CN115197240A - Quinoline compound, synthesis method, pharmaceutical composition and application - Google Patents
Quinoline compound, synthesis method, pharmaceutical composition and application Download PDFInfo
- Publication number
- CN115197240A CN115197240A CN202110770732.9A CN202110770732A CN115197240A CN 115197240 A CN115197240 A CN 115197240A CN 202110770732 A CN202110770732 A CN 202110770732A CN 115197240 A CN115197240 A CN 115197240A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- quinoline
- pharmaceutically acceptable
- formula
- 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.)
- Granted
Links
- -1 Quinoline compound Chemical class 0.000 title claims abstract description 44
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 182
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 150000003248 quinolines Chemical class 0.000 claims abstract description 23
- 102100021657 Tyrosine-protein phosphatase non-receptor type 6 Human genes 0.000 claims abstract description 19
- 101710128901 Tyrosine-protein phosphatase non-receptor type 6 Proteins 0.000 claims abstract description 14
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 208000026278 immune system disease Diseases 0.000 claims abstract description 6
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims description 29
- 229940111121 antirheumatic drug quinolines Drugs 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- ZEXKKIXCRDTKBF-UHFFFAOYSA-N quinoline-2-carboxamide Chemical class C1=CC=CC2=NC(C(=O)N)=CC=C21 ZEXKKIXCRDTKBF-UHFFFAOYSA-N 0.000 claims description 6
- 239000012190 activator Substances 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- 208000025966 Neurological disease Diseases 0.000 claims description 3
- 230000002503 metabolic effect Effects 0.000 claims description 3
- ITSKABFKYNWBMC-UHFFFAOYSA-N 3-aminothieno[2,3-b]quinoline-2-carboxamide Chemical class C1=CC=C2C=C(C(=C(C(=O)N)S3)N)C3=NC2=C1 ITSKABFKYNWBMC-UHFFFAOYSA-N 0.000 claims description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 238000011282 treatment Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 18
- 230000008569 process Effects 0.000 abstract description 10
- 230000004071 biological effect Effects 0.000 abstract description 4
- 230000003213 activating effect Effects 0.000 abstract description 3
- 230000008827 biological function Effects 0.000 abstract description 3
- 230000004060 metabolic process Effects 0.000 abstract description 3
- 230000019491 signal transduction Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000011160 research Methods 0.000 abstract description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 167
- 238000006243 chemical reaction Methods 0.000 description 157
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 72
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 72
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 72
- 239000000243 solution Substances 0.000 description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 238000005406 washing Methods 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 239000007787 solid Substances 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 48
- 238000000967 suction filtration Methods 0.000 description 44
- 238000001035 drying Methods 0.000 description 41
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 36
- 238000010992 reflux Methods 0.000 description 36
- 239000012065 filter cake Substances 0.000 description 35
- 238000010438 heat treatment Methods 0.000 description 33
- 239000012295 chemical reaction liquid Substances 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 27
- 238000012544 monitoring process Methods 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 24
- 239000003153 chemical reaction reagent Substances 0.000 description 21
- 239000007821 HATU Substances 0.000 description 19
- 229910000027 potassium carbonate Inorganic materials 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000001914 filtration Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 12
- 239000005457 ice water Substances 0.000 description 12
- 229910052763 palladium Inorganic materials 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 11
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 230000007935 neutral effect Effects 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 101001053395 Arabidopsis thaliana Acid beta-fructofuranosidase 4, vacuolar Proteins 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 102000004495 STAT3 Transcription Factor Human genes 0.000 description 9
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 239000012528 membrane Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- PVBRSNZAOAJRKO-UHFFFAOYSA-N ethyl 2-sulfanylacetate Chemical compound CCOC(=O)CS PVBRSNZAOAJRKO-UHFFFAOYSA-N 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 7
- PNVPNXKRAUBJGW-UHFFFAOYSA-N (2-chloroacetyl) 2-chloroacetate Chemical compound ClCC(=O)OC(=O)CCl PNVPNXKRAUBJGW-UHFFFAOYSA-N 0.000 description 6
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 6
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 229960001701 chloroform Drugs 0.000 description 6
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 6
- FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 5
- 101000617285 Homo sapiens Tyrosine-protein phosphatase non-receptor type 6 Proteins 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 5
- 230000003301 hydrolyzing effect Effects 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 238000009987 spinning Methods 0.000 description 5
- 150000005645 2-bromoquinolines Chemical class 0.000 description 4
- 101001053401 Arabidopsis thaliana Acid beta-fructofuranosidase 3, vacuolar Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000003472 neutralizing effect Effects 0.000 description 4
- BXVSAYBZSGIURM-UHFFFAOYSA-N 2-phenoxy-4h-1,3,2$l^{5}-benzodioxaphosphinine 2-oxide Chemical compound O1CC2=CC=CC=C2OP1(=O)OC1=CC=CC=C1 BXVSAYBZSGIURM-UHFFFAOYSA-N 0.000 description 3
- 239000006180 TBST buffer Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- QKJAZPHKNWSXDF-UHFFFAOYSA-N 2-bromoquinoline Chemical compound C1=CC=CC2=NC(Br)=CC=C21 QKJAZPHKNWSXDF-UHFFFAOYSA-N 0.000 description 2
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000012474 protein marker Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 102000014400 SH2 domains Human genes 0.000 description 1
- 108050003452 SH2 domains Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 101710204865 Tyrosine-protein phosphatase 1 Proteins 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000001045 blue dye Substances 0.000 description 1
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000003248 enzyme activator Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000003331 infrared imaging Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 1
- 229960004378 nintedanib Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 238000010023 transfer printing Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Abstract
The invention discloses a quinoline compound, a synthesis method, a pharmaceutical composition and application, and belongs to the technical field of medicines and preparation and application thereof. The quinoline compounds with the structure shown in the general formula I have the biological activity of activating protein tyrosine phosphatase SHP1, can be used as tool compounds to research the biological function relevance of the protein tyrosine phosphatase SHP1 in the cell signal transduction process, and provide a new means for preventing and treating cancers, metabolism and immune diseases.
Description
Technical Field
The invention belongs to the technical field of medicines and preparation and application thereof, and particularly relates to a quinoline compound, a synthesis method, a pharmaceutical composition and application thereof.
Background
The protein tyrosine phosphatase 1 (SHP-1) containing Src homology 2 domain is a non-receptor type protein tyrosine phosphatase widely existing in vivo, and consists of two SH2 domains (N-SH 2 and C-SH 2), a PTP domain with catalytic activity, rich proline group and tyrosine phosphorylation tail. SHP-1 is mainly present in hematopoietic and epithelial cells and controls sig by negatively regulating cell signaling processes, particularly in the nuclear transcription and activator of transcription (STAT) pathways, and is therefore widely recognized as a tumor suppressor. Over-activation of oncogenic STAT3 was observed in diffuse large B-cell lymphoma (DLBCL), the most common non-hodgkin lymphoma, highly aggressive and heterogeneous. Blocking the STAT3 pathway is a potential therapeutic strategy for DLBCL. The loss of function of SHP-1 caused by the mutation promotes the deregulation of STAT3 in DLBCL. Down-regulation of expression occurs in approximately 50% of primary DLBCL tumors. Thus, increasing SHP-1 activity represents a potentially promising strategy for DLBCL treatment. Enzyme activators are generally more difficult to develop than enzyme inhibitors. To our knowledge, the compounds reported to directly activate SHP-1 are all kinase inhibitors, including dovidinib, nintedanib, regorafenib, sorafenib and derivatives thereof, with the following specific structures:
the number and structural diversity of SHP1 activators is significantly less than that of modulators of other subtypes in the family, and there is an urgent need to develop potent and specific SHP-1 activators with structural diversity.
Disclosure of Invention
The invention provides quinoline compounds shown as the following general formula I and a preparation method thereof, and the quinoline compounds have the biological activity of activating protein tyrosine phosphatase SHP1, can be used as tool compounds to research the biological function relevance of the protein tyrosine phosphatase SHP1 in the cell signal transduction process, and provide a new means for preventing and treating cancers, metabolism and immune diseases.
A quinoline compound shown in a general formula I or pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
represents a single or double bond; x 1 Selected from the group consisting of no (H), S, O, NH; x 2 Selected from (H), CH, CNH 2 A thiophene ring;
R 1 selected from the group consisting of,
represents the attachment site:
R 2 ，R 3 ，R 4 ，R 5 each independently selected from hydrogen, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 A haloalkyl group.
In one embodiment of the invention, R 2 ，R 3 ，R 4 ，R 5 Each independently selected from-F, -Cl, -Br, -H, -CF 3 、 -CH 3 、-OCH 3
In one embodiment of the present invention, the structure of the quinoline compound includes the following structures represented by formula II, formula III, formula IV, formula V, formula VI, and formula VII:
wherein R is 1 ，R 2 ，R 3 ，R 4 ，R 5 Are as defined above, respectively.
In one embodiment of the present invention, when X is 1 Is S, X 2 When the compound is CH, the structure of the quinoline compound is thieno [2,3-b ] shown as a formula II]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
wherein R is 1 ：
R 2 ，R 3 ，R 4 ，R 5 Each independently selected from hydrogen, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 A haloalkyl group; specifically, it may be selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of one class of quinoline compounds is:
in one embodiment of the present invention, when X 1 Is O, X 2 When the compound is CH, the structure of the quinoline compound is furo [2,3-b ] shown as a formula III]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
R 1 independently selected from:
R 2 ，R 3 ，R 4 ，R 5 each independently selected from hydrogen, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 A haloalkyl group; specifically, it may be selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of a class of quinoline compounds is:
in one embodiment of the present invention, when X is 1 Is NH, X 2 When the compound is CH, the structure of the quinoline compound is pyrrolo [2,3-b ] shown as a formula IV]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
wherein R is 1 Selected from:
R 2 ，R 3 ，R 4 ，R 5 each independently selected from hydrogen, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 A haloalkyl group; specifically, it may be selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of one class of quinoline compounds is:
in one embodiment of the present invention, when X is 1 Is S, X 2 Is CNH 2 When the quinoline compound is represented by the formula V, the structure of the quinoline compound is 3-aminothieno [2,3-b]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
R 1 selected from:
R 2 ，R 3 ，R 4 ，R 5 each independently selected from hydrogen, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 A haloalkyl group; specifically, it may be selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of a class of quinoline compounds is:
in one embodiment of the present invention, when X is 1 Is absent, X 2 When the quinoline compound is 4-thienyl, the structure of the quinoline compound is 4- (quinoline-3-yl) thiophene-2-formamide derivatives shown in a formula VI or pharmaceutically acceptable salts thereof,
R 1 selected from:
R 2 ，R 3 ，R 4 ，R 5 each independently selected from hydrogen, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 A haloalkyl group; specifically, it may be selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of one class of quinoline compounds is:
in one embodiment of the present invention, X 1 Is S, X 2 When the structure is none, the structure of a class of quinoline compounds is 2 shown as a formula VII- (quinolin-2-ylsulfanyl) acetamide derivative or a pharmaceutically acceptable salt thereof,
R 1 selected from the group consisting of:
R 2 ，R 3 ，R 4 ，R 5 each independently selected from hydrogen, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 A haloalkyl group; specifically, it may be selected from-F, -Cl, -Br, -H, -CF 3 、-CH 3 、-OCH 3 。
Most preferably, the specific structure of one class of quinoline compounds is:
in one embodiment of the invention, the pharmaceutically acceptable salt is selected from: hydrochloride, hydrobromide, phosphate, metaphosphate, nitric acid and sulphate, acetate, benzenesulphonate, benzoate, citrate, ethanesulphonate, fumarate, gluconate, glycolate, isethionate, lactate, lactobionate, maleate, malate, methanesulphonate, succinate, p-toluenesulphonate and tartrate, ammonium, alkali metal, alkaline earth metal, trometamol, diethanolamine, lysine, ethylenediamine salts.
The invention also provides a method for preparing the quinoline compound shown in the formula II, which has the following reaction route:
wherein, reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Ethyl thioglycolate, DMF, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-Azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The specific process comprises the following steps:
refluxing a mixture of the compound II-1 and acetic anhydride in a solvent, neutralizing a reaction solution by using an inorganic alkali solution after the reaction is completed, carrying out suction filtration, and washing a filter cake to obtain a solid compound II-2 which is directly put into the next step; dissolving a compound II-2 in excessive phosphorus oxychloride, adding dimethylformamide, heating reaction liquid, monitoring the reaction, dripping into cold water, filtering, washing a filter cake, and drying to obtain a compound II-3; heating a DMF solution of a compound II-3, triethylamine and ethyl thioglycolate, monitoring the reaction, dripping the solution into cold water, performing suction filtration, washing a filter cake, and drying to obtain a compound II-4; hydrolyzing the ethanol solution of the compound II-4 by using lithium hydroxide, adding acid to adjust the pH value to be acidic, filtering, washing and drying a filter cake to obtain a compound II-5; heating a dimethylformamide solution of the compound II-5, the organic base 6, the 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and the N, N-diisopropylethylamine, after the reaction is completed, dripping the reaction solution into water, performing suction filtration, and recrystallizing a filter cake to obtain the compound II-7.
The invention also provides a method for preparing the quinoline compound shown in the formula III, which comprises the following reaction route:
wherein, reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃;70% acetic acid, 95 ℃; c) Ethyl bromoacetate, DMF, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-Azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The specific process comprises the following steps:
refluxing a mixture of the compound III-1 and acetic anhydride in a solvent, neutralizing a reaction solution by using an inorganic alkali solution after the reaction is completed, carrying out suction filtration, and washing a filter cake to obtain a solid compound III-2 which is directly put into the next step; dissolving a compound III-2 in excessive phosphorus oxychloride, adding dimethylformamide, heating reaction liquid, monitoring the reaction, dripping into cold water, performing suction filtration, washing a filter cake, drying, floating the compound in 70% acetic acid, refluxing, cooling, performing suction filtration, and washing with water to obtain a compound III-3; heating a DMF solution of the compound III-3, triethylamine and ethyl thioglycolate, monitoring the completion of the reaction, reversely dripping into cold water, performing suction filtration, washing a filter cake, and drying to obtain a compound III-4; hydrolyzing the ethanol solution of the compound III-4 by using lithium hydroxide, adding acid to adjust the pH value to be acidic, filtering, washing and drying a filter cake to obtain a compound III-5; and heating a dimethylformamide solution of the compound III-5, the organic base 6, the 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and the N, N-diisopropylethylamine, after the reaction is completed, dripping the reaction solution into water, performing suction filtration, and recrystallizing a filter cake to obtain the compound III-7.
The invention also provides a method for preparing the quinoline compound shown in the formula IV, which comprises the following reaction route:
reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Isocyanoacetic acid ethyl ester, DMSO, K 2 CO 3 CuI,50 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-Azabenzotriazole) -N, N, N ', N' -Tetramethyluronium Hexafluorophosphate (HATU), N, N-diisopropylethylamine(DIPEA)，50℃。
The specific process comprises the following steps:
refluxing a mixture of the compound IV-1 and acetic anhydride in a solvent, neutralizing a reaction solution by using an inorganic alkali solution after the reaction is completed, carrying out suction filtration, and washing a filter cake to obtain a solid compound IV-2 which is directly put into the next step; dissolving a compound IV-2 in excessive phosphorus oxychloride, adding dimethylformamide, heating reaction liquid, monitoring the reaction, dripping into cold water, filtering, washing a filter cake, and drying to obtain a compound IV-3; heating a DMSO solution of a compound IV-3, potassium carbonate and ethyl isocyanoacetate, adding a catalytic amount of cuprous iodide, carrying out suction filtration after monitoring reaction, dripping filtrate into cold water, carrying out suction filtration, washing a filter cake, and drying to obtain a compound IV-4; hydrolyzing the ethanol solution of the compound IV-4 by using lithium hydroxide, adding acid to adjust the pH value to be acidic, filtering, washing and drying a filter cake to obtain a compound IV-5; and heating a dimethylformamide solution of the compound IV-5, the organic base 6, the 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and the N, N-diisopropylethylamine, after the reaction is completed, dripping the reaction solution into water, performing suction filtration, and recrystallizing a filter cake to obtain the compound IV-7.
The invention also provides a method for preparing the quinoline compound shown in the formula V, which comprises the following reaction route:
(1) Preparation of important intermediate:
reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Hydroxylamine hydrochloride, water, trichloromethane, thionyl chloride; d) Thiourea, ethanol;
(2) Preparing a quinoline compound:
reagents and conditions: e) Chloroacetic anhydride, dichloromethane; f) Dimethylformamide, triethylamine, 90 ℃.
Wherein, step (1) possesses the process to include:
refluxing a mixture of the compound V-1 and acetic anhydride in a solvent, neutralizing a reaction solution by using an inorganic alkali solution after the reaction is completed, performing suction filtration, and washing a filter cake to obtain a solid compound V-2 which is directly put into the next step; dissolving the compound V-2 in excessive phosphorus oxychloride, adding dimethylformamide, heating the reaction solution, monitoring the reaction, dripping into cold water, filtering, washing a filter cake, and drying to obtain the compound V-3. Mixing a tetrahydrofuran solution of a compound V-3 with an aqueous solution of hydroxylamine hydrochloride, stirring at room temperature, after complete reaction, concentrating to remove a solvent, washing with water, dissolving a solid in chloroform, adding thionyl chloride, refluxing and stirring, after complete reaction, concentrating to remove an organic solvent, recrystallizing with ethanol to obtain a compound V-4, dissolving the compound V-4 and thiourea in ethanol, refluxing and reacting for 1 hour, cooling, adding water, precipitating, and performing suction filtration to obtain a solid V-5.
The step (2) includes the steps of:
dissolving an amino compound 6 in dichloromethane, adding chloroacetic anhydride, after the reaction is finished, concentrating reaction liquid, and carrying out alkali washing to obtain a product V-7, dissolving V-7 and V-5 in a proper amount of DMF, adding triethylamine, reacting at 90 ℃, adding water after the reaction is finished, and separating out solids to obtain a compound V-8.
The invention also provides a method for preparing the quinoline compound shown in the formula VI, which comprises the following reaction route:
reagents and conditions: a) Pinacol diborate, palladium tetratriphenylphosphine, potassium carbonate, water, 1,4-dioxane, 80 ℃; b) Substituted 2-bromoquinoline, palladium tetratriphenylphosphine, potassium carbonate, water, 1,4-dioxane, 80 ℃; c) Ethanol, lithium hydroxide, normal temperature; d) 2- (7-Azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The specific process comprises the following steps:
dissolving a compound VI-1 and pinacol ester diboron, palladium tetratriphenylphosphine and potassium carbonate in a mixed solution of 1,4-dioxane and water, refluxing and heating, after complete reaction, spin-drying an organic solvent, and extracting by ethyl acetate; concentrating the organic phase, and purifying by a chromatographic column to obtain a compound VI-2; VI-2 and various substituted 2-bromoquinolines, palladium tetratriphenylphosphine and potassium carbonate are dissolved in a mixed solution of 1,4-dioxane and water, reflux heating is carried out, after the reaction is completed, the organic solvent is dried in a spinning mode, and ethyl acetate is used for extraction; the organic phase is concentrated and purified by a chromatographic column to obtain the compound VI-3. Hydrolyzing the methanol solution of the compound VI-4 by using lithium hydroxide, adding acid to adjust the pH value to be acidic, filtering, washing and drying a filter cake to obtain a compound VI-4; heating a dimethylformamide solution of the compound VI-4, the organic base 6, the 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate and the N, N-diisopropylethylamine, after the reaction is completed, dripping the reaction solution into water, performing suction filtration, and recrystallizing a filter cake to obtain the compound VI-5.
The invention also provides a method for preparing the quinoline compound shown in the formula VII, which has the following reaction route:
reagents and conditions: a) Thiourea, ethanol; b) Bromoacetyl bromide, dichloromethane; c) N, N dimethylformamide, potassium carbonate, 60 ℃.
The specific process comprises the following steps:
dissolving a compound VII-1 and thiourea in ethanol, mixing and refluxing, after the reaction is completed, spin-drying the solvent, and washing with water to obtain a compound VII-2. Dissolving a compound VII-3 in dichloromethane, dropwise adding bromoacetyl bromide, stirring at room temperature for reaction, after the reaction is completed, spin-drying the solvent, washing with water, and extracting with ethyl acetate to obtain a compound VII-4; dissolving a compound VII-2 and a compound VII-4 in N, N dimethylformamide, adding potassium carbonate, and stirring at 60 ℃ for reaction; and after the reaction is completed, adding ethyl acetate for dilution, washing with water to remove N, N dimethylformamide, and purifying by using an organic phase chromatographic column to obtain a compound VII-5.
The invention also provides application of the quinoline compound shown in the general formula I or the pharmaceutically acceptable salt thereof in preparation of the protein tyrosine phosphatase SHP1 activator.
The invention also provides application of the quinoline compound shown in the general formula I or pharmaceutically acceptable salt thereof in preparing medicaments for preventing and treating cancers, metabolic and immune diseases, cardiovascular diseases and neurological diseases.
The invention also provides a pharmaceutical composition, which comprises the quinoline compound shown in the general formula I or pharmaceutically acceptable salt thereof, and optionally pharmaceutically acceptable auxiliary materials.
The invention also provides a medicament for preventing and treating cancer, metabolic and immune diseases, cardiovascular diseases or neurological diseases, which comprises the quinoline compound shown in the general formula I or pharmaceutically acceptable salt thereof, and optional pharmaceutically acceptable auxiliary materials.
Has the advantages that:
the quinoline compound or the pharmaceutically acceptable salt thereof has the biological activity of activating the protein tyrosine phosphatase SHP1, can be used as a tool compound for researching the biological function association of the protein tyrosine phosphatase SHP1 in the cell signal transduction process, and provides a new means for preventing and treating cancers, metabolism and immune diseases.
Drawings
FIG. 1 is a graph of concentration versus fold activation for compounds CD-13, XY-5, XY-6 (from left to right).
FIG. 2 is a graph comparing the effect of CD 13 on STAT3 (Y705) phosphorylation; (A) The protein expression of STAT3 (Y705) and STAT3 was detected 4 hours after OCI-Ly10, OCI-Ly10R and DHL-2 cells were treated with different CD-13 concentrations, respectively, and GAPDH was used as an internal control; (B) OCI-Ly10, OCI-Ly10R and DHL2 cells were treated with 40. Mu.M CD-13 for various periods of time, and STAT3 (Y705) and STAT3 protein expression were detected with GAPDH as an internal control.
Detailed Description
The procedure for the preparation of the following examples:
reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Ethyl thioglycolate, DMF, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-Azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The preparation process comprises the following steps: adding compound II-1 (1 eq) into acetic anhydride (1.5 eq), stirring uniformly, reacting at 40 ℃, monitoring the reaction, slowly dropping saturated sodium bicarbonate solution into the reaction solution until the reaction solution becomes neutral, filtering the solid, washing and drying to obtain compound II-2. Dissolving the compound II-2 in excess phosphorus oxychloride (8 eq), adding dimethylformamide (2 eq), refluxing at 90 ℃ for reaction overnight, monitoring the reaction to be complete, slowly dropping the reaction liquid into ice water, leaching after all solids are separated out, washing and drying a filter cake to obtain the compound II-3. Dissolving the compound II-3 (1 eq) in 10ml of DMF, adding triethylamine (6 eq) and ethyl thioglycolate (1.2 eq), heating the reaction system to 90 ℃, and reacting for 1h. And (3) after the reaction is monitored to be complete, dropping the reaction liquid into cold water, leaching after the solid is completely separated out, washing and drying the filter cake to obtain a compound II-4. Dissolving the compound II-4 (1 eq) in ethanol, adding lithium hydroxide (3 eq), heating and stirring until the reaction is monitored to be complete, adding dilute hydrochloric acid to adjust the pH value to 5-6 after the reaction liquid is concentrated, carrying out suction filtration, washing and drying a filter cake to obtain the compound II-5. Compound II-5 (1 eq) was dissolved in DMF (20 ml) and HATU (1.5 eq), DIPEA (1.5 eq) and organic amine 6 (1.2 eq) were added in that order. Heating the reaction system at 50 ℃ for reflux reaction, monitoring the reaction completion, dropping the reaction liquid into cold water, performing suction filtration and washing the solid, and reacting the solid with ethyl acetate: mixed solvent of petroleum ether =1:5 recrystallized solid to give pure compound II-7.
reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃;70% acetic acid, 95 ℃; c) Ethyl bromoacetate, DMF, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-Azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The preparation process comprises the following steps: adding the compound III-1 (1 eq) into acetic anhydride (1.5 eq), uniformly stirring, reacting at 40 ℃, monitoring the reaction to be complete, slowly dripping saturated sodium bicarbonate solution into the reaction solution until the reaction solution becomes neutral, filtering the solid by suction, washing and drying to obtain the compound III-2. Dissolving a compound III-2 in excessive phosphorus oxychloride (8 eq), adding dimethylformamide (2 eq), carrying out reflux reaction at 90 ℃ overnight, monitoring the reaction to be complete, slowly dropping the reaction liquid into ice water, carrying out suction filtration after all solids are separated out, floating the solids in 70% acetic acid solution (20 ml), carrying out reflux stirring for 10h, cooling, carrying out suction filtration, washing and drying a filter cake to obtain a compound III-3. Dissolving the compound III-3 (1 eq) in 10ml of DMF, adding triethylamine (6 eq) and ethyl bromoacetate (1.2 eq), heating the reaction system to 90 ℃, and reacting for 1h. And after the reaction is monitored to be complete, dripping the reaction liquid into cold water, performing suction filtration after the solid is completely separated out, washing and drying a filter cake to obtain a compound III-4. Dissolving the compound III-4 (1 eq) in ethanol, adding lithium hydroxide (3 eq), heating and stirring until the reaction is monitored to be complete, adding dilute hydrochloric acid to adjust the pH value to 5-6 after the reaction liquid is concentrated, carrying out suction filtration, washing and drying a filter cake to obtain the compound III-5. Compound III-5 (1 eq) was dissolved in DMF (20 ml) and HATU (1.5 eq), DIPEA (1.5 eq) and organic amine 6 (1.2 eq) were added in that order. Heating the reaction system at 50 ℃ for reflux reaction, monitoring the reaction completion, dropping the reaction liquid into cold water, performing suction filtration and washing the solid, and reacting the solid with ethyl acetate: mixed solvent of petroleum ether =1:5 recrystallizes the solid to give pure compound III-7.
reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Ethylisocyanoacetate, DMSO, K 2 CO 3 CuI,50 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
The preparation process comprises the following steps: adding compound IV-1 (1 eq) into acetic anhydride (1.5 eq), stirring uniformly, reacting at 40 ℃, monitoring the reaction, slowly dropping saturated sodium bicarbonate solution into the reaction solution until the reaction solution becomes neutral, filtering the solid, washing and drying to obtain compound IV-2. Dissolving the compound IV-2 in excessive phosphorus oxychloride (8 eq), adding dimethylformamide (2 eq), carrying out reflux reaction at 90 ℃ overnight, monitoring the reaction to be complete, slowly dripping the reaction liquid into ice water, carrying out suction filtration after all solids are separated out, washing and drying a filter cake to obtain a compound IV-3. Compound IV-3 (1 eq) was dissolved in 10ml DMSO and K was added 2 CO 3 (3 eq), ethylisocyanoacetate (1.2 eq), cuI (0.1 eq) the reaction system was heated to 90 ℃ for 1h. And after the reaction is monitored completely, carrying out suction filtration, dripping the filtrate into cold water, carrying out suction filtration after the solid is separated out completely, washing and drying a filter cake to obtain a compound IV-4. Dissolving a compound IV-4 (1 eq) in ethanol, adding lithium hydroxide (3 eq), heating and stirring until the reaction is monitored to be complete, adding dilute hydrochloric acid to adjust the pH value to 5-6 after the reaction liquid is concentrated, carrying out suction filtration, washing and drying a filter cake to obtain a compound IV-5. Compound IV-5 (1 eq) was dissolved in DMF (20 ml), and HATU (1.5 eq), DIPEA (1.5 eq), and organic amine IV-6 (1.2 eq) were added in that order. Heating the reaction system at 50 ℃ for reflux reaction, monitoring the reaction completion, dropping the reaction liquid into cold water, performing suction filtration and washing the solid, and reacting the solid with ethyl acetate: mixed solvent of petroleum ether =1:5 recrystallizes the solid to give pure compound IV-7.
Reaction operation 4, preparation of quinoline compound of formula V:
(1) Preparation of important intermediates
Reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Hydroxylamine hydrochloride, water, chloroform, thionyl chloride; d) Thiourea and ethanol
The preparation process comprises the following steps: adding the compound V-1 (1 eq) into acetic anhydride (1.5 eq), uniformly stirring, reacting at 40 ℃, monitoring the reaction to be complete, slowly dripping saturated sodium bicarbonate solution into the reaction solution until the reaction solution becomes neutral, filtering the solid by suction, washing and drying to obtain the compound V-2. Dissolving the compound V-2 in excess phosphorus oxychloride (8 eq), adding dimethylformamide (2 eq), refluxing at 90 ℃ for reaction overnight, monitoring the reaction to be complete, slowly dropping the reaction liquid into ice water, leaching after all solids are separated out, washing and drying a filter cake to obtain a compound V-3. Mixing a tetrahydrofuran solution of a compound V-3 (1 eq) with an aqueous solution of hydroxylamine hydrochloride (1 eq), stirring at room temperature, after complete reaction, concentrating to remove the solvent, washing with water, dissolving the solid in chloroform, adding thionyl chloride (1 eq), refluxing and stirring, after complete reaction, concentrating to remove the organic solvent, recrystallizing with ethanol to obtain a compound V-4, dissolving the compound V-4 (1 eq) and thiourea (2 eq) in ethanol, refluxing and reacting for 1h, cooling, adding water, precipitating, and performing suction filtration to obtain a solid V-5.
(2) Synthesizing a quinoline structure:
reagents and conditions: e) Chloroacetic anhydride, dichloromethane; f) Dimethylformamide, triethylamine, 90 deg.C
Dissolving an amino compound V-6 (1 eq) in dichloromethane, adding chloroacetic anhydride (1.5 eq), after the reaction is finished, concentrating the reaction solution, slowly dripping saturated sodium bicarbonate solution into the reaction solution until the reaction solution becomes neutral, extracting and concentrating by ethyl acetate to obtain a product V-7, dissolving the V-7 (1.5 eq) and the V-5 (1 eq) in a proper amount of DMF, adding triethylamine (3 eq), reacting at 90 ℃, adding water after the reaction is finished, and separating out a solid to obtain a compound V-8.
reagents and conditions: a) Pinacol diborate, palladium tetratriphenylphosphine, potassium carbonate, water, 1,4-dioxane, 80 ℃; b) Substituted 2-bromoquinoline, palladium tetratriphenylphosphine, potassium carbonate, water, 1,4-dioxane, 80 ℃; c) Ethanol, lithium hydroxide, normal temperature; d) 2- (7-Azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
Dissolving compound VI-1 (1 eq) and pinacol diboron (1.2 eq), palladium tetratriphenylphosphine (0.05 eq) and potassium carbonate (2 eq) in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL), refluxing and heating, after the reaction is completed, drying the organic solvent by spinning, and extracting by ethyl acetate. The organic phase is concentrated and purified by a chromatographic column to obtain the compound VI-2. VI-2 (1 eq) and various substituted 2-bromoquinolines (1 eq), palladium tetratriphenylphosphine (0.05 eq) and potassium carbonate (2 eq) are dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL), reflux heating is carried out, after the reaction is completed, the organic solvent is dried by spinning, and ethyl acetate extraction is carried out. The organic phase is concentrated and purified by a chromatographic column to obtain the compound VI-3. Hydrolyzing the methanol solution of the compound VI-3 (1 eq) with lithium hydroxide (8 eq), adding acid to adjust the pH value to acidity, filtering, washing and drying the filter cake to obtain the compound VI-4. Heating a dimethylformamide solution (10 mL) of a compound VI-4 (1 eq), an organic base 6 (1.2 eq), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.2 eq) and N, N-diisopropylethylamine (2 eq), after the reaction is completed, dropping the reaction solution into water, carrying out suction filtration, and recrystallizing a filter cake to obtain a compound VI-5.
Reaction operation 6, preparation of quinoline compounds of formula VII:
reagents and conditions: a) Thiourea, ethanol; b) Bromoacetyl bromide, dichloromethane; c) N, N dimethylformamide, potassium carbonate, 60 ℃.
And (3) dissolving the compound VII-1 (1 eq) and thiourea (1.5 eq) in ethanol (5 mL), mixing and refluxing, after complete reaction, spin-drying the solvent, and washing with water to obtain a compound VII-2. Dissolving the compound VII-3 (1 eq) in dichloromethane (5 mL), dropwise adding bromoacetyl bromide (1.3 eq), stirring at room temperature for reaction, after the reaction is completed, spin-drying the solvent, washing with water and extracting with ethyl acetate to obtain a compound VII-4. Compound VII-2 (1 eq) and compound VII-4 (1 eq) were dissolved in N, N dimethylformamide (5 mL), potassium carbonate (3 eq) was added, and the reaction was stirred at 60 ℃. After the reaction is completed, adding ethyl acetate for dilution, washing with water to remove N, N dimethylformamide, and purifying by an organic phase chromatographic column to obtain a compound VII-5.
Example 1
Reagents and conditions: a) Acetic anhydride, 40 ℃; b) N, N-dimethylformamide, phosphorus oxychloride, 90 ℃; c) DMF, ethyl thioglycolate, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-Azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
Dissolving the compound II-1 (5.35g, 0.05mol) in acetic anhydride (7.5g, 0.075mol), uniformly stirring, reacting at 40 ℃, and after the reaction is completed, dripping saturated sodium bicarbonate solution into the reaction liquid until the reaction liquid becomes neutral. The solid was filtered with suction, washed and dried to give Compound II-2 (6.48 g, yield 87%). 1 H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.53 –7.46(m,2H),7.10(dq,J＝7.3,1.2Hz,2H),2.33(d,J＝1.1Hz,3H),2.10(s,3H).MS(ESI):m/z calcd.For C 9 H 11 NO[M+H] + 150.2,found 150.1[M+H] + .
Dissolving compound II-2 (5g, 0.03mol) in excess phosphorus oxychloride (41.2g, 0.27mol), adding N, N-dimethylformamide (5.1g, 0.07mol), refluxing at 90 ℃ for overnight reaction, monitoring the reaction completion, slowly dropping the reaction liquid into ice water to precipitate a large amount of solid, filtering, washing and drying to obtain compound II-3 (5.5 g, yield 80%). 1 H NMR (400MHz,Chloroform-d)δ10.14(s,1H),8.55(d,J＝1.8Hz,1H),7.94(d,J＝7.6Hz,1H),7.70 (dd,J＝7.5,1.5Hz,1H),7.60(t,J＝1.5Hz,1H),2.50(s,3H).MS(ESI):m/z calcd.For C 11 H 8 ClNO[M+H] + 206.0,found 206.0[M+H] + .
Compound II-3 (5 g, 0.024mol) was dissolved in 20ml of DMF solution, triethylamine (14.8g, 0.15mol) and ethyl thioglycolate (3.5g, 0.03mol) were added, and the reaction system was heated to 90 ℃ and reacted for 1 hour. After completion of the reaction was monitored, the reaction solution was dropped into ice water to precipitate a large amount of solid, which was then subjected to suction filtration, washed and dried to obtain Compound II-4 (5.5 g, yield 83%). 1 H NMR(400MHz,CDCl 3 )δ8.56(s,1H),8.09(s,1H),8.05(d,J＝8.7Hz,1H),7.73(s,1H),7.63 (dd,J＝8.7,2.0Hz,1H),4.45(q,J＝7.1Hz,2H),2.61–2.55(m,3H),1.45(t,J＝7.1Hz,3H).MS (ESI):m/z calcd.For C 15 H 13 NO 2 S[M+H] + 272.0,found 272.0[M+H] +
Compound II-4 (3g, 0.011mol) was dissolved in ethanol, and lithium hydroxide (0.83g, 0.033mol) was added thereto, followed by heating and stirring. After completion of the reaction was monitored, the reaction solution was concentrated, diluted hydrochloric acid was added to adjust pH to 5-6, followed by suction filtration, washing and drying of the filter cake to obtain Compound II-5 (2 g, yield 73%). 1 H NMR(400MHz,Chloroform-d)δ10.90(s,1H),8.35(t,J＝1.6Hz, 1H),8.11(d,J＝1.4Hz,1H),8.04(d,J＝7.5Hz,1H),7.63(t,J＝1.5Hz,1H),7.51(dd,J＝7.5,1.4 Hz,1H),2.50(s,3H).MS(ESI):m/z calcd.For C 13 H 9 NO 2 S[M+H] + 244.0,found 244.1[M+H] + .
Compound II-5 (200mg, 0.82mmol) was dissolved in DMF (20 ml), and HATU (467.4 mg,1.23 mmol), DIPEA (158.7 mg, 1.23mmol), and organic amine 6 (232.2mg, 0.98mmol) were added in this order. Heating the mixture at 50 ℃ for reflux reaction, monitoring the reaction completion, dropping the reaction liquid into cold water, performing suction filtration and washing the solid, and adding ethyl acetate: mixed solvent of petroleum ether =1:5 recrystallized solid to give pure compound II-7 (156 mg, yield 41.1%). 1 H NMR(400MHz,Chloroform-d)δ8.60(s,1H),8.46(t,J＝1.5Hz,1H),8.25(d,J＝1.4Hz,1H), 8.16(d,J＝7.5Hz,1H),8.06–7.86(m,2H),7.68(t,J＝1.5Hz,1H),7.66–7.56(m,2H),7.51(dd, J＝7.5,1.5Hz,1H),4.30(t,J＝7.1Hz,2H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝7.1Hz,2H),2.50 (s,3H),1.09(t,J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 26 H 27 N 3 O 3 S[M+H] + 462.2, found462.2[M+H] + .
The following compounds were prepared according to the preparation method in example 1, except that the corresponding reaction compounds were appropriately replaced.
Example 2
Reagents and conditions: a) Acetic anhydride, 40 ℃; b) N, N-dimethylformamide, phosphorus oxychloride, 90 ℃;70% acetic acid, 95 ℃; c) Ethyl bromoacetate, DMF, triethylamine, 90 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-Azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
Dissolving the compound III-1 (5.35g, 0.05mol) in acetic anhydride (7.5g, 0.075mol), uniformly stirring, reacting at 40 ℃, and after the reaction is completed, dripping saturated sodium bicarbonate solution into the reaction liquid until the reaction liquid becomes neutral. The solid was suction-filtered, washed and dried to give Compound III-2 (6.48 g, yield 87%). 1 H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.53 –7.46(m,2H),7.10(dq,J＝7.3,1.2Hz,2H),2.33(d,J＝1.1Hz,3H),2.10(s,3H).MS(ESI):m/z calcd.For C 9 H 11 NO[M+H] + 150.2,found 150.1[M+H] + .
Dissolving a compound III-2 (5 g, 0.03mol) in excessive phosphorus oxychloride (41.2g, 0.27mol), adding N, N-dimethylformamide (5.1g, 0.07mol), carrying out reflux reaction at 90 ℃ overnight, monitoring the reaction to be complete, slowly dripping the reaction liquid into ice water to separate out a large amount of solid, carrying out suction filtration, floating the solid in 30ml of 70% acetic acid solution, carrying out heating reflux for 10 hours, cooling, carrying out suction filtration, washing and drying to obtain a compound III-3 (5.1 g, yield 81.27%). 1 H NMR(400MHz, Chloroform-d)δ10.14(d,J＝0.8Hz,1H),9.26(s,1H),8.42(d,J＝1.0Hz,1H),7.91(d,J＝7.7 Hz,1H),7.53(d,J＝1.5Hz,1H),7.34(dd,J＝7.5,1.4Hz,1H),2.30(s,3H).MS(ESI):m/z calcd. For C 11 H 9 NO 2 [M+H] + 188.1,found 188.0[M+H] + .
Compound III-3 (4.5 g, 0.024mol) was dissolved in 20ml of DMF solution, and triethyl ether was addedAmine (14.8g, 0.15mol), ethyl bromoacetate (5.0g, 0.03mol), and the reaction system was heated to 90 ℃ to react for 1 hour. After completion of the reaction was monitored, the reaction solution was dropped into ice water, and a large amount of solid was precipitated, followed by suction filtration, washing and drying to obtain Compound III-4 (4.9 g, yield 79%). 1 H NMR(400MHz,Chloroform-d)δ8.20(t,J＝1.6Hz,1H),7.99(d,J＝7.5Hz,1H),7.62(t,J＝ 1.6Hz,1H),7.51(dd,J＝7.5,1.5Hz,1H),7.42(d,J＝1.5Hz,1H),4.30(q,J＝8.0Hz,2H),2.50 (s,3H),1.32(t,J＝8.0Hz,3H).MS(ESI):m/z calcd.For C 15 H 13 NO 3 [M+H] + 256.0,found 256.0[M+H] + .
Compound III-4 (2.8g, 0.011mol) was dissolved in ethanol, and lithium hydroxide (0.83g, 0.033mol) was added thereto, followed by heating and stirring. After completion of the reaction was monitored, the reaction solution was concentrated, diluted hydrochloric acid was added to adjust pH to 5-6, followed by suction filtration, washing and drying of the filter cake to obtain Compound III-5 (1.7 g, yield 68%). 1 H NMR(400MHz,Chloroform-d)δ12.54(s,1H),8.21(t,J ＝1.6Hz,1H),7.99(d,J＝7.5Hz,1H),7.62(t,J＝1.6Hz,1H),7.57–7.47(m,2H),2.50(s, 3H).MS(ESI):m/z calcd.For C 13 H 9 NO 3 [M+H] + 228.0,found 228.0[M+H] + .
Compound III-5 (187mg, 0.82mmol) was dissolved in DMF (20 ml), and HATU (467.4 mg,1.23 mmol), DIPEA (158.7 mg, 1.23mmol), and organic amine II-6 (232.2mg, 0.98mmol) were added in that order. Heating the mixture at 50 ℃ for reflux reaction, monitoring the reaction completion, dropping the reaction liquid into cold water, performing suction filtration and washing the solid, and adding ethyl acetate: mixed solvent of petroleum ether =1:5 recrystallized solid to give pure compound III-7 (117 mg, yield 31.92%). 1 H NMR(400MHz,Chloroform-d)δ8.11(d,J＝7.7Hz,1H),8.02–7.94(m,3H),7.69–7.57(m, 3H),7.51(dd,J＝7.5,1.5Hz,1H),7.33(d,J＝1.5Hz,1H),4.30(t,J＝7.1Hz,2H),2.89(q,J＝ 8.0Hz,4H),2.78(t,J＝7.1Hz,2H),2.50(s,3H),1.09(t,J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 26 H 27 N 3 O 4 [M+H] + 446.2,found446.2[M+H] + .
The following compounds were prepared according to the preparation method in example 2, except that the corresponding reaction compounds were appropriately replaced.
Example 3
Reagents and conditions: a) Acetic anhydride, 40 ℃;b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Isocyanoacetic acid ethyl ester, DMSO, K 2 CO 3 CuI,50 ℃; d) Ethanol, lithium hydroxide, normal temperature; e) 2- (7-Azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
Dissolving the compound IV-1 (5.35g, 0.05mol) in acetic anhydride (7.5g, 0.075mol), uniformly stirring, reacting at 40 ℃, and after the reaction is completed, dropwise adding a saturated sodium bicarbonate solution into the reaction liquid until the reaction liquid becomes neutral. The solid was filtered with suction, washed and dried to give Compound IV-2 (6.48 g, yield 87%). 1 H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.53 –7.46(m,2H),7.10(dq,J＝7.3,1.2Hz,2H),2.33(d,J＝1.1Hz,3H),2.10(s,3H).MS(ESI):m/z calcd.For C 9 H 11 NO[M+H] + 150.2,found 150.1[M+H] + .
Dissolving compound IV-2 (5g, 0.03mol) in excess phosphorus oxychloride (41.2g, 0.27mol), adding N, N-dimethylformamide (5.1g, 0.07mol), refluxing at 90 ℃ for overnight reaction, monitoring the reaction completion, slowly dropping the reaction liquid into ice water to precipitate a large amount of solid, filtering, washing and drying to obtain compound IV-3 (5.5 g, yield 80%). 1 H NMR (400MHz,Chloroform-d)δ10.14(s,1H),8.55(d,J＝1.8Hz,1H),7.94(d,J＝7.6Hz,1H),7.70 (dd,J＝7.5,1.5Hz,1H),7.60(t,J＝1.5Hz,1H),2.50(s,3H).MS(ESI):m/z calcd.For C 11 H 8 ClNO[M+H] + 206.0,found 206.0[M+H] + .
Compound IV-3 (5 g, 0.024mol) was dissolved in 20ml of DMSO solution, and K was added 2 CO 3 (10.35g, 0.075mol), ethyl isocyanoacetate (3.4g, 0.03mol), and CuI (0.46g, 2.4mmol), the reaction system was heated to 90 ℃ and reacted for 1 hour. After completion of the reaction was monitored, suction filtration was performed, the filtrate was dropped into ice water, a large amount of solid was precipitated, suction filtration, washing and drying were performed, and then, column chromatography (ethyl acetate: petroleum ether = 20). 1 H NMR(400MHz, Chloroform-d)δ8.68(s,1H),8.33(t,J＝1.6Hz,1H),8.01(d,J＝7.5Hz,1H),7.62(t,J＝1.5Hz, 1H),7.51(dd,J＝7.5,1.4Hz,1H),7.35(d,J＝1.5Hz,1H),4.37(q,J＝8.0Hz,2H),2.50(s,3H), 1.36(t,J＝8.0Hz,3H).MS(ESI):m/z calcd.For C 15 H 14 N 2 33/24O 2 [M+H] + 255.1,found 255.1[M+H] +
Compound IV-4 (3 g, 0.012mol) was dissolved in ethanol, and lithium hydroxide (0.89g, 0.036 mol) was added thereto, followed by stirring with heating. After monitoring the reaction, the reaction solution was concentrated, diluted hydrochloric acid was added to adjust the pH to 5-6, and compound IV-5 (2.3 g, yield 86.2%) was obtained by suction filtration, washing and drying of the filter cake. 1 H NMR(400MHz,Chloroform-d)δ10.60(s,1H),9.00(s,1H), 8.33(t,J＝1.6Hz,1H),8.02(d,J＝7.5Hz,1H),7.62(t,J＝1.5Hz,1H),7.51(dd,J＝7.5,1.4Hz, 1H),7.44(d,J＝1.4Hz,1H),2.50(s,3H).MS(ESI):m/z calcd.For C 13 H 10 N 2 O 2 [M+H] + 227.0, found 227.1[M+H] + .X
Compound IV-5 (185mg, 0.82mmol) was dissolved in DMF (20 ml), and HATU (467.4 mg,1.23 mmol), DIPEA (158.7 mg, 1.23mmol), and organic amine 6 (232.2mg, 0.98mmol) were added in that order. Heating the mixture at 50 ℃ for reflux reaction, monitoring the reaction completion, dropping the reaction liquid into cold water, performing suction filtration and washing the solid, and adding ethyl acetate: mixed solvent of petroleum ether =1:5 recrystallized solid to give pure compound IV-7 (117 mg, yield 32.2%). 1 H NMR(400MHz,Chloroform-d)δ8.67(s,1H),8.44(t,J＝1.6Hz,1H),8.26(s,1H),8.14(d,J＝ 7.5Hz,1H),8.02–7.94(m,2H),7.66(t,J＝1.6Hz,1H),7.62–7.54(m,2H),7.51(dd,J＝7.5, 1.4Hz,1H),7.36(d,J＝1.5Hz,1H),4.30(t,J＝7.1Hz,2H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝ 7.1Hz,2H),2.50(s,3H),1.09(t,J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 26 H 28 N 4 O 3 [M+H] + 445.2,found445.0[M+H] + .
The following compounds were prepared according to the preparation method in example 3, except that the corresponding reaction compounds were appropriately replaced.
Example 4
Reagents and conditions: a) Acetic anhydride, 40 ℃; b) Dimethylformamide, phosphorus oxychloride, 90 ℃; c) Hydroxylamine hydrochloride, water, chloroform, thionyl chloride; d) Thiourea and ethanol.
Dissolving a compound V-1 (5.35g, 0.05mol) in acetic anhydride (7.5g, 0.075mol), uniformly stirring, reacting at 40 ℃, and after the reaction is completed, carrying out the next reactionSaturated sodium bicarbonate solution is dropped into the solution until the reaction solution becomes neutral. The solid was suction-filtered, washed and dried to give Compound V-2 (6.48 g, yield 87%). 1 H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.53 –7.46(m,2H),7.10(dq,J＝7.3,1.2Hz,2H),2.33(d,J＝1.1Hz,3H),2.10(s,3H).MS(ESI):m/z calcd.For C 9 H 11 NO[M+H] + 150.2,found 150.1[M+H] + .
Dissolving the compound V-2 (5 g, 0.03mol) in excess phosphorus oxychloride (41.2g, 0.27mol), adding N, N-dimethylformamide (5.1g, 0.07mol), refluxing at 90 ℃ for overnight reaction, monitoring the reaction completion, slowly dropping the reaction liquid into ice water to precipitate a large amount of solid, performing suction filtration, washing and drying to obtain the compound V-3 (5.5 g, yield 80%). 1 H NMR (400MHz,Chloroform-d)δ10.14(s,1H),8.55(d,J＝1.8Hz,1H),7.94(d,J＝7.6Hz,1H),7.70 (dd,J＝7.5,1.5Hz,1H),7.60(t,J＝1.5Hz,1H),2.50(s,3H).MS(ESI):m/z calcd.For C 11 H 8 ClNO[M+H] + 206.0,found 206.0[M+H] + .
A tetrahydrofuran (5 ml) solution of compound V-3 (1g, 4.88mmol) was mixed with a water (1 ml) solution of hydroxylamine hydrochloride (0.34g, 4.88mmol) and stirred at room temperature, after completion of the reaction, the solvent was removed by concentration, the solid was washed with water, dissolved in chloroform and sulfoxide chloride (0.58g, 4.88mmol) was added thereto, after completion of the reaction by stirring under reflux, the organic solvent was removed by concentration, and ethanol (5 ml) was recrystallized to give compound V-4 (0.89 g, yield 90%). 1 H NMR(400MHz,Chloroform-d)δ8.36(d,J＝1.4 Hz,1H),7.96(d,J＝7.5Hz,1H),7.73(dd,J＝7.6,1.6Hz,1H),7.61(t,J＝1.6Hz,1H),2.50(s, 3H).MS(ESI):m/z calcd.For C 11 H 7 ClN 2 [M+H] + 203.0,found 203.0[M+H] + .
Compound V-4 (0.89g, 4.4 mmol) and thiourea (0.67g, 8.8 mmol) were dissolved in ethanol (10 ml), reacted under reflux for 1h, cooled, added with water to precipitate, and suction-filtered to give solid V-5 (0.81 g, yield 92%). 1 H NMR(400MHz, Chloroform-d)δ12.04(s,1H),9.58(s,1H),8.33(d,J＝7.7Hz,1H),7.76(d,J＝1.8Hz,1H),7.06 (dd,J＝7.5,1.5Hz,1H),2.30(s,3H).MS(ESI):m/z calcd.For C 11 H 8 N 2 S[M+H] + 201.0,found 201.0[M+H] + .
Reagents and conditions: e) Chloroacetic anhydride, dichloromethane; f) Dimethylformamide, triethylamine, 90 ℃.
Dissolving amino compound V-6 (200mg, 0.85mmol) in dichloromethane (15 ml), adding chloroacetic anhydride (222 mg, 1.3 mmol), after the reaction at normal temperature is completed, concentrating the reaction solution, slowly dropping saturated sodium bicarbonate solution into the reaction solution until the reaction solution becomes neutral, extracting with ethyl acetate, and concentrating the organic phase to obtain product V-7 (260 mg, yield 98%). 1 H NMR(400MHz, Chloroform-d)δ10.10(s,1H),7.87–7.79(m,2H),7.51–7.43(m,2H),4.34–4.26(m,4H),2.89 (q,J＝8.0Hz,4H),2.78(t,J＝7.1Hz,2H),1.09(t,J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 15 H 21 ClN 2 O 3 [M+H] + 313.1,found 313.1[M+H] + .
V-7 (200mg, 0.64mmol) and IV-5 (128mg, 0.64mmol) were dissolved in an appropriate amount of DMF, triethylamine (200mg, 2mmol) was added, and after completion of the reaction at 90 ℃, the reaction solution was dropped into ice water, and a solid precipitated to give compound V-8 (98 mg, yield 32%). 1 H NMR(400MHz,Chloroform-d)δ8.60(s,1H),8.45(d,J＝1.4Hz,1H), 8.01–7.95(m,2H),7.79(d,J＝7.4Hz,1H),7.75–7.69(m,2H),7.62(t,J＝1.6Hz,1H),7.51(dd, J＝7.6,1.5Hz,1H),4.30(t,J＝4.7Hz,2H),3.50(s,2H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝4.7 Hz,2H),2.50(s,3H),1.09(t,J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 26 H 28 N 4 O 3 S[M+H] + 488.1,found 488.1[M+H] + .
The following compounds were prepared according to the preparation method in example 4, except that the corresponding reaction compounds were appropriately replaced.
Example 5
Reagents and conditions: a) Pinacol diborate, palladium tetratriphenylphosphine, potassium carbonate, water, 1,4-dioxane, 80 ℃; b) 2-bromoquinoline, palladium tetratriphenylphosphine, potassium carbonate, water, 1,4-dioxane, 80 ℃; c) Ethanol, lithium hydroxide, normal temperature; d) Procaine, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), 50 ℃.
Compound VI-1 (2.21g, 10mmol) and pinacol diboron ester (3.05g, 12mol), tetratriphenylphosphine palladium (577 mg, 0.5 mmol) and potassium carbonate (2.76g, 20mmol) were dissolved in a mixed solution of 1,4-dioxane (16 mL) and water (4 mL), and after completion of the reaction, the organic solvent was spin-dried and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to give Compound VI-2 (2.52g, 94%). 1 H NMR(400MHz,Chloroform-d)δ7.70(d,J＝1.6Hz,1H), 7.40(d,J＝1.6Hz,1H),3.85(s,3H),1.28(s,12H).MS(ESI):m/z calcd.For C 12 H 18 BO 4 S[M+H] + 269.1,found 269.1[M+H] + .
VI-2 (1.34g, 5 mmol), 2-bromoquinoline (1.04g, 5 mmol), tetratriphenylphosphine palladium (290 mg, 0.25 mmol) and potassium carbonate (1.38g, 10 mmol) are dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL), heated under reflux, after the reaction is completed, the organic solvent is dried by spinning, and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to give compound VI-3 (1.0 g, 74%). 1 H NMR(400MHz,Chloroform-d)δ8.28(dd,J＝7.6,1.6Hz,1H),8.19 (d,J＝1.6Hz,1H),8.17–8.04(m,2H),7.89–7.79(m,2H),7.72(td,J＝7.6,1.6Hz,1H),7.54(td, J＝7.6,1.6Hz,1H),3.85(s,3H).MS(ESI):m/z calcd.For C 15 H 12 NO 2 S[M+H] + 270.1,found 270.1[M+H] + .
A methanol solution of compound VI-4 (0.8g, 3mmol) was hydrolyzed with lithium hydroxide (0.6g, 24mmol), the pH was adjusted to acidity by addition of an acid, suction filtration was conducted, and the filter cake was washed and dried to give compound VI-4 (0.72g, 94%). 1 H NMR(400MHz,Chloroform-d)δ 10.90(s,1H),8.40(d,J＝1.6Hz,1H),8.34–8.24(m,2H),8.08(dd,J＝7.6,1.6Hz,1H),7.89–7.79(m,2H),7.72(td,J＝7.6,1.6Hz,1H),7.54(td,J＝7.6,1.6Hz,1H).MS(ESI):m/z calcd.For C 14 H 10 NO 2 S[M+H] + 256.1,found 256.1[M+H] + .
Compound VI-4 (210mg, 0.82mmol) was dissolved in DMF (10 ml), and HATU (467.4 mg,1.23 mmol), DIPEA (158.7 mg, 1.23mmol) and organic amine V-6 (232.2mg, 0.98mmol) were added in that order. Heating the mixture at 50 ℃ for reflux reaction, monitoring the reaction completion, dropping the reaction liquid into cold water, performing suction filtration and washing the solid, and adding ethyl acetate: mixed solvent recrystallization of solid with petroleum ether =1:5 yielded pure compound VI-5 (120 mg, 30% yield). 1 H NMR(400MHz,Chloroform-d)δ8.60(s,1H),8.46(d,J＝1.6Hz,1H),8.34(dd,J＝7.6,1.6 Hz,1H),8.17(dd,J＝7.6,1.6Hz,1H),8.04–7.91(m,4H),7.85(dt,J＝7.6,1.6Hz,1H),7.72(td, J＝7.6,1.6Hz,1H),7.54(td,J＝7.6,1.6Hz,1H),7.46–7.38(m,2H),4.30(t,J＝3.6Hz,2H), 2.89(q,J＝7.6Hz,4H),2.78(t,J＝3.6Hz,2H),1.09(t,J＝7.6Hz,6H).MS(ESI):m/z calcd.For C 27 H 28 N 3 O 3 S[M+H] + 474.2,found 474.1[M+H] + .
The following compounds were prepared according to the preparation method in example 5, except that the corresponding reaction compounds were appropriately replaced.
Example 6
Reagents and conditions: a) Thiourea, ethanol; b) Bromoacetyl bromide, dichloromethane; c) N, N dimethylformamide, potassium carbonate, 60 ℃.
Compound VII-1 (2.07g, 10mmol) and thiourea (1.14g, 15mmol) were dissolved in ethanol (20 mL), mixed under reflux, and after completion of the reaction, the solvent was spin-dried and washed with water to give compound VII-2 (1.58g, 98%). 1 H NMR(400MHz, Chloroform-d)δ8.02(dd,J＝7.2,1.6Hz,1H),7.79–7.64(m,3H),7.47–7.35(m,2H),3.29(s, 1H)。MS(ESI):m/z calcd.For C 9 H 8 NS[M+H] + 162.0,found 162.0[M+H] + .
Compound VII-3 (1.18g, 5mmol) was dissolved in methylene chloride (10 mL), bromoacetyl bromide (1.41 g,7 mmol) was added dropwise, the reaction was stirred at room temperature, after completion of the reaction, the solvent was dried by spinning, washed with water and extracted with ethyl acetate to give compound VII-4 (1.66g, 83%). 1 H NMR(400MHz,Chloroform-d)δ9.90(s,1H),7.87–7.79(m,2H),7.51– 7.43(m,2H),4.34–4.22(m,4H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝7.2Hz,2H),1.09(t,J＝8.0 Hz,6H)。MS(ESI):m/z calcd.For C 15 H 22 BrN 2 O 3 [M+H] + 357.1,found 357.1[M+H] + .
Compound VII-2 (161mg, 1mmol) and compound VI-4 (356mg, 1mmol) were dissolved in N, N-dimethylformamide (5 mL), and potassium carbonate (414mg, 3mmol) was added to stir the reaction at 60 ℃. After completion of the reaction, ethyl acetate was added for dilution, and N, N-dimethylformamide was removed by washing with water, and the mixture was purified by organic phase chromatography to obtain Compound VII-5 (280mg, 64%). 1 H NMR(400MHz,Chloroform-d)δ9.50(s,1H),8.18(dd,J＝7.6,1.6Hz,1H),7.94(dd,J＝7.6, 1.6Hz,1H),7.87–7.79(m,2H),7.79–7.65(m,4H),7.69–7.59(m,1H),7.43(td,J＝7.6,1.6Hz, 1H),4.30(t,J＝7.2Hz,2H),4.07(s,2H),2.89(q,J＝8.0Hz,4H),2.78(t,J＝7.2Hz,2H),1.09(t, J＝8.0Hz,6H).MS(ESI):m/z calcd.For C 24 H 28 N 2 O 3 S[M+H] + 438.2,found 438.2[M+H] + .
The following compounds were prepared according to the preparation method in example 6, except that the corresponding reaction compounds were appropriately replaced.
Experimental example 7: SHP1 activation activity test of quinolines
1. And (3) detecting the activity of the SHP1 protein:
10uL of the compound at different concentrations were added to 384 black flat-bottom plates. Then, 20ul SHP1-GST fusion protein was added, and the SHP1 protein was dissolved in 50mmol/L HEPES pH =7.2, 100mmol/L NaCl, 0.05% BSA, 1mM DTT at a concentration of 10nmol/L. After incubation for 15 min at room temperature, 20ul of the substrate DiFUMP was added and dissolved in 50mmol/L HEPES pH =7.2, 100mmol/L NaCl, 0.05% BSA, 1mM DTT at a concentration of 25. Mu. Mol/L. The change of fluorescence is detected by a dynamic method on a multifunctional microplate reader under the excitation of 355nm and the emission of 460nm, and the value is read once every 1min for 10 times. And calculating the slope of the enzymatic reaction in unit time by using an Excel macro tool to obtain a corresponding SHP1 protein activity result.
2. Western blotting:
cells were collected at 800rpm/min for 3min. After removal of the supernatant medium, the cells were resuspended once again in precooled PBS. The samples were placed on ice and the cells were lysed with RIPA for 30 minutes. After centrifugation at 12000rpm for 20 minutes, the supernatant from the cell lysis was subjected to protein quantification. Shaking on a vortex shaker while adding 4 × loading buffer. Mixing, placing on a metal dry bath instrument, and heating at 100 deg.C for 15 min to fully crack and denature protein. Protein samples were added to SDA-PAGE gels at 20 ug/well, electrophoresis conditions: constant current 20mA per block of glue. And stopping electrophoresis when the blue dye of the protein Marker electrophoreses to the outer side of the gel, and putting the sponge pad, the filter paper, the protein gel and the cellulose acetate membrane NC into a transfer printing groove according to the sequence of the molecular biology operation manual. Then transferring for a proper time according to the principle that 1KD protein is transferred for 1 min. After the target protein is transferred to an NC membrane, the NC membrane is developed by ponceau red, and the NC membrane is cut according to a protein Marker. And putting the cut NC film into a closed groove. The corresponding blocking solution was added, placed on a shaker and blocked for 2 hours at room temperature (protein changes were examined, blocked with 5% skim milk, and if protein phosphorylation was examined, with 5% fetal bovine albumin). The blocking solution was removed and the NC membrane was washed twice with TBST for 5 minutes each. After addition of the corresponding primary antibody, the cells were incubated overnight at 4 ℃ on a shaker. The following day, the NC membranes were washed 3 times with TBST on a shaker for 10 minutes each, followed by addition of the corresponding fluorescent secondary antibody and 1 hour incubation on a shaker at room temperature. The NC membrane was washed 3 more times with TBST on a shaker for 10 minutes each. The membrane is put on an infrared imaging system (Odyssey) instrument, and different detection fluorescence channels are selected to scan the target protein bands according to the fluorescence property of the secondary antibody.
FIGS. 1 and 2 show that the compounds of the present invention have significant activation of shp1 and downstream STAT3 dephosphorylation on OCI-Ly10, OCI-Ly10R and DHL-2 cells at the concentrations tested.
The results of the bioactivity test of the quinoline compounds with various structural types are shown in table 1.
TABLE 1 results of biological Activity of different quinolines
Claims (10)
1. Quinoline compounds shown in a general formula I or pharmaceutically acceptable salts thereof,
wherein, the first and the second end of the pipe are connected with each other,
represents a single or double bond; x 1 Selected from the group consisting of no (H), S, O, NH; x 2 Selected from (H), CH, CNH 2 A thiophene ring;
R 1 selected from the group consisting of,
represents the attachment site:
R 2 ，R 3 ，R 4 ，R 5 each independently selected from hydrogen, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy radical, C 1 -C 4 A haloalkyl group.
2. The quinolines compound or its pharmaceutically acceptable salt according to claim 1, wherein when X is 1 Is S, X 2 When the compound is CH, the structure of the quinoline compound is thieno [2,3-b ] shown as a formula II]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 are each as defined in claim 1.
3. The quinolines or pharmaceutically acceptable salts thereof as in claim 1, wherein when X is 1 Is O, X 2 When the compound is CH, the structure of the quinoline compound is furo [2,3-b ] shown as a formula III]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 are each as defined in claim 1.
4. The quinolines or pharmaceutically acceptable salts thereof as in claim 1, wherein when X is 1 Is NH, X 2 When the compound is CH, the structure of the quinoline compound is pyrrolo [2,3-b ] shown in formula IV]Quinoline-2-carboxamide derivatives or pharmaceutically acceptable salts thereof,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 are each as defined in claim 1.
5. The quinolines compound or its pharmaceutically acceptable salt according to claim 1, wherein when X is 1 Is S, X 2 Is CNH 2 When the quinoline compound is represented by the formula V, the structure of the quinoline compound is 3-aminothieno [2,3-b]Quinoline-2-carboxamide derivatives orA pharmaceutically acceptable salt thereof,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 are each as defined in claim 1.
6. The quinolines or pharmaceutically acceptable salts thereof as in claim 1, wherein when X is 1 Is absent, X 2 When the quinoline compound is 4-thienyl, the structure of the quinoline compound is 4- (quinoline-3-yl) thiophene-2-formamide derivatives shown in a formula VI or pharmaceutically acceptable salts thereof,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 are each as defined in claim 1.
7. The quinolines or pharmaceutically acceptable salts thereof as in claim 1, wherein X is 1 Is S, X 2 If not, the structure of the quinoline compound is 2- (quinoline-2-yl sulfenyl) acetamide derivative shown in a formula VII or pharmaceutically acceptable salt thereof,
R 1 ，R 2 ，R 3 ，R 4 ，R 5 are each as defined in claim 1.
8. Use of the quinolines as in any one of claims 1-7, or a pharmaceutically acceptable salt thereof, for the preparation of an activator of protein tyrosine phosphatase SHP 1.
9. Use of a quinoline compound as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis and treatment of cancer, metabolic and immune disorders, cardiovascular disease and neurological disorders.
10. A pharmaceutical composition comprising a quinolinic compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, and optionally pharmaceutically acceptable excipients.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110770732.9A CN115197240B (en) | 2021-07-08 | 2021-07-08 | Quinoline compound, synthesis method, pharmaceutical composition and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110770732.9A CN115197240B (en) | 2021-07-08 | 2021-07-08 | Quinoline compound, synthesis method, pharmaceutical composition and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115197240A true CN115197240A (en) | 2022-10-18 |
| CN115197240B CN115197240B (en) | 2024-03-26 |
Family
ID=83574006
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110770732.9A Active CN115197240B (en) | 2021-07-08 | 2021-07-08 | Quinoline compound, synthesis method, pharmaceutical composition and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115197240B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2371444C1 (en) * | 2008-01-24 | 2009-10-27 | Андрей Александрович Иващенко | FURO- AND THIENO[2,3-b]-QUINOLINE-2-CARBOXAMIDES, METHOD OF PRODUCTION AND ANTITUBERCULOUS ACTIVITY |
| CN102757447A (en) * | 2011-07-05 | 2012-10-31 | 北京大学 | Urea transporter inhibitors, and preparation method and application thereof |
-
2021
- 2021-07-08 CN CN202110770732.9A patent/CN115197240B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2371444C1 (en) * | 2008-01-24 | 2009-10-27 | Андрей Александрович Иващенко | FURO- AND THIENO[2,3-b]-QUINOLINE-2-CARBOXAMIDES, METHOD OF PRODUCTION AND ANTITUBERCULOUS ACTIVITY |
| CN102757447A (en) * | 2011-07-05 | 2012-10-31 | 北京大学 | Urea transporter inhibitors, and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| ACS: "STN检索报告", STN检索报告 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115197240B (en) | 2024-03-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2905564T3 (en) | Mutant IDH1 inhibitors useful in treating cancer | |
| US20060270668A1 (en) | Methods of synthesizing substituted 3-cyanoquinolines and intermediates thereof | |
| CA2627630A1 (en) | Nicotinic acid derivatives as modulators of metabotropic glutamate receptors | |
| WO2011113366A1 (en) | Method for preparing deuterated diphenylurea | |
| CN106220641A (en) | Indole volution compound containing the blue hydrocarbon structure of more wound and preparation method and application | |
| Wright Jr et al. | Thromboxane synthetase inhibitors and antihypertensive agents. 4. N-[(1H-imidazol-1-yl) alkyl] derivatives of quinazoline-2, 4 (1H, 3H)-diones, quinazolin-4 (3H)-ones, and 1, 2, 3-benzotriazin-4 (3H)-ones | |
| CN110483418B (en) | 3-substituted quinazolinone-2-formamide derivative and preparation method and application thereof | |
| KR102507328B1 (en) | Crystal forms and salt forms of TGF-βRI inhibitors and methods for their preparation | |
| WO2020244530A1 (en) | 5-pyrimidine-6-oxy-pyrazolopyridine derivative, preparation method therefor and application thereof | |
| CN103508960A (en) | Benzoheterocyclic derivatives | |
| CN115197240A (en) | Quinoline compound, synthesis method, pharmaceutical composition and application | |
| CN110680813B (en) | Use of naphthoquinone derivatives as IDO1 and/or TDO inhibitors | |
| CN114835640B (en) | Fibroblast growth factor receptor inhibitor, preparation method and application | |
| CN116554103A (en) | Phenylpyrazoles and application thereof | |
| CN111606888B (en) | Pyrrole derivative and preparation method and application thereof | |
| TWI793207B (en) | Salt form, crystal form as fgfr4 inhibitor compound and preparation method thereof | |
| Yao et al. | Synthesis and Antiproliferative Activitiy of Novel Diaryl Ureas Possessing a 4H‐Pyrido [1, 2‐a] pyrimidin‐4‐one Group | |
| BG61262B1 (en) | Cyclic derivatives of the aminophenylacetic acid, method fortheir preparation and application | |
| CN113121485B (en) | 3-aryl coumarin derivative and preparation method and application thereof | |
| CN115057860B (en) | ERK inhibitor and pharmaceutical application thereof | |
| CN109705117A (en) | Tricyclic compounds, preparation method and the usage | |
| CN113493437B (en) | Compound containing benzimidazole structure and preparation method and application thereof | |
| CN110272388B (en) | 4-dithioformic acid piperazine-3-nitro-1, 8-naphthalimide derivative and synthesis method and application thereof | |
| WO2023033097A1 (en) | Method for producing heterocyclic sulfonamide derivative, and synthetic intermediate thereof | |
| CN108912035B (en) | Indole amide compound with anti-tumor activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |