WO2019047824A1 - Novel imidazoquinoline compound and preparation method and use thereof - Google Patents

Novel imidazoquinoline compound and preparation method and use thereof Download PDF

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WO2019047824A1
WO2019047824A1 PCT/CN2018/103963 CN2018103963W WO2019047824A1 WO 2019047824 A1 WO2019047824 A1 WO 2019047824A1 CN 2018103963 W CN2018103963 W CN 2018103963W WO 2019047824 A1 WO2019047824 A1 WO 2019047824A1
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amino
cancer
ethyl
butyl
quinolin
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PCT/CN2018/103963
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French (fr)
Chinese (zh)
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赵旭阳
白骅
徐肖杰
刘礼飞
冯仁田
王海彬
林赟
汪建洁
董文献
张文彪
程英雀
李译
王二文
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浙江海正药业股份有限公司
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Priority to CN201880053123.8A priority Critical patent/CN111094285B/en
Publication of WO2019047824A1 publication Critical patent/WO2019047824A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • 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 invention relates to a novel class of imidazoquinoline compounds which have TLR7 and TLR8 agonistic activities and are useful in the treatment of cancer and in the prevention and treatment of viral infections.
  • the invention also relates to a process for the preparation of such compounds.
  • Innate immunity is the first line of defense against infectious diseases.
  • the main functions of innate immunity are opsonization, activation of the complement pathway, enhancement of phagocytosis, activation of inflammatory signals, and induction of apoptosis (Janeway et al. Annu. Rev. Immunol. 2002, 20, 197.).
  • Pathogen recognition receptors PRRs
  • PRRs are important components of the innate immune system. These receptors recognize the highly conserved structure of pathogens, the Pathogen-associated molecular pattern (PAMP).
  • Toll like receptors (TLRs) were first discovered in Drosophila, which are involved in the innate immunity of Drosophila and are the most important family of pattern recognition receptors.
  • TLRs were later discovered in humans, with TLRs 1, 2, 4, 5, 6, and 10 located on the cell surface, while TLRs 3, 7, 8, and 9 were located in endosomes or lysosomes (Akira Curr Top Microbiol Immunol). .2006, 311, 1.).
  • TLRs are mainly expressed in spleen, macrophages, mast cells and dendritic cells, and each TLR can recognize and bind to its unique ligand to exert immune activation.
  • TLR7 is mainly expressed in plasmacytoid dendritic cells and has a certain degree of expression in B cells and monocytes/macrophages.
  • Viral or non-viral single-stranded RNA is capable of inducing the production of TLR7-dependent interferon to exert an antiviral effect (Hemmi et al. Nat Immunol. 2002, 3, 196.).
  • the TLR7 agonist imiquimod has been approved for the treatment of basal cell carcinoma and genital warts caused by HPV infection.
  • TLR8 is mainly expressed in monocytes/macrophages and bone marrow dendritic cells.
  • the high degree of homology between TLR7 and TLR8 in the sequence makes them recognize the same ligands, all of which are single-stranded RNA viruses.
  • TLR8 recognizes RNA released by bacteria. Activation of the TLR8 signal is capable of upregulating the expression of inflammatory factors (Cervantes et al. Cell Mol. Immunol. 2012, 9, 434.).
  • TLR8 agonists have the potential to be used in the treatment of cancer and as a vaccine adjuvant.
  • 3M-052 is a TLR7 and TLR8 dual agonist developed by 3M Company (Wightman US7799800). Compared with imiquimod and resiquimod, 3M-052 contains a very long fatty chain, which makes this The compound is deposited in the oil-water mixture solvent and in the liposome to act as a sustained release, and stays at the site of administration of the injection to prevent the drug from entering the blood circulation, thereby avoiding a drastic systemic inflammatory response. In experiments with Balb/c mice, subcutaneous injection of 3M-052 and H1N1 A/Perto Rico/8/34 virus hemagglutinin as adjuvants can induce a strong Th1 response, and the antibodies produced can be effective.
  • 3M-052 combined with TLR9 agonist CpG ODN intratumoral injection can significantly enhance intratumoral CTL activity and promote the production of Th1 factor, while down-regulating the immunosuppressive MDSC cell activity.
  • This compound has now entered the anti-cancer clinical trial.
  • 3M-052 is promising as a new anti-cancer and anti-viral drug, there is still a need to develop other drugs for treating or preventing diseases associated with stimulating TLR7 and/or TLR8, such as viral infections or cancer.
  • One of the objects of the present invention is to disclose a novel class of imidazoquinoline compounds or pharmaceutically acceptable salts thereof.
  • the compounds of the invention may be represented by formula (I):
  • R is -(CH 2 ) m NR 1 R 2 , -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 ;
  • R 1 and R 2 are independently selected from hydrogen and (C 1 -C 17 )alkyl, but R 1 and R 2 are not simultaneously hydrogen;
  • R 3 is (C 1 -C 17 )alkyl
  • R 4 is (C 1 -C 17 )alkyl
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R is -(CH 2 ) m NR 1 R 2 , wherein R 1 and R 2 are independently selected from hydrogen and (C 1 -C 17 )alkyl, but R 1 and R 2 are not At the same time, it is hydrogen; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R is -(CH 2 ) m NR 1 R 2 , wherein R 1 and R 2 are independently selected from hydrogen and (C 1 -C 15 )alkyl, but R 1 and R 2 are not At the same time it is hydrogen; m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
  • R is -(CH 2 ) m NR 1 R 2 , wherein R 1 and R 2 are independently selected from (C 1 -C 15 )alkyl; m is 1, 2, 3, 4 , 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
  • R is -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 ; wherein R 3 and R 4 are (C 1 -C 17 )alkyl, n and q are 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R is -(CH 2 ) n OR 3 ; wherein R 3 is (C 1 -C 17 )alkyl; n is 1, 2, 3, 4, 5, 6, 7, 8 , 9 or 10.
  • R is -(CH 2 ) n OR 3 ; wherein R 3 is (C 1 -C 15 )alkyl, preferably (C 3 -C 15 )alkyl, more preferably (C 7 - C 15 )alkyl, most preferably (C 10 -C 15 )alkyl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
  • R is -(CH 2 ) q SR 4 ; wherein R 4 is selected from (C 1 -C 17 )alkyl; q is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
  • R is -(CH 2 ) q SR 4 , wherein R 4 is selected from (C 1 -C 15 )alkyl, preferably (C 3 -C 15 )alkyl, more preferably (C 7 -C 15 )alkyl, most preferably (C 10 -C 15 )alkyl; q is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
  • the compound of formula (I) is selected from the group consisting of:
  • a pharmaceutical composition comprising an effective amount of a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable carriers compatible with the compounds of formula (I) may also be included in the pharmaceutical compositions of the invention.
  • the dosage form of the compound of formula (I) is generally an injection, and the pharmaceutical compositions and dosage forms of the present invention can be prepared by conventional formulation techniques using conventional pharmaceutically suitable solvents and additional agents, including pharmaceutically acceptable solvents and additional agents.
  • a compound of formula (I) and a pharmaceutical composition thereof for the manufacture of a medicament for the treatment or prevention of a disease associated with agonizing TLR7 and/or TLR8.
  • the disease described therein is a viral infection or cancer.
  • a compound of formula (I) and a pharmaceutical composition thereof for the manufacture of a medicament for the treatment or prevention of a viral infection.
  • the virus therein is preferably selected from the group consisting of hepatitis B virus (HBV), HIV (HIV), respiratory syncytial virus (RSV), human papillomavirus (HPV), influenza virus, hepatitis C virus (HCV), and B.
  • Encephalitis virus dengue virus, forest encephalitis virus, yellow fever virus, West Nile virus, Zika virus, bovine viral diarrhea virus, Omsk hemorrhagic fever virus, Junin virus, Murray Valley encephalitis virus And St. Louis encephalitis virus.
  • the cancer is preferably selected from the group consisting of bone cancers, including: Ewing sarcoma, osteosarcoma, chondrosarcoma; brain and CNS tumors, including: acoustic neuroma, neuroblastoma, glioma; spinal cord tumor; breast cancer; endocrine cancer , including: adrenal cortical cancer, pancreatic cancer, pituitary cancer, thyroid cancer, thyroid-rich cancer, thymic cancer, multiple endocrine cancer; lung cancer: small cell lung cancer and non-small cell lung cancer; gastrointestinal and liver cancer, including: gastric cancer , esophageal cancer, small intestine cancer, colorectal cancer, liver cancer, extrahepatic cholangiocarcinoma, gastrointestinal carcinoid tumor, gallbladder cancer; genitourinary cancer, including: testicular cancer, pen
  • a process for producing a compound (I) by reacting a compound represented by the formula (II) with a compound represented by the formula (III) or a salt thereof (as shown in the reaction formula 1).
  • the method is applicable to the preparation of a compound of formula (I) when R is -(CH 2 ) m NR 1 R 2 , -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 , wherein R 1 , R 2 , R 3 and R 4 are independently selected from (C 1 -C 17 )alkyl; m, n and q are 1 , 2 , 3 , 4 , 5, 6, 7, 8, 9, or 10.
  • the method is applicable to the preparation of a compound of formula (I) when R is -(CH 2 ) m NR 1 R 2 wherein R 1 is selected from (C 1 -C 17 )alkyl and R 2 is hydrogen; R 5 is an amino protecting group, preferably a benzyl group; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • intermediate compounds of formula (II) are provided.
  • Step 1 reacting a compound represented by the formula (VII) with a compound represented by the formula (VIII) to obtain a compound represented by the formula (VI),
  • R 6 is an amino protecting group, preferably benzyloxycarbonyl (Cbz).
  • Step 2 introducing an amino group onto the quinoline ring of the compound represented by the formula (VI), and then removing the branched amino protecting group,
  • R 6 is a protecting group for an amino group, preferably benzyloxycarbonyl (Cbz).
  • R 1 is selected from (C 1 -C 17 )alkyl;
  • R 5 is an amino protecting group, preferably benzyl;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R 1 is selected from (C 1 -C 17 )alkyl;
  • R 5 is an amino protecting group, preferably benzyl;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • Halogen means fluoro, chloro, bromo and iodo.
  • alkyl group as a group means a linear or branched saturated aliphatic hydrocarbon group, and in the present invention, it is preferably a (C 1 -C 17 )alkyl group, further preferably (C 3 -C) 15 ) an alkyl group, more preferably a (C 7 -C 15 )alkyl group, most preferably a (C 10 -C 15 )alkyl group.
  • (C 1 -C 17 )alkyl includes methyl, ethyl, n-propyl, 2-propyl, n-butyl and all of its isomers, n-pentyl and all its isomers, And all its isomers, n-heptyl and all its isomers, n-octyl and all its isomers, n-decyl and all its isomers, n-decyl and All of its isomers, n-undecyl and all its isomers, n-dodecyl and all its isomers, n-tridecyl and all its isomers, N-tetradecyl and all its isomers, n-pentadecyl and all its isomers, n-hexadecyl and all its isomers, n-heptadecyl and all of them Isomer; (C 1 -C 15 )alkyl includes
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) may be a salt formed with a suitable acid, and the suitable acid includes an inorganic acid and an organic acid such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid.
  • ethanesulfonic acid fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid , sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.
  • Particularly preferred are hydrochloric acid, phosphoric acid and sulfuric acid.
  • TLR7 and TLR8 agonists which are effective in activating the immune system and are useful in the treatment of cancer as well as in the prevention and treatment of viral infections.
  • the glassware is dried in an oven and/or dried by heating.
  • the reaction was followed by glass silica gel-60F254 plate (0.25 mm) (TLC).
  • Analytical thin layer chromatography was carried out and developed in a suitable solvent ratio (v/v). The end point of the reaction was taken when the starting material was depleted on TLC.
  • Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.
  • Root temperature in the present application means 20-30 °C.
  • Figure 1 is a graph showing the tumor growth inhibition curves of Compounds I-17 and I-21 on a B16F10 tumor-bearing model (*, p ⁇ 0.05; **, p ⁇ 0.01; ***, p ⁇ 0.001) compared with the control group. .
  • Figure 2 is a graph showing the tumor growth inhibition curve of Compound I-21 on a CT26.WT tumor-bearing model (**, p ⁇ 0.01; ***, p ⁇ 0.001 compared to the control group).
  • Figure 3 is a graph showing the tumor growth inhibition curve of Compound I-21 on the RM-1 tumor-bearing model (*, p ⁇ 0.05; **, p ⁇ 0.01) compared with the control group.
  • Figure 4 is the total tumor growth inhibition curve of compound I-17 and I-21 on the CT26.WT bilateral tumor-bearing model (administered side + unadministered side) (*, p ⁇ 0.05 compared with the control group; **, p ⁇ 0.01).
  • Figure 5 is a graph showing the tumor growth inhibition curves of the compounds I-17 and I-21 on the CT26.WT bilateral tumor-bearing model (*, p ⁇ 0.05; **, p ⁇ 0.01; * compared with the control group) **, p ⁇ 0.001).
  • Figure 6 is a graph showing the tumor growth inhibition curves of compounds I-17 and I-21 on the distal (non-administered side) CT26.WT bilateral tumor-bearing model (*, p ⁇ 0.05; **, compared with the control group). p ⁇ 0.01).
  • Figure 7 is the inhibition of Compound I-21 on 4T1 lung metastasis (*, p ⁇ 0.05; **, p ⁇ 0.01) compared to the control group.
  • Figure 8 is the inhibition of B16F10 lung metastasis by Compounds I-2 and I-21 (**, p ⁇ 0.01; ***, p ⁇ 0.001 compared to the control group).
  • Step 1 Preparation of benzyl N-[2-(2-hydroxyethoxy)ethyl]carbamate:
  • Step 4 Preparation of 1-[2-(2-aminoethoxy)ethoxy]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (Compound II):
  • Example 21 Preparing compound I-20 according to the method of Example 21 using suitable 1-bromoundecane and thiourea as raw materials; or using commercially available 1-alkyl mercaptan as raw material, according to step 2 and step 3 of Example 21.
  • the compounds were prepared to give compounds I-21, I-22 and I-23.
  • Step 1 Preparation of 4-[benzyl(dodecyl)amino]butyric acid methyl ester
  • murine melanoma cell B16F10 murine colon cancer cell line CT26.WT, human colon cancer cell HCT-116, human lung cancer cell A549, human ovarian cancer cell OVCAR-5, human prostate cancer cell PC -3, human lung cancer cell NCI-H460, human breast cancer cell MCF-7, human renal clear cell carcinoma cell Caki-2, human liver cancer cell HepG2, human neuroblastoma cell SH-Y5Y, human oral epidermoid carcinoma cell KB
  • Human esophageal cancer cell line EC109, human osteosarcoma cell MG-63 was purchased from ATCC, and cultured in DMEM medium or RPMI1640 medium containing 10% fetal bovine serum.
  • Table 1 Compound inhibits tumor cell proliferation activity in vitro
  • Experimental method Compounds were serially diluted with pH 7.2 PBS, and each group was added to a 96-well plate according to the experimental design by adding 20 ⁇ l of the compound or PBS.
  • the HEK-TLR7 or HEK-TLR8 cells in the logarithmic growth phase were mechanically blown off, and the SEAP reaction solution was added to prepare a cell solution of 220,000 cells/ml, and 180 ⁇ l of the cell solution was added to each well.
  • the cells were cultured for 16 h in a CO 2 incubator, and the absorbance at 620 nm was measured on a MD 5 plate reader.
  • the experimental data was statistically analyzed by Graphpad prism 5.0 software, and the EC 50 was calculated. The experimental results are shown in Table 2.
  • Compound (I-17 and I-21) inhibits proliferation of murine melanin B16F10 tumor
  • mice B16F10 cells in the exponential growth phase were collected, and the RPMI1640 medium was resuspended to the appropriate concentration for subcutaneous inoculation of C57BL/6 mice.
  • the tumors were grown to about 100 mm 3 and grouped on day 0, day 4, and eighth. 25 ⁇ l (50 ⁇ g) was administered intratumorally, and the control group was intratumorally injected with an equal volume of solvent.
  • Tumor inhibition rate (%) (1-T (drug group tumor volume) / C (solvent group tumor volume)) * 100.
  • Compounds I-17 and I-21 had excellent tumor growth inhibition on the B16F10 tumor-bearing model (Table 3), which significantly inhibited the growth of B16F10 tumors over 3M-052 (Fig. 1).
  • Compound I-21 inhibits the proliferation of murine colon cancer CT26.WT tumor
  • the tumor inhibition rate of compound I-21 in the CT26.WT tumor-bearing model of 6.25 ⁇ g, 12.5 ⁇ g, 25 ⁇ g, 50 ⁇ g was 61.4%, 96.2%, 91.5%, 86.6%; 3M-052 in CT26.WT
  • the tumor inhibition rates of the 6.25 ⁇ g, 12.5 ⁇ g, 25 ⁇ g, and 50 ⁇ g dose groups were 23.1%, 86.7%, 94.7%, and 80.1%, respectively.
  • Fig. 2 at the same time, all the 3M-052 and I-21 dose groups had tumor-bearing mice, the tumor disappeared completely and cured.
  • the cure rate of I-21 low dose 6.25 ⁇ g group was 40%, which was much better than
  • the cure rate of 3M-052 at a dose of 6.25 ⁇ g was 10% (Table 4).
  • RM-1 cells in the exponential growth phase were collected, and RPMI1640 medium was resuspended to the appropriate concentration for subcutaneous inoculation of C57BL/6 mice.
  • the tumors were grown to about 100 mm 3 and grouped on day 0 and day 4, respectively.
  • 25 ⁇ l (50 ⁇ g) was intratumorally administered, and the control group was intratumorally injected with an equal volume of solvent.
  • the tumor volume of the mice was measured three times per week, and the tumor inhibition rate was calculated after the end of the experiment.
  • Tumor volume calculation formula: tumor volume (mm 3 ) 0.5 ⁇ (tumor long diameter ⁇ tumor short diameter 2 ).
  • Tumor inhibition rate (%) (1-T (drug group tumor volume) / C (solvent group tumor volume)) * 100.
  • the total tumor inhibition rates of compounds 3M-052, I-17 and I-21 on the CT26.WT bilateral tumor-bearing model in mice were 20.4%, 52.8% and 64.3%, respectively (Fig. 4), I-17 and I-21.
  • the drug-effect side of the murine colon cancer tumor-bearing model was significantly better than that of 3M-052 (Fig. 5), and the growth inhibitory effects of I-17 and I-21 on the distal (non-administered side) tumor were also significant. Better than 3M-052 ( Figure 6).
  • mice Female BabL/C mice were inoculated with 20 ⁇ l of 1 ⁇ 10 6 4T1 cells in situ in the mammary fat pad, and grouped when the average tumor volume reached 80-120 mm 3 , respectively on day 0, day 4, 25 ⁇ l of intratumoral administration was given for 8 days (50 ⁇ g and 12.5 ⁇ g dose groups were set for each test drug), and the control group was intratumorally injected with an equal volume of solvent.
  • the animals were anesthetized on the 14th day, the lungs of the animals were removed, and the number of lung nodules was calculated under a dissecting microscope and statistical analysis was performed.
  • the inhibitory rates of 4T1 lung metastases in the 12.5 ⁇ g and 50 ⁇ g groups of the compound I-21 were 39% and 57%, respectively, while the 3M-052 12.5 ⁇ g and 50 ⁇ g dose groups could not reduce the formation of 4T1 lung metastases.
  • mice C57BL/6 mice were injected with tumor cells (anhydrous ethanol inactivated) and a mixture of drugs (1.5 ⁇ 10 5 B16F10 cells + 50 ⁇ g drug) on the right hind leg muscle on day 0, and the tail vein was injected on the third day. 3x10 5 B16F10 cells. After inoculation of the tail vein tumor cells, the animals were anesthetized on the 21st day, the lungs of the animals were taken out, the number of lung nodules was counted under a dissecting microscope, and statistical analysis was performed.
  • tumor cells anhydrous ethanol inactivated
  • a mixture of drugs 1.5 ⁇ 10 5 B16F10 cells + 50 ⁇ g drug
  • the present invention provides a new class of imidazoquinoline compounds which are potent TLR7 and TLR8 agonists and which can reside at the site of injection to avoid influx into the bloodstream and produce a fierce systemic inflammatory response.
  • the heteroatoms (oxygen, nitrogen, sulfur) contained in the long chain of fats of such compounds produce unexpected biological activity, making such new imidazoquinoline compounds have far greater anticancer activity than 3M-052 in vitro. And anti-cancer effects in the body.
  • 3M-052 in the 4T1 spontaneous metastasis model, 3M-052 not only failed to inhibit tumor metastasis to the lungs, but promoted its transfer; in contrast, the imidazoquinoline compounds provided by the present invention were large. To a certain extent, it can inhibit the metastasis of tumors to the lungs.
  • the prospect of this new imidazoquinoline compound as an anticancer and antiviral drug is very bright.

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Abstract

A novel imidazoquinoline compound and a preparation method of the compound. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof has TLR7 and TLR8 agonist activities and can be used to treat cancer and to prevent or treat a viral infection.

Description

新型咪唑喹啉化合物及其制备方法和用途Novel imidazoquinoline compound, preparation method and use thereof 技术领域Technical field
本发明涉及一类新的咪唑喹啉化合物，这类化合物具有TLR7和TLR8激动活性，可以用于治疗癌症以及预防和治疗病毒感染。本发明也涉及到这类化合物的制备方法。The present invention relates to a novel class of imidazoquinoline compounds which have TLR7 and TLR8 agonistic activities and are useful in the treatment of cancer and in the prevention and treatment of viral infections. The invention also relates to a process for the preparation of such compounds.
背景技术Background technique
固有免疫是机体防御感染性疾病的第一道防线。固有免疫的主要功能有调理作用，激活补体途径，增强吞噬作用，激活炎症信号以及凋亡诱导作用(Janeway et al.Annu.Rev.Immunol.2002,20,197.)。模式识别受体(Pathogen recognition receptors,PRRs)是固有免疫系统的重要组成部分，这类受体能够识别病原体的高度保守结构，即病原相关的分子模式(Pathogen-associated molecular pattern,PAMP)。Toll样受体(Toll like receptors,TLRs)最初发现于果蝇，与果蝇固有免疫相关，是模式识别受体中最主要的家族。后来在人体中发现了10种TLRs，其中TLR1、2、4、5、6、10位于细胞表面，而TLR3、7、8、9则位于细胞内体或溶酶体中(Akira Curr Top Microbiol Immunol.2006,311,1.)。TLRs主要表达于脾脏、巨噬细胞、肥大细胞和树突细胞等，每一个TLR能够识别其独特的配体并与之结合而发挥免疫激活作用。TLR7主要在浆细胞样树突细胞中表达，在B细胞和单核细胞/巨噬细胞中有一定程度的表达。病毒或非病毒的单链RNA能够诱导依赖于TLR7的干扰素的产生以发挥抗病毒作用(Hemmi et al.Nat Immunol.2002,3,196.)。TLR7激动剂咪喹莫特已被批准用于治疗基底细胞癌和由HPV感染而引起的生殖器疣。Innate immunity is the first line of defense against infectious diseases. The main functions of innate immunity are opsonization, activation of the complement pathway, enhancement of phagocytosis, activation of inflammatory signals, and induction of apoptosis (Janeway et al. Annu. Rev. Immunol. 2002, 20, 197.). Pathogen recognition receptors (PRRs) are important components of the innate immune system. These receptors recognize the highly conserved structure of pathogens, the Pathogen-associated molecular pattern (PAMP). Toll like receptors (TLRs) were first discovered in Drosophila, which are involved in the innate immunity of Drosophila and are the most important family of pattern recognition receptors. Ten TLRs were later discovered in humans, with TLRs 1, 2, 4, 5, 6, and 10 located on the cell surface, while TLRs 3, 7, 8, and 9 were located in endosomes or lysosomes (Akira Curr Top Microbiol Immunol). .2006, 311, 1.). TLRs are mainly expressed in spleen, macrophages, mast cells and dendritic cells, and each TLR can recognize and bind to its unique ligand to exert immune activation. TLR7 is mainly expressed in plasmacytoid dendritic cells and has a certain degree of expression in B cells and monocytes/macrophages. Viral or non-viral single-stranded RNA is capable of inducing the production of TLR7-dependent interferon to exert an antiviral effect (Hemmi et al. Nat Immunol. 2002, 3, 196.). The TLR7 agonist imiquimod has been approved for the treatment of basal cell carcinoma and genital warts caused by HPV infection.
TLR8主要表达在单核细胞/巨噬细胞和骨髓树突状细胞中。TLR7与TLR8在序列上的高度同源性使得它们识别的配体相同，均为单链RNA病毒。有研究表明，病毒感染时，TLR8能介导I型干扰素的产生。此外，TLR8还能识别细菌释放的RNA。TLR8信号的激活能够上调炎症因子的表达(Cervantes et al.Cell Mol.Immunol.2012,9,434.)。因此，TLR8激动剂具有用于治疗癌症和用作疫苗佐剂的潜力。TLR8 is mainly expressed in monocytes/macrophages and bone marrow dendritic cells. The high degree of homology between TLR7 and TLR8 in the sequence makes them recognize the same ligands, all of which are single-stranded RNA viruses. Studies have shown that TLR8 can mediate the production of type I interferon when the virus is infected. In addition, TLR8 recognizes RNA released by bacteria. Activation of the TLR8 signal is capable of upregulating the expression of inflammatory factors (Cervantes et al. Cell Mol. Immunol. 2012, 9, 434.). Thus, TLR8 agonists have the potential to be used in the treatment of cancer and as a vaccine adjuvant.
3M-052是由3M公司开发的TLR7和TLR8双重激动剂(Wightman US7799800)，与咪喹莫特和瑞喹莫德(resiquimod)相比，3M-052含有一条很长的脂肪链，这使得该化合物在油水混合物溶剂中和脂质体中沉积以持续释放而发挥作用，并且停留在注射给药部位以避免药物进入血液循环，从而避免激烈的全身性炎症反应。用Balb/c小鼠进行实验，将用作佐剂的3M-052与H1N1 A/Perto Rico/8/34病毒的血凝素进行皮下注射，能够诱导很强的Th1应答，产生的抗体能有效地中和H1N1 A/Perto Rico/8/34病毒，但血液中TNF-α和Th1细胞因子的水平并没有升高，表明皮下注 射3M-052不会引起激烈的全身性炎症反应(Smirnov et al.Vaccine 2011,29(33),5434.)。在小鼠B16F10双侧荷瘤模型上，3M-052单侧瘤内注射能够产生系统性的抗肿瘤免疫反应，即不仅能显著性抑制药物注射瘤的生长，而且还能显著性抑制远端无药物注射瘤的生长(Singh et al.J Immunol.2014,193(9),4722.)。另外，在小鼠CT26荷瘤模型上，3M-052与TLR9激动剂CpG ODN联用瘤内注射，能够显著性增强瘤内CTL活性并促进Th1因子的产生，同时下调免疫抑制性的MDSC细胞活性，从而根除CT26荷瘤，并发挥长效免疫保护作用(Zhao et al.J Immunother.Cancer 2014,2,12.)。该化合物目前已进入抗癌临床试验。3M-052 is a TLR7 and TLR8 dual agonist developed by 3M Company (Wightman US7799800). Compared with imiquimod and resiquimod, 3M-052 contains a very long fatty chain, which makes this The compound is deposited in the oil-water mixture solvent and in the liposome to act as a sustained release, and stays at the site of administration of the injection to prevent the drug from entering the blood circulation, thereby avoiding a drastic systemic inflammatory response. In experiments with Balb/c mice, subcutaneous injection of 3M-052 and H1N1 A/Perto Rico/8/34 virus hemagglutinin as adjuvants can induce a strong Th1 response, and the antibodies produced can be effective. In situ and H1N1 A/Perto Rico/8/34 virus, but the levels of TNF-α and Th1 cytokines in the blood did not increase, indicating that subcutaneous injection of 3M-052 does not cause intense systemic inflammatory response (Smirnov et al .Vaccine 2011, 29 (33), 5434.). In the mouse B16F10 bilateral tumor-bearing model, 3M-052 unilateral intratumoral injection can produce a systemic anti-tumor immune response, which can not only significantly inhibit the growth of drug-injected tumors, but also significantly inhibit distal end. Growth of drug-injected tumors (Singh et al. J Immunol. 2014, 193(9), 4722.). In addition, in the mouse CT26 tumor-bearing model, 3M-052 combined with TLR9 agonist CpG ODN intratumoral injection can significantly enhance intratumoral CTL activity and promote the production of Th1 factor, while down-regulating the immunosuppressive MDSC cell activity. In order to eradicate the CT26 tumor, and play a long-term immune protection (Zhao et al. J Immunother. Cancer 2014, 2, 12.). This compound has now entered the anti-cancer clinical trial.
虽然3M-052有希望成为抗癌、抗病毒的新药，但目前仍然存在研发其它治疗或者预防与激动TLR7和/或TLR8相关疾病(如病毒感染或癌症)的药物的需求。Although 3M-052 is promising as a new anti-cancer and anti-viral drug, there is still a need to develop other drugs for treating or preventing diseases associated with stimulating TLR7 and/or TLR8, such as viral infections or cancer.
发明内容Summary of the invention
本发明的目的之一在于公开了一类新的咪唑喹啉化合物或其药学上可接受的盐。One of the objects of the present invention is to disclose a novel class of imidazoquinoline compounds or pharmaceutically acceptable salts thereof.
本发明所述的化合物可用式(I)表示：The compounds of the invention may be represented by formula (I):
Figure PCTCN2018103963-appb-000001
Figure PCTCN2018103963-appb-000001
其中among them
R为-(CH 2) mNR 1R 2、-(CH 2) nOR 3或-(CH 2) qSR 4； R is -(CH 2 ) m NR 1 R 2 , -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 ;
R 1和R 2独立地选自氢和(C 1-C 17)烷基，但R 1和R 2不同时为氢； R 1 and R 2 are independently selected from hydrogen and (C 1 -C 17 )alkyl, but R 1 and R 2 are not simultaneously hydrogen;
R 3为(C 1-C 17)烷基；R 4为(C 1-C 17)烷基； R 3 is (C 1 -C 17 )alkyl; R 4 is (C 1 -C 17 )alkyl;
m为1、2、3、4、5、6、7、8、9或10；m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
n为1、2、3、4、5、6、7、8、9或10；n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
q为1、2、3、4、5、6、7、8、9或10。q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
或者其药学上可以接受的盐。Or a pharmaceutically acceptable salt thereof.
在另一些实施方案中，R为-(CH 2) mNR 1R 2，其中，R 1和R 2独立地选自氢和(C 1-C 17)烷基，但R 1和R 2不同时为氢；m为1、2、3、4、5、6、7、8、9或10。 In other embodiments, R is -(CH 2 ) m NR 1 R 2 , wherein R 1 and R 2 are independently selected from hydrogen and (C 1 -C 17 )alkyl, but R 1 and R 2 are not At the same time, it is hydrogen; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
在另一些实施方案中，R为-(CH 2) mNR 1R 2，其中，R 1和R 2独立地选自氢和(C 1-C 15)烷基，但R 1和R 2不同时为氢；m为1、2、3、4、5、6、7、8、9或10，优选为1或3。 In other embodiments, R is -(CH 2 ) m NR 1 R 2 , wherein R 1 and R 2 are independently selected from hydrogen and (C 1 -C 15 )alkyl, but R 1 and R 2 are not At the same time it is hydrogen; m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
在另一些实施方案中，R为-(CH 2) mNR 1R 2，其中，R 1和R 2独立地选自(C 1-C 15)烷基；m为1、2、3、4、5、6、7、8、9或10，优选为1或3。 In other embodiments, R is -(CH 2 ) m NR 1 R 2 , wherein R 1 and R 2 are independently selected from (C 1 -C 15 )alkyl; m is 1, 2, 3, 4 , 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
在另一些实施方案中，R为-(CH 2) nOR 3或-(CH 2) qSR 4；其中，R 3和R 4为(C 1-C 17)烷基，n和q为1、2、3、4、5、6、7、8、9或10。 In other embodiments, R is -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 ; wherein R 3 and R 4 are (C 1 -C 17 )alkyl, n and q are 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10.
在另一些实施方案中，R为-(CH 2) nOR 3；其中，R 3为(C 1-C 17)烷基；n为1、2、3、4、5、6、7、8、9或10。 In other embodiments, R is -(CH 2 ) n OR 3 ; wherein R 3 is (C 1 -C 17 )alkyl; n is 1, 2, 3, 4, 5, 6, 7, 8 , 9 or 10.
在另一些实施方案中，R为-(CH 2) nOR 3；其中，R 3为(C 1-C 15)烷基，优选(C 3-C 15)烷基，更优选(C 7-C 15)烷基，最优选(C 10-C 15)烷基；n为1、2、3、4、5、6、7、8、9或10，优选为1或3。 In other embodiments, R is -(CH 2 ) n OR 3 ; wherein R 3 is (C 1 -C 15 )alkyl, preferably (C 3 -C 15 )alkyl, more preferably (C 7 - C 15 )alkyl, most preferably (C 10 -C 15 )alkyl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
在另一些实施方案中，R为-(CH 2) qSR 4；其中，R 4选自(C 1-C 17)烷基；q为1、2、3、4、5、6、7、8、9或10 In other embodiments, R is -(CH 2 ) q SR 4 ; wherein R 4 is selected from (C 1 -C 17 )alkyl; q is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
在另一些实施方案中，R为-(CH 2) qSR 4，其中，R 4选自(C 1-C 15)烷基，优选(C 3-C 15)烷基，更优选(C 7-C 15)烷基，最优选(C 10-C 15)烷基；q为1、2、3、4、5、6、7、8、9或10，优选为1或3。 In other embodiments, R is -(CH 2 ) q SR 4 , wherein R 4 is selected from (C 1 -C 15 )alkyl, preferably (C 3 -C 15 )alkyl, more preferably (C 7 -C 15 )alkyl, most preferably (C 10 -C 15 )alkyl; q is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
更具体地说，所述的化合物式(I)选自：More specifically, the compound of formula (I) is selected from the group consisting of:
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(十三烷基)氨基]丁酰胺(I-1)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [methyl(tridecyl)amino]butanamide (I-1);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(十二烷基)氨基]丁酰胺(I-2)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [methyl(dodecyl)amino]butanamide (I-2);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(十四烷基)氨基]丁酰胺(I-3)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [Methyl (tetradecyl) amino] butanamide (I-3);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(十一烷基)氨基]丁酰胺(I-4)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [Methyl(undecyl)amino]butanamide (I-4);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(癸基)氨基]丁酰胺(I-5)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [methyl(indenyl)amino]butanamide (I-5);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[乙基(十二烷基)氨基]丁酰胺(I-6)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [ethyl (dodecyl) amino] butanamide (I-6);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[丙基(十二烷基)氨基]丁酰胺(I-7)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [propyl (dodecyl) amino] butanamide (I-7);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[丁基(十二烷基)氨基]丁酰胺(I-8)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [butyl (dodecyl) amino] butanamide (I-8);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二己氨基)丁酰胺(I-9)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (dihexylamino)butanamide (I-9);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二庚 氨基)丁酰胺(I-10)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (diheptylamino)butanamide (I-10);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二辛氨基)丁酰胺(I-11)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (dioctylamino)butanamide (I-11);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二壬氨基)丁酰胺(I-12)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (diamino)butyric acid amide (I-12);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二癸氨基)丁酰胺(I-13)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (diamino)butyric acid amide (I-13);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-[甲基(十五烷基)氨基]乙酰胺(I-14)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- [methyl(pentadecyl)amino]acetamide (I-14);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-[甲基(十四烷基)氨基]乙酰胺(I-15)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- [Methyl (tetradecyl) amino] acetamide (I-15);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-[甲基(十三烷基)氨基]乙酰胺(I-16)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- [methyl(tridecyl)amino]acetamide (I-16);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷氧基)丁酰胺(I-17)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (tridecyloxy) butanamide (I-17);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十二烷氧基)丁酰胺(I-18)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (dodecyloxy)butanamide (I-18);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷硫基)丁酰胺(I-19)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (tridecylthio)butanamide (I-19);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十一烷硫基)丁酰胺(I-20)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (undecylthio)butanamide (I-20);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十二烷硫基)丁酰胺(I-21)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (dodecylthio)butanamide (I-21);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十四烷硫基)丁酰胺(I-22)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (tetradecylthio)butanamide (I-22);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(癸硫基)丁酰胺(I-23)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (indolyl) butanamide (I-23);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-(十五烷硫基)乙酰胺(I-24)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- (pentadecanethio)acetamide (I-24);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-(十三烷硫基)乙酰胺(I-25)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- (tridecylthio)acetamide (I-25);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-(十四烷硫基)乙酰胺(I-26)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- (tetradecylthio)acetamide (I-26);
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十二 烷基氨基)丁酰胺(I-27)；和N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (dodecylamino)butanamide (I-27); and
N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷基氨基)丁酰胺(I-28)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (tridecylamino)butanamide (I-28);
或其药学上可接受的盐。Or a pharmaceutically acceptable salt thereof.
在本发明的第二方面，提供了一种药物组合物，其包含有效剂量的本发明式(I)化合物或者它们药学上可接受的盐。本发明药物组合物中还可以包含与式(I)化合物相容的药学上适用载体。式(I)化合物的剂型一般为注射剂，本发明的药物组合物和剂型可以用常用的药学上适用的溶剂和附加剂通过常用的制剂技术制得，所述药学上适用的溶剂和附加剂包括无毒性的可配伍的注射用水、蓖麻油、环糊精、脂质体、脂肽和糖脂等。In a second aspect of the invention, there is provided a pharmaceutical composition comprising an effective amount of a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable carriers compatible with the compounds of formula (I) may also be included in the pharmaceutical compositions of the invention. The dosage form of the compound of formula (I) is generally an injection, and the pharmaceutical compositions and dosage forms of the present invention can be prepared by conventional formulation techniques using conventional pharmaceutically suitable solvents and additional agents, including pharmaceutically acceptable solvents and additional agents. Non-toxic compatible water for injection, castor oil, cyclodextrin, liposome, lipopeptide and glycolipid.
在本发明的又一方面，提供了式(I)化合物及其药物组合物在制备用于治疗或者预防与激动TLR7和/或TLR8相关的疾病的药物中的应用。其中所述的疾病为病毒感染或癌症。In a further aspect of the invention there is provided the use of a compound of formula (I) and a pharmaceutical composition thereof for the manufacture of a medicament for the treatment or prevention of a disease associated with agonizing TLR7 and/or TLR8. The disease described therein is a viral infection or cancer.
在本发明的又一方面，提供了式(I)化合物及其药物组合物在制备用于治疗或者预防病毒感染的药物中的应用。其中所述的病毒优选选自乙型肝炎病毒(HBV)、艾滋病病毒(HIV)、呼吸道合胞病毒(RSV)、人类乳头瘤病毒(HPV)、流感病毒、丙型肝炎病毒(HCV)、乙型脑炎病毒、登革病毒、森林脑炎病毒、黄热病毒、西尼罗病毒、寨卡病毒、牛病毒性腹泻病毒、鄂木斯克出血热病毒、胡宁病毒、墨累山谷脑炎病毒和圣路易脑炎病毒。In a further aspect of the invention there is provided the use of a compound of formula (I) and a pharmaceutical composition thereof for the manufacture of a medicament for the treatment or prevention of a viral infection. The virus therein is preferably selected from the group consisting of hepatitis B virus (HBV), HIV (HIV), respiratory syncytial virus (RSV), human papillomavirus (HPV), influenza virus, hepatitis C virus (HCV), and B. Encephalitis virus, dengue virus, forest encephalitis virus, yellow fever virus, West Nile virus, Zika virus, bovine viral diarrhea virus, Omsk hemorrhagic fever virus, Junin virus, Murray Valley encephalitis virus And St. Louis encephalitis virus.
在本发明的又一方面，提供了式(I)化合物在制备用于治疗癌症的药物中的应用。其中所述癌症优选选自骨癌类，包括：尤因肉瘤、骨肉瘤、软骨肉瘤；脑和CNS肿瘤，包括：听神经瘤、神经母细胞瘤、神经胶瘤；脊髓肿瘤；乳癌；内分泌癌类，包括：肾上腺皮质癌、胰腺癌、脑垂体癌、甲状腺癌、富甲状腺癌、胸腺癌、多发性内分泌癌；肺癌类：小细胞肺癌和非小细胞肺癌；胃肠和肝癌类，包括：胃癌、食道癌、小肠癌、结直肠癌、肝癌、肝外胆管癌、胃肠类癌性肿瘤、胆囊癌；泌尿生殖癌类，包括：睾丸癌、阴茎癌、前列腺癌；妇科癌类，包括：子宫颈癌、卵巢癌、阴道癌、子宫/子宫内膜癌、阴部癌、妊娠滋养细胞肿瘤、输卵管癌、子宫肉瘤；头部和颈部肿瘤类，包括：口腔癌、唇癌、唾腺癌、喉头癌、下咽癌、上咽癌、正咽癌、鼻癌、鼻窦癌、鼻咽癌；眼癌类，包括：视网膜母细胞瘤、葡萄膜黑色素瘤；皮肤癌类，包括：黑色素瘤、非黑色素瘤皮肤癌、梅克尔细胞癌；软组织肉瘤类，包括：儿童软组织肉瘤、成人软组织肉瘤、卡波希肉瘤；泌尿系统癌症，包括：肾癌、维尔姆斯瘤、膀胱癌、尿道癌和转移性细胞癌。In yet another aspect of the invention, there is provided the use of a compound of formula (I) in the manufacture of a medicament for the treatment of cancer. Wherein the cancer is preferably selected from the group consisting of bone cancers, including: Ewing sarcoma, osteosarcoma, chondrosarcoma; brain and CNS tumors, including: acoustic neuroma, neuroblastoma, glioma; spinal cord tumor; breast cancer; endocrine cancer , including: adrenal cortical cancer, pancreatic cancer, pituitary cancer, thyroid cancer, thyroid-rich cancer, thymic cancer, multiple endocrine cancer; lung cancer: small cell lung cancer and non-small cell lung cancer; gastrointestinal and liver cancer, including: gastric cancer , esophageal cancer, small intestine cancer, colorectal cancer, liver cancer, extrahepatic cholangiocarcinoma, gastrointestinal carcinoid tumor, gallbladder cancer; genitourinary cancer, including: testicular cancer, penile cancer, prostate cancer; gynecological cancer, including: Cervical cancer, ovarian cancer, vaginal cancer, uterus/endometrial cancer, genital cancer, gestational trophoblastic tumor, fallopian tube cancer, uterine sarcoma; head and neck tumors, including: oral cancer, lip cancer, salivary gland cancer , laryngeal cancer, hypopharyngeal cancer, upper pharyngeal cancer, orthopharyngeal cancer, nasal cancer, sinus cancer, nasopharyngeal cancer; eye cancer, including: retinoblastoma, uveal melanoma; skin cancer, including: Melanoma, non-melanoma skin cancer, Merkel cell carcinoma; soft tissue sarcoma, including: children's soft tissue sarcoma, adult soft tissue sarcoma, Kaposi sarcoma; urinary system cancer, including: kidney cancer, Wilms tumor, bladder cancer , urethral cancer and metastatic cell carcinoma.
在本发明的又一方面，提供了所述式(I)的新型的咪唑喹啉化合物的制备方法。In still another aspect of the present invention, there is provided a process for the preparation of the novel imidazoquinoline compound of the formula (I).
在本发明制备方法的一方面，提供了使式(II)所示的化合物与式(III)所示 的化合物或其盐反应制备化合物(I)的方法(如反应式1所示)。该方法适用于当R为-(CH 2) mNR 1R 2、-(CH 2) nOR 3或-(CH 2) qSR 4时，式(I)所示的化合物的制备，其中R 1、R 2、R 3和R 4独立地选自(C 1-C 17)烷基；m、n和q为1、2、3、4、5、6、7、8、9或10。 In one aspect of the production process of the present invention, there is provided a process for producing a compound (I) by reacting a compound represented by the formula (II) with a compound represented by the formula (III) or a salt thereof (as shown in the reaction formula 1). The method is applicable to the preparation of a compound of formula (I) when R is -(CH 2 ) m NR 1 R 2 , -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 , wherein R 1 , R 2 , R 3 and R 4 are independently selected from (C 1 -C 17 )alkyl; m, n and q are 1 , 2 , 3 , 4 , 5, 6, 7, 8, 9, or 10.
Figure PCTCN2018103963-appb-000002
Figure PCTCN2018103963-appb-000002
反应式1Reaction formula 1
在本发明制备方法的又一方面，提供了以化合物(IV)为原料，脱除式(IV)所示的化合物的氨基保护基得到化合物(I)的方法(如反应式2所示)。该方法适用于当R为-(CH 2) mNR 1R 2时，式(I)所示的化合物的制备，其中R 1选自(C 1-C 17)烷基，R 2为氢；R 5为氨基保护基，优选苄基；m为1、2、3、4、5、6、7、8、9或10。 In still another aspect of the production method of the present invention, there is provided a method of removing the amino-protecting group of the compound of the formula (IV) using the compound (IV) as a starting material to obtain the compound (I) (as shown in the reaction formula 2). The method is applicable to the preparation of a compound of formula (I) when R is -(CH 2 ) m NR 1 R 2 wherein R 1 is selected from (C 1 -C 17 )alkyl and R 2 is hydrogen; R 5 is an amino protecting group, preferably a benzyl group; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
Figure PCTCN2018103963-appb-000003
Figure PCTCN2018103963-appb-000003
反应式2Reaction formula 2
在本发明的另一方面，提供了用于制备式(I)化合物所需的新中间体，即式(II)化合物和式(IV)化合物，及其制备方法。In another aspect of the invention, there are provided novel intermediates for the preparation of compounds of formula (I), namely compounds of formula (II) and compounds of formula (IV), and processes for their preparation.
在本发明新中间体的一方面，提供了中间体式(II)化合物。In one aspect of the novel intermediates of the invention, intermediate compounds of formula (II) are provided.
Figure PCTCN2018103963-appb-000004
Figure PCTCN2018103963-appb-000004
在本发明新中间体的又一方面，提供了式(II)化合物的制备方法，所述方法包括：In yet another aspect of the novel intermediate of the present invention, there is provided a process for the preparation of a compound of formula (II), the process comprising:
步骤一：使式(VII)所示的化合物与式(VIII)所示的化合物反应得到式(VI)所示的化合物，Step 1: reacting a compound represented by the formula (VII) with a compound represented by the formula (VIII) to obtain a compound represented by the formula (VI),
Figure PCTCN2018103963-appb-000005
Figure PCTCN2018103963-appb-000005
其中，R 6为氨基保护基，优选苄氧羰基(Cbz)。 Wherein R 6 is an amino protecting group, preferably benzyloxycarbonyl (Cbz).
步骤二：在式(VI)所示的化合物的喹啉环上引入氨基，然后脱除支链的氨基保护基，Step 2: introducing an amino group onto the quinoline ring of the compound represented by the formula (VI), and then removing the branched amino protecting group,
Figure PCTCN2018103963-appb-000006
Figure PCTCN2018103963-appb-000006
其中，R 6为氨基的保护基，优选苄氧羰基(Cbz)。 Wherein R 6 is a protecting group for an amino group, preferably benzyloxycarbonyl (Cbz).
在本发明新中间体的又一方面，提供了中间体式(IV)化合物。In yet another aspect of the novel intermediates of the invention, intermediate compounds of formula (IV) are provided.
Figure PCTCN2018103963-appb-000007
Figure PCTCN2018103963-appb-000007
其中，R 1选自(C 1-C 17)烷基；R 5为氨基保护基，优选苄基； Wherein R 1 is selected from (C 1 -C 17 )alkyl; R 5 is an amino protecting group, preferably benzyl;
m为1、2、3、4、5、6、7、8、9或10。m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
在本发明新中间体的另一方面，提供了式(IV)化合物的制备方法，所述方法包括：使式(II)所示的化合物与式(V)所示的化合物反应，In another aspect of the novel intermediate of the present invention, there is provided a process for the preparation of a compound of formula (IV), which comprises reacting a compound of formula (II) with a compound of formula (V),
Figure PCTCN2018103963-appb-000008
Figure PCTCN2018103963-appb-000008
其中，among them,
R 1选自(C 1-C 17)烷基；R 5为氨基保护基，优选苄基； R 1 is selected from (C 1 -C 17 )alkyl; R 5 is an amino protecting group, preferably benzyl;
m为1、2、3、4、5、6、7、8、9或10。m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
如无特别定义，本发明中所使用的术语具有本领域普遍所接受的含义，进一步地，本发明所使用的部分术语定义如下：Unless otherwise defined, the terms used in the present invention have the meanings generally accepted in the art. Further, some of the terms used in the present invention are defined as follows:
“卤素”是指氟、氯、溴和碘。"Halogen" means fluoro, chloro, bromo and iodo.
“烷基”当作一基团时是指直链或者带有支链的饱和脂肪烃基团，在本发明中，其优选为(C 1-C 17)烷基，进一步优选(C 3-C 15)烷基，更优选为(C 7-C 15)烷基，最优选为(C 10-C 15)烷基。(C 1-C 17)烷基包括甲基、乙基、正丙基、2-丙基、正丁基及其所有同分异构体、正戊基及其所有同分异构体、正己基及其所有同分异构体、正庚基及其所有同分异构体、正辛基及其所有同分异构体、正壬基及其所有同分异构体、正癸基及其所有同分异构体、正十一烷基及其所有同分异构体、正十二烷基及其所有同分异构体、正十三烷基及其所有同分异构体、正十四烷基及其所有同分异构体、正十五烷基及其所有同分异构体、正十六烷基及其所有同分异构体、正十七烷基及其所有同分异构体；(C 1-C 15)烷基包括甲基、乙基、正丙基、2-丙基、正丁基及其所有同分异构体、正戊基及其所有同分异构体、正己基及其所有同分异构体、正庚基及其所有同分异构体、正辛基及其所有同分异构体、正壬基及其所有同分异构体、正癸基及其所有同分异构体、正十一烷基及其所有同分异构体、正十二烷基及其所有同分异构体、正十三烷基及其所有同分异构体、正十四烷基及其所有同分异构体、正十五烷基及其所有同分异构体；(C 3-C 15)烷基包括正丙基、2-丙基、正丁基及其所有同分异构体、正戊基及其所有同分异构体、正己基及其所有同分异构体、正庚基及其所有同分异构体、正辛基及其所有同分异构体、正壬基及其所有同分异构体、正癸基及其所有同分异构体、正十一烷基及其所有同分异构体、正十二烷基及其所有同分异构体、正十三烷基及其所有同分异构体、正十四烷基及其所有同分异构体、正十五烷基及其所有同分异构体；(C 7-C 15)烷基包括正庚基及其所有同分异构体、正辛基及其所有同分异构体、正壬基及其所有同分异构体、正癸基及其所有同分异构体、正十一烷基及其所有同分异构体、正十二烷基及其所有同分异构体、正十三烷基及其所有同分异构体、正十四烷基及其所有同分异构体、正十五烷基及其所有同分异构体；(C 10-C 15)烷基包括正癸基及其所有同分异构体、正十一烷基及其所有同分异构体、正十二烷基及其所有同分异构体、正十三烷基及其所有同分异构体、正十四烷基及其所有同分异构体和正十五烷基及其所有同分异构体。 The "alkyl group" as a group means a linear or branched saturated aliphatic hydrocarbon group, and in the present invention, it is preferably a (C 1 -C 17 )alkyl group, further preferably (C 3 -C) 15 ) an alkyl group, more preferably a (C 7 -C 15 )alkyl group, most preferably a (C 10 -C 15 )alkyl group. (C 1 -C 17 )alkyl includes methyl, ethyl, n-propyl, 2-propyl, n-butyl and all of its isomers, n-pentyl and all its isomers, And all its isomers, n-heptyl and all its isomers, n-octyl and all its isomers, n-decyl and all its isomers, n-decyl and All of its isomers, n-undecyl and all its isomers, n-dodecyl and all its isomers, n-tridecyl and all its isomers, N-tetradecyl and all its isomers, n-pentadecyl and all its isomers, n-hexadecyl and all its isomers, n-heptadecyl and all of them Isomer; (C 1 -C 15 )alkyl includes methyl, ethyl, n-propyl, 2-propyl, n-butyl and all their isomers, n-pentyl and all of them Isomers, n-hexyl and all its isomers, n-heptyl and all its isomers, n-octyl and all its isomers, n-decyl and all their isomeric Body, n-decyl group and all its isomers, positive eleven Alkyl and all its isomers, n-dodecyl and all its isomers, n-tridecyl and all its isomers, n-tetradecyl and all their isoforms a conformation, n-pentadecyl and all its isomers; (C 3 -C 15 )alkyl includes n-propyl, 2-propyl, n-butyl and all its isomers, n-pentyl And all its isomers, n-hexyl and all its isomers, n-heptyl and all its isomers, n-octyl and all its isomers, n-decyl and its All isomers, n-decyl groups and all their isomers, n-undecyl and all their isomers, n-dodecyl and all their isomers, Alkyl and all its isomers, n-tetradecyl and all its isomers, n-pentadecyl and all its isomers; (C 7 -C 15 )alkyl includes positive Heptyl and all its isomers, n-octyl and all its isomers, n-decyl and all its isomers, n-decyl and all its isomers, positive eleven Alkyl and all its isomers, n-dodecane And all its isomers, n-tridecyl and all its isomers, n-tetradecyl and all its isomers, n-pentadecyl and all its isomers (C 10 -C 15 )alkyl includes n-decyl and all its isomers, n-undecyl and all its isomers, n-dodecyl and all its isomers , n-tridecyl and all its isomers, n-tetradecyl and all of its isomers and n-pentadecyl and all its isomers.
此外，术语“药学上可接受的盐”是指能让上述化合物保持原有生物活性并且适合于医药用途的某些盐类。式(I)所表示的化合物药学上可接受的盐可以为与合适的酸形成的盐，合适的酸包括无机酸和有机酸，例如乙酸、苯磺酸、苯甲酸、樟 脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、苹果酸、马来酸、扁桃酸、甲磺酸、硝酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。特别优选的是盐酸、磷酸和硫酸。Furthermore, the term "pharmaceutically acceptable salt" refers to certain salts which permit the above compounds to retain their original biological activity and which are suitable for pharmaceutical use. The pharmaceutically acceptable salt of the compound represented by the formula (I) may be a salt formed with a suitable acid, and the suitable acid includes an inorganic acid and an organic acid such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid. , ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid , sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Particularly preferred are hydrochloric acid, phosphoric acid and sulfuric acid.
我们已经发现，本发明所提供的化合物是TLR7和TLR8激动剂，能有效地激活免疫系统，可用于治疗癌症以及预防和治疗病毒感染。We have found that the compounds provided by the present invention are TLR7 and TLR8 agonists which are effective in activating the immune system and are useful in the treatment of cancer as well as in the prevention and treatment of viral infections.
下面通过实施例进一步阐明本发明。实施例给出了式(I)所表示的代表性化合物的制备及结构鉴定数据。必须说明，下述实施例是用于说明本发明而不是对本发明的限制。The invention is further illustrated by the following examples. The examples give the preparation and structural identification data of representative compounds represented by formula (I). It is to be understood that the following examples are intended to illustrate the invention and not to limit the invention.
在下列实例中，除非另有指明，所有温度均为摄氏温度；除非另有指明，各种起始原料和试剂均来自市售。市售原料和试剂均不经进一步纯化直接使用，除非另有指明。In the following examples, all temperatures are in degrees Celsius unless otherwise indicated; unless otherwise indicated, various starting materials and reagents are commercially available. Commercially available starting materials and reagents were used without further purification unless otherwise indicated.
玻璃器皿用烘箱干燥和/或加热干燥。反应用玻璃硅胶-60F254平板(0.25mm)(TLC)上进行跟踪。分析性薄层层析并以适当的溶剂比例(v/v)加以展开。以TLC上起始物质耗尽时为反应终点。The glassware is dried in an oven and/or dried by heating. The reaction was followed by glass silica gel-60F254 plate (0.25 mm) (TLC). Analytical thin layer chromatography was carried out and developed in a suitable solvent ratio (v/v). The end point of the reaction was taken when the starting material was depleted on TLC.
1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，td＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。 The 1 H NMR spectrum was measured using a Bruker instrument (400 MHz) and the chemical shift was expressed in ppm. The internal standard of tetramethylsilane (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, td = doublet of triplet. If a coupling constant is provided, its unit is Hz.
质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.
所有熔点均未经修正。All melting points have not been corrected.
本申请文件中的“室温”是指20-30℃。"Room temperature" in the present application means 20-30 °C.
下面的实例仅仅是用来说明所发明的具体化合物的合成方法，但在合成方法上并没有任何限制。在下面未列出的化合物，也可以用与下面同样的合成路线与合成方法，选择适当的起始原材料、在有必要的地方稍加适当的常识性的反应条件调整即可加以制备。The following examples are merely illustrative of the synthesis of the specific compounds of the invention, but there are no limitations on the method of synthesis. The compounds which are not listed below can also be prepared by the same synthetic route and synthesis method as below, by selecting an appropriate starting material, and adjusting the reaction conditions with appropriate common-sense conditions where necessary.
附图说明DRAWINGS
图1是化合物I-17和I-21在B16F10荷瘤模型上的肿瘤生长抑制曲线(与对照组相比，*,p<0.05；**,p<0.01；***,p<0.001)。Figure 1 is a graph showing the tumor growth inhibition curves of Compounds I-17 and I-21 on a B16F10 tumor-bearing model (*, p<0.05; **, p<0.01; ***, p<0.001) compared with the control group. .
图2是化合物I-21在CT26.WT荷瘤模型上的肿瘤生长抑制曲线(与对照组相比，**,p<0.01；***,p<0.001)。Figure 2 is a graph showing the tumor growth inhibition curve of Compound I-21 on a CT26.WT tumor-bearing model (**, p < 0.01; ***, p < 0.001 compared to the control group).
图3是化合物I-21在RM-1荷瘤模型上的肿瘤生长抑制曲线(与对照组相比，*,p<0.05；**,p<0.01)。Figure 3 is a graph showing the tumor growth inhibition curve of Compound I-21 on the RM-1 tumor-bearing model (*, p < 0.05; **, p < 0.01) compared with the control group.
图4是化合物I-17和I-21在CT26.WT双侧荷瘤模型上的肿瘤生长总抑制曲线 (给药侧+未给药侧)(与对照组相比，*,p<0.05；**,p<0.01)。Figure 4 is the total tumor growth inhibition curve of compound I-17 and I-21 on the CT26.WT bilateral tumor-bearing model (administered side + unadministered side) (*, p < 0.05 compared with the control group; **, p<0.01).
图5是化合物I-17和I-21在CT26.WT双侧荷瘤模型上的给药侧肿瘤生长抑制曲线(与对照组相比，*,p<0.05；**,p<0.01；***,p<0.001)。Figure 5 is a graph showing the tumor growth inhibition curves of the compounds I-17 and I-21 on the CT26.WT bilateral tumor-bearing model (*, p<0.05; **, p<0.01; * compared with the control group) **, p < 0.001).
图6是化合物I-17和I-21在CT26.WT双侧荷瘤模型上的远端(未给药侧)肿瘤生长抑制曲线(与对照组相比，*,p<0.05；**,p<0.01)。Figure 6 is a graph showing the tumor growth inhibition curves of compounds I-17 and I-21 on the distal (non-administered side) CT26.WT bilateral tumor-bearing model (*, p<0.05; **, compared with the control group). p<0.01).
图7是化合物I-21对4T1肺转移瘤的抑制作用(与对照组相比，*,p<0.05；**,p<0.01)。Figure 7 is the inhibition of Compound I-21 on 4T1 lung metastasis (*, p < 0.05; **, p < 0.01) compared to the control group.
图8是化合物I-2和I-21对B16F10肺转移瘤的抑制作用(与对照组相比，**,p<0.01；***,p<0.001)。Figure 8 is the inhibition of B16F10 lung metastasis by Compounds I-2 and I-21 (**, p < 0.01; ***, p < 0.001 compared to the control group).
具体实施方式Detailed ways
下述实施例只是为了进一步说明本发明，而不是对本发明的任何限制。The following examples are merely illustrative of the invention and are not intended to limit the invention in any way.
实施例1：N-(4-氯-3-喹啉基)戊酰胺(化合物VII)的制备：Example 1: Preparation of N-(4-chloro-3-quinolinyl)pentanamide (Compound VII):
Figure PCTCN2018103963-appb-000009
Figure PCTCN2018103963-appb-000009
将20.5g(0.115mol)3-氨基-4-氯喹啉和17.4g(0.173mol)N-甲基吗啉溶于200ml二氯甲烷中，搅拌，冷却至0℃，逐滴加入20.8g(0.173mol)戊酰氯，滴加完毕后，室温反应2h，反应完毕，加入200ml饱和NaHCO 3溶液，搅拌0.5h，分层，有机相依次用饱和NaHCO 3溶液、饱和食盐水洗涤，干燥，浓缩，乙酸乙酯/石油醚(1/1)重结晶，得21.0g N-(4-氯-3-喹啉基)戊酰胺(化合物VII，淡黄色固体)，收率69.4％。 20.5 g (0.115 mol) of 3-amino-4-chloroquinoline and 17.4 g (0.173 mol) of N-methylmorpholine were dissolved in 200 ml of dichloromethane, stirred, cooled to 0 ° C, and 20.8 g (0.173) was added dropwise. Mol) valeryl chloride, after the addition is completed, the reaction is carried out at room temperature for 2 h, the reaction is completed, 200 ml of saturated NaHCO 3 solution is added, stirred for 0.5 h, and the layers are separated. The organic phase is washed successively with saturated NaHCO 3 solution and brine, dried and concentrated. The ethyl ester/petroleum ether (1/1) was recrystallized to give 21.0 g of N-(4-chloro-3-quinolinyl)pentanamide (Compound VII, pale yellow solid).
1H NMR(DMSO-d 6):0.94(t,3H,J＝7.3Hz)；1.37-1.42(m,2H)；1.61-1.66(m,2H)；2.46-2.51(m,2H)；7.77(t,1H,J＝7.3Hz)；7.84(t,1H,J＝6.9Hz)；8.08(d,1H,J＝8.2Hz)；8.19(d,1H,J＝8.3Hz)；9.04(s,1H)；10.05(s,1H)；ESI-MS:263、265[M+H] +。 1 H NMR (DMSO-d 6 ): 0.94 (t, 3H, J = 7.3 Hz); 1.37-1.42 (m, 2H); 1.61-1.66 (m, 2H); 2.46-2.51 (m, 2H); (t, 1H, J = 7.3 Hz); 7.84 (t, 1H, J = 6.9 Hz); 8.08 (d, 1H, J = 8.2 Hz); 8.19 (d, 1H, J = 8.3 Hz); 9.04 (s 1H); 10.05 (s, 1H); ESI-MS: 263, 265 [M+H] + .
实施例2：1-[2-(2-氨基乙氧基)乙氧基]-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(化合物II)的制备：Example 2: Preparation of 1-[2-(2-aminoethoxy)ethoxy]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (Compound II) :
Figure PCTCN2018103963-appb-000010
Figure PCTCN2018103963-appb-000010
步骤一：N-[2-(2-羟基乙氧基)乙基]氨基甲酸苄酯的制备：Step 1: Preparation of benzyl N-[2-(2-hydroxyethoxy)ethyl]carbamate:
将22.1g(0.21mol)2-(2-氨乙氧基)乙醇、69g(0.5mol)碳酸钾溶于60ml水、60ml乙醇和120ml丙酮的混合溶液中，冷却至0℃，逐滴加入溶有34.1g(0.2mol)氯甲酸苄酯的丙酮(50ml)溶液，30min滴加完毕，室温反应2h，TLC检测反应完毕，加200ml水和300ml乙酸乙酯，分层，有机相依次用100ml盐酸(1.2mol/L)、水、饱和食盐水洗涤，干燥，浓缩，得39.2g N-[2-(2-羟基乙氧基)乙基]氨基甲酸苄酯(淡黄色液体)，收率81.9％。2.1 g (0.21 mol) of 2-(2-aminoethoxy)ethanol and 69 g (0.5 mol) of potassium carbonate were dissolved in a mixed solution of 60 ml of water, 60 ml of ethanol and 120 ml of acetone, cooled to 0 ° C, and dissolved by dropwise addition. There is a solution of 34.1 g (0.2 mol) of benzyl chloroformate in acetone (50 ml), and the mixture is added dropwise in 30 min, and reacted at room temperature for 2 h. The reaction is completed by TLC. 200 ml of water and 300 ml of ethyl acetate are added, and the organic phase is successively treated with 100 ml of hydrochloric acid. (1.2 mol / L), water, saturated brine, washed, dried, concentrated to give 39.2 g of N-[2-(2-hydroxyethoxy)ethyl]carbamate (light yellow liquid), yield 81.9 %.
1H NMR(DMSO-d 6):3.14(q,2H,J＝5.7Hz)；3.38-3.41(m,4H)；3.44-3.48(m,2H)；4.56(t,1H,J＝5.3Hz)；5.00(s,2H,CH 2)；7.26-7.37(m,6H).ESI-MS:240[M+H] +；262[M+Na] +。 1 H NMR (DMSO-d 6 ): 3.14 (q, 2H, J = 5.7 Hz); 3.38-3.41 (m, 4H); 3.44-3.48 (m, 2H); 4.56 (t, 1H, J = 5.3 Hz) 5.00 (s, 2H, CH 2 ); 7.26-7.37 (m, 6H). ESI-MS: 240 [M+H] + 262 [M+Na] + .
步骤二：N-[2-(2-氨氧基乙氧基)乙基]氨基甲酸苄酯盐酸盐(化合物VIII-1)的制备：Step 2: Preparation of benzyl N-[2-(2-aminooxyethoxy)ethyl]carbamate hydrochloride (Compound VIII-1):
将8.96g(0.375mol)N-[2-(2-羟基乙氧基)乙基]氨基甲酸苄酯、6.72g(0.412mol)N-羟基琥珀酰亚胺和14.82g(0.56mol)三苯基膦溶于300ml四氢呋喃(THF)中，冷却至0℃，逐滴加入溶有11.30g(0.56mol)偶氮二甲酸二异丙酯的THF(50ml)溶液，10min滴加完毕，室温搅拌反应过夜，再逐滴加入3.26g水合肼(85％)，继续搅拌5h，反应完毕，过滤，浓缩除去大部分溶剂，加入200ml乙醚，搅拌1h，过滤，向滤液中通入氯化氢气体，逐渐有大量固体生成，并继续搅拌1h，过滤，甲苯(200ml)重结晶，得4.35g白色固体(化合物VIII-1)，收率39.9％。8.96 g (0.375 mol) of N-[2-(2-hydroxyethoxy)ethyl]carbamate, 6.72 g (0.412 mol) of N-hydroxysuccinimide and 14.82 g (0.56 mol) of triphenyl The phosphine was dissolved in 300 ml of tetrahydrofuran (THF), cooled to 0 ° C, and a solution of 11.30 g (0.56 mol) of diisopropyl azodicarboxylate in THF (50 ml) was added dropwise, and the mixture was stirred at 10 min. After overnight, 3.26g of hydrazine hydrate (85%) was added dropwise, stirring was continued for 5 hours, the reaction was completed, filtered, concentrated to remove most of the solvent, 200 ml of diethyl ether was added, stirred for 1 h, filtered, and hydrogen chloride gas was introduced into the filtrate. The solid was formed, and the mixture was stirred for 1 hr, filtered, and then evaporated toluene (200 ml) to yield 4.35 g of white solid (compound VIII-1).
1H NMR(DMSO-d 6):3.17(q,2H,J＝5.8Hz)；3.44(t,2H,J＝6.0Hz)；3.63(t,2H,J＝4.2Hz)；4.13(t,2H,J＝4.2Hz)；5.02(s,2H)；7.29-7.39(m,6H)；10.90(br s,3H,)；ESI-MS:255[M-Cl] +。 1 H NMR (DMSO-d 6 ): 3.17 (q, 2H, J = 5.8 Hz); 3.44 (t, 2H, J = 6.0 Hz); 3.63 (t, 2H, J = 4.2 Hz); 4.13 (t, 2H, J = 4.2 Hz); 5.02 (s, 2H); 7.29-7.39 (m, 6H); 10.90 (br s, 3H,); ESI-MS: 255 [M-Cl] + .
步骤三：N-[2-[2-[(2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]氨基甲酸苄酯(化合物VI-1)的制备：Step 3: N-[2-[2-[(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]carbamic acid benzyl ester Preparation of (Compound VI-1):
将2.63g(10mmol)N-(4-氯-3-喹啉基)戊酰胺(化合物VII)，4.06g(14mmol)N-[2-(2-氨氧乙氧基)乙基]氨基甲酸苄酯盐酸盐(化合物VIII-1)和1.16g(11.5mmol)三乙胺溶于80ml异丙醇中，加热至80℃反应3h。反应完毕，浓缩除去异丙醇， 加入80ml二氯甲烷，搅拌0.5h，过滤，滤液用饱和食盐水洗涤两次，干燥，浓缩，柱层析分离纯化，得4.2g浅红色油状液体(化合物VI-1)，收率90.9％。2.63 g (10 mmol) of N-(4-chloro-3-quinolinyl)pentanamide (Compound VII), 4.06 g (14 mmol) of N-[2-(2-aminooxyethoxy)ethyl]carbamic acid Benzyl ester hydrochloride (Compound VIII-1) and 1.16 g (11.5 mmol) of triethylamine were dissolved in 80 ml of isopropanol and heated to 80 ° C for 3 h. After completion of the reaction, the isopropyl alcohol was removed by concentration, and the mixture was stirred for 0.5 hr, and the mixture was stirred for 0.5 hr. The filtrate was washed twice with brine, dried, concentrated and purified by column chromatography -1), the yield was 90.9%.
1H NMR(DMSO-d 6):0.95(t,3H,J＝7.3Hz)；1.40-1.48(m,2H)；1.82-1.90(m,2H)；3.06(t,2H,J＝7.4Hz)；3.30(q,2H,J＝5.7Hz)；3.58(t,2H,J＝5.9Hz)；3.89(br s,2H)；4.57(br s,2H)；5.03(s,2H)；7.28-7.40(m,6H)；7.81(t,2H,J＝3.8Hz)；8.22(d,1H,J＝9.2Hz)；8.63(d,1H,J＝8.9Hz)；9.31(s,1H)；ESI-MS:463[M+H] +。 1 H NMR (DMSO-d 6 ): 0.95 (t, 3H, J = 7.3 Hz); 1.40-1.48 (m, 2H); 1.82-1.90 (m, 2H); 3.06 (t, 2H, J = 7.4 Hz) 3.30 (q, 2H, J = 5.7 Hz); 3.58 (t, 2H, J = 5.9 Hz); 3.89 (br s, 2H); 4.57 (br s, 2H); 5.03 (s, 2H); 7.28 - 7.40 (m, 6H); 7.81 (t, 2H, J = 3.8 Hz); 8.22 (d, 1H, J = 9.2 Hz); 8.63 (d, 1H, J = 8.9 Hz); 9.31 (s, 1H) ;ESI-MS: 463 [M+H] + .
步骤四：1-[2-(2-氨基乙氧基)乙氧基]-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(化合物II)的制备：Step 4: Preparation of 1-[2-(2-aminoethoxy)ethoxy]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (Compound II):
将12.0g(26mmol)N-[2-[2-[(2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]氨基甲酸苄酯(VI-1)溶于170ml二氯甲烷中，加7.39g(36.4mmol)间氯过氧苯甲酸，搅拌，室温反应5h，反应完毕，再加入20ml氨水(25％)，充分搅拌，冷却至0℃，逐滴加入6.79g(38.5mmol)苯磺酰氯，滴加完毕后室温反应过夜，加饱和碳酸氢钠溶液洗涤(75ml×2)，浓缩，浓缩液中加入50ml正戊醇和50ml浓盐酸，80℃反应3h，反应完毕，加100ml水，充分搅拌，分层，收集水相，向水相中加入100ml氯仿和100ml二氯甲烷，用碳酸钾固体调至水相pH>9，继续搅拌0.5h，分层，收集有机相，水洗两次，干燥，浓缩，柱层析分离纯化得4.75g淡黄色固体(化合物II)，收率53.3％。12.0 g (26 mmol) of N-[2-[2-[(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]amino Benzyl formate (VI-1) was dissolved in 170 ml of dichloromethane, 7.39 g (36.4 mmol) of m-chloroperoxybenzoic acid was added, stirred, and reacted at room temperature for 5 h. After completion of the reaction, 20 ml of ammonia water (25%) was added and stirred well. After cooling to 0 ° C, 6.79 g (38.5 mmol) of benzenesulfonyl chloride was added dropwise, and the reaction was completed at room temperature overnight, washed with saturated sodium hydrogen carbonate solution (75 ml × 2), concentrated, and 50 ml of n-pentanol was added to the concentrate. 50ml concentrated hydrochloric acid, reacted at 80 ° C for 3h, the reaction is completed, add 100ml water, stir well, layer, collect the aqueous phase, add 100ml chloroform and 100ml dichloromethane to the aqueous phase, adjust to the aqueous phase pH>9 with potassium carbonate solids After stirring for 0.5 h, the layers were separated, and the organic phase was collected, washed twice, dried, concentrated, and purified by column chromatography to yield 4.75 g of pale yellow solid (Comp. II).
1H NMR(DMSO-d 6):0.95(t,3H,J＝7.2Hz)；1.40-1.46(m,2H)；1.78-1.84(m,2H)；2.79(t,2H,J＝5.4Hz)；2.98(t,2H,J＝7.3Hz)；3.51(t,2H,J＝5.6Hz)；3.86(br s,2H)；4.49(br s,2H)；6.62(s,2H)；7.24(t,1H,J＝7.3Hz)；7.45(t,1H,J＝7.7Hz)；7.58(d,1H,J＝8.1Hz)；8.27(d,1H,J＝7.9Hz)；ESI-MS:344[M+H] +。 1 H NMR (DMSO-d 6 ): 0.95 (t, 3H, J = 7.2 Hz); 1.40-1.46 (m, 2H); 1.78-1.84 (m, 2H); 2.79 (t, 2H, J = 5.4 Hz) 2.98 (t, 2H, J = 7.3 Hz); 3.51 (t, 2H, J = 5.6 Hz); 3.86 (br s, 2H); 4.49 (br s, 2H); 6.62 (s, 2H); 7.24 (t, 1H, J = 7.3 Hz); 7.45 (t, 1H, J = 7.7 Hz); 7.58 (d, 1H, J = 8.1 Hz); 8.27 (d, 1H, J = 7.9 Hz); ESI-MS :344[M+H] + .
实施例3：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(十三烷基)氨基]丁酰胺(化合物I-1)的制备：Example 3: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl Preparation of -4-[methyl(tridecyl)amino]butanamide (Compound I-1):
Figure PCTCN2018103963-appb-000011
Figure PCTCN2018103963-appb-000011
步骤一：N-苄基-N-甲基十三烷-1-胺的制备：Step 1: Preparation of N-benzyl-N-methyltridecane-1-amine:
将2.42g(0.02mol)N-甲基苄胺，5.52g(0.021mol)1-溴十三烷和6.9g(0.05mol)碳酸钾溶于50ml丙酮中，50℃回流反应18h，过滤，滤饼用20ml丙酮洗涤， 合并滤液，浓缩，柱层析分离纯化(洗脱剂为二氯甲烷:甲醇＝30:1)，得5.42g N-苄基-N-甲基十三烷-1-胺(无色液体)。收率89.4％。2.42 g (0.02 mol) of N-methylbenzylamine, 5.52 g (0.021 mol) of 1-bromotridecane and 6.9 g (0.05 mol) of potassium carbonate were dissolved in 50 ml of acetone, refluxed at 50 ° C for 18 h, filtered and filtered. The cake was washed with 20 ml of acetone, and the filtrate was combined, concentrated and purified by column chromatography (eluent: methylene chloride:methanol = 30:1) to give 5.42 g of N-benzyl-N-methyltridecane-1- Amine (colorless liquid). The yield was 89.4%.
1H NMR(CDCl 3-d):0.90(t,3H,J＝6.6Hz)；1.27-1.31(m,20H)；1.51-1.54(m,2H)；2.20(s,3H)；2.38(t,2H,J＝7.4Hz)；3.50(s,2H)；7.24-7.27(m,1H)；7.30-7.33(m,4H)；ESI-MS:304[M+H] +。 1 H NMR (CDCl 3 -d): 0.90 (t, 3H, J = 6.6 Hz); 1.27-1.31 (m, 20H); 1.51-1.54 (m, 2H); 2.20 (s, 3H); 2.38 (t) , 2H, J = 7.4 Hz); 3.50 (s, 2H); 7.24-7.27 (m, 1H); 7.30-7.33 (m, 4H); ESI-MS: 304 [M+H] + .
步骤二：4-[甲基(十三烷基)氨基]丁酸甲酯的制备：Step 2: Preparation of methyl 4-[methyl(tridecyl)amino]butanoate:
将3.64g(0.012mol)N-苄基-N-甲基十三烷-1-胺溶于30ml甲醇中，加入0.72g 20％Pd(OH) 2/C，置于H 2氛围中，室温反应8h，过滤，滤饼用20ml甲醇洗涤，合并滤液，浓缩，将浓缩物、3.26g(0.018mol)4-溴丁酸甲酯和4.14g(0.030mol)碳酸钾溶于30ml丙酮中，50℃回流反应过夜，过滤，滤饼用10ml丙酮洗涤，合并滤液，浓缩，柱层析分离纯化(洗脱剂为二氯甲烷:甲醇＝30:1)，得2.45g 4-[甲基(十三烷基)氨基]丁酸甲酯(浅黄色液体)，收率65.2％。 3.64 g (0.012 mol) of N-benzyl-N-methyltridecane-1-amine was dissolved in 30 ml of methanol, and 0.72 g of 20% Pd(OH) 2 /C was added and placed in a H 2 atmosphere at room temperature. After 8 h of reaction, filtration, the filter cake was washed with 20 ml of methanol, and the filtrate was concentrated, and concentrated, 3.26 g (0.018 mol) of methyl 4-bromobutyrate and 4.14 g (0.030 mol) of potassium carbonate in 30 ml of acetone, 50 The reaction mixture was refluxed at °C overnight, filtered, and then filtered and washed with 10 ml of acetone, and the filtrate was concentrated and purified by column chromatography (eluent: methylene chloride:methanol = 30:1) to give 2.45 g of 4-[methyl (10) Methyl trialkyl)amino]butyrate (light yellow liquid) in a yield of 65.2%.
1H NMR(CDCl 3-d):0.89(t,3H,J＝6.6Hz)；1.27-1.33(m,20H)；1.50(m,2H)；1.84-1.90(m,2H)；2.31(s,3H)；2.38(t,2H,J＝7.4Hz)；2.41-2.48(m,4H)；3.69(s,3H)；ESI-MS:314[M+H] +。 1 H NMR (CDCl 3 -d): 0.89 (t, 3H, J = 6.6 Hz); 1.27-1.33 (m, 20H); 1.50 (m, 2H); 1.84-1.90 (m, 2H); , 3H); 2.38 (t, 2H, J = 7.4 Hz); 2.41-2.48 (m, 4H); 3.69 (s, 3H); ESI-MS: 314 [M+H] + .
步骤三：4-[甲基(十三烷基)氨基]丁酸盐酸盐(III-1)的制备：Step 3: Preparation of 4-[methyl(tridecyl)amino]butyrate (III-1):
将1.67g(5mmol)4-[甲基(十三烷基)氨基]丁酸甲酯和1.12g(20mmol)氢氧化钾溶于10ml甲醇，80℃回流反应4h，浓缩，加入20ml水，用2mol/L HCl调至pH＝1，再用二氯甲烷与甲醇(V/V＝10:1)的混合液60ml分三次萃取，合并有机相，干燥，浓缩，乙酸乙酯与甲醇的混合溶液重结晶得1.08g白色固体(化合物III-1)，收率64.3％。1.67 g (5 mmol) of methyl 4-[methyl(tridecyl)amino]butanoate and 1.12 g (20 mmol) of potassium hydroxide were dissolved in 10 ml of methanol, refluxed at 80 ° C for 4 h, concentrated, and added with 20 ml of water. 2mol/L HCl was adjusted to pH=1, and then extracted with 60ml of a mixture of dichloromethane and methanol (V/V=10:1) three times, the organic phase was combined, dried, concentrated, mixed solution of ethyl acetate and methanol Recrystallization gave 1.08 g of a white solid (Compound III-1) in a yield of 64.3%.
1H NMR(DMSO-d):0.87(t,3H,J＝6.6Hz)；1.24(m,20H)；1.65(m,2H)；1.84-1.92(m,2H)；2.33(t,2H,J＝7.3Hz)；2.68(s,3H)；2.97-3.05(m,4H)；10.57(s,1H)；12.29(br s,1H)；ESI-MS:300[M-Cl] +。 1 H NMR (DMSO-d): 0.87 (t, 3H, J = 6.6 Hz); 1.24 (m, 20H); 1.65 (m, 2H); 1.84-1.92 (m, 2H); 2.33 (t, 2H, J = 7.3 Hz); 2.68 (s, 3H); 2.97-3.05 (m, 4H); 10.57 (s, 1H); 12.29 (br s, 1H); ESI-MS: 300 [M-Cl] + .
步骤四：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(十三烷基)氨基]丁酰胺(化合物I-1)的制备：Step 4: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl] Preparation of -4-[methyl(tridecyl)amino]butanamide (Compound I-1):
将0.74g(2.2mmol)化合物III-1，0.45g(2.2mmol)N,N’-二环己基碳酰亚胺和0.25g(2.2mmol)N-羟基丁二酰亚胺溶于20ml二氯甲烷中，室温反应4h。过滤，滤饼用10ml二氯甲烷洗涤，合并滤液。并将滤液加入到溶有0.69g(2.0mmol)化合物II、0.40g(2.0mmol)N-甲基吗啉的二氯甲烷(20ml)溶液中，室温反应过夜。加50ml水，充分搅拌后，分层，收集有机相，水洗，干燥，浓缩，柱层析分离纯化(二氯甲烷:甲醇＝30:1)，得0.72g粗产品，再用制备液相分离纯化得0.46g淡黄色固体(化合物I-1)，收率33.6％。0.74 g (2.2 mmol) of compound III-1, 0.45 g (2.2 mmol) of N,N'-dicyclohexylcarbimide and 0.25 g (2.2 mmol) of N-hydroxysuccinimide were dissolved in 20 ml of dichloro In methane, react at room temperature for 4 h. Filter and filter cake was washed with 10 ml of dichloromethane and the filtrate was combined. The filtrate was added to a solution of 0.69 g (2.0 mmol) of Compound II, 0.40 g (2.0 mmol) of N-methylmorpholine in dichloromethane (20 ml), and allowed to react overnight at room temperature. Add 50 ml of water, stir well, layer, collect the organic phase, wash with water, dry, concentrate, and purify by column chromatography (dichloromethane:methanol = 30:1) to obtain 0.72 g of crude product, Purification gave 0.46 g of a pale yellow solid (Compound I-1), yield 33.6%.
1H NMR(CDCl 3-d):0.91(t,3H,J＝6.6Hz)；1.02(t,3H,J＝7.3Hz)；1.25(m,20H)；1.47-1.56(m,4H)；1.87-1.96(m,4H)；2.28(s,3H)；2.34-2.50(m,6H)；3.00(t,2H,J＝7.5Hz)；3.54-3.58(m,2H)；3.67(t,2H,J＝5.2Hz)；3.93(t,2H,J＝4.4Hz)；4.50(t,2H,J＝3.6Hz)；5.47(br s,2H)；6.80(br s,1H)；7.34(t,1H,J＝7.3Hz)；7.55(td,1H,J＝8.4、1.4Hz)；7.80(d,1H,J＝8.2Hz)；8.29(d,1H,J＝7.3Hz)；ESI-MS:625[M+H] +。 1 H NMR (CDCl 3 -d): 0.91 (t, 3H, J = 6.6 Hz); 1.02 (t, 3H, J = 7.3 Hz); 1.25 (m, 20H); 1.47-1.56 (m, 4H); 1.87-1.96 (m, 4H); 2.28 (s, 3H); 2.34-2.50 (m, 6H); 3.00 (t, 2H, J = 7.5 Hz); 3.54-3.58 (m, 2H); 3.67 (t, 2H, J = 5.2 Hz); 3.93 (t, 2H, J = 4.4 Hz); 4.50 (t, 2H, J = 3.6 Hz); 5.47 (br s, 2H); 6.80 (br s, 1H); 7.34 ( t, 1H, J = 7.3 Hz); 7.55 (td, 1H, J = 8.4, 1.4 Hz); 7.80 (d, 1H, J = 8.2 Hz); 8.29 (d, 1H, J = 7.3 Hz); ESI- MS: 625 [M+H] + .
以合适的N-烷基苄胺及烷基溴为原料，按照实施例3方法制备得到了以下化合物：The following compounds were prepared according to the method of Example 3 using the appropriate N-alkylbenzylamine and alkyl bromide as starting materials:
Figure PCTCN2018103963-appb-000012
Figure PCTCN2018103963-appb-000012
Figure PCTCN2018103963-appb-000013
Figure PCTCN2018103963-appb-000013
Figure PCTCN2018103963-appb-000014
Figure PCTCN2018103963-appb-000014
实施例11：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二己氨基)丁酰胺(I-9)的制备Example 11: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl Preparation of -4-(dihexylamino)butanamide (I-9)
Figure PCTCN2018103963-appb-000015
Figure PCTCN2018103963-appb-000015
步骤一：4-(二己氨基)丁酸甲酯的制备：Step 1: Preparation of methyl 4-(dihexylamino)butanoate:
将8.33g(45mmol)二己胺、5.43g(30mmol)4-溴丁酸甲酯和10.35g(75mmol)碳酸钾溶于80ml丙酮中，加热回流反应过夜，过滤，滤饼用20ml丙酮洗涤，合 并滤液，浓缩，柱层析分离纯化(洗脱剂为二氯甲烷:甲醇＝30:1)，得5.20g 4-(二己氨基)丁酸甲酯(浅色液体)，收率61.0％。8.33 g (45 mmol) of dihexylamine, 5.43 g (30 mmol) of methyl 4-bromobutyrate and 10.35 g (75 mmol) of potassium carbonate were dissolved in 80 ml of acetone, and the mixture was heated under reflux overnight, filtered, and the filter cake was washed with 20 ml of acetone. The filtrate was combined, concentrated, and purified by column chromatography (eluent: methylene chloride:methanol = 30:1) to give 5.20 g of methyl 4-(dihexylamino)butyrate (light liquid), yield 61.0% .
1H NMR(CDCl 3-d):0.88(t,6H,J＝6.6Hz)；1.25-1.32(m,12H)；1.42-1.43(m,4H)；1.75-1.82(m,2H)；2.35(t,2H,J＝7.4Hz)；2.41-2.51(m,6H)；3.66(s,3H)；ESI-MS:286[M+H] +。 1 H NMR (CDCl 3 -d): 0.88 (t, 6H, J = 6.6 Hz); 1.25-1.32 (m, 12H); 1.42-1.43 (m, 4H); 1.75-1.82 (m, 2H); (t, 2H, J = 7.4 Hz); 2.41-2.51 (m, 6H); 3.66 (s, 3H); ESI-MS: 286 [M+H] + .
步骤二：4-(二己氨基)丁酸盐酸盐(化合物III-9)的制备：Step 2: Preparation of 4-(dihexylamino)butyrate (Compound III-9):
将8.60g(0.03mol)4-(二己氨基)丁酸甲酯，6.72g(0.12mol)氢氧化钾溶于50ml甲醇，80℃回流反应4h，浓缩，加100ml水溶解，用2mol/L HCl调至pH<2，再用二氯甲烷与甲醇(V/V＝10:1)的混合液100ml分三次萃取，合并有机相，干燥，浓缩，乙酸乙酯与甲醇的混合溶液重结晶得8.05g白色固体(化合物III-9)，收率90.7％。8.60 g (0.03 mol) of methyl 4-(dihexylamino)butanoate, 6.72 g (0.12 mol) of potassium hydroxide was dissolved in 50 ml of methanol, refluxed at 80 ° C for 4 h, concentrated, dissolved in 100 ml of water, using 2 mol / L HCl was adjusted to pH<2, and then extracted with 100 ml of a mixture of dichloromethane and methanol (V/V=10:1), and the organic phase was combined, dried, concentrated, and recrystallized from a mixture of ethyl acetate and methanol. 8.05 g of a white solid (Compound III-9) in a yield of 90.7%.
1H NMR(DMSO-d):0.86(t,6H,J＝6.5Hz)；1.25-1.30(m,12H)；1.38-1.40(m,4H)；1.59-1.63(m,2H)；2.24(t,2H,J＝6.9Hz)；2.42-2.51(m,6H)；ESI-MS:272[M+H] +。 1 H NMR (DMSO-d): 0.86 (t, 6H, J = 6.5 Hz); 1.25-1.30 (m, 12H); 1.38-1.40 (m, 4H); 1.59-1.63 (m, 2H); t, 2H, J = 6.9 Hz); 2.42-2.51 (m, 6H); ESI-MS: 272 [M+H] + .
步骤三：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二己氨基)丁酰胺(化合物I-9)的制备Step 3: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl] Preparation of -4-(dihexylamino)butanamide (Compound I-9)
将0.68g(2.2mmol)化合物III-9，0.45g(2.2mmol)N,N’-二环己基碳酰亚胺，0.25g(2.2mmol)N-羟基丁二酰亚胺溶于20ml二氯甲烷中，室温下反应4h。过滤，滤饼用10ml二氯甲烷洗涤，合并滤液。并将滤液加入到溶有0.69g(2.0mmol)化合物II、0.40g(2.0mmol)N-甲基吗啉的二氯甲烷(20ml)溶液中，室温反应过夜。加50ml水，充分搅拌后，分层，收集有机相，饱和食盐水洗涤一次，干燥，浓缩，柱层析分离纯化(二氯甲烷:甲醇＝30:1～10:1)，得0.72g粗品，再用制备液相纯化分离得0.46g淡黄色固体(化合物I-9)，收率33.6％。0.68 g (2.2 mmol) of compound III-9, 0.45 g (2.2 mmol) of N,N'-dicyclohexylcarbimide, 0.25 g (2.2 mmol) of N-hydroxysuccinimide dissolved in 20 ml of dichloro In methane, the reaction was carried out for 4 h at room temperature. Filter and filter cake was washed with 10 ml of dichloromethane and the filtrate was combined. The filtrate was added to a solution of 0.69 g (2.0 mmol) of Compound II, 0.40 g (2.0 mmol) of N-methylmorpholine in dichloromethane (20 ml), and allowed to react overnight at room temperature. Add 50 ml of water, stir well, layer, collect the organic phase, wash once with saturated brine, dry, concentrate, and purify by column chromatography (dichloromethane: methanol = 30:1 to 10:1) to obtain 0.72 g of crude product Further, 0.46 g of a pale yellow solid (Compound I-9) was obtained by preparative liquid phase purification, yield 33.6%.
1H NMR(CDCl 3-d):0.88(t,6H,J＝6.6Hz)；1.02(t,3H,J＝7.4Hz)；1.26-1.31(m,12H)；1.39-1.43(m,4H)；1.48-1.54(m,2H)；1.77-1.80(m,2H)；1.87-1.95(m,2H)；2.28(t,2H,J＝7.2Hz)；2.40(t,4H,J＝7.6Hz)；2.46(t,2H,J＝6.8Hz)；2.99(t,2H,J＝7.6Hz)；3.53-3.58(m,2H)；3.67(t,2H,J＝5.4Hz)；3.92(t,2H,J＝4.2Hz)；4.48(t,2H,J＝3.9Hz)；5.46(br s,2H)；6.64(br s,1H)；7.33(t,1H,J＝7.3Hz)；7.54(td,1H,J＝8.3、1.2Hz)；7.79(d,1H,J＝8.3Hz)；8.28(d,1H,J＝7.4Hz)；ESI-MS:597[M+H] +。 1 H NMR (CDCl 3 -d): 0.88 (t, 6H, J = 6.6 Hz); 1.02 (t, 3H, J = 7.4 Hz); 1.26-1.31 (m, 12H); 1.39-1.43 (m, 4H) ); 1.48-1.54 (m, 2H); 1.77-1.80 (m, 2H); 1.87-1.95 (m, 2H); 2.28 (t, 2H, J = 7.2 Hz); 2.40 (t, 4H, J = 7.6) Hz); 2.46 (t, 2H, J = 6.8 Hz); 2.99 (t, 2H, J = 7.6 Hz); 3.53-3.58 (m, 2H); 3.67 (t, 2H, J = 5.4 Hz); 3.92 ( t, 2H, J = 4.2 Hz); 4.48 (t, 2H, J = 3.9 Hz); 5.46 (br s, 2H); 6.64 (br s, 1H); 7.33 (t, 1H, J = 7.3 Hz); 7.54 (td, 1H, J = 8.3, 1.2 Hz); 7.79 (d, 1H, J = 8.3 Hz); 8.28 (d, 1H, J = 7.4 Hz); ESI-MS: 597 [M+H] + .
以合适的二取代胺和4-溴丁酸甲酯为原料，按照实施例11方法制备得到了以下化合物：The following compounds were prepared according to the method of Example 11 using the appropriate disubstituted amine and methyl 4-bromobutyrate as starting materials:
Figure PCTCN2018103963-appb-000016
Figure PCTCN2018103963-appb-000016
Figure PCTCN2018103963-appb-000017
Figure PCTCN2018103963-appb-000017
Figure PCTCN2018103963-appb-000018
Figure PCTCN2018103963-appb-000018
实施例16：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-[甲基(十五烷基)氨基]乙酰胺(化合物I-14)的制备Example 16: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl Preparation of 2-[methyl(pentadecyl)amino]acetamide (Compound I-14)
Figure PCTCN2018103963-appb-000019
Figure PCTCN2018103963-appb-000019
步骤一：N-苄基-N-甲基十五烷-1-胺的制备Step 1: Preparation of N-benzyl-N-methylpentadecan-1-amine
将3.63g(0.03mol)N-甲基苄胺，9.61g(0.033mol)1-溴十五烷和8.28g(0.06mol)碳酸钾溶于50ml丙酮中，50℃回流反应18h，反应结束，过滤，滤饼用50ml丙酮再洗一遍，合并滤液，浓缩，柱层析分离纯化(洗脱剂为二氯甲烷:甲醇＝30:1)，得8.38g N-苄基-N-甲基十五烷-1-胺(无色液体)，收率84.2％。3.63 g (0.03 mol) of N-methylbenzylamine, 9.61 g (0.033 mol) of 1-bromopentadecane and 8.28 g (0.06 mol) of potassium carbonate were dissolved in 50 ml of acetone, and refluxed at 50 ° C for 18 h, and the reaction was completed. After filtration, the filter cake was washed again with 50 ml of acetone, and the filtrate was combined, concentrated, and purified by column chromatography (eluent: methylene chloride:methanol = 30:1) to obtain 8.38 g of N-benzyl-N-methyl Penta-1-amine (colorless liquid), yield 84.2%.
1H NMR(CDCl 3-d):0.90(t,3H,J＝6.5Hz)；1.28(m,24H)；1.50-1.55(m,2H)；2.21(s,3H)；2.38(t,2H,J＝7.4Hz)；3.50(s,3H)；7.25-7.27(m,1H)；7.30-7.34(m,4H)；ESI-MS:332[M+H] +。 1 H NMR (CDCl 3 -d): 0.90 (t, 3H, J = 6.5 Hz); 1.28 (m, 24H); 1.50-1.55 (m, 2H); 2.21 (s, 3H); 2.38 (t, 2H) , J = 7.4 Hz); 3.50 (s, 3H); 7.25-7.27 (m, 1H); 7.30-7.34 (m, 4H); ESI-MS: 332 [M+H] + .
步骤二：2-[甲基(十五烷基)氨基]乙酸甲酯的制备Step 2: Preparation of methyl 2-[methyl(pentadecyl)amino]acetate
将6.62g(0.02mol)N-苄基-N-甲基十五烷-1-胺溶于30ml甲醇中，加入1.56g 20％Pd(OH) 2/C，置于H 2氛围中，室温下反应8h。反应结束，过滤，滤饼用50ml甲醇再洗一遍，合并滤液，浓缩；将浓缩物、3.16g(0.03mol)氯乙酸甲酯和5.52g(0.04mol)碳酸钾于30ml丙酮中，50℃回流反应过夜，过滤，滤饼用50ml丙酮洗涤， 合并滤液，浓缩，柱层析分离纯化(洗脱剂为二氯甲烷:甲醇＝30:1)，得4.92g 2-[甲基(十五烷基)氨基]乙酸甲酯(浅黄色液体)，收率78.5％。 6.62 g (0.02 mol) of N-benzyl-N-methylpentadecane-1-amine was dissolved in 30 ml of methanol, and 1.56 g of 20% Pd(OH) 2 /C was added and placed in a H 2 atmosphere at room temperature. The reaction was carried out for 8 h. The reaction was completed, filtered, and the filter cake was washed again with 50 ml of methanol, and the filtrate was combined and concentrated. The concentrate, 3.16 g (0.03 mol) of methyl chloroacetate and 5.52 g (0.04 mol) of potassium carbonate in 30 ml of acetone, refluxed at 50 ° C After reacting overnight, filtration, the filter cake was washed with 50 ml of acetone, the filtrate was combined, concentrated, and purified by column chromatography (eluent: methylene chloride:methanol = 30:1) to give 4.92 g of 2-[methyl(pentadecane) Methylamino)acetate (light yellow liquid), yield 78.5%.
1H NMR(CDCl 3-d):0.89(t,6H,J＝6.6Hz)；1.26-1.28(m,24H)；1.46-1.48(m,2H)；2.36(s,3H)；2.46(t,2H,J＝7.6Hz)；3.25(s,2H)；3.73(s,3H)；ESI-MS:314[M+H] +。 1 H NMR (CDCl 3 -d): 0.89 (t, 6H, J = 6.6 Hz); 1.26-1.28 (m, 24H); 1.46-1.48 (m, 2H); 2.36 (s, 3H); , 2H, J = 7.6 Hz); 3.25 (s, 2H); 3.73 (s, 3H); ESI-MS: 314 [M+H] + .
步骤三：2-[甲基(十五烷基)氨基]乙酸盐酸盐(化合物III-14)的制备Step 3: Preparation of 2-[methyl(pentadecyl)amino]acetic acid hydrochloride (Compound III-14)
将3.13g(0.01mol)2-[甲基(十五烷基)氨基]乙酸甲酯，2.24g(0.04mol)氢氧化钾溶于15ml甲醇，80℃回流反应4h，浓缩，加20ml水溶解，用2mol/L HCl调至pH<2，再用二氯甲烷与甲醇(V/V＝10:1)的混合液60ml分三次萃取，合并有机相，干燥，浓缩，乙酸乙酯与甲醇的混合溶液重结晶得2.74g白色固体(化合物III-14)，收率81.5％。3.13 g (0.01 mol) of methyl 2-[methyl(pentadecyl)amino]acetate, 2.24 g (0.04 mol) of potassium hydroxide was dissolved in 15 ml of methanol, refluxed at 80 ° C for 4 h, concentrated, and dissolved in 20 ml of water. , adjusted to pH < 2 with 2 mol / L HCl, and then extracted with 60 ml of a mixture of dichloromethane and methanol (V / V = 10:1) three times, the organic phase was combined, dried, concentrated, ethyl acetate and methanol The mixed solution was recrystallized to give 2.74 g of a white solid ( Compound III-14).
1H NMR(DMSO-d):0.87(t,3H,J＝6.4Hz)；1.22(m,24H)；1.64(m,2H)；2.79(s,3H)；0.87(t,3H,J＝6.0Hz)；3.99(s,3H)；11.27(br s,2H)；ESI-MS:300[M-Cl] +。 1 H NMR (DMSO-d): 0.87 (t, 3H, J = 6.4 Hz); 1.22 (m, 24H); 1.64 (m, 2H); 2.79 (s, 3H); 0.87 (t, 3H, J = 6.0 Hz); 3.99 (s, 3H); 11.27 (br s, 2H); ESI-MS: 300 [M-Cl] + .
步骤四：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-[甲基(十五烷基)氨基]乙酰胺(化合物I-14)的制备Step 4: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl] Preparation of -2-[methyl(pentadecyl)amino]acetamide (Compound I-14)
将0.74g(2.2mmol)化合物III-14，0.44g(2.2mmol)N,N’-二环己基碳酰亚胺，0.25g(2.2mmol)N-羟基丁二酰亚胺溶于20ml二氯甲烷中，室温反应4h。过滤，滤饼用10ml二氯甲烷再洗一次，合并滤液。并将滤液加入到溶有0.69g(2.0mmol)化合物II、0.40g(2.0mmol)N-甲基吗啉的二氯甲烷(20ml)溶液中，室温反应过夜。加50ml水，充分搅拌后，分层，收集有机相，饱和食盐水洗涤一次，干燥，浓缩，柱层析分离纯化(二氯甲烷:甲醇＝20:1)，得1.06g粗品，再用制备液相纯化分离得0.44g淡黄色固体(化合物I-14)，收率35.0％。0.74 g (2.2 mmol) of compound III-14, 0.44 g (2.2 mmol) of N,N'-dicyclohexylcarbimide, 0.25 g (2.2 mmol) of N-hydroxysuccinimide dissolved in 20 ml of dichloro In methane, react at room temperature for 4 h. After filtration, the filter cake was washed once more with 10 ml of dichloromethane and the filtrate was combined. The filtrate was added to a solution of 0.69 g (2.0 mmol) of Compound II, 0.40 g (2.0 mmol) of N-methylmorpholine in dichloromethane (20 ml), and allowed to react overnight at room temperature. Add 50 ml of water, stir well, layer, collect the organic phase, wash once with saturated brine, dry, concentrate, and purify by column chromatography (dichloromethane: methanol = 20:1) to obtain 1.06 g of crude product. Purification by liquid phase gave 0.44 g of a pale yellow solid (Compounds I-14).
1H NMR(CDCl 3-d):0.89(t,3H,J＝6.1Hz)；1.02(t,3H,J＝7.3Hz)；1.19-1.33(m,24H)；1.37(m,2H)；1.49-1.54(m,2H)；1.88-1.96(m,2H)；2.23(s,3H)；2.35(t,2H,J＝7.2Hz)；3.00(t,2H,J＝7.7Hz)；3.01(s,2H)；3.62-3.64(m,2H)；3.71(t,2H,J＝5.2Hz)；3.94(t,2H,J＝3.4Hz)；4.49(s,2H)；5.71(br s,2H)；7.36(t,1H,J＝7.6Hz)；7.56(t,1H,J＝7.5Hz)；7.65(br s,1H)；7.82(d,1H,J＝8.5Hz)；8.32(d,1H,J＝8.0Hz)；ESI-MS:625[M+H] +。 1 H NMR (CDCl 3 -d): 0.89 (t, 3H, J = 6.1 Hz); 1.02 (t, 3H, J = 7.3 Hz); 1.19-1.33 (m, 24H); 1.37 (m, 2H); 1.49-1.54 (m, 2H); 1.88-1.96 (m, 2H); 2.23 (s, 3H); 2.35 (t, 2H, J = 7.2 Hz); 3.00 (t, 2H, J = 7.7 Hz); 3.01 (s, 2H); 3.62-3.64 (m, 2H); 3.71 (t, 2H, J = 5.2 Hz); 3.94 (t, 2H, J = 3.4 Hz); 4.49 (s, 2H); 5.71 (br s , 2H); 7.36 (t, 1H, J = 7.6 Hz); 7.56 (t, 1H, J = 7.5 Hz); 7.65 (br s, 1H); 7.82 (d, 1H, J = 8.5 Hz); 8.32 ( d, 1H, J = 8.0 Hz); ESI-MS: 625 [M+H] + .
以合适的N-烷基苄胺及烷基溴为原料，按照实施例16方法制备得到了以下化合物：The following compounds were prepared according to the method of Example 16 using the appropriate N-alkylbenzylamine and alkyl bromide as starting materials:
Figure PCTCN2018103963-appb-000020
Figure PCTCN2018103963-appb-000020
Figure PCTCN2018103963-appb-000021
Figure PCTCN2018103963-appb-000021
实施例19：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷氧基)丁酰胺(化合物I-17)的制备Example 19: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl Preparation of -4-(tridecyloxy)butanamide (Compound I-17)
步骤一：4-十三烷氧基-1-丁醇的制备Step 1: Preparation of 4-tridecyloxy-1-butanol
将7.20g(80mmol)1,4-丁二醇溶于40ml DMF中，N 2保护，冷却至0℃，加入0.88g(22mmol)NaH，0℃下反应1h后，逐滴加入5.26g(20mmol)1-溴十 三烷，滴加完毕，室温反应5h，向反应液中加入100ml水及100ml二氯甲烷，充分搅拌，分层，收集有机相，饱和食盐水洗涤(100ml×3)，Na 2SO 4干燥，浓缩，柱层析分离纯化(洗脱液为二氯甲烷:甲醇＝30:1)，得4.06g 4-十三烷氧基-1-丁醇(白色固体)，收率75.4％。 7.20 g (80 mmol) of 1,4-butanediol was dissolved in 40 ml of DMF, protected with N 2 , cooled to 0 ° C, added 0.88 g (22 mmol) NaH, and reacted at 0 ° C for 1 h, then added 5.26 g (20 mmol) 1-bromotridecane, after completion of dropwise addition, reacted at room temperature for 5 h, 100 ml of water and 100 ml of dichloromethane were added to the reaction mixture, stirred well, and the layers were separated, and the organic phase was collected, washed with saturated brine (100 ml × 3), Na 2 SO 4 was dried, concentrated and purified by column chromatography (eluent: methylene chloride:methanol = 30:1) to give 4.06 g of 4-tridecyloxy-1-butanol (white solid). 75.4%.
1H NMR(CDCl 3-d):0.88(t,3H,J＝6.5Hz)；1.25-1.32(m,20H)；1.54-1.59(m,2H)；1.65-1.70(m,4H)；2.54(s,1H)；3.41-3.47(m,4H)；3.64(t,2H,J＝5.6Hz)；ESI-MS:273[M+H] + 1 H NMR (CDCl 3 -d): 0.88 (t, 3H, J = 6.5 Hz); 1.25-1.32 (m, 20H); 1.54-1.59 (m, 2H); 1.65-1.70 (m, 4H); (s, 1H); 3.41-3.47 (m, 4H); 3.64 (t, 2H, J = 5.6 Hz); ESI-MS: 273 [M+H] +
步骤二：4-十三烷氧基丁酸(III-17)的制备：Step 2: Preparation of 4-tridecyloxybutyric acid (III-17):
将9.52g(35mmol)4-十三烷氧基-1-丁醇和52.5g(140mmol)重铬酸吡啶盐溶于120ml DMF中，室温下搅拌60h，向反应液中加入400ml水及400ml二氯甲烷，充分搅拌，分层，收集有机相，饱和盐水洗涤(400ml×3)，Na 2SO 4干燥，浓缩，柱层析分离纯化(洗脱液为二氯甲烷:甲醇＝50:1)，得1.52g白色固体(化合物III-17)，收率16.0％。 9.52 g (35 mmol) of 4-tridecyloxy-1-butanol and 52.5 g (140 mmol) of pyridinium dichromate were dissolved in 120 ml of DMF, stirred at room temperature for 60 h, and 400 ml of water and 400 ml of dichloride were added to the reaction solution. The methane was stirred well, the organic phase was separated, washed with saturated brine (400 ml×3), dried over Na 2 SO 4 and concentrated, and purified by column chromatography (dichloromethane:methanol = 50:1). 1.52 g of a white solid (compound III-17) was obtained in a yield of 16.0%.
1H NMR(DMSO-d):0.85(t,3H,J＝5.8Hz)；1.23-1.35(m,20H)；1.44-1.46(m,2H)；1.68-1.71(m,2H)；2.23(t,2H,J＝7.4Hz)；3.29-3.34(m,4H)；12.00(s,1H)；ESI-MS:285[M-H] - 1 H NMR (DMSO-d): 0.85 (t, 3H, J = 5.8 Hz); 1.23-1.35 (m, 20H); 1.44-1.46 (m, 2H); 1.68-1.71 (m, 2H); t, 2H, J = 7.4 Hz); 3.29-3.34 (m, 4H); 12.00 (s, 1H); ESI-MS: 285 [MH] -
步骤三：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷氧基)丁酰胺(I-17)的制备Step 3: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl] Preparation of -4-(tridecyloxy)butanamide (I-17)
将0.63g(2.2mmol)化合物III-17，0.45g(2.2mmol)N,N’-二环己基碳酰亚胺，0.25g(2.2mmol)N-羟基丁二酰亚胺溶于20ml二氯甲烷中，室温下反应4h。过滤，滤饼用10ml二氯甲烷再洗一次，合并滤液。并将滤液加入到溶有0.69g(2.0mmol)化合物II、0.40g N-甲基吗啉(2.0mmol)的二氯甲烷(20ml)溶液中，室温反应过夜。加50ml水，充分搅拌后，分层，收集有机相，饱和食盐水洗涤一次，干燥，浓缩，柱层析分离纯化(二氯甲烷:甲醇＝30:1)，得0.80g粗产品，再用制备液相纯化分离得0.46g淡黄色固体(化合物I-17)，收率33.6％。0.63 g (2.2 mmol) of compound III-17, 0.45 g (2.2 mmol) of N,N'-dicyclohexylcarbimide, 0.25 g (2.2 mmol) of N-hydroxysuccinimide dissolved in 20 ml of dichloro In methane, the reaction was carried out for 4 h at room temperature. After filtration, the filter cake was washed once more with 10 ml of dichloromethane and the filtrate was combined. The filtrate was added to a solution of 0.69 g (2.0 mmol) of Compound II, 0.40 g of N-methylmorpholine (2.0 mmol) in dichloromethane (20 ml). Add 50 ml of water, stir well, layer, collect the organic phase, wash once with saturated brine, dry, concentrate, and purify by column chromatography (dichloromethane: methanol = 30:1) to obtain 0.80 g of crude product, and then use Purification by preparative liquid phase gave 0.46 g of pale yellow solid (Compound I-17).
1H NMR(CDCl 3-d):0.91(t,3H,J＝6.6Hz)；1.04(t,3H,J＝7.6Hz)；1.27(m,20H)；1.49-1.58(m,4H)；1.90-1.98(m,4H)；2.35(t,2H,J＝7.3Hz)；3.02(t,2H,J＝7.6Hz)；3.41(t,2H,J＝6.8Hz)；3.47(t,2H,J＝6.0Hz)；3.53-3.59(m,2H)；3.67(t,2H,J＝5.2Hz)；3.95(t,2H,J＝4.2Hz)；4.52(t,2H,J＝4.0Hz)；5.58(br s,2H)；6.05(br s,1H)；7.36(t,1H,J＝7.2Hz)；7.58(t,1H,J＝7.2Hz)；7.83(d,1H,J＝8.4Hz)；8.30(d,1H,J＝7.9Hz)；ESI-MS:612[M+H] + 1 H NMR (CDCl 3 -d): 0.91 (t, 3H, J = 6.6 Hz); 1.04 (t, 3H, J = 7.6 Hz); 1.27 (m, 20H); 1.49-1.58 (m, 4H); 1.90-1.98 (m, 4H); 2.35 (t, 2H, J = 7.3 Hz); 3.02 (t, 2H, J = 7.6 Hz); 3.41 (t, 2H, J = 6.8 Hz); 3.47 (t, 2H) , J=6.0Hz); 3.53-3.59(m, 2H); 3.67(t, 2H, J=5.2Hz); 3.95(t, 2H, J=4.2Hz); 4.52(t, 2H, J=4.0Hz ); 5.58 (br s, 2H); 6.05 (br s, 1H); 7.36 (t, 1H, J = 7.2 Hz); 7.58 (t, 1H, J = 7.2 Hz); 7.83 (d, 1H, J = 8.4 Hz); 8.30 (d, 1H, J = 7.9 Hz); ESI-MS: 612 [M+H] +
实施例20：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十二烷氧基)丁酰胺(I-18)的制备Example 20: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl Preparation of -4-(dodecyloxy)butanamide (I-18)
Figure PCTCN2018103963-appb-000023
Figure PCTCN2018103963-appb-000023
以1,4-丁二醇和1-溴十二烷为原料，参照实施例19方法制备(化合物I-18)；Prepared by the method of Example 19 using 1,4-butanediol and 1-bromododecane as starting materials (Compound I-18);
1H NMR(CDCl 3-d):0.87(t,3H,J＝6.6Hz)；1.00(t,3H,J＝7.3Hz)；1.23-1.26(m,18H)；1.45-1.54(m,4H)；1.86-1.94(m,4H)；2.32(t,2H,J＝7.3Hz)；2.97(t,2H,J＝7.6Hz)；3.37(t,2H,J＝6.7Hz)；3.44(t,2H,J＝6.0Hz)；3.52-3.56(m,2H)；3.64(t,2H,J＝5.1Hz)；3.90(t,2H,J＝4.2Hz)；4.47(t,2H,J＝3.8Hz)；5.55(br s,2H)；6.09(br s,1H)；7.31(t,1H,J＝7.2Hz)；7.53(td,1H,J＝8.3、1.2Hz)；7.78(d,1H,J＝8.3Hz)；8.25(d,1H,J＝7.2Hz)；ESI-MS:596[M-H] - 1 H NMR (CDCl 3 -d): 0.87 (t, 3H, J = 6.6 Hz); 1.00 (t, 3H, J = 7.3 Hz); 1.23-1.26 (m, 18H); 1.45-1.54 (m, 4H) ); 1.86-1.94 (m, 4H); 2.32 (t, 2H, J = 7.3 Hz); 2.97 (t, 2H, J = 7.6 Hz); 3.37 (t, 2H, J = 6.7 Hz); 3.44 (t , 2H, J = 6.0 Hz); 3.52-3.56 (m, 2H); 3.64 (t, 2H, J = 5.1 Hz); 3.90 (t, 2H, J = 4.2 Hz); 4.47 (t, 2H, J = 3.8 Hz); 5.55 (br s, 2H); 6.09 (br s, 1H); 7.31 (t, 1H, J = 7.2 Hz); 7.53 (td, 1H, J = 8.3, 1.2 Hz); 7.78 (d, 1H, J = 8.3 Hz); 8.25 (d, 1H, J = 7.2 Hz); ESI-MS: 596 [MH] -
实施例21：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷硫基)丁酰胺(I-19)的制备Example 21: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl Preparation of -4-(tridecylthio)butanamide (I-19)
Figure PCTCN2018103963-appb-000024
Figure PCTCN2018103963-appb-000024
步骤一：1-十三烷硫醇的制备：Step 1: Preparation of 1-tridecyl mercaptan:
将5.26g(20mmol)1-溴十三烷，1.82g(24mmol)硫脲溶于50ml乙醇中，80℃回流反应3h，再加入5ml NaOH溶液(6mol/L)，80℃下继续反应4h。反应完毕，冷却，用1mol/L盐酸调至pH<1，加入40ml二氯甲烷及40ml水，充分搅拌后，分层，收集有机相，饱和食盐水(40ml)洗涤，Na 2SO 4干燥，浓缩，柱层析分离纯化(洗脱液为正己烷)，得3.71g 1-十三烷硫醇(无色液体)，收率87.1％。 5.26 g (20 mmol) of 1-bromotridecane, 1.82 g (24 mmol) of thiourea were dissolved in 50 ml of ethanol, refluxed at 80 ° C for 3 h, and then 5 ml of NaOH solution (6 mol / L) was added, and the reaction was continued at 80 ° C for 4 h. After completion of the reaction, the mixture was cooled, and adjusted to pH <1 with 1 mol/L hydrochloric acid, 40 ml of dichloromethane and 40 ml of water were added thereto, and the mixture was stirred well, the layers were separated, and the organic phase was collected, washed with saturated brine (40 ml), and dried over Na 2 SO 4 . The mixture was concentrated and purified by column chromatography (yield: n-hexane) to give 3.71 g of 1-tridecanethiol (colorless liquid) in a yield of 87.1%.
1H NMR(CDCl 3-d):0.90(t,3H,J＝6.6Hz)；1.28-1.41(m,20H)；1.56-1.63(m,2H)；2.52(t,2H,J＝7.4Hz)；ESI-MS:215[M-H] - 1 H NMR (CDCl 3 -d): 0.90 (t, 3H, J = 6.6 Hz); 1.28-1.41 (m, 20H); 1.56-1.63 (m, 2H); 2.52 (t, 2H, J = 7.4 Hz) ); ESI-MS: 215 [MH] -
步骤二：4-十三烷硫基丁酸(III-19)的制备：Step 2: Preparation of 4-tridecylthiobutyric acid (III-19):
将3.27g(15mmol)1-十三烷硫醇，2.72g(15mmol)4-溴丁酸甲酯和1.85g(33mmol)氢氧化钾溶于30ml甲醇，加热回流反应6h，浓缩，加20ml水溶解，用2mol/L HCl调至pH<2，过滤，滤饼用正己烷重结晶，得2.95g白色固体(化合物III-19)，收率65.0％。3.27 g (15 mmol) of 1-tridecyl mercaptan, 2.72 g (15 mmol) of methyl 4-bromobutyrate and 1.85 g (33 mmol) of potassium hydroxide were dissolved in 30 ml of methanol, refluxed for 6 h, concentrated, and added with 20 ml of water. Dissolved, adjusted to pH <2 with 2 mol/L HCl, filtered, and the filter cake was recrystallized from n-hexane to give 2.95 g of white solid (Compound III-19).
1H NMR(CDCl 3-d):0.92(t,3H,J＝6.6Hz)；1.28-1.40(m,20H)；1.55-1.63(m,2H)；1.90-1.98(m,2H)；2.50-2.54(m,4H)；2.59(t,2H,J＝7.1Hz)；ESI-MS:301[M-H] - 1 H NMR (CDCl 3 -d): 0.92 (t, 3H, J = 6.6 Hz); 1.28-1.40 (m, 20H); 1.55-1.63 (m, 2H); 1.90-1.98 (m, 2H); -2.54 (m, 4H); 2.59 (t, 2H, J = 7.1 Hz); ESI-MS: 301 [MH] -
步骤三：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷硫基)丁酰胺(I-19)的制备Step 3: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl] Preparation of -4-(tridecylthio)butanamide (I-19)
将0.67g(2.2mmol)化合物III-19，0.45g(2.2mmol)N,N’-二环己基碳酰亚胺，0.25g(2.2mmol)N-羟基丁二酰亚胺溶于20ml二氯甲烷中，室温反应4h。过滤，滤饼用10ml二氯甲烷再洗一次，合并滤液。并将滤液加入到溶有0.69g(2.0mmol)化合物II、0.40g(2.0mmol)N-甲基吗啉的二氯甲烷(20ml)溶液中，室温反应过夜。加50ml水，充分搅拌后，分层，收集有机相，饱和食盐水洗涤一次，干燥，浓缩，柱层析分离纯化(二氯甲烷:甲醇＝30:1)，得0.72g粗产品，再用制备液相纯化分离得0.42g淡黄色固体(化合物I-19)，收率33.4％。0.67 g (2.2 mmol) of compound III-19, 0.45 g (2.2 mmol) of N,N'-dicyclohexylcarbimide, 0.25 g (2.2 mmol) of N-hydroxysuccinimide dissolved in 20 ml of dichloro In methane, react at room temperature for 4 h. After filtration, the filter cake was washed once more with 10 ml of dichloromethane and the filtrate was combined. The filtrate was added to a solution of 0.69 g (2.0 mmol) of Compound II, 0.40 g (2.0 mmol) of N-methylmorpholine in dichloromethane (20 ml), and allowed to react overnight at room temperature. Add 50 ml of water, stir well, layer, collect the organic phase, wash once with saturated brine, dry, concentrate, and purify by column chromatography (dichloromethane: methanol = 30:1) to obtain 0.72 g of crude product, and then use Purification by preparative liquid phase gave 0.42 g of pale yellow solid (Compound I-19).
1H NMR(CDCl 3-d):0.88(t,3H,J＝6.6Hz)；1.01(t,3H,J＝7.3Hz)；1.25-1.35(m,20H)；1.47-1.56(m,4H)；1.89-1.95(m,4H)；2.33(t,2H,J＝7.2Hz)；2.46(t,2H,J＝7.4Hz)；2.54(t,2H,J＝7.0Hz)；2.98(t,2H,J＝7.6Hz)；3.53-3.57(m,2H)；3.64(t,2H,J＝5.1Hz)；3.92(t,2H,J＝4.1Hz)；4.50(t,2H,J＝3.9Hz)；5.89(br s,1H)；6.05(br s,2H)；7.37(t,1H,J＝7.6Hz)；7.55(t,1H,J＝7.2Hz)；7.83(d,1H,J＝8.4Hz)；8.28(d,1H,J＝8.1Hz)；ESI-MS:628[M+H] +。 1 H NMR (CDCl 3 -d): 0.88 (t, 3H, J = 6.6 Hz); 1.01 (t, 3H, J = 7.3 Hz); 1.25-1.35 (m, 20H); 1.47-1.56 (m, 4H) ); 1.89-1.95 (m, 4H); 2.33 (t, 2H, J = 7.2 Hz); 2.46 (t, 2H, J = 7.4 Hz); 2.54 (t, 2H, J = 7.0 Hz); 2.98 (t , 2H, J = 7.6 Hz); 3.53-3.57 (m, 2H); 3.64 (t, 2H, J = 5.1 Hz); 3.92 (t, 2H, J = 4.1 Hz); 4.50 (t, 2H, J = 3.9 Hz); 5.89 (br s, 1H); 6.05 (br s, 2H); 7.37 (t, 1H, J = 7.6 Hz); 7.55 (t, 1H, J = 7.2 Hz); 7.83 (d, 1H, J = 8.4 Hz); 8.28 (d, 1H, J = 8.1 Hz); ESI-MS: 628 [M+H] + .
以合适的1-溴十一烷和硫脲为原料，按照实施例21方法制备化合物I-20；或以市购的1-烷基硫醇为原料，按照实施例21中步骤二和步骤三的方法制备得到了化合物I-21、I-22和I-23。Preparing compound I-20 according to the method of Example 21 using suitable 1-bromoundecane and thiourea as raw materials; or using commercially available 1-alkyl mercaptan as raw material, according to step 2 and step 3 of Example 21. The compounds were prepared to give compounds I-21, I-22 and I-23.
Figure PCTCN2018103963-appb-000025
Figure PCTCN2018103963-appb-000025
Figure PCTCN2018103963-appb-000026
Figure PCTCN2018103963-appb-000026
Figure PCTCN2018103963-appb-000027
Figure PCTCN2018103963-appb-000027
实施例26：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-(十五烷硫基)乙酰胺(I-24)的制备Example 26: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl Preparation of 2-(pentadecanethio)acetamide (I-24)
Figure PCTCN2018103963-appb-000028
Figure PCTCN2018103963-appb-000028
步骤一：1-十五烷硫醇的制备：Step 1: Preparation of 1-pentadecanethiol:
将8.93g(30.0mmol)1-溴十五烷，2.51g(33.0mmol)硫脲溶于50ml乙醇中，80℃回流反应6h，再加入10ml 4mol/L NaOH溶液，80℃下继续反应4h。反应完毕，冷却，用1mol/L盐酸调至pH<1，加入50ml二氯甲烷及50ml水，充分搅拌后，分层，收集有机相，用50ml饱和食盐水洗涤一次，Na 2SO 4干燥，浓缩，柱层析分离纯化(洗脱液为纯正己烷)，得7.20g 1-十五烷硫醇(无色液体)，收率98.1％。 8.93 g (30.0 mmol) of 1-bromopentadecane, 2.51 g (33.0 mmol) of thiourea were dissolved in 50 ml of ethanol, refluxed at 80 ° C for 6 h, and then 10 ml of a 4 mol/L NaOH solution was added, and the reaction was continued at 80 ° C for 4 h. After the reaction was completed, it was cooled, adjusted to pH <1 with 1 mol/L hydrochloric acid, 50 ml of dichloromethane and 50 ml of water were added thereto, and the mixture was thoroughly stirred, and the layers were separated. The organic phase was collected, washed once with 50 ml of brine, and dried over Na 2 SO 4 . The mixture was concentrated and purified by column chromatography (yield of pure hexane) to give 7.20 g of 1-pentadecanethiol (colorless liquid) in a yield of 98.1%.
1H NMR(CDCl 3-d):0.90(t,3H,J＝6.6Hz)；1.27-1.32(m,20H)；1.34-1.41(m,4H)；1.56-1.68(m,2H)；2.49-2.57(m,2H). 1 H NMR (CDCl 3 -d): 0.90 (t, 3H, J = 6.6 Hz); 1.27-1.32 (m, 20H); 1.34-1.41 (m, 4H); 1.56-1.68 (m, 2H); -2.57 (m, 2H).
步骤二：2-十五烷硫基乙酸(化合物III-24)的制备：Step 2: Preparation of 2-pentadecanethioacetic acid (Compound III-24):
将4.89g(20mmol)1-十五烷硫醇，2.16g(20mmol)氯乙酸甲酯和3.36g(60mmol)氢氧化钾溶于40ml甲醇，加热回流反应6h，浓缩，加50ml水溶解，用2mol/L HCl调至pH<2，过滤，滤饼用正己烷重结晶，得0.87g白色固体(化合物III-24)，收率14.5％。4.89 g (20 mmol) of 1-pentadecanethiol, 2.16 g (20 mmol) of methyl chloroacetate and 3.36 g (60 mmol) of potassium hydroxide were dissolved in 40 ml of methanol, refluxed for 6 h, concentrated, and dissolved in 50 ml of water. 2 mol/L HCl was adjusted to pH < 2, filtered, and the filter cake was recrystallized from n-hexane to give a white solid (comp. III-24).
1H NMR(CDCl 3-d):0.90(t,3H,J＝6.6Hz)；1.27-1.32(m,22H)；1.36-1.41(m,2H)；1.59-1.66(m,2H)；2.67(t,2H,J＝7.4Hz)；3.27(s,2H)；ESI-MS:301[M-H] - 1 H NMR (CDCl 3 -d): 0.90 (t, 3H, J = 6.6 Hz); 1.27-1.32 (m, 22H); 1.36-1.41 (m, 2H); 1.59-1.66 (m, 2H); (t, 2H, J = 7.4 Hz); 3.27 (s, 2H); ESI-MS: 301 [MH] -
步骤三：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-(十五烷硫基)乙酰胺(化合物I-24)的制备Step 3: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl] Preparation of -2-(pentadecanethio)acetamide (Compound I-24)
将0.66g(2.2mmol)化合物III-24，0.45g(2.2mmol)N,N’-二环己基碳酰亚胺，0.25g(2.2mmol)N-羟基丁二酰亚胺溶于20ml二氯甲烷中，室温反应4h。过滤，滤饼用10ml二氯甲烷再洗一次，合并滤液。并将滤液加入到溶有0.69g(2.0mmol)化合物II、0.40g(2.0mmol)N-甲基吗啉的二氯甲烷(20ml)溶液中，室温反应过夜。加50ml水，充分搅拌后，分层，收集有机相，饱和食盐水洗涤一次，干燥，浓缩，柱层析分离纯化(二氯甲烷:甲醇＝30:1)，得0.93g粗产品，再用制备液相纯化分离得0.52g淡黄色固体(化合物I-24)，收率41.4％。0.66 g (2.2 mmol) of compound III-24, 0.45 g (2.2 mmol) of N,N'-dicyclohexylcarbimide, 0.25 g (2.2 mmol) of N-hydroxysuccinimide dissolved in 20 ml of dichloro In methane, react at room temperature for 4 h. After filtration, the filter cake was washed once more with 10 ml of dichloromethane and the filtrate was combined. The filtrate was added to a solution of 0.69 g (2.0 mmol) of Compound II, 0.40 g (2.0 mmol) of N-methylmorpholine in dichloromethane (20 ml), and allowed to react overnight at room temperature. Add 50 ml of water, stir well, layer, collect the organic phase, wash once with saturated brine, dry, concentrate, and purify by column chromatography (dichloromethane: methanol = 30:1) to obtain 0.93 g of crude product, and then use Purification by preparative liquid phase gave 0.52 g of pale yellow solid (Compound I-24).
1H NMR(CDCl 3-d):0.89(t,3H,J＝6.5Hz)；1.02(t,3H,J＝7.4Hz)；1.21-1.26(m,24H)；1.47-1.56(m,4H)；1.88-1.96(m,2H)；2.50(t,2H,J＝7.4Hz)；3.00(t,2H,J＝7.6Hz)；3.25(s,2H)；3.62-3.64(m,2H)；3.70(t,2H,J＝5.0Hz)；3.95(s,2H)；4.50(s,2H)；5.87(br s,2H)；7.28(br s,1H)；7.38(t,1H,J＝7.6Hz)；7.57(t,1H,J＝7.8Hz)；7.83(d,1H,J＝8.2Hz)；8.29(d,1H,J＝8.0Hz)；ESI-MS:628[M+H] + 1 H NMR (CDCl 3 -d): 0.89 (t, 3H, J = 6.5 Hz); 1.02 (t, 3H, J = 7.4 Hz); 1.21-1.26 (m, 24H); 1.47-1.56 (m, 4H) ); 1.88-1.96 (m, 2H); 2.50 (t, 2H, J = 7.4 Hz); 3.00 (t, 2H, J = 7.6 Hz); 3.25 (s, 2H); 3.62-3.64 (m, 2H) ; 3.70 (t, 2H, J = 5.0 Hz); 3.95 (s, 2H); 4.50 (s, 2H); 5.87 (br s, 2H); 7.28 (br s, 1H); 7.38 (t, 1H, J = 7.6 Hz); 7.57 (t, 1H, J = 7.8 Hz); 7.83 (d, 1H, J = 8.2 Hz); 8.29 (d, 1H, J = 8.0 Hz); ESI-MS: 628 [M+H ] +
分别以1-十三烷硫醇、1-十四烷硫醇为原料，按照实施例26中步骤二和步骤三的方法制备得到了以下化合物：The following compounds were prepared according to the procedures of Step 2 and Step 3 in Example 26 using 1-tridecyl mercaptan and 1-tetradecyl mercaptan as raw materials respectively:
Figure PCTCN2018103963-appb-000029
Figure PCTCN2018103963-appb-000029
Figure PCTCN2018103963-appb-000030
Figure PCTCN2018103963-appb-000030
实施例29：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十二烷基氨基)丁酰胺(I-27)的制备Example 29: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl Preparation of -4-(dodecylamino)butanamide (I-27)
Figure PCTCN2018103963-appb-000031
Figure PCTCN2018103963-appb-000031
步骤一：4-[苄基(十二烷基)氨基]丁酸甲酯的制备Step 1: Preparation of 4-[benzyl(dodecyl)amino]butyric acid methyl ester
将2.12g(20.0mmol)苯甲醛，3.62g(20.0mmol)1-十二胺溶于40ml乙醇中，80℃回流反应3h，冷却，降温至0℃，分两次加入1.80g(60.0mmol)硼氢化钠，室温反应5h，浓缩，加入50ml二氯甲烷和50ml水，充分搅拌，分层，有机相经Na 2SO 4干燥，过滤，浓缩，浓缩液中加入5.43g(30.0mmol)4-溴丁酸甲酯，6.9g碳酸钾和80ml丙酮，50℃下搅拌过夜，反应完毕，停止加热，过滤，滤饼用50ml丙酮洗涤，合并滤液，浓缩，柱层析分离纯化(洗脱剂为二氯甲烷:甲醇＝30:1)，得4.57g 4-[苄基(十二烷基)氨基]丁酸甲酯(无色液体)，收率61.0％。 2.12 g (20.0 mmol) of benzaldehyde, 3.62 g (20.0 mmol) of 1-dodecylamine was dissolved in 40 ml of ethanol, refluxed at 80 ° C for 3 h, cooled, cooled to 0 ° C, and added 1.80 g (60.0 mmol) in two portions. The sodium borohydride was reacted at room temperature for 5 h, concentrated, 50 ml of dichloromethane and 50 ml of water were added, and the mixture was stirred well, and the organic layer was dried over Na 2 SO 4 , filtered, concentrated, and 5.43 g (30.0 mmol) Methyl bromobutyrate, 6.9 g of potassium carbonate and 80 ml of acetone, stirred at 50 ° C overnight, the reaction is completed, the heating is stopped, filtered, the filter cake is washed with 50 ml of acetone, the filtrate is combined, concentrated, and purified by column chromatography (eluent is Methylene chloride:methanol = 30:1) gave 4.57 g of methyl 4-[benzyl(dodecyl)amino]butanoate (colorless liquid) in a yield of 61.0%.
1H NMR(CDCl 3-d):0.90(t,3H,J＝6.0Hz)；1.26-1.32(m,18H)；1.46(m,2H)；1.80(m,2H)；2.35(t,2H,J＝7.4Hz)；2.43(m,4H)；3.56(s,2H)；3.65(s,3H)；7.24-7.33(m,5H)；ESI-MS:376[M+H] +。 1 H NMR (CDCl 3 -d): 0.90 (t, 3H, J = 6.0 Hz); 1.26-1.32 (m, 18H); 1.46 (m, 2H); 1.80 (m, 2H); 2.35 (t, 2H) , J = 7.4 Hz); 2.43 (m, 4H); 3.56 (s, 2H); 3.65 (s, 3H); 7.24-7.33 (m, 5H); ESI-MS: 376 [M+H] + .
步骤二：4-[苄基(十二烷基)氨基]丁酸盐酸盐(化合物V-27)的制备Step 2: Preparation of 4-[benzyl(dodecyl)amino]butyrate (Compound V-27)
将3.76g(0.01mol)4-[苄基(十二烷基)氨基]丁酸甲酯，2.24g(0.04mol)氢氧化钾溶于15ml甲醇，80℃回流反应4h，浓缩，加20ml水溶解，用2mol/L HCl调至pH<1，再用二氯甲烷与甲醇(V/V＝10:1)的混合液60ml分三次萃取，合并有机相，干燥，浓缩，乙酸乙酯重结晶得3.85g 4-[苄基(十二烷基)氨基]丁酸盐酸盐(化合物V-27，白色固体)，收率96.7％。3.76 g (0.01 mol) of methyl 4-[benzyl(dodecyl)amino]butanoate, 2.24 g (0.04 mol) of potassium hydroxide was dissolved in 15 ml of methanol, refluxed at 80 ° C for 4 h, concentrated, and added with 20 ml of water Dissolved, adjusted to pH<1 with 2 mol/L HCl, and extracted with 60 ml of a mixture of dichloromethane and methanol (V/V = 10:1). The organic phase was combined, dried, concentrated, and recrystallized from ethyl acetate. 3.85 g of 4-[benzyl(dodecyl)amino]butyrate (Compound V-27, white solid) was obtained in a yield of 96.7%.
1H NMR(DMSO-d):0.86(t,3H,J＝5.8Hz)；1.23-1.27(m,18H)；1.70(m,2H)；1.92-1.96(m,2H)；2.30(t,2H,J＝7.0Hz)；2.90-3.00(m,4H)；4.29(s,2H)；7.44-7.65(m,5H)；ESI-MS:362[M+H] +。 1 H NMR (DMSO-d): 0.86 (t, 3H, J = 5.8 Hz); 1.23-1.27 (m, 18H); 1.70 (m, 2H); 1.92-1.96 (m, 2H); 2.30 (t, 2H, J=7.0 Hz); 2.90-3.00 (m, 4H); 4.29 (s, 2H); 7.44-7.65 (m, 5H); ESI-MS: 362[M+H] + .
步骤三：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[苄基(十二烷基)氨基]丁酰胺(化合物IV-27)的制备Step 3: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl] Preparation of -4-[benzyl(dodecyl)amino]butanamide (Compound IV-27)
将0.88g(2.2mmol)4-[苄基(十二烷基)氨基]丁酸盐酸盐，0.45g(2.2mmol)N,N’-二环己基碳酰亚胺和0.25g(2.2mmol)N-羟基丁二酰亚胺溶于20ml二氯甲烷中，室温反应4h，过滤，滤饼用10ml二氯甲烷洗涤，合并滤液，将滤液加入到溶有0.69g(2.0mmol)化合物II和0.40g(2.0mmol)N-甲基吗啉的二氯甲烷(20ml)溶液中，室温反应过夜。加50ml水，充分搅拌后，分层，收集有机相，水洗，干燥，浓缩，柱层析分离纯化(洗脱剂为二氯甲烷:甲醇＝20:1)，得1.15g浅红色油状液体(化合物IV-27)，收率83.8％。0.88 g (2.2 mmol) of 4-[benzyl(dodecyl)amino]butyrate, 0.45 g (2.2 mmol) of N,N'-dicyclohexylcarbimide and 0.25 g (2.2 mmol) N-hydroxysuccinimide was dissolved in 20 ml of dichloromethane, reacted at room temperature for 4 h, filtered, and the filter cake was washed with 10 ml of dichloromethane, the filtrate was combined, and the filtrate was added to dissolve 0.69 g (2.0 mmol) of compound II and A solution of 0.40 g (2.0 mmol) of N-methylmorpholine in dichloromethane (20 mL) Add 50 ml of water, stir well, layer, collect the organic phase, wash with water, dry, concentrate, and purify by column chromatography (eluent: dichloromethane: methanol = 20:1) to give 1.15 g of light red oily liquid ( Compound IV-27), yield 83.8%.
1H NMR(CDCl 3-d):0.89(t,3H,J＝6.1Hz)；1.01(t,3H,J＝7.4Hz)；1.23-1.30(m,18H)；1.47-1.52(m,4H)；1.78-1.94(m,4H)；2.22(t,2H,J＝7.2Hz)；2.40-2.47(m,4H)；2.97(t,2H,J＝7.6Hz)；3.49-3.50(m,2H)；3.55(s,2H)；3.61-3.63(m,2H)；3.90(m,2H)；4.46-4.47(m,2H)；5.90(br s,1H)；6.12(s,1H)；7.22-7.33(m,5H)；7.37(t,1H,J＝7.0Hz)；7.54(t,1H,J＝7.2Hz)；7.80(d,1H,J＝8.4Hz)；8.27(t,1H,J＝8.1Hz)；ESI-MS:687[M+Na] +。 1 H NMR (CDCl 3 -d): 0.89 (t, 3H, J = 6.1 Hz); 1.01 (t, 3H, J = 7.4 Hz); 1.23-1.30 (m, 18H); 1.47-1.52 (m, 4H) ); 1.78-1.94 (m, 4H); 2.22 (t, 2H, J = 7.2 Hz); 2.40-2.47 (m, 4H); 2.97 (t, 2H, J = 7.6 Hz); 3.49-3.50 (m, 2H); 3.55 (s, 2H); 3.61-3.63 (m, 2H); 3.90 (m, 2H); 4.46-4.47 (m, 2H); 5.90 (br s, 1H); 6.12 (s, 1H); 7.22-7.33 (m, 5H); 7.37 (t, 1H, J = 7.0 Hz); 7.54 (t, 1H, J = 7.2 Hz); 7.80 (d, 1H, J = 8.4 Hz); 8.27 (t, 1H) , J = 8.1 Hz); ESI-MS: 687 [M+Na] + .
步骤四：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十二烷基氨基)丁酰胺(化合物I-27)的制备Step 4: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl] Preparation of -4-(dodecylamino)butanamide (Compound I-27)
将1.10g(1.6mmol)化合物IV-27溶于甲醇中，加入0.22g Pd(OH) 2/C，置于H 2氛围中，室温反应6h。反应结束，过滤，滤液浓缩，所得油状粘稠液体用制备液相分离纯化，得532mg白色固体(化合物I-27)，收率55.7％。 1.10 g (1.6 mmol) of compound IV-27 was dissolved in methanol, 0.22 g of Pd(OH) 2 /C was added, and the mixture was placed in a H 2 atmosphere and allowed to react at room temperature for 6 h. After completion of the reaction, filtration and concentration of the filtrate, the obtained oily viscous liquid was purified by preparative liquid phase to give 532 mg of white solid (Compound I-27).
1H NMR(CDCl 3-d):0.88(t,3H,J＝6.6Hz)；1.00(t,3H,J＝7.4Hz)；1.24-1.31(m,18H)；1.42-1.54(m,4H)；1.77-1.85(m,2H)；1.86-1.94(m,2H)；2.29(t,2H,J＝7.3Hz)；2.55(t,2H,J＝7.2Hz)；2.64(t,2H,J＝6.8Hz)；2.97(t,2H,J＝7.5Hz)；3.50-3.54(m,2H)；3.63(t,2H,J＝5.2Hz)；3.90(t,2H,J＝4.0Hz)；4.47(t,2H,J＝3.7Hz)；5.60(br s,2H)；6.50(br s,1H)；7.31(t,1H,J＝7.7Hz)；7.52(t,1H,J＝8.2Hz)；7.77(d,1H,J＝8.3Hz)；8.25(d,1H,J＝8.1Hz)；ESI-MS:597[M+H] +。 1 H NMR (CDCl 3 -d): 0.88 (t, 3H, J = 6.6 Hz); 1.00 (t, 3H, J = 7.4 Hz); 1.24-1.31 (m, 18H); 1.42-1.54 (m, 4H) ); 1.7-1.85 (m, 2H); 1.86-1.94 (m, 2H); 2.29 (t, 2H, J = 7.3 Hz); 2.55 (t, 2H, J = 7.2 Hz); 2.64 (t, 2H, J = 6.8 Hz); 2.97 (t, 2H, J = 7.5 Hz); 3.50 - 3.54 (m, 2H); 3.63 (t, 2H, J = 5.2 Hz); 3.90 (t, 2H, J = 4.0 Hz) ;4.47(t,2H,J=3.7Hz); 5.60(br s,2H); 6.50(br s,1H);7.31(t,1H,J=7.7Hz);7.52(t,1H,J=8.2 Hz); 7.77 (d, 1H, J = 8.3 Hz); 8.25 (d, 1H, J = 8.1 Hz); ESI-MS: 597 [M+H] + .
实施例30：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷基氨基)丁酰胺(I-28)的制备Example 30: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl Preparation of -4-(tridecylamino)butanamide (I-28)
Figure PCTCN2018103963-appb-000032
Figure PCTCN2018103963-appb-000032
步骤一：4-[苄基(十三烷基)氨基]丁酸甲酯的制备Step 1: Preparation of 4-[benzyl(tridecyl)amino]butyric acid methyl ester
将1.59g(15.0mmol)苯甲醛，2.99g(15.0mmol)1-十三胺溶于20ml乙醇中，80℃回流反应3h，冷却并降温至0℃，分两次加入1.35g(45.0mmol)硼氢化钠，室温反应5h，浓缩，加入50ml二氯甲烷和50ml水，充分搅拌，分层，有机相经Na 2SO 4干燥，过滤，浓缩，浓缩液中加入1.07g(22.5mmol)4-溴丁酸甲酯，5.18g(37.5mmol)碳酸钾和50ml丙酮，50℃下搅拌过夜，反应完毕，过滤，滤饼用20ml丙酮洗涤，合并滤液，浓缩，柱层析分离纯化(洗脱剂为二氯甲烷:甲醇＝30:1)，得3.64g 4-[苄基(十三烷基)氨基]丁酸甲酯(无色液体)，收率64.6％。 1.59 g (15.0 mmol) of benzaldehyde, 2.99 g (15.0 mmol) of 1-tridecylamine was dissolved in 20 ml of ethanol, refluxed at 80 ° C for 3 h, cooled and cooled to 0 ° C, and added to 1.35 g (45.0 mmol) twice. The sodium borohydride was reacted at room temperature for 5 h, concentrated, 50 ml of dichloromethane and 50 ml of water were added, and the mixture was stirred well, and the organic layer was dried over Na 2 SO 4 , filtered, and concentrated. Methyl bromobutyrate, 5.18g (37.5mmol) potassium carbonate and 50ml of acetone, stirred at 50 ° C overnight, the reaction is completed, filtered, the filter cake is washed with 20ml of acetone, the filtrate is combined, concentrated, purified by column chromatography (eluent) Methylene chloride:methanol = 30:1) gave 3.64 g of methyl 4-[benzyl(tridecyl)amino]butanoate (colorless liquid) in a yield of 64.6%.
1H NMR(CDCl 3-d):0.90(t,3H,J＝6.3Hz)；1.26-1.32(m,20H)；1.46(m,2H)；1.77-1.81(m,2H)；2.35(t,2H,J＝7.3Hz)；2.42-2.43(m,4H)；3.55(s,2H)；3.65(s,3H)；7.24-7.28(m,1H)；7.31-7.32(m,4H).ESI-MS:390[M+H] +。 1 H NMR (CDCl 3 -d): 0.90 (t, 3H, J = 6.3 Hz); 1.26-1.32 (m, 20H); 1.46 (m, 2H); 1.77-1.81 (m, 2H); , 2H, J = 7.3 Hz); 2.42 - 2.43 (m, 4H); 3.55 (s, 2H); 3.65 (s, 3H); 7.24 - 7.28 (m, 1H); 7.31 - 7.32 (m, 4H). ESI-MS: 390 [M+H] + .
步骤二：4-[苄基(十三烷基)氨基]丁酸盐酸盐(化合物V-28)的制备Step 2: Preparation of 4-[benzyl(tridecyl)amino]butyrate (Compound V-28)
将3.60g(9.3mmol)4-[苄基(十三烷基)氨基]丁酸甲酯，2.24g(37.2mmol)氢氧化钾溶于15ml甲醇，80℃回流反应4h，浓缩，加20ml水溶解，用2mol/L HCl调至pH<1，再用二氯甲烷与甲醇(V/V＝10:1)的混合液60ml分三次萃取，合并有机相，干燥，浓缩，乙酸乙酯重结晶得3.72g 4-[苄基(十三烷基)氨基]丁酸盐酸盐(化合物V-28，白色固体)，收率97.3％。3.60 g (9.3 mmol) of methyl 4-[benzyl(tridecyl)amino]butanoate, 2.24 g (37.2 mmol) of potassium hydroxide were dissolved in 15 ml of methanol, refluxed at 80 ° C for 4 h, concentrated, and added with 20 ml of water Dissolved, adjusted to pH<1 with 2 mol/L HCl, and extracted with 60 ml of a mixture of dichloromethane and methanol (V/V = 10:1). The organic phase was combined, dried, concentrated, and recrystallized from ethyl acetate. 3.72 g of 4-[benzyl(tridecyl)amino]butanoic acid hydrochloride (Compound V-28, white solid).
1H NMR(DMSO-d):0.87(t,3H,J＝6.5Hz)；1.22-1.29(m,20H)；1.71(m,2H)；1.91-1.99(m,2H)；2.30(t,2H,J＝7.2Hz)；2.89-2.98(m,4H)；4.29(s,2H)；7.43-7.44(m,3H)；7.66-7.69(m,2H).ESI-MS:376[M+H] +。 1 H NMR (DMSO-d): 0.87 (t, 3H, J = 6.5 Hz); 1.22-1.29 (m, 20H); 1.71 (m, 2H); 1.91-1.99 (m, 2H); 2.30 (t, 2H, J=7.2 Hz); 2.89-2.98 (m, 4H); 4.29 (s, 2H); 7.43-7.44 (m, 3H); 7.66-7.69 (m, 2H). ESI-MS: 376 [M+ H] + .
步骤三：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[苄基(十三烷基)氨基]丁酰胺(化合物IV-28)的制备Step 3: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl] Preparation of -4-[benzyl(tridecyl)amino]butanamide (Compound IV-28)
将0.91g(2.2mmol)4-[苄基(十三烷基)氨基]丁酸盐酸盐，0.45g(2.2mmol) N,N’-二环己基碳酰亚胺和0.25g(2.2mmol)N-羟基丁二酰亚胺溶于20ml二氯甲烷中，室温反应4h，过滤，滤饼用10ml二氯甲烷洗涤，合并滤液，将滤液加入到溶有0.69g(2.0mmol)化合物II及0.40g(2.0mmol)N-甲基吗啉的二氯甲烷(20ml)溶液中，室温反应过夜。加50ml水，充分搅拌后，分层，收集有机相，水洗，干燥，浓缩，柱层析分离纯化(二氯甲烷:甲醇＝20:1)，得1.15g浅红色油状液体(化合物IV-28)，收率82.0％。0.91 g (2.2 mmol) of 4-[benzyl(tridecyl)amino]butyrate, 0.45 g (2.2 mmol) of N,N'-dicyclohexylcarbimide and 0.25 g (2.2 mmol) N-hydroxysuccinimide is dissolved in 20 ml of dichloromethane, reacted at room temperature for 4 h, filtered, and the filter cake is washed with 10 ml of dichloromethane, the filtrate is combined, and the filtrate is added to dissolve 0.69 g (2.0 mmol) of compound II and A solution of 0.40 g (2.0 mmol) of N-methylmorpholine in dichloromethane (20 mL) Add 50 ml of water, stir well, layer, collect the organic phase, wash with water, dry, concentrate, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain 1.15 g of light red oily liquid (Compound IV-28) ), the yield was 82.0%.
1H NMR(CDCl 3-d):0.89(t,6H,J＝6.6Hz)；1.00(t,3H,J＝7.4Hz)；1.23-1.31(m,20H)；1.45-1.52(m,4H)；1.80-1.92(m,4H)；2.23(t,2H,J＝7.3Hz)；2.40-2.48(m,4H)；2.97(t,2H,J＝7.6Hz)；3.49-3.51(m,2H)；3.55(s,2H)；3.61-3.63(m,2H)；3.89-3.91(m,2H)；4.45-4.47(m,2H)；6.18(m,2H)；7.22-7.33(m,5H)；7.37(t,1H,J＝7.4Hz)；7.53(t,1H,J＝8.4Hz)；7.80(d,1H,J＝8.3Hz)；8.26(t,1H,J＝7.2Hz).ESI-MS:701[M+Na] + 1 H NMR (CDCl 3 -d): 0.89 (t, 6H, J = 6.6 Hz); 1.00 (t, 3H, J = 7.4 Hz); 1.23-1.31 (m, 20H); 1.45-1.52 (m, 4H) ); 1.80-1.92 (m, 4H); 2.23 (t, 2H, J = 7.3 Hz); 2.40-2.48 (m, 4H); 2.97 (t, 2H, J = 7.6 Hz); 3.49-3.51 (m, 2H); 3.55 (s, 2H); 3.61-3.63 (m, 2H); 3.89-3.91 (m, 2H); 4.45-4.47 (m, 2H); 6.18 (m, 2H); 7.22-7.33 (m, 5H); 7.37 (t, 1H, J = 7.4 Hz); 7.53 (t, 1H, J = 8.4 Hz); 7.80 (d, 1H, J = 8.3 Hz); 8.26 (t, 1H, J = 7.2 Hz) .ESI-MS: 701 [M+Na] +
步骤四：N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷基氨基)丁酰胺(化合物I-28)的制备Step 4: N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl] Preparation of -4-(tridecylamino)butanamide (Compound I-28)
将1.15g(1.6mmol)化合物IV-28溶于甲醇中，加入0.23g Pd(OH) 2/C，置于H 2氛围中，室温反应6h。反应结束，过滤，滤液浓缩，所得油状粘稠液体用制备液相分离纯化，得367mg白色固体(化合物I-28)，收率36.0％。 1.15 g (1.6 mmol) of compound IV-28 was dissolved in methanol, 0.23 g of Pd(OH) 2 /C was added, and the mixture was placed in a H 2 atmosphere and allowed to react at room temperature for 6 h. After completion of the reaction, filtration and concentration of the filtrate, the obtained oily viscous liquid was purified by preparative liquid phase to give 367 mg of white solid (Compound I-28).
1H NMR(DMSO-d):0.86(t,3H,J＝6.5Hz)；0.95(t,3H,J＝7.3Hz)；1.21-1.24(m,22H)；1.31-1.34(m,2H)；1.40-1.45(m,2H)；1.59-1.63(m,2H)；1.80-1.84(m,2H)；2.12(t,2H,J＝7.4Hz)；2.39-2.45(m,4H)；2.97(t,2H,J＝7.6Hz)；3.56(t,2H,J＝6.1Hz)；3.86(t,2H,J＝3.8Hz)；4.48(t,2H,J＝3.5Hz)；6.58(br s,2H)；7.26(t,1H,J＝7.0Hz)；7.44(t,1H,J＝8.4Hz)；7.58(d,1H,J＝8.0Hz)；7.89(t,1H)；8.23(d,1H,J＝8.1Hz)；ESI-MS:611[M+H] +。 1 H NMR (DMSO-d): 0.86 (t, 3H, J = 6.5 Hz); 0.95 (t, 3H, J = 7.3 Hz); 1.21-1.24 (m, 22H); 1.31-1.34 (m, 2H) ;1.40-1.45 (m, 2H); 1.59-1.63 (m, 2H); 1.80-1.84 (m, 2H); 2.12 (t, 2H, J = 7.4 Hz); 2.39-2.45 (m, 4H); 2.97 (t, 2H, J = 7.6 Hz); 3.56 (t, 2H, J = 6.1 Hz); 3.86 (t, 2H, J = 3.8 Hz); 4.48 (t, 2H, J = 3.5 Hz); 6.58 (br s, 2H); 7.26 (t, 1H, J = 7.0 Hz); 7.44 (t, 1H, J = 8.4 Hz); 7.58 (d, 1H, J = 8.0 Hz); 7.89 (t, 1H); 8.23 ( d, 1H, J = 8.1 Hz); ESI-MS: 611 [M+H] + .
本发明化合物的药效学筛选，按下列方式进行The pharmacodynamic screening of the compounds of the invention is carried out in the following manner
一.体外药效学筛选I. In vitro pharmacodynamic screening
1.体外抗肿瘤活性实验：鼠源黑色素瘤细胞B16F10，鼠源结肠癌细胞CT26.WT，人结肠癌细胞HCT-116，人肺癌细胞A549，人卵巢癌细胞OVCAR-5，人前列腺癌细胞PC-3，人肺癌细胞NCI-H460，人乳腺癌细胞MCF-7，人肾透明细胞癌细胞Caki-2，人肝癌细胞HepG2，人神经母细胞瘤细胞SH-Y5Y，人口腔表皮样癌细胞KB，人食管癌细胞EC109，人成骨肉瘤细胞MG-63购自ATCC，采用含10％胎牛血清的DMEM培养基或RPMI1640培养基培养。取增殖良好处于对数生长期的细胞，制成细胞悬液，细胞以2000-6000个细胞/孔接种至96孔板中，置37℃，5％CO 2，100％相对湿度培养箱中培养24h。对照孔加入不含药物的培养基50μl，其 他孔加入50μl培养基配制的不同浓度梯度药物，置于CO 2培养箱中培养72h。采用SRB方法检测细胞活率，Graphpad prism 5.0软件统计试验数据，计算GI 50。以3M-052作为对照药，实验结果见表1。 1. In vitro anti-tumor activity test: murine melanoma cell B16F10, murine colon cancer cell line CT26.WT, human colon cancer cell HCT-116, human lung cancer cell A549, human ovarian cancer cell OVCAR-5, human prostate cancer cell PC -3, human lung cancer cell NCI-H460, human breast cancer cell MCF-7, human renal clear cell carcinoma cell Caki-2, human liver cancer cell HepG2, human neuroblastoma cell SH-Y5Y, human oral epidermoid carcinoma cell KB Human esophageal cancer cell line EC109, human osteosarcoma cell MG-63 was purchased from ATCC, and cultured in DMEM medium or RPMI1640 medium containing 10% fetal bovine serum. Take cells with good proliferation in logarithmic growth phase, make cell suspension, inoculate cells into 96-well plates at 2000-6000 cells/well, incubate at 37 ° C, 5% CO 2 , 100% relative humidity incubator 24h. 50 μl of the drug-free medium was added to the control wells, and the other wells were added with different concentration gradient drugs prepared in 50 μl of the medium, and cultured in a CO 2 incubator for 72 hours. Cell viability was measured by SRB method, and experimental data was calculated by Graphpad prism 5.0 software to calculate GI 50 . 3M-052 was used as a control drug, and the experimental results are shown in Table 1.
表1 化合物体外抑制肿瘤细胞增殖活性Table 1 Compound inhibits tumor cell proliferation activity in vitro
Figure PCTCN2018103963-appb-000033
Figure PCTCN2018103963-appb-000033
Figure PCTCN2018103963-appb-000034
Figure PCTCN2018103963-appb-000034
“-”表示未测试"-" means not tested
结果显示：所有化合物均具有体外抗肿瘤作用，且均优于3M-052。The results showed that all compounds had anti-tumor effects in vitro and were superior to 3M-052.
2.HEK-TLR7和HEK-TLR8激动实验2. HEK-TLR7 and HEK-TLR8 activation experiments
实验方法：化合物用pH 7.2PBS进行梯度稀释，试验各组按试验设计加入20μl化合物或PBS于96孔板中。将处于对数生长期稳转细胞株HEK-TLR7或HEK-TLR8细胞机械吹散，并加入SEAP反应液，制成220000个/ml的细胞溶液，试验每孔加入180μl细胞溶液。CO 2培养箱中培养16h，在MD 5酶标仪上检测620nm吸收值，Graphpad prism 5.0软件统计试验数据，计算EC 50。实验结果见表2。 Experimental method: Compounds were serially diluted with pH 7.2 PBS, and each group was added to a 96-well plate according to the experimental design by adding 20 μl of the compound or PBS. The HEK-TLR7 or HEK-TLR8 cells in the logarithmic growth phase were mechanically blown off, and the SEAP reaction solution was added to prepare a cell solution of 220,000 cells/ml, and 180 μl of the cell solution was added to each well. The cells were cultured for 16 h in a CO 2 incubator, and the absorbance at 620 nm was measured on a MD 5 plate reader. The experimental data was statistically analyzed by Graphpad prism 5.0 software, and the EC 50 was calculated. The experimental results are shown in Table 2.
表2 化合物对人TLR 7和TLR 8的激动作用Table 2 The agonistic effects of compounds on human TLR 7 and TLR 8
Figure PCTCN2018103963-appb-000035
Figure PCTCN2018103963-appb-000035
“-”表示未测试"-" means not tested
结果显示：所有的化合物均表现出对人TLR7和TLR8的激动作用。The results showed that all of the compounds exhibited agonistic effects on human TLR7 and TLR8.
二.体内药效学筛选2. In vivo pharmacodynamic screening
1.化合物(I-17和I-21)对鼠源黑色素B16F10荷瘤增殖抑制作用1. Compound (I-17 and I-21) inhibits proliferation of murine melanin B16F10 tumor
实验方法：收集指数生长期的B16F10细胞，RPMI1640培养基重悬至适合浓度用于C57BL/6鼠皮下接种，荷瘤长至约100mm 3后分组，分别于第0天，第4天，第8天瘤内给药25μl(50μg)，对照组瘤内注射等体积溶剂。每周测量三 次小鼠肿瘤体积，试验结束后计算抑瘤率。其中，肿瘤体积计算公式：肿瘤体积(mm 3)＝0.5×(肿瘤长径×肿瘤短径 2)。抑瘤率(％)＝(1-T(药物组瘤体积)/C(溶剂组瘤体积))*100。 Experimental method: B16F10 cells in the exponential growth phase were collected, and the RPMI1640 medium was resuspended to the appropriate concentration for subcutaneous inoculation of C57BL/6 mice. The tumors were grown to about 100 mm 3 and grouped on day 0, day 4, and eighth. 25 μl (50 μg) was administered intratumorally, and the control group was intratumorally injected with an equal volume of solvent. The tumor volume of the mice was measured three times per week, and the tumor inhibition rate was calculated after the end of the experiment. Among them, the tumor volume calculation formula: tumor volume (mm 3 ) = 0.5 × (tumor long diameter × tumor short diameter 2 ). Tumor inhibition rate (%) = (1-T (drug group tumor volume) / C (solvent group tumor volume)) * 100.
化合物I-17和I-21在B16F10荷瘤模型上具有很好肿瘤生长抑制作用(表3)，其抑制B16F10肿瘤的生长能力显著优于3M-052(图1)。Compounds I-17 and I-21 had excellent tumor growth inhibition on the B16F10 tumor-bearing model (Table 3), which significantly inhibited the growth of B16F10 tumors over 3M-052 (Fig. 1).
表3 化合物在B16F10荷瘤模型上的抑瘤率Table 3 Inhibition rate of compounds on B16F10 tumor-bearing model
B16F10瘤株B16F10 tumor strain 抑瘤率Tumor inhibition rate
I-17I-17 75.8％75.8%
I-21I-21 85.1％85.1%
3M-0523M-052 45.7％45.7%
2.化合物I-21对鼠源结肠癌CT26.WT荷瘤增殖抑制作用2. Compound I-21 inhibits the proliferation of murine colon cancer CT26.WT tumor
实验方法：收集指数生长期的CT26.WT细胞，RPMI1640培养基重悬至适合浓度用于BABL/C鼠皮下接种，荷瘤长至约100mm 3后分组，分别于第0天，第4天，第8天，第12天瘤内给药25μl(3M-052和I-21各设6.25μg，12.5μg，25μg和50μg剂量组)，对照组瘤内注射等体积溶剂。每周测量三次小鼠肿瘤体积，试验结束后计算抑瘤率。肿瘤体积计算公式：肿瘤体积(mm 3)＝0.5×(肿瘤长径×肿瘤短径 2)。抑瘤率(％)＝(1-T(药物组瘤体积)/C(溶剂组瘤体积))*100。 Experimental method: CT26.WT cells in the exponential growth phase were collected, and the RPMI1640 medium was resuspended to the appropriate concentration for subcutaneous inoculation of BABL/C mice. The tumors were grouped up to about 100 mm 3 and grouped on day 0 and day 4, respectively. On day 8, on the 12th day, intratumoral administration of 25 μl (3M-052 and I-21 were set at 6.25 μg, 12.5 μg, 25 μg and 50 μg dose groups), and the control group was intratumorally injected with an equal volume of solvent. The tumor volume of the mice was measured three times per week, and the tumor inhibition rate was calculated after the end of the experiment. Tumor volume calculation formula: tumor volume (mm 3 ) = 0.5 × (tumor long diameter × tumor short diameter 2 ). Tumor inhibition rate (%) = (1-T (drug group tumor volume) / C (solvent group tumor volume)) * 100.
化合物I-21在小鼠CT26.WT荷瘤模型上6.25μg，12.5μg，25μg，50μg剂量组的抑瘤率分别为61.4％，96.2％，91.5％，86.6％；3M-052在CT26.WT荷瘤模型上6.25μg，12.5μg，25μg，50μg剂量组的抑瘤率分别为23.1％，86.7％，94.7％，80.1％。(图2)，同时3M-052和I-21各个剂量组均有荷瘤小鼠用药后，肿瘤彻底消失，达到治愈，I-21低剂量6.25μg组的治愈率达到40％，远优于3M-052在6.25μg剂量下10％的治愈率(表4)。The tumor inhibition rate of compound I-21 in the CT26.WT tumor-bearing model of 6.25μg, 12.5μg, 25μg, 50μg was 61.4%, 96.2%, 91.5%, 86.6%; 3M-052 in CT26.WT The tumor inhibition rates of the 6.25 μg, 12.5 μg, 25 μg, and 50 μg dose groups were 23.1%, 86.7%, 94.7%, and 80.1%, respectively. (Fig. 2), at the same time, all the 3M-052 and I-21 dose groups had tumor-bearing mice, the tumor disappeared completely and cured. The cure rate of I-21 low dose 6.25μg group was 40%, which was much better than The cure rate of 3M-052 at a dose of 6.25 μg was 10% (Table 4).
表4 化合物I-21在CT26.WT荷瘤模型上的治愈数Table 4 Number of cures of compound I-21 on CT26.WT tumor-bearing model
组别Group 第32天治愈只数The only number of cures on the 32nd day 治愈率％Cure rate%
对照(n＝10)Control (n=10) 00 00
3M-052 6.25μg(n＝10)3M-052 6.25μg (n=10) 11 1010
3M-052 12.5μg(n＝10)3M-052 12.5μg (n=10) 44 4040
3M-052 25μg(n＝10)3M-052 25μg (n=10) 66 6060
3M-052 50μg(n＝10)3M-052 50μg (n=10) 33 3030
I-21 6.25μg(n＝10)I-21 6.25μg (n=10) 33 4040
I-21 12.5μg(n＝10)I-21 12.5μg (n=10) 55 5050
I-21 25μg(n＝10)I-21 25μg (n=10) 55 5050
I-21 50μg(n＝10)I-21 50μg (n=10) 66 6060
3.化合物对鼠源前列腺癌RM-1荷瘤增殖抑制作用3. Compound inhibits proliferation of mouse prostate cancer RM-1 tumor
实验方法：收集指数生长期的RM-1细胞，RPMI1640培养基重悬至适合浓度用于C57BL/6鼠皮下接种，荷瘤长至约100mm 3后分组，分别于第0天，第4天，第8天瘤内给药25μl(50μg)，对照组瘤内注射等体积溶剂。每周测量三次小鼠肿瘤体积，试验结束后计算抑瘤率。肿瘤体积计算公式：肿瘤体积(mm 3)＝0.5×(肿瘤长径×肿瘤短径 2)。抑瘤率(％)＝(1-T(药物组瘤体积)/C(溶剂组瘤体积))*100。 Experimental method: RM-1 cells in the exponential growth phase were collected, and RPMI1640 medium was resuspended to the appropriate concentration for subcutaneous inoculation of C57BL/6 mice. The tumors were grown to about 100 mm 3 and grouped on day 0 and day 4, respectively. On the 8th day, 25 μl (50 μg) was intratumorally administered, and the control group was intratumorally injected with an equal volume of solvent. The tumor volume of the mice was measured three times per week, and the tumor inhibition rate was calculated after the end of the experiment. Tumor volume calculation formula: tumor volume (mm 3 ) = 0.5 × (tumor long diameter × tumor short diameter 2 ). Tumor inhibition rate (%) = (1-T (drug group tumor volume) / C (solvent group tumor volume)) * 100.
化合物3M-052和I-21在小鼠RM-1荷瘤模型上抑瘤率分别为29.2％和47.1％。显然，I-21优于3M-052(图3)。The tumor inhibition rates of compounds 3M-052 and I-21 on the mouse RM-1 tumor-bearing model were 29.2% and 47.1%, respectively. Obviously, I-21 is better than 3M-052 (Figure 3).
4.化合物对CT26.WT鼠源结肠癌皮下双侧荷瘤的增殖抑制作用4. The inhibitory effect of compound on the proliferation of CT26.WT mouse colon cancer subcutaneous tumor
实验方法：收集指数生长期的CT26.WT细胞，RPMI1640培养基重悬至适合浓度用于BABL/C鼠皮下接种左右两侧各接种1×10 6细胞，总瘤体积在150mm 3左右进行分组，药物处理组仅在一侧分别于第0天，第4天，第8天，和第12天瘤内给药25μl(50μg)。每周测量三次小鼠肿瘤体积，试验结束后计算抑瘤率。肿瘤体积计算公式：肿瘤体积(mm 3)＝0.5×(肿瘤长径×肿瘤短径 2)。抑瘤率(％)＝(1-T(药物组瘤体积)/C(溶剂组瘤体积))*100。 Experimental methods: CT26.WT cells in the exponential growth phase were collected, and RPMI1640 medium was resuspended to the appropriate concentration for inoculation of 1×10 6 cells on both sides of BABL/C mice subcutaneously, and the total tumor volume was grouped at 150 mm 3 . The drug-treated group was intratumorally administered with 25 μl (50 μg) on the 0th day, the 4th day, the 8th day, and the 12th day, respectively. The tumor volume of the mice was measured three times per week, and the tumor inhibition rate was calculated after the end of the experiment. Tumor volume calculation formula: tumor volume (mm 3 ) = 0.5 × (tumor long diameter × tumor short diameter 2 ). Tumor inhibition rate (%) = (1-T (drug group tumor volume) / C (solvent group tumor volume)) * 100.
化合物3M-052，I-17和I-21在小鼠CT26.WT双侧荷瘤模型上总抑瘤率分别为20.4％，52.8％和64.3％(图4)，I-17和I-21在鼠源结肠癌荷瘤模型上给药侧药效均显著优于3M-052(图5)，且I-17和I-21对远端(未给药侧)肿瘤的生长抑制作用也显著优于3M-052(图6)。The total tumor inhibition rates of compounds 3M-052, I-17 and I-21 on the CT26.WT bilateral tumor-bearing model in mice were 20.4%, 52.8% and 64.3%, respectively (Fig. 4), I-17 and I-21. The drug-effect side of the murine colon cancer tumor-bearing model was significantly better than that of 3M-052 (Fig. 5), and the growth inhibitory effects of I-17 and I-21 on the distal (non-administered side) tumor were also significant. Better than 3M-052 (Figure 6).
5.化合物对4T1肺转移瘤的抑制作用5. Inhibition of 4T1 lung metastasis by compounds
实验方法：雌性BabL/C小鼠在乳腺脂肪垫原位接种20μl的1×10 6的4T1细胞，当平均肿瘤体积约达到80-120mm 3时分组，分别于第0天，第4天，第8天瘤内给药25μl(各测试药设置50μg和12.5μg剂量组)，对照组瘤内注射等体积溶剂。于第14天麻醉处死动物，取出动物肺脏，解剖显微镜下计算肺结节数，并进行统计学分析。 Experimental method: Female BabL/C mice were inoculated with 20 μl of 1×10 6 4T1 cells in situ in the mammary fat pad, and grouped when the average tumor volume reached 80-120 mm 3 , respectively on day 0, day 4, 25 μl of intratumoral administration was given for 8 days (50 μg and 12.5 μg dose groups were set for each test drug), and the control group was intratumorally injected with an equal volume of solvent. The animals were anesthetized on the 14th day, the lungs of the animals were removed, and the number of lung nodules was calculated under a dissecting microscope and statistical analysis was performed.
相对于对照组，化合物I-21 12.5μg和50μg剂量组对4T1肺转移瘤的抑制率分别为39％和57％，而3M-052 12.5μg和50μg剂量组不仅不能减少4T1肺转移瘤的形成，反而显著性地促进了4T1细胞向肺部的转移，肺部转移结节数显著性多于对照组(图7)。Compared with the control group, the inhibitory rates of 4T1 lung metastases in the 12.5μg and 50μg groups of the compound I-21 were 39% and 57%, respectively, while the 3M-052 12.5μg and 50μg dose groups could not reduce the formation of 4T1 lung metastases. On the contrary, it significantly promoted the metastasis of 4T1 cells to the lungs, and the number of lung metastasis nodules was significantly higher than that of the control group (Fig. 7).
6.化合物对B16F10肺转移瘤的抑制作用6. Inhibition of compound on B16F10 lung metastasis
实验方法：C57BL/6小鼠第0天右侧后腿部肌肉接种肿瘤细胞(无水乙醇灭活)和药物的混合液(1.5×10 5B16F10细胞+50μg药物)，第3天尾静脉注射3x10 5B16F10细胞。尾静脉肿瘤细胞接种后，于第21天麻醉处死动物，取出动物肺脏，解剖显微镜下计数肺结节数，并进行统计学分析。 Experimental method: C57BL/6 mice were injected with tumor cells (anhydrous ethanol inactivated) and a mixture of drugs (1.5×10 5 B16F10 cells + 50 μg drug) on the right hind leg muscle on day 0, and the tail vein was injected on the third day. 3x10 5 B16F10 cells. After inoculation of the tail vein tumor cells, the animals were anesthetized on the 21st day, the lungs of the animals were taken out, the number of lung nodules was counted under a dissecting microscope, and statistical analysis was performed.
化合物I-2和I-21能够显著性地抑制B16F10肺部转移瘤的形成，抑制率分别为78.3％和79.6％(图8)。Compounds I-2 and I-21 significantly inhibited the formation of B16F10 pulmonary metastases with inhibition rates of 78.3% and 79.6%, respectively (Fig. 8).
本发明提供一类新的咪唑喹啉化合物，这类化合物是有效的TLR7和TLR8激动剂，并可以停留在注射部位以避免进入血液循环而产生激烈的全身性炎症反应。含在这类化合物的脂肪长链中的杂原子(氧、氮、硫)产生了预料不到的生物活性，使得这类新的咪唑喹啉化合物具有远强于3M-052的体外抗癌活性和体内抗癌药效。尤其令人惊讶的是，在4T1自发性转移瘤模型上，3M-052不仅不能抑制肿瘤向肺部的转移，反而促进其转移；与之相反，本发明提供的咪唑喹啉化合物在很大的程度上能抑制肿瘤向肺部的转移。这类新的咪唑喹啉化合物作为抗癌和抗病毒药物，前景非常光明。The present invention provides a new class of imidazoquinoline compounds which are potent TLR7 and TLR8 agonists and which can reside at the site of injection to avoid influx into the bloodstream and produce a fierce systemic inflammatory response. The heteroatoms (oxygen, nitrogen, sulfur) contained in the long chain of fats of such compounds produce unexpected biological activity, making such new imidazoquinoline compounds have far greater anticancer activity than 3M-052 in vitro. And anti-cancer effects in the body. Particularly surprisingly, in the 4T1 spontaneous metastasis model, 3M-052 not only failed to inhibit tumor metastasis to the lungs, but promoted its transfer; in contrast, the imidazoquinoline compounds provided by the present invention were large. To a certain extent, it can inhibit the metastasis of tumors to the lungs. The prospect of this new imidazoquinoline compound as an anticancer and antiviral drug is very bright.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the present invention.

Claims (21)

  1. 式(I)所表示的化合物，或其药学上可接受的盐：a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2018103963-appb-100001
    Figure PCTCN2018103963-appb-100001
    其中among them
    R为-(CH 2) mNR 1R 2、-(CH 2) nOR 3或-(CH 2) qSR 4； R is -(CH 2 ) m NR 1 R 2 , -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 ;
    R 1和R 2独立地选自氢和(C 1-C 17)烷基，但R 1和R 2不同时为氢； R 1 and R 2 are independently selected from hydrogen and (C 1 -C 17 )alkyl, but R 1 and R 2 are not simultaneously hydrogen;
    R 3为(C 1-C 17)烷基； R 3 is (C 1 -C 17 )alkyl;
    R 4为(C 1-C 17)烷基； R 4 is (C 1 -C 17 )alkyl;
    m为1、2、3、4、5、6、7、8、9或10；m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
    n为1、2、3、4、5、6、7、8、9或10；n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
    q为1、2、3、4、5、6、7、8、9或10。q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  2. 如权利要求1所述的化合物，其中，R为-(CH 2) mNR 1R 2；R 1和R 2独立地选自氢和(C 1-C 17)烷基，但R 1和R 2不同时为氢；m为1、2、3、4、5、6、7、8、9或10。 The compound according to claim 1, wherein R is -(CH 2 ) m NR 1 R 2 ; R 1 and R 2 are independently selected from hydrogen and (C 1 -C 17 )alkyl, but R 1 and R 2 is not hydrogen at the same time; m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  3. 如权利要求2所述的化合物，其中，R 1和R 2独立地选自氢和(C 1-C 15)烷基，但R 1和R 2不同时为氢；m为1、2、3、4、5、6、7、8、9或10，优选为1或3。 The compound according to claim 2, wherein R 1 and R 2 are independently selected from hydrogen and (C 1 -C 15 )alkyl, but R 1 and R 2 are not hydrogen at the same time; m is 1, 2, 3 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
  4. 如权利要求3所述的化合物，其中，R 1和R 2独立地选自(C 1-C 15)烷基。 The compound according to claim 3, wherein R 1 and R 2 are independently selected from (C 1 -C 15 )alkyl.
  5. 如权利要求1所述的化合物，其中，R为-(CH 2) nOR 3或-(CH 2) qSR 4；R 3和R 4为(C 1-C 17)烷基，n和q为1、2、3、4、5、6、7、8、9或10。 The compound according to claim 1, wherein R is -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 ; R 3 and R 4 are (C 1 -C 17 )alkyl, n and q It is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  6. 如权利要求5所述的化合物，其中，R为-(CH 2) nOR 3；R 3为(C 1-C 17)烷基；n为1、2、3、4、5、6、7、8、9或10。 The compound according to claim 5, wherein R is -(CH 2 ) n OR 3 ; R 3 is (C 1 -C 17 )alkyl; n is 1, 2, 3, 4, 5, 6, 7 8, 8, or 10.
  7. 如权利要求6所述的化合物，其中，R 3选自(C 1-C 15)烷基，优选(C 3-C 15)烷基，更优选(C 7-C 15)烷基，最优选(C 10-C 15)烷基；n为1、2、3、4、5、6、7、8、9或10，优选为1或3。 The compound according to claim 6, wherein R 3 is selected from (C 1 -C 15 )alkyl, preferably (C 3 -C 15 )alkyl, more preferably (C 7 -C 15 )alkyl, most preferably (C 10 -C 15 )alkyl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
  8. 如权利要求5所述的化合物，其中，R为-(CH 2) qSR 4；R 4选自(C 1-C 17)烷 基；q为1、2、3、4、5、6、7、8、9或10。 The compound according to claim 5, wherein R is -(CH 2 ) q SR 4 ; R 4 is selected from (C 1 -C 17 )alkyl; q is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  9. 如权利要求8所述的化合物，其中，R 4选自(C 1-C 15)烷基，优选(C 3-C 15)烷基，更优选(C 7-C 15)烷基，最优选(C 10-C 15)烷基；q为1、2、3、4、5、6、7、8、9或10，优选为1或3。 The compound according to claim 8, wherein R 4 is selected from (C 1 -C 15 )alkyl, preferably (C 3 -C 15 )alkyl, more preferably (C 7 -C 15 )alkyl, most preferably (C 10 -C 15 )alkyl; q is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 3.
  10. 如权利要求1所述的化合物，其选自：The compound of claim 1 selected from the group consisting of:
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(十三烷基)氨基]丁酰胺(I-1)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [methyl(tridecyl)amino]butanamide (I-1);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(十二烷基)氨基]丁酰胺(I-2)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [methyl(dodecyl)amino]butanamide (I-2);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(十四烷基)氨基]丁酰胺(I-3)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [Methyl (tetradecyl) amino] butanamide (I-3);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(十一烷基)氨基]丁酰胺(I-4)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [Methyl(undecyl)amino]butanamide (I-4);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[甲基(癸基)氨基]丁酰胺(I-5)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [methyl(indenyl)amino]butanamide (I-5);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[乙基(十二烷基)氨基]丁酰胺(I-6)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [ethyl (dodecyl) amino] butanamide (I-6);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[丙基(十二烷基)氨基]丁酰胺(I-7)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [propyl (dodecyl) amino] butanamide (I-7);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-[丁基(十二烷基)氨基]丁酰胺(I-8)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- [butyl (dodecyl) amino] butanamide (I-8);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二己氨基)丁酰胺(I-9)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (dihexylamino)butanamide (I-9);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二庚氨基)丁酰胺(I-10)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (diheptylamino)butanamide (I-10);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二辛氨基)丁酰胺(I-11)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (dioctylamino)butanamide (I-11);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二壬氨基)丁酰胺(I-12)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (diamino)butyric acid amide (I-12);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(二癸氨基)丁酰胺(I-13)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (diamino)butyric acid amide (I-13);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-[甲基(十五烷基)氨基]乙酰胺(I-14)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- [methyl(pentadecyl)amino]acetamide (I-14);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-[甲基(十四烷基)氨基]乙酰胺(I-15)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- [Methyl (tetradecyl) amino] acetamide (I-15);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-[甲基(十三烷基)氨基]乙酰胺(I-16)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- [methyl(tridecyl)amino]acetamide (I-16);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷氧基)丁酰胺(I-17)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (tridecyloxy) butanamide (I-17);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十二烷氧基)丁酰胺(I-18)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (dodecyloxy)butanamide (I-18);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷硫基)丁酰胺(I-19)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (tridecylthio)butanamide (I-19);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十一烷硫基)丁酰胺(I-20)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (undecylthio)butanamide (I-20);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十二烷硫基)丁酰胺(I-21)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (dodecylthio)butanamide (I-21);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十四烷硫基)丁酰胺(I-22)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (tetradecylthio)butanamide (I-22);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(癸硫基)丁酰胺(I-23)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (indolyl) butanamide (I-23);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-(十五烷硫基)乙酰胺(I-24)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- (pentadecanethio)acetamide (I-24);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-(十三烷硫基)乙酰胺(I-25)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- (tridecylthio)acetamide (I-25);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-2-(十四烷硫基)乙酰胺(I-26)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-2- (tetradecylthio)acetamide (I-26);
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十二烷基氨基)丁酰胺(I-27)；和N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (dodecylamino)butanamide (I-27); and
    N-[2-[2-[(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)氧基]乙氧基]乙基]-4-(十三烷基氨基)丁酰胺(I-28)；N-[2-[2-[(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)oxy]ethoxy]ethyl]-4- (tridecylamino)butanamide (I-28);
    或其药学上可接受的盐。Or a pharmaceutically acceptable salt thereof.
  11. 药物组合物，其包含有效剂量的权利要求1～10中任一项的式(I)化合物或者它们药学上可接受的盐。A pharmaceutical composition comprising an effective amount of a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.
  12. 如权利要求1～10中任一项所述的化合物或如权利要求11所述的药物组合物在制备用于治疗或者预防与激动TLR7和/或TLR8相关的疾病的药物中的 应用。Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for the preparation of a medicament for the treatment or prevention of a disease associated with agonistic TLR7 and/or TLR8.
  13. 如权利要求12所述的应用，其中所述的疾病为病毒感染或癌症。The use according to claim 12, wherein the disease is a viral infection or cancer.
  14. 如权利要求13所述的应用，其中所述的病毒选自乙型肝炎病毒(HBV)、艾滋病病毒(HIV)、呼吸道合胞病毒(RSV)、人类乳头瘤病毒(HPV)、流感病毒、丙型肝炎病毒(HCV)、乙型脑炎病毒、登革病毒、森林脑炎病毒、黄热病毒、西尼罗病毒、寨卡病毒、牛病毒性腹泻病毒、鄂木斯克出血热病毒、胡宁病毒、墨累山谷脑炎病毒和圣路易脑炎病毒。The use according to claim 13, wherein said virus is selected from the group consisting of hepatitis B virus (HBV), HIV (HIV), respiratory syncytial virus (RSV), human papillomavirus (HPV), influenza virus, C Hepatitis B virus (HCV), Japanese encephalitis virus, dengue virus, forest encephalitis virus, yellow fever virus, West Nile virus, Zika virus, bovine viral diarrhea virus, Omsk hemorrhagic fever virus, Hu Ning Virus, Murray Valley encephalitis virus and St. Louis encephalitis virus.
  15. 如权利要求13所述的应用，其中所述癌症选自骨癌类，包括：尤因肉瘤、骨肉瘤、软骨肉瘤；脑和CNS肿瘤，包括：听神经瘤、神经母细胞瘤、神经胶瘤；脊髓肿瘤；乳癌；内分泌癌类，包括：肾上腺皮质癌、胰腺癌、脑垂体癌、甲状腺癌、富甲状腺癌、胸腺癌、多发性内分泌癌；肺癌类：小细胞肺癌和非小细胞肺癌；胃肠和肝癌类，包括：胃癌、食道癌、小肠癌、结直肠癌、肝癌、肝外胆管癌、胃肠类癌性肿瘤、胆囊癌；泌尿生殖癌类，包括：睾丸癌、阴茎癌、前列腺癌；妇科癌类，包括：子宫颈癌、卵巢癌、阴道癌、子宫/子宫内膜癌、阴部癌、妊娠滋养细胞肿瘤、输卵管癌、子宫肉瘤；头部和颈部肿瘤类，包括：口腔癌、唇癌、唾腺癌、喉头癌、下咽癌、上咽癌、正咽癌、鼻癌、鼻窦癌、鼻咽癌；眼癌类，包括：视网膜母细胞瘤、葡萄膜黑色素瘤；皮肤癌类，包括：黑色素瘤、非黑色素瘤皮肤癌、梅克尔细胞癌；软组织肉瘤类，包括：儿童软组织肉瘤、成人软组织肉瘤、卡波希肉瘤；泌尿系统癌症，包括：肾癌、维尔姆斯瘤、膀胱癌、尿道癌和转移性细胞癌。The use according to claim 13, wherein the cancer is selected from the group consisting of bone cancer, including: Ewing's sarcoma, osteosarcoma, chondrosarcoma; brain and CNS tumors, including: acoustic neuroma, neuroblastoma, neuroglioma; Spinal cord tumor; breast cancer; endocrine cancer, including: adrenal cortical cancer, pancreatic cancer, pituitary cancer, thyroid cancer, thyroid-rich cancer, thymic cancer, multiple endocrine cancer; lung cancer: small cell lung cancer and non-small cell lung cancer; stomach Intestinal and liver cancer, including: gastric cancer, esophageal cancer, small intestine cancer, colorectal cancer, liver cancer, extrahepatic cholangiocarcinoma, gastrointestinal carcinoid tumor, gallbladder cancer; genitourinary cancer, including: testicular cancer, penile cancer, prostate Cancer; gynecological cancer, including: cervical cancer, ovarian cancer, vaginal cancer, uterus / endometrial cancer, genital cancer, gestational trophoblastic tumor, fallopian tube cancer, uterine sarcoma; head and neck tumors, including: oral Cancer, lip cancer, salivary gland cancer, laryngeal cancer, hypopharyngeal cancer, upper pharyngeal cancer, orthopharyngeal cancer, nasal cancer, sinus cancer, nasopharyngeal cancer; eye cancer, including: retinoblastoma, uveal melanin Skin cancer, including: melanoma, non-melanoma skin cancer, Merkel cell carcinoma; soft tissue sarcoma, including: children with soft tissue sarcoma, adult soft tissue sarcoma, Kaposi sarcoma; urinary cancer, including: kidney cancer, Wilms tumor, bladder cancer, urethral cancer, and metastatic cell carcinoma.
  16. 权利要求1所述的式(I)化合物的制备方法，包括使式(II)所示的化合物与式(III)所示的化合物或其盐反应，A process for producing a compound of the formula (I) according to Claim 1, which comprises reacting a compound represented by the formula (II) with a compound represented by the formula (III) or a salt thereof,
    Figure PCTCN2018103963-appb-100002
    Figure PCTCN2018103963-appb-100002
    其中among them
    R为-(CH 2) mNR 1R 2、-(CH 2) nOR 3或-(CH 2) qSR 4； R is -(CH 2 ) m NR 1 R 2 , -(CH 2 ) n OR 3 or -(CH 2 ) q SR 4 ;
    R 1、R 2、R 3和R 4独立地选自(C 1-C 17)烷基； R 1 , R 2 , R 3 and R 4 are independently selected from (C 1 -C 17 )alkyl;
    m、n、q如权利要求1所定义。m, n, q are as defined in claim 1.
  17. 权利要求1所述的式(I)化合物的制备方法，包括脱除式(IV)所示的化合物的氨基保护基，A process for the preparation of a compound of formula (I) according to claim 1 which comprises removing an amino-protecting group of a compound of formula (IV),
    Figure PCTCN2018103963-appb-100003
    Figure PCTCN2018103963-appb-100003
    其中，among them,
    R为-(CH 2) mNR 1R 2，R 1选自(C 1-C 17)烷基，R 2为氢； R is -(CH 2 ) m NR 1 R 2 , R 1 is selected from (C 1 -C 17 )alkyl, and R 2 is hydrogen;
    R 5为氨基保护基，优选苄基； R 5 is an amino protecting group, preferably a benzyl group;
    m如权利要求1所定义。m is as defined in claim 1.
  18. 如权利要求17所述的制备方法，其中式(IV)化合物通过以下方法进行制备，包括使式(II)所示的化合物与式(V)所示的化合物反应，The process according to claim 17, wherein the compound of the formula (IV) is produced by reacting a compound represented by the formula (II) with a compound represented by the formula (V),
    Figure PCTCN2018103963-appb-100004
    Figure PCTCN2018103963-appb-100004
    其中，among them,
    R 1选自(C 1-C 17)烷基；R 5为氨基保护基，优选苄基； R 1 is selected from (C 1 -C 17 )alkyl; R 5 is an amino protecting group, preferably benzyl;
    m如权利要求1所定义。m is as defined in claim 1.
  19. 如权利要求16或18所述的制备方法，其中式(II)化合物通过以下方法进行制备，包括：The production method according to claim 16 or 18, wherein the compound of the formula (II) is produced by the following method, comprising:
    步骤一：使式(VII)所示的化合物与式(VIII)所示的化合物反应得到式(VI)所示的化合物，Step 1: reacting a compound represented by the formula (VII) with a compound represented by the formula (VIII) to obtain a compound represented by the formula (VI),
    Figure PCTCN2018103963-appb-100005
    Figure PCTCN2018103963-appb-100005
    其中，R 6为氨基保护基，优选苄氧羰基(Cbz)。 Wherein R 6 is an amino protecting group, preferably benzyloxycarbonyl (Cbz).
    步骤二：在式(VI)所示的化合物的喹啉环上引入氨基，然后脱除支链的氨基保护基，Step 2: introducing an amino group onto the quinoline ring of the compound represented by the formula (VI), and then removing the branched amino protecting group,
    Figure PCTCN2018103963-appb-100006
    Figure PCTCN2018103963-appb-100006
    其中，R 6为氨基保护基，优选苄氧羰基(Cbz)。 Wherein R 6 is an amino protecting group, preferably benzyloxycarbonyl (Cbz).
  20. 式(II)化合物：Compound of formula (II):
    Figure PCTCN2018103963-appb-100007
    Figure PCTCN2018103963-appb-100007
  21. 式(IV)化合物：Compound of formula (IV):
    Figure PCTCN2018103963-appb-100008
    Figure PCTCN2018103963-appb-100008
    其中，R 1选自(C 1-C 17)烷基；R 5为氨基保护基，优选苄基； Wherein R 1 is selected from (C 1 -C 17 )alkyl; R 5 is an amino protecting group, preferably benzyl;
    m如权利要求1所定义。m is as defined in claim 1.
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WO2020160054A1 (en) * 2019-02-01 2020-08-06 Canwell Biotech Limited Imidazoquinoline amine derivatives, pharmaceutical composition, use thereof
US10954239B2 (en) 2019-02-01 2021-03-23 Canwell Biotech Limited Imidazoquinoline amine derivatives, pharmaceutical compositions and therapeutic methods thereof
CN114585621A (en) * 2019-02-01 2022-06-03 康威(广州)生物科技有限公司 Imidazoquinoline amine derivative, and pharmaceutical composition and application thereof
CN114585621B (en) * 2019-02-01 2023-11-14 康威(广州)生物科技有限公司 Imidazoquinoline amine derivative, pharmaceutical composition and application thereof
WO2022037631A1 (en) * 2020-08-21 2022-02-24 浙江海正药业股份有限公司 Heterocyclic derivative and preparation method therefor and use thereof

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