WO2022022489A1 - 吲哚稠环类衍生物、其制备方法及其在医药上的应用 - Google Patents

吲哚稠环类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2022022489A1
WO2022022489A1 PCT/CN2021/108577 CN2021108577W WO2022022489A1 WO 2022022489 A1 WO2022022489 A1 WO 2022022489A1 CN 2021108577 W CN2021108577 W CN 2021108577W WO 2022022489 A1 WO2022022489 A1 WO 2022022489A1
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general formula
alkyl
group
pharmaceutically acceptable
tautomer
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PCT/CN2021/108577
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English (en)
French (fr)
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张晓敏
胡伟民
叶超百慧
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2022022489A1 publication Critical patent/WO2022022489A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present disclosure belongs to the field of medicine, and relates to an indole fused ring derivative, a preparation method thereof and its application in medicine.
  • the present disclosure relates to indole fused ring derivatives represented by general formula (I), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as TLR7/8/9 inhibitors in the treatment of inflammatory and Use in autoimmune disease.
  • TLRs Toll-like receptors
  • PAMPs pathogen-associated molecular patterns
  • TLR7/8/9 were mainly highly expressed in DC cells and B cells, TLR7/8 mainly recognized ssRNA, and TLR9 mainly recognized CpG-DNA.
  • TLR7/8/9 is activated after binding its ligand, and binds to the adaptor protein MyD88 in the cytoplasm to initiate NF- ⁇ B and IRF pathways, activate DC cells, and produce type I interferon and various other inflammatory cytokines;
  • B cells the combination of TLR7/8/9 and nucleic acids plays an important role in the production of antinuclear antibodies by B cells, and the type I interferon secreted by DC cells also promotes this autoimmunity
  • the further proliferation and activation of B cells causes a series of inflammatory responses.
  • SLE Systemic lupus erythematosus
  • hormones include hormones, immunosuppressants and antimalarial drugs.
  • belimumab Only one new drug, belimumab, has been approved by the FDA this century, but it has only modest and delayed efficacy in a small subset of SLE patients (Navarra, SV et al., Lancet 2011, 377, 721), and the treatment options are very limited. Therefore, there is an urgent need for new treatments that improve a larger proportion of the patient population and that can be used safely and long-term.
  • TLR7/9 and type I interferon were found to be significantly up-regulated in PBMCs of systemic lupus erythematosus (SLE) patients (Beverly D.LC et al., Mol Immunol., 2014, 61:38-43).
  • Mice overexpressing TLR7 have been reported to exacerbate autoimmune disease and autoinflammation (Santiago-Raber ML, et al., J Immunol., 2008, 181:1556-1562), while functional inhibition of TLR7/9 alleviates B6-Fas Pathological manifestations of lupus mice such as lpr and BXSB (Dwight H.
  • TLR7/8/9 TLR7/8/9 with antinuclear antibodies and type I interferons
  • small-molecule inhibitors targeting TLR7/8/9 are likely to have potential in the treatment of SLE.
  • the purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or its N-oxide or its pharmaceutically acceptable salt:
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Ring B is a 3- to 8-membered cycloalkyl or a 4- to 8-membered heterocyclyl
  • R 0 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkane base,
  • L is selected from bond, alkylene and heteroalkylene, wherein said alkylene and heteroalkylene are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkane substituted with one or more substituents in the group consisting of radical, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 1 is the same or different, and is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkane alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero substituted with one or more substituents in the aryl group;
  • R is selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, deuterated alkyl, haloalkoxy, deuterated alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl substituted with one or more substituents in the radical and heteroaryl;
  • each R is the same or different, and is each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;
  • Each R 4 is the same or different, and is each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkane base;
  • Each R 5 is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, oxo, haloalkyl, haloalkoxy, cyano, amino , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro group, hydroxyl, hydroxyalkyl, -C(O)OR 6 , -C(O)NR 7 R 8 , -NR 7 R 8 , -
  • R 6 is selected from hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group;
  • R 7 and R 8 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heterocyclic group Aryl;
  • R 7 and R 8 together with the attached nitrogen atom form a heterocyclyl group optionally selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, Substituted with one or more substituents of haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 9 is selected from hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, amino, hydroxyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • s 0, 1, 2, 3, or 4;
  • t 0, 1, 2, 3 or 4.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or its mixture form, or its N-oxide, or its pharmaceutically acceptable salt which is the compound represented by general formula (II) or its tautomer, meso, racem isomers, enantiomers, diastereomers, or mixtures thereof, or N-oxides, or pharmaceutically acceptable salts thereof:
  • J is 0, 1 or 2;
  • k 0, 1 or 2;
  • Rings A, R 0 , R 1 to R 4 , n, m and s are as defined in general formula (I).
  • the compound represented by the general formula (I) or the general formula (II) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or their mixtures, or their N-oxides, or their pharmaceutically acceptable salts which are the compounds represented by the general formula (III) or their tautomers, internal eliminations A mer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A, Ring C, R 1 to R 5 , n, m, s, t, J and k are as defined in general formula (II).
  • the compound represented by general formula (I), general formula (II) or general formula (III) or its tautomer, meso, racemic isomers, enantiomers, diastereomers, or mixtures thereof, or N-oxides, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (IV) or their tautomerization Isomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
  • Rings A, R 1 to R 4 , n, m, s, J and k are as defined in general formula (II).
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or an N-oxide thereof, or a method of a pharmaceutically acceptable salt thereof, comprising:
  • Ring A, Ring C, R 1 to R 5 , n, s, m, t, J and k are as defined in general formula (III).
  • Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or an N-oxide thereof, or a method of a pharmaceutically acceptable salt thereof, comprising:
  • R w is amino protecting group; preferably tert-butoxycarbonyl
  • Rings A , R1 to R4, n, s, m, J and k are as defined in general formula ( IV ).
  • compositions contains the compounds shown in general formula (I), general formula (II), general formula (III), general formula (IV) and Table A of the present disclosure Compounds or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or N-oxides thereof, or pharmaceutically acceptable compounds thereof salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to compounds of general formula (I), general formula (II), general formula (III), general formula (IV), and Table A, or tautomers, mesomers, racemates thereof isomers, enantiomers, diastereomers, or mixtures thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in preparation for the inhibition of TLR7 and/or Use of TLR8 and/or TLR9 in medicine.
  • the present disclosure further relates to compounds of general formula (I), general formula (II), general formula (III), general formula (IV), and Table A, or tautomers, mesomers, racemates thereof isomers, enantiomers, diastereomers, or mixtures thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in preparation for the inhibition of TLR7, TLR8 or Use of TLR9 in medicine.
  • the present disclosure further relates to compounds of general formula (I), general formula (II), general formula (III), general formula (IV), and Table A, or tautomers, mesomers, racemates thereof isomers, enantiomers, diastereomers, or mixtures thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in preparation for the inhibition of TLR7, TLR8 and Use in a medicament for TLR9; preferably in the manufacture of a medicament for inhibiting TLR7 and TLR9; or preferably in the manufacture of a medicament for inhibiting TLR7 and TLR9.
  • the present disclosure further relates to compounds of general formula (I), general formula (II), general formula (III), general formula (IV), and Table A, or tautomers, mesomers, racemates thereof isomers, enantiomers, diastereomers, or mixtures thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of therapeutic and/or prophylactic Use in a medicament for an inflammatory or autoimmune disease; wherein said inflammatory or autoimmune disease is preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Shogger Len syndrome.
  • SLE systemic lupus erythematosus
  • MS multiple sclerosis
  • the present disclosure further relates to a method of inhibiting TLR7 and/or TLR8 and/or TLR9, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), formula (III), formula ( IV) and the compounds shown in Table A or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or N-oxidation thereof substance, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to a method of inhibiting TLR7, TLR8 or TLR9, comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II), Formula (III), Formula (IV) and Table
  • the present disclosure further relates to a method of inhibiting TLR7, TLR8 and TLR9, preferably a method of inhibiting TLR7 and TLR9, or preferably a method of inhibiting TLR7 and TLR9, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), general formula (III), general formula (IV) and compounds shown in Table A or their tautomers, mesomers, racemates, enantiomers, diastereomers isomer, or a mixture thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure further relates to the use in a medicament for the treatment and/or prevention of inflammatory or autoimmune diseases, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), formula (II), formula (III) ), the compounds shown in general formula (IV) and Table A or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or its N-oxide, or its pharmaceutically acceptable salt or its pharmaceutical composition; wherein said inflammatory or autoimmune disease is preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, Multiple Sclerosis (MS) and Sjogren's Syndrome.
  • SLE systemic lupus erythematosus
  • MS Multiple Sclerosis
  • the present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III), general formula (IV) and shown in Table A or its tautomer, meso, exoisomer A racemate, an enantiomer, a diastereomer, or a mixture thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III), general formula (IV) and shown in Table A or its tautomer, meso, exoisomer Racemates, enantiomers, diastereomers, or mixtures thereof, or N-oxides, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting TLR7 and /or TLR8 and/or TLR9.
  • the present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III), general formula (IV) and shown in Table A or its tautomer, meso, exoisomer A racemate, an enantiomer, a diastereomer, or a mixture thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting TLR7, TLR8 or TLR9.
  • the present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III), general formula (IV) and shown in Table A or its tautomer, meso, exoisomer A racemate, an enantiomer, a diastereomer, or a mixture thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting TLR7, TLR8 and TLR9; preferably for inhibiting TLR7 and TLR8; or preferably for inhibiting TLR7 and TLR.
  • the present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III), general formula (IV) and shown in Table A or its tautomer, meso, exoisomer Racemates, enantiomers, diastereomers, or mixtures thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in therapy and/or or prevention of inflammatory or autoimmune diseases; wherein said inflammatory or autoimmune diseases are preferably selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS) and Shoghren's syndrome .
  • SLE systemic lupus erythematosus
  • MS multiple sclerosis
  • TLR7, TLR8 or TLR9 compounds of general formula (I), general formula (II), general formula (III), general formula (IV) and Table A are useful for the treatment of TLR7, TLR8 or TLR9 family receptor-related diseases, including but not limited to: inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune Diseases such as Graves disease, rheumatoid arthritis, systemic lupus erythema, lupus nephritis, cutaneous lupus, psoriasis; autoinflammatory diseases such as Cryopyrin-associated periodic syndrome (CAPS), TNF receptors Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), Adult Still's Disease, Generalized-Onset Juvenile Idiopathic Arthritis, Gout, Gouty Arthritis;
  • inflammatory diseases such as Crohn'
  • specific conditions or diseases that can be treated with compounds of the present disclosure include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid joints Inflammation, systemic lupus erythema, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy Dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, Atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis
  • the condition is selected from the group consisting of Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris .
  • the condition is ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury caused by stroke and myocardial ischemia-reperfusion injury caused by myocardial infarction.
  • the disorder is multiple myeloma.
  • the active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation.
  • the compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils.
  • the oily suspensions may contain thickening agents.
  • the aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase can be vegetable oil, or mineral oil, or a mixture thereof.
  • Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • fatty acids are also available in the preparation of injectables.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension.
  • These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.
  • the optimal treatment modality such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to conventional treatment regimens.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms.
  • 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-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, 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-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • the alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, One or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituents.
  • heteroalkyl means that one or more -CH2- in an alkyl group is substituted with a heteroatom selected from N, O, S and S(O); wherein said alkyl group is as defined above; heteroalkane
  • the radicals may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally selected from H atoms, D atoms, halogens, alkyl groups , alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents.
  • alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 straight or branched chain groups of up to 20 carbon atoms, preferably containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, More preferred are alkylene groups containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • the alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from alkenyl, alkynyl, alkoxy, haloalkane Oxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, One or more substituents of cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • heteroalkylene refers to an alkylene where one or more -CH2- is substituted with a heteroatom selected from N, O, S and S(O); wherein said alkylene is as defined above ; Heteroalkylene may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably independently optionally selected from H atoms, D atoms, One or more substituents of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • alkenyl refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy group, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkynyl refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy group, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms (eg 3, 4, 5, 6, 7 and 8) carbon atoms, more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably, it is 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicycloalkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include etc.; preferred
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from halogen, alkyl, alkoxy, haloalkyl , one or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl a substituent.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy alkyl, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur , the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone) but does not include -OO-, -OS- or -SS- ring moieties, the remaining ring atoms being carbon.
  • It preferably contains 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heterocyclic atom; more preferably contains 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8) of which 1-3 are heteroatoms (eg 1, 2 and 3); more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1-3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholine base, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur.
  • the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds in which one or more ring atoms are selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan Member/5-membered and 6-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from halogen, alkyl, alkoxy, haloalkyl , one or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl a substituent.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, One or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl Substituents.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl one or more substituents.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or by removing two hydrogen atoms from the same or two different ring atoms of the parent. Derived residues, ie "divalent cycloalkyl”, “divalent heterocyclyl”, “arylene”, “heteroarylene”.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or or both and Two configurations.
  • amino protecting group is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted.
  • Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy and nitro.
  • hydroxyl protecting group is a suitable group known in the art for protecting a hydroxyl group, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts) for hydroxyl protecting groups.
  • the hydroxyl protecting group can be a (C 1-10 alkyl or aryl) 3 silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy substituted C 1-6 alkyl or phenyl substituted C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, tert-butyl, allyl, benzyl , methoxymethyl (MOM), ethoxyethyl, etc.; can be (C 1-10 alkyl or aryl) acyl, such as: formyl, acetyl, benzoyl, p-nitro
  • heterocyclylalkyl refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.
  • heteroarylalkyl refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
  • the compounds of the present disclosure include isotopic derivatives thereof.
  • isotopic derivatives refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, having the structures of the present disclosure, replacing hydrogen with “deuterium” or “tritium”, or replacing fluorine with18F -fluorine labeling ( 18F isotope), or enriching with11C- , 13C- , or14C- Compounds in which carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) are replaced by carbon atoms are within the scope of the present disclosure.
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
  • each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds.
  • deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.
  • heterocyclic group optionally substituted with alkyl means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refers to salts of the compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity.
  • the salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia.
  • Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
  • Ring A, Ring C, R 1 to R 5 , n, s, m, t, J and k are as defined in general formula (III).
  • the compounds of the general formula (IVA-1) and the general formula (IVA-2) undergo a coupling reaction under basic conditions and in the presence of a catalyst to obtain the compound of the general formula (IVA),
  • X is a halogen, preferably a bromine atom
  • R w is amino protecting group; preferably tert-butoxycarbonyl
  • Rings A , R1 to R4, n, s, m, J and k are as defined in general formula ( IV ).
  • the reducing agent includes but is not limited to sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium acetylborohydride, etc., preferably triacetoxyborohydride sodium.
  • the reagents that provide alkaline conditions include organic bases and inorganic bases
  • the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyl Base lithium, lithium diisopropylamide, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate , potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably potassium phosphate and sodium acetate.
  • the catalysts include but are not limited to 1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex, palladium/carbon, Raney nickel, tetrakis -Triphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride , 1,1'-bis(dibenzylphosphorus)dichlorodipentyl iron palladium or tris(dibenzylideneacetone)dipalladium;
  • the reagents that provide acidic conditions include but are not limited to hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf, preferably hydrogen chloride in 1,4-dioxane.
  • the above synthetic schemes one and two are preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, acetic acid Ethyl ester, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide and mixtures thereof.
  • the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, acetic acid Ethyl ester, n-hexane, dimethyl sulfoxide, 1,
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS used Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • HPLC preparations were performed using Waters 2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying the compound include: A: n-hexane Alkane/ethyl acetate system, B: dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • 6-Amino-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl ester 1a (9.0 g, 36.0 mmol, Bidder) was dissolved in dichloromethane (200 mL) and methanol (40 mL) , cooled to 0 °C, sodium bicarbonate (5.6 g, 54.8 mmol) was added, followed by a solution of iodine chloride (6.4 g, 39.4 mmol, adamas) in dichloromethane (40 mL). Stir at room temperature for 0.5 hour.
  • Test Example 1 Inhibitory effect of the disclosed compound on human TLR7 activation pathway
  • Neomycin Normal, Invivogen
  • HEK-Blue TM hTLR7 cells were purchased from Invivogen. This cell was co-transfected with human Toll-like receptor 7 (TLR7) gene and secreted alkaline phosphatase reporter gene (SEAP) into HEK293 cells, and alkaline phosphatase reporter
  • TLR7 Toll-like receptor 7
  • SEAP alkaline phosphatase reporter gene
  • the gene (SEAP) is under the regulation of the IFN- ⁇ minimal promoter containing 5 NF-kB and AP-1 binding sites, and upon activation of TLR7 with agonists, downstream NF-kB and AP-1 SEAP secretion was induced, and the above-mentioned pathways were inhibited after the addition of antagonistic compounds, and SEAP secretion was reduced.
  • OD620 was measured by SEAP substrates to evaluate the activity of compounds on the TLR7 pathway.
  • the 20mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256 ⁇ M, the blank well was 100% DMSO, and then diluted 20 times in 10% DMSO.
  • FBS-inactivated DMEM/high glucose medium complete medium. Dilute R848 to 10 ⁇ M with sterile water.
  • HEK-Blue TM hTLR7 cells were cultured in DMEM/high glucose medium containing 10% inactivated FBS, 100 ⁇ g/mL neomycin, 10 ⁇ g/mL blasticidin and 100 ⁇ g/mL bleomycin.
  • the final concentration of R848 is 1 ⁇ M
  • the final concentration of the test compound is 10000, 2000, 400, 80, 16 , 3.2, 0.64, 0.128 nM.
  • the cells were cultured in a 37°C, 5% CO2 incubator for 20 hours, then 20 ⁇ L of the supernatant was taken, 180 ⁇ L of the prepared alkaline phosphatase detection medium was added, and the cells were incubated at 37°C in the dark for 120 minutes.
  • the standard instrument reads the OD620 absorbance value.
  • Use Graphpad Prism software to draw the inhibition curve according to each concentration of the compound and the corresponding inhibition rate, and calculate the concentration of the compound when the inhibition rate reaches 50%, that is, the IC 50 value, as shown in Table 1 below.
  • Test Example 2 Inhibitory effect of compounds of the present disclosure on human TLR8 pathway
  • Neomycin Normal, Invivogen
  • HEK-Blue TM hTLR8 cells were purchased from Invivogen. The cells were co-transfected with human Toll-like receptor 8 (TLR8) gene and secreted alkaline phosphatase reporter gene (SEAP) into HEK293 cells, and alkaline phosphatase reporter
  • TLR8 human Toll-like receptor 8
  • SEAP alkaline phosphatase reporter gene
  • the gene (SEAP) is under the regulation of the IFN- ⁇ minimal promoter containing 5 NF-kB and AP-1 binding sites, and upon activation of TLR8 with an agonist, SEAP secretion is induced through downstream NF-kB and AP-1, After the addition of antagonistic compounds, the above pathways were inhibited and SEAP secretion was reduced, and OD620 was measured by SEAP substrates to assess the activity of the compounds on the TLR8 pathway.
  • the 20mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256 ⁇ M, the blank well was 100% DMSO, and then diluted 20 times in 10% DMSO.
  • FBS-inactivated DMEM/high glucose medium complete medium. Dilute R848 to 60 ⁇ M with sterile water, add 20 ⁇ L/well of 60 ⁇ M R848 diluted in sterile water to a 96-well cell culture plate, and then add the above-mentioned compound diluted in complete medium and 100% DMSO at 20 ⁇ L per well to the containing solution.
  • 20 ⁇ L of sterile water and 20 ⁇ L of 100% DMSO diluted in complete medium were added to the negative control wells.
  • HEK-Blue TM hTLR8 cells were cultured in DMEM/high glucose medium containing 10% inactivated FBS, 100 ⁇ g/mL neomycin, 10 ⁇ g/mL blasticidin and 100 ⁇ g/mL bleomycin.
  • the final concentration of the test compound is 10000, 2000, 400, 80, 16 , 3.2, 0.64, 0.128 nM.
  • the cells were cultured in a 37°C, 5% CO 2 incubator for 20 hours, then 20 ⁇ L of the supernatant was taken, 180 ⁇ L of the prepared alkaline phosphatase detection medium was added, and the cells were incubated in a 37°C incubator for 120 minutes in the dark.
  • the instrument reads the OD620 absorbance value.
  • Use Graphpad Prism software to draw the inhibition curve according to each concentration of the compound and the corresponding inhibition rate, and calculate the concentration of the compound when the inhibition rate reaches 50%, that is, the IC 50 value, as shown in Table 2 below.
  • Test Example 3 Inhibitory effect of the disclosed compounds on human TLR9 activation pathway
  • Neomycin Normal, Invivogen
  • HEK-Blue TM hTLR9 cells were purchased from Invivogen. The cells were co-transfected with human Toll-like receptor 9 (TLR9) gene and secreted alkaline phosphatase reporter gene (SEAP) into HEK293 cells, and alkaline phosphatase reporter
  • TLR9 human Toll-like receptor 9
  • SEAP alkaline phosphatase reporter gene
  • the gene (SEAP) is under the regulation of an IFN- ⁇ minimal promoter containing 5 NF-kB and AP-1 binding sites, and upon activation of TLR9 with an agonist, SEAP secretion is induced through downstream NF-kB and AP-1, After the addition of antagonistic compounds, the above pathways were inhibited and SEAP secretion was reduced, and OD620 was measured by SEAP substrates to assess the activity of the compounds on the TLR9 pathway.
  • the 20mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256 ⁇ M, the blank well was 100% DMSO, and then diluted 20 times in 10% DMSO.
  • Inactivate FBS in DMEM/high glucose medium Dilute CpG ODN2006 to 10 ⁇ M with sterile water, add 20 ⁇ L/well of 10 ⁇ M CpG ODN2006 diluted in sterile water to a 96-well cell culture plate, and then add the compound diluted in complete medium and 100% DMSO at 20 ⁇ L per well.
  • negative control wells were added 20 ⁇ L sterile water and 20 ⁇ L 100% DMSO diluted in complete medium.
  • HEK-Blue TM hTLR9 cells were cultured in DMEM/high glucose medium containing 10% FBS, 100 ⁇ g/mL neomycin, 10 ⁇ g/mL blasticidin and 100 ⁇ g/mL bleomycin.
  • the final concentration of CpG ODN2006 is 1 ⁇ M
  • the final concentrations of the test compounds are 10000, 2000, 400, 80, 16 , 3.2, 0.64, 0.128 nM.
  • the cells were cultured in a 37°C, 5% CO 2 incubator for 20 hours, then 20 ⁇ L of the supernatant was taken, 180 ⁇ L of the prepared alkaline phosphatase detection medium was added, and the cells were incubated at 37°C in the dark for 15 minutes.
  • the standard instrument reads the OD620 absorbance value.
  • Use Graphpad Prism software to draw the inhibition curve according to each concentration of the compound and the corresponding inhibition rate, and calculate the concentration of the compound when the inhibition rate reaches 50%, that is, the IC 50 value, as shown in Table 3 below.

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Abstract

本公开涉及吲哚稠环类衍生物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(I)所示的吲哚稠环类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂的用途，特别是作为TLR7/8/9抑制剂的用途和用于制备治疗和/或预防炎性和自身免疫性疾病的药物中的用途。

Description

吲哚稠环类衍生物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种吲哚稠环类衍生物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的吲哚稠环类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为TLR7/8/9抑制剂在治疗炎性和自身免疫性疾病的用途。
背景技术
Toll样受体(Toll like receptors，TLR)是一类进化保守的跨膜先天免疫受体，它们是参与保护人体健康的第一线防御，对于识别病原体相关分子模式(PAMP)起重要作用(Kawai,T.等人,Nature Immunol.,11,2010,373-384)。TLR表达于各种免疫细胞，根据其表达部位的不同可分为两类：表达于细胞膜的TLR(TLR1/2/4/5/6)和表达于内体膜的TLR(TLR3/7/8/9)，分别识别PAMP中的不同成分和分子。其中，TLR7/8/9主要在DC细胞和B细胞中高表达，TLR7/8主要识别ssRNA，TLR9主要识别CpG-DNA。TLR7/8/9结合其配体后被激活，在胞质中与接头蛋白MyD88相结合，启动NF-κB和IRF通路，活化DC细胞，产生I型干扰素和其他多种炎性细胞因子；在B细胞中，TLR7/8/9和核酸类物质相结合后，在B细胞产生抗核抗体的过程中起重要作用，并且，DC细胞分泌的I型干扰素还会促进这种自身免疫性B细胞的进一步增殖和活化，从而引起一系列的炎症反应。
系统性红斑狼疮(SLE)属于一种自身免疫性结缔组织病，SLE的临床一线药物有三大类：激素、免疫抑制剂和抗疟类药物。本世纪仅有一款新药贝利木单抗获FDA批准，但它仅对一小部分SLE病人有适度和延迟的疗效(Navarra,S.V.等人，Lancet 2011,377,721)，治疗手段非常有限。因此，迫切需要改善更大比例的患者群体的新疗法，并且可以长期、安全使用。在系统性红斑狼疮(SLE)患者的PBMC中发现了TLR7/9以及I型干扰素的表达被明显上调的现象(Beverly D.LC等人,Mol Immunol.,2014,61:38-43)。据报道过度表达TLR7的小鼠可以加剧自身免疫疾病和自身炎症(Santiago-Raber ML,等人,J Immunol.,2008,181:1556-1562)，而功能性抑制TLR7/9可以缓解B6-Fas lpr和BXSB等狼疮小鼠的病理表现(Dwight H.Kono等人,PNAS,2009,106(29):12061-12066)。鉴于TLR7/8/9与抗核抗体以及I型干扰素的紧密关系，靶向TLR7/8/9的小分子抑制剂很可能具有治疗SLE的潜力。
公开的TLR7/8/9的抑制剂专利申请包括WO2019233941A1、WO2020020800A1、WO2018049089A1、WO2017106607A1、CN109923108A和WO2020048605A1等。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物或其可药用的盐：
Figure PCTCN2021108577-appb-000001
其中：
环A选自环烷基、杂环基、芳基和杂芳基；
环B为3至8元环烷基或4至8元杂环基；
R 0选自氢原子、卤素、烷基、烯基、炔基、杂烷基、烷氧基、卤代烷基、氘代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、
Figure PCTCN2021108577-appb-000002
Figure PCTCN2021108577-appb-000003
L选自键、亚烷基和杂亚烷基，其中所述的亚烷基和杂亚烷基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
环C选自环烷基、杂环基、芳基和杂芳基；
各个R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 2选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、氘代烷基、卤代烷氧基、氘代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
各个R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基；
各个R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基；
各个R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、杂烷基、烯基、炔基、烷氧基、氧代基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、杂烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、氧代基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、-C(O)OR 6、-C(O)NR 7R 8、-NR 7R 8、-S(O) 2R 9、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 6选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 7和R 8相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
或者R 7和R 8与相连的氮原子一起形成杂环基，所述的杂环基任选被选自卤素、烷基、氧代基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 9选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
n为0、1、2、3或4；
m为0、1或2；
s为0、1、2、3或4；且
t为0、1、2、3或4。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中环B为5至6元杂环基；优选为哌啶基。
在本公开一些优选的实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐：
Figure PCTCN2021108577-appb-000004
其中：
J为0、1或2；
k为0、1或2；
环A、R 0、R 1至R 4、n、m和s如通式(I)中所定义。
在本公开一些优选的实施方案中，所述的通式(I)或通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 0为氢原子或
Figure PCTCN2021108577-appb-000005
环C、R 5和t如通式(I)中所定义。
在本公开一些优选的实施方案中，所述的通式(I)或通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐：
Figure PCTCN2021108577-appb-000006
其中：
环A、环C、R 1至R 5、n、m、s、t、J和k如通式(II)中所定义。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其为通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐：
Figure PCTCN2021108577-appb-000007
其中：
环A、R 1至R 4、n、m、s、J和k如通式(II)中所定义。
在本公开一些优选的实施方案中，所述的通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中J为1，且k为1。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中环A为6至10元芳基或5至10元杂芳基；优选为吡啶基。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中环C为3至8元杂环基；优选为哌啶基。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和卤代C 1-6烷基。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 1相同或不同，且各自独立地为C 1-6烷基。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 2选自卤素、C 1-6烷基和卤代C 1-6烷基。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 2为C 1-6烷基。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 3选自氢原子、卤素、C 1-6烷基和卤代C 1-6烷基；优选地，R 3为氢原子。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基和卤代C 1-6烷基；优选地，R 4为氢原子。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和卤代C 1-6烷基。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 5相同或不同，且各自独立地为C 1-6烷基。
在本公开一些优选的实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中n为2。
在本公开一些优选的实施方案中，所述的通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中环A为5至10元杂芳基；环C为3至8元杂环基；R 1相同或不同，各自独立地为C 1-6烷基；R 2为C 1-6烷基；R 3为氢原子；R 4为氢原子；R 5相同或不同，且各自独立地为C 1-6烷基；n为2；J为1；k为1。
表A本公开的典型化合物包括但不限于：
Figure PCTCN2021108577-appb-000008
本公开的另一方面涉及一种制备通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐的方法，该方法包括：
Figure PCTCN2021108577-appb-000009
通式(IV)的化合物与通式(IIIA)的化合物发生还原胺化反应，得到通式(III)的化合物，
其中：
环A、环C、R 1至R 5、n、s、m、t、J和k如通式(III)中所定义。
本公开的另一方面涉及一种制备通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐的方法，该方法包括：
Figure PCTCN2021108577-appb-000010
通式(IVA)的化合物脱去保护基R w，得到通式(IV)的化合物，
其中：
R w为氨基保护基；优选为叔丁氧羰基；
环A、R 1至R 4、n、s、m、J和k如通式(IV)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物在制备用于抑制TLR7和/或TLR8和/或TLR9的药物中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物在制备用于抑制TLR7、TLR8或TLR9的药物中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物在制备用于抑制TLR7、TLR8和TLR9的药物中的用途；优选在制备用于抑制TLR7和TLR9的药物中的用途；或者优选在制备用于抑制TLR7和TLR9的药物中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物在制备用于治疗和/或预防炎性或自身免疫性疾病的药物中的用途；其中所述的炎性或自身 免疫性疾病优选选自系统性红斑狼疮(SLE)、类风湿性关节炎、多发性硬化(MS)和肖格伦综合症。
本公开进一步涉及一种抑制TLR7和/或TLR8和/或TLR9的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物。
本公开进一步涉及一种抑制TLR7、TLR8或TLR9的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物。
本公开进一步涉及一种抑制TLR7、TLR8和TLR9的方法，优选抑制TLR7和TLR9的方法，或者优选抑制TLR7和TLR9的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物。
本公开进一步涉及一种治疗和/或预防炎性或自身免疫性疾病的药物中的用途，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物；其中所述的炎性或自身免疫性疾病优选选自系统性红斑狼疮(SLE)、类风湿性关节炎、多发性硬化(MS)和肖格伦综合症。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物，其用作药物。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物，其用于抑制TLR7和/或TLR8和/或TLR9。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物，其用于抑制TLR7、TLR8或TLR9。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物，其 用于抑制TLR7、TLR8和TLR9；优选用于抑制TLR7和TLR8；或者优选用于抑制TLR7和TLR。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)及表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者包含其的药物组合物，其用作治疗和/或预防炎性或自身免疫性疾病；其中所述的炎性或自身免疫性疾病优选选自系统性红斑狼疮(SLE)、类风湿性关节炎、多发性硬化(MS)和肖格伦综合症。
鉴于它们作为TLR7、TLR8或TLR9的选择性抑制剂的活性，通式(I)、通式(II)、通式(III)、通式(IV)及表A的化合物可用于分别治疗TLR7、TLR8或TLR9家族受体相关疾病，包括但不限于：炎性疾病如克罗恩病、溃疡性结肠炎、哮喘、移植物抗宿主病、同种异体移植排斥、慢性阻塞性肺病；自身免疫性疾病，如格雷夫斯病、类风湿性关节炎、系统性狼疮红斑、狼疮性肾炎、皮肤狼疮、银屑病；自身炎性疾病，如Cryopyrin相关的周期性综合征(CAPS)、TNF受体相关的周期性综合征(TRAPS)、家族性地中海热(FMF)、成人斯蒂尔病、全身性发作的幼年特发性关节炎、痛风、痛风性关节炎；代谢疾病，如2型糖尿病、动脉粥样硬化、心肌梗塞；破坏性骨障碍，如骨吸收疾病、骨关节炎、骨质疏松症、多发性骨髓瘤相关骨障碍；增殖性障碍，如急性骨髓性白血病、慢性骨髓性白血病；血管生成障碍，如包括实体瘤、眼部新生血管和婴儿血管瘤的血管生成障碍；感染性疾病，如败血症、败血性休克和志贺氏菌病；神经变性疾病，如阿尔茨海默病、帕金森病、由创伤性损伤引起的脑缺血或神经变性疾病；肿瘤疾病和病毒性疾病，所述肿瘤疾病如转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤；以及HIV感染、CMV视网膜炎和AIDS。
更具体地，可用本公开化合物治疗的具体病症或疾病包括但不限于胰腺炎(急性或慢性)、哮喘、过敏、成人呼吸窘迫综合征、慢性阻塞性肺病、肾小球肾炎、类风湿性关节炎、系统性狼疮红斑、硬皮病、慢性甲状腺炎、格雷夫斯病、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性中性粒细胞减少症、血小板减少症、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化、炎性肠病、溃疡性结肠炎、克罗恩病、银屑病、移植物抗宿主病、内毒素诱导的炎症反应、肺结核、动脉粥样硬化、肌肉退化、恶病质、银屑病关节炎、莱特尔氏综合征(Reiter’s syndrome)、痛风、创伤性关节炎、风疹性关节炎、急性滑膜炎、胰腺β细胞病；以大量嗜中性粒细胞浸润为特征的疾病；类风湿性脊椎炎、痛风性关节炎和其他关节炎病症、脑型疟疾、慢性肺部炎性疾病、矽肺病、肺结节病、骨吸收疾病、同种异体移植排斥、感染引起的发热和肌痛、继发于感染的恶病质、瘢痕疙瘩形成、瘢痕组织形成、溃疡性结肠炎、热病(pyresis)、流感、骨质疏松症、骨关节炎、急性骨髓性白血病、慢性骨髓性白血病、转移性黑色素瘤、卡波 西肉瘤、多发性骨髓瘤、败血症、败血性休克和志贺氏菌病；阿尔茨海默病、帕金森病、创伤性损伤引起的脑缺血或神经变性疾病；血管生成障碍，包括实体瘤、眼部新生血管和婴儿血管瘤；病毒性疾病，包括急性肝炎感染(包括甲型肝炎、乙型肝炎和丙型肝炎)、HIV感染和CMV视网膜炎、AIDS、ARC或恶性肿瘤和疱疹；中风、心肌缺血、中风心脏病发作中的局部缺血、器官缺氧、血管增生、心脏和肾脏再灌注损伤、血栓形成、心脏肥大、凝血酶诱导的血小板聚集、内毒素血症和/或中毒性休克综合征、与前列腺素内过氧化酶合酶-2相关的病症、以及寻常型天疱疮。优选的治疗方法中，其病症选自克罗恩病、溃疡性结肠炎、同种异体移植物排斥、类风湿性关节炎、牛皮癣、强直性脊柱炎、牛皮癣性关节炎和寻常型天疱疮。可替代地优选治疗方法中，其病症为缺血再灌注损伤，所述缺血再灌注损伤包括由中风引起的脑缺血再灌注损伤和由心肌梗塞引起的心肌缺血再灌注损伤。另一种优选的治疗方法中，其病症为多发性骨髓瘤。
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药、吸入或吹入给药的各种剂型。本公开的化合物也可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。
作为一般性指导，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、或矿物油、或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳，可通过局部大量注射将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合、疾病的严重性等。另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基，更优选为含有1至6个碳原子的烷基。非限制性实例包括甲基、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。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、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、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“杂烷基”指烷基中的一个或多个-CH 2-被选自N、O、S和S(O)的杂原子所取代；其中所述的烷基如上所定义；杂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，所述取代基优选独立地任选选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其为从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基。
术语“杂亚烷基”指亚烷基中的一个或多个-CH 2-被选自N、O、S和S(O)的杂原子所取代；其中所述的亚烷基如上所定义；杂亚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，所述取代基优选独立地任选选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“烯基”指分子中含有至少一个碳碳双键的烷基化合物，其中烷基的定义如上所述。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
术语“炔基”指分子中含有至少一个碳碳三键的烷基化合物，其中烷基的定义如上所述。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，优选包含3至8个(例如3、4、5、6、7和8个)碳原子，更优选包含3至6个碳原子。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、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元，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。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021108577-appb-000011
术语“稠环烷基”指5至20元，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，其中一个或多个环可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，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/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元的双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021108577-appb-000012
术语“桥环烷基”指5至20元，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，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2021108577-appb-000013
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)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，非限制性实例包括
Figure PCTCN2021108577-appb-000014
等；优选
Figure PCTCN2021108577-appb-000015
Figure PCTCN2021108577-appb-000016
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个环原子(例如3、4、5、6、7和8个)，其中1-3是杂原子(例如1、2和3个)；更优选 包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括氧杂环丁基、吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2021108577-appb-000017
术语“稠杂环基”指5至20元，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基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，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/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2021108577-appb-000018
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的 数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2021108577-appb-000019
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)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基，其非限制性实例包括：
Figure PCTCN2021108577-appb-000020
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021108577-appb-000021
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)， 更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021108577-appb-000022
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同或两个不同的环原子上除去两个氢原子所衍生的残基，即“二价环烷基”、“二价杂环基”、“亚芳基”、“亚杂芳基”。
本公开所述化合物的化学结构中，键
Figure PCTCN2021108577-appb-000023
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021108577-appb-000024
可以为
Figure PCTCN2021108577-appb-000025
或
Figure PCTCN2021108577-appb-000026
或者同时包含
Figure PCTCN2021108577-appb-000027
和
Figure PCTCN2021108577-appb-000028
两种构型。
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基和硝基中的1-3个取代基所取代。
术语“羟基保护基”是本领域已知的适当的用于保护羟基的基团，参见文献(“Protective Groups in Organic Synthesis”，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基等；可以是C 1-10烷基或取代烷基，优选烷氧基或芳基取代的烷基，更优选C 1-6烷氧基取代的C 1-6烷基或苯基取代的C 1-6烷基，最优选C 1-4烷氧基取代的C 1-4烷基， 例如：甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基；也可以是(C 1-6烷氧基或C 6-10芳基氧基)羰基。
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基和烷基如上所定义。
术语“杂芳基烷基”指烷基被一个或多个杂芳基取代，其中杂芳基和烷基如上所定义。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”或“氧代”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。
本公开的化合物包括其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-、 13C-、或者 14C-富集的碳( 11C-、 13C-、或者 14C-碳标记； 11C-、 13C-、或者 14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。其中氘化形式的化合物为与碳原子连接 的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为1～5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。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。
“可药用的盐”是指本公开化合物的盐，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。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒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，取决于受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。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键的时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2021108577-appb-000029
通式(IV)的化合物与通式(IIIA)的化合物在碱性条件下，在还原剂存在下发生还原胺化反应，得到通式(III)的化合物，
其中：
环A、环C、R 1至R 5、n、s、m、t、J和k如通式(III)中所定义。
方案二
本公开通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2021108577-appb-000030
第一步，通式(IVA-1)和通式(IVA-2)的化合物在碱性条件下，催化剂存在下，发生偶联反应得到通式(IVA)的化合物，
第二步，通式(IVA)的化合物在酸性条件下脱去保护基R w，得到通式(IV)的化合物，
其中：
X为卤素，优选为溴原子；
R w为氨基保护基；优选为叔丁氧羰基；
R m为
Figure PCTCN2021108577-appb-000031
环A、R 1至R 4、n、s、m、J和k如通式(IV)中所定义。
上述合成方案一中，所述的还原剂包括但不限于三乙酰氧基硼氢化钠、硼氢 化钠、硼氢化锂、氰基硼氢化钠和乙酰硼氢化钠等，优选三乙酰氧基硼氢化钠。
上述合成方案一和方案二中，提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、乙酸钠、乙醇钠、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、醋酸钠、醋酸钾、碳酸钾或碳酸铯、氢氧化钠、氢氧化锂一水合物、氢氧化锂和氢氧化钾；优选磷酸钾和乙酸钠。
上述合成方案二中，所述的催化剂包括但不限于1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、钯/碳、雷尼镍、四-三苯基膦钯、二氯化钯、醋酸钯、双(二亚芐基丙酮)钯、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯或三(二亚苄基丙酮)二钯；优选1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物；
上述合成方案二中，提供酸性的条件的试剂包括但不限于氯化氢、氯化氢的1,4-二氧六环溶液、三氟乙酸、甲酸、乙酸、盐酸、硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸、Me 3SiCl和TMSOTf，优选为氯化氢的1,4-二氧六环溶液。
上述合成方案一和二优选在溶剂中进行，所用溶剂包括但不限于：乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺及其混合物。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE NEO 500M核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP 和Gilson-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂体系和薄层色谱法的展开剂体系包括：A：正己烷/乙酸乙酯体系，B：二氯甲烷/甲醇体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
2-(2,6-二甲基吡啶-4-基)-7-(1-异丁基哌啶-4-基)-1-异丙基-6,7,8,9-四氢-3H-吡咯并[3,2-f]异喹啉1
Figure PCTCN2021108577-appb-000032
Figure PCTCN2021108577-appb-000033
第一步
6-氨基-5-碘-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯1b
将6-氨基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯1a(9.0g，36.0mmol，毕得医药)溶于二氯甲烷(200mL)和甲醇(40mL)，冷却到0℃，加入碳酸氢钠(5.6g，54.8mmol)，再加入氯化碘(6.4g，39.4mmol，adamas)的二氯甲烷(40mL)溶液。室温搅拌0.5小时。加饱和亚硫酸氢钠水溶液(200mL)，乙酸乙酯(80mL×2)萃取，无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物1b(9.3g，产率：68.8％)。
MS m/z(ESI)：375.0[M+1]。
第二步
5-碘-6-((3-甲基丁-2-烯-1-基)氨基)-3,4-二氢异喹啉-2(1H)-羧酸叔丁脂1d
将化合物1b(3.0g，7.97mmol)和3-甲基丁-2-烯醛1c(1.0g，11.9mmol，adamas)溶于甲醇(30mL)，室温搅拌16小时。冷却到室温，加入硼氢化钠(610mg,16.1mmol)，搅拌反应1小时。加入水(100mL)，乙酸乙酯(100mL×2)萃取，无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物1d(2.8g，产率：79.0％)。
MS m/z(ESI)：387.0[M-55]。
第三步
1-(丙-1-烯-2-基)-3,6,8,9-四氢-7H-吡咯并[3,2-f]异喹啉-7-羧酸叔丁酯1e
将化合物1d(1.0g，2.26mmol)、醋酸钯(100mg，0.472mmol，adamas)、三乙胺(460mg，4.55mmol)、四丁基溴化铵(730mg，2.26mmol)溶于N,N二甲基甲酰胺(30mL)，氮气氛下，于85℃反应16小时，反应液降至室温，加水(50mL)，乙酸乙酯(50mL×2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物1e(300mg，产率：42.5％)。
MS m/z(ESI)：257.1[M-55]。
第四步
1-异丙基-3,6,8,9-四氢-7H-吡咯并[3,2-f]异喹啉-7-羧酸叔丁酯1f
将化合物1e(300mg，3.28mmol)溶于乙酸乙酯(2.0mL)和甲醇(2.0mL)，加入10％钯/碳(100mg)，氢气氛下，室温反应16小时。过滤，滤液减压浓缩，得到标题产物1f(200mg，产率：66.2％)。
MS m/z(ESI)：259.1[M-55]。
第五步
2-溴-1-异丙基-3,6,8,9-四氢-7H-吡咯并[3,2-f]异喹啉-7-羧酸叔丁脂1g
将化合物1f(200mg，0.636mmol)溶于1,2-二氯乙烷(7.0mL)，-10℃滴加N-溴代丁二酰亚胺(113mg，0.635mmol)的1,2-二氯乙烷(7.0mL)溶液，加毕，用饱和亚硫酸氢钠水溶液(50mL)淬灭，二氯甲烷(50mL×2)萃取，无水硫酸钠干燥，过滤，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物1g(50mg，产率：20.0％)。
MS m/z(ESI)：337.0[M-55]。
第六步
2-(2,6-二甲基吡啶-4-基)-1-异丙基-3,6,8,9-四氢-7H-吡咯并[3,2-f]异喹啉-7-羧酸叔丁酯1i
将化合物1g(50mg，0.127mmol)和(2,6-二甲基吡啶-4-基)硼酸1h(30mg，0.199mmol，药明康德)溶于1,4-二氧六环(2.5mL)和水(0.5mL)中，加入磷酸钾(81.0mg，0.382mmol)和1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(11mg，0.013mmol，毕得医药)。氮气氛下，90℃反应4小时。反应液冷却至室温，加水(10mL)，乙酸乙酯(10mL×2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物1i(46.0mg，产率：86.2％)。
MS m/z(ESI)：420.2[M+1]。
第七步
2-(2,6-二甲基吡啶-4-基)-1-异丙基-6,7,8,9-四氢-3H-吡咯并[3,2-f]异喹啉1j
将化合物1i(46.0mg，0.110mmol)溶于二氯甲烷(1.0mL)中，加入4M氯化氢的1,4-二氧六环溶液(1.0mL)。室温搅拌反应1小时。反应液浓缩，用7M氨甲醇溶液碱化，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物1j(35.0mg，产率：99.9％)。
MS m/z(ESI)：320.2[M+1]。
第八步
2-(2,6-二甲基吡啶-4-基)-7-(1-异丁基哌啶-4-基)-1-异丙基-6,7,8,9-四氢-3H-吡咯并[3,2-f]异喹啉1
将化合物1j(35.0mg，0.110mmol)和1-异丁基哌啶-4-酮1k(35.0mg，0.225mmol，毕得医药)溶于N,N-二甲基甲酰胺(1.5mL)，加入乙酸钠(20mg,0.244mmol)， 室温搅拌3小时。加入三乙酰氧基硼氢化钠(80mg，0.330mmol，韶远科技)，加完室温反应16小时。过滤，滤液减压浓缩,用高效液相色谱法纯化(Boston Phlex Prep C18 5μm 30×150mm；流动相：A-水(10mmol碳酸氢铵)：B-乙腈＝50％-95％B(15min)，流速：30mL/min)，得到标题产物1(10mg，产率：19.9％)。
MS m/z(ESI)：459.3[M+1]。
1H NMR(500MHz,CD 3OD)δ7.27(s,2H),7.23(d,1H),6.92(d,1H),4.17(s,2H),3.76-3.72(m,1H),3.54-3.51(m,2H),3.28-3.25(m,2H),2.94-2.89(m,2H),2.58(s,6H),2.48-2.45(m,2H),2.23-2.19(m,2H),2.00-1.88(m,5H),1.38-1.34(m,1H),1.33(d,6H),1.00(d,6H)。
生物学评价
以下结合测试例进一步描述解释本公开，但这些实施例并非意味着限制本公开的范围。
测试例1本公开化合物对人TLR7激活通路的抑制作用
一、实验材料及仪器
1)HEK-Blue TM hTLR7细胞(Invivogen)
2)雷西莫特(R848/Resiquimod，Invivogen)
3)碱性磷酸酶检测培养基(Quanti-Blue Detection，Invivogen)
4)杀稻瘟菌素(Blasticidin，Invivogen)
5)博莱霉素(Zeocin，Invivogen)
6)新霉素(Normocin，Invivogen)
7)DMEM/高糖培养基(DMEM/HIGH Glucose，GE Healthcare)
8)胎牛血清(FBS)(Gibco)
9)磷酸盐缓冲液(上海源培生物科技有限公司)
10)无菌水(上海恒瑞自制)
11)15ml离心管(Corning)
12)96孔配药板(Corning)
13)96孔平底细胞培养板(Corning)
14)恒温细胞培养箱(Thermo scientific)
15)恒温箱(上海一恒科学仪器有限公司)
16)PHERAstar FS酶标仪(BMG Labtech)
二、实验步骤
在Invivogen购得HEK-Blue TM hTLR7细胞，此细胞是将人Toll样受体7(TLR7)基因和含分泌型碱性磷酸酶报告基因(SEAP)共转染到HEK293细胞，碱性磷酸酶报告基因(SEAP)处于含5个NF-kB和AP-1结合位点的IFN-β最小启动子(minimal promoter)的调控下，当用激动剂激活TLR7后，通过下游NF-kB和AP-1引起SEAP分泌，加入拮抗化合物后，上述通路被抑制，SEAP分泌降低，通过 SEAP底物测定OD620，从而评估化合物对TLR7通路的活性。
将溶于100％DMSO的20mM受试化合物用100％DMSO系列稀释至2000、400、80、16、3.2、0.64、0.128、0.0256μM，空白孔为100％DMSO，再20倍稀释于含10％灭活FBS的DMEM/高糖培养基(完全培养基)中。用无菌水将R848稀释至10μM。在96孔细胞培养板中加入20μL/孔无菌水稀释的10μM R848，再将上述稀释于完全培养基的化合物和100％DMSO按每孔20μL加入到含有R848的孔中，阴性对照孔加入20μL无菌水和20μL稀释于完全培养基的100％DMSO。
HEK-Blue TM hTLR7细胞培养于含10％灭活FBS、100μg/mL新霉素、10μg/mL杀稻瘟菌素和100μg/mL博莱霉素的DMEM/高糖培养基中。取生长良好，到达70％-80％的细胞，弃去生长培养基，加5-10mL 37℃预热的PBS洗细胞一次，再加2-5mL预热的PBS置于37℃培养1-2分钟，用移液器吹散细胞，转移细胞到一个15mL离心管，计数细胞，用含10％灭活FBS的DMEM/高糖培养基调整细胞密度至4.8×10 5/mL。加160μL调整密度后的细胞悬液到上述96孔细胞培养板中，最终每孔细胞数为76500/孔，R848终浓度为1μM，受试化合物终浓度分别为10000、2000、400、80、16、3.2、0.64、0.128nM。将细胞置于37℃，5％CO 2培养箱中培养20小时，随后取上清20μL，加入180μL配制好的碱性磷酸酶检测培养基，于37℃恒温箱避光孵育120分钟后，酶标仪读取OD620吸光值。使用以下公式计算抑制率：抑制率＝{1-(OD受试化合物-OD阴性对照孔)/(OD空白孔-OD阴性对照孔)}×100％。用Graphpad Prism软件根据化合物各浓度与相应的抑制率绘出抑制曲线，并计算抑制率达到50％时化合物的浓度，即IC 50值，见下表1。
表1本公开化合物对人TLR7激活通路的抑制IC 50值
实施例编号 IC 50(nM)
1 52
结论：本公开化合物对TLR7通路具有很好的抑制作用。
测试例2 本公开化合物对人TLR8通路的抑制作用
一、实验材料及仪器
1)HEK-Blue TM hTLR8细胞(Invivogen)
2)雷西莫特(R848/Resiquimod，Invivogen)
3)碱性磷酸酶检测培养基(Quanti-Blue Detection，Invivogen)
4)杀稻瘟菌素(Blasticidin，Invivogen)
5)博莱霉素(Zeocin，Invivogen)
6)新霉素(Normocin，Invivogen)
7)DMEM/高糖培养基(DMEM/HIGH Glucose，GE Healthcare)
8)胎牛血清(Gibco)
9)磷酸盐缓冲液(上海源培生物科技有限公司)
10)无菌水(上海恒瑞自制)
11)15ml离心管(Corning)
12)96孔配药板(Corning)
13)96孔平底细胞培养板(Corning)
14)恒温细胞培养箱(Thermo scientific)
15)恒温箱(上海一恒科学仪器有限公司)
16)PHERAstar FS酶标仪(BMG Labtech)
二、实验步骤
在Invivogen购得HEK-Blue TM hTLR8细胞，此细胞是将人Toll样受体8(TLR8)基因和含分泌型碱性磷酸酶报告基因(SEAP)共转染到HEK293细胞，碱性磷酸酶报告基因(SEAP)处于含5个NF-kB和AP-1结合位点的IFN-β最小启动子的调控下，当用激动剂激活TLR8后，通过下游NF-kB和AP-1引起SEAP分泌，加入拮抗化合物后，上述通路被抑制，SEAP分泌降低，通过SEAP底物测定OD620，从而评估化合物对TLR8通路的活性。
将溶于100％DMSO的20mM受试化合物用100％DMSO系列稀释至2000、400、80、16、3.2、0.64、0.128、0.0256μM，空白孔为100％DMSO，再20倍稀释于含10％灭活FBS的DMEM/高糖培养基(完全培养基)中。用无菌水将R848稀释至60μM，在96孔细胞培养板中加入20μL/孔无菌水稀释的60μM R848，再将上述稀释于完全培养基的化合物和100％DMSO按每孔20μL加入到含有R848的孔中，阴性对照孔加入20μL无菌水和20μL稀释于完全培养基的100％DMSO。
HEK-Blue TM hTLR8细胞培养于含10％灭活FBS、100μg/mL新霉素、10μg/mL杀稻瘟菌素和100μg/mL博莱霉素的DMEM/高糖培养基中。取生长良好，到达70％-80％的细胞，弃去生长培养基，加5-10mL 37℃预热的PBS洗细胞一次，再加2-5mL预热的PBS置于37℃培养1-2分钟，用移液器吹散细胞，转移细胞到一个15mL离心管，计数细胞，用含10％灭活FBS的DMEM/高糖培养基调整细胞密度到4.8×10 5/mL。加160μL调整密度后的细胞悬液到上述96孔细胞培养板中，最终每孔细胞数为76500/孔，R848终浓度为6μM，受试化合物终浓度分别为10000、2000、400、80、16、3.2、0.64、0.128nM。将细胞置于37℃，5％CO 2培养箱中培养20小时，随后取上清20μL，加入180μL配制好的碱性磷酸酶检测培养基，于37℃恒温箱避光孵育120分钟，酶标仪读取OD620吸光值。使用以下公式计算抑制率：抑制率＝{1-(OD受试化合物-OD阴性对照孔)/(OD空白孔-OD阴性对照孔)}×100％。用Graphpad Prism软件根据化合物各浓度与相应的抑制率绘出抑制曲线，并计算抑制率达到50％时化合物的浓度，即IC 50值，见下表2。
表2本公开化合物对人TLR8通路的抑制IC 50值
实施例编号 IC 50(nM)
1 5.76
结论：本公开化合物对TLR8通路具有很好的抑制作用。
测试例3 本公开化合物对人TLR9激活通路的抑制作用
一、实验材料及仪器
1)HEK-Blue TM hTLR9细胞(Invivogen)
2)CpG ODN2006(Invivogen)
3)碱性磷酸酶检测培养基(Quanti-Blue Detection，Invivogen)
4)杀稻瘟菌素(Blasticidin，Invivogen)
5)博莱霉素(Zeocin，Invivogen)
6)新霉素(Normocin，Invivogen)
7)DMEM/高糖培养基(DMEM/HIGH Glucose，GE Healthcare)
8)胎牛血清(Gibco)
9)磷酸盐缓冲液(上海源培生物科技有限公司)
10)无菌水(上海恒瑞自制)
11)15ml离心管(Corning)
12)96孔配药板(Corning)
13)96孔平底细胞培养板(Corning)
14)恒温细胞培养箱(Thermo scientific)
15)恒温箱(上海一恒科学仪器有限公司)
16)PHERAstar FS酶标仪(BMG Labtech)
二、实验步骤
在Invivogen购得HEK-Blue TM hTLR9细胞，此细胞是将人Toll样受体9(TLR9)基因和含分泌型碱性磷酸酶报告基因(SEAP)共转染到HEK293细胞，碱性磷酸酶报告基因(SEAP)处于含5个NF-kB和AP-1结合位点的IFN-β最小启动子的调控下，当用激动剂激活TLR9后，通过下游NF-kB和AP-1引起SEAP分泌，加入拮抗化合物后，上述通路被抑制，SEAP分泌降低，通过SEAP底物测定OD620，从而评估化合物对TLR9通路的活性。
将溶于100％DMSO的20mM受试化合物用100％DMSO系列稀释至2000、400、80、16、3.2、0.64、0.128、0.0256μM，空白孔为100％DMSO，再20倍稀释于含10％灭活FBS的DMEM/高糖培养基中。用无菌水将CpG ODN2006稀释至10μM，在96孔细胞培养板中加入20μL/孔无菌水稀释的10μM CpG ODN2006，再将上述稀释于完全培养基的化合物和100％DMSO按每孔20μL加入到含有CpG ODN2006的孔中，阴性对照孔加入20μL无菌水和20μL稀释于完全培养基的100％DMSO。
HEK-Blue TM hTLR9细胞培养于含10％FBS、100μg/mL新霉素、10μg/mL杀稻瘟菌素和100μg/mL博莱霉素的DMEM/高糖培养基中。取生长良好，到达70％-80％ 的细胞，弃去生长培养基，加5-10mL 37℃预热的PBS洗细胞一次，再加2-5mL预热的PBS置于37℃培养1-2分钟，用移液器吹散细胞，转移细胞到一个15mL离心管，计数细胞，用含10％灭活FBS的DMEM/高糖培养基调整细胞密度到4.8×10 5/mL。加160μL调整密度后细胞悬液到上述96孔细胞培养板中，最终每孔细胞数为76500/孔，CpG ODN2006终浓度为1μM，受试化合物终浓度分别为10000、2000、400、80、16、3.2、0.64、0.128nM。将细胞置于37℃，5％CO 2培养箱中培养20小时，随后取上清20μL，加入180μL配制好的碱性磷酸酶检测培养基，于37℃恒温箱避光孵育15分钟后，酶标仪读取OD620吸光值。使用以下公式计算抑制率：抑制率＝{1-(OD受试化合物-OD阴性对照孔)/(OD空白孔-OD阴性对照孔)}×100％。用Graphpad Prism软件根据化合物各浓度与相应的抑制率绘出抑制曲线，并计算抑制率达到50％时化合物的浓度，即IC 50值，见下表3。
表3本公开化合物对人TLR9激活通路的抑制IC 50值
实施例编号 IC 50(nM)
1 258
结论：本公开化合物对TLR9通路具有很好的抑制作用。

Claims (22)

  1. 一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐：
    Figure PCTCN2021108577-appb-100001
    其中：
    环A选自环烷基、杂环基、芳基和杂芳基；
    环B为3至8元环烷基或4至8元杂环基；
    R 0选自氢原子、卤素、烷基、烯基、炔基、杂烷基、烷氧基、卤代烷基、氘代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、
    Figure PCTCN2021108577-appb-100002
    Figure PCTCN2021108577-appb-100003
    L选自键、亚烷基和杂亚烷基，其中所述的亚烷基和杂亚烷基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    环C选自环烷基、杂环基、芳基和杂芳基；
    各个R 1相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 2选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、氘代烷基、卤代烷氧基、氘代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    各个R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基；
    各个R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、 烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基和羟烷基；
    各个R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、杂烷基、烯基、炔基、烷氧基、氧代基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、杂烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、氧代基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、-C(O)OR 6、-C(O)NR 7R 8、-NR 7R 8、-S(O) 2R 9、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 6选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R 7和R 8相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
    或者R 7和R 8与相连的氮原子一起形成杂环基，所述的杂环基任选被选自卤素、烷基、氧代基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 9选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、氨基、羟基、环烷基、杂环基、芳基和杂芳基；
    n为0、1、2、3或4；
    m为0、1或2；
    s为0、1、2、3或4；且
    t为0、1、2、3或4。
  2. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中环B为5至6元杂环基；优选为哌啶基。
  3. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐：
    Figure PCTCN2021108577-appb-100004
    其中：
    J为0、1或2；
    k为0、1或2；
    环A、R 0、R 1至R 4、n、m和s如权利要求1中所定义。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 0为氢原子或
    Figure PCTCN2021108577-appb-100005
    环C、R 5和t如权利要求1中所定义。
  5. 根据权利要求1、3和4中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐：
    Figure PCTCN2021108577-appb-100006
    其中：
    环A、环C、R 1至R 5、n、m、s、t、J和k如权利要求3中所定义。
  6. 根据权利要求1、3和4中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其为通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐：
    Figure PCTCN2021108577-appb-100007
    其中：
    环A、R 1至R 4、n、m、s、J和k如权利要求3中所定义。
  7. 根据权利要求3至6中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中J为1，且k为1。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中环A为6至10元芳基或5至10元杂芳基；优选为吡啶基。
  9. 根据权利要求1至5、7和8中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中环C为3至8元杂环基；优选为哌啶基。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 1相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和卤代C 1-6烷基。
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 2选自卤素、C 1-6烷基和卤代C 1-6烷基。
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 3选自氢原子、卤素、C 1-6烷基和卤代C 1-6烷基。
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 4相同或不同，且各自独立地选自氢原子、C 1-6烷基和卤代C 1-6烷基。
  14. 根据权利要求1至5和7至13中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其中R 5相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和卤代C 1-6烷基。
  15. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，其选自以下任一化合物：
    Figure PCTCN2021108577-appb-100008
  16. 一种制备通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐的方法，该方法包括：
    Figure PCTCN2021108577-appb-100009
    通式(IV)的化合物与通式(IIIA)的化合物发生还原胺化反应，得到通式(III)的化合物，
    其中：
    环A、环C、R 1至R 5、n、s、m、t、J和k如权利要求5中所定义。
  17. 一种制备通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐的方法，该方法包括：
    Figure PCTCN2021108577-appb-100010
    通式(IVA)的化合物脱去保护基R w，得到通式(IV)的化合物，
    其中：
    R w为氨基保护基；优选为叔丁氧羰基；
    环A、R 1至R 4、n、s、m、J和k如权利要求6中所定义。
  18. 一种药物组合物，所述药物组合物含有根据权利要求1至15中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、 非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  19. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者根据权利要求18所述的药物组合物在制备用于抑制TLR7、TLR8或TLR9的药物中的用途。
  20. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者根据权利要求18所述的药物组合物在制备用于抑制TLR7、TLR8和TLR9的药物中的用途；优选在制备用于抑制TLR7和TLR8的药物中的用途；或者优选在制备用于抑制TLR7和TLR9的药物中的用途。
  21. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其N-氧化物、或其可药用的盐或者根据权利要求18所述的药物组合物在制备用于治疗和/或预防炎性或自身免疫性疾病的药物中的用途。
  22. 根据权利要求21所述的用途，其中所述的炎性或自身免疫性疾病选自系统性红斑狼疮(SLE)、类风湿性关节炎、多发性硬化(MS)和肖格伦综合症。
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