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WO2025067298A1 - 作为谷氨酰胺环化酶抑制剂的化合物 - Google Patents

作为谷氨酰胺环化酶抑制剂的化合物 Download PDF

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Publication number
WO2025067298A1
WO2025067298A1 PCT/CN2024/121304 CN2024121304W WO2025067298A1 WO 2025067298 A1 WO2025067298 A1 WO 2025067298A1 CN 2024121304 W CN2024121304 W CN 2024121304W WO 2025067298 A1 WO2025067298 A1 WO 2025067298A1
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Prior art keywords
compound
alkyl
pharmaceutically acceptable
stereoisomer
acceptable salt
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English (en)
French (fr)
Inventor
杨圣伟
唐锋
刘乐
赵晨
周旻昀
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Simcere Pharmaceutical Co Ltd
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Simcere Pharmaceutical Co Ltd
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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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00

Definitions

  • the present disclosure belongs to the field of medical technology, and specifically relates to a compound as a glutamine cyclase inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and a use thereof in preventing or treating diseases or conditions mediated by QPCT and/or QPCTL.
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • a ⁇ ⁇ -amyloid protein
  • Tau protein Tau protein
  • Glutamine cyclase (QC, also known as glutaminyl-peptide cyclotransferase, QPCT) catalyzes the post-translational chemical reactions of proteins or peptides, converting N-terminal glutamine or glutamate residues to N-terminal pyroglutamate (pE) by releasing ammonia or water molecules, respectively.
  • QPCT and its isoenzyme QPCTL glutaminyl-peptide cyclotransferase-like mediate the formation of pE-A ⁇ modifications in the brain. After A ⁇ forms pE at the N-terminus, its hydrophobicity increases.
  • a ⁇ has higher neurotoxicity due to its stronger stability and hydrophobicity.
  • upregulation of proinflammatory factors is also a characteristic of the AD pathological process.
  • the chemokine CCL2 [also known as monocyte chemoattractant protein-1 (MCP-1)] plays an important role in the stimulation and overactivation of glial cells.
  • Glutamine cyclase can also modify the N-terminal glutamine residue to form pE-CCL2. This modification can give CCL2 anti-degradation ability and mediate receptor activation.
  • CCL2 and other chemokines can induce the expression of QC, thereby triggering a vicious cycle between pE-A ⁇ deposition and neuroinflammation.
  • inhibiting QC activity is a potential therapeutic strategy for treating pE-related diseases, including but not limited to Alzheimer's disease, cancer, etc.
  • the present disclosure discloses a class of QPCT and/or QPCTL inhibitors with novel structure, excellent efficacy, high bioavailability and high drugability.
  • the present disclosure provides a compound of formula (AI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from Said Optionally substituted with R 5 ;
  • R 5 is selected from D, halogen, CN, NH 2 , OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl;
  • Ring B is selected from
  • R 1 is selected from H, halogen, OH, NH 2 , SH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl, and the OH, NH 2 , SH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R 1a ;
  • R 1a is selected from halogen, CN, OH, NH 2 or C 1 -C 6 alkyl, said OH, NH 2 or C 1 -C 6 alkyl being optionally substituted by R 1b ;
  • R 1b is selected from halogen or C 1 -C 6 alkyl
  • R 2 is selected from H, D or C 1 -C 6 alkyl
  • R3 and R4 are independently selected from H, D, halogen, OH, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl or 4-7 membered heterocyclyl, wherein the OH, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R3a ; or R3 , R4 and the atoms to which they are attached together form a C3 - C6 cycloalkyl or 4-7 membered heterocyclyl, wherein the C3 - C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R3a ;
  • R 3a is selected from D, halogen, OH or C 1 -C 6 alkyl.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as described herein or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • the present disclosure provides a compound of formula (I) as described herein or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a compound of formula (I) as described herein for use in treating or preventing a disease or condition mediated by QPCT and/or QPCTL in a subject in need thereof.
  • Pharmaceutical composition a compound of formula (I) as described herein or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a compound of formula (I) as described herein for use in treating or preventing a disease or condition mediated by QPCT and/or QPCTL in a subject in need thereof.
  • the present disclosure relates to a compound of formula (AI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from Said Optionally substituted with R 5 ;
  • R 5 is selected from D, halogen, CN, NH 2 , OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl.
  • Ring B is selected from
  • R 1 is selected from H, halogen, OH, NH 2 , SH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl, and the OH, NH 2 , SH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R 1a ;
  • R 1a is selected from halogen, CN, OH, NH 2 or C 1 -C 6 alkyl, said OH, NH 2 or C 1 -C 6 alkyl being optionally substituted by R 1b ;
  • R 1b is selected from halogen or C 1 -C 6 alkyl
  • R 2 is selected from H, D or C 1 -C 6 alkyl
  • R3 and R4 are independently selected from H, D, halogen, OH, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl or 4-7 membered heterocyclyl, wherein the OH, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R3a ; or R3 , R4 and the atoms to which they are attached together form a C3 - C6 cycloalkyl or 4-7 membered heterocyclyl, wherein the C3 - C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R3a ;
  • R 3a is selected from D, halogen, OH or C 1 -C 6 alkyl.
  • the compound of formula (AI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from formula (I) a compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from
  • Ring B is selected from
  • R 1 is selected from H, halogen, OH, NH 2 , SH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl, and the OH, NH 2 , SH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R 1a .
  • R 1a is selected from halogen, CN, OH, NH 2 or C 1 -C 6 alkyl, said OH, NH 2 or C 1 -C 6 alkyl being optionally substituted by R 1b .
  • R 1b is selected from halogen or C 1 -C 6 alkyl.
  • R 2 is selected from H, D or C 1 -C 6 alkyl.
  • ring A is selected from
  • Ring A is selected from
  • Ring A is selected from
  • R 5 is selected from C 1 -C 6 alkyl.
  • R 5 is selected from CH 3 .
  • R 1 is selected from H, halogen, OH, NH 2 , C 1 -C 6 alkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, said OH, NH 2 , C 1 -C 6 alkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl being optionally substituted with R 1a .
  • R 1 is selected from H, halogen, OH, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, said OH, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl being optionally substituted with R 1a .
  • R 1 is selected from H, halogen, OH, NH 2 , C 1 -C 6 alkyl, phenyl, pyridinyl, or morpholinyl, said OH, NH 2 , C 1 -C 6 alkyl, phenyl, pyridinyl, or morpholinyl being optionally substituted with R 1a .
  • R 1 is selected from H, halogen, OH, phenyl, pyridinyl, or morpholinyl, said OH, phenyl, pyridinyl, or morpholinyl being optionally substituted with R 1a .
  • R 1 is selected from H, F, Cl, OH, NH 2 , CH 3 , The OH, NH 2 , CH 3 , Optionally substituted with R 1a .
  • R 1 is selected from H, F, OH, The OH, Optionally substituted with R 1a .
  • R 1a is selected from halogen, CN, or C 1 -C 6 alkyl.
  • R 1a is selected from F, CN, CH 3 or propyl.
  • R 1a is selected from F, CN or propyl.
  • R 1 is selected from H, F, Cl, CH 3 , CH 2 F, OCH 3 ,
  • R 1 is selected from H, F,
  • R 2 is selected from H or C 1 -C 6 alkyl.
  • R 2 is selected from H or D.
  • R 2 is selected from H.
  • R 3 and R 4 are independently selected from H, OH or C 1 -C 6 alkyl, said OH or C 1 -C 6 alkyl being optionally substituted with R 3a .
  • R3 and R4 are independently selected from H, D, OH, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3- C6 cycloalkyl or 4-7 membered heterocyclyl, and the OH, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R3a ; or R3 , R4 and the atoms to which they are attached together form C3 - C6 cycloalkyl or 4-7 membered heterocyclyl, and the C3 - C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R3a ;
  • R 3 and R 4 are independently selected from H, halogen or C 1 -C 6 alkyl, or R 3 and R 4 together with the atoms to which they are attached form C 3 -C 6 cycloalkyl, and the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl are optionally substituted with R 3a .
  • R 3 and R 4 are independently selected from H , halogen, or C 1 -C 6 alkyl, which is optionally substituted with R 3a .
  • R 3 and R 4 together with the atoms to which they are attached form a C 3 -C 6 cycloalkyl group, which is optionally substituted with R 3a .
  • R 3a is selected from halogen or C 1 -C 6 alkyl.
  • R 3 and R 4 are independently selected from H, F or methyl, or R 3 and R 4 together with the atoms to which they are attached form a cyclobutyl group.
  • R3 and R4 are both H.
  • the compound of formula (AI) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt
  • R 1 and R 2 are as defined above in formula (AI).
  • the compound of formula (AI) of the present disclosure or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (II-1) or its stereoisomer or its pharmaceutically acceptable salt,
  • R 1 and R 2 are as defined above in formula (AI).
  • the compound of formula (AI) of the present disclosure or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (III) or its stereoisomer or its pharmaceutically acceptable salt,
  • R1 and R2 are as defined above in formula (AI).
  • the compound of formula (AI) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (III-1) or its stereoisomer or its pharmaceutically acceptable salt
  • R1 and R2 are as defined above in formula (AI).
  • the compound of formula (AI) of the present disclosure or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or its stereoisomer or its pharmaceutically acceptable salt:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (A-I) of the present disclosure or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for treating a disease mediated by QPCT and/or QPCTL in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (AI) or a stereoisomer thereof or A pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • a mammal preferably a human
  • the present disclosure provides use of a compound of formula (A-I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating a disease mediated by QPCT and/or QPCTL.
  • the present disclosure provides use of a compound of formula (A-I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating a disease mediated by QPCT and/or QPCTL.
  • the present disclosure provides a compound of formula (A-I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease mediated by QPCT and/or QPCTL.
  • the QPCT and/or QPCTL mediated disease is selected from a neurodegenerative disease.
  • the neurodegenerative disease is Alzheimer's disease.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
  • Tautomers refer to isomers produced by the rapid movement of an atom in a molecule between two positions. Tautomers can transform into each other and may reach an equilibrium state and coexist under certain conditions. Examples of tautomers include but are not limited to
  • 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 mixtures or other mixtures thereof, such as enantiomers. or a mixture enriched in diastereomers, all of which are within the definition of the compounds of the present invention.
  • asymmetric carbon atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention.
  • the compounds of the present invention containing asymmetric atoms may be isolated in an optically pure form or in a racemic form, and the optically pure form may be resolved from a racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), polysubstituted (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 understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or cannot be synthesized will be introduced.
  • any variable eg, Ra , Rb
  • its definition is independent at each occurrence. For example, if a group is substituted with 2 Rb , each Rb has an independent option.
  • Cm - Cn refers to an integer number of carbon atoms in the range of mn.
  • C1 - C10 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 of the general formula CnH2n +1 , which may be straight or branched.
  • C1 - C6 alkyl is understood to mean a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.
  • C1 - C3 alkyl may be understood to mean a straight or branched saturated monovalent hydrocarbon group having 1 to 3 carbon atoms.
  • the " C1 - C10 alkyl” may include a range such as “ C1 - C6 alkyl” or " C1 - C3 alkyl", and the “ C1 - C6 alkyl” may further include “ C1 - C3 alkyl”.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
  • C2 - C6 alkenyl should be understood to mean a straight or branched unsaturated monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms.
  • C2 - C6 alkenyl is preferably " C2 - C4 alkenyl", and more preferably C2 or C3 alkenyl. It should be understood that when the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other.
  • alkenyl examples include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)- but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond.
  • C 2 -C 6 alkynyl may be understood to mean a straight or branched unsaturated monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms.
  • Examples of “C 2 -C 6 alkynyl” include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (-C ⁇ CCH 3, -CH 2 C ⁇ CH), but-1-ynyl, but-2-ynyl or but-3-ynyl.
  • C 2 -C 6 alkynyl may include “C 2 -C 3 alkynyl", examples of “C 2 -C 3 alkynyl” include ethynyl (-C ⁇ CH), prop-1-ynyl (-C ⁇ CCH 3 ), prop-2-ynyl (propargyl).
  • cycloalkyl refers to a fully saturated carbon ring in the form of a monocyclic, fused, bridged or spirocyclic ring.
  • C 3 -C 6 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms, and specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • C 6 -C 10 aryl should be understood as a monovalent aromatic or partially aromatic all-carbon monocyclic or bicyclic group having 6 to 10 carbon atoms.
  • C 6 aryl such as phenyl
  • C 9 aryl such as indanyl or indenyl
  • C 10 aryl a ring having 10 carbon atoms
  • heteroaryl refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monovalent 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 containing 1, 2, 3, 4, 5, preferably 1, 2, 3 heteroatoms independently selected from N, O and S.
  • the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, in
  • 4-10 membered heterocyclyl refers to a group having 12, 3, 4 or 5 heteroatoms or heteroatomic groups in the ring atoms.
  • the heterocyclic group is 4, 5, 6, 7, 8, 9 or 10, and the ring atoms contain 1-5 heteroatoms or heteroatom groups independently selected from the above.
  • 4-membered heterocyclic group includes “4-7 membered heterocyclic group", wherein specific examples of 4-membered heterocyclic groups include, but are not limited to, azetidinyl or oxetanyl; specific examples of 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 are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrole-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazine-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 benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic group, specific examples of which include, but are not limited to, dihydroisoquinolinyl and the like.
  • “4-10 membered heterocyclyl” may include “5-10 membered heterocyclyl”, “4-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “6-8 membered heterocyclyl”, “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered heterocycloalkyl”, etc., and “4-7 membered heterocyclyl” may further include “4-6 membered heterocyclyl", “5-6 membered heterocyclyl”, “4-7 membered heterocycloalkyl”, “4-6 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, etc. Although some bicyclic heterocyclyls in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl as a whole is still non-aromatic.
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • amino refers to a -NH2 group.
  • alkoxy refers to a straight or branched alcohol in which the hydrogen atom on the hydroxyl group is substituted with an alkyl group.
  • C 1 -C 6 alkoxy may further include “C 1 -C 3 alkoxy”.
  • alkylamino refers to an amino group in which one or two hydrogen atoms are replaced by the same or different alkyl groups.
  • C 1 -C 6 alkylamino may further include “C 1 -C 3 alkylamino”.
  • haloalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by the same or different halogen atoms.
  • C 1 -C 6 haloalkyl may further include “C 1 -C 3 haloalkyl”.
  • deuterated alkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by a deuterium atom.
  • C 1 -C 6 deuterated alkyl may further include “C 1 -C 3 deuterated alkyl”.
  • treatment means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays 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” varies 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 based on their own knowledge and the present disclosure.
  • the term "patient” includes mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.
  • non-human mammals include, but are not limited to, birds and fish, etc.
  • the term "disease or condition mediated by QPCT and/or QPCTL” includes, but is not limited to, neurodegenerative diseases, cancer, etc., wherein the neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), different types of spinocerebellar ataxia (SCA), Pick's disease, etc.
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • HD Huntington's disease
  • ALS amyotrophic lateral sclerosis
  • SCA spinocerebellar ataxia
  • Pick's disease etc.
  • 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 the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or an organic acid, and a salt formed between a compound and an inorganic base or an organic base.
  • composition refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do 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 present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may 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., respectively.
  • Certain isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to 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 present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they 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 the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions 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 manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound 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, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.
  • the daily dosage of the compound of formula I is 0.01 mg/kg to 1000 mg/kg body weight, for example 0.01 mg/kg to 500 mg/kg body weight, in the form of single or divided doses.
  • the compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the embodiments with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.
  • Ti(OiPr) 4 tetraisopropyl titanate; THF: tetrahydrofuran; MeOH: methanol; LDA: lithium diisopropylamide; CuI: cuprous iodide; dioxane: dioxane; TFA: trifluoroacetic acid; DCM: dichloromethane; EBA: ethyl bromoacetate; TMSCl: trimethylchlorosilane; SEM: (trimethylsilyl)ethoxymethyl; TsOH: p-toluenesulfonic acid; Pd/C: palladium/carbon; LAH or LiAlH 4 : lithium tetrahydrogen aluminum; DMP: Dess-Martin periodinane, (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzidoyl-3(1H)-one; DIC: N,N'-diisopropylcarbodiimide;
  • the ratios expressed for mixed solvents are volume mixing ratios. Unless otherwise specified, % means wt %.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • the eluents mentioned below can be mixed eluents formed by two or more solvents, and the ratio is the volume ratio of each solvent, such as "0-10% ethyl acetate/petroleum ether” means that during the gradient elution process, the volume ratio of ethyl acetate to petroleum ether in the mixed eluent is 0:100-10:90.
  • intermediates 5-1 and 6-1 refers to the synthesis steps of intermediate 4-1, except that p-fluoroiodobenzene in step 2 is replaced by 4-iodopyridine and 4-iodobenzonitrile, respectively.
  • oxalyl chloride (5.41 g) was dissolved in 40 mL of dichloromethane, and a solution of DMSO (6.66 g) in dichloromethane (20 mL) was slowly added dropwise at -78 ° C, and the reaction solution was stirred at -78 ° C for 0.5 hours. Then a solution of 10-002 (3.70 g) in dichloromethane (20 mL) was slowly added dropwise, and the reaction solution was stirred at -78 ° C for 1 hour after the addition was complete. Then a solution of triethylamine (17.3 g) in dichloromethane (20 mL) was slowly added dropwise.
  • reaction solution was slowly warmed to room temperature and stirred at room temperature for 16 hours.
  • the reaction solution was washed with saturated brine (20 mL), and the organic phase was dried and concentrated to obtain intermediate 10-1, which was directly used in the next step.
  • oxalyl chloride (5.04 g) was dissolved in dichloromethane (30 mL), and a solution of DMSO (6.21 g) in dichloromethane (10 mL) was slowly added dropwise at -78 ° C. The reaction solution was stirred at -78 ° C for 0.5 hours. Then a solution of 11-002 (2.60 g) in dichloromethane (20 mL) was slowly added dropwise, and the reaction solution was stirred at -78 ° C for 1 hour after the addition was complete. A solution of triethylamine (16.08 g) in dichloromethane (20 mL) was slowly added dropwise.
  • reaction solution was slowly warmed to room temperature and stirred at room temperature for 16 hours.
  • the reaction solution was washed with saturated brine (20 mL), and the organic phase was dried to obtain intermediate 11-1 (2.50 g), which was directly used in the next step.
  • oxalyl chloride (1.15 g) was dissolved in 20 mL of dichloromethane, the reaction solution was cooled to -78 ° C, dimethyl sulfoxide (1.41 g) was slowly added dropwise, and stirred for 30 minutes. Then 13-004 (800 mg) was slowly added dropwise, and triethylamine (3.66 g) was added dropwise after stirring at -78 ° C for 1 hour and the temperature was raised to 25 ° C. The reaction solution was stirred at 25 ° C for 4 hours and the reaction was completed.
  • reaction solution was quenched with 100mL saturated ammonium chloride solution, extracted with ethyl acetate (100mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the crude product was purified by silica gel column chromatography (gradient: 0-25% ethyl acetate/petroleum ether) to obtain intermediate 1-3 (3.70g).
  • the intermediate 1-5 (40.0 mg) was dissolved in 2 mL of dioxane, and 2-[(5-iodobenzimidazol-1-yl)methoxy]ethyltrimethylsilane (120 mg,), cuprous iodide (22.2 mg), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (16.6 mg) and potassium phosphate (185 mg) were added, and the temperature was raised to 80 ° C and stirred for 2 hours.
  • the crude product was purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini NX, 150 ⁇ 30 mm, 5 ⁇ m; mobile phase: [Phase A: water (0.05% ammonia v/v); Phase B: acetonitrile]; gradient elution: mobile phase B from 17% to 57%) to obtain compound 1 (18.1 mg).
  • intermediate 1-5 (50.0 mg) was dissolved in 2 mL of dioxane, and 7-iodoimidazole [1,2-a] pyridine (97.0 mg), cuprous iodide (27.7 mg), (1R, 2R) -N, N'-dimethyl 1,2-cyclohexanediamine (20.7 mg) and potassium phosphate (232 mg) were added, and the temperature was raised to 80 ° C and stirred for 2 hours. After the reaction was completed, water (20 mL) and ethyl acetate (10 mL) were added to the reaction solution for extraction.
  • intermediate 1-6 (600 mg) was dissolved in 10 mL tetrahydrofuran, and LDA (1.17 mL, 2 M in THF) was slowly added dropwise at -78 °C. After the addition was completed, the reaction solution was stirred at -78 °C for 1 hour. Subsequently, iodomethane (244 mg) was added dropwise to the reaction solution, and the reaction was completed after stirring at -78 °C for 1 hour.
  • reaction solution was quenched with saturated aqueous ammonium chloride solution, the aqueous phase was extracted with ethyl acetate (10 mL*3), the organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol gradient elution) to obtain intermediate 15-1 (50 mg).
  • the intermediate 15-1 (50.0 mg) was dissolved in tetrabutylammonium fluoride tetrahydrofuran solution (5.0 mL, 1 M), and the reaction solution was stirred at 60°C for 1 hour before the reaction was completed.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Phenomenex Gemini NX, 150 ⁇ 30 mm, 5 ⁇ m; mobile phase: [Phase A: water (0.5% ammonia v/v); Phase B: acetonitrile]; gradient elution: mobile phase B from 50% to 80%) to obtain the title compound 15 (15.0 mg).
  • the title compound 16 was prepared by the same method as in Example 1, except that ethyl bromoacetate in step 2 was replaced by methyl 1-bromocyclobutane-1-carboxylate.
  • Step 2 and step 3 refer to the synthesis method of step 5 and step 6 in Example 1, except that 2-[(5-iodobenzimidazol-1-yl)methoxy]ethyltrimethylsilane in step 5 is replaced by 17-2, and the title compound 17 is prepared in the same manner.
  • the intermediate 1-6 (500 mg) was dissolved in 10 mL of tetrahydrofuran, and LDA (2M in THF, 2 mL) was slowly added dropwise under nitrogen protection at -70°C, and the reaction solution was stirred at this temperature for 30 minutes.
  • a solution of N-fluorobisbenzenesulfonamide (492 mg) in THF (2 ml) was slowly added dropwise, and the reaction was completed after stirring at -70°C for 1 hour.
  • the reaction was quenched with 20 mL of saturated ammonium chloride aqueous solution, diluted with ethyl acetate, separated, and the aqueous phase was extracted twice with ethyl acetate.
  • the organic phases were combined, dried, and concentrated to obtain a crude product.
  • the experimental methods used in the following experimental examples are all conventional methods; the materials and reagents used are reagents and materials that can be obtained from commercial channels unless otherwise specified.
  • Green Glutaminyl Cyclase Activity Assay Kit is used to detect the inhibition of compounds on human QPCT/QPCTL enzyme activity.
  • 0.5mM QPCT enzyme substrate was diluted to 5 ⁇ M with buffer at 1:100; 50 ⁇ g/mL QPCT enzyme was diluted to 125ng/mL with buffer and placed on ice for use; QPCT developer was diluted to 1:250 with buffer and placed on ice for use (QPCT Enzyme substrate, QPCT enzyme, buffer and QPCT developer are all from the kit); the starting concentration of the test compound working solution is 200 ⁇ M, 6-fold gradient dilution, a total of 7 concentration points. In the 75 ⁇ L reaction system, the starting working concentration of the test compound is 13.3 ⁇ M, and the final concentration of DMSO is 0.3%.
  • Inhibition rate (inhibition%) (RFU no treatment -RFU treated ) ⁇ (RFU no treatment -RFU background ) ⁇ 100%.
  • GraphPad Prism 9 software was used to plot the curve with compound concentration (nM) as the abscissa and enzyme activity inhibition rate (%) as the ordinate, and four-parameter fitting was performed to calculate the IC 50 of the compound on the inhibition of QPCT enzyme activity. Specific results are shown in Table 1.
  • membrane permeability and transport properties of the disclosed compounds were determined using the following test methods.
  • test steps are as follows:
  • MDCKII-MDR1 Source: Netherlands Cancer institute
  • transport buffer Hanks balanced salt solution containing 25 mM HEPES, pH 7.4: accurately weigh 5.958 g 4-hydroxyethylpiperazineethanesulfonic acid and 0.35 g NaHCO 3 , add 900 mL pure water to dissolve them, then add 100 mL 10 ⁇ HBSS and stir evenly, adjust the pH to 7.4, and filter.
  • MDCKII-MDR1 cell culture medium Add 10% FBS, 1% Pen Strep Liquid (source: Gibco), 1% GlutaMAXTM-I (source: Gibco) and 400 ⁇ g/mL G418 (source: Solarbio) to MEM culture medium (source: Gibco).
  • TEER value TEER ( ⁇ ) measured value ⁇ membrane area (cm 2 )
  • the resistance of the cell monolayer membrane was ⁇ 42 ⁇ cm 2 , indicating that the cell monolayer membrane had poor compactness and could not be used for the experiment.
  • I acceptor refers to the fluorescence density on the receiving side (0.3 mL), and I donor refers to the fluorescence density on the donating side (0.1 mL).
  • LY%>1.0% indicates poor cell monolayer membrane tightness, and the corresponding results will be excluded from the evaluation.
  • VA is the volume of the receiving end solution (A ⁇ B is 0.235 mL, B ⁇ A is 0.075 mL), Area is the Transwell-96 plate membrane area (0.143 cm 2 ); incubation time is the incubation time (unit: s).
  • P app(BA) is the apparent permeability from the base to the apex
  • P app(AB) is the apparent permeability from the apex to the base.
  • the inhibition of the disclosed compounds on the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes was determined using the following test method.
  • test steps are as follows:
  • Dilute positive inhibitor stock solution with DMSO to obtain 200 ⁇ concentration of positive inhibitor working solution (sulfaphenazole, 1000, 300, 100, 30, 10, 3, 0 ⁇ M; quinidine/ketoconazole, 100, 30, 10, 3, 1, 0.3, 0 ⁇ M; ⁇ -naphthoflavone, 50, 15, 5, 1.5, 0.5, 0.15, 0 ⁇ M; nootkatone, 6000, 1800, 600, 180, 60, 18, 0 ⁇ M).
  • IC50 values of the disclosed compounds against CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 were calculated using Excel XLfit 5.3.1.3 and are shown in Table 3.
  • test steps are as follows:

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Abstract

公开了作为谷氨酰胺环化酶抑制剂的式(A-I)化合物或其立体异构体或其药学上可接受的盐、其制备方法、含有所述式(A-I)化合物或其立体异构体或其药学上可接受的盐的药物组合物、以及所述式(A-I)化合物或其立体异构体或其药学上可接受的盐在预防或治疗包括神经退行性疾病在内的由QPCT和/或QPCTL介导的疾病或病症中的用途。

Description

作为谷氨酰胺环化酶抑制剂的化合物
相关申请的交叉引用
本申请要求于2023年9月27日向中国国家知识产权局提交的第202311273882.4号中国专利申请以及于2023年12月15日向中国国家知识产权局提交的第202311736403.8号中国专利申请的优先权和权益，所述申请的全部内容通过援引并入本文中。
技术领域
本公开属于医药技术领域，具体涉及作为谷氨酰胺环化酶抑制剂的化合物、其制备方法、含有该化合物的药物组合物、以及其在预防或治疗由QPCT和/或QPCTL介导的疾病或病症中的用途。
背景技术
阿尔茨海默病(Alzheimer's disease,AD)是一种神经退行性疾病，特征是全脑不可逆性脑功能损害，导致认知功能、理解力和/或意识逐渐衰退。
AD的主要组织病理学标志为β淀粉样蛋白(Aβ)和Tau蛋白等异常沉积而导致的Aβ斑块和神经原纤维缠结。现今较为流行的学说认为，导致阿尔茨海默病早期病理改变的不是斑块，而是可溶性Aβ聚集体，称为Aβ寡聚体。AD患者脑中大多数Aβ肽都以N端剪切和翻译后修饰的形式存在。谷氨酰胺环化酶(glutaminyl cyclase，QC，又称glutaminyl-peptide cyclotransferase，QPCT)可催化蛋白质或肽的翻译后化学反应，分别通过释放氨或水分子将N-末端谷氨酰胺或谷氨酸残基转化为N-末端焦谷氨酸(pE)。在神经退行性疾病中，QPCT及其同工酶QPCTL(glutaminyl-peptide cyclotransferase-like)介导大脑中pE-Aβ修饰的形成。Aβ在N端形成pE后疏水性增强，这种形式的Aβ由于具有更强的稳定性和疏水性，而具有更高的神经毒性。除此之外，促炎因子(细胞因子、趋化因子)上调也是AD病理过程的特征。其中，趋化因子CCL2[又称单核细胞趋化蛋白-1(MCP-1)]在胶质细胞的刺激和过度活化中起着重要作用。谷氨酰胺环化酶也可修饰N端谷氨酰胺残基形成pE-CCL2，这种修饰可赋予CCL2抗降解能力，介导受体激活。CCL2和其他趋化因子可诱导QC的表达，从而引发pE-Aβ沉积和神经炎症之间的恶性循环。因此，抑制QC活性是一种潜在的治疗pE相关疾病的治疗策略，包括但不限于阿尔茨海默病、癌症等，鉴于此，本公开公开了一类结构新颖、药效优异、生物利用度高、成药性高的QPCT和/或QPCTL抑制剂。
发明内容
一方面，本公开提供了式(A-I)化合物或其立体异构体或其药学上可接受的盐，
其中，
环A选自所述任选地被R5取代；
R5选自D、卤素、CN、NH2、OH、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基、C1-C6卤代烷基或C1-C6氘代烷基；
环B选自
R1选自H、卤素、OH、NH2、SH、CN、C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、5-10元杂芳基、C3-C6环烷基或4-10元杂环基，所述OH、NH2、SH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、5-10元杂芳基、C3-C6环烷基或4-10元杂环基任选地被R1a取代；
R1a选自卤素、CN、OH、NH2或C1-C6烷基，所述OH、NH2或C1-C6烷基任选地被R1b取代；
R1b选自卤素或C1-C6烷基；
R2选自H、D或C1-C6烷基；
R3和R4独立地选自H、D、卤素、OH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基或4-7元杂环基，所述OH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、4-7元杂环基任选地被R3a取代；或者R3、R4与其相连的原子共同形成C3-C6环烷基或4-7元杂环基，所述C3-C6环烷基或4-7元杂环基任选地被R3a取代；
R3a选自D、卤素、OH或C1-C6烷基。
另一方面，本公开提供了药物组合物，其包含本文所述的式(I)化合物或其立体异构体或其药学上可接受的盐，以及任选的药学上可接受的辅料。
又一方面，本公开提供了用于治疗或者预防有需要的对象的由QPCT和/或QPCTL介导的疾病或病症的本文所述的式(I)化合物或其立体异构体或其药学上可接受的盐或本文所述的 药物组合物。
具体实施方式
本公开涉及式(A-I)化合物或其立体异构体或其药学上可接受的盐，
其中，
环A选自所述任选地被R5取代；
R5选自D、卤素、CN、NH2、OH、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基、C1-C6卤代烷基或C1-C6氘代烷基。
环B选自
R1选自H、卤素、OH、NH2、SH、CN、C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、5-10元杂芳基、C3-C6环烷基或4-10元杂环基，所述OH、NH2、SH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、5-10元杂芳基、C3-C6环烷基或4-10元杂环基任选地被R1a取代；
R1a选自卤素、CN、OH、NH2或C1-C6烷基，所述OH、NH2或C1-C6烷基任选地被R1b取代；
R1b选自卤素或C1-C6烷基；
R2选自H、D或C1-C6烷基；
R3和R4独立地选自H、D、卤素、OH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基或4-7元杂环基，所述OH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、4-7元杂环基任选地被R3a取代；或者R3、R4与其相连的原子共同形成C3-C6环烷基或4-7元杂环基，所述C3-C6环烷基或4-7元杂环基任选地被R3a取代；
R3a选自D、卤素、OH或C1-C6烷基。
在一些实施方案中，式(A-I)化合物或其立体异构体或其药学上可接受的盐选自式(I) 化合物或其立体异构体或其药学上可接受的盐，
其中，
环A选自
环B选自
R1选自H、卤素、OH、NH2、SH、CN、C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、5-10元杂芳基、C3-C6环烷基或4-10元杂环基，所述OH、NH2、SH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、5-10元杂芳基、C3-C6环烷基或4-10元杂环基任选地被R1a取代。
R1a选自卤素、CN、OH、NH2或C1-C6烷基，所述OH、NH2或C1-C6烷基任选地被R1b取代。
R1b选自卤素或C1-C6烷基。
R2选自H、D或C1-C6烷基。在一些实施方案中，环A选自
在一些实施方案中，环A选自
在一些实施方案中，环A选自
在一些实施方案中，R5选自C1-C6烷基。
在一些实施方案中，R5选自CH3。
在一些实施方案中，R1选自H、卤素、OH、NH2、C1-C6烷基、苯基、5-6元杂芳基或4-7元杂环基，所述OH、NH2、C1-C6烷基、苯基、5-6元杂芳基或4-7元杂环基任选地被R1a取代。
在一些实施方案中，R1选自H、卤素、OH、苯基、5-6元杂芳基或4-7元杂环基，所述OH、苯基、5-6元杂芳基或4-7元杂环基任选地被R1a取代。
在一些实施方案中，R1选自H、卤素、OH、NH2、C1-C6烷基、苯基、吡啶基或吗啉基，所述OH、NH2、C1-C6烷基、苯基、吡啶基或吗啉基任选地被R1a取代。
在一些实施方案中，R1选自H、卤素、OH、苯基、吡啶基或吗啉基，所述OH、苯基、吡啶基或吗啉基任选地被R1a取代。
在一些实施方案中，R1选自H、F、Cl、OH、NH2、CH3、所述OH、NH2、CH3、任选地被R1a取代。
在一些实施方案中，R1选自H、F、OH、所述OH、 任选地被R1a取代。
在一些实施方案中，R1a选自卤素、CN或C1-C6烷基。
在一些实施方案中，R1a选自F、CN、CH3或丙基。
在一些实施方案中，R1a选自F、CN或丙基。
在一些实施方案中，R1选自H、F、Cl、CH3、CH2F、OCH3、
在一些实施方案中，R1选自H、F、
在一些实施方案中，R2选自H或C1-C6烷基。
在一些实施方案中，R2选自H或D。
在一些实施方案中，R2选自H。
在一些实施方案中，R3和R4独立地选自H、OH或C1-C6烷基，所述OH或C1-C6烷基任选地被R3a取代。
在一些实施方案中，R3和R4独立地选自H、D、OH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基或4-7元杂环基，所述OH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、4-7元杂环基任选地被R3a取代；或者R3、R4与其相连的原子共同形成C3-C6环烷基或4-7元杂环基，所述C3-C6环烷基或4-7元杂环基任选地被R3a取代；
在一些实施方案中，R3和R4独立地选自H、卤素或C1-C6烷基，或者R3和R4与其相连的原子共同形成C3-C6环烷基，所述C1-C6烷基和C3-C6环烷基任选地被R3a取代。
在一些实施方案中，R3和R4独立地选自H、卤素或C1-C6烷基，所述C1-C6烷基任选地被R3a取代。
在一些实施方案中，R3和R4与其相连的原子共同形成C3-C6环烷基，所述C3-C6环烷基任选地被R3a取代。
在一些实施方案中，R3a选自卤素或C1-C6烷基。
在一些实施方案中，R3和R4独立地选自H、F或甲基，或者R3和R4与其相连的原子共同形成环丁基。
在一些实施方案中，R3和R4均为H。
在一些实施方案中，本公开的式(A-I)化合物或其立体异构体或其药学上可接受的盐选自式(II)化合物或其立体异构体或其药学上可接受的盐，
其中R1和R2如上文式(A-I)定义。在一些实施方案中，本公开的式(A-I)化合物或其立体异构体或其药学上可接受的盐选自式(II-1)化合物或其立体异构体或其药学上可接受的盐，
其中R1和R2如上文式(A-I)定义。在一些实施方案中，本公开的式(A-I)化合物或其立体异构体或其药学上可接受的盐选自式(III)化合物或其立体异构体或其药学上可接受的盐，
其中R1和R2如上文式(A-I)定义。
在一些实施方案中，本公开的式(A-I)化合物或其立体异构体或其药学上可接受的盐选自式(III-1)化合物或其立体异构体或其药学上可接受的盐，
其中R1和R2如上文式(A-I)定义。
在一些实施方案中，本公开的式(A-I)化合物或其立体异构体或其药学上可接受的盐选自以下化合物或其立体异构体或其药学上可接受的盐：

另一方面，本公开提供药物组合物，其包含本公开的式(A-I)化合物或其立体异构体或其药学上可接受的盐，以及药学上可接受的辅料。
另一方面，本公开提供治疗哺乳动物由QPCT和/或QPCTL介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(A-I)化合物或其立体异构体或其 药学上可接受的盐、或其药物组合物。
另一方面，本公开提供式(A-Ⅰ)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物在制备预防或者治疗QPCT和/或QPCTL介导的疾病的药物中的用途。
另一方面，本公开提供式(A-Ⅰ)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物在预防或者治疗QPCT和/或QPCTL介导的疾病中的用途。
另一方面，本公开提供预防或者治疗QPCT和/或QPCTL介导的疾病的式(A-Ⅰ)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物。
在一些实施方案中，QPCT和/或QPCTL介导的疾病选自神经退行性疾病。
在一些实施方案中，所述神经退行性疾病为阿尔茨海默病。
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，用楔形键和虚楔键表示一个立体中心的绝对构型，用黑实键和虚键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“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。
本公开的化合物包含其互变异构体形式，互变异构体指因分子中某一原子在两个位置迅速移动而产生的异构体，互变异构体之间可以互相转变，在某一状态下可能会达到一种平衡状态而共存。互变异构体的示例包括但不限于
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(CH2CH3)、单取代的(CH2CH2F、CH2CH2Cl等)、多取代的(CHFCH2F、CH2CHF2、CHFCH2Cl、CH2CHCl2等)或完全被取代的(CF2CF3、CF2CCl3、CCl2CCl3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Ra、Rb)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Rb所取代，则每个Rb都有独立的选项。
本文中的Cm-Cn是指具有m-n范围中的整数个碳原子。例如“C1-C10”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CnH2n+1的烃基，该烷基可以是直链或支链的。术语“C1-C6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基的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“C1-C3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一价烃基。所述“C1-C10烷基”可以包含“C1-C6烷基”或“C1-C3烷基”等范围，所述“C1-C6烷基”可以进一步包含“C1-C3烷基”。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的且具有至少一个双键的不饱和脂肪族烃基。术语“C2-C6烯基”应理解为表示直链或支链的不饱和一价烃基，其包含一个或多个双键并且具有2、3、4、5或6个碳原子，“C2-C6烯基”优选“C2-C4烯基”，进一步优选C2或C3烯基。应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或共轭。所述烯基的具体实例包括但不限于乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)- 丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基或(Z)-1-甲基丙-1-烯基等。
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。术语“C2-C6炔基”可理解为表示直链或支链的不饱和一价烃基，其包含一个或多个三键并且具有2、3、4、5或6个碳原子。“C2-C6炔基”的实例包括但不限于乙炔基(-C≡CH)、丙炔基(-C≡CCH3、-CH2C≡CH)、丁-1-炔基、丁-2-炔基或丁-3-炔基。“C2-C6炔基”可以包含“C2-C3炔基”，“C2-C3炔基”实例包括乙炔基(-C≡CH)、丙-1-炔基(-C≡CCH3)、丙-2-炔基(炔丙基)。
术语“环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的碳环。术语“C3-C6环烷基”可理解为表示饱和的一价单环或双环烃环，其具有3、4、5或6个碳原子，具体实例包括但不限于环丙基、环丁基、环戊基或环己基等。
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。术语“C6-C10芳基”应理解为具有6～10个碳原子的一价芳香性或部分芳香性的全碳单环或双环基团。特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或者具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基。
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”应理解为包括这样的一价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、2、3、4、5个，优选1、2、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“5-6元杂芳基”指具有5或6个环原子的芳族环系，且其包含1-3个，优选1-2个独立选自N、O和S的杂原子。
术语“杂环基”是指完全饱和的或部分饱和的(整体上不是具有芳香性的杂芳族)一价单环、并环、螺环或桥环基团，其环原子中含有12、3、4或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)-以及任选被取代的-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-、-C(＝NH)-、-S(＝O)2NH-、S(＝O)NH-或-NHC(＝O)NH-等。术语“4-10元杂环基”是指环原子数目 为4、5、6、7、8、9或10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。“4-10元杂环基”包括“4-7元杂环基”，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。“4-10元杂环基”可以包含“5-10元杂环基”、“4-7元杂环基”、“5-6元杂环基”、“6-8元杂环基”、“4-10元杂环烷基”、“5-10元杂环烷基”、“4-7元杂环烷基”、“5-6元杂环烷基”、“6-8元杂环烷基”等范围，“4-7元杂环基”进一步可以包含“4-6元杂环基”、“5-6元杂环基”、“4-7元杂环烷基”、“4-6元杂环烷基”、“5-6元杂环烷基”等范围。本公开中尽管有些双环类杂环基部分地含有一个苯环或一个杂芳环，但所述杂环基整体上仍是无芳香性的。
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“氨基”是指-NH2基团。
术语“烷氧基”是指直链或支链醇类的羟基上的氢原子被烷基取代。术语“C1-C6烷氧基”可以进一步包含“C1-C3烷氧基”。
术语“烷氨基”是指氨基上一个或两个氢原子被相同或不同的烷基所取代。术语“C1-C6烷氨基”可以进一步包含“C1-C3烷氨基”。
术语“卤代烷基”是指烷基上一个或多个氢原子被相同或不同的卤素原子取代。术语“C1-C6卤代烷基”可以进一步包含“C1-C3卤代烷基”。
术语“氘代烷基”是指烷基上一个或多个氢原子被氘原子取代。术语“C1-C6氘代烷基”可以进一步包含“C1-C3氘代烷基”。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
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，包括预防疾病或疾病状态在哺乳动物中出现，特别是当这类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“治疗有效量”意指(i)治疗特定疾病、病况或病症，(ii)减轻、改善或消除特定疾病、病况或病症的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或病症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“患者”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。
术语“由QPCT和/或QPCTL介导的疾病或病症”包括但不限于神经退行性疾病、癌症等，所述神经退行性疾病包括阿尔茨海默病(AD)、帕金森病(PD)、亨廷顿病(HD)、肌萎缩性侧索硬化(ALS)、不同类型脊髓小脑共济失调(SCA)、Pick病等。
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应理解为开放的、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体重到1000mg/kg体重，例如0.01mg/kg体重到500mg/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。
本公开采用下述缩略词：
Ti(OiPr)4：钛酸四异丙酯；THF：四氢呋喃；MeOH：甲醇；LDA：二异丙基氨基锂；CuI：碘化亚铜；dioxane：二氧六环；TFA：三氟乙酸；DCM：二氯甲烷；EBA：溴乙酸乙酯；TMSCl：三甲基氯硅烷；SEM：(三甲基硅)乙氧基甲基；TsOH:对甲苯磺酸；Pd/C：钯/碳；LAH或LiAlH4：四氢铝锂；DMP:戴斯-马丁氧化剂，(1,1,1-三乙酰氧基)-1,1-二氢-1,2-苯碘酰-3(1H)-酮；DIC：N,N'-二异丙基碳二亚胺；DMAP：4-二甲氨基吡啶；NiBr2(dme):溴化镍乙二醇二甲醚络合物；DMA:二甲基乙酰胺；DIBAL-H：二异丁基氢化铝；DMSO：二甲基亚砜；TEA：三乙胺；TBAF:四丁基氟化铵；BH3 THF:硼烷四氢呋喃溶液；TosCl：对甲苯磺酰氯；DAST:二乙氨基三氟化硫；AlD4Li：氘代氢化锂铝；Oxalyl chloride：草酰氯；Sodium Pyrithione：吡啶硫酮钠；AIBN：偶氮二异丁腈；NFSI:N-氟代双苯磺酰胺。
实施例
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，否则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wt％。
化合物经手工或软件命名，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)；“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
下文的洗脱剂可由两种或多种溶剂形成混合洗脱剂，其比值为各溶剂的体积比，如“0～10％乙酸乙酯/石油醚”表示梯度洗脱过程中，混合洗脱剂中的乙酸乙酯与石油醚的体积用量比为0:100～10:90。或者“二氯甲烷/甲醇＝20：1”表示梯度洗脱过程中，混合洗脱剂中的二氯甲烷与甲醇的体积用量比为20:1。
中间体的制备
中间体3-1的合成：
步骤1：中间体3-002的合成
将3-001(3.70g)溶于100mL二氯甲烷中，加入2,2,2-三氯乙酰胺烯丙酯(7.90g)和三氟甲磺酸(781mg)，25℃搅拌16小时。反应完毕后向反应液中加入200mL二氯甲烷萃取，饱和碳酸氢钠洗涤(50mL*2)。有机相干燥，浓缩得粗产品。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝0％-5％)纯化得中间体3-002(3.60g)。
1H-NMR(400MHz,CDCl3)δ5.98-5.90(m,1H),5.34-5.29(m,1H),5.22-5.18(m,1H),4.03-4.01(m,2H),3.72(s,3H),2.23(s,6H).
步骤2：中间体3-003的合成
将3-002(3.60g)溶于50mL甲醇中，加入10％的Pd/C(700mg)，反应液在氢气环境下(15psi)、25℃搅拌16小时。反应完毕后过滤，滤液减压浓缩得粗产品。粗产品经硅胶柱层析(乙酸乙酯/石油醚＝0％-5％)纯化得中间体3-003(2.30g)。
1H-NMR(400MHz,CDCl3)δ3.62(s,3H),3.33(t,J＝6.8Hz,2H),2.12(s,6H),1.58-1.46(m,2H),0.86(t,J＝7.4Hz,3H).
步骤3：中间体3-004的合成
氮气保护下，将3-003(2.30g)溶于40mL四氢呋喃中，降温至0℃，缓慢滴加四氢铝锂溶液(2.5M,7.49mL)，在25℃搅拌2小时后反应完毕。向反应液中先后加入水(8mL)、15％氢氧化钠溶液(8mL)、水(24mL)，淬灭反应，加入无水硫酸镁干燥，过滤，浓缩后得粗中间体3-004(1.80g)。
步骤4：中间体3-1的合成
氮气保护下，将3-004(1.80g)溶于80mL二氯甲烷中，降温至0℃，分批加入戴斯-马丁氧化剂(7.33g)，在0℃搅拌2小时后反应完毕。过滤，滤液用100mL二氯甲烷稀释，饱和碳酸氢钠(50mL)洗两次，用50mL饱和食盐水洗涤，有机相干燥后浓缩得粗产品。经硅胶柱层析(四氢呋喃/石油醚＝0％-5％)纯化得中间体3-1(1.10g)。
1H-NMR(400MHz,CDCl3)δ9.70(s,1H),3.47-3.38(m,2H),2.19(s,6H),1.65-1.58(m,2H), 0.98-0.91(m,3H).
中间体4-1的合成：
步骤1：中间体4-002的合成
将4-001(15.0g)和N-羟基邻苯二甲酰亚胺(14.4g)溶于500mL二氯甲烷中。0℃条件下加入4-二甲氨基吡啶(1.08g)和N,N'-二异丙基碳二亚胺(13.4g)。25℃搅拌16小时后反应完毕。反应液过滤，滤液浓缩后得粗产品。粗产品经硅胶柱层析法(二氯甲烷/石油醚，梯度0～100％)纯化得中间体4-002(14.4g)。
1H-NMR(400MHz,CDCl3)δ7.98-7.88(m,2H),7.86-7.77(m,2H),3.74(s,3H),2.57(s,6H).
步骤2：中间体4-003的合成
将4-002(8.00g)和对氟碘苯(7.89g)溶于80mL二甲基乙酰胺中，加入锌粉(4.31g),溴化镍乙二醇二甲醚络合物(783mg)和吡啶-2,6-双(甲脒)二盐酸盐(599mg)。反应液在氮气保护下25℃搅拌16小时后反应完毕。加入600mL乙酸乙酯稀释，饱和食盐水洗涤(100mL*4)。有机相用无水硫酸钠干燥，过滤，浓缩后粗产品经硅胶柱层析纯化(梯度：0～5％乙酸乙酯/石油醚)得中间体4-003(1.30g)。
1H-NMR(400MHz,CDCl3)δ7.24-7.11(m,2H),7.08-6.93(m,2H),3.74(s,3H),2.33(s,6H).
步骤3：中间体4-004的合成
在氮气保护下，将4-003(2.20g)溶于25mL四氢呋喃中，0℃条件下缓慢滴加氢化铝锂的四氢呋喃溶液(2.5M,5.99mL)。25℃搅拌16小时后反应完毕。反应液在0℃依次用水(600uL)、15％氢氧化钠水溶液(600uL)和水(1800uL)淬灭,然后加入无水硫酸镁搅拌30分钟。过滤，滤液浓缩得到中间体4-004(1.80g)。
1H-NMR(400MHz,CDCl3)δ7.26-7.15(m,2H),7.06-6.95(m,2H),3.78-3.68(m,2H),2.00(s,6H).
步骤4：中间体4-1的合成
氮气保护下将4-004(1.80g)溶于30mL二氯甲烷中，0℃条件下加入戴斯-马丁氧化剂(5.96g)。反应液在0℃搅拌2小时后反应完毕。向反应液中加入100mL二氯甲烷，用饱和碳酸氢钠水溶液洗涤(50mL*3)。有机相干燥浓缩后得粗产品。粗产品经硅胶柱层析法纯化(梯度：0～5％乙酸乙酯/石油醚)制得中间体4-1(1.78g)。
1H-NMR(400MHz,CDCl3)δ9.70(s,1H),7.25-7.14(m,2H),7.08-6.97(m,2H),2.40-2.26(m,6H).
中间体5-1和中间体6-1的合成：
中间体5-1和中间体6-1的合成参考中间体4-1的合成步骤，不同的是将步骤2中的对氟碘苯分别替换为4-碘吡啶和4-碘苯甲腈。
中间体7-1的合成：
步骤1：中间体7-002的合成：
将7-001(3.00g)溶于30mL四氢呋喃中，氮气保护下降温至-78℃，逐滴缓慢加入DIBAL-H的甲苯溶液(1M,21.3mL)，15分钟滴加完，反应液-78℃搅拌2小时后反应完毕，将反应液升温至0℃，缓慢滴加饱和氯化铵水溶液淬灭，乙酸乙酯(30.0mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗产品经柱层析(二氯甲烷/甲醇＝20：1)纯化制得中间体7-002(1.70g)。
1H-NMR(400MHz,DMSO-d6)δ4.47(t,J＝5.6Hz,1H),3.60-3.52(m,4H),3.46(d,J＝5.6Hz,2H),2.35-2.28(m,4H),1.53(s,6H).
MS m/z(ESI)＝184.20
步骤2：中间体7-1的合成：
在-78℃和氮气氛围下，将二甲基亚砜(1.62g)逐滴缓慢加入草酰氯(1.58g)的二氯甲烷(30mL)溶液中，反应液-78℃搅拌1小时。随后将7-002(1.70g)加入反应液中，反应液-78℃搅拌1小时。将三乙胺(5.25g)缓慢加入反应液中，反应液-78℃搅拌30分钟后反应完毕。升温至0℃，缓慢滴加水淬灭，乙酸乙酯(30.0mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓 缩，粗品经柱层析(二氯甲烷/甲醇＝20/1)纯化制得中间体7-1(1.15g)。
1H-NMR(400MHz,DMSO-d6)δ9.64(s,1H),3.59-3.57(m,4H),2.39-2.33(m,4H),1.93(s,6H).
MS m/z(ESI)＝182.1.
中间体9-1的合成：
步骤1：中间体9-001的合成
将4-001(5.00g)溶于80mL四氢呋喃中，在氮气保护下，0℃缓慢滴加硼烷四氢呋喃溶液(1M,35.26mL)，反应液在25℃搅拌反应16小时后反应结束。于0℃向反应液加入甲醇(80mL)，搅拌30分钟，有机相干燥，浓缩，得粗产品。粗产品经快速硅胶柱层析纯化(梯度：0～20％乙酸乙酯/石油醚)得中间体9-001(4.53g)。
1H NMR(400MHz,Chloroform-d)δ3.61(s,3H),3.56(s,2H),1.93(s,6H).
步骤2：中间体9-002的合成
将9-001(9.50g),对甲苯磺酰氯(13.9g)，三乙胺(7.39g)溶于二氯甲烷(100mL)溶液中，反应液在25℃搅拌反应16小时后反应结束，反应液浓缩后经硅胶柱层析法纯化(梯度：0～20％乙酸乙酯/石油醚)得中间体9-002(15.6g)。
1H-NMR(400MHz,Chloroform-d)δ7.79(d,J＝8.1Hz,2H),7.36(d,J＝7.9Hz,2H),4.04(s,2H),3.67(s,3H),2.47(s,3H),1.99(s,6H)
MS m/z(ESI):＝311.0[M+H]+
步骤3：中间体9-003的合成
在氮气保护下，将9-002(15.0g)溶于200mL四氢呋喃中,0℃缓慢滴加氢化锂铝的四氢呋喃溶液(2.5M,38.66mL)。反应液在25℃搅拌反应16小时后反应结束，向反应液依次加入水(3.7mL)、15％氢氧化钠水溶液(3.7mL)、水(11.1mL)，搅拌10min，加入无水硫酸镁干燥，过滤，滤液浓缩，得粗产品。粗产品经硅胶柱层析法纯化(梯度：0～10％乙酸乙酯/石油醚)得中间体9-003(3.14g)。
1H-NMR(400MHz,Chloroform-d)δ3.58(s,2H),1.59(s,6H),1.19(s,3H).
步骤4：中间体9-1的合成
在氮气保护下，将草酰氯(4.41g)溶于15mL二氯甲烷中，-78℃缓慢滴加二甲基亚砜(5.43g)的二氯甲烷(5mL)溶液，-78℃搅拌30分钟，然后缓慢滴加9-003(2.60g)的二氯甲烷(5mL)溶液，-78℃搅拌30分钟，最后缓慢滴加三乙胺(14.1g)的二氯甲烷(20mL)溶液，反应液在25℃搅拌反应16小时后反应结束，反应液用饱和食盐水(50mL)洗涤一次，浓缩至50mL，得中间体9-1，直接用于下一步反应。
中间体10-1的合成：
步骤1：中间体10-001的合成：
在氮气保护下，将9-001(9.00g)溶于100mL二氯甲烷中，0℃将二乙氨基三氟化硫(18.5g)缓慢滴加到反应液中。反应液在25℃搅拌反应16小时后反应结束。将反应液缓慢倒入搅拌中带有碎冰的饱和碳酸氢钠(100mL)溶液，搅拌后溶液用二氯甲烷(20mL*3)萃取,用饱和食盐水(20mL*3)洗涤，合并有机相，有机相干燥，浓缩，得粗产品。粗产品经硅胶柱层析法纯(梯度：0～3％四氢呋喃/石油醚)制得中间体10-001(9.05g)。
1H NMR(400MHz,Chloroform-d)δ4.46(s,1H),4.34(s,1H),3.70(s,3H),2.09(s,6H)
步骤2：中间体10-002的合成：
在氮气保护下，将10-001(5.00g)溶于100mL四氢呋喃中，在0℃缓慢滴加氢化铝锂(2.5M,18.97mL)。反应液在25℃搅拌16小时。TLC(石油醚:乙酸乙酯＝3:1,高锰酸钾显色)监测反应完成。反应液在0℃依次用H2O(2mL)、15％ NaOH(6mL)和H2O(2mL)淬灭,然后加入无水硫酸镁搅拌30分钟。过滤，滤液浓缩得到中间体10-002(3.70g)。
1H NMR:(400MHz,Chloroform-d)δ4.44(s,1H),4.32(s,1H),3.63(s,2H),1.73(s,6H).
步骤3：中间体10-1的合成：
在氮气保护下，将草酰氯(5.41g)溶于40mL二氯甲烷中，在-78℃下缓慢滴加DMSO(6.66g)的二氯甲烷(20mL)溶液，反应液在-78℃搅拌0.5小时。然后缓慢滴加10-002(3.70g)的二氯甲烷(20mL)溶液，滴加完毕后反应液在-78℃搅拌1小时。再缓慢滴加三乙胺(17.3g)的二氯甲烷(20mL)溶液。反应液缓慢升至室温，在室温下搅拌16小时。TLC(石油醚:乙酸乙酯＝4:1,高锰酸钾显色)监测反应完成。反应液用饱和食盐水(20mL)洗涤，有机相干燥浓缩，得中间体10-1，直接用于下一步反应。
中间体11-1的合成：
步骤1：中间体11-002的合成
在氮气保护下，将11-001(3.00g)溶于四氢呋喃(50mL)中，在0℃下缓慢加入氘代氢化锂铝(1.70g)。反应液在25℃搅拌16小时。TLC(石油醚:乙酸乙酯＝2:1,高锰酸钾显色)监测反应完成。反应液在0℃依次用H2O(1.5mL),15％ NaOH水溶液(1.5mL)和H2O(4.5mL)淬灭,然后加入无水硫酸镁搅拌30分钟。过滤，滤液浓缩得到中间体11-002(2.6g)。
1H NMR(400MHz,Chloroform-d)δ2.56(s,1H),1.81-1.73(m,6H).
步骤2：中间体11-1的合成
在氮气保护下，将草酰氯(5.04g)溶于二氯甲烷(30mL)中，在-78℃下缓慢滴加DMSO(6.21g)的二氯甲烷(10mL)溶液。反应液在-78℃搅拌0.5小时。然后缓慢滴加11-002(2.60g)的二氯甲烷(20mL)溶液，滴加完毕后反应液在-78℃搅拌1小时。再缓慢滴加三乙胺(16.08g)的二氯甲烷(20mL)溶液。反应液缓慢升至室温，在室温下搅拌16小时。TLC(石油醚:乙酸乙酯＝2:1,高锰酸钾显色)监测反应完成。反应液用饱和食盐水(20mL)洗涤，有机相干燥，制得中间体11-1(2.50g)，直接用于下步反应。
中间体13-1的合成：
步骤1：中间体13-002的合成
氮气保护下将13-001(10.0g)和草酰氯(15.1g)溶于100mL二氯甲烷中，0℃条件下缓慢滴加N,N-二甲基甲酰胺(200mg)，在25℃反应液搅拌6小时后反应完毕。将有机相浓缩后制得粗中间体13-002(11.0g)，直接用于下一步反应。
步骤2：中间体13-003的合成
在氮气保护下，将吡啶硫酮钠(11.0g)、偶氮二异丁腈(581mg)和4-二甲氨基吡啶(144mg)溶于100mL四氯化碳中。在80℃搅拌1小时，随后，缓慢滴加13-002(11.1g,59.00mmol in 50mL CCl4)溶液。80℃搅拌6小时后反应完毕。加入100mL水淬灭反应，用50mL二氯甲烷稀释，分液后水相用二氯甲烷(100mL*2)萃取两次，合并有机相，有机相干燥，浓缩，得粗产品。粗产品经硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得中间体13-003(8.00g)。
步骤3：中间体13-004的合成
在氮气保护下，将13-003(1.00g)溶于10mL四氢呋喃中，将反应液冷却至0℃。缓慢滴加四氢铝锂的四氢呋喃溶液(2.5M,2.5mL)。在0℃反应液搅拌3小时后反应完毕。加入10mL水淬灭反应，加10mL乙酸乙酯稀释，分层，水相用乙酸乙酯(30mL*2)萃取两次，合并有机相，用30mL饱和食盐水洗涤，有机相干燥，浓缩，制得800mg粗中间体13-004，直接用于下一步。
步骤4：中间体13-1的合成
在氮气保护下，将草酰氯(1.15g)溶于20mL二氯甲烷中，将反应液冷却至-78℃，缓慢滴加二甲基亚砜(1.41g)，搅拌30分钟。然后缓慢滴加13-004(800mg)，于-78℃搅拌1小时后滴加三乙胺(3.66g)并升温至25℃，在25℃反应液搅拌4小时后反应完毕。加入10mL水淬灭反应，分层，水相用10mL二氯甲烷萃取两次，合并有机相，用饱和食盐水洗涤，有机相干燥后制得788mg中间体13-1，直接用于下一步反应。
实施例1：(R)-1-(1H-苯并[d]咪唑-5-基)-4-(双环[1.1.1]戊烷-1-基)氮杂环丁烷-2-酮
步骤1：中间体1-2的合成
在氮气保护下，将化合物1-1(2.50g)、(S)-叔丁基亚磺酰胺(3.15g)和钛酸四异丙酯(14.78g)溶于100mL二氯甲烷中，反应液在25℃搅拌反应16小时。反应结束后，加入饱和碳酸氢钠水溶液(100mL)搅拌，过滤固体后使用乙酸乙酯(100mL*2)萃取，有机相干燥，浓缩，得粗产品。粗产品经硅胶柱层析纯化(梯度：0～10％乙酸乙酯/石油醚)制得中间体1-2(2.60g)。
1H-NMR(400MHz,CDCl3)δ7.98-7.90(m,1H),2.62-2.53(m,1H),2.08(s,6H),1.23-1.18(m,9H).
步骤2：中间体1-3的合成
在氮气保护下，将锌粉(5.12g)溶于50mL四氢呋喃中，向其中加入三甲基氯硅烷(425mg)，反应液在25℃搅拌30分钟。将反应液温度升至40℃，向其中缓慢滴加溴乙酸乙酯(6.54g)，在40℃搅拌反应1小时后制得乙酸乙酯溴化锌。将中间体1-2(2.60g)溶于50mL四氢呋喃中,25℃条件下缓慢滴加乙酸乙酯溴化锌，25℃搅拌1小时后反应完毕。反应液用100mL饱和氯化铵溶液淬灭,乙酸乙酯萃取(100mL*3),有机相用无水硫酸钠干燥，过滤，浓缩后粗产品经硅胶柱层析纯化(梯度：0～25％乙酸乙酯/石油醚)得中间体1-3(3.70g)。
1H-NMR(400MHz,CDCl3)δ4.20-4.12(m,3H),3.65-3.60(m,1H),2.73-2.63(m,1H),2.61-2.48(m,2H),1.73-1.70(m,6H),1.30-1.27(m,3H),1.24(s,9H).
步骤3：中间体1-4的合成
将中间体1-3(1.80g)溶于氯化氢的甲醇溶液(4M，40mL)中，反应液在25℃搅拌16小时。LCMS显示反应完毕。将反应液浓缩，残留物用水溶解(40mL)，然后用乙酸乙酯萃取(40mL*3)。水相用饱和的碳酸氢钠溶液调节pH至7～8，再用乙酸乙酯萃取(50mL*4)。有机相合并，用无水硫酸钠干燥，过滤，浓缩后制得中间体1-4(1.20g)。
1H-NMR(400MHz,CDCl3)δ3.71(s,3H),3.25-3.24(m,1H),2.58-2.43(m,2H),2.27-2.23(m,1H),1.73-1.66(m,6H).
步骤4：中间体1-5的合成
在氮气保护下，将中间体1-4(150mg)溶于1.5mL四氢呋喃中，-78℃缓慢滴加二异丙基氨基锂的THF溶液(2M,2.46mL)，5分钟滴加完毕。-78℃搅拌10小时后反应完毕。用5mL饱和氯化铵水溶液淬灭反应，反应液用乙酸乙酯(20mL*2)萃取两次，合并有机相，有机相经无水硫酸钠干燥，过滤，浓缩后粗产品经硅胶柱层析纯化(石油醚:乙酸乙酯＝2:1)制得中间体1-5(40.0mg)。
1H-NMR(400MHz,CDCl3)δ5.82(s,1H),3.68-3.62(m,1H),2.98-2.93(m,1H),2.71-2.63(m,1H),2.62-2.57(m,1H),1.82-1.72(m,6H).
步骤5：中间体1-6的合成
在氮气保护下，将中间体1-5(40.0mg)溶于2mL二氧六环中，加入2-[(5-碘苯并咪唑-1-基)甲氧基]乙基三甲基硅烷(120mg,)、碘化亚铜(22.2mg)、反-(1R,2R)-N,N’-二甲基1,2-环己烷二胺(16.6mg)和磷酸钾(185mg)，升温至80℃搅拌2小时。反应完毕后向反应液中加入水(20mL)和乙酸乙酯(10mL)萃取，有机相用饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤， 浓缩后粗产品经硅胶柱层析法纯化(梯度：0～30％四氢呋喃/石油醚)制得中间体1-6(110mg)。
MS m/z(ESI):＝384.1[M+H]+。
步骤6：化合物1的合成
将中间体1-6(140mg)溶于四丁基氟化铵(1.85mL,1M in THF)中，60℃搅拌2小时后反应完毕。将反应液减压浓缩。粗产品加入50mL乙酸乙酯，然后分别用水(10mL*4)和饱和食盐水(10mL)洗涤。有机相经无水硫酸钠干燥，过滤，浓缩后粗产品经制备高效液相色谱法(色谱柱:Phenomenex Gemini NX，150×30mm，5μm；流动相：[A相：水(0.05％氨水v/v)；B相：乙腈]；梯度洗脱：流动相B从17％到57％)纯化制得化合物1(18.1mg)。
1H-NMR(400MHz,CDCl3)δ8.03(s,1H),7.79(d,J＝1.9Hz,1H),7.64(d,J＝8.7Hz,1H),7.34-7.11(m,1H),4.19-4.13(m,1H),3.18-3.04(m,1H),2.84-2.72(m,1H),2.53(s,1H),1.80(s,6H).
1H-NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.17(s,1H),7.60-7.51(m,2H),7.24(d,J＝8.4Hz,1H),4.30-4.24(m,1H),3.15-3.04(m,1H),2.84-2.68(m,1H),2.49(s,1H),1.74(s,6H).
MS m/z(ESI):＝254.1[M+H]+。
参考实施例1的合成方法，用下表中的起始物料替换化合物1-1，合成如下化合物：


实施例14：(R)-4-(双环[1.1.1]戊烷-1-基)-1-(咪唑并[1,2-a]吡啶-7-基)氮杂环丁烷-2-酮
在氮气保护下，将中间体1-5(50.0mg)溶于2mL二氧六环中，加入7-碘咪唑并[1,2-a]吡啶(97.0mg)、碘化亚铜(27.7mg)、(1R,2R)-N,N’-二甲基1,2-环己烷二胺(20.7mg)和磷酸钾(232mg)，升温至80℃搅拌2小时。反应完毕后向反应液中加入水(20mL)和乙酸乙酯(10mL)萃取，有机相用饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤，浓缩得粗产品，经制备高效液相色谱法(Phenomenex Gemini NX，150×30mm,5μm；流动相:[A相：水(0.5％氨水v/v)；B相：乙腈]；梯度洗脱：流动相B从12％到52％)纯化得化合物14(33.8mg)。
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.00-7.50(m,2H),7.24-7.15(m,2H),4.34-4.33(m,1H),3.21-3.16(m,1H),2.84-2.80(m,1H),2.50(s,1H),1.79(s,6H).
MS m/z(ESI):254.2[M+H]+.
实施例15：(R)-1-(1H-苯并[d]咪唑-6-基)-4-(双环[1.1.1]戊烷-1-基)-3-甲基氮杂环丁烷-2-酮
步骤1：中间体15-1的合成
在氮气氛围下，将中间体1-6(600mg)溶于10mL四氢呋喃中，-78℃缓慢滴加LDA(1.17mL,2M in THF)，滴毕后反应液在-78℃搅拌1小时。随后向反应液中滴加碘甲烷(244mg)，-78℃搅拌1小时后反应完全。反应液用饱和氯化铵水溶液淬灭,水相用乙酸乙酯(10mL*3)萃取，合并有机相，用饱和食盐水(10mL)洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，残留物经柱层析纯化(二氯甲烷/甲醇梯度洗脱)制得中间体15-1(50mg)。
MS m/z(ESI):398.30[M+H]+.
步骤2：化合物15的合成
氮气氛围下将中间体15-1(50.0mg)溶解于四丁基氟化铵的四氢呋喃溶液(5.0mL,1M)中，反应液在60℃搅拌1小时后反应完毕。反应液减压浓缩,残留物经制备高效液相色谱法(Phenomenex Gemini NX，150×30mm,5μm；流动相:[A相：水(0.5％氨水v/v)；B相：乙腈]；梯度洗脱：流动相B从50％到80％)纯化制得标题化合物15(15.0mg)。
MS m/z(ESI):268.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.61-7.51(m,2H),7.23(d,J＝8.7Hz,1H),3.90(d,J＝2.2Hz,1H),3.08-2.98(m,1H),1.76(s,6H),1.25(d,J＝7.6Hz,3H).
实施例16：(S)-2-(1H-苯并[d]咪唑-5-基)-3-(双环[1.1.1]戊烷-1-基)-2-氮杂螺[3.3]庚烷-1-酮的合成
参考实施例1的合成方法，不同的是将步骤2中的溴乙酸乙酯替换为1-溴环丁烷-1-甲酸甲酯，同法制得标题化合物16。
MS m/z(ESI):294.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.60-7.49(m,2H),7.21(d,J＝8.6Hz,1H),4.08(s,1H),2.59-2.52(m,1H),2.46(s,1H),2.42-2.32(m,1H),2.27-2.16(m,2H),2.06-1.97(m,1H),1.94-1.69(m,7H).
实施例17:(R)-4-(双环[1.1.1]戊烷-1-基)-1-(2-甲基-1H-苯并[d]咪唑-5-基)氮杂环丁烷-2-酮
步骤1：中间体17-2的合成：
将中间体17-1(3.00g)溶于30mL N,N-二甲基甲酰胺中，置于冰水浴中，缓慢加入氢化钠(60％in oil,522mg)。搅拌1小时后缓慢滴加2-(三甲基硅烷基)乙氧甲基氯(2.27g)。25℃下搅拌2小时后反应完毕。用30mL饱和氯化铵水溶液淬灭反应，用30mL乙酸乙酯稀释，分层，水相用乙酸乙酯萃取两次，合并有机相，有机相干燥，浓缩，得粗产品。粗产品经硅胶柱(石油醚/乙酸乙酯＝1/1)纯化得3.00g中间体17-2。
步骤2和步骤3参考实施例1的步骤5和步骤6的合成方法，不同的是将步骤5中的2-[(5-碘苯并咪唑-1-基)甲氧基]乙基三甲基硅烷替换为17-2，同法制得标题化合物17。
1H-NMR(400MHz,DMSO-d6)δ12.16(s,1H),7.45-7.37(m,2H),7.15(d,J＝8.7Hz,1H),4.28-4.21(m,1H),3.10-3.05(m,1H),2.76-2.71(m,1H),2.50-2.47(m,4H),1.73(s,6H).
MS m/z(ESI):＝268.2[M+H]+。
实施例18:(4S)-1-(1H-苯并[d]咪唑-6-基)-4-(双环[1.1.1]戊烷-1-基)-3-氟氮杂环丁烷-2-酮的合成
步骤1：18-1的合成
在氮气保护下，将中间体1-6(500mg)溶于10mL四氢呋喃中，-70℃氮气保护下缓慢滴加LDA(2M in THF,2mL)并在该温度下反应液搅拌30分钟。缓慢滴加N-氟代双苯磺酰胺(492mg)的THF(2ml)溶液，-70℃搅拌1小时后反应完毕。用20mL饱和氯化铵水溶液淬灭，乙酸乙酯稀释，分层，水相用乙酸乙酯萃取两次，合并有机相，有机相干燥，浓缩，得粗产 品。粗产品经硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化制得中间体18-1(170mg)。
MS m/z(ESI):＝402.30[M+H]+
步骤2：化合物18的合成
在氮气保护下，将18-1(50.0mg)溶于四丁基氟化铵溶液(1M in THF,1.25mL)中，60℃搅拌2小时后反应完毕。将反应液浓缩，浓缩液经硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化制得标题化合物18(15.0mg)。
1H-NMR(400MHz,Methanol-d4)δ8.19(s,1H),7.68(d,J＝1.9Hz,1H),7.63(d,J＝8.6Hz,1H),7.38(s,1H),5.42(dd,J＝55.1,1.4Hz,1H),4.41(dd,J＝12.1,1.3Hz,1H),3.30(t,J＝1.7Hz,6H),2.50(s,1H)；
19F-NMR(376MHz,Methanol-d4)δ-198.82.
MS m/z(ESI):＝272.10[M+H]+
生物学活性及相关性质测试
下述实验例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
实验例1：本公开实施例人QPCT/QPCTL酶活性抑制实验
采用Green Glutaminyl Cyclase Activity Assay Kit检测化合物对人QPCT/QPCTL酶活性的抑制。
1.实验试剂、耗材及仪器
2.实验方法:
0.5mM QPCT酶底物用缓冲液按照1:100稀释至5μM；50μg/mL QPCT酶用缓冲液稀释至125ng/mL，置于冰上待用；QPCT developer用缓冲液按1:250稀释，置于冰上待用(QPCT 酶底物、QPCT酶、缓冲液和QPCT developer均来源于试剂盒内)；待测化合物工作液起始浓度200μM，6倍梯度稀释，共7个浓度点。在75μL反应体系中待测化合物起始工作浓度为13.3μM,DMSO终浓度为0.3％。
在384孔板中每孔依次加入配制好的20μL QPCT酶溶液，5μL待测化合物和25μL QPCT酶底物，微孔板震荡仪混匀1分钟，在400g离心1分钟，37℃孵育30分钟。随后每孔加入25μL QPCT developer，震荡仪混匀1分钟，在400g离心1分钟；37℃继续孵育60分钟。孵育结束后，酶标仪读取荧光值，参数设置：Ex/Em＝490nm/520nm。化合物对QPCT酶活力抑制率计算公式为:抑制率(inhibition％)＝(RFUno treatment-RFUtreated)÷(RFUno treatment-RFUbackground)×100％。采用GraphPad Prism 9软件，以化合物浓度(nM)为横坐标，酶活抑制率(％)为纵坐标，绘制曲线并进行四参数拟合，计算化合物对QPCT酶活力抑制的IC50。具体结果见表1。
对Green Glutaminyl Cyclase Activity Assay Kit进行适当调整，将其中的QPCT酶替换为人QPCTL酶(义翘神州，货号NXS6-1)(工作液浓度保持不变)，用于检测化合物抑制人QPCTL酶活的IC50。其余实验试剂、仪器、工作液配制和操作步骤及数据处理方式均与人QPCT酶活检测方法相同。具体结果见表1。
表1本公开化合物对人QPCT/QPCTL酶抑制活性测试结果

“-”表示未检测
实验例2:本公开化合物的膜渗透性及转运特性测定
本公开化合物的膜渗透性及转运特性采用如下试验方法测定。
试验步骤如下：
1.MDCKII-MDR1(来源：Netherlands Cancer institute)细胞培养
1)转运缓冲液(含25mM HEPES的Hanks平衡盐溶液，pH 7.4)的配制：精确称量5.958g 4-羟乙基哌嗪乙磺酸和0.35g NaHCO3，加900mL纯水使其溶解，然后加100mL 10×HBSS搅拌均匀，调pH至7.4，过滤。
2)MDCKII-MDR1细胞培养基的配制：MEM培养基(来源：Gibco)中加入10％ FBS、1％Pen Strep Liquid(来源：Gibco)、1％ GlutaMAXTM-I(来源：Gibco)以及400μg/mL G418(来源：Solarbio)。
3)在37℃、5％ CO2的培养箱中用T-75培养瓶培养细胞，细胞生长达到80-90％密度时弃去培养基。用5mL PBS冲洗细胞，加入1.5mL Trypsin/EDTA(来源：Gibco)，然后在37℃培养箱中孵育5-10分钟直至细胞呈流沙状脱落，最后用含FBS的培养基中和Trypsin/EDTA。
4)细胞混悬液在120x g下离心10分钟，弃去上清液。
5)加步骤2中的细胞传代培养基重悬细胞，调至密度为1.56×106cells/mL的细胞悬浮液。
2.MDCKII-MDR1细胞接种
1)Transwell(来源：Corning Corporation)小室每孔加入75μL培养基，下层加入25mL培养基，置于37℃，5％ CO2培养箱中预热1小时。
2)预热的Transwell小室每孔加入50μL细胞悬浮液，最终接种密度为5.45×105cells/cm2。
3)培养4-8天，隔一天换一次培养基，在最初种板以后的24小时之内更换培养基。实验前一天培养基必须更换。
3.评估单层细胞膜完整性
1)细胞培养4-8天后融合并且分化，准备进行转运实验。
2)用电阻仪测量单层膜电阻，记录每孔电阻。
3)测量完毕后，将Transwell培养板重新孵育。
4)计算TEER值：
TEER值＝TEER(Ω)测量值×膜面积(cm2)
单层细胞膜的电阻<42Ω·cm2，指示单层细胞膜致密性差，不能用于试验。
4.转运实验
1)用DMSO稀释10mM的本公开化合物或阳性对照化合物(美托洛尔、哌唑嗪、伊马替尼)的储备液得到0.2mM的储备液，然后用转运缓冲液稀释0.2mM的储备液得到1μM的本公开化合物或阳性对照化合物的工作液。
2)从培养箱中取出MDCKII-MDR1细胞板，然后用预热的转运缓冲液清洗Transwell培养板两次，再置于37℃培养箱孵育30分钟。
3)为测定化合物从顶端到基底端(A→B)的转运速率，加125μL化合物的工作液到Transwell小室(顶端)，同时立即从顶端取出50μL样品加入200μL含内标的终止液终止转运以作为初始顶端样品。同时，接收端(基底端)加入235μL转运缓冲液。试验设双样本。
4)为测定化合物从基底端到顶端(B→A)的转运速率，加285μL化合物的工作液到接收端(基底端)，同时立即从基底端取出50μL样品加入200μL含内标的终止液终止转运以作为初始基底端样品。同时，Transwell小室(顶端)加入75μL转运缓冲液。试验设双样本。
5)将细胞培养板置于37℃、CO2培养箱中孵育2小时。
6)转运实验结束后，从给药端(即A→B方向的顶端和B→A方向的基底端)取50μL样品，然后加入200μL含内标的终止液终止转运。从接收端(即A→B方向的基底端和B→A方向的顶端)取50μL样品至200μL含内标的终止液中，1000rpm下涡旋10分钟，3,220g下离心30分钟。取100μl上清液至进样板，加入100μL超纯水混匀，用于LC-MS/MS分析。
7)转运实验结束后测量荧光值，用水配制10mM荧光黄(来源：Sigma)储备液，然后用转运缓冲溶液稀释至100μM。往Transwell小室(顶端)中加入100μL荧光黄溶液，基底端加入300μL转运缓冲溶液，置于37℃的CO2培养箱中孵育30分钟。从基底端取80μL溶液至96孔板中，在激发波长为485nm及发射波长为530nm下用酶标仪(200PRO多功能酶标仪)测量细胞荧光值(检测膜完整性)。
用以下公式计算MDCKII-MDR1细胞单层膜的荧光渗漏值(Leakage(％)或LY(％))：
LY(％)＝{Iacceptor×0.3/(Iacceptor×0.3+Idonor×0.1)}×100％
Iacceptor指接收侧(0.3mL)的荧光密度，Idonor指给药侧(0.1mL)的荧光密度。LY％>1.0％表示单层细胞膜致密性差，相应的结果将从评估中排除。
测定化合物在给药侧和接收侧的峰面积。计算化合物的表观渗透系数(Papp，单位：cm/s)和外排比(Efflux ratio,ER)：
Papp＝{VA×[drug]acceptor/(Area×incubation time×[drug]initial dono}
VA为接收端溶液的体积(A→B是0.235mL，B→A是0.075mL)，Area为Transwell-96孔板膜面积(0.143cm2)；incubation time为孵育时间(单位：s)。
Papp(B-A)为由基底端到顶端的表观渗透系数；Papp(A-B)为由顶端到基底端的表观渗透系数。
计算得到的本公开化合物的表观渗透系数和外排比见表2。
表2本公开化合物的表观渗透系数和外排比

实验例3:发明化合物对CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4酶活性的抑制作用
本公开化合物对CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4酶活性的抑制采用如下试验方法测定。
试验步骤如下：
1.100mM磷酸缓冲液(PBS)的配制：称取7.098g Na2HPO4，加入500mL纯水超声溶解，作为溶液A。称取3.400g KH2PO4，加入250mL纯水超声溶解，作为溶液B。将A溶液放置在搅拌器上缓慢加入B溶液直到pH值达到7.4配制成100mM的PBS缓冲液。
2.用100mM的PBS缓冲液配制10mM的NADPH溶液。用DMSO稀释10mM的本公开化合物储备液得到200×浓度的化合物工作液(10000、3333.3、1111.1、370.37、123.46、41.15、13.7、0μM)。用DMSO稀释阳性抑制剂储备液得到200×浓度的阳性抑制剂工作液(磺胺苯吡唑，1000、300、100、30、10、3、0μM；奎尼丁/酮康唑，100、30、10、3、1、0.3、0μM；α-萘黄酮，50、15、5、1.5、0.5、0.15、0μM；诺卡酮，6000、1800、600、180、60、18、0μM)。用水、乙腈或乙腈/甲醇配制200×浓度的底物工作液(8000μM非那西汀、1000μM双氯芬酸、8000μM S-美芬妥因、1000μM右美沙芬和400μM咪达唑仑)。
3.取1μl 20mg/ml的肝微粒体溶液、1μl底物工作液、1μl化合物工作液和177μl PBS缓冲液，混合均匀，置于37℃水浴中预孵育10分钟。阳性对照组加入1μl阳性抑制剂工作液代替化合物工作液。同时将10mM的NADPH溶液一起在37℃水浴中预孵育10分钟。10分钟后，取20μl NADPH加入到各个孔中，启动反应，37℃下孵育15分钟(CYP1A2)、15分钟(CYP2C9)、60分钟(CYP2C19)、15分钟(CYP2D6)或15分钟(CYP3A4)。所有孵育样品设双样本。孵育相应时间后向所有样本中加入400ul含内标的冰甲醇终止反应。涡旋混匀，4000rpm、4℃离心30分钟。离心结束后转移100μL上清液到进样板，加入200μL超纯水混匀，用于LC-MS/MS分析。
数值经Excel XLfit 5.3.1.3计算得到本公开化合物对CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4的IC50值见表3。
表3本公开化合物对CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4的IC50值

“-”表示未检测
实验例4本公开化合物在肝微粒体中的代谢稳定性测定
试验步骤如下：
1.100mM磷酸缓冲液(PBS)的配制：称取7.098g Na2HPO4，加入500mL纯水超声溶解，作为溶液A。称取3.400g KH2PO4，加入250mL纯水超声溶解，作为溶液B。将A溶液放置在搅拌器上缓慢加入B溶液直到pH值达到7.4配制成100mM的PBS缓冲液。
2.反应体系的配制
按下表配制反应体系
3.将反应体系置于37℃水浴中预孵育10分钟。向反应体系中加入20μL 10mM NADPH溶液(NADPH由100mM的磷酸缓冲液溶解)，NADPH的最终浓度为1mM。用20μL磷酸缓冲液代替NADPH溶液作为阴性对照。阴性对照的作用是排除化合物自身化学稳定性的影响。
4.在反应体系中加入2μL 100μM的本公开化合物和阳性对照化合物维拉帕米启动反应，化合物的最终浓度为1μM。
5.在0.5、15、30、45和60分钟，分别取出25μL孵育样品，用4倍的含有内标的冰乙 腈溶液终止反应。样品在4000rpm转速下离心15分钟。离心结束后转移50μL上清液到进样板，加入150μL超纯水混匀，用于LC-MS/MS分析。
所有的数据均通过Microsoft Excel软件进行计算。通过提取离子图谱得到峰面积。通过对母药消除百分比的自然对数与时间进行线性拟合，检测母药的体外半衰期(t1/2)。
体外半衰期(t1/2)通过斜率(k)计算：
in vitro t1/2＝0.693/k
经上述公式计算得到的t1/2值见表4。
表4本公开化合物在不同种属肝微粒体中的半衰期(t1/2，分钟)

“-”表示未检测

Claims (15)

  1. 式(A-I)化合物或其立体异构体或其药学上可接受的盐，
    其中，
    环A选自所述任选地被R5取代；
    R5选自D、卤素、CN、NH2、OH、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基、C1-C6卤代烷基或C1-C6氘代烷基；
    环B选自
    R1选自H、卤素、OH、NH2、SH、CN、C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、5-10元杂芳基、C3-C6环烷基或4-10元杂环基，所述OH、NH2、SH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、5-10元杂芳基、C3-C6环烷基或4-10元杂环基任选地被R1a取代；
    R1a选自卤素、CN、OH、NH2或C1-C6烷基，所述OH、NH2或C1-C6烷基任选地被R1b取代；
    R1b选自卤素或C1-C6烷基；
    R2选自H、D或C1-C6烷基；
    R3和R4独立地选自H、D、卤素、OH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基或4-7元杂环基，所述OH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、4-7元杂环基任选地被R3a取代；或者R3、R4与其相连的原子共同形成C3-C6环烷基或4-7元杂环基，所述C3-C6环烷基或4-7元杂环基任选地被R3a取代；
    R3a选自D、卤素、OH或C1-C6烷基。
  2. 如权利要求1所述的化合物或其立体异构体或其药学上可接受的盐，其中，R1选自H、卤素、OH、NH2、C1-C6烷基、苯基、5-6元杂芳基或4-7元杂环基，所述OH、NH2、C1- C6烷基、苯基、5-6元杂芳基或4-7元杂环基任选地被R1a取代；
    或者，R1选自H、卤素、OH、NH2、C1-C6烷基、苯基、吡啶基或吗啉基，所述OH、NH2、C1-C6烷基、苯基、吡啶基或吗啉基任选地被R1a取代；
    或者，R1选自H、F、Cl、OH、NH2、CH3、所述OH、NH2、CH3、任选地被R1a取代；
    或者，R1选自H、F、CH3、CH2F、Cl或OCH3。
  3. 如权利要求1或2所述的化合物或其立体异构体或其药学上可接受的盐，其中，R1a选自卤素、CN或C1-C6烷基。
  4. 如权利要求1-3任一项所述的化合物或其立体异构体或其药学上可接受的盐，其中，
    R2选自H或D。
  5. 如权利要求1-4任一项所述的化合物或其立体异构体或其药学上可接受的盐，其中，R3和R4独立地选自H、卤素或C1-C6烷基，或者R3和R4与其相连的原子共同形成C3-C6环烷基，所述C1-C6烷基和C3-C6环烷基任选地被R3a取代；
    或者，R3和R4独立地选自H、F或甲基，或者R3和R4与其相连的原子共同形成环丁基；
    或者，R3和R4均为H。
  6. 如权利要求1-5任一项所述的化合物或其立体异构体或其药学上可接受的盐，其中，
    R5为CH3。
  7. 如权利要求1-6任一项所述的化合物或其立体异构体或其药学上可接受的盐，其中，所述式(A-I)化合物选自式(I)化合物或其立体异构体或其药学上可接受的盐：
    其中环A、环B和R2如权利要求1-6任一项中所定义。
  8. 如权利要求7所述的化合物或其立体异构体或其药学上可接受的盐，其中，
    所述式(A-I)化合物选自式(II)化合物或其立体异构体或其药学上可接受的盐：
    (II)其中R1和R2如权利要求1-6任一项中所定义。
  9. 如权利要求8所述的化合物或其立体异构体或其药学上可接受的盐，其中，
    所述式(A-I)化合物选自式(II-1)化合物或其立体异构体或其药学上可接受的盐：
    其中R1和R2如权利要求1-6任一项中定义。
  10. 如权利要求7所述的化合物或其立体异构体或其药学上可接受的盐，其中，所述式(A-I)化合物选自式(III)化合物或其立体异构体或其药学上可接受的盐：
    其中R1和R2如权利要求1-6任一项中定义。
  11. 如权利要求10所述的化合物或其立体异构体或其药学上可接受的盐，其中，所述式(A-I)化合物选自式(III-1)化合物或其立体异构体或其药学上可接受的盐：
    其中R1和R2如权利要求1-6任一项中定义。
  12. 如权利要求1～6任一项所述的化合物或其立体异构体或其药学上可接受的盐，其中，式(A-I)化合物选自如下化合物或其立体异构体或其药学上可接受的盐：

  13. 药物组合物，其中，所述的药物组合物包含权利要求1～12中任一项所述的式(I)化合物或其立体异构体或其药学上可接受的盐，以及任选的药学上可接受的辅料。
  14. 用于治疗或者预防有需要的对象的由QPCT和/或QPCTL介导的疾病或病症的权利要求1-12中任一项所述的式(I)化合物或其立体异构体或其药学上可接受的盐或权利要求13所述的药物组合物。
  15. 如权利要求14所述的式(I)化合物或其立体异构体或其药学上可接受的盐或药物组合物，其中，所述由QPCT和/或QPCTL介导的疾病或病症为神经退行性疾病，优选阿尔茨海默病。
PCT/CN2024/121304 2023-09-27 2024-09-26 作为谷氨酰胺环化酶抑制剂的化合物 Pending WO2025067298A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111315738A (zh) * 2017-09-29 2020-06-19 维沃永治疗股份公司 谷氨酰胺酰环化酶的抑制剂
WO2022268179A1 (en) * 2021-06-24 2022-12-29 Insilico Medicine Ip Limited Beta-lactam derivatives for the treatment of diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111315738A (zh) * 2017-09-29 2020-06-19 维沃永治疗股份公司 谷氨酰胺酰环化酶的抑制剂
WO2022268179A1 (en) * 2021-06-24 2022-12-29 Insilico Medicine Ip Limited Beta-lactam derivatives for the treatment of diseases

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