加入氰基硼氢化钠(28mg,0.45mmol),反应1小时后所得残余物经反向色谱柱(C18,0.05％氨水:乙腈＝20:1～1:20)得化合物6h(50mg,产率75％)。
m/z(ESI):587[M+H] +。
步骤7:(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-(2-(4-(二甲基氨基)环己烷)-2-(2,2,2-三氟乙酰胺基)乙酰基)-6,6-二甲基-3-氮杂双环[3.1.0]环己烷-2-甲酰胺(化合物6)
室温条件下，将6h(13mg,22μmol)溶于二氯甲烷(0.5mL)和乙腈(0.5mL)中，然后加入伯吉斯试剂(12mg,53μmol)，搅拌反应12h。所得残余物经反相色谱柱纯化(C18,0.05％氨水:乙腈＝20:1～1:20)得化合物6(5mg,产率39％)。
m/z(ESI):569[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ9.91(d,J＝7.7Hz,1H),9.04(d,J＝8.5Hz,1H),7.70(s,1H),5.08–4.87(m,2H),4.31(m,1H),4.13(s,1H),3.87(m,1H),3.11-3.04(m,4H),2.27–2.07(m,11H),1.80–1.34(m,9H),1.04-1.01(m,4H),0.84(s,3H).
实施例7:(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-(N 6,N 6-二甲基-N 2-(2,2,2-三氟乙酰基)-L-赖氨酰基)-6,6-二甲基-3-氮杂双环[3.1.0]环己烷-2-甲酰胺(化合物7)的制备合成路线如下:
Figure PCTCN2022134262-appb-000061
步骤1:N 6-(苄氧羰基)-N 2-(2,2,2-三氟乙酰基)-L-赖氨酸(7b)
将N 6-Cbz-L-赖氨酸7a(1.0g,3.6mmol)溶于无水甲醇(3.5mL)，向其中加入三乙胺(0.7g,7.1mmol)和三氟乙酸乙酯(0.6g,4.6mmol)，室温搅拌过夜，减压浓缩后用水稀释并调pH至4，用乙酸乙酯萃取3次，合并有机相，有机相用饱和食盐水洗涤(100mL)无水硫酸钠干燥，过滤，滤液浓缩，得到的粗产物7b(1.0g,收率74％)不经纯化直接用于下一步反应。
MS(ESI)m/z:377[M+H] +；
步骤2:(2,2,2-三氟乙酰基)-L-赖氨酸(2c)
将上一步得到的粗产物7b(0.24g,0.64mmol)溶于无水甲醇(5mL)中，然后加入10％钯碳 (70mg,0.63mmol),用氢气球置换体系空气3次，该反应体系在室温下搅拌12小时。硅藻土过滤，减压蒸馏除去溶剂得化合物7c(0.14g,收率90％)。MS(ESI)m/z:243[M+H] +；
步骤3:N 6,N 6-二甲基-N 2-(2,2,2-三氟乙酰基)-L-赖氨酸(7d)的合成
将7c(0.14g,0.58mmol)溶于无水甲醇(5mL)中,然后加入37％的甲醛水溶液(0.5mL),室温搅拌10分钟，再向其中加入氰基硼氢化钠(0.14g,2.31mmol)，室温反应4小时。所得残余物经反相色谱柱纯化(C18,0.05％甲酸:乙腈＝20:1-1:20)得化合物7d(0.11g,收率70％)。
MS(ESI)m/z:271[M+H] +；
步骤4:(1R,2S,5S)-N-((S)-1-胺基-1-氧-3-((S)-2-氧吡咯烷-3-基)丙烷-2-基)-3-(N 6,N 6-二甲基-N 2-(2,2,2-三氟乙酰基)-L-赖氨酰基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-甲酰胺(7e)
将化合物7d(100mg,0.26mmol),化合物2c(89mg,0.26mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(117mg,0.31mmol)溶于N,N-二甲基甲酰胺(1.5mL)并加入二异丙基乙胺(134mg,1.04mmol),室温搅拌1小时。所得残余物经反向色谱柱(C18,0.05％甲酸:乙腈＝20:1～1:20)得化合物7e(56mg,产率38％)。
m/z(ESI):561[M+H] +。
步骤5:(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧吡咯烷-3-基)乙基)-3-(N 6,N 6-二甲基-N 2-(2,2,2-三氟乙酰基)-L-赖氨酰基)-6,6-二甲基-3-氮杂双环[3.1.0]环己烷-2-甲酰胺(7)
室温条件下，将7e(34mg,60μmol)溶于N,N-二甲基乙酰胺(1mL)，然后加入伯吉斯试剂(74mg,314μmol)，室温搅拌12小时。所得残余物经反相色谱柱纯化(C18,0.05％甲酸:乙腈＝20:1～1:20)得化合物7(15mg,产率45％)。
m/z(ESI):543[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ9.77(d,J＝6.7Hz,1H),8.97(d,J＝8.1Hz,1H),8.20(s,1H),7.73(s,1H),4.95-4.94(m,2H),4.37-4.35(m,1H),4.14(s,1H),3.88–3.80(m,1H),3.74-3.71(m,1H),3.19–3.08(m,2H),2.44–2.28(m,3H),2.26–2.07(m,6H),1.83–1.55(m,5H),1.49–1.19(m,5H),1.03(s,3H),0.90(s,3H).
实施例8:(1R,2S,5S)-N-((1S)-1-氰基-2-(2-羰基-2,3-二氢-1H-吡咯并[2,3-b]吡啶-3-基)乙基)-3-((S)-3,3-二甲基-2-(2,2,2-三氟乙酰氨基)丁酰)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-甲酰胺(化合物8)
合成路线如下：
Figure PCTCN2022134262-appb-000062
步骤1:甲基(2S)-2-((叔-丁氧基羰基)氨基)-3-(2-羰基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-3-基)丙酸酯(8b)
室温条件下，将1-[[2-(三甲基硅基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-2(3H)-酮(1.0g,3.78mmol)溶于无水四氢呋喃(20mL)，然后用氮气置换其中的空气，然后在-78℃条件下向该反应液中滴加双(三甲基硅基)氨基钠(2.25mL,4.5mmol,2M/L)的四氢呋喃溶液,滴加完毕后继续在该温度条件下反应30分钟。与此同时，在-10℃条件下，将N-叔丁氧羰基-O-对甲 苯磺酰基丝氨酸甲酯(1.4g,3.78mmol)溶于无水四氢呋喃中，向其中加入钠氢(0.11g.4.54mmol)并在该温度下继续反应30分钟，然后再将该溶液滴加到上述经双(三甲基硅基)氨基钠处理过的1-[[2-(三甲基硅基)乙氧基]甲基]-1H-吡咯并[2,3-b]吡啶-2(3H)-酮的无水四氢呋喃溶液中，并继续在-78℃条件下反应2小时，然后再升至室温再反应2小时.反应液用饱和氯化钠水溶液淬灭，将反应液浓缩，所残余物直接经反相色谱法纯化(
Figure PCTCN2022134262-appb-000063
C 18快速硅胶柱，0.05％甲酸水溶液:乙腈＝20:1～1:20梯度洗脱)得化合物8b(1.8g)。m/z(ESI):466.
步骤2：(2S)-2-((叔-丁氧基羰基)氨基)-3-(2-羰基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-3-基)丙酸(8c)
室温条件下，将化合物8b(0.95g,2.0mmol)溶于无水四氢呋喃溶液中，然后加入氢氧化锂(2.5mL,10mmol,4M/L)水溶液，室温继续搅拌30分钟。加入1M盐酸将反应液调至pH＝3，将反应液浓缩，所残余物直接经反相色谱法纯化(
Figure PCTCN2022134262-appb-000064
C 18快速硅胶柱，0.05％甲酸水溶液:乙腈＝20:1～1:20梯度洗脱)得化合物8c(0.70g)。m/z(ESI):452.
步骤3：叔丁基((2S)-1-氨基-1-氧代-3-(2-氧代-1-((2-(三甲基硅烷基)乙氧基)甲基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-3-基)丙-2-基)氨基甲酸酯(8d)
室温条件下，将化合物8c(0.7g,1.6mmol)以及氯化铵(0.16g,3.2mmol)溶于无水N,N-二甲基甲酰胺(5mL)中，然后依加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.88g,2.3mmol)以及N,N-二异丙基乙胺(0.6g,4.6mmol),室温反应1小时。反应混合物直接经反相色谱法纯化(
Figure PCTCN2022134262-appb-000065
C 18快速硅胶柱，0.05％甲酸水溶液:乙腈＝20:1～1:20梯度洗脱)得化合物8d(0.60g)。m/z(ESI):451[M+H] +.
步骤4：(2S)-2-氨基-3-(2-氧代-2,3-二氢-1H-吡咯并[2,3-b]吡啶-3-基)丙烯酰胺(8e)
将化合物8d(0.60g,1.3mmol)溶于TFA(5mL)中，室温反应30分钟，将反应液冻干得化合物8e,化合物8e可不经纯化直接用于下一步。
以化合物8e替换化合物1c,采用与实施例1相同的制备方法制得化合物8.
m/z(ESI):549[M+H] +。
1HNMR:(400MHz,DMSO-d 6)δ11.1(s,1H),9.40-9.04(m,1H),8.09-8.01(m,1H),7.72-7.70(m,1H),7.01-6.91(m,1H),4.39-4.33(m,1H),4.20(s,1H),3.70-3.28(m,1H),3.05-2.98(m,2H),2.58-2.52(m,1H),2.35-2.31(m,1H),1.66-1.59(m,1H),1.37(d,J＝10.0Hz,1H),1.26-1.20(m,2H),1.04-0.78(m,15H).
实施例9:(1R,2S,5S)-3-((S)-2-(2-氯-2,2-二氟乙酰胺基)-3,3-二甲基丁酰基)-N-((1S)-1-氰基-2-(2-氧代吲哚-3-基)乙基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-甲酰胺(化合物9)
合成路线如下：
Figure PCTCN2022134262-appb-000066
步骤1:(1R,2S,5S)-3-((S)-2-(2-氯-2,2-二氟乙酰氨基)-3,3-二甲基丁酰基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸(9c)
在20℃下，将化合物9a(90mg,0.3mmol)溶于甲醇(10ml)中，再加入三乙胺(0.11g,1.1mmol)、二氟氯乙酸乙酯9b(94mg,0.6mmol)，反应液加热至50℃反应16h。将反应液浓缩，加入1M盐酸调整pH至3-4。用乙酸乙酯(3×10ml)萃取，有机相经无水硫酸钠干燥，过滤，浓缩。得化合物9c(65mg)。m/z(ESI):338.1[M+H] +。
步骤2:(1R,2S,5S)-3-((S)-2-(2-氯-2,2-二氟乙酰氨基)-3,3-二甲基丁酰)-N-((1S)-1-氰基-2-(2-羰基二氢吲哚-3-基)乙基)-6,6-二甲基-3-氮杂二环[3.1.0]己烷-2-甲酰胺(9)
以化合物9c替换化合物1d,采用与实施例1相同的方法制得化合物9.
m/z(ESI):564[M+H] +。
1HNMR:(400MHz,DMSO-d 6)δ10.50(s,1H),9.31(d,J＝8.0Hz,1H),9.18-9.03(m,1H),7.34(d,J＝7.6Hz,1H),7.18(t,J＝7.6Hz,1H),6.89(t,J＝7.6Hz,1H),6.82(d,J＝7.6Hz,1H),5.25-5.20(m,1H),4.40-4.34(m,1H),4.22(s,1H),3.94-3.90(m,1H),3.69(d,J＝10.0Hz,1H),3.56-3.52(m,1H),2,36-2.28(m,1H),2.18-2.10(m,1H),1.61-1.58(m,1H),1.35(d,J＝7.6Hz,1H),1.03-0.94(m,6H),0.83(s,9H).
实施例10:(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-2-((1R,3R,5R,7S)-3-羟基金刚烷-1-基)-2-(2,2,2-三氟乙酰胺基)乙酰基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-甲酰胺(化合物10)
合成路线如下：
Figure PCTCN2022134262-appb-000067
步骤1:(1R,2S,5S)-N-((S)-1-氨基-1-氧代-3-((S)-2-氧代吡咯烷-3-基)丙烷-2-基)-3-((S)-2-((1R,3R,5R,7S)-3-羟基金刚烷-1-基)-2-(2,2,2-三氟乙酰胺基)乙酰基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-甲酰胺(10b)
室温条件下，将化合物(1R,2S,5S)-3-((S)-2-((1R,3R,5R,7S)-3-羟基金刚烷-1-基)-2-(2,2,2-三氟乙酰氨基)乙酰基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸5e(92mg,0.2mmol)以及(S)-2-氨基-3-((S)-2-氧代吡咯烷-3-基)丙酰胺10a(41mg,0.24mmol)溶于无水DMF中，然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(91mg,0.24mmol)，N,N-二异丙基乙胺(31mg,0.24mmol)然后在该条件下反应10分钟，反应混合物直接经反相色谱法纯化(
Figure PCTCN2022134262-appb-000068
C 18快速硅胶柱，0.05％甲酸水溶液:乙腈＝20:1～1:20梯度洗脱)得化合物10b(89mg，收率73％)。
m/z(ESI):612[M+H] +。
步骤2：(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯烷-3-基)乙基)-3-((S)-2-((1R,3R,5R,7S)-3-羟基金刚烷-1-基)-2-(2,2,2-三氟乙酰胺基)乙酰基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-甲酰胺(10)
室温条件下，将10b(89mg,0.15mmol)溶于二氯甲烷(0.5mL)中，然后加入伯吉斯试剂(0.11g,0.45mmol)，室温搅拌12小时。反应液浓缩，所得残余物经反相色谱柱纯化(C18,0.05％氨水:乙腈＝20:1～1:20)得白色固体目标产物10(36mg,收率42％)。
m/z(ESI):594[M+H] +。
1HNMR:(400MHz,DMSO-d 6)δ9.45(d,J＝8.4Hz,1H),9.02(d,J＝8.4Hz,1H),7.68(s,1H),5.08-4.96(m,1H),4.40(s,1H),4.33(d,J＝8.4Hz,1H),4.14(s,1H),3.93-3.89(m,1H),3.67(d,J＝8.8Hz,1H),3.16-3.07(m,2H),2.46-2.33(m,1H),2.16-2.06(m,4H),1.72-1.39(m,15H),1.32(d,J＝7.6Hz,1H),1.03(s,3H),0.85(s,3H).
参考上述实施例的合成路线，合成如下化合物，其结构和质谱数据为：
Figure PCTCN2022134262-appb-000069
Figure PCTCN2022134262-appb-000070
Figure PCTCN2022134262-appb-000071
生物学活性及相关性质测试例
测试例1、SARS-CoV-2 3CL蛋白酶抑制活性测试
1、实验仪器及材料
仪器名称 设备厂家 型号
纳升级声波移液系统 Labcyte Echo650
酶标仪 Perkin Elmer Envision2014
检测使用BPS试剂盒(3CL Protease,MBP-tagged(SARS-CoV-2)Assay Kit)进行，试剂盒包含3CL蛋白酶，荧光底物，反应缓冲液。3CL蛋白酶水解荧光底物，生成可检测的荧光产物，通过对荧光产物的检测反应蛋白酶活性。
实验所需其它试剂及耗材信息如下：
Figure PCTCN2022134262-appb-000072
2、实验步骤
将200nL的3倍梯度稀释化合物(终浓度为10μM-0.5nM)与10μL的200nM重组3CL蛋白酶(BPS Kit)在室温孵育30分钟。在反应板中加入10μL的100μM荧光底物起始反应，在Envision(Perkin Elmer)上采用连读模式每间隔1分钟读取荧光信号(Ex360/Em460)，收集60分钟内荧光值，计算Slope。以底物孔作为100％抑制对照，酶反应孔作为0％抑制对照计算化合物抑制率。使用IDBS XLfit计算IC 50。
3、数据分析
化合物对3CL蛋白酶活性抑制率计算公式为：
抑制率％＝(平均0％抑制孔-样品孔)/(平均0％抑制孔-平均100％抑制孔)x 100％。
通过XLfit进行数据分析处理，浓度-效应曲线采用非线性四参数曲线拟合，并计算化合物的IC 50：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))
其中：
X:化合物浓度的Log值；
Y:百分抑制率(％inhibition)；
Bottom为最小抑制百分比；
Top为最大抑制百分比；
HillSlope为曲线斜率系数。
本公开化合物对3CL蛋白酶活性抑制作用通过以上试验进行测定，测得的IC 50值见表1。
表1
化合物编号 IC 50(nM) IC 50(nM)
1-P2 A 35.3
2 A 74.1
3 B 525
4 B 273.37
5 A 69.82
6 B 449.44
7 C 1110.29
8 A 33.4
9 A 25.24
10 A 69.8
A:<100nM；B:≥100nM且<1000nM；C:≥1000nM且<10000nM。

Claims (14)

  1. 一种式(I)所示化合物或其药学上可接受的盐：
    Figure PCTCN2022134262-appb-100001
    其中，
    R 1选自C 1-C 10烷基，所述C 1-C 10烷基任选被卤素取代；
    R 2选自C 1-C 10烷基或(CH 2) n-R 4，n选自0或者1，R 4选自C 3-C 12环烷基、C 4-C 12环烯基、4-14元杂环基、C 6-C 10芳基或5-10元杂芳基，所述C 1-C 10烷基、C 3-C 12环烷基、C 4-C 12环烯基、4-14元杂环基、C 6-C 10芳基或5-10元杂芳基任选被R 2a取代；
    R 3选自4-14元杂环基或5-10元杂芳基，所述4-14元杂环基或5-10元杂芳基任选被R 3a取代；
    每一个R 2a、R 3a独立地选自F、Cl、Br、I、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R b取代；
    每一个R b独立地选自F、Cl、Br、I、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R c取代；
    每一个R c独立地选自F、Cl、Br、I、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基、4-7元杂环基、C 1-C 6烷氧基、C 3-C 6环烷基氧基或4-7元杂环基氧基；
    条件是，式(I)所示化合物不包含
    Figure PCTCN2022134262-appb-100002
  2. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R 1选自C 1-C 3烷基，所述C 1-C 3烷基任选被卤素取代。
  3. 根据权利要求1或2所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R 2选自C 1-C 6烷基或(CH 2) n-R 4，n选自0或者1，R 4选自C 5-C 12环烷基、4-7元杂环基或C 6-C 10芳基，所述C 1-C 6烷基、C 5-C 12环烷基、4-7元杂环基或C 6-C 10芳基任选被R 2a取代；或者
    R 2选自C 1-C 4烷基、C 6-C 10环烷基、5-6元杂环基或CH 2-(C 6-C 10芳基)，所述C 1-C 4烷基、C 6-C 10环烷基、5-6元杂环基或CH 2-(C 6-C 10芳基)任选被R 2a取代；或者
    R 2选自C 1-C 4烷基、C 6-C 10环烷基或CH 2-(C 6-C 10芳基)，所述C 1-C 4烷基、C 6-C 10环烷基或CH 2-(C 6-C 10芳基)任选被R 2a取代。
  4. 根据权利要求1-3任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R 2a选自F、Cl、Br、I、CN、＝O、OH、NH 2或C 1-C 6烷基，所述OH、NH 2或C 1-C 6烷基任选被R b取代；或者
    R 2a选自OH、C 1-C 3烷基或NH 2，所述NH 2任选被R b取代，所述R b选自C 1-C 3烷基。
  5. 根据权利要求1-4任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R 2选自
    Figure PCTCN2022134262-appb-100003
    Figure PCTCN2022134262-appb-100004
  6. 根据权利要求1-5任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R 3选自4-7元单杂环基、6-14元稠合杂环基、6-14元螺杂环基或6-14元桥杂环基，所述4-7元单杂环基、6-14元稠合杂环基、6-14元螺杂环基或6-14元桥杂环基任选被R 3a取代；或者
    R 3选自4-7元单杂环基或6-14元稠合杂环基，所述4-7元单杂环基或6-14元稠合杂环基任选被R 3a取代。
  7. 根据权利要求1-6任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R 3选自
    Figure PCTCN2022134262-appb-100005
    Figure PCTCN2022134262-appb-100006
    所述
    Figure PCTCN2022134262-appb-100007
    Figure PCTCN2022134262-appb-100008
    Figure PCTCN2022134262-appb-100009
    任选被R 3a取代；或者
    R 3选自
    Figure PCTCN2022134262-appb-100010
    所述
    Figure PCTCN2022134262-appb-100011
    Figure PCTCN2022134262-appb-100012
    任选被R 3a取代。
  8. 根据权利要求1-7任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R 3a独立地选自F、Cl、Br、I、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基；或者
    R 3a独立地选自F、Cl、Br、I、CN、＝O或C 1-C 6烷基；或者
    R 3a独立地选自F、Cl或＝O。
  9. 根据权利要求1-8任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R 3选自
    Figure PCTCN2022134262-appb-100013
    Figure PCTCN2022134262-appb-100014
    Figure PCTCN2022134262-appb-100015
    或者
    R 3选自
    Figure PCTCN2022134262-appb-100016
    Figure PCTCN2022134262-appb-100017
  10. 根据权利要求1-9任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，所述式(I)所示化合物或其药学上可接受的盐选自式(Ia)所示化合物或其药学上可接受的盐：
    Figure PCTCN2022134262-appb-100018
  11. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，所述式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：
    Figure PCTCN2022134262-appb-100019
    Figure PCTCN2022134262-appb-100020
    Figure PCTCN2022134262-appb-100021
    Figure PCTCN2022134262-appb-100022
  12. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，所述式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：
    Figure PCTCN2022134262-appb-100023
    Figure PCTCN2022134262-appb-100024
    Figure PCTCN2022134262-appb-100025
  13. 一种药物组合物，所述组合物包含权利要求1至12任一项的化合物或其药学上可接受的盐，以及药学上可接受的辅料。
  14. 权利要求1至12任一项的化合物或其药学上可接受的盐、或权利要求13所述的药物组合物在制备预防或者治疗冠状病毒3CL蛋白酶相关疾病的药物中的用途。
PCT/CN2022/134262 2021-11-26 2022-11-25 一种吡咯烷类抗病毒化合物 WO2023093834A1 (zh)

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