WO2023116811A1 - COMPOSÉ DE PEPTIDE COURT CONTENANT DE LA β-AMINOCÉTONE ET UTILISATION ASSOCIÉE - Google Patents

COMPOSÉ DE PEPTIDE COURT CONTENANT DE LA β-AMINOCÉTONE ET UTILISATION ASSOCIÉE Download PDF

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WO2023116811A1
WO2023116811A1 PCT/CN2022/140910 CN2022140910W WO2023116811A1 WO 2023116811 A1 WO2023116811 A1 WO 2023116811A1 CN 2022140910 W CN2022140910 W CN 2022140910W WO 2023116811 A1 WO2023116811 A1 WO 2023116811A1
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compound
pharmaceutically acceptable
acceptable salt
reaction
synthesis
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PCT/CN2022/140910
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English (en)
Chinese (zh)
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陈曙辉
杨亚讯
张建臣
李鹏
罗志
贺海鹰
王正
黎健
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福建广生中霖生物科技有限公司
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Priority to CN202280016132.6A priority Critical patent/CN116888099A/zh
Publication of WO2023116811A1 publication Critical patent/WO2023116811A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to a short peptide compound containing ⁇ -aminoketone and its application.
  • (3CL pro ) protease belongs to cysteine proteases. Its substrate binding site is highly conserved and has a similar catalytic mechanism. It is a key protease that catalyzes the cleavage of RNA virus precursor protein and plays an important role in virus replication. As a key enzyme for coronavirus replication, 3CL protease (3CL pro ) is an important target for the treatment of diseases caused by various coronaviruses including COVID-19. Using the structural characteristics of 3CL protease to develop drugs for the treatment of new coronavirus infection has great clinical value.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • Each R 1 is independently selected from halogen, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, and each of the C 1-3 alkyl or C 1-3 alkoxy is independently optionally substituted by 1, 2 or 3 halogens;
  • R 1 and the atoms connected to them form a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is optionally substituted by 1, 2 or 3 R a ;
  • R a is each independently selected from halogen and C 1-3 alkyl
  • n is selected from 0, 1, 2 or 3;
  • R 2 is selected from tert-butyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl and phenyl, each of said C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl and phenyl independently optionally substituted by 1, 2 or 3 R ;
  • R b are each independently selected from halogen and C 1-3 alkyl
  • R 3 is selected from C 1-3 alkyl, C 1-3 alkoxy, -CH 2 R 4 and -CH 2 OR 4 , and the C 1-3 alkyl and C 1-3 alkoxy are each independently optionally substituted by 1, 2 or 3 halogens;
  • R is selected from phenyl and 5-6 membered heteroaryl, each of which is independently optionally substituted by 1, 2 or 3 R;
  • R is selected from halogen and C 1-3 alkyl
  • T1 is selected from O and S;
  • Ring A is selected from
  • a 1 , A 2 , A 3 and A 4 are each independently selected from CH and N.
  • R 1 is selected from F and methyl, and other variables are as defined in the present invention.
  • the above two R 1 and the atoms connected to them form a C 3-6 cycloalkyl group, and other variables are as defined in the present invention.
  • the above two R 1 and the atoms connected to them form a cyclopropyl group, and other variables are as defined in the present invention.
  • R 2 is selected from tert-butyl and adamantyl, and the adamantyl is optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 2 is selected from tert-butyl and adamantyl, and other variables are as defined in the present invention.
  • R 2 is selected from tert-butyl, Other variables are as defined herein.
  • R 3 is selected from -CF 3 , and other variables are as defined in the present invention.
  • the present invention also provides compounds represented by (II-1), (II-2) and (II-3) or pharmaceutically acceptable salts thereof,
  • t is selected from 0, 1 and 2;
  • R 1 , R b , A 1 , A 2 , A 3 , A 4 , T 1 and n are as defined in the present invention.
  • the present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Each R 1 is independently selected from halogen, CN, OH, NH 2 , C 1-3 alkyl or C 1-3 alkoxy, and the C 1-3 alkyl or C 1-3 alkoxy is optionally each independently substituted by 1, 2 or 3 halogens;
  • R 1 and the atoms connected to them form a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is optionally substituted by 1, 2 or 3 R a ;
  • n is selected from 0, 1, 2 or 3;
  • R a is each independently selected from halogen or C 1-3 alkyl
  • R 2 is selected from tert-butyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl or phenyl, the C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl and phenyl are any optionally replaced by 1, 2 or 3 R b ;
  • Each R b is independently selected from halogen or C 1-3 alkyl
  • R 3 is selected from C 1-3 alkyl, C 1-3 alkoxy, -CH 2 R 4 or -CH 2 OR 4 , and the C 1-3 alkyl and C 1-3 alkoxy are optionally 1, 2 or 3 halogen substitutions;
  • R 4 is selected from phenyl or 5-6 membered heteroaryl, said phenyl and 5-6 membered heteroaryl are optionally substituted independently by 1, 2 or 3 R;
  • R is selected from halogen or C 1-3 alkyl
  • a 1 , A 2 , A 3 and A 4 are each independently selected from CH or N, and 0, 1 or 2 of A 1 , A 2 , A 3 and A 4 are selected from N, and the rest are selected from CH.
  • R 1 is selected from F or methyl, and other variables are as defined in the present invention.
  • the above two R 1 and the atoms connected to them form a C 3-6 cycloalkyl group, and other variables are as defined in the present invention.
  • the above two R 1 and the atoms connected to them form a cyclopropyl group, and other variables are as defined in the present invention.
  • R 2 is selected from tert-butyl, and other variables are as defined in the present invention.
  • R 3 is selected from -CF 3 , and other variables are as defined in the present invention.
  • the present invention also provides the compound represented by (I-1) or a pharmaceutically acceptable salt thereof,
  • R 1 and n are as defined in the present invention.
  • the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:
  • the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof.
  • the present invention also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating coronavirus infection.
  • the present invention also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned composition in the preparation of a medicament for treating coronavirus infection.
  • the aforementioned coronavirus infection is selected from COVID-19.
  • the compound of the present invention has better in vitro anti-new coronavirus Mpro protease activity; better in vitro anti-coronavirus activity at the cellular level, and has no cytotoxicity.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • the chemical bonds that the site is connected with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the carbon atoms at positions 1 and 2 in the phenyl group are connected to other groups.
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • 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 The amount of a compound of the invention for the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound of the invention 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.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • a substituent can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the linking group L is -MW-, at this time -MW- can be connected to ring A and ring A in the same direction as the reading order from left to right to form It can also be formed by linking loop A and loop A in the opposite direction to the reading order from left to right
  • Combinations of the described linking groups, substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site is connected with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means a “ring” with 5-7 atoms arranged around it.
  • C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n to n +m means that the number of atoms on the ring is from n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-member
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which includes monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include Spiral, parallel and bridged rings.
  • the C 3-6 cycloalkyl group includes C 3-5 , C 4-6 , C 4-5 or C 5-6 and the like; it may be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 3-10 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 10 carbon atoms, which includes monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include Spiral, parallel and bridged rings.
  • the C 3-10 cycloalkyl group includes C 3-8 , C 3-6 , C 3-5 , C 4-10 , C 4-8 , C 4-6 , C 4- 5 , C 5-8 or C 5-6 etc.; it may be monovalent, divalent or multivalent.
  • C 3-10 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.
  • the term "3-10 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 10 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, N, P, or Se, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen, sulfur, and phosphorus heteroatoms can be optionally oxidized (i.e., NO, S (O) p and P(O) p , where p is 1 or 2).
  • the 3-10 membered heterocycloalkyl group includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, merged and bridged rings.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl group to the rest of the molecule.
  • the 3-10 membered heterocycloalkyl group includes 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups.
  • 3-10 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidin,
  • the terms “5-6-membered heteroaryl ring” and “5-6-membered heteroaryl” in the present invention can be used interchangeably, and the term “5-6-membered heteroaryl” means that there are 5 to 6 ring atoms A monocyclic group with a conjugated ⁇ -electron system, 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
  • the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • the "connected atoms” may be the same atom or different atoms.
  • "two R 1 and the atoms connected to them form a C 3-6 cycloalkyl group", which may form a spiro ring, a bridged ring or a fused ring with ring A.
  • the compounds of the present invention 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 Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • the solvent used in the present invention is commercially available.
  • HATU stands for 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • THF stands for tetrahydrofuran
  • Boc stands for tert-butyloxycarbonyl
  • n-BuLi stands for n-butyl lithium
  • HCl stands for hydrochloric acid
  • ACN stands for acetonitrile
  • MeOH stands for methanol
  • EtOAc or EA stands for ethyl acetate
  • TEA stands for triethylamine
  • DIEA or DIPEA stands for N,N-di Isopropylethylamine
  • DMF stands for N,N-dimethylformamide
  • DMSO stands for dimethyl sulfoxide
  • HPLC stands for high performance liquid chromatography
  • TLC stands for thin layer chromatography
  • PEG stands for polyethylene glycol.
  • reaction solution was poured into 5% citric acid solution for separation, the aqueous phase was extracted with ethyl acetate (20 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Lithium hydroxide monohydrate (51.25 mg, 1.22 mmol) was added to a solution of starting material 1-9 (0.3 g, 814.19 ⁇ mol) in tetrahydrofuran (2 mL) and water (1 mL), and reacted at 20° C. for 16 hr.
  • Compounds 1-10 were obtained.
  • reaction solution was extracted by adding ethyl acetate (10 mL) and 1M hydrochloric acid (5 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Dissolve compound 2-10 (160 mg, 409.81 ⁇ mol) and 1-5 (160.23 mg, 491.78 ⁇ mol) in acetonitrile (2 mL), cool to 0 ° C, add 1-ethyl-(3-dimethylaminopropyl) Carbodimethimide hydrochloride (79.35mg, 413.91 ⁇ mol) was added dropwise to pyridine (129.66mg, 1.64mmol), and the reaction was stirred at 0°C for 2h.
  • compound 4-2 (8g, 30.97mmol) and dichloromethane (80mL) were added to a dry three-necked flask, and stirring was started; then sodium bicarbonate (2.73g, 32.52mmol, 1.26mL) and Dessert -Martin periodinane (13.79g, 32.52mmol)
  • the reaction solution changed from cloudy to clear, replaced with nitrogen 3 times, stirred for about 20min, the reaction solution turned into a white suspension, and stirred at 15°C for 16hr.
  • the substrate compound 4-5 (0.2 g, 532.74 ⁇ mol) was dissolved in hydrochloric acid/ethyl acetate (4M, 10.00 mL), and stirring was continued for 1 h. Direct concentration gave the hydrochloride salt of compound 4-6.
  • the substrate compound 3-4 (0.35 g, 783.74 ⁇ mol) was dissolved in N,N-dimethylformamide (10 mL), added HATU (447.00 mg, 1.18 mmol), and stirred for 0.5 h.
  • the hydrochloride salt of compound 4-6 (258.92mg) and diisopropylethylamine (405.17mg, 3.13mmol) were added to the reaction system, and stirred at 20°C for 1 hour.
  • the substrate compound 4-9 trifluoroacetate (0.034g, 56.50 ⁇ mol) was dissolved in dichloromethane (1mL), cooled to 0°C, pyridine (31.29mg, 395.52 ⁇ mol) and trifluoroacetic anhydride (47.47mg ,226.01 ⁇ mol), continue stirring for 0.2h.
  • the reaction was washed with saturated sodium bicarbonate solution (10 mL), extracted three times with dichloromethane (10 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • reaction bottle was replaced with nitrogen, added n-hexane (4000mL), added diethyl zinc solution (1M n-hexane solution, 1.05L), cooled to 0°C, stirred at 0°C for 0.2hr, until the reaction system was clear, added trifluoro Boronium diethyl ether (223.82g, 1.58mol), stirred at 0°C for 0.5hr, added diiodomethane (563.15g, 2.10mol) at 0°C, stirred at 0°C for 0.5hr, added compound 8-1 (50g, 131.41 mmol), raised to 40°C and stirred for 16hr.
  • the compound was dissolved in DMSO, and was diluted with Echo655 according to the 3-fold gradient according to the concentration to be tested, and 10 concentration points were added to the 384-well plate in duplicate wells for each concentration.
  • Dilute Mpro protein and substrate with test buffer 100mM NaCl, 20mM Tris-HCL, 1mM EDTA
  • add Mpro protein to a 384-well test plate and incubate with compound for 30min at room temperature, then add substrate, Mpro protein
  • Inhibition rate% [(Compound-BG Compound )-(ZPE-BG ZPE )]/[(HPE-BG HPE )-(ZPE-BG ZPE )]*100%
  • ZPE no inhibition control, containing 25nM Mpro protein + 25 ⁇ M substrate, no compound
  • test compound well containing 25nM Mpro protein + 25 ⁇ M substrate + compound
  • BG Background control wells containing 25 ⁇ M substrate+compound without Mpro protein
  • the compound of the present invention has better anti-new coronavirus Mpro protease activity in vitro.
  • MRC5 cells and coronavirus HCoV OC43 were purchased from ATCC.
  • MRC5 cells were cultured in MEM (Sigma) medium supplemented with 10% fetal bovine serum (Excell), 1% double antibody (Hyclone), 1% L-glutamine (Gibco) and 1% non-essential amino acids (Gibco).
  • MEM (Sigma) medium supplemented with 5% fetal bovine serum (Excell), 1% double antibody (Hyclone), 1% L-glutamine (Gibco) and 1% non-essential amino acid (Gibco) was used as the experimental medium.
  • Cells were seeded into 96 microwell plates at a certain density (Table 2) and cultured overnight in a 5% CO 2 , 37° C. incubator. On the second day, the compound after doubling dilution (8 concentration points, duplicate wells) was added, 50 ⁇ L per well. Then the diluted virus was added to the cells at 100 TCID 50 per well, 50 ⁇ L per well. Set up cell control (cells, no compound treatment or virus infection), virus control (cells infected with virus, no compound treatment) and culture medium control (only culture medium). The final volume of the experimental culture solution was 200 ⁇ L, and the final concentration of DMSO in the culture solution was 0.5%. The cells were cultured in a 5% CO 2 , 33°C incubator for 5 days. Cell viability was detected using the cell viability assay kit CellTiter Glo (Promega). Cytotoxicity experiments were performed under the same conditions as antiviral experiments, but without virus infection.
  • the antiviral activity and cytotoxicity of the compound are represented by the inhibitory rate (%) and cell viability (%) of the compound on the cytopathic effect caused by the virus at different concentrations, respectively. Calculated as follows:
  • Inhibition rate (%) (test hole reading value-virus control average value)/(cell control average value-virus control average value) ⁇ 100
  • GraphPad Prism was used to conduct nonlinear fitting analysis on the inhibition rate and cell viability of the compound, and calculate the half effective concentration (EC 50 ) and half cytotoxic concentration (CC 50 ) of the compound.
  • the compound of the present invention has good in vitro anti-coronavirus activity at the cellular level, and has no cytotoxicity.
  • C57BL/6J suckling mice were infected with a lethal dose of coronavirus by intranasal instillation, and the suckling mice were treated with vehicle (5% DMSO+40% PEG400+55% water) and the compound of the present invention 2 hours before infection.
  • vehicle 5% DMSO+40% PEG400+55% water
  • the compound of the present invention 2 hours before infection.
  • the body weight, health status and survival of the suckling mice were monitored daily to evaluate the protective effect of the compound of the present invention on the suckling mice at different doses.
  • the compound of the present invention has good anti-coronavirus efficacy in vivo.

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Abstract

L'invention concerne un composé de peptide court contenant de la β-aminocétone et une utilisation associée, et en particulier un composé représenté par la formule (II) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2022/140910 2021-12-22 2022-12-22 COMPOSÉ DE PEPTIDE COURT CONTENANT DE LA β-AMINOCÉTONE ET UTILISATION ASSOCIÉE WO2023116811A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021226546A1 (fr) * 2020-05-08 2021-11-11 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs de protéase pour le traitement ou la prévention d'une maladie à coronavirus
WO2021252491A1 (fr) * 2020-06-10 2021-12-16 Aligos Therapeutics, Inc. Composés antiviraux pour le traitement d'infections à coronavirus, picornavirus et norovirus
WO2021250648A1 (fr) * 2020-09-03 2021-12-16 Pfizer Inc. Composés antiviraux contenant du nitrile
WO2021252644A1 (fr) * 2020-06-09 2021-12-16 Pardes Biosciences, Inc. Inhibiteurs de cystéine protéases et leurs procédés d'utilisation
WO2022013684A1 (fr) * 2020-07-11 2022-01-20 Pfizer Inc. Dérivés d'hétéroaryl cétone antiviraux
WO2022020242A1 (fr) * 2020-07-20 2022-01-27 Enanta Pharmaceuticals, Inc. Peptides fonctionnalisés en tant qu'agents antiviraux
WO2022119858A1 (fr) * 2020-12-01 2022-06-09 Purdue Research Foundation Composés pour le traitement du sars

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021226546A1 (fr) * 2020-05-08 2021-11-11 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs de protéase pour le traitement ou la prévention d'une maladie à coronavirus
WO2021252644A1 (fr) * 2020-06-09 2021-12-16 Pardes Biosciences, Inc. Inhibiteurs de cystéine protéases et leurs procédés d'utilisation
WO2021252491A1 (fr) * 2020-06-10 2021-12-16 Aligos Therapeutics, Inc. Composés antiviraux pour le traitement d'infections à coronavirus, picornavirus et norovirus
WO2022013684A1 (fr) * 2020-07-11 2022-01-20 Pfizer Inc. Dérivés d'hétéroaryl cétone antiviraux
WO2022020242A1 (fr) * 2020-07-20 2022-01-27 Enanta Pharmaceuticals, Inc. Peptides fonctionnalisés en tant qu'agents antiviraux
WO2021250648A1 (fr) * 2020-09-03 2021-12-16 Pfizer Inc. Composés antiviraux contenant du nitrile
WO2022119858A1 (fr) * 2020-12-01 2022-06-09 Purdue Research Foundation Composés pour le traitement du sars

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