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WO2025092928A1 - 一种可抑制连接蛋白相关激酶1的化合物、制备及其用途 - Google Patents

一种可抑制连接蛋白相关激酶1的化合物、制备及其用途 Download PDF

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Publication number
WO2025092928A1
WO2025092928A1 PCT/CN2024/129056 CN2024129056W WO2025092928A1 WO 2025092928 A1 WO2025092928 A1 WO 2025092928A1 CN 2024129056 W CN2024129056 W CN 2024129056W WO 2025092928 A1 WO2025092928 A1 WO 2025092928A1
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alkyl
nhc
membered
deuterium
pharmaceutically acceptable
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English (en)
French (fr)
Inventor
李瑶
石宗军
任磊
程凤凯
唐平明
张晨
严庞科
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Tibet Haisco Pharmaceutical Co Ltd
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Tibet Haisco Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 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 a use thereof in preparing medicines.
  • AAK1 adaptor associated kinase 1
  • Connexin-associated kinase 1 is a member of the Ark1/Prk1 family of serine/threonine kinases.
  • AAK1 mRNA exists in two splice forms, referred to as the short form and the long form. The long form is predominant 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 endocytosis of clathrin-coated cells, a process important in synaptic vesicle recycling and receptor-mediated endocytosis.
  • AAK1 binds to the AP2 complex, a heterotetramer that links receptor cargo to the clathrin coat. Clathrin binding to AAK1 stimulates AAK1 kinase activity. AAK1 phosphorylates the mu-2 subunit of AP-2, which promotes binding of mu-2 to tyrosine-containing sorting motifs on cargo receptors. Mu2 phosphorylation is not essential for receptor uptake, but phosphorylation increases the efficiency of internalization.
  • mice with AAK1 knockout significantly reduced their response to persistent pain in the phase II of the formalin model and significantly reduced mechanical allodynia caused by SNL (spinal nerve ligation).
  • the AAK1 small molecule inhibitor LP-935509 can significantly reduce the pain response in the phase II of the formalin mouse model, mechanical allodynia caused by SNL in mice, the pain response in the mouse CCI (sciatic nerve ligation) model, and the streptozotocin-induced mouse diabetic neuropathy model (Kostich et al., J Pharmacol Exp Ther, 2016).
  • 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 ErbB4KO mouse models have shown morphological changes and behavioral phenotypes associated with schizophrenia.
  • viruses there are many ways for viruses to enter cells, such as endocytosis and membrane fusion. Most viruses use endocytosis as the main entry method, among which clathrin-mediated endocytosis is the main endocytosis pathway. Vesicular stomatitis virus (VSV), influenza virus (IAV), Congo hemorrhagic fever virus (CCHFV) and others all enter cells through clathrin-dependent pathways. Studies have found that the infection process of many viruses depends on AAK1, such as vesicular stomatitis virus (VSV), rabies virus (RABV), hepatitis C virus (HCV), etc. These results show that inhibiting the activity of AAK1 may have potential therapeutic effects on diseases related to viral infection.
  • VSV vesicular stomatitis virus
  • RABV rabies virus
  • HCV hepatitis C virus
  • the present invention provides a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which has an inhibitory effect on AAK1, can inhibit cell proliferation, has good pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, low toxicity and side effects, and has the advantages of oral administration, rapid absorption, high clearance rate, etc.
  • the compound of the present invention has good brain penetration.
  • the object of the present invention is to provide a compound represented by the general formula (I), (IIA), (IIB), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • Y 1 , Y 2 and Y 3 are each independently CR a or N;
  • Ra is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C6-10 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, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 hydroxyalkyl, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, C3-8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S, C6-10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, -C(O)C1-6 alkyl, -NHC(O) C1-6 alkyl, -NHC(O) OC1-6 alkyl, -NHC(O) NHC1-6 alkyl, -NHC(O) C -NHC(O)C 3-8 cycloalkyl, -NHC
  • Y 1 , Y 2 and Y 3 are each independently CH or N; in some embodiments, Y 1 , Y 2 and Y 3 are each independently CH or N, and Y 1 , Y 2 and Y 3 are not CH at the same time; in some embodiments, Y 1 is N, Y 2 and Y 3 are CH, or Y 2 is N, Y 1 and Y 3 are CH, or Y 3 is N, Y 1 and Y 2 are CH.
  • Ra is hydrogen, halogen, or C1-6 alkyl; in some embodiments, Ra is hydrogen, halogen, or C1-3 alkyl; in some embodiments, Ra is hydrogen.
  • R 1 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; in some embodiments, R 1 is C 1-3 haloalkyl or -NHC(O)OC 1-3 alkyl; in some embodiments, R 1 is -CH 2 F, -CHF 2 , -CHF 3 , -NHC(O)OCH 3 , -NHC(O)OCH 2 CH 3 , -NHC(O)OCH 2 CH 2 CH 3 ; in some embodiments, R 1 is -CHF 2 or -NHC(O)OCH 3 .
  • R 2 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy; in some embodiments, R 2 is cyano, C 1-3 alkyl or C 1-3 haloalkyl; in some embodiments, R 2 is cyano, methyl or -CHF 2 .
  • the compound represented by the general formula (I) is selected from:
  • R 1 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; in some embodiments, R 1 is C 1-6 haloalkyl or -NHC(O)OC 1-6 alkyl; in some embodiments, R 1 is C 1-3 haloalkyl or -NHC(O)OC 1-3 alkyl; in some embodiments, R 1 is -CHF 2 or -NHC(O)OCH 3 ;
  • R 2 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; in some embodiments, R 2 is C 1-6 alkyl, cyano, C 1-6 haloalkyl; in some embodiments, R 2 is C 1-6 alkyl or C 1-6 haloalkyl; in some embodiments, R 2 is C 1-3 alkyl or C 1-3 haloalkyl; in some embodiments, R 2 is methyl, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 F, -CHF 2 , or -CF 3 ; in some embodiments, R 2 is methyl
  • the general formula (II) is further represented by the general formula (IIA) or the general formula (IIB):
  • R1 and R2 are as described in any of the above technical solutions.
  • the compound represented by the general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are selected from the following compounds:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose 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 comprises 1-1500 mg of any one of the above compounds, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.
  • 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.
  • the AAK1-mediated disease is diabetic neuropathy or post-herpetic pain.
  • the present invention also provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of any one of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts, 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.
  • an "effective amount” or “therapeutically effective amount” described in this application refers to the administration of a sufficient amount of the compound disclosed in this application, which will alleviate one or more symptoms of the disease or condition being treated to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms or causes of the disease, or any other desired changes in the biological system.
  • an "effective amount” for therapeutic use is the amount of a composition comprising a peptide compound, conjugate, or a pharmaceutically acceptable salt thereof disclosed in this application that is required to provide a clinically significant reduction in disease symptoms.
  • 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, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 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, 10-1 500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-
  • the pharmaceutical composition or preparation 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.
  • the present invention further relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of any of the above compounds, stereoisomers 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 preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
  • 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 0mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 850mg
  • the present invention further relates to a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of any of the above-mentioned compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable
  • the carrier or excipient, the therapeutically effective amount is preferably 1-1500 mg
  • the disease is preferably neuropathic pain, more preferably diabetic neuropathy, postherpetic pain.
  • the present invention further relates to a method for treating a disease in a mammal, the method comprising administering a compound as described in any one of the above-mentioned embodiments of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, to a subject at a daily dose of 1-1500 mg/day, wherein the daily dose may be a single dose or divided doses.
  • 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.
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains the compound shown in any one of the above items of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof, 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.
  • the amount of the compound according to the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • references books and monographs in the field detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide reference to articles describing such preparation methods. 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.
  • 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, i.e., " C1-20 alkyl”.
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C1-12 alkyl), more preferably an alkyl group having 1 to 8 carbon atoms (i.e., C1-8 alkyl), further preferably an alkyl group having 1 to 6 carbon atoms (i.e., C1-6 alkyl), and most preferably an alkyl group having 1 to 3 carbon atoms (i.e., C1-3 alkyl).
  • Non-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
  • the alkyl group may be substituted or unsubstituted, and 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.
  • the alkyl group is substituted with a substituent, the substituent is no longer substituted further.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) 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) carbon atoms, i.e., a C3-20 cycloalkyl.
  • the cycloalkyl is preferably a cycloalkyl having 3 to 12 carbon atoms (i.e., a C3-12 cycloalkyl), more preferably a cycloalkyl having 3 to 8 carbon atoms (i.e., a C3-8 cycloalkyl), further preferably a cycloalkyl having 3 to 6 carbon atoms (i.e., a C3-6 cycloalkyl), most preferably a cycloalkyl having 3 to 5 carbon atoms (i.e., a C3-5 cycloalkyl), or, alternatively, a cycloalkyl having 5 to 6 carbon atoms.
  • Alkyl i.e.
  • Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.
  • Non-limiting examples of the polycyclic cycloalkyl include: spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between monocyclic rings, which may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ 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., C5-20 spirocycloalkyl).
  • the spirocycloalkyl preferably has 6 to 14 ring atoms (i.e., C6-14 spirocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., C7-10 spirocycloalkyl).
  • the spirocycloalkyl group is divided into monospirocycloalkyl group, bispirocycloalkyl group or polyspirocycloalkyl group according to the number of spiro atoms shared between rings, preferably monospirocycloalkyl group or bispirocycloalkyl 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, 6-membered/3-member
  • fused cycloalkyl refers to a full carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the 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., C5-20 fused cycloalkyl). It may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the fused cycloalkyl preferably has a fused cycloalkyl having 6 to 14 ring atoms (i.e., C6-14 fused cycloalkyl), and more preferably has a fused cycloalkyl having 7 to 10 ring atoms (i.e., C7-10 fused cycloalkyl).
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups preferably bicyclic condensed cycloalkyl groups or tricyclic condensed cycloalkyl 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-membere
  • bridged cycloalkyl refers to a full-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 bridged cycloalkyl). It contains one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the bridged cycloalkyl preferably has a bridged cycloalkyl with 6 to 14 ring atoms (i.e., C 6-14 bridged cycloalkyl), and more preferably has a bridged cycloalkyl with 7 to 10 ring atoms (i.e., C 7-10 bridged cycloalkyl). According to the number of constituent rings, it is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl.
  • the cycloalkyl group may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and 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.
  • the substituent is no longer substituted further.
  • 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 from 0 to 2) heteroatoms, but excluding -OO-, -OS- or -SS-
  • the heterocycloalkyl group preferably has 3 to 12 ring atoms (i.e., 3-12 membered heterocycloalkyl groups), wherein 1 to 4 heteroatoms are
  • 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.
  • spiroheterocycloalkyl refers to a polycyclic heterocycloalkyl group in which one atom (called spiro atom) is shared between monocyclic rings, 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., 5-20 membered spiroheterocycloalkyl), 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, but excluding -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon.
  • the spiroheterocycloalkyl preferably has a spiroheterocycloalkyl having 6 to 14 ring atoms (i.e., 6-14 membered spiroheterocycloalkyl), and more preferably has a spiroheterocycloalkyl having 7 to 10 ring atoms (i.e., 7-10 membered spiroheterocycloalkyl).
  • the spiro heterocycloalkyl group is divided into monospiro heterocycloalkyl group, bispiro heterocycloalkyl group or polyspiro heterocycloalkyl group according to the number of spiro atoms shared between rings, preferably monospiro heterocycloalkyl group or bispiro heterocycloalkyl 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, 6-
  • fused heterocycloalkyl refers to a polycyclic heterocycloalkyl group in which each ring in the system shares a pair of adjacent atoms with other rings in the 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., 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 of 0-2) heteroatoms, but excluding -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon.
  • the fused heterocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6-14-membered fused heterocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7-10-membered fused heterocycloalkyl).
  • 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
  • bridged heterocycloalkyl refers to a polycyclic heterocycloalkyl group in which any two rings share two 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., 5-20 membered bridged 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, but excluding -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon.
  • the bridged heterocycloalkyl preferably has a bridged heterocycloalkyl having 6 to 14 ring atoms.
  • the heterocyclic alkyl group is preferably a 6- to 14-membered heterocyclic alkyl group, more preferably a 7- to 10-membered heterocyclic alkyl group.
  • the heterocyclic alkyl group is classified into bicyclic, tricyclic, tetracyclic or polycyclic heterocyclic alkyl groups according to the number of constituent rings, and is preferably a bicyclic or tricyclic heterocyclic alkyl group.
  • the heterocycloalkyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is the heterocycloalkyl group.
  • the heterocycloalkyl group may be optionally substituted or unsubstituted, and 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.
  • the heterocycloalkyl group is substituted by a substituent, the substituent is no longer substituted further.
  • aryl refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated ⁇ 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 aryl).
  • the aryl preferably has an aryl having 6 to 12 carbon atoms (i.e., C 6-12 aryl), more preferably an aryl having 6 to 10 carbon atoms (i.e., C 6-10 aryl), further preferably phenyl or naphthyl, most preferably phenyl.
  • the monocyclic aryl for example, phenyl.
  • Non-limiting examples of the polycyclic aryl include: naphthyl, anthracenyl, phenanthrenyl, etc.
  • the aryl group may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.
  • the aryl group may be optionally substituted or unsubstituted, and 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 aryl group is substituted by a substituent, the substituent is no longer substituted further.
  • 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 ⁇ 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 heteroatoms selected from nitrogen, oxygen, P(O) m , and S(O) n (wherein m and n are integers of 0-2), 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.
  • 5 to 14 e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14
  • ring atoms
  • the heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-10-membered heteroaryl).
  • the monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furanyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, and the like.
  • the polycyclic heteroaryl group is preferably a 5-6-membered heteroaryl and a 5-6-membered heteroaryl, a 5-10-membered heteroaryl and a C 6-10 aryl, or a C 6-10 aryl and a 5-10-membered heteroaryl, and is further preferably a 5-6-membered heteroaryl and a 5-6-membered heteroaryl, a 5-6-membered heteroaryl and a phenyl group, or a phenyl and a 5-6-membered heteroaryl group.
  • Non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, thienophenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridyl, pyridothiphenyl, pyridopyrrolyl, and the like.
  • the heteroaryl group may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • the heteroaryl group may be optionally substituted or unsubstituted, and 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 heteroaryl group is substituted by a substituent, the substituent is no longer further substituted.
  • 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 alkoxy).
  • the alkoxy is preferably an alkoxy having 1 to 8 carbon atoms (i.e., C 1-8 alkoxy), more preferably an alkoxy having 1 to 6 carbon atoms (i.e., C 1-6 alkoxy), and most preferably an alkoxy having 1 to 3 carbon atoms (i.e., C 1-3 alkoxy).
  • Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and 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 alkoxy group is substituted with a substituent, the substituent is no longer substituted further.
  • 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 alkylthio).
  • the alkylthio is preferably an alkylthio having 1 to 8 carbon atoms (i.e., C 1-8 alkylthio), more preferably an alkylthio having 1 to 6 carbon atoms (i.e., C 1-6 alkylthio), and most preferably an 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, and the like.
  • the alkylthio group may be optionally substituted or unsubstituted, and 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.
  • the alkylthio group is substituted with a substituent, the substituent is no longer substituted further.
  • 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.
  • 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,
  • 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-fluor
  • thiol refers to -SH.
  • hydroxy refers to -OH.
  • nitro refers to -NO2 .
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • aminoacyl refers to -C(O) NH2 .
  • sulfonyl refers to -S(O)2.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined above.
  • deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium, wherein alkoxy is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • alkylamino refers to an alkyl-NH- group, wherein alkyl is as defined above.
  • mn used herein refers to the range of m to n and the sub-ranges consisting of the individual point values therein and the individual point values.
  • C2 - C8 " or " C2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any sub-ranges 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.
  • C3 - C10 or " C3-10” should also be understood in a similar manner, e.g., may encompass any sub-ranges and point values contained therein, such as C3 - C9 , C6 - C9 , C6 - C8 , C6 - C7 , C7 - C10 , C7 - C9 , C7 - C8 , C8-C9, etc. , as well as C3 , C4 , C5 , C6 , C7 , C8 , C9, C10 , etc.
  • C 1 -C 6 or "C 1-6” encompasses a range of 1-6 carbon atoms and should be understood to also encompass any subranges and individual point values therein, such as C 2 -C 5 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 , etc., as well as C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc.
  • the expression "three yuan to ten yuan” should be understood to include any sub-ranges therein and each point value, such as three yuan to five yuan, three yuan to six yuan, three yuan to seven yuan, three yuan to eight yuan, four yuan to five yuan, four yuan to six yuan, four yuan to seven yuan, four yuan to eight yuan, five yuan to seven yuan, five yuan to eight yuan, six yuan to seven yuan, six yuan to eight yuan, nine yuan to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc.
  • Other similar expressions in this document should also be understood in a similar manner.
  • cycloalkyl optionally substituted with alkyl means that alkyl can but does not have to be present, and the description includes the situation that cycloalkyl is substituted with alkyl and the situation that cycloalkyl is not substituted with alkyl.
  • substituted and “substituted” refer to one or more (e.g., one, two, three, or four) hydrogens on the designated atom being replaced by a selection from the indicated 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 when such combinations form stable compounds.
  • substituent can be one or more hydrogen atoms, provided that the structure enables the compound to reach a stable state.
  • each carbon atom in a group can be optionally replaced by a heteroatom, the condition is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.
  • variable e.g., R
  • variables with labels e.g., R1 , R2 , R3 , R4 , R5 , R6 , R7 , etc.
  • 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 mixtures enriched in enantiomers or diastereomers, 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 included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that show better biological activity.
  • Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures are also included within the scope of the present invention.
  • the purification and separation of such substances can be achieved by standard techniques known in the art.
  • the hydrogen atoms described in the present invention can 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.
  • the compounds of the present invention include all suitable isotopic derivatives of the compounds thereof.
  • 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.
  • isotopes that can be introduced into the compounds of the present invention include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 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.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.
  • the position 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • pharmaceutically acceptable refers to a substance that is, within the scope of normal medical judgment, suitable for 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.
  • pharmaceutically acceptable salt refers to salts of the compounds of the present invention which are safe and effective when used in mammals and have the desired biological activity.
  • composition refers to a composition containing one or more compounds of the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs, 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, facilitate the absorption of the active ingredients, and thus exert biological activity.
  • pharmaceutically acceptable carrier refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.
  • administration 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 intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.
  • the term "treat” includes alleviating, reducing 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 improvement of the condition being treated.
  • a therapeutic benefit is achieved by eradicating or improving one or more physiological signs associated with the underlying disease, and although the patient may still suffer from the underlying disease, an improvement in the patient's disease can be observed.
  • a prophylactic benefit refers to the use of the composition by a patient to prevent the risk of a certain disease, or when a patient takes it when one or more physiological symptoms of a disease occur, although the disease has not yet been diagnosed.
  • active ingredient refers to a chemical entity that is effective in treating or preventing a target disorder, disease or condition.
  • neuropsychiatric disease refers to a general term for neurological diseases and psychiatric diseases, including neurological diseases and/or psychiatric diseases.
  • the term "effective amount”, “therapeutically effective amount” or “prophylactically effective amount” refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.
  • “individual” includes humans or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals.
  • “Non-human animals” in the present invention 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.).
  • 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.
  • the compounds shown in this invention have an inhibitory effect on AAK1, can inhibit cell proliferation, have good pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, low toxicity and side effects, and have the advantages of oral administration, rapid absorption, high clearance rate, etc.
  • the compounds of the present invention have good brain penetration and can be used to prevent and/or treat diabetic neuropathy or postherpetic pain.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • reaction solution was reacted at room temperature (28°C) for 16 hours, and the reaction was monitored by TLC.
  • the reaction solution was concentrated under reduced pressure to remove most of the tetrahydrofuran, and then diluted with water (100 mL), and extracted 5 times with a dichloromethane/methanol system (200 mL, 10:1, v:v), and the organic phases were combined, dried, and concentrated to obtain a crude product.
  • the sample was further subjected to chiral separation to obtain P1 (retention time: 1.788 min, 785 mg, set as compound 1-1) and P2 (retention time: 1.987 min, 826 mg, set as compound 1-2).
  • Preparation method Instrument: Waters 150Prep-SFC, Column: Chiral OX Column; Mobile phase: A: CO 2 , B: 0.1% NH 3 ⁇ H 2 O 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 each time. After separation, the fractions were dried by rotary evaporator at a bath temperature of 35°C to obtain P1 and compound P2.
  • Test Example 1 In vitro AAK1 enzyme activity detection experiment
  • the 10mM compound stock solution (dissolved in DMSO) was diluted to 0.2mM with DMSO, and then diluted 5-fold with DMSO to obtain 10 concentrations of compound solutions, and then diluted 50-fold with 1 ⁇ kinase reaction buffer (containing 40mM Tris, 20mM MgCl2, 0.1% BSA and 0.5mM DTT) for use.
  • 1 ⁇ kinase reaction buffer containing 40mM Tris, 20mM MgCl2, 0.1% BSA and 0.5mM DTT
  • AAK1 (Signalchem, Cat#A01-11G-10) was diluted to 2 times the final concentration (final concentrations were 30nM and 28nM, respectively) with 1 ⁇ kinase reaction buffer, AAK1 was added to a 384-well white plate at 2 ⁇ L/well, and then 1 ⁇ L/well of the compound was added, the plate was sealed with a sealing film, centrifuged at 1000rpm for 30 seconds, and left at room temperature for 10 minutes.
  • the compounds of the present invention show high inhibitory activity against AAK1 receptors, for example, the IC50 value of compound 1-2 is 9.62 nM.
  • Test Example 2 hERG potassium channel effect test
  • Experimental preparation Experimental platform: electrophysiological manual patch clamp system; cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channel.
  • CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature.
  • the glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller.
  • the tip resistance after perfusion of the electrode liquid was about 2-5 M ⁇ .
  • the glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier.
  • the 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.
  • the cell was clamped at -80 mV, and the step voltage to induce the hERG potassium current (I hERG) was given a 2s depolarization voltage from -80 mV to +20 mV, and then repolarized to -50 mV, which lasted for 1 s before returning to -80 mV.
  • the voltage stimulation was given every 10 seconds, and the administration process was started after the hERG potassium current was confirmed to be stable (at least 1 minute).
  • the compound was administered for at least 1 minute at each test concentration, and at least 2 cells (n ⁇ 2) were tested for each concentration.
  • Inhibition% represents the inhibition percentage of the compound on hERG potassium current
  • I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.
  • X is the Log value of the test sample detection concentration
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum inhibition percentages, respectively.
  • the compounds of the present invention have less cardiotoxicity and are significantly better than the control compounds.
  • mice Male ICR mice, 20-25 g, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice 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 one day before administration and fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% HS-15 + 90% NS; intragastric administration solvent: 0.5% MC; 0.06 mL of blood was collected from the eye sockets under isoflurane anesthesia before and after administration, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm, 4°C for 10 minutes, and plasma was collected.
  • the blood collection time points for the intravenous group and the intragastric administration group were: 0, 5, 15, 30 minutes, 1, 2, 4, 7, 24 hours. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic characteristics in mice.
  • 0.1 ml of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.
  • the time points for blood collection in the venous group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h; the time points for blood collection in the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. All samples were stored at -80°C before analysis and testing.
  • 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.
  • test substance was incubated with microsomal proteins and coenzyme NADPH. After a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS. T 1/2 was calculated by the ln value of the drug residual rate in the incubation system and the incubation time, and the liver microsomal intrinsic clearance CL int(mic) and liver intrinsic clearance CL int(Liver) were further calculated.
  • the compounds of the present invention are stable in liver microsomal metabolism.

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Abstract

本发明涉及一种AAK1抑制剂、其制备方法和应用。特别地，本发明涉及通式(I)所示的化合物、其制备方法、其药物组合物，以及通式(I)所示的化合物或其药物组合物在制备预防和/或治疗AAK1介导的疾病中的应用，其中通式(I)中的各取代基与说明书中的定义相同。

Description

一种可抑制连接蛋白相关激酶1的化合物、制备及其用途
本发明要求享有于2023年11月2日向中国国家知识产权局提交的专利申请号为CN202311445800.X，名称为“一种可抑制连接蛋白相关激酶1的化合物、制备及其用途”的在先申请的优先权。
技术领域
本发明属于药物领域，尤其涉及可抑制连接蛋白相关激酶1(adaptor associated kinase1)(AAK1)的化合物、其制备方法、组合物以及其在制备药物中的用途。
背景技术
连接蛋白相关激酶1(AAK1)为丝氨酸/苏氨酸激酶的Ark1/Prk1家族的成员。AAK1mRNA以被称为短形式和长形式的两种剪切形式存在。长形式占主导且在脑和心脏中高度表达。AAK1富集在突触体制备物(synaptosomal preparation)中且在培养的细胞中与细胞内吞结构共定位。AAK1调节网格蛋白(clatherin)包覆的细胞内吞作用，其为突触小泡循环利用和受体介导的细胞内吞中重要的过程。AAK1与AP2复合物结合，该复合物为使受体运载物(cargo)与网格蛋白包覆物连接的异源四聚体。网格蛋白与AAK1的结合刺激AAK1激酶活性。AAK1磷酸化AP-2的mu-2亚基，其促进mu-2与运载物受体上含酪氨酸的分选模序(sorting motif)结合。Mu2磷酸化对于受体摄入不是必需的，但磷酸化提高了内化的效率。
研究表明，AAK1基因敲除的小鼠，在福尔马林模型的II期时相中对持续性疼痛的反应显著降低，显著减轻SNL(脊神经结扎)引起的机械痛觉超敏。AAK1小分子抑制剂LP-935509，可显著减轻福尔马林小鼠模型的II期时相中的疼痛反应、小鼠SNL引起的机械痛觉超敏、小鼠CCI(坐骨神经结扎)模型和链脲霉素诱导小鼠糖尿病神经病变模型中的疼痛反应(Kostich et al.,J Pharmacol Exp Ther,2016)。这些研究结果表明，抑制AAK1的活性可能对疼痛具有潜在的治疗作用。
AAK1已被鉴定为PC12细胞中神经调节蛋白-1/ErbB4信号传导的抑制剂。经由RNA干扰介导的基因沉默或用激酶抑制剂K252a(其抑制AAK1激酶活性)处理使AAK1表达丧失导致神经调节蛋白-1诱导的神经突过度增生(outgrowth)的增强。这些处理导致ErbB4表达增加和ErbB4在质膜中或在质膜附近累积增加。NRG1和ErbB4为推定的(putative)精神分裂症敏感基因(susceptibilitygene)。两种基因中的SNP与多种精神分裂症内表型有关。神经调节蛋白1和ErbB4KO小鼠模型已显示精神分裂症相关的形态变化和行为表型。此外，AAK1基因的内含子中单核苷酸多态性(polymorphism)与帕金森病的发作年龄有关。这些结果表明抑制AAK1活性可用于治疗精神分裂症(schizophrenia)、精神分裂症中的认知缺陷(cognitive deficit)、帕金森病(Parkinson’s disease)、神经病理性疼痛(neuropathic pain)、双相型精神障碍(bipolar disorder)和阿尔茨海默病(Alzheimer’s disease)。
病毒进入细胞有内吞和膜融合等多种方式，大多数病毒以内吞作为主要的进入方式，其中由网格蛋白介导的为主要内吞途径。水疱性口炎病毒(VSV)，流感病毒(IAV)，刚果出血热病毒(CCHFV)等都是通过网格蛋白依赖的途径进入细胞。研究发现，多种病毒的感染过程都依赖AAK1，如水疱性口炎病毒 (VSV)，狂犬病毒(RABV)，丙型肝炎病毒(HCV)等。这些结果显示，抑制AAK1的活性可能对病毒感染相关疾病有潜在的疗效。
发明内容
本发明提供了一种通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，对AAK1具有抑制作用，能抑制细胞增殖，具有良好的药代动力学特征，高的生物利用度，安全性好，选择性高，毒副作用小，具有口服给药、吸收快、清除率高等优点。同时，我们还意外地发现本发明化合物具有良好的脑穿透性。
本发明的目的在于提供一种通式(I)、(IIA)、(IIB)所示的化合物、其立体异构体或其药学上可接受的盐：
其中：
Y1、Y2和Y3各自独立地为CRa或N；
Ra为氢、氘、卤素、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、含1-3个选自N、O或S的杂原子的3-8元杂环烷基、C6-10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基；
R1和R2各自独立地为氢、氘、卤素、氰基、氨基、巯基、氨酰基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C1-6羟烷基、卤代C1-6烷氧基、氘代C1-6烷氧基、C3-8环烷基、含1-3个选自N、O或S的杂原子的3-8元杂环烷基、C6-10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、-C(O)C1-6烷基、-NHC(O)C1-6烷基、-NHC(O)OC1-6烷基、-NHC(O)NHC1-6烷基、-NHC(O)C3-8环烷基、-NHC(O)OC3-8环烷基、-NHC(O)C4-6杂环烷基或-NHC(O)OC4-6杂环烷基；
且不包含如下化合物：
在一些实施方案中，Y1、Y2和Y3各自独立地为CH或N；在一些实施方案中，Y1、Y2和Y3各自独立地为CH或N，且Y1、Y2和Y3不同时为CH；在一些实施方案中，Y1为N，Y2和Y3为CH，或者Y2为N，Y1和Y3为CH，或者Y3为N，Y1和Y2为CH。
在一些实施方案中，Ra为氢、卤素或C1-6烷基；在一些实施方案中，Ra为氢、卤素或C1-3烷基，在一些实施方案中，Ra为氢。
在一些实施方案中，R1为氢、氘、卤素、氰基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、-C(O)C1-6烷基、-NHC(O)C1-6烷基、-NHC(O)OC1-6烷基或-NHC(O)NHC1-6烷基；在一些实施方案 中，R1为C1-3卤代烷基或-NHC(O)OC1-3烷基；在一些实施方案中，R1为-CH2F、-CHF2、-CHF3、-NHC(O)OCH3、-NHC(O)OCH2CH3、-NHC(O)OCH2CH2CH3；在一些实施方案中，R1为-CHF2或-NHC(O)OCH3。
在一些实施方案中R2为氢、氘、卤素、氰基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基；在一些实施方案中，R2为氰基、C1-3烷基或C1-3卤代烷基；在一些实施方案中，R2为氰基、甲基或-CHF2。
在一些实施方案中，所述通式(I)所示的化合物选自：
或其混合物。
在本发明进一步的实施例中，所述通式(I)进一步如通式(II)所示：
其中：
R1为氢、氘、卤素、氰基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、-C(O)C1-6烷基、-NHC(O)C1-6烷基、-NHC(O)OC1-6烷基或-NHC(O)NHC1-6烷基；在一些实施方案中，R1为C1-6卤代烷基或-NHC(O)OC1-6烷基；在一些实施方案中，R1为C1-3卤代烷基或-NHC(O)OC1-3烷基；在一些实施方案中，R1为-CHF2或-NHC(O)OCH3；
R2为氢、氘、卤素、氰基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、-C(O)C1-6烷基、-NHC(O)C1-6烷基、-NHC(O)OC1-6烷基或-NHC(O)NHC1-6烷基；在一些实施方案中，R2为C1-6烷基、氰基、C1-6卤代烷基；在一些实施方案中，R2为C1-6烷基或C1-6卤代烷基；在一些实施方案中，R2为C1-3烷基或C1-3卤代烷基；在一些实施方案中，R2为甲基、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2F、-CHF2或-CF3；在一些实施方案中，R2为甲基或-CHF2。
在本发明进一步的实施例中，所述通式(II)进一步如通式(IIA)或通式(IIB)所示：
其中：
R1和R2如上任意技术方案所述。
在本发明进一步的实施例中，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，选自如下化合物：
本发明还提供了一种药物组合物，其包含治疗有效剂量的上述的任一项所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
在本发明进一步的实施例中，所述的药物组合物，其包含1-1500mg上述的任一项所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
本发明还提供了一种上述的任一项所示的化合物、其立体异构体或其药学上可接受的盐，或上述的药物组合物在制备药物中的用途，优选所述药物为预防和/或治疗AAK1介导的疾病的药物。
在本发明进一步的实施例中，所述AAK1介导的疾病为糖尿病神经痛或疱疹后遗痛。
本发明还提供了一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的上述的任一项所述的化合物、其立体异构体或其药学上可接受的盐，或上述的药物组合物，其中所述治疗有效量优选1-1500mg，所述疾病优选糖尿病神经痛或疱疹后遗痛。
本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统的任何其它希望改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的肽化合物、缀合物或其药学上可接受的盐的组合物的量。治疗有效量的实例包括但不限于1-1500mg、1-1400mg、1-1300mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、1-500mg、1-400mg、1-300mg、1-250mg、1-200mg、1-150mg、1-125mg、1-100mg、1-80mg、1-60mg、1-50mg、1-40mg、1-25mg、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、10-200mg、10-150mg、10-125mg、10-100mg、10-90mg、10-80mg、10-70mg、10-60mg、10-50mg、10-40mg、10-30mg、10-20mg；20-1500mg、20-1000mg、20-900mg、20-800mg、20-700mg、20-600mg、20-500mg、20-400mg、20-350mg、20-300mg、20-250mg、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、50-100mg；100-1500mg、100-1000mg、100-900mg、100-800mg、100-700mg、100-600mg、100-500mg、100-400mg、100-300mg、100-250mg、100-200mg；
在一些实施方案中，本发明的药物组合物或制剂含有上述治疗有效量的上述的任一项所示的化合物、其立体异构体或其药学上可接受的盐。
本发明进一步地还涉及一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含治疗有效量的上述的任一项所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。该药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。在一些实施方案中，该药物组合物包括但不限于1mg、1.25mg、2.5mg、5mg、10mg、12.5mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg、600mg、625mg、650mg、675mg、700mg、725mg、750mg、775mg、800mg、850mg、900mg、950mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg的上述的任一项所示的化合物、其立体异构体或其药学上可接受的盐。
本发明进一步地还涉及一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的上述的任一项所示的化合物、其立体异构体或其药学上可接受的盐，以及一种或多种药学上可接受的 载体或赋形剂，治疗有效量优选1-1500mg，所述的疾病优选神经性疼痛，更优选糖尿病神经痛、疱疹后遗痛。
本发明进一步地还涉及一种用于治疗哺乳动物的疾病的方法，所述方法包括，将药物本发明上述的任一项所示的化合物、其立体异构体或其药学上可接受的盐，以及以及一种或多种药学上可接受的载体或赋形剂，以1-1500mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于10-1500mg/天、20-1500mg/天、25-1500mg/天、50-1500mg/天、75-1500mg/天、100-1500mg/天、200-1500mg/天、10-1000mg/天、20-1000mg/天、25-1000mg/天、50-1000mg/天、75-1000mg/天、100-1000mg/天、200-1000mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于1mg/天、5mg/天、10mg/天、20mg/天、25mg/天、50mg/天、75mg/天、100mg/天、125mg/天、150mg/天、200mg/天、300mg/天、400mg/天、600mg/天、800mg/天、1000mg/天、1200mg/天、1400mg/天、1500mg/天。
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本发明上述的任一项所示的化合物、其立体异构体或其药学上可接受的盐，本发明化合物或者其立体异构体或药学上可接受的盐量与上述药物组合物中其量相同。
本发明中本发明化合物或者其立体异构体或药学上可接受的盐的量在每种情况下以游离碱的形式换算。
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。
合成路线
本领域技术人员可以结合WO2023284838、WO2017059085、WO2017059080、WO2015153720文献以及已知的有机合成技术制备本发明的化合物，其起始原料为市售化学品和(或)化学文献中所述的化合物。“市售化学品”是从正规商业来源获得的，供应商包括：泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。
本领域的参考书和专著，详细介绍了可用于制备本文所述化合物的反应物的合成，或提供了描述该制备方法的文章以供参考。这些参考书和专著包括：“Synthetic Organic Chemistry”,John Wiley&Sons,Inc.,New York；S.R.Sandler et al.,“Organic Functional Group Preparations,”2nd Ed.,Academic Press,New York,1983；H.O.House,“Modern Synthetic Reactions”,2nd Ed.,W.A.Benjamin,Inc.Menlo Park,Calif.1972；T.L.Gilchrist,“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,R.V.“Organic Chemistry,An Intermediate Text”(1996)Oxford University Press,ISBN 0-19-509618-5；Larock,R.C.“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.
通过美国化学会化学文摘社制备的已知化学物质的索引，可以选择性地识别特定和类似的反应物，这些索引可在大多数公共图书馆和大学图书馆以及在线获得。已知但在目录中不可商购的化学品可选地由定制化学合成工厂制备，其中许多标准化学供应工厂(例如，上面列出的那些)提供定制合成服务。制备和选择本文所述化合物的药用盐的参考文献是P.H.Stahl&C.G.Wermuth“Handbook of Pharmaceutical Salts”,Verlag Helvetica Chimica Acta,Zurich,2002.
发明的详细说明
除非另有定义，本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。若存在矛盾，则以本申请提供的定义为准。当本文中出现商品名时，意在指代其对应的商品或其活性成分。本文引用的所有专利、已经公开的专利申请和出版物均通过引用并入到本文中。
术语“烷基”是指饱和的直链或带有支链的脂肪族烃基团，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子，即“C1-20烷基”。所述烷基优选具有1至12个碳原子的烷基(即C1-12烷基)，更优选具有1至8个碳原子的烷基(即C1-8烷基)，进一步优选具有1至6个碳原子的烷基(即C1-6烷基)，最优选具有1至3个碳原子的烷基(即C1-3烷基)。非限制性的实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自氘、烷基、烯基、炔基、烷氧基、烷硫基、卤素、巯基、羟基、硝基、氨基、氰基、羧基、氧代基、环烷基、杂环烷基、芳基或杂芳基。当所述烷基被取代基取代时，所述取代基不再被进一步取代。
术语“环烷基”指饱和或部分不饱和单环环状烃取代基(即单环环烷基)或多环环状烃取代基(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子，即C3-20环烷基。所述环烷基优选具有3至12个碳原子的环烷基(即C3-12环烷基)，更优选具有3至8个碳原子的环烷基(即C3-8环烷基)，进一步优选具有3至6个碳原子的环烷基(即C3-6环烷基)，最优选具有3至5个碳原子的环烷基(即C3-5环烷基)，或者，具有5至6个碳原子的环 烷基(即C3-5环烷基)。所述的单环环烷基的非限制性实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等。所述的多环环烷基的非限制性实例包括：螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即C5-20螺环烷基)。所述的螺环烷基优选具有6至14个环原子的螺环烷基(即C6-14螺环烷基)，更优选具有7至10个环原子的螺环烷基(即C7-10螺环烷基)。根据环与环之间共用的螺原子的数目将所述螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基或双螺环烷基，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。
术语“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即C5-20稠环烷基)。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述的稠环烷基优选具有6至14个环原子的稠环烷基(即C6-14稠环烷基)，更优选具有7至10个环原子的稠环烷基(即C7-10稠环烷基)。根据组成环的数目分为双环、三环、四环或多环稠环烷基，优选双环稠环烷基或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。
术语“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即C5-20桥环烷基)。其含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述的桥环烷基优选具有6至14个环原子的桥环烷基(即C6-14桥环烷基)，更优选具有7至10个环原子的桥环烷基(即C7-10桥环烷基)。根据组成环的数目分为双环、三环、四环或多环桥环烷基，优选为双环桥环烷基或三环桥环烷基。
所述的环烷基可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基。
所述环烷基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自氘、烷基、烯基、炔基、烷氧基、烷硫基、卤素、巯基、羟基、硝基、氨基、氰基、羧基、氧代基、环烷基、杂环烷基、芳基或杂芳基。当所述环烷基被取代基取代时，所述取代基不再被进一步取代。
术语“杂环烷基”指饱和或部分不饱和的单环杂环状烃取代基(即单环杂环烷基)或多环杂环状烃取代基(即多环杂环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3-20元杂环烷基)，其中一个或多个(例如1、2、3或4个)环原子选自氮、氧、P(O)m和S(O)n(其中m、n为0-2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的 环部分，其余环原子为碳。所述杂环烷基优选具有3至12个环原子(即3-12元杂环烷基)，其中含1-4个选自N、O和S原子的杂原子，更优选具有3至8个环原子(即3-8元杂环烷基)，其中含1-4个、1-3个或1-2个选自N、O和S原子的杂原子，进一步优选具有3至6个环原子(即3-6元杂环烷基)，其中含1-4个、1-3个或1-2个选自N、O和S原子的杂原子，最优选具有5至6个环原子(即5-6元杂环烷基)，其中含1-4个、1-3个或1-2个选自N、O和S原子的杂原子。所述的单环杂环烷基的非限制性实例包括：氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、二氢咪唑基、二氢呋喃基、二氢吡唑基、哌啶基、哌嗪基、吗啉基、1,3-二氧环戊基、2,2-二氟-1,3-二氧环戊基、环戊酮基、2,2-二氟环戊酮基、吖庚基、氧杂环戊基或氮杂环戊基等。所述的多环杂环烷基的非限制性实例包括：螺杂环烷基、稠杂环烷基和桥杂环烷基。
术语“螺杂环烷基”指单环之间共用一个原子(称螺原子)的多环杂环烷基团，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5-20元螺杂环烷基)，其中一个或多个(例如1、2、3或4个)环原子选自氮、氧、P(O)m和S(O)n(其中m、n为0-2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述的螺杂环烷基优选具有6至14个环原子的螺杂环烷基(即6-14元螺杂环烷基)，更优选具有7至10个环原子的螺杂环烷基(即7-10元螺杂环烷基)。根据环与环之间共用的螺原子的数目将所述螺杂环烷基分为单螺杂环烷基、双螺杂环烷基或多螺杂环烷基，优选为单螺杂环烷基或双螺杂环烷基，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环烷基。
术语“稠杂环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环烷基团，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5-20元稠杂环烷基)，其中一个或多个(例如1、2、3或4个)环原子选自氮、氧、P(O)m和S(O)n(其中m、n为0-2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述的稠杂环烷基优选具有6至14个环原子的稠杂环烷基(即6-14元稠杂环烷基)，更优选具有7至10个环原子的稠杂环烷基(即7-10元稠杂环烷基)。根据组成环的数目分为双环、三环、四环或多环稠杂环烷基，优选双环稠杂环烷基或三环稠杂环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环烷基。
术语“桥杂环烷基”指任意两个环共用两个不直接连接的原子的多环杂环烷基团，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5-20元桥杂环烷基)，其中一个或多个(例如1、2、3或4个)环原子选自氮、氧、P(O)m和S(O)n(其中m、n为0-2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述的桥杂环烷基优选具有6至14个环原子的桥杂环烷 基(即6-14元桥杂环烷基)，更优选具有7至10个环原子的桥杂环烷基(即7-10元桥杂环烷基)。根据组成环的数目分为双环、三环、四环或多环桥杂环烷基，优选为双环桥杂环烷基或三环桥杂环烷基。
所述的杂环烷基可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环烷基。
所述的杂环烷基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自氘、烷基、烯基、炔基、烷氧基、烷硫基、卤素、巯基、羟基、硝基、氨基、氰基、羧基、氧代基、环烷基、杂环烷基、芳基或杂芳基。当所述杂环烷基被取代基取代时，所述取代基不再被进一步取代。
术语“芳基”指具有共轭的π电子体系的全碳单环基团(即单环芳基)或稠合多环基团(即多环芳基)，其具有6至14个(例如6、7、8、9、10、11、12、13或14个)碳原子(即C6-14芳基)。所述芳基优选具有6至12个碳原子的芳基(即C6-12芳基)，更优选具有6至10个碳原子的芳基(即C6-10芳基)，进一步优选苯基或萘基，最优选苯基。所述的单环芳基，例如苯基。所述的多环芳基的非限制性的实例包括：萘基、蒽基、菲基等。
所述的芳基可以稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环。所述的芳基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自氘、烷基、烯基、炔基、烷氧基、烷硫基、卤素、巯基、羟基、硝基、氨基、氰基、羧基、氧代基、环烷基、杂环烷基、芳基或杂芳基。当所述芳基被取代基取代时，所述取代基不再被进一步取代。
术语“杂芳基”指具有共轭的π电子体系的单环杂芳基团(即单环杂芳基)或稠合多环杂芳基团(即多环杂芳基)，其具有5至14个(例如5、6、7、8、9、10、11、12、13或14个)环原子(即5-14元杂芳基)，其中一个或多个(例如1、2、3或4个)环原子为选自氮、氧、P(O)m和S(O)n(其中m、n为0-2的整数)的杂原子，优选为选自氮、氧、或硫的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。所述杂芳基优选具有5至10个环原子的杂芳基(即5-10元杂芳基)。所述的单环杂芳基，优选具有5至6个环原子的杂芳基(即5-6元杂芳基)，非限制性的实例包括：呋喃基、吡喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、三唑基、四唑基、吡咯基、吡啶基、嘧啶基、吡啶酮基、吡嗪基、哒嗪基等。所述的多环杂芳基，优选5-6元杂芳基并5-6元杂芳基、5-10元杂芳基并C6-10芳基或C6-10芳基并5-10元杂芳基，进一步优选5-6元杂芳基并5-6元杂芳基、5-6元杂芳基并苯基或苯基并5-6元杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、噻吩并苯基、喹唑啉基、苯并噻唑基、咔唑基、噻吩并吡啶基、吡啶并噻吩基、吡啶并吡咯基等。
所述的杂芳基可以稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。所述的杂芳基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自氘、烷基、烯基、炔基、烷氧基、烷硫基、卤素、巯基、羟基、硝基、氨基、氰基、羧基、氧代基、环烷基、杂环烷基、芳基或杂芳基。当所述杂芳基被取代基取代时，所述取代基不再被进一步取代。
术语“烷氧基”指-O-(烷基)或-O-(非取代的环烷基)，其中烷基、环烷基的定义如上所述，其具有1至10个(例如1、2、3、4、5、6、7、8、9或10个)碳原子(即C1-10烷氧基)。所述烷氧基优选具有1至8个碳原子的烷氧基(即C1-8烷氧基)，更优选具有1至6个碳原子的烷氧基(即C1-6烷氧基)，最更优具有1至3个碳原子的烷氧基(即C1-3烷氧基)。非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。所述烷氧基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自氘、烷基、烯基、炔基、烷氧基、烷硫基、卤素、巯基、羟基、硝基、氨基、氰基、羧基、氧代基、环烷基、杂环烷基、芳基或杂芳基。当所述烷氧基被取代基取代时，所述取代基不再被进一步取代。
术语“烷硫基”指-S-(烷基)或-S-(非取代的环烷基)，其中烷基、环烷基的定义如上所述，其具有1至10个(例如1、2、3、4、5、6、7、8、9或10个)碳原子(即C1-10烷硫基)。所述烷硫基优选具有1至8个碳原子的烷硫基(即C1-8烷硫基)，更优选具有1至6个碳原子的烷硫基(即C1-6烷硫基)，最更优具有1至3个碳原子的烷硫基(即C1-3烷硫基)。非限制性实例包括：甲硫基、乙硫基、丙硫基、丁硫基、环丙硫基、环丁硫基、环戊硫基、环己硫基等。所述烷硫基可以是任选取代或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自氘、烷基、烯基、炔基、烷氧基、烷硫基、卤素、巯基、羟基、硝基、氨基、氰基、羧基、氧代基、环烷基、杂环烷基、芳基或杂芳基。当所述烷硫基被取代基取代时，所述取代基不再被进一步取代。
术语“卤”或“卤素”或“卤代”应理解为表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子，优选氟、氯、溴原子。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。非限制性实例包括：氟甲基、氯甲基、溴甲基、碘甲基、二氟甲基、氯氟甲基、二氯甲基、溴氟甲基、三氟甲基、氯二氟甲基、二氯氟甲基、三氯甲基、溴二氟甲基、溴氯氟甲基、二溴氟甲基、2-氟乙基、2-氯乙基、2-溴乙基、2,2-二氟乙基、2-氯-2-氟乙基、2,2-二氯乙基、2-溴-2-氟乙基、2,2,2-三氟乙基、2-氯-2,2-二氟乙基、2,2-二氯-2-氟乙基、2,2,2-三氯乙基、2-溴-2,2-二氟乙基、2-溴-2-氯-2-氟乙基、2-溴-2,2-二氯乙基、1,1,2,2-四氟乙基、五氟乙基、1-氯-1,2,2,2-四氟乙基、2-氯-1,1,2,2-四氟乙基、1,2-二氯-1,2,2-三氟乙基、2-溴-1,1,2,2-四氟乙基等，优选氟甲基、二氟甲基、三氟甲基、2-氟乙基、2-氯乙基、2-溴乙基、2,2-二氟乙基。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。非限制性实例包括：氟甲氧基、氯甲氧基、溴甲氧基、碘甲氧基、二氟甲氧基、氯氟甲氧基、二氯甲氧基、溴氟甲氧基、三氟甲氧基、氯二氟甲氧基、二氯氟甲氧基、三氯甲氧基、溴二氟甲氧基、溴氯氟甲氧基、二溴氟甲氧基等；优选氟甲氧基、二氟甲氧基、三氟甲氧基、2-氟乙氧基、2-氯乙氧基、2-溴乙氧基、2,2-二氟乙氧基、2-氯-2-氟乙氧基、2,2-二氯乙氧基、2-溴-2-氟乙氧基、2,2,2-三氟乙氧基、2-氯-2,2-二氟乙氧基、2,2-二氯-2-氟乙氧基、2,2,2-三氯乙氧基、2-溴-2,2-二氟乙氧基、2-溴-2-氯-2-氟乙氧基、2-溴-2,2-二氯乙氧基、1,1,2,2-四氟乙氧基、五氟乙氧基、1-氯-1,2,2,2-四氟乙氧基、2-氯-1,1,2,2-四氟乙氧基、1,2-二氯-1,2,2-三氟乙氧基、2-溴-1,1,2,2-四氟乙氧基，优选氟甲氧基、二氟甲氧基、三氟甲氧、2-氟乙氧基、2-氯乙氧基、2-溴乙氧基、2,2-二氟乙氧基。
术语“巯基”指-SH。
术语“羟基”指-OH。
术语“硝基”指-NO2。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“羧基”指-C(O)OH。
术语“氧代”或“氧代基”指＝O。
术语“羰基”指C＝O。
术语“氨酰基”指-C(O)NH2。
术语“磺酰基”指-S(O)2。
术语“氘代烷基”指被一个或多个氘取代的烷基，其中烷基如上所定义。
术语“氘代烷氧基”指被一个或多个氘取代的烷氧基，其中烷氧基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟烷基”指被一个或多个羟基取代的烷基，其中烷基如上所定义。
术语“烷胺基”指烷基-NH-，其中烷基如上所定义。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的，且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解，上述术语如“包括”涵盖“由…组成”的含义。
术语“一个(种)或多个(种)”或者类似的表述“至少一个(种)”可以表示例如1、2、3、4、5、6、7、8、9、10个(种)或更多个(种)。
当公开了数值范围的下限和上限时，落入该范围中的任何数值和任何包括的范围都被具体公开。特别地，本文公开的值的每个取值范围应理解为表示涵盖于较宽范围中的每个数值和范围。
在本文中，“Z”和“-Z-”均表示为同一特定的基团，其可以互换使用。
本文所用的表述m-n指m至n的范围以及由其中的各个点值组成的亚范围以及各个点值。例如，表述“C2-C8”或“C2-8”涵盖2-8个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C2-C5、C3-C4、C2-C6、C3-C6、C4-C6、C4-C7、C4-C8等，以及C2、C3、C4、C5、C6、C7、C8等。例如，表述“C3-C10”或“C3-10”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如C3-C9、C6-C9、C6-C8、C6-C7、C7-C10、C7-C9、C7-C8、C8-C9等以及C3、C4、C5、C6、C7、C8、C9、C10等。又例如，表述“C1-C6”或“C1-6”涵盖1-6个碳原子的范围，并应理解为还涵盖其中的任意亚范围以及每个点值，例如C2-C5、C3-C4、C1-C2、C1-C3、C1-C4、C1-C5、C1-C6等，以及C1、C2、C3、C4、C5、C6等。又例如，表述“三元至十元”应理解为涵盖其中的任意亚范围以及每个点值，例如三元至五元、三元至六元、三元至七元、三元至八元、四元至五元、四元至六元、四元至七元、四元至八元、五元至七元、五元至八元、六元至七元、六元至八元、九元至十元，等，以及三、四、五、六、七、八、九、十元，等。本文中其他类似的表述也应当以类似的方式理解。
本文所用的表述“X选自A、B或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，“任选(地)被烷基取代的环烷基”意味着烷基可以但不必须存在，该说明包括环烷基被烷基取代的情形和环烷基不被烷基取代的情形。
术语“取代”和“取代的”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。当描述某取代基不存在时，应当理解该取代基可以为一个或多个氢原子，前提是所述结构能使化合物达到稳定的状态。当描述基团中的每个碳原子可以任选地被杂原子代替时，条件是未超过基团中的所有原子在当前情况下的正常原子价，并且形成稳定的化合物。
如果取代基被描述为“任选地…被取代”，则取代基可以是未被取代的，或者可以是被取代的。如果某个原子或基团被描述为任选地被取代基列表中的一个或多个取代，则该原子或基团上的一个或多个氢可被独立地选择的、任选的取代基替代。当取代基为氧代(即＝O)时，意味着两个氢原子被替代。当取代基为氢时，这也可以表示对应的基团为“非取代”或者“未被取代”的。除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代环中的任一成环原子。
当任何变量(例如R)，以及带有标记的变量(例如R1、R2、R3、R4、R5、R6、R7等)在化合物的组成或结构中出现一次以上时，其在每次出现时在每一种情况下的定义都是独立的。例如，如果一个基团被0、1、2、3或4个R取代基所取代，则所述基团可以任选地至多被四个R取代基所取代，并且每种情况下的每个R取代基的选项都是相互独立的。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。本发明化合物的取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。在某些实施方案中，优选化合物为那些显示更优生物活性的异构体化合物。本发明化合物已纯化的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映异构体混合物也均包括于本发明范围内。此类物质的纯化和分离可通过本领域已知的标准技术实现。
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。
本发明的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、 3H(氚，T)、11C、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，优选氘。
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。
在本发明化合物中，当一个位置被特别地指定为氘D时，该位置应理解为氘的丰度比天然丰度(其为0.015％)大至少1000倍(即，至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少1000倍(即，至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少2000倍(即，至少30％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3000倍的丰度的氘(即，至少45％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3340倍(即，至少50.1％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3500倍(即，至少52.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4000倍(即，至少60％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4500倍(即，至少67.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5000倍(即，至少75％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5500倍(即，至少82.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6000倍(即，至少90％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6333.3倍(即，至少95％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6466.7倍(即，至少97％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6600倍(即，至少99％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6633.3倍(即，至少99.5％的氘掺入)。
术语“药学上可接受”的物质指这样的物质，其在正常的医学判断范围内适用于与患者的组织接触而不会有不适当毒性、刺激性、过敏反应等，具有合理的利弊比，且能有效用于其目的用途。
术语“药学上可接受的盐”指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
术语“药物组合物”指含有一种或多种本发明所述的化合物或其生理学上/药学上可接受的盐或前体药物，以及其他组分例如生理学上/药学上可接受的载体或赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些物质。“药学上可接受的载体”包括但不限于助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、崩解剂、稳定剂、溶剂或乳化剂。
术语“给药”或“给予”等指可以使化合物或组合物能够递送至期望的生物作用位点的方法。这些方法包括但不限于口服或肠胃外(包括脑室内、静脉内、皮下、腹膜内、肌内、血管内注射或输注)、局部、直肠给药等。特别是注射或口服。
如本文所用，术语“治疗”包括缓解、减轻或改善疾病或症状，预防其他症状，改善或预防症状的潜在代谢因素，抑制疾病或症状，例如，阻止疾病或症状发展，减轻疾病或症状，促进疾病或症状缓解，或使疾病或症状的病征停止，和延伸至包括预防。“治疗”还包括实现治疗性获益和/或预防性获益。治疗性获益是指根除或改善所治疗的病症。此外，治疗性获益通过根除或改善一个或多个与潜在疾病相关的生理病征达到，尽管患者可能仍患有潜在疾病，但可观察到患者疾病的改善。预防性获益是指，患者为预防某种疾病风险而使用组合物，或患者出现一个或多个疾病生理病症时服用，尽管尚未诊断此疾病。
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体，其可以有效地治疗或预防目标紊乱、疾病或病症。术语“神经精神类疾病”是指神经类疾病与精神类疾病的总称，包含神经类疾病和/或精神类疾病。
针对药物、药物单元或活性成分而言，术语“有效量”、“治疗有效量”或“预防有效量”是指副作用可接受的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于个体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
术语“室温”指的是温度由10℃到40℃。在一些实施例中，“室温”指的是温度由15℃到30℃；在另一些实施例中，“室温”指的是温度由18℃到25℃。
“当量”或其缩写“eq”，是按照化学反应的当量关系，以每步中所用基本原料为基准(1当量)，所需要的其他原材料的当量用量。
在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，均表示在给定的值或范围的10％以内，适当地在5％以内，特别是在1％以内。或者，对于本领域普通技术人员而言，术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时，任何具有N+/–1％，N+/–2％，N+/–3％，N+/–5％，N+/–7％，N+/–8％或N+/–10％值以内的数字会被明确地公开，其中“+/–”是指加或减。
下述发明详述旨在举例说明非限制性实施方案，使本领域其它技术人员更充分地理解本发明的技术方案、其原理及其实际应用，以便本领域其它技术人员可以以许多形式修改和实施本发明，使其可最佳地适应特定用途的要求。
本表明的化合物对AAK1具有抑制作用，能抑制细胞增殖，具有良好的药代动力学特征，高的生物利用度，安全性好，选择性高，毒副作用小，具有口服给药、吸收快、清除率高等优点。同时，本发明化合物具有良好的脑穿透性，能用于预防和/或治疗糖尿病神经痛或疱疹后遗痛。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员会理解，下列实施例仅用于说明本发明，而不应视为限制本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本发明保留时间指分析液相色谱的出峰时间。
实施例1：
将化合物1A(10.00g,25.82mmol，以2-二氟甲基-4-溴吡啶为原料，参照专利WO2023284838A1的合成方法合成)溶于四氢呋喃和水(280mL,3:1,v:v)的混合溶液中，然后降温至0℃后加入4-甲基吗啉-4-氧化物(9.36g,77.46mmol)。反应液置换氮气后在0℃下缓慢滴加锇酸钾二水合物(1.46g,3.87mmol)的水溶液(10mL)。滴加完成后反应液在室温下(28℃)反应16h，TLC监测反应结束。将反应液减压浓缩出大部分四氢呋喃，然后加入水(100mL)稀释，并用二氯甲烷/甲醇体系(200mL,10:1,v:v)重复萃取5次，合并有机相干燥浓缩得到粗品。将粗品用硅胶柱层析分离(二氯甲烷：甲醇＝20:1至5:1)后经反相分离(乙腈：水＝5:95至95:5)得到8.00g粗产品化合物1。将该样品再经过手性拆分得到P1(保留时间：1.788min,785mg,设定为化合物1-1)和P2(保留时间：1.987min,826mg,设定为化合物1-2)。
分析方法:仪器:SHIMADZU LC-30AD，柱:Chiral OX Column；流动相:A:CO2,B:0.05％DEA in MEOH；梯度:5-40％ B in A；流速:3mL/min柱温:35℃波长:220nm.
制备方法:仪器:Waters 150Prep-SFC，柱:Chiral OX Column；流动相:A:CO2,B:0.1％NH3·H2O in MEOH；梯度:35％ B梯度洗脱，流速:100mL/min，柱温:25℃波长:220nm循环时间:4.2min样品制备:样品浓度5mg/ml，甲醇溶液进样:每次1ml。分离后，通过旋转蒸发仪浴温35℃下干燥馏分得到P1和化合物P2。
化合物1-1:
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),7.42–6.90(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).
LC-MS(ESI):m/z＝418.6[M+H]+.
化合物1-2:
1H 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).
LC-MS(ESI):m/z＝418.5[M+H]+.
本发明记载的其余公开的化合物的合成路线参考实施例1的合成路线。
生物学测试评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
测试例1、体外AAK1酶活检测实验
将浓度为10mM的化合物储备液(溶于DMSO)用DMSO稀释至0.2mM后，用DMSO以5倍稀释，获得10个浓度的化合物溶液，再用1×激酶反应缓冲液(含40mM Tris、20mM MgCl2、0.1％ BSA与0.5mM DTT)将各浓度化合物稀释50倍备用。用1×激酶反应缓冲液将AAK1(Signalchem,Cat#A01-11G-10)稀释至终浓度的2倍(终浓度分别为30nM与28nM)，将AAK1以2μL/孔加入384孔白板中，再加入1μL/孔的化合物，用封板膜封住板子于1000rpm离心30秒，室温放置10分钟。配制4倍终浓度的ATP(Promega,Cat#V914B)与底物Micro2(GenScript,Cat#PE0890)的混合液(AAK1对应的ATP终浓度分别为15μM与5μM，Micro2的终浓度为0.1mg/mL)，向反应板中加入1μL/孔的ATP与底物混合液，用封板膜封住板子于1000rpm离心30秒，室温反应60分钟(AAK1)。转移4μL/孔ADP-Glo(Promega,Cat#V9102)到384孔板中，于1000rpm离心1分钟，25℃条件下孵育40分钟；转移8μL/孔Detection溶液到384孔板中，于1000rpm离心1分钟，25℃条件下孵育40分钟；使用Biotek多功能酶标仪读取RLU(Relative luminescence unit)信号值，并按下式计算百分抑制率：[1-(LUM化合物-LUM阳性对照)/(LUM阴性对照-LUM阳性对照)]×100。使用Graphpad 7.0软件中四参数非线性拟合方程计算IC50值，具体结果见表1。
表1 AAK1抑制活性
结论:本发明化合物对于AAK1受体显示出很高的抑制活性，例如化合物1-2的IC50值为9.62nM。测试例2、hERG钾离子通道作用测试
2.1试验准备：实验平台：电生理手动膜片钳系统；细胞系：稳定表达hERG钾离子通道的中国仓鼠卵巢(CHO)细胞系。
2.2试验方法：稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10，Sutter)经拉制仪拉制而成，灌注电极内液后的尖端电阻为2-5MΩ左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录，采样频率为10kHz，滤波频率为2kHz。在得到全细胞记录后，细胞钳制在-80mV，诱发hERG钾电流(I hERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV，再复极化到-50mV，持续1s后回到-80mV。每10s给予此电压刺激，确定hERG钾电流稳定后(至少1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟，每个浓度至少测试2个细胞(n≥2)。
2.3数据处理：数据分析处理采用pClamp 10，GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：
Inhibition％＝[1–(I/Io)]×100％
其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。
化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。
实验结果：测试化合物对hERG钾通道电流抑制作用的IC50值见下表：
表2测试化合物对hERG钾通道电流抑制作用的IC50值

注：LX9211结构为WO2015153720A1(实施例123)。
结论：本发明化合物对心脏毒性小，明显优于对照化合物。
测试例3、小鼠药代动力学测试
3.1试验动物：雄性ICR小鼠，20～25g，6只/化合物。购于成都达硕实验动物有限公司。
3.2试验设计：试验当天，将ICR小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。
表3给药信息
3.3试验方法：
静脉给药溶媒:5％DMA+5％HS-15+90％NS；灌胃给药溶媒：0.5％ MC；于给药前及给药后异氟烷麻醉经眼眶取血0.06mL，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,7,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。
表4测试化合物在小鼠血浆中的药代动力学参数
给药溶媒：0.5％MC
结论：本发明化合物，例如实施例化合物在小鼠体内具有良好的药代动力学特征。
测试例4、大鼠药代动力学测试
4.1试验动物：雄性SD大鼠，220g左右，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。
4.2试验设计：试验当天，6只SD大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。
表5给药信息
给药溶媒：0.5％MC
于给药前及给药后异氟烷麻醉经眼眶取血0.1ml，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组采血时间点：0,5,15,30min,1,2,4,6,8,24h；灌胃组采血时间点：0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃。
实验结果见表6。
表6测试化合物在大鼠血浆中的药代动力学参数
结论：本发明化合物例如化合物1-2在大鼠中具有良好的药代动力学。
测试例5、肝微粒体稳定性测试
本实验采用人、猴、犬、大鼠和小鼠五种属肝微粒体作为体外模型来评价受试物的代谢稳定性。
在37℃条件下，1μM的受试物与微粒体蛋白、辅酶NADPH共同孵育，反应至一定时间(5,10,20,30,60min)加入冰冷含内标的乙腈终止反应，采用LC-MS/MS方法检测样品中受试物浓度，以孵育体系中药物剩余率的ln值和孵育时间求得T1/2，并进一步计算肝微粒体固有清除率CLint(mic)和肝固有清除率CLint(Liver)。
表7测试化合物在大鼠肝微粒体模型中的结果
结论：本发明化合物例如实施例化合物五种属肝微粒体代谢稳定。

Claims (10)

  1. 一种通式(I)所示的化合物、其立体异构体或其药学上可接受的盐：
    其中：
    Y1、Y2和Y3各自独立地为CRa或N；
    Ra为氢、氘、卤素、羟基、氰基、氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、含1-3个选自N、O或S的杂原子的3-8元杂环烷基、C6-10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基；
    R1和R2各自独立地为氢、氘、卤素、氰基、氨基、巯基、氨酰基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷胺基、C1-6羟烷基、卤代C1-6烷氧基、氘代C1-6烷氧基、C3-8环烷基、含1-3个选自N、O或S的杂原子的3-8元杂环烷基、C6-10芳基、含1-3个选自N、O或S的杂原子的5-10元杂芳基、-C(O)C1-6烷基、-NHC(O)C1-6烷基、-NHC(O)OC1-6烷基、-NHC(O)NHC1-6烷基、-NHC(O)C3-8环烷基、-NHC(O)OC3-8环烷基、-NHC(O)C4-6杂环烷基或-NHC(O)OC4-6杂环烷基；
    且不包含如下化合物：
  2. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，其满足如下条件中的一种或多种：
    (1)Y1、Y2和Y3各自独立地为CH或N，优选Y1、Y2和Y3各自独立地为CH或N，且Y1、Y2和Y3不同时为CH，更优选Y1为N，Y2和Y3为CH，或者Y2为N，Y1和Y3为CH，或者Y3为N，Y1和Y2为CH；
    (2)Ra为氢、卤素或C1-6烷基，优选氢、卤素或C1-3烷基，更优选氢；
    (3)R1为氢、氘、卤素、氰基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、-C(O)C1-6烷基、-NHC(O)C1-6烷基、-NHC(O)OC1-6烷基或-NHC(O)NHC1-6烷基，优选C1-3卤代烷基或-NHC(O)OC1-3烷基，更优选-CHF2或-NHC(O)OCH3；
    (4)R2为氢、氘、卤素、氰基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基，优选氰基、C1-3烷基或C1-3卤代烷基，更优选氰基、甲基或-CHF2；
    (5)通式(I)所示的化合物选自：
    或其混合物。
  3. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，通式(I)进一步如通式(II)所示：
    其中：
    R1为氢、氘、卤素、氰基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、-C(O)C1-6烷基、-NHC(O)C1-6烷基、-NHC(O)OC1-6烷基或-NHC(O)NHC1-6烷基；
    R2为氢、氘、卤素、氰基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、-C(O)C1-6烷基、-NHC(O)C1-6烷基、-NHC(O)OC1-6烷基或-NHC(O)NHC1-6烷基。
  4. 根据权利要求3所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，通式(II)进一步如通式(IIA)或通式(IIB)所示：
    其中：
    R1和R2如权利要求3所述。
  5. 根据权利要求1-4中任一项所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：
  6. 一种药物组合物，其包含治疗有效剂量的权利要求1-5中任一项所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
  7. 根据权利要求6所述的药物组合物，其包含1-1500mg的权利要求1-5中任一项所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
  8. 根据权利要求1-5中任一项所示的化合物、其立体异构体或其药学上可接受的盐，或权利要求6或7所述的药物组合物在制备药物中的用途，优选所述药物为预防和/或治疗AAK1介导的疾病的药物。
  9. 根据权利要求8所述的用途，所述AAK1介导的疾病为糖尿病神经痛或疱疹后遗痛。
  10. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-5中任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求6或7所述的药物组合物，其中所述治疗有效量优选1-1500mg，所述疾病优选糖尿病神经痛或疱疹后遗痛。
PCT/CN2024/129056 2023-11-02 2024-10-31 一种可抑制连接蛋白相关激酶1的化合物、制备及其用途 Pending WO2025092928A1 (zh)

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Publication number Priority date Publication date Assignee Title
CN106458994A (zh) * 2014-04-02 2017-02-22 百时美施贵宝公司 联芳激酶抑制剂
CN108290843A (zh) * 2015-10-01 2018-07-17 百时美施贵宝公司 联芳基激酶抑制剂
CN108368084A (zh) * 2015-10-01 2018-08-03 百时美施贵宝公司 联芳基激酶抑制剂
WO2023284838A1 (zh) * 2021-07-15 2023-01-19 四川海思科制药有限公司 Aak1抑制剂及其用途
CN115872927A (zh) * 2021-09-30 2023-03-31 武汉人福创新药物研发中心有限公司 Aak1抑制剂及其用途

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CN106458994A (zh) * 2014-04-02 2017-02-22 百时美施贵宝公司 联芳激酶抑制剂
CN108290843A (zh) * 2015-10-01 2018-07-17 百时美施贵宝公司 联芳基激酶抑制剂
CN108368084A (zh) * 2015-10-01 2018-08-03 百时美施贵宝公司 联芳基激酶抑制剂
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