A compound capable of inhibiting connexin-related kinase 1, preparation and use thereof

Abstract

The present application relates to AAK1 inhibitors, methods of preparation and use thereof. In particular, the present application relates to compounds of general formula (I), methods of preparation thereof, pharmaceutical compositions thereof, and use of compounds of general formula (I) or pharmaceutical compositions thereof in the preparation of a medicament for the prevention and / or treatment of AAK1 mediated diseases, wherein the substituents of general formula (I) are as defined in the specification.

Description

Compound capable of inhibiting connexin-associated kinase 1, preparation thereof and use thereof

[0001] The present invention claims the priority of the prior application with patent application number CN202311445800.X filed with the State Intellectual Property Office of China on November 2, 2023, entitled "A compound capable of inhibiting connexin-related kinase 1, its preparation and use". Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a compound capable of inhibiting adaptor associated kinase 1 (AAK1), a preparation method and a composition thereof, and use thereof in preparing medicines. Background Art

[0003] Connexin-associated kinase 1 (AAK1) is a member of the Ark1 / Prk1 family of serine / threonine kinases. AAK1 mRNA exists in two spliced ​​forms, referred to as the short and long forms. The long form predominates and is highly expressed in the brain and heart. AAK1 is enriched in synaptosomal preparations and colocalizes with endocytic structures in cultured cells. AAK1 regulates clathrin-coated endocytosis, a process important in synaptic vesicle recycling and receptor-mediated endocytosis. AAK1 associates with the AP2 complex, a heterotetramer that connects receptor cargo to the clathrin coating. Clathrin binding to AAK1 stimulates AAK1 kinase activity. AAK1 phosphorylates the mu-2 subunit of AP-2, which promotes binding of mu-2 to the tyrosine-containing sorting motif on the cargo receptor. Mu2 phosphorylation is not essential for receptor uptake, but phosphorylation increases the efficiency of internalization.

[0004] Studies have shown that AAK1 knockout mice exhibit significantly reduced responses to persistent pain during phase II of the formalin model and significantly alleviate mechanical allodynia induced by SNL (spinal nerve ligation). The AAK1 small molecule inhibitor LP-935509 significantly alleviates pain responses during phase II of the formalin model, mechanical allodynia induced by SNL in mice, pain responses in the CCI (sciatic nerve ligation) model in mice, and pain responses in the streptozotocin-induced diabetic neuropathy model in mice (Kostich et al., J Pharmacol Exp Ther, 2016). These findings suggest that inhibiting AAK1 activity may have potential therapeutic effects on pain.

[0005] AAK1 has been identified as an inhibitor of neuregulin-1 / ErbB4 signaling in PC12 cells. Loss of AAK1 expression via RNA interference-mediated gene silencing or treatment with the kinase inhibitor K252a (which inhibits AAK1 kinase activity) leads to enhanced neuregulin-1-induced neurite outgrowth. These treatments lead to increased ErbB4 expression and increased accumulation of ErbB4 in or near the plasma membrane. NRG1 and ErbB4 are putative schizophrenia susceptibility genes. SNPs in the two genes are associated with a variety of schizophrenia endophenotypes. Neuregulin 1 and ErbB4 KO mouse models have shown morphological changes and behavioral phenotypes associated with schizophrenia. In addition, single nucleotide polymorphisms in the introns of the AAK1 gene are associated with the age of onset of Parkinson's disease. These results suggest that inhibiting AAK1 activity could be useful in treating schizophrenia, cognitive deficits in schizophrenia, Parkinson's disease, neuropathic pain, bipolar disorder, and Alzheimer's disease.

[0006] Viruses enter cells through various pathways, including endocytosis and membrane fusion. Most viruses primarily utilize endocytosis, with clathrin-mediated endocytosis being the primary pathway. Vesicular stomatitis virus (VSV), influenza virus (IAV), and Congo hemorrhagic fever virus (CCHFV) all enter cells via clathrin-dependent pathways. Studies have shown that the infection process of several viruses, including VSV, rabies virus (RABV), and hepatitis C virus (HCV), depends on AAK1. These findings suggest that inhibiting AAK1 activity may have potential therapeutic applications in the treatment of viral infections.

[0007] Summary of the Invention

[0008] The present invention provides a compound represented by general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, which inhibit AAK1 and cell proliferation, exhibit favorable pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, minimal toxicity and side effects, and possess advantages such as oral administration, rapid absorption, and high clearance. Furthermore, the invention unexpectedly discovered that the compound of the present invention exhibits good brain penetrance.

[0009] The object of the present invention is to provide a compound represented by general formula (I), (IIA), (IIB), its stereoisomers or pharmaceutically acceptable salts thereof:

[0010] in:

[0011] Y1, Y2 and Y3 are each independently CR a or N;

[0012] R a For hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S;

[0013] R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, amino, thiol, aminoacyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Hydroxyalkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, -C(O)C 1-6 Alkyl, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl, -NHC(O)NHC 1-6 Alkyl, -NHC(O)C 3-8 Cycloalkyl, -NHC(O)OC 3-8 Cycloalkyl, -NHC(O)C 4-6 Heterocycloalkyl or -NHC(O)OC 4-6 heterocycloalkyl;

[0014] It does not contain the following compounds:

[0015] In some embodiments, Y1, Y2 and Y3 are each independently CH or N; in some embodiments, Y1, Y2 and Y3 are each independently CH or N, and Y1, Y2 and Y3 are not CH at the same time; in some embodiments, Y1 is N, Y2 and Y3 are CH, or Y2 is N, Y1 and Y3 are CH, or Y3 is N, Y1 and Y2 are CH.

[0016] In some embodiments, R a is hydrogen, halogen or C 1-6 Alkyl; in some embodiments, R a is hydrogen, halogen or C 1-3 Alkyl, in some embodiments, R a For hydrogen.

[0017] In some embodiments, R1 is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl or -NHC(O)NHC 1-6 In some embodiments, R1 is C 1-3 Haloalkyl or -NHC(O)OC 1-3 Alkyl; in some embodiments, R1 is -CH2F, -CHF2, -CHF3, -NHC(O)OCH3, -NHC(O)OCH2CH3, -NHC(O)OCH2CH2CH3; in some embodiments, R1 is -CHF2 or -NHC(O)OCH3.

[0018] In some embodiments, R2 is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 In some embodiments, R2 is cyano, C 1-3 Alkyl or C 1-3 Haloalkyl; in some embodiments, R2 is cyano, methyl, or -CHF2.

[0019] In some embodiments, the compound represented by general formula (I) is selected from:

[0020] or a mixture thereof.

[0021] In a further embodiment of the present invention, the general formula (I) is further represented by the general formula (II):

[0022] in:

[0023] R1 is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl or -NHC(O)NHC 1-6 In some embodiments, R1 is C 1-6 Haloalkyl or -NHC(O)OC 1-6 In some embodiments, R1 is C 1-3 Haloalkyl or -NHC(O)OC 1-3 Alkyl; in some embodiments, R1 is -CHF2 or -NHC(O)OCH3;

[0024] R2 is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl or -NHC(O)NHC 1-6 In some embodiments, R2 is C 1-6 Alkyl, cyano, C 1-6 In some embodiments, R2 is C 1-6 Alkyl or C 1-6 In some embodiments, R2 is C 1-3 Alkyl or C 1-3 haloalkyl; in some embodiments, R2 is methyl, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2F, -CHF2, or -CF3; in some embodiments, R2 is methyl or -CHF2.

[0025] In a further embodiment of the present invention, the general formula (II) is further represented by the general formula (IIA) or the general formula (IIB):

[0026] in:

[0027] R1 and R2 are as described in any of the above technical solutions.

[0028] In a further embodiment of the present invention, the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are selected from the following compounds:

[0029] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of any one of the above-mentioned compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.

[0030] In a further embodiment of the present invention, the pharmaceutical composition comprises 1-1500 mg of any one of the above compounds, its stereoisomers or pharmaceutically acceptable salts and one or more pharmaceutically acceptable carriers or excipients.

[0031] The present invention also provides a use of any of the above-mentioned compounds, stereoisomers or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug, preferably a drug for preventing and / or treating AAK1-mediated diseases.

[0032] In a further embodiment of the present invention, the AAK1-mediated disease is diabetic neuropathy or postherpetic pain.

[0033] The present invention also provides a method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of any one of the above-mentioned compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably diabetic neuropathy or postherpetic pain.

[0034] As used herein, an "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a compound disclosed herein to provide a sufficient amount of relief to some extent from one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a peptide compound, conjugate, or a pharmaceutically acceptable salt thereof disclosed herein that is required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0035] In some embodiments, the pharmaceutical composition or formulation of the present invention contains the above-mentioned therapeutically effective amount of any one of the above-mentioned compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0036] The present invention further relates to a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of any of the above-mentioned compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "drug strength"). In some embodiments, the pharmaceutical composition includes but is not limited to 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 0 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of the compound represented by any of the above, its stereoisomers or pharmaceutically acceptable salts thereof.

[0037] The present invention further relates to a method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of any one of the compounds described above, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients, wherein the therapeutically effective amount is preferably 1-1500 mg. The disease is preferably neuropathic pain, more preferably diabetic neuropathy or postherpetic pain.

[0038] The present invention further relates to a method for treating a disease in a mammal, comprising administering to a subject a compound as described above in any one of the foregoing embodiments of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-100 0 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day. In some embodiments, the daily dose includes but is not limited to 1 mg / day. g / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 300mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, 1500mg / day.

[0039] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains the compound shown in any one of the above items of the present invention, its stereoisomer or pharmaceutically acceptable salt, and the amount of the compound of the present invention or its stereoisomer or pharmaceutically acceptable salt is the same as its amount in the above-mentioned pharmaceutical composition.

[0040] The amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.

[0041] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0042] Synthesis route

[0043] Those skilled in the art can prepare the compounds of the present invention by combining references in WO2023284838, WO2017059085, WO2017059080, and WO2015153720 with known organic synthesis techniques, using commercially available chemicals and / or compounds described in chemical literature as starting materials. "Commercially available chemicals" are obtained from legitimate commercial sources, including suppliers such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0044] Reference books and monographs in the field detailing the synthesis of reactants that can be used to prepare the compounds described herein, or articles describing such preparations, are provided for reference. These reference books and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions", 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials",Second,Revised and Enlarged Edition(1994)John Wiley&Sons ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4th Edition(1992)John Wiley&Sons,ISBN:0-471-60180-2;Otera,J.(editor)“Modern Carbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.“Patai’s 1992Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9;Solomons,T.W.G.“Organic Chemistry”7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0;Stowell,J.C.,“Intermediate Organic Chemistry”2nd Edition(1993)Wiley-Interscience,ISBN:0-471-57456-2;“Industrial Organic Chemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia”(1999)John Wiley&Sons,ISBN:3-527-29645-X,in 8volumes;“Organic Reactions”(1942-2000)John Wiley&Sons,in over 55volumes;and“Chemistry of Functional Groups”John Wiley&Sons,in 73volumes.

[0045] Specific and similar reactants can be selectively identified by indexing known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society, which is available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog can alternatively be prepared by custom chemical synthesis facilities, many of which standard chemical supply houses (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0046] Detailed Description of the Invention

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0048] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms. 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), further preferably an alkyl having 1 to 6 carbon atoms (ie, C 1-6 Alkyl), most preferably an alkyl group having 1 to 3 carbon atoms (i.e., C 1-3Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. When the alkyl group is substituted with a substituent, the substituent is not further substituted.

[0049] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C 3-20 The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably a cycloalkyl having 3 to 8 carbon atoms (i.e., C 3-8 cycloalkyl), further preferably a cycloalkyl having 3 to 6 carbon atoms (i.e., C 3-6 cycloalkyl), most preferably a cycloalkyl having 3 to 5 carbon atoms (i.e., C 3-5 Cycloalkyl), or a cycloalkyl having 5 to 6 carbon atoms (i.e., C 3-5Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Non-limiting examples of polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0050] The term "spiroalkyl" refers to a polycyclic group in which the rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but no ring has a completely conjugated π electron system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., C 5-20 The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (ie, C 6-14 Spirocycloalkyl), more preferably a spirocycloalkyl having 7 to 10 ring atoms (ie, C 7-10 Spirocycloalkyl). The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of spiro atoms shared between rings, preferably a monospirocycloalkyl group or a bispirocycloalkyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocycloalkyl group.

[0051] The term "fused cycloalkyl" refers to an all-carbon polycyclic group having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20 The fused cycloalkyl group may contain one or more double bonds, but no ring has a completely conjugated π electron system. The fused cycloalkyl group preferably has 6 to 14 ring atoms (i.e., C 6-14 fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (ie, C 7-10 The condensed cycloalkyl group is classified into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl group according to the number of constituent rings, preferably a bicyclic condensed cycloalkyl group or a tricyclic condensed cycloalkyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic condensed cycloalkyl group.

[0052] The term "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., C 5-20 The bridged cycloalkyl group preferably has a bridged cycloalkyl group with 6 to 14 ring atoms (i.e., C 6-14 bridged cycloalkyl), more preferably a bridged cycloalkyl having 7 to 10 ring atoms (ie, C 7-10 According to the number of constituent rings, the cycloalkyl group may be classified into bicyclic, tricyclic, tetracyclic or polycyclic cycloalkyl groups, and is preferably a bicyclic or tricyclic cycloalkyl group.

[0053] The cycloalkyl group may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring that is attached to the parent structure is a cycloalkyl group.

[0054] The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. When the cycloalkyl group is substituted with a substituent, the substituent is not further substituted.

[0055] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocycloalkyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n(wherein m and n are integers of 0-2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The heterocycloalkyl group preferably has 3 to 12 ring atoms (i.e., 3-12 membered heterocycloalkyl), wherein 1 to 4 heteroatoms are selected from N, O and S atoms, more preferably has 3 to 8 ring atoms (i.e., 3-8 membered heterocycloalkyl), wherein 1 to 4, 1 to 3 or 1 to 2 heteroatoms are selected from N, O and S atoms, further preferably has 3 to 6 ring atoms (i.e., 3-6 membered heterocycloalkyl), wherein 1 to 4, 1 to 3 or 1 to 2 heteroatoms are selected from N, O and S atoms, and most preferably has 5 to 6 ring atoms (i.e., 5-6 membered heterocycloalkyl), wherein 1 to 4, 1 to 3 or 1 to 2 heteroatoms are selected from N, O and S atoms. Non-limiting examples of the monocyclic heterocycloalkyl include: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolane, 2,2-difluoro-1,3-dioxolane, cyclopentanone, 2,2-difluorocyclopentanone, azepanyl, oxolanyl or azacyclopentanyl, etc. Non-limiting examples of the polycyclic heterocycloalkyl include: spiroheterocycloalkyl, fused heterocycloalkyl and bridged heterocycloalkyl.

[0056] The term "spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which the monocyclic rings share one atom (called a spiro atom), which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5-20 membered spiroheterocycloalkyl group), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n (wherein m and n are integers from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The spiroheterocycloalkyl group preferably has 6 to 14 ring atoms (i.e., 6-14 membered spiroheterocycloalkyl), more preferably 7 to 10 ring atoms (i.e., 7-10 membered spiroheterocycloalkyl). The spiroheterocycloalkyl group is divided into monospiroheterocycloalkyl group, bispiroheterocycloalkyl group or polyspiroheterocycloalkyl group according to the number of spiro atoms shared between rings, preferably monospiroheterocycloalkyl group or bispiroheterocycloalkyl group, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospiroheterocycloalkyl group.

[0057] The term "fused heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and which has from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5-20 membered fused heterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n (wherein m and n are integers from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The fused heterocycloalkyl group preferably has 6 to 14 ring atoms (i.e., a 6-14-membered fused heterocycloalkyl group), and more preferably has 7 to 10 ring atoms (i.e., a 7-10-membered fused heterocycloalkyl group). According to the number of constituent rings, it is classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, preferably bicyclic fused heterocycloalkyl groups or tricyclic fused heterocycloalkyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocycloalkyl groups.

[0058] The term "bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two atoms that are not directly connected, having from 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5-20 membered bridged heterocycloalkyl group), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n (wherein m and n are integers from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The bridged heterocycloalkyl group preferably has a bridged heterocycloalkyl group with 6 to 14 ring atoms (i.e., a 6-14-membered bridged heterocycloalkyl group), and more preferably a bridged heterocycloalkyl group with 7 to 10 ring atoms (i.e., a 7-10-membered bridged heterocycloalkyl group). According to the number of constituent rings, it is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl groups, preferably bicyclic bridged heterocycloalkyl groups or tricyclic bridged heterocycloalkyl groups.

[0059] The heterocycloalkyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocycloalkyl group.

[0060] The heterocycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. When the heterocycloalkyl group is substituted with a substituent, the substituent is no longer further substituted.

[0061] The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., C 6-14 The aryl group is preferably an aryl group having 6 to 12 carbon atoms (i.e., C 6-12 aryl), more preferably an aryl group having 6 to 10 carbon atoms (i.e., C 6-10 The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracenyl, phenanthrenyl, etc.

[0062] The aryl group may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring. The aryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. When the aryl group is substituted with a substituent, the substituent may not be further substituted.

[0063] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., a monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n(wherein m, n are integers of 0-2) heteroatoms, preferably heteroatoms selected from nitrogen, oxygen, or sulfur, but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The heteroaryl preferably has a heteroaryl of 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl). The monocyclic heteroaryl preferably has a heteroaryl of 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl), non-limiting examples of which include furyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, etc. The polycyclic heteroaryl, preferably a 5-6 membered heteroaryl, a 5-6 membered heteroaryl, a 5-10 membered heteroaryl, and C 6-10 Aryl or C 6-10 Aryl and 5-10 membered heteroaryl, further preferably 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and phenyl or phenyl and 5-6 membered heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, thienophenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridyl, pyridothiphenyl, pyridopyrrolyl and the like.

[0064] The heteroaryl group may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. When the heteroaryl group is substituted with a substituent, the substituent is not further substituted.

[0065] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C 1-10 The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C 1-8 Alkoxy), more preferably an alkoxy having 1 to 6 carbon atoms (ie, C 1-6 Alkoxy), most preferably alkoxy having 1 to 3 carbon atoms (ie C 1-3Alkoxy). Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. When the alkoxy group is substituted with a substituent, the substituent may not be further substituted.

[0066] The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C 1-10 The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C 1-8 alkylthio), more preferably an alkylthio group having 1 to 6 carbon atoms (ie, C 1-6 alkylthio), more preferably alkylthio having 1 to 3 carbon atoms (i.e., C 1-3 Alkylthio). Non-limiting examples include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc. The alkylthio group can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. When the alkylthio group is substituted with a substituent, the substituent is not further substituted.

[0067] The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0068] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0069] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, and the like; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2 ,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0070] The term "mercapto" refers to -SH.

[0071] The term "hydroxy" refers to -OH.

[0072] The term "nitro" refers to -NO2.

[0073] The term "amino" refers to -NH2.

[0074] The term "cyano" refers to -CN.

[0075] The term "carboxy" refers to -C(O)OH.

[0076] The term "oxo" or "oxo" refers to =0.

[0077] The term "carbonyl" refers to C=O.

[0078] The term "aminoacyl" refers to -C(O)NH2.

[0079] The term "sulfonyl" refers to -S(O)2.

[0080] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium groups, wherein alkyl is as defined above.

[0081] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium groups, wherein alkoxy is as defined above.

[0082] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0083] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0084] The term "alkylamino" refers to an alkyl-NH- group, wherein alkyl is as defined above.

[0085] The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art will understand that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0086] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0087] When the lower limit and upper limit of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood to mean each value and range encompassed within the broader range.

[0088] Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

[0089] The expression mn used herein refers to the range from m to n and the subranges and individual point values ​​therein. For example, the expression "C2-C8" or "C 2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C 10 ” or “C 3-10 " should also be understood in a similar manner, for example, any sub-ranges and point values ​​contained therein may be encompassed, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C9, etc. and C3, C4, C5, C6, C7, C8, C9, C 10 For example, the expression "C1-C6" or "C 1-6 " covers a range of 1-6 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. For another example, the expression "three-membered to ten-membered" should be understood to cover any subranges and each point value therein, such as three-membered to five-membered, three-membered to six-membered, three-membered to seven-membered, three-membered to eight-membered, four-membered to five-membered, four-membered to six-membered, four-membered to seven-membered, four-membered to eight-membered, five-membered to seven-membered, five-membered to eight-membered, six-membered to seven-membered, six-membered to eight-membered, nine-membered to ten-membered, etc., as well as three, four, five, six, seven, eight, nine, ten-membered, etc. Other similar expressions herein should be understood in a similar manner.

[0090] As used herein, different expressions such as “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all convey the same meaning, that is, X can be any one or more of A, B, and C.

[0091] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl may but need not be present, and the description includes both the case where the cycloalkyl is substituted with alkyl and the case where the cycloalkyl is not substituted with alkyl.

[0092] The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom being replaced by a selection from the designated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. When a substituent is described as not being present, it is understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When each carbon atom in a group is described as optionally substituted by a heteroatom, the proviso is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.

[0093] If a substituent is described as being "optionally substituted with...", the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted with one or more of the substituents listed, one or more hydrogen atoms on the atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =0), this means that two hydrogen atoms are replaced. When the substituent is hydrogen, this may also mean that the corresponding group is "non-substituted" or "unsubstituted." Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0094] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0095] When any variable (e.g., R), as well as variables with labels (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may be optionally substituted with up to four R substituents, and the options for each R substituent at each occurrence are independent of each other.

[0096] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of the present invention. All of these isomers and their mixtures are within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures, are also within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0097] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0098] The compounds of the present invention include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, respectively. 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 P. 33 P. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0099] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0100] In the compounds of the present invention, when a position is specifically designated as deuterium, D, the position is understood to have an abundance of deuterium at least 1000 times greater than the natural abundance (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0101] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.

[0102] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0103] The term "pharmaceutical composition" refers to a composition containing one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0104] The term "pharmaceutically acceptable carrier" refers to substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0105] The term "administration" or "administering" refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. In particular, injection or oral administration.

[0106] As used herein, the term "treating" includes alleviating, alleviating or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease is observed. A prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or when a patient develops one or more physiological symptoms of a disease, even though the disease has not yet been diagnosed.

[0107] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition. The term "neuropsychiatric disorder" refers to a general term encompassing neurological and / or psychiatric disorders.

[0108] With respect to a drug, pharmaceutical unit, or active ingredient, the terms "effective amount," "therapeutically effective amount," or "prophylactically effective amount" refer to a sufficient amount of the drug or pharmaceutical agent to achieve the desired effect with acceptable side effects. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine testing.

[0109] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0110] The term "room temperature" refers to a temperature from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature from 18°C ​​to 25°C.

[0111] "Equivalent" or its abbreviation "eq" refers to the equivalent amount of other raw materials required based on the equivalent relationship of chemical reactions, with the basic raw material used in each step as the benchmark (1 equivalent).

[0112] In the context of the present invention, when or whether the words "about" or "approximately" are used, they mean within 10%, suitably within 5%, and particularly within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% is expressly disclosed, where "+ / -" means plus or minus.

[0113] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses.

[0114] The compounds shown herein inhibit AAK1 and cell proliferation, exhibit favorable pharmacokinetic properties, high bioavailability, good safety, high selectivity, minimal toxicity and side effects, and possess advantages such as oral administration, rapid absorption, and high clearance. Furthermore, the compounds have good brain penetration and can be used to prevent and / or treat diabetic neuropathy or postherpetic pain. DETAILED DESCRIPTION

[0115] Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the present invention.In addition, should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the appended claims of the application.

[0116] Example

[0117] Below in conjunction with embodiment, embodiment of the present invention is described in detail, but those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. In the embodiment, if specific conditions are not specified, it is carried out according to normal conditions or the conditions recommended by the manufacturer. Reagents or instruments used are not specified by the manufacturer and are all conventional products that can be obtained commercially. Retention time of the present invention refers to the peak time of analytical liquid chromatography.

[0118] Example 1:

[0119] Compound 1A (10.00 g, 25.82 mmol, synthesized using 2-difluoromethyl-4-bromopyridine as starting material, according to the synthesis method of patent WO2023284838A1) was dissolved in a mixture of tetrahydrofuran and water (280 mL, 3:1, v:v). The mixture was then cooled to 0°C and 4-methylmorpholine-4-oxide (9.36 g, 77.46 mmol) was added. After nitrogen was purged from the reaction mixture, a 10 mL aqueous solution of potassium osmate dihydrate (1.46 g, 3.87 mmol) was slowly added dropwise at 0°C. After the addition was complete, the reaction mixture was allowed to react at room temperature (28°C) for 16 hours, and the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran, then diluted with water (100 mL) and extracted five times with dichloromethane / methanol (200 mL, 10:1, v:v). The combined organic phases were dried and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (dichloromethane:methanol = 20:1 to 5:1) followed by reverse phase separation (acetonitrile:water = 5:95 to 95:5) to afford 8.00 g of crude compound 1. This sample was further subjected to chiral separation to afford P1 (retention time: 1.788 min, 785 mg, designated as compound 1-1) and P2 (retention time: 1.987 min, 826 mg, designated as compound 1-2).

[0120] Analytical methods: Instrument: SHIMADZU LC-30AD, Column: Chiral OX Column; Mobile phase: A: CO2, B: 0.05% DEA in MEOH; Gradient: 5-40% B in A; Flow rate: 3 mL / min; Column temperature: 35°C; Wavelength: 220 nm.

[0121] Preparation method: Instrument: Waters 150Prep-SFC, Column: Chiral OX Column; Mobile Phase: A: CO2, B: 0.1% NH3·H2O in MEOH; Gradient: 35% B gradient elution, Flow rate: 100 mL / min, Column temperature: 25°C, Wavelength: 220 nm, Cycle time: 4.2 min. Sample preparation: Sample concentration: 5 mg / mL, methanol solution, injection: 1 mL per sample. After separation, the fractions were dried on a rotary evaporator at 35°C to yield Compound P1 and Compound P2.

[0122] Compound 1-1:

[0123] 1H NMR(400MHz,DMSO-d6)δ8.80-8.78(m,1H),8.41-8.39(m,1H),8.32(s,1H),8.21–8.20(m,1H),7.77-7.75(m,1H),7.4 2–6.90(m,2H),4.08–4.03(m,2H),3.30–3.28(m,5H),3.21-3.18(m,1H),1.72–1.61(m,2H),1.26(s,3H),1.10(s,3H).

[0124] LC-MS (ESI): m / z = 418.6 [M+H] + .

[0125] Compound 1-2:

[0126] 1 H NMR(400MHz,DMSO-d6)δ8.79-8.78(m,1H),8.41-8.38(m,1H),8.32(s,1H),8.22–8.20(m,1H),7.78-7.76(m,1H),7.43–6.90(m,2H),4.09–4.08 (m,1H),3.97–3.92(m,2H),3.32(s,2H),3.23–3.18(m,2H),3.17-3.15( m,1H),1.77–1.73(m,1H),1.54–1.50(m,1H),1.30(s,3H),1.14(s,3H).

[0127] LC-MS (ESI): m / z = 418.5 [M+H] + .

[0128] The synthetic routes of the remaining disclosed compounds described in the present invention refer to the synthetic route of Example 1.

[0129] Biological test evaluation

[0130] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0131] Test Example 1: In vitro AAK1 enzyme activity detection experiment

[0132] A 10 mM compound stock solution (dissolved in DMSO) was diluted to 0.2 mM with DMSO and then diluted 5-fold with DMSO to obtain 10 compound concentrations. Each compound concentration was then diluted 50-fold with 1× kinase reaction buffer (containing 40 mM Tris, 20 mM MgCl2, 0.1% BSA, and 0.5 mM DTT) for later use. AAK1 (Signalchem, Cat#A01-11G-10) was diluted to twice the final concentration (30 nM and 28 nM, respectively) with 1× kinase reaction buffer. 2 μL / well of AAK1 was added to a 384-well white plate, followed by 1 μL / well of compound. The plate was sealed with a film and centrifuged at 1000 rpm for 30 seconds. The plate was then incubated at room temperature for 10 minutes. A mixture of ATP (Promega, Cat#V914B) and substrate Micro2 (GenScript, Cat#PE0890) was prepared at 4 times the final concentration (the final ATP concentrations for AAK1 were 15 μM and 5 μM, respectively, and the final concentration of Micro2 was 0.1 mg / mL). 1 μL / well of the ATP-substrate mixture was added to the reaction plate. The plate was sealed with a sealing film and centrifuged at 1000 rpm for 30 seconds. The reaction was allowed to react at room temperature for 60 minutes (AAK1). Transfer 4 μL / well of ADP-Glo ​​(Promega, Cat# V9102) to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Transfer 8 μL / well of detection solution to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Read the RLU (Relative luminescence unit) signal using a Biotek multi-function microplate reader, and calculate the percentage inhibition rate as follows: [1-(LUM compound-LUM positive control) / (LUM negative control-LUM positive control)] × 100. IC was calculated using a four-parameter nonlinear fitting equation in Graphpad 7.0 software. 50 The specific results are shown in Table 1.

[0133] Table 1 AAK1 inhibitory activity

[0134] Conclusion: The compounds of the present invention showed high inhibitory activity against AAK1 receptors. For example, the IC50 value of compound 1-2 was 9.62 nM. Test Example 2: hERG potassium channel effect test

[0135] 2.1 Experimental preparation: Experimental platform: electrophysiological manual patch clamp system; cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channel.

[0136] 2.2 Experimental Methods: hERG potassium channel currents were recorded using the whole-cell patch-clamp technique at room temperature in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch-clamp amplifier by inserting them into the amplifier headstage. Clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -80 mV. To elicit hERG potassium currents (I hERG ), a 2-second depolarization step from -80 mV to +20 mV was applied, followed by repolarization to -50 mV, which was maintained for 1 second before returning to -80 mV. This voltage stimulus was applied every 10 seconds, and drug administration was initiated after confirming the stability of the hERG potassium current (at least 1 minute). Compounds were administered for at least 1 minute at each tested concentration, and at least two cells were tested at each concentration (n≥2).

[0137] 2.3 Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1 – (I / Io)] × 100%

[0138] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0139] Compound IC 50 Calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)×HillSlope))

[0140] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0141] Experimental results: IC of the test compound's inhibitory effect on hERG potassium channel current 50 The values ​​are shown in the table below:

[0142] Table 2 IC of the inhibitory effect of the test compounds on hERG potassium channel current 50 value Note: The structure of LX9211 is WO2015153720A1 (Example 123).

[0143] Conclusion: The compound of the present invention has low cardiotoxicity and is significantly better than the control compound.

[0144] Test Example 3: Pharmacokinetic Test in Mice

[0145] 3.1 Experimental Animals: Male ICR mice, 20-25 g, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0146] 3.2 Experimental Design: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0147] Table 3 Dosage information

[0148] 3.3 Test method:

[0149] The vehicle for intravenous administration was 5% DMA + 5% HS-15 + 90% NS; the vehicle for oral administration was 0.5% MC. Before and after administration, 0.06 mL of blood was collected via orbital microscopy under isoflurane anesthesia. Plasma was collected by centrifugation at 5000 rpm at 4°C for 10 minutes in an EDTAK2 centrifuge tube. Blood was collected at 0, 5, 15, 30 minutes, and 1, 2, 4, 7, and 24 hours for both the intravenous and oral administration groups. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0150] Table 4 Pharmacokinetic parameters of test compounds in mouse plasma

[0151] Dosing vehicle: 0.5% MC

[0152] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in mice.

[0153] Test Example 4: Pharmacokinetic Test in Rat

[0154] 4.1 Experimental Animals: Male SD rats, approximately 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0155] 4.2 Experimental Design: On the day of the experiment, six SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0156] Table 5 Dosage information

[0157] Dosing vehicle: 0.5% MC

[0158] Before and after drug administration, 0.1 ml of blood was collected intraorbitally under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from the venous group at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours; from the gavage group at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours. All samples were stored at −80°C prior to analysis.

[0159] The experimental results are shown in Table 6.

[0160] Table 6 Pharmacokinetic parameters of test compounds in rat plasma

[0161] Conclusion: The compounds of the present invention, such as compound 1-2, have good pharmacokinetics in rats.

[0162] Test Example 5: Liver microsome stability test

[0163] In this study, liver microsomes from five species, including humans, monkeys, dogs, rats and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.

[0164] At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. The T value was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CL int(mic) and hepatic intrinsic clearance CL int(Liver) .

[0165] Table 7 Results of test compounds in rat liver microsome model

[0166] Conclusion: The compounds of the present invention, such as the five compounds in the examples, are stable in liver microsomal metabolism.

Claims

1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: in: Y1, Y2 and Y3 are each independently CR a or N; R a is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S; R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, amino, thiol, aminoacyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Hydroxyalkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, -C(O)C 1-6 Alkyl, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl, -NHC(O)NHC 1-6 Alkyl, -NHC(O)C 3-8 Cycloalkyl, -NHC(O)OC 3-8 Cycloalkyl, -NHC(O)C 4-6 Heterocycloalkyl or -NHC(O)OC 4-6 Heterocycloalkyl; And does not contain the following compounds:

2. The compound represented by the general formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) Y1, Y2 and Y3 are each independently CH or N, preferably Y1, Y2 and Y3 are each independently CH or N, and Y1, Y2 and Y3 are not CH at the same time, more preferably Y1 is N, Y2 and Y3 are CH, or Y2 is N, Y1 and Y3 are CH, or Y3 is N, Y1 and Y2 are CH; (2)R a is hydrogen, halogen or C 1-6 Alkyl, preferably hydrogen, halogen or C 1-3 Alkyl, more preferably hydrogen; (3) R1 is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl or -NHC(O)NHC 1-6 Alkyl, preferably C 1-3 Haloalkyl or -NHC(O)OC 1-3 Alkyl, more preferably -CHF2 or -NHC(O)OCH3; (4) R2 is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl, more preferably cyano, methyl or -CHF2; (5) The compound represented by the general formula (I) is selected from: or a mixture thereof.

3. The compound represented by the general formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) is further shown in the general formula (II): in: R1 is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl or -NHC(O)NHC 1-6 alkyl; R2 is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C(O)C 1-6 Alkyl, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl or -NHC(O)NHC 1-6 alkyl.

4. The compound represented by general formula (I) according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (II) is further shown as the general formula (IIA) or the general formula (IIB): in: R1 and R2 are as described in claim 3.

5. The compound represented by the general formula (I) according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds:

6. A pharmaceutical composition comprising a therapeutically effective dose of the compound as claimed in any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

7. The pharmaceutical composition according to claim 6, comprising 1-1500 mg of the compound shown in any one of claims 1-5, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

8. Use of the compound according to any one of claims 1 to 5, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 6 or 7 in the preparation of a drug, preferably the drug is a drug for preventing and / or treating AAK1-mediated diseases.

9. The use according to claim 8, wherein the AAK1-mediated disease is diabetic neuropathy or post-herpetic pain.

10. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6 or 7, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably diabetic neuropathy or postherpetic pain.

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