Compounds as glutamine cyclase inhibitors

Abstract

Compounds of Formula (A-I) or stereoisomers or pharmaceutically acceptable salts thereof as glutamine cyclase inhibitors, processes for their preparation, pharmaceutical compositions containing the compounds of Formula (A-I) or stereoisomers or pharmaceutically acceptable salts thereof, and the Formula (A-I) The invention relates to a use of a compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the prevention or treatment of QPCT and / or QPCTL mediated diseases or conditions including neurodegenerative diseases.

Description

Compounds as glutamine cyclase inhibitors

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202311273882.4 filed with the State Intellectual Property Office of China on September 27, 2023 and Chinese Patent Application No. 202311736403.8 filed with the State Intellectual Property Office of China on December 15, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure belongs to the field of medical technology, and particularly relates to compounds that serve as glutamine cyclase inhibitors, methods for preparing the compounds, pharmaceutical compositions containing the compounds, and uses thereof in preventing or treating diseases or conditions mediated by QPCT and / or QPCTL. Background Art

[0004] Alzheimer's disease (AD) is a neurodegenerative disease characterized by irreversible global brain damage, leading to a gradual decline in cognitive function, comprehension and / or consciousness.

[0005] The primary histopathological hallmarks of Alzheimer's disease (AD) are abnormal deposition of proteins such as amyloid-β (Aβ) and tau, resulting in Aβ plaques and neurofibrillary tangles. A currently prevalent theory holds that it is not plaques but soluble Aβ aggregates, known as Aβ oligomers, that cause the early pathological changes in AD. Most Aβ peptides in the brains of AD patients exist in N-terminally cleaved and post-translationally modified forms. Glutamine cyclase (QC, also known as glutaminyl-peptide cyclotransferase (QPCT)), an enzyme that catalyzes post-translational chemical reactions in proteins or peptides, converting N-terminal glutamine or glutamate residues to N-terminal pyroglutamate (pE) by releasing ammonia or water molecules, respectively. In neurodegenerative diseases, QPCT and its isoenzyme, glutaminyl-peptide cyclotransferase-like (QPCTL), mediate the formation of pE-Aβ modifications in the brain. After Aβ forms pE at the N-terminus, its hydrophobicity increases. This form of Aβ has higher neurotoxicity due to its greater stability and hydrophobicity. In addition, upregulation of proinflammatory factors (cytokines, chemokines) is also a characteristic of the AD pathological process. Among them, 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-Aβ deposition and neuroinflammation. Therefore, inhibiting QC activity is a potential therapeutic strategy for treating pE-related diseases, including but not limited to Alzheimer's disease, cancer, etc. In view of this, the present disclosure discloses a class of QPCT and / or QPCTL inhibitors with novel structure, excellent efficacy, high bioavailability and high drugability.

[0006] Summary of the Invention

[0007] In one aspect, the present disclosure provides a compound of formula (AI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] Ring A is selected from described Optionally R 5 replace;

[0010] R 5 is selected from D, halogen, CN, NH2, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0011] Ring B is selected from

[0012] R 1 Selected from H, halogen, OH, NH2, SH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl or 4-10 membered heterocyclic group, the OH, NH2, SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl or 4-10 membered heterocyclic group is optionally replaced by R 1a replace;

[0013] R 1a is selected from halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R 1b replace;

[0014] R 1b Selected from halogen or C1-C6 alkyl;

[0015] R 2 Selected from H, D or C1-C6 alkyl;

[0016] R 3 and R 4 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, 4-7 membered heterocyclyl is optionally replaced by R 3a Replacement; or R 3 、R 4 The atoms to which it is connected together form a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-7 membered heterocyclic group is optionally replaced by R 3a replace;

[0017] R 3a Selected from D, halogen, OH or C1-C6 alkyl.

[0018] In another aspect, the present disclosure provides 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.

[0019] In another aspect, the present disclosure provides a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating or preventing a disease or condition mediated by QPCT and / or QPCTL in a subject in need thereof. DETAILED DESCRIPTION

[0020] The present disclosure relates to a compound of formula (AI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0021] in,

[0022] Ring A is selected from described Optionally R 5 replace;

[0023] R 5 is selected from D, halogen, CN, NH2, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkyl or C1-C6 deuterated alkyl.

[0024] Ring B is selected from

[0025] R 1 Selected from H, halogen, OH, NH2, SH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl or 4-10 membered heterocyclic group, the OH, NH2, SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl or 4-10 membered heterocyclic group is optionally replaced by R 1a replace;

[0026] R 1a is selected from halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R 1b replace;

[0027] R 1b Selected from halogen or C1-C6 alkyl;

[0028] R 2 Selected from H, D or C1-C6 alkyl;

[0029] R 3 and R 4independently 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, 4-7 membered heterocyclyl is optionally replaced by R 3a Replacement; or R 3 、R 4 The atoms to which it is connected together form a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-7 membered heterocyclic group is optionally replaced by R 3a replace;

[0030] R 3a Selected from D, halogen, OH or C1-C6 alkyl.

[0031] In some embodiments, the compound of formula (AI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0032] in,

[0033] Ring A is selected from

[0034] Ring B is selected from

[0035] R 1 Selected from H, halogen, OH, NH2, SH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl or 4-10 membered heterocyclic group, the OH, NH2, SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl or 4-10 membered heterocyclic group is optionally replaced by R 1a replace.

[0036] R 1a is selected from halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R 1b replace.

[0037] R 1b Selected from halogen or C1-C6 alkyl.

[0038] R 2 In some embodiments, ring A is selected from H, D or C1-C6 alkyl.

[0039] In some embodiments, Ring A is selected from

[0040] In some embodiments, Ring A is selected from

[0041] In some embodiments, R 5 Selected from C1-C6 alkyl.

[0042] In some embodiments, R 5 Selected from CH3.

[0043] In some embodiments, R 1 is selected from H, halogen, OH, NH2, C1-C6 alkyl, phenyl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl, wherein the OH, NH2, C1-C6 alkyl, phenyl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl is optionally replaced by R 1a replace.

[0044] In some embodiments, R 1 is selected from H, halogen, OH, phenyl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group, wherein the OH, phenyl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group is optionally replaced by R 1a replace.

[0045] In some embodiments, R 1 is selected from H, halogen, OH, NH2, C1-C6 alkyl, phenyl, pyridyl or morpholinyl, wherein the OH, NH2, C1-C6 alkyl, phenyl, pyridyl or morpholinyl is optionally replaced by R 1a replace.

[0046] In some embodiments, R 1 is selected from H, halogen, OH, phenyl, pyridyl or morpholinyl, wherein the OH, phenyl, pyridyl or morpholinyl is optionally replaced by R 1a replace.

[0047] In some embodiments, R 1 Selected from H, F, Cl, OH, NH2, CH3, The OH, NH2, CH3, Optionally R 1a replace.

[0048] In some embodiments, R 1 Selected from H, F, OH, The OH, Optionally R 1a replace.

[0049] In some embodiments, R 1a Selected from halogen, CN or C1-C6 alkyl.

[0050] In some embodiments, R 1a Selected from F, CN, CH3 or propyl.

[0051] In some embodiments, R 1a is selected from F, CN or propyl.

[0052] In some embodiments, R 1 Selected from H, F, Cl, CH3, CH2F, OCH3,

[0053] In some embodiments, R 1 Selected from H, F,

[0054] In some embodiments, R 2 Selected from H or C1-C6 alkyl.

[0055] In some embodiments, R 2 Select from H or D.

[0056] In some embodiments, R 2 Selected from H.

[0057] In some embodiments, R 3 and R 4 are independently selected from H, OH or C1-C6 alkyl, wherein the OH or C1-C6 alkyl is optionally replaced by R 3a replace.

[0058] In some embodiments, R 3 and R 4 independently selected from H, D, 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, 4-7 membered heterocyclyl is optionally replaced by R 3a Replacement; or R 3 、R 4 The atoms to which it is connected together form a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-7 membered heterocyclic group is optionally replaced by R 3a replace;

[0059] In some embodiments, R 3 and R 4 are independently selected from H, halogen or C1-C6 alkyl, or R3 and R 4 The atoms to which it is connected together form a C3-C6 cycloalkyl group, wherein the C1-C6 alkyl group and the C3-C6 cycloalkyl group are optionally replaced by R 3a replace.

[0060] In some embodiments, R 3 and R 4 are independently selected from H, halogen or C1-C6 alkyl, the C1-C6 alkyl being optionally replaced by R 3a replace.

[0061] In some embodiments, R 3 and R 4 The atoms to which it is attached together form a C3-C6 cycloalkyl group, wherein the C3-C6 cycloalkyl group is optionally replaced by R 3a replace.

[0062] In some embodiments, R 3a Selected from halogen or C1-C6 alkyl.

[0063] In some embodiments, R 3 and R 4 are independently selected from H, F or methyl, or R 3 and R 4 The atoms to which it is attached together form a cyclobutyl group.

[0064] In some embodiments, R 3 and R 4 Both are H.

[0065] In some embodiments, the compound of formula (AI) or its stereoisomer or its pharmaceutically acceptable salt of the present disclosure is selected from the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt,

[0066] where R 1 and R 2 As defined above for formula (AI). In some embodiments, the compound of formula (AI) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula (II-1), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0067] where R 1 and R 2 As defined above for formula (AI). In some embodiments, the compound of formula (AI) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0068] where R 1 and R 2 As defined above in formula (AI).

[0069] In some embodiments, the compound of formula (AI) or its stereoisomer or its pharmaceutically acceptable salt of the present disclosure is selected from the compound of formula (III-1) or its stereoisomer or its pharmaceutically acceptable salt,

[0070] where R 1 and R 2 As defined above in formula (AI).

[0071] In some embodiments, the compound of formula (AI) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0072] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (AI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0073] In another aspect, the present disclosure provides a method for treating a disease mediated by QPCT and / or QPCTL in a mammal, comprising administering a therapeutically effective amount of a compound of formula (AI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0074] In another aspect, the present disclosure provides use of a compound of formula (A-I) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating diseases mediated by QPCT and / or QPCTL.

[0075] In another aspect, the present disclosure provides use of a compound of formula (A-I) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating diseases mediated by QPCT and / or QPCTL.

[0076] In another aspect, the present disclosure provides a compound of formula (A-I) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating diseases mediated by QPCT and / or QPCTL.

[0077] In some embodiments, the QPCT and / or QPCTL mediated disease is selected from a neurodegenerative disease.

[0078] In some embodiments, the neurodegenerative disease is Alzheimer's disease.

[0079] Definitions and Explanations of Terms

[0080] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, may be combined and coupled with each other in any manner. A particular term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0081] In this article Indicates the attachment site.

[0082] The diagrammatic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge and dotted wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0083] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0084] The compounds disclosed herein include their tautomer forms. 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

[0085] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present invention 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 mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus 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 and mixtures thereof. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0086] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0087] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0088] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0089] In this article, C m -C nIt means having an integer number of carbon atoms in the range mn. For example, "C1-C 10 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0090] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C6 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. Specific examples of the alkyl group 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. The term "C1-C3 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0091] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The term "C2-C6 alkenyl" should be understood to mean a linear 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 group contains more than one double bond, the double bonds may be separated or conjugated. Specific examples of the alkenyl group 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.

[0092] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The term "C2-C6 alkynyl" is 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 "C2-C6 alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、"C2-C6 alkynyl" may include "C2-C3 alkynyl", and examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), and prop-2-ynyl (propargyl).

[0093] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. The term "C3-C6 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.

[0094] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. 10 "Aryl" is understood to be a monovalent aromatic or partially aromatic all-carbon monocyclic or bicyclic group having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 "aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0095] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system with aromatic character, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "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. In particular, the heteroaryl group is selected from thienyl, furyl, 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 acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and containing 1-3, preferably 1-2, heteroatoms independently selected from N, O and S.

[0096] The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monovalent monocyclic, fused, spiro or bridged ring group containing 12, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing groups) in the ring atoms, wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S), phosphorus atoms (P), boron atoms (B), -S(=O)2-, -S(=O)-, and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, S(=O)NH- or -NHC(=O)NH-. The term "4-10 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups in the ring atoms. “4-10 membered heterocyclyl” includes “4-7 membered heterocyclyl”, wherein specific examples of 4 membered heterocyclyl include but are not limited to azetidinyl or oxetanyl; specific examples of 5 membered heterocyclyl 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 heterocyclyl 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 heterocyclyl include but are not limited to diazepanyl. 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]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include but are not limited to hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic groups, 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 heterocyclyl groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl group as a whole is still non-aromatic.

[0097] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0098] The term "hydroxy" refers to an -OH group.

[0099] The term "cyano" refers to a -CN group.

[0100] The term "amino" refers to a -NH2 group.

[0101] The term "alkoxy" refers to a straight-chain or branched alcohol in which the hydrogen atom on the hydroxyl group is substituted by an alkyl group. The term "C1-C6 alkoxy" may further include "C1-C3 alkoxy".

[0102] The term "alkylamino" refers to an amino group in which one or two hydrogen atoms are replaced by the same or different alkyl groups. The term "C1-C6 alkylamino" may further include "C1-C3 alkylamino".

[0103] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by the same or different halogen atoms. The term "C1-C6 haloalkyl" may further include "C1-C3 haloalkyl".

[0104] The term "deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a deuterium atom. The term "C1-C6 deuterated alkyl" may further include "C1-C3 deuterated alkyl".

[0105] The term "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:

[0106] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0107] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0108] The term "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.

[0109] The term "therapeutically 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 as 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 this disclosure.

[0110] The term "patient" includes mammals and non-mammals. Examples of 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, and pigs; domestic animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish.

[0111] 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.

[0112] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, 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.

[0113] The term "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 organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0114] The term "pharmaceutical 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.

[0115] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0116] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0117] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the 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 et al.

[0118] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 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 disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0119] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and 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.

[0120] 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, and intravenous administration.

[0121] 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.

[0122] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, 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, and the like for oral administration to a patient.

[0123] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0124] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0125] In all methods of administration of the compounds of formula I described herein, the daily dosage is 0.01 mg / kg to 1000 mg / kg, for example 0.01 mg / kg to 500 mg / kg, in single or divided doses.

[0126] 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 same with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0127] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0128] This disclosure uses the following abbreviations:

[0129] 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 on carbon; LAH or LiAlH4: lithium aluminum tetrahydride; DMP : Dess-Martin periodinane, (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzidoyl-3(1H)-one; DIC: N,N'-diisopropylcarbodiimide; DMAP: 4-dimethylaminopyridine; NiBr2(dme): nickel bromide glycol dimethyl ether complex; DMA: dimethylacetamide; DIBAL-H: diisobutylaluminum hydride; DMSO: dimethyl sulfoxide; TEA: triethylamine; TBAF: tetrabutylammonium fluoride; BH3THF: borane in tetrahydrofuran; TosCl: p-toluenesulfonyl chloride; DAST: diethylaminosulfur trifluoride; AlD4Li: deuterated lithium aluminum hydride; Oxalyl chloride: oxalyl chloride; Sodium Pyrithione: sodium pyrithione; AIBN: azobisisobutyronitrile; NFSI: N-fluorobisbenzenesulfonamide.

[0130] Example

[0131] The invention is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and used without further purification.

[0132] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios. Unless otherwise specified, % refers to wt%.

[0133] Compounds are manually or The software named the commercially available compounds using the supplier's catalog name.

[0134] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0135] The eluents described below may be mixed eluents formed from two or more solvents, with the ratios being the volume ratios of the solvents. For example, "0-10% ethyl acetate / petroleum ether" indicates that during gradient elution, the volume ratio of ethyl acetate to petroleum ether in the mixed eluent is 0:100 to 10:90. Alternatively, "dichloromethane / methanol = 20:1" indicates that during gradient elution, the volume ratio of dichloromethane to methanol in the mixed eluent is 20:1.

[0136] Preparation of intermediates

[0137] Synthesis of intermediate 3-1:

[0138] Step 1: Synthesis of Intermediate 3-002

[0139] Dissolve 3-001 (3.70 g) in 100 mL of dichloromethane, add allyl 2,2,2-trichloroacetamide (7.90 g) and trifluoromethanesulfonic acid (781 mg), and stir at 25°C for 16 hours. After completion of the reaction, extract the mixture with 200 mL of dichloromethane and wash with saturated sodium bicarbonate (50 mL x 2). The organic phase is dried and concentrated to obtain the crude product. The crude product is purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-5%) to obtain intermediate 3-002 (3.60 g).

[0140] 1 H-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).

[0141] Step 2: Synthesis of Intermediate 3-003

[0142] 3-002 (3.60 g) was dissolved in 50 mL of methanol, and 10% Pd / C (700 mg) was added. The reaction mixture was stirred at 25°C under a hydrogen atmosphere (15 psi) for 16 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-5%) to obtain intermediate 3-003 (2.30 g).

[0143] 1 H-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).

[0144] Step 3: Synthesis of Intermediate 3-004

[0145] Under nitrogen, 3-003 (2.30 g) was dissolved in 40 mL of tetrahydrofuran, cooled to 0°C, and lithium aluminum tetrahydride solution (2.5 M, 7.49 mL) was slowly added dropwise. The reaction was stirred at 25°C for 2 hours until completion. Water (8 mL), 15% sodium hydroxide solution (8 mL), and water (24 mL) were added to the reaction solution to quench the reaction. The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain crude intermediate 3-004 (1.80 g).

[0146] Step 4: Synthesis of Intermediate 3-1

[0147] Under nitrogen, 3-004 (1.80 g) was dissolved in 80 mL of dichloromethane, cooled to 0°C, and Dess-Martin periodinane (7.33 g) was added portionwise. The reaction was stirred at 0°C for 2 hours until complete. The mixture was filtered, and the filtrate was diluted with 100 mL of dichloromethane, washed twice with saturated sodium bicarbonate (50 mL), and then washed with 50 mL of saturated brine. The organic phase was dried and concentrated to obtain the crude product. The product was purified by silica gel column chromatography (tetrahydrofuran / petroleum ether = 0%-5%) to obtain intermediate 3-1 (1.10 g).

[0148] 1 H-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).

[0149] Synthesis of intermediate 4-1:

[0150] Step 1: Synthesis of Intermediate 4-002

[0151] Dissolve 4-001 (15.0 g) and N-hydroxyphthalimide (14.4 g) in 500 mL of dichloromethane. Add 4-dimethylaminopyridine (1.08 g) and N,N'-diisopropylcarbodiimide (13.4 g) at 0°C. Stir at 25°C for 16 hours until the reaction is complete. Filter the reaction mixture, and concentrate the filtrate to obtain the crude product. Purify the crude product by silica gel column chromatography (dichloromethane / petroleum ether, gradient 0-100%) to obtain intermediate 4-002 (14.4 g).

[0152] 1 H-NMR (400MHz, CDCl3) δ7.98-7.88(m,2H),7.86-7.77(m,2H),3.74(s,3H),2.57(s,6H).

[0153] Step 2: Synthesis of Intermediate 4-003

[0154] Dissolve 4-002 (8.00 g) and p-fluoroiodobenzene (7.89 g) in 80 mL of dimethylacetamide. Add zinc powder (4.31 g), nickel bromide glycol dimethyl ether complex (783 mg), and pyridine-2,6-bis(carboxamidine) dihydrochloride (599 mg). Stir the reaction mixture at 25°C under nitrogen for 16 hours until complete. Dilute with 600 mL of ethyl acetate and wash with saturated brine (100 mL x 4). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate. The crude product is then purified by silica gel column chromatography (gradient: 0-5% ethyl acetate / petroleum ether) to yield intermediate 4-003 (1.30 g).

[0155] 1 H-NMR (400MHz, CDCl3) δ7.24-7.11(m,2H),7.08-6.93(m,2H),3.74(s,3H),2.33(s,6H).

[0156] Step 3: Synthesis of Intermediate 4-004

[0157] Under nitrogen, 4-003 (2.20 g) was dissolved in 25 mL of tetrahydrofuran. A 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (5.99 mL) was slowly added dropwise at 0°C. The reaction was complete after stirring at 25°C for 16 hours. The reaction mixture was quenched at 0°C with water (600 μL), 15% aqueous sodium hydroxide solution (600 μL), and water (1800 μL). Anhydrous magnesium sulfate was then added and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated to yield intermediate 4-004 (1.80 g).

[0158] 1 H-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).

[0159] Step 4: Synthesis of Intermediate 4-1

[0160] Under nitrogen, 4-004 (1.80 g) was dissolved in 30 mL of dichloromethane. Dess-Martin periodinane (5.96 g) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours until complete. 100 mL of dichloromethane was added to the reaction mixture, and the mixture was washed with saturated sodium bicarbonate solution (50 mL x 3). The organic phase was dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient: 0-5% ethyl acetate / petroleum ether) to obtain intermediate 4-1 (1.78 g).

[0161] 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).

[0162] Synthesis of intermediate 5-1 and intermediate 6-1:

[0163] The synthesis of intermediates 5-1 and 6-1 follows the synthesis steps of intermediate 4-1, except that p-fluoroiodobenzene in step 2 is replaced by 4-iodopyridine and 4-iodobenzonitrile, respectively.

[0164] Synthesis of intermediate 7-1:

[0165] Step 1: Synthesis of intermediate 7-002:

[0166] 7-001 (3.00 g) was dissolved in 30 mL of tetrahydrofuran and cooled to -78°C under nitrogen protection. A toluene solution of DIBAL-H (1 M, 21.3 mL) was slowly added dropwise over 15 minutes. The reaction solution was stirred at -78°C for 2 hours until the reaction was complete. The reaction solution was warmed to 0°C and quenched by slowly adding saturated aqueous ammonium chloride solution. The product was extracted with ethyl acetate (30.0 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 20:1) to obtain intermediate 7-002 (1.70 g).

[0167] 1 H-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).

[0168] MS m / z (ESI) = 184.20

[0169] Step 2: Synthesis of intermediate 7-1:

[0170] At -78°C under a nitrogen atmosphere, dimethyl sulfoxide (1.62g) was slowly added dropwise to a solution of oxalyl chloride (1.58g) in dichloromethane (30mL). The reaction mixture was stirred at -78°C for 1 hour. 7-002 (1.70g) was then added to the reaction mixture, and the reaction mixture was stirred at -78°C for 1 hour. Triethylamine (5.25g) was slowly added to the reaction mixture, and the reaction mixture was stirred at -78°C for 30 minutes. The reaction was complete after the temperature was raised to 0°C and water was slowly added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (30.0mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain intermediate 7-1 (1.15g).

[0171] 1 H-NMR (400MHz, DMSO-d6) δ9.64(s,1H),3.59-3.57(m,4H),2.39-2.33(m,4H),1.93(s,6H).

[0172] MS m / z (ESI) = 182.1.

[0173] Synthesis of intermediate 9-1:

[0174] Step 1: Synthesis of Intermediate 9-001

[0175] Dissolve 4-001 (5.00 g) in 80 mL of tetrahydrofuran. Under nitrogen, slowly add 1 M borane tetrahydrofuran solution (35.26 mL) dropwise at 0°C. Stir the reaction mixture at 25°C for 16 hours before the reaction is complete. Add methanol (80 mL) at 0°C and stir for 30 minutes. The organic phase is dried and concentrated to obtain the crude product. The crude product is purified by flash silica gel column chromatography (gradient: 0-20% ethyl acetate / petroleum ether) to obtain intermediate 9-001 (4.53 g).

[0176] 1 H NMR(400MHz,Chloroform-d)δ3.61(s,3H),3.56(s,2H),1.93(s,6H).

[0177] Step 2: Synthesis of Intermediate 9-002

[0178] 9-001 (9.50 g), p-toluenesulfonyl chloride (13.9 g), and triethylamine (7.39 g) were dissolved in dichloromethane (100 mL). The reaction mixture was stirred at 25° C. for 16 hours until the reaction was complete. The reaction mixture was concentrated and purified by silica gel column chromatography (gradient: 0-20% ethyl acetate / petroleum ether) to obtain intermediate 9-002 (15.6 g).

[0179] 1 H-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)

[0180] MS m / z(ESI):=311.0[M+H] +

[0181] Step 3: Synthesis of Intermediate 9-003

[0182] Under nitrogen, 9-002 (15.0 g) was dissolved in 200 mL of tetrahydrofuran. A 2.5 M solution of lithium aluminum hydride in tetrahydrofuran (38.66 mL) was slowly added dropwise at 0°C. The reaction mixture was stirred at 25°C for 16 hours. Water (3.7 mL), 15% aqueous sodium hydroxide solution (3.7 mL), and water (11.1 mL) were added sequentially to the reaction mixture. The mixture was stirred for 10 minutes, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient: 0-10% ethyl acetate / petroleum ether) to obtain intermediate 9-003 (3.14 g).

[0183] 1 H-NMR(400MHz,Chloroform-d)δ3.58(s,2H),1.59(s,6H),1.19(s,3H).

[0184] Step 4: Synthesis of Intermediate 9-1

[0185] Under nitrogen protection, oxalyl chloride (4.41 g) was dissolved in 15 mL of dichloromethane, and a solution of dimethyl sulfoxide (5.43 g) in dichloromethane (5 mL) was slowly added dropwise at -78°C, and stirred at -78°C for 30 minutes. Then, a solution of 9-003 (2.60 g) in dichloromethane (5 mL) was slowly added dropwise, and stirred at -78°C for 30 minutes. Finally, a solution of triethylamine (14.1 g) in dichloromethane (20 mL) was slowly added dropwise. The reaction solution was stirred at 25°C for 16 hours until the reaction was completed. The reaction solution was washed once with saturated brine (50 mL) and concentrated to 50 mL to obtain intermediate 9-1, which was directly used in the next reaction.

[0186] Synthesis of intermediate 10-1:

[0187] Step 1: Synthesis of intermediate 10-001:

[0188] Under nitrogen, 9-001 (9.00 g) was dissolved in 100 mL of dichloromethane. Diethylaminosulfur trifluoride (18.5 g) was slowly added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 16 hours, and the reaction was complete. The reaction mixture was slowly poured into a saturated sodium bicarbonate solution (100 mL) with crushed ice. After stirring, the solution was extracted with dichloromethane (20 mL x 3) and washed with saturated brine (20 mL x 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (gradient: 0-3% tetrahydrofuran / petroleum ether) to obtain intermediate 10-001 (9.05 g).

[0189] 1 H NMR(400MHz,Chloroform-d)δ4.46(s,1H),4.34(s,1H),3.70(s,3H),2.09(s,6H)

[0190] Step 2: Synthesis of intermediate 10-002:

[0191] Under nitrogen, 10-001 (5.00 g) was dissolved in 100 mL of tetrahydrofuran, and lithium aluminum hydride (2.5 M, 18.97 mL) was slowly added dropwise at 0°C. The reaction mixture was stirred at 25°C for 16 hours. TLC (petroleum ether:ethyl acetate = 3:1, potassium permanganate) was used to monitor the reaction completion. The reaction mixture was quenched at 0°C with H₂O (2 mL), 15% NaOH (6 mL), and H₂O (2 mL), followed by the addition of anhydrous magnesium sulfate and stirring for 30 minutes. The mixture was filtered, and the filtrate was concentrated to yield intermediate 10-002 (3.70 g).

[0192] 1 H NMR: (400MHz, Chloroform-d) δ4.44(s,1H),4.32(s,1H),3.63(s,2H),1.73(s,6H).

[0193] Step 3: Synthesis of intermediate 10-1:

[0194] Under nitrogen, oxalyl chloride (5.41 g) was dissolved in 40 mL of dichloromethane. A solution of DMSO (6.66 g) in dichloromethane (20 mL) was slowly added dropwise at -78°C. The reaction mixture was stirred at -78°C for 0.5 hours. A solution of 10-002 (3.70 g) in dichloromethane (20 mL) was then slowly added dropwise. After the addition was complete, the reaction mixture was stirred at -78°C for 1 hour. A solution of triethylamine (17.3 g) in dichloromethane (20 mL) was then slowly added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 16 hours. Completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 4:1, potassium permanganate colorimetry). The reaction mixture was washed with saturated brine (20 mL), and the organic phase was dried and concentrated to yield intermediate 10-1, which was used directly in the next step.

[0195] Synthesis of intermediate 11-1:

[0196] Step 1: Synthesis of Intermediate 11-002

[0197] Under nitrogen, 11-001 (3.00 g) was dissolved in tetrahydrofuran (50 mL) and lithium aluminum hydride (1.70 g) was slowly added at 0°C. The reaction was stirred at 25°C for 16 hours. TLC (petroleum ether:ethyl acetate = 2:1, potassium permanganate) was used to monitor the reaction completion. The reaction was quenched at 0°C with H₂O (1.5 mL), 15% aqueous NaOH (1.5 mL), and H₂O (4.5 mL), followed by the addition of anhydrous magnesium sulfate and stirring for 30 minutes. The mixture was filtered, and the filtrate was concentrated to yield intermediate 11-002 (2.6 g).

[0198] 1 H NMR (400MHz, Chloroform-d) δ2.56 (s, 1H), 1.81-1.73 (m, 6H).

[0199] Step 2: Synthesis of Intermediate 11-1

[0200] Under nitrogen, oxalyl chloride (5.04 g) was dissolved in dichloromethane (30 mL). A solution of DMSO (6.21 g) in dichloromethane (10 mL) was slowly added dropwise at -78°C. The reaction mixture was stirred at -78°C for 0.5 hours. A solution of 11-002 (2.60 g) in dichloromethane (20 mL) was then slowly added dropwise. After the addition was complete, the reaction mixture was stirred at -78°C for 1 hour. A solution of triethylamine (16.08 g) in dichloromethane (20 mL) was then slowly added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 16 hours. Reaction completion was monitored by TLC (petroleum ether:ethyl acetate = 2:1, potassium permanganate colorimetry). The reaction mixture was washed with saturated brine (20 mL), and the organic phase was dried to obtain intermediate 11-1 (2.50 g), which was used directly in the next step.

[0201] Synthesis of intermediate 13-1:

[0202] Step 1: Synthesis of Intermediate 13-002

[0203] Under nitrogen, 13-001 (10.0 g) and oxalyl chloride (15.1 g) were dissolved in 100 mL of dichloromethane. N,N-dimethylformamide (200 mg) was slowly added dropwise at 0°C. The reaction mixture was stirred at 25°C for 6 hours until completion. The organic phase was concentrated to obtain crude intermediate 13-002 (11.0 g), which was used directly in the next reaction.

[0204] Step 2: Synthesis of Intermediate 13-003

[0205] Under nitrogen, sodium pyrithione (11.0 g), azobisisobutyronitrile (581 mg), and 4-dimethylaminopyridine (144 mg) were dissolved in 100 mL of carbon tetrachloride. The mixture was stirred at 80°C for 1 hour, followed by the slow dropwise addition of a solution of 13-002 (11.1 g, 59.00 mmol in 50 mL of CCl4). After stirring at 80°C for 6 hours, the reaction was complete. The reaction was quenched by the addition of 100 mL of water and diluted with 50 mL of dichloromethane. After separation, the aqueous phase was extracted twice with dichloromethane (100 mL x 2). The organic phases were combined, dried, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford intermediate 13-003 (8.00 g).

[0206] Step 3: Synthesis of Intermediate 13-004

[0207] Under nitrogen, 13-003 (1.00 g) was dissolved in 10 mL of tetrahydrofuran and the reaction mixture was cooled to 0°C. A 2.5 M solution of lithium aluminum tetrahydride in tetrahydrofuran (2.5 mL) was slowly added dropwise. The reaction mixture was stirred at 0°C for 3 hours until complete. 10 mL of water was added to quench the reaction, which was then diluted with 10 mL of ethyl acetate. The layers were separated and the aqueous phase was extracted twice with ethyl acetate (30 mL x 2). The organic phases were combined and washed with 30 mL of saturated brine. The organic phases were dried and concentrated to yield 800 mg of crude intermediate 13-004, which was used directly in the next step.

[0208] Step 4: Synthesis of Intermediate 13-1

[0209] Under nitrogen, oxalyl chloride (1.15 g) was dissolved in 20 mL of dichloromethane. The reaction mixture was cooled to -78°C and dimethyl sulfoxide (1.41 g) was slowly added dropwise. The mixture was stirred for 30 minutes. Then, 13-004 (800 mg) was slowly added dropwise. After stirring at -78°C for 1 hour, triethylamine (3.66 g) was added dropwise and the temperature was raised to 25°C. The reaction mixture was stirred at 25°C for 4 hours until the reaction was complete. 10 mL of water was added to quench the reaction. The layers were separated and the aqueous phase was extracted twice with 10 mL of dichloromethane. The organic phases were combined, washed with saturated brine, and dried to obtain 788 mg of intermediate 13-1, which was used directly in the next step.

[0210] Example 1: (R)-1-(1H-benzo[d]imidazol-5-yl)-4-(bicyclo[1.1.1]pentan-1-yl)azetidin-2-one

[0211] Step 1: Synthesis of intermediate 1-2

[0212] Under nitrogen, compound 1-1 (2.50 g), (S)-tert-butylsulfenamide (3.15 g), and tetraisopropyl titanate (14.78 g) were dissolved in 100 mL of dichloromethane. The reaction mixture was stirred at 25°C for 16 hours. After the reaction, saturated aqueous sodium bicarbonate (100 mL) was added with stirring. The solid was filtered and extracted with ethyl acetate (100 mL x 2). The organic phase was dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient: 0-10% ethyl acetate / petroleum ether) to obtain intermediate 1-2 (2.60 g).

[0213] 1 H-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).

[0214] Step 2: Synthesis of Intermediates 1-3

[0215] Under nitrogen, zinc powder (5.12 g) was dissolved in 50 mL of tetrahydrofuran, and trimethylsilyl chloride (425 mg) was added. The reaction mixture was stirred at 25°C for 30 minutes. The reaction temperature was raised to 40°C, and ethyl bromoacetate (6.54 g) was slowly added dropwise. The mixture was stirred at 40°C for 1 hour to produce ethyl acetate zinc bromide. Intermediate 1-2 (2.60 g) was dissolved in 50 mL of tetrahydrofuran, and ethyl acetate zinc bromide was slowly added dropwise at 25°C. The reaction was stirred at 25°C for 1 hour, and the reaction was complete. The reaction mixture was quenched with 100 mL of saturated ammonium chloride solution and extracted with ethyl acetate (100 mL x 3). 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 (3.70 g).

[0216] 1 H-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).

[0217] Step 3: Synthesis of Intermediates 1-4

[0218] Intermediate 1-3 (1.80 g) was dissolved in a 4 M solution of hydrogen chloride in methanol (40 mL). The reaction mixture was stirred at 25°C for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated, and the residue was dissolved in water (40 mL) and extracted with ethyl acetate (40 mL x 3). The aqueous phase was adjusted to pH 7-8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield Intermediate 1-4 (1.20 g).

[0219] 1 H-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).

[0220] Step 4: Synthesis of Intermediates 1-5

[0221] Under nitrogen, Intermediate 1-4 (150 mg) was dissolved in 1.5 mL of tetrahydrofuran. A 2M solution of lithium diisopropylamide in THF (2.46 mL) was slowly added dropwise at -78°C over 5 minutes. The reaction was complete after stirring at -78°C for 10 hours. The reaction was quenched with 5 mL of saturated aqueous ammonium chloride. The reaction solution was extracted twice with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain Intermediate 1-5 (40.0 mg).

[0222] 1 H-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).

[0223] Step 5: Synthesis of Intermediates 1-6

[0224] Under nitrogen, Intermediate 1-5 (40.0 mg) was dissolved in 2 mL of dioxane. 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. The mixture was heated to 80°C and stirred for 2 hours. After completion of the reaction, water (20 mL) and ethyl acetate (10 mL) were added to the reaction mixture for extraction. The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (gradient: 0-30% tetrahydrofuran / petroleum ether) to obtain Intermediate 1-6 (110 mg).

[0225] MS m / z(ESI):=384.1[M+H] + .

[0226] Step 6: Synthesis of Compound 1

[0227] Intermediate 1-6 (140 mg) was dissolved in tetrabutylammonium fluoride (1.85 mL, 1 M in THF) and stirred at 60°C for 2 hours, resulting in completion of the reaction. The reaction solution was concentrated under reduced pressure. The crude product was added to 50 mL of ethyl acetate and then washed with water (10 mL x 4) and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (column: Phenomenex Gemini NX, 150 × 30 mm, 5 μm; mobile phase: [Phase A: water (0.05% ammonia v / v); Phase B: acetonitrile]; gradient elution: mobile phase B from 17% to 57%) to yield compound 1 (18.1 mg).

[0228] 1 H-NMR (400MHz, CDCl3) δ8.03(s,1H),7.79(d,J=1.9Hz,1H),7.64(d,J=8.7Hz,1H),7.34-7.1 1(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).

[0229] 1 H-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).

[0230] MS m / z(ESI):=254.1[M+H] + .

[0231] Referring to the synthesis method of Example 1, the following compounds were synthesized by replacing compound 1-1 with the starting materials in the table below:

[0232] Example 14: (R)-4-(bicyclo[1.1.1]pentan-1-yl)-1-(imidazo[1,2-a]pyridin-7-yl)azetidin-2-one

[0233] Under nitrogen protection, intermediate 1-5 (50.0 mg) was dissolved in 2 mL of dioxane, and 7-iodoimidazo[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. The temperature was raised to 80°C and stirred for 2 hours. After completion of the reaction, water (20 mL) and ethyl acetate (10 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by preparative HPLC (Phenomenex Gemini NX, 150×30 mm, 5 μm; mobile phase: [phase A: water (0.5% ammonia v / v); phase B: acetonitrile]; gradient elution: mobile phase B from 12% to 52%) to obtain compound 14 (33.8 mg).

[0234] 1 H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.00-7.50(m,2H),7.24-7.15(m,2H),4.3 4-4.33(m,1H),3.21-3.16(m,1H),2.84-2.80(m,1H),2.50(s,1H),1.79(s,6H).

[0235] MS m / z(ESI):254.2[M+H] + .

[0236] Example 15: (R)-1-(1H-benzo[d]imidazol-6-yl)-4-(bicyclo[1.1.1]pentan-1-yl)-3-methylazetidin-2-one

[0237] Step 1: Synthesis of Intermediate 15-1

[0238] Under a nitrogen atmosphere, Intermediate 1-6 (600 mg) was dissolved in 10 mL of tetrahydrofuran, and LDA (1.17 mL, 2 M in THF) was slowly added dropwise at -78°C. The reaction was stirred at -78°C for 1 hour. Iodomethane (244 mg) was then added dropwise, and the reaction was complete after stirring at -78°C for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were 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).

[0239] MS m / z(ESI):398.30[M+H] + .

[0240] Step 2: Synthesis of compound 15

[0241] Under a nitrogen atmosphere, intermediate 15-1 (50.0 mg) was dissolved in a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (5.0 mL). The reaction mixture was stirred at 60°C for 1 hour, after which the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Phenomenex Gemini NX, 150×30 mm, 5 μm; mobile phase: [Phase A: water (0.5% ammonia v / v); Phase B: acetonitrile]; gradient elution: mobile phase B from 50% to 80%) to afford the title compound 15 (15.0 mg).

[0242] MS m / z(ESI):268.2[M+H] + .

[0243] 1 H 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).

[0244] Example 16: Synthesis of (S)-2-(1H-benzo[d]imidazol-5-yl)-3-(bicyclo[1.1.1]pentan-1-yl)-2-azaspiro[3.3]heptan-1-one

[0245] 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.

[0246] MS m / z(ESI):294.2[M+H] + .

[0247] 1 H 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).

[0248] Example 17: (R)-4-(Bicyclo[1.1.1]pentan-1-yl)-1-(2-methyl-1H-benzo[d]imidazol-5-yl)azetidin-2-one

[0249] Step 1: Synthesis of intermediate 17-2:

[0250] Intermediate 17-1 (3.00 g) was dissolved in 30 mL of N,N-dimethylformamide and placed in an ice-water bath. Sodium hydride (60% in oil, 522 mg) was slowly added. After stirring for 1 hour, 2-(trimethylsilyl)ethoxymethyl chloride (2.27 g) was slowly added dropwise. The reaction was complete after stirring at 25°C for 2 hours. The reaction was quenched with 30 mL of saturated aqueous ammonium chloride and diluted with 30 mL of ethyl acetate. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain 3.00 g of intermediate 17-2.

[0251] Step 2 and step 3 were prepared by referring to the synthetic method of step 5 and step 6 of Example 1, except that 2-[(5-iodobenzimidazol-1-yl)methoxy]ethyltrimethylsilane in step 5 was replaced by 17-2, and the title compound 17 was prepared by the same method.

[0252] 1 H-NMR (400MHz, DMSO-d6) δ12.16 (s, 1H), 7.45-7.37 (m, 2H), 7.15 (d, J = 8.7Hz, 1H), 4.2 8-4.21(m,1H),3.10-3.05(m,1H),2.76-2.71(m,1H),2.50-2.47(m,4H),1.73(s,6H).

[0253] MS m / z(ESI):=268.2[M+H] + .

[0254] Example 18: Synthesis of (4S)-1-(1H-benzo[d]imidazol-6-yl)-4-(bicyclo[1.1.1]pentan-1-yl)-3-fluoroazetidine-2-one

[0255] Step 1: Synthesis of 18-1

[0256] Under nitrogen, intermediate 1-6 (500 mg) was dissolved in 10 mL of tetrahydrofuran. LDA (2 M in THF, 2 mL) was slowly added dropwise at -70°C under nitrogen, and the reaction mixture 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 complete after stirring at -70°C for 1 hour. The reaction was quenched with 20 mL of saturated aqueous ammonium chloride solution, diluted with ethyl acetate, and the layers separated. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain intermediate 18-1 (170 mg).

[0257] MS m / z(ESI):=402.30[M+H] +

[0258] Step 2: Synthesis of compound 18

[0259] Under nitrogen, 18-1 (50.0 mg) was dissolved in tetrabutylammonium fluoride solution (1 M in THF, 1.25 mL) and stirred at 60°C for 2 hours, after which the reaction was complete. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound 18 (15.0 mg).

[0260] 1 H-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,1 H),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);

[0261] 19 F-NMR(376MHz,Methanol-d4)δ-198.82.

[0262] MS m / z(ESI):=272.10[M+H] +

[0263] Biological activity and related properties testing

[0264] Unless otherwise specified, the experimental methods used in the following experimental examples are conventional methods; the materials and reagents used are commercially available reagents and materials unless otherwise specified.

[0265] Experimental Example 1: Human QPCT / QPCTL enzyme activity inhibition experiment in the disclosed embodiment

[0266] use Green Glutaminyl Cyclase Activity Assay Kit is used to detect the inhibition of compounds on human QPCT / QPCTL enzyme activity.

[0267] 1. Experimental reagents, consumables and instruments

[0268] 2. Experimental methods:

[0269] Dilute 0.5 mM QPCT substrate with buffer at a 1:100 dilution to 5 μM; dilute 50 μg / mL QPCT enzyme with buffer to 125 ng / mL and place on ice until use; dilute QPCT developer with buffer at a 1:250 dilution dilution and place on ice until use (QPCT substrate, QPCT enzyme, buffer, and QPCT developer are all provided in the kit). The starting concentration of the test compound working solution was 200 μM, and a six-fold serial dilution was performed for a total of seven concentration points. The starting working concentration of the test compound in a 75 μL reaction was 13.3 μM, and the final DMSO concentration was 0.3%.

[0270] In each well of a 384-well plate, 20 μL of the prepared QPCT enzyme solution, 5 μL of the test compound, and 25 μL of the QPCT enzyme substrate were added in sequence. The plate was mixed on a microplate shaker for 1 minute, centrifuged at 400 g for 1 minute, and incubated at 37°C for 30 minutes. Subsequently, 25 μL of QPCT developer was added to each well, mixed on a shaker for 1 minute, centrifuged at 400 g for 1 minute, and incubated at 37°C for another 60 minutes. After incubation, the fluorescence value was read on a microplate reader with the parameter setting: Ex / Em=490nm / 520nm. The formula for calculating the inhibition rate of the compound on QPCT enzyme activity is: 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 horizontal axis and enzyme activity inhibition rate (%) as the vertical axis. Four-parameter fitting was performed to calculate the IC50 of the compound on QPCT enzyme activity inhibition. 50 The specific results are shown in Table 1.

[0271] right The Green Glutaminyl Cyclase Activity Assay Kit was appropriately adjusted to replace the QPCT enzyme with human QPCTL enzyme (Sino Biological, Cat. No. NXS6-1) (the working solution concentration remained unchanged) for the detection of IC values ​​of compounds that inhibit human QPCTL enzyme activity. 50 The remaining experimental reagents, instruments, working solution preparation, operating procedures, and data processing methods were the same as those for the human QPCT enzyme activity assay. Specific results are shown in Table 1.

[0272] Table 1 Test results of the inhibitory activity of the disclosed compounds on human QPCT / QPCTL enzyme “-” means not detected

[0273] Experimental Example 2: Determination of membrane permeability and transport properties of the disclosed compounds

[0274] The membrane permeability and transport properties of the disclosed compounds were determined using the following test methods.

[0275] The test steps are as follows:

[0276] 1. MDCKII-MDR1 (Source: Netherlands Cancer Institute) cell culture

[0277] 1) Preparation of transport buffer (Hanks balanced salt solution containing 25 mM HEPES, pH 7.4): Accurately weigh 5.958 g of 4-hydroxyethylpiperazineethanesulfonic acid and 0.35 g of NaHCO3, add 900 mL of pure water to dissolve them, then add 100 mL of 10× HBSS, stir well, adjust the pH to 7.4, and filter.

[0278] 2) Preparation of MDCKII-MDR1 cell culture medium: MEM medium (source: Gibco) was supplemented with 10% FBS, 1% Pen Strep Liquid (source: Gibco), 1% GlutaMAXTM-I (source: Gibco), and 400 μg / mL G418 (source: Solarbio).

[0279] 3) Culture cells in a T-75 flask in a 37°C, 5% CO2 incubator. Discard the culture medium when cells reach 80-90% confluence. Rinse the cells with 5 mL of PBS and add 1.5 mL of Trypsin / EDTA (source: Gibco). Incubate in a 37°C incubator for 5-10 minutes until the cells detach as a quicksand. Finally, neutralize the Trypsin / EDTA with FBS-containing culture medium.

[0280] 4) Centrifuge the cell suspension at 120 x g for 10 minutes and discard the supernatant.

[0281] 5) Add the cell culture medium from step 2 to resuspend the cells and adjust the density to 1.56×10 6 cells / mL of cell suspension.

[0282] 2. MDCKII-MDR1 Cell Inoculation

[0283] 1) Add 75 μL of culture medium to each well of a Transwell (source: Corning Corporation) chamber, add 25 mL of culture medium to the lower layer, and preheat in a 37°C, 5% CO2 incubator for 1 hour.

[0284] 2) Add 50 μL of cell suspension to each well of the preheated Transwell chamber, and the final seeding density is 5.45×10 5 cells / cm2.

[0285] 3) Culture for 4-8 days, changing the medium every other day. Change the medium within 24 hours of initial seeding. The medium must be changed the day before the experiment.

[0286] 3. Assessing Monolayer Cell Membrane Integrity

[0287] 1) After 4-8 days of culture, cells are confluent and differentiated and ready for transport experiments.

[0288] 2) Use a resistance meter to measure the resistance of the single-layer membrane and record the resistance of each hole.

[0289] 3) After the measurement is completed, re-incubate the Transwell culture plate.

[0290] 4) Calculate TEER value:

[0291] TEER value = TEER (Ω) measured value × membrane area (cm 2 )

[0292] The resistance of a single cell membrane is less than 42Ω·cm 2 , indicating that the cell monolayer membrane has poor density and cannot be used for the experiment.

[0293] 4. Transport Experiment

[0294] 1) Dilute a 10 mM stock solution of the disclosed compound or positive control compound (metoprolol, prazosin, imatinib) with DMSO to obtain a 0.2 mM stock solution, and then dilute the 0.2 mM stock solution with transport buffer to obtain a 1 μM working solution of the disclosed compound or positive control compound.

[0295] 2) Remove the MDCKII-MDR1 cell plate from the incubator, wash the Transwell plate twice with preheated transport buffer, and then incubate in a 37°C incubator for 30 minutes.

[0296] 3) To measure the transport rate of the compound from the apical to the basolateral side (A→B), add 125 μL of the compound working solution to the top of the Transwell chamber. Immediately, remove 50 μL of the sample from the top and add 200 μL of stop solution containing an internal standard to terminate transport, serving as the initial top sample. Simultaneously, add 235 μL of transport buffer to the receiving end (basolateral side). This experiment is performed in duplicate.

[0297] 4) To measure the transport rate of the compound from the basolateral to the apical side (B→A), add 285 μL of the compound working solution to the receiving end (basolateral side). Immediately, remove 50 μL of the sample from the basolateral side and add 200 μL of the stop solution containing the internal standard to terminate transport, thus serving as the initial basolateral sample. Simultaneously, add 75 μL of transport buffer to the apical side of the Transwell chamber. This experiment is performed in duplicate.

[0298] 5) Place the cell culture plate in a 37°C, CO2 incubator and incubate for 2 hours.

[0299] 6) After the transport experiment is complete, remove 50 μL of sample from the dosing end (i.e., the top end in the A→B direction and the base end in the B→A direction) and add 200 μL of stop solution containing an internal standard to terminate transport. Remove 50 μL of sample from the receiving end (i.e., the base end in the A→B direction and the top end in the B→A direction) and add 200 μL of stop solution containing an internal standard. Vortex at 1000 rpm for 10 minutes and centrifuge at 3,220 g for 30 minutes. Transfer 100 μL of the supernatant to the sample injection plate and add 100 μL of ultrapure water to mix thoroughly before LC-MS / MS analysis.

[0300] 7) After the transport experiment, measure the fluorescence value. Prepare a 10mM Lucifer Yellow (source: Sigma) stock solution with water and dilute it to 100μM with transport buffer. Add 100μL of Lucifer Yellow solution to the top of the Transwell chamber and 300μL of transport buffer to the base. Incubate in a 37°C CO2 incubator for 30 minutes. Take 80μL of the solution from the base and transfer it to a 96-well plate. Analyze the fluorescence value using a microplate reader ( 200PRO multifunctional microplate reader) to measure cell fluorescence value (to detect membrane integrity).

[0301] The fluorescence leakage value (Leakage (%) or LY (%)) of MDCKII-MDR1 cell monolayer was calculated using the following formula: LY (%) = {I acceptor ×0.3 / (I acceptor×0.3+I donor ×0.1)}×100%

[0302] I acceptor Refers to the fluorescence density on the receiving side (0.3 mL), I donor Refers to the fluorescence density of the administration side (0.1 mL). LY% > 1.0% indicates poor monolayer membrane tightness, and the corresponding results will be excluded from the evaluation.

[0303] The peak areas of the compound at the administration side and the receiving side were measured. The apparent permeability coefficient (P app , unit: cm / s) and efflux ratio (ER): P app ={V A ×[drug] acceptor / (Area×incubation time×[drug] initial dono}

[0304] V A 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 well plate membrane area (0.143 cm 2 ); incubation time is the incubation time (unit: s).

[0305] P app(B-A) is the apparent permeability coefficient from the base to the top; P app(A-B) is the apparent permeability from the top to the base.

[0306] The calculated apparent permeability coefficients and efflux ratios of the compounds of the present disclosure are shown in Table 2.

[0307] Table 2 Apparent permeability coefficient and efflux ratio of the compounds disclosed herein

[0308] Experimental Example 3: Inhibitory effect of the inventive compounds on CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzyme activities

[0309] The inhibition of the disclosed compounds on the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes was determined using the following test method.

[0310] The test steps are as follows:

[0311] Preparation of 100 mM phosphate buffer (PBS): Weigh 7.098 g of Na₂HPO₄ and dissolve it in 500 mL of pure water by sonication to prepare Solution A. Weigh 3.400 g of KH₂PO₄ and dissolve it in 250 mL of pure water by sonication to prepare Solution B. Place Solution A on a stirrer and slowly add Solution B until the pH reaches 7.4 to prepare 100 mM PBS buffer.

[0312] 2. Prepare a 10 mM NADPH solution using 100 mM PBS buffer. Dilute a 10 mM stock solution of the disclosed compound with DMSO to obtain a 200× concentration working solution of the compound (10000, 3333.3, 1111.1, 370.37, 123.46, 41.15, 13.7, 0 μM). Dilute a positive inhibitor stock solution with DMSO to obtain a 200× concentration working solution of the positive inhibitor (sulfaphenazole, 1000, 300, 100, 30, 10, 3, 0 μM; quinidine / ketoconazole, 100, 30, 10, 3, 1, 0.3, 0 μM; α-naphthoflavone, 50, 15, 5, 1.5, 0.5, 0.15, 0 μM; nootkatone, 6000, 1800, 600, 180, 60, 18, 0 μM). A 200× working solution of substrates (8000 μM phenacetin, 1000 μM diclofenac, 8000 μM S-mephenytoin, 1000 μM dextromethorphan, and 400 μM midazolam) was prepared in water, acetonitrile, or acetonitrile / methanol.

[0313] 3. Mix 1 μl of 20 mg / ml liver microsome solution, 1 μl of substrate working solution, 1 μl of compound working solution, and 177 μl of PBS buffer, and preincubate in a 37°C water bath for 10 minutes. For the positive control, add 1 μl of positive inhibitor working solution instead of compound working solution. Simultaneously, preincubate with 10 mM NADPH solution in a 37°C water bath for 10 minutes. After 10 minutes, add 20 μl of NADPH to each well to initiate the reaction. Incubate at 37°C for 15 minutes (CYP1A2), 15 minutes (CYP2C9), 60 minutes (CYP2C19), 15 minutes (CYP2D6), or 15 minutes (CYP3A4). All incubations should be performed in duplicate. After the appropriate incubation time, terminate the reaction by adding 400 μl of ice-cold methanol containing the internal standard to all samples. Vortex to mix thoroughly and centrifuge at 4000 rpm at 4°C for 30 minutes. After centrifugation, 100 μL of supernatant was transferred to the sample injection plate, and 200 μL of ultrapure water was added and mixed for LC-MS / MS analysis.

[0314] The IC values ​​of the disclosed compounds for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 were calculated using Excel XLfit 5.3.1.3.50 See Table 3 for values.

[0315] Table 3 IC values ​​of the disclosed compounds against CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 50 value “-” means not detected

[0316] Experimental Example 4 Metabolic Stability Determination of the Disclosed Compounds in Liver Microsomes

[0317] The test steps are as follows:

[0318] Preparation of 100 mM phosphate buffer (PBS): Weigh 7.098 g of Na₂HPO₄ and dissolve it in 500 mL of pure water by sonication to prepare Solution A. Weigh 3.400 g of KH₂PO₄ and dissolve it in 250 mL of pure water by sonication to prepare Solution B. Place Solution A on a stirrer and slowly add Solution B until the pH reaches 7.4 to prepare 100 mM PBS buffer.

[0319] 2. Preparation of reaction system

[0320] Prepare the reaction system according to the table below

[0321] 3. Preincubate the reaction system in a 37°C water bath for 10 minutes. Add 20 μL of 10 mM NADPH solution (dissolved in 100 mM phosphate buffer) to the reaction system for a final NADPH concentration of 1 mM. Substitute 20 μL of phosphate buffer for the NADPH solution as a negative control. This negative control is intended to eliminate the effects of the chemical stability of the compound itself.

[0322] 4. 2 μL of 100 μM of the disclosed compound and the positive control compound verapamil were added to the reaction system to initiate the reaction. The final concentration of the compound was 1 μM.

[0323] 5. Remove 25 μL of the incubated sample at 0.5, 15, 30, 45, and 60 minutes and terminate the reaction with 4x the volume of glacial acetonitrile containing the internal standard. Centrifuge the sample at 4000 rpm for 15 minutes. After centrifugation, transfer 50 μL of the supernatant to the injection plate and mix with 150 μL of ultrapure water for LC-MS / MS analysis.

[0324] All data were calculated using Microsoft Excel software. Peak areas were obtained by extracting ion spectra. The in vitro half-life (t 1 / 2 ).

[0325] In vitro half-life (t1 / 2 ) is calculated by the slope (k):

[0326] in vitro 1 / 2 =0.693 / k

[0327] The t calculated by the above formula is 1 / 2 See Table 4 for values.

[0328] Table 4 Half-life of the compounds of the present disclosure in liver microsomes of different species (t 1 / 2， minute) “-” means not detected

Claims

1. A compound of formula (AI) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, Ring A is selected from Said Optionally R 5 replace; R 5 is selected from D, halogen, CN, NH2, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkyl or C1-C6 deuterated alkyl; Ring B is selected from R 1 is selected from H, halogen, OH, NH2, SH, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl or 4-10 membered heterocyclic group, the OH, NH2, SH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl is optionally replaced by R 1a replace; R 1a is selected from halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R 1b replace; R 1b Selected from halogen or C1-C6 alkyl; R 2 Selected from H, D or C1-C6 alkyl; R 3 and R 4 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, 4-7 membered heterocyclyl is optionally replaced by R 3a Replace; or R 3 , R 4 The atoms connected thereto together form a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-7 membered heterocyclic group is optionally substituted by R 3a replace; R 3a Selected from D, halogen, OH or C1-C6 alkyl.

2. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from H, halogen, OH, NH2, C1-C6 alkyl, phenyl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group, wherein the OH, NH2, C1-C6 alkyl, phenyl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group is optionally replaced by R 1a replace; Or, R 1 is selected from H, halogen, OH, NH2, C1-C6 alkyl, phenyl, pyridyl or morpholinyl, wherein the OH, NH2, C1-C6 alkyl, phenyl, pyridyl or morpholinyl is optionally replaced by R 1a replace; Or, R 1 Selected from H, F, Cl, OH, NH2, CH3, The OH, NH2, CH3, Optionally R 1a replace; Or, R 1 Selected from H, F, CH3、CH2F、 Cl or OCH3.

3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1a Selected from halogen, CN or C1-C6 alkyl.

4. The compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 Select from H or D.

5. The compound according to any one of claims 1 to 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 are independently selected from H, halogen or C1-C6 alkyl, or R 3 and R 4 The atoms connected thereto together form a C3-C6 cycloalkyl group, wherein the C1-C6 alkyl group and the C3-C6 cycloalkyl group are optionally substituted by R 3a replace; Or, R 3 and R 4 are independently selected from H, F or methyl, or R 3 and R 4 The atoms to which it is attached together form a cyclobutyl group; Or, R 3 and R 4 Both are H.

6. The compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 5 For CH3.

7. The compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (AI) is selected from the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof: Among them, ring A, ring B and R 2 As defined in any one of claims 1 to 6.

8. The compound according to claim 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (AI) is selected from the compound of formula (II) or its stereoisomer or a pharmaceutically acceptable salt thereof: (II) where R 1 and R 2 As defined in any one of claims 1 to 6.

9. The compound according to claim 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (AI) is selected from the compound of formula (II-1) or its stereoisomer or a pharmaceutically acceptable salt thereof: Where R 1 and R 2 As defined in any one of claims 1 to 6.

10. The compound according to claim 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (AI) is selected from the compound of formula (III) or its stereoisomer or a pharmaceutically acceptable salt thereof: Where R 1 and R 2 As defined in any one of claims 1 to 6.

11. The compound according to claim 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (AI) is selected from the compound of formula (III-1) or its stereoisomer or a pharmaceutically acceptable salt thereof: Where R 1 and R 2 As defined in any one of claims 1 to 6.

12. The compound according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (AI) is selected from the following compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof:

13. A pharmaceutical composition, wherein The pharmaceutical composition comprises the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 12, and optional pharmaceutically acceptable excipients.

14. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 or a pharmaceutical composition according to claim 13 for use in treating or preventing a disease or condition mediated by QPCT and / or QPCTL in a subject in need thereof.

15. The compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt or pharmaceutical composition according to claim 14, wherein: The disease or disorder mediated by QPCT and / or QPCTL is a neurodegenerative disease, preferably Alzheimer's disease.

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