Glutamine cyclase inhibitor and application thereof

Abstract

Compounds of Formula (I) or stereoisomers or pharmaceutically acceptable salts thereof as glutamine cyclase inhibitors, processes for their preparation, pharmaceutical compositions containing the compounds of Formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, and the Formula (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. # imgabs0 #

Description

[0001] The present invention claims priority to a prior application filed with the State Intellectual Property Office on September 27, 2023, with patent application number CN202311270943.1 and invention name “Glutamine cyclase inhibitors and their applications”. The entire text of the above-mentioned prior application is incorporated herein by reference. Technical Field

[0002] The present disclosure belongs to the field of medical technology. Specifically, the present disclosure relates to a glutamine cyclase inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and a use thereof in preventing or treating Alzheimer's disease. Background Art

[0003] Alzheimer's disease (AD) is a neurodegenerative disease characterized by irreversible damage to brain function throughout the brain, leading to a gradual decline in cognitive function, comprehension and / or consciousness.

[0004] The main histopathological hallmarks of AD are Aβ plaques and neurofibrillary tangles caused by abnormal deposition of β-amyloid protein (Aβ) and Tau protein. The more popular theory nowadays believes that it is not plaques but soluble Aβ aggregates, called Aβ oligomers, that cause the early pathological changes in Alzheimer's disease. Most Aβ peptides in the brain of AD patients exist in the form of N-terminal cleavage and post-translational modification. Glutamine cyclase (QC, also known as glutaminyl-peptide cyclotransferase, QPCT) catalyzes the post-translational chemical reaction of 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 QPCTL (glutaminyl-peptide cyclotransferase-like) 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 stronger 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. Summary of the invention

[0005] The present disclosure relates to a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0006]

[0007] in,

[0008] Ring A is selected from

[0009] R 1 , R 2 , R 4 and R 5independently selected from H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R a Substitution, where R 1 , R 2 , R 4 and R 5 At least one is not H;

[0010] R 3 is selected from H, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally substituted by R b replace;

[0011] R a and R b independently selected from D or halogen;

[0012] R 6 Selected from H or C1-C6 alkyl.

[0013] In some embodiments, R 1 , R 2 , R 4 and R 5 independently selected from H, halogen, CN, C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkynyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl, wherein the C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkynyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R a Substitution, where R 1 , R 2 , R 4 and R 5 At least one is not H.

[0014] In some embodiments, R 1 Selected from H or halogen.

[0015] In some embodiments, R 1 Select from H or F.

[0016] In some embodiments, R 2is selected from CN, C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkynyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl, wherein the C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkynyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R a replace.

[0017] In some embodiments, R a Select from D or F.

[0018] In some embodiments, R 2 Selected from OCH3, OCD3, CN, OCHF2, OCF3, OC2H5, N(CH3)2, -C≡CH or -C≡CCH3.

[0019] In some embodiments, R 2 Selected from OCH3, OCD3, CN, OCHF2, OCF3 or N(CH3)2.

[0020] In some embodiments, R 3 Selected from H or halogen.

[0021] In some embodiments, R 3 is selected from H, F or Cl.

[0022] In some embodiments, R 4 Selected from H.

[0023] In some embodiments, R 5 Selected from H or halogen.

[0024] In some embodiments, R 5 is selected from H, F or Cl.

[0025] In some embodiments, R 6 Selected from H.

[0026] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (I-1) or its stereoisomer or its pharmaceutically acceptable salt,

[0027]

[0028] Among them, ring A, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 As defined above for formula (I).

[0029] In some embodiments, the compound of formula (I) 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:

[0030]

[0031]

[0032] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0033] 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 (I) 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.

[0034] In another aspect, the present disclosure provides use of a compound of formula (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.

[0035] In another aspect, the present disclosure provides use of a compound of formula (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.

[0036] 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 thereof for preventing or treating a disease mediated by QPCT and / or QPCTL.

[0037] In some embodiments, the QPCT and / or QPCTL mediated disease is selected from a neurodegenerative disease.

[0038] In some embodiments, the neurodegenerative disease is Alzheimer's disease.

[0039] Definitions and explanations of terms

[0040] Unless otherwise specified, the terms used in this disclosure have the following meanings, and the groups and term definitions recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. A specific term should not be considered as uncertain or unclear in the absence of special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient.

[0041] In this article Indicates the connection site.

[0042] The graphic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the wedge and dotted wedge bonds ( and ) represents the absolute configuration of a stereocenter, with black real and imaginary bonds ( and ) represents the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0043] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0044] 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 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-type and Z-type 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 their mixtures. 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 these isomers and their mixtures involved in all substituents are also included within the definition of the compounds of the present invention. The 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 chiral reagents.

[0045] The term "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. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

[0046] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, ethyl is "optionally" substituted by halogen, meaning that ethyl can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2 etc.) or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3 etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any substitution or substitution pattern that may not exist and / or cannot be synthesized in space will not be introduced.

[0047] When any variable (such as R a , R b ) occurs 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 2 R b is replaced, then each R b All have independent options.

[0048] In this article, C m -C n It means having an integer number of carbon atoms in the range of 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.

[0049] 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 "Alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0050] 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. 10"Alkynyl" is understood to mean a linear or branched, unsaturated, monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C 10 "Alkynyl" may include "C2-C6 alkynyl"; "C2-C6 alkynyl" may include "C2-C3 alkynyl", examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), prop-2-ynyl (propargyl).

[0051] The term "cycloalkyl" refers to a fully saturated carbon ring in the form of a monocyclic, fused, bridged or spirocyclic ring. The term "C3-C6 cycloalkyl" may be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, and specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0052] The term "heterocyclyl" refers to a fully saturated or partially saturated (not aromatic as a whole) monovalent monocyclic, fused, spiro or bridged ring group, whose ring atoms contain 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., atomic groups containing heteroatoms), wherein the "heteroatoms or heteroatomic groups" include but are not limited to nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (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-, etc. The term "4-10 membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1-5 heteroatoms or heteroatom groups independently selected from the above. "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]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. Optionally, 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.

[0053] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0054] The term "alkoxy" refers to a monovalent group generated by the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, and can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-"; the term "C1-C3 alkoxy" can be understood as "C1-C3 alkyloxy" or "C1-C3 alkyl-O-". The "C1-C6 alkoxy" may further include a "C1-C3 alkoxy".

[0055] The term "alkylamino" means that one or two hydrogen atoms on the amino group are replaced by the same or different alkyl groups, including "monoalkylamino" and "dialkylamino", for example, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -N(CH3)(CH2CH3), etc. The term "C1-C6 alkylamino" may further include "C1-C3 alkylamino".

[0056] 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 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.

[0057] 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, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc. Examples of non-human mammals include, but are not limited to, birds and fish, etc.

[0058] 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.

[0059] The term "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.

[0060] 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 an organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0061] 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.

[0062] The term "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.

[0063] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0064] 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 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 et al.

[0065] 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.

[0066] The pharmaceutical 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.

[0067] 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.

[0068] 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.

[0069] 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, etc., for oral administration to patients.

[0070] 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.

[0071] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0072] In all methods of administration of the compounds of formula I described herein, the dosage administered is from 0.01 mg / kg to 1000 mg / kg body weight per day, in single or divided doses.

[0073] 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.

[0074] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes 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 the synthesis steps or reaction processes based on the existing embodiments.

[0075] This disclosure uses the following abbreviations:

[0076] 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:

[0077] Trimethylchlorosilane. DETAILED DESCRIPTION

[0078] The disclosure is described in detail below by way of examples, but this does not imply any adverse limitation to the disclosure. The disclosure has been described in detail herein, and specific embodiments thereof are also disclosed therein, and it will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments of the disclosure without departing from the spirit and scope of the disclosure. All reagents used in the disclosure are commercially available and can be used without further purification.

[0079] Unless otherwise specified, the ratios expressed for mixed solvents are volume mixing ratios. Unless otherwise specified, % means wt%.

[0080] Compounds are manually or The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0081] 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 inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0082] The eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio is the volume ratio of each solvent. For example, "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.

[0083] Preparation of intermediate 14-1

[0084]

[0085] 2-Fluoro-3-hydroxy-benzaldehyde (2.00 g) was added to 10 mL of acetonitrile, and silver oxide (3.30 g) and deuterated iodomethane (4.13 g) were added under nitrogen protection. The reaction solution was stirred at room temperature for 5 hours until the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate) gradient elution to obtain 1.80 g.

[0086] Example 1: (R)-1-(1H-benzo[d]imidazol-5-yl)-4-(3-methoxyphenyl)azetidin-2-one

[0087]

[0088] Step 1: Synthesis of intermediate 1-2

[0089] Under nitrogen protection, 1-1 (5.00 g), intermediate (S)-tert-butylsulfenamide (5.34 g) and tetraisopropyl titanate (20.8 g) were added to 180 mL of tetrahydrofuran, heated to 70 ° C and stirred for 16 hours to complete the reaction, 200 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution and stirred, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (gradient: ethyl acetate / petroleum ether = 0-15%) to obtain the title intermediate 1-2 (8.01 g).

[0090] 1 H NMR: (400MHz, chloroform-d)δ8.58(s,1H),7.46-7.39(m,3H),7.12-7.06(m,1H),3.89(s,3H),1.29(s,9H)

[0091] MS m / z(ESI):=240.2[M+H] +

[0092] Step 2: Synthesis of intermediate 1-3

[0093] Under nitrogen protection, zinc powder (4.26g) was dissolved in 15mL tetrahydrofuran, trimethylsilyl chloride (236mg) was added, and the mixture was stirred at 25℃ for 30 minutes. The temperature of the reaction solution was raised to 40℃, ethyl bromoacetate (5.44g) was slowly added dropwise, and ethyl acetate zinc bromide was obtained after stirring at 40℃ for 1 hour. Intermediate 1-2 (2.6g) was dissolved in 20mL tetrahydrofuran, ethyl acetate zinc bromide was slowly added dropwise at 25℃, and the reaction was completed after stirring for 2 hours. The reaction solution was quenched with 20mL saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (gradient: tetrahydrofuran / petroleum ether = 0-23%) to obtain the title intermediate 1-3 (3.50g).

[0094] 1 H NMR(400MHz,chloroform-d)δ7.22-7.15(m,1H),6.87-6.80(m,2H),6.81-6.74(m,1H),4 .72-4.62(m,2H),4.07-4.04(m,2H),3.73(s,3H),2.81-2.74(m,2H),1.18-1.14(m,12H).

[0095] MS m / z(ESI):=349.9[M+Na] +

[0096] Step 3: Synthesis of intermediate 1-4

[0097] 1-3 (3.50 g) was dissolved in a methanol solution of hydrogen chloride (4M, 10.69 mL), and the reaction solution was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate (200 mL). The pH was adjusted to 7-8 with a saturated aqueous sodium bicarbonate solution, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (gradient: methanol / dichloromethane = 0-3%) to obtain the title intermediate 1-4 (1.70 g).

[0098] 1H NMR(400MHz,chloroform-d)δ7.30-7.23(m,1H),6.98-6.92(m,2H),6.85-6.79(m, 1H),4.43-4.40(m,1H),3.83(s,3H),3.71(s,3H),2.71-2.65(m,2H),1.77(s,2H).

[0099] Step 4: Synthesis of intermediate 1-5

[0100] Under nitrogen protection, 1-4 (1.73 g) was dissolved in 25 mL of tetrahydrofuran. At -78 ° C, a tetrahydrofuran solution of lithium diisopropylamide (2M, 12.4 mL) was slowly added to the reaction solution over 5 minutes. Stir at -78 ° C for 2 hours. LCMS showed that the reaction was complete. The reaction was quenched with saturated NH4Cl aqueous solution (20 mL), and ethyl acetate (30 mL*3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (gradient: ethyl acetate / petroleum ether = 0-50%) to obtain the title intermediate 1-5 (770 mg).

[0101] 1 H-NMR (400MHz, DMSO-d6) δ8.40 (s, 1H), 7.30 (t, J = 7.8Hz, 1H), 6.95-6.90 (m, 2H), 6.9 0-6.83(m,1H),4.64-4.61(m,1H),3.76(s,3H),3.34-3.29(m,1H),2.69-2.65(m,1H).

[0102] MS m / z(ESI):=178.2[M+H] +

[0103] Step 5: Synthesis of Intermediate 1-6

[0104] Under nitrogen protection, 1-5 (100 mg), cuprous iodide (43.0 mg), trans-(1R, 2R)-N, N'-dimethyl 1,2-cyclohexanediamine (32.1 mg), 2-[(5-iodobenzimidazole-1-yl) methoxy] ethyltrimethylsilane (253 mg) and potassium phosphate (359 mg) were dissolved in 5 mL of dioxane, heated to 80 ° C, stirred at 80 ° C for 3 hours, and LCMS showed that the reaction was complete. Add 20 mL of water to dilute, extract with ethyl acetate (5 mL * 3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was purified by rapid silica gel column chromatography (gradient: ethyl acetate / petroleum ether = 50-100%) to obtain the title intermediate 1-6 (210 mg).

[0105] MS m / z(ESI):=424.1[M+H] +

[0106] Step 6: Synthesis of compound 1

[0107] Under nitrogen protection, 1-6 (100 mg) was dissolved in 6 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was completed after stirring at 20°C for 8 hours. The crude product was dried under reduced pressure and purified by HPLC (C18 150 mm × 30 mm; mobile phase: [Phase A: water (additive ammonium bicarbonate: prepared according to 30 L of water and 24 g of ammonium bicarbonate), Phase B: acetonitrile]; B%: 25%-45%, 9 min) to obtain the title compound 1 (30.0 mg).

[0108] 1 H-NMR(400MHz,DMSO-d6)δ12.35(s,1H),8.15(s,1H),7.60-7.35(m,2H),7.33-7.29(m,1H),7.26-7.05(m,1H) ,7.04-6.97(m,2H),6.91-6.89(m,1H),5.24-5.22(m,1H),3.74(s,3H),3.62-3.57(m,1H),2.92-2.88(m,1H).

[0109] MS m / z(ESI):=294.2[M+H] + .

[0110] Referring to the synthesis method of Example 1, the starting materials in the following table were used to replace 1-1 to synthesize the following examples:

[0111]

[0112]

[0113]

[0114]

[0115] Example 15: (R)-4-(2-fluoro-3-methoxyphenyl)-1-(imidazo[1,2-a]pyridin-7-yl)azetidin-2-one

[0116]

[0117] Referring to the synthesis method of intermediate 1-5 in Example 1, the starting material 7-1 was used instead of 1-1, and intermediate 15-5 was synthesized through steps 1 to 4.

[0118] Step 5: Synthesis of Example 15

[0119] Under nitrogen protection, the intermediate 15-5 (100 mg) and 7-iodoimidazole [1,2-a] pyridine (150 mg) were dissolved in 2 mL of dioxane, and N, N-dimethyl-1,2-cyclohexanediamine (29.5 mg), cuprous iodide (39.0 mg) and potassium phosphate (326 mg) were added. The reaction was completed after stirring at 80°C for 3 hours. 10 mL of water was added to the reaction solution, diluted with 20 mL of ethyl acetate, separated, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, and the organic phases were dried and concentrated to obtain a crude product. The crude product was purified by preparative liquid chromatography (Boston Prime C18 column; water (containing 0.225% ammonium bicarbonate): acetonitrile = 1%-41%) to obtain Example 15 (25.1 mg). 1 H-NMR(400MHz,DMSO-d6)δ8.51-7.48(m,3H),7.23-7.10(m,3H),7.06-6.86( m,2H),5.50-5.43(m,1H),3.83(s,3H),3.76-3.65(m,1H),3.17-3.04(m,1H).

[0120] MS m / z(ESI):=312.3[M+H] + .

[0121] Referring to the synthesis method of Example 15, the starting materials in the following table were used to replace 15-1 to synthesize the following examples:

[0122]

[0123]

[0124] Biological activity and related properties testing

[0125] Experimental Example 1: Human QPCT / QPCTL enzyme activity inhibition experiment in the disclosed embodiment

[0126] use Green Glutaminyl Cyclase Activity Assay Kit is used to detect the inhibition of compounds on human QPCT / QPCTL enzyme activity.

[0127] 1. Experimental reagents, consumables and instruments

[0128]

[0129] 2. Experimental methods:

[0130] 0.5mM QPCT enzyme substrate was diluted to 5μM with buffer at 1:100; 50μg / mL QPCT enzyme was diluted to 125ng / mL with buffer and placed on ice for use; QPCT developer was diluted with buffer at 1:250 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 working solution of the test compound was 200μM, and the gradient was diluted 6 times, with a total of 7 concentration points. The starting working concentration of the test compound in the 75μL reaction system was 13.3μM, and the final DMSO concentration was 0.3%.

[0131] 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, 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 the incubation, the fluorescence value was read on an ELISA reader, and the parameter setting was: Ex / Em=490nm / 520nm. The formula for calculating the inhibition rate of the compound on the QPCT enzyme activity is: Inhibition rate (inhibition%)=(RFU n o treatment -RFU treated )÷(RFU n o treatment -RFU background )×100%. GraphPad Prism 9 software was used to draw a curve with compound concentration (nM) as the horizontal axis and enzyme activity inhibition rate (%) as the vertical axis, and four-parameter fitting was performed to calculate the IC of the compound on QPCT enzyme activity inhibition 50 The specific results are shown in Table 1.

[0132] right 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 detecting the IC of compounds inhibiting human QPCTL enzyme activity 50 The remaining experimental reagents, instruments, working solution preparation, operation steps and data processing methods are the same as those of the human QPCT enzyme activity detection method. The specific results are shown in Table 1.

[0133] Table 1 Test results of the disclosed embodiments on human QPCT / QPCTL enzyme inhibition activity

[0134]

[0135] “-” means not detected.

Claims

1. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, Ring A is selected from R 1 , R 2 , R 4 and R 5 independently selected from H, halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R a Substitution, where R 1 , R 2 , R 4 and R 5 At least one is not H; R 3 is selected from H, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally substituted by R b replace; R a and R b independently selected from D or halogen; R 6 Selected from H or C1-C6 alkyl.

2. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 Select from H or F.

3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 is selected from H, F or Cl.

4. The compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 5 is selected from H, F or Cl.

5. The compound according to any one of claims 1 to 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from CN, C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkynyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl, wherein the C1-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkynyl, C3-C6 cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R a Replace; or, R 2 Selected from OCH3, OCD3, CN, OCHF2, OCF3, OC2H5, N(CH3)2, -C≡CH or -C≡CCH3.

6. The compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (I) is selected from the compound of formula (I-1) or its stereoisomer or a pharmaceutically acceptable salt thereof: Among them, ring A, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 As defined in any one of claims 1 to 5.

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 (I) is selected from the following compounds or their stereoisomers or pharmaceutically acceptable salts:

8. A pharmaceutical composition comprising the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

9. Use of the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating or preventing a disease or condition mediated by QPCT and / or QPCTL in a mammal, preferably a human.

10. The use according to claim 9, wherein the disease or condition mediated by QPCT and / or QPCTL is selected from neurodegenerative diseases, preferably Alzheimer's disease.

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