WO2023134730A1 - Composé antiviral amide - Google Patents

Composé antiviral amide Download PDF

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Publication number
WO2023134730A1
WO2023134730A1 PCT/CN2023/071925 CN2023071925W WO2023134730A1 WO 2023134730 A1 WO2023134730 A1 WO 2023134730A1 CN 2023071925 W CN2023071925 W CN 2023071925W WO 2023134730 A1 WO2023134730 A1 WO 2023134730A1
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Prior art keywords
alkyl
compound
cycloalkyl
pharmaceutically acceptable
membered
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PCT/CN2023/071925
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English (en)
Chinese (zh)
Inventor
邹昊
祝伟
祝东星
金京海
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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Publication of WO2023134730A1 publication Critical patent/WO2023134730A1/fr

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 amide compound and a pharmaceutically acceptable salt thereof, and its use as a coronavirus 3CL protease inhibitor in the prevention or treatment of 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, C 3 -C 12 cycloalkyl, 4-14 membered heterocyclyl, C 1 -C 10 alkoxy, C 3 -C 12 cycloalkyloxy or 4 -14-membered heterocyclyloxy, the C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, 4-14 membered heterocyclyl, C 1 -C 10 alkoxy, C 3 -C 12 Cycloalkyloxy or 4-14 membered heterocyclyloxy is optionally substituted by one or more R 1a ;
  • R 1 is selected from N(R 4 )(R 5 ), said R 4 and R 5 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered Heterocyclic group, or R 4 , R 5 and the N atom they are connected to together form a 4-7 membered heterocyclic group, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclic group
  • the cyclic group is optionally substituted by one or more R 4a ;
  • C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl are optionally substituted by one or more R 4b ;
  • R 2 is selected from C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl or 4-14 membered heterocyclic group, the C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl or 4- 14-membered heterocyclyl is optionally substituted by one or more R 2a ;
  • R 3 is selected from 4-14 membered heterocyclic groups, and the 4-14 membered heterocyclic groups are optionally substituted by one or more R 3a ;
  • R 1 is selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyloxy, said C 1 -C 3 alkyl, C 3 - C Cycloalkyl or 4-7 membered heterocyclyloxy is optionally substituted by one or more (for example, 1, 2 or 3) R 1a ; or, R 1 is selected from N(R 4 )( R 5 ), said R 4 and R 5 are independently selected from H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, or R 4 , R 5 and their connected N atoms together form 4- 7-membered heterocyclic group, the C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group or 4-7 membered heterocyclic group is optionally replaced by one or more (for example, 1, 2 or 3 ) R 4a is substituted.
  • R 1a is independently selected from F, CF 3 ,
  • R 4a is independently selected from halogen, such as F.
  • R is selected from methyl
  • R is selected from methyl
  • R 2 is selected from C 1 -C 6 alkyl or 4-10 membered heterocyclyl, which is optionally replaced by one or more (eg, 1, 2 or 3) C 1 -C 3 alkyl or phenyl substitution.
  • R is selected from
  • R is selected from 5-12 membered heterocyclyl optionally substituted with one or more (eg, 1, 2 or 3) R 3a .
  • R is selected from said Optionally substituted with one or more (eg, 1, 2 or 3) R 3a .
  • R is selected from said Optionally substituted with one or more (eg, 1, 2 or 3) R 3a .
  • 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 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 the patient a therapeutically effective dose 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 the patient a therapeutically effective dose of a drug comprising the compound of formula (I) described in the present disclosure or a pharmaceutically acceptable salt thereof preparation.
  • 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 form or in racemic form, the optically active form can be resolved from a racemic mixture, or by using a chiral starting material or a chiral Reagent synthesis.
  • 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.
  • an ethyl group “optionally” substituted with one or more halogens means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted ( CH2CH2F , CH2CH2Cl , etc.) , multi-substituted (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2 , etc.) or fully substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3 , 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 ".
  • the substituent When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring.
  • the structural unit Indicates that R 5 can be substituted at any position on the benzene ring.
  • 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.
  • C 1 -C 6 alkyl can be understood to mean an alkyl group having 1 to 6 carbon atoms, specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.
  • 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 12 cycloalkyloxy can be understood as “C 3 -C 12 cycloalkyl-O-”.
  • C 3 -C 6 cycloalkyloxy can be understood as “C 3 -C 6 cycloalkyl-O-”.
  • cycloalkenyl refers to a non-aromatic carbocyclic group that is not fully saturated and exists in the form of a monocyclic 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 "4-10 membered heterocyclic group", “5-10 membered heterocyclic group”, “4-7 membered heterocyclic group”, “5-6 membered heterocyclic group” , "4-7 membered monoheterocyclic group”, “4-14 membered fused heterocyclic group”, “4-14 membered spiroheterocyclic group” or “4-14 membered bridged heterocyclic group”.
  • 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-", for example, “4-14 membered heterocyclyloxy” can be understood as “4-14 membered 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 or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying Amounts of a compound of the disclosure for the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • 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.
  • 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, etc.
  • 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 under reduced pressure to obtain compound 1c (0.070 g).
  • Step 3 tert-butyl ((2S)-1-((1R,2S,5S)-2-(((2S)-1-amino-1-oxo-3-(2-oxoindoline- 3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl)-3,3-dimethyl-1- Oxobutyl-2-yl)carbamate (1e)
  • Step 4 (1R,2S,5S)-Nitro-((2S)-1-amino-1-oxo-3-(2-oxoindolin-3-yl)propan-2-yl)-3 -((S)-2-Amino-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (1f)
  • Step 5 (1R,2S,5S)-Nitro-((2S)-1-amino-1-oxo-3-(2-oxoindolin-3-yl)propan-2-yl)-3 -((S)-2-(3-cyclopropylurea)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2 -Formamide (1g)
  • Step 6 (1R,2S,5S)-N-((1S)-1-cyano-2-(2-oxoindolin-3-yl)ethyl)-3-((S)-2 -(3-cyclopropylurea)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (1)
  • Example 2 For the synthesis steps of Example 2, refer to Example 1, wherein the compound 2 was prepared by replacing cyclopropylamine in Step 5 of Example 1 with tert-butylamine.
  • Example 3 For the synthesis steps of Example 3, refer to Example 1, wherein 1c in Step 3 of Example 1 is replaced with 6d (see Example 6), and cyclopropylamine in Step 5 of Example 1 is replaced with 3,3-difluoroazetidine Compound 3 was prepared.
  • the synthetic route is as follows:
  • compound 4a 2.0g, 9.8mmol
  • compound 4b 2.3g, 10mmol
  • 2-(7-azabenzotriazepine was added Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.8g, 10mmol)
  • N,N-diisopropylethylamine 3.0g, 23mmol
  • compound 4c (1.8g, 4.7mmol) was dissolved in 1,4-dioxane (5.0mL), and hydrochloric acid 1,4-dioxane solution (4.0M, 5.0mL, 20mmol) was added , the reaction solution was reacted at room temperature for 12 hours. The reaction solution was lyophilized under reduced pressure to obtain compound 4d (1.1 g).
  • Step 3 Methyl(1R,2S,5S)-3-((S)-2-((S)-2-((tert-butoxycarbonyl)amino)propionylamino)-3,3-di Methylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4f)
  • compound 4d (1.1g, 3.4mmol) and compound 4e (0.71g, 3.7mmol) were dissolved in N,N-dimethylformamide (10mL), and 2-(7-azabenzotri Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.4g, 3.7mmol), then add N,N-diisopropylethylamine (1.4g, 11mmol), react The solution was reacted at 20°C for 10 min.
  • Step 4 Methyl(1R,2S,5S)-3-((S)-2-((S)-2-aminopropionylamino)-3,3-dimethylbutyryl)-6,6- Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (4g)
  • compound 4f (0.50 g, 1.1 mmol) was dissolved in 1,4-dioxane (10 mL), and 1,4-dioxane hydrochloride solution (4.0 M, 1.0 mL, 4 mmol) was added, The reaction solution was reacted at room temperature for 12 hours. The reaction solution was lyophilized under reduced pressure to obtain compound 4g (0.36g).
  • Step 5 Methyl(1R,2S,5S)-3-((S)-2-((S)-2-(Cyclopropaneoxalylamino ⁇ oxalylamino>)propionylamino)-3 ,3-Dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4i)
  • compound 4g (0.20g, 0.57mmol) and compound 4h (54mg, 0.63mmol) were dissolved in N,N-dimethylformamide (5.0mL), and 2-(7-azabenzotri Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.24g, 0.63mmol), then add N,N-diisopropylethylamine (0.24g, 1.9mmol), The reaction solution was reacted at 20° C. for 10 min.
  • Step 6 (1R,2S,5S)-3-((S)-2-((S)-2-(cyclopropaneoxalylamino ⁇ oxalylamino>)propionylamino)-3,3 -Dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (4j)
  • Step 7 (1R,2S,5S)-N-((2S)-1-amino-1-carbonyl-3-(2-carbonylindolin-3-yl)propan-2-yl)-3- ((S)-2-((S)-2-(cyclopropaneoxalylamino ⁇ oxalylamino>)propionylamino)-3,3-dimethylbutyryl)-6,6-di Methyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (4k)
  • compound 4j (66mg, 0.16mmol) and compound 1c (40mg, 0.18mmol) were dissolved in N,N-dimethylformamide (4.0mL), and 2-(7-azabenzotriazine was added Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (61mg, 0.16mmol), then N,N-diisopropylethylamine (65mg, 0.5mmol) was added, and the reaction solution was React at 20°C for 10 minutes.
  • Step 8 (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-3-((S)-2 -((S)-2-(cyclopropaneoxalylamino ⁇ oxalylamino>)propionylamino)-3,3-dimethylbutyryl)-6,6-dimethyl-3-nitrogen Heterobicyclo[3.1.0]hexane-2-carboxamide (4)
  • Example 5 For the synthesis steps of Example 5, refer to Example 4, wherein compound 5 was prepared by replacing Compound 4h in Step 5 in Example 4 with trifluoroacetic acid.
  • the synthetic route is as follows:
  • Step 1 (1R,2S,5S)-3-((S)-3,3-Dimethyl-2-((((3-(trifluoromethyl)oxetan-3-yl)oxo )carbonyl)amino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (6c)
  • Step 2 3-(Trifluoromethyl)oxetan-3-yl((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-carbonyl- 3-((S)-2-carbonylpyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 3-yl)-3,3-dimethyl-1-carbonylbutan-2-yl)carbamate (6e)
  • Step 3 3-(Trifluoromethyl)oxetan-3-yl((S)-1-((1R,2S,5S)-2-(((S)-1-1-cyano-2 -((S)-2-carbonylpyrrolidin-3-yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl) -3,3-Dimethyl-1-carbonylbutan-2-yl)carbamate (6)
  • Example 7 and Example 8 (1R,2S,5S)-N-((1S)-1-cyano-2-(3-fluoro-2-carbonylindolin-3-yl)ethyl) -3-((S)-3,3-Dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1 .0] Preparation of hexane-2-carboxamide (compound 7 and compound 8)
  • the synthetic route is as follows:
  • N-fluorobisbenzenesulfonamide (NFSI, 104mg, 0.54mmol), 1-((1R)-((2R,4R,5S)-5-ethylquinuclidin-2-yl )(6-methoxyquinolin-4-yl)methoxy)-4-((1R)-((2R,4S,5R)-5-ethylquinuclidin-2-yl)(6- Methoxyquinolin-4-yl)methoxy)phthalazine (35 mg, 0.045 mmol) and sodium carbonate (57 mg, 0.54 mmol) were added to a solution of compound 1a (0.15 g, 0.45 mmol) in ethyl acetate (10 mL) , the reaction solution was reacted at 20°C for 48 hours.
  • N-fluorobisbenzenesulfonamide (NFSI, 104mg, 0.54mmol)
  • Step 2 tert-Butyl((2S)-1-amino-3-(3-fluoro-2-carbonylindolin-3-yl)-1-carbonylpropan-2-yl)carbamate (7b)
  • Step 4 (1R,2S,5S)-N-((2S)-1-amino-3-(3-fluoro-2-carbonylindolin-3-yl)-1-carbonylpropan-2-yl )-3-((S)-3,3-
  • Step 5 (1R,2S,5S)-N-((1S)-1-cyano-2-(3-fluoro-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-formamide (7 and 8)
  • Example 9 and Example 10 (1R,2S,5S)-N-((1S)-1-cyano-2-(3-fluoro-2-carbonylindolin-3-yl)ethyl) -3-((S)-3,3-Dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1 .0] Preparation of hexane-2-carboxamide (compound 9 and compound 10)
  • Example 9 and Example 10 For the synthesis steps of Example 9 and Example 10, refer to Example 7 and Example 8, wherein methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(2-carbonyl-2, 3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl)propionate was prepared by substituting step 1 compound 1a in Example 7 and Example 8 to obtain Compound 9 and Compound 10.
  • Example 7 For the synthesis steps of Example 11, see Example 7 and Example 8, wherein methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(6-carbonyl-6,7-dihydro -5H-[1,3]dioxazolo[4,5-f]indol-7-yl)propionate was replaced by intermediate 7a in step 2 to obtain compound 11.
  • Example 12 and Example 13 (1R,2S,5S)-N-((1S)-1-cyano-2-(7-fluoro-6-carbonyl-6,7-dihydro-5H-[1 ,3] Dioxazolo[4,5-f]indol-7-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-tri Preparation of fluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 12 and compound 13)
  • Example 12 and Example 13 For the synthesis steps of Example 12 and Example 13, refer to Example 7 and Example 8, wherein methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(6-carbonyl-6, 7-dihydro-5H-[1,3]dioxazolo[4,5-f]indol-7-yl)propionate was prepared by replacing compound 1a in step 1 to obtain compound 12 and compound 13.
  • Example 14 For the synthesis steps of Example 14, see Example 7 and Example 8, wherein methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro-6-carbonyl Compound 14 was prepared by replacing intermediate 7a in step 2 with -6,7-dihydro-5H-[1,3]dioxazolo[4,5-f]indol-7-yl)propionate.
  • Example 15 and Example 16 (1R,2S,5S)-N-((1S)-1-cyano-2-(2,2,7-trifluoro-6-carbonyl-6,7-dihydro -5H-[1,3]dioxazolo[4,5-f]indol-7-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2, Preparation of 2,2-trifluoroacetylamino)butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 15 and compound 16)
  • Example 15 and Example 16 For the synthesis steps of Example 15 and Example 16, refer to Example 7 and Example 8, wherein methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(2,2-difluoro -6-carbonyl-6,7-dihydro-5H-[1,3]dioxazolo[4,5-f]indol-7-yl)propionate to replace step 1 compound 1a to obtain the aforementioned compound 15 and compound 16.
  • the synthetic route is as follows:
  • Step 2 (1R,2S,5S)-3-((S)-2-(Cyclopropaneoxalylamino ⁇ oxalylamino>)-3,3-dimethylbutyryl)-6,6 -Dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (17d)
  • Step 3 (1R,2S,5S)-N-((2S)-1-Amino-1-carbonyl-3-(2-carbonylindolin-3-yl)propan-2-yl)-3- ((S)-2-(cyclopropaneoxalylamino ⁇ oxalylamino>)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1 .0] hexane-2-carboxamide (17e)
  • Step 4 (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-3-((S)-2 -(cyclopropaneoxalylamino ⁇ oxalylamino>)-3,3-dimethylbutyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-Formamide (17)
  • Example 18 For the synthesis steps of Example 18, refer to Example 17. Compound 18 was prepared by replacing 17a in step 1 with acetic acid.
  • Example 19 For the synthesis steps of Example 19, refer to Example 17. Compound 19 was prepared by substituting difluoroacetic acid for 17a in step 1.
  • Example 22 (1R,2S,5S)-N-((1S)-1-cyano-2-(2-carbonylindolin-3-yl)ethyl)-6,6-dimethyl -3-((S)-2-(4-methyl-2-oxabicyclo[2.1.1]hexane-1-yl)-2-(2,2,2-trifluoroacetylamino)acetyl base)-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 22)
  • the synthetic route is as follows:
  • Step 1 (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyryl)-6,6-dimethyl -3-Azabicyclo[3.1.0]hexane-2-carboxylic acid (24a)
  • Step 2 tert-butyl ((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-carbonyl-3-((S)-2-carbonylpyrrolidine -3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)-3,3-dimethyl -1-carbonylbutan-2-yl)carbamate (24b)
  • Step 5 (1R,2S,5S)-N-((S)-1-amino-1-carbonyl-3-((S)-2-carbonylpyrrolidin-3-yl)propan-2-yl)- 3-((S)-2-((S)-2-((2,6-difluorophenyl)amino)propionylamino)-3,3-dimethylbutyryl)-6,6-di Methyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (24g)
  • Step 6 (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-3-((S) -2-((S)-2-((2,6-difluorophenyl)amino)propionylamino)-3,3-dimethylbutyryl)-6,6-dimethyl-3-nitrogen Heterobicyclo[3.1.0]hexane-2-carboxamide (24)
  • Example 25 For the synthesis steps of Example 25, refer to Example 24, wherein Compound 25 was prepared by substituting 2,4-difluoro-1-iodobenzene for Compound 24d.
  • Example 26 For the synthesis steps of Example 26, refer to Example 24, wherein Compound 26 was prepared by substituting 2,4,6-trifluoro-1-iodobenzene for Compound 24d.
  • Example 27 For the synthesis procedure of Example 27, refer to Example 24, wherein Compound 27 was prepared by substituting 4-chloro-2-fluoro-1-iodobenzene for Compound 24d.
  • Example 28 (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-carbonylpyrrolidin-3-yl)ethyl)-3-((S )-3,3-Dimethyl-2-((S)-2-((2,2,2-trifluoroethyl)amino)propionylamino)butyryl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide (compound 28)
  • Example 28 For the synthesis steps of Example 28, refer to Example 24, in which 2,2,2-trifluoroethyltrifluoromethanesulfonic acid was used instead of Compound 24d to obtain the aforementioned Example 28.
  • Example 29 For the synthesis steps of Example 29, refer to Example 24, wherein 3-fluoro-4-iodobenzonitrile was used to replace Compound 24d to obtain the aforementioned Example 29.
  • Test example 1 SARS-CoV-2 3CL protease inhibitory activity test
  • the detection system includes 3CL protease, Beyotime fluorescent substrate Dabcyl-KTSAVLQSGFRKME-Edans, the reaction buffer is 20mM Tris-HCl (pH7.3), 100mM NaCl, 1mM EDTA, 0.01% BSA (bivine serum albumin), 1mM DTT.
  • the detection principle is fluorescence resonance energy transfer: 3CL protease hydrolyzes the fluorescent substrate to generate a detectable fluorescent product, and the detection of the fluorescent product reflects the protease activity.
  • 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.
  • A ⁇ 50nM
  • B ⁇ 50nM and ⁇ 500nM.

Abstract

La présente invention concerne un composé pyrrolidine représenté par la formule (I) et un sel pharmaceutiquement acceptable de celui-ci, et leur utilisation comme inhibiteur de la protéase 3CL de coronavirus dans la prévention ou le traitement de maladies associées provoquées par une infection à coronavirus.
PCT/CN2023/071925 2022-01-13 2023-01-12 Composé antiviral amide WO2023134730A1 (fr)

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