WO2010037249A1 - 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, their preparation methods, compositions and use - Google Patents

5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, their preparation methods, compositions and use Download PDF

Info

Publication number
WO2010037249A1
WO2010037249A1 PCT/CN2009/000970 CN2009000970W WO2010037249A1 WO 2010037249 A1 WO2010037249 A1 WO 2010037249A1 CN 2009000970 W CN2009000970 W CN 2009000970W WO 2010037249 A1 WO2010037249 A1 WO 2010037249A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
alkyl
disubstituted
alkoxy
Prior art date
Application number
PCT/CN2009/000970
Other languages
French (fr)
Chinese (zh)
Inventor
龙亚秋
曾立凡
王勇
丁健
Original Assignee
中国科学院上海药物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院上海药物研究所 filed Critical 中国科学院上海药物研究所
Publication of WO2010037249A1 publication Critical patent/WO2010037249A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medical technology, and in particular to 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compounds, and to 5,8-disubstituted-1,6-diaza A method for preparing a naphthalene-7-carbonylamide compound.
  • Various tumor cells (MDA-MB-435, Hctl l6p53-/-, Hctl l6p53+/+, Mcf-7, NIH189, SkBr-3, LnCap, LnHer, HT29, HEY) inhibit growth experiments and show that the compounds are good.
  • the anti-tumor activity can be used to treat diseases caused by malignant proliferation of tumor cells.
  • the invention further relates to a pharmaceutical composition comprising the above compounds.
  • Cancer tumor, tumor, neoplasm
  • human tumors are divided into two categories: benign and malignant.
  • Benign neoplasm is called a tumor.
  • Malignant neoplasm is divided into two groups: Carcinoma, Sarcoma, Blastoma, and Leukemia.
  • the main differences between benign tumors and malignant tumors are: benign tumors are enclosed in the capsule, have slow proliferation, do not invade surrounding tissues, ie do not metastasize; malignant tumors do not entrap in the capsule, proliferate rapidly, and can invade surrounding tissues (metastasis). The potential danger is great.
  • Malignant tumors are a common and frequently-occurring disease that seriously threaten human health. Death caused by malignant tumors is the second highest among all diseases, second only to cardiovascular and cerebrovascular diseases.
  • Antineoplastic drugs refer to drugs against malignant tumors, also known as anticancer drugs. Since the use of nitrogen mustard in the treatment of malignant tumors in the 1940s, the chemotherapy of tumors has been greatly developed. It has entered the stage of combination therapy and comprehensive chemotherapy by a single chemotherapy, and can successfully cure patients or Prolonging the lifespan of patients, therefore, anti-tumor drugs play an increasingly important role in cancer treatment. In addition, in the research of tumors, the research on tumor characteristics and the research progress of molecular biology and cell biology have provided new directions and new targets for the research of anti-tumor drugs, and successively produced a batch. A compound having a novel chemical structure or a unique mechanism of action.
  • Tyrosine protease kinase is an important factor in the signal transduction process and participates in a series of cell functions, which are closely related to cell growth, differentiation and proliferation [Microsc Res Tech. 2003 Jan l;60(l):70-5], [Trends Pharmacol Sci. 2002 Dec;23(12):576-82] contradictory effects.
  • quinoline vascular endothelial growth factor inhibitors are disclosed in WO 98/13350. Also included are 1,8-naphthyridine derivatives, such as Example 53 in this patent: 2-acetamido-5-(2-fluoro-5-hydroxy-4-methylaniline)-1,8 - diazepine.
  • a 4-hydroxyquinoline-2-carboxylic acid amine derivative is disclosed in WO 99/32450 for the treatment of herpes virus infection.
  • 8-hydroxyquinoline-7-carboxylic acid amine derivatives are disclosed in WO 98/11073 for the treatment of herpes virus infection.
  • 8-hydroxy-1,6-naphthyridin-7-carboxamides are disclosed in WO 02/30931 for the treatment of HIV-1 viral infections.
  • One object of the present invention is to disclose a class of 5,8-disubstituted-1,6-diazaphthalen-7-carbonylamide compounds having novel structures and potent antitumor activities.
  • Another object of the present invention is to provide a process for producing the above 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound.
  • Still another object of the present invention is to provide the use of the above 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compounds in the field of medicine, which can be used for the treatment of various diseases including breast cancer. Tumor disease.
  • a further object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a 5,8-disubstituted-1,6-diazaphthalen-7-carbonylamide compound.
  • the antitumor activity of the 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound is as shown in the following structural formula I:
  • A is: (1) a benzene ring; (2) a C 8 -C 10 ⁇ synthesized double carbon ring, one of which is a benzene ring and the other is a saturated or unsaturated ring; (3) 8 to 10 atoms ⁇ a ring which is synthesized and contains 0-3 heteroatoms selected from N, 0 and S, one of which is an aromatic or aromatic heterocyclic ring, and the other is a saturated or unsaturated carbocyclic or heterocyclic ring; (4) Containing 1 to 3 heteroatoms selected from N, 0 and S a five- or six-membered aromatic heterocyclic ring; or (5) a three- to seven-membered aliphatic ring containing 0 to 3 hetero atoms selected from N, 0 and S;
  • R 2 , R 3 , R 4 and R 6 are each independently hydrogen, halogen, hydroxy, decyl, -CF 3 , -CN, -N0 2 or substituted or each independently substituted with 1 to 3 substituents.
  • R 5 is hydrogen, hydroxy or the following groups which are unsubstituted or substituted by 1 to 3 independent substituents: dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, dC 6 alkoxy, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, phenyl, benzyl, naphthyl, C 5 -C 1Q aromatic heterocyclic or C 4 -C 7 saturated heterocyclic
  • the heterocyclic ring includes 1-3 heteroatoms selected from N, 0 and S; the substituent is selected from the group consisting of dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, Halogen, amino, nitro, thiol, hydroxy, -CN and -CF 3 ;
  • B is: (l) R d or R e ; ( 2 ) a ternary to seven-membered aliphatic ring containing 0 to 3 hetero atoms selected from N, 0 and S, and 1-3 each independently on the heterocyclic ring Substituting substituents from R d or R e ; ( 3 ) 5- or 6-membered heteroaryl rings containing 1-3 heteroatoms selected from N, 0 and S, 1-3 on heterocycle Each of the substituents independently selected from R d or R e ; or ( 4 ) a ring synthesized by 8 to 10 carbon atoms, and containing 0 to 3 hetero atoms selected from N, 0 and S, One of which is an aromatic ring, the other is a saturated or unsaturated carbocyclic or heterocyclic ring; and the heterocyclic ring has 1-3 independently substituents selected from R d or R e ;
  • R a is hydrogen, dC 6 alkyl, C 3 -C 8 cycloalkyl or C 6 -C 1 () arene;
  • R b is hydrogen, hydroxy or the following groups which are unsubstituted or substituted by 1 to 3 substituents: dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, dC 6 alkoxy, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, phenyl, phenol, benzyl, naphthyl, C 5 -d.
  • An aromatic heterocyclic group or a C 4 -C 7 saturated heterocyclic group comprising 1 to 3 hetero atoms selected from N, 0 and S; said substituent being selected from the group consisting of the following atoms or groups: dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, halogen, Amino, nitro, thiol, hydroxy, -CN and -CF 3 ;
  • R 2 , R 6 and B have the same definitions as in Formula I, and further preferably: And each independently are hydrogen, halogen, -CN, -CF 3 , -N0 2 , hydroxy, amino, Ci-C 6 alkylamino, dC 6 alkylheterocyclylamino, C 6 -C 10 arylamino, dC 8 alkoxy, C 3 -C 8 cycloalkoxy, Ci-C 6 alkylsiloxy, Ci-C 6 alkylheterocyclyl Ci-Cs alkyloxy, heterocyclyl dC 8 alkyl An oxy group, a heterocyclic carbonyl group dC 8 alkyloxy group or a C 6 -C 10 aryl dC 8 alkyloxy group; wherein the heterocyclic group means 1 to 3 kinds of impurities selected from N, 0 and S A ternary to seven-membered aliphatic ring of atoms; R 6 is hydrogen,
  • the structural formula II is further preferably:
  • each independently are hydrogen, halogen, -CN, -CF 3 , amino, dC 4 alkylamino, dC 4 alkylheterocyclylamino, dC 4 alkoxy, C 3 -C 6 cycloalkoxy, dC a 4- alkylsilyloxy group, a dC 4 alkylheterocyclyl group dC 4 alkyloxy group, a heterocyclic group dC 4 alkyloxy group or a heterocyclic carbonyl group dC 4 alkyloxy group; wherein the heterocyclic group means 1 to 2 ternary to seven-membered aliphatic rings selected from heteroatoms of N and 0;
  • R 6 is hydrogen, halogen, or
  • B is an amino dC 6 alkyl group, dC 4 alkylaminoalkyl group, alkoxycarbonylalkyl group, dC 4 alkylsulfonylaminoalkyl group, benzoylamino dC 4 alkyl group, aminophenyl group,
  • R is 11 or dC 4 alkyl.
  • R 2 and R 6 have the same meanings as in the above formula II.
  • the 5,8-disubstituted-1,6-diazaphthalene-7-carbonylamide compound of the formula I is the following compound:
  • R 6 and B have the same definitions as in Formula I;
  • R 7 is Wherein A, L, Ri, R 2 , R 3 and R 4 have the same definitions as in the formula I, and are preferably a group shown in the table.
  • Reaction reagents and conditions (a) isopropanol, reflux, 68%; (b) thionyl chloride, reflux; (c) sodium borohydride, tetrahydrofuran, 0 ° C, two-step yield 38%; TsNHCH 2 COOCH 3 , DEAD (diethyl azodicarboxylate), triphenylphosphine, tetrahydrofuran, 0 ° C; (e) sodium methoxide, methanol, 0 ° C ⁇ room temperature, two-step yield of 65%; NBS (N-bromosuccinimide), dichloromethane, room temperature, yield 85%; (g) amine, toluene, reflux 24 hours, yield 88%; (h) TsCl, triethylamine, Trichloromethane, yield 90%; (i) amine, tetrahydrofuran, reflux, yield 75%-85%; (j) LiOH solution/methanol, or NaOH
  • the synthesis method of the compound S28 is as follows: Compound S3-1 and NIS (N-iodosuccinimide) are stirred at room temperature for 1 hour in dichloromethane to obtain a compound S28-1, a compound S28-1 and TsCl, Triethylamine is refluxed in dichloromethane for 5 hours to obtain compound S28-2. Compound S28-2 and trans-1,4-cyclohexanediamine are heated under reflux in triethylamine and tetrahydrofuran for 8 hours to obtain compound S28-3.
  • NIS N-iodosuccinimide
  • the synthesis method of the compound S30 is as follows: Compound 12 and a single Boc-protected trans 1,4-cyclohexanediamine are heated under reflux in K 2 CO 3 and tetrahydrofuran for 8 hours to obtain a compound S30-1, a compound S30-1 Compound S30-2 was formed in IN NaOH solution / THF at 60 ° for 10 h. Compound S30-2 was reacted with the corresponding amine in EDCI, HOBT, DIPEA and dichloromethane at room temperature for 3 h to give compound S30-3. Compound S30-3 was removed from Boc in 20% trifluoroacetic acid / dichloromethane to give 5, 8-disubstituted-1,6-naphthyridin-7-carbonylamide compound S30.
  • the compounds represented by the above formula I have potent inhibitory activity against the following cells within 20 ⁇ M: MDA-MB-435 , Hctl l6 ⁇ 53-/-, Hctll6p53+/+, Mcf-7, NIH 189, SkBr-3, LnCap, LnHer, HT 29, HEY. Therefore, the compound represented by the structural formula I can effectively treat MDA-MB-435, Hctll6 p53-/-, Hctll6p53+/+, Mcf-7, NIH 189, SkBr-3, LnCap, LnHer, HT 29, HEY tumor cells. A disease caused by malignant proliferation.
  • the pharmaceutically acceptable pharmaceutical composition containing the compound represented by the structural formula I is also effective for the treatment of MDA-MB-435, Hctl 16 p53-/-, Hctl 16 p53+/+, Mcf-7, NIH 189, SkBr-3, LnCap, LnHer, HT 29, HEY A disease caused by malignant proliferation of tumor cells.
  • Typical compounds of the invention and their targeting to a variety of tumor cells (MDA-MB-435, Hctll6p53-/-, Hctll6p53+/+, Mcf-7, NIH 189, SkBr-3, LnCap, LnHer, HT 29, HEY)
  • the semi-growth inhibitory activity data (IC 5 ) were determined under standard conditions.
  • RPMII640 was purchased from Gibco; sulforhodamine B was purchased from Sigma; trichloroacetic acid (TCA), acetic acid (HAC) and Tris base unbuffer were of analytical grade.
  • human breast cancer cells MDA-MB-435 and SKBr-3 in logarithmic growth phase were inoculated into 96-well culture plates at 90 ⁇ l/well, adherently grown for 24 hours, and then ⁇ /well. Three holes are provided for each concentration. The corresponding concentration of physiological saline vehicle control and cell-free withering holes were set.
  • the tumor cells were cultured at 37 ° C, 5% CO 2 for 72 hours, then the culture solution was decanted, and the cells were fixed with 10% cold TCA, left at 4 ° C for 1 hour, and washed 5 times with steamed water, naturally in the air. dry.
  • Inhibition rate (A492 control well - A492 administration well) / A492 Control well ⁇ 100% Activity data are shown in Tables 1 and 2. A space in the table indicates that no relevant tests have been performed and no relevant data. Table 1 Antitumor activity data of compounds against various tumor cell lines (ICso/ ⁇ )
  • Representative compounds S24, S26 of the present invention show good anti-tumor activity IC 5 o of 1 ⁇ for various tumor cells.
  • the compound represented by the structural formula I has good inhibitory activity against various tumor cells, and the applicant further develops the antitumor mechanism of the 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound.
  • ELISA enzyme-linked immunosorbent assay
  • the compound of the present invention is effective for the above tyrosine kinase and is a novel structural tyrosine kinase inhibitor.
  • S25 has the best inhibitory activity against Src, and the inhibition rate is as high as 90% at 10 ⁇ .
  • the ifi-NMR spectral data of the compounds were measured using a Varian Mercury-300 MHz or Varian Mercury-400 MHz NMR, elemental analysis using a Vario EL meter, melting point determined by Buchi-510 capillary method, and temperature uncorrected.
  • Infrared spectra were determined by a Bio-Rad FTS-185 infrared light meter; mass spectrometry EI-MS was determined using a Finnigan MAT 95 mass spectrometer, ESI-MS using a Finnigan LCQ Deca mass spectrometer. Specific optical rotation was measured by P-1030 (A012360639) automatic polarimeter. Flash column chromatography was performed on silica gel H (10-40 ⁇ ). For purification of reagents, Purification of laboratory Chemicals; D. D. Perrin; W. L. F. Armarego and D. R. Perrin Eds., Pergamon Press: Oxiford, 1980.
  • the purity of some of the compounds was determined by two-system analysis HPLC.
  • the model number of the column is: Vydac C 18 column (10x250 mm). 254nm UV detector.
  • the solvent system used was: 0.05% trifluoroacetic acid in methanol / 0.05% trifluoroacetic acid in aqueous solution with a gradient of 30% to 90% over 20 minutes at a flow rate of 2 mL/min.
  • the solvent system used was: 0.05% trifluoroacetic acid, 95% aqueous acetonitrile / 0.05% aqueous trifluoroacetic acid solution, gradient from 30% to 90% in 20 minutes, flow rate 2 mL/min
  • the compound 5 (8.89 mmol) obtained in the previous reaction was dissolved in 50 mL of anhydrous methanol and cooled to 0 °C.
  • Sodium methoxide (1.681 g, 31.123 mmol) was added slowly. Remove the ice bath and stir for 3 hours.
  • the solvent was spun off, 20 mL of water, 20 mL of ethyl acetate was added and the organic phase was stripped with saturated sodium carbonate.
  • the aqueous phases were combined, the pH was adjusted to 7, the aqueous phase was maintained at pH 7 and extracted with dichloromethane for 5 times.
  • p-Toluene-cross-acid chloride (268 mg, 1.4 mmol) was added to a solution of compound 8-1 (283 mg, 0.75 mmol), triethylamine (161.92 mg, 1.6 mmol) in 5 mL chloroform. After stirring at 50 ° C for 5 hours, it was washed successively with 5 mL of saturated ammonium chloride, saturated brine, and dried.
  • the preparation method of the compound S3-1 is similar to the preparation method of the compound 8-1 except that the compound 6 is used instead of the compound 7-1.
  • the preparation method of the compound S3-2 was similar to the preparation method of the compound 9-1 except that the compound S3-1 was used instead of the compound 8-1.
  • the preparation method of the compound S6 is similar to the preparation method of the compound SI, and the final step is to replace the propylenediamine with N-(3-aminopropyl)-methanesulfonamide. Yellow solid, Yield: 75-85%.
  • the preparation method of the compound S8 is similar to the preparation method of the compound SI, and the last step is to use the second method.
  • the reaction was cooled to room temperature, filtered, the filter cake washed with 10mL of chloroform, was added the filtrate by rotary evaporation 20 mL of chloroform, 1.2 g of EDTA, 120 mL of water, stirred for 16 hours, and the organic phase was dried over anhydrous sodium chloride.
  • the preparation method of the compound S16-2 was similar to the preparation method of the compound 9-1 except that the compound S16-1 was used instead of the compound 8-1.
  • the preparation method of the compound S17-1 was similar to the preparation method of the compound 8-1 except that benzylamine was used instead of p-fluorobenzylamine. Yellow solid, yield: 75-85%.
  • the preparation method of the compound S17-2 was similar to the preparation method of the compound 9-1 except that the compound S17-1 was used instead of the compound 8-1.
  • the preparation method of the compound S18-1 is similar to the preparation method of the compound 8-1 except that the methoxy group is used.
  • the benzylamine replaces the p-fluorobenzylamine. Yellow solid, yield: 75-85%.
  • the preparation method of the compound S18-2 was similar to the preparation method of the compound 9-1 except that the compound S18-1 was used instead of the compound 8-1.
  • the preparation method of the compound S19-1 was similar to the preparation method of the compound 8-1 except that 5-(1,3-benzodioxan)methylamine was used instead of p-fluorobenzylamine. Yellow solid, yield: 75-85%.
  • the preparation method of the compound S19-2 was similar to the preparation method of the compound 9-1 except that the compound 8-1 was replaced with S19-1.
  • the preparation of the compound S20-1 was carried out in a similar manner to the preparation of the compound 8-1 except that (S)-l-(4-fluorophenyl)ethylamine was used instead of p-fluorobenzylamine. Yellow solid, Yield: 75-85%.
  • the preparation method of the compound S20-2 was similar to the preparation method of the compound 9-1 except that the compound S20-1 was used instead of the compound 8-1.
  • the preparation method of the compound S21-1 was similar to the preparation method of the compound 8-1 except that 2-furanmethylamine was used instead of p-fluorobenzylamine. Yellow solid, Yield: 75-85%.
  • the preparation method of the compound S21-2 was similar to the preparation method of the compound 9-1 except that the compound S21-1 was used instead of the compound 8-1.
  • the preparation method of the compound S22-1 was similar to the preparation method of the compound 8-1 except that 3-methoxybenzylamine was used instead of p-fluorobenzylamine. Yellow solid, yield: 75-85%.
  • the preparation method of the compound S22-2 was similar to the preparation method of the compound 9-1 except that the compound S22-1 was used instead of the compound 8-1.
  • the preparation method of the compound S23-1 was similar to the preparation method of the compound 8-1 except that 2-phenylethylamine was used instead of p-fluorobenzylamine. Yellow solid, Yield: 75-85%.
  • EI-MS m/z: 371 (M) + , 373(M+2) + .
  • the preparation method of the compound S23-2 was similar to the preparation method of the compound 9-1 except that the compound 8-1 was replaced with S23-1.
  • the preparation method of the compound S24-2 was similar to the preparation method of the compound 9-1 except that the compound S24-1 was used instead of the compound 8-1.
  • the preparation method of the compound S25-2 was similar to the preparation method of the compound 9-1 except that the compound 8-1 was replaced with S25-1.
  • Triphosgene (150 mg, 0.735 mmol) was added to a solution of compound 11 (0.234 mmol, 45 mg), DIPEA (0.398 mmol, 160 L) in DMF. After stirring for 1 hour, an excess of aniline was added at room temperature, and after stirring for 16 hours, 50 mL of saturated brine and dichloromethane were added, and the organic phase was washed with 5 x 50 mL of saturated brine. Dry with anhydrous sodium sulfate, filter, and spin dry to obtain the crude compound S26-1, which was used directly in the next step.
  • the preparation method of the compound S26-2 is similar to the preparation method of the compound 9-1 except that the compound is used. S26-1 is substituted for compound 8-1. White solid, Yield: 85-95%.
  • the method for producing the compound 14 was similar to the method for producing the compound 11, except that the compound 13 was used instead of the compound 7-1. Light green solid, Yield: 85-95%.
  • the preparation method of the compound S28-1 was similar to the preparation method of the compound 7-1 except that the compound S3-1 was used instead of the compound 6, and NIS was used instead of the NBS. Yellow solid.
  • the preparation method of the compound S28-2 was similar to the preparation method of the compound 9-1 except that the compound S28-1 was used instead of the compound 8-1.
  • the preparation method of the compound S28-3 is similar to the preparation method of the compound S15 except that the compound S28-2 is used instead of the compound 9-1. Yellow-green solid, Yield: 75-85%.
  • the preparation method of the compound S30-1 was similar to the preparation method of the compound S15 except that K 2 CO 3 was used instead of triethylamine. Yellow-green solid, Yield: 75-85%.
  • the preparation method of the compound S30-3 was similar to the preparation method of the compound 15, except that the compound S30-2 was used instead of the compound 14. Yellow-green solid, Yield: 87%.
  • the preparation method of the compound S31 is similar to the preparation method of the compound S25.

Abstract

The invention discloses 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, their preparation methods, their use and the pharmaceutical compositions comprising the compounds. More specifically, the invention discloses 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds with the following structure represented by formula I, their preparation methods and their use. The suppressing tests of several kinds of tumor cell lines (human breast cancer cell MDA-MB-435, p53 absent poorly-differentiated colonic adenocarcinoma cell Hct116p53-/-, p53 enriched poorly-differentiated colonic adenocarcinoma cell Hct116p53+/+, human breast cancer cell Mcf-7, NIH189, human breast cancer cell SKBr-3, prostate cancer cell LnCap, LnHer, human colon cancer cell HT29, human ovarian cancer cell HEY) show that the compounds possess good inhibiting activities and could be used in treating the diseases induced by tumor cell malignant proliferation. The invention also discloses the pharmaceutical compositions comprising the above-said compounds.

Description

5,8-·^代 -1,6-二氮杂萘 酰胺类化合物及其制备方法、 组合物和 用途 技术领域  5,8-·^ generation-1,6-diazaphthalenamide compound and preparation method, composition and use thereof
本发明涉及医药技术领域， 具体涉及 5,8-二取代 -1,6-二氮杂萘 -7-羰酰 胺类化合物， 本发明还涉及 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物的 制备方法。 多种肿瘤细胞（MDA-MB-435 , Hctl l6p53-/-, Hctl l6p53+/+, Mcf-7, NIH189, SkBr-3 , LnCap, LnHer, HT29, HEY )抑制生长实验表 明， 该类化合物具有良好的抗肿瘤活性， 可以用于治疗由肿瘤细胞恶性增 殖引起的疾病。 本发明还涉及包含上述化合物的药物组合物。  The present invention relates to the field of medical technology, and in particular to 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compounds, and to 5,8-disubstituted-1,6-diaza A method for preparing a naphthalene-7-carbonylamide compound. Various tumor cells (MDA-MB-435, Hctl l6p53-/-, Hctl l6p53+/+, Mcf-7, NIH189, SkBr-3, LnCap, LnHer, HT29, HEY) inhibit growth experiments and show that the compounds are good. The anti-tumor activity can be used to treat diseases caused by malignant proliferation of tumor cells. The invention further relates to a pharmaceutical composition comprising the above compounds.
背景技术  Background technique
肿瘤 （Cancer, tumor, neoplasm )的特点是细胞或变异细胞异常增殖， 常形成肿块。 临床上将人体瘤分为良性和恶性两大类。 良性肿瘤 （Benign neoplasm )称为瘤。 恶性肿瘤 ( Malignant neoplasm )才艮据发生部位不同， 又分为： 癌 （ Carcinoma )、 肉瘤 （ Sarcoma )、 母细月包瘤 （Blastoma )、 白血 病（ Leukemia )。 良性肿瘤和恶性肿瘤的主要差别为： 良性肿瘤包在荚膜内， 增殖慢， 不侵入周围组织， 即不转移； 恶性肿瘤不包在荚膜内， 增殖迅速， 能侵入周围组织 （转移）， 潜在的危险大。 恶性肿瘤是一种严重威胁人类健 康的常见病和多发病， 人类因恶性肿瘤而引起的死亡是所有疾病死亡率的 第二位， 仅次于心脑血管疾病。  Cancer (tumor, tumor, neoplasm) is characterized by abnormal proliferation of cells or mutant cells, often forming a mass. Clinically, human tumors are divided into two categories: benign and malignant. Benign neoplasm is called a tumor. Malignant neoplasm is divided into two groups: Carcinoma, Sarcoma, Blastoma, and Leukemia. The main differences between benign tumors and malignant tumors are: benign tumors are enclosed in the capsule, have slow proliferation, do not invade surrounding tissues, ie do not metastasize; malignant tumors do not entrap in the capsule, proliferate rapidly, and can invade surrounding tissues (metastasis). The potential danger is great. Malignant tumors are a common and frequently-occurring disease that seriously threaten human health. Death caused by malignant tumors is the second highest among all diseases, second only to cardiovascular and cerebrovascular diseases.
抗肿瘤药是指抗恶性肿瘤的药， 又称抗癌药。 自四十年代氮芥用于治 疗恶性肿瘤以来， 对于肿瘤的化学治疗已经有了很大的发展， 已由单一的 化学治疗进入了联合治疗和综合化疗的阶段， 并且能成功的治愈病人或明 显延长病人的寿命， 因此， 抗肿瘤药物在肿瘤治疗中占有越来越重要的地 位。 此外， 在对肿瘤的研究过程中， 对肿瘤特性的研究和分子生物学、 细 胞生物学的研究进展， 为抗肿瘤药物的研究提供了新的方向和新的作用靶 点， 相继产生了一批具有新颖化学结构或独特作用机制的化合物。  Antineoplastic drugs refer to drugs against malignant tumors, also known as anticancer drugs. Since the use of nitrogen mustard in the treatment of malignant tumors in the 1940s, the chemotherapy of tumors has been greatly developed. It has entered the stage of combination therapy and comprehensive chemotherapy by a single chemotherapy, and can successfully cure patients or Prolonging the lifespan of patients, therefore, anti-tumor drugs play an increasingly important role in cancer treatment. In addition, in the research of tumors, the research on tumor characteristics and the research progress of molecular biology and cell biology have provided new directions and new targets for the research of anti-tumor drugs, and successively produced a batch. A compound having a novel chemical structure or a unique mechanism of action.
近年来， 酪氨酸蛋白酶（Protein tyrosine kinase, PTK ) 的研究已引起 广泛的兴趣。 酪氨酸蛋白酶激酶是信号传递过程种的重要因子， 参与一系 列细胞功能， 与细胞生长、 分化、 增殖密切相关 [Microsc Res Tech. 2003 Jan l;60(l):70-5], [Trends Pharmacol Sci. 2002 Dec;23(12):576-82]„  In recent years, research on tyrosine protease (PTK) has attracted wide interest. Tyrosine protease kinase is an important factor in the signal transduction process and participates in a series of cell functions, which are closely related to cell growth, differentiation and proliferation [Microsc Res Tech. 2003 Jan l;60(l):70-5], [Trends Pharmacol Sci. 2002 Dec;23(12):576-82]„
许多癌症基因的表达产物也都具有 PTK活性， 很多恶性转化细胞中的 PTK活性远远高于正常细胞。 因此若能抑制 PTK活性， 就有可能阻断肿瘤 细胞的生长。 PTK已经成为引人注目的抗肿瘤药物新靶点 [Curr Drug Targets. 2003 Feb;4(2): 113-21]。  The expression products of many cancer genes also have PTK activity, and the PTK activity in many malignant transformed cells is much higher than that of normal cells. Therefore, if PTK activity is inhibited, it is possible to block the growth of tumor cells. PTK has become a new target for compelling anti-tumor drugs [Curr Drug Targets. 2003 Feb; 4(2): 113-21].
发明人对 5,8-二取代 -1,6-二氮杂萘 -7-碳酰胺类化合物的研究起源于该 类结构较为新颖， 而且与一些血管内皮生长因子抑制剂， EGFR抑制剂结构 很相似。 ？ I起发明人兴趣的相关文献如下列出： The inventors' research on 5,8-disubstituted-1,6-naphthyridin-7-carboxamides originated from the relatively novel structure, and with some vascular endothelial growth factor inhibitors, the structure of EGFR inhibitors is very similar. ? The relevant literature on the interests of inventors is listed below:
WO98/13350 中披露了一系列喹啉类血管内皮生长因子抑制剂。其中也 包括 1,8-二氮杂萘类衍生物， 例如该专利中的实施例 53 : 2-乙酰氨基 -5-(2- 氟—5—羟基—4-甲基苯胺)— 1,8-二氮杂萘。  A series of quinoline vascular endothelial growth factor inhibitors are disclosed in WO 98/13350. Also included are 1,8-naphthyridine derivatives, such as Example 53 in this patent: 2-acetamido-5-(2-fluoro-5-hydroxy-4-methylaniline)-1,8 - diazepine.
WO99/32450 中披露了 4-羟基喹啉 -2-羧酸胺衍生物用于治疗疱疹病毒 感染。  A 4-hydroxyquinoline-2-carboxylic acid amine derivative is disclosed in WO 99/32450 for the treatment of herpes virus infection.
WO98/11073中披露了 8-羟基喹啉 -7-羧酸胺衍生物用于治疗疱疹病毒感 染。  8-hydroxyquinoline-7-carboxylic acid amine derivatives are disclosed in WO 98/11073 for the treatment of herpes virus infection.
WO02/30931中披露了 8-羟基 -1,6-二氮杂萘 -7-碳酰胺类化合物用于治疗 HIV-1病毒感染。  8-hydroxy-1,6-naphthyridin-7-carboxamides are disclosed in WO 02/30931 for the treatment of HIV-1 viral infections.
发明内容  Summary of the invention
本发明的一个目的是公开一类具有全新结构、 强效抗肿瘤活性的 5,8-二 取代 -1,6-二氮杂萘 -7-羰酰胺类化合物。  SUMMARY OF THE INVENTION One object of the present invention is to disclose a class of 5,8-disubstituted-1,6-diazaphthalen-7-carbonylamide compounds having novel structures and potent antitumor activities.
本发明的另一目的是提供上述 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化 合物的制备方法。  Another object of the present invention is to provide a process for producing the above 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound.
本发明的还一目的是提供上述 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化 合物在医药领域的用途， 它们可以用于治疗包括乳腺癌在内的多种肿瘤疾 病。通过筛选， 首次发现 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺在 20μΜ内对下 列细胞有高效的抑制活性： 人乳腺癌细胞 MDA-MB-435 , ρ53缺失的低分 化结肠腺癌细胞 Hctl l6 p53-/- , p53 富集的低分化结肠腺癌细胞 Hctl l6 p53+/+, 人乳腺癌细胞 Mcf-7, NIH 189 , 人乳腺癌细胞 SkBr-3 , 前列腺癌 细胞 LnCap, LnHer, 人结肠癌细胞 HT 29, 人卵巢癌细胞 HEY。  Still another object of the present invention is to provide the use of the above 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compounds in the field of medicine, which can be used for the treatment of various diseases including breast cancer. Tumor disease. By screening, 5,8-disubstituted-1,6-naphthyridin-7-carboxamide was found to have potent inhibitory activity against the following cells within 20 μΜ: human breast cancer cell MDA-MB-435, ρ53 deleted Poorly differentiated colon adenocarcinoma cells Hctl l6 p53-/- , p53 enriched poorly differentiated colon adenocarcinoma cells Hctl l6 p53+/+, human breast cancer cells Mcf-7, NIH 189, human breast cancer cells SkBr-3, prostate cancer The cells LnCap, LnHer, human colon cancer cells HT 29, human ovarian cancer cells HEY.
本发明的再一目的是提供一种包含治疗有效量的 5,8-二取代 -1,6-二氮 杂萘 -7-羰酰胺类化合物的药物组合物。  A further object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a 5,8-disubstituted-1,6-diazaphthalen-7-carbonylamide compound.
根据本发明，所述的抗肿瘤活性的 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类 化合物如下面的结构通式 I所示：  According to the present invention, the antitumor activity of the 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound is as shown in the following structural formula I:
Figure imgf000004_0001
Figure imgf000004_0001
A为： （1 )苯环； （2 ) C8-C10骈合成的双碳环， 其中一个是苯环， 另一 个为饱和的或者不饱和的环； （3 ) 8 ~ 10个原子骈合成的环， 并含有 0-3个 选自 N、 0和 S中的杂原子， 其中一个是芳环或者芳杂环， 另一个为饱和 的或者不饱和的碳环或杂环； （4 )含有 1 ~ 3个选自 N、 0和 S中的杂原子 的五元或六元芳杂环； 或 （5 )含有 0 ~ 3个选自 N、 0和 S中的杂原子的 三元至七元脂肪环； A is: (1) a benzene ring; (2) a C 8 -C 10骈 synthesized double carbon ring, one of which is a benzene ring and the other is a saturated or unsaturated ring; (3) 8 to 10 atoms 骈a ring which is synthesized and contains 0-3 heteroatoms selected from N, 0 and S, one of which is an aromatic or aromatic heterocyclic ring, and the other is a saturated or unsaturated carbocyclic or heterocyclic ring; (4) Containing 1 to 3 heteroatoms selected from N, 0 and S a five- or six-membered aromatic heterocyclic ring; or (5) a three- to seven-membered aliphatic ring containing 0 to 3 hetero atoms selected from N, 0 and S;
L是: ( 1 )直接键; ( 2 ) Ci-C6烷基； ( 3 ) C2-C6烯基； ( 4 ) ( C0-C6烷基 ) - ( C3-C6环烷基 ) - ( C0-C6烷基 )； 或（ 5 ) ( C0-C6烷基 ) -M- ( C0-C6烷基）， 其中 M为 N ( Ra )、 OC ( = 0 )或 C ( = 0 ) 0; 其中， （3 )中的烯基和（2 )、 ( 4 )、（ 5 )中的烷基可以被 1-3个各自独立的取代基取代， 所述取代基选自 下列原子或基团之中： d-C6烷基、 d-C6烷氧基 d-C6烷基、 C3-C8环烷基、 卤素、氨基、巯基、羟基、 -CF3、 -CN、 -N02、 -NRaRb、 -NRaCORb、 -NRaCOORb、 -NRaS02Rb、 -COORb、 -CORb、 -CONRaRb、 -S02Rb、 -S02NRaRb、 -0Ra和 -OCORb; L is: (1) a direct bond; (2) a Ci-C 6 alkyl group; (3) a C 2 -C 6 alkenyl group; (4) a (C 0 -C 6 alkyl group) - (C 3 -C 6 ring) Alkyl) - (C 0 -C 6 alkyl); or ( 5 ) ( C 0 -C 6 alkyl) -M- (C 0 -C 6 alkyl), wherein M is N (R a ), OC ( = 0 ) or C ( = 0 ) 0; wherein, the alkenyl group in (3) and the alkyl group in (2), (4), (5) may be substituted by one to three independent substituents, The substituent is selected from the group consisting of: dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, C 3 -C 8 cycloalkyl, halogen, amino, fluorenyl, hydroxy, -CF 3 , -CN, -N0 2 , -NR a R b , -NR a COR b , -NR a COOR b , -NR a S0 2 R b , -COOR b , -COR b , -CONR a R b , -S0 2 R b , -S0 2 NR a R b , -0R a and -OCOR b ;
、 R2、 R3、 R4和 R6各自独立地为氢、 卤素、 羟基、 巯基、 -CF3、 -CN、 -N02或者 取代或各自独立地被 1-3个取代基取代的下列基团： CrC6烷基、 d-C6烷氧基、 C2-C6烯基、 C2-C6炔基、 C3-C8环烷基、 C3-C8环烷氧基、 硅 氧基、 氨基、 苯基、 苄基、 萘基、 C5-C1G芳香性杂环基或 C3-C7饱和杂环基； 所述取代基选自下列原子或基团之中： d-C6烷基、 d-C6烷氧基 d-C6烷基、 杂环基、 杂环基羰基、 d-C6烷基杂环基、 C6-C10芳基、 C3-C8环烷基、 卤素、 巯基、羟基、 -CF3、 -CN、 -N02、 -NRaRb、 -NRaCORb、 -NRaCOORb、 -NRaS02Rb、 -COORb、 -CORb、 -CONRaRb、 -S02Rb、 -S02NRaRb、 -ORa和 -OCORb, 且 NRaRb可共同组成环胺； 所述杂环包括 1-3个选自 N、 0和 S中的杂原子；And R 2 , R 3 , R 4 and R 6 are each independently hydrogen, halogen, hydroxy, decyl, -CF 3 , -CN, -N0 2 or substituted or each independently substituted with 1 to 3 substituents. Group: C r C 6 alkyl, dC 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy , siloxy, amino, phenyl, benzyl, naphthyl, C 5 -C 1G aromatic heterocyclic or C 3 -C 7 saturated heterocyclic; the substituent is selected from the following atoms or groups : dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, heterocyclic group, heterocyclylcarbonyl, dC 6 alkylheterocyclyl, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, Halogen, fluorenyl, hydroxy, -CF 3 , -CN, -N0 2 , -NR a R b , -NR a COR b , -NR a COOR b , -NR a S0 2 R b , -COOR b , -COR b , -CONR a R b , -S0 2 R b , -S0 2 NR a R b , -OR a and -OCOR b , and NR a R b may together constitute a cyclic amine; the heterocyclic ring includes 1-3 selected Heteroatoms from N, 0 and S;
R5为氢、 羟基或者未取代或被 1-3个各自独立的取代基取代的下列基 团： d-C6烷基、 d-C6烷氧基 d-C6烷基、 d-C6烷氧基、 C2-C6烯基、 C2-C6 炔基、 C3-C8环烷基、 苯基、 苄基、 萘基、 C5-C1Q芳香性杂环基或 C4-C7饱 和杂环基； 所述杂环包括 1-3个选自 N、 0和 S中的杂原子； 所述取代基选 自下列原子或基团： d-C6烷基、 d-C6烷氧基 d-C6烷基、 卤素、 氨基、 硝 基、 巯基、 羟基、 -CN和 -CF3; R 5 is hydrogen, hydroxy or the following groups which are unsubstituted or substituted by 1 to 3 independent substituents: dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, dC 6 alkoxy, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, phenyl, benzyl, naphthyl, C 5 -C 1Q aromatic heterocyclic or C 4 -C 7 saturated heterocyclic The heterocyclic ring includes 1-3 heteroatoms selected from N, 0 and S; the substituent is selected from the group consisting of dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, Halogen, amino, nitro, thiol, hydroxy, -CN and -CF 3 ;
B为： （l ) Rd或 Re; ( 2 )含有 0 ~ 3个选自 N、 0和 S中的杂原子的三 元至七元脂肪环，杂环上有 1-3个各自独立的从 Rd或 Re中选取取代基取代； ( 3 )含有 1-3个选自 N、 0和 S中的杂原子的五元或六元杂芳环， 杂环上 有 1-3个各自独立的从 Rd或 Re中选取取代基的取代基； 或（ 4 ) 8 ~ 10个碳 原子骈合成的环， 并含有 0-3个选自 N、 0和 S中的杂原子， 其中一个是芳 环， 另一个为饱和的或者不饱和的碳环或杂环； 杂环上有 1-3个各自独立的 从 Rd或 Re中选取取代基的取代基； B is: (l) R d or R e ; ( 2 ) a ternary to seven-membered aliphatic ring containing 0 to 3 hetero atoms selected from N, 0 and S, and 1-3 each independently on the heterocyclic ring Substituting substituents from R d or R e ; ( 3 ) 5- or 6-membered heteroaryl rings containing 1-3 heteroatoms selected from N, 0 and S, 1-3 on heterocycle Each of the substituents independently selected from R d or R e ; or ( 4 ) a ring synthesized by 8 to 10 carbon atoms, and containing 0 to 3 hetero atoms selected from N, 0 and S, One of which is an aromatic ring, the other is a saturated or unsaturated carbocyclic or heterocyclic ring; and the heterocyclic ring has 1-3 independently substituents selected from R d or R e ;
Ra为氢、 d-C6烷基、 C3-C8环烷基或 C6-C1()芳烃基； R a is hydrogen, dC 6 alkyl, C 3 -C 8 cycloalkyl or C 6 -C 1 () arene;
Rb为氢、 羟基或者未取代或被 1-3个各自独立地取代基取代的下列基 团： d-C6烷基、 d-C6烷氧基 d-C6烷基、 d-C6烷氧基、 C2-C6烯基、 C2-C6 炔基、 C3-C8环烷基、 苯基、 苯酚基、 苄基、 萘基、 C5-d。芳香性杂环基或 C4-C7饱和杂环基； 所述杂环包括 1-3个选自 N、 0和 S中的杂原子； 所述 取代基选自下列原子或基团： d-C6烷基、 d-C6烷氧基 d-C6烷基、 卤素、 氨基、 硝基、 巯基、 羟基、 -CN和 -CF3; R b is hydrogen, hydroxy or the following groups which are unsubstituted or substituted by 1 to 3 substituents: dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, dC 6 alkoxy, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, phenyl, phenol, benzyl, naphthyl, C 5 -d. An aromatic heterocyclic group or a C 4 -C 7 saturated heterocyclic group; said heterocyclic ring comprising 1 to 3 hetero atoms selected from N, 0 and S; said substituent being selected from the group consisting of the following atoms or groups: dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, halogen, Amino, nitro, thiol, hydroxy, -CN and -CF 3 ;
Rd是： （ 1 )饱和或者不饱和的五元或者六元环， 该环包括至少一个碳 原子， 0 ~ 4个选自 N、 0和 S中的杂原子； （ 2 )饱和或者不饱和的 C8-C10 骈合的环， 其中该环包括至少一个碳原子， 0 ~ 4个选自 N、 0和 S中的杂 原子； 在 （1 )和（2 ) 中所包括的杂环可以是饱和的也可以是不饱和的； 且可以有如下取代基： 卤素、 腈基、 羟基、 -(C¾V4OH、 -N(Ra)(Rb)、 硝基、 烷基、 d-C6烷氧基、 面代的 d-C6 烷基、 面代的 d-C6烷氧基、 -(CH2)0-4C(=O)N(Ra)(Rb)、 -(CH2)0-4CO2Ra、 -(CH2)0-4SO2Ra、 -(CH2)1-4N(Ra)(Rb)、 -(CH2)0-4N(Ra)C(=O)(Rb), -(CH2)0-4SO2N(Ra)(Rb), -(CH2)0-4N(Ra)SO2(Rb), C2-C8 烷氧烷基、 面代的 c2-c8烷氧烷基、 苯基或苄基； R d is: ( 1 ) a saturated or unsaturated five- or six-membered ring comprising at least one carbon atom, 0 to 4 heteroatoms selected from N, 0 and S; (2) saturated or unsaturated a C 8 -C 10 conjugated ring wherein the ring includes at least one carbon atom, 0 to 4 heteroatoms selected from N, 0 and S; heterocycles included in (1) and (2) It may be saturated or unsaturated; and may have the following substituents: halogen, nitrile group, hydroxyl group, -(C3⁄4V 4 OH, -N(R a )(R b ), nitro group, alkyl group, dC 6 Alkoxy, halo dC 6 alkyl, dihydrocarbyl dC 6 alkoxy, -(CH 2 ) 0-4 C(=O)N(R a )(R b ), -(CH 2 ) 0 -4 CO 2 R a , -(CH 2 ) 0-4 SO 2 R a , -(CH 2 ) 1-4 N(R a )(R b ), -(CH 2 ) 0-4 N(R a C(=O)(R b ), -(CH 2 ) 0-4 SO 2 N(R a )(R b ), -(CH 2 ) 0-4 N(R a )SO 2 (R b ) a C 2 -C 8 alkoxyalkyl group, a c 2 -c 8 alkoxyalkyl group, a phenyl group or a benzyl group;
Re为： 氢、 卤素、 羟基、 氨基、 硝基、 -CN、 d-C6烷基、 d-C6烷氧基、 卤代的 d-C6烷基、 面代的 d-C6烷氧基、 C2-C8烷氧烷基、 面代的 C2-C8 烷氧烷基、 -(C¾)0-6N(Ra)(Rb)、 -(C¾)0-6RC、 -O(C¾)0-6Rc、 -O(C¾)0-6ORc、 -(CH2)0-6Rd、 -O(CH2)0-6Rd、 -C(=0)N(Ra)(Rb)、 -(C¾)1-6C(=0)N(Ra)(Rb)、 -(C¾)0-6N(Ra)C(=O)(Rb)、 -S02Ra、 -S02Rd、 -S02(C¾)1-6Rd、 -(C¾)1-6S02Ra、 -(CH2)0-6SO2N(Ra)(Rb), -(CH2)0-6N(Ra)SO2(Rb), -(CH2)0-6CO2Ra, -(CH2)0-6SRa, C2-C6烯基、 -0-C1-6烷基 -ORa、 -0-Ci-6烷基 -SRa、 -0-Ci-6烷基 -N(Ra)C(=0)(Rb)、 -O-d.6烷基 -N(Ra)(Rb)、 -NfR -Cw烷基 -SRa、
Figure imgf000006_0001
烷基- ORa、 -N(Ra)-C1-6烷基 -N(Ra)(Rb)、 -N(Ra)-C1-6烷基 -N(Ra)C(=0)(Rb)、 -C2-6烯基 -Rd、 -C2-6 炔基 -Rd 、 -(CH2)0-6SO2N(Ra)(Rd) 、 -(CH2)0-6SO2N(Ra)(-C1-6-Rd) 、 -(C¾)0-6S(O)nRd、 -(。¾)0-6(^(0) ((^¾)0-6 或-((^¾)0-68(0)11 -(^-6 ( 11 = 0、 1 或 2 )。 R e is: hydrogen, halogen, hydroxy, amino, nitro, -CN, dC 6 alkyl, dC 6 alkoxy, halogenated dC 6 alkyl, halo dC 6 alkoxy, C 2 -C 8 alkoxyalkyl, a C 2 -C 8 alkoxyalkyl group, -(C3⁄4) 0-6 N(R a )(R b ), -(C3⁄4) 0-6 R C , -O(C3⁄4 0-6 R c , -O(C3⁄4) 0-6 OR c , -(CH 2 ) 0-6 Rd, -O(CH 2 ) 0-6 Rd, -C(=0)N(R a ) (R b ), -(C3⁄4) 1-6 C(=0)N(R a )(R b ), -(C3⁄4) 0-6 N(R a )C(=O)(R b ), - S0 2 R a , -S0 2 R d , -S0 2 (C3⁄4) 1-6 R d , -(C3⁄4) 1-6 S0 2 R a , -(CH 2 ) 0-6 SO 2 N(R a ) (R b ), -(CH 2 ) 0-6 N(R a )SO 2 (R b ), -(CH 2 ) 0-6 CO 2 R a , -(CH 2 ) 0-6 SR a , C 2 -C 6 alkenyl, -0-C 1-6 alkyl-OR a , -0-Ci -6 alkyl-SR a , -0-Ci -6 alkyl-N(R a )C(=0 (R b ), -Od.6 alkyl-N(R a )(R b ), -NfR -Cw alkyl-SR a ,
Figure imgf000006_0001
Alkyl-OR a , -N(R a )-C 1-6 alkyl-N(R a )(R b ), -N(R a )-C 1-6 alkyl-N(R a )C (=0)(R b ), -C 2-6 alkenyl-R d , -C 2 6 alkynyl-R d , -(CH 2 ) 0-6 SO 2 N(R a )(R d ) , -(CH 2 ) 0-6 SO 2 N(R a )(-C 1-6 -R d ) , -(C3⁄4) 0-6 S(O) n R d , -(.3⁄4) 0-6 (^(0) ((^3⁄4) 0-6 or -((^3⁄4) 0-6 8(0) 11 -(^ -6 ( 11 = 0, 1 or 2 ).
Rc为： 芳基或取代的芳基； 所述取代基为卤素、 氰基、 氨基、 羟基、 -(C¾)1-4OH、 -N(Ra)(Rb)、 硝基、 d-C6烷基、 d-C6烷氧基、 卤代的 d-C6 烷基、 卤代的 d-C6烷氧基、 -(CH2)0-4C(=O)N(Ra)(Rb) , -(C¾V4C02Ra、 -(CH2)0-4SO2Ra 、 -(CH2)1-4N(Ra)(Rb) 、 -(CH2)0-4N(Ra)C(=O)(Rb) 、 -(CH2)0-4SO2N(Ra)(Rb)、 -(CH2)0-4N(Ra)SO2(Rb)、 C2-C8烷氧烷基或卤代的 c2-c8烷氧烷基。 R c is: aryl or substituted aryl; the substituent is halogen, cyano, amino, hydroxy, -(C3⁄4) 1-4 OH, -N(R a )(R b ), nitro, dC 6 alkyl, dC 6 alkoxy, halogenated dC 6 alkyl, halogenated dC 6 alkoxy, -(CH 2 ) 0-4 C(=O)N(R a )(R b ) , -(C3⁄4V 4 C0 2 R a , -(CH 2 ) 0-4 SO 2 R a , -(CH 2 ) 1-4 N(R a )(R b ) , -(CH 2 ) 0-4 N( R a )C(=O)(R b ) , -(CH 2 ) 0-4 SO 2 N(R a )(R b ), -(CH 2 ) 0-4 N(R a )SO 2 (R b ), C 2 -C 8 alkoxyalkyl or halogenated c 2 -c 8 alkoxyalkyl.
本发明的结构通式 I表示的化合物中优选的化合物可以用结构通式 II 表示：  Preferred compounds among the compounds represented by the structural formula I of the present invention can be represented by the structural formula II:
Figure imgf000006_0002
Figure imgf000006_0002
其中， 、 R2、 R6和 B的定义与通式 I中相同， 并进一步优选: 和 各自独立地为氢、 卤素、 -CN、 -CF3、 -N02、羟基、氨基、 Ci-C6 烷基氨基、 d-C6烷基杂环基氨基、 C6-C10芳基氨基、 d-C8烷氧基、 C3-C8 环烷氧基、 Ci-C6烷基硅氧基、 Ci-C6烷基杂环基 Ci-Cs烷基氧基、 杂环基 d-C8烷基氧基、 杂环基羰基 d-C8烷基氧基或 C6-C10芳基 d-C8烷基氧基； 其中的杂环基是指含有 1 ~ 3个选自 N、 0和 S中的杂原子的三元至七元脂 肪环； R6为氢、 卤素、
Figure imgf000007_0001
或 '|' ； B为氨基 d-C6烷基、 d-C4烷基氨 基（^-。4烷基、 d-C4烷氧基羰基 烷基、 d-C4烷基磺酰氨基 烷 基、 苯甲酰氨基 d-C4烷基、 氨基苯基、 氨基 c.3-c6环烷基或卤代苄基， 或 者 B与所连接的 N形成
Figure imgf000007_0002
Figure imgf000007_0003
Wherein, R 2 , R 6 and B have the same definitions as in Formula I, and further preferably: And each independently are hydrogen, halogen, -CN, -CF 3 , -N0 2 , hydroxy, amino, Ci-C 6 alkylamino, dC 6 alkylheterocyclylamino, C 6 -C 10 arylamino, dC 8 alkoxy, C 3 -C 8 cycloalkoxy, Ci-C 6 alkylsiloxy, Ci-C 6 alkylheterocyclyl Ci-Cs alkyloxy, heterocyclyl dC 8 alkyl An oxy group, a heterocyclic carbonyl group dC 8 alkyloxy group or a C 6 -C 10 aryl dC 8 alkyloxy group; wherein the heterocyclic group means 1 to 3 kinds of impurities selected from N, 0 and S A ternary to seven-membered aliphatic ring of atoms; R 6 is hydrogen, halogen,
Figure imgf000007_0001
Or '|'; B is amino dC 6 alkyl, dC 4 alkylamino (^-.4 alkyl, dC 4 alkoxycarbonylalkyl, dC 4 alkylsulfonylaminoalkyl, benzoylamino dC 4 alkyl, aminophenyl, amino c. 3 -c 6 cycloalkyl or halobenzyl, or B forms with the attached N
Figure imgf000007_0002
Figure imgf000007_0003
C6"Cio芳基。  C6" Cio aryl.
结构通式 II进一步优选：  The structural formula II is further preferably:
和 各自独立地为氢、 卤素、 -CN、 -CF3、 氨基、 d-C4烷基氨基、 d-C4烷基杂环基氨基、 d-C4烷氧基、 C3-C6环烷氧基、 d-C4烷基硅氧基、 d-C4烷基杂环基 d-C4烷基氧基、杂环基 d-C4烷基氧基或杂环基羰基 d-C4 烷基氧基； 其中的杂环基是指含有 1 ~ 2个选自 N和 0的杂原子的三元至 七元脂肪环； And each independently are hydrogen, halogen, -CN, -CF 3 , amino, dC 4 alkylamino, dC 4 alkylheterocyclylamino, dC 4 alkoxy, C 3 -C 6 cycloalkoxy, dC a 4- alkylsilyloxy group, a dC 4 alkylheterocyclyl group dC 4 alkyloxy group, a heterocyclic group dC 4 alkyloxy group or a heterocyclic carbonyl group dC 4 alkyloxy group; wherein the heterocyclic group means 1 to 2 ternary to seven-membered aliphatic rings selected from heteroatoms of N and 0;
R6为氢、 卤素、
Figure imgf000007_0004
或 R 6 is hydrogen, halogen,
Figure imgf000007_0004
or
B为氨基 d-C6烷基、 d-C4烷基氨基 烷基、 烷氧基羰基 烷基、 d-C4烷基磺酰氨基 烷基、 苯甲酰氨基 d-C4烷基、 氨基苯基、 B is an amino dC 6 alkyl group, dC 4 alkylaminoalkyl group, alkoxycarbonylalkyl group, dC 4 alkylsulfonylaminoalkyl group, benzoylamino dC 4 alkyl group, aminophenyl group,
. / ~ \  . / ~ \
5-N NH 氨基 C3-C6环烷基或面代苄基， 或者 B 与所连接的 N 形成 ^ 、
Figure imgf000007_0005
5-N NH amino C 3 -C 6 cycloalkyl or epi-benzyl, or B forms a bond with the attached N,
Figure imgf000007_0005
R为 11或 d-C4烷基。 R is 11 or dC 4 alkyl.
进一步地， 上述结构通式 II表示的化合物中优选的化合物可以用结构 通式 m表示: Further, among the compounds represented by the above structural formula II, preferred compounds may be used in the structure. The general formula m means:
Figure imgf000008_0001
Figure imgf000008_0001
其中， 、 R2和 R6的定义同上与通式 II中相同。 Wherein, R 2 and R 6 have the same meanings as in the above formula II.
通式 I所述的 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物， 具体地， 为 下述化合物：  The 5,8-disubstituted-1,6-diazaphthalene-7-carbonylamide compound of the formula I, specifically, is the following compound:
Figure imgf000008_0002
Figure imgf000008_0003
Figure imgf000008_0002
Figure imgf000008_0003
Figure imgf000009_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000010_0001
丄 J 、
Figure imgf000011_0001
丄J,
Figure imgf000011_0001
其中， R6和 B的定义与通式 I中相同； R7为
Figure imgf000011_0002
, 其中 A、 L、 Ri , R2、 R3和 R4的定义与通式 I中相同， 并优选为表中所示的基团。 Wherein R 6 and B have the same definitions as in Formula I; R 7 is
Figure imgf000011_0002
Wherein A, L, Ri, R 2 , R 3 and R 4 have the same definitions as in the formula I, and are preferably a group shown in the table.
反应试剂和条件： （a)异丙醇,回流, 68%; (b)二氯亚砜,回流； （c)硼氢化钠, 四氢呋喃, 0°C ,两步产率 38%; (d) TsNHCH2COOCH3,DEAD (偶氮二甲酸二 乙酯） ，三苯基膦,四氢呋喃, 0°C ; (e)甲醇钠，甲醇, 0°C〜室温，两步产率 65%; (f)NBS ( N-溴代丁二酰亚胺），二氯甲烷,室温， 产率 85%; (g)胺,甲苯,回流 24小时， 产率 88%; (h)TsCl,三乙胺，三氯甲烷， 产率 90%; (i)胺,四氢呋喃,回 流， 产率 75%-85%； ( j ) LiOH溶液 /甲醇,或 NaOH溶液 /THF,回流； （k )二 (三氯甲基)碳酸酯, DIPEA,DMF,苯胺； ( 1 ) EDCI,HOBT,DIPEA,胺,二氯甲烷； ( m )三氟醋酸 /二氯甲烷。 Reaction reagents and conditions: (a) isopropanol, reflux, 68%; (b) thionyl chloride, reflux; (c) sodium borohydride, tetrahydrofuran, 0 ° C, two-step yield 38%; TsNHCH 2 COOCH 3 , DEAD (diethyl azodicarboxylate), triphenylphosphine, tetrahydrofuran, 0 ° C; (e) sodium methoxide, methanol, 0 ° C ~ room temperature, two-step yield of 65%; NBS (N-bromosuccinimide), dichloromethane, room temperature, yield 85%; (g) amine, toluene, reflux 24 hours, yield 88%; (h) TsCl, triethylamine, Trichloromethane, yield 90%; (i) amine, tetrahydrofuran, reflux, yield 75%-85%; (j) LiOH solution/methanol, or NaOH solution/THF, reflux; (k) bis(trichloromethane) Carbonate, DIPEA, DMF, aniline; (1) EDCI, HOBT, DIPEA, amine, dichloromethane; (m) trifluoroacetic acid/dichloromethane.
( 1 )化合物 S1-S25和 S29, S31-S43的合成方法如下： 将化合物 1吡 啶 2,3-二酸酐选择性酯化得到化合物 2 , 产率 68%。 化合物 3以酰氯形式选 择性还原得到化合物 4, 产率为 38%。 化合物 4通过 Mitsunobo反应得到化 合物 5, 化合物 5在甲醇钠下关环得到 1 ,6-二氮杂萘羰酸甲酯 6, 两步产率 65%。化合物 6与含 R6的化合物（如 N-碘代丁二酰亚胺或 N-溴代丁二酰亚 胺）反应得到 5-R6-l,6-二氮杂萘羰酸甲酯 7, 产率 85%。 化合物 7与含 R7 的胺酰胺化得到 1,6-二氮杂萘羰酰胺化合物 8, 产率 88%。 化合物 8的 8位 羟基用 Ts保护以 90%产率得到化合物 9。 化合物 9的合成路线见参考文献 WO2002030426和 WO2002030930。化合物 9与相应的胺发生芳基亲核取代 反应得到一系列 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物 S1-S25和 S29, S31-S43 , 产率 75%-85%。 (1) The synthesis of the compounds S1-S25 and S29, S31-S43 is as follows: Compound 1 pyridine 2,3-dianhydride is selectively esterified to give compound 2 in a yield of 68%. Compound 3 was selectively reduced in the form of an acid chloride to give compound 4 in a yield of 38%. Compound 4 was subjected to a Mitsunobo reaction to give Compound 5, and Compound 5 was closed under sodium methoxide to give methyl 1,6-diazanaphthalenecarboxylate 6 in a two-step yield of 65%. Compound 6 is reacted with a compound containing R 6 such as N-iodosuccinimide or N-bromosuccinimide to give methyl 5-R 6 -l,6-naphthyridinylcarboxylate 7 , yield 85%. Amidation of compound 7 with an amine containing R 7 gave 1,6-diazanaphthalenecarboxamide compound 8 in 88% yield. The hydroxyl group at position 8 of compound 8 was protected with Ts to give compound 9 in 90% yield. The synthetic route of compound 9 is described in the references WO2002030426 and WO2002030930. The nucleophilic substitution reaction of compound 9 with the corresponding amine gives a series of 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compounds S1-S25 and S29. S31-S43, yield 75%-85%.
( 2 )化合物 S26的合成方法如下： 化合物 7在 IN LiOH溶液 /甲醇中回流 5h得到化合物 11 , 化合物 11在三光气、 DIPEA (二异丙基乙胺 )和 DMF ( N, N-二甲基甲酰胺）中与苯胺反应 2h得到化合物 S26-l。化合物 S26-1再由与制 备 S15相似的合成方法制得 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物 S26。  (2) The synthesis method of the compound S26 is as follows: Compound 7 is refluxed in IN LiOH solution / methanol for 5 h to obtain compound 11, compound 11 in triphosgene, DIPEA (diisopropylethylamine) and DMF (N, N-dimethyl Reaction with aniline in formamide for 2 h gave compound S26-1. Compound S26-1 was further prepared by a synthesis method similar to the preparation of S15 to obtain 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound S26.
( 3 )化合物 S27的合成方法如下： 化合物 7与 TsCl和三乙胺在二氯甲烷 中回流 5 'J、时得到化合物 12 , 化合物 12与对氟苄胺在三乙胺和四氢呋喃中加 热回流 8小时得到化合物 13 , 化合物 13在 IN NaOH溶液 /THF中 60。C下 10h生 成化合物 14。 化合物 14与胺在 EDCI ( 1-乙基 -3-(3-二甲胺丙基)碳二亚胺）、 HOBT ( 1-羟基苯并三唑）、 DIPEA (二异丙基乙胺）和二氯甲烷中， 常温 下反应 3h得到化合物 15。 化合物 15在 20%的三氟醋酸 /二氯甲烷中脱除 Boc 生成 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物 S27。 (3) The synthesis method of the compound S27 is as follows: Compound 7 is refluxed with TsCl and triethylamine in dichloromethane to give a compound 12, and compound 12 is heated under reflux with p-fluorobenzylamine in triethylamine and tetrahydrofuran. Compound 13 was obtained in an hour and Compound 13 was 60 in IN NaOH solution / THF. Compound 14 was produced 10 hours after C. Compound 14 and amine in EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), HOBT (1-hydroxybenzotriazole), DIPEA (diisopropylethylamine) and The compound 15 was obtained by reacting at room temperature for 3 hours in dichloromethane. Compound 15 was removed from Boc in 20% trifluoroacetic acid / dichloromethane to give 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound S27.
Figure imgf000012_0001
Figure imgf000012_0001
14 15 S27  14 15 S27
( 4 )化合物 S28的合成方法如下： 化合物 S3-1与 NIS ( N-碘代丁二酰亚 胺）在二氯甲烷中常温下搅拌 1小时得到化合物 S28-1 , 化合物 S28-1与 TsCl、 三乙胺在二氯甲烷中回流 5小时得到化合物 S28-2 , 化合物 S28-2与反式 1 ,4- 环己二胺在三乙胺、 四氢呋喃中加热回流 8小时得到化合物 S28-3 , 化合物 S28-3在氯化钯、 三苯基膦、 碘化亚铜、 碳酸钾和 THF中回流与丙炔酸甲酯 反应得到化合物 S28-4 , 化合物 S28-4在 20%三氟醋酸 /二氯甲烷中脱去 Boc得 到 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物 S28。
Figure imgf000013_0001
(4) The synthesis method of the compound S28 is as follows: Compound S3-1 and NIS (N-iodosuccinimide) are stirred at room temperature for 1 hour in dichloromethane to obtain a compound S28-1, a compound S28-1 and TsCl, Triethylamine is refluxed in dichloromethane for 5 hours to obtain compound S28-2. Compound S28-2 and trans-1,4-cyclohexanediamine are heated under reflux in triethylamine and tetrahydrofuran for 8 hours to obtain compound S28-3. S28-3 is reacted with palladium chloride, triphenylphosphine, cuprous iodide, potassium carbonate and THF to react with methyl propiolate to give compound S28-4, and compound S28-4 is in 20% trifluoroacetic acid/dichloro Removal of Boc from methane affords the 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound S28.
Figure imgf000013_0001
( 5 )、 化合物 S30的合成方法如下： 化合物 12与单 Boc保护的反式 1,4- 环己二胺在 K2C03和四氢呋喃中加热回流 8小时得到化合物 S30-1 , 化合物 S30-1在 IN NaOH溶液 /THF中 60度下 10h生成化合物 S30-2。 化合物 S30-2在 EDCI、 HOBT、 DIPEA和二氯甲烷中， 常温下与相应的胺反应 3h得到化合 物 S30-3。 化合物 S30-3在 20%的三氟醋酸 /二氯甲烷中脱除 Boc生成 5, 8-二取 代 -1,6-二氮杂萘 -7-羰酰胺类化合物 S30。(5), the synthesis method of the compound S30 is as follows: Compound 12 and a single Boc-protected trans 1,4-cyclohexanediamine are heated under reflux in K 2 CO 3 and tetrahydrofuran for 8 hours to obtain a compound S30-1, a compound S30-1 Compound S30-2 was formed in IN NaOH solution / THF at 60 ° for 10 h. Compound S30-2 was reacted with the corresponding amine in EDCI, HOBT, DIPEA and dichloromethane at room temperature for 3 h to give compound S30-3. Compound S30-3 was removed from Boc in 20% trifluoroacetic acid / dichloromethane to give 5, 8-disubstituted-1,6-naphthyridin-7-carbonylamide compound S30.
Figure imgf000013_0002
Figure imgf000013_0002
S30-3 S30  S30-3 S30
通过对多种肿瘤细胞株筛选， 申请人发现： 上述结构通式 I表示的化合 物在 20μΜ内对下列细胞有高效的抑制活性： MDA-MB-435 , Hctl l6 ρ53-/-, Hctll6p53+/+, Mcf-7, NIH 189, SkBr-3, LnCap, LnHer, HT 29, HEY。 因此，结构通式 I表示的化合物能够有效的治疗 MDA-MB-435, Hctll6 p53-/-, Hctll6p53+/+, Mcf-7, NIH 189, SkBr-3, LnCap, LnHer, HT 29, HEY肿瘤细胞恶性增殖引起的疾病。 By screening a variety of tumor cell lines, Applicants have found that the compounds represented by the above formula I have potent inhibitory activity against the following cells within 20 μM: MDA-MB-435 , Hctl l6 ρ53-/-, Hctll6p53+/+, Mcf-7, NIH 189, SkBr-3, LnCap, LnHer, HT 29, HEY. Therefore, the compound represented by the structural formula I can effectively treat MDA-MB-435, Hctll6 p53-/-, Hctll6p53+/+, Mcf-7, NIH 189, SkBr-3, LnCap, LnHer, HT 29, HEY tumor cells. A disease caused by malignant proliferation.
制剂学上允许的含有结构通式 I表示的化合物的药物组合物同样能起 到有效的治疗 MDA-MB-435 , Hctl 16 p53-/- , Hctl 16 p53+/+ , Mcf-7 , NIH 189 , SkBr-3 , LnCap, LnHer, HT 29, HEY肿瘤细胞恶性增殖引起的疾病。  The pharmaceutically acceptable pharmaceutical composition containing the compound represented by the structural formula I is also effective for the treatment of MDA-MB-435, Hctl 16 p53-/-, Hctl 16 p53+/+, Mcf-7, NIH 189, SkBr-3, LnCap, LnHer, HT 29, HEY A disease caused by malignant proliferation of tumor cells.
具体实施方式  detailed description
抗肿瘤活性测试：  Antitumor activity test:
本发明中的典型的化合物以及它们针对多种肿瘤细胞（ MDA-MB-435, Hctll6p53-/-, Hctll6p53+/+, Mcf-7, NIH 189, SkBr-3, LnCap, LnHer, HT 29, HEY) 的半生长抑制活性数据 (IC5。)均在标准条件下测定。 Typical compounds of the invention and their targeting to a variety of tumor cells (MDA-MB-435, Hctll6p53-/-, Hctll6p53+/+, Mcf-7, NIH 189, SkBr-3, LnCap, LnHer, HT 29, HEY) The semi-growth inhibitory activity data (IC 5 ) were determined under standard conditions.
例： 化合物对人乳腺癌细胞 MDA-MB-435、 SKBr-3的生长抑制实验。 ( 1 )主要试剂的产生方法和来源  Example: Growth inhibition test of compounds on human breast cancer cells MDA-MB-435, SKBr-3. (1) Methods and sources of main reagents
RPMII640 购自 Gibco公司； 磺酰罗丹明 B 由 Sigma公司购得； 三氯 醋酸（TCA)、 醋酸（HAC)和 Tris base unbuffer 均为分析纯。  RPMII640 was purchased from Gibco; sulforhodamine B was purchased from Sigma; trichloroacetic acid (TCA), acetic acid (HAC) and Tris base unbuffer were of analytical grade.
(2) 实验操作步骤（磺酰罗丹明 B (SRB)蛋白染色法）  (2) Experimental procedure (sulfonhodamine B (SRB) protein staining)
根据细胞生长速率， 分别将处于对数生长期的人乳腺癌细胞 MDA-MB-435、 SKBr-3以 90μ1/孔接种于 96 孔培养板， 贴壁生长 24小时， 再加药 ΙΟμΙ/孔。 每个浓度设三复孔。 并设相应浓度的生理盐水溶媒对照及 无细胞凋零孔。 肿瘤细胞在 37°C、 5%C02条件下培养 72小时， 然后倾去 培养液， 用 10%冷 TCA 固定细胞， 4°C放置 1小时后， 用蒸微水洗涤 5次， 空气中自然干燥。 然后加入由 1%冰醋酸配制的 SRB (Sigma) 4mg/mL溶 液 ΙΟΟμΙ/孔， 室温中染色 15 分钟， 去上清液， 用 1%醋酸洗涤 5 次， 空气 干燥， 最后加入 150μ1/孔的 Tris溶液， 酶标仪（VERSAmax) 540nm 波长 下测定 A值。 According to the cell growth rate, human breast cancer cells MDA-MB-435 and SKBr-3 in logarithmic growth phase were inoculated into 96-well culture plates at 90 μl/well, adherently grown for 24 hours, and then ΙΟμΙ/well. Three holes are provided for each concentration. The corresponding concentration of physiological saline vehicle control and cell-free withering holes were set. The tumor cells were cultured at 37 ° C, 5% CO 2 for 72 hours, then the culture solution was decanted, and the cells were fixed with 10% cold TCA, left at 4 ° C for 1 hour, and washed 5 times with steamed water, naturally in the air. dry. Then add SRB (Sigma) 4 mg/mL solution prepared in 1% glacial acetic acid to ΙΟΟμΙ/well, stain for 15 minutes at room temperature, remove the supernatant, wash 5 times with 1% acetic acid, air dry, and finally add 150 μl/well of Tris. Solution, microplate reader (VERSAmax) A value was measured at 540 nm.
(3)计算方法  (3) Calculation method
以肿瘤细胞系 A492为例， 用下列公式计算肿瘤细胞生长的抑制率： 抑制率 = ( A492 对照孔 -A492 给药孔） /A492 对照孔<100% 活性数据见表格 1和 2。 表中空格表示未进行相关测试， 无相关数据。 表 1 化合物针对多种肿瘤细胞株的抗肿瘤活性数据（ICso/μΜ)  Taking the tumor cell line A492 as an example, the inhibition rate of tumor cell growth was calculated by the following formula: Inhibition rate = (A492 control well - A492 administration well) / A492 Control well <100% Activity data are shown in Tables 1 and 2. A space in the table indicates that no relevant tests have been performed and no relevant data. Table 1 Antitumor activity data of compounds against various tumor cell lines (ICso/μΜ)
MDA-MB Hctl 16 Hctl 16  MDA-MB Hctl 16 Hctl 16
化合物 Mcf-7 SkBr-3 LnCap LnHer HT 29 Compound Mcf-7 SkBr-3 LnCap LnHer HT 29
435 p53-/- p53+/+  435 p53-/- p53+/+
S1 5±2 18 >20 6.5  S1 5±2 18 >20 6.5
S2 11.8±5.5 >20 >20 6 ±0.5  S2 11.8±5.5 >20 >20 6 ±0.5
S3 16 >10 >10 >10 >10 >10 >10 S3 16 >10 >10 >10 >10 >10 >10
S4 7.25±1.06 >10 >10 7.5±3 <1 8.5 6±1.9S4 7.25±1.06 >10 >10 7.5±3 <1 8.5 6±1.9
S5 〜10 >10 >10 >10 1 5;5 >10S5 ～10 >10 >10 >10 1 5;5 >10
S6 11±1.5 >10 8.7 >10 <1 8 >10S6 11±1.5 >10 8.7 >10 <1 8 >10
S7 >20 >10 >10 2.5±0.7 <1 >10 >10 S8 6 >10 7 1.8±0.1 2.6 8±1.5 5±1.5S7 >20 >10 >10 2.5±0.7 <1 >10 >10 S8 6 >10 7 1.8±0.1 2.6 8±1.5 5±1.5
S9 7.5±0.5 7.4 〜10 4±2 4.1 7±0.5 >10S9 7.5±0.5 7.4 ~10 4±2 4.1 7±0.5 >10
S10 7.83±0.76 >10 >10 7.7 >10 8±1 >10S10 7.83±0.76 >10 >10 7.7 >10 8±1 >10
Sl l 8.1±2.68 >10 >10 6.6±0.6 6.5 5;4;>10 <1 10Sl l 8.1±2.68 >10 >10 6.6±0.6 6.5 5;4;>10 <1 10
S12 〜10 >10 >10 >10 3 >10 <1 >10S12 ~10 >10 >10 >10 3 >10 <1 >10
S13 6.85±0.49 6 9.2 3.4±0.6 <1 6.5 <1 4±1S13 6.85±0.49 6 9.2 3.4±0.6 <1 6.5 <1 4±1
S14 20 9 >10 >10 1 >10 <1 >10S14 20 9 >10 >10 1 >10 <1 >10
S15 5.6±0.49 4 7 2.4±0.5 2 5±1 <1 <1S15 5.6±0.49 4 7 2.4±0.5 2 5±1 <1 <1
S16 >10 >10 8.5±1 8.3±0.5 >10 表 2 化合物针对多种肿瘤细胞株的抗肿瘤活性 IC50 ( μΜ ) S16 >10 >10 8.5±1 8.3±0.5 >10 Table 2 Antitumor activity of compounds against various tumor cell lines IC 50 ( μΜ )
化合物 MDA-MB 435 HEY SkBr-3 Hctl l6 53+/+ Compound MDA-MB 435 HEY SkBr-3 Hctl l6 53+/+
S17 6.6±0.4 7.8 7.8 7.0±0.9S17 6.6±0.4 7.8 7.8 7.0±0.9
S18 5.5±0.5 4.1 5.5 3.5±0.2 S18 5.5±0.5 4.1 5.5 3.5±0.2
S19 7.0±0.5 3.8 6.2 6.8±0.5 S19 7.0±0.5 3.8 6.2 6.8±0.5
S20 >10 >10 8.8 >10 S20 >10 >10 8.8 >10
S21 >10 >10 10 >10  S21 >10 >10 10 >10
S22 6.9±0.1 7.1 5.8 5.8±0.3 S22 6.9±0.1 7.1 5.8 5.8±0.3
S23 7.8 5.8 7.1 8.8 S23 7.8 5.8 7.1 8.8
S24 1.2±0.2 1.4 1.7 3.9  S24 1.2±0.2 1.4 1.7 3.9
S25 5.8±0.2 5.3 6.6 6.7±0.6 S25 5.8±0.2 5.3 6.6 6.7±0.6
S26 1.1±0.3 1.3 2.2 1.8 S26 1.1±0.3 1.3 2.2 1.8
S27 6.6±0.4 7.8 7.8 7.0±0.9  S27 6.6±0.4 7.8 7.8 7.0±0.9
本发明的代表性化合物 S24、 S26对多种肿瘤细胞显示良好的抗肿瘤活 IC5o达到 1μΜ。 Representative compounds S24, S26 of the present invention show good anti-tumor activity IC 5 o of 1 μΜ for various tumor cells.
基于结构通式 I表示的化合物对多种肿瘤细胞有良好的抑制活性，申请 人进一步对 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物的抗肿瘤机理进行 了研究。 申请人采用酶联免疫吸附测定（ELISA )发现 5,8-二取代 -1,6-二氮 杂萘 -7-羰酰胺类化合物在 ΙΟμΜ下对酪氨酸激酶（EGFR, Src, KDR )有 很好的活性， 见表 3。 表中空格表示未进行相关测试， 无相关数据。  The compound represented by the structural formula I has good inhibitory activity against various tumor cells, and the applicant further develops the antitumor mechanism of the 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound. Research. Applicants used enzyme-linked immunosorbent assay (ELISA) to find that 5,8-disubstituted-1,6-diazaphthalene-7-carbonylamide compounds have tyrosine kinases (EGFR, Src, KDR) under ΙΟμΜ Very good activity, see Table 3. A space in the table indicates that no relevant tests have been performed and no relevant data.
表 3 化合物在 ΙΟμΜ下对酪氨酸激酶（EGFR, Src, KDR ) 的抑制率  Table 3 Inhibition rates of compounds against tyrosine kinases (EGFR, Src, KDR) at ΙΟμΜ
( ΙΟμΜ ) EGFR ( ΙΟμΜ ) EGFR
S9 6.7 1.4 1.1 S9 6.7 1.4 1.1
S13 4.6 9.4 0.7S13 4.6 9.4 0.7
S15 20.5 12.8 7.4S15 20.5 12.8 7.4
S16 0 0 21.4S16 0 0 21.4
S27 4.7 0.3 2.7S27 4.7 0.3 2.7
S17 19.8 S17 19.8
S18 51.1 76.2 2.3 S18 51.1 76.2 2.3
S19 19.6 11.2 11S19 19.6 11.2 11
S21 40.6 32 3.5S21 40.6 32 3.5
S22 22.4 S22 22.4
S24 59.2 70.4 33.6 S25 68 90 41.4S24 59.2 70.4 33.6 S25 68 90 41.4
528 30.2 68.7 8.9528 30.2 68.7 8.9
529 3 529 3
S30 1 L9  S30 1 L9
从表 3 的实验结果可以看出， 本发明的化合物有效作用于上述酪氨酸 激酶， 是结构新颖的酪氨酸激酶抑制剂。 其中以 S25对 Src抑制活性最好， 在 10 μΜ下抑制率高达 90%。  As can be seen from the experimental results in Table 3, the compound of the present invention is effective for the above tyrosine kinase and is a novel structural tyrosine kinase inhibitor. Among them, S25 has the best inhibitory activity against Src, and the inhibition rate is as high as 90% at 10 μΜ.
制备实施例：  Preparation examples:
下面结合制备实施例对本发明作进一步描述， 但不限制本发明。  The invention is further described below in conjunction with the preparation examples, without limiting the invention.
化合物的 ifi-NMR 光谱数据测量使用 Varian Mercury-300 MHz 或 Varian Mercury-400 MHz核磁共振， 元素分析使用 Vario EL测定仪， 熔点 用 Buchi-510毛细管法测定， 温度未经校正。 红外光谱由 Bio-Rad FTS-185 红外光普仪测定； 质谱 EI-MS用 Finnigan MAT 95质普仪， ESI-MS使用 Finnigan LCQ Deca质普仪测定。 比旋光由 P-1030 ( A012360639 ) 自动旋 光仪测定。 快速柱层析在硅胶 H ( 10-40 μΜ ) 上进行。 试剂纯化参照 Purification of laboratory Chemicals; D.D.Perrin; W.L.F.Armarego and D.R.Perrin Eds., Pergamon Press: Oxiford, 1980。  The ifi-NMR spectral data of the compounds were measured using a Varian Mercury-300 MHz or Varian Mercury-400 MHz NMR, elemental analysis using a Vario EL meter, melting point determined by Buchi-510 capillary method, and temperature uncorrected. Infrared spectra were determined by a Bio-Rad FTS-185 infrared light meter; mass spectrometry EI-MS was determined using a Finnigan MAT 95 mass spectrometer, ESI-MS using a Finnigan LCQ Deca mass spectrometer. Specific optical rotation was measured by P-1030 (A012360639) automatic polarimeter. Flash column chromatography was performed on silica gel H (10-40 μΜ). For purification of reagents, Purification of laboratory Chemicals; D. D. Perrin; W. L. F. Armarego and D. R. Perrin Eds., Pergamon Press: Oxiford, 1980.
部分化合物的纯度由双系统分析 HPLC 测定。柱子的型号为： Vydac C 18 column (10x250 mm)。 254nm紫外检测器。  The purity of some of the compounds was determined by two-system analysis HPLC. The model number of the column is: Vydac C 18 column (10x250 mm). 254nm UV detector.
系统 A: 使用的溶剂系统为： 0.05% 三氟醋酸的甲醇溶液 / 0.05% 三氟 醋酸的水溶液， 在 20分钟内梯度由 30%到 90%, 流速为 2 mL/min。  System A: The solvent system used was: 0.05% trifluoroacetic acid in methanol / 0.05% trifluoroacetic acid in aqueous solution with a gradient of 30% to 90% over 20 minutes at a flow rate of 2 mL/min.
系统 B: 使用的溶剂系统为： 0.05% 三氟醋酸， 95%的乙腈的水溶液 / 0.05% 三氟醋酸的水溶液， 在 20 分钟内梯度由 30%到 90%, 流速为 2 mL/min„  System B: The solvent system used was: 0.05% trifluoroacetic acid, 95% aqueous acetonitrile / 0.05% aqueous trifluoroacetic acid solution, gradient from 30% to 90% in 20 minutes, flow rate 2 mL/min
吡啶 -2,3-二甲酸 -2-异丙酯（ 2 )
Figure imgf000016_0001
Pyridine-2,3-dicarboxylic acid-2-isopropyl ester ( 2 )
Figure imgf000016_0001
将化合物 1吡啶 2,3-二酸酐 （48.1 g, 0.32 mol) 溶解在 lOOmL 的 2-异丙 醇中加热回流 16小时， 然后将溶液冷却到 -20°C得到白色固体化合物 2 (44.4 g, 68%)。熔点： WO-WrC ^H NMR (CDC13, 300ΜΗζ): δ 8.87 (d, J= 4.2 Hz, 1H) 8.35 (d, J= 7.8 Hz, 1H), 7.55 (dd, J= 5.1, 8.1 Hz, 1 H), 5.36 (septet (七重峰)， J= 6.3 Hz, 1H), 1.41 (d, J= 6.3 Hz, 6H)。 The compound 1 pyridine 2,3-dianhydride (48.1 g, 0.32 mol) was dissolved in 100 mL of 2-isopropanol and heated under reflux for 16 hours, then the solution was cooled to -20 ° C to give a white solid compound 2 (44.4 g, 68%). Melting point: WO-WrC ^ H NMR ( CDC1 3, 300ΜΗζ): δ 8.87 (d, J = 4.2 Hz, 1H) 8.35 (d, J = 7.8 Hz, 1H), 7.55 (dd, J = 5.1, 8.1 Hz, 1 H), 5.36 (septet), J = 6.3 Hz, 1H), 1.41 (d, J = 6.3 Hz, 6H).
3-羟基甲基 -吡啶 -2-甲酸异丙酯（4 )
Figure imgf000016_0002
3-hydroxymethyl-pyridine-2-carboxylic acid isopropyl ester (4)
Figure imgf000016_0002
将化合物 2 (52.7 g, 0.25mol) 溶解在 400mL的二氯亚砜中加热回流至溶 液成均相， 然后旋干溶剂。 加 2x50mL无水 THF旋蒸， 去除残留的二氯亚砜。 将所得到的红色液体溶于 400mL无水 THF中冷却到 0°C ,分批加入硼氢化钠 (28.6 g, 0.76 mol), 0°C下搅拌 4个小时， 将反应溶液小心的倒入冰水中， 3x200mL二氯甲烷萃取， 加无水 Na2S04干燥。 柱层析 （石油醚:乙酸乙酯 = 3:2 )得到黄色固体化合物 4 (18.8 g, 38%)。 ^ NMR (CDC13, 300ΜΗζ) δ 8.69 (dd, J = 1.5, 4.7 Hz, 1H ), 7.88 (dd, J = 1.5, 7.7 Hz, 1H), 7.46 (dd, J = 4.7, 7.8 Hz, 1 H), 5.35 (septet, J = 6.4 Hz, 1H), 4.81 (m, 2 H), 1.45 (d, J = 6.3 Hz, 6H). EI-MS m/z: 195(M)+。 Compound 2 (52.7 g, 0.25 mol) was dissolved in 400 mL of thionyl chloride and heated to reflux until the solution became homogeneous, then the solvent was evaporated. The residual thionyl chloride was removed by steaming with 2 x 50 mL of anhydrous THF. The obtained red liquid was dissolved in 400 mL of anhydrous THF and cooled to 0 ° C, sodium borohydride (28.6 g, 0.76 mol) was added in portions, and stirred at 0 ° C for 4 hours, and the reaction solution was carefully poured into ice. In water, 3x200 mL of dichloromethane was extracted and dried over anhydrous Na 2 SO 4 . Column chromatography (petroleum ether: ethyl acetate = 3:2) gave Compound 4 (18.8 g, 38%). ^ NMR (CDC1 3 , 300ΜΗζ) δ 8.69 (dd, J = 1.5, 4.7 Hz, 1H ), 7.88 (dd, J = 1.5, 7.7 Hz, 1H), 7.46 (dd, J = 4.7, 7.8 Hz, 1 H ), 5.35 (septet, J = 6.4 Hz, 1H), 4.81 (m, 2 H), 1.45 (d, J = 6.3 Hz, 6H). EI-MS m/z: 195(M) + .
3-{[甲氧 甲基- (甲苯 -4·^酰基) - ]-甲基 } -吡啶 酸异丙酯（ 5 )  3-{[methoxymethyl-(toluene-4·^acyl)-]-methyl}-pyridyl isopropylate ( 5 )
Figure imgf000017_0001
Figure imgf000017_0001
将化合物 4 (1.734 g, 8.89 mmol), 2-对甲苯磺酰胺基乙酸甲酯 ( TsNHCH2COOCH3 ) (2.163 g, 8.89 mmol), 以及三苯基膦 (3.499 g, 13.338 mmol) 溶解在 100 mL无水 THF中， 冷却到 0°C , 充氮气保护。 DEAD (2.165 mL, 13.338 mmol) 溶解在 10 mL无水 THF中， 逐滴加入 DEAD。撤去冰浴， 搅 拌两小时后旋干得到红色油状液体化合物 5直接用于下步反应。 Compound 4 (1.734 g, 8.89 mmol), methyl 2-p-toluenesulfonamidate (TsNHCH 2 COOCH 3 ) (2.163 g, 8.89 mmol), and triphenylphosphine (3.499 g, 13.338 mmol) were dissolved in 100 In mL anhydrous THF, cooled to 0 ° C and protected with nitrogen. DEAD (2.165 mL, 13.338 mmol) was dissolved in 10 mL of dry THF and DEAD was added dropwise. The ice bath was removed, stirred for two hours and then spun dry to give the red oily liquid compound 5 directly to the next step.
8-羟基 -1,6-二氮杂萘 酸甲酯（6 )
Figure imgf000017_0002
Methyl 8-hydroxy-1,6-naphthyridinium (6)
Figure imgf000017_0002
将上步反应得到的化合物 5 (8.89 mmol )溶解在 50 mL无水甲醇里， 冷却 到 0°C。 緩慢加入甲醇钠（1.681 g, 31.123 mmol)。 撤去冰浴， 搅拌 3个小时。 旋掉溶剂， 加 20 mL水， 20 mL乙酸乙酯， 有机相用饱和碳酸钠反萃。 合并水 相， 调 pH到 7, 维持水相 pH到 7, 用二氯甲烷萃取 5次。 有机相用无水硫酸钠 干燥， 柱层析 （石油醚:乙酸乙酯 = 2: 1 ) 得到灰白色固体化合物 6 (0.62 g, 二步产率 65%)。 熔点: 179-180 °C ; ^ NMR (CDC13, 300ΜΗζ) δ 11.79 (s, 1H), 9.20 (s, 1H), 8.85 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.71 (dd, J = 4.1, 8.2 Hz, 1H), 4.12 (s,3H)。 The compound 5 (8.89 mmol) obtained in the previous reaction was dissolved in 50 mL of anhydrous methanol and cooled to 0 °C. Sodium methoxide (1.681 g, 31.123 mmol) was added slowly. Remove the ice bath and stir for 3 hours. The solvent was spun off, 20 mL of water, 20 mL of ethyl acetate was added and the organic phase was stripped with saturated sodium carbonate. The aqueous phases were combined, the pH was adjusted to 7, the aqueous phase was maintained at pH 7 and extracted with dichloromethane for 5 times. The organic phase was dried over anhydrous sodium sulfate (EtOAcjjjjjjjjjjj Melting point: 179-180 ° C; ^ NMR (CDC1 3 , 300 ΜΗζ) δ 11.79 (s, 1H), 9.20 (s, 1H), 8.85 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.71 (dd, J = 4.1, 8.2 Hz, 1H), 4.12 (s, 3H).
5-溴 -8-羟基 -1，6-二氮杂萘 酸甲酯（7-1 )
Figure imgf000017_0003
Methyl 5-bromo-8-hydroxy-1,6-naphthyridinate (7-1)
Figure imgf000017_0003
常温下将 NBS (30 mg, 0.167 mmol) 加入到化合物 6 (34 mg, 0.167 mmol) 的 1 mL CH2Cl2溶液中， 搅拌 1小时。 过滤， 干燥得到白色固体化合物 7-1 (30 mg, 产率 85%); ιΥί NMR (d6 DMSO, 300ΜΗζ) δ 9.26 (dd, J= 1.5, 4.2 Hz, 1H ), 8.59 (dd, J= 1.6, 8.4 Hz, 1H), 8.00 (dd, J= 4.2, 8.4 Hz, 1 H), 3.94 (s,NBS (30 mg, 0.167 mmol) was added to a solution of Compound 6 (34 mg, 0.167 mmol) in 1 mL CH 2 Cl 2 and stirred for 1 hour. Filtered and dried to give a white solid compound 7-1 (30 mg, yield 85%); ι Υί NMR ( d 6 DMSO, 300ΜΗζ) δ 9.26 (dd, J = 1.5, 4.2 Hz, 1H), 8.59 (dd, J = 1.6, 8.4 Hz, 1H), 8.00 (dd, J= 4.2, 8.4 Hz, 1 H), 3.94 (s,
3H)。 N_(4-氟-千基) -5-溴 -8-羟基 -1，6-二氮杂萘 -7 酸胺 ( 8-1 )
Figure imgf000018_0001
3H). N _(4-fluoro-thyl)-5-bromo-8-hydroxy-1,6-naphthyridin-7-amine (8-1)
Figure imgf000018_0001
将化合物 7-1 (25 mg, 0.0883 mmol) 和 4-氟苄胺 (12 mg, 0.0883 mmol) 2 mL甲苯在氮气保护下加热回流 20小时， 冷却至室温。 过滤， 固体用 0.5 mL甲醇洗， 得到白色固体化合物 8-1 , 熔点: Πδ-ΙδθΤ^Η NMR (300MHz, CDC13) δ 13.31 (s, 1Η), 9.20 (dd, J= 1.4, 4.2 Hz, 1H), 8.54 (dd, J= 1.4, 8.8 Hz, 1H), 8.17 (m, 1H), 7.74 (dd, J= 4.4, 8.6 Hz, 1H), 7.38 (dd, J= 5.4, 8.4 Hz, 2H), 7.07 (t, J = 8.4 Hz, 2H), 4.67 (d, J = 6.3 Hz, 2H). EI-MS m/z: 375 (M)+, 377 (M+2)+; 元素分析理论值 C16HuBrFN302: C 51.08, H 2.95, N 11.17; 实际值 C 51.45, H 3.05, N 11.03。 Compound 7-1 (25 mg, 0.0883 mmol) and 4-fluorobenzylamine (12 mg, 0.0883 mmol) 2 mL of toluene were heated to reflux under nitrogen for 20 hr and then cooled to room temperature. Filtered, and solid was washed with 0.5 mL of methanol, to give compound 8-1 as a white solid, mp: Πδ-ΙδθΤ ^ Η NMR ( 300MHz, CDC1 3) δ 13.31 (s, 1Η), 9.20 (dd, J = 1.4, 4.2 Hz, 1H), 8.54 (dd, J= 1.4, 8.8 Hz, 1H), 8.17 (m, 1H), 7.74 (dd, J= 4.4, 8.6 Hz, 1H), 7.38 (dd, J= 5.4, 8.4 Hz, 2H ), 7.07 (t, J = 8.4 Hz, 2H), 4.67 (d, J = 6.3 Hz, 2H). EI-MS m/z: 375 (M) + , 377 (M+2) + ; Elemental Analysis Theory For C 16 H u BrFN 3 0 2 : C 51.08, H 2.95, N 11.17; mp. 51.45, H 3.05, N 11.03.
甲苯 _4_ ^酸 5-溴 -7-(4-氟-苄基 ^甲酰 )-l，6-二氮杂萘 -8 酸酯（9-1 )
Figure imgf000018_0002
Toluene_4_^acid 5-bromo-7-(4-fluoro-benzylformyl)-l,6-naphthyridin-8 acid ester (9-1)
Figure imgf000018_0002
将对甲苯横酰氯 (268 mg, 1.4 mmol)加入到化合物 8-1 (283 mg, 0.75 mmol), 三乙胺 （161.92 mg, 1.6 mmol)的 5 mL氯仿溶液中。 50°C搅拌 5小 时后依次用 5 mL的饱和氯化铵， 饱和食盐水洗， 干燥。 柱层析 （二氯甲烷: 甲醇 = 40:1 ) 得到白色固体化合物 9-1 (360 mg, 产率 90%), 熔 点: 152-154°C ; ^ NMR (CDC13): δ 9.03 (dd, 1H, J= 1.5, 4.2 Hz), 8.58 (dd, 1H, J= 1.5, 8.7 Hz), 7.96 (m,lH), 7.94 (d, 2H, J= 8.1 Hz), 7.69 (dd, 1H, J= 4.2, 8.7 Hz), 7.36 (m, 2H), 7.32 (d, 2H, J= 8.1 Hz), 7.04 (t, 2H, J= 8.7 Hz), 4.60 (d, J = 6.6 Hz, 2H), 2.47 (s, 3H); EI-MS m/z: 530 (M+l)+, 532 (M+3)+; 元素分析理论 值 C24H20BrFN4O: C 52.09, H 3.23, N 7.92; 实际值 C 51.94, H 3.17, N 7.94。 p-Toluene-cross-acid chloride (268 mg, 1.4 mmol) was added to a solution of compound 8-1 (283 mg, 0.75 mmol), triethylamine (161.92 mg, 1.6 mmol) in 5 mL chloroform. After stirring at 50 ° C for 5 hours, it was washed successively with 5 mL of saturated ammonium chloride, saturated brine, and dried. Column chromatography (dichloromethane: methanol = 40: 1) to give a white solid compound 9-1 (360 mg, 90% yield), mp: 152-154 ° C; ^ NMR ( CDC1 3): δ 9.03 (dd , 1H, J= 1.5, 4.2 Hz), 8.58 (dd, 1H, J= 1.5, 8.7 Hz), 7.96 (m,lH), 7.94 (d, 2H, J= 8.1 Hz), 7.69 (dd, 1H, J= 4.2, 8.7 Hz), 7.36 (m, 2H), 7.32 (d, 2H, J= 8.1 Hz), 7.04 (t, 2H, J= 8.7 Hz), 4.60 (d, J = 6.6 Hz, 2H) , 2.47 (s, 3H); EI-MS m/z: 530 (M+l) + , 532 (M+3) + ; Elemental analysis of C 24 H 20 BrFN 4 O: C 52.09, H 3.23, N 7.92; Actual value C 51.94, H 3.17, N 7.94.
N_(4-氟-苄基) -8-(3- J ^丙基 J _5-溴 -1，6-二氮杂萘 -7 ( SI ) N _(4-fluoro-benzyl)-8-(3-J ^propyl J _5-bromo-1,6-naphthyridin-7 (SI)
Figure imgf000018_0003
Figure imgf000018_0003
将化合物 9-1甲苯 -4-磺酸 5-溴 -7-(4-氟-苄基氨基甲酰) -1,6-二氮杂萘 -8- 歡酸酯 (53 mg, 0.1 mmol), 丙二胺（1.0 mmol), 三乙胺 （30 mg, 0.3 mmol), 加 入到 5 mL THF (四氢呋喃）中，加热回流 8小时，旋干 THF ,加入 20 mL CH2C12 (二氯甲烷)， 依次用 20 mL的饱和 Na2C03水溶液， 20 mL的饱和氯化铵水 溶液， 20 mL的饱和食盐水洗， 无水 Na2S04干燥。 碱性氧化铝柱层析 (二氯 甲烷:甲醇 = 50:1), 得到黄色固体化合物 Sl。 产率： 75-85%。 熔点： 78-80°C ; Ή NMR (CDCI3, 300MHz): δ 9.60 (t, 1H, J = 5.4 Hz), 8.97 (d, 1H, J = 3 Hz), 8.42 (d, 1H, J = 8.4 Hz), 8.32 (t,lH, J = 6.0 Hz), 7.60 (dd, 1H, J = 4.5, 8.4 Hz), 7.36 (m, 2H), 7.04 (t, 2H, J = 8.7 Hz), 4.60(d, 2H, J = 6.6 Hz), 4.19(q, 2H, J = 6.3 Hz), 3.96(t, 2H, J= 6.6 Hz), 1.93(m, 2H); EI-MS m/z: 431(M)+, 433(M+2)+; 分析 HPLC tR= 19.083 min, 100 % (A), tR = 12.928 min, 100% (B)。 Compound 9-1 toluene-4-sulfonic acid 5-bromo-7-(4-fluoro-benzylcarbamoyl)-1,6-naphthyridin-8-carboxylate (53 mg, 0.1 mmol) , propylenediamine (1.0 mmol), triethylamine (30 mg, 0.3 mmol), added to 5 mL THF (tetrahydrofuran), heated under reflux for 8 hrs, THF dried, and 20 mL CH 2 C1 2 (dichloromethane) Then, it was washed with 20 mL of a saturated aqueous solution of Na 2 CO 3 , 20 mL of a saturated aqueous solution of ammonium chloride, and 20 mL of saturated brine, and dried over anhydrous Na 2 SO 4 . Basic alumina column chromatography (dichloromethane:methanol = 50:1) afforded a yellow solid compound S. Yield: 75-85%. Melting point: 78-80 ° C; NMR NMR (CDCI3, 300MHz): δ 9.60 (t, 1H, J = 5.4 Hz), 8.97 (d, 1H, J = 3 Hz), 8.42 (d, 1H, J = 8.4 Hz), 8.32 (t,lH , J = 6.0 Hz), 7.60 (dd, 1H, J = 4.5, 8.4 Hz), 7.36 (m, 2H), 7.04 (t, 2H, J = 8.7 Hz), 4.60 (d, 2H, J = 6.6 Hz) ), 4.19(q, 2H, J = 6.3 Hz), 3.96(t, 2H, J= 6.6 Hz), 1.93(m, 2H); EI-MS m/z: 431(M) + , 433(M+ 2) + ; Analytical HPLC t R = 19.083 min, 100 % (A), t R = 12.928 min, 100% (B).
N-(4-氟-苄基) -8-(2- J ^乙基 J -5-溴 -1，6-二氮杂萘 -7 ( S2 )  N-(4-fluoro-benzyl)-8-(2-J^ethyl J-5-bromo-1,6-naphthyridin-7 (S2)
Figure imgf000019_0001
Figure imgf000019_0001
化合物 S2的制备方法与化合物 SI的制备方法类似， 除了用乙二胺代 替丙二胺。 黄色固体， 产率： 75-85%。 熔点: 82-84°C ; NMR (CDC13, 300 MHz): δ 9.73 (m, 1Η), 8.94 (d, 1H, J = 3 Hz), 8.40 (d, 1H, J = 8.4 Hz), 8.30 (m, lH), 7.57 (dd, 1H, J = 4.5, 8.4 Hz), 7.33 (m, 2H), 7.02 (t, 2H, J = 8.4 Hz), 4.59 (d, 2H, J = 6.6 Hz), 4.19 (q, 2H, J = 6.3 Hz), 3.09 (t, 2H, J = 6.3 Hz); EI-MS m/z: 417(M)+, 419(M+2)+; 分析 HPLC tR= 19.475 min, 100% (A), tR = 11.792 min, 99.29% (B)。 The preparation of the compound S2 is similar to the preparation of the compound SI except that ethylenediamine is used in place of the propylenediamine. Yellow solid, Yield: 75-85%. Melting point: 82-84 ° C; NMR (CDC1 3 , 300 MHz): δ 9.73 (m, 1 Η), 8.94 (d, 1H, J = 3 Hz), 8.40 (d, 1H, J = 8.4 Hz), 8.30 (m, lH), 7.57 (dd, 1H, J = 4.5, 8.4 Hz), 7.33 (m, 2H), 7.02 (t, 2H, J = 8.4 Hz), 4.59 (d, 2H, J = 6.6 Hz) , 4.19 (q, 2H, J = 6.3 Hz), 3.09 (t, 2H, J = 6.3 Hz); EI-MS m/z: 417 (M) + , 419 (M+2) + ; Analytical HPLC t R = 19.475 min, 100% (A), t R = 11.792 min, 99.29% (B).
N-(4-氟-苄基) -8-羟基 -1，6-二氮杂萘 -7 ^^(S3-l)
Figure imgf000019_0002
N-(4-fluoro-benzyl)-8-hydroxy-1,6-naphthyridin-7^^(S3-l)
Figure imgf000019_0002
化合物 S3-1的制备方法与化合物 8-1的制备方法类似， 除了用化合物 6代替化合物 7-1。 白色固体， 产率： 75-85%。 lR NMR (300MHz, CDC13) δ 9.18 (dd, J = 1.8, 4.5 Hz, 1H), 8.64 (s, 1H), 8.42 (m, 1H), 8.28 (dd, J = 1.8, 8.4 Hz, 1H), 7.65 (dd, J= 4.2, 8.4 Hz, 1H), 7.38 (m, 2H), 7.06 (m, 2H), 4.68 (d, J = 6.0 Hz, 2H)。 The preparation method of the compound S3-1 is similar to the preparation method of the compound 8-1 except that the compound 6 is used instead of the compound 7-1. White solid, Yield: 75-85%. l R NMR (300MHz, CDC1 3 ) δ 9.18 (dd, J = 1.8, 4.5 Hz, 1H), 8.64 (s, 1H), 8.42 (m, 1H), 8.28 (dd, J = 1.8, 8.4 Hz, 1H ), 7.65 (dd, J= 4.2, 8.4 Hz, 1H), 7.38 (m, 2H), 7.06 (m, 2H), 4.68 (d, J = 6.0 Hz, 2H).
甲苯 _4_ ^酸 7-(4-氟-苄基 ^甲酰 )-l，6-二氮杂萘 -8 酸酯 (S3-2)
Figure imgf000019_0003
Toluene_4_^acid 7-(4-fluoro-benzyloxycarbonyl)-l,6-naphthyridin-8-ester (S3-2)
Figure imgf000019_0003
化合物 S3-2的制备方法与化合物 9-1的制备方法类似， 除了用化合物 S3-1代替化合物 8-1。 白色固体， 产率： 85-95%。 NMR (CDC13): δ 9.11 (s,lH), 9.02 (dd, 1H, J = 1.5, 4.2 Hz), 8.34 (dd, 1H, J = 1.5, 8.7 Hz), 8.12 (m, lH), 7.95 (d, 2H, J = 8.1 Hz), 7.61 (dd, 1H, J = 4.2, 8.7 Hz), 7.37 (m, 2H), 7.33 (d, 2H, J = 8.1 Hz), 7.04 (t, 2H, J = 8.7 Hz), 4.62 (d, J = 6.0 Hz, 2H), 2.47 (s, 3H); EI-MS m/z: 452 (M+l)+。 The preparation method of the compound S3-2 was similar to the preparation method of the compound 9-1 except that the compound S3-1 was used instead of the compound 8-1. White solid, Yield: 85-95%. NMR (CDC1 3 ): δ 9.11 (s, lH), 9.02 (dd, 1H, J = 1.5, 4.2 Hz), 8.34 (dd, 1H, J = 1.5, 8.7 Hz), 8.12 (m, lH), 7.95 (d, 2H, J = 8.1 Hz), 7.61 (dd, 1H, J = 4.2, 8.7 Hz), 7.37 (m, 2H), 7.33 (d, 2H, J = 8.1 Hz), 7.04 (t, 2H, J = 8.7 Hz), 4.62 (d, J = 6.0 Hz, 2H), 2.47 (s, 3H); EI-MS m/z: 452 (M+l) + .
8-(3-氨基丙氨) -N-(4-氟苄基） -1，6-二氮杂萘 酸胺 ( S3 )
Figure imgf000020_0001
8-(3-Aminopropylamino)-N-(4-fluorobenzyl)-1,6-naphthyridiniumamine (S3)
Figure imgf000020_0001
化合物 S3的制备方法与化合物 S1的制备方法类似，除了用化合物 S3-2 代替化合物 9-1。棕色固体，产率： 75-85%。熔点： 62-64 °C ; ^ NMR (300MHz, CDC13): δ 9.59 (d, 1Η, J= 7.5 Hz), 8.91 (dd, 1H, J= 1.5, 3.9 Hz), 8.62 (t, 1H, J = 6.3 Hz), 8.19 (s, 1H), 8.08 (dd, 1H, J= 1.5, 8.4 Hz), 7.48 (dd, 1H, J= 4.2, 8.4 Hz), 7.34 (m, 2H), 7.02 (t, 2H, J= 8.7 Hz), 4.60(d, 2H, J= 6.3 Hz), 4.23 (q, 2H, J= 6.6 Hz), 2.91 (t, 2H, J= 6.6 Hz), 2.00 (s, 2H), 1.89 (m, 2H); EI-MS m/z: 353 (M)+; 分析 HPLC tR= 18.167 min, 100% (A), tR = 12.742 min, 98.29% (B)。 The preparation method of the compound S3 is similar to the preparation method of the compound S1 except that the compound S3-2 is used instead of the compound 9-1. Brown solid, yield: 75-85%. Melting point: 62-64 ° C; ^ NMR (300MHz, CDC1 3 ): δ 9.59 (d, 1 Η, J = 7.5 Hz), 8.91 (dd, 1H, J = 1.5, 3.9 Hz), 8.62 (t, 1H, J = 6.3 Hz), 8.19 (s, 1H), 8.08 (dd, 1H, J= 1.5, 8.4 Hz), 7.48 (dd, 1H, J= 4.2, 8.4 Hz), 7.34 (m, 2H), 7.02 ( t, 2H, J= 8.7 Hz), 4.60(d, 2H, J= 6.3 Hz), 4.23 (q, 2H, J= 6.6 Hz), 2.91 (t, 2H, J= 6.6 Hz), 2.00 (s, 2H), 1.89 (m, 2H ); EI-MS m / z: 353 (m) +; analysis HPLC t R = 18.167 min, 100 % (A), t R = 12.742 min, 98.29% (B).
8-(3- (二甲氨基）丙氨基) -N-(4-氟-苄基) -5-溴 -1,6-二氮杂萘 -7-羧酸胺 ( S4 )  8-(3-(Dimethylamino)propylamino)-N-(4-fluoro-benzyl)-5-bromo-1,6-naphthyridin-7-carboxylic acid amine (S4)
Figure imgf000020_0002
Figure imgf000020_0002
化合物 S4的制备方法与化合物 S1的制备方法类似， 最后一步用二甲 基氨基丙二胺代替丙二胺。 黄绿色固体， 产率： 75-85%。 熔点： 60-62 °C ; NMR (300MHz, CDC13): δ 9.74 (t, 1H, J = 6.6 Hz), 8.94 (dd, 1H, J = 1.8, 4.2 Hz), 8.42 (dd, 1H, J = 1.5, 8.4 Hz), 8.31 (t, 1H, J = 6.3 Hz), 7.68 (dd, 1H, J = 4.2, 8.4 Hz), 7.35 (m, 2H), 7.04 (t, 2H, J = 8.7 Hz), 4.61 (d, 2H, J = 6.0 Hz), 4.17 (q, 2H, J = 6.6 Hz), 2.54 (m, 2H), 1.96 (m, 2H); EI-MS m/z: 459(M)+, 461(M+2)+; 分析 HPLC tR = 18.867 min, 100% (A), tR = 12.808 min, 100% (B)。 The preparation method of the compound S4 is similar to the preparation method of the compound S1, and the final step is to replace the propylenediamine with dimethylaminopropanediamine. Yellow-green solid, Yield: 75-85%. Melting point: 60-62 °C; NMR (300MHz, CDC1 3 ): δ 9.74 (t, 1H, J = 6.6 Hz), 8.94 (dd, 1H, J = 1.8, 4.2 Hz), 8.42 (dd, 1H, J = 1.5, 8.4 Hz), 8.31 (t, 1H, J = 6.3 Hz), 7.68 (dd, 1H, J = 4.2, 8.4 Hz), 7.35 (m, 2H), 7.04 (t, 2H, J = 8.7 Hz) ), 4.61 (d, 2H, J = 6.0 Hz), 4.17 (q, 2H, J = 6.6 Hz), 2.54 (m, 2H), 1.96 (m, 2H); EI-MS m/z: 459 (M + , 461 (M+2) + ; Analytical HPLC t R = 18.867 min, 100% (A), t R = 12.808 min, 100% (B).
2-(7-(4-氟苄 ^甲酰 )-5-溴 -1，6-二氮杂萘 -8- J 醋酸甲酯（ S5 )  2-(7-(4-fluorobenzylformyl)-5-bromo-1,6-naphthyridin-8-J methyl acetate (S5)
Figure imgf000020_0003
Figure imgf000020_0003
化合物 S5的制备方法与化合物 S1的制备方法类似， 最后一步用甘氨 酸甲酯代替丙二胺。 黄绿色固体， 产率： 75-85%。 熔点： 184-185°C ; ^ NMR (300MHz, CDCI3): δ 10.17 (br, 1Η), 8.86 (dd, 1H, J= 1.5, 4.2 Hz), 8.43 (dd, 1H; J= 1.5, 8.4 Hz), 8.34 (t, 1H, J= 6.0 Hz), 7.58 (dd, 1H, J= 4.2, 8.4 Hz), 7.36 (m, 2H), 7.04 (t, 2H, J= 8.7 Hz), 4.82 (s, 2H), 4.63 (d, 2H, J= 6.3 Hz), 3.73 (s, 3H); EI-MS m/z: 446 (M)+, 448 (M+2)+; 分析 HPLC tR= 21.025 min, 100% (A), tR = 16.158 min, 100% (B)。 The preparation method of the compound S5 is similar to the preparation method of the compound S1, and the final step is to replace the propylenediamine with methyl glycinate. Yellow-green solid, Yield: 75-85%. Melting point: 184-185°C; ^ NMR (300MHz, CDCI3): δ 10.17 (br, 1Η), 8.86 (dd, 1H, J= 1.5, 4.2 Hz), 8.43 (dd, 1H ; J= 1.5, 8.4 Hz ), 8.34 (t, 1H, J = 6.0 Hz), 7.58 (dd, 1H, J= 4.2, 8.4 Hz), 7.36 (m, 2H), 7.04 (t, 2H, J= 8.7 Hz), 4.82 (s , 2H), 4.63 (d, 2H, J = 6.3 Hz), 3.73 (s, 3H); EI-MS m/z: 446 (M) + , 448 (M+2) + ; Analytical HPLC t R = 21.025 Min, 100% (A), t R = 16.158 min, 100% (B).
5-溴 -8-(3-甲磺酰 J ^丙 J -1，6-二氮杂萘 酸 -4-氟-苄酰胺 ( S6 )  5-bromo-8-(3-methanesulfonyl J ^ propyl J -1,6-naphthyridinic acid-4-fluoro-benzylamide (S6)
Figure imgf000021_0001
Figure imgf000021_0001
化合物 S6的制备方法与化合物 SI的制备方法类似， 最后一步用 N-(3-氨 基丙基) -甲磺酰胺代替丙二胺。 黄色固体， 产率： 75-85%。 熔点： 153-155°C ; ^ NMR (300MHz, CDC13): δ 9.21 (m, 1H), 9.11 (dd, 1H, J= 1.8, 4.2 Hz), 8.53 (dd, 1H, J= 1.5, 8.4 Hz), 8.40 (t, 1H, J= 6.3 Hz), 7.68 (dd, 1H, J= 4.2, 8.4 Hz), 7.35 (m, 2H), 7.05 (t, 2H, J = 8.7 Hz), 6.61 (t, 1H, J = 6.0 Hz), 4.61 (d, 2H, J = 6.0 Hz), 4.14 (m, 2H), 3.42 (q, 2H, J = 6.0 Hz), 2.91 (s, 3H), 2.01 (m, 2H); EI-MS m/z: 509(M)+, 511(M+2)+; 分析 RP-HPLC tR= 20.833 min, 100% (A), tR = 6.067 min, 99.46% (B)。 The preparation method of the compound S6 is similar to the preparation method of the compound SI, and the final step is to replace the propylenediamine with N-(3-aminopropyl)-methanesulfonamide. Yellow solid, Yield: 75-85%. Melting point: 153-155°C; ^ NMR (300MHz, CDC1 3 ): δ 9.21 (m, 1H), 9.11 (dd, 1H, J = 1.8, 4.2 Hz), 8.53 (dd, 1H, J= 1.5, 8.4 Hz), 8.40 (t, 1H, J= 6.3 Hz), 7.68 (dd, 1H, J= 4.2, 8.4 Hz), 7.35 (m, 2H), 7.05 (t, 2H, J = 8.7 Hz), 6.61 ( t, 1H, J = 6.0 Hz), 4.61 (d, 2H, J = 6.0 Hz), 4.14 (m, 2H), 3.42 (q, 2H, J = 6.0 Hz), 2.91 (s, 3H), 2.01 ( m, 2H); EI-MS m/z: 509 (M) + , 511 (M+2) + ; Analytical RP-HPLC t R = 20.833 min, 100% (A), t R = 6.067 min, 99.46% (B).
8-(3- (苯甲酰胺) J _N-(4-氟苄基 )-5-溴 -1，6-二氮杂萘 -7 ( S7 )  8-(3-(benzamide) J _N-(4-fluorobenzyl)-5-bromo-1,6-naphthyridin-7 (S7)
Figure imgf000021_0002
Figure imgf000021_0002
化合物 S7的制备方法与化合物 SI的制备方法类似， 最后一步用 N-(3- 氨基丙基) -苯甲酰胺代替丙二胺。棕色固体，产率： 75-85%。熔点： 144-146°C ; ^ NMR (300MHz, CDC13): δ 9.63 (br, 1H), 8.83 (dd, 1H, J= 1.8, 4.2 Hz), 8.43 (dd, 1H, J= 1.5, 8.4 Hz), 8.34 (t, 1H, J= 6.3 Hz), 7.75 (d, 2H, J= 6.9 Hz), 7.57 (dd, 1H, J = 4.2, 8.4 Hz), 7.50-7.32 (m, 5H), 7.04 (t, 2H, J = 8.7 Hz), 6.68 (br, 1H), 4.59 (d, 2H, J = 6.6 Hz), 4.26 (t, 2H, J = 6.6 Hz), 3.66 (q, 2H, J= 6.3 Hz), 2.08 (m, 2H); EI-MS m/z: 535(M)+, 537(M+2)+; 分析 RP-HPLC tR= 6.408 min, 100% (A), tR = 6.208 min, 100% (B)。 The preparation of the compound S7 is similar to the preparation of the compound SI, and the final step is to replace the propylenediamine with N-(3-aminopropyl)-benzamide. Brown solid, yield: 75-85%. Melting point: 144-146°C; ^ NMR (300MHz, CDC1 3 ): δ 9.63 (br, 1H), 8.83 (dd, 1H, J= 1.8, 4.2 Hz), 8.43 (dd, 1H, J= 1.5, 8.4 Hz), 8.34 (t, 1H, J = 6.3 Hz), 7.75 (d, 2H, J = 6.9 Hz), 7.57 (dd, 1H, J = 4.2, 8.4 Hz), 7.50-7.32 (m, 5H), 7.04 (t, 2H, J = 8.7 Hz), 6.68 (br, 1H), 4.59 (d, 2H, J = 6.6 Hz), 4.26 (t, 2H, J = 6.6 Hz), 3.66 (q, 2H, J = 6.3 Hz), 2.08 (m, 2H); EI-MS m/z: 535 (M) + , 537 (M+2) + ; Analytical RP-HPLC t R = 6.408 min, 100% (A), t R = 6.208 min, 100% (B).
N-(4-氟苄基 )-8-(6- ^己 J -5-溴 -1，6-二氮杂萘 -7 ( S8 )  N-(4-fluorobenzyl)-8-(6-^hexyl J-5-bromo-1,6-naphthyridin-7 (S8)
Figure imgf000021_0003
Figure imgf000021_0003
化合物 S8的制备方法与化合物 SI的制备方法类似， 最后一步用己二 胺代替丙二胺。 黄绿色固体， 产率： 75-85%。 熔点： 108-112°C ; lR NMR (300MHz, CDC13): δ 9.65 (br, 1H), 8.91 (dd, 1H, J= 1.8, 4.2 Hz), 8.38 (dd, 1H, J= 1.5, 8.4 Hz), 8.30 (t, 1H, J= 6.3 Hz), 7.56 (dd, 1H, J= 4.2, 8.4 Hz), 7.35 (m, 2H), 7.03 (t, 2H, J = 8.7 Hz), 4.60 (d, 2H, J = 6.6 Hz), 4.26 (m, 2H), 2.75 (m, 2H), 1.8-1.15 (m, 8H); EI-MS m/z: 473 (M)+, 475 (M+2)+; 分析 HPLC tR = 19.558 min, 100% (A), tR = 13.508 min, 96.32% (B)。 The preparation method of the compound S8 is similar to the preparation method of the compound SI, and the last step is to use the second method. The amine replaces the propylene diamine. Yellow-green solid, Yield: 75-85%. Melting point: 108-112 ° C; l R NMR (300 MHz, CDC1 3 ): δ 9.65 (br, 1H), 8.91 (dd, 1H, J = 1.8, 4.2 Hz), 8.38 (dd, 1H, J = 1.5, 8.4 Hz), 8.30 (t, 1H, J= 6.3 Hz), 7.56 (dd, 1H, J= 4.2, 8.4 Hz), 7.35 (m, 2H), 7.03 (t, 2H, J = 8.7 Hz), 4.60 (d, 2H, J = 6.6 Hz), 4.26 (m, 2H), 2.75 (m, 2H), 1.8-1.15 (m, 8H); EI-MS m/z: 473 (M) + , 475 (M +2) + ; Analytical HPLC t R = 19.558 min, 100% (A), t R = 13.508 min, 96.32% (B).
8-(4- J^苯胺) -N-(4-氟苄基 )-5-溴 -1，6-二氮杂萘 -7 ( S9 )  8-(4-J^phenylamine)-N-(4-fluorobenzyl)-5-bromo-1,6-naphthyridin-7 (S9)
Figure imgf000022_0001
Figure imgf000022_0001
化合物 S9的制备方法与化合物 SI的制备方法类似， 最后一步用对苯 二胺代替丙二胺。 深红色固体， 产率： 75-85%。 熔点： 190-192°C ; NMR (300MHz, CDCI3): δ 10.64 (s, 1Η), 8.73 (dd, 1H, J= 1.8, 4.2 Hz), 8.44 (dd, 1H, J= 1.5, 8.4 Hz), 8.38 (t, 1H, J= 6.3 Hz), 7.54 (dd, 1H, J= 4.2, 8.4 Hz), 7.36 (m, 2H), 7.03 (t, 2H, J= 8.7 Hz), 6.80 (d, 2H, J = 8.4 Hz), 6.56 (d, 2H, J= 8.4 Hz), 4.60 (d, 2H, J = 6.6 Hz); EI-MS m/z: 465 (M)+, 467 (M+2)+; 分析 HPLC tR = 16.067 min, 100% (A), tR = 10.667 min, 99.18% (B)。 The preparation method of the compound S9 is similar to the preparation method of the compound SI, and the final step is to replace the propylenediamine with p-phenylenediamine. Dark red solid, Yield: 75-85%. Melting point: 190-192°C; NMR (300MHz, CDCI3): δ 10.64 (s, 1Η), 8.73 (dd, 1H, J= 1.8, 4.2 Hz), 8.44 (dd, 1H, J= 1.5, 8.4 Hz) , 8.38 (t, 1H, J = 6.3 Hz), 7.54 (dd, 1H, J= 4.2, 8.4 Hz), 7.36 (m, 2H), 7.03 (t, 2H, J= 8.7 Hz), 6.80 (d, 2H, J = 8.4 Hz), 6.56 (d, 2H, J = 8.4 Hz), 4.60 (d, 2H, J = 6.6 Hz); EI-MS m/z: 465 (M) + , 467 (M+2 + ; Analytical HPLC t R = 16.067 min, 100% (A), t R = 10.667 min, 99.18% (B).
8-(3- ^苯胺) -N-(4-氟苄基 )-5-溴 -1，6-二氮杂萘 -7 ( S10 )  8-(3-^Benzylamine)-N-(4-fluorobenzyl)-5-bromo-1,6-naphthyridin-7 (S10)
Figure imgf000022_0002
Figure imgf000022_0002
化合物 S10的制备方法与化合物 SI的制备方法类似， 最后一步用间苯 二胺代替丙二胺。 黄色固体， 产率： 75-85%。 熔点： 167-169°C ; NMR (300MHz, CDCI3): δ 10.54 (s, 1Η), 8.85 (dd, 1H, J= 1.8, 4.2 Hz), 8.47 (dd, 1H, J= 1.5, 8.4 Hz), 8.38 (t, 1H, J= 6.3 Hz), 7.59 (dd, 1H, J= 4.2, 8.4 Hz), 7.35 (m, 2H), 7.04 (t, 2H, J = 8.7 Hz), 6.95 (t, 1H, J = 8.0 Hz), 6.36 (d, 1H, J = 8.0 Hz), 6.28 (m, 2H), 4.61 (d, 2H, J= 6.3 Hz), 3.56 (br, 2H); EI-MS m/z: 465 (M)+, 467 (M+2)+; 分析 HPLC tR= 16.292 min, 100% (A), tR = 11.067 min, 100% (B)。 The preparation method of the compound S10 is similar to the preparation method of the compound SI, and the last step is to replace the propylenediamine with m-phenylenediamine. Yellow solid, Yield: 75-85%. Melting point: 167-169°C; NMR (300MHz, CDCI3): δ 10.54 (s, 1Η), 8.85 (dd, 1H, J= 1.8, 4.2 Hz), 8.47 (dd, 1H, J= 1.5, 8.4 Hz) , 8.38 (t, 1H, J = 6.3 Hz), 7.59 (dd, 1H, J= 4.2, 8.4 Hz), 7.35 (m, 2H), 7.04 (t, 2H, J = 8.7 Hz), 6.95 (t, 1H, J = 8.0 Hz), 6.36 (d, 1H, J = 8.0 Hz), 6.28 (m, 2H), 4.61 (d, 2H, J = 6.3 Hz), 3.56 (br, 2H); EI-MS m /z: 465 (M) + , 467 (M+2) + ; Analytical HPLC t R = 16.292 min, 100% (A), t R = 11.067 min, 100% (B).
N-(4-氟苄基 )-5-溴 -8-(l-哌嗪) -1，6-二氮杂萘 -7 酸胺 ( Sll )  N-(4-fluorobenzyl)-5-bromo-8-(l-piperazine)-1,6-naphthyridin-7-amine (Sll)
Figure imgf000022_0003
Figure imgf000022_0003
化合物 Sll的制备方法与化合物 SI的制备方法类似， 最后一步用哌嗪 代替丙二胺。棕色固体，产率： 75-85%。熔点： 191-195°C ; lR NMR (300MHz, CDCI3): δ 9.07 (dd, 1H, J= 1.5, 4.2 Hz), 8.59 (t, 1H, J= 6.0 Hz), 8.53 (dd, 1H, J = 1.5, 8.4 Hz), 7.63 (dd, 1H, J = 4.2, 8.4 Hz), 7.39 (m, 2H), 7.04 (t, 2H, J = 8.7 Hz), 4.66 (d, 2H, J = 6.3 Hz), 3.59 (t, 4H, J = 4.5 Hz), 3.13 (t, 4H, J = 4.5 Hz), 2.74 (br, 1H); EI-MS m/z: 443 (M)+, 445 (M+2)+; 分析 HPLC tR= 19.808 min, 100% (A), tR = 12.050 min, 96.48% (B)。 The preparation method of the compound S11 is similar to the preparation method of the compound SI, and the last step is piperazine. Instead of propylene diamine. Brown solid, yield: 75-85%. Melting point: 191-195°C; l R NMR (300MHz, CDCI3): δ 9.07 (dd, 1H, J= 1.5, 4.2 Hz), 8.59 (t, 1H, J = 6.0 Hz), 8.53 (dd, 1H, J = 1.5, 8.4 Hz), 7.63 (dd, 1H, J = 4.2, 8.4 Hz), 7.39 (m, 2H), 7.04 (t, 2H, J = 8.7 Hz), 4.66 (d, 2H, J = 6.3 Hz), 3.59 (t, 4H, J = 4.5 Hz), 3.13 (t, 4H, J = 4.5 Hz), 2.74 (br, 1H); EI-MS m/z: 443 (M) + , 445 (M +2) + ; Analytical HPLC t R = 19.808 min, 100% (A), t R = 12.050 min, 96.48% (B).
叔丁基 4-(7-(4-氟苄氨基甲酰 )-5-溴 -1，6-二氮杂萘 -8- J 哌嗪 -1-羧酸 酯（ S12 )  tert-Butyl 4-(7-(4-fluorobenzylcarbamoyl)-5-bromo-1,6-diazaphthalene-8-J piperazine-1-carboxylate (S12)
Figure imgf000023_0001
Figure imgf000023_0001
化合物 S12的制备方法与化合物 S1的制备方法类似， 最后一步用哌嗪 -1-羧酸叔丁酯代替丙二胺。 黄色固体， 产率： 75-85%。 熔点： 118-122°C ; NMR (300MHz, CDC13): δ 9.02 (dd, 1Η, J= 1.5, 4.2 Hz), 8.47 (dd, 1H, J= 1.8, 8.4 Hz), 8.18 (t, 1H, J = 8.7 Hz), 7.59 (dd, 1H, J = 4.2, 8.4 Hz), 7.35 (m, 2H), 6.99 (t, 2H, J= 8.7 Hz), 4.61 (d, 2H, J= 6.3 Hz), 3.59 (s, 4H), 3.47 (s, 4H), 1.49 (s, 9H); EI-MS m/z: 543 (M)+, 545(M+2)+; 分析 HPLC tR= 20.483 min, 100% (A), tR = 14.767 min, 99.35% (B)。 The preparation of the compound S12 is similar to the preparation of the compound S1, and the final step is to replace the propylenediamine with piperazine-1-carboxylic acid tert-butyl ester. Yellow solid, Yield: 75-85%. Melting point: 118-122°C; NMR (300MHz, CDC1 3 ): δ 9.02 (dd, 1Η, J= 1.5, 4.2 Hz), 8.47 (dd, 1H, J= 1.8, 8.4 Hz), 8.18 (t, 1H , J = 8.7 Hz), 7.59 (dd, 1H, J = 4.2, 8.4 Hz), 7.35 (m, 2H), 6.99 (t, 2H, J= 8.7 Hz), 4.61 (d, 2H, J= 6.3 Hz) ), 3.59 (s, 4H), 3.47 (s, 4H), 1.49 (s, 9H); EI-MS m/z: 543 (M) + , 545 (M+2) + ; Analytical HPLC t R = 20.483 Min, 100% (A), t R = 14.767 min, 99.35% (B).
N-(4-氟苄基 )-5-溴 -8- (哌啶 -4- J -l，6-二氮杂萘 -7 酸胺 ( S13 )  N-(4-fluorobenzyl)-5-bromo-8-(piperidin-4- J-l,6-naphthyridin-7-amine (S13)
Figure imgf000023_0002
Figure imgf000023_0002
化合物 S13 的制备方法与化合物 S1的制备方法类似， 最后一步用 4- 氨基 -哌啶代替丙二胺。 黄绿色固体， 产率： 75-85%。 熔点： >200°C ; ^ NMR (300MHz, CDCI3): δ 8.94 (dd, 1Η, J = 2.1, 4.2 Hz), 8.46 (dd, 1H, J = 1.8, 8.4 Hz), 8.32 (t, 1H, J = 6.0 Hz), 7.63 (dd, 1H, J = 4.2, 8.4 Hz), 7.33 (m, 2H), 7.02 (t, 2H, J= 8.7 Hz), 5.27 (m, 1H), 4.56 (d, 2H, J= 6.0 Hz), 3.39 (m, 2H), 2.31 (m 2H), 1.84 (m, 2H); EI-MS m/z: 571(M)+, 573(M+2)+; 分析 HPLC tR = 6.292 min, 100% (A), tR = 12.658 min, 100% (B)。 The preparation method of the compound S13 is similar to the preparation method of the compound S1, and the final step is to replace the propylenediamine with 4-amino-piperidine. Yellow-green solid, Yield: 75-85%. Melting point: >200°C ; ^ NMR (300MHz, CDCI3): δ 8.94 (dd, 1Η, J = 2.1, 4.2 Hz), 8.46 (dd, 1H, J = 1.8, 8.4 Hz), 8.32 (t, 1H, J = 6.0 Hz), 7.63 (dd, 1H, J = 4.2, 8.4 Hz), 7.33 (m, 2H), 7.02 (t, 2H, J= 8.7 Hz), 5.27 (m, 1H), 4.56 (d, 2H, J= 6.0 Hz), 3.39 (m, 2H), 2.31 (m 2H), 1.84 (m, 2H); EI-MS m/z: 571(M) + , 573(M+2) + ; HPLC t R = 6.292 min, 100% (A), t R = 12.658 min, 100% (B).
4-(7-(4-氟苄 ^甲酰 )-5-溴 -1，6-二氮杂萘 -8- J哌啶 -1-叔丁基羧酸酯 ( S14 )
Figure imgf000024_0001
4-(7-(4-fluorobenzylformyl)-5-bromo-1,6-naphthyridin-8-J piperidin-1-tert-butylcarboxylate (S14)
Figure imgf000024_0001
化合物 S14的制备方法与化合物 S1的制备方法类似， 最后一步用哌啶 -1-羧酸叔丁酯代替丙二胺。 黄色固体， 产率： 75-85%。 熔点： 134-137°C ; NMR (300MHz, CDC13): δ 8.96 (dd, 1Η, J= 1.5, 3.9 Hz), 8.44 (dd, 1H, J= 1.5, 8.4 Hz), 8.32 (t, 1H, J = 6.0 Hz), 7.61 (dd, 1H, J = 4.2, 8.4 Hz), 7.35 (m, 2H),The preparation of the compound S14 is similar to the preparation of the compound S1, and the final step is to replace the propylenediamine with piperidine-1-carboxylic acid tert-butyl ester. Yellow solid, Yield: 75-85%. Melting point: 134-137°C; NMR (300MHz, CDC1 3 ): δ 8.96 (dd, 1Η, J= 1.5, 3.9 Hz), 8.44 (dd, 1H, J= 1.5, 8.4 Hz), 8.32 (t, 1H , J = 6.0 Hz), 7.61 (dd, 1H, J = 4.2, 8.4 Hz), 7.35 (m, 2H),
7.04 (t, 2H, J = 8.7 Hz), 5.18 (m, 1H), 4.60 (d, 2H, J = 6.0 Hz), 3.99 (m, 2H),7.04 (t, 2H, J = 8.7 Hz), 5.18 (m, 1H), 4.60 (d, 2H, J = 6.0 Hz), 3.99 (m, 2H),
3.05 (m, 2H), 2.06 (m, 2H), 1.62 (m, 2H); 1.45 (s, 9H); EI-MS m/z: 557 (M)+, 559 (M+2)+; 分析 HPLC tR = 23.967 min, 100% (A), tR = 19.517 min, 100% (B)。 3.05 (m, 2H), 2.06 (m, 2H), 1.62 (m, 2H); 1.45 (s, 9H); EI-MS m / z: 557 (M) +, 559 (M + 2) +; Analysis HPLC t R = 23.967 min, 100% (A), t R = 19.517 min, 100% (B).
8-((lr，4r)-4-氨基环己氨基) -N-(4-氟苄基 )-5-溴 -1，6-二氮杂萘 -7-羧酸胺 ( S15 )  8-((lr,4r)-4-Aminocyclohexylamino)-N-(4-fluorobenzyl)-5-bromo-1,6-naphthyridin-7-carboxylic acid amine (S15)
Figure imgf000024_0002
Figure imgf000024_0002
化合物 S15的制备方法与化合物 S1的制备方法类似， 最后一步用反式 1,4-环己二胺代替丙二胺。 黄绿色固体， 产率： 75-85%。 熔点： 147-152°C ; NMR (300MHz, CDC13): δ 9.63 (d, 1H, J = 7.5Hz), 8.94 (dd, 1H, J = 1.5, 3.9 Hz), 8.40 (dd, 1H, J = 1.5, 8.4 Hz), 8.33 (t, 1H, J = 6.0 Hz), 7.58 (dd, 1H, J = 4.2, 8.4 Hz), 7.35 (m, 2H), 7.04 (t, 2H, J = 8.7 Hz), 4.97 (m, 1H), 4.60(d, 2H, J = 6.0 Hz), 2.76 (m, 1H), 2.18 (m, 2H), 1.92 (m, 4H), 1.42 (m, 4H); EI-MS m/z: 471 (M)+, 473 (M+2)+; HR-EIMS 理论值 C22H23N5OFBr: 471.1070, 实际值： 471.1063. 分析 HPLC tR = 5.325 min, 93.63% (A), tR = 12.692 min, 99.60% (B)。 The preparation method of the compound S15 is similar to the preparation method of the compound S1, and the final step is to replace the propylenediamine with trans 1,4-cyclohexanediamine. Yellow-green solid, Yield: 75-85%. Melting point: 147-152°C; NMR (300MHz, CDC1 3 ): δ 9.63 (d, 1H, J = 7.5Hz), 8.94 (dd, 1H, J = 1.5, 3.9 Hz), 8.40 (dd, 1H, J = 1.5, 8.4 Hz), 8.33 (t, 1H, J = 6.0 Hz), 7.58 (dd, 1H, J = 4.2, 8.4 Hz), 7.35 (m, 2H), 7.04 (t, 2H, J = 8.7 Hz) ), 4.97 (m, 1H), 4.60 (d, 2H, J = 6.0 Hz), 2.76 (m, 1H), 2.18 (m, 2H), 1.92 (m, 4H), 1.42 (m, 4H); EI -MS m/z: 471 (M) + , 473 (M+2) + ; HR-EIMS calcd for C 22 H 23 N 5 OFBr: 471.1070, actual value: 471.1063. Analytical HPLC t R = 5.325 min, 93.63% (A), t R = 12.692 min, 99.60% (B).
N-(4-氟-苄基) -5-(l，l-二氧 -1λ6-过氢 -1,2-噻嗪 -2-基) -8-羟基 -1,6-二氮杂 萘 -7 (S16-1) N-(4-fluoro-benzyl)-5-(l,l-dioxo-1λ 6 -perhydro-1,2-thiazin-2-yl)-8-hydroxy-1,6-diaza Naphthalene-7 (S16-1)
Figure imgf000024_0003
Figure imgf000024_0003
将过氢 -1,2-噻嗪 -1,1-二氧化物 （制备参考 J. Org. Chem. 1987, 52, 2162) (135mg, lmmol), N-(4-氟-苄基) -5-溴 -8-羟基 -1,6-二氮杂萘 -7-羧酰胺 8-1 (375mg, lmmol), 以及氧化亚铜 （170mg, 1.2mmol)加入到 lmL吡1定中， 氮 气保护， 加热回流 16小时. 反应体系冷却至室温， 过滤， 滤渣用 10mL 氯仿 洗， 旋干滤液加入 20mL氯仿， 1.2g EDTA, 120mL水， 搅拌 16小时， 有机相 用无水 J交钠干燥. 柱层析 （二氯甲烷:甲醇 = 70:1 )得到浅黄色固体化合 物 S16-l。 ^ NMR (300MHz, CDC13) δ 13.34 (br, 1H), 9.19 (dd, J= 1.5, 4.2 Hz, 1H), 8.61(d, J = 1.5, 8.7 Hz, 1H), 7.96 (m, 1H), 7.69(dd, J = 4.8, 8.7 Hz, 1H), 7.37 (m, 2H), 7.07 (t, J= 8.6 Hz, 2H), 4.67(m, 2H), 3.93 (m, 2H), 3.30 (t, J = 6.3 Hz, 2H), 2.45-2.36 (m, 2H), 2.18-2.15 (m, 1H), 1.85-1.82 (m, 1H); EI-MS m/z: 430(M)+; 分析 HPLC tR= 17.042 min, 100% (A), tR = 12.350 min, 99.45% (B)。 Hydrogen-1,2-thiazine-1,1-dioxide (preparation reference J. Org. Chem. 1987, 52, 2162) (135 mg, 1 mmol), N-(4-fluoro-benzyl)- 5-bromo-8-hydroxy-1,6-naphthyridin-7-carboxamide 8-1 (375mg, lmmol), and cuprous oxide (170mg, 1.2mmol) was added to a pyridine 1 lmL given in nitrogen atmosphere, was heated at reflux for 16 h. The reaction was cooled to room temperature, filtered, the filter cake washed with 10mL of chloroform, was added the filtrate by rotary evaporation 20 mL of chloroform, 1.2 g of EDTA, 120 mL of water, stirred for 16 hours, and the organic phase was dried over anhydrous sodium chloride. ^ NMR (300MHz, CDC1 3 ) δ 13.34 (br, 1H), 9.19 (dd, J= 1.5, 4.2 Hz, 1H), 8.61 (d, J = 1.5, 8.7 Hz, 1H), 7.96 (m, 1H) , 7.69 (dd, J = 4.8, 8.7 Hz, 1H), 7.37 (m, 2H), 7.07 (t, J = 8.6 Hz, 2H), 4.67 (m, 2H), 3.93 (m, 2H), 3.30 ( t, J = 6.3 Hz, 2H), 2.45-2.36 (m, 2H), 2.18-2.15 (m, 1H), 1.85-1.82 (m, 1H); EI-MS m/z: 430(M) + ; Analytical HPLC t R = 17.042 min, 100% (A), t R = 12.350 min, 99.45% (B).
甲苯 -4-磺酸 5-(l，l-二氧 -1λ6-过氢 -1，2-噻嗪 -2-基) -7-(4-氟-苄基氨基甲 酰) -1,6-二氮杂萘 酸酯（S16-2) Toluene-4-sulfonic acid 5-(l,l-dioxo-1λ 6 -perhydro-1,2-thiazin-2-yl)-7-(4-fluoro-benzylcarbamoyl)-1, 6-diazaphthalate (S16-2)
Figure imgf000025_0001
Figure imgf000025_0001
化合物 S16-2的制备方法与化合物 9-1的制备方法类似，除了用化合物 S16-1代替化合物 8-1。白色固体，产率： 85-95%。 ^ NMR (300MHz, CDC13): δ 8.92 (d, 1Η, J = 3.9 Hz), 8.60 (d, 1H, J = 8.4 Hz), 7.93 (d, 2H, J = 8.1 Hz), 7.59 (dd, 1H, J = 4.2, 8.7 Hz), 7.49 (m, 1H), 7.36 (m, 4H), 7.05 (t, 2H, J = 8.7 Hz), 4.63 (d, J = 6.0 Hz, 2H), 4.03 (m, 2H), 3.31 (m, 2H), 2.47(s, 3H), 2.36 (m, 2H), 1.66 (m, 2H); EI-MS m/z: 584 (M)+。 The preparation method of the compound S16-2 was similar to the preparation method of the compound 9-1 except that the compound S16-1 was used instead of the compound 8-1. White solid, yield: 85-95%. ^ NMR (300MHz, CDC1 3 ): δ 8.92 (d, 1Η, J = 3.9 Hz), 8.60 (d, 1H, J = 8.4 Hz), 7.93 (d, 2H, J = 8.1 Hz), 7.59 (dd, 1H, J = 4.2, 8.7 Hz), 7.49 (m, 1H), 7.36 (m, 4H), 7.05 (t, 2H, J = 8.7 Hz), 4.63 (d, J = 6.0 Hz, 2H), 4.03 ( m, 2H), 3.31 (m, 2H), 2.47 (s, 3H), 2.36 (m, 2H), 1.66 (m, 2H); EI-MS m/z: 584 (M) + .
8-((l，4反式) -4-氨基环己氨基 )-5-(l，l-二氧 -1λ6-过氢 -1，2-噻嗪 -2-基） -1,6- 二氮杂萘 酸 4-氟苄酰胺（S16 ) 8 - ((l, 4-trans) -4-amino-cyclohexylamino) -5- (l, l- dioxo -1λ 6 - Hydrogen-1,2-thiazin-2-yl) -1,6 - bis-naphthoic acid 4-fluorobenzylamide (S16)
Figure imgf000025_0002
Figure imgf000025_0002
化合物 S16的制备方法与化合物 S15的制备方法类似， 除了用化合物 S16-2代替化合物 9-1。黄绿色固体，产率： 75-85%。熔点： 174- 176 °C ; ^ NMR (CDC13, 300MHz) δ 9.65 (d, 1Η, J= 7.8 Hz), 8.92 (m, 1H), 8.48 (dd, 1H, J= 1.5 8.7 Hz), 8.07 (m, 1H), 7.54 (dd, 1H, J = 4.2, 8.4 Hz), 7.34 (dd, 2H, J = 5.4, 8.4 Hz), 7.04 (t, 2H, J= 8.4Hz), 5.00 (m, 1H), 4.56 (m, 2H), 3.92 (m, 1H), 3.74 (m, 1H), 3.24 (m, 2H), 2.75 (m, 1H), 2.40 (m, 1H), 2.20 (m, 4H), 1.90 (m, 2H), 1.65 (m, 2H), 1.43 (m, 4H); EI-MS m/z: 526 (M)+; 分析 HPLC tR = 17.875 min, 95.23% (A), tR = 7.375 min, 100% (B)。 The preparation method of the compound S16 is similar to the preparation method of the compound S15 except that the compound S16-2 is used instead of the compound 9-1. Yellow-green solid, yield: 75-85%. Melting point: 174-176 °C; ^ NMR (CDC1 3 , 300MHz) δ 9.65 (d, 1 Η, J = 7.8 Hz), 8.92 (m, 1H), 8.48 (dd, 1H, J = 1.5 8.7 Hz), 8.07 (m, 1H), 7.54 (dd, 1H, J = 4.2, 8.4 Hz), 7.34 (dd, 2H, J = 5.4, 8.4 Hz), 7.04 (t, 2H, J= 8.4Hz), 5.00 (m, 1H), 4.56 (m, 2H), 3.92 (m, 1H), 3.74 (m, 1H), 3.24 (m, 2H), 2.75 (m, 1H), 2.40 (m, 1H), 2.20 (m, 4H) ), 1.90 (m, 2H), 1.65 (m, 2H), 1.43 (m, 4H); EI-MS m/z: 526 (M) + ; Analytical HPLC t R = 17.875 min, 95.23% (A), t R = 7.375 min, 100% (B).
N_千基 _5-溴 -8-羟基 -1,6-二氮杂萘 -7 ^^(S17-l)
Figure imgf000026_0001
 N _ benzyl _5-bromo-8-hydroxy-1,6-diazepine-7 ^^(S17-l)
Figure imgf000026_0001
S17-1  S17-1
化合物 S17-1的制备方法与化合物 8-1的制备方法类似，除了用苄胺代 替对氟苄胺。 黄色固体，产率： 75-85%。 lR NMR (300MHz, CDC13) 3 9.19 (dd J= 4.2 Hz, 1H), 8.54 (d, J= 7.8 Hz, 1H), 8.21 (m, 1H), 7.74 (dd, J= 4.2, 7.8 Hz: 1H), 7.40-7.29 (m, 5H), 4.70 (d, J= 6.0 Hz, 2H)。 The preparation method of the compound S17-1 was similar to the preparation method of the compound 8-1 except that benzylamine was used instead of p-fluorobenzylamine. Yellow solid, yield: 75-85%. l R NMR (300MHz, CDC1 3 ) 3 9.19 (dd J= 4.2 Hz, 1H), 8.54 (d, J= 7.8 Hz, 1H), 8.21 (m, 1H), 7.74 (dd, J= 4.2, 7.8 Hz : 1H), 7.40-7.29 (m, 5H), 4.70 (d, J = 6.0 Hz, 2H).
甲苯 _4_ ^酸 5-溴 -7-苄基 ^甲酰 -1，6-二氮杂萘 酸酯 （S17-2)
Figure imgf000026_0002
Toluene_4_^acid 5-bromo-7-benzylformyl-1,6-diazaphthalate (S17-2)
Figure imgf000026_0002
化合物 S17-2的制备方法与化合物 9-1的制备方法类似，除了用化合物 S17-1代替化合物 8-1。白色固体，产率： 85-95%。 ^ NMR (CDC13): δ 9.04 (dd, 1H, J = 1.5, 4.2 Hz), 8.56 (dd, 1H, J= 1.8, 8.7 Hz), 7.93 (m, 3H), 7.68 (dd, 1H, J= 4.5, 8.7 Hz), 7.38-7.30 (m, 7H), 4.62 (d, J= 6.0 Hz, 2H), 2.46 (s, 3H)。 The preparation method of the compound S17-2 was similar to the preparation method of the compound 9-1 except that the compound S17-1 was used instead of the compound 8-1. White solid, yield: 85-95%. ^ NMR (CDC1 3 ): δ 9.04 (dd, 1H, J = 1.5, 4.2 Hz), 8.56 (dd, 1H, J= 1.8, 8.7 Hz), 7.93 (m, 3H), 7.68 (dd, 1H, J = 4.5, 8.7 Hz), 7.38-7.30 (m, 7H), 4.62 (d, J = 6.0 Hz, 2H), 2.46 (s, 3H).
8-((lr，4r)-4- ^环己 J _N-苄基 -5-溴 -1，6-二氮杂萘 -7"ϋ ( S17 )  8-((lr,4r)-4-^cyclohexene J _N-benzyl-5-bromo-1,6-naphthyridin-7"ϋ (S17)
Figure imgf000026_0003
Figure imgf000026_0003
化合物 S17的制备方法与化合物 S15的制备方法类似， 除了用化合物 S17-2代替化合物 9-1。黄绿色固体，产率： 75-85%。熔点： 123-126°C ; ^ NMR (300MHz, CDC13): δ 9.62 (d, 1Η, J = 7.5 Hz), 8.94 (dd, 1H, J = 1.5, 3.9 Hz), 8.41 (d, 1H, J= 8.4 Hz), 8.31 (m, 1H), 7.58 (dd, 1H, J= 4.2, 8.4 Hz), 7.37-7.27 (m, 5H), 4.97 (m, 1H), 4.63 (d, 2H, J = 6.0 Hz), 2.76 (m, 1H), 2.18 (m, 2H), 1.92 (m, 4H), 1.42 (m, 4H); EI-MS m/z: 453 (M)+, 455 (M+2)+; 分析 HPLC tR = 5.8 min, 100% (A), tR = 8.79 min, 95.72% (B)。 The preparation method of the compound S17 is similar to the preparation method of the compound S15 except that the compound S17-2 is used instead of the compound 9-1. Yellow-green solid, yield: 75-85%. Melting point: 123-126°C; ^ NMR (300MHz, CDC1 3 ): δ 9.62 (d, 1Η, J = 7.5 Hz), 8.94 (dd, 1H, J = 1.5, 3.9 Hz), 8.41 (d, 1H, J = 8.4 Hz), 8.31 (m, 1H), 7.58 (dd, 1H, J= 4.2, 8.4 Hz), 7.37-7.27 (m, 5H), 4.97 (m, 1H), 4.63 (d, 2H, J = 6.0 Hz), 2.76 (m, 1H), 2.18 (m, 2H), 1.92 (m, 4H), 1.42 (m, 4H); EI-MS m/z: 453 (M) + , 455 (M+ 2) + ; Analytical HPLC t R = 5.8 min, 100% (A), t R = 8.79 min, 95.72% (B).
N-(4-甲 HJ^-苄基) -5-溴 -8-羟基 -1，6-二氮杂萘 -7 (S18-l)
Figure imgf000026_0004
N-(4-methyl HJ^-benzyl)-5-bromo-8-hydroxy-1,6-naphthyridin-7 (S18-l)
Figure imgf000026_0004
化合物 S18-1的制备方法与化合物 8-1的制备方法类似，除了用对甲氧 基苄胺代替对氟苄胺。黄色固体，产率： 75-85%。 NMR (300MHz, CDC13) δ 9.19 (d, J = 4.2 Hz, IH), 8.53 (d, J = 8.1 Hz, IH), 8.12 (m, IH), 7.72 (dd, J = 4.2, 8.7 Hz, IH), 7.33 (d, J = 8.4 Hz, 2H), 6.91 (t, J = 8.7 Hz, 2H), 4.63 (d, J = 6.6 Hz, 2H), 3.80 (s, 3H)。 分析 HPLC tR= 22.47 min, 99.99% (A), tR = 14.81 min, 99.81% (B)。 The preparation method of the compound S18-1 is similar to the preparation method of the compound 8-1 except that the methoxy group is used. The benzylamine replaces the p-fluorobenzylamine. Yellow solid, yield: 75-85%. NMR (300MHz, CDC1 3 ) δ 9.19 (d, J = 4.2 Hz, IH), 8.53 (d, J = 8.1 Hz, IH), 8.12 (m, IH), 7.72 (dd, J = 4.2, 8.7 Hz, IH), 7.33 (d, J = 8.4 Hz, 2H), 6.91 (t, J = 8.7 Hz, 2H), 4.63 (d, J = 6.6 Hz, 2H), 3.80 (s, 3H). Analytical HPLC t R = 22.47 min, 99.99% (A), t R = 14.81 min, 99.81% (B).
甲苯 -4-磺酸 5-溴 -7-(4-甲氧基 -苄基 甲酰) -1,6-二氮杂萘 -8-羧酸酯 (S18-2)
Figure imgf000027_0001
Toluene-4-sulfonic acid 5-bromo-7-(4-methoxy-benzylformyl)-1,6-naphthyridine-8-carboxylate (S18-2)
Figure imgf000027_0001
化合物 S18-2的制备方法与化合物 9-1的制备方法类似，除了用化合物 S18-1代替化合物 8-1。白色固体，产率: 85-95%。 ^ NMR (CDC13): δ 8.98 (dd, IH, J = 1.5, 4.2 Hz), 8.52 (dd, IH, J = 1.5, 8.7 Hz), 7.90 (d, 2H, J = 8.4 Hz), 7.87 (m, IH), 7.65 (dd, IH, J = 4.2, 8.4 Hz), 7.31-7.27 (m, 4H), 6.87 (d, 2H, J = 8.4 Hz), 4.52 (d, 2H, J= 5.7 Hz), 3.78 (s, 3H), 2.44 (s, 3H)。 The preparation method of the compound S18-2 was similar to the preparation method of the compound 9-1 except that the compound S18-1 was used instead of the compound 8-1. White solid, yield: 85-95%. ^ NMR (CDC1 3 ): δ 8.98 (dd, IH, J = 1.5, 4.2 Hz), 8.52 (dd, IH, J = 1.5, 8.7 Hz), 7.90 (d, 2H, J = 8.4 Hz), 7.87 ( m, IH), 7.65 (dd, IH, J = 4.2, 8.4 Hz), 7.31-7.27 (m, 4H), 6.87 (d, 2H, J = 8.4 Hz), 4.52 (d, 2H, J= 5.7 Hz) ), 3.78 (s, 3H), 2.44 (s, 3H).
8-((lr，4r)-4-氨基环己氨基) -N-(4-甲氧苄基) -5-溴 -1,6-二氮杂萘 -7-羧酸 胺（S18 )  8-((lr,4r)-4-Aminocyclohexylamino)-N-(4-methoxybenzyl)-5-bromo-1,6-naphthyridin-7-carboxylic acid Amine (S18)
Figure imgf000027_0002
Figure imgf000027_0002
化合物 S18的制备方法与化合物 S15的制备方法类似， 除了用化合物 S18-2代替化合物 9-1。 黄绿色固体， 产率： 75-85%。 熔点： 96-99 °C ; NMR (300MHz, CDC13): δ 9.64 (d, IH, J = 8.1Hz), 8.93 (dd, IH, J = 1.2, 4.2 Hz), 8.40 (dd, IH, J = 1.2, 8.4 Hz), 8.23 (m, IH), 7.58 (dd, IH, J = 4.2, 8.4 Hz), 7.30 (d, 2H, J = 8.4 Hz), 6.89 (d, 2H, J = 8.4 Hz), 4.95 (m, IH), 4.56(d, 2H, J = 6.3 Hz), 3.80 (s, 3H), 2.75 (m, IH), 2.63 (m, IH), 2.18 (m, 2H), 1.85 (m, 4H), 1.34 (m, 4H); EI-MS m/z: 483 (M)+, 485 (M+2)+; 分析 HPLC tR = 22.367 min, 97.28% (A), tR = 13.950 min, 97.37% (B)。 The preparation method of the compound S18 is similar to the preparation method of the compound S15 except that the compound S18-2 is used instead of the compound 9-1. Yellow-green solid, Yield: 75-85%. Melting point: 96-99 °C; NMR (300MHz, CDC1 3 ): δ 9.64 (d, IH, J = 8.1Hz), 8.93 (dd, IH, J = 1.2, 4.2 Hz), 8.40 (dd, IH, J = 1.2, 8.4 Hz), 8.23 (m, IH), 7.58 (dd, IH, J = 4.2, 8.4 Hz), 7.30 (d, 2H, J = 8.4 Hz), 6.89 (d, 2H, J = 8.4 Hz) ), 4.95 (m, IH), 4.56 (d, 2H, J = 6.3 Hz), 3.80 (s, 3H), 2.75 (m, IH), 2.63 (m, IH), 2.18 (m, 2H), 1.85 (m, 4H), 1.34 (m, 4H); EI-MS m/z: 483 (M) + , 485 (M+2) + ; Analytical HPLC t R = 22.367 min, 97.28% (A), t R = 13.950 min, 97.37% (B).
N-(5-(l，3-苯并二噁茂)甲基) -5-溴 -8-羟基 -1，6-二氮杂萘 -7 (S19-l)  N-(5-(l,3-benzodioxan)methyl)-5-bromo-8-hydroxy-1,6-diazaphthalene-7 (S19-l)
Figure imgf000027_0003
Figure imgf000027_0003
化合物 S19-1的制备方法与化合物 8-1的制备方法类似，除了用 5-(1,3- 苯并二噁茂）甲胺代替对氟苄胺。黄色固体，产率： 75-85%。 ^ NMR (300MHz: CDCI3) S 13.32 (s, IH), 9.20 (dd, J= 1.5, 3.9 Hz, IH), 8.54 (dd, J= 1.2, 8.4 Hz, 1H), 8.11 (m, 1H), 7.72 (dd, J = 4.2, 8.4 Hz, 1H), 6.89-6.79 (m, 3H), 5.97 (s, 2H), 4.60 (d, J= 6.3 Hz, 2H)。 The preparation method of the compound S19-1 was similar to the preparation method of the compound 8-1 except that 5-(1,3-benzodioxan)methylamine was used instead of p-fluorobenzylamine. Yellow solid, yield: 75-85%. ^ NMR (300MHz : CDCI3) S 13.32 (s, IH), 9.20 (dd, J= 1.5, 3.9 Hz, IH), 8.54 (dd, J= 1.2, 8.4 Hz, 1H), 8.11 (m, 1H), 7.72 (dd, J = 4.2, 8.4 Hz, 1H), 6.89-6.79 (m, 3H), 5.97 (s, 2H), 4.60 (d, J= 6.3 Hz, 2H ).
甲苯 _4-磺酸 5-溴 -7-(5-(l，3-苯并二噁茂)甲基氨基甲酰 )-l，6-二氮杂萘 -8 酸酯 （S19-2)
Figure imgf000028_0001
Toluene_4-sulfonic acid 5-bromo-7-(5-(l,3-benzodioxan)methylcarbamoyl)-l,6-naphthyridin-8-ester (S19-2)
Figure imgf000028_0001
化合物 S19-2的制备方法与化合物 9-1的制备方法类似， 除了用 S19-1 代替化合物 8-1。 白色固体，产率： 85-95%。 ^ NMR (CDC13): ^ 9.01 (dd, 1H, J= 1.2, 4.2 Hz), 8.54 (dd, 1H, J= 1.5, 8.7 Hz), 7.91 (d, 2H, J= 8.1 Hz), 7.87 (m 1H), 7.67 (dd, 1H, J= 4.2, 8.4 Hz), 7.33 (d, 2H, J= 8.1 Hz), 6.86-6.75 (m, 3H), 5.94 (s, 3H), 4.51 (d, 2H, J= 6.0 Hz), 2.46 (s, 3H)。 The preparation method of the compound S19-2 was similar to the preparation method of the compound 9-1 except that the compound 8-1 was replaced with S19-1. White solid, yield: 85-95%. ^ NMR (CDC1 3 ): ^ 9.01 (dd, 1H, J = 1.2, 4.2 Hz), 8.54 (dd, 1H, J = 1.5, 8.7 Hz), 7.91 (d, 2H, J = 8.1 Hz), 7.87 ( m 1H), 7.67 (dd, 1H, J= 4.2, 8.4 Hz), 7.33 (d, 2H, J= 8.1 Hz), 6.86-6.75 (m, 3H), 5.94 (s, 3H), 4.51 (d, 2H, J = 6.0 Hz), 2.46 (s, 3H).
8-((lr，4r)-4-氨基环己氨基) -N-(5-(l，3-苯并二噁茂）甲基) -5-溴 -1,6-二氮 杂萘 -7 ( S19 )  8-((lr,4r)-4-Aminocyclohexylamino)-N-(5-(l,3-benzodioxan)methyl)-5-bromo-1,6-naphthyridine- 7 ( S19 )
Figure imgf000028_0002
Figure imgf000028_0002
化合物 S19的制备方法与化合物 S15的制备方法类似， 除了用化合物 S19-2代替化合物 9-1。黄绿色固体，产率： 75-85%。熔点： 131-134°C ; ^ NMR (300MHz, CDC13): δ 9.62 (d, 1Η, J = 8.4 Hz), 8.93 (dd, 1H, J = 1.2, 4.2 Hz), 8.40 (dd, 1H, J = 1.2, 8.4 Hz), 8.23 (m, 1H), 7.58 (dd, 1H, J = 4.2, 8.4 Hz), 6.87-6.76 (m, 3H), 5.94 (s, 2H), 4.95 (m, 1H), 4.53(d, 2H, J = 6.0 Hz), 2.75 (m, 1H), 2.18 (m, 2H), 1.92 (m, 4H), 1.34 (m, 4H); EI-MS m/z: 401 (M)+, 403 (M+2)+; 分析 HPLC tR= 14.43 min, 100% (A), ¾ = 5.54 min, 100% (B)。 The preparation method of the compound S19 is similar to the preparation method of the compound S15 except that the compound S19-2 is used instead of the compound 9-1. Yellow-green solid, yield: 75-85%. Melting point: 131-134°C; ^ NMR (300MHz, CDC1 3 ): δ 9.62 (d, 1Η, J = 8.4 Hz), 8.93 (dd, 1H, J = 1.2, 4.2 Hz), 8.40 (dd, 1H, J = 1.2, 8.4 Hz), 8.23 (m, 1H), 7.58 (dd, 1H, J = 4.2, 8.4 Hz), 6.87-6.76 (m, 3H), 5.94 (s, 2H), 4.95 (m, 1H) ), 4.53(d, 2H, J = 6.0 Hz), 2.75 (m, 1H), 2.18 (m, 2H), 1.92 (m, 4H), 1.34 (m, 4H); EI-MS m/z: 401 (M) + , 403 (M+2) + ; Analytical HPLC t R = 14.43 min, 100% (A), 3⁄4 = 5.54 min, 100% (B).
N-((S)-l-(4-氟苯基)乙基) -5-溴 -8-羟基 -1，6-二氮杂萘 -7 酸胺 (S20-1)  N-((S)-l-(4-fluorophenyl)ethyl)-5-bromo-8-hydroxy-1,6-naphthyridin-7-amine (S20-1)
Figure imgf000028_0003
Figure imgf000028_0003
化合物 S20-1的制备方法与化合物 8-1的制备方法类似，除了用（S)-l-(4- 氟苯基）乙胺代替对氟苄胺。 黄色固体， 产率： 75-85%。 NMR (300MHz, CDCI3) S 13.30 (s, 1H), 9.17 (dd, J= 1.5, 4.2 Hz, 1H), 8.53 (dd, J= 1.5, 8.4 Hz, 1H), 8.03 (d, J= 8.1 Hz, 1H), 7.71 (dd, J= 4.2, 8.4 Hz, 1H), 7.40 (m, 2H), 7.06 (d, J= 8.7 Hz, 2H), 5.30 (m, 1H), 1.67 (d, J= 6.9 Hz, 3H)。  The preparation of the compound S20-1 was carried out in a similar manner to the preparation of the compound 8-1 except that (S)-l-(4-fluorophenyl)ethylamine was used instead of p-fluorobenzylamine. Yellow solid, Yield: 75-85%. NMR (300MHz, CDCI3) S 13.30 (s, 1H), 9.17 (dd, J= 1.5, 4.2 Hz, 1H), 8.53 (dd, J= 1.5, 8.4 Hz, 1H), 8.03 (d, J= 8.1 Hz , 1H), 7.71 (dd, J= 4.2, 8.4 Hz, 1H), 7.40 (m, 2H), 7.06 (d, J= 8.7 Hz, 2H), 5.30 (m, 1H), 1.67 (d, J= 6.9 Hz, 3H).
甲苯 _4 ^酸 5-溴 -7-((S)-l-(4-氟苯基)乙基氣基甲酰 )-l，6-二氮杂萘 酸酯（S20-2)
Figure imgf000029_0001
Toluene_4^acid 5-bromo-7-((S)-l-(4-fluorophenyl)ethylcarbamoyl)-l,6-diazaphthalate (S20-2)
Figure imgf000029_0001
化合物 S20-2的制备方法与化合物 9-1的制备方法类似，除了用化合物 S20-1代替化合物 8-1。白色固体，产率： 85-95%。 ^ NMR (CDC13): δ 9.01 (dd, 1H, J= 1.2, 4.2 Hz), 8.56 (d, 1H, J= 8.7 Hz), 7.88 (d, 2H, J= 8.1 Hz), 7.84 (m, 1H), 7.67 (dd, 1H, J = 4.5, 8.7 Hz), 7.40 (m, 2H), 7.28 (d, 2H, J= 8.7 Hz), 5.26 (m, 1H), 2.45 (s, 3H), 1.60 (d, 6H, J= 6.9 Hz). The preparation method of the compound S20-2 was similar to the preparation method of the compound 9-1 except that the compound S20-1 was used instead of the compound 8-1. White solid, yield: 85-95%. ^ NMR (CDC1 3 ): δ 9.01 (dd, 1H, J = 1.2, 4.2 Hz), 8.56 (d, 1H, J = 8.7 Hz), 7.88 (d, 2H, J = 8.1 Hz), 7.84 (m, 1H), 7.67 (dd, 1H, J = 4.5, 8.7 Hz), 7.40 (m, 2H), 7.28 (d, 2H, J = 8.7 Hz), 5.26 (m, 1H), 2.45 (s, 3H), 1.60 (d, 6H, J = 6.9 Hz).
8-((lr，4r)-4-氨基环己氨基 )-5-溴 -N-((S)-l-(4-氟苯基）乙基) -1,6-二氮杂 萘 -7 ( S20 )  8-((lr,4r)-4-Aminocyclohexylamino)-5-bromo-N-((S)-l-(4-fluorophenyl)ethyl)-1,6-naphthyridine- 7 ( S20 )
Figure imgf000029_0002
Figure imgf000029_0002
化合物 S20的制备方法与化合物 S15的制备方法类似， 除了用化合物 S20-2代替化合物 9-1。黄绿色固体，产率： 75-85%。熔点： 129-131 °C ; ^ NMR (300MHz, CDC13): δ 9.57 (d, 1Η, J = 7.5Hz), 8.93 (dd, 1H, J = 1.5, 3.9 Hz), 8.41 (dd, 1H, J =1.5, 8.4 Hz), 8.21 (m, 1H), 7.58 (dd, 1H, J= 4.2, 8.4 Hz), 7.37 (m, 2H), 7.01 (t, 2H, J= 8.7 Hz), 5.24 (m, 1H), 4.97 (m, 1H), 4.93 (m, 1H), 2.76 (m, 1H), 2.18 (m, 2H), 1.92 (m, 2H), 1.60 (d, 3H, J = 6.9 Hz), 1.42 (m, 4H); EI-MS m/z: 485 (M)+, 487 (M+2)+; 分析 HPLC tR= 14.31 min, 94.70% (A), tR = 8.33 min, 100% (B)。 The preparation method of the compound S20 is similar to the preparation method of the compound S15 except that the compound S20-2 is used instead of the compound 9-1. Yellow-green solid, yield: 75-85%. Melting point: 129-131 °C; ^ NMR (300MHz, CDC1 3 ): δ 9.57 (d, 1Η, J = 7.5Hz), 8.93 (dd, 1H, J = 1.5, 3.9 Hz), 8.41 (dd, 1H, J = 1.5, 8.4 Hz), 8.21 (m, 1H), 7.58 (dd, 1H, J= 4.2, 8.4 Hz), 7.37 (m, 2H), 7.01 (t, 2H, J= 8.7 Hz), 5.24 ( m, 1H), 4.97 (m, 1H), 4.93 (m, 1H), 2.76 (m, 1H), 2.18 (m, 2H), 1.92 (m, 2H), 1.60 (d, 3H, J = 6.9 Hz ), 1.42 (m, 4H) ; EI-MS m / z: 485 (m) +, 487 (m + 2) +; analysis HPLC t R = 14.31 min, 94.70 % (A), t R = 8.33 min, 100% (B).
N-((2-呋喃)甲基) -5-溴 -8-羟基 -1，6-二氮杂萘 -7 酸胺 (S21-1)  N-((2-furan)methyl)-5-bromo-8-hydroxy-1,6-naphthyridin-7-amine (S21-1)
Figure imgf000029_0003
Figure imgf000029_0003
化合物 S21-1的制备方法与化合物 8-1的制备方法类似，除了用 2-呋喃 甲胺代替对氟苄胺。 黄色固体， 产率： 75-85%。 NMR (300MHz, CDC13): 3 13.20 (brs, 1H), 8.19 (dd, 1H, J = 1.5, 4.2 Hz), 8.54 (dd, 1H, J = 1.5, 8.4 Hz), 8.13 (m, 1H), 7.73 (dd, 1H, J= 4.2, 8.4 Hz), 7.42 (m, 1H), 6.37 (m, 2H), 4.70 (d, 2H, J= 6.0 Hz). EI-MS m/z: 347 (M)+, 349(M+2)+。 The preparation method of the compound S21-1 was similar to the preparation method of the compound 8-1 except that 2-furanmethylamine was used instead of p-fluorobenzylamine. Yellow solid, Yield: 75-85%. NMR (300MHz, CDC1 3 ): 3 13.20 (brs, 1H), 8.19 (dd, 1H, J = 1.5, 4.2 Hz), 8.54 (dd, 1H, J = 1.5, 8.4 Hz), 8.13 (m, 1H) , 7.73 (dd, 1H, J= 4.2, 8.4 Hz), 7.42 (m, 1H), 6.37 (m, 2H), 4.70 (d, 2H, J= 6.0 Hz). EI-MS m/z: 347 ( M) + , 349(M+2) + .
甲苯 -4-磺酸 5-溴 -7-((2-呋喃）甲基氨基甲酰 )-l，6-二氮杂萘 -8-羧酸酯 (S21-2)
Figure imgf000030_0001
Toluene-4-sulfonic acid 5-bromo-7-((2-furan)methylcarbamoyl)-l,6-naphthyridin-8-carboxylate (S21-2)
Figure imgf000030_0001
化合物 S21-2的制备方法与化合物 9-1的制备方法类似，除了用化合物 S21-1代替化合物 8-1。白色固体，产率: 85-95%。 ^ NMR (CDC13): δ 9.03 (dd, 1H, J = 1.5, 4.2 Hz), 8.56 (dd, 1H, J = 1.5, 8.7 Hz), 7.91 (d, 2H, J = 8.1 Hz), 7.89 (m, 1H), 7.68 (dd, 1H, J = 4.2, 8.7 Hz), 7.40 (m, 1H), 7.32 (d, 2H, J = 8.1 Hz), 6.33 (m, 2H), 4.58 (d, 2H, J= 6.0 Hz), 2.47 (s, 3H)。 The preparation method of the compound S21-2 was similar to the preparation method of the compound 9-1 except that the compound S21-1 was used instead of the compound 8-1. White solid, yield: 85-95%. ^ NMR (CDC1 3 ): δ 9.03 (dd, 1H, J = 1.5, 4.2 Hz), 8.56 (dd, 1H, J = 1.5, 8.7 Hz), 7.91 (d, 2H, J = 8.1 Hz), 7.89 ( m, 1H), 7.68 (dd, 1H, J = 4.2, 8.7 Hz), 7.40 (m, 1H), 7.32 (d, 2H, J = 8.1 Hz), 6.33 (m, 2H), 4.58 (d, 2H) , J = 6.0 Hz), 2.47 (s, 3H).
8-((lr，4r)-4- JJT、己 ^)_5-溴 -N-((2-呋喃)甲基) -1，6-二氮杂萘 酸 胺（ S21 )  8-((lr,4r)-4-JJT, hexane^)_5-bromo-N-((2-furan)methyl)-1,6-naphthyridiniumamine (S21)
Figure imgf000030_0002
Figure imgf000030_0002
化合物 S21的制备方法与化合物 S15的制备方法类似， 除了用化合物 S21-2代替化合物 9-1。 黄绿色固体， 产率： 75-85%。 熔点： 96-98 °C ; NMR (300MHz, CDC13): δ 9.56 (d, 1H, J = 8.1Hz), 8.90 (dd, 1H, J = 1.5, 3.9 Hz), 8.37 (d, 1H, J = 8.4 Hz), 8.23 (m, 1H), 7.54 (dd, 1H, J = 4.2, 8.4 Hz), 7.36 (s, 1H), 6.30 (m, 2H), 4.93 (m, 1H), 4.57 (d, 2H, J= 6.0 Hz), 2.71 (m, 1H), 2.18 (m 2H), 1.92 (m, 4H), 1.42 (m, 4H); EI-MS m/z: 443 (M)+, 445 (M+2)+; 分析 HPLC tR= 5.91 min, 100% (A), tR = 6.55 min, 100% (B)。 The preparation method of the compound S21 is similar to the preparation method of the compound S15 except that the compound S21-2 is used instead of the compound 9-1. Yellow-green solid, Yield: 75-85%. Melting point: 96-98 °C; NMR (300MHz, CDC1 3 ): δ 9.56 (d, 1H, J = 8.1Hz), 8.90 (dd, 1H, J = 1.5, 3.9 Hz), 8.37 (d, 1H, J = 8.4 Hz), 8.23 (m, 1H), 7.54 (dd, 1H, J = 4.2, 8.4 Hz), 7.36 (s, 1H), 6.30 (m, 2H), 4.93 (m, 1H), 4.57 (d , 2H, J= 6.0 Hz), 2.71 (m, 1H), 2.18 (m 2H), 1.92 (m, 4H), 1.42 (m, 4H); EI-MS m/z: 443 (M) + , 445 (M+2) + ; Analytical HPLC t R = 5.91 min, 100% (A), t R = 6.55 min, 100% (B).
N-(3-甲 HJ^-苄基) -5-溴 -8-羟基 -1，6-二氮杂萘 -7 (S22-l)  N-(3-methyl HJ^-benzyl)-5-bromo-8-hydroxy-1,6-diazaphthalene-7 (S22-l)
Figure imgf000030_0003
Figure imgf000030_0003
化合物 S22-1的制备方法与化合物 8-1的制备方法类似，除了用 3-甲氧 基苄胺代替对氟苄胺。黄色固体，产率： 75-85%。 NMR (300MHz, CDC13) δ 9.14 (dd, J = 1.5, 4.2 Hz, 1H), 8.48 (dd, J = 1.5, 8.4 Hz, 1H), 8.26 (m, 1H), 7.68 (dd, J = 4.2, 8.4 Hz, 1H), 7.23 (m, 2H), 6.84 (m, 2H), 4.64 (d, J = 6.0 Hz, 2H), 3.78 (s, 3H)。 The preparation method of the compound S22-1 was similar to the preparation method of the compound 8-1 except that 3-methoxybenzylamine was used instead of p-fluorobenzylamine. Yellow solid, yield: 75-85%. NMR (300MHz, CDC1 3 ) δ 9.14 (dd, J = 1.5, 4.2 Hz, 1H), 8.48 (dd, J = 1.5, 8.4 Hz, 1H), 8.26 (m, 1H), 7.68 (dd, J = 4.2 , 8.4 Hz, 1H), 7.23 (m, 2H), 6.84 (m, 2H), 4.64 (d, J = 6.0 Hz, 2H), 3.78 (s, 3H).
甲苯 -4-磺酸 5-溴 -7-(3-甲氧基 -苄基 甲酰) -1,6-二氮杂萘 -8-羧酸酯  Toluene-4-sulfonic acid 5-bromo-7-(3-methoxy-benzylformyl)-1,6-diazaphthalene-8-carboxylate
Figure imgf000030_0004
化合物 S22-2的制备方法与化合物 9-1的制备方法类似，除了用化合物 S22-1代替化合物 8-1。白色固体，产率: 85-95%。 ^ NMR (CDC13): δ 8.97 (dd, IH, J= 1.5, 4.2 Hz), 8.50 (dd, IH, J= 1.8, 7.5 Hz), 7.94 (m, IH), 7.88 (d, 2H, J = 8.4 Hz), 7.64 (dd, IH, J= 4.2, 8.4 Hz), 7.28 (d, 2H, J= 8.4 Hz), 7.25 (m, IH), 6.92 (m, 2H), 6.80 (m, IH), 5.68 (d, 2H, J= 6.0 Hz), 3.78 (s, 3H), 2.42 (s, 3H)。
Figure imgf000030_0004
The preparation method of the compound S22-2 was similar to the preparation method of the compound 9-1 except that the compound S22-1 was used instead of the compound 8-1. White solid, yield: 85-95%. ^ NMR (CDC1 3 ): δ 8.97 (dd, IH, J = 1.5, 4.2 Hz), 8.50 (dd, IH, J = 1.8, 7.5 Hz), 7.94 (m, IH), 7.88 (d, 2H, J = 8.4 Hz), 7.64 (dd, IH, J= 4.2, 8.4 Hz), 7.28 (d, 2H, J= 8.4 Hz), 7.25 (m, IH), 6.92 (m, 2H), 6.80 (m, IH) ), 5.68 (d, 2H, J = 6.0 Hz), 3.78 (s, 3H), 2.42 (s, 3H).
8-((lr，4r)-4-氨基环己氨基) -N-(3-甲氧苄基 )-5-溴 -1,6-二氮杂萘 -7-羧酸 胺（ S22 )  8-((lr,4r)-4-aminocyclohexylamino)-N-(3-methoxybenzyl)-5-bromo-1,6-naphthyridin-7-carboxylic acid amine (S22)
Figure imgf000031_0001
Figure imgf000031_0001
化合物 S22的制备方法与化合物 S15的制备方法类似， 除了用化合物 S22-2代替化合物 9-1。 黄绿色固体， 产率： 75-85%。 熔点： 84-87 °C ; NMR (300MHz, CDC13): δ 9.62 (d, IH, J = 8.4Hz), 8.92 (dd, IH, J = 1.5, 4.2 Hz), 8.39 (dd, IH, J= 1.5, 8.4 Hz), 8.31 (m, IH), 7.56 (dd, IH, J= 4.2, 8.4 Hz), 7.30 (d, 2H, J = 8.4 Hz), 6.89 (d, 2H, J = 8.4 Hz), 4.95 (m, IH), 4.56(d, 2H, J = 6.3 Hz), 3.80 (s, 3H), 2.75 (m, IH), 2.63 (m, IH), 2.18 (m, 2H), 1.85 (m, 4H), 1.34 (m, 4H); EI-MS m/z: 483 (M)+, 485 (M+2)+; 分析 HPLC tR= 5.71 min, 100% (A), tR = 8.80 min, 99.27% (B)。 The preparation method of the compound S22 is similar to the preparation method of the compound S15 except that the compound S22-2 is used instead of the compound 9-1. Yellow-green solid, Yield: 75-85%. Melting point: 84-87 °C; NMR (300MHz, CDC1 3 ): δ 9.62 (d, IH, J = 8.4Hz), 8.92 (dd, IH, J = 1.5, 4.2 Hz), 8.39 (dd, IH, J = 1.5, 8.4 Hz), 8.31 (m, IH), 7.56 (dd, IH, J= 4.2, 8.4 Hz), 7.30 (d, 2H, J = 8.4 Hz), 6.89 (d, 2H, J = 8.4 Hz) ), 4.95 (m, IH), 4.56 (d, 2H, J = 6.3 Hz), 3.80 (s, 3H), 2.75 (m, IH), 2.63 (m, IH), 2.18 (m, 2H), 1.85 (m, 4H), 1.34 (m, 4H); EI-MS m/z: 483 (M) + , 485 (M+2) + ; Analytical HPLC t R = 5.71 min, 100% (A), t R = 8.80 min, 99.27% (B).
N-苯乙基 -5-溴 -8-羟基 -1，6-二氮杂萘 -7 酸胺 (S23-1)  N-phenethyl 5-5-bromo-8-hydroxy-1,6-naphthyridin-7 acid amine (S23-1)
Figure imgf000031_0002
Figure imgf000031_0002
化合物 S23-1的制备方法与化合物 8-1的制备方法类似，除了用 2-苯基 乙胺代替对氟苄胺。 黄色固体， 产率： 75-85%。 iH NMR pOOMHz, CDC13) 3 9.18 (dd, J= 1.5, 4.2 Hz, IH), 8.53 (dd, J= 1.5, 8.4 Hz, IH), 7.93 (m, IH), 7.71 (dd, J= 4.2, 8.4 Hz, IH), 7.73-7.18 (m, 10H), 3.75 (q, 2H, J= 6.9 Hz), 2.98 (m, 4H), 2.76 (m, 2H). EI-MS m/z: 371 (M)+, 373(M+2)+。 The preparation method of the compound S23-1 was similar to the preparation method of the compound 8-1 except that 2-phenylethylamine was used instead of p-fluorobenzylamine. Yellow solid, Yield: 75-85%. iH NMR pOOMHz, CDC1 3 ) 3 9.18 (dd, J= 1.5, 4.2 Hz, IH), 8.53 (dd, J= 1.5, 8.4 Hz, IH), 7.93 (m, IH), 7.71 (dd, J= 4.2 , 8.4 Hz, IH), 7.73-7.18 (m, 10H), 3.75 (q, 2H, J= 6.9 Hz), 2.98 (m, 4H), 2.76 (m, 2H). EI-MS m/z: 371 (M) + , 373(M+2) + .
甲苯 -4^酸 5-溴 -7- (苯乙基氨基甲酰) -1，6-二氮杂萘 酸酯 （S23-2)  Toluene -4^ Acid 5-Bromo-7-(phenethylcarbamoyl)-1,6-diazaphthalate (S23-2)
Figure imgf000031_0003
Figure imgf000031_0003
化合物 S23-2的制备方法与化合物 9-1的制备方法类似， 除了用 S23-1 代替化合物 8-1。 白色固体，产率： 85-95%。 ^ NMR (CDC13): δ 8.98 (dd, IH, J= 3.6 Hz), 8.51 (d, IH, J= 8.4 Hz), 7.90 (d, 2H, J= 7.8 Hz), 7.65 (dd, IH, J = 4.2, 8.4 Hz), 7.64 (m, IH), 7.35-7.21 (m, 7H), 3.63 (q, 2H, J = 6.9 Hz), 2.90 (t, 2H, J= 8.1 Hz), 2.44 (s, 3H)。 The preparation method of the compound S23-2 was similar to the preparation method of the compound 9-1 except that the compound 8-1 was replaced with S23-1. White solid, yield: 85-95%. ^ NMR (CDC1 3 ): δ 8.98 (dd, IH, J = 3.6 Hz), 8.51 (d, IH, J = 8.4 Hz), 7.90 (d, 2H, J = 7.8 Hz), 7.65 (dd, IH, J = 4.2, 8.4 Hz), 7.64 (m, IH), 7.35-7.21 (m, 7H), 3.63 (q, 2H, J = 6.9 Hz), 2.90 (t, 2H, J= 8.1 Hz), 2.44 (s, 3H).
8-((lr，4r)-4-氨基环己氨基) -N-苯乙基 -5-溴 -1,6-二氮杂萘 -7-羧酸胺 ( S23 )  8-((lr,4r)-4-Aminocyclohexylamino)-N-phenethyl-5-bromo-1,6-naphthyridin-7-carboxylic acid amine (S23)
Figure imgf000032_0001
Figure imgf000032_0001
化合物 S23的制备方法与化合物 S15的制备方法类似， 除了用化合物 S23-2代替化合物 9-1。 黄绿色固体， 产率： 75-85%。 熔点： 64-65 °C； NMR (300MHz, CDC13): δ 9.60 (d, IH, J = 8.4 Hz), 8.93 (d, IH, J = 3.9 Hz), 8.40 (d, IH, J= 8.4 Hz), 8.11 (m, IH), 7.57 (dd, IH, J= 4.2, 8.4 Hz), 7.36-7.24 (m, 5H), 4.93 (m, IH), 3.65 (m, 2H), 2.95 (m, 2H), 2.75 (m, IH), 2.18 (m, 2H), 1.94 (m, 2H), 1.42 (m, 4H); EI-MS m/z: 467 (M)+, 469 (M+2)+; 分析 HPLC tR= 15.05 min, 97.78% (A), tR = 8.30 min, 99.26% (B)。 The preparation method of the compound S23 is similar to the preparation method of the compound S15 except that the compound S23-2 is used instead of the compound 9-1. Yellow-green solid, Yield: 75-85%. Melting point: 64-65 °C; NMR (300MHz, CDC1 3 ): δ 9.60 (d, IH, J = 8.4 Hz), 8.93 (d, IH, J = 3.9 Hz), 8.40 (d, IH, J= 8.4 Hz), 8.11 (m, IH), 7.57 (dd, IH, J= 4.2, 8.4 Hz), 7.36-7.24 (m, 5H), 4.93 (m, IH), 3.65 (m, 2H), 2.95 (m , 2H), 2.75 (m, IH), 2.18 (m, 2H), 1.94 (m, 2H), 1.42 (m, 4H); EI-MS m/z: 467 (M) + , 469 (M+2 + ; Analytical HPLC t R = 15.05 min, 97.78% (A), t R = 8.30 min, 99.26% (B).
N-(4-氯-苄基) -5-溴 -8-羟基 -1，6-二氮杂萘 -7 酸胺 (S24-1)
Figure imgf000032_0002
N-(4-chloro-benzyl)-5-bromo-8-hydroxy-1,6-naphthyridin-7-amine (S24-1)
Figure imgf000032_0002
化合物 S24-1的制备方法与化合物 8-1的制备方法类似，除了用 4-氯苄 胺代替对氟苄胺。 黄色固体， 产率： 75-85%。 ifi NMR (300MHz, CDC13): 3 9.20 (d, J= 3.9 Hz, IH), 8.54 (d, J= 9 Hz, IH), 8.19 (m, IH), 7.74 (dd, J= 4.2, 8.4 Hz, IH), 7.35-7.23 (m, 8H), 4.67 (d, J= 6.3 Hz, 2H), 2.85 (s, 2H)。 The preparation of the compound S24-1 was similar to the preparation of the compound 8-1 except that 4-chlorobenzylamine was used instead of p-fluorobenzylamine. Yellow solid, Yield: 75-85%. Ifi NMR (300MHz, CDC1 3 ): 3 9.20 (d, J= 3.9 Hz, IH), 8.54 (d, J= 9 Hz, IH), 8.19 (m, IH), 7.74 (dd, J= 4.2, 8.4 Hz, IH), 7.35-7.23 (m, 8H), 4.67 (d, J = 6.3 Hz, 2H), 2.85 (s, 2H).
甲苯 -4-磺酸 5-溴 -7-(4-氯-苄基氨基甲酰) -1,6-二氮杂萘 -8-羧酸酯  Toluene-4-sulfonic acid 5-bromo-7-(4-chloro-benzylcarbamoyl)-1,6-diazaphthalene-8-carboxylate
Figure imgf000032_0003
Figure imgf000032_0003
化合物 S24-2的制备方法与化合物 9-1的制备方法类似，除了用化合物 S24-1代替化合物 8-1。 白色固体， 产率： 85-95%。 ^ NMR (CDC13): δ 9.01 (dd, IH, J = 1.5, 4.2 Hz), 8.56 (dd, IH, J = 1.5, 8.7 Hz), 7.98 (m,lH), 7.92 (d, 2H, J = 8.4 Hz), 7.68 (dd, IH, J = 4.2, 8.7 Hz), 7.32-7.30 (m, 6H), 4.61 (d, J = 6.0 Hz, 2H), 2.46 (s, 3H)。 The preparation method of the compound S24-2 was similar to the preparation method of the compound 9-1 except that the compound S24-1 was used instead of the compound 8-1. White solid, Yield: 85-95%. ^ NMR (CDC1 3 ): δ 9.01 (dd, IH, J = 1.5, 4.2 Hz), 8.56 (dd, IH, J = 1.5, 8.7 Hz), 7.98 (m,lH), 7.92 (d, 2H, J = 8.4 Hz), 7.68 (dd, IH, J = 4.2, 8.7 Hz), 7.32-7.30 (m, 6H), 4.61 (d, J = 6.0 Hz, 2H), 2.46 (s, 3H).
8-((lr，4r)-4-氨基环己氨基) -N-(4-氯苄基 )-5-溴 -1，6-二氮杂萘 -7-羧酸胺 ( S24 )
Figure imgf000033_0001
化合物 S24的制备方法与化合物 S15的制备方法类似， 除了用化合物 S24-2代替化合物 9-1。黄绿色固体，产率： 75-85%。熔点： 128-130°C ; ^ NMR (300MHz, CDC13): δ 9.60 (d, 1Η, J = 8.1Hz), 9.30 (dd, 1H, J = 1.5, 4.2 Hz), 8.40 (dd, 1H, J= 1.2, 8.7 Hz), 8.33 (m, 1H), 7.58 (dd, 1H, J= 4.2, 8.4 Hz), 7.30 (s, 4H), 4.96 (m, 1H), 4.59 (d, 2H, J= 6.0 Hz), 2.77 (m, 1H), 2.17 (m, 2H), 1.94 (m, 2H), 1.43-1.24 (m, 4H); EI-MS m/z: 487 (M)+, 489 (M+2)+; HR-EIMS 理 论值 C22H23N5OClBr: 487.0775, 实际值： 487.0774. 分析 HPLC tR = 30.39 min, 95.29% (A), tR = 20.43 min, 100% (B)。 8-((lr,4r)-4-Aminocyclohexylamino)-N-(4-chlorobenzyl)-5-bromo-1,6-naphthyridin-7-carboxylic acid amine (S24)
Figure imgf000033_0001
The preparation method of the compound S24 is similar to the preparation method of the compound S15 except that the compound S24-2 is used instead of the compound 9-1. Yellow-green solid, yield: 75-85%. Melting point: 128-130 ° C; ^ NMR (300 MHz, CDC1 3 ): δ 9.60 (d, 1 Η, J = 8.1 Hz), 9.30 (dd, 1H, J = 1.5, 4.2 Hz), 8.40 (dd, 1H, J = 1.2, 8.7 Hz), 8.33 (m, 1H), 7.58 (dd, 1H, J= 4.2, 8.4 Hz), 7.30 (s, 4H), 4.96 (m, 1H), 4.59 (d, 2H, J = 6.0 Hz), 2.77 (m, 1H), 2.17 (m, 2H), 1.94 (m, 2H), 1.43-1.24 (m, 4H); EI-MS m/z: 487 (M) + , 489 ( M + 2) +; HR- EIMS theory C 22 H 23 N 5 OClBr: . 487.0775, Found: 487.0774 analysis HPLC t R = 30.39 min, 95.29 % (A), t R = 20.43 min, 100% (B ).
N-(2，4-二氯苄基) -5-溴 -8-羟基 -1，6-二氮杂萘 -7 酸胺 (S25-1)  N-(2,4-dichlorobenzyl)-5-bromo-8-hydroxy-1,6-naphthyridin-7-amine (S25-1)
Figure imgf000033_0002
Figure imgf000033_0002
化合物 S25-1的制备方法与化合物 8-1的制备方法类似， 除了用 2,4-二 氯苄胺代替对氟苄胺。黄色固体，产率： 75-85%。 ^ NMR (300MHz, CDC13) δ 9.20 (d, J= 1.5, 4.2 Hz, 1H), 8.55 (d, J= 7.8 Hz, 1H), 8.27 (m, 1H), 7.75 (dd, J= 4.2, 7.8 Hz, 1H), 7.42 (m, 3H), 4.76 (d, J= 6.3 Hz, 2H)。 The preparation of the compound S25-1 was similar to the preparation of the compound 8-1 except that 2,4-dichlorobenzylamine was used instead of p-fluorobenzylamine. Yellow solid, yield: 75-85%. ^ NMR (300MHz, CDC1 3 ) δ 9.20 (d, J = 1.5, 4.2 Hz, 1H), 8.55 (d, J = 7.8 Hz, 1H), 8.27 (m, 1H), 7.75 (dd, J= 4.2, 7.8 Hz, 1H), 7.42 (m, 3H), 4.76 (d, J = 6.3 Hz, 2H).
甲苯 -4-磺酸 5-溴 -7-(2，4-二氯-苄基氨基甲酰 )-l，6-二氮杂萘 -8-羧酸酯  Toluene-4-sulfonic acid 5-bromo-7-(2,4-dichloro-benzylcarbamoyl)-l,6-naphthyridin-8-carboxylate
Figure imgf000033_0003
Figure imgf000033_0003
化合物 S25-2的制备方法与化合物 9-1的制备方法类似， 除了用 S25-1 代替化合物 8-1。白色固体，产率： 85-95%。 ^ NMR (CDC13): δ 9.02 (dd, 1H, J= 1.5, 4.2 Hz), 8.57 (dd, 1H, J= 1.8, 8.7 Hz), 8.08 (m,lH), 7.90 (d, 2H, J= 8.4 Hz), 7.68 (dd, 1H, J = 4.2, 8.7 Hz), 7.42 (m, 2H), 7.32 (d, 2H, J = 8.4 Hz), 7.24 (m, 1H), 4.67 (d, J= 6.3 Hz, 2H), 2.47 (s, 3H).The preparation method of the compound S25-2 was similar to the preparation method of the compound 9-1 except that the compound 8-1 was replaced with S25-1. White solid, yield: 85-95%. ^ NMR (CDC1 3 ): δ 9.02 (dd, 1H, J= 1.5, 4.2 Hz), 8.57 (dd, 1H, J= 1.8, 8.7 Hz), 8.08 (m,lH), 7.90 (d, 2H, J = 8.4 Hz), 7.68 (dd, 1H, J = 4.2, 8.7 Hz), 7.42 (m, 2H), 7.32 (d, 2H, J = 8.4 Hz), 7.24 (m, 1H), 4.67 (d, J = 6.3 Hz, 2H), 2.47 (s, 3H).
Figure imgf000033_0004
Figure imgf000033_0004
胺（ S25 )
Figure imgf000034_0001
化合物 S25的制备方法与化合物 S15的制备方法类似， 除了用化合物 S25-2代替化合物 9-1。 黄绿色固体， 产率： 75-85%。 熔点： 72-74 °C ; NMR (300MHz, CDC13): δ 9.55 (d, 1H, J = 7.8 Hz), 8.94 (dd, 1H, J = 1.5, 3.9 Hz), 8.41 (d, 1H, J = 7.2 Hz), 8.40 (m, 1H), 7.59 (dd, 1H, J = 1.5, 8.7 Hz), 7.37 (s, 2H), 7.23 (m, 1H), 4.96 (m, 1H), 4.67 (d, 2H, J= 6.0 Hz), 2.76 (m, 1H), 2.18 (m 2H), 1.87 (m, 2H), 1.37 (m, 4H); EI-MS m/z: 521 (M)+; HR-EIMS 理论值 C22H22N5OCl2Br: 521.0385, 实际值： 521.0388. 分析 HPLC tR = 29.56 min, 94.27% (A), tR = 23.65 min, 95.94% (B)。 Amine ( S25 )
Figure imgf000034_0001
The preparation method of the compound S25 is similar to the preparation method of the compound S15 except that the compound S25-2 is used instead of the compound 9-1. Yellow-green solid, Yield: 75-85%. Melting point: 72-74 °C; NMR (300MHz, CDC1 3 ): δ 9.55 (d, 1H, J = 7.8 Hz), 8.94 (dd, 1H, J = 1.5, 3.9 Hz), 8.41 (d, 1H, J = 7.2 Hz), 8.40 (m, 1H), 7.59 (dd, 1H, J = 1.5, 8.7 Hz), 7.37 (s, 2H), 7.23 (m, 1H), 4.96 (m, 1H), 4.67 (d , 2H, J= 6.0 Hz), 2.76 (m, 1H), 2.18 (m 2H), 1.87 (m, 2H), 1.37 (m, 4H); EI-MS m/z: 521 (M) + ; HR -EIMS theory C 22 H 22 N 5 OCl 2 Br: 521.0385, Found:. 521.0388 analysis HPLC t R = 29.56 min, 94.27 % (A), t R = 23.65 min, 95.94% (B).
5-溴 -8-羟基 -1，6-二氮杂萘 酸 (11)
Figure imgf000034_0002
5-bromo-8-hydroxy-1,6-naphthyridic acid (11)
Figure imgf000034_0002
将化合物 7-1 (150mg, 0.735mmol) 溶解在 4.5mL 甲醇和 2.2mL IN LiOH溶液中， 加热回流 5h。 冷却至室温后滴加 2.1mL IN HC1溶液调节 pH至 3左右， 旋蒸掉大部分甲醇， 加稀的 NaHC03溶液调节 pH至 5 , 过 滤，烘干，得固体化合物 ll(116mg, 81%)。 ^ NMR (300MHz, CD3OD): δ 9.21 (s, 1Η), 8.57 (d, 1H, J= 7.8Hz), 7.97 (s, 1H). EI-MS m/z: 269 (M)+。Compound 7-1 (150 mg, 0.735 mmol) was dissolved in 4.5 mL of methanol and 2.2 mL of IN LiOH and heated to reflux for 5 h. After cooling to room temperature, add 2.1 mL of IN HC1 solution to adjust the pH to about 3, and steam off most of the methanol. Add the diluted NaHC0 3 solution to adjust the pH to 5, filter and dry to obtain solid compound ll (116 mg, 81%). . ^ NMR (300 MHz, CD 3 OD): δ 9.21 (s, 1 Η), 8.57 (d, 1H, J = 7.8 Hz), 7.97 (s, 1H). EI-MS m/z: 269 (M) + .
Figure imgf000034_0003
Figure imgf000034_0003
0度下，将三光气 （150 mg, 0.735 mmol) 加入到化合物 11 (0.234 mmol, 45 mg), DIPEA (0.398 mmol, 160 L)的 DMF溶液中。 搅拌 lh后， 常温下 加过量的苯胺， 搅拌 16个小时后， 加入 50 mL饱和食盐水和二氯甲烷， 有 机相用 5x50 mL饱和水食盐水洗。 无水^ £酸钠干燥， 过滤， 旋干得粗品化 合物 S26-1 , 直接用于下步反应。  Triphosgene (150 mg, 0.735 mmol) was added to a solution of compound 11 (0.234 mmol, 45 mg), DIPEA (0.398 mmol, 160 L) in DMF. After stirring for 1 hour, an excess of aniline was added at room temperature, and after stirring for 16 hours, 50 mL of saturated brine and dichloromethane were added, and the organic phase was washed with 5 x 50 mL of saturated brine. Dry with anhydrous sodium sulfate, filter, and spin dry to obtain the crude compound S26-1, which was used directly in the next step.
甲苯 _4_ ^酸 5-溴 -7-苯基 ^甲酰 -1,6-二氮杂萘 酸酯 （S26-2)
Figure imgf000034_0004
Toluene_4_^acid 5-bromo-7-phenyl-formyl-1,6-diazaphthalate (S26-2)
Figure imgf000034_0004
化合物 S26-2的制备方法与化合物 9-1的制备方法类似，除了用化合物 S26-1代替化合物 8-1。 白色固体， 产率： 85-95%。 ^ NMR (CDC13): δ 9.36 (s, IH), 9.14 (dd, IH, J = 1.5, 4.2 Hz), 8.59 (dd, IH, J = 1.8, 8.4 Hz), 7.88 (d, 2H, J= 8.1 Hz), 7.73 (dd, IH, J= 4.2, 8.4 Hz), 7.63 (d, 2H, J= 8.1 Hz), 7.34 4H), 7.13 (m, IH), 2.35 (s, 3H)。 The preparation method of the compound S26-2 is similar to the preparation method of the compound 9-1 except that the compound is used. S26-1 is substituted for compound 8-1. White solid, Yield: 85-95%. ^ NMR (CDC1 3 ): δ 9.36 (s, IH), 9.14 (dd, IH, J = 1.5, 4.2 Hz), 8.59 (dd, IH, J = 1.8, 8.4 Hz), 7.88 (d, 2H, J = 8.1 Hz), 7.73 (dd, IH, J= 4.2, 8.4 Hz), 7.63 (d, 2H, J= 8.1 Hz), 7.34 4H), 7.13 (m, IH), 2.35 (s, 3H).
8-((lr，4r)-4- J ^环己處基) -N-苯基 -5-溴 -1，6-二氮杂萘 -7 ^ ( S26 )  8-((lr,4r)-4-J^cyclohexyl)-N-phenyl-5-bromo-1,6-diazaphthalene-7 ^ (S26)
Figure imgf000035_0001
Figure imgf000035_0001
化合物 S26的制备方法与化合物 S15的制备方法类似， 除了用化合物 S26-2代替化合物 9-1。黄绿色固体，产率： 75-85%。熔点： 208-210°C ; ^ NMR (300MHz, CD3OD): δ 10.12 (s, IH), 9.02 (d, IH, J = 4.2 Hz), 8.55 (d, IH, J = 8.7 Hz), 7.77 (dd, IH, J= 4.2, 8.7 Hz), 7.71 (m, 2H), 7.31 (m, 2H), 7.14 (m, 1H): 4.98 (m, IH), 3.18 (m, IH), 2.33 (m, 2H), 2.11 (m, 2H), 1.53 (m, 4H); EI-MS m/z: 471(M)+, 473(M+2)+; 分析 HPLC tR= 15.07 min, 97.83% (A), tR = 9.25 min, 94.67% (B)。 The preparation method of the compound S26 is similar to the preparation method of the compound S15 except that the compound S26-2 is used instead of the compound 9-1. Yellow-green solid, yield: 75-85%. Melting point: 208-210°C; ^ NMR (300MHz, CD 3 OD): δ 10.12 (s, IH), 9.02 (d, IH, J = 4.2 Hz), 8.55 (d, IH, J = 8.7 Hz), 7.77 (dd, IH, J= 4.2, 8.7 Hz), 7.71 (m, 2H), 7.31 (m, 2H), 7.14 (m, 1H) : 4.98 (m, IH), 3.18 (m, IH), 2.33 (m, 2H), 2.11 ( m, 2H), 1.53 (m, 4H); EI-MS m / z: 471 (m) +, 473 (m + 2) +; analysis HPLC t R = 15.07 min, 97.83 % (A), t R = 9.25 min, 94.67% (B).
甲苯 _4 ^酸 5-溴 -7-甲氧甲酰 -1，6-二氮杂萘 酸酯 （12)
Figure imgf000035_0002
Toluene_4^acid 5-bromo-7-methoxycarbonyl-1,6-diazaphthalate (12)
Figure imgf000035_0002
化合物 12的制备方法与化合物 9-1的制备方法类似， 除了用 7-1代替 化合物 8-1。白色固体，产率： 85-95%。 ^ NMR (300MHz, CDC13): δ 9.06 (dd, IH, J = 1.5, 4.2 Hz), 8.60 (dd, IH, J = 1.5, 8.7 Hz), 7.86 (d, 2H, J = 8.4 Hz), 7.72 (dd, IH, J = 4.2, 8.4 Hz), 7.34 (d, 2H, J = 8.4 Hz), 3.83 (s, 3H), 2.47 (s, 3H); EI-MS m/z: 436 (M)+。 The preparation method of Compound 12 was similar to the preparation method of Compound 9-1 except that 7-1 was used instead of Compound 8-1. White solid, yield: 85-95%. ^ NMR (300MHz, CDC1 3 ): δ 9.06 (dd, IH, J = 1.5, 4.2 Hz), 8.60 (dd, IH, J = 1.5, 8.7 Hz), 7.86 (d, 2H, J = 8.4 Hz), 7.72 (dd, IH, J = 4.2, 8.4 Hz), 7.34 (d, 2H, J = 8.4 Hz), 3.83 (s, 3H), 2.47 (s, 3H); EI-MS m/z: 436 (M ) +.
8-(4-氟苄基 J _5-溴 -1，6-二氮杂萘 -7 酸甲酯 (13)  8-(4-Fluorobenzyl J _5-bromo -1,6-naphthyridin-7-methyl ester (13)
Figure imgf000035_0003
Figure imgf000035_0003
化合物 13的制备方法与化合物 S15的制备方法类似， 除了用对氟苄胺 代替反式 1,4-环己二胺。 浅绿色固体， 产率： 85-95%。 NMR (300MHz, CDCI3): δ 9.15 (m, IH), 8.93 (dd, IH, J= 1.5, 4.2 Hz), 8.48 (dd, IH, J= 1.8, 8.4 Hz), 7.64 (dd, IH, J= 4.2, 8.4 Hz), 7.37-7.32 (m, 2H), 7.02 (m, 2H), 5.30 (d, 2H: J= 6.0 Hz), 3.97 (s, 3H)。 The preparation of the compound 13 was carried out in a similar manner to the preparation of the compound S15 except that p-fluorobenzylamine was used in place of the trans-1,4-cyclohexanediamine. Light green solid, Yield: 85-95%. NMR (300MHz, CDCI3): δ 9.15 (m, IH), 8.93 (dd, IH, J= 1.5, 4.2 Hz), 8.48 (dd, IH, J= 1.8, 8.4 Hz), 7.64 (dd, IH, J = 4.2, 8.4 Hz), 7.37-7.32 (m, 2H), 7.02 (m, 2H), 5.30 (d, 2H : J = 6.0 Hz), 3.97 (s, 3H).
8-(4-氟苄基氨基) -5-溴 -1，6-二氮杂萘 -7 酸 (14)
Figure imgf000036_0001
8-(4-Fluorobenzylamino)-5-bromo-1,6-naphthyridin-7-acid (14)
Figure imgf000036_0001
化合物 14的制备方法与化合物 11的制备方法类似， 除了用化合物 13 代替化合物 7-1。 浅绿色固体， 产率： 85-95%。 NMR (300MHz, CDC13): 3 9.37 (m, IH), 8.96 (dd, IH, J= 1.5, 4.2 Hz), 8.48 (dd, IH, J= 1.8, 8.4 Hz), 7.67 (dd, IH, J= 4.5, 8.4 Hz), 7.35 (m, 2H), 6.99 (m, 2H), 5.42 (d, 2H, J= 5.7 Hz); The method for producing the compound 14 was similar to the method for producing the compound 11, except that the compound 13 was used instead of the compound 7-1. Light green solid, Yield: 85-95%. NMR (300MHz, CDC1 3 ): 3 9.37 (m, IH), 8.96 (dd, IH, J= 1.5, 4.2 Hz), 8.48 (dd, IH, J= 1.8, 8.4 Hz), 7.67 (dd, IH, J= 4.5, 8.4 Hz), 7.35 (m, 2H), 6.99 (m, 2H), 5.42 (d, 2H, J= 5.7 Hz);
化合物 15  Compound 15
Figure imgf000036_0002
Figure imgf000036_0002
将 EDCI ( 40 mg, 0.2 mmol )加入到化合物 14 ( 37.6 mg, 0.1 mmol ), 单 Boc保护的反式 1,4-环己二胺（33.6 mg, 0.15 mmol ), HOBT ( 27 mg, 0.2 mmol )和 DIPEA ( 26 mg, 0.2 mmol )的 15 mL无水二氯甲烷中， 常温下搅 拌 3h。 用 15 mL饱和 NaHC03溶液， 饱和氯化铵溶液， 饱和食盐水依次洗 涤， 无水 Na2S04干燥， 浓缩。 柱层析（石油醚 /乙酸乙酯 = 4:1 ) 纯化， 得 浅绿色粉末化合物 15 ( 50 mg, 95% )。 熔点： 189-191 °C ; ¾ NMR (300MHz, CDC13): δ 8.90 (dd, IH, J= 1.5, 3.9 Hz), 8.42 (dd, IH, J= 1.5, 8.4 Hz), 7.81 (m, IH), 7.57 (dd, IH, J = 4.2, 8.4 Hz), 7.37 (m, 2H), 6.97 (m, 2H), 5.33 (s, 2H), 4.40 (m, IH), 3.80 (m, IH), 3.48 (m, 2H), 2.06 (m, 4H), 1.45 (s, 9H), 1.36 (m, 4H)。 Add EDCI (40 mg, 0.2 mmol) to compound 14 (37.6 mg, 0.1 mmol), mono Boc-protected trans 1,4-cyclohexanediamine (33.6 mg, 0.15 mmol), HOBT (27 mg, 0.2 mmol) And DIPEA (26 mg, 0.2 mmol) in 15 mL of anhydrous dichloromethane, stirring at room temperature for 3 h. . 15 mL of saturated NaHC0 3 solution, saturated ammonium chloride solution, washed successively with water and brine and dried over anhydrous Na 2 S0 4, and concentrated. Purification by column chromatography (petrole ether / ethyl acetate = 4:1) gave pale green powder compound 15 (50 mg, 95%). Melting point: 189-191 °C; 3⁄4 NMR (300MHz, CDC1 3 ): δ 8.90 (dd, IH, J = 1.5, 3.9 Hz), 8.42 (dd, IH, J = 1.5, 8.4 Hz), 7.81 (m, IH), 7.57 (dd, IH, J = 4.2, 8.4 Hz), 7.37 (m, 2H), 6.97 (m, 2H), 5.33 (s, 2H), 4.40 (m, IH), 3.80 (m, IH) ), 3.48 (m, 2H), 2.06 (m, 4H), 1.45 (s, 9H), 1.36 (m, 4H).
8-(4-氟苄胺基) -N-((lr，4r)-4-氨基环己基) -5-溴 -1,6-二氮杂萘 -7-羧酸胺  8-(4-Fluorobenzylamino)-N-((lr,4r)-4-aminocyclohexyl)-5-bromo-1,6-diazaphthalene-7-carboxylic acid amine
Figure imgf000036_0003
Figure imgf000036_0003
化合物 S27由化合物 15在 TFA/DCM中脱 Boc制得。 黄绿色固体， 产 率： 95%。熔点： 210-213 °C ; ^ NMR (300MHz, d6-DMSO): δ 9.07 (d, IH, J= 3 Hz), 8.47 (d, IH, J= 8.7 Hz), 8.25 (d, IH, J= 7.8 Hz), 7.86 (dd, IH, J= 4.2, 8.4 Hz), 7.40 (m, 2H), 7.15 (m, 2H), 5.26 (s, 2H), 3.72 (m, 2H), 2.99 (m, 2H), 2.73 (m, IH), 1.93 (m, 4H), 1.48 (m, 4H); EI-MS m/z: 471 (M)+, 473 (M+2)+; 分析 HPLC tR= 26.14 min, 100% (A), tR = 29.26 min, 100% (B)。 N-(4-氟-苄基) -5- -8-羟基 -1，6-二氮杂萘 -7 (S28-l)
Figure imgf000037_0001
Compound S27 was prepared by decarboxylation of compound 15 in TFA/DCM. Yellow-green solid, Yield: 95%. Melting point: 210-213 ° C; ^ NMR (300 MHz, d 6 -DMSO): δ 9.07 (d, IH, J = 3 Hz), 8.47 (d, IH, J = 8.7 Hz), 8.25 (d, IH, J = 7.8 Hz), 7.86 (dd, IH, J = 4.2, 8.4 Hz), 7.40 (m, 2H), 7.15 (m, 2H), 5.26 (s, 2H), 3.72 (m, 2H), 2.99 ( m, 2H), 2.73 (m, IH), 1.93 (m, 4H), 1.48 (m, 4H); EI-MS m/z: 471 (M) + , 473 (M+2) + ; R = 26.14 min, 100% (A), t R = 29.26 min, 100% (B). N-(4-fluoro-benzyl)-5--8-hydroxy-1,6-naphthyridin-7 (S28-l)
Figure imgf000037_0001
化合物 S28-1的制备方法与化合物 7-1的制备方法类似，除了用化合物 S3-1代替化合物 6,用 NIS代替 NBS。黄色固体。 ^ NMR (300MHz, CDC13) δ 13.27 (s, 1Η), 9.14 (dd, J = 1.8, 4.2 Hz, 1H), 8.36 (dd, J = 1.5, 8.4 Hz, 1H), 8.20 (m, 1H), 7.71 (dd, J= 4.5, 8.4 Hz, 1H), 7.39 (m, 2H), 7.05 (m, 2H), 4.67 (d, J= 6.3 Hz, 2H). EI-MS m/z: 423 (M)+。 The preparation method of the compound S28-1 was similar to the preparation method of the compound 7-1 except that the compound S3-1 was used instead of the compound 6, and NIS was used instead of the NBS. Yellow solid. ^ NMR (300MHz, CDC1 3 ) δ 13.27 (s, 1Η), 9.14 (dd, J = 1.8, 4.2 Hz, 1H), 8.36 (dd, J = 1.5, 8.4 Hz, 1H), 8.20 (m, 1H) , 7.71 (dd, J= 4.5, 8.4 Hz, 1H), 7.39 (m, 2H), 7.05 (m, 2H), 4.67 (d, J= 6.3 Hz, 2H). EI-MS m/z: 423 ( M) + .
甲苯 -4-磺酸 5-碘 -7-(4-氟-苄基氨基甲酰) -1,6-二氮杂萘 -8-羧酸酯 (S28-2)
Figure imgf000037_0002
Toluene-4-sulfonic acid 5-iodo-7-(4-fluoro-benzylcarbamoyl)-1,6-diazaphthalene-8-carboxylate (S28-2)
Figure imgf000037_0002
化合物 S28-2的制备方法与化合物 9-1的制备方法类似，除了用化合物 S28-1代替化合物 8-1。 白色固体。 ^ NMR (CDC13): δ 8.09 (dd, 1H, J= 1.5, 4.5 Hz), 8.38 (dd, 1H, J = 1.5, 8.4 Hz), 7.97 (m,lH), 7.92 (d, 2H, J = 8.1 Hz), 7.65 (dd, 1H, J = 4.2, 8.4 Hz), 7.37 (m, 2H), 7.32 (d, 2H, J = 8.1 Hz), 7.04 (m, 2H), 4.61 (d, J= 6.0 Hz, 2H), 2.46 (s, 3H)。 The preparation method of the compound S28-2 was similar to the preparation method of the compound 9-1 except that the compound S28-1 was used instead of the compound 8-1. White solid. ^ NMR (CDC1 3 ): δ 8.09 (dd, 1H, J = 1.5, 4.5 Hz), 8.38 (dd, 1H, J = 1.5, 8.4 Hz), 7.97 (m,lH), 7.92 (d, 2H, J = 8.1 Hz), 7.65 (dd, 1H, J = 4.2, 8.4 Hz), 7.37 (m, 2H), 7.32 (d, 2H, J = 8.1 Hz), 7.04 (m, 2H), 4.61 (d, J = 6.0 Hz, 2H), 2.46 (s, 3H).
8-((lr，4r)-4-氨基环己氨基) -N-(4-氟苄基 )-5-碘 -1，6-二氮杂萘 -7-羧酸胺 (S28-3)  8-((lr,4r)-4-Aminocyclohexylamino)-N-(4-fluorobenzyl)-5-iodo-1,6-naphthyridin-7-carboxylic acid amine (S28-3)
Figure imgf000037_0003
Figure imgf000037_0003
化合物 S28-3的制备方法与化合物 S15的制备方法类似， 除了用化合 物 S28-2代替化合物 9-1。 黄绿色固体， 产率： 75-85%。 NMR (300MHz, CDC13): δ 9.65 (d, 1H, J= 6.0 Hz), 8.86 (dd, 1H, J= 1.2, 3.3 Hz), 8.32 (m, 1H), 8.23 (dd, 1H, J= 1.2, 6.3 Hz), 7.56 (dd, 1H, J= 3.3, 6.3 Hz), 7.34 (m, 2H), 7.04 (m, 2H), 4.93 (m, 1H), 4.60(d, 2H, J= 4.8 Hz), 4.38 (m, 1H), 3.49 (m, 1H), 2.18 (m, 2H), 2.06 (m, 2H), 1.45 (s, 9H), 1.29 (m, 4H)。 The preparation method of the compound S28-3 is similar to the preparation method of the compound S15 except that the compound S28-2 is used instead of the compound 9-1. Yellow-green solid, Yield: 75-85%. NMR (300MHz, CDC1 3 ): δ 9.65 (d, 1H, J = 6.0 Hz), 8.86 (dd, 1H, J = 1.2, 3.3 Hz), 8.32 (m, 1H), 8.23 (dd, 1H, J= 1.2, 6.3 Hz), 7.56 (dd, 1H, J= 3.3, 6.3 Hz), 7.34 (m, 2H), 7.04 (m, 2H), 4.93 (m, 1H), 4.60(d, 2H, J= 4.8 Hz), 4.38 (m, 1H), 3.49 (m, 1H), 2.18 (m, 2H), 2.06 (m, 2H), 1.45 (s, 9H), 1.29 (m, 4H).
化合物 S28-4 Compound S28-4
Figure imgf000038_0001
Figure imgf000038_0001
将化合物 S28-3 (10mg, 0.016mmol), 丙炔酸甲酯 (2.7mg,0.032mmol), 氯 化钯（lmg, 0.05mmol) , 三 苯基膦（2.6mg,0.01mmol), 埃化 亚铜 (2.0mg,0.01mmol), 和碳酸钾 (4mg,0.03mmol)溶于 3mL THF 中， 氮气保护, 加热回流 14小时。 反应体系冷却，旋干 THF, 加入 20mL二氯甲烷， 饱和食 盐水洗两次， 有机相用无水硫酸钠干燥。 硅胶柱层析 （石油醚： 乙酸乙酯= 4: 1)得到黄绿色固体化合物 S28-4 (6.0mg, 65%)。 ^ NMR (300MHz, CDC13): δ 10.47 (m, 1H), 8.91 (dd, 1H, J = 1.8, 4.2 Hz), 8.57 (m, 1H), 8.51 (dd, 1H, J = 1.5, 8.7 Hz), 7.58 (dd, 1H, J= 4.5, 8.4 Hz), 7.35 (m, 2H), 7.06 (m, 2H), 5.14 (m, 1H), 4.59 (d, 2H, J= 6.0 Hz), 4.39 (m, 1H), 3.87 (s, 3H), 3.50 (m, 1H), 2.23 (m, 2H), 2.06 (m, 2H), 1.43 (s, 9H), 1.35 (m, 4H); EI-MS m/z: 575 (M)+。 Compound S28-3 (10 mg, 0.016 mmol), methyl propiolate (2.7 mg, 0.032 mmol), palladium chloride (1 mg, 0.05 mmol), triphenylphosphine (2.6 mg, 0.01 mmol), A. Copper (2.0 mg, 0.01 mmol), and potassium carbonate (4 mg, 0.03 mmol) were dissolved in 3 mL THF. The reaction system was cooled, and the THF was evaporated to dryness. Silica gel column chromatography (petrole ether: EtOAc = 4:1) ^ NMR (300MHz, CDC1 3 ): δ 10.47 (m, 1H), 8.91 (dd, 1H, J = 1.8, 4.2 Hz), 8.57 (m, 1H), 8.51 (dd, 1H, J = 1.5, 8.7 Hz ), 7.58 (dd, 1H, J= 4.5, 8.4 Hz), 7.35 (m, 2H), 7.06 (m, 2H), 5.14 (m, 1H), 4.59 (d, 2H, J = 6.0 Hz), 4.39 (m, 1H), 3.87 (s, 3H), 3.50 (m, 1H), 2.23 (m, 2H), 2.06 (m, 2H), 1.43 (s, 9H), 1.35 (m, 4H); EI- MS m/z: 575 (M) + .
3-{5-[8-((lr，4r)-4-氨基环己氨基 )-7-(4-氟苄基氨基甲酰) -1,6-二氮杂萘 基】 }丙炔酸甲酯 (S 8)  3-{5-[8-((lr,4r)-4-aminocyclohexylamino)-7-(4-fluorobenzylcarbamoyl)-1,6-diazanaphthyl]}propynoic acid Methyl ester (S 8)
Figure imgf000038_0002
Figure imgf000038_0002
化合物 S28由化合物 S28-4在 TFA/DCM中脱 Boc得到。 黄绿色固体， 产率： 95%。 熔点： 116-118°C ; ¾ NMR (300MHz, CDC13): δ 10.82 (m, 1H), 9.67 (dd, 1H, J= 1.8, 8.7 Hz), 8.89 (dd, 1H, J= 1.8, 3.9 Hz), 8.65 (m, 1H), 7.59 (dd, 1H, J= 4.2, 8.7 Hz), 7.42 (m, 2H), 7.02 (m, 2H), 5.20 (m, 1H), 4.61 (d, 2H, J = 6.3 Hz), 3.92 (s, 3H), 2.68 (m, 1H), 2.25 (m, 2H), 1.97 (m, 2H), 1.42 (m, 4H); EI-MS m/z: 589 (M+CF3COOH)+; 分析 HPLC tR = 22.23 min, 96.12% (A), tR = 22.10 min, 92.83% (B)。 Compound S28 was obtained by decarboxylation of compound S28-4 in TFA/DCM. Yellow-green solid, Yield: 95%. Melting point: 116-118°C; 3⁄4 NMR (300MHz, CDC1 3 ): δ 10.82 (m, 1H), 9.67 (dd, 1H, J= 1.8, 8.7 Hz), 8.89 (dd, 1H, J= 1.8, 3.9 Hz), 8.65 (m, 1H), 7.59 (dd, 1H, J= 4.2, 8.7 Hz), 7.42 (m, 2H), 7.02 (m, 2H), 5.20 (m, 1H), 4.61 (d, 2H , J = 6.3 Hz), 3.92 (s, 3H), 2.68 (m, 1H), 2.25 (m, 2H), 1.97 (m, 2H), 1.42 (m, 4H); EI-MS m/z: 589 (M+CF 3 COOH) + ; Analytical HPLC t R = 22.23 min, 96.12% (A), t R = 22.10 min, 92.83% (B).
N-(4-氟苄基 )-5-溴 -8-(4- (异丁酰胺)哌啶 -1-基) -1,6-二氮杂萘 -7-羧酸胺 ( S29)
Figure imgf000039_0001
N-(4-fluorobenzyl)-5-bromo-8-(4-(isobutyramide)piperidin-1-yl)-1,6-naphthyridin-7-carboxylic acid amine (S29)
Figure imgf000039_0001
化合物 S29的制备方法与化合物 S15的制备方法类似， 除了用 4- (异丁 酰胺)哌啶代替反式 1,4-环己二胺。 黄绿色固体， 产率： 75-85%。 熔点： 200-202 °C ; lR NMR (300MHz, CDC13): δ 9.05 (dd, 1H, J = 1.8, 4.2 Hz), 8.63 (m, 1H), 8.52 (dd, 1H, J = 1.8, 8.4 Hz), 7.62 (dd, 1H, J = 4.2, 8.4 Hz), 7.39 (m, 2H), 7.07 (m, 2H), 5.33 (m, 1H), 4.66 (d, 2H, J = 6.0 Hz), 4.09 (m, 1H), 3.63 (m 2H), 3.44 (m, 2H), 1.98 (m, 4H), 1.22 (d, 2H, J= 3.9 Hz); EI-MS m/z: 527 (M)+, 529 (M+2)+; 分析 HPLC tR = 4.62 min, 99.41% (A), tR = 19.22 min, 92.63% (B)。 The preparation method of the compound S29 was similar to the preparation of the compound S15 except that 4-(isobutyramide) piperidine was used instead of the trans 1,4-cyclohexanediamine. Yellow-green solid, Yield: 75-85%. Melting point: 200-202 °C; l R NMR (300MHz, CDC1 3 ): δ 9.05 (dd, 1H, J = 1.8, 4.2 Hz), 8.63 (m, 1H), 8.52 (dd, 1H, J = 1.8, 8.4 Hz), 7.62 (dd, 1H, J = 4.2, 8.4 Hz), 7.39 (m, 2H), 7.07 (m, 2H), 5.33 (m, 1H), 4.66 (d, 2H, J = 6.0 Hz) , 4.09 (m, 1H), 3.63 (m 2H), 3.44 (m, 2H), 1.98 (m, 4H), 1.22 (d, 2H, J = 3.9 Hz); EI-MS m/z: 527 (M + , 529 (M+2) + ; Analytical HPLC t R = 4.62 min, 99.41% (A), t R = 19.22 min, 92.63% (B).
叔丁基（lr，4r)-4-(7- (甲氧碳酰基 )-5-溴 -1，6-二氮杂萘 -8- J 环己 ^ 甲酸酯 (S30-1) tert-Butyl (lr,4r)-4-(7-(methoxycarbamoyl)-5-bromo-1,6-naphthyridin-8-J cyclohexylformate (S 3 0-1)
Figure imgf000039_0002
Figure imgf000039_0002
化合物 S30-1的制备方法与化合物 S15的制备方法类似， 除了用 K2C03 代替三乙胺。 黄绿色固体， 产率： 75-85%。 NMR (300MHz, CDC13): 3 8.95 (dd, 1H, J= 1.5, 4.2 Hz), 8.88 (d, 1H, J= 7.5 Hz), 8.47 (dd, 1H, J= 1.5, 8.4 Hz): 7.64 (dd, 1H, J= 4.2, 8.4 Hz), 4.92 (m, 1H), 4.42 (m, 1H), 3.97 (s, 3H), 3.47 (m, 1H), 2.20 (m, 2H), 2.05 (m, 2H), 1.44 (s, 9H), 1.43-1.23 (m, 4H); EI-MS m/z: 478 (M)+, 480 (M+2)+。 The preparation method of the compound S30-1 was similar to the preparation method of the compound S15 except that K 2 CO 3 was used instead of triethylamine. Yellow-green solid, Yield: 75-85%. NMR (300MHz, CDC1 3 ): 3 8.95 (dd, 1H, J= 1.5, 4.2 Hz), 8.88 (d, 1H, J= 7.5 Hz), 8.47 (dd, 1H, J= 1.5, 8.4 Hz): 7.64 (dd, 1H, J= 4.2, 8.4 Hz), 4.92 (m, 1H), 4.42 (m, 1H), 3.97 (s, 3H), 3.47 (m, 1H), 2.20 (m, 2H), 2.05 ( m, 2H), 1.44 (s, 9H), 1.43-1.23 (m, 4H); EI-MS m/z: 478 (M) + , 480 (M+2) + .
5-溴 -8-( (lr，4r)-4-叔丁氧羰基氨基环己氨基 )-l，6-二氮杂萘 -7-羧酸  5-bromo-8-((lr,4r)-4-tert-butoxycarbonylaminocyclohexylamino)-l,6-diazaphthalene-7-carboxylic acid
Figure imgf000039_0003
Figure imgf000039_0003
化合物 S30-2由化合物 S30-1在 IN NaOH溶液 /THF中， 60度下， 10h 水解制得， 黄绿色固体， 产率： 75-85%。 熔点: 122-126°C ; ^ NMR (300MHz, CDC13): δ 8.96 (dd, 1Η, J = 1.5, 4.2 Hz), 8.88 (d, 1H, J = 7.5 Hz), 8.45 (dd, 1H, J = 1.5, 8.4 Hz), 7.64 (dd, 1H, J= 4.2, 8.4 Hz), 4.96 (m, 1H), 4.41 (m, 1H), 3.47 (m, IH), 2.21 (m, 2H), 2.08 (m, 2H), 1.44 (s, 9H), 1.43-1.23 (m, 4H); EI-MS m/z: 464 (M)+, 466 (M+2)+。 Compound S30-2 was obtained by hydrolysis of compound S30-1 in IN NaOH solution / THF at 60 ° C for 10 h, yellow solid, yield: 75-85%. Melting point: 122-126°C; ^ NMR (300MHz, CDC1 3 ): δ 8.96 (dd, 1Η, J = 1.5, 4.2 Hz), 8.88 (d, 1H, J = 7.5 Hz), 8.45 (dd, 1H, J = 1.5, 8.4 Hz), 7.64 (dd, 1H, J= 4.2, 8.4 Hz), 4.96 (m, 1H), 4.41 (m, 1H), 3.47 (m, IH), 2.21 (m, 2H), 2.08 (m, 2H), 1.44 (s, 9H), 1.43-1.23 (m, 4H); EI-MS m/z: 464 (M) + , 466 (M+2) + .
化合物 S30-3  Compound S30-3
Figure imgf000040_0001
Figure imgf000040_0001
化合物 S30-3的制备方法与化合物 15的制备方法类似， 除了用化合物 S30-2代替化合物 14。 黄绿色固体， 产率： 87%。 iH NMRpOOMHz, CDC13): δ 8.93 (dd, J= 1.5, 4.2 Hz, IH), 8.68 (dd, J= 1.5, 4.2 Hz, IH), 8.43 (dd, J= 1.5, 8.4 Hz, IH), 8.37 (d, J= 8.4 Hz, IH), 7.61 (dd, J= 4.5, 8.4 Hz, IH), 7.37 (dd, J = 4.5, 8.4 Hz, IH), 6.70 (m, IH), 5.61 (m, IH), 5.18 (m, IH), 4.93 (m, IH), 4.69 (m, IH), 3.87 (m, IH), 3.54 (m, IH), 2.87(m, 2H), 2.37 (m, 5H), 2.18 (m, 2H), 2.06 (m, 5H), 1.46 (s, 9H), 1.37 (m, 2H); EI-MS m/z: 675 (M)+, 677 (M+2)+。 The preparation method of the compound S30-3 was similar to the preparation method of the compound 15, except that the compound S30-2 was used instead of the compound 14. Yellow-green solid, Yield: 87%. iH NMRpOOMHz, CDC1 3 ): δ 8.93 (dd, J= 1.5, 4.2 Hz, IH), 8.68 (dd, J= 1.5, 4.2 Hz, IH), 8.43 (dd, J= 1.5, 8.4 Hz, IH), 8.37 (d, J = 8.4 Hz, IH), 7.61 (dd, J= 4.5, 8.4 Hz, IH), 7.37 (dd, J = 4.5, 8.4 Hz, IH), 6.70 (m, IH), 5.61 (m , IH), 5.18 (m, IH), 4.93 (m, IH), 4.69 (m, IH), 3.87 (m, IH), 3.54 (m, IH), 2.87 (m, 2H), 2.37 (m, 5H), 2.18 (m, 2H), 2.06 (m, 5H), 1.46 (s, 9H), 1.37 (m, 2H); EI-MS m/z: 675 (M) + , 677 (M+2) + .
(8-((lr,4r)-4- 氨 基 环 己 氨 基 ）-5- 溴 -1,6- 二 氮 杂 萘 -7- 基) ((lS，3s，5R)-3-(3H-[l，2，3】三氮唑 [4,5-】吡啶 -3-基) -8-氮杂 -二环 [3.2.1】辛烷 •8-i)甲基酮 (S30) (8-((lr,4r)-4-aminocyclohexylamino)-5-bromo-1,6-diazaphthalen-7-yl) ((lS,3s,5R)-3-(3H-[ l,2,3]triazole [4,5-]pyridin-3-yl)-8-aza-bicyclo[3.2.1]octane• 8- i)methylketone (S 3 0)
Figure imgf000040_0002
Figure imgf000040_0002
化合物 S30由化合物 S30-3在 TFA/DCM中脱 Boc制得。 黄绿色固体， 产率： 75-85%。 熔点： 135-138°C ; ^ NMR(300MHz, CDC13): δ 8.91 (d, J= 3.9 Hz, IH), 8.68 (d, J = 3.9 Hz, IH), 8.43 (d, J = 7.5 Hz, IH), 8.38 (d, J = 8.1 Hz, IH), 7.61 (dd, J = 4.2, 8.7 Hz, IH), 7.36 (dd, J = 4.5, 8.1 Hz, IH), 6.81 (d, J = 9.3 Hz, IH), 5.60 (m, IH), 5.20 (m, IH), 4.69 (m, IH), 3.98 (brs, IH), 2.86(m, IH), 2.78 (m, IH), 2.23-1.93 (m, 10H), 1.43-1.33 (m, 4H); EI-MS m/z: 575 (M)+, 577 (M+2)+; 分析 HPLC tR = 7.90 min, 98.78% (A), tR= 10.90 min, 96.77% (B)。 Compound S30 was prepared by decarboxylation of compound S30-3 in TFA/DCM. Yellow-green solid, Yield: 75-85%. Melting point: 135-138°C; ^ NMR (300MHz, CDC1 3 ): δ 8.91 (d, J = 3.9 Hz, IH), 8.68 (d, J = 3.9 Hz, IH), 8.43 (d, J = 7.5 Hz , IH), 8.38 (d, J = 8.1 Hz, IH), 7.61 (dd, J = 4.2, 8.7 Hz, IH), 7.36 (dd, J = 4.5, 8.1 Hz, IH), 6.81 (d, J = 9.3 Hz, IH), 5.60 (m, IH), 5.20 (m, IH), 4.69 (m, IH), 3.98 (brs, IH), 2.86 (m, IH), 2.78 (m, IH), 2.23- 1.93 (m, 10H), 1.43-1.33 (m, 4H); EI-MS m/z: 575 (M) + , 577 (M+2) + ; Analytical HPLC t R = 7.90 min, 98.78% (A) , t R = 10.90 min, 96.77% (B).
8-((lr，4r)-4-氨基环己氨基) -N-(3，4-二氯苄基) -5-溴 -1，6-二氮杂萘 酸 胺（ S31 )  8-((lr,4r)-4-Aminocyclohexylamino)-N-(3,4-dichlorobenzyl)-5-bromo-1,6-naphthyridiniumamine (S31)
Figure imgf000040_0003
化合物 S31的制备方法与化合物 S25的制备方法类似。 浅黄色固体, ： 75-85% 熔点： 141-143 °C ; ^ NMR (300MHz, CDC13): δ 9.56 (d, IH, J 8.1 Hz), 8.94 (d, IH, J = 3.9 Hz), 8.42-8.35 (m, 3H), 7.59 (dd, IH, J = 4.2, 8.7 Hz), 7.44-7.38 (m, 2H), 7.20 (m, IH), 4.96 (m, IH), 4.57 (d, 2H, J = 6.0 Hz), 2.76 (m, IH), 2.18 (m, 2H), 1.91(m, 2H), 1.37(m, 4H); EI-MS m/z: 521 (M)+。
Figure imgf000040_0003
The preparation method of the compound S31 is similar to the preparation method of the compound S25. Light yellow solid, : 75-85%, melting point: 141-143 °C; ^ NMR (300MHz, CDC1 3 ): δ 9.56 (d, IH, J 8.1 Hz), 8.94 (d, IH, J = 3.9 Hz), 8.42-8.35 (m, 3H), 7.59 (dd, IH, J = 4.2, 8.7 Hz), 7.44-7.38 (m, 2H), 7.20 ( m, IH), 4.96 (m, IH), 4.57 (d, 2H, J = 6.0 Hz), 2.76 (m, IH), 2.18 (m, 2H), 1.91 (m, 2H), 1.37 (m, 4H) ); EI-MS m/z: 521 (M) + .
8-((lr，4r)-4-氨基环己氨基) -N-(3-三氟甲基苄基 )-5-溴 -1,6-二氮杂萘 -7- ( S32 )  8-((lr,4r)-4-Aminocyclohexylamino)-N-(3-trifluoromethylbenzyl)-5-bromo-1,6-naphthyridin-7-(S32)
Figure imgf000041_0001
与化合物 S25 的制备方法类似。 黄绿色固体， 产率： 75-85%。 熔点: 94-96 °C ; ¾ NMR (300MHz, CDC13): δ 9.59 (d, IH, J = 8.2Hz), 8.59 (s, IH), 8.42 (m, 2H), 7.61-7.44 (m, 5H), 4.97 (m, IH), 4.69 (d, 2H, J= 6.0 Hz), 2.78 (m IH), 2.17 (m, 2H), 2.00-1.83(m, 4H), 1.43-1.25(m, 4H); EI-MS m/z: 521 (M)+, 523(M+2)+。
Figure imgf000041_0001
It is similar to the preparation method of the compound S25. Yellow-green solid, Yield: 75-85%. Melting point: 94-96 °C; 3⁄4 NMR (300MHz, CDC1 3 ): δ 9.59 (d, IH, J = 8.2Hz), 8.59 (s, IH), 8.42 (m, 2H), 7.61-7.44 (m, 5H), 4.97 (m, IH), 4.69 (d, 2H, J = 6.0 Hz), 2.78 (m IH), 2.17 (m, 2H), 2.00-1.83 (m, 4H), 1.43-1.25 (m, 4H); EI-MS m/z: 521 (M) + , 523 (M+2) + .
8-((lr，4r)-4-氨基环己氨基 )- V_(3_氯 _4-甲氧苄基 )-5-溴 -1,6-二氮杂萘 -7- 羧 ( S33 ) 8-((lr,4r)-4-Aminocyclohexylamino)-V_ (3 _chloro-4-methoxybenzyl)-5-bromo-1,6-naphthyridin-7-carboxy (S33)
Figure imgf000041_0002
与化合物 S25的制备方法类似。 浅黄色固体，产率： 68%。 ifi NMR pOO MHz, CDC13) δ: 9.61 (d, 2H), 8.94 (d, IH, J = 6Hz), 8.41 (d, IH, J =8.4Hz), 8.28 (brs, IH), 7.59 (q, IH, J = 6Hz, 8.4Hz), 7.22-7.39 (m, 2H), 6.91 (d, IH, J=8.4Hz), 4.98 (m, IH), 4.54 (d, 2H), 3.89 (s, 3H), 3.6 (s, IH), 2.82 (m, IH), 2.19 (d, 2H, J =9.9Hz), 1.95 (d, 2H, J =11.7Hz), 1.38 (m, 4H); MS-EI m/z: 517 (calcd: 518.83)。
Figure imgf000041_0002
It is similar to the preparation method of the compound S25. Light yellow solid, yield: 68%. Ifi NMR pOO MHz, CDC1 3 ) δ: 9.61 (d, 2H), 8.94 (d, IH, J = 6Hz), 8.41 (d, IH, J = 8.4Hz), 8.28 (brs, IH), 7.59 (q , IH, J = 6Hz, 8.4Hz), 7.22-7.39 (m, 2H), 6.91 (d, IH, J=8.4Hz), 4.98 (m, IH), 4.54 (d, 2H), 3.89 (s, 3H), 3.6 (s, IH), 2.82 (m, IH), 2.19 (d, 2H, J = 9.9 Hz), 1.95 (d, 2H, J = =11.7 Hz), 1.38 (m, 4H); MS- EI m/z: 517 (calcd: 518.83).
8-((lr，4r)-4-氨基环己氨基) - V-(4-二甲胺基苄基 )-5-溴 -1,6-二氮杂萘 -7- 羧 ( S34 )  8-((lr,4r)-4-Aminocyclohexylamino)-V-(4-dimethylaminobenzyl)-5-bromo-1,6-naphthyridin-7-carboxy (S34)
Figure imgf000041_0003
与化合物 S25的制备方法类似。 浅黄色固体，产率： 70%。 ifi NMR pOO MHz, CDCI3) δ: 9.7(d, 2H), 8.93(d, IH, J =2.7Hz), 8.38(d, IH, J =3.9Hz), 8.19(brs, IH), 7.54(q, IH, J =2.7Hz, 3.9Hz), 7.24(d, 2H, J =7.8Hz), 6.72(d, 2H, J=8.7Hz), 45.01(m, IH), 4.5(d, 2H), 3.23(m, IH), 2.92(s, 6H), 2.29(m, 4H), 1.76(d, 2H, J =11.7Hz), 1.43(d, 2H, J =13.2Hz); MS-EI w/z: 496 (calcd: 497.43)。
Figure imgf000041_0003
It is similar to the preparation method of the compound S25. Light yellow solid, yield: 70%. Ifi NMR pOO MHz, CDCI3) δ: 9.7(d, 2H), 8.93(d, IH, J = 2.7Hz), 8.38(d, IH, J = 3.9Hz), 8.19(brs, IH), 7.54(q , IH, J = 2.7 Hz, 3.9 Hz), 7.24 (d, 2H, J = 7.8 Hz), 6.72 (d, 2H, J=8.7Hz), 45.01(m, IH), 4.5(d, 2H), 3.23(m, IH), 2.92(s, 6H), 2.29(m, 4H), 1.76(d, 2H, J =11.7 Hz), 1.43 (d, 2H, J = 13.2 Hz); MS-EI w/z: 496 (calcd: 497.43).
8-((lr，4r)-4-氨基环己氨基) - V-(4-苄氧基苄基) -5-溴 -1，6-二氮杂萘 -7-羧 ( S35 )  8-((lr,4r)-4-aminocyclohexylamino)-V-(4-benzyloxybenzyl)-5-bromo-1,6-naphthyridin-7-carboxy (S35)
Figure imgf000042_0001
与化合物 S25的制备方法类似。 浅黄色固体，产率： 85%。 ifi NMR pOO MHz, CDC13) δ: 9.66(d, 2H), 8.94(d, IH, J =4.2Hz), 8.41(d, IH, J =10.2Hz), 8.25(brs, IH), 7.58(q, IH, J =4.2Hz, 10.2Hz), 7.3-7.45(m, 9H), 6.96(d, 2H, J=8.7Hz), 5.06(s, IH), 4.94(m, IH), 4.56(d, 2H), 2.76(m, IH), 2.17(d, 2H, J =12.3Hz), 1.9(d, 2H, J=13.5Hz), 1.39(m, 4H); MS-EI w/z: 559 (calcd: 560.48)。
Figure imgf000042_0001
It is similar to the preparation method of the compound S25. Light yellow solid, yield: 85%. Ifi NMR pOO MHz, CDC1 3 ) δ: 9.66(d, 2H), 8.94(d, IH, J = 4.2Hz), 8.41(d, IH, J = 10.2Hz), 8.25(brs, IH), 7.58( q, IH, J = 4.2 Hz, 10.2 Hz), 7.3-7.45 (m, 9H), 6.96 (d, 2H, J = 8.7 Hz), 5.06 (s, IH), 4.94 (m, IH), 4.56 ( d, 2H), 2.76(m, IH), 2.17(d, 2H, J = 12.3Hz), 1.9(d, 2H, J=13.5Hz), 1.39(m, 4H); MS-EI w/z: 559 (calcd: 560.48).
8-((lr，4r)-4-氨基环己氨基) -ΛΗ4- 基苄基 )-5-溴 -1，6-二氮杂萘 -7-羧酸 胺（ S36 )  8-((lr,4r)-4-Aminocyclohexylamino)-inden-4-ylbenzyl)-5-bromo-1,6-naphthyridin-7-carboxylic acid amine (S36)
Figure imgf000042_0002
与化合物 S25 的制备方法类似。 浅黄色固体， 产率： 81%。 NMR (300MHz, CDCI3): δ 9.10 (d, IH, J= 8.2Hz), 8.76 (s, IH), 8.23 (d, IH), 7.46 (m IH), 7.39 (d, 2H), 7.24 (d, 2H), 6.80 (s, 2H), 4.22 (m, 2H), 3.15 (m, IH), 2.0 (m, 2H), 2.00-1.83(m, 4H), 1.43-1.25(m, 4H); EI-MS m/z: 478 (M)+, 480(M+2)+。
Figure imgf000042_0002
It is similar to the preparation method of the compound S25. Light yellow solid, Yield: 81%. NMR (300MHz, CDCI3): δ 9.10 (d, IH, J = 8.2Hz), 8.76 (s, IH), 8.23 (d, IH), 7.46 (m IH), 7.39 (d, 2H), 7.24 (d , (2, 2H) EI-MS m/z: 478 (M) + , 480 (M+2) + .
8-((lr，4r)-4-氨基环己氨基) -N-(4-环己基氧苄基) -5-溴 -1,6-二氮杂萘 -7- 羧 ( S37 )  8-((lr,4r)-4-aminocyclohexylamino)-N-(4-cyclohexyloxybenzyl)-5-bromo-1,6-naphthyridin-7-carboxy (S37)
Figure imgf000042_0003
与化合物 S25的制备方法类似。 浅黄色固体，产率： 72%。 ifi NMR pOO MHz, CDCI3) δ: 9.69(d, 2H), 8.95(d, IH, J =4.5Hz), 8.41(d, IH, J =8.4Hz), 8.25(brs, IH), 7.58(q, IH, J=4.5Hz, 8.4Hz), 7.27(d, 2H, J=10.8Hz), 6.88(d, 2H J=8.7Hz), 5.01(m, IH), 4.55(d, 2H), 4.22(m, IH), 3.56(m, IH), 3.08(m, IH), 2.27(d, 2H, J =13.5Hz), 2.16(d, 2H, J =13.9Hz), 1.97(m, 4H), 1.78(m, 4H), 1.31-1.49(m, 6H); EI-MS m/z: 551 (calcd: 552.51)。
Figure imgf000042_0003
It is similar to the preparation method of the compound S25. Light yellow solid, yield: 72%. Ifi NMR pOO MHz, CDCI3) δ: 9.69(d, 2H), 8.95(d, IH, J = 4.5Hz), 8.41(d, IH, J = 8.4Hz), 8.25(brs, IH), 7.58(q , IH, J=4.5Hz, 8.4Hz), 7.27(d, 2H, J=10.8Hz), 6.88(d, 2H J=8.7Hz), 5.01(m, IH), 4.55(d, 2H), 4.22 (m, IH), 3.56(m, IH), 3.08(m, IH), 2.27(d, 2H, J = 13.5Hz), 2.16(d, 2H, J = 13.9Hz), 1.97(m, 4H), 1.78(m, 4H), 1.31-1.49(m, 6H); EI-MS m/z: 551 (calcd: 552.51).
8-((lr，4r)-4- J ^环己 J^)- V-(4-(2-吗啡啉基乙氧)苄基) -5-溴 -1，6-二氮 杂萘 -7 ( S38 )  8-((lr,4r)-4-J^cyclohexyl J^)-V-(4-(2-morpholine ethoxy)benzyl)-5-bromo-1,6-naphthyridine- 7 ( S38 )
Figure imgf000043_0001
与化合物 S25 的制备方法类似。 浅黄色固体， 产率： 70%。 NMR (300MHz, CDC13): δ 9.25 (d, IH), 8.76 (s, IH), 8.32 (d, IH), 7.46 (m, IH), 6.95 (d, 2H), 6.65 (d, 2H), 4.22 (s, 2H), 4.06 (t, 2H), 3.52 (t, 4H), 3.15 (m, IH), 2.69 (t, 2H), 2.37 (t, 4H), 2.0 (s, 2H), 2.00-1.83(m, 4H), 1.43-1.25(m, 4H); EI-MS m/z: 582 (M)+, 584(M+2)+。
Figure imgf000043_0001
It is similar to the preparation method of the compound S25. Light yellow solid, Yield: 70%. NMR (300MHz, CDC1 3 ): δ 9.25 (d, IH), 8.76 (s, IH), 8.32 (d, IH), 7.46 (m, IH), 6.95 (d, 2H), 6.65 (d, 2H) , 4.22 (s, 2H), 4.06 (t, 2H), 3.52 (t, 4H), 3.15 (m, IH), 2.69 (t, 2H), 2.37 (t, 4H), 2.0 (s, 2H), 2.00-1.83 (m, 4H), 1.43-1.25 (m, 4H); EI-MS m/z: 582 (M) + , 584 (M+2) + .
Figure imgf000043_0002
己處基)- -(4-(2-哌嗪 -1-基)乙氧)苄基) -5-溴 -1,6-二氮 杂萘 -7 ( S39 )
Figure imgf000043_0002
己))-(4-(2-Piperazin-1-yl)ethoxy)benzyl)-5-bromo-1,6-naphthyridin-7 (S39)
Figure imgf000043_0003
与化合物 S25 的制备方法类似。 浅黄色固体， 产率： 66%。 NMR (300MHz, CDCI3): δ 9.25 (d, IH), 8.76 (s, IH), 8.32 (d, IH), 7.46 (m, IH), 6.95 (d, 2H), 6.65 (d, 2H), 4.22 (s, 2H), 4.06 (t, 2H), 3.52 (t, 4H), 3.15 (m, IH), 2.69 (t, 2H), 2.37 (t, 4H), 2.10 (m, IH), 2.0 (s, 2H), 2.00-1.83(m, 4H), 1.43-1.25(m, 4H); EI-MS m/z: 581 (M)+ (计算值： 581.2)。
Figure imgf000043_0003
It is similar to the preparation method of the compound S25. Light yellow solid, Yield: 66%. NMR (300MHz, CDCI3): δ 9.25 (d, IH), 8.76 (s, IH), 8.32 (d, IH), 7.46 (m, IH), 6.95 (d, 2H), 6.65 (d, 2H), 4.22 (s, 2H), 4.06 (t, 2H), 3.52 (t, 4H), 3.15 (m, IH), 2.69 (t, 2H), 2.37 (t, 4H), 2.10 (m, IH), 2.0 (s, 2H), 2.00-1.83 (m, 4H), 1.43-1.25 (m, 4H); EI-MS m/z: 581 (M) + (calc.: 581.2).
8-((lr，4r)-4- ^环己 ^)- -(4- (叔丁基二甲硅氧)苄基) -5-溴 -1，6-二氮 杂萘 -7 ( S40 )  8-((lr,4r)-4-^cyclohexyl)--(4-(tert-butyldimethylsiloxane)benzyl)-5-bromo-1,6-naphthyridin-7 (S40 )
Figure imgf000043_0004
与化合物 S25的制备方法类似。 浅黄色固体，产率： 78%。 ^ NMR POO MHz, CDCI3) δ: 9.66 (d, IH), 8.94 (d, IH, J =4.2Hz), 8.41(d, IH, J =10.2Hz), 8.24 (brs, IH), 7.58 (dd, IH, J=4.2Hz, 10.2Hz), 7.23 (d, 2H, J=8.8Hz), 6.82 (d, 2H, J=8.4Hz), 4.96 (m, IH), 4.56 (d, 2H), 2.75 (m, IH), 2.17 (d, 2H, J=12.9Hz) 1.9 (d, 2H, J=14.1Hz), 1.34 (m, 4H), 0.98 (s, 9H), 0.19 (s, IH). EI-MS m/z: 583 (M)+ (计算值： 583.2)。
Figure imgf000043_0004
It is similar to the preparation method of the compound S25. Light yellow solid, yield: 78%. ^ NMR POO MHz, CDCI3) δ: 9.66 (d, IH), 8.94 (d, IH, J = 4.2 Hz), 8.41 (d, IH, J = 10.2 Hz), 8.24 (brs, IH), 7.58 (dd , IH, J=4.2Hz, 10.2Hz), 7.23 (d, 2H, J=8.8Hz), 6.82 (d, 2H, J=8.4Hz), 4.96 (m, IH), 4.56 (d, 2H), 2.75 (m, IH), 2.17 (d, 2H, J = 12.9Hz) 1.9 (d, 2H, J = 14.1Hz), 1.34 (m, 4H), 0.98 (s, 9H), 0.19 (s, IH) . EI-MS m/z: 583 (M) + (Calc: 583.2).
8-((lr，4r)-4-氨基环己氨基) - -(4-(2-吗啡啉基 -2-乙酰氧)苄基) -5-溴 -1，6- 二氮杂萘 酸胺 ( S41 )  8-((lr,4r)-4-Aminocyclohexylamino)-(4-(2-morphinolinyl-2-acetoxy)benzyl)-5-bromo-1,6-naphthyridinic acid Amine (S41)
Figure imgf000044_0001
Figure imgf000044_0001
与化合物 S25 的制备方法类似。 浅黄色固体， 产率： 68%。 NMR (300MHz, CDC13): NMR (300 MHz, CDC13) S: 9.64 (d, IH), 8.95 (d, IH, J =3.9Hz), 8.4 (d, IH, J =8.4Hz), 8.28 (brs, IH), 7.57 (dd, IH, J =3.9Hz, 8.4Hz), 7.31 (d, 2H, J=8.7Hz), 6.93 (d, 2H, J=8.4Hz), 5.0 (m, IH), 4.69 (s, 2H), 4.56 (d, 2H), 3.56-3.66 (m, 8H), 3.22 (m, IH), 2.28 (m, 4H), 1.71-1.82 (m, 2H), 1.4-1.47 (m, 2H); MS-EI m/z: 596 (计算值： 597.5). It is similar to the preparation method of the compound S25. Light yellow solid, Yield: 68%. NMR (300MHz, CDC1 3 ): NMR (300 MHz, CDC1 3 ) S: 9.64 (d, IH), 8.95 (d, IH, J = 3.9 Hz), 8.4 (d, IH, J = 8.4 Hz), 8.28 (brs, IH), 7.57 (dd, IH, J = 3.9Hz, 8.4Hz), 7.31 (d, 2H, J=8.7Hz), 6.93 (d, 2H, J=8.4Hz), 5.0 (m, IH ), 4.69 (s, 2H), 4.56 (d, 2H), 3.56-3.66 (m, 8H), 3.22 (m, IH), 2.28 (m, 4H), 1.71-1.82 (m, 2H), 1.4- 1.47 (m, 2H); MS-EI m/z: 596 (calc.: 597.5).
8-((lr，4r)-4-氨基环己氨基) - -(2，4-二甲氧苄基 )-5-溴 -1,6-二氮杂萘 -7^ ( S42 )  8-((lr,4r)-4-Aminocyclohexylamino)-(2,4-dimethoxybenzyl)-5-bromo-1,6-naphthyridin-7- (S42)
Figure imgf000044_0002
Figure imgf000044_0002
与化合物 S25的制备方法类似。 浅黄色固体，产率： 78%。 ifi NMR pOO MHz, CDCI3) δ: 9.63 (d, IH), 8.92 (d, 1H, J = 6Hz), 8.45(brs, IH), 8.39 (d, IH, J = 6.9Hz), 7.56 (dd, IH, J = 6Hz, 6.9Hz), 7.25 (d, IH, J = 9Hz), 6.49 (d, IH, J=2.1Hz), 6.45 (dd, IH, J=9, 2.1Hz), 4.93 (m, IH), 4.55 (d, 2H), 3.9 (s, 3H), 3.8 (s, 3H), 2.75 (m, IH), 2.15 (d, 2H, J =12Hz), 1.89 (d, 2H, J =12.6Hz), 1.37 (m, 4H); MS-EI m/z: 513 (M-1)"(MW计算值： 514.41)。  It is similar to the preparation method of the compound S25. Light yellow solid, yield: 78%. Ifi NMR pOO MHz, CDCI3) δ: 9.63 (d, IH), 8.92 (d, 1H, J = 6Hz), 8.45(brs, IH), 8.39 (d, IH, J = 6.9Hz), 7.56 (dd, IH, J = 6Hz, 6.9Hz), 7.25 (d, IH, J = 9Hz), 6.49 (d, IH, J=2.1Hz), 6.45 (dd, IH, J=9, 2.1Hz), 4.93 (m , IH), 4.55 (d, 2H), 3.9 (s, 3H), 3.8 (s, 3H), 2.75 (m, IH), 2.15 (d, 2H, J = 12Hz), 1.89 (d, 2H, J =12.6Hz), 1.37 (m, 4H); MS-EI m/z: 513 (M-1)" (MW: 514.41).
8-((lr，4r)-4-氨基环己氨基) - -(3，4-二甲氧苄基 )-5-溴 -1,6-二氮杂萘 -7^ ( S43 )  8-((lr,4r)-4-Aminocyclohexylamino)-(3,4-dimethoxybenzyl)-5-bromo-1,6-naphthyridin-7- (S43)
Figure imgf000044_0003
Figure imgf000044_0003
与化合物 S25的制备方法类似。 浅黄色固体，产率： 78%。 ifi NMR pOO MHz, CDCI3) δ: 9.64 (d, IH), 8.95 (d, IH, J = 4.2Hz), 8.42 (d, IH, J = 8.4Hz), 8.26 (br s, IH), 7.59 (dd, IH, J = 4.2Hz, 8.4Hz), 6.84-6.95 (m, 3H), 4.97 (m, IH), 4.57 (d, 2H), 3.89 (s, 3H), 3.88(s, 3H), 2.79 (m, IH), 2.18 (d, 2H, J = 12.6Hz), 1.93 (d, 2H, J = 12Hz), 1.3-1.45 (m, 4H); MS-EI m/z: 513 (M-1)"(MW 计算值： 514.41)。 It is similar to the preparation method of the compound S25. Light yellow solid, yield: 78%. Ifi NMR pOO MHz, CDCI3) δ: 9.64 (d, IH), 8.95 (d, IH, J = 4.2 Hz), 8.42 (d, IH, J = 8.4 Hz), 8.26 (br s, IH), 7.59 ( Dd, IH, J = 4.2Hz, 8.4Hz), 6.84-6.95 (m, 3H), 4.97 (m, IH), 4.57 (d, 2H), 3.89 (s, 3H), 3.88(s, 3H), 2.79 (m, IH), 2.18 (d, 2H, J = 12.6Hz), 1.93 (d, 2H, J = 12Hz), 1.3-1.45 (m, 4H); MS-EI m/z: 513 (M-1)" (MW: 514.41).

Claims

权 利 要 求 Rights request
1、 结构通式 I所示的 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物:  1. 5,8-Disubstituted-1,6-diazaphthalene-7-carbonylamide compound of the formula I:
Figure imgf000046_0001
Figure imgf000046_0001
A为： （1 )苯环； （2 ) C8-C10骈合成的双碳环， 其中一个是苯环， 另一 个为饱和的或者不饱和的环； （3 ) 8 ~ 10个原子骈合成的环， 并含有 0-3个 选自 N、 0和 S中的杂原子， 其中一个是芳环或者芳杂环， 另一个为饱和 的或者不饱和的碳环或杂环； （4 )含有 1 ~ 3个选自 N、 0和 S中的杂原子 的五元或六元芳杂环； 或 （5 )含有 0 ~ 3个选自 N、 0和 S中的杂原子的 三元至七元脂肪环； A is: (1) a benzene ring; (2) a C 8 -C 10骈 synthesized double carbon ring, one of which is a benzene ring and the other is a saturated or unsaturated ring; (3) 8 to 10 atoms 骈a ring which is synthesized and contains 0-3 heteroatoms selected from N, 0 and S, one of which is an aromatic or aromatic heterocyclic ring, and the other is a saturated or unsaturated carbocyclic or heterocyclic ring; (4) a five- or six-membered aromatic heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 and S; or (5) a ternary containing 0 to 3 hetero atoms selected from N, 0 and S to Seven-membered fat ring;
L是: ( 1 )直接键; ( 2 ) Ci-C6烷基； ( 3 ) C2-C6烯基； ( 4 ) ( C0-C6烷基 ) - ( C3-C6环烷基 ) - ( C0-C6烷基 )； 或（ 5 ) ( C0-C6烷基 ) -M- ( C0-C6烷基）， 其中 M为 N ( Ra )、 OC ( = 0 )或 C ( = 0 ) 0; 其中， （3 )中的烯基和（2 )、 ( 4 )、（ 5 )中的烷基可以被 1-3个各自独立的取代基取代， 所述取代基选自 下列原子或基团之中： d-C6烷基、 d-C6烷氧基 d-C6烷基、 C3-C8环烷基、 卤素、氨基、巯基、羟基、 -CF3、 -CN、 -N02、 -NRaRb、 -NRaCORb、 -NRaCOORb、 -NRaS02Rb、 -COORb、 -CORb、 -CONRaRb、 -S02Rb、 -S02NRaRb、 -ORa和 -OCORb; L is: (1) a direct bond; (2) Ci-C 6 alkyl; (3) C 2 -C 6 alkenyl group; (4) (C 0 -C 6 alkyl) - (C 3 -C 6 cycloalkyl Alkyl) - (C 0 -C 6 alkyl); or ( 5 ) ( C 0 -C 6 alkyl) -M- (C 0 -C 6 alkyl), wherein M is N (R a ), OC ( = 0 ) or C ( = 0 ) 0; wherein, the alkenyl group in (3) and the alkyl group in (2), (4), (5) may be substituted by one to three independent substituents, The substituent is selected from the group consisting of: dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, C 3 -C 8 cycloalkyl, halogen, amino, fluorenyl, hydroxy, -CF 3 , -CN, -N0 2 , -NR a R b , -NR a COR b , -NR a COOR b , -NR a S0 2 R b , -COOR b , -COR b , -CONR a R b , -S0 2 R b , -S0 2 NR a R b , -OR a and -OCOR b ;
、 R2、 R3、 R4和 R6各自独立地为氢、 卤素、 羟基、 巯基、 -CF3、 -CN、 -N02或者 取代或各自独立地被 1-3个取代基取代的下列基团： d-C8烷基、 d-C8烷氧基、 C2-C8烯基、 C2-C8炔基、 C3-C8环烷基、 C3-C8环烷氧基、 硅 氧基、 氨基、 苯基、 苄基、 萘基、 C5-C1G芳香性杂环基或 C3-C7饱和杂环基； 所述取代基选自下列原子或基团之中： d-C6烷基、 d-C6烷氧基 d-C6烷基、 杂环基、 杂环基羰基、 d-C6烷基杂环基、 C6-C10芳基、 C3-C8环烷基、 卤素、 巯基、 羟基、 -CF3、 -CN、 -N02、 -NRaRb、 -NRaCORb、 -NRaCOORb、 -NRaS02Rb、 -COORb、 -CORb、 -CONRaRb、 -S02Rb、 -S02NRaRb、 -ORa 和 -OCORb, 且 NRaRb可共同组成环胺； 所述杂环包括 1-3个选自 N、 0 和 S中的杂原子； And R 2 , R 3 , R 4 and R 6 are each independently hydrogen, halogen, hydroxy, decyl, -CF 3 , -CN, -N0 2 or substituted or each independently substituted with 1 to 3 substituents. Group: dC 8 alkyl, dC 8 alkoxy, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, silicon An oxy group, an amino group, a phenyl group, a benzyl group, a naphthyl group, a C 5 -C 1G aromatic heterocyclic group or a C 3 -C 7 saturated heterocyclic group; the substituent is selected from the group consisting of the following atoms or groups: dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, heterocyclic, heterocyclylcarbonyl, dC 6 alkylheterocyclyl, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, halogen, Mercapto, hydroxy, -CF 3 , -CN, -N0 2 , -NRaRb, -NRaCORb, -NRaCOORb, -NRaS0 2 Rb, -COORb, -CORb, -CONRaRb, -S0 2 Rb, -S0 2 NRaRb, -ORa And -OCORb, and NRaRb may together constitute a cyclic amine; the heterocyclic ring comprising 1-3 heteroatoms selected from N, 0 and S;
R5为氢、 羟基或者未取代或被 1-3个各自独立的取代基取代的下列基 团： d-C8烷基、 d-C8烷氧基 d-C8烷基、 d-C8烷氧基、 C2-C8烯基、 C2-C8 炔基、 C3-C8环烷基、 苯基、 苄基、 萘基、 C5-C1Q芳香性杂环基或 C3-C8饱 和杂环基； 所述杂环包括 1-3个选自 N、 0和 S中的杂原子； 所述取代基选 自下列原子或基团： d-C6烷基、 d-C6烷氧基 d-C6烷基、 卤素、 氨基、 硝 基、 巯基、 羟基、 -CN和 -CF3; R 5 is hydrogen, hydroxy or the following groups which are unsubstituted or substituted by 1 to 3 independent substituents: dC 8 alkyl, dC 8 alkoxy dC 8 alkyl, dC 8 alkoxy, C 2 - C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, phenyl, benzyl, naphthyl, C 5 -C 1Q aromatic heterocyclic or C 3 -C 8 And a heterocyclic group; the heterocyclic ring comprising 1-3 heteroatoms selected from N, 0 and S; the substituent being selected from the group consisting of: dC 6 alkyl, dC 6 alkoxy dC 6 Alkyl, halogen, amino, nitro, decyl, hydroxy, -CN and -CF 3 ;
B为： （l ) Rd或 Re; ( 2 )含有 0 ~ 3个选自 N、 0和 S中的杂原子的三 元至七元脂肪环，杂环上有 1-3个各自独立地从 Rd或 Re中选取取代基取代； ( 3 )含有 1-3个选自 N、 0和 S中的杂原子的五元或六元杂芳环， 杂环上 有 1-3个各自独立的从 Rd或 Re中选取取代基的取代基； 或（ 4 ) 8 ~ 10个碳 原子骈合成的环， 并含有 0-3个选自 N、 0和 S中的杂原子， 其中一个是芳 环， 另一个为饱和的或者不饱和的碳环或杂环； 杂环上有 1-3个各自独立的 从 Rd或 Re中选取取代基的取代基； B is: (l) R d or R e ; ( 2 ) a ternary to seven-membered aliphatic ring containing 0 to 3 hetero atoms selected from N, 0 and S, and 1-3 each independently on the heterocyclic ring Substituting substituents from R d or R e ; ( 3 ) 5- or 6-membered heteroaryl rings containing 1-3 heteroatoms selected from N, 0 and S, 1-3 on heterocycle Each of the substituents independently selected from R d or R e ; or ( 4 ) a ring synthesized by 8 to 10 carbon atoms, and containing 0 to 3 hetero atoms selected from N, 0 and S, One of which is an aromatic ring, the other is a saturated or unsaturated carbocyclic or heterocyclic ring; and the heterocyclic ring has 1-3 independently substituents selected from R d or R e ;
Ra为氢、 d-C6烷基、 C3-C8环烷基或 C6-C1()芳烃基； R a is hydrogen, dC 6 alkyl, C 3 -C 8 cycloalkyl or C 6 -C 1 () arene;
Rb为氢、 羟基或者未取代或被 1-3个各自独立地取代基取代的下列基 团： d-C6烷基、 d-C6烷氧基 d-C6烷基、 d-C6烷氧基、 C2-C6烯基、 C2-C6 炔基、 C3-C8环烷基、 苯基、 苯酚基、 苄基、 萘基、 C5-d。芳香性杂环基或 C4-C7饱和杂环基； 所述杂环包括 1-3个选自 N、 0和 S中的杂原子； 所述 取代基选自下列原子或基团： d-C6烷基、 d-C6烷氧基 d-C6烷基、 卤素、 氨基、 硝基、 巯基、 羟基、 -CN和 -CF3; R b is hydrogen, hydroxy or the following groups which are unsubstituted or substituted by 1 to 3 substituents: dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, dC 6 alkoxy, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, phenyl, phenol, benzyl, naphthyl, C 5 -d. An aromatic heterocyclic group or a C 4 -C 7 saturated heterocyclic group; said heterocyclic ring comprising 1 to 3 hetero atoms selected from N, 0 and S; said substituent being selected from the group consisting of the following atoms or groups: dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, halogen, amino, nitro, fluorenyl, hydroxy, -CN and -CF 3 ;
Rd是： （ 1 )饱和或者不饱和的五元或者六元环， 该环包括至少一个碳 原子， 0 ~ 4个选自 N、 0和 S中的杂原子； （ 2 )饱和或者不饱和的 C8-C10 骈合的环， 其中该环包括至少一个碳原子， 0 ~ 4个选自 N、 0和 S中的杂 原子； 在 （1 )和（2 ) 中所包括的杂环可以是饱和的也可以是不饱和的； 且可以有如下取代基： 卤素、 腈基、 羟基、 -(C¾V4OH、 -N(Ra)(Rb)、 硝基、 烷基、 d-C6烷氧基、 面代的 d-C6 烷基、 面代的 d-C6烷氧基、 -(CH2)0-4C(=O)N(Ra)(Rb)、 -(CH2)0-4CO2Ra、 -(CH2)0-4SO2Ra、 -(CH2)1-4N(Ra)(Rb)、 -(CH2)0-4N(Ra)C(=O)(Rb), -(CH2)0-4SO2N(Ra)(Rb), -(CH2)0-4N(Ra)SO2(Rb), C2-C8 烷氧烷基、 面代的 c2-c8烷氧烷基、 苯基或苄基； R d is: ( 1 ) a saturated or unsaturated five- or six-membered ring comprising at least one carbon atom, 0 to 4 heteroatoms selected from N, 0 and S; (2) saturated or unsaturated a C 8 -C 10 conjugated ring wherein the ring includes at least one carbon atom, 0 to 4 heteroatoms selected from N, 0 and S; heterocycles included in (1) and (2) It may be saturated or unsaturated; and may have the following substituents: halogen, nitrile group, hydroxyl group, -(C3⁄4V 4 OH, -N(R a )(R b ), nitro group, alkyl group, dC 6 Alkoxy, halo dC 6 alkyl, dihydrocarbyl dC 6 alkoxy, -(CH 2 ) 0-4 C(=O)N(R a )(R b ), -(CH 2 ) 0 -4 CO 2 R a , -(CH 2 ) 0-4 SO 2 R a , -(CH 2 ) 1-4 N(R a )(R b ), -(CH 2 ) 0-4 N(R a C(=O)(R b ), -(CH 2 ) 0-4 SO 2 N(R a )(R b ), -(CH 2 ) 0-4 N(R a )SO 2 (R b ) a C 2 -C 8 alkoxyalkyl group, a c 2 -c 8 alkoxyalkyl group, a phenyl group or a benzyl group;
Re为： 氢、 卤素、 羟基、 氨基、 硝基、 -CN、 d-C6烷基、 d-C6烷氧基、 卤代的 d-C6烷基、 面代的 d-C6烷氧基、 C2-C8烷氧烷基、 面代的 C2-C8 烷氧烷基、 -(C¾)0-6N(Ra)(Rb)、 -(C¾)0-6RC、 -O(C¾)0-6Rc、 -O(C¾)0-6ORc、 -(CH2)0-6Rd、 -O(CH2)0-6Rd、 -C(=0)N(Ra)(Rb)、 -(C¾)1-6C(=0)N(Ra)(Rb)、 -(C¾)0-6N(Ra)C(=O)(Rb)、 -S02Ra、 -S02Rd、 -S02(C¾)1-6Rd、 -(C¾)1-6S02Ra、 -(CH2)0-6SO2N(Ra)(Rb), -(CH2)0-6N(Ra)SO2(Rb), -(CH2)0-6CO2Ra, -(CH2)0-6SRa, C2-C6烯基、 -0-C1-6烷基 -ORa、 -0-Ci-6烷基 -SRa、 -0-Ci-6烷基 -N(Ra)C(=0)(Rb)、 -O-d.6烷基 -N(Ra)(Rb)、 -NfR -Cw烷基 -SRa、
Figure imgf000047_0001
烷基- ORa、 -N(Ra)-C1-6烷基 -N(Ra)(Rb)、 -N(Ra)-C1-6烷基 -N(Ra)C(=0)(Rb)、 -C2-6烯基 -Rd、 -C2-6 炔基 -Rd 、 -(CH2)0-6SO2N(Ra)(Rd) 、 -(CH2)0-6SO2N(Ra)(-C1-6-Rd) 、 -(CH2)0-6S(O)nRd、 -(CH2)0-6C(O) (CH2)0-6Rd或- (CH2)0-6S(O)n-C1-6Rd, 其中 n = 0、 1或 2; Rc为： 芳基或取代的芳基； 所述取代基为卤素、 氰基、 氨基、 羟基、 -(C¾)1-4OH、 -N(Ra)(Rb)、 硝基、 d-C6烷基、 d-C6烷氧基、 卤代的 d-C6 烷基、 卤代的 d-C6烷氧基、 -(CH2)0-4C(=O)N(Ra)(Rb) , -(C¾V4C02Ra、 -(CH2)0-4SO2Ra 、 -(CH2)1-4N(Ra)(Rb) 、 -(CH2)0-4N(Ra)C(=O)(Rb) 、 -(CH2)0-4SO2N(Ra)(Rb)、 -(CH2)0-4N(Ra)SO2(Rb)、 C2-C8烷氧烷基或卤代的 C2-C8 烷氧烷基。 R e is: hydrogen, halogen, hydroxy, amino, nitro, -CN, dC 6 alkyl, dC 6 alkoxy, halogenated dC 6 alkyl, halo dC 6 alkoxy, C 2 -C 8 alkoxyalkyl, a C 2 -C 8 alkoxyalkyl group, -(C3⁄4) 0-6 N(R a )(R b ), -(C3⁄4) 0-6 R C , -O(C3⁄4 0-6 R c , -O(C3⁄4) 0-6 OR c , -(CH 2 ) 0-6 Rd, -O(CH 2 ) 0-6 Rd, -C(=0)N(R a ) (R b ), -(C3⁄4) 1-6 C(=0)N(R a )(R b ), -(C3⁄4) 0-6 N(R a )C(=O)(R b ), - S0 2 R a , -S0 2 R d , -S0 2 (C3⁄4) 1-6 R d , -(C3⁄4) 1-6 S0 2 R a , -(CH 2 ) 0-6 SO 2 N(R a ) (R b ), -(CH 2 ) 0-6 N(R a )SO 2 (R b ), -(CH 2 ) 0-6 CO 2 R a , -(CH 2 ) 0-6 SR a , C 2 -C 6 alkenyl, -0-C 1-6 alkyl-OR a , -0-Ci -6 alkyl-SR a , -0-Ci -6 alkyl-N(R a )C(=0 (R b ), -Od.6 alkyl-N(R a )(R b ), -NfR -Cw alkyl-SR a ,
Figure imgf000047_0001
Alkyl-OR a , -N(R a )-C 1-6 alkyl-N(R a )(R b ), -N(R a )-C 1-6 alkyl-N(R a )C (=0)(R b ), -C 2-6 alkenyl-R d , -C 2 6 alkynyl-Rd , -(CH 2 ) 0-6 SO 2 N(R a )(R d ) , -(CH 2 ) 0-6 SO 2 N(R a )(-C 1-6 -R d ) , -(CH 2 ) 0-6 S(O) n R d , -(CH 2 ) 0-6 C(O) (CH 2 ) 0-6 R d or -(CH 2 ) 0-6 S(O) n -C 1-6 R d , wherein n = 0, 1 or 2; R c is: aryl or substituted aryl; the substituent is halogen, cyano, amino, hydroxy, -(C3⁄4) 1-4 OH, -N(R a )(R b ), nitro, dC 6 alkyl, dC 6 alkoxy, halogenated dC 6 alkyl, halogenated dC 6 alkoxy, -(CH 2 ) 0-4 C(=O)N(R a )(R b ) , -(C3⁄4V 4 C0 2 R a , -(CH 2 ) 0-4 SO 2 R a , -(CH 2 ) 1-4 N(R a )(R b ) , -(CH 2 ) 0-4 N( R a )C(=O)(R b ) , -(CH 2 ) 0-4 SO 2 N(R a )(R b ), -(CH 2 ) 0-4 N(R a )SO 2 (R b ), C 2 -C 8 alkoxyalkyl or halogenated C 2 -C 8 alkoxyalkyl.
2、根据权利要求 1所述的 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物， 其特征在于， 为结构通式 II表示的化合物：  The 5,8-disubstituted-1,6-diazaphthalen-7-carbonylamide compound according to claim 1, which is a compound represented by the structural formula II:
Figure imgf000048_0001
Figure imgf000048_0001
其中， 、 R2、 R6和 B的定义与权利要求 1相同。 Wherein, R 2 , R 6 and B have the same definitions as in claim 1.
3、根据权利要求 2所述的 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物， 其特征在于，  The 5,8-disubstituted-1,6-diazaphthalene-7-carbonylamide compound according to Claim 2, which is characterized in that
和 各自独立地为氢、 卤素、 -CN、 -CF3、 -N02、羟基、氨基、 Ci-C6 烷基氨基、 d-C6烷基杂环基氨基、 C6-C10芳基氨基、 d-C8烷氧基、 C3-C8 环烷氧基、 Ci-C6烷基硅氧基、 Ci-C6烷基杂环基 Ci-Cs烷基氧基、 杂环基 d-C8烷基氧基、 杂环基羰基 d-C8烷基氧基或 C6-C10芳基 d-C8烷基氧基； 其中的杂环基是指含有 1 ~ 3个选自 N、 0和 S中的杂原子的三元至七元脂 肪环； And are each independently hydrogen, halogen, -CN, -CF 3, -N0 2 , hydroxy, amino, Ci-C 6 alkylamino, dC 6 alkyl heterocyclic group, C 6 -C 10 aryl group, dC 8 alkoxy, C 3 -C 8 cycloalkoxy, Ci-C 6 alkylsiloxy, Ci-C 6 alkylheterocyclyl Ci-Cs alkyloxy, heterocyclyl dC 8 alkyl An oxy group, a heterocyclic carbonyl group dC 8 alkyloxy group or a C 6 -C 10 aryl dC 8 alkyloxy group; wherein the heterocyclic group means 1 to 3 kinds of impurities selected from N, 0 and S Atomic ternary to seven-membered fat ring;
R6为氢、 卤素、
Figure imgf000048_0002
或 R 6 is hydrogen, halogen,
Figure imgf000048_0002
or
B为氨基 d-C6烷基、 d-C4烷基氨基 烷基、 烷氧基羰基 Ci-C^ 烷基、 d-C4烷基磺酰氨基 烷基、 苯甲酰氨基 d-C4烷基、 氨基苯基、 氨基 C3-C6环烷基或面代苄基， 或者 B 与所连接的 N 形成 B is an amino dC 6 alkyl group, dC 4 alkylaminoalkyl group, alkoxycarbonyl Ci-C^ alkyl group, dC 4 alkylsulfonylaminoalkyl group, benzoylamino dC 4 alkyl group, aminophenyl group, An amino C 3 -C 6 cycloalkyl or a benzyl group, or B forms a N with a bond
Figure imgf000048_0003
Figure imgf000049_0001
； 为！!、 d-C6烷基、 C3-C8环烷基或 C6-C10芳基。
Figure imgf000048_0003
Figure imgf000049_0001
; for! !, dC 6 alkyl, C 3 -C 8 cycloalkyl or C 6 -C 10 aryl.
4、根据权利要求 3所述的 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物， 其特征在于，  The 5,8-disubstituted-1,6-diazaphthalen-7-carbonylamide compound according to claim 3, which is characterized in that
和 各自独立地为氢、 卤素、 -CN、 -CF3、 氨基、 d-C4烷基氨基、 d-C4烷基杂环基氨基、 d-C4烷氧基、 C3-C6环烷氧基、 d-C4烷基硅氧基、 d-C4烷基杂环基 d-C4烷基氧基、杂环基 d-C4烷基氧基或杂环基羰基 d-C4 烷基氧基； 其中的杂环基是指含有 1 ~ 2个选自 N和 0的杂原子的三元至 七元脂肪环； And each independently are hydrogen, halogen, -CN, -CF 3 , amino, dC 4 alkylamino, dC 4 alkylheterocyclylamino, dC 4 alkoxy, C 3 -C 6 cycloalkoxy, dC a 4- alkylsilyloxy group, a dC 4 alkylheterocyclyl group dC 4 alkyloxy group, a heterocyclic group dC 4 alkyloxy group or a heterocyclic carbonyl group dC 4 alkyloxy group; wherein the heterocyclic group means 1 to 2 ternary to seven-membered aliphatic rings selected from heteroatoms of N and 0;
R6为氢、 卤素、
Figure imgf000049_0002
R 6 is hydrogen, halogen,
Figure imgf000049_0002
B为氨基 d-C6烷基、 d-C4烷基氨基 烷基、 烷氧基羰基 烷基、 d-C4烷基磺酰氨基 烷基、 苯甲酰氨基 d-C4烷基、 氨基苯基、 B is an amino dC 6 alkyl group, dC 4 alkylaminoalkyl group, alkoxycarbonylalkyl group, dC 4 alkylsulfonylaminoalkyl group, benzoylamino dC 4 alkyl group, aminophenyl group,
. / ~ \  . / ~ \
5-N NH 氨基 C3-C6环烷基或面代苄基， 或者 B 与所连接的 N 形成 ^ 、
Figure imgf000049_0003
5-N NH amino C 3 -C 6 cycloalkyl or epi-benzyl, or B forms a bond with the attached N,
Figure imgf000049_0003
R为 11或 d-C4烷基。 R is 11 or dC 4 alkyl.
5、根据权利要求 4所述的 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物， 其特征在于， 为结构通式 III表示的化合物：  The 5,8-disubstituted-1,6-diazaphthalene-7-carbonylamide compound according to claim 4, which is a compound represented by the structural formula III:
Figure imgf000049_0004
Figure imgf000049_0004
其中， Ri R2和 R6的定义与权利要求 4相同。 Here, the definitions of Ri R 2 and R 6 are the same as those in claim 4.
6、根据权利要求 1所述的 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物， 其特征在于， 具体为：
Figure imgf000050_0001
The 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound according to claim 1, which is specifically:
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000053_0001
7、 权利要求 1-5所述的 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物的 制备方法， 其特征在于， 为下述制备方法中的任意一种：  The method for producing a 5,8-disubstituted-1,6-diazaphthalen-7-carbonylamide compound according to any one of claims 1 to 5, which is characterized in that it is any one of the following production methods :
( 1 )将化合物 1吡啶 2,3-二酸酐选择性酯化得到化合物 2, 化合物 3 以酰氯形式选择性还原得到化合物 4,化合物 4通过 Mitsunobo反应得到化 合物 5, 化合物 5在碱性条件下关环得到 1,6-二氮杂萘羰酸甲酯 6,化合物 6 与含 R6的化合物反应得到 5-R6-l,6-二氮杂萘羰酸甲酯 7; 化合物 7作为共 同中间体， 可以通过三条路线制备目标化合物； (1) Selective esterification of compound 1 pyridine 2,3-dianhydride to obtain compound 2, compound 3 is selectively reduced in the form of acid chloride to obtain compound 4, compound 4 is obtained by Mitsunobo reaction to obtain compound 5, and compound 5 is kept under alkaline conditions. Ring to obtain methyl 1,6-diazanaphthalenecarboxylate 6, compound 6 is reacted with a compound containing R 6 to give methyl 5-R 6 -l,6-naphthyridinylcarboxylate 7; compound 7 as a common intermediate The target compound can be prepared by three routes;
第一条路线， 化合物 7与含 R7的化合物酰胺化得到 1,6-二氮杂萘羰酰 胺化合物 8, 化合物 8的 8位羟基用 Ts保护得到化合物 9, 化合物 9与相 应的胺发生芳基亲核取代反应得到 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化 合物； In the first route, compound 7 is amidated with a compound containing R 7 to give 1,6-diazanaphthalene carboxamide compound 8, and the hydroxyl group at position 8 of compound 8 is protected with Ts to give compound 9, which is aryl with the corresponding amine. Nucleophilic substitution reaction to give 5,8-disubstituted-1,6-diazaphthalen-7-carbonylamide compounds;
第二条路线， 化合物 7在碱性条件下回流水解得到化合物 11 , 化合物 11在三光气、 DIPEA和 DMF中与苯胺反应得到化合物 S26-1 , 然后采用第 一条路线的方法将 8位羟基用 Ts保护再与相应的胺发生芳基亲核取代反 应， 制得 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物；  In the second route, compound 7 is reflux-hydrolyzed under basic conditions to give compound 11 which is reacted with aniline in triphosgene, DIPEA and DMF to give compound S26-1, which is then used in the first route. The Ts protection is followed by aryl nucleophilic substitution reaction with the corresponding amine to obtain a 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound;
第三条路线， 首先将化合物 7的 8位羟基用 Ts保护得到化合物 12, 然 后与相应的胺发生芳基亲核取代反应得到化合物 13 ,化合物 13在碱性条件 下水解生成化合物 14, 化合物 14在偶联试剂 EDCI、 HOBT、 DIPEA存在 下与相应的胺生成酰胺， 再脱去官能团上的保护基， 生成 5,8-二取代 -1,6- 二氮杂萘 -7-羰酰胺类化合物； In the third route, the 8-hydroxyl group of compound 7 is first protected with Ts to obtain compound 12, and then aryl nucleophilic substitution reaction with the corresponding amine is carried out to obtain compound 13, which is hydrolyzed under basic conditions to give compound 14, compound 14 In the presence of the coupling reagents EDCI, HOBT, DIPEA, an amide is formed with the corresponding amine, and the protecting group on the functional group is removed to form a 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound. ;
Figure imgf000054_0001
Figure imgf000054_0001
、^ , ^
其中， R6和 B的定义与通式 I中相同； R7为
Figure imgf000054_0002
Wherein R 6 and B have the same definitions as in Formula I; R 7 is
Figure imgf000054_0002
、 R2、 R3和 R4的定义与通式 I中相同； , R 2 , R 3 and R 4 have the same definitions as in Formula I;
反应试剂和条件： （a)异丙醇,回流； （b)二氯亚砜,回流； （c)硼氢化钠,四氢 呋喃, 0°C ; (d) TsNHC¾COOCH3,DEAD,三苯基膦,四氢呋喃, 0°C ; (e)甲醇钠, 甲醇, 0°C〜室温； （f)NBS,二氯甲烷,室温； （g)胺,甲苯,回流 24小时； （h)TsCl,三 乙胺,三氯甲烷；（i)胺,四氢呋喃,回流；（j )LiOH溶液 /甲醇,或 NaOH溶液 /THF, 回流； （k )二 (三氯甲基)碳酸酯, DIPEA,DMF,苯胺； ( 1 ) EDCI,HOBT,DIPEA, 胺,二氯甲烷； （m )三氟醋酸 /二氯甲烷； Reaction reagents and conditions: (a) isopropanol, reflux; (b) thionyl chloride, reflux; (c) sodium borohydride, tetrahydrofuran, 0 ° C; (d) TsNHC3⁄4COOCH 3 , DEAD, triphenylphosphine, Tetrahydrofuran, 0 ° C; (e) sodium methoxide, methanol, 0 ° C ~ room temperature; (f) NBS, dichloromethane, room temperature; (g) amine, toluene, reflux for 24 hours; (h) TsCl, triethylamine , chloroform; (i) amine, tetrahydrofuran, reflux; (j) LiOH solution / methanol, or NaOH solution / THF, reflux; (k) bis (trichloromethyl) carbonate, DIPEA, DMF, aniline; 1) EDCI, HOBT, DIPEA, amine, dichloromethane; (m) trifluoroacetic acid / dichloromethane;
( 2 )化合物 S3-1与 NIS在二氯甲烷中常温下搅拌得到化合物 S28-1 , 化 合物 S28-1与 TsCl、三乙胺在二氯甲烷中回流得到化合物 S28-2,化合物 S28-2 与反式 1,4-环己二胺在三乙胺和四氢呋喃中加热回流得到化合物 S28-3 , 化 合物 S28-3在氯化钯、 三苯基膦、 碘化亚铜、 碳酸钾和 THF中回流与丙炔酸 甲酯反应得到化合物 S28-4 , 化合物 S28-4在三氟醋酸 /二氯甲烷中脱去 Boc 得到 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物；
Figure imgf000055_0001
(2) Compound S3-1 and NIS are stirred at room temperature in dichloromethane to obtain compound S28-1. Compound S28-1 is refluxed with TsCl and triethylamine in dichloromethane to give compound S28-2, compound S28-2 and The trans 1,4-cyclohexanediamine is heated under reflux in triethylamine and tetrahydrofuran to give the compound S28-3. The compound S28-3 is refluxed in palladium chloride, triphenylphosphine, cuprous iodide, potassium carbonate and THF. Reaction with methyl propiolate to give compound S28-4, compound S28-4 is removed from Boc in trifluoroacetic acid / dichloromethane to give 5,8-disubstituted-1,6-naphthyridin-7-carboxamide Class of compounds;
Figure imgf000055_0001
( 3 )化合物 12与单 Boc保护的反式 1,4-环己二胺在 K2C03和四氢呋喃中 加热回流得到化合物 S30-1 , 化合物 S30-1在 NaOH溶液 /THF中生成化合物 S30-2; 化合物 S30-2在 EDCI、 HOBT、 DIPEA和二氯甲烷中， 与相应的胺反 应 3h得到化合物 S30-3； 化合物 S30-3在 20%的三氟醋酸 /二氯甲烷中脱除 Boc 生成 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类化合物； (3) Compound 12 and a single Boc-protected trans 1,4-cyclohexanediamine are heated under reflux in K 2 CO 3 and tetrahydrofuran to give compound S30-1. Compound S30-1 is formed in NaOH solution / THF to form compound S30- 2; Compound S30-2 is reacted with the corresponding amine in EDCI, HOBT, DIPEA and dichloromethane for 3 h to obtain compound S30-3; Compound S30-3 is removed in 20% trifluoroacetic acid/dichloromethane to form Boc. 5,8-disubstituted-1,6-diazaphthalene-7-carbonylamides;
Figure imgf000055_0002
Figure imgf000055_0002
S30-3 S30  S30-3 S30
8、 权利要求 1-6中任一项所述的 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺类 化合物在制备治疗肿瘤的药物中的应用。 The use of the 5,8-disubstituted-1,6-naphthyridin-7-carbonylamide compound according to any one of claims 1 to 6 for the preparation of a medicament for treating a tumor.
9、 根据权利要求 8 所述的应用， 其特征在于， 所述的肿瘤是由 MDA-MB-435 , Hctl l6 p53-/-, Hctl l6 p53+/+, Mcf-7 , NIH 189 , SkBr-3 , LnCap, LnHer, HT 29或 HEY肿瘤细胞恶性增殖引起的。 9. The use according to claim 8, wherein the tumor is composed of MDA-MB-435, Hctl l6 p53-/-, Hctl l6 p53+/+, Mcf-7, NIH 189, SkBr-3 , LnCap, LnHer, HT 29 or HEY tumor cells caused by malignant proliferation.
10、 根据权利要求 9所述的应用， 其特征在于， 所述的肿瘤为乳腺癌、 结肠癌、 卵巢癌或前列腺癌。  10. The use according to claim 9, wherein the tumor is breast cancer, colon cancer, ovarian cancer or prostate cancer.
11、 一种用于治疗肿瘤的药物组合物， 其特征在于， 该组合物包含治 疗有效量的权利要求 1-5中任一项所述的 5,8-二取代 -1,6-二氮杂萘 -7-羰酰胺 类化合物中的一种或多种。  A pharmaceutical composition for treating a tumor, characterized in that the composition comprises a therapeutically effective amount of the 5,8-disubstituted-1,6-diazonium according to any one of claims 1 to 5. One or more of the naphthalene-7-carbonylamide compounds.
PCT/CN2009/000970 2008-09-27 2009-08-24 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, their preparation methods, compositions and use WO2010037249A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2008102006454A CN101684119B (en) 2008-09-27 2008-09-27 5,8-disubstituted-1,6-quinazoline-7-amidocarbonylation compound, preparing method, composite and application thereof
CN200810200645.4 2008-09-27

Publications (1)

Publication Number Publication Date
WO2010037249A1 true WO2010037249A1 (en) 2010-04-08

Family

ID=42047525

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2009/000970 WO2010037249A1 (en) 2008-09-27 2009-08-24 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, their preparation methods, compositions and use

Country Status (2)

Country Link
CN (1) CN101684119B (en)
WO (1) WO2010037249A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102558172B (en) * 2010-12-30 2015-11-25 中国科学院上海药物研究所 5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof, Preparation Method And The Use
CN102653521B (en) * 2012-04-27 2014-08-06 首都师范大学 Piperazine thiocarbohydrazide derivate of indole-2-ketone and preparation method and application of piperazine thiocarbohydrazide derivate
CN103709162B (en) * 2012-09-29 2016-12-07 中国科学院上海药物研究所 Tri-substituted imidazole benzodiazine ketonic compound and its production and use
CN104003986B (en) * 2013-02-22 2016-06-08 中国科学院上海药物研究所 Pyridine a pair of horses going side by side lopps compound and its preparation method, its pharmaceutical composition and purposes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999009030A1 (en) * 1997-08-20 1999-02-25 Warner-Lambert Company Naphthyridinones for inhibiting protein tyrosine kinase and cell cycle kinase mediated cellular proliferation
CN1863774A (en) * 2003-10-08 2006-11-15 Irm责任有限公司 Compounds and compositions as protein kinase inhibitors
CN101155588A (en) * 2005-04-12 2008-04-02 默克公司 Inhibitors of akt activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999009030A1 (en) * 1997-08-20 1999-02-25 Warner-Lambert Company Naphthyridinones for inhibiting protein tyrosine kinase and cell cycle kinase mediated cellular proliferation
CN1863774A (en) * 2003-10-08 2006-11-15 Irm责任有限公司 Compounds and compositions as protein kinase inhibitors
CN101155588A (en) * 2005-04-12 2008-04-02 默克公司 Inhibitors of akt activity

Also Published As

Publication number Publication date
CN101684119B (en) 2012-11-28
CN101684119A (en) 2010-03-31

Similar Documents

Publication Publication Date Title
US6087368A (en) Quinazolinone inhibitors of cGMP phosphodiesterase
CN104470902B (en) N-(3-heteroarylaryl)-4-arylarylcarboxamtdes and analogs as hedgehog pathway inhibitors and use thereof
Zhang et al. Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors
CA2857405C (en) Phthalic hydrazide (phthalazine ketone) compounds as parp inhibitors and composition thereof
US8486945B2 (en) Heterocyclic inhibitors of an Hh-signal cascade, medicinal compositions based thereon and methods for treating diseases caused by the aberrant activity of an Hh-signal system
JP4287649B2 (en) Aza- and polyaza-naphthalenylcarboxamides useful as HIV integrase inhibitors
JP5522371B2 (en) Compound, method for producing the same, and pharmaceutical composition
Ohashi et al. Discovery of pyrrolo [3, 2-c] quinoline-4-one derivatives as novel hedgehog signaling inhibitors
KR101260116B1 (en) Disubstituted phthalazine hedgehog pathway antagonists
EP2460787A1 (en) Amide compounds and their use as PGE2 antagonists.
BG108325A (en) Novel 4-anilinoquinoline-3-carboxamides
WO2003000660A1 (en) Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus proliferator receptor, and medicinal composition containing the same
JP2006509840A (en) Indolylpyrazinone derivatives useful for treating hyperproliferative diseases and diseases associated with angiogenesis
EP0596406A1 (en) Imidazo (1,2-a) Pyridines as bradykinin antagonists
JP2004511483A (en) Aza- and polyaza-naphthalenylcarboxamides useful as HIV integrase inhibitors
AU2005299384A1 (en) (2-carboxamido)(3-amino) thiophene compounds
KR20040048995A (en) Quinoline compound
KR20100053468A (en) Novel tricyclic derivatives or pharmaceutically acceptable salts thereof, process for the preparation thereof and pharmaceutical composition comprising the same
JP2017537947A (en) Heterocyclic compounds as antibiotic potentiators
JP2007176809A (en) Heterocyclic ring-substituted amide compound, method for preparing same, and pharmaceutical composition
WO2005019188A1 (en) Fused pyrimidine derivative and use thereof
TW201625620A (en) Heterocyclic hydroxamic acids as protein deacetylase inhibitors and dual protein deacetylase-protein kinase inhibitors and methods of use thereof
WO2013013614A1 (en) 4-(3-heteroarylarylamino)quinazoline and 1-(3-heteroarylarylamino)isoquinoline as hedgehog pathway inhibitor and use thereof
JP2010513386A5 (en)
JP4494020B2 (en) N- (substituted benzyl) -8-hydroxy-1,6-naphthyridine-7-carboxamide useful as an HIV integrase inhibitor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09817163

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09817163

Country of ref document: EP

Kind code of ref document: A1