CN100457737C - Quinolyl amide derivative and its prepn process and use - Google Patents
Quinolyl amide derivative and its prepn process and use Download PDFInfo
- Publication number
- CN100457737C CN100457737C CNB2005100631457A CN200510063145A CN100457737C CN 100457737 C CN100457737 C CN 100457737C CN B2005100631457 A CNB2005100631457 A CN B2005100631457A CN 200510063145 A CN200510063145 A CN 200510063145A CN 100457737 C CN100457737 C CN 100457737C
- Authority
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- China
- Prior art keywords
- hydroxy
- quinoline
- carboxamide
- methyl
- ethyl
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
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- -1 Quinolyl amide Chemical class 0.000 title claims abstract description 168
- 238000000034 method Methods 0.000 title description 10
- 239000003814 drug Substances 0.000 claims abstract description 13
- 206010018367 Glomerulonephritis chronic Diseases 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims abstract description 8
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 7
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 152
- 208000023275 Autoimmune disease Diseases 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 18
- 201000010099 disease Diseases 0.000 abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 7
- 206010025135 lupus erythematosus Diseases 0.000 abstract 1
- 230000009885 systemic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 234
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 126
- 238000005160 1H NMR spectroscopy Methods 0.000 description 125
- 150000001412 amines Chemical class 0.000 description 106
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 93
- 239000007787 solid Substances 0.000 description 80
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 62
- 238000010438 heat treatment Methods 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
- 230000015572 biosynthetic process Effects 0.000 description 47
- 238000003786 synthesis reaction Methods 0.000 description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- 238000005406 washing Methods 0.000 description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- 239000003208 petroleum Substances 0.000 description 33
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 32
- 238000004440 column chromatography Methods 0.000 description 32
- 239000003480 eluent Substances 0.000 description 32
- 239000000741 silica gel Substances 0.000 description 32
- 229910002027 silica gel Inorganic materials 0.000 description 32
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 30
- 238000001914 filtration Methods 0.000 description 27
- 238000005303 weighing Methods 0.000 description 27
- 238000001816 cooling Methods 0.000 description 26
- 125000000217 alkyl group Chemical group 0.000 description 23
- 239000013078 crystal Substances 0.000 description 22
- 239000002904 solvent Substances 0.000 description 19
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 238000002156 mixing Methods 0.000 description 16
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 15
- MCSVQCDNSCMOAS-UHFFFAOYSA-N 1-n',1-n',2,2-tetramethylpropane-1,1-diamine Chemical compound CN(C)C(N)C(C)(C)C MCSVQCDNSCMOAS-UHFFFAOYSA-N 0.000 description 15
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 15
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- UNRBEYYLYRXYCG-UHFFFAOYSA-N (1-ethylpyrrolidin-2-yl)methanamine Chemical compound CCN1CCCC1CN UNRBEYYLYRXYCG-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 125000004430 oxygen atom Chemical group O* 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 11
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 description 11
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 9
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical group 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 230000003393 splenic effect Effects 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 125000004434 sulfur atom Chemical group 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 4
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 4
- 206010061598 Immunodeficiency Diseases 0.000 description 4
- 208000029462 Immunodeficiency disease Diseases 0.000 description 4
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 4
- 230000005784 autoimmunity Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- YBEOYBKKSWUSBR-UHFFFAOYSA-N ethyl 4-oxo-1h-quinoline-3-carboxylate Chemical class C1=CC=C2C(=O)C(C(=O)OCC)=CNC2=C1 YBEOYBKKSWUSBR-UHFFFAOYSA-N 0.000 description 4
- 230000002519 immonomodulatory effect Effects 0.000 description 4
- 230000007813 immunodeficiency Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- SLLIIFQCPVUDMP-UHFFFAOYSA-N 4-hydroxy-n,1-dimethyl-6-methylsulfanyl-2-oxo-n-phenylquinoline-3-carboxamide Chemical compound OC=1C2=CC(SC)=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SLLIIFQCPVUDMP-UHFFFAOYSA-N 0.000 description 3
- QLZVLHDKIJRVRV-UHFFFAOYSA-N 7-fluoro-n-methyl-4-oxo-n-phenyl-1h-quinoline-3-carboxamide Chemical compound C=1N=C2C=C(F)C=CC2=C(O)C=1C(=O)N(C)C1=CC=CC=C1 QLZVLHDKIJRVRV-UHFFFAOYSA-N 0.000 description 3
- YZZOCMXYOCMHDA-UHFFFAOYSA-N 7-methoxy-n-methyl-4-oxo-n-phenyl-1h-quinoline-3-carboxamide Chemical compound C1=NC2=CC(OC)=CC=C2C(O)=C1C(=O)N(C)C1=CC=CC=C1 YZZOCMXYOCMHDA-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 150000001448 anilines Chemical class 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000003018 immunosuppressive agent Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- GKWPCEFFIHSJOE-UHFFFAOYSA-N laquinimod Chemical compound OC=1C2=C(Cl)C=CC=C2N(C)C(=O)C=1C(=O)N(CC)C1=CC=CC=C1 GKWPCEFFIHSJOE-UHFFFAOYSA-N 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- YCUDHDQLAPWYOU-UHFFFAOYSA-N n-methyl-4-oxo-n-phenyl-7-(trifluoromethyl)-1h-quinoline-3-carboxamide Chemical compound C=1N=C2C=C(C(F)(F)F)C=CC2=C(O)C=1C(=O)N(C)C1=CC=CC=C1 YCUDHDQLAPWYOU-UHFFFAOYSA-N 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 229960003522 roquinimex Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- CZZZABOKJQXEBO-UHFFFAOYSA-N 2,4-dimethylaniline Chemical compound CC1=CC=C(N)C(C)=C1 CZZZABOKJQXEBO-UHFFFAOYSA-N 0.000 description 2
- MKARNSWMMBGSHX-UHFFFAOYSA-N 3,5-dimethylaniline Chemical compound CC1=CC(C)=CC(N)=C1 MKARNSWMMBGSHX-UHFFFAOYSA-N 0.000 description 2
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 2
- ZJPTYOCWYPKMNL-UHFFFAOYSA-N 7-chloro-3-(piperidine-1-carbonyl)-1h-quinolin-4-one Chemical compound C=1C(Cl)=CC=C(C2=O)C=1NC=C2C(=O)N1CCCCC1 ZJPTYOCWYPKMNL-UHFFFAOYSA-N 0.000 description 2
- HIJZTYXWNSFRDJ-UHFFFAOYSA-N 7-chloro-n-methyl-4-oxo-n-phenyl-1h-quinoline-3-carboxamide Chemical compound C=1NC2=CC(Cl)=CC=C2C(=O)C=1C(=O)N(C)C1=CC=CC=C1 HIJZTYXWNSFRDJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229960004050 aminobenzoic acid Drugs 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- PYPCDUKQEIPHAF-UHFFFAOYSA-N diethyl 2-(anilinomethylidene)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=CNC1=CC=CC=C1 PYPCDUKQEIPHAF-UHFFFAOYSA-N 0.000 description 2
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- XXODEWFYVLTJFT-UHFFFAOYSA-N n-methyl-7-methylsulfanyl-4-oxo-n-phenyl-1h-quinoline-3-carboxamide Chemical compound C1=NC2=CC(SC)=CC=C2C(O)=C1C(=O)N(C)C1=CC=CC=C1 XXODEWFYVLTJFT-UHFFFAOYSA-N 0.000 description 2
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- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 2
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- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
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- 235000019250 sodium sorbate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to quinolyl amide derivatives, their preparation process, medicine compositions and use in preparing medicines for treating and/or preventing chronic nephritis, rheumarthritis, insulin dependent diabetes mellitus, systemic lupus erythematous, multiple sclerosis and other diseases.
Description
Technical Field
The invention relates to 4-hydroxy-quinoline-3-amide compounds, a preparation method thereof, a pharmaceutical composition containing the compounds and application of the compounds in preparing medicaments for treating and/or preventing diseases such as chronic nephritis, rheumatoid arthritis, insulin-dependent diabetes mellitus, systemic lupus erythematosus and multiple sclerosis.
Background
Chronic nephritis is a serious health-threatening disease, often resulting in renal failure that endangers the life of the patient. At present, the pathogenesis of chronic nephritis is not clear, the chronic nephritis is generally considered to be related to immune dysfunction, the chronic nephritis belongs to autoimmune diseases, and no specific medicine is available for treating the chronic nephritis. At present, hormone drugs (cortisone, prednisone, corticosterone, cortisol and the like) and immunosuppressive drugs (cyclosporine A, cyclophosphamide, FK506 and the like) are generally adopted clinically to relieve the disease condition, the drugs need to be taken for a long time or even be used for a lifetime in order to control the development of the disease condition, and the long-term application of the hormone drugs and the immunosuppressant is easy to cause immunologic hypofunction, such as Cushing's syndrome, and is also easy to cause serious infection, tumorigenesis and other side effects.
Modern immunology has held that autoimmune diseases do not occur due to the patient's hyperimmunity, but are usually caused by immune disorders and are often accompanied by the occurrence of immunodeficiency. Immunodeficiency can induce the occurrence of autoimmunity through various ways, wherein persistent infection caused by incapability of effectively eliminating antigens due to immunodeficiency is the most main reason, and various immunodeficiency is directly related to the autoimmunity, so that the treatment of the autoimmunity by using an immunosuppressant is a temporary treatment and a permanent treatment, has great side effects after long-term use, and is a method for treating both symptoms and root causes of the autoimmunity only by regulating an unbalanced immune system to be normal.
Several quinoline amide compounds have been reported in the literature to have immunomodulatory activity, for example: linomide (1, 2-dihydro-4-hydroxy-N, 1-dimethyl-2-oxo-N-phenyl-quinoline-3-carboxamide), FR-137316(1, 2-dihydro-4-hydroxy-N, 1-dimethyl-2-oxo-6-methylsulfanyl-N-phenyl-quinoline-3-carboxamide), ABR-215062(1, 2-dihydro-4-hydroxy-1-methyl-2-oxo-5-chloro-N-ethyl-N-phenyl-quinoline-3-carboxamide) all have immunomodulatory activity and have therapeutic effects on a number of autoimmune diseases (Tsuji K et al, synthesis and antibiotic activities of quinoline-3-carboxamides and dried compounds, bioorg. Med. chem. Lett.2002 Jan 7; 12(1): 85-8 parts of; brunmark C et al, The new organic active immunoregulating requirements (ABR-215062) effective inhibitory fragments and drivers of experimental autoimmune encephalomycetis, J.Neuroimmumunal.2002 Sep; 130(1-2): 163-72; gross DJ et al, the immunomodulator Linomide: role in traffic and preservation of autoimmune diabetes mellitis, int. immunopharmacol.2001jun; 1(6): 1131-9).
Disclosure of Invention
The object of the present invention is to find new compounds with immunomodulatory activity that can be used for the treatment and/or prevention of autoimmune diseases such as: chronic nephritis, rheumatic arthritis, insulin dependent diabetes mellitus, systemic lupus erythematosus, multiple sclerosis and the like.
It has now been found that compounds having the following general formula I have immunomodulatory activity and are useful in the treatment and/or prevention of autoimmune diseases such as: chronic nephritis, rheumatic arthritis, insulin dependent diabetes mellitus, systemic lupus erythematosus, multiple sclerosis and the like.
Accordingly, a first aspect of the present invention relates to a compound of formula I:
wherein:
r1 and R2 are each independently hydrogen, halogen, C1-C8Straight or branched alkyl, C1-C8Alkoxy radical, C1-C8Alkylthio, trifluoromethyl, nitro, carboxyl, C3-C8Straight-chain or branched alkyl containing nitrogen atoms, C5-C10Cycloalkyl radical, C5-C10Heterocyclic ring containing nitrogen or oxygen or sulfur atoms or C6-C10Aryl, said alkyl or heterocycle being unsubstituted or substituted by one or more groups selected from: c1-C3Straight chain carboxyl group, C5-C6Cycloalkyl radical, C5-C6A heterocyclic ring containing a nitrogen atom or an oxygen atom or a benzyl group;
r3 is hydrogen, C1-C8Straight or branched alkyl, C1-C5A linear nitrogen atom-or oxygen atom-containing alkyl group;
r4 is C1-C8A linear or branched alkyl, phenyl, said alkyl or phenyl being unsubstituted or substituted by one or more groups selected from: halogen, methyl, methoxy, trifluoromethyl, nitro, hydroxy, carboxy, C1-C5Straight-chain nitrogen or oxygen atom-containing alkyl, -N (CH)2CH2OH)2、C5-C6A cycloalkyl group;
alternatively, R3 and R4 taken together form a 3-9 membered cyclic structure selected from the group consisting of a morpholine ring, a piperazine ring, a piperidine ring.
A second aspect of the present invention relates to pharmaceutical compositions comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
A third aspect of the present invention relates to a process for the preparation of a compound of formula I, said process comprising starting from a substituted aniline, synthesizing a substituted 4-hydroxy-quinoline-3-carboxylic acid ethyl ester, and subjecting the resulting product to ammonolysis to obtain a compound of formula I according to the present invention.
In a fourth aspect, the present invention relates to the use of at least one compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of autoimmune diseases, such as chronic nephritis, rheumatoid arthritis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, multiple sclerosis, and the like.
The present invention also relates to a method for the treatment and/or prophylaxis of autoimmune diseases, such as chronic nephritis, rheumatoid arthritis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, multiple sclerosis and the like, which method comprises administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.
The present invention will be described in more detail below.
The present invention relates to compounds of formula I:
accordingly, a first aspect of the present invention relates to a compound of formula I:
wherein:
r1 and R2 are each independently hydrogen, halogen, C1-C8Straight or branched alkyl, C1-C8Alkoxy radical, C1-C8Alkylthio, trifluoromethyl, nitro, carboxyl, C3-C8Straight-chain or branched alkyl containing nitrogen atoms, C5-C10A cycloalkyl group,C5-C10heterocyclic ring containing nitrogen or oxygen or sulfur atoms or C6-C10Aryl, said alkyl or heterocycle being unsubstituted or substituted by one or more groups selected from: c1-C3Straight chain carboxyl group, C5-C6Cycloalkyl radical, C5-C6A heterocyclic ring containing a nitrogen atom or an oxygen atom or a benzyl group;
r3 is hydrogen, C1-C8Straight or branched alkyl, C1-C5A linear nitrogen atom-or oxygen atom-containing alkyl group;
r4 is C1-C8A linear or branched alkyl, phenyl, said alkyl or phenyl being unsubstituted or substituted by one or more groups selected from: halogen, methyl, methoxy, trifluoromethyl, nitro, hydroxy, carboxy, C1-C5Straight-chain nitrogen or oxygen atom-containing alkyl, -N (CH)2CH2OH)2、C5-C6A cycloalkyl group;
alternatively, R3 and R4 taken together form a 3-9 membered cyclic structure selected from the group consisting of a morpholine ring, a piperazine ring, a piperidine ring.
The term "halogen" in the present invention means fluorine, chlorine, bromine, iodine.
The term "linear or branched alkyl group containing a nitrogen atom or an oxygen atom" means that the terminal of the alkyl group contains a substituent such as an N-methyl group, an N, N-dimethyl group, an N, N-diethyl group or an O-methyl group, or one methylene group in the linear or branched alkyl group is substituted with a nitrogen atom or an oxygen atom.
The term "heterocyclic ring containing a nitrogen atom or an oxygen atom or a sulfur atom" means a saturated cycloalkyl group containing one nitrogen atom or an oxygen atom or a sulfur atom in the ring system, and containing two nitrogen atoms, one nitrogen atom and an oxygen atom, and one nitrogen atom and a sulfur atom, for example, piperidyl, morpholinyl, tetrahydrofuryl, pyrrolidinyl and the like.
According to a preferred embodiment of the present invention, the present invention relates to a compound of formula I:
wherein,
r1, R2 are each independently hydrogen, halogen, methyl, methoxy, methylthio or nitro;
r3 is hydrogen, C1-C8A linear or branched alkyl group;
r4 is C1-C8A linear or branched alkyl, phenyl, said alkyl or phenyl being unsubstituted or substituted by one or more groups selected from: halogen, methyl, methoxy, trifluoromethyl, nitro, hydroxy, carboxy, C1-C5Straight-chain nitrogen or oxygen atom-containing alkyl, -N (CH)2CH2OH)2、C5-C6A cycloalkyl group.
According to the invention, the compounds of formula I according to the invention are preferably the following compounds or pharmaceutically acceptable salts thereof:
n- (3-chlorophenyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
N-methyl-N-phenyl-4-hydroxy-7-chloro-quinoline-3-carboxamide;
n-phenyl-4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- (4-nitrophenyl) -4-hydroxy-7-chloro-quinoline-3-amide;
n- (4-methyl-2-pyridinyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
(4-hydroxy-7-chloro-3-quinolinyl) -1-piperidinylmethanone;
N-ethyl-N-phenyl-4-hydroxy-7-chloro-quinoline-3-carboxamide;
n, N-di-N-propyl-4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- ((2-diethanolamino) -phenyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- ((4-diethanolamino) -phenyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- (2-ethanoyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- (4-hydroxy-phenyl) -4-hydroxy-7-chloro-quinoline-3-amide;
(4-hydroxy-7-chloro-3-quinolinyl) -4-morpholinomethanone;
(4-hydroxy-7-chloro-3-quinolinyl) - (4-methyl-1-piperazinyl) -methanone;
n- (3-pyridin-methyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-chloro-quinoline-3-amide;
n- (3-chloro-phenyl) -4-hydroxy-quinoline-3-carboxamide;
N-methyl-N-phenyl-4-hydroxy-quinoline-3-carboxamide;
n- (4-carboxy-phenyl) -4-hydroxy-quinoline-3-carboxamide;
n- ((4-diethanolamino) -phenyl) -4-hydroxy-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-3-quinolinyl) -4-morpholinomethanone;
(4-hydroxy-3-quinolinyl) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-quinoline-3-carboxamide;
n- (3-chlorophenyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide;
N-methyl-N-phenyl-4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide;
n- ((4-diethanolamino) -phenyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide;
(4-hydroxy-8-methylsulfanyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-8-methylsulfanyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-8-methylsulfanyl-quinoline-3-amide;
n- (3-chlorophenyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide;
N-methyl-N-phenyl-4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide;
n- ((4-diethanolamino) -phenyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide;
(4-hydroxy-7-methylsulfanyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-7-methylsulfanyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-methylsulfanyl-quinoline-3-amide;
n- (3-chlorophenyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide;
N-methyl-N-phenyl-4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide;
(4-hydroxy-6-methylsulfanyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-methylsulfanyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- (3-pyridin-methyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-methylsulfanyl-quinoline-3-amide;
n- (3-chlorophenyl) -4-hydroxy-6-nitro-quinoline-3-carboxamide;
N-methyl-N-phenyl-4-hydroxy-6-nitro-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-nitro-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-nitro-quinoline-3-carboxamide;
(4-hydroxy-6-nitro-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-nitro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-nitro-quinoline-3-amide;
n- (3-chlorophenyl) -4-hydroxy-6-methyl-quinoline-3-carboxamide;
N-methyl-N-phenyl-4-hydroxy-6-methyl-quinoline-3-carboxamide;
n-phenyl-4-hydroxy-6-methyl-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-methyl-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-methyl-quinoline-3-carboxamide;
(4-hydroxy-6-methyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-methyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-methyl-quinoline-3-carboxamide;
n- (3-chlorophenyl) -4-hydroxy-6-chloro-quinoline-3-carboxamide;
N-methyl-N-phenyl-4-hydroxy-6-chloro-quinoline-3-carboxamide;
n-phenyl-4-hydroxy-6-chloro-quinoline-3-carboxamide;
n- (4-carboxy-phenyl) -4-hydroxy-6-chloro-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-chloro-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-chloro-quinoline-3-carboxamide;
(4-hydroxy-6-chloro-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-chloro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-chloro-quinoline-3-amide;
n- (3-chlorophenyl) -4-hydroxy-6-bromo-quinoline-3-carboxamide;
N-methyl-N-phenyl-4-hydroxy-6-bromo-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-bromo-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-bromo-quinoline-3-amide;
(4-hydroxy-6-bromo-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-bromo-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-bromo-quinoline-3-amide;
n- (3-chlorophenyl) -6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide;
N-methyl-N-phenyl-6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide;
N-ethyl-N-phenyl-6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-6, 8-dimethyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6, 8-dimethyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6, 8-dimethyl-quinoline-3-carboxamide;
N-methyl-N-phenyl-5, 7-dimethyl-4-hydroxy-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -5, 7-dimethyl-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -5, 7-dimethyl-4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-5, 7-dimethyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-5, 7-dimethyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-5, 7-dimethyl-quinoline-3-carboxamide;
N-methyl-N-phenyl-7-methoxy-4-hydroxy-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -7-methoxy-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -7-methoxy-4-hydroxy-quinoline-3-carboxamide;
n- (4-hydroxy-phenyl) -7-methoxy-4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-7-methoxy-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-7-methoxy-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-methoxy-quinoline-3-carboxamide;
N-methyl-N-phenyl-7-trifluoromethyl-4-hydroxy-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -7-trifluoromethyl-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -7-trifluoromethyl-4-hydroxy-quinoline-3-amide;
(4-hydroxy-7-trifluoromethyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-7-trifluoromethyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-trifluoromethyl-quinoline-3-amide;
N-methyl-N-phenyl-7-fluoro-4-hydroxy-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -7-fluoro-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -7-fluoro-4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-7-fluoro-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-7-fluoro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- ((2-dimethylamino) -ethyl) -6-fluoro-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -6-fluoro-4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-6-fluoro-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-fluoro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- (3-pyridin-methyl) -4-hydroxy-6-fluoro-quinoline-3-carboxamide;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-fluoro-quinoline-3-carboxamide.
According to the present invention, the compounds of formula I of the present invention or pharmaceutically acceptable salts thereof can be synthesized according to methods well known in the art.
Specifically, the compounds of formula I of the present invention can be obtained by starting with substituted aniline, synthesizing a substituted ethyl 4-hydroxy-quinoline-3-carboxylate, and then aminolyzing the above-mentioned ethyl 4-hydroxy-quinoline-3-carboxylate with a substituted amine.
More specifically, the compounds of formula I of the present invention can be synthesized using the following synthetic routes:
the compound of formula (III) is condensed with various commercial amine compounds by using diphenyl ether as a solvent at 180-230 ℃ for 0.5-2 hours to obtain the compound of formula I of the invention.
If desired, the compounds of formula I may also be converted into their pharmaceutically acceptable salts by reaction with acids or bases.
Accordingly, the process for the preparation of the compounds of formula (I) according to the invention comprises the following steps:
(1) reacting a substituted aniline of the formula
Wherein the substituents R1, R2 are as defined above for compounds of formula I;
reacting with ethoxy methylene diethyl malonate to obtain a compound of a formula II
Wherein the substituents R1, R2 are as defined above;
(2) cyclizing the compound of the formula II at high temperature to obtain the compound of the formula III
Wherein the substituents R1, R2 are as defined above;
(3) reacting a compound of formula III with a substituted amine R3R4NH wherein R3 and R4 are as defined above for a compound of formula I to provide a compound of formula I
Wherein the substituents R1, R2, R3 and R4 are as defined above for the compounds of formula I.
The compound of formula I and the salt thereof can form solvates, such as hydrates, alcohol compounds and the like. The compounds may also be in the form of prodrugs or may be metabolized in the body to release the active ingredient. The selection and preparation of appropriate prodrug derivatives is well known to those skilled in the art.
According to the present invention, pharmaceutically acceptable salts of the compounds of the present invention include salts with inorganic or organic acid forms, including but not limited to: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogensulfate, phosphate, hydrogenphosphate, acetate, butyrate, oxalate, pivalate, oxalate, alginate, glycolate, lactate, pyruvate, glycolate, citrate, tartrate, malonate, succinate, maleate, fumarate, trifluoroacetate, picrate, gluconate, benzoate, salicylate, p-aminosalicylate, ascorbate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate, and the like.
According to the invention, when the compound of formula I contains phenolic hydroxyl and/or carboxyl, it may also be salified with a pharmaceutical base, which is selected from sodium, potassium, lithium, magnesium, calcium, iron or zinc salts.
The compounds of formula I of the present invention may be administered as such or in the form of pharmaceutical compositions. According to the present invention, the pharmaceutical compositions of the present invention comprise an effective amount of a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof, in combination with one or more suitable pharmaceutically acceptable carriers. Such pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, sodium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, polyethylene-polyoxypropylene-block polymers and lanolin.
The pharmaceutical compositions of the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers, excipients and auxiliaries, which facilitate processing of the active compounds into pharmaceutically acceptable preparations. Suitable formulations depend on the route of administration chosen and may be prepared according to methods well known in the art.
The compounds of formula I of the present invention, or pharmaceutically acceptable salts thereof, may be delivered to a patient by a variety of routes or modes of administration. Suitable routes of administration include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, enteral and parenteral administration, including intramuscular, subcutaneous and intravenous injection.
The oral pharmaceutical preparation comprises capsules, tablets and the like. When the patient has difficulty swallowing, the medicine can also be administered by sublingual tablet or other non-swallowing mode.
The compounds of the invention may also be formulated for parenteral or transdermal or transmucosal administration. Or by means of suppositories or implants.
It will be appreciated by those skilled in the art that, based on the compounds of the present invention, suitable Drug Delivery Systems (DDS) may be employed to achieve a more advantageous effect.
The particular mode of administration and the choice of effective dose will vary depending on the nature of the disease, the age, weight and severity of the disease in the patient. The choice of mode of administration and dosage is within the ability of those skilled in the art.
The term "administering" as used herein includes all means of directly and indirectly releasing a compound to its intended site of action.
The unit dosage forms of the compounds of the invention generally contain from 0.1 to 99% by weight of active substance, preferably from 5 to 75% by weight of active substance. For example, a unit dosage form may contain 1mg to 1g of the compound, preferably 10mg to 500mg, more preferably between 50mg and 400mg, most preferably 100mg to 200 mg.
Generally, the daily dosage of a compound of the invention will be in the range of 0.01mg/kg to 100mg/kg body weight, more preferably 0.1mg/kg to 10mg/kg body weight, most preferably 1mg/kg to 5mg/kg body weight.
Detailed Description
The following examples are intended to illustrate the invention without, however, limiting it in any way.
Example 1: synthesis of N- (3-chlorophenyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide
1.13-chloro-anilino-methylene diethyl malonate synthesis: mixing 7.00 g (0.055mol) of m-chloroaniline and 12.00 g (0.056mol) of diethyl ethoxymethylene malonate, adding 50ml of toluene, heating to about 100 ℃, reacting for 5 hours, and evaporating the solvent under reduced pressure to obtain white wax, white needle-shaped crystals recrystallized from petroleum ether, weighing 14.20 g, m.p.56-57 ℃ and the yield of 87.0 percent.
1.Synthesis of 24-hydroxy-7-chloro-quinoline-3-carboxylic acid ethyl ester: dissolving 14.20 g (0.048mol) of 3-chloroanilino methylene diethyl malonate in 100ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, washing with absolute ethyl alcohol and washing with absolute ethyl ether to obtain a white solid, weighing 10.50 g, and obtaining the yield of 87.5 percent, wherein m.p. is more than 300 ℃.
Synthesis of 3N- (3-chlorophenyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide: mixing 0.50 g (0.002mol) of 4-hydroxy-7-chloro-quinoline-3-carboxylic acid ethyl ester and 1.20 g (0.009mol) of m-chloroaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 h, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a white solid, weighing 0.58 g, and obtaining the yield of 87.3% when the m.p. is more than 300 ℃.1HNMR(DMSO-d6，δ)：12.93(s，1H，OH)，12.44(S，1H，CONH)，8.90(S，1H)，8.31(d，1H，J＝8.7Hz)，8.02(d，1H，J＝2.2Hz)，7.8(S，1H)，7.57(dd，1H，J＝2.0，8.7Hz)，7.50(d，1H，J＝7.9Hz)，7.38(t，1H，J＝7.9)，7.15(d，1H，J＝7.9Hz)。
Example 2: N-methyl-N-phenyl-4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, with the substituted amine being N-methylaniline. m.p.276-278 ℃ and the yield is 41.1 percent.1HNMR(DMSO-d6，δ)：11.91(s，1H，OH)，8.04(d，1H，J＝5.9Hz)，7.96(d，1H，J＝8.8Hz)，7.51(d，1H，J＝1.7Hz)，7.20-7.30(m，5H)，7.10(t，1H，J＝7.0Hz)，3.37(s，3H)。
Example 3: n-phenyl-4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, using aniline as the amine. m.p. > 300 ℃ and yield 88.7%.1HNMR(DMSO-d6，δ)：12.89(S，1H)，12.29(S，1H)，8.86(S，1H)，8.34(d，1H，J＝8.7Hz)，7.3-7.8(m，6H)，7.14(t，1H，J＝7.3Hz)。
Example 4: n- (4-nitrophenyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, the substituted amine used being 4-nitroaniline. m.p. > 300 ℃ yield 79.4%.1HNMR(TFA-d1，δ)：9.52(s，1H)，8.46(d，1H，J＝9.0Hz)，8.26(d，2H，J＝9.3Hz)，8.02(d，1H，J＝1.6Hz)，7.84(d，2H，J＝9.1Hz)，7.75(dd，1H，J＝1.7Hz，9.0Hz)。
Example 5: n- (4-methyl-2-pyridinyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, using 4-methyl-2-pyridylamine as the amine. m.p. > 300 ℃ yield 84.2%.1HNMR(TFA-d1，δ)：9.14(s，1H)，8.27(d，1H，J＝8.8Hz)，8.18(d，1H，J＝6.3Hz)，7.76(s，1H)，7.58-7.63(m，2H)，7.38(d，1H，J＝6.1Hz)，2.59(s，3H)。
Example 6: (4-hydroxy-7-chloro-3-quinolinyl) -1-piperidinylmethanone
This compound was prepared as in 1.3 of example 1, using piperidine as the amine. m.p.288 deg.C (dec), yield 46.4%. N-methylaniline.1HNMR(DMSO-d6，δ)：12.11(s，1H)，8.12(d，1H，J＝8.7Hz)，8.10(s，1H)，7.63(d，1H，J＝2.0Hz)，7.38(dd，1H，J＝2.2，8.7Hz)，3.55(brs，2H)，3.28(brs，2H)，1.48-1.52(m，6H)。
Example 7: N-ethyl-N-phenyl-4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, using N-ethylaniline as the amine. m.p.266-268 ℃ with a yield of 32.1%.1HNMR(DMSO-d6，δ)：11.86(brs，1H)，7.90-8.05(m，2H)，7.49(s，1H)，7.10-7.30(m，6H)，3.79(q，2H，J＝7.0Hz)，1.08(t，3H，J＝7.0Hz)。
Example 8: n, N-di-N-propyl-4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound is prepared as in 1.3 of example 1, using the amine di-n-propylamine. m.p.168-170 deg.c, yield 30.1%.1HNMR(DMSO-d6，δ)：12.05(brs，1H)，8.12(d，1H，J＝8.7Hz)，8.07(brs，1H)，7.64(d，1H，J＝2.0Hz)，7.38(dd，1H，J＝2.0，8.7Hz)，3.35(t，2H，J＝7.0Hz)，3.11(t，2H，J＝7.0Hz)，1.45-1.60(m，4H)，0.92(t，3H，J＝7.3Hz)，0.67(t，3H，J＝7.3Hz)。
Example 9: n- ((2-diethanolamino) -phenyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, using 2-diethanolamino-aniline as amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). The yield thereof was found to be 10.1%.1HNMR(DMSO-d6，δ)：12.90(brs，1H)，12.56(s，1H)，8.95(s，1H)，8.51(d，1H，J＝8.1Hz)，8.31(d，1H，J＝8.9Hz)，7.8(d，1H，J＝1.7Hz)，7.55(dd，1H，J＝1.7，8.9Hz)，7.39(d，1H，J＝7.9Hz)，7.06-7.16(m，2H)，4.41(t，2H，J＝5.7Hz)，3.46(q，4H，J＝6.4Hz)，3.11(t，4H，J＝6.4Hz)。
Example 10: n- ((4-diethanolamino) -phenyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, using 4-diethanolamino-aniline as amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). The yield thereof was found to be 7.6%. MS (m/z, C)20H20ClN3O4)：402(M+1，ESI)；1HNMR(DMSO-d6，δ)：12.87(brs，1H)，11.97(s，1H)，8.89(s，1H)，8.30(d，1H，J＝8.7Hz)，7.79(d，1H，J＝1.7Hz)，7.49-7.57(m，3H)，6.68(d，2H，J＝8.9Hz)，4.75(s，2H)，3.33-3.53(m，8H)。
Example 11: n- (2-ethanolyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, using 2-ethanolamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1) yield 40.0%. MS (m/z, C)12H11ClN2O3)：267(M+1，ESI)；1HNMR(DMSO-d6，δ)：10.37(br，1H)，8.77(s，1H)，8.20(d，1H，J＝8.7Hz)，7.64(s，1H)，7.35(d，1H，J＝8.7Hz)，3.50(m，2H)，3.37(q，2H，J＝5.7Hz)，2.78(t，1H，J＝5.6Hz)。
Example 12: n- ((2-dimethylamino) -ethyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, using N, N-dimethylethylenediamine as the amine. m.p.206-208 deg.C, yield 68.5%.1HNMR(DMSO-d6，δ)：12.45(brs，1H)，9.96(t，1H，J＝5.3Hz)，8.76(s，1H)，8.24(d，1H，J＝8.7Hz)，7.73(d，1H，J＝1.9Hz)，7.48(dd，1H，J＝2.0，8.7Hz)，3.42(q，2H，J＝5.9Hz)，2.43(t，2H，J＝5.9Hz)，2.22(s，6H)。
Example 13: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, using N, N, 2, 2-tetramethylpropanediamine as the amine. m.p.146-148 ℃ and the yield is 24.0 percent.1HNMR(DMSO-d6，δ)：12.60(brs，1H)，10.08(t，1H，J＝5.6Hz)，8.78(s，1H)，8.26(d，1H，J＝8.7Hz)，7.75(d，1H，J＝2.0Hz)，7.49(dd，1H，J＝2.0，8.7Hz)，3.24(d，2H，J＝5.9Hz)，2.27(s，6H)，2.15(s，2H)，0.89(s，6H)。
Example 14: n- (4-hydroxy-phenyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, using 4-hydroxy-aniline as the amine. m.p. > 300 ℃ yield 80.0%.1HNMR(DMSO-d6，δ)：12.88(brs，1H)，12.05(s，1H)，9.27(s，1H)，8.89(s，1H)，8.30(d，1H，J＝9.0Hz)，7.80(d，1H，J＝1.7Hz)，7.50-7.56(m，3H)，6.75(d，2H，J＝8.7Hz)。
Example 15: (4-hydroxy-7-chloro-3-quinolinyl) -4-morpholinomethanone
The compound was prepared as in 1.3 of example 1, using amine morpholine. m.p.288-290 deg.C, yield 34.4%.1HNMR(DMSO-d6，δ)：12.27(d，1H，J＝5.6Hz)，8.19(d，1H，J＝6.16)，8.13(d，1H，J＝8.7Hz)，7.65(d，1H，J＝2.0Hz)，7.40(dd，1H，J＝2.0，8.7Hz)，3.57(brs，6H)，3.34(s，2H)。
Example 16: (4-hydroxy-7-chloro-3-quinolyl) - (4-methyl-1-piperazinyl) -methanone
This compound was prepared as in 1.3 of example 1, using 4-methyl-piperazine as the amine. m.p.278 deg.C (dec), yield 49.4%.1HNMR(DMSO-d6，δ)：12.20(brs，1H)，8.16(s，1H)，8.12(d，1H，J＝8.7Hz)，7.64(d，1H，J＝2.0Hz)，7.39(dd，1H，J＝8.7Hz)，3,59(brs，2H)，3.24(brs，2H)，2.33(brs，4H)，2.18(s，3H)。
Example 17: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-chloro-quinoline-3-carboxamide
This compound was prepared as in 1.3 of example 1, using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.158-160 deg.c and yield 30.2%.1HNMR(DMSO-d6，δ)：12.36(brs，1H)，10.02(s，1H)，8.77(s，1H)，8.24(d，1H，J＝8.7)，7.73(d，1H，J＝2.0Hz)，7.47(dd，1H，J＝2.0，8.7Hz)，3.52-3.57(m，1H)，3.18-3.23(m，1H)，3.08-3.13(m，1H)，2.82-2.91(m，1H)，2.60(brs，1H)，2.24-2.35(m，1H)，2.13-2.20(m，1H)，1.81-1.87(m，1H)，1.63-1.68(m，2H)，1.49-1.57(m，1H)，1.07(t，3H，J＝7.3Hz)。
Example 18: n- (3-chloro-phenyl) -4-hydroxy-quinoline-3-carboxamide
18.1 Synthesis of Anilinomethylidene malonic acid diethyl ester: mixing 7.20 g (0.077mol) aniline and 16.80 g (0.077mol) diethyl ethoxymethylene malonate, adding 50ml toluene, heating to about 100 deg.C, reacting for 5 hr, and removing solvent by evaporation under reduced pressure to obtain white wax, white needle-like crystals recrystallized from petroleum ether, and weighing 18.40 g. m.p.48-49 deg.C, yield 90.4%.
Synthesis of ethyl 24-hydroxy-quinoline-3-carboxylate: 18.2 g (0.069mol) of Anilinomethylidene malonic acid diethyl ester is dissolved in 100ml of diphenyl ether, heated to about 250 ℃, reacted for 0.5 hour, stopped being heated, cooled to room temperature, precipitated solid, filtered and collected, washed by petroleum ether, washed by absolute ethyl alcohol and absolute ethyl ether to obtain white solid, the weight of which is 12.00 g, the m.p.275-277 ℃, and the yield of which is 80.0 percent.
Synthesis of 3N- (3-chlorophenyl) -4-hydroxy-quinoline-3-carboxamide: mixing 0.50 g (0.002mol) of 4-hydroxy-quinoline-3-carboxylic acid ethyl ester and 1.20 g (0.009mol) of m-chloroaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 h, stopping heating, cooling to room temperature, precipitating a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a white solid, weighing 0.60 g, and obtaining the yield of 87.3 percent, wherein m.p. is more than 300 ℃.1HNMR(DMSO-d6，δ)：12.95(s，1H，OH)，12.61(S，1H，CONH)，8.87(S，1H)，8.33(dd，1H，J＝1.0，8.1Hz)，8.04(t，1H，J＝2.0Hz)，7.75-7.83(m，2H)，7.48-7.58(m，2H)，7.38(t，1H，J＝8.0Hz)，7.15(m，1H)。
Example 19: N-methyl-N-phenyl-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 18.3 of example 18, using N-methyl-aniline as the amine and recrystallized from absolute ethanol. m.p.246-248 deg.C, yield 57.6%.1HNMR(DMSO-d6，δ)：11.86(s，1H，OH)，7.98(m，2H)，7.58(m，1H)，7.46(d，1H，J＝8.0Hz)，7.20-7.30(m，5H)，7.10(t，1H，J＝7.0Hz)，3.31(s，3H)。
Example 20: n- (4-Carboxyphenyl) -4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 18.3 of example 18, using p-aminobenzoic acid as amine. m.p. > 300 ℃ and yield 85.9%.1HNMR(DMSO-d6，δ)：13.03(brs，1H)，12.80(s，1H)，12.76(brs，1H)，8.91(s，1H)，8.34(d，1H，J＝8.1Hz)，7.95(d，2H，J＝8.7Hz)，7.76-7.86(m，4H)，7.56(t，1H，J＝7.1Hz)。
Example 21: n- ((4-diethanolamino) -phenyl) -4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 18.3 of example 18, using 4-diethanolamino-aniline as amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.218-222 deg.c, yield 6.0%.1HNMR(DMSO-d6，δ)：12.86(brs，1H)，12.12(s，1H)，8.84(s，1H)，8.30(d，1H，J＝8.2Hz)，7.78(m，2H)，7.48-7.54(m，3H)，6.68(d，2H，J＝8.9Hz)，4.74(t，2H，J＝5.0Hz)，3.53(m，4H)，3.40(t，4H，J＝6.2Hz)。
Example 22: n- ((2-dimethylamino) -ethyl) -4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 18.3 of example 18, using N, N-dimethylethylenediamine as the amine. m.p.102-104 deg.C, yield 53.6%.1HNMR(DMSO-d6，δ)：12.59(brs，1H)，10.05(t，1H，J＝5.4Hz)，8.72(s，1H)，8.25(d，1H，J＝8.1Hz)，7.65-7.79(m，2H)，7.47(t，1H，J＝7.5Hz)，3.42(q，2H，J＝5.9Hz)，2.41(t，2H，J＝6.0Hz)，2.20(s，6H)。
Example 23: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 18.3 of example 18 using N, N, 2, 2-tetramethylpropanediamine as the amine. m.p.157-159 ℃, yield 44.9%.1HNMR(DMSO-d6，δ)：12.61(brs，1H)，10.18(t，1H，J＝5.6Hz)，8.74(s，1H)，8.27(d，1H，J＝7.7Hz)，7.63-7.78(m，2H)，7.47(t，1H，J＝7.3Hz)，3.24(d，2H，J＝5.9Hz)，2.26(s，6H)，2.15(s，2H)，0.89(s，6H)。
Example 24: (4-hydroxy-3-quinolyl) -4-morpholinyl methanone
This compound was prepared as in 18.3 of example 18, using morpholine as the amine. m.p.230-232 ℃ and yield 42.1%.1HNMR(DMSO-d6，δ)：12.23(s，1H)，8.13(m，2H)，7.69(m，1H)，7.59(d，1H，J＝8.1Hz)，3.60(brs，6H)，3.32(s，2H)。
Example 25: (4-hydroxy-3-quinolyl) - (4-methyl-1-piperazinyl) -methanone
This compound was prepared as in 18.3 of example 18, using 4-methyl-piperazine as the amine. m.p.200-202 deg.c, yield 38.5%.1HNMR(DMSO-d6，δ)：12.18(brs，1H)，8.13(d，1H，J＝8.1Hz)，8.10(s，1H)，7.68(t，1H，J＝7.0Hz)，7.59(d，1H，J＝8.4Hz)，7.39(t，1H，J＝7.5Hz)，3,59(brs，2H)，3.26(brs，2H)，2.33(brs，4H)，2.19(s，3H)。
Example 26: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-quinoline-3-carboxamide
This compound is prepared as in 18.3 of example 18 using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.166-168 deg.C, yield 63.8%.1HNMR(DMSO-d6，δ)：12.46(brs，1H)，10.06(t，1H，J＝5.7Hz)，8.72(s，1H)，8.26(dd，1H，J＝1.0，8.0Hz)，7.76(m，1H)，7.68(d，1H，J＝8.0Hz)，7.46(m，1H)，3.52-3.59(m，1H)，3.16-3.23(m，1H)，3.04-3.13(m，1H)，2.80-2.90(m，1H)，2.55(brs，1H)，2.20-2.29(m，1H)，2.09-2.16(m，1H)，1.79-1.86(m，1H)，1.61-1.68(m，2H)，1.49-1.57(m，1H)，1.06(t，3H，J＝7.3Hz)。
Example 27: n- (3-chlorophenyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide
27.1 Synthesis of diethyl (2-methylthioanilino) methylenemalonate: 5.00 g (0.036mol) of 2-methylthioaniline and 7.80 g (0.036mol) of diethyl ethoxymethylene malonate were mixed, 50ml of toluene was added, the mixture was heated to about 100 ℃ to react for 5 hours, and the solvent was distilled off under reduced pressure to obtain a pale yellow wax, pale yellow needle crystals recrystallized from petroleum ether, and 11.1 g of the pale yellow needle crystals were obtained. m.p.67-69 ℃ and 100 percent of yield.
27.synthesis of ethyl 24-hydroxy-8-methylsulfanyl-quinoline-3-carboxylate: dissolving 11.1 g (0.036mol) of (2-methylthioanilino) diethyl methylene malonate in 100ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a white solid, weighing 7.88 g, m.p.208-210 ℃, and obtaining the yield of 83.4%.
27.3 Synthesis of N- (3-chlorophenyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide: mixing 0.50 g (0.002mol) of 4-hydroxy-8-methylthio-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.008mol) of m-chloroaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, washing with absolute ethyl alcohol and washing with absolute ethyl ether to obtain a white solid, weighing 0.62 g, m.p.269-271 ℃ and having the yield of 95.0%.1HNMR(DMSO-d6，δ)：12.45(s，1H，OH)，12.19(S，1H，CONH)，8.78(S，1H)，8.24(dd，1H，J＝1.5，8.1Hz)，8.03(t，1H，J＝2.0Hz)，7.94(dd，1H，J＝1.5，J＝7.6Hz)，7.48-7.56(m，2H)，7.38(t，1H，J＝8.0Hz)，7.15(m，1H)，2.60(s，3H)。
Example 28: N-methyl-N-phenyl-4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as in 27.3 of example 27 using N-methylaniline as the amine. m.p.116-118 deg.c and yield 30.2%.1HNMR(Aceton-d6，δ)：10.62(br，1H)，8.02(m，2H)，7.77(m，1H)，7.20-7.33(m，5H)，7.10-7.12(m，1H)，3.38(s，3H)，2.47(s，3H).
Example 29: n- ((4-diethanolamino) -phenyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as in 27.3 of example 27 using 4-diethanolamino-aniline as amine. m.p.252 deg.C (dec), yield 10.8%. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.252(dec) deg.C, yield 10.8%.1HNMR(DMSO-d6，δ)：12.00(s，1H)，8.76(s，1H)，8.23(dd，1H，J＝1.4，8.1Hz)，7.92(d，1H，J＝7.3Hz)，7.49-7.53(m，3H)，6.68(d，2H，J＝8.9Hz)，4.74(t，2H，J＝5.3Hz)，3.51-3.54(m，4H)，3.40(t，4H，J＝6.2Hz)，2.51(s，3H)。
Example 30: n- ((2-dimethylamino) -ethyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as in 27.3 of example 27 using N, N-dimethylethylenediamine as the amine. m.p.176-178 deg.C, yield 41.4%.1HNMR(CCl3D，δ)：10.04(t，1H，J＝5.3Hz)，8.91(s，1H)，8.40(dd，1H，J＝1.4，8.1Hz)，7.88(d，1H，J＝1.4Hz)，7.42(t，1H，J＝8.1Hz)，3.61(m，2H)，2.60(t，2H，J＝6.5Hz)，2.59(s，3H)，2.34(s，6H)。
Example 31: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as in 27.3 of example 27 using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.154-156 ℃ and the yield is 65.2 percent.1HNMR(DMSO-d6，δ)：11.85(brs，1H)，10.14(s，1H)，8.68(s，1H)，8.18(d，1H，8.2Hz)，7.85(d，1H，J＝7.3Hz)，7.45(t，1H，J＝7.8Hz)，3.24(d，2H，J＝5.9Hz)，2.57(s，3H)，2.29(s，6H)，2.18(s，2H)，0.89(s，6H)。
Example 32: (4-hydroxy-8-methylthio-3-quinolinyl) -4-morpholinomethanone
This compound is prepared as in 27.3 of example 27 using morpholine as the amine. m.p.200-202 deg.c, yield 57.1%.1HNMR(DMSO-d6，δ)：11.51(s，1H)，8.06(d，1H，J＝8.1Hz)，7.98(s，1H)，7.83(d，1H，J＝7.6Hz)，7.38(t，1H，J＝7.9Hz)，3.60(brs，6H)，3.32(s，2H)，2.55(s，3H)。
Example 33: (4-hydroxy-8-methylthio-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
The compound was prepared as in 27.3 of example 27The amine used is 4-methyl-piperazine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.176-178 deg.C, yield 26.5%.1HNMR(DMSO-d6，δ)：11.45(brs，1H)，8.06(dd，1H，J＝1.4，8.3Hz)，7.94(s，1H)，7.82(dd，1H，J＝1.4，7.6Hz)，7.38(t，1H，J＝7.8Hz)，3,59(brs，2H)，3.25(brs，2H)，2.54(s，3H)，2.33(brs，4H)，2.19(s，3H)。
Example 34: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide
This compound is prepared as in 27.3 of example 27 using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.134-136 deg.C, yield 74.7%.1HNMR(DMSO-d6，δ)：11.50(brs，1H)，10.20(brs，1H)，8.68(s，1H)，8.14(d，1H，J＝7.7Hz)，7.76(m，1H)，7.41(t，1H，J＝7.7Hz)，3.52-3.59(m，1H)，3.16-3.23(m，1H)，3.04-3.13(m，1H)，2.80-2.90(m，1H)，2.72(s，3H)，2.55(brs，1H)，2.20-2.29(m，1H)，2.09-2.16(m，1H)，1.79-1.86(m，1H)，1.61-1.68(m，2H)，1.49-1.57(m，1H)，1.09(t，3H，J＝7.2Hz)。
Example 35: n- (3-chlorophenyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide
35.1 Synthesis of diethyl (3-methylthioanilino) methylenemalonate: 10.00 g (0.072mol) of 3-methylthioaniline and 15.60 g (0.072mol) of diethyl ethoxymethylene malonate were mixed, 100ml of toluene was added, the mixture was heated to about 100 ℃ to react for 5 hours, and the solvent was distilled off under reduced pressure to obtain 22.2 g of brown wax with a yield of 100%.
35.Synthesis of ethyl 24-hydroxy-7-methylsulfanyl-quinoline-3-carboxylate: dissolving 22.2 g (0.072mol) (3-methylthioanilino) diethyl methylene malonate in 200ml diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a brown solid, weighing 10.80 g, m.p.294 ℃ (dec), and obtaining the yield of 57.14%.
35.3 Synthesis of N- (3-chlorophenyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide: mixing 0.50 g (0.002mol) of 4-hydroxy-7-methylthio-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.008mol) of m-chloroaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, washing with absolute ethyl alcohol and washing with absolute ethyl ether to obtain a light brown solid, weighing 0.48 g, and obtaining the yield of 72.5%, wherein m.p. is more than 300 ℃.1HNMR(DMSO-d6，δ)：12.75(s，1H，OH)，12.60(S，1H，CONH)，8.81(S，1H)，8.18(d，1H，J＝8.8Hz)，8.02(d，1H，J＝2.0Hz)，7.48(m，2H)，7.38(m，2H)，7.14(m，1H)，2.60(s，3H)。
Example 36: N-methyl-N-phenyl-4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as in 35.3 of example 35 using N-methylaniline as the amine and ethanol as the solvent. m.p.238-240 deg.c, yield 24.4%.1HNMR(DMSO-d6，δ)：11.71(s，1H)，7.93(s，1H)，7.85(d，1H，J＝8.7Hz)，7.20-7.30(m，5H)，7.07-7.14(m，2H)，3.30(s，3H)，2.50(s，3H)。
Example 37: n- ((4-diethanolamino) -phenyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as in 35.3 of example 35 using 4-diethanolamino-aniline as amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.246-248 deg.C, yield 10.8%.1HNMR(DMSO-d6，δ)：12.69(brs，1H)，12.00(s，1H)，8.79(s，1H)，8.17(d，1H，J＝8.4Hz)，7.45-7.50(m，3H)，7.38(d，1H，J＝9.0Hz)，6.67(d，2H，J＝9.2Hz)，4.74(t，2H，J＝5.3Hz)，3.51-3.55(m，4H)，3.40(t，4H，J＝6.2Hz)，2.59(s，3H)。
Example 38: n- ((2-dimethylamino) -ethyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as in 35.3 of example 35 using N, N-dimethylethylenediamine as the amine. m.p.164-166 deg.C, yield 34.5%.1HNMR(CCl3D，δ)：12.21(brs，1H)，10.29(t，1H，J＝5.3Hz)，8.50(s，1H)，7.85(d，1H，J＝8.7Hz)，7.05-7.10(m，2H)，3..69(q，2H，J＝5.9Hz)，2.70(t，2H，J＝5.9Hz)，2.55(s，3H)，2.43(s，6H)。
Example 39: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as in 35.3 of example 35 using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.168-170 deg.c, yield 42.4%.1HNMR(DMSO-d6，δ)：12.45(brs，1H)，10.16(t，1H，J＝5.6Hz)，8.69(s，1H)，8.13(d，1H，8.7Hz)，7.42(s，1H)，7.32(d，1H，J＝8.6Hz)，3.22(d，2H，J＝5.9Hz)，2.58(s，3H)，2.26(s，6H)，2.14(s，2H)，0.88(s，6H)。
Example 40: (4-hydroxy-7-methylthio-3-quinolinyl) -4-morpholinomethanone
This compound was prepared as in 35.3 of example 35, using morpholine as the amine. m.p.232-234 deg.c and yield 48.4%.1HNMR(DMSO-d6，δ)：12.08(s，1H)，8.08(s，1H)，8.08(d，1H，8.8Hz)，7.33(d，1H，J＝1.5Hz)，7.24(dd，1H，J＝1.7，8.7Hz)，3.60(brs，6H)，3.34(s，2H)，2.56(s，3H)。
Example 41: (4-hydroxy-7-methylthio-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound was prepared as in 35.3 of example 35, using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.164-166 deg.C, yield 38.1%.1HNMR(DMSO-d6，δ)：12.02(brs，1H)，8.05(s，1H)，8.00(d，1H，J＝8.5Hz)，7.33(d，1H，J＝1.7Hz)，7.23(dd，1H，J＝8.6Hz)，3,58(brs，2H)，3.24(brs，2H)，2.56(s，3H)，2.32(brs，4H)，2.18(s，3H)。
Example 42: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide
This compound is prepared as in 35.3 of example 35 using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.78-80 deg.C, yield 61.0%.1HNMR(DMSO-d6，δ)：12.36(brs，1H)，10.06(brs，1H)，8.68(s，1H)，8.12(d，1H，J＝8.4Hz)，7.40(d，1H，J＝1.4Hz)，7.31(dd，1H，J＝1.6，8.4Hz)，3.52-3.58(m，1H)，3.14-3.23(m，1H)，3.06-3.12(m，1H)，2.81-2.87(m，1H)，2.57(s，3H)，2.55(brs，1H)，2.20-2.29(m，1H)，2.09-2.16(m，1H)，1.79-1.86(m，1H)，1.61-1.68(m，2H)，1.49-1.57(m，1H)，1.06(t，3H，J＝7.2Hz)。
Example 43: n- (3-chlorophenyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide
43.1 Synthesis of diethyl (4-methylthioanilino) methylenemalonate: 8.00 g (0.058mol) of 4-methylthioaniline and 12.44 g (0.058mol) of diethyl ethoxymethylene malonate were mixed, 100ml of toluene was added, the mixture was heated to about 100 ℃ and reacted for 5 hours, and the solvent was distilled off under reduced pressure to obtain 17.8 g of a brown wax with a yield of 100%.
43.Synthesis of ethyl 24-hydroxy-6-methylsulfanyl-quinoline-3-carboxylate: dissolving 17.8 g (0.058mol) of (4-methylthioanilino) diethyl methylene malonate in 200ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a brown solid, weighing 9.60 g, m.p.282 ℃ (dec), and obtaining the yield of 63.5%.
43.3 Synthesis of N- (3-chlorophenyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide: mixing 0.50 g (0.002mol) of 4-hydroxy-6-methylthio-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.008mol) of m-chloroaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 h, stopping heating, coolingCooling to room temperature, separating out solid, filtering and collecting solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain light brown solid with weight of 0.53 g, m.p.266-268 ℃ and yield of 80.2%.1HNMR(DMSO-d6，δ)：12.96(s，1H，OH)，12.62(S，1H，CONH)，8.83(S，1H)，8.06(s，1H)，8.03(t，1H，J＝2.0Hz)，7.69(m，2H)，7.49(dd，1H，J＝1.1，J＝8.3Hz)，7.38(t，1H，J＝8.0Hz)，7.15(m，1H)，2.59(s，3H)。
Example 44: N-methyl-N-phenyl-4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as described in 43.3 of example 43, using N-methylaniline as the amine and ethanol anhydrous recrystallization. m.p.228-230 ℃ and the yield is 64.9 percent.1HNMR(DMSO-d6，δ)：11.91(s，1H)，8.00(s，1H)，7.73(s，1H)，7.53(dd，1H，J＝2.0，8.7Hz)，7.43(d，1H，J＝8.7Hz)，7.21-7.29(m，4H)，7.11(m，1H)，3.31(s，3H)，2.50(s，3H)。
Example 45: n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as in 43.3 of example 43, using N, N-dimethylethylenediamine as the amine. m.p175-177 deg.C, yield 24.1%.1HNMR(DMSO-d6，δ)：12.55(brs1H)，10.06(s，1H)，8.69(s，1H)，8.00(d，1H，J＝1.7Hz)，7.65(m，2H)，3.42(q，2H，J＝5.9Hz)，2.57(s，3H)，2.41(t，2H，J＝6.1Hz)，2.20(s，6H)。
Example 46: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as in 43.3 of example 43 using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p176-178 ℃ with a yield of 45.6%.1HNMR(DMSO-d6，δ)：12.70(brs，1H)，10.16(t，1H，J＝5.6Hz)，8.71(s，1H)，8.02(s，1H)，7.65(m，2H)，3.23(d，2H，J＝5.9Hz)，2.57(s，3H)，2.26(s，6H)，2.14(s，2H)，0.89(s，6H)。
Example 47: (4-hydroxy-6-methylthio-3-quinolinyl) -4-morpholinomethanone
This compound was prepared as in 43.3 of example 43, using morpholine as the amine. m.p102-104 ℃ and the yield is 48.4 percent.1HNMR(DMSO-d6，δ)：12.26(s，1H)，8.11(s，1H)，7.91(d，1H，8.2Hz)，7.60(dd，1H，J＝2.2，8.7Hz)，7.55(d，1H，J＝8.9Hz)，3.60(brs，6H)，3.33(s，2H)，2.55(s，3H)。
Example 48: (4-hydroxy-6-methylthio-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound was prepared as in 43.3 of example 43, using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p204-206 ℃ and the yield is 39.8 percent.1HNMR(DMSO-d6，δ)：12.64(brs，1H)，8.87(s，1H)，8.45(d，1H，J＝8.5Hz)，8.27(s.1H)，7.78(d，1H，J＝8.7Hz)，3,60(brs，2H)，3.26(brs，2H)，2.50(s，3H)，2.29(brs，4H)，2.20(s，3H)。
Example 49: n- (3-pyridin-methyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide
This compound was prepared as in 43.3 of example 43, using 3-aminomethyl-pyridine as the amine. m.p234-236 deg.C, yield 72.8%.1HNMR(DMSO-d6，δ)：12.26(brs，1H)，10.48(t，1H，5.6Hz)，8.73(s，1H)，8.57(s，1H，)，8.47(d，1H，J＝4.8Hz)，8.00(s，1H)，7.65-7.75(m，3H)，7.37(m，1H，)，4.58(d，2H，5.9Hz)，2.56(s，3H)。
Example 50: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide
This compound is prepared as in 43.3 of example 43 using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p158 deg.C (dec), yield 56.4%.1HNMR(DMSO-d6，δ)：12.50(brs，1H)，10.07(brs，1H)，8.70(s，1H)，8.00(d，1H，J＝1.7Hz)，7.61-7.67(m，2H)，3.54-3.62(m，1H)，3.12-3.21(m，1H)，3.06-3.12(m，1H)，2.81-2.87(m，1H)，2.57(s，3H)，2.55(brs，1H)，2.20-2.29(m，1H)，2.09-2.16(m，1H)，1.79-1.86(m，1H)，1.61-1.68(m，2H)，1.49-1.57(m，1H)，1.06(t，3H，J＝7.2Hz)。
Example 51: n- (3-chlorophenyl) -4-hydroxy-6-nitro-quinoline-3-carboxamide
51.1 Synthesis of diethyl (4-nitroanilino) methylenemalonate: 8.00 g (0.058mol) of 4-nitroaniline and 12.52 g (0.058mol) of diethyl ethoxymethylene malonate are mixed, 100ml of toluene is added, the mixture is heated to about 100 ℃, the reaction is carried out for 5 hours, the solvent is evaporated under reduced pressure, and 13.9 g of yellow flaky crystals are obtained, wherein m.p.148-150 ℃ and the yield is 77.9%.1HNMR(CCl3D，δ)：11.20(d，1H，J＝12.8Hz)，8.50(d，1H，J＝13.1Hz)，8.28(d，2H，J＝9.1Hz)，7.22(d，2H，J＝9.1Hz)，4.33(q，2H，J＝7.1Hz)，4.27(q，2H，J＝7.1Hz)，1.39(t，3H，J＝7.0Hz)，1.35(t，3H，J＝7.1Hz).
51.Synthesis of 24-hydroxy-6-nitro-quinoline-3-carboxylic acid ethyl ester: dissolving 13.9 g (0.058mol) of (4-nitroanilino) diethyl methylene malonate in 200ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a yellow solid, weighing 9.60 g, m.p. > 300 ℃, and obtaining the yield of 81.4%.
Synthesis of 3N- (3-chlorophenyl) -4-hydroxy-6-nitro-quinoline-3-carboxamide: mixing 0.60 g (0.002mol) of 4-hydroxy-6-nitro-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.008mol) of m-chloroaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 h, stopping heating, cooling to room temperature, separating out solid, filtering and collecting solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain yellow solid, weighing 0.66 g, and obtaining yield of 83.9% when m.p. is more than 300 ℃.1HNMR(TFA-d1，δ)：9.62(s，1H)，9.41(d，1H，J＝6.4Hz)，8.77(dd，1H，J＝2.2，9.3Hz)，8.15(d，1H，J＝9.3Hz)，7.59(s，1H)，7.23-7.37(m，3H)。
Example 52: N-methyl-N-phenyl-4-hydroxy-6-nitro-quinoline-3-carboxamide
This compound was prepared as in 51.3 of example 51, using N-methylaniline as the amine and ethanol anhydrous recrystallization. m.p298-300 deg.C, yield 23.6%.1HNMR(DMSO-d6，δ)：12.48(s，1H)，8.69(s，1H)，8.38(d，1H，J＝9.2Hz)，8.21(s，1H)，7.66(d，1H，J＝8.9Hz)，7.22-7.29(m，4H)，7.12(m，1H)，3.33(s，3H)。
Example 53: n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-nitro-quinoline-3-carboxamide
This compound was prepared as in 51.3 of example 51, using N, N-dimethylethylenediamine as amine. m.p262-264 ℃ and yield 62.1%.1HNMR(DMSO-d6，δ)：12.40(brs，1H)，10.02(t，1H，J＝5.3Hz)，8.99(d，1H，J2.5Hz)，8.86(s，1H)，8.44(dd，1H，J＝2.5，9.1Hz)，7.84(d，1H，J＝9.2Hz)，3.48(q，2H，J＝5.9Hz)，2.60(t，2H，J＝5.9Hz)，2.34(s，6H)。
Example 54: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-nitro-quinoline-3-carboxamide
This compound was prepared as in 51.3 of example 51, using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.246-248 ℃ and yield 30.3%.1HNMR(DMSO-d6，δ)：12.60(brs，1H)，10.05(t，1H，J＝5.5Hz)，8.99(d，1H，2.5Hz)，8.87(s，1H)，8.47(dd，1H，J＝2.5，9.0Hz)，7.87(d，1H，J＝9.0Hz)，3.27(d，2H，J＝5.9Hz)，2.34(s，6H)，2.25(s，2H)，0.91(s，6H)。
Example 55: (4-hydroxy-6-nitro-3-quinoline) -4-morpholinyl methanone
According to example 51 in 51.3, the amine used is morpholine. m.p > 300 ℃ and yield 67.5%.1HNMR(DMSO-d6，δ)：12.73(s，1H)，8.88(d，1H，J＝2.5Hz)，8.47(dd，1H，J＝2.8，9.2Hz)，8.29(s，1H)，7.79(d，1H，9.2Hz)，3.62(brs，6H)，3.29(s，2H)。
Example 56: (4-hydroxy-6-nitro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound is prepared as in 51.3 of example 51, using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.240 deg.C (dec), yield 18.2%.1HNMR(DMSO-d6，δ)：12.23(brs，1H)，8.10(s，1H)，7.90(d，1H，J＝2.0Hz)，7.61(dd，1H，J＝2.2，8.7Hz)，7.55(d，1H，J＝8.7Hz)，3,60(brs，2H)，3.26(brs，2H)，2.28(brs，4H)，2.19(s，3H)。
Example 57: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-nitro-quinoline-3-carboxamide
This compound is prepared as in 51.3 of example 51 using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.115 deg.C (dec), yield 22.9%.1HNMR(DMSO-d6，δ)：11.95(brs，1H)，10.18(brs，1H)，8.99(s，1H)，8.87(s，1H)，8.42(dd，1H，J＝2.6，9.1Hz)，7.83(d，1H，J＝9.2Hz)，3.54-3.62(m，1H)，3.32-3.42(m，1H)，3.20-3.30(m，1H)，2.97-3.04(m，1H)，2.91(brs，1H)，2.42-2.48(m，1H)，2.20-2.29(m，1H)，1.88-1.95(m，1H)，1.70-1.78(m，1H)，1.59-1.66(m，2H)，1.06(t，3H，J＝7.3Hz)。
Example 58: n- (3-chlorophenyl) -4-hydroxy-6-methyl-quinoline-3-carboxamide
58.1 Synthesis of diethyl (4-methylanilino) methylenemalonate: 8.00 g (0.075mol) of 4-methylaniline and 16.15 g (0.075mol) of diethyl ethoxymethylene malonate were mixed, 100ml of toluene was added, the mixture was heated to about 100 ℃ to react for 5 hours, and the solvent was distilled off under reduced pressure to obtain 20.7 g of a pale yellow solid with a yield of 100%.
58.Synthesis of 24-hydroxy-6-methyl-quinoline-3-carboxylic acid ethyl ester: dissolving 20.7 g (0.075mol) of (4-methylanilino) diethyl methylene malonate in 200ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain an orange solid, weighing 13.8 g, washing with m.p. > 300 ℃, and obtaining the yield of 80.0%.
Synthesis of 3N- (3-chlorophenyl) -4-hydroxy-6-methyl-quinoline-3-carboxamide: mixing 0.60 g (0.003mol) of 4-hydroxy-6-methyl-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.008mol) of m-chloroaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, washing with absolute ethyl alcohol and washing with absolute ethyl ether to obtain a light brown solid, weighing 0.70 g, and obtaining the yield of 87.5 percent, wherein m.p. is more than 300 ℃.1HNMR(DMSO-d6，δ)：12.88(s，1H，OH)，12.68(S，1H，CONH)，8.82(S，1H)，8.11(s，1H)，8.03(t，1H，J＝2.0Hz)，7.65(m，2H)，7.49(m，1H)，7.38(t，1H，J＝8.0Hz)，7.15(m，1H)，2.47(s，3H)。
Example 59: N-methyl-N-phenyl-4-hydroxy-6-methyl-quinoline-3-carboxamide
This compound was prepared as described in 58.3 of example 58, using N-methylaniline as the amine and ethanol as a solvent. m.p296-298 ℃ and yield 38.0%.1HNMR(DMSO-d6，δ)：11.87(s，1H)，7.97(s，1H)，7.75(s，1H)，7.35-7.44(m，2H)，7.19-7.27(m，4H)，7.11(m，1H)，3.31(s，3H)，2.35(s，3H)。
Example 60: n-phenyl-4-hydroxy-6-methyl-quinoline-3-carboxamide
This compound was prepared as in 58.3 of example 58, using aniline as the amine. m.p > 300, yield 88.3%.1HNMR(DMSO-d6，δ)：12.90(S，1H)，12.55(S，1H)，8.84(S，1H)，8.12(S，1H)，7.73(d，2H，J＝7.6Hz)，7.65(s，2H)，7.37(t，2H，J＝7.9Hz)，7.09(t，1H，J＝7.3Hz)，2.48(s，3H)。
Example 61: n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-methyl-quinoline-3-carboxamide
This compound was prepared as in 58.3 of example 58, using N, N-dimethylethylenediamine as the amine. m.p196-198 deg.C, yield 78.0%.1HNMR(DMSO-d6，δ)：12.54(brs，1H)，10.09(t，1H，J＝5.3Hz)，8.68(s，1H)，8.05(s，1H)，7.59(s，2H)，3.41(q，2H，J＝5.9Hz)，2.45(s，3H)，2.39(t，2H，J＝5.9Hz)，2.19(s，6H)。
Example 62: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-methyl-quinoline-3-carboxamide
This compound was prepared as in 58.3 of example 58 using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p. 197-199 deg.C, yield 73.5%.1HNMR(DMSO-d6，δ)：12.60(brs，1H)，10.23(t，1H，J＝5.9Hz)，8.70(s，1H)，8.07(s，1H)，7.65(m，2H)，3.23(d，2H，J＝5.9Hz)，2.45(s，3H)，2.26(s，6H)，2.14(s，2H)，0.89(s，6H)。
Example 63: (4-hydroxy-6-methyl-3-quinoline) -4-morpholinyl methanone
The compound was prepared as in 58.3 of example 58, using morpholine as the amine. m.p. 272-274 ℃ and the yield is 25.5%.1HNMR(DMSO-d6，δ)：12.16(s，1H)，8.09(s，1H)，7.93(s，1H)，7.48-7.53(m，2H)，3.60(brs，6H)，3.33(s，2H)，2.41(s，3H)。
Example 64: (4-hydroxy-6-methyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound was prepared as in 58.3 of example 58, using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.260 ℃ and 262 ℃ in a yield of 48.6 percent.1HNMR(DMSO-d6，δ)：12.13(brs，1H)，8.06(s，1H)，7.92(s，1H)，7.48-7.53(m，2H)，3,60(brs，2H)，3.25(brs，2H)，2.41(s，3H)，2.29(brs，4H)，2.18(s，3H)。
Example 65: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-methyl-quinoline-3-carboxamide
This compound is prepared as described in 58.3 of example 58, using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.158 ℃ and 160 ℃ in a yield of 72.4%.1HNMR(DMSO-d6，δ)：12.50(brs，1H)，10.11(brs，1H)，8.68(s，1H)，8.06(s，1H)，7.58(m，2H)，3.52-3.59(m，1H)，3.14-3.22(m，1H)，3.04-3.13(m，1H)，2.80-2.90(m，1H)，2.52-2.58(m，1H)，2.45(s，3H)，2.20-2.29(m，1H)，2.08-2.16(m，1H)，1.79-1.86(m，1H)，1.61-1.68(m，2H)，1.49-1.57(m，1H)，1.06(t，3H，J＝7.3Hz)。
Example 66: n- (3-chlorophenyl) -4-hydroxy-6-chloro-quinoline-3-carboxamide
66.1 Synthesis of diethyl (4-chloroanilino) methylenemalonate: 7.00 g (0.055mol) of 4-chloroaniline and 12.00 g (0.055mol) of diethyl ethoxymethylidene malonate were mixed, 100ml of toluene was added, the mixture was heated to about 100 ℃ to react for 5 hours, and the solvent was distilled off under reduced pressure to obtain 16.33 g of white crystals with a yield of 100%.
66.Synthesis of 24-hydroxy-6-chloro-quinoline-3-carboxylic acid ethyl ester: dissolving 20.7 g (0.075mol) of (4-chloroanilino) diethyl methylene malonate in 200ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain white crystals, weighing 12.5 g, m.p. > 300 ℃, and obtaining the yield of 80.0%.
66.3 Synthesis of N- (3-chlorophenyl) -4-hydroxy-6-chloro-quinoline-3-carboxamide: mixing 0.60 g (0.002mol) of 4-hydroxy-6-chloro-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.008mol) of m-chloroaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 h, stopping heating,cooling to room temperature, separating out solid, filtering and collecting solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain white solid with weight of 0.75 g, m.p.82-84 ℃, m.p. greater than 300 ℃ and yield of 92.6%.1HNMR(DMSO-d6，δ)：13.01(s，1H，OH)，12.43(S，1H，CONH)，8.91(S，1H)，8.25(s，1H)，8.03(s，1H)，7.87(d，1H，J＝9.0Hz)，7.81(d，1H，J＝9.0Hz)，7.51(d，1H，J＝8.0Hz)，7.39(t，1H，J＝8.0Hz)，7.16(d，1H，J＝8.1Hz)。
Example 67: N-methyl-N-phenyl-4-hydroxy-6-chloro-quinoline-3-carboxamide
This compound was prepared as in 66.3 of example 66 using N-methylaniline as the amine and ethanol recrystallization. P.288 deg.C (dec), yield 51.2%.1HNMR(DMSO-d6，δ)：12.13(s，1H)，8.09(s，1H)，7.88(s，1H)，7.65(dd，1H，J＝2.5，8.7Hz)，7.52(d，1H，J＝8.9Hz)，7.20-7.28(m，4H)，7.11(m，1H)，3.33(s，3H)，。
Example 68: n-phenyl-4-hydroxy-6-chloro-quinoline-3-carboxamide
This compound was prepared as in 66.3 of example 66 using aniline as the amine. m.p. > 300 ℃ yield 91.5%.1HNMR(DMSO-d6，δ)：13.05(s，1H)，12.28(S，1H)，8.91(S，1H)，8.26(d，1H，J＝2.5Hz)，7.85(dd，1H，J＝2.5，8.8Hz)，7.79(d，1H，J＝8.7Hz)，7.72(m，2H)，7.37(m，2H)，7.10(m，1H)。
Example 69: n- (4-Carboxyphenyl) -4-hydroxy-6-chloro-quinoline-3-carboxamide
This compound was prepared as in 66.3 of example 66 using p-aminobenzoic acid as the amine. m.p. > 300 ℃ yield 93.0%.1HNMR(DMSO-d6，δ)：13.05(S，1H)，12.27(S，1H)，8.91(S，1H)，8.26(d，1H，J＝2.5Hz)，7.85(dd，2H，J＝2.5，9.0Hz)，7.79(d，1H，J＝8.8Hz)，7.71-7.73(m，2H)，7.37(m，1H)，7.09(t，1H，J＝6.5Hz)。
Example 70: n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-chloro-quinoline-3-carboxamide
This compound is prepared as in 66.3 of example 66 using N, N-dimethylethylenediamine as amine. m.p.214-216 deg.C, yield 75.9%.1HNMR(DMSO-d6，δ)：12.59(brs，1H)，9.95(brs，1H)，8.76(s，1H)，8.18(d，1H，J＝2.2Hz)，7.79(dd，1H，J＝2.2，8.7Hz)，7.73(d，1H，J＝8.8Hz)，3.42(q，2H，J＝5.9Hz)，2.43(t，2H，J＝6.1Hz)，2.21(s，6H)。
Example 71: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-chloro-quinoline-3-carboxamide
This compound is prepared as in 66.3 of example 66 using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.214-216 deg.C, yield 64.5%.1HNMR(DMSO-d6，δ)：12.70(brs，1H)，10.07(t，1H，J＝5.9Hz)，8.78(s，1H)，8.20(d，1H，J＝2.2Hz)，7.80(dd，1H，J＝2.3，9.0Hz)，7.74(d，1H，J＝9.0Hz)，3.23(d，2H，J＝5.9Hz)，2.27(s，6H)，2.15(s，2H)，0.89(s，6H)。
Example 72: this compound is prepared as described in 66.3 of example 66 using (4-hydroxy-6-chloro-3-quinolino) -4-morpholinomethanone and morpholine as the amine. m.p.266 deg.C (dec), yield 46.5%.1HNMR(DMSO-d6，δ)：12.40(d，1H，J＝6.2Hz)，8.19(d，1H，J＝6.4Hz)，8.06(d，1H，J＝2.5Hz)，7.74(dd，1H，J＝2.5，9.0Hz)，7.65(d，1H，J＝9.0Hz)，3.62(brs，6H)，3.29(s，2H)。
Example 73: (4-hydroxy-6-chloro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound is prepared as in 66.3 of example 66 using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.222-224 deg.C, yield 47.8%.1HNMR(DMSO-d6，δ)：12.36(brs，1H)，8.17(s，1H)，8.06(d，1H，J＝2.5Hz)，7.73(dd，1H，J＝2.5，9.0Hz)，7.64(d，1H，J＝8.7Hz)，3,60(brs，2H)，3.25(brs，2H)，2.28(brs，4H)，2.19(s，3H)。
Example 74: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-chloro-quinoline-3-carboxamide
This compound is prepared as in 66.3 of example 66 using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.130-132 deg.c, yield 28.8%.1HNMR(DMSO-d6，δ)：12.36(brs，1H)，10.02(brs，1H)，8.77(s，1H)，8.18(s，1H)，7.75(m，2H)，3.50-3.59(m，1H)，3.15-3.22(m，1H)，3.04-3.13(m，1H)，2.80-2.90(m，1H)，2.58(brs，1H)，2.20-2.29(m，1H)，2.10-2.16(m，1H)，1.79-1.86(m，1H)，1.61-1.68(m，2H)，1.49-1.57(m，1H)，1.07(t，3H，J＝7.3Hz)。
Example 75: n- (3-chlorophenyl) -4-hydroxy-6-bromo-quinoline-3-carboxamide
75.1 Synthesis of diethyl (4-bromoanilino) methylenemalonate: 10.00 g (0.058mol) of 4-bromoaniline and 12.56 g (0.058mol) of diethyl ethoxymethylene malonate are mixed, 100ml of toluene is added, the mixture is heated to about 100 ℃, the reaction is carried out for 5 hours, and the solvent is removed by evaporation under reduced pressure, so as to obtain 19.88 g of white crystals, m.p.102-104 ℃, and the yield is 100%.
Synthesis of ethyl 24-hydroxy-6-bromo-quinoline-3-carboxylate: dissolving 19.88 g (0.075mol) of (4-bromoanilino) diethyl methylene malonate in 200ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain white crystals, weighing 16.5 g, washing with m.p. > 300 ℃, and obtaining the yield of 95.9%.
Synthesis of N- (3-chlorophenyl) -4-hydroxy-6-bromo-quinoline-3-carboxamide: mixing 0.81 g (0.003mol) of 4-hydroxy-6-bromo-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.008mol) of m-chloroaniline, adding 10ml of diphenyl ether, heating to 220 ℃ -230 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, and separatingAnd (3) discharging a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a white solid, weighing 0.95 g, wherein m.p. is more than 300 ℃, and the yield is 95.0%.1HNMR(DMSO-d6，δ)：13.08(s，1H，OH)，12.41(S，1H，CONH)，8.91(S，1H)，8.40(d，1H，J＝2.2Hz)，8.02(m，2H)，7.97(dd，1H，J＝2.3，8.7Hz)，7.73(d，1H，J＝9.0Hz)，7.50(d，1H，J＝9.2Hz)，7.38(t，1H，J＝8.0Hz)，7.15(m，1H)。
Example 76: N-methyl-N-phenyl-4-hydroxy-6-bromo-quinoline-3-carboxamide
This compound was prepared as in 75.3 of example 75, using N-methylaniline as the amine and ethanol as a solvent. m.p. > 300 ℃ yield 41.5%.1HNMR(DMSO-d6，δ)：12.12(s，1H)，8.10(s，1H)，8.03(s，1H)，7.76(dd，1H，J＝2.0，8.7Hz)，7.45(d，1H，J＝8.6Hz)，7.20-7.28(m，4H)，7.11(m，1H)，3.34(s，3H)，。
Example 77: n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-bromo-quinoline-3-carboxamide
This compound was prepared as in 75.3 of example 75, using N, N-dimethylethylenediamine as the amine. m.p.202-204 deg.C, yield 43.0%.1HNMR(DMSO-d6，δ)：12.67(brs，1H)，9.95(t，1H，J＝5.5Hz)，8.76(s，1H)，8.32(d，1H，J＝2.2Hz)，7.89(dd，1H，J＝2.2，8.9Hz)，7.66(d，1H，J＝8.4Hz)，3.42(q，2H，J＝6.2Hz)，2.43(t，2H，J＝6.2Hz)，2.21(s，6H)。
Example 78: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-bromo-quinoline-3-carboxamide
This compound was prepared as in 75.3 of example 75 using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.200-202 deg.c, yield 82.8%.1HNMR(DMSO-d6，δ)：12.59(brs，1H)，10.07(t，1H，J＝5.6Hz)，8.78(s，1H)，8.35(d，1H，J＝2.2Hz)，7.90(dd，1H，J＝2.2，9.0Hz)，7.67(d，1H，J＝9.0Hz)，3.23(d，2H，J＝5.9Hz)，2.27(s，6H)，2.15(s，2H)，0.89(s，6H)。
Example 79: (4-hydroxy-6-bromo-3-quinoline) -4-morpholinomethanone
This compound is prepared as in 75.3 of example 75 using morpholine as the amine. m.p.264-266 ℃ with a yield of 50.9%.1HNMR(DMSO-d6，δ)：12.39(d，1H，J＝4.2Hz)，8.21(d，1H，J＝2.0Hz)，8.20(d，1H，J＝5.6Hz)，7.74(dd，1H，J＝2.5，9.0Hz)，7.57(d，1H，J＝9.0Hz)，43.60(brs，6H)，3.26(s，2H)。
Example 80: (4-hydroxy-6-bromo-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound was prepared as in 75.3 of example 75, using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.226-228 deg.C, yield 30.5%.1HNMR(DMSO-d6，δ)：12.36(brs，1H)，8.21(d，1H，J＝2.2Hz)，8.17(s，1H)，7.84(dd，1H，J＝2.2，8.7Hz)，7.57(d，1H，J＝8.7Hz)，3,59(brs，2H)，3.24(brs，2H)，2.27(brs，4H)，2.18(s，3H)。
Example 81: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-bromo-quinoline-3-carboxamide
This compound is prepared as in 75.3 of example 75 using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.154-156 ℃ and yield 78.1%.1HNMR(DMSO-d6，δ)：12.56(brs，1H)，10.00(brs，1H)，8.77(s，1H)，8.33(d，1H，J＝2.0Hz)，7.87(dd，1H，J＝2.0，9.0Hz)，7.65(d，1H，J＝9.0Hz)，3.50-3.59(m，1H)，3.15-3.22(m，1H)，3.04-3.13(m，1H)，2.80-2.90(m，1H)，2.58(brs，1H)，2.20-2.29(m，1H)，2.10-2.16(m，1H)，1.79-1.86(m，1H)，1.61-1.68(m，2H)，1.49-1.57(m，1H)，1.07(t，3H，J＝7.3Hz)。
Example 82: n- (3-chlorophenyl) -6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide
82.1 Synthesis of diethyl (2, 4-dimethylanilino) methylenemalonate: 9.22 g (0.076mol) of 2, 4-dimethylaniline and 16.43 g (0.076mol) of diethyl ethoxymethylidene malonate were mixed, 100ml of toluene was added, the mixture was heated to about 100 ℃ to react for 5 hours, and the solvent was distilled off under reduced pressure to obtain 22.17 g of white crystals m.p.83-85 ℃ with a yield of 100%.
82.24 Synthesis of hydroxy-6, 8-dimethyl-quinoline-3-carboxylic acid Ethyl ester: dissolving 22.17 g (0.075mol) of (2, 4-dimethyl-anilino) diethyl methylene malonate in 200ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a white crystal, weighing 17.2 g, m.p.288-290 ℃, and obtaining the yield of 92.1%.
82.3 Synthesis of N- (3-chlorophenyl) -4-hydroxy-6, 8-dimethyl-quinoline-3-carboxamide: mixing 0.60 g (0.003mol) of 4-hydroxy-6, 8-dimethyl-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.008mol) of m-chloroaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 h, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, washing with absolute ethyl alcohol and washing with absolute ethyl ether to obtain a white solid, weighing 0.75 g, and obtaining the yield of 93.8%, wherein m.p. is more than 300 ℃.1HNMR(DMSO-d6，δ)：12.65(s，1H，OH)，12.18(S，1H，CONH)，8.67(S，1H)，8.03(s，1H)，7.98(s，1H)，7.48(m，2H)，7.38(t，1H，J＝8.0Hz)，7.14(m，1H)，2.54(s，3H)，2.43(s，3H)。
Example 83: N-methyl-N-phenyl-6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as described in 82.3 of example 82, using N-methylaniline as the amine and ethanol anhydrous recrystallization. m.p.294-296 deg.C, yield 33.9%.1HNMR(DMSO-d6，δ)：11.20(s，1H)，7.85(s，1H)，7.63(s，1H)，7.19-7.29(m，5H)，7.08-7.11(m，1H)，3.34(s，3H)，2.39(s，3H)，2.31(s，3H)。
Example 84: H1108N-Ethyl-N-phenyl-6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as described in 82.3 of example 82, using N-ethylaniline as the amine and ethanol anhydrous recrystallization. m.p.216-218 deg.c, yield 53.8%.1HNMR(DMSO-d6，δ)：11.07(s，1H)，7.79(d，1H，J＝6.2Hz)，7.62(s，1H)，7.18-7.29(m，5H)，7.08-7.11(m，1H)，3.79(q，2H，J＝7.0Hz)，2.38(s，3H)，2.31(s，3H)，1.07(t，3H，J＝7.0Hz)。
Example 85: n- ((2-dimethylamino) -ethyl) -6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 82.3 of example 82, using N, N-dimethylethylenediamine as the amine. m.p.210-212 deg.C, yield 46.1%.1HNMR(DMSO-d6，δ)：11.87(brs，1H)，10.08(t，1H，J＝5.5Hz)，8.56(s，1H)，7.91(s，1H)，7.44(s，1H)，3.41(q，2H，J＝6.1Hz)，2.50(s，3H)，2.41(m，5H)，2.19(s，6H)。
Example 86: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 82.3 of example 82, using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.200-202 deg.c, yield 82.1%.1HNMR(DMSO-d6，δ)：11.86(brs，1H)，10.29(t，1H，J＝5.6Hz)，8.57(s，1H)，7.94(s，1H)，7.45(m，2H)，3.23(d，2H，J＝5.9Hz)，2.40(s，3H)，2.26(s，6H)，2.14(s，2H)，0.89(s，6H)。
Example 87: (4-hydroxy-6, 8-dimethyl-3-quinoline) -4-morpholinylmethanone
This compound was prepared as in 82.3 of example 82, using morpholine as the amine. m.p.260-262 deg.c and yield 71.9%.1HNMR(DMSO-d6，δ)：11.06(s，1H)，7.93(s，1H)，7.80(s，1H)，7.38(s，1H)，3.60(brs，6H)，3.33(s，2H)，2.47(s，3H)，2.37(s，3H)。
Example 88: (4-hydroxy-6, 8-dimethyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound was prepared as in 82.3 of example 82, using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.252 deg.C (dec), yield 63.9%.1HNMR(DMSO-d6，δ)：11.46(brs，1H)，7.90(s，1H)，7.80(s，1H)，7.38(s，1H)，3,59(brs，2H)，3.24(brs，2H)，2.46(s，3H)，2.37(s，3H)，2.27(brs，4H)，2.18(s，3H)。
Example 89: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6, 8-dimethyl-quinoline-3-carboxamide
This compound was prepared as in 82.3 of example 82, using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.202-204 deg.c, yield 71.6%.1HNMR(DMSO-d6，δ)：11.87(brs，1H)，10.10(brs，1H)，8.57(s，1H)，7.92(s，1H)，7.45(s，1H)，3.50-3.59(m，1H)，3.13-3.20(m，1H)，3.04-3.13(m，1H)，2.80-2.90(m，1H)，2.58(brs，1H)，2.52(s，3H)，2.41(s，3H)，2.20-2.29(m，1H)，2.09-2.16(m，1H)，1.79-1.86(m，1H)，1.61-1.68(m，2H)，1.49-1.57(m，1H)，1.07(t，3H，J＝7.3Hz)。
Example 90: N-methyl-N-phenyl-5, 7-dimethyl-4-hydroxy-quinoline-3-carboxamide
90.1 Synthesis of diethyl (3, 5-dimethylanilino) methylenemalonate: 9.22 g (0.076mol) of 3, 5-dimethylaniline and 16.43 g (0.076mol) of diethyl ethoxymethylidene malonate were mixed, 100ml of toluene was added, the mixture was heated to about 100 ℃ to react for 5 hours, and the solvent was distilled off under reduced pressure to obtain 22.17 g of white crystals m.p.82-84 ℃ with a yield of 100%.
Synthesis of 24-hydroxy-5, 7-dimethyl-quinoline-3-carboxylic acid ethyl ester: 22.17 g (0.075mol) (3,5-dimethyl-anilino) methylene diethyl malonate is dissolved in 200ml diphenyl ether, heated to about 250 ℃, reacted for 0.5 hour, stopped heating, cooled to room temperature, precipitated solid, filtered and collected, washed by petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain white crystals, the weight of the white crystals is 13.5 g, the m.p.298 ℃ (dec) and the yield is 72.3%.1HNMR(DMSO-d6，δ)：11.95(S，1H)，8.34(s，1H)，7.17(s，1H)，6.93(s，1H)，4.19(q，2H，J＝7.0Hz)，2.75(s，3H)，2.35(s，3H)，1.27(t，3H，J＝7.0Hz).
Synthesis of 3N-methyl-N-phenyl-5, 7-dimethyl-4-hydroxy-quinoline-3-carboxamide: 0.56 g (0.002mol) of 4-hydroxy-5, 7-dimethyl-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.009mol) of N-methylaniline are mixed, 10ml of diphenyl ether is added, the mixture is heated to 220 ℃ to 230 ℃ to react for 0.5 hour, the heating is stopped, the mixture is cooled to room temperature, solid is separated out, filtered and collected, washed by petroleum ether, absolute ethyl alcohol and absolute ethyl ether, white solid is obtained, the weight is 0.36 g, the m.p.126-128 ℃ and the yield is 51.4 percent.1HNMR(DMSO-d6，δ)：11.55(s，1H)，7.83(d，1H，J＝5.9Hz)，7.19-7.24(m，4H)，7.10(t，1H，J＝7.0Hz)，7.08(s，1H)，6.77(s，1H)，3.29(s，3H)2.52(s，3H)，2.28(s，3H)。
Example 91: n- ((2-dimethylamino) -ethyl) -5, 7-dimethyl-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 90.3 of example 90 using N, N-dimethylethylenediamine as the amine. m.p.214-216 deg.C, yield 51.2%.1HNMR(DMSO-d6，δ)：12.28(brs，1H)，10.06(t，1H，J＝5.4Hz)，8.56(s，1H)，7.23(s，1H)，6.98(s，1H)，3.41(q，2H，J＝6.2Hz)，2.81(s，3H)，2.38(m，5H)，2.18(s，6H)。
Example 92: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -5, 7-dimethyl-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 90.3 of example 90 using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography separation (200-300 mesh silica gel, eluent two)Methyl chloride to methanol 25: 1). m.p.202-204 deg.c, yield 74.6%.1HNMR(DMSO-d6，δ)：12.28(brs，1H)，10.27(t，1H，J＝5.9Hz)，8.57(s，1H)，7.24(s，1H)，6.99(s，1H)，3.21(d，2H，J＝5.9Hz)，2.82(s，3H)，2.37(s，3H)，2.25(s，6H)，2.13(s，2H)，0.88(s，6H)。
Example 93: (4-hydroxy-5, 7-dimethyl-3-quinoline) -4-morpholinylmethanone
The compound was prepared as in 90.3 of example 90 using morpholine as the amine. m.p.244-246 deg.C, yield 85.6%.1HNMR(DMSO-d6，δ)：11.82(d，1H，J＝4.2Hz)，7.92(d，1H，J＝5.6Hz)，7.14(s，1H)，6.89(s，1H)，3.59(brs，6H)，3.33(s，2H)，2.75(s，3H)，2.34(s，3H)。
Example 94: (4-hydroxy-5, 7-dimethyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound was prepared as in 90.3 of example 90 using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.166-168 deg.c, yield 41.0%.1HNMR(DMSO-d6，δ)：11.79(brs，1H)，7.89(s，1H)，7.14(s，1H)，6.88(s，1H)，3,57(brs，2H)，3.25(brs，2H)，2.76(s，3H)，2.34(s，3H)，2.27(brs，4H)，2.19(s，3H)。
Example 95: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-5, 7-dimethyl-quinoline-3-carboxamide
This compound is prepared as in 90.3 of example 90 using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.196-198 deg.c, yield 68.7%.1HNMR(DMSO-d6，δ)：12.49(brs，1H)，10.12(brs，1H)，8.56(s，1H)，7.23(s，1H)，6.99(s，1H)，3.47-3.55(m，1H)，3.12-3.20(m，1H)，3.04-3.09(m，1H)，2.80-2.90(m，1H)，2.79(s，3H)，2.52(brs，1H)，2.37(s，3H)，2.20-2.29(m，1H)，2.09-2.16(m，1H)，1.79-1.86(m，1H)，1.61-1.68(m，2H)，1.49-1.57(m，1H)，1.06(t，3H，J＝7.3Hz)。
Example 96: N-methyl-N-phenyl-7-methoxy-4-hydroxy-quinoline-3-carboxamide
96.1 Synthesis of diethyl (3-methoxyanilino) methylenemalonate: 9.00 g (0.073mol) of 3-methoxyaniline and 15.80 g (0.073mol) of diethyl ethoxymethylene malonate were mixed, 100ml of toluene was added, the mixture was heated to about 100 ℃ to react for 5 hours, and the solvent was distilled off under reduced pressure to obtain 21.44 g of white crystals m.p.38-40 ℃ with a yield of 100%.
96.24 Synthesis of hydroxy-7-methoxy-quinoline-3-carboxylic acid Ethyl ester: dissolving 22.17 g (0.075mol) of (3-methoxy-anilino) diethyl methylene malonate in 200ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a white crystal, weighing 11.0 g, m.p.290-292 ℃, and obtaining the yield of 60.8%.1HNMR(DMSO-d6，δ)：12.10(S，1H)，8.48(d，1H，J＝5.4Hz)，8.05(d，1H，J＝9.8Hz)，6.91-7.01(m，2H)，4.20(q，2H，J＝7.0Hz)，3.86(s，3H)，1.27(t，3H，J＝7.0Hz).
Synthesis of N-methyl-N-phenyl-7-methoxy-4-hydroxy-quinoline-3-carboxamide 96.3: mixing 0.55 g (0.002mol) of 4-hydroxy-7-methoxy-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.009mol) of N-methylaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 h, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a white solid, weighing 0.46 g, m.p.262-264 ℃, and the yield is 67.1%.1HNMR(DMSO-d6，δ)：11.70(s，1H)，7.91(brs，1H)，7.87(d，1H，J＝8.8Hz)，7.20-7.27(m，4H)，7.10(t，1H，J＝7.7Hz)，6.84-6.91(m，2H)，3.85(s，3H)，3.34(s，3H)。
Example 97: n- ((2-dimethylamino) -ethyl) -7-methoxy-4-hydroxy-quinoline-3-carboxamide
Prepared by the method of 96.3 in example 96The amine used in the compound is N, N-dimethylethylenediamine. m.p.160-162 deg.C, yield 35.9%.1HNMR(DMSO-d6，δ)：12.38(brs，1H)，10.07(t，1H，J＝5.3Hz)，8.65(s，1H)，8.14(m，1H)，7.06(m，2H)，3.88(s，3H)，3.41(q，2H，J＝6.2Hz)，2.39(t，2H，J＝6.3)，2.18(s，6H)。
Example 98: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -7-methoxy-4-hydroxy-quinoline-3-carboxamide
This compound is prepared as in 96.3 of example 96 using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.158-160 deg.c and yield 62.7%.1HNMR(DMSO-d6，δ)：12.46(brs，1H)，10.21(t，1H，J＝5.9Hz)，8.66(s，1H)，8.16(d，1H，J＝9.2Hz)，7.05(m，2H)，3.88(s，3H)，3.23(d，2H，J＝5.9Hz)，2.25(s，6H)，2.13(s，2H)，0.88(s，6H)。
Example 99: n- (4-hydroxy-phenyl) -7-methoxy-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 96.3 of example 96, using 4-hydroxy-aniline as the amine. m.p. > 300 ℃ yield 71.8%.1HNMR(DMSO-d6，δ)：12.69(brs，1H)，12.26(s，1H)，9.25(s，1H)，8.77(s，1H)，8.20(d，1H，J＝9.5Hz)，7.51(d，2H，J＝9.0Hz)，7.11(m，2H)，6.74(d，2H，J＝9.0Hz)，3.90(s，3H)。
Example 100: (4-hydroxy-7-methoxy-3-quinoline) -4-morpholinyl methanone
The compound was prepared as in 96.3 of example 96, using morpholine as the amine. m.p.210-212 deg.C, yield 41.2%.1HNMR(DMSO-d6，δ)：12.00(s，1H)，8.03(m，2H)，6.97(m，2H)，3.85(s，3H)，3.59(brs，6H)，3.33(s，2H)。
Example 101: (4-hydroxy-7-methoxy-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound is prepared as in 96.3 of example 96 using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.160-162 deg.C, yield 44.3%.1HNMR(DMSO-d6，δ)：11.96(brs，1H)，8.02(m，2H)，6.97(m，2H)，3.86(s，3H)，3,58(brs，2H)，3.24(brs，2H)，2.27(brs，4H)，2.18(s，3H)。
Example 102: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-methoxy-quinoline-3-carboxamide
This compound is prepared as in 96.3 of example 96 using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.156-158 deg.C, yield 44.3%.1HNMR(DMSO-d6，δ)：12.30(brs，1H)，10.09(brs，1H)，8.65(s，1H)，8.15(d，1H，J＝2.5Hz)，7.05(m，1H)，3.88(s，3H)，3.47-3.57(m，1H)，3.08-3.18(m，1H)，3.02-3.08(m，1H)，2.75-2.85(m，1H)，2.52(brs，1H)，2.13-2.23(m，1H)，2.03-2.11(m，1H)，1.79-1.86(m，1H)，1.61-1.68(m，2H)，1.49-1.57(m，1H)，1.06(t，3H，J＝7.3Hz)。
Example 103: N-methyl-N-phenyl-7-trifluoromethyl-4-hydroxy-quinoline-3-carboxamide
103.1 Synthesis of diethyl (3-trifluoromethylanilino) methylenemalonate: 12.39 g (0.077mol) of 3-trifluoromethylaniline and 16.62 g (0.077mol) of diethyl ethoxymethylidene malonate were mixed, 100ml of toluene was added, the mixture was heated to about 100 ℃ to react for 5 hours, and the solvent was distilled off under reduced pressure to obtain 25.47 g of white crystals m.p.36-39 ℃ with a yield of 100%.
103.24 Synthesis of hydroxy-7-trifluoromethyl-quinoline-3-carboxylic acid Ethyl ester: dissolving 25.47 g (0.077mol) of (3-trifluoromethyl-anilino) diethyl methylene malonate in 200ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a white crystal, weighing 18.50 g, m.p. > 300 ℃, and obtaining the yield of 84.4%.1HNMR(DMSO-d6，δ)：11.50(S，1H)，9.39(S，1H)，8.75(d，1H，J＝9.0Hz)，8.43(s，1H)，8.10(d，1H，J＝8.7Hz)，4.62(q，2H，J＝7.0Hz)，1.47(t，3H，J＝7.0Hz).
103.3 Synthesis of N-methyl-N-phenyl-7-trifluoromethyl-4-hydroxy-quinoline-3-carboxamide: mixing 0.60 g (0.002mol) of 4-hydroxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.009mol) of N-methylaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 h, stopping heating, cooling to room temperature, precipitating a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a white solid, weighing 0.60 g, m.p.266-268 ℃, and the yield is 82.2%.1HNMR(DMSO-d6，δ)：12.21(s，1H)，8.21(s，1H)，8.15(d，1H，J＝7.6Hz)，7.84(s，1H)，7.56(d，1H，J＝8.1Hz)，7.22-7.28(m，4H)，7.11(m，1H)，3.34(s，3H)。
Example 104: n- ((2-dimethylamino) -ethyl) -7-trifluoromethyl-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 103.3 of example 103 using N, N-dimethylethylenediamine as the amine. m.p.188-190 deg.c, yield 66.7%.1HNMR(DMSO-d6，δ)：12.59(brs，1H)，10.01(t，1H，J＝5.3Hz)，8.88(s，1H)，8.44(d，1H，J＝8.4)，8.05(m，1H)，7.73(dd，1H，J＝1.4，8.6Hz)，3.44(q，2H，J＝6.2Hz)，2.48(t，2H，J＝6.3)，2.25(s，6H)。
Example 105: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -7-trifluoromethyl-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 103.3 of example 103 using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.136-138 deg.c, yield 54.1%.1HNMR(DMSO-d6，δ)：12.72(brs，1H)，10.09(t，1H，J＝5.9Hz)，8.89(s，1H)，8.46(d，1H，J＝8.4Hz)，8.07(s，1H)，7.74(d，1H，J＝8.7Hz)，3.26(d，2H，J＝5.9Hz)，2.29(s，6H)，2.18(s，2H)，0.90(s，6H)。
Example 106: (4-hydroxy-7-trifluoromethyl-3-quinoline) -4-morpholinylmethanone
This compound is prepared as described in example 103.3 using morpholine as the amine. m.p.262-264 deg.C, yield 47.2%.1HNMR(DMSO-d6，δ)：12.46(s，1H)，8.33(d，1H，J＝8.7Hz)，8.30(s，1H)，7.97(s，1H)，7.66(d，1H，J＝8.7Hz)，3.59(brs，6H)，3.28(s，2H)。
Example 107: (4-hydroxy-7-trifluoromethyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound was prepared as in 103.3 of example 103, using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.270-272 deg.C, yield 45.4%.1HNMR(DMSO-d6，δ)：11.96(brs，1H)，8.33(d，1H，J＝8.4Hz)，8.27(s，1H)，7.97(s，1H)，7.65(d，1H，J＝8.5Hz)，3,60(brs，2H)，3.26(brs，2H)，2.28(brs，4H)，2.19(s，3H)。
Example 108: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-trifluoromethyl-quinoline-3-carboxamide
This compound is prepared as described in example 103.3 using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p.164-166 deg.C, yield 46.9%.1HNMR(DMSO-d6，δ)：12.44(brs，1H)，10.09(brs，1H)，8.88(s，1H)，8.45(d，1H，J＝8.7Hz)，8.04(s，1H)，7.71(d，1H，J＝8.4Hz)，3.54-3.62(m，1H)，3.23-3.30(m，1H)，3.10-3.18(m，1H)，2.88-2.95(m，1H)，2.70(brs，1H)，2.31-2.39(m，1H)，2.20-2.28(m，1H)，1.82-1.90(m，1H)，1.65-1.72(m，2H)，1.54-1.62(m，1H)，1.09(t，3H，J＝7.3Hz)。
Example 109: N-methyl-N-phenyl-7-fluoro-4-hydroxy-quinoline-3-carboxamide
109.1 Synthesis of diethyl (3-fluoroanilino) methylenemalonate: 5.23 g (0.047mol) of 3-fluoroaniline and 10.16 g (0.047mol) of diethyl ethoxymethylenemalonate were mixed, 100ml of toluene was added, the mixture was heated to about 100 ℃ to react for 5 hours, and the solvent was distilled off under reduced pressure to obtain 12.10 g of white crystals m.p.46 to 48 ℃ with a yield of 91.5%.
109.24 Synthesis of hydroxy-7-fluoro-quinoline-3-carboxylic acid Ethyl ester: dissolving 12.10 g (0.043mol) of (3-fluoroanilino) diethyl methylene malonate in 200ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain white crystals, weighing 8.90 g, washing with m.p. > 300 ℃, and obtaining the yield of 87.9%.1HNMR(DMSO-d6，δ)：12.32(S，1H)，8.59(S，1H)，8.20(dd，1H，J＝6.4，9.0Hz)，7.38(dd，1H，J＝2.5，9.8Hz)，7.28(dt，1H，J＝2.3，8.7Hz)，4.22(q，2H，J＝7.0Hz)，1.28(t，3H，J＝7.0Hz).
Synthesis of N-methyl-N-phenyl-7-fluoro-4-hydroxy-quinoline-3-carboxamide 109.3: mixing 0.54 g (0.002mol) of 4-hydroxy-7-fluoro-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.009mol) of N-methylaniline, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 h, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a white solid, weighing 0.38 g, m.p.254-256 ℃, and the yield is 55.9%.1HNMR(CCl3D，δ)：11.87(brs，1H)，8.21(m，1H)，7.82(s，1H)，7.12-7.29(m，6H)，7.00(t，1H，J＝8.1Hz)，3.43(s，3H)。
Example 110: n- ((2-dimethylamino) -ethyl) -7-fluoro-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 109.3 of example 109 using N, N-dimethylethylenediamine as amine. m.p.180-182 deg.C, yield 64.5%.1HNMR(DMSO-d6，δ)：12.59(brs，1H)，9.98(t，1H，J＝5.3Hz)，8.75(s，1H)，8.30(m，1H)，7.44(m，1H)，7.33(m，1H)，3.41(q，2H，J＝6.0Hz)，2.42(t，2H，J＝6.2Hz)，2.20(s，6H)。
Example 111: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -7-fluoro-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 109.3 of example 109 using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.224-226 deg.C, yield 36.8%.1HNMR(DMSO-d6，δ)：12.66(brs，1H)，10.10(t，1H，J＝5.9Hz)，8.77(s，1H)，8.32(m，1H)，7.45(m，1H)，7.40(m，1H)，3.23(d，2H，J＝5.9Hz)，2.26(s，6H)，2.15(s，2H)，0.89(s，6H)。
Example 112: (4-hydroxy-7-fluoro-3-quinolinyl) -4-morpholinomethanone
The compound was prepared as in 109.3 of example 109, using morpholine as the amine. m.p.280-282 deg.c and yield 20.4%.1HNMR(DMSO-d6，δ)：12.24(s，1H)，8.16-8.20(m，2H)，7.21-7.36(m，2H)，3.60(brs，6H)，3.26(s，2H)。
Example 113: (4-hydroxy-7-fluoro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound was prepared as in 109.3 of example 109, using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.248-250 deg.C, yield 42.3%.1HNMR(DMSO-d6，δ)：12.25(brs，1H)，8.14-8.18(m，2H)，7.24-7.35(m，2H)，3,59(brs，2H)，3.25(brs，2H)，2.28(brs，4H)，2.19(s，3H)。
Example 114: n- ((2-dimethylamino) -ethyl) -6-fluoro-4-hydroxy-quinoline-3-carboxamide
114.1 Synthesis of diethyl (4-fluoroanilino) methylenemalonate: 5.31 g (0.048mol) of 4-fluoroaniline and 10.31 g (0.048mol) of diethyl ethoxymethylenemalonate were mixed, 100ml of toluene was added, the mixture was heated to about 100 ℃ to react for 5 hours, and the solvent was distilled off under reduced pressure to obtain 11.86 g of brown crystals m.p.66-68 ℃ with a yield of 87.0%.
114.24 Synthesis of hydroxy-6-fluoro-quinoline-3-carboxylic acid Ethyl ester: dissolving 11.86 g (0.042mol) of (4-fluoroanilino) diethyl methylene malonate in 200ml of diphenyl ether, heating to about 250 ℃, reacting for 0.5 hour, stopping heating, cooling to room temperature, separating out a solid, filtering and collecting the solid, washing with petroleum ether, absolute ethyl alcohol and absolute ethyl ether to obtain a white crystal, weighing 7.50 g, washing with m.p. > 300 ℃, and obtaining the yield of 75.6%.1HNMR(DMSO-d6，δ)：12.46(S，1H)，8.59(S，1H)，7.90(dd，1H，J＝3.0，9.5Hz)，7.72(dd，1H，J＝4.7，8.9Hz)，7.63(dt，1H，J＝2.8，8.9Hz)，4.22(q，2H，J＝7.0Hz)，1.28(t，3H，J＝7.0Hz).
114.3 Synthesis of N- ((2-dimethylamino) -ethyl) -6-fluoro-4-hydroxy-quinoline-3-carboxamide: mixing 0.50 g (0.002mol) of 4-hydroxy-6-fluoro-quinoline-3-carboxylic acid ethyl ester and 1.00 g (0.011mol) of N, N-dimethylethylenediamine, adding 10ml of diphenyl ether, heating to 220-230 ℃, reacting for 0.5 h, stopping heating, cooling to room temperature, precipitating a solid, filtering and collecting the solid, washing with petroleum ether, washing with absolute ethyl alcohol and washing with absolute ethyl ether to obtain a white solid, weighing 0.42 g, m.p.214-216 ℃, and obtaining the yield of 71.3%.1HNMR(DMSO-d6，δ)：12.66(brs，1H)，10.00(t，1H，J＝5.3Hz)，8.72(s，1H)，7.89(m，1H)，7.78(m，1H)，7.67(m，1H)，3.41(q，2H，J＝6.0Hz)，2.42(t，2H，J＝6.1Hz)，2.20(s，6H)。
Example 115: n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -6-fluoro-4-hydroxy-quinoline-3-carboxamide
This compound was prepared as in 109.3 of example 109 using N, N, 2, 2-tetramethylpropanediamine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1). m.p.204-206 ℃ and the yield is 54.4 percent.1HNMR(DMSO-d6，δ)：12.79(brs，1H)，10.11(t，1H，J＝5.9Hz)，8.77(s，1H)，7.92(m，1H)，7.78(m，1H)，7.67(m，1H)，3.23(d，2H，J＝5.9Hz)，2.26(s，6H)，2.15(s，2H)，0.89(s，6H)。
Example 116: (4-hydroxy-6-fluoro-3-quinolinyl) -4-morpholinomethanone
The compound was prepared as in 109.3 of example 109, using morpholine as the amine. m.p.278 deg.C (dec), yield 13.6%.1HNMR(DMSO-d6，δ)：12.39(brs，1H)，8.18(s，1H)，7.38-7.80(m，3H)，3.60(brs，6H)，3.26(s，2H)。
Example 117: (4-hydroxy-6-fluoro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone
This compound was prepared as in 109.3 of example 109, using 4-methyl-piperazine as the amine. Column chromatography (200-300 mesh silica gel, eluent dichloromethane: methanol 25: 1-15: 1). m.p.194-196 ℃ and the yield is 58.5 percent.1HNMR(DMSO-d6，δ)：12.33(brs，1H)，8.16(s，1H)，7.58-7.80(m，3H)，3,60(brs，2H)，3.25(brs，2H)，2.28(brs，4H)，2.19(s，3H)。
Example 118: n- (3-pyridin-methyl) -4-hydroxy-6-fluoro-quinoline-3-carboxamide
This compound was prepared as in 109.3 of example 109, using 3-aminomethyl-pyridine as the amine. m.p.224-226 deg.C, yield 41.1%.1HNMR(DMSO-d6，δ)：12.83(brs，1H)，10.38(s，1H)，8.80(s，1H)8.57(d，1H，J＝1.7Hz)，8.47(dd，1H，J＝1.4，4.8Hz)，7.89(dd，1H，J＝2.8，9，2Hz)，7.68-7.82(m，3H)，7.35-7.38(m，1H)，4.58(d，2H，J＝6.1Hz)。
Example 119: n- { [ 1-Ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-fluoro-quinoline-3-carboxamide
This compound is prepared as in 109.3 of example 109 using 1-ethyl-2-aminomethyl-pyrrolidine as the amine. m.p118-120 deg.C, yield 20.8%.1HNMR(DMSO-d6，δ)：12.55(brs，1H)，10.03(brs，1H)，8.75(s，1H)，7.90(dd，1H，J＝2.8，9.6Hz)，7.77(q，1H，J＝4.5Hz)，7.67(d t，1H，J＝2.8，9.4Hz)，3.54-3.62(m，1H)，3.23-3.30(m，1H)，3.08-3.18(m，1H)，2.80-2.90(m，1H)，2.57(brs，1H)，2.23-2.32(m，1H)，2.13-2.18(m，1H)，1.80-1.90(m，1H)，1.60-1.69(m，2H)，1.50-1.58(m，1H)，1.07(t，3H，J＝7.3Hz)。
Example 120 inhibition of splenic lymphocyte proliferative responses in vitro.
Linomide and FR137316 are positive control drugs reported in literature and have a therapeutic effect on autoimmune nephritis, have an inhibitory effect on in vitro splenic lymphocyte proliferation reaction, and are primarily screened by taking the percentage inhibition rate of the in vitro splenic lymphocyte proliferation reaction as an index.
Splenic lymphocyte proliferation response: dislocation of cervical vertebra of mouse is lethal, taking spleen aseptically, cutting into pieces, and making into single cell suspension with 200 mesh nylon net. 0.16M NH for erythrocytes4Dissolving with Cl-Tris buffer solution, washing the cells twice, culturing in RPMI1640 culture solution containing 10% calf serum, adding the above culture solution into 96-well plate, and culturing at cell concentration of 2 × 106Perml, adding ConA at a concentration of 0.5. mu.g/ml to stimulate proliferation of T cells; LPS was added at a concentration of 10. mu.g/ml to stimulate proliferation of B cells. The drug to be tested was added in three doses, 1. mu.g/ml, 10. mu.g/ml, 100. mu.g/ml. The final volume of each well was 200. mu.l, the wells without drug were blank, and three wells were repeated for each concentration. 5% CO at 37 ℃2After 56 hours of culture in the incubator, 0.5. mu. Ci of [ alpha ], [ alpha ] was added to each well3H]TdR, and culturing is continued for 16 h. The cells were collected on filter paper using a multiheaded cell harvester, radioactivity was measured using a liquid scintillation counter from Perkin Elmer, and the results were expressed as mean. + -. standard deviation and analyzed for differences between groups using a t-test, and the results are shown in Table 1. Percent inhibition%
TABLE 1 Effect of Compounds of the invention on the proliferative response of splenic lymphocytes
P < 0.01, P < 0.05 to blank control (t-test). The numerical value is negative, which indicates that the product has enhancement effect
Claims (4)
1. A compound selected from:
n- (4-methyl-2-pyridinyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- ((2-diethanolamino) -phenyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- ((4-diethanolamino) -phenyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- (2-ethanoyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
(4-hydroxy-7-chloro-3-quinolinyl) -4-morpholinomethanone;
(4-hydroxy-7-chloro-3-quinolinyl) - (4-methyl-1-piperazinyl) -methanone;
n- (3-pyridin-methyl) -4-hydroxy-7-chloro-quinoline-3-carboxamide;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-chloro-quinoline-3-amide;
n- ((4-diethanolamino) -phenyl) -4-hydroxy-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-3-quinolinyl) -4-morpholinomethanone;
(4-hydroxy-3-quinolinyl) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-quinoline-3-carboxamide;
n- ((4-diethanolamino) -phenyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-8-methylsulfanyl-quinoline-3-carboxamide;
(4-hydroxy-8-methylsulfanyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-8-methylsulfanyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-8-methylsulfanyl-quinoline-3-amide;
n- ((4-diethanolamino) -phenyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-7-methylsulfanyl-quinoline-3-carboxamide;
(4-hydroxy-7-methylsulfanyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-7-methylsulfanyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-methylsulfanyl-quinoline-3-amide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide;
(4-hydroxy-6-methylsulfanyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-methylsulfanyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- (3-pyridin-methyl) -4-hydroxy-6-methylsulfanyl-quinoline-3-carboxamide;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-methylsulfanyl-quinoline-3-amide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-nitro-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-nitro-quinoline-3-carboxamide;
(4-hydroxy-6-nitro-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-nitro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-nitro-quinoline-3-amide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-methyl-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-methyl-quinoline-3-carboxamide;
(4-hydroxy-6-methyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-methyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-methyl-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-chloro-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-chloro-quinoline-3-carboxamide;
(4-hydroxy-6-chloro-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-chloro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-chloro-quinoline-3-amide;
n- ((2-dimethylamino) -ethyl) -4-hydroxy-6-bromo-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -4-hydroxy-6-bromo-quinoline-3-amide;
(4-hydroxy-6-bromo-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-bromo-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-bromo-quinoline-3-amide;
n- ((2-dimethylamino) -ethyl) -6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -6, 8-dimethyl-4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-6, 8-dimethyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6, 8-dimethyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6, 8-dimethyl-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -5, 7-dimethyl-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -5, 7-dimethyl-4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-5, 7-dimethyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-5, 7-dimethyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-5, 7-dimethyl-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -7-methoxy-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -7-methoxy-4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-7-methoxy-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-7-methoxy-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-methoxy-quinoline-3-carboxamide;
n- ((2-dimethylamino) -ethyl) -7-trifluoromethyl-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -7-trifluoromethyl-4-hydroxy-quinoline-3-amide;
(4-hydroxy-7-trifluoromethyl-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-7-trifluoromethyl-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-7-trifluoromethyl-quinoline-3-amide;
n- ((2-dimethylamino) -ethyl) -7-fluoro-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -7-fluoro-4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-7-fluoro-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-7-fluoro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- ((2-dimethylamino) -ethyl) -6-fluoro-4-hydroxy-quinoline-3-carboxamide;
n- ((3-dimethylamino-2, 2-dimethyl) -propyl) -6-fluoro-4-hydroxy-quinoline-3-carboxamide;
(4-hydroxy-6-fluoro-3-quinoline) -4-morpholinomethanone;
(4-hydroxy-6-fluoro-3-quinoline) - (4-methyl-1-piperazinyl) -methanone;
n- (3-pyridin-methyl) -4-hydroxy-6-fluoro-quinoline-3-carboxamide; and
n- { [ 1-ethyl-2-pyrrolidinyl ] -methyl } -4-hydroxy-6-fluoro-quinoline-3-carboxamide.
2. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
3. Use of a compound according to claim 1 for the preparation of a medicament for the treatment and/or prevention of autoimmune diseases.
4. The use of claim 3, wherein the autoimmune disease is chronic nephritis, rheumatoid arthritis, insulin dependent diabetes mellitus, systemic lupus erythematosus, multiple sclerosis.
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| CN1037335A (en) * | 1988-03-11 | 1989-11-22 | 拜尔公司 | The preparation method of 1-cyclopropyl Quinolone carboxylic acid and derivative thereof |
| CN1281439A (en) * | 1997-12-22 | 2001-01-24 | 法玛西雅厄普约翰美国公司 | 4-Hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents |
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| CN1037335A (en) * | 1988-03-11 | 1989-11-22 | 拜尔公司 | The preparation method of 1-cyclopropyl Quinolone carboxylic acid and derivative thereof |
| CN1281439A (en) * | 1997-12-22 | 2001-01-24 | 法玛西雅厄普约翰美国公司 | 4-Hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents |
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